ANNUAL DRUG DATA REPORT Vol I 1971

J. R. PROUS, Editor
Prof. A. Dept. Anim. Physiol. Fac. Cienc., University of Barcelona (Spain)

D. VEDRILLA, Ass. Editor

Phil D of the University of Vienna (Austria)

Medicamentos de Actualidad Drugs of Today Barcelona (Spain)

PREFACE

This volume initiates a new series of annual publications designed to provide an up-to-date and useful reference tool for all researchers concerned with the chemical and biological aspects of drugs and other substances of pharmacological or biochemical interest. The source material for Annual Drug Data Report are the drugs which during the year, have gained place in clinical practice, those to which have been assigned a new non-proprietary name, and others which are under study, and are mentioned in about 600 biomedical journals, and congress and symposium proceedings. Each drug is described in monograph form to provide whenever possible, the following data: nonproprietary name, research code number, commercial name, chemical or biologic identity, inclu ding pertinent properties, synthesis, pharmacological action toxicity, manufacturer and references; the latter giving access to the international literature on drugs. For the drugs which are in clinical practice uses, dosage and preparations are also set out. Monographs are arranged alphabetically according to their nonproprietary name or research codes. The data given in the monographs has been taken from literature, and does not represent specifications for products available commercially from the manufacturers. To facilitate location of drugs, four indexes are provided. The Cross Index of Names, which contains entries enabling the reader to locate drugs by proprietary. chemical and generic names, and research code numbers. The Pharmacological Index, in which the drugs are grouped according to pharmacological action. The Manufacturer's Index, where the drugs are listed under the manufacturer's name, and finally the Chemical Formula Index, which permits the location of drugs by means of their chemical composition. The publication of cumulative indexes every four years is under consideration.

CONTRIBUTORS
Chemistry
Dr. J . Castaner. Lic. Quim., Invest. Numer., Instituto de Quimica, CSIC, Barcelona J . J . Taratiel. Lic. Quim., Bec. Invest. Aerospacial, Instituto de Quimica, CSIC. Barcelona

Pharmacology
Dr. J. Balasch. Prof. Dept. Physiology. Fac. Ciene., University of Barcelona Dr. M. Neuman, MD, Prof. Laureat Acad. Med. Paris Dr. C. Villaverde. Lic. Med, Dept. Pharmacology, CSIC. Barcelona

Microbiology
P. Blancafort. Lic. BioI., Dept. Microbiology, Fac. Ciene . University of Barcelona

ABBREVIATIONS AND SYMBOLS

Specific optical rotation at 25 for D (sodium) line abs abstract Appl Application approx approximately aq aqueous BAN British Approved Name Belg Belgian bp boiling point Brit British C concentration by volume (after optical rotation only) ca (circa) about Can Canadian Cis stereochemical opposite of trans d density; specific gravity d dextro (rotatory) D dextro (in configurations! sense only) dec decomposes dil dilute dl and DL racemic E (1%, 1 cm) The absorbancy of a solution containing one gram per 100 ml contained in a cell having an absorption path of one centimeter e.g for example et al (et alii) and others FDA Food and Drug Administration Fr French g gram g/kg gram per kilogram (gamma) microgram Ger German ibid at the same place

[]D25

IAN ICI im ip IU iv Jap kg I L Ib LD50 Log m M max. mg g min ml mm m mp no n N Neth NF oO ppat pk po

Italian Approved Name Imperial Chemical Industries intramuscular intraperitoneal international unit intravenous Japanese kilogram levo (rotatory) levo (in configurational sense only) pound lethal dose in 50% of cases logarithm meta molar maximum milligram microgram minimum milliliter (cubic centimeter) millimeter millimicron melting point index of refraction (sodium light) normal normal Netherlands National Formulary ortho denoting attachment to oxygen para patent log 1/K oral

CONTENTS

Preface ............................................................................... vii Contributors ....................................................................... ix Abbreviations..................................................................... xi Monographs............................................................... 1 - 202 Pharmacological Index .............................................. Manufacturer's Index .................................................

MONOGRAPHS

A 025
7-Chloro-2H-1,2,4-benzothiadiazine-1,1-dioxide

Action
A 124 is a new phenothiazine derivative closely related in its chemical structure to thioridazine and propericiazine. It exhibits a mildly neuroleptik effect.

Manufacturer
Siegfried AG (Switzerland)

References Action
A 025, an analogue of diazoxide without the methyl group in position 3, has proved to have hyperglycemic, but not antidiuretic, activity in rats and monkeys, and weakly hypotensive activity. The results of investigation of the mode of action have indicated that the primary mechanism of hyperglycemia is inhibition of insulin release and that this inhibition is reversible. Clinical study on a new piperidyl-phenothiazine derivative (A 124) H. Berzewski et al. Arzneim-Forsch 20 (7), 949-952 (1970).

A-396-I
Production
Isolated from a culture broth of Streptoverticillium eurocidicus A-396.

Toxicity
LD50 ip in mice: 560 mg/kg

References
1. J. K. Wales et al. J Pharmacol Exptl Ther 164, 421-432 (1968). 2. Mode of action of a diazoxide analog (A 025). Its effects on insulin secretion A. M. Grant et al. Diabetes 19,630-639 (1970).

Description
Water-soluble basic material; []D=+11,60 (in water).

Action
Antibiotic active against gram-positive and gramnegative bacteria, mycobacteria and some fungi and protozoa.

A 124
2-Acetyl-10-[3-(4-methoxypiperidyl) propyl] phenothiazine

Toxicity
LD50 iv in mice: 12.50 mg/kg.

Manufacturer
Shionogi and Co, Ltd (Japan)

References
Isolation of a new water-soluble basic antibiotic A396I J. Shoji et al. J. Antibiotics 23(6), 291-294 (1970).

Acetylenic Gallamine Triethiodide

[-Phenenyltris-(oxybutynylene)]tris(triethylammonium iodide)

Synthesis
From thiourea and bromoethylamine hydrobromide.

Description
Crystals, mp 194-195 .

Action
Radioprotective drug. The effects of AET on bonemarrow, heart and circulation, and intestine have 3,4,5 been reported .

Manufacturer
SVST Bratislava (Czechoslovakia); Abbott (USA).

Description
Amorphous powder, mp 205 .

References
1. Clinton et al. J Am Chem Soc 70, 950 (1948). 2. Doherty et al. J Amer Chem Soc 79, 5667 (1957). 3. Effect of prophylactic administration of AET on hematological changes in irradiated rats. M. Arient et al. Strahlentherapie 139 (5),619-625 (1970). 4. Studies on the effect of AET on heart and circulation of cats and guinea pigs. K. Gutschow and A. Schmid. Arzneim-Forsch 20 (4), 509-511 (1970). 5. Studies on the effect of AET on the intestine (rabbit, guinea pig, rat). A. Schmidt and K. Gutschow. Arzneim-Forsch 20 (4),511-513 (1970).

Action
The introduction of an acetylenic group in each lateral chain of gallamine enhances the curarizing activity in vitro as well as in vivo. It has been shown that the neuromuscular blockade produced by the acetylenic compound is not strictly competitive as has been shown for gallamine.

Toxicity
LD50 po in mice: 350 mg/kg and LD50 ip in mice: 3.1 mg/kg. The corresponding values for gallamine are respectively 700 and 9.6 mg/kg.

References
1. Evaluation pharmacodynamique d'un nouveau curarisant de synthese: La Gallamine-Acethylenique G. Cloutier at al. Arch Int Pharmacodyn Ther 184 (1), 75-92 (1970). 2. Etude in vitro du mecanisme de raction curarisante de la GallamineAcetylenique. G. Cloutier and G. R. Goyer. Arch Int Pharmacodyn Ther 184 (2), 299-308 (1970).

Agr 614
3-(Morpholinoethoxy)-4-methyl-6-(2-naphthyl)pyridazine hydrochloride 4-Methyl-3-(morpholinylethoxy)-6-(2-naphthyl) pyridazine hydrochloride

AET
S-(2-Aminoethyl) isothiouronium bromide hydrobromide

Action
Agr 614 is a powerful analgesic agent of long duration. The analgesic activity of this compound appears to involve a medullary mechanism.

References
1. A stereotaxic study of the analgesic activity of 3ethoxymorpholinyl-4-methyl-2-naphtyl-6-pyridazine hydrochloride (Agr 614).

3
H. Laborit et al. Agressologie 11 (3), 221-242 (1970). 2. A pharmacological approach 10 the analgesic properties of Agr 614. B. Weber et al. Agressologie 11 (3),243-253 (1970). 3. The medullar localisation of the action of an analgesic. Agr 614: synergy with strychnine. B. Weber et al. Agressologie 11 (3), 255-267 (1970). 4. The action of 3-ethoxymorpholinyl-4-methyl (2naphtyl)-6-pyridazine hydrochloride (Agr 614) on rabbit ventilation. G. Laborit and C. Baron. Agressologie 11 (3). 269273 (1970).

Action
Muscarinic agent.

Manufacturer
Allen Hanburys Ltd (England)

References
A new muscarinic agent. R. J. Marshall. Brit J Pharmacol 39(1), 191P (1970).

AHR-800B AH 5183
2-(4-Phenylpiperidino) cyclohexanol Diphenylcarbamic acid, 1-methyl-3-pyrrolidinyl ester maleate 1-Methyl-3-pyrrolidinyl diphenylcarbamate maleate

Action
Neuromuscular curariform blocking agent.

Manufacturer
Allen Hanburys Ltd (England)

Synthesis
Prepared by the reaction of 1-methyl-3-pyrrolidinol with sodium amide and N, N-diphenylcarbamyl chloride.

References
1. The neuromuscular blocking action of AH 5183. R. T. Brittain et al. Eurap J Pharmacal 8, 93-99 (1969). 2. Studies on the blocking action of AH 5183. I. G. Marshall. Brit J Pharmacal 38 (3), 503-516 (1970).

Description
Crystals, mp 133-134 The free base melts at 63. 64

Action
AHR 800B, an anticholinergic compound with antitremorine activity comparable to desmethylimipramine in the laboratory, is under clinical study to assess its efficacy as an antidepressant.

AH 6405
1,4,5,6-Tetrahydro-5-phenoxypyrimidine

Manufacturer
A. H. Robins (USA)

References
1. A. H. Robins Co Inc. US pat 3,228,835; Belg pat 639,009. 2. The clinical evaluation of four proposed antidepressants. Relationship to their animal pharmacology.

4
L. J. Hekimian et al. Int Pharmacopsychiat 3, 65-76 (1970).

AHR 1900
1-[3-(p-Fluorobenzoyl)-propyI]-3-(omethoxyphenoxy)-pyrrolidine hydrochloride 4'-Fluoro-4-[(3-o-methoxyphenoxy)-1-pyrrolidinyI]butyrophenone hydrochloride

AHR 1118
3-(Diphenylmethylene)-1-ethyl-pyrrolidine hydrochloride

Synthesis
Prepared by the reaction of 3-(o-methoxyphenoxy)pyrrolidine with p-fluoro--chlorobutyrophenone and sodium bicarbonate in refluxing methyl isobutyl ketone,

Description Synthesis
Prepared by dehydration of 1-ethyl-,-diphenyl-31,2 pyrrolidinemethanol . Crystals, mp 166-168 (methyl isobutyl ketone)

Action
AHR 1900 is a fluorobutyrophenone compound which in animal studies has shown pharmacological properties resembling those of phenothiazine and butyrophenone antipsychotic drugs. The drug has appeared to lack efficacy in the treatment of chronic schizophrenic patients at doses up to 300 mg daily.

Description
White crystalline powder, readily soluble in water. The free base boils at 140 (5 mm); the methiodide melts at 164-166 .

Action
Neuropharmacological tests have proved that AHR 1118 is an antidepressant drug. The weak anticholinergic properties coupled with the presence of paradoxical sleep during AHR 1118 administration, may offer distinct advantages for this drug in the treatment of mental depression.

Manufacturer
A. H. Robins (USA)

References
1, A. H. Robins Co, Inc, S African Appl 67 05,136. 2. A butyrophenone derivative, D M Gallant et al. Curr Ther Res 11 (12),793-795 (1969). 3. A pilot study o(AHR-1900 in chronic schizophrenic patients, A. A. Sugerman et al. Curr Ther Res 12 (4), 234-236 (1970).

Manufacturer
A. H. Robins Co (USA)

References
1. F. Hamaguchi et al. Yakugaku Zasshi 86 (2), 148 (1966). 2. Sadao Ohzi. Jap pat 68 18,545. 3. Preclinical evaluation of AHR-1118 a potential antidepressant drug. D. N. Johnson et al. Curr Ther Res 12 (6), 402-413 (1970).

AHR 1911
2-Thio-2-(10-undecen-1-yl) pseudourea monohydroiodide 2-Undecenyl-2-thiopseudourea hydroiodide

Manufacturer
A. H. Robins Laboratories (USA)

References Synthesis
Prepared by treating undecenylalcohol with benzenesulfonylchloride, and subsequent reaction with thiourea. Pharmacology of AHR 2776, a new centrally acting muscle relaxant drug. D. N. Johnson at al. Fed Proc 29 (2) 779 abs (1970).

Description
White crystalline powder, mp 65.5-68 ,

Alanosine
L-2-Amino-3-(N-nitrosohydroxylamino) propionic acid

Action
AHR 1911 is a non-steroid compound with local anti-inflammatory and anti-pruritic effects.

Manufacturer
A. H. Robins Co, Inc (USA)

References
1. A. H. Robins Co, Inc. South African pat 67 06, 822. 2. The treatment of contact dermatitis with AHR1911, a new non-steroid anti-inflammatory agent. C. J. Riobueno. Curr Ther Res 12 (11), 718-723 (1970).

Production
Isolated from the fermentation broth of Streptomyces alanosinicus.

Description
Crystalline powder, decomposes at 190 ]D= + 8 .[ (in 0.1 N HCI); []D =-460 (in 0.1 N NaOH). Ultraviolet absorption max. in 0.1N HCI at 228 m [E(1%, 1cm) = 505]; in 0.1 N NaOH at 250 m [E (1%, 1cm) = 630]. It is slightly soluble in water.

AHR 2776
N-Ethyl-3-(m-trifluoromethylphenyl)-1pyrrolidinecarboxamide

Action
Alanosine is a new antibiotic with antiviral antitumor activity. It has been found to inhibit several immunological reactions in animals.

Manufacturer
Lepetit (Italy)

References
1. C. Coronelli et al. Farmaco, Ed Sci, 21, 269-277 (1966). 2. Y. K. S.Murthy et al. Nature 211,1198-1199 (1966). 3. J. E. Thiemann and G. Beretta. J. Antibiot 19,155-160 (1966), 4. Preliminary studies on the immunosuppressive action of alanosine. D. Fumarola. Pharmacology 2,107-112 (1970).

Action
AHR 2776 is a new centrally acting muscle relaxant. Initial studies have shown the drug to be more potent than mephenesin in preventing the convulsive and lethal effects of strychnine in mice.

6
5. Further investigations on the immunosuppressive effect of alanosine. D. Fumarola. Pharmacology 3, 215-219 (1970). 7. Albutoin in the teatment of epilepsy. C. H. Carter. Clin Med 78 (1), 33 (1971).

Albutoin (USAN) Bax-422 Z

3-Allyl-5-isobutyl-2-thiohydantoin

Alclofenac (USAN; Rec INN) CP 1044CG 24

Alclofenacum (Lat). Alclofenaco (Sp) [4-(Allyloxy)-3-chlorophenyI] acetic acid

Synthesis
By reacting leucine with allyl isothiocyanate under alkaline conditions 5-allyl-2-isobutyl-4-thiohydantoic acid is obtained, which is converted upon heating to albutoin.

Action
Alclofenac is a new potent analgesic, antipyretic and anti-inflammatory agent. In clinical studies the drug has proved to be equivalent in analgesic and antiinflammatory activity to phenylbutazone and indomethacin, but with fewer side effects.

Description
Crystals, mp 110-111 .

Manufacturer
Continental Pharma (Belgium) Proprietary Name Mervan

Action
Albutoin is a potent anticonvulsant agent. In man, it has anticonvulsant potency equal to that of diphenylhydantoin. Recent laboratory studies suggest no pharmacologic incompatibilities based on potency or toxicity for albutoin paired with phenobarbital, diphenylhydantoin or trimethadione.

References
1. N. P. Buu-Hoi et al. Belg pat 704,368. 2. Pharmacology of a new analgesic, antipyretic, and anti-inflammatory agent, 4-allyloxy-3chlorophenylacetic acid. G. Lambelin et al. Arzneim-Forsch 20 (5), 610-618 (1970). 3. Toxicity studies of 4-allyloxy-3-chlorophenylacetic acid, a new analgesic, antipyretic, and antiinflammatory agent. G. Lambelin et al. Arzneim-Forsch 20 (5), 618-630 (1970). 4. Metabolic patterns of 4-allyloxy-3chlorophenylacetic acid in rat, rabbit, dog, monkey, and man. A. Roncucci et al. Arzneim-Forsch 20 (5), 631-636 (1970). 5. Therapeutic activity of 4-allyloxy-3chlorophenylacetic acid. F. Lambotte. Arzneim-Forsch 20 (4), 569-571 (1970). 6. Double-blind comparison between alclofenac and phenylbutazone in osteoarthritis. J. Van Hoek et al. Curr Ther Res 12 (9), 351-556 (1970).

Manufacturer
Baxter Laboratories Inc (USA) Proprietary Name Euprax

References
1. A. Berger et al. (to Baxter Laboratories Inc). US pat 3,121,111. 2. R. M. Gesler et al. Fed Proc 18. 1553 (1959). 3. R. M. Gesler et al. Toxicol Appl Pharmacol 3, 107-121 (1961). 4. J. G. Millichap and W. R. Ortiz. Neurology 17, 162-165 (1967). 5. Clinical evaluation of albutoin. John R. Green et al. Neurology 19,1207-1212 (1969). 6. Pharmacologic interactions of albutoin with other anticonvulsant drugs Richard F. Wallin et al. J Pharmacol Exp Ther 174. 276-282 (1970).

Alisol A 24 Monoacetate ALMA

Alletorphine (BAN; Prop INN) R &S 218M

17-Allyl-17-demethyl-7-(R)-1-hydroxy-1methylbutyl-6,14-endo-ethenotetrahydrooripavine

Isolation Alisol A 24-monoacetate is a triterpene isolated from the rhizoma of AIisma Plantagoaquatica L var 1,2 orientale

Synthesis
Prepared by the reaction of 7-(1-hydroxy-1methylbutyl)-6,14-endo-ethenotetrahydrothebaine with cyanogen bromide. Combined hydrolysis and O-demethylation with sodium hydroxide of the Ncyano analog obtained and subsequent reaction with allyl bromide yields alletorphine, mp 126 th e ; hydrochloride melts at 254 .

Description
Crystals, mp 194-196 [ ]D=+86 (chloroform,at 21; 28 )

Action
Alisol A 24-monoacetate has proved to show a hypocholesterolemic action in the cholesterolfed rats. It has been suggested that this action depends at least partly, on the inhibition of intestinal absorption of cholesterol.

Action
Alletorphine hydrochloride has been found to be a potent analgesic, after parenteral administration to rats, mice and dogs, using a variety of antinociceptive assays. It has been shown that in the drug there is a dissociation of analgesic and 4 respiratory depressant properties .

Manufacturer
Takeda Chemical Industries Ltd (Japan)

References
1. T. Murata et al. Tetrahedron Letters 1. 103 (1968). 2. T. Murata et al. Tetrahedron Letters 7, 849 (1968). 3. Hypocholesterolemic effect of alisol A-24monoacetate and its related compounds in rats. Y. Imai et al. Jap J Pharmac 20 (2), 222-228 (1970). 4. Effect of alisol A-24-monoacetate on the intestinal absorption of cholesterol and fatly acids in rats. Y. Imai and H. Matsumura. J Takeda Res Lab 29 (3), 462-466 (1970). 5. Effect ofalisol A-24-monoacetate on the cholesterol esterification in the rat small intestine. S. Tamura and Y. Imai J Takeda Res Lab 29 (3), 467-469 (1970).

Manufacturer Reckitt and Sons (England) References

1. WHO Chron 25 (3), 124 (1971). 2. Chem Drug 194, 446 (1970). 3. K. W. Bentley and D. G. Hardy. J Am Chem Soc 89, 3281-3292 (1967). 4. Dissociation of analgesic and respiratory depressant properties of N-substituted analogues of etorphine. G. F. Blane et al. J Pharm Pharmacol 20 (10), 796798 (1968).

Althiomycin
Production
It is produced by Streptomyces althioticus 3 Its chemical structure has been reported .
1.2

Description
Crystals, mp 180-181.6 (dec). [ ]D= +37.8 (c=2 in alcohol/methylene chloride)

Dosage
1.44 to 2.16 g daily in divided doses.

Action
Althiomycin is an antibiotic which inhibits the growth of both gram-positive and gram-negative bacteria. The mode of action of this antibiotic has been 4 recently described .

Supplied as
Tablets, 360 mg.

Proprietary Name
Atherolip.

Manufacturer
National Institute of Health (Japan)

Manufacturer
Lab Solac (France); Vifor SA (Switzerland).

References
1. H. Yamaguchi et al. J Antibiotics, Ser A 10,195 (1957). 2. K. Maeda et al. Jap pat 34-6248. 3. D. J. Cram et al. J Am Chern Soc 85, 1430-1437 (1963). 4. Studies on the mode of action of althiomycin. H. Fujimoto et al. J Antibiotics 23 (6), 271-275 (1970).

References
1. J. Daver et al. Therapie 24. 419-428 (1969). 2. Med Act (Drugs of Today) 6 (1), 6-8 (1970).

Amadinone Acetate (USAN) RS 2208

6-Chloro-17-hydroxy-19-norpregna-4, 6-diene-3, 20dione, acetate

Alufibrate
Hydroxyaluminum bis-[2-(p-chlorophenoxy)-2methylpropionate] Hydroxyaluminum bis-[-(p-chlorophenoxy) isobutyrate]

Synthesis
Prepared by converting 17--acetoxy-6-chloro-4,6pregnadien-19-ol-3,20-dione to the 19-oic acid, followed by decarboxylation.

Description
White amorphous powder.

Description
Crystals, mp 159-161 (methylene chloridepetroleum ether); UV max. 284 m =24.100)

Action and Uses

Alufibrate is a new anti hypercholesteremic agent. It is the aluminum salt of 2-(p-chlorophenoxy)-2methyl-propionic acid, and is closely related to clofibrate, which is the ethyl ester of the same acid. For use in the treatment of the hyperchlolesterolemia and hyperlipemia.

Action
Amadinone acetate is a new progestogen

Manufacturer
Syntex Laboratories Inc (USA)

9
Triamcinolone, 16,17-acetal with diethyl ketone

References
1. JAMA 213 (13), 2247 (1970). 2. CIBA Ltd. Belg pat 620,226.

Ambenoxan (Rec INN)

Ambenoxanum (Lat). Ambenoxano (Sp) N-[2-(2-Methoxyethoxy)ethyl]-1,4-benzodioxan-2methylamine 2-(-methoxyethoxyethyl) aminomethyl-1,4benzodioxan

Synthesis
Prepared by reacting triamcinolone with 3pentanone

Description
Crystals, mp 265-268 [ ]D= 91 (c=0.69 in ; chloroform)

Synthesis
Prepared by the reaction of 2-aminomethyl-1,4benzodioxan with -methoxyethoxyethylchloride

Action
Amcinafal is a new topical anti-inflammatory agent. It is closely related to amcinafide which is the acetal with acetophenone.

Description
Light yellow oil, bp 180-186 (11.5 mm). The hydrochloride salt (white crystals), mp 104-106.

Manufacturer
E. R. Squibb and Sons (USA)

Action
Ambenoxan is a centrally acting muscle relaxant. The results of a detailed pharmacological investigation have been reported

References
1. JAMA 214, 741 (1970). 2. Josef Fried at al. J Am Chem Soc 80, 2338-9 (1958). 3. Olin Mathieson Chemical Corp. Ger pat 1,099,529. 4. Olin Mathieson Chemical Corp. US pat 3,048,581.

Manufacturer
Ward Blenkinsop and Co, Ltd (England)

References
1. Ward Blenkinsop and Co, Ltd. Neth Appl 6.410,198. 2. The pharmacology of ambenoxan [2-(3',6'dioxaheptyl)-aminomethyl-1:4-benzodioxane]. a centrally acting muscfe relaxant. M. Shapero and P. J. Southgate. Br J Pharmac 38, 263-270 (1970).

Amcinafide (USAN; Prop INN) SQ 15112

9-Fluoro-11,16,17,21-tetrahydroxy-pregna-1,4diene-3,20-dione, cyclic 16,17-acetal with acetophenone Triamcinolone, 16, 17-acetal with acetophenone

Amcinafal (USAN) SQ 15,102

9-Fluoro-11,16,17,21-tetrahydroxy-pregna-1,4diene-3,20-dione, cyclic 16,17-acetal with 3pentanone.

10

Synthesis
Prepared in several steps, starting by the reaction of diphenylamine with -chloropropionylchloride

Description
Buff colored crystals, mp 168-170 (chloroformethylacetate)

Action Synthesis
Prepared by reacting triamcinolone with propiophenone Both the neurophysiologic animal and clinical data has indicated that this compound does possess antidepressant properties. However, the inconvenient side effect of difficulty in initiating urination and scrotal discomfort might outweigh the therapeutic advantages of this compound.

Description
Crystals mp 281-283 [ ]D= 23 (c=0.98 in ; chloroform)

Manufacturer
Pfizer Inc (USA).

Action
Amcinafide is a new topical anti-inflammatory agent. It is closely related to amcinafal, which is the acetal with 3-pentanone.

References
1. JAMA 213 (13), 2247 (1970). 2. Manuf Chem 41 (3),29 (1970). 3. Pfizer Corp. S African Appl 68 01.099. 4. A preliminary evaluation of a potential antidepressant compound: animal and human correlation. D. M. Gallant et al. Curr Ther Res 11 (5), 296-299 (1969).

Manufacturer E. R. Squibb and Sons (USA) References

1. JAMA 213, 325 (1970). 2. WHO Chron 25 (3), 125 (1971). 3. Josef Fried et al. J Am Chem Soc 80, 2338-9 (1958). 4. Olin Mathieson Chemical Corp. Ger pat 1,099,529. 5. Olin Mathieson Chemical Corp. US pat 3,048,581.

Amfonelic Acid Win 25,978

7-Benzyl-1-ethyl-1,4-dihydro-4-oxo-1,8naphthyridine-3-carboxylic acid

Amedalin Hydrochloride (USAN) UK 3540-1

3-Methyl-3-(3-methylaminopropyl)-1-phenyl-2indolinone hydrochloride

Action
Amfonelic acid is known to be a potent locomotor 1,2 stimulant drug . The pharmacological properties and mechanism of action of the drug have been 3 described . The drug is under clinical study to 4 assess its efficacy as an antidepressant .

11

Manufacturer
Sterling-Winthrop (England)

Proprietary Name
Colectril

References
1. M. D. Aceto at al. Pharmacologist 8,222 (1966). 2. M. D. Acato et al. J Pharmacal Exptl Therap 158, 286 (1967). 3. Pharmacologic properties and mechanism of action of amfonelic acid M. D. Aceto et al. Europ J Pharmacal 10, 344-354 (1970). 4. The clinical evaluation of four proposed antidepressants. Relationship to their animal pharmacology. L. J . Hekiminian et al. Int Pharmacopsychiat 3, 6576 (1970).

References
1. Merck Co, Inc. Belg pat 639,386. 2. Tolerance and ionic effects in hypertensive patients of prolonged administration of an aldosterone antagonist (amiloride) as compared with a thiazide. J. C. Demanet et al. J Clin Pharmac 10 (4), 269-273 (1970).

AminagIutethimide
-(p-Aminophenyl)--ethylglutarimide

Amiloride (USAN; BAN) MK 870

N-Amidino-3,5-diamino-6-chloropyrazinecarboxamide (3,5-Diamino-6-chloropyrazinoyl) guanidine

Description
White crystalline powder, mp at about 151 . Soluble in organic solvents, and very slightly soluble in water.

Action Synthesis
Prepared by the reaction of methyl 3aminopyrazinoate with sulfuryl chloride, followed by the reaction with ammonia and finally with guanidine New inhibitor of adrenal steroidogenesis which has the advantage that its main site of inhibition lies early in the biosynthetic pathways. A recent clinical study has suggested that aminoglutethimide may be used with advantage for the treatment of selected patients with secondary hyperaldosteronism and oedema. The drug was used as an anticonvulsant agent; it was withdrawn from the U. S. market in 1966 because its prolonged use produces untoward effects.

Description
Crystals, mp 240.5-241.5 Hydrochloride salt, mp . 293.5

Action
Amiloride is a potassium-sparing diuretic agent. In a recent study the long-term effect of amiloride has been appraised, either alone or combined with hydrochlorothiazide, on the ionic metabolism of hypertensive patients.

Manufacturer
Ciba Pharmaceutical Co (USA)

Proprietary Name
Elipten

Manufacturer
Merck Sharp Dohme (USA)

References
1. R. L. Dexter et al. J Clin Endocr 27, 473 (1967). 2. L. M. Fishmann et al. J Clin Endocr 27,481 (1967).

12
3. The treatment of secondary hyperaldosteroism with oedema by aminoglutethimide. O. Kuchel et al. Pharmacol Clin 2, 138-142 (1970).

Amiquinsin Hydrochloride (USAN, Rec INN) U-935

Synthesis
Prepared from butyryl chloride and 1cinnamylpiperazine Amiquinsinum (Lat). Amiquinsina (Sp) 4-Amino-6, 7-dimethoxyquinoline hydrochloride monohydrate

Description
White crystalline powder, mp 202-204; easily soluble in water. The free base boils at 203-207 (0.6 mm Hg).

Action Synthesis
By reacting 4-chloro-6,7-dimethoxy-quinoline with ammonia Pharmacological studies have shown AP-237 to possess significant analgesic effects. It has been suggested that AP-237 might exert some modes of action different from that of antipyretic analgesics

Manufacturer
Kyorin Pharmaceutical Co, Ltd (Japan)

Description
White crystalline powder, mp 266-267 (dec). It is soluble in water (at least 50 mg/ml) with a pH of 5.3 at saturation.

References
1. Kyorin Pharmaceutical Co, Ltd. Fr pat 1.537.552. 2. T. Irikura et al. J Med Chern 11 (4),801-804 (1968). 3. Analgesic effect of AP 237. T. Irikura et al. Jap J Pharmac 20. 287-293 (1970).

Action
Amiquinsin hydrochloride is a new hypotensive drug. The absorption, distribution and elimination of the drug in dog has been recently studied.

Manufacturer
Eaton Laboratoires (USA)

References
1. Norwich Pharmacol Co. Fr pat 1,388,756. 2. B. S. Jandhyala et al. Arch Int Pharmacodyn 167 (1), 217-226 (1967). 3. Studies on the absorption. distribution. and elimination of amiquinsin hydrochloride, a hypotensive drug. J. D. Conklin and R. D. Hollifield. EurJ Pharmacol10, 360-368 (1970).

ara-IC
1--D-Arabinofuranosyl-5-iodocytosine

AP 237
1-Butyryl-4-cinnamyl-piperazine hydrochloride

Action
A comparison of the activities of ara-IC with several other structurally related nucleosides has indicated that ara-IC is unique in its activity. These conclusions are based on the spectrum of DNA viruses inhibited. the agents which block the

13
antiviral activity. the cytotoxicity. and the blocking of the cytotoxicity.

Production
Obtained from the culture filtrate of Aspergillus ochraceus

Manufacturer
The Upjohn eo (USA)

Description
Pale yellow powder

References
1. H. E. Renis et al. Antimicrobial Agents and Chemotherapy. 675-679 (1967). 2. Comparison of cytotoxicity and antiviral activity of 1--D-arabinofuranosyl-5-iodocytosine with related compounds. H. E. Renis. Cancer Res 30 (1). 189-194 (1970).

Action
Aspochracin is a new insecticidal antibiotic

References
1. R. Myokei et al. Agr and Bioi Chem 33, 1491 (1969). 2. Jap Med Gazz 7 (4), 9 (1970).

Aranoflavin
Aranoflavin is a new antibiotic which has been isolated from the culture broth of Arachniotus flavoluteus. It was separated into two related components designated as aranoflavin A (C23H33NO6) and aranoflavin B (C26H39NO9). The two components occur as a colorless powder.

AY 11483
3-Acetoxy-17-[3-furyI]-1,3,5(10)-7-oestratetraen17-ol

Action
Aranoflavin inhibits growth of bacteria, protozoa and tumor cells in vivo.

Manufacture
Toyo Jozo Co, Ltd (Japan)

References
Aranoflavia a new antibiotic. K. Mizuno et al. J Antibiotics, 23 (10) 493-496 (1970).

Action
AY-11483 has proved to be a potent orally active oestrogen in the vaginal cornification test in rats and mice with weak effect on the uterine weight in rats, mice and rabbits and endometrium in rabbits. It has been suggested that the compound might be a useful drug in the menopause, and for contraception.

Aspochracin

Manufacturer
Ayerst Laboratories (Canada)

References
1. Prepalation and biological properties of 17substituted estradiol derivatives in the 8-normal and 8-iso series. Y. Lefebvre et al. Am Chem Soc Meet Chicago, abstr no 154, p 10(1967).

14
2. Orally active oestrogens and Plogestins in prevention of pregnancy in rats. U. K. Banik et al. J Reprod Fert 18, 509 (1969). 3. AY-11483, a new type of orally active oestrogen. C. Revesz et al. J Reprod Fert 22,27-32 (1970). 4. Induction of ovulation in progestin-treated adult rats. U. K. Banik et al. Acta endocrino! 63 (4), 747 (1970).

Azacosterol (USAN; Rec INN) SC 12937 760

17-[1-[(3Dimethylaminopropyl)methylamino]androst-5-en-3ol 20, 25-Diazacholesterol

IMD

Azabicyclane Citrate
4-Methoxy-1-methyl-4-phenyl-3,5propanopiperidine hydrogen citrate

Synthesis
Prepared by the reaction of 3-hydroxyandrost-5en-17-one, 3-dimethylaminopropylamine with formic acid and the reduction of the resulting formamido intermediate with lithium aluminum hydride

Description
White crystalline powder, soluble in water

Description
Crystals, mp 146-148 (acetone-methanol); [ ]D= 54.5 (chloroform). Hydrochloride: [ ]D= -32 (methanol)

Action
Azabicyclane is a new analgesic agent. It has proved to show an analgesic potency about 3 times greater than meperidine.

Action
Azacosterol was found to be a potent anticholesteremic agent, but untoward side effects precluded its use in humans. Now it is used to sterilize pigeons without harming them. Azacosterol works on a physiological principle entirely different from that of human oral contraceptives.

Toxicity LD50 po in mouse: 300 mg/kg; iv 56 mg/kg; sc 200 mg/kg Manufacturer

Sankyo Co, Ltd (Japan)

Manufacturer
G. D. Searly and Co (USA)

References
1. S. Oida et al. Chern Pharm Bull 14. 1418-1424 (1966). 2. The pharmacology of azabicyclane, a new analgesic agent. s. Kobayashi at al. Toxicol Appl Pharmaeol 17. 344354 (1970).

Proprietary Name
Ornitrol

References
1. D. Klimstra et al. J Med Chem 9 (3), 323-326 (1966). 2. R. E. Counseil et al. (to G D Searle and Co), US pat 3.084,156. 3. The Wall Street J. p 8 (Feb 16. 1970). 4. Drug Topics. p 3 (March 2. 1970).

15
Prepared by the reaction of 3-hydroxy-8-azaestra1,3,5(10)-trien-17-one with sodium methoxide and cyclopentyl bromide. The resulting 3-cyclopentyloxyderivate is allowed to react with lithium acetylide.

Azaphen Hydrochloride Azafen hydrochloride

2-(4-Methyl-piperazinyl)-10-methyl-3,4diazaphenoxazine dihydrochloride 5-Methyl-3-(4-methylpiperazinyl)-5H-pyridazino [3,4b][1,4] benzoxazine dihydrochloride

Description
Crystals, mp 83-85 (water)

Action
8-Aza quinestrol is an orally active oestrogenic steroid. In a recent study the biological properties of the same were compared to quinestrol and ethynyl oestradiol. It has been concluded that substitution of a nitrogen atom in position 8 decreased both the biological and fat storage properties of quinestrol.

Manufacturer Action
Azaphen is a new antidepressant, which has been approved for use in medical practice. Warner-Lambert (USA)

References
1. Warner-Lambert Pharm Co Ger Offen 1,902,840. 2. J. Bowler et al. J Chem Soc (C), 2111 (1968). 3. The biological profile of 8-aza quinestrol. T. W. Mischler and D. Gawlak. J Reprod Fert 22, 49-56 (1970).

Manufacturer
All Union Chemo-Pharmaceutical Research Institute, Moscow (USSR)

References
1 . Pharmacological properties of azaphen a new antidepressant. M. D. Mashkovsky and A. I. Polezhaeva. Farmakol Toksikol 32, 656-662 (1969). 2. A new Soviet made antidepressant agent azaphen. A. I. Polezhaeva et al. Khim-Farm Zh 4 (2), 59 (1970).

Azaribine (Rec INN)

6-Azauridine 2',3',5'-triacetate 2--D-Ribofuranosyl-as-triazine-3,5(2H,4H)-dione, 2',3',5' triacetate

8-Aza quinestrol

AQ

3-Cyclopentyloxy-17-ethynyl-8-azaestra-1,3,5(10)trien-17-ol 3-Cyclopentyloxy-8-aza-19-nor-pregna-1,3,5(10)trien-20-yn-17-ol

Synthesis
Prepared by the reaction of 6-azauridine with acetyl chloride or with acetic anhydride.

Description
Crystals, mp 102-103

Synthesis

Action

16
Azarabine is an antitumor agent that has recently found new uses in human therapy, especially in the 4,6 5 treatment of psoriasis and viral eye infections . Promising results were obtained with smallpox.

Proprietary Name
Triazure (Calbio, USA)

References
1. J. Beranek et al. Coll Czech Chem Commun 28, 469 (1963); 29, 625 (1964). 2, J. Pitha et al. Coll Czech Chem Commun 28, 1507 (1963); 29, 410 (1964). 3, V. Cerneckij et al. Coll Czech Chem Commun 27, 87 (1962). 4. R. W. Turner and P. Calabresi. J Inv Derm 43, 551 (1964). 5. V. Miska et al. Lancet 2, 1230 (1967). 6, Therapeutic effects of 6-azauridine-lriacetate in psoriasis. M. Slavik et al. Pharmacal Clin 2, 120-125 (1970). 7. Toxicity of 6-azauridine triacetate. J. Plenova at al. Toxicol Appl Pharmacol 17 (2), 511-518 (1970). 8. The deacetylation of 6-azauridine-triacetate in the plasma of various species correlated with toxicity. J. Planova et al. The Problems of Species Differences and Statics in Toxicology. Proceedings of the European Society for the Study of Drug Toxicity. Excerpta Medica International Congress Series No 198, Vol XI. 240-243 (1970). 9. The antifertility effect of 2'-3'-5'-tri-O-acetyl-6azauridine. S. K. Saksena and R. R. Chandhury. Ind J Med Res 57, 1940-1945 (1969). 10. Abortifacient and teratogenic effects of triacetyl6-azauridine. G. van Wagenen and R. C. De Conti. Amer J Obstet Gynecol 108 (2), 272 (1970). 11. Side effects of 6-azauridine triacetate in rheumatoid arthritis. J. Elis et al. Clin Pharmacol Ther 11 (3),404-407 (1970). 12. Treatment of polycythemia vera with azauridine and azaribine. R. C. Deconti and P. Calabresi. Ann Intern Med 73 (4),575 (1970). 13. American Druggist. pg 57 (Jan 12, 1970).

Synthesis
Prepared in 3 steps from 4-p-chlorobenzoylpyridine and 3-dimethylaminopropyl magnesium chloride. The resulting carbinol is treated with sodium hydride to give 4-[2-(p-chlorophenyl) tetrahydro-2-furyl]1,2 pyridine, which is reduced catalytically .

Description
The free base, bp 134-135 (0.02 mm). The hydrochloride salt, mp 240-242 .

Action
Ba 41,799, one of a series of 14 substituted tetrahydrofurans, has been found to have marked antimalarial activity.

Manufacturer
Ciba Ltd (Switzerland)

References
1. A. Marxer. Helv Chim Acta 52, 262 (1969). 2. Ciba Ltd. Brit pat 1,133,302. 3. The chemotherapy of rodent malaria, XII. Substituted tetrahydrofurans, a new Chemical family of antimalarials. The action of 2-(p-chlorophenyl)-2(4-piperidyl)-tetrahydrofuran against Plasmodium berghei and Plasmodium chabaudi. W. Peters. Ann Trop Med Parasitol 64 (2), 189-202 (1970).

Baclofen (Prop INN) BA 34,647 Ba 41,799

4-[2-(p-Chlorophenyl)tetrahydro-2-furyl] piperidine 2-(p-Chlorophenyl)-2-(4-piperidyl) oxolan Baclofenum (Lat). Baclofeno (Sp) -(Aminomethyl)-p-chlorohydrocinnamic acid -Amino--(p-chlorophenyl) butyric acid

17
By reacting -isopropylmandelic acid with 3(dimethylamino)propyl chloride. Bay 1433 hydrochloride melts at 135-136 .

Action
Antidepressant

Manufacturer
Bayer (Germany)

Synthesis
Prepared from -(p-chlorophenyl) glutaric acid amide, from 4-(p-chlorophenyl)-2-pyrrolidone, from 2 -acetylamino--(p-chlorophenyl) butyric acid . Also from -cyano-p-chlorohydrocinnamic acid ethyl 3 ester .

References
1. Farbenfabriken Bayer AG. Ger. pat. 1.135.007. 2. Present Status Psychotr Drugs (Proc VI Internat Coni Coil Internat Neuro-Psychopharm. Tarragona. Spain. Apr 1968): 180. 1969.

Description
Crystals, mp 206-208 (water)

Action
Baclofen is a new skeletal muscle relaxant. It has been suggested that it acts at the spinal level.

BC-347
1 (2H)-Quinoline carboxylic acid, ethyl ester N-Ethoxycarbonyl-1, 2-dihydroquinoline 1-Carbethoxy-1, 2-dihydroquinoline

Manufacturer
Ciba (Switzerland)

References
1. WHO Chran 24(9). 414 (1970). 2. CIBA Ltd. Neth Appl 6,407.755. 3. CIBA, Swiss pat 449,046. 4. A new agent for the control of spasticity. R. F. Janes et al. J Neural Neuro Surg 33(4). 464468 (1970).

Synthesis
Prepared by treating 1, 2-dihydroquinoline with ethyl 1 chloroformate in the presence of triethylamine . Also by reducing 1-carbethoxyquinolinium chloride with 1,2 sodium borohydride , bp: 98-1000 (0.04 mm); bp: 108-114 (0.05-0.08 mm).

BAY 1433
-Isopropylmandelic acid, 3-(dimethylamino)propyl ester hydrochloride -Phenyl--isopropyl-glycolic acid 3-(N, Ndimethylamino) propylester hydrochloride

Action
With a preclinical profile of a tranquilizer BC-347 clinically has proved to be a stimulant for schizophrenics and depressives with neither 4 antipsychotic nor antidepressant effects .

Manufacturer
Bristol Laboratories (USA)

References
1. Bristol-Myers Co. Neth Appl 6,614,408. 2. B. Bellean et al. J Amer Chern Soc 90 (3), 823824 (1968) . 3. R. R. Martel et al. J Pharmacol Exp Ther 166 (1), 44-51 (1969).

Synthesis

18
4. The clinical evaluation of four proposed antidepressants. Relationship to their animal pharmacology. L. J. Hekimian et al. Int Pharmacopsychiat 3, 65-76 (1970). J. Edelson et al. J Pharm Sci 59(5), 680-682 (1970). 7. Oxidation of cholesterol by rat liver mitochondria: Effect of N--phenylpropyl-N-benzyloxy acetamide. D. Kritchevsky and S. A. Tepper. Arzneim-Forsch 20 (4).384-385 (1970). 8. Gas chromatography determination of W1372 in blood. J. F. Douglas and J. A. Stockage. J Pharm Sci 59(6), 850 (1970).

Beloxamide (USAN; Rec INN) W1372 Bendazac (Rec INN) AF 983

Bendazacum (Lat). Bendazaco (Sp) [(1-Benzyl-1-H-indazol-3-yl) oxy] acetic acid Beloxamidum (Lat). Beloxamida (Sp) N-(Benzyloxy)-N-(3-phenylpropyl) acetamide N--Phenylpropyl-N-benzyloxy acetamide Benzyl-N--phenylpropyl acetohydroxamate

Synthesis
By saponification and decarboxylation of benzyl-N(3-phenylpropyl) carbethoxyhydroxamate to yield N(3-phenylpropyl) benzyloxyamine, and by reaction of this amine with acetylchloride.

Description
White crystalline powder, mp 158-159 Insoluble in . water, rather soluble in chloroform, ethanol and acetone. UV max 306 m [E(1%, 1 cm)=191].

Description
Beloxamide is a bitter oily liquid essentially insoluble in water and readily miscible with most organic solvents. bp 155 (0.03 mm Hg); [n]D = 1, 5500.

Action
Bendazac is a topical anti-inflammatory drug.

Action
Beloxamide is a new hypolipidemic agent that has been shown to reduce the extent of atherosclerotic lesions and to lower serum cholesterol levels in 4,5 animals maintained on a highcholesterol diet .

Manufacturer
A. C. R. Angelini Francesco (Italy)

References
1. WHO Chron 24 (11), 527 (1970). 2. Pharmacological properties of bendazac (AF 983) with particular reference to its topical action on some experimental inflammatory processes. B. Silveslrini el al. Arzneim-Forsch 19 (1),30 (1969). 3. Studies on the mechanism of action of bendazac (AF 983). B. Silveslrini et al. Arzneim-Forsch 20 (2), 250-253 (1970).

Manufacturer
Carter-Wallace (USA)

References
1. JAMA 211, 2149 (1970). 2. WHO Chron 24 (11), 527 (1970). 3. B. J. Ludwig et al. J Med Chern 10 (4), 556-564 (1967). 4. F. M. Berger et al. J Pharmacol Exp Ther 170, 371-381 (1969). 5. F. M. Berger et al. Proc Exp Bioi Med 132, 293297 (1969). 6. Metabolic fate of N--phenylpropyl-N-benzyloxy acetamide (W-1372) in rats, dogs. and monkeys.

19
2-[1-(Succinoyloxy)ethyl]-3-methyl-5-(2-oxo-2,5dihydro-4-furyl)benzo-[b]-furan

Beneprizine Hydrochloride BRL1288

Benzilic acid, 2-(ethylpropylamino)ethyl ester hydrochloride ,-Diphenylglycolic acid, 2-(ethylpropylamino)ethyl ester hydrochloride

Synthesis
Prepared from 4-(3-acetyl-4-hydroxyphenyl)-2(5H)furanone in several steps; the last being the esterification of 4-[2-(1-hydroxyethyl)-3-methyl-5benzofuranoyl]-2(5H)-furanone with succinic anhydride.

Synthesis
Prepared from the methyl ester of ,diphenylglycolic acid and 2ethylpropylaminoethanol.

Description
White to pale yellow crystalline powder, mp 144 . Soluble in alkaline solutions.

Description
Plates, mp 164-166 (butanone)

Action and Uses

Benfurodil hemisuccinate is a new coronary vasodilator. For use in the treatment of arteriopathies; vasomotor disorders; coronaritis.

Action
Anticonvulsant-anti-parkinson agent, which is under clinical study. In patients with Parkinson's disease beneprizine has been shown to relieve the symptoms without showing psychotoxic or peripheral antiacetylcholine activity.

Toxicity
LD50 (oral) in mice: 52032 mg/kg

Supplied as
Tablets 50 mg

Manufacturer
Beecham Research Laboratories (U.K.)

Dosage
50 to 100 mg three times daily

References
1. Beecham Group Ltd. Neth. Appl. 6.409,696. 2. Nature 223, 416-417 (1969). 3. B. O. Hughes and B. Spicer. Brit J Pharmacol Chemotherapy 37, 501 P-502P (1969). 4. Mad. Praticienne 26(399), 3 (1970) .

Proprietary Name
Eudilat

Manufacturer
Clin Byla (France)

References

Benfurodil Hemisuccinate (Rec INN) CB 4091

2-(1-Hydroxyethyl)--(hydroxymethyl)-3-methyl-5benzofuranacrylic acid -lactone succinic acid ester 4-[2-(1-Hydroxyethyl)-3-methyl-5-benzofuranoyl]-2(5H)furanone succinate (ester)

1. Establissements Clin Byla Fr pat 1 408,721. 2. J. Schmitt et al. Chim Ther 305-308 (1966). 3. J. Schmitt et al. Bull Soc Chim Fr 74-84 (1967). 4. Med Act (Drugs of Today) 6 (6), 202-205 (1970). (Review with 10 references).

20
5-Benzyldihydro-6-thioxo-2H-1,3,5-thiadiazine-3(4H) acetic acid 2-Thioxo-3-benzyl-5-carboxymethyl-tetrahydro1,3,5-thiadiazine

Benorylate (BAN)

Win 11450

Salicylic acid, acetate, ester with 4'hydroxyacetanilide 4-Acetamidophenyl-2-acetoxybenzoate

Synthesis Synthesis
Prepared by the reaction of N-acetyl-p-aminophenol with acetylsalicyloylchloride. By the reaction of benzylamine with carbon disulfide and by the condensation of the dithiocarbamate formed with formaldehyde and aminoacetic acid

Action Action
Benorylate is a recently synthesized analgesic compound at present being evaluated in clinical trials for the treatment of rheumatoid arthritis. Bensuldazic acid is a veterinary fungicide. For use in the treatment of trichophytosis in cattle.

Manufacturer
Hoechst (Germany)

Manufacturer
Sterling-Winthrop (England)

Proprietary Name
Defungit (is the sodium salt)

References
1. Sterling Drug Inc. US pat 3.431,293. 2. Sterwin A. G. Neth Appl 6,504,517. 3. Pharmacology of 4-acetamidophenyl-2acetoxybenzoate. I. Rosner et al. Therapie 23 (3), 525 (1968). 4. Comparison of 4-acetamidophenyl-2acetoxybenzoate (Win 11450), aspirin, and placebo in stomatology. V. Vialatel et al. Therapie 23 (3). 535 (1968). 5. 4-Acetamidophenyl-2-acetoxybenzoate, a new antipyretic for padiatric use. Jean Weill et al. Therapie 23 (3), 541 (1968). 6. The treatment of rheumatoid disease. A doubleblind trial comparing buffered aspirin with benorylate. L. S. Bain and R. A. P. Burt. Clin Trials J 7 (2), 307312 (1970). 7. The treatment of rheumatoid disease. Preliminary assessment of a new drug: benorylate. N. Cardoe. Clin Trials J 7 (2), 313-318 (1970).

References
1. WHO Chron 24 (11). 526 (1970). 2. A. Rieche et al. Arch Pharm 296(11) 770-784 (1963). 3. Deutsche Akademie der Wissenschaften zu Berlin. Gar pat 1,220,429. 4. Arzneim-Forsch 19(11), 1817 (1969).

Benzbromarone L-2214
3,5-Dibromo-4-hydroxyphenyl-2-ethyl-3benzofuranyl ketone 2-Ethyl-3-(3,5-dibromo-4-hydroxybenzoyl) benzofuran 2-Ethyl-3-(4-hydroxy-3,5dibromobenzoyl)coumarone

Bensuldazic Acid (Rec INN)

Acidum Bensuldazicum (Lat). Bensuldacico Acido (Sp)

21

Synthesis
Prepared by demethylating 2-ethyl-3anisoylcoumarone and subsequent bromination.

Description
White crystalline powder, mp 320-322; soluble in water, insoluble in ether.

Description
Yellowish prisms, mp 151 .

Action and Uses

Pharmacologically, benzoctamine has a profile midway between chlorpromazine and imipramine. For use in the treatment of psychoneurotic states manifested by anxiety and tension, and psychovegetative syndrome.

Action
Benzbromarone first experimented as a spasmolytic agent was recently shown to decrease plasma uric acid by increasing acid clearance and urinary excretion of uric acid.

Dosage
10 mg three times daily.

Manufacturer
Societe Beige de I'Azote and Laboratories Labaz (France)

Supplied as
Scored tablets, 10 mg.

Registered Name References

1. Societe des Laboratoires Labaz. Belg pat 553,621. 2. Societe Beige de I'Azote. US pat 3,012,042. 3. Buu Hoi et al. J Chem Soc, 625 (1957). 4. R. Kotzaurek et al. Wien Med Wochenschr 118 (47), 1014-18 (1968). 5. N. Zoelineret al. Klin Wochenschr 46 (24), 131819 (1968). 6. Florian Delbarre et al. Chim Ther 3 (6), 470-4 (1968). 7. Die Wirkung von Benzbromaronum auf die renale Harnsaureausscheidung Gesunder. N. Zollner et al. Klin Wochenschr 48 (7), 426-32 (1970). Tacitine

Manufacturer
CIBA (Switzerland; France)

References
1. CIBA Ltd. Belg pat 610,863. 2. Med Act (Drugs of Today), 6 (4), 122-124 (1970). (Review with 11 references) . 3. Effects of benzoctamine (30803-Ba, tacitin), a new psychoactive drug, on catecholamine metabolism. L. Maitre et al. Biochem Pharmac 19, 2875-2892 (1970).

Benzoctamine Hydrochloride (Rec INN) Ba 30803

N-Methyl-9,10-ethanoanthracene-9-(10H)methylamine hydrochloride 1-Methylaminomethyl-dibenzo-[b,e]-bicyclo-[2,2,2]octadiene hydrochloride 1-Methylaminomethyl-[2,3:5,6]-dibenzo-[2,2,2]bicyclooctane hydrochloride

Benzpiperylone (Rec INN; NFN) KB 95

4-Benzyl-1-(1-methyl-4-piperidyl)-3-phenyl-3pyrazolin-5-one

Synthesis

22
Prepared from (N-methyl-piperidyl)-hydrazine and ethyl-2-benzyl-3-oxo-3-phenylpropionate.

Manufacturer
Pfizer Co, Inc (USA)

Description
Crystals, mp 181-183 (ethanol).

Proprietary Name
Quantril

Action
Benzpiperylone, a pyrazol derivative, shows antiphlogistic and antiserotonin activity. In a recent study no influence of the drug on blood coagulation 2 could be found .

References
1. Pfizer Co and Inc. US pat 3,053,845. 2. A clinical pharmacological evaluation of benzquinamid,. a new antiemetic agent. N. E. Pitts. Curr Ther Res 11, 325 (1969). 3. 8enzquinamide parenteral for the treatment of postoperative nausea and vomiting. R. M. Larrauri. Curr Ther Res 11,118 (1969). 4. Inhibition of apomorphine-induced vomiting by benzquinamide. R. L. Klein, Clin Pharmacal Ther 11 , 530 (1970). 5. A double-blind evaluation of the anti-emetic efficacy of benzquinamide, prochlorperazine and trimethobenzamide in office practice. J. Medoff. Curr Ther Res 12, 706-710 (1970).

Manufacturer
Sandoz (Switzerland)

Proprietary Name
Reublonil

References
1. Ebnther et al. Helv Chim Acta 42, 1201 (1959). 2. The behaviour of the blood coagulation factors under the influence of a new pyrazol derivative in long-term therapy with anticoagulants. H. Wolf. Arzneim-Forsch 20 (9), 1252-1218 (1970).

Bezitramide (Prop INN)

1-[1-(2-Cyano-3,3-diphenylpropyl) piperid-4-yl]-3propionyl-2-benzimidazolinone 1-(3-Cyano-3,3-diphenylpropyl)-4-(2-oxo-3propionyI-1-benzimidazolinyl) piperidine

Benzquinamide (USAN; Rec INN) P 2647

Benzquinamidum (lat) . Benzquinamida (Sp) N,N-Diethyl-1,3,4,5,6,11b-hexahydro-2-hydroxy9,10-dimethoxy-(2H)-benzo-(a)-quinolizine-3carboxamide acetate

Action
Bezitramide is an orally active analgesic. From the results of a recent double blind study it has been concluded that benzitramide 5 mg given orally has a more potent and longer-acting analgesic effect than dextromoramide on postoperative pain.

Manufacturer Description
Crystals mp 130-131.5. Janssen Pharmaceutica (Belgium)

References Action
Benzquinamide is a well-tolerated and effective antiemetic agent. Bezitramide, an orally active analgesic. An investigation on pain following operations for lumbar disc protrusion (preliminary report). H. Knape. Brit J Anaesth 42, 325-328 (1970).

23

Bisobrin Lactate (USAN) EN 1661L

meso-1,1'-Tetramethylene-bis-[1,2,3,4-tetrahydro6,7-dimethoxyisoquinoline] dilactate

Synthesis
Prepared by the reaction of thionyl chloride with 2,4dichlorophenol.

Action
Bithionol sulfoxide has been proved to have a 1 stronger anthelmintic activity than bithionol . The metabolic fate and distribution of the drug have 2,3 been reported .

Synthesis
Bisobrin base is allowed to react with lactic acid in ethanolic solution.

Manufacturer
Tanabe Seiyaku Co, Ltd (Japan)

Proprietary Name
Bitin S

Description
White crystalline powder, mp 217-218 (95% ethanol).

References
1. M. Hamada. Med J Kagoshima Univ 16, 236 (1964). 2. Studies on the distribution of radioisotopes by whole body autoradiography (XIX) Distribution of Sbis (3,5-dichlor-2-hydroxyphenyl) sulfoxide in mice, rats and cockerels. T. Takahashi et al. Radioisotopes 18 (12), 552558 (1969). 3. Metabolic fate of bis (3,5dichloro-2hydroxyphenyl)-sulfoxide (bithianol sulfoxide). T. Meshi et al. Biochem Pharmacol 19, 1351-1361 (1970).

Action
Bisobrin has been found highly active in dissolving blood clots in the veins of animals. The drug is under clinical study.

Manufacturer
Endo (USA)

References
1. JAMA 207, 2272 (1969). 2. Endo Laboratories Inc. S. African pat 677730. 3. Clinical pharmacologic study of an isoquinoline derivative (EN 1661) and of its ability to induce fibrinolytic activity in the circulation of man. J. L. Ambrus et al. Curr Ther Res 12 (7), 451-473 (1970).

Bitipazone (Prop INN)

Bitipazonum (Lat). Bitipazona (Sp) 2,3-Butandione, bis [4-(2-piperidinoethyl)-3thiosemicarbazone]

Bithionol Sulfoxide
Bis-(3,5-dichloro-2-hydroxyphenyl) sulfoxide

24
use in the treatment of infections due to Ancylostoma duodenale and Necator americanus.

Dosage
Adults, three doses of 100 mg, each at 12 hour intervals after food.

Supplied as
Capsules, 50 mg

Proprietary Name Synthesis

Prepared in three steps from acetophenone methyldithiocarbazate which is condensed with (piperidino)ethylamine. The resulting acetophenone 4'-[-piperidino) ethyl] thiosemicarbazone is steam distilled to remove acetophenone and finally condensed with butan-2,3-dione. The compound obtained melts at 235 (ethanol). Jonit

Manufacturer
Hoechst (Germany)

References
1. A. Billeter and A. Steiner. Ber Dtsch Chem Ges 20, 230 (1887). 2. Nederlandse Centrale Organisatie Voor Toegepast-Natuurwetenschappelijk Onderzoek. Brit pat 793,802. 3. Farbwerke Hoechst. Brit pat 1,001,314. 4. Med Act (Drugs of Today) 6 (5), 162 (1970). (Review with 6 references). 5. Evaluation of bitoscanate-Jonie. in intestinal parasitic infection: a field study. G. S. Mutalik et al. Ann Trop Med Parasitol 64 (1), 79 (1970).

Action
Bitipazone shows coccidiostatic activity.

References
1. WHO Chron 24 (9), 415 (1970). 2. Well come Foundation Ltd. Belg pat 667,355.

Bitoscanate
Isothiocyanic acid, p-phenylene ester p-Phenylene bis (dithiocarbamate) p-Phenylene-1, 4-diisothiocyanate

BL-P 1654
6-[R--(Guanylureido) phenylacetamido] penicillanic acid

Synthesis
From 1,4-diaminobenzol and thiophosgene ; from p2 phenylenediamine .
1

Action
BL-P 1654 a new orally absorbed, semi-synthetic penicillin with a very broad spectrum of activity. In systemic P. aeruginosa infections it has proved to be 6-8 times more active than carbenicillin and almost 100 times more active than ampicillin.

Description
Nearly tasteless, odorless, and colorless crystalline product, mp 132 .

Action and Uses

Bitoscanate has been found to be effective in helminthiasis in laboratory animals and in man. For

Manufacturer
Bristol Laboratories (USA)

25

References
Tenth Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, Oct 18-21 (1970); abstr. 107-108.

Bromazepam (USAN; Rec INN)

Bromazepamum (Lat) 7-Bromo-1,3-dihydro-5-(2-pyridyl)-2H-1,4benzodiazepin-2-one

Ro 5-3350

BP 400
9-(N-Methyl-4-piperidylidene) thioxanten maleate

Synthesis
Prepared from 2-amino-5-bromophenyl-2-pyridyl ketone

Description
Colorless prisms, mp 237-238.5 (acetone).

Action
Bromazepam is a new psychoactive agent of the 1,4-benzodiazepine class of compounds, which has some qualitative similar pharmacological actions to those of diazepam in most animal laboratory tests.

Action
BP 400 is an antamine (anti-histamine, serotonin, 1 bradykinin) with slight sedative effects . Its distribution has been studied in 65 structures of the 2 rat brain, using autoradiography .

Manufacturer
Hoffmann-La Roche Inc (USA)

Manufacturer
Sandoz AG (Switzerland)

References
1. WHO Chron 24 (11), 527 (1970). 2. Hoffmann-La Roche Inc. US pat 3,182,065; US pat 3,100,770; Belg pat 619.101; US pat 3.182.067. 3. R. Ian Fryer et al. J Pharm Sci 53 (3). 264 (1964). 4. A behavioral and autonomic nervous system study of Ro-5-3350 and diazepam in conscious dogs. B. Korol at al. Pharmacology 1(2).115-128 (1968). 5. Effects of a new benzodiazepine compound (Ro 5-3350) on subcortical and cortical nervous system structures in the cat. C. Guerrero Figueroa et al. Vll lnternat Congr Collinternationale Neuro-Psychopharm. Prague. Czechoslovakia. Aug. 11-15 (1970) p. 175.

References
1. Wien Klin Wschr 80, 250 (1968). 2. Autoradiographic studies on the distribution of the 14 thioxanthene derivative C-BP400 in the rat brain. H. Eckert and A. Hopi. Arzneim-Forsch 20 (11), 1712-1716 (1970).

26

Bromebric Acid (BAN; Prop INN)

Acidum bromebricum (Lat) cis-3-p-Anisoyl-3-bromoacrylic acid cis-3-Bromo-4-(4-methoxybenzoyl)acrylic acid

Action
Bucrylate is a tissue adhesive.

Manufacturer
Ethieon, Inc (USA)

Proprietary Name Synthesis

By hydrolisis of -4-methoxyphenyl-,-dibromo, , 3,5 - -crotonolactone . Also by splitting off hydrobromic acid from p-(4-methoxybenzoyl) acrylic 3,4,5 acid dibromide Coapt

References
1. WHO Chron 24 (11), 527 (1970). 2. JAMA 209. 406 (1969). 3. Healing of skin wounds under butyl cyanoacrylate dressing. S. N. Bhaskar and D. E. Cutright. J D Res 48, 294297 (1969). 4. Modified delayed closure of facial wounds with isobutyl cyanoacrylate. E. H. Hunsuck et al. Oral Surg, Oral Med, Oral Path 29 (2), 305-312 (1970).

Description
Crystals, mp 146-147 UV max 223 m [Ig = 4.17] . and 301 m [lg =4.18] at pH 2.8; 218 m [lg =4.17] 6 and 299 m [lg =4.19] at pH 8.1 .

Action
Prophylaxis of migraine.

Manufacturer
Leciva (Poland)

Bufexamac (Rec INN; BAN) CP 1044 J3

Bufexamacum (Latin). Bufexamaeo (Sp) 2-(p-Butoxyphenyl)-acetohydroxamic acid

References
1. Chem Drug 194, 446 (1970). 2. WHO Chron 25 (3), 123 (1971). 3. M. Semonsky et al. Coll Czech Chem Commun 28, 377 (1963). 4. Robert E. Lutz et al. J Org Chem 26, 746 (1961). 5. Spofa. Brit pat 881,617. 6. B. Kakac et al. Coll Czech Chem Commun 33, 1256 (1968).

Bucrylate (USAN)
Bucrilate (Rec INN). Bucrilatum (Lat). Bucrilato (Sp) Isobutyl 2-cyanoacrylate

Synthesis
Prepared in several steps from phydroxyacetophenone; the last being the reaction of ethyl-p-butoxyphenylacetate with hydroxylamine.

Description
Crystalline powder, which melts at 153-155 .

Action

27
Non-steroidal analgesic and anti-inflammatory agent. Bulgerin is a new antibiotic, active against some phytopathogenic fungi.

Toxicity
LD50 orally in rats: 4,600 mg/kg; in mice orally: 8,000 mg/kg.

Manufacturer
Shionogi and Co, Ltd (Japan)

Manufacturer
Continental Pharma Laboratories (Belgium)

References
A new antibiotic, bulgerin, active against phytopathogenic fungi. J. Shoji et al. J Antibiotics 23 (6), 295-299 (1970).

Proprietary Name
Droxaryl

References
1. Pharm. J. 202, 719 (1969). 2. Madan AG. Belg. pat. 661226 (1965). 3. Teratological studies of pbutoxyphenylacetohydroxamic acid in rats and rabbits. J. Roba et al. Arzneim-Forsch 20 (4). 565-569 (1970). 4. Therapeutic efficacy of bufexamac in rheumatoid arthritis; a doubleblind comparison with indomethacin. K. Pavelka and F. Wagenhauser. Curr Ther Res 12 (2), 69-72 (1970). 5. Use of bufexamac for rheumatoid arthritis. B. S. Rose et al. Curr Ther Res 12 (3). 150-153 (1970). 6. Pharmacological studies of bufexamac topically applied on the skin. G. Lambelin et al. Arch Int Pharmacodyn Ther 187 (2),394 (1970). 7. Preliminary study of the action of pbutoxyphenylacethydroxamic acid in the treatment of osteoarthritis of the hip. H. Bloch-Michel and M. Parrot, Therapie 25 (5), 969 (1970).

Bunolol Hydrochloride (USAN; Rec INN) W 6412A

Bunololum (Lat) ()-5-[3-(tert-Butylamino)-2-hydroxypropoxy]-3,4dihydro-1(2H)-naphthalenone hydrochloride

Synthesis
By the reaction of 5-hydroxy-1-tetralone with tbutylamino-2,3-epoxy-propane in the presence of sodium hydroxide. Also by the reaction of 53 hydroxy-1-tetralone with t-butylamine .

Description

Bulgerin
Production
Bulgerin has been isolated from a culture broth of a streptomyces strain S-288 Streptomyces aburaviensis var tuftformis.

White crystalline powder, mp 224-226 (ethanol)

Action
Bunolol is a new potent beta receptor antagonist 4 recently described . It exhibits much less local anesthetic and nonspecific antiarrhythmic activity 5 than propranolol .

Manufacturer
Warner Lambert (USA)

Description
Bulgerin is a water-soluble amphoteric subsstance. UV max 289 m, and shoulder 230 m, in 0.05 N HCI. []D= +24 (in water).

References
1. JAMA 212, 2247 (1970). 2. WHO Chron 24 (11), 527 (1970).

Action

28
3. Derivatives of 3,4-dihydro-1 (2H)-naphthalenone as -adrenergic blocking agents, 1. Bunolol and related analogs. C.F. Schwender et al. J Med Chem 13(4), 684-688 (1970). 4. The cardiovascular pharmacology of bunolol, a new beta adrenergic blocking agent. R. D. Robson and H. R. Kaplan. J Pharmacal Exp Ther 175, 157-167 (1970). 5. Antiarrythmic activity of bunolol, a new beta adrenergic blocking agent H. R. Kaplan and R. D. Robson. J Pharmacal Exp Ther 175, 168-177 (1970). 2. C. F. Spencer et al. J Med Chem 9 (6), 934-936 (1966). 3. E. C. McManus et al. J Parasit 54, 1190-1193 (1968). 4. T. V. Raines, Poultry Sci 47, 1425-1432 (1968). 5. Efficacy of buquinolate against ten strains of Eimeria tenella and the development of a resistant strain. D. K. McLoughlin. Avian Dis 14 (1), 126-130 (1970).

Calcium polystyrene sulfonate

Description
Calcium polystyrene sulfonate, a cation-exchange resin charged with calcium, is available as an insoluble buff colored, finely ground powder.

Buquinolate (USAN)
6, 7-Diisobutoxy-4-hydroxy-3-quinolinecarboxylic acid ethyl ester

Action and Uses

The calcium ions of the exchange resin are released and replaced by potassium ions in the alimentary canal. The excretion of potassium ion decreases serum potassium ion concentration. For use in the treatment of hyperkalemia.

Dosage
Adults. 15 g 3 or 4 times daily by mouth or 30 g as a retention enema.

Proprietary Name
Calcium Resonium

Synthesis
Prepared in five steps from pyrocatechol and isobutyl bromide. Nitration, followed by reduction gives 3, 4-diisobutoxyaniline which is condensed with ethyl ethoxymethylenemalonate and finally cyclized.

Manufacturer
Bayer Prod (England)

References
1. Pharm J 203. 59 (1969). 2. Med Act (Drugs of Today) 6(1), 9-10 (1970).

Description
Crystals, mp 288-291 (dimethylformamide).

Action
Buquinolate is a broad-spectrum coccidiostat for poultry.

Calusterone (USAN; Rec INN) U-22,550

Calusteronum (Lat). Calusterona (Sp) 17-Hydroxy-7,17-dimethylandrost-4-en-3-one 7,17-Dimethyltestosterone

Manufacturer
Eaton Laboratories (USA)

References
1. The Norwich Pharmacal Co. Belg pat 659,237.

29

Synthesis
The reaction of 6-dehydro-17-methyltestosterone with methylmagnesium bromide and cuprous chloride in anhydrous tetrahydrofurane gives a mixture of 7 and 7-methyl isomers which is separated chromatographically to give 7, 17dimethyltestoterona.

Action
Cambendazole, a derivative of thiabendazole, is a new broad spectrum anthelmintic. It has all the advantages of the parent chemical plus a considerably longer effective half-life in animals

Manufacturer
Merck Sharp and Dohme (USA)

Description
Crystals. mp 127-129 (acetone).

References
1. JAMA 212, 466 (1970). 2. WHO Chron 24 (9), 416 (1970). 3. Chem Engineer News, p 77 (June 8.1970). 4. The efficacy of 5-isopropoxy-carbonylamino-2-(4thiazolyl) benzimidazole against helminths of sheep. J. R. Egerton and W. C. Campbell. Res vet Sci 11, 193-195 (1970). 5. The efficacy of cambendazole against gastrointestinal nematodes of cattle. J. R. Egerton et al. Res vet Sci 11, 495-499 (1970). 6. A new broad spectrum anthelminthic. D. R. Hoff et al. Experientia 26, 550 (1970). 7. Anthelmintic efficacy of cambendazole in cattle. N. F. Baker and G. T. Walters. Amer J Vet Res 32 (1), 29 (1971).

Action
Calusterone has been reported to have potent antitumor efficacy in women with advanced breast cancer. and to be better tolerated than most chemotherapeutic or steroidal antitumor agents.

Manufacturer
The Upjohn Co (USA)

References
1. JAMA 211, 819 (1970). 2. WHO Chron 24 (11), 527 (1970). 3. J. C. Babcock et al (to the Upjohn Co). US pat 3.341.557. 4. Progress in the treatment of advanced breast cancer. R. M. Walter and G. S. Gordan. Calif Med 111. 3845 (1969). 5. Antitumor efficacy of calustelone in advanced female breast cancer. G. S. Gordan et al. Calif Med 113. 1-10 (1970).

Campesteryl Acetate
(24R)-24-Methyl-3--acetoxycholesten-5-ene

Cambendazole (USAN; Prop INN)

Isopropyl 2-(4-thiazolyl)-5-benzimidazole-carbamate 2-(4-Thiazolyl)-5-isopropoxy-carbonylaminobenzimidazole

Synthesis
The isolation of campesterol from many plant 1 sources has been described . Its synthesis has been recently accomplished starting from the

30
optically active (-)-3,4-dimethylpentylmagnesium 2 bromide and pregnenolone acetate .

References
1. M. E. Wall et al. J Am Chem Soc 88, 3888 (1966). 2. J. A. Kepler et al. J Org Chem 34, 3853 (1969). 3. M. Shamma and L. Novak. Tetrahedron 25, 2275 (1969). 4. T. Kametan; et al. Chem Ind (41),1323 (1970). 5. Proc Am Canc Res 11, abs 121 (March 1970). 6 Preliminary pharmacologic and clinical evaluation of camptothecin sodium. Jeffrey A. Gottlieb et al. Cancer Chemother Rep, Pt 1, 54 (6), 461-470 (1970)

Description
Crystals mp 138 (ethanol); []D= -33 (c=1) Rf=0.86 (TLC), hexane-ether-acetic acid (20:4:1 ).

Action
Biological tests have revealed that synthetic campesteryl acetate has considerable utility for larval growth of Dermestes maculatus.

References
1. Fernholz and McPhiliamy. J Am Chem Soc 63,1155 (1941). 2. Synthesis of campesteryl acetate [(24R)-24methyl-3--acetoxycholesten-5-ene] and its 24Sepimer. R. Ikan et al. Steroids 16 (5), 517-522 (1970).

l-Canadine Methochloride Camptothecin NSC100880

4--Ethyl-4,12-dihydroxy-1H-pyrano [3',4',6,7] indolizino [1,2-b] quinolin-3,14-dione

Isolation Alkaloid isolated from the bark of Zanthoxylum 1 martinicense DC .

Action Synthesis
Camptothecin is a novel alkaloid isolated from the stem wood of the Chinese tree, Camptotheca acuminata. The structural elucidation of this alkaloid 1 has been reported by Wall and co-workers . Attempts to synthesize it have been examined, but 2,3,4 have not yet succeeded . Pharmacological studies have shown that lcanadine methochloride causes a significant fall in blood pressure in intact anesthetized cats and dogs and that it shows ganglion-blocking activity.

Toxicity
LD50 ip in mice: 842.8 mg/kg.

Description
Pale yellow needles, mp 264-267 dec. [ ]D= +31.3 (chloroform/methanol, 8:2). UV max 220 m [=37.320], 254 m [=29,320], 290 m [=4,980] and 370 m [=19,900].

References
1. J. Tomko et al. Lloydia 30. 231 (1967). 2. A pharmacological study of the alkaloids Icanadine methochloride and d-tembetarine chloride. D. G. Patel et al. Lloydia 33. 36-42 (1970).

Action
Camptothecin has been found effective in treatment of advanced cancer of the intestine and rectum, investigators from the National Cancer Institute said at the recent annual meeting of the American Asssociation for Cancer Research.

31

Capuride (USAN; Rec INN)

-Ethyl--methylvaleric acid, ureide (Ethyl-sec-butylacetyl) urea

McN-X-94

Production
From the broth filtrate of Streptomyces No 547.

Action Synthesis
Prepared form the -ethyl--methylvaleric acid chloride. O-Carbamyl-D-serine inhibits the growth of Mycobacterium tuberculosis at relatively high concentrations and potentiates the inhibitory activity of D-cycloserine. The synergism exhibited by the combination of D-cycloserine with O-carbamyl-Dserine makes the latter antimicrobial agent of potential interest in therapy because of the importance of D-cycloserine in the treatment of tuberculosis.

Description
Crystals, mp 172

Action
Capuride is a non barbiturate sedative. Early animal and human pharmacological studies of this investigational drug have suggested it may have anxiolytic activity. In recent double-blind studies its efficacy as presurgical anxiolytic has been evaluated.

Manufacturer
Commercial Solvents Corp (USA)

References
1. Y. Okami et al. J Antibiotics Ser A, 15. 147-151 (1962). 2. C. Neuhaus. Antibiotics 1. 40-83 (1967). 3. Effect of O-carbamyl-D-serine on the growth of mycobacterium tuberculosis. H. L. David. Amer Rev Resp Dis 102 (1). 68-74 (1970). 4. Susceptibility of mycobacterium intracel/ulare to O-carbamyl-D-serine. H. L. David. Amer Rev Resp Dis 102 (1),105-106 (1970).

Manufacturer
McNeil Laboratories (USA)

Proprietary Name
Pacinox

References
1. E. H. Wolwilder et al. J Am Chem Soc 58, 1352 (1936). 2. A double-blind evaluation of Capuride (Pacinox) as a presurgical aid to sleep. J. Katz et al. Curr Ther Res 12, 255-260 (1970). 3. Capuride versus methyprylon and placebo in treating sleeplessness due to presurgical anxiety. F. J. Tornetta. Anesthesia and Analgesia 49 (6), 862-865 (1970) .

Carbazochrome Salicylate
3-Hydroxy-1-methyl-5,6-indolinedione semicarbazone compound with sodium salicylate Adrenochrome semicarbazone compound with sodium salicylate

O-Carbamyl-D-Serine
D-Serine carbamate (ester)

O-CS
Description

32
A fine, orange-red odourless powder with a sweetish taste. A solution in water has a pH of about 7. Soluble in water and alcohol, and practically insoluble in ether and chloroform. Melting point, 196-197.5 (dec). 1. H. H. Fox and J. T. Gibas. J Org Chem 23, 64 (1958). 2. D. R. Grassetti et al. J Med Chem 13 (2), 273-276 (1970). 3. D. R. Grassetti. Chem Eng News 48 (44). 71 (1970).

Action and Uses

Carbazochrome salicylate has been used for over a decade as a systemic hemostatic agent. Recently it has been studied for possible effectiveness in psichiatry. Quantitative EEG amplitude analysis has provided evidence of effects of carbazochrome on the brain of the schizophrenic.

Carmustine (USAN; Prop INN) NSC 409962 BCNU

Carmustinum (Latin). Carmustina (Sp) 1, 3-bis (2-Chloroethyl)-1-nitrosourea

Manufacturer
S. E. Massengill Co (USA)

References
Electroencephalographic effects of adrenochrome semicarbazone in schizophrenia: quantitative amplitude analysis. A. A. Sugerman and L. Hyams. Res Comm Chem Pathol Pharmacol 1 (1), 86-98 (1970).

Action

Carboxypyridine Disulfide CPDS

2, 2'-Dithiodiisonicotinic acid

Carmustine, an alkylating agent, has been proved to be definitely beneficial in Hodgkin's disease, useful in gastrointestinal cancer, and promising in brain tumors.

Supplied by
The Cancer Chemotherapy National Service Center, Public Health Service (USA)

References
1. WHO Chron 24 (9), 416 (1970). 2. T. P. Johnston et al. J Med Chem 6 (6), 669-81 (1963). 3. T. P. Johnston et al. J Med Chem 9 (6), 892-910 (1966). 4. Medical World News 11 (2), 13 (1970). 5. BCNU in the treatment of malignant brain tumor-a preliminary report. Michael D. Walker et al. Cancer Chemother Rep 54 (4), 263-270 (1970). 6. BCNU in the treatment of brain tumors. Charles B. Wilson et al. Cancer Chemother Rep 54 (4), 273-280 (1970). 7. 1,3-bis (2-Chloroethyl)-1-nitrosourea (BCNU; NSC-409962) given concomitantly with cytosine arabinoside (NSC-63878) in the treatment of cancer. E. B. van Eden et al. Cancer Chemother Rep (Pan 1) 54 (5), 347-359 (1970). 8. Studies on the chemotherapy of experimental brain tumors: Evaluation of 1,3-bis (2-chloroethyl)-1nitrosourea. cyclophosphamide, mithramycin. and methotrexate.

Synthesis
Prepared by the reaction of 2-chloroisonicotinic acid with potassium bisulfide, and by subsequent oxidation with iodine.

Description
White microcrystalline powder, dec 277 .

Action
Carboxypyridine disulfide has been found to prevent the spread of cancerous tumor cells in mice, from one area of the body to another.

References

33
W. R. Shapiro et al. Cancer Research 30, 24012413 (1970). 1. Dr. Andreu, S A Sp pat 331,061, 2. Med Act (Drugs of Today) 6 (1), 11-19 (1970). (Review with 6 references).

Carperone (Prop INN) Carnitine Orotate DAN-221 AL 1021

Carperonum (Latin); Carperona (Sp) Isopropylcarbamic acid, ester with 4'-fluoro-4-(4hydroxy-piperidino) butyrophenone 1-[3-(4-Fluorobenzoyl) propyl]-4-piperidyl Nisopropylcarbamate. D, L-Carnitine orotate D, L-(2-Hydroxy-3-carboxypropyl)trimethylammonium, 2,4-dihydroxypyrimidine-6carboxylate D, L-(2-Hydroxy-3-carboxypropyl)trimethylammonium uracil-6-carboxylate

Synthesis
Monohydrated orotic acid is dissolved in hot methanolic solution of carnitine base and the mixture is allowed to cool.

Synthesis
Prepared by reacting 1-[3-(4-fluorobenzoyl)-propyl]4-piperidinol with isopropyl isocyanate; also, from 1[3-(4-fluorobenzoyl) propyl]-4-piperidinol chloroformate and isopropylamine.

Description
White crystalline powder, mp 191-193 .

Description
White, fine needles, mp 105-105.5 .

Action and Uses

Regulator of the protein and the enzyme metabolism, lipotropic and antilipemic protector of the liver cells.

Action
Carperone is a fluorobutyrophenone compound which in animal studies has showed calming or tranquilizing effects resembling those of haloperidol and chlorpromazine. The results of pilot studies in chronic schizophrenic patients has suggested that carperone has definite antipsychotic effects.

Dosage
The usual oral dose for adults is 600 to 900 mg per day, divided into two or three doses.

Supplied as
Effervescent tablets, 300 mg. Solution for oral use, each 10 ml containing 300 mg. Injectable solution, each vial containing 300 mg.

Manufacturer
Bristol Laboratories (USA)

References
1. Aldrich Cemical Co. S African Appl 680.029. 2. Effects of a new butyrophenone compound (AL1021) on subcortical and cortical nervous system structures in cat. R. Guerrero Figueroa et al. Curr Ther Res 11 (3), 121-133 (1969). 3. A pilot study of AL-1021 in chronic schizophrenic patients. A. Arthur Sugerman. Curr Ther Res 11 (12), 775778 (1969).

Proprietary Names
Hepadif and Dif-Hepal

Manufacturer
Lab Andreu (Spain)

References

34
4. Pilot study on the use of AL-1021 in the treatment of chronic schizophrenia. J. W. S. Angus et al. Curr Ther Res 11 (12),779-783 (1969). 5. WHO Chronicle 24 (9),416 (1970).

CCNU

NSC 79037

1-(2-Chloroethyl)-3-cyclohexyl-1-nitrosourea

CCB Hydrochloride
3,3'-(Iminodimethylene) dipyridine hydrochloride Bis-(4-pyridylmethyl) amine hydrochloride

Action
CCNU is an antitumor agent of the family of nitrosoureas, which is at least as active as carmustine, or more so, against mouse leukemia L 1210. Its physiological disposition has been studied in animals in hopes of better elucidating its own metabolic fate and mode of action and that of the class of nitrosoureas.

Synthesis
Prepared by Rosenmund reduction of 31,2 methylaminopyridine . Also by catalytic reduction 3 of 3~cyanopyridine in the presence of rhodium or in 4 the presence of Raney nickel .

Supplied by
The Cancer Chemotherapy National Service Center, Public Health Service (USA)

Description
Crystals, mp 263-265 UV max 258 m in 0.2M . KCI-HCI buffer pH 2.2.

References
1. The absorption, distribution. excretion, and biotransformation of the carcinostatic 1-(2chloroethyl)-3-cyclohexyl-1-nitrosourea in animals. Vincent T. Oliverio et al. Cancer Res 30, 1330-1337 (1970). 2. The uptake, distribution, and antitumor activity of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea in the murine glioma. V. A. Levin et al. Cancer Res 30. 2451-2455 (1970).

Action
CCB has been found to be a coronary vasodilatator which may possibly be used for treatment of angina 5,6 pectoris . The drug has proved to exert some sedative action depressing the spontaneous 7 locomotor activity in rats and mice .

Manufacturer
Polfa (Poland)

References
1. S. Biniecki et al. Ann Pharm Franc 22, 685 (1964). 2. Polfa, Belg pat 647,723. 3. M. Freifelder et al. J Org Chem 26, 3805 (1961). 4. H. Adkins et al. J Am Chem Soc 66, 1293 (1944). 5. W. Kostowski and J. Majcharzyk. Acta Physiol Pol 26, 2 (1965). 6. E. Kostka-Trabka et al. Dissert Pharm Pharmacol 21(2), 93-106 (1969). 7. The central action of CCB. Z. Kleinrok et al. ibid 22(1), 1-6 (1970).

Cefazolin (Prop INN)

7-[1-(1H)-Tetrazolylacetamido]-3-[2-(5-methyl-1,3,43 thiadiazolyl)-thiomethyl]- -cephem-4-carboxylic acid

Synthesis

35
Acylation of 7-aminocephaloporanic acid with 1(1H)-tetrazolylacetic acid chloride yields 7-[1-(1 H)tetrazolylacetamido]cephalosporanic acid. By displacement of the acetoxyl group of the latter by 2-mercapto-5-methyl-1,3,4-thiadiazole cefazolin is obtained.

Description
Colorless needles, mp 198-200 (dec). Ultraviolet absorption maximum at 272 m [=13150].

Action
Cefazolin is a new semisynthetic antibiotic derived from 7-aminocephalosporanic acid. It is active in vitro against most Gram-positive and Gram-negative species of bacteria except for Ps. aeruginosa and is also active against penicillinase-producing strains of Staph. aureus. After parenteral administration in rats and rabbits, and in human volunteers, the serum levels and urinary recovery of cefazolin were higher than those of cephaloridine, cephalothin and ampicillin.

Synthesis
By the reaction of purified cellulose with acetic and butyric anhydrides in the presence of sulfuric acid as catalyst and glacial acetic acid as solvent.

Description
White flakes or granules. Soluble in ketones, organic acetates and ethylene chloride.

Action
Plastic film former.

Manufacturer
Fujisawa Pharmaceutical Co, Ltd (Japan)

Manufacturer
Tennessee Eastman, Division of Eastman Kodak Co. (USA)

Proprietary Name
Cefamezin

References
1. WHO Chron 24 (11), 528 (1970). 2. JAMA 211. 818 (1970).

References
1. WHO Chron 25 (3), 129 (1971). 2. Cefazolin a new semisynthetic cephalosporin antibiotic. I. Synthesis and chemical properties of cefazolin. K. Kariyone et al. J. Antibiotics. 23 (3), 131-136 (1970). 3. II. In vitro and in vivo antimicrobial activity. M. Nishida at al. J. Antibiotics 23 (3), 137-148 (1970). 4. III. Absorption. excretion and tissue distribution in parenteral administration. M. Nishida et al. J. Antibiotics 23 (3). 184-194 (1970). 5. IV. Antigenicity of cefazolin and its cross reactivity with benzylpenicillin-ampicilin and cephaloridine. Y. Mine et al. J. Antibiotics 23 (3), 195-203 (1970).

Celluline
A mixture of lignin and methycellulose (99.5:0.50 w/w)

Action
Celluline is a new hypocholesteremic agent. The drug absorbs bile acids in the gastrointestinal tract and enhances their fecal excretion, thus stimulating hepatic conversion of cholesterol to bile acids.

References
Traitement de I'hyperlipoproteinemie essentielle de type II par un nouvel agent therapeutique, la celluline. C. Thiffault et al. Can Med Ass J 103, 165-167 (1970).

Cellaburate (USAN; Rec INN)

Cellaburatum (Lat.). Celaburato (Sp.) Cellulose acetate butyrate

36

Cephacetrile Sodium (USAN; Prop INN) BA 36278A

Sodium 7-(2-cyanacetamido)-3-(hydroxymethyl)-8oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2carboxylate acetate (ester) Sodium 7-(2-cyanoacetamido) cephalosporanic acid Cephalexin is a desacetoxycephalosporanic acid derivative, structurally related to cephaloridine, cephalothin and cephaloglycin. It differs from the latter in having a methyl group at position 3 instead of an acetoxyl group

Description
White crystalline powder, soluble at approximately 2 mg/ml in water at 25 .

Synthesis
Prepared by the reaction of 7-amino-3(hydroxymethyl)-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate acetate (ester) with cyanoacetylchloride.

Action and Uses

Cephalexin has interesting pharmacological properties; its excellent absorption after oral administration provides high concentrations in serum and urine. The spectrum of antibacterial activity is virtually identical to that of other cephalosporins.

Description
The free acid melts at 160-170 (dec).

Dosage
For use in the treatment of bacterial infections due to susceptible organisms; Adults: 1 to 4 g daily in divided doses. Children: usually 60 mg per kg body weight daily in divided doses (15 mg/kg six hourly).

Action
Cephacetrile is a new broad-spectrum semisynthetic antibiotic. It has proved to be more potent than cephalothin and less potent and less toxic than cephaloridine.

Supplied as
Capsules 250 and 500 mg; Granules for syrup; 250 mg in 5 ml.

Manufacturer
Ciba Pharmaceutical Co (USA)

Proprietary Names and Manufacturer

Ceporex (Glaxo); Keflex (Eli Lilly); Kefloridina (Eli Lilly)

References
1. JAMA 214, 741 (1970). 2. CIBA Ltd. Neth Appl 6,600,586. 3. Abstr Intersc Conf Antimicr 10:6, Oct 1970.

References
Med Act (Drugs of Today) 6 (5), 164 (1970). (Review with 17 references).

Cephalexin (USAN) Lilly 66873

7-(D-2-Amino--phenylacetamido)-3-methyl-3cephem-5-carboxylic acid 7-(D-2-Amino-2-phenylacetamido)-3-methyl-8-oxo5-thia-1-azabicyclo-[4,2,0]-oct-2-ene-2-carboxylic acid

Cephaloglycin (USAN)
7-(D--Aminophenylacetamido) cephalosporanic acid 7-(Amino-2-phenylacetamido)-3-(hydroxymethyl)-8oxo-5-thia-1-azabicyclo [4,2,0] oct-2-ene-2carboxylic acid acetate

37

Cephaloglycin is a new cephalosporanic acid derivative, structurally related to cephaloridine, cephalothin and cephalexin. It differs from the latter in having an acetoxyl instead of a methyl group

Synthesis
Prepared from 7-(-bromoacetamido)cephalosporanate and 4-mercaptopyridine.

Description
White powder, slightly soluble in water, ethanol and acetone, and practically insoluble in chloroform []D = 88 to 98. UV max at about 262 m [E(1 %, 1 cm) =214 to 227].

Description
White crystalline solid, soluble in water.

Action
Cephapirin sodium, a new semisynthetic derivative of 7-aminocephalosporanic acid, has been selected from a cephalosporin screening program as an interesting candidate for clinical use.

Action and Uses

Cephaloglycin dihydrate is a new orally active member of the cephalosporin family. For use in the treatment of acute and chronic infections of the urinary tract due to susceptible strains of E. coli, Klebsiella-Aerobacter, staphylococci, certain of the Proteus species, and enterococci.

Manufacturer
Bristol Laboratories (USA)

Dosage
Usually, 250 mg every six hours. For more severe infections 500 mg every six hours.

References
1. Bristol Mayers Co. South African Appl 677783; US pat 3,422,100. 2. JAMA 211, 1362 (1970). 3. WHO Chronicle 24(3), 134 (1970). 4. Laboratory studies with a new cephalosporanic acid derivative. D. R. Chisholm et al. Antimicrobial Agents Chemotherapy, p. 244-246 (1969).

Supplied as
Pulvules and capsules 250 mg (in Japan)

Proprietary Name and Manufacturer

Kafozin (Eli Lilly, USA); Kefglycin (Shionogi, Japan)

References
Med Act (Drugs of Today) 6 (5), 168 (1970). (Review)

CG 603
N-[1-(Morpholinomethyl)-2, 6-dioxo-3-piperidyl] phthalimide

Cephapirin Sodium (USAN; INN) BL-P 1322

Cefapirinum sodium (Lat); Cefapirina sodica (Sp) 3-(Hydroxymethyl)-8-oxa-7-[2-(4pyridylthio)acetamido)]-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid acetate (ester) sodium salt 7-[-(4-Pyridylthio )acetamido] cephalosporanic acid sodium salt

Synthesis
By heating 4-phthalimidopiperidine-2,6-dione with aq formaldehyde and morpholine. mp 203-5 (dioxane-ether).

38

Action
CG 603 has proved to show curative action on DMBA-induced tumors in rats and to increase the antitumor activity of drostanolone propionate.

References
Isolierung und Strukturaufklarung von Chaetocin. D. Hauser et al. Helv Chim Acta 53 (5), 1061 (1970).

Manufacturer
Chem Grunenthal (Germany)

References
1. Chemie Grunenthal GmbH. Neth Appl 6,606,210. 2. H. Muckter et al. Z Krebsfarch 69, 60-69 (1967). 3. H. Muckter et al. Cancer Res 29, 1212-17 (1969). 4. Experimental investigations with CG 603 and drostanolone propionate in dimethylbenzanthracene-induced tumors of Sprague-Dawley rats. H. Mucker et al. Cancer Res 30, 430-8 (1970).

Chloramphenicol Arginine Succinate

Arginine salt of the 3-monosuccinic ester of chloramphenicol

Chaetocin

Description
White to faintly yellow needle-like crystals, mp 135145 (dec). Very soluble in water, slightly soluble in ethanol and practically insoluble in methanol and acetone.

Action and Uses

Chloramphenicol arginine succinate has been recently marketed in Japan with the purpose of alleviating pain at the site of injection, as a result of the replacement of the sodium salt of the monosuccinic ester of chloramphenicol by the arginine salt. It is used for the treatment of infections due to chloramphenicol susceptible organisms.

Isolation
Chaetocin has been isolated from Chaetomium minutum.

Description
Colorless crystals, mp 240 (dec), []D = 379 (c=1, pyridine) and []D = 789 (c=1, dimethylsulfoxide). UV max 306 m (lg=3.78) in dimethylsulfoxide).

Dosage
The usual intramuscular dosage for adults is 1 g (potency) 1 to 2 times daily.

Action
Chaetocin shows antibacterial and cytostatic activity.

Supplied as
Vials, 0.25, 0.5 and 1 g (potency).

Propritary Name
Paraxin Succinate A

Manufacturer
Sandoz (Switzerland)

Manufacturer

39
Yamanouchi Pharmaceutical Co Ltd (Jap)

References
1. Chlorophillipe. a new antibacterial drug. V. L. Nadtoka Antibiotiki 15 (10). 888 (1970). 2. Soviet pat (Author Certificate) 240.932.

References
Med Act (Drugs of Today) 7 (1), 8 (1971). (Review)

Chlorflavonin

Cholestyramine
Cholestyramine is the chloride of an anionexchange resin containing quaternary ammonium groups which are attached to a styrene-divinyl benzene copolymer

Description
Cholestyramine is a white, tasteless powder. It is slightly acid in reaction (pH about 5,6) insoluble in water and not hydrolyzed by digestive enzymes.

Production
It is obtained from cultures of Aspergillus candidus.

Action and Uses

Cholestyramine lowers the amount of cholesterol in the blood. It seems that cholestyramine forces the body to use up its supply of cholesterol by interfering with the fat absorption process in the intestines and thereby lower the serum cholesterol content.

Description
Yellow microcrystalline solid, mp 212 .

Action
Chlorflavonin is a new antifungal antibiotic.

Dosage
Usually 4 g three times daily before meals.

Manufacturer
Beecham Research Laboratories (England)

Supplied as
Dry powder.

References
1. M. Richards et al. J Antibiotics 22, 388-389 (1969). 2. Jap Med Gazz 7 (4), 13 (1970).

Proprietary Name
Questran

Manufacturer
Bristol (England)

Chlorophillipe
Description
Greenish microcrystalline substance, soluble in organic solvents.

References
Med Act (Drugs of Today) 6 (5), 174 (1970). (Review)

Action
Chlorophillipe exhibits anti-staphylococcal activity. It has proved to be highly effective in clinic as topical and visceral rinse.

Chymostatin

40

Production
Chymostatin can be obtained from the culture filtrate of actinomycetes.

Manufacturer
Parke Davis and Co (USA)

Description
White crystals, mp 205-207 (dec). []D = 9 (c=0.25 in acetic acid). Ultraviolet absorption maxima at 253 m, 260 m, 265 m and 270 m. The infrared absorption spectrum indicates a peptide nature.

References
1. Parke, Davis and Co. Belg pat 668,124 2. CI-601, a butyrophenone derivative, in the treatment of chronically withdrawn schizophrenic patients. C. Villeneuve et al. Curr The, Res 12 (4), 223-229 (1970).

Action
Chymostatin is an inhibitor of chymotrypsin and papain.

Manufacturer
Institute of Microbial Chemistry, Tokyo (Japan)

CI 679
2,4-Diamino-6-[(3,4-dichlorobenzyl)nitrosamino]quinazoline

References
1. Chymostatin a new chymotrypsin inhibitor produced by actinomycetes. H. Umezawa et al. J Antibiotics 23 (8),425-427 (1970).

CI 601
4-[2-(o-Ethoxyphenoxy)ethylaminoj-4'-fluorobutyrophenone hydrochloride.

Action
Antimalarial agent.

Manufacturer
Parke Davis (USA)

References
Antimalalial activity of 2, 4-diamino-6-[(3, 4dichlorobenzyl) nitrosamino] quinazoline (CI-679 base) and CI-679 acetate. Laboratory studies in mice and rhesus monkeys. P. E. Thompson et al. Amer J Trop Med Hyg 19,12 (1970).

Synthesis
Prepared by the reaction of 2-(o-ethoxyphenoxy)ethylamine with --chloro-p-fluoro-butyrophenone ethylene ketal in refluxing xylene and by refluxing the ketal intermediate with isopropyl alcohol and 1 N aqueous hydrochloric acid.

Cintazone (USAN) Scha-306

AHR-3015

Description
Crystals, mp 108-110 .

Action
CI 601 is a butyrophenone derivative showing pharmacological action in animals, similar to that of major tranquilizers. In a double-blind controlled clinical study, the drug has been found to be comparable in overall therapeutic effectiveness to haloperidol.

Cinnopentazone (Rec INN) Clintazone (FDAN)

2-Pentyl-6-phenyl-1 H-pyrazolo [1, 2-a] cinnoline1,3(2H)-dione 1,2-(Pentylmalonyl)-4-phenyl-1,2-dihydrocinnoline

41
Needles, mp 111.5-112.5 .

Action and Uses

Citiolone is an hepatic anticytolytic agent, recently marketed in France. Indications: Hepatitis, cholecystitis, biliary dyskinesia, cirrhosis, chronic alcoholism.

Dosage
Orally 200 mg 2 to 3 times daily before meals.

Synthesis
By the reaction of 4-phenyl-1, 2-dihydrocinnoline with triethylamine and n-pentylmalonyldichloride.

Supplied as
Granules, 4%. Vials, 500 mg.

Description
Crystals, mp 122-123 .

Manufacturer
Laboratories Bottu (France)

Action
Cintazone is a new anti-inflammatory agent.

Proprietary Name
Thioxidrene

Manufacturer
A H Robins Co, Inc (USA)

References
1. WHO Chron 24 (3). 123 (1970). 2. R. Laliberte et al. J Chem Soc 2756 (1963). 3. R. Benesch et al. J Am Chem Soc 78. 1597 (1956). 4. Yoshimoto Pharm Ind Ltd, Jap pat 16,712 (62). 5. Sumitomo Chemical Co Ltd, Jap pat 3420 (64) and 1376 (65). 6. Med Act (Drugs of Today), 7 (1). 14-15 (1971). (Review)

References
1. Fed Reg 35 (179), 14450-14451 (1970). 2. Siegfried Aktiengesellschait. Brit pat 1,054,291. 3. H. Jahn et al. Arzneim-Folsch 18 (1), 121-124 (1968).

Citiolone (Prop INN) BO 714

N-(Tetrahydro-2-oxo-3-thienyl) acetamide 2-Acetamido-4-mercaptobutyric acid, thio lactone N-Acetylhomocysteinethiolactone

Clindamycin (USAN) U 21251

Methyl 7-chloro-6,7,8-trideoxy-6-trans-(1-methyl-4propyl-L-2-pyrrolidine-carboxamido)-1-thio-Derythro-,D-galacto-octopyranoside hydrochloride monohydrate 7-Chloro-7-deoxylincomycin hydrochloride hydrate

Synthesis
From homocysteine thiolactone hydrochloride and 2 acetic anhydride . Other methods have been 3,5 described .

Description

42

Synthesis
It is prepared from lincomycin and thionylchloride.

Action
Clindamycin-2-palmitate hydrochloride is a water soluble ester of ciindamycin and palmitic acid. It has been found to be safe and well tolerated with good absorption and effective blood levels when administered to children and infants. It is particularly effective in the treatment of infections due to grampositive organisms. It has been found virtually devoid of the characteristic bitter taste of clindamycin.

Action and Uses

Clindamycin is a semi-synthetic derivative of lincomycin. The antibacterial spectrum of clindamycin is identical with that of parent antibiotic, but is more rapidly and completely absorbed from the gastrointestinal tract.

Dosage
Adults, 150 to 300 mg 6-hourly, or more forsevere infections.

Manufacturer
The Upjohn Co (USA)

Supplied as
Capsules 75 and 150 mg.

References
1. Absorption and tolerance of clindamycin-2palmitate in infants below 6 months of age. N. Lwin et al. Curr Ther Res 12 (10), 648-657 (1970). 2. Am Pharm Ass 117th Annual Meeting, April 1217, 1970, Washington, abstr. 74.

Proprietary Names and Manufacturer

Dalcin C (Upjohn, England); Sobelin (Upjohn, Germany); Cleocin (Upjohn, USA)

References
Med Act (Drugs of Today) 6 (5). 171-174 (1970). (Review with 10 references)

Clindamycin-2-palmitate Hydrochloride Clindamycin-2-phosphate

43
By condensing 3,5-diiodosalicylic acid with pchloroaniline, and subsequent acetylation with acetic anhydride.

Description
Crystals, mp 215-216 .

Action
Clioxanide has proved to be highly active against mature and immature fluke. Recently a series of studies designed to determine the tolerance of sheep in the field to clioxanide, has been reported.

Action
Clindamycin hydrochloride is poorly soluble at pH values above 6 and its intramuscular administration is painful. The phosphate ester exhibits a higher water solubility near neutral pH and improves muscle tolerance. The phosphate ester is rapidly hydrolyzed in vivo and gives acceptable blood levels of free clindamycin.

Manufacturer
Parke Davis (USA)

Proprietary Name
Tremerad

References
1. Parke Davis Co. Neth Appl 6,604,303. 2. A. Campbell et al. Experientia 23 (12), 992-993 (1967). 3. H. C. Tewari. Aust Vet J 44 (9), 401-402 (1968). 4. Clioxanide, a new anthelmintic active against Fasciola hepatica and Haemonchus contortus in sheep. I. G. Pearson et al. Aust Vet J 46 (10), 480-484 (1970). 5. The anthelmintic efficiency of clioxanide and rafoxanide against fasciola hepatica and haemonchus contortus in sheep. N. J. Campbell and I. K. Hotson. Aust Vet J 47 (1), 5 (1971).

Manufacturer
The Upjohn Co (USA)

References
1. Hydrolysis of Iincomycin-2-phosphate and clindamycin-2-phosphate. T. O. Oesterling and E. I. Rowe. J Pharm Sci 59 (2), 175-179 (1970). 2. Am Pharm Ass 117th Annual Meeting, April 1217, 1970, Washington abstr 73.

Clioxanide (Rec INN) SYD 230

Clioxanidum (Lat). Clioxanida (Sp) 4-Chloro-3,5-diiodo-salicylanilide, acetate (ester) 2-Acetoxy-4'-chloro-3,5-diiodobenzanilide

Clofazimine (USAN; Rec INN) G-30320

Clofaziminum (Lat). (Sp)Rimonophenazine

B 663
Clofacimina

3-(p-Chloroanilino)-10-(p-chlorophenyl)-2,10dihydro-2-isopropyliminophenazine

Synthesis

44

Synthesis
Prepared by heating in the autoclave at 80 a solution of 3-p-chloroanilino-10-p-chlorophenyl-2,10dihydro-2-iminophenazine hydrochloride and 1 isopropylamine in ethanol .

Description
Orange dye. Insoluble in water; fat soluble. UV max 284 m [E(1%, 1 cm) about 1000], and a visible max between 486 and 492 m in ethanolic solution 2 (1 to 10 g/ml) .

Synthesis
Prepared by the reaction of 2-chloroacridine with 3dimethylaminopropyl-magnesium chloride in refluxing tetrahydrofurane.

Action and Uses

Clofazimine is a substituted iminophenazine dye with anti-micobacterial and anti-inflammatory properties. For use in the treatment of all forms of leprosy and inflammatory episods that frequently complicate lepromatous leprosy.

Action
Clomacran, a new neuroleptic structurally related to phenothiazines, has been found to have significant antidepressant and antipsychotic effects in clinical studies. The toxic side effects of the drug have been 5 recently reviewed .

Dosage
For previously untreated adults, 100 mg three times weekly. For patients with sul phoneresistant bacilli, 600 mg weekly. To suppress lepra reactions up to 400 mg daily may be needed.

Manufacturer
Smith Kline and French Laboratories (USA)

References
1. Smith Kline and French Lab. US pat 3,131,190. 2. J. L. Claghorn et al. Psychosomatics 8 (4), 212215 (1968). 3. Double-blind study comparing the intramuscular usage of an acridan derivative, SKF 14336, to chlorpromazine. Ching-Piao Chien et al. Cun Ther Res 12 (1), 52-56 (1970). 4. Clinical trial of clomacran phosphate (SKF-14336) in chronic psychotic male patients. K. C. Radhakrishnan Nair et al. Cun Ther Res 12 (6), 394-401 (1970). 5. Adverse effects with clomacran. W. T. Lampe. J Clin Pharmacol 10 (3), 171-174 (1970).

Supplied as
Brown, hard gelatin capsules, which contain a suspension of 100 mg of very fine particles of clofazimine in an oil/wax base.

Proprietary Name
Lamprene

Manufacturer
Geigy

References
1. V. C. Barry et al. J Chem Soc 896 (1956); 3347 (1956); 859 (1958). 2. E. Regazzi. Boll Chim Farm 100, 402-410 (1961). 3. Med Act (Drugs of Today) 6 (2), 47-51 (1970). (Review with 16 references)

Clonazepam (USAN; Rec INN) Ro 5-4023 Clomacran (USAN; Rec INN) SKF14336
(for the phosphate) Clomacranum (Lat). Clomacrano (Sp) 2-Chloro-9-[3-(dimethylamino) propyl] acridane 5-(o-Chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4benzo-diazepin-2-one

45

Description
Almost white crystals, mp 236.5-238.5 (ethanolmethylene chloride).

Synthesis
Prepared in several steps from 2-chloronicotinic acid and 2-methyl-3-chloroaniline.

Action
Clonazepam is a new, very active, anticonvulsive benzodiazepine.

Description
Crystals, mp 113-114 (benzene).

Action Manufacturer
Hoffman-La Roche Clonixeril is a new anti-inflammatory-analgesic agent.

References
1. JAMA 209, 926 (1969). 2. WHO Chron 24 (11), 528 (1970). 3. Drug Trade News, p 43 (October 20, 1969). 4. Experimental properties of a new anticonvulsive benzodiazepine:Ro 5-4023. M. Boucard et al. Therapie 25 (5), 893 (1970). 5. Risposte cerebrali evocate da stimoli visivi e somatici in soggetti affetti da mioclano-epilessia familiare. Effetti di una nuova benzodiazepina. F. Giunta et al. Boll Soc It Bioi Sper 45 (22), 14711473 (1969). 6. Evaluation of anticonvulsant drugs: Methodological considerations. R. A. Hanson at al. Pharmacologist 12 (2), 219 (1970).

Manufacturer
Schering Corp (USA)

References
1. JAMA 209, 2044 (1969). 2. WHO Chron 24 (11), 528 (1970). 3. Scherico Ltd. S African pat 6.802,185.

Clonixin (USAN; Rec INN) Sch 10304

2-(3-Chloro-o-toluidino) nicotinic acid 2-(2-Methyl-3-chloroanilino) nicotinic acid

Clonixeril (USAN; Ree INN) Sch 12707

Clonixerilum (Lat) 2,3-Dihydroxypropyl 2-(3-chloro-o-toluidino) nicotinate Glyceryl 2-(2-methyl-3-chloroanilino) nicotinate

Synthesis
Prepared by heating 2-methyl-3-chloroaniline with 2chloronicotinic acid or 2-chloronicotinic acid ethyl ester, followed by hydrolysis.

Description
Crystals, mp 233-235 (isopropylacetate). The diethanolamine salt, mp 129-131 .

46
2. May and Baker Ltd. Brit pat 1,027,611. 3. J. P. Johnston. Biochem Pharmacol 17, 1285 (1968). 4. J. A. Herd. Clin Trials J 6, 219-227 (1969). 5. Comparative trial of a new mono-amine oxidase inhibitor in depression. D. Wheatley Brit J Psychiat 117, 573-574 (1970).

Action
Clonixin exhibits analgesic, anti-inflammatory and antipyretic properties.

Manufacturer
Schering Corp (USA)

References
1. WHO Chron 24 (11), 528 (1970). 2. Scherico Ltd. Neth Appl 6.603.357. 3. Fed Proc 27 (3), 533, abstr 1780, 1781 (1968).

Clortermine Hydrochloride (USAN; Rec INN) Su10568

o-Chloro-,-dimethylphenethylamine hydrochloride 1-(o-Chlorophenyl)-2-methyl-2-propylamine hydrochloride

Clorgiline Hydrochloride (Rec INN) M&B 9302

Clorgilinum (Lat). Clorgilina (Sp) N-[3-(2,4-Dichlorophenoxy)propyl]-N-methyl-2propynylamine hydrochloride N-Methyl-N-propargyl-3-(2,4-dichlorophenoxy) propylamine hydrochloride

Synthesis
Prepared from 1-(o-chlorophenyl)-2-methyl-2propanol.

Description Synthesis
Prepared by condensing 3-(2,4-dichlorophenoxy) propyl bromide with methylamine and subsequent treatment with propargyl bromide. Also prepared from 2, 4-dichlorophenoxypropyl bromide and Nmethyl propargylamine. Crystals from ethanol, which melt at 245-246 The . free base boils at 116-118 (16 mm).

Action
Anorexiant. It is the o-chloro derivative of phentermine while chlorphentermine is the p-chloro derivative.

Description
Crystals, mp 102-103 (ethyl acetate).

Manufacturer
Ciba Pharmaceutical Co. (USA)

Action
Clorgiline hydrochloride is a new mono-amine oxidase inhibitor, reported to be a highly potent antidepressant. The results of a recent comparative trial indicate that both therapeutic effects and sideeffects were similar with clorgiline and the control drug, imipramine.

Proprietary Name
Voranil

References
1. JAMA 208, 1399 (1969). 2. WHO Chronicle 24 (11), 528 (1970). 3. Ciba S. A. Belg pat 665,244 (1965). 4. J Amer Osteop Ass 89,161-164 (1969).

Manufacturer
May and Baker Ltd (England)

References
1. WHO Chron 24 (11). 528 (1970).

47

Closiramine Aceturate (USAN; Rec INN) Sch 12169

8-Chloro-11-[2-(dimethylamino)ethyl]-6,11-dihydro5H-benzo [5,6]-cyclohepta [1,2-b] pyridine compound with N-acetyl-glycine (1:1)

Description
White crystalline powder.

Action
Clotrimazole is a new broad spectrum orally effective antifungal.

Manufacturer
Bayer (Germany). Delbay Pharmaceuticals (USA)

References
1. Farbenfabriken Bayer AG. S African Appl 68 05.590. 2. Erste Erfahrungen mit dem Breitbandantimykotikum Bay b 5097. W. Marget and D. Adam. Med Klin 64. 1235 (1969). 3. Erste klinische Erfahrungen bei System-Mykosen mit einem neuen oralen Antimykotikum. H. Oberste-Lehn et al. Dtsch med Wschr 94. 1365 (1969). 4. Experimentelle Befunde libar ein neues. oral wirksames Antimykotikum mit breitem Wirkungsspektrum. M. Plempel at al. Dtsch med Wschr 94. 1356 (1969). 5. Keine Liquorwirksamkeit des Antimykoticums Bay b 5097 einem Fall von Candida-Meningitis. U. Keuth and J. Wilhelmi. Monatsschr Kinderheilk 118.654-655 (1970). 6. A new broad spectrum antifungal agent. W. E. Herrell. Clin Med 77 (2), 13-16 (1970).

Action
Closiramine aceturate is a new anti histaminic agent.

Manufacturer
Schering Corp (USA)

References
1. WHO Chron 24 (11), 528 (1970). 2. JAMA 209, 2044 (1969).

Clotrimazole (USAN.BAN.PropINN) Bay b 5097 FB 5097

1-(o-Chloro-,-diphenylbenzyl) imidazole 1-(o-Chlorotrityl)imidazole Clozapinum (Lat). Clozapina (Sp) 8-Chloro-11-(4-methyl-1-piperazinyI)-5H-dibenzo [b,e]-1,4-diazepine

Clozapine (USAN; Ree INN) HF1854

Synthesis
By the reaction of o-chlorophenylbisphenylchloromethane with imidazole.

Synthesis
Prepared in several steps from 8-chloro-10,11dihydro (5H)-dibenzo [b,e]-1 ,4-diazepin-11-one.

48

Description
Yellow crystals, mp 183-184 (acetone/petroleumether); ultraviolet absorption max. at 215 m [=27,400], 230 m [=25,800], 261 m [=16,800] and 297 m [=10,500].

Manufacturer
The Upjohn Co (USA)

References
1. JAMA 209, 926 (1969). 2. WHO Chron 24 (11), 528 (1970) . 3. Chem and Engineer News 47 (48), 39 (1969). 4. Arner Drug 161 (9), 63 (1970) . 5. Effects of colestipol (U-26. 597 A), a new bile acid sequestrant, on serum lipids in experimental animals and man. T. M. Parkinson et a!. Atherosclerosis 11, 531-537 (1970).

Action
Sedative.

Manufacturer
Dorsey Laboratories (USA); Wander AG (Switzerland)

References
1. WHO Chron 24 (11). 528 (1970). 2. JAMA 209, 407 (1969). 3. F. Hunziker et al. Helv Chim Acta 50, 1588-1599 (1967). 4. Dr. Wander AG. Brit. pat. 1,042,634. 5. Wien Med Wschr 116, 814 (1966).

Compound VI
6-Bromo-17-hydroxy-17-methyl-4-oxa-5androstan-3-one

Colestipol (USAN; Ree INN) U 26,597A

Colestipolum (Lat) Tetraethylenepentamine polymer with 1-ehloro-2,3epoxypropane Tetraethylenepentamine polymer with epichlorhydrin

Synthesis
By bromination of 17-hydroxy-17-methyl-5-oxo3,5-seco-A-norandrostane-3-carboxylic acid, followed by cyclization.

Description
Crystals, mp 163-174 dec (ethanol); [ ]D = -9.6 (c 0.39; methanol).

Description
Colestipol is an insoluble high molecular weight copolymer of tetraethylenepentamine and epichlorhydrin with approximately one out of five amine nitrogens protonated (chloride salt). The native material is essentially odorless and tasteless.

Action
Experimental studies have shown compound VI to be an antiandrogen agent.

Manufacturer
Hoffmann-La Roche Inc (USA)

Action
Colestipol is a new hypocholesteremic agent. The drug is not absorbed into the blood stream but binds with bile acids in the gastrointestinal tract and enhances their fecal excretion, thus stimulating hepatic conversion of cholesterol to bile acids.

References
1. F. Hoffmann-La Roche Co, AG. Ger Offen 1,805,857. 2. A new antiandrogen, 6-bromo-17-hydroxy-17methyl-4-oxa-5-androstan-3-one. A. Boris and M. Uskokovic. Experientia 26, 9 (1970).

49

Cortivazol (USAN; Rec INN)

11-,17,21-Trihydroxy-6,16--dimethyl-2'-phenylpregna-4,6-dieno [3,2-c]pyrazol-20-one 21-acetate 6,16--Dimethyl-4,6-pregnadiene-11-,17,21-triol20-one [3,2-c]-2'-phenylpyrazole 21-acetate

CP 264
2-Allyloxy-4-chloro-N-(2-piperidinoethyl)-benzamide

Action
264 CP has proved to show much more potent antitussive action, weaker toxicity and milder adverse effects than 264 CE (Hexacol). 264 CP differs from the latter only in having a piperidinoethyl group instead of a diethylaminoethyl group. This has supported the hypotesis of Kase et al that a piperidino group strengthens antitussive activity.

Synthesis
From 17-,20,20,21-bis (methylendioxy)-11-1,2 hydroxy-6,16,-dimethyl-4,6-pregnadiene-3-one . Also from 6-,16--dimethyl-3,11-dioxo-2hydroxymethylene-4,6,17(20) pregnatriene-21-oic 3 acid methyl ester .

Toxicity
LD50 sc in mice: 204 mg/kg.

Manufacturer
Fujisawa Pharmaceutical Co, Ltd (Japan)

Description
Crystals, double mp: 160-165 and 229-230 (ethyl acetate-benzene). []D = +14 (chloroform). UV max 283 m [=15.700] and 315 m [=19,000] in methanol.

References
Antitussive activity and other related pharmacological properties of 2-allyloxy-4-chloro-n(2-piperidinoethyl) benzamide and its congeners. Y. Kase et al. Jap J Pharmacol 20, 1-9 (1970).

Action
Cortivazol is a new anti-inflammatory agent.

Manufacturer
Merck Sharp and Dohme (USA)

References
1. J. H. Fried et al. J Am Chem Soc 85, 236 (1963). 2. M. Tishler et al. (to Merck Co Inc). US pat 3,067,194, 3. R. Hirschmann et al. (to Merck Co Inc) US pat 3,233.70. 4. JAMA 211, 1363 (1970). 5. WHO Chron 24 (3). 124 (1970).

Cryptosporiopsin
(1S,5S)-(E)-3,5-Dichloro-1-hydroxy-4-oxo-2propenyl-2-cyclopentene-1-carboxylic acid, methyl ester

50
and more active as a central sedative than octoclothepin.

Production
By a species of Cryptosporiopsis . The total synthesis of the racemic compound has been 2 reported .
1

Manufacturer
Res Inst Pharm Biochem Prague (Czechoslovakia)

Description
Colorless crystals, mp 133-137 []D = +129 ; (c=1.35, chloroform); UV max 292 m [= 22,800 in alcohol).

References
J. O. Jilek et al. Coll Czech Chem Commun 35 (1), 276 (1970).

Action
Cryptosporiopsin is a fungitoxic antibiotic; it inhibits sporangial germination (Phytospora infestans).

References
1. G. M. Strunz et al. Can J Chem 47, 2087 and 3700 (1969). 2. The total synthesis of racemic cryptosporiopsin, a fungitoxic antibiotic. G. M. Slrunz and A. S. Court. Experientia 26 (10), 1054 (1970).

Cyasterone

Cyanothepin
8-Cyano-10-(4-methylpiperazino)-10,11dihydrodibenzo [b.f] thiepine

Description
Screening of Israeli plants for insect moulting hormones (ecdysones) has led to the isolation and identification of cyasterone from Ajuga and Achyrantes species.

References
Insect hormones (phytoecdysones) from Israeli plants. R. Ikan at a!. Israel J Chem 8 Suppl Proc Israel Chem Soc (1970).

Synthesis
Prepared in several steps from 8-bromo-10,11dihydroxydibenzo [b,f] thiepin-10-one.

Description
Cyanothepin melts at 171-173 (ethanol). Ultraviole t absorption max at 231 m [log = 4.22] and 294 m [log = 4.05]. The maleate melts at 187-189 (ethanol).

Cyclacillin (USAN; Prop INN) WY 4508

Ciclacillinum (Lat). Ciclacilina (Sp) 6-(1-Aminocyclohexanecarboxamido)-3,3-dimethyl7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-2carboxylic acid 6-(1-Aminocyclohexanecarboxamido) penicillanic acid

Action
Cyanothepin is a new member of the parathiepin group of neuroleptics. The drug has proved to be less efficient in the cataleptic test than trifluthepin,

51

Synthesis
Prepared by condensation of 6-aminopecillanic acid with the N-carboxyanhydride of 1aminocyclohexanecarboxylic acid.

Synthesis
By acetylation of p,p'-dihydroxybenzhydrylidenecyclohexane with acetic anhydride. p,p'Dihydroxybenzhydrylidene cyclohexane can be obtained either from p-hydroxy-p'methoxybenzhydrylidene-cyclohexane or from p,p'dibenzylbenzhydrylidene cyclohexane or from p,p'dimethoxybenzhydrylidene cyclohexane.

Action
Cyclacillin is a new semisynthetic penicillin, which was found to resemble ampicillin in its antibacterial spectrum. In a recent study cyclacillin was compared with ampicillin and cephalexin. Cyclacillin was superior to cephalexin in vitro and in vivo against penicillin-sensitive S. aureus and Strep. pyogenes. Against penicillinase-producing staphylococci, cyclacillin was clearly superior to cephalexin in vivo, while in vitro cephalexin was the more active of the two. Cyclacillin and ampicillin were about equally active in vivo against Strep. pyogenes, D. pneumoniae and penicillin-sensitive staphylococci, while in vitro cyclacillin was somewhat less active than ampicillin. Against penicillin-resistant staphylococci, cyclacillin was active while ampicillin was not. Against gramnegative organisms cyclacillin was less active both in vitro and in vivo than ampicillin.

Description
Crystals, mp 135-136 .

Action and Uses

Cyclofenil is an ovulation stimulant. For use in the treatment of menopause, amenorrhea, hypomenorrhea, irregular cycles, premenstrual syndrome, menometrorrhagia and sterility.

Dosage
Menopause, 400 mg daily during 20 days each month. In other indications: 400 mg daily from the first day of the cycle for 10 days; or 800 mg daily from sixth day of the cycle for 5 days.

Manufacturer
Wyeth Lab Inc (USA)

Supplied as References
1. H. E. Album et al. (American Home Prod Corp). US pat 3,194,802. 2. M. W. Hopper et al. Antimicrobial Agents and Chemotherapy-1967, 597 (1968). 3. S. B. Rosenman et al. ibid-1967. 590 (1968). 4. J. A. Yurchenco et al. ibid-1967. 602 (1968). 5. Cyclacillin a semisynthetic aminoalicyclic penicillin. J. A. Yurchenco et al. Chemotherapy 15, 209-221 (1970). Tablets, 400 mg.

Manufacturer
Ferrosan (Sweden), Roussel (France)

Proprietary Name
Sexovid; Ondogyne.

References
1, J.F. Miquel et al. J Med Chem 6, 774 (1963). 2. US pat. 3,287,397. 3. Med Act (Drugs of Today) 7 (1), 10-12 (1971). (Review with 7 references)

Cyclofenil 3452 ICI 48,213

F 6066

-Cyclohexylidene--(p-hydroxyphenyl)-p-cresol diacetate bis-(p-Acetoxyphenyl) cyclohexylidene methane p, p'-Diacetoxybenzhydrylidene cyclohexane

52

Cylindrochlorin
The partial structure is:

Description
Crystals, mp 237.5-240 (ethyl acetate).

Action
Cyproterone has been reported to be a potent anti2 androgen in animal experiments . The antiandrogenic effect of the drug is based on the competitive inhibition of the action of testosterone. The use of cyproterone has been reported in the treatment of precocious sexual development, 3 congenital adrenal virilism and hirsutism .

Production
Isolated from the mycelium of a fungus, Cylindroc!adium Sp.

Manufacturer
Schering AG (Germany)

Description
Pale yellow crystals, mp 150-150.5

References
1. R. Wiechert (Schering AG). Ger pat 1.158,966 and 1,189,991. 2. F. Neuman et al. In: Wirkungsmechanismen der Hormone. 18th Symp of Gesellschaft fr Physiologische Chemie, Karlson P., Ed., Mosbach (1967), p 218. 3. Acta Pediat Scand 58. 203 (1969). 4. Biodinamics of cyproterone in man following oral and intravenous administration. E. Gerhards et al. Acta Endocrin 64, 228-252 (1970). 5. Investigations on the cyproterone-induced effect on the testosterone metabolism in normally developing children and adult males. D. Gupta and J. R. Bierich. Third International Congress on Hormonal Steroids, Hamburg, 7-12 Sept 1970. Excerpta Medica, International Congress Series No 210, abs 414.

Action
Cylindrochlorin is a new antiviral antibiotic.

Manufacturer
The University of Tokyo (Japan)

References
1. Jap Med Gazz 7(4), 9 (1970). 2. Cylindrochlorin. a new antibiotic produced by Cylindrocladium. A. Kato et al. J Antibiot 23 (3). 168 (1970).

Cyproterone (Rec INN) SH 80881

6-Chloro-17-hydroxy-1,2-methylenepregna-4,6diene-3,20-dione

Cyproterone Acetate SH 714

Cyproterone 1--acetate

Description
Crystals, mp 200-201 (diisopropyl ether). UV max 281 m [=17,280] in methanol.

Action
In contrast to cyproterone, cyproterone acetate possesses marked progestational properties in addition to antiandrogenic activity.

Manufacturer
Schering AG (Germany)

53

References
1. F. Neuman et al. In: Wirkungsmechanismen der Hormone, 18th Symp of Gesellschaft fur Physiologische Chemie, Karlson P., Ed., Mosbach (1967) p 218. 2. K. H. Kolb and H. Roepke.lntJ Clin Pharmacol 1(3),184-190 (1968). 3. H. Hoffet. Praxis 57 (7), 221-230 (1968). 4. Antagonism between masculinizing steroids and cyproterone acetate in the rat fetus. T. Mischler and D. Gawlak. Eur J Pharmacol 9 (3),391 (1970). 5. Effect of the antiandrogen cyproterone acetate on estradiol production and metabolism in man. J. Fishman and J. Geller. Steroids 16 (4), 351 (1970). 6. Adrenocortical function. corticotrophic responsiveness and fertility of men during long-term treatment with cyproterone acetate. U. Lashet and U. Laschet. Third International Congress on Hormonal Steroids, Hamburg, 7-12 Sept 1970. Excerpta Medica, International Congress Series No 210, abs 415.

Action
Many biochemical and clinical studies have suggested that cystathionine may have a function in the brain other than its being an intermediary in the formation of cysteine from methionine. From the results of a recent experimental study in cats, it has been concluded that in the free form cystathionine, or its cleavage product cysteine, may be important in the normal functioning of the brain and play a role in the pathogenesis of certain in born errors of metabolism independent of their importance as metabolic intermediaries.

References
1. V. du Vigneaud et al. J Biol Chem 143, 59 (1942). 2. S. Weiss et al. J Am Chem Soc 73. 2497 (1951). 3. A. Schoberl and G. Tauber, Ann 599, 23 (1956). 4. Neuropharmacological comparison of cystathionine. cysteine, homoserine and alphaketobutyric acid in cats. B. J. Key and R. P. White. Neuropharmacol 9, 349357 (1970).

L-Cystathionine
L-2-Amino-4-[(2-amino-2-carboxyethyl)-thio]-butyric acid

D 58 SI
2,3-Dihydro-N-methyl-7-nitro-2-oxo-5-phenyl-1H1,4-benzodiazepin-1-carboxamide

Synthesis Synthesis
Prepared by condensation of L-cystine with L-3,6bis-(-chloroethyl)-2,5-diketopiperazine followed by 1 hydrolysis . Prepared by the reaction of 7-nitro-5-phenyl-1,2dihydro-3H-1,4-benzodiazepin-2-one with methyl isocyanate.

Description
Crystals, mp 160-161 .

Description
Crystals, mp 312 dec (darkening at 270 []D = ); 23.7 (c=1 in N HCI).

Action
New benzodiazepine compound which exhibits hypnotic and sedative properties.

Manufacturer
Takeda Yakuhin Kogyo KK (Japan)

54

References
1. Takeda Chemical Industries ltd. Jap pat 70 06.544. 2. J Takeda Res Lab 29 (1). 153-169 (1970). 3. Shinryo to Sinyaku 7 (8), 1553 (1970).

DA 2047
6-(-Cyclogeranoyl)penicillanic acid sodium salt

Synthesis
Prepared in several steps from 3,17diacetoxyandrosta-2,16-diene.

Action
Dacuronium bromide is a non-depolarising muscle relaxant based on a steroid nucleus. It is similar to pancuronium bromide but has the acetoxy group at position 17 replaced by a hydroxyl group. Its clinical effects are very similar to those of gallamine.

Manufacturer Synthesis
Prepared from a-cyclogeranoyl chloride and 6aminopenicillanic acid. Organon Laboratories Ltd.

References
1. Organon Laboratories Ltd. Neth. Appl. 6,602,098. 2. A new steroid muscle relaxant. S. A. Feldman and M. F. Tyrrell. Anesthesia 25 (3), 349-355 (1970).

Description
Colourless solid. mp 192-193 (dec).

Action
Semisynthetic penicillin with an activity in all alike to methicillin.

Manufacturer
Instituto De Angeli (Italy)

Daledalin Tosylate UK-3557-15 (USAN; Prop INN)

3-Methyl-3-(3-methylaminopropyl)-1-phenylindoline mono-p-toluenesulfonate

References
1. Terpene compounds as drugs. VIII. Bacteriological and pharmacological properties of terpenyl penicillins. G. Pala et al. Arzneim-Forsch 20 (1). 62-68 (1970) .

Dacuronium Bromide (Rec INN; BAN) Org NB 68

Dacuronii bromidum (Lat). Dacuronio bromuro (Sp) 2,16-Dipiperidino-5-androstane-3,17-diol 3acetate dimethobromide

Synthesis
Prepared by the reduction of 3-methyl-3-(3methylaminopropyl)-1-phenyl-2-indolinone hydrochloride (amedalin HCI) with diborane, followed by neutralization with p-toluensulfonic acid.

55
2. Harry R. Snyder et al. J Med Chem 10 (5),807-10 (1967). 3. The Pharmacologist 12 (2), 301, abs 553 (Fall, 1970). 4. Studies relaxant in hemiplegies. Drug Trade News 39, March 23, 1970.

Description
Crystals, mp 122-122.5 (acetone). Maleate: crystals, mp 130-131 (ethyl acetate).

Action
Daledalin tosylate is an antidepressant agent.

Manufacturer
Pfizer Inc (USA)

References
1. JAMA 213 (13), 2248 (1970). 2. WHO Chron 25 (3), 130 (1971). 3. Pfizer Corp. S African Appl 68 01.099.

Decadonium
N, N'-Bis-(adamantanyl)-bis-(dimethyl)decamethylenediammonium diiodide

Dantrolene (USAN; Rec INN) F 368 F 440 (sodium)

Dantrolenum (Lat) 1-[[5-(p-Nitrophenyl) furfurylidene] amino] hydantoin

Action
Decadonium is a curariform muscle relaxant.

References
1. Comparative sensitivity of neuromuscular synapses at different muscles to diadonium and decadonium. V. K. Lepakhin at al. Farmakol Toksik 33 (3), 288 (1970). 2. On the curariform activitv of decadonium diiodidum. D. A. Kharkevich. Farmakol Toksik 33 (4), 395 (1970).

Synthesis
By condensing 5-(p-nitrophenyl)-2-furaldehyde with 1-aminohydantoin hydrochloride.

Description
Crystals, mp 279-80 (aq. dimethylformamide).

Decloxizine (Rec INN) UCB1402

Decloxizinum (Lat). Decloxizina (Sp) 2-[2-[4-(Diphenylmethyl)-1-piperazinyl] ethoxy] ethanol 1-Benzhydryl-4-[2-(2-hydroxyethoxy) ethyl] piperazine

Action
Dantrolene sodium is a muscle relaxant that seems to act directly upon muscles rather than through the central nervous system. The drug is under clinical studies.

Manufacturer
Eaton Laboratories (USA)

References
1. Norwich Pharmacal Co. Neth Appl 6,612,588.

56
DEHT, a dichlorinated analogue of phenobarbital, is a potent inhibitor of Coxsakie A21 virus multiplication in mice.

Toxicity
LD50 po in mice: 190 mg/kg (24 hour observation 1 period) .

Synthesis
Prepared by the reaction of 2-[(4-diphenylmethyl)-1piperazinyl] ethanol with thionyl chloride, and subsequent reaction with monosodium ethylene 1 glycolate . Also by reaction of diphenylmethylpiperazine with 2-(2-chloroethoxy) 2 ethanol .

Manufacturer
Eli Lilly and Co (USA)

References
1. E. A. Swinyard et al. J Pharm Sci 52, 463-465 (1963). 2. Preclinical studies with DEHT. D. C. DeLong et al. Ann NY Acad Sci 173, 516-526 (1970).

Action
The free base boils a 185 (0.005 mm). Decloxizine is a new bronchodilator and antihistaminic agent.

Manufacturer
UCB (Belgium)

Delmadinone Acetate (USAN; RecINN; BAN) RS 1301

Delmadinonum (Lat). Delmadinona (Sp) 6-Chloro-17-hydroxypregna-1,4,6-triene-3,20-dione acetate 1 -Dehydroxychlormadinone acetate

References
1. H. G. Morren. Belg pat 523,899. 2. H. G. Morren et al. Ind Chim Belg 19, 1176-1185 (1954). 3. J. Lulling et al. Arzneim-Forsch. 18 (8), 995 (1968). 4. Clinical investigation of a new broncholyticumdecloxizine-as compared with franol and placebo treatment. J. Keihla et al. Respiration 27 (6), 582 (1970).

DEHT
5-(3,4-Dichlorophenyl)-5-ethyl-barbituric acid 5-(3,4-Dichlorophenyl)-5-ethylhexahydropyrimidine2,4,6-trione

Synthesis
Prepared by oxidation of 6-chloro-17acetoxyprogesterone with chloranil, followed by 1.2 oxidation with SeO2 .

Description
Crystals, mp 168-170 (acetone-hexane); [ ]D = -83 (chloroform). UV max 229 m [lg=4.00], 258 m [lg=4.00] and 297 m [lg=4.03].

Action

Action
Delmadinone acetate exhibits progestational, antiandrogenic and anti-estrogenic activity.

57
Isolation of 1-(p-Hydroxybenzyl)-6. 7-dihydroxy-l, 2. 3, 4-tetrahydroisoquinoline (demethylcoclaurine), an active alkaloid from Nelumbo nucifera H. Koshiyama et al. Chem Pharm Bull 18 (12), 2564-2568 (1970).

Manufacturer
Syntex Laboratories (USA)

References
1. WHO Chron 24 (11). 528 (1970). 2. Upjohn Co. Brit pat 890,315; Ger pat 1,243,682. 3. H. J. Ringold et al. J Am Chem Soc 81, 3485 (1959). 4. F. A. Kincl. Endokrinol 40, 257-266 (1961). 5. R. I. Dorfman et a!. Steroids 1, 185-209 (1963). 6. R. Wiechert et al. Arzneim-Forsch 17 (9), 11031107 (1967).

Demoxepam (USAN; Rec INN) Ro 5-2092

7-Chloro-1,3-dihydro-5-phenyl-2H-1,4benzodiazepin-2-one-4-oxide 7-Chloro-5-phenyl-3H-1,4-benzodiazepin-2(1H)one-4-oxide

Demethylcoclaurine Hydrochloride
dl-Demethylcoclaurine hydrochloride 1-(p-Hydroxybenzyl)-6,7-dihydroxy-1,2,3,4tetrahydroisoquinoline hydrochloride

Synthesis
Several methods have been described .
1-5

Description
Plates, mp 245-246 dec (ethanol) ; 238-239 also 2 reported .
1

Action Isolation and Synthesis

Isolated from the embryo of the seeds of Nelumbo nucifera collected in Taiwan. Synthesized from dlcoclaurine. Demoxepam is a tranquilizer of the 1,4benzodiazepine series.

Manufacturer
Hoffmann-La Roche

Description
Colorless prims, mp 242-244 (dec); mp of the synthesized product: 256-263 UV max 228.5 m ; [=14,400] and 288 m [=5,100].

References
1. L. H. Sternbach et al. J Org Chem 26, 4936 (1961). 2. S. C. Bell et al. J Org Chem 27. 562 (1962). 3. A. Stempel et al. J Org Chem 30, 4267 (1965). 4. Hoffmann-La Roche. Ger pat 1,145,625; Neth Appl 6,412,484; Ger pat 1,190,946. 5. American Home Products Corp. US pat 3,313,805; Fr pat 1,378,343; Brit pat 1.067.745. 6. Fed Proc 26 (2), 505 (1967). 7. JAMA 211, 2149 (1970). 8. WHO Chron 24 (11). 528 (1970).

Action
Demethylcoclaurine is an active alkaloid from Nelumbo nucifera, which possesses a significant activity to relax the smooth muscle and uterine strips.

Manufacturer
Bristol-Banyu (Japan)

References

58
1. K. L. Rinehart et al. J Am Chem Soc 83. 37293731 (1961). 2. Deoxynybomycin from a streptomyces. H. Naganawa et al. J Antibiotics 23 (7), 365-368 (1970).

Denofungin (USAN) U 28009 Desonide (USAN; Prop INN)

Production
An unspecified substance from Streptomyces hygroscopicus. Desonidum (Lat). Desonida (Sp) 11,16,17,21-Tetrahydroxy-pregna-1,4-diene-3,20dione cyclic 16,17-acetal with acetone 16-Hydroxy-prednisolone 16,17-acetonide 11,21-Dihydroxy-16,17-isopropylidenedioxy-1,4pregnadiene-3,20-dione

D 2083

Action
Denofungin is a new antifungal and antibacterial antibiotic.

Manufacturer
The Upjohn Co (USA)

References
JAMA 212. 466 (1970).

Deoxynybomycin

Synthesis
By the reaction of 16-hydroxy-prednisolone with refluxing acetone and a catalityc amount of hydrochloric acid.

Description
Crystals, mp 263-266 (ethyl acetate/petroleum ether). []D = +122 (methanol). UV max 242 m [=15,800].

Action
Deoxynybomycin is an antibiotic which was derived 1 chemically from nybomycin . Recently it has been isolated from the culture broth of a Streptomyces, isolated from a soil sample collected in Okinawa. Anti-inflammatory agent.

Manufacturer
Miles (USA)

Description
Colorless needles, which do not melt up to 300

References
1. JAMA 213, 1325 (1970). 2. WHO Chron 24 (9), 419 (1970). 3. S. Bernstein et al. J Am Chem Soc 81. 45734574 (1959) . 4. I. Ringler et al. Proc Soc Exptl Biol Med 107, 451455 (1961).

Action
Deoxynybomycin exhibits antibacterial activity.

Manufacturer
Institute of Microbial Chemistry, Tokyo (Japan)

References

59

Deterenol Hydrochloride (USAN; Prop INN) AL842

dl-p-Hydroxy--[(isopropylamino) methyl] benzyl alcohol hydrochloride dl-1-(p-Hydroxyphenyl)-2-isopropylaminoethanol hydrochloride dl-1-(p-Hydroxyphenyl)-1-hydroxy-2isopropylaminoethane hydrochloride

Synthesis
Prepared from 1-benzyl-4-(1,3-dicyano-1phenylpropyl)-piperidine hydrochloride.

Synthesis
Prepared by catalytic hydrogenation of 1(phydroxyphenyl)-1-keto-2-isopropylaminoethane hydrochloride.

Description
dl-Dexbenzetimide hydrochloride occurs as a white amorphous powder, mp 299-301.5 .

Description
White crystals, which melt at 155-157. The free base melts at 138-140 and its d-tartrate at 183184 (dec).

Action
dl-Benzetimide is a potent periferally and centrally long-acting anticholinergic agent. The pharmacological activities of the drug are exclusively due to the (+)-isomer.

Action
Anti-glaucoma agent. It reduces experimental ocular hypertension in rabbits without causing mydriasis.

Manufacturer
Janssen Pharmaceutica (Belgium)

Manufacturer
Alcon Laboratories, Inc (USA)

References
1. WHO Chron 25 (3), 149 (1971). 2. B. Hermans et al. J Med Chem 11, 797-800 (1968). 3. N. V. Research Lab. Dr C Janssen. US pat 3,125,578, 4. Dexbenzetimide in neuroleptic-induced parkinsonism. A double-blind crossover study with a 16-week follow-up. R. De Smedt et al. J elin Pharmacal 10 (3), 207-211 (1970). 5. Prognosis of the absolute configuration of the anticholinergic drug dextrobenzetimide. I. van Wijngaarden et al. Life Sciences 9 (1). 12891302 (1970).

References
1. JAMA 213 (13), 2247 (1970). 2. WHO Chron 25 (3), 130 (1971) . 3. M. L. Moore et al. (to Sterling Drug Inc) US pat 2,460,144. 4. Pharmacology of AL 842, an ocular hypotensive agent in rabbits. M. Van Hoose et al. Fed Proc 29 (2), 273 Abs (1970).

Dexetimide (Prop INN) R 16470

Dexbenzetimide. Dextrobenzetimide (+)-2-(1-Benzyl-4-piperidyl)-2-phenylglutarimide (+)-1-Benzyl-4-[(2,6-dioxo-3-phenyl)-3-piperidyl] piperidine

Dextranase
-1,6-Glucan 6-glucanohydrolase

Production
Derived from Penicillium funiculosum.

60

International Unit
One International Unit of enzyme is that amount producing one micromole of reducing sugar per minute at 35 to 40 and pH ranges from 6 to 8 using a Somogyi assay.

References
1. Comparative sensitivity of neuromuscular synapses at different muscles to diadonium and decadonium, V. K. Lepakhin et al. Farmakol Toksik 33 (3), 288 (1970).

Action
Dextranase attacks dextrans to produce oligosacharides of various lengths and the end product of the reaction appears to be isomaltose with trace amounts of glucose. In both in vitro and animal studies it has been shown that certain dextranases lyse some of the dextrans formed by certain types of acidogenic streptococci found in the oral cavity inthe presence of sucrose. These dextrans appear to favor not only the colonization of bacteria on surfaces of teeth but also the formation of plaques with a highly destructive and invasive potential. The effect of dextranase on human dental plaque is under clinical study.

Diapamide (USAN) Tiamizide Thiamizide CI456 D 1593

4-Chloro-N-methyl-3-(methylsulfamoyl) benzamide 4-Chloro-3-(N-methylsulfonamido)-Nmethylbenzamide

References
1. Dextranase and dental caries. S. A. Leach, Brit Dent J 127, 325 (1969). 2. Effect of dextranase on caries in rats harbouring an indigenous cariogenic bacterial flora. B. Guggenheim et al. Arch Oral Biol 14, 555 (1969). 3. The effect of dextranase mouthwash on dental plaque in young adults and children. R. C. Caldwell et al. J Amer Dent Ass 82 (1), 123 (1971). 4. A clinical study of the effect of dextranase on human dental plaque. R. R. Lobene. J Amer Dent Ass 82 (1), 132 (1971). 5. Dispersion of dextranous bacterial plaques on human teeth with dextranase. P. H. Keyes et al. J Amer Dent Ass 82 (1), 136 (1971).

Synthesis
By reacting 4-chloro-3-(methylsulfamoyl)benzoyl chloride with methylamine.

Description
Crystals, mp 165-166.

Action
Diapamide is a new diuretic and antihypertensive agent. Experimental studies in dog have proved that its main site of action is in the ascending limb of the loop of Henle.

Diadonium
Diadoniy

Manufacturer
Parke Davis and Co (USA)

Proprietary Name
Vectren

References
1. Parke Davis and Co US pat 3.203.987: Ger pat 1.158.957. 2. L. T. Blouin et al. J New Drugs 3, 302-308 (1963). 3. Amer Soc Nephrol 3. 27 (1969). 4. Med J Aust 1. 607-612 (1969). 5. Renal effects of Vectren: a new diuretic agent. C. G. Duarte. Fed Proc 29 (2).481 Abst (1970) .

Action
Diadonium is a new potent non-depolarizing myorelaxant and spasmolytic agent.

61

DIC

NSC 45388

Dichlorvos (Rec INN)

2,2-Dichlorovinyl dimethyl phosphate

5 (or 4)-(3,3-Dimethyl-1-triazeno) imidazole-4 (or 5)carboxamide

Action Synthesis
Prepared by the reaction of 5-aminoimidazole-4carboxamide with sodium nitrite in acid solution, and by the reaction of the resulting 5-diazoimidazole-4carboxamide with a solution of dimethylamine in methanol. Dichlorvos, an orally administered, single-dose drug, has proved to be effective against a variety of helminths infecting the gastrointestinal tract in a 1,2,3 variety of mammals . Recently, the safety and anthelmintic efficacy for man of dichlorvos has been 4 evaluated . Pharmacologically, the drug is a cholinesterase inhibitor.

Manufacturer
Shell Chemical Co (USA)

Description
Ivory microcrystalline substance, explosive dec 250255 .

Proprietary Name
Dichlorman

Action
DIC is an antineoplastic agent which has shown 3,4 significant antitumr activity in mice , and in man 5,6,8 during preliminary clinical trials . AIC [4(5)aminoimidazole-5(4)-carboxamide] has been 7 identified as a metabolite of DIC . The ribotide of DIC occupies a central position in the de novo 2 purine synthetic pathway .

References
1. E. F. Batte and A. C. Todd. Vet Med / Sm An Clin 60, 539-545 (1966). 2. E. G. Batte at al. ibid 60, 567-570 (1966). 3. N. F. Baker et al. Am J Vet Res 20, 278-280 (1969). 4. A. Pena Chavarria et al. Am J Trap Med Hyg 18 (6), 907-911 (1969).

References
1. Y. Fulmer Shealy et al. J Org Chem 27, 2150 (1962). 2. J. M. Buchanan and S. C. Hartman. Adv Enzymol 21, 199 (1959). 3. Y. F. Shealy et al. J Biochem Pharmac 11, 674 (1962). 4. K. Hano et al. Gann 56, 417 (1965). 5. C. MacDonald et al. Proc Am Ass Cancer Res 8, 43 (1967). 6. J. L. Skibba et al. Cancer Res 29, 1944 (1969). 7. J. L. Skibba et al. Biochem Pharmac 19,20432051 (1970). 8. J. K. Luce et al. Cancer Chemother Rep 54 (2), 119-124 (1970).

Dienomycins
Dienomycin A: 4-isobutyroyloxy-3-methyl-2-(4phenylbutadienyl) piperidine Dienomycin B: 4-acetoxy-3-methyl-2-(4-phenylbutadienyl) piperidine Dienomycin C: 4-hydroxy-3-methyl-2-(4phenylbutadienyl) piperidine

62

Description
White crystalline powder, soluble in alcohol, mp 182 The free base melts at 56 the hydrobromide . ; at 173 and the nitrate at 175 , .

Action and Uses

Difemerine hydrochloride is a new aminopropanol compound which exerts a pronounced antispasmodic effect. In addition to this it also exhibits psychosedative and local anesthetic effects. The drug is proposed for the treatment of spasm of the gastrointestinal and genitourinary tracts.

Production
Dienomycins A, B and C have been isolated from the culture filtrate of the strain MC 67-CI by a chemical screening method using Wood reagent.

Dosage
The oral dose is 7.5 to 10 mg daily. The daily parenteral dose is 1 to 3 mg intramuscularly, or 1 to 2 mg intravenously. The rectal dose is 15 to 30 mg daily.

Action
Dienomycins are weakly antibacterial, and dienomycin A is the most active. The same is active against mycobacteria.

Supplied as
Gelules, 2.5 mg. Suppositories, 7.5 mg. Solution (injection) 1 mg/ml

References
1. A new antibiotic, dienomycin. I Screening method, isolation and chemical studies. S. Umezawa et al. J Antibiot 23 (1), 20-27 (1970). 2. Studies on dienomycins. II Chemical structures of dienomycins A, B and C. S. Umezawa et al. J Antibiot 23 (1). 28-34 (1970).

Proprietary Name
Luostyl

Manufacturer
Lab UPSA (France)

References
1. Lab UPSA Fr pat M 3406. 2. S. G. Kuznetsov et al. Zh Obshch Khim 32, 511 (1962). 3. Med Act (Drugs of Today) 6 (6), 205-207 (1970). (Review with 7 references)

Difemerine (Rec INN)

Benzilic acid, 2-(dimethylamino)-2-methyl propyl ester hydrochloride 2-Dimethylamino-2-methylpropyl diphenylglycolate hydrochloride

Diflumidone Sodium Ba 4164-8 MBR 4164-8

(USAN; Rec INN)
3'-Benzoyl-1,1-difluoromethanesulfonanilide sodium salt

Synthesis
Prepared from potassium benzilate or benzilic acid with 2-(dimethylamino)-2-methyl-1-propanol.

63

Synthesis
Prepared by N-sulfonylation of 3aminobenzophenone with difluoromethanesulfonyl chloride.

Description
White crystalline powder, mp 228-230 (dec). Diflumidone melts at 99-100.5 .

Action
Diflumidone is a new anti-inflammatory agent, In a carrageenin rat paw edema test and in a uv erythema test the ED50 potency values for the drug were approximately 1.5-2.0 and 2.2 times that of phenylbutazone, respectively, It was equipotent with phenylbutazone in the adjuvant arthritis test.

Action
By means of 6, 6-difluoro substitution, both the oral pregestational and oral anti-uterotrophic activities of norethindrone have been enhanced. 6,6-Difluoronorethindrone may therefore be a more potent oral contraceptive agent than norethindrone itself.

Toxicity
LD50 po in male rats: 45026 mg/kg; in the male mouse: 72062 mg/kg.

Manufacturer
Syntex (USA)

Manufacturer
Minnesota Mining and Mfg Co (USA)

References
The biological activity of a series of 6, 6-difluoro norethindrone derivatives. W. H. Rooks and R. I. Dorfman. Contraception 1 (6). 403-407 (1970).

References I
1. Anti-inflammatory activity of 3benzayldifluoromethanesulfonanilide, sodium salt. K. F. Swingle et al. The Pharmacologist 11 (2), abs 204 (1969). 2. Absorption disposition and excretion of an antiinflammatory agent in the rat. D. R. Hoogland et al. The Pharmacologist 11 (2), abs 291 (1969). 3. Anti-inflammatory agents. I. Benzoylfluoroalkanesulfonanilides. J. Kenneth Harrington et al. J Med Chem 13 (1), 137 (1970). 4. Diflumidone Sodium, MBR 4164-8: a new antiinflammatory agent K. F. Swingle et al. Arch Int Pharmacodyn Ther 189 (1), 129 (1971).

Difluprednate (USAN; Rec INN) W6309

Difluprednatum (Lat). Difluprednato (Sp) 6,9-Difluoro-11,17,21-trihydroxypregna-1,4-diene3,20-dione-21-acetate 17-butyrate 6, 9-Difluoroprednisolone 17-butyrate 21-acetate

6,6-Difluoronorethindrone
17-Hydroxy-6,6-difluoro-19-nor-17-pregn-4-en-20yn-3-one 17-Ethynyl-6,6-difluoro-17-hydroxyestr-4-en-3one

Synthesis
Prepared by the reaction of 6,9difluoroprednisolone with methyl butyrate and ptoluenesulfonic acid in dimethylformamide and by

64
the reaction of the resulting 17-monoester with acetic anhydride.

Isolation
It has been isolated in pure form from the plasma of pigs given large doses of vitamin D3.

Description
Crystals, mp 191-194 [ ]D = +31.7 (c=0.5, in ; dioxane). UV max 237-238 m [E(1%, 1 cm) =320] in ethanol.

Action
21,25-Dihydroxycholecalciferol is a metabolite of vitamin D3. It has proved to be one-half as active as vitamin D3 in the rat in the cure of rickets and in intestinal calcium transport, but to be more active than vitamin D3 in the mobilization of bone mineral.

Action
Anti-inflammatory

Manufacturer
Warner-Lambert (USA)

References
21,25-Dihydroxycholecalciferol. A metabolite of vitamin D3 preferentially active on bone. T. Suda at at. Biochemistry 9,2917-2922 (1970).

References
1. JAMA 212, 2247 (1970). 2. Warner-Lambert Pharmaceutical Co. S African Appl 68 03,686. 3. Comparative anti-inflammatory properties of systemically administered betamethasone 17-and 6,9-difluoroprednisolone 21-acetate 17-butyrate. G. DiPasquale et al. Steroids 16 (6), 663-678 (1970). 4. The local anti-inflammatory properties of betamethasone 17-benzoate and 6,9difluoroprednisolone 21-acetate 17-butyrate. G. DiPasquale et al. Steroids 16 (6), 679-692 (1970). 5. Effect of betamethasone 17,benzoate and 6,9difluoroprednisolone 21-acetate 17-butyrate on the survival of adrenalectomized rats. G. DiPasquale et al. Steroids 16 (6), 693-701 (1970).

Dimepregnen (BAN)
3-Hydroxy-6,16-dimethyl-pregn-4-en-20-one 6,16-Dimethyl-pregn-4-en-3-ol-20-one

Synthesis

21,25 Dihydroxycholecalciferol 21,25DHCC

Prepared by reducing 6,16-dimethylprogesterone with lithium aluminium tri-ter-butoxyhydride.

Description
Crystals, mp 131-134 .

Action
Antiestrogenic

References
1. Chem Drug 193, 228 (1970). 2. E. Merck AG. Brit pat 1,130,115.

65

Dimethylphaeanthine Diiodide
N, N'-Dimethylphaeanthine diiodide N, N'-Dimethyl-I-tetrandrine diiodide

Synthesis
Prepared from 2-isopropyl-4-methyl-6hydroxypyrimidine

Description
Liquid, bp 123-125 (0.03 mm); bp 83-84 (0.002 mm). nD = 1.4978-1.4981.

Action
Dimpylate, an insecticide of great commercial value, has recently been found to possess nematocidal activity.

Isolation
From Triclisia dictyophylla and T. patens.

Manufacturer
J. R. Geigy AG (Switzerland)

Description
The di-iodide, mp 231 and []D = -253 in ethanol. The diperchlorate, mp 259 .

Proprietary Name
Diazinon, Basudin

Action
D imethylphaeanthine is a new quaternary alkaloid with muscle relaxant effect.

References
1. Gasser Z Naturforsch 8b, 225 (1953). 2. J. R. Geigy AG US pat 2,754,243. 3. Methods for controlling nematodes with compositions containing Diazinon. A. Margot and C. Kocher (to J. R. Geigy AG) US pat 3,492,404 (1970).

References
The occurrence af phaeanthine and N, N'dimethylphaeanthine in Triclisia dictyaphylla and T. patens. A new simple method far estimation of muscle relaxant effect. A. Kronlund et al. Acta Pharm Suecica 7, 279-284 (1970).

Dioxopromethazine Hydrochloride Dimpylate (Prop INN)

Dimpylatum (Lat) O,O-Diethyl-O-(2-isopropyl-6-methyl-4pyrimidinyl)ester of phosphorothioic acid O,O-Diethyl-O-[2-isopropyl-4-methylpyrimidinyl-(6)] thiophosphate

Wu

3227
10-[2-(Dimethylamino)propyl]-phenothiazine 5,5dioxide hydrochloride

Synthesis
Prepared by the oxidation of promethazine with hydrogen peroxide. Also by oxidation of

66
phenothiazine with hydrogen peroxide and 1 treatment with 2-dimethylaminopropylchloride .

Description
White to faint yellow, practically odorless, crystalline powder. Soluble in water, slightly soluble in alcohol and practically insoluble in ether. mp 265-268 th e ; free base melts at 128-130 UV max in 0,1N . hydrochloric acid 264 m [E(1%, 1 cm) = 365 15] and at 328 m [E(1%, 1 cm) = 165 15].

Action and Uses

When applied rectally dioxopromethazine hydrochloride exhibits antihistaminic, local anesthetic, spasmolytic and anti-inflammatory properties. For use in the treatment of hemorrhoids. Dioxopromethazine hydrochloride was introduced into the pharmaceutical market in 1968 as an anti histaminic agent for oral use.

Synthesis
Prepared from 4-diisopropylamino-2-phenyI-2-(22 pyridyl) butyronitrile .

Description
Crystals, mp 94.5-95 .

Action and Uses

Disopyramide is a new anti-arrhythmic drug. Its major clinical uses are for the prevention or abolition of certain cardiac arrhythmias. These include extrasystoles, paroxysmal supraventricular and ventricular tachycardia, atrial fibrillation, and atrial flutter.

Supplied as
Suppositories, 10 mg

Proprietary Name
Prothanon

Supplied as
Capsules, 100 mg. Also gelules, 75 mg of disopyramide and 20 mg of amobarbital.

Manufacturer
VEB Arzneimittelwerk (Germany, East)

References
1. VEB Arzneimittelwerk Dresden. Fr pat 1.470,195; Fr pat 1.470,196; Ger (East) pat 51855; Gar (East) pat 54,363. 2. Die Pharmazie 25 (1), 78-121 (1970) . 3 . Protanon Suppositorien K. Zieloff. Zbl Pharm 109 (1), 41 (1970). 4. Dioxopromethazinhydrochlorid Zbl. Pharm 109 (1), 46 (1970). 5. Med Act (Drugs of Today) 6 (6), 208-212 (1970). (Review with 16 references)

Proprietary Names and Manufacturer

Rythmodan (Roussel, France); Norpace [for the phosphate (Searle, USA)].

References
1. G. D. Searle Co. Belg pat 617.730; US pat 3.225.054. 2. Med Act (Drugs of Today) 6 (6).212-215 (1970). (Review with 23 references)

Disopyramide (USAN) SC7031

-[2-(Diisopropylamino )ethyl]--phenyl-2pyridineacetamide 4-Diisopropylamino-2-phenyl-2-(2-pyridyl) butyramide

Disparlure
cis-7,8-Epoxy-2-methyloctadecane

Synthesis
Prepared in several steps from 6-methyl-1-heptene

67

Action
Disparlure is a sex attractant substance of female gypsy moth. It is used for insect control.

Manufacturer
USDA Agric Res Service (USA)

References
Chem Eng News 48 (41), 35 (1970).

Synthesis
Prepared by the reduction of 1-(4-ethyl-2,5dimethoxyphenyl)-2-nitropropane with aluminum 1 lithium hydride .

DithiogIycol-bis-choline ChSSCh

Description
Crystals, mp 195 . The free base melts at 61-61.5 .

Action
DOET is a methoxylated amphetamine compound related to both mescaline and amphetamine. This new psychotropic agent, in low doses, appears to be particularly effective in altering normal cognition without producing disorganization in thinking or perception.

References
1. A. T. Shulgin (Dow Chemical Co) Brit pat 1,147,739. 2. DOET. a new psychotropic agent: Psychological and physiological effects in man. S. H. Snyder et al. Arch Gen Psych 21, 95-101 (1969). 3. DOM (STP) a new hallucinogenic drug, and DOET: effects of low doses in man. S. H. Snyder et al. Amer J Psychiat 125,357-364 (1968). 4. Altered free associations: some cognitive effects of DOET. H. Weingartner et al. Behav Sci 15 (4), 297-303 (1970). 5. DOET, a new psychotropic drug. S. H. Snyder et al. Arch Gen Psych 24, 50-56 (1971).

Action
Dithioglycol-bis-choline, a new analogue of acetylcholine, possesses a strong nicotinic activity, and a very weak muscarinic activity.

References
1. I. Janczarki et al. Acta Physiol Polon 19, 256 (1968). 2. Cholinergic activity of dithioglycol-bis-choline, a new analogue of acetylcholine. P. Kubikowski and S. Chustecki. Dissert Pharm Pharmacol 22 (2/3), 97-104 (1970).

DOET Hydrochloride
2,5-Dimethoxy-4-ethyl--methylphenethylamine hydrochloride 2,5-Dimethoxy-4-ethylamphetamine hydrochloride 1-(2, 5-Dimethoxy-4-ethylphenyl)-2-aminopropane hydrochloride

DOM

STP

2.5-Dimethoxy-4--dimethyl phenethylamine 2.5-Dimethoxy-4-methylamphetamine 1-(2. 5-Dimethoxy-4-methylphenyl)-2-aminopropane

68

Dorastine Hydrochloride (USAN; Prop INN) 5-9110/1

Dorastinum (Lat). Dorastina (Sp) 8-Chloro-2,3,4,5-tetrahydro-2-methyl-5-[2-(6-methyl3-pyridyl)ethyl]-1H-pyrido[4,3-b] indole dihydrochloride

Ro

Synthesis
By the reduction of 1-(4-methyl-2.5dimethoxyphenyl)-2-nitropropane with aluminum lithium hydride. DOM melts at 60.5-61 .

Action
DOM is a new hallucinogenic drug. The data from a recent clinical evaluation has indicated that low doses of DOM produced significantly increased feelings of anxiety, euphoria, dysphoria with somatic and LSD-like symptoms.

Toxicity
LD50 ip in mouse: 824.2 mg/kg.

References
1. A. T. Shulgin (Dow Chemical Co) Brit pat 1.147.739. 2. 2,5-Dimethoxy-4-methyl-amphetamine (STP): A new hallucinogenic drug. S. H. Snyder et al. Science 158. 669-670 (1967). 3. DOM (STP) A new hallucinogenic drug and DOET: Effects in normal subjects. S. H. Snyder at al. Amer J Psychiat 125.357-364 (1968). 4. Analogs of -methylphenethylamine (amphetamine). 1. Synthesis and pharmacological activity of some methoxyand/or methyl analogs. B. T. Ho et al. J Med Chem 13 (1). 26-30 (1970). 5. 2,5-Dimethoxy-4-methylamphetamine: Clinical evaluation of a new hallucinogenic drug. L. A. Faillace at al. J Nerv Ment Dis 150 (2). 119126 (1970). 6. 2,5-Dimethoxy-4-methyl-amphetamine-Tissue distribution and neurochemical action. J. E. Idanpaan-Heikkila and W. M. Mcisaac. Biochem Pharmac 19. 935-937 (1970). 7. Analogs of Amphetamine. 4. Synthesis of metabolites of 1-(2,5-dimethoxy-4-methylphenyl)-2aminopropane. B. T. Ho and L. W. Tansey. J Med Chemistry 14 (2). 156-157 (1971). 8. Analogs of amphetamine. 5. Studies of excretory metabolites of 1-(2,5-dimethoxy-4-methylphenyl)-2aminopropane (DOM) in rats. B. T. Ho. J Med Chemistry 14 (2). 158-160 (1971).

Synthesis
Prepared in several steps from 2-methyl-5-vinyl pyridine and p-chloroaniline.

Description
Crystals, mp 264-266 (ethanol-ether); the free bas e melts at 114.5-115.5 (ethyl acetate).

Action
Dorastine hydrochloride is a new anti histaminic agent.

Manufacturer
Hoffmann-La Roche (USA)

References
1. JAMA 211, 1363 (1970). 2. WHO Chron 24 (3). 126 (1970). 3. Hoffmann-La Roche Inc US pat 3.409.628. 4. Clin Pharm Ther 10, 250 (1969).

Doxepin Hydrochloride (USAN; Rec INN)

11-(3-Dimethylaminopropylidene)-6,11dihydrodinbenz[b,e]oxepine hydrochloride (isomeric mixture)

69
3. C. F. Boehringer and Sohne GmbH Belg pat 623,259. 4. Chas Pfizer and Co, Inc Belg pat 641.498. 5. Chas Pfizer and Co, Inc Brit pat 1,085,406. 6. Med Act (Drugs of Today) 6 (2), 51-55 (1970). (Review with 14 references)

Synthesis
Doxepin may be prepared by treatment of the corresponding dibenzoxepinone with a dimethylaminopropylmagnesiumhalide Grignard reagent, followed by hydrolysis and dehydration of 1-4 the carbinol formed thereby . It may be also prepared by reaction of the dibenzoxepinone with 3dimethylaminopropyltriphenylphosphonium-bromide 5 hydrobromide in presence of butyl lithium . In both processes a mixture of cis and trans isomers is obtained; in the mixture prepared by the organophosphorous reaction the more pharmacological active cis-isomer predominates, (approx. 75%) and when the Grignard reagent is used, the trans-isomer of lesser activity predominates.

Dropropizine (Rec INN) UCB 1967

Dropropizinum (Lat). Dropropizina (Sp) 1-Phenyl-4-(2,3-dihydroxypropyl)-diethylenediamine 3-(4-Phenyl-1-piperazinyl)-1,2-propane-diol

Description
White crystalline powder. A mixture of the cis/trans hydrochlorides obtained by the Grignard route has 4 been reported to melt at 188-189 . From this mixture the isomers were separated; the tr.ansisomer hydrochloride melts at 192-193 and the cis , isomer (cidoxepin) at 209-210.5 .

Action
Pharmacological screening has indicated that dropropizine shows antitussive activity similar to that of codeine.

Toxicity LD50 po in mice: 450 mg/kg; in rats: 650

mg/kg

Action and Uses

Experimental studies in animals have demonstrated that doxepin possesses both tranquillizing and antidepressant activity; also a potent spasmolytic and muscle-relaxant activity, and mild peripheral vasodililtor properties. Doxepin is useful clinically in the treatment of patients with anxiety, depression, and mixed anxiety/depression.

Manufacturer
UCB (Belgium)

Proprietary Name
Katril

Dosage
30 to 300 mg daily, usually administered in three divided doses.

References
1. Dropropizine (UCB 1967), an antitussive: Oral toxicity study in pure bred dogs. P. R. B. Noel. Arzneim-Forsch 19 (8), 1246 (1969). 2. Chem Drug 193, 228 (1970).

Supplied as
Capsules, 10 mg, 25 mg and 50 mg.

Proprietary Names and Manufacturer

Aponal (Boehringer, Germany); Sinequan (Pfizer, USA Germany, Switzerland, U.K.)

Ecdysterone

References
1. Stach and Bickelhaupt. Monatsch 93, 896 (1962). 2. Bickelhaupt et al. ibid. 95, 485 (1964).

70

Enpiprazole Hydrochloride (BAN; Prop INN) H 3608

Enpiprazolum (Lat). Empiprazol (Sp) 1-(o-Chlorophenyl)-4-[2-(1-methylpyrazol-4-yl) ethyl] piperazine dihydrochloride

Description
Screening of Israeli plants for insect moulting hormones (ecdysones) has led to the isolation and identification of ecdysterone from Ajuga and Achyrantes species. Insect hormones (phytoecdysones) from Israeli plants.

References
R. Ikan et al. Israel J Chem 8 Suppl Proc Israel Chem Soc (1970).

Synthesis
Prepared by the condensation of 1-methyl-4-(2chloroethyl)pyrazol with N-(ochlorophenyl)piperazine. The dihydrochloride salt of the product so obtained melts at 223-225 .

Enflurane (USAN; Prop INN) Compound 347

2-Chloro-1,1,2-trifluoroethyl difluoromethyl ether

Action
Enpiprazole dihydrochloride is a new psychotropic agent.

References
1. Chem Drug 193, 228 (1970). 2. WHO Chron 24 (9), 421 (1970). 3. E. Merck AG Neth Appl 6,514,242.

Action
Enflurane is a new inhalation anesthetic.

Enpromate (USAN; Rec INN) NSC 112682 59156 Lilly

Enpromatum (Lat). Empromato (Sp) Cyclohexanecarbamic acid, 1,1-diphenyl-2-propynyl ester 1, 1-Diphenyl-2-propynyl cyclohexanecarbamate

Manufacturer
Ohio Medical Products Division of Air Reduction Co, Inc (USA)

Proprietary Name
Ethrane

References
1. JAMA 214,1693 (1970). 2. WHO Chron 25 (3), 131 (1971).

71

Description
White or pale yellow powder, mp 234-238 (dec). Very soluble in diluted hydrochloric acid, soluble in methanol and insoluble in ether and benzene; []D = 89.2 (c=0.5% in dimethylformamide).

Action
Enramycin hydrochloride is a new antibiotic which has been recently marketed in Japan. It is very active against gram-positive bacteria, active against Neisseria and Mycobacterium and Treponema, but inactive against gramnegative bacteria. Indications: Treatment of infections due to sensitive organisms including infections affecting skin, respiratory tract, and ear, nose and throat.

Synthesis
Prepared by the reaction of 1,1-diphenyl-2-propyn1-ol with phenyl chloroformate and by the reaction of the resulting carbonate with cyclohexylamine. Also by the reaction of 1,1-diphenyl-2-propyn-1-ol with cyclohexyl isocyanate.

Description
Crystals, mp 160-161

Dosage
The initial intramuscular dose in adults is 200 mg divided into 1 to 4 doses, followed by a daily dosage of 100 mg divided into 1 to 2 doses.

Action
Enpromate has proved to have potent antitumor effects against various tumor systems in mice.

Supplied as
Vials, 50 and 100 mg (potency).

Manufacturer
Eli Lilly and Co (USA)

Proprietary Name
Enradin

References
1. JAMA 211. 2148 (1970). 2. WHO Chron 24 (11), 529 (1970). 3. Acetylenic carbamates. A new class of potential oncolytic agents. R. D. Dillard et al. J Med Chem 10 (1). 40-47 (1967). 4. Eli Lilly and Co. Neth Appl 6,516.922. 5. Clinical trial of acetylenic carbamate: 1, 1diphenyl-2-propynyl cyclohexanecarbamate (NSC112682). S. Gailani and M. Blais. Cancer Chemotherapy Rep (Pt-1) 54(3) 187-190 (1970).

Manufacturer
Takeda Chemical Industries Ltd (Japan)

References
1. WHO Chronicle 24 (3), 126 (1970). 2. Med Act (Drugs of Today) 7 (1). 15-17 (1971). (Review)

Enramycin Hydrochloride (Prop INN)

Enramycinum (Lat). Enduracidin Antibiotic of polypeptide nature which contains chlorine in its molecule

Epicillin (USAN; Prop INN) SQ-11,302

6-[D-2-Amino-2-(1,4-cyclohexadien-1-yl)acetamido]3,3-dimethyl-7-oxo-4-thia-1azabicyclo[3.2.0]heptane-2-carboxylic acid

Production
Enramycin is obtained from cultures of Streptomyces fungicidicus No. B 5477.

72

Synthesis
By reacting 17-epiestriol with dimethyl sulphate.

Action
Epimestrol is a new ovulation stimulant.

Manufacturer
NV Organon (Netherlands)

Synthesis
Prepared by coupling 6-aminopenicillanic acid with the methyl acetoacetate enamine of D-2-amino-2(1,4-cyciohexadienyl)acetic acid in the form of a mixed anhydride.

References
1. JAMA 209,1212 (1969). 2. WHO Chron 24 (11), 529 (1970) . 3. Organon Laboratories Ltd Brit pat 911.600.

Description
Crystals, the hemihydrate decomposes at 202 .

Action
Epicillin is a new semi-synthetic penicillin, which has proved to be active in vitro against a wide range of gram-positive bacteria.

Manufacturer
Squibb (USA)

Eprazinone Hydrochloride (Rec INN) CE 746

Eprazinonum (Lat). Eprazinona (Sp) 3-[4-(-Ethoxyphenethyl)-1-piperazinyl]-2methylpropiophenone dihydrochloride 1-(2-Ethoxy-2-phenylethyl)-4-(3-keto-2-methyl-3phenyl-propyl)piperazine dihydrochloride 1-[(2-Phenyl-2-ethoxy)ethyl]-4-[(3-phenyl-2methyl)propan-3-one] piperazine dihydrochloride

References
1. JAMA 213 (13). 2247 (1970). 2. WHO Chron 25 (3), 132 (1971). 3. E. R. Squibb and Sons, Inc US pat 3,485,819. 4. Tenth Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, Oct 18-21 (1970); abst 119-120.

EpimestroI (USAN; Rec INN) Org 817

Epimestrolum (Lat) 3-Methoxyestra-1,3,5(10)-triene-16,17-diol 17-Epiestriol 3-methyl ether

Synthesis
Prepared by reacting2-phenyl-2-ethoxyethyl bromide with piperazine, and subsequent condensation with trioxymethylene and propiophenone.

Description
White crystalline powder, mp 160; soluble in water.

Action

73
Eprazinone hydrochloride is an antitussive compound; it also exhibits analgesic activity.

Toxicity
LD50 po in mice: 730 mg/kg.

Etifoxine (Prop INN) HOE 36801

Etifoxinum (Lat)r Etifoxina (Sp) 6-Chloro-2-(ethylamino)-4-methyl-4-phenyl-4H-3,1benzoxazine

Manufacturer
Centre Europ Rech Mauvernay (France).

References
1. WHO Chron 24 (9), 421 (1970). 2. Roland Mauvernay Brit pat 1,097,572. 3. J. Vacher et al. Arch Int Pharmacodyn Ther 165 (1), 1-13 (1967).

Etidronic Acid (USAN; Rec INN) EHDP

Synthesis
Prepared from 2-amino-5-chloro--methyl-phenylbenzylalcohol. Acidum etidronicum (Lat). Etidronico Acido (Sp) (1-Hydroxyethylidene) diphosphonic acid Hydroxyethane diphosphonic acid

Description
Crystals, mp 90-92 The hydrochloride salt melts a t . 150-151 UV max 273 m [ =21,200] .

Action
Etifoxine is a new psychotropic compound. According to the action on animal behaviour it may be considered a tranquiliizing drug with additional stimulating properties.

Synthesis
Prepared by the reaction of acetic acid with phosphorus trichloride or tribromide. By the reaction of ketene with phosphoric acid and also by the reaction of acetic anhydride with dimethyl phosphite.

Manufacturer
Farbwerke Hoechst A.G. (Germany)

References
1. Farbwerke Hoechst A. G. S African pat 67 06,887. 2. WHO Chron 24 (9), 422 (1970) . 3. 2-Ethylamino-6-chloro-4-methyl-4-phenyl4H 3,1benzoxazine a new psychotropic compound. I. Hoffmann et al. Arzneim-Forsch 20 (7), 975 (1970).

Action
Etidronic acid is a calcium homeostatic agent.

Manufacturer
Monsanto Co (USA)

References
1. JAMA 211. 819 (1970). 2. WHO Chron 24 (11). 526 (1970) . 3. Monsanto Co. Fr pat 1,521,962; Fr pat 1,521,963; Fr pat 1,521,961; Fr pat 1,548,936; US pat 3,475,486; Fr pat 1.546.145.

74

Etorphine Hydrochloride (BAN; Rec INN) M 99

Tetrahydro-7-(1-hydroxy-1-methyl-butyl)-6,14endoethenooripavine hydrochloride 19-Propylorvinol hydrochloride

Synthesis
By condensing 2-piperidyl-1,2-ethanediol hydrochloride with propiophenone a racemic mixture (HCI) is obtained which melts at 256-257 . The use of the separated alpha or beta racemate of the starting glycol leads to the corresponding alpha or beta racemate. The alpha racemate (HCI) melts at 251.5-253 and the beta racemate (HCI) at 250, 251 The gamma racemate (HCI) has also been . obtained, melting at 175-177 resolidifying at 195 , and remelting at 241

Description
Crystals, mp 266-267 the free base, mp 215 ; .

Action
Etorphine has a potency in laboratory animals 2 approximately 1,000 times that of morphine . Like the latter, it is addictive in monkeys and causes respiratory depression. I n a recent pilot study of safety and efficacy, the drug has been found to be a clinically efficacious analgesic at doses of 1 g/kg having rapid onset and moderately short duration of 3 action after intramuscular injection .

Action
Etoxadrol hydrochloride is a new parenterally administered dissociative anesthetic that has appeared promising in non-human primates and other animals. In a group of normal human volunteers the drug has been found to be psychologically acceptable, physiologically safe and apparently useful.

Manufacturer
Cutter Laboratories (USA)

Manufacturer
Reckitt and Colman Pharm Div (England)

References
1. JAMA 211, 2149 (1970). 2. WHO Chronicle 24 (11), 527 (1970). 3. W. Richard Hardie (to Cutter Lab. Inc.) US pat 3,262,938, 4. Cardiopulmonary response to CL-7848C, a new dissociative anesthetic. D. L. Traber and R. D. Wilson. Pharmacologist 11 (2), 236 (1969). 5. The cardiovascular effects of CL-1848C in normal human volunteers. R. D. Wilson and C. R. Allen. Fed. Proc. 29. 354 (1970). 6. Effects of CL-1848C, a new dissociative anesthetic on the cardiovascular and respiratory systems. D. L. Traber. Fed Proc 29. 354 (1970). 7. Evaluation of CL-1848C: a new dissociative anesthetic in normal human volunteers. R. D. Wilson et al. Anesthesia and Analgesia 49 (2). 236-241 (1970). 8. Effects of CL-1848C, a new dissociative anesthetic, on the canine cardiovascular and respiratory systems. A. H. Goldberg at al. J Pharmacal Exptl Ther 175 (2). 395 (1970).

References
1. J. F. Macfarlan and Co Belg pat 618,392. 2. G. F. Blane et al. Brit J Pharmac 30, 11-22 (1967). 3. Trial of etorphine hydrochloride (M99 Reckitt) in carcinoma pain: preliminary report. G. F. Blane and D. S. Robbie. Brit J Pharmac 39 (1), 252P (1970).

Etoxadrol Hydrochloride (USAN; Rec INN)

Etoxadrolum (Latin) (+)-2-(2-Ethyl-2-phenyl-1,3-dioxolan-4-yl )piperidine hydrochloride (+)-2-Ethyl-2-phenyl-4-(2-piperidyl)-1,3-dioxalane hydrochloride

CL1848C

75
5. Prophylaxis of influenza B with UK 2054. P. N. Meenan and I. B. Hillary. Lancet, ii, 614-615 (1969). 6. The effects of UK 2054 on the multiplication of influenza viruses. R. D. Barry and P. Davies. J Hyg Camb 68, 151-158 (1970). 7. Studies of isoquinoline derivatives (UK 2371 and UK 2054) in respiratory infections of volunteers, using influenza viruses, a parainfluenza virus and a rhinovifus. Sylvia E. Reed et al. Ann NY Acad Sci 173, 760-769 (1970).

Famotine Hydrochloride (USAN; Rec INN) 2054

1-[( p-Chlorophenoxy)methyl]-3,4dihydroisoquinoline hydrochloride

UK

Fenaftic Acid
1-Diethylamino-3-phenyl-6,6-dimethyl1,2,3,4,5,6,7,8-octahydro-8-oxo-2-naphthoic acid

Synthesis
Prepared by cyclodehydration of N-(pchlorophenoxyacetyl)--phenylethylamine with phosphorus pentoxide.

Description
Colorless needles, mp 205-207 .

Action
Famotine hydrochloride is a weak, non-competitive 5 inhibitor of bacterial and viral neuraminidases . It has been found to have a spectrum of antiviral activity which includes those viruses which possess neuraminidase, namely, the influenza and parainfluenza viruses responsible for a large proportion of common respiratory infections. It is also effective however against many other viruses, such as rubella and respiratory syncytial viruses, which do not possess neuraminidase. Inhibition of influenza virus multiplication by famotine might result from interaction of the inhibitor with both virus 7 and cells . In experimental trials the overall protective effect of famotine has proved to be significant in volunteers 6 infected with B influenza virus .

Action and Uses

Fenaftic acid increases bile secretion and improves its composition. For use in the treatment of dyspepsia, cholelithiasis, postcholecystectomy.

Supplied as
Sugar coated tablets, 250 mg.

Dosage
0.5 to 1 g daily.

Registered Name
Vesifluyl

Manufacturer
Chas Pfizer and Co, Inc (USA)

Manufacturer
Allard (France)

References
1. WHO Chron 24 (11), 529 (1970). 2.JAMA 210,1454 (1969). 3. Pfizer Corp. Neth Appl 6,516,328. 4. K. W. Brammer et al. Nature 219 (5153), 515-517 (1968).

References
Med Act (Drugs of Today) 6 (5), 177-178 (1970). (Review)

76

Fenclexonium Methylsulfate (Rec INN) HOE 019

Synthesis
Several methods have been described .
1-4

Fenclexonii Metilsulfas (lat.) Fenclexonio Metilsulfato (Sp.) 1-[3-(1-Cyclohexenyl)-3-phenylpropyl]-1-methyl piperidinium methylsulfate

Description
Crystals mp 265-266 .

Action
Fenclonine is a potent selective inhibitor of serotonin synthesis. In recent experiments its aphrodisiac activity has been investigated in laboratory animals.

Synthesis
Prepared in several steps from benzyl cyanide and cyclohexanone.

Manufacturer
Chas Pfizer and Co (USA)

Description
Crystals, mp 106-107 .

References
1. Judd C. Nevenzel et al. J Am Chem Soc 71,3024 (1949). 2. A. H. Cook et al. J Chem Soc (London)., 1947-54 (1950). 3. J. H. Burckhalter et al. J Am Chem Soc 73, 56 (1951). 4. George H. Cleland. J Org Chem 26, 3362 (1961). 5. Pfizer. Fr pat M 5,734. 6. Science 166 (3911) (1969). 7. Experimental drug makes rats sexy. Med World News 11 (4),20 (Jan 23, 1970). 8. Behavioral effects of serotonin depletion and of pchlorophenylalanine (a serotonin depletor) in rats. J. F. Brody. Psychopharmacologia (Berl) 17, 14-33 (1970). 9. The effect of parachlorophenylalanine on social interaction of male rats. E. E. Shillito. Br J Pharmac 38, 305-315 (1970). 10. Inhibitory effect of p-chlorophenylalanine on the sexual maturation of female rats. A. B. Fajer et al. J Reprod Fert 22, 379-380 (1970). 11. Serotonin Now: Clinical implications of inhibiting its synthesis with para-chlorophenylaline. A. Sjoerdsma et al. An Int Med 73 (4), 607-629 (1970). 12. The effects of p-chlorophenylalanine on behavior: III. Facilitation of brightness discrimination in satiated rats. D. A. Stevens. Life Sci 9 (P 1) 1127-1134 (1970). 13. Effect of para-chlorophenylalanine on basal forebrain stimulation. J. A. Wada and A. Terao. Experimental Neurology 28,501-506 (1970).

Action
Spasmolytic agent.

Manufacturer
Farbwerke Hoechst AG (Germany)

References
1. Anticholinergic effects in relation to chemical constitution in a series of tertiary and quaternary propylamine-derivalives. G. Ehrhart et al. Arzneim Forsch 20 (8), 1094-6 (1970). 2. The influence of HOE 019 on gastric secretion in the rat. G. Aus! and P. A. van Zwieten. Arzneim Forsch 20 (8), 1097-1100 (1970).

Fenclonine (USAN) CP-10188

3-(p-Chlorophenyl)alanine

77
F. D. Hart et al. Ann Rheum Dis 29 (6), 684 (1970). 8. The metabolism of C14-Myalex in various species. An in vivo NIH shift. D. M. Foulkes. J Pharmacal Exp Ther 172,115-121 (1970).

Fenclozic Acid lCI 54,450

2-(4-Chlorophenyl)thiazol-4-ylacetic acid

Fenoxazolin Hydrochloride (Rec INN)

2-(2-lsopropylphenoxymethyl)-2-imidazoline hydrochloride

Synthesis
Prepared from p-chlorothiobenzamide.

Description
Colorless solid mp 155-156 soluble in most ; organic solvents, but only sparingly soluble in water.

Synthesis
Prepared starting by the reaction of 2isopropylphenol with chloroacetonitrile.

Action
Fenclozic acid is one representative of a new class of compounds, which exhibit anti-inflammatory, analgesic and antipyretic effects. Preliminary clinical trials have shown the drug to be effective in the treatment of rheumatoid arthritis in man.

Description
White or almost white, odorless, crystalline powder with a bitter taste, mp 134-135 Soluble in water, . insoluble in benzene and ether.

Manufacturer
Imperial Chemical Ind, Ltd (England)

Action and Uses

Fenoxazolin, a new imidazoline compound, causes vasoconstriction when applied topically to the nasal mucosa. It is used as nasal decongestant.

Proprietary Name
Myalex

References
1. Brit pat 1,099,389. 2. W. Hepworth et al. Nature (London) 221, 582-583 (1969). 3. Pharmacology of fenclozic acid; a new compound with antiinflammatory, analgesic and antipytetic activity. B. B. Newbould. Brit J Pharmacal 35 (3),487-497 (1969). 4. Evaluation in man of fenclozic acid. Serum concentration studies. T. M. Chalmers et al. Ann Rheum Dis 28 (6), 590 (1969). 5. II. Clinical trial in patients with rheumatoid arthritis. T. M. Chalmers et al. Ann Rheum Dis 28 (6), 595 (1969). 6. Fenclozic acid Lancet 1 (7648), 662 (1970). 7. Hepatic effects of fenclozic acid.

Supplied as
Solution (spray), 10 mg/10 ml.

Proprietary Name
Snup

Manufacturer
Karlspharma (Germany)

References
1. L Dausse SA, Fr pat 1,312,410. 2. Med Act (Drugs of Today) 6 (1), 19-21 (1970).

78
14-Deoxylagosin 3,5,7,9,11,13,15,26,27Nonahydroxy-2-(1-hydroxyhexyl}-16-methyl16,18,20,22,24-octocosapentaenoic acid 1,27lactone. 4,6,8,10,12,14,16,27-Octohydroxy-3-(1-hydroxyhexyl)-17,28-dimethyloxacyclooctacosa17,19,21,23,25-pentaen-2-one

Fezatione (Rec INN)

3-[(p-Methylbenzylidene)amino]-4-phenyl-4thiazoline-2-thione

Synthesis
Prepared by the condensation of 4-phenyl-3aminothiazoline-2-thione with p-tolualdehyde.

Production
Antibiotic produced by Streptomyces filipinensis

Description
Light yellow needle-crystalline powder, mp 120-126 (dec) Freely soluble in chloroform and acetone, slightly soluble in ethanol and practically insoluble in water.

Description
Yellow, feathery, needles, mp 195-205 .

Action and Uses

Fezatione is active against bacteria, yeasts and fungi. It is used for the treatment of trichophytia.

Action
Filipin is an antifungal antibiotic. Recently, it has also shown to block cholesterol assimilation by the insects and to be effective against cereal leaf beatles.

Toxicity
LD50 po in mouse and rat> 10,000 mg/kg.

Toxicity
LD50 ip in mice: 17 mg/kg.

Manufacturer
Takeda Chemical Industries Ltd (Japan)

Manufacturer
The Upjohn Co (USA)

Proprietary Name
Polydin

References
1. Whitfield et al. J. Am. Chem. Soc. 77, 4799 (1955). 2. Golding-Rickards. Tetrahedron Letter 2615 (1964). 3. US pat. 3,188,272. 4. Chem. Week 107 (25), 60 (1970).

Supplied as
Ointment and solution 2%.

References
1. Takeda Chemical Industries Ltd. Jap pat 3382 (,67). 2. Jap Med Gaz 7 (9), 9 (1970).

Flavodate Disodium Filipin (Rec INN) Filimarisin. NSC 3364

Filipinum (Lat). Filipina (Sp) [( 4-0xo-2-phenyl-4H-1-benzopyran-5,7-diyl)dioxy] diacetic acid disodium salt 5,7-Flavone-bis (oxyacetic acid) disodium salt

79
2,3-Dihydroxypropyl N-[8-(trifluoromethyl)-4quinolinyl] anthranilate

Flavodate is chemically related to rutin and quercetin.

Synthesis
By reaction of 5,7-dihydroxy-flavone with bromoacetic acid in alkaline solution a mixture of 5,7-flavone-bis (oxyacetic) acid and 5-hydroxy-7flavonoxyacetic acid is obtained. The difference of solubility of the ammonium salts permit the 1 separation of the two acids . Flavodic acid melts at about 280 .

Synthesis
Prepared by condensing 2,2-dimethyl-4hydroxymethyl-1,3-dioxolan with 4-[(omethoxycarbonyl)phenyl] amino-8trifluoromethylquinoline and subsequent hydrolysis of the resulting aceton ketal.

Action and Uses

Flavodate disodium, a new flavone derivative, protects the capillaries, increasing their resistance and hence reducing their permeability. The main indications for use of flavodate are:arteritis, varicose vein, capillaritis, ulcus cruris, hemorrhoids, cerebral and peripheral vascular disorders.

Description
Colorless crystals, mp 179-180 (methanol). Soluble in alcohols, acetone; slightly soluble in ether and chloroform, and insoluble in water.

Action
Analgesic and anti-inflammatory. It differs from glafenine in having a 8-trifluoromethyl group instead of a 7-chloro.

Dosage
In acute cases, 600 to 800 mg daily; in prolonged treatment, 300 to 600 mg daily.

Manufacturer
Roussel Uclaf (Fance)

Supplied as
Gelules, 100 mg.

References
1. WHO Chron 24 (9), 423 (1970). 2. Roussel-Uclaf. Ger Offen 1,815,467.

Proprietary Name
Intercyton

Manufacturer
Lab Roland-Marie (France)

References
1. M. R. Blaise. Fr Addn 80,122. 2. Med Act (Drugs of Today) 6 (3), 8284 (1970). (Review)

Flucloxacillin BRL 2039 FK 900

6-[3-(2-Chloro-6-fluorophenyl)-5-methyl-4isoxazolecarboxamidoj-3,3-dimethyl-7-oxo-4-thia-1azabicyclo[3,2,0] heptane-2-carboxylic acid 3-(2'-Chloro-6'-fluorophenyl)-5-methyl-4isoxazolylpenicillin

Floctafenine (Prop INN)

Floctateninum (Lat). Floctatenina (Sp) N-[8-(Trifluoromethyl)-4-quinolinyl]anthranilic acid 2,3-dihydroxypropyl ester

80

Flucrylate (USAN) BA 4197 MBR 4197

Flucrilate (Rec INN). Flucrilatum (Lat). Flucrilato (Sp) 2,2,2-Trifluoro-1-methylethyl 2-cyanoacrylate

Synthesis
Prepared by reacting 6-amino-penicillanic acid with 3-(2'-chloro-6'-fluorophenyl)-5-methylisoxazole-4carbonyl chloride.

Action and Uses

Flucloxacillin is a new isoxazolyl penicillin. Like cloxacillin it is acid stable and well absorbed after oral administration, and earlier work has shown that serum levels are twice as high as those obtained after an equivalent oral dose of cloxacillin. Flucloxacillin is active against staphylcocci, streptococci and pneumococci. It is stable to staphylococcal penicillinase. Indications; Infections due to sensitive gram-positive organisms, including infections affecting skin, respiratory tract, and ear, nose and throat.

Action
Flucrylate is a new fluoroalkyl cyanoacrylate surgical adhesive. In both rodent and dog experiments, this substance has proved to have high bond strength, good handling properties, improved flexibility, and good hemostasis.

Manufacturer
Minnesota Mining and Mfg Co (USA)

Dosage
Orally or intramuscularly: Adults, 250 mg four times a day Children (2 to 10 years), half the adult dose; (under 2 years), one quarter the adult dose. In severe infections, dosages may be safely increased. Oral doses should be taken one hour before meals.

References
1. JAMA 210, 713 (1969). 2. WHO Chron 24 (11), 529 (1970). 3. A new fluoroalkyl cyanoacrylate surgical adhesive. R. A. Nelson et al. Arch Surg 100,295-298 (1970).

Supplied as
Capsules and vials, 250 mg (flucloxacillin, as the monohydrate of the sodium salt).

Flufenisal (USA; Rec INN) MK835

Flufenisalum (Lat) 4'-Fluoro-4-hydroxy-3-biphenyl carboxylic acid acetate 2-Acetoxy-5-(4-fluorophenyl) benzoic acid

Manufacturer
Beecham Research Laboratories (England)

Proprietary Name
Floxapen

References
1. Beecham Research Laboratories. Brit pat 978,299. 2. Med Act (Drugs of Today) 7 (1), 18-21 (1971). (Review with 5 references)

Synthesis
Prepared by the reaction of 4-(4'fluorophenyl)phenol with potassium carbonate and carbon dioxide at 175 C under pressure, and

81
subsequent acetylation with acetic anhydride and pyridine at 100 .

Description
White crystalline powder, mp 206 Very slightly soluble in water. []D =300 (in chloroform); UV max 234 m [=15,600].

Description
Crystals, mp 134-137 (benzene).

Action
Flufenisal is related to aspirin structurally and pharmacologically. In most tests for analgesia in animals, flufenisal administered orally has been found to be twice as potent as aspirin and in equianalgesic doses appeared to produce substantially longer periods of analgesia. In a recent clinical study, it has been suggested that in some clinical conditions the drug may be effective in providing prolonged pain relief.

Action and Uses

Flumedroxone is useful as a prophylactic treatment for migraine.

Dosage
5 to 20 mg daily.

Supplied as
Sugar coated tablets, 10 mg.

Manufacturer
Merck Sharp and Dohme (USA)

Proprietary Names
Demigran

References
1. JAMA 209, 2044 (1969). 2. WHO Ch,on 24 (11), 530 (1970). 3. Merck and Co, Inc. S African Appl 67 01,021. 4. Analgesic efficacy of flufenisal in patients with episiotomy pain. S. Bloomfield et al. Fed Proc 29 (2), 686 (1970). 5. Clinical evaluation of flufenisal. a long-acting analgesic. S. Bloomfield et al. Clin Pha,mac The, 11 (5), 747754 (1970).

Manufacturer
Leo (Sweden, Denmark, Germany and Austria)

References
1. Lovens Kemiske Fabrik. Brit pat 905,694. 2. Med Act (Drugs of Today), 6 (5),178-181 (1970). (Review with 11 references)

Flunarizine (USAN; Ree INN) Flumedroxone (BAN; Rec INN) WC 537

17-Hydroxy-6-(trifluoromethyl)-pregn-4-ene-3,20dione acetate 6-Trifluoromethyl-17-acetoxyprogesterone .

R 14,950
Flunarizinum (Lat). Flunarieina (Sp) 1-Cinnamyl-4-[bis(p-fluorophenyl) methyl] piperazine

Action
Vasodilator

Synthesis
Flumedroxone is prepared in several steps from 17-acetoxyprogesterone.

Manufacturer
Janssen Pharmaeeutiea (Belgium)

82

References
1. WHO Chron 24 (11). 530 (1970). 2. JAMA 212. 466 (1970) .

Fluocinonide (USAN; Prop INN)

The former USAN for this compound was fluocinolide

Flunidazole (USAN) 5 NI
Flunidazol (Rec INN). Flunidazolum (Lat) 2-(p-Fluorophenyl)-5-nitro-imidazole-1-ethanol 1-(2-Hydroxyethyl)-2-(p-fluorophenyl)-5nitroimidazole

6,9-Difluoro-11,16,17,21-tetrahydroxypregna1,4-diene-3,20-dione, cyclic 16,17-acetal with acetone, 21-acetate 16,17-lsopropylidene 6fluorotriamcinolone Fluocinolone acetonide acetate

Synthesis
Prepared by the reaction of 2-(p-fluorophenyl)-4(5)nitroimidazole with ethylene oxide in anhydrous acetic acid by means of boron trifluoride ethearate. Also, by the reaction of 2-(p-fluorophenyl)-4( 5)nitroimidazole with -ethoxyethyl tosylate at 170-5 , followed by hydrolysis of the reaction product with sulfuric acid at 100.

Synthesis
6-Fluorotriamcinolone is allowed to react with acetone in the presence of strong bases; the resulting 16,17-acetonide is treated with acetic 3 anhydride .

Action
Fluocinonide is a glucocorticoid.

Description
Crystals, mp 165-168 (benzene).

Manufacturer
Syntex Laboratories Inc (USA)

Action
Flunidazole is an antitrichomonal compound, which is rapidly absorbed in both man and dog after oral administration.

Proprietary Name
Lidex

Manufacturer
Merck Sharp and Oohme (USA)

References
1. JAMA 214, 1693 (1970). 2. WHO Chron 25 (3), 133 (1971). 3. US pat 3,197,469. 4. B. J. Poulsen et al. J Pharm Sci 57 (6), 928-933 (1968).

References
1. Merck Co, Inc. Belg pat 660,836; US pat 3,349,096; Neth Appl 6,605,106. 2. Excretion and metabolism of 1-(2-hydroxyethyl)14 2-(p-fluorophenyl)-5-nitroimidazole-2-C in rat, dog and human. A. G. Zaechei et al. Fed Proc 29 (2), 677 (1970).

83

Flurazepam Dihydrochloride (Prop INN) RO 5-6901 Fluspirilene (USAN; Rec INN) R 6218 McN-JR-6218
8-[4,4-bis( p-Fluorophenyl)-butyl]-1-phenyl-1,3,8triazaspiro [4,5] decan-4-one 7-Chloro-1-[2-(diethylamino) ethyl]-5-(ofluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2one dihydrochloride

Synthesis
Prepared from 7-chloro-5-(o-fluorophenyl)-1,3dihydro-2H-1,4-benzodiazepin-2-one dihydrochloride.

Description Description
Pale yellow, crystalline compound, mp 190-220 . Freely soluble in alcohol and very soluble in water. White to yellowish amorphous or crystalline solid, mp 187.5-190 It is almost insoluble in water. .

Action Action and Uses

Flurazepam dihydrochloride, a new benzodiazepine derivative, is a hypnotic agent useful in all types of insomnia characterized by difficulty in falling asleep, frequent nocturnal awakenings and/or early morning awakening. Fluspirilene belongs to a new class of neuroleptic agents, the diphenylbutyl-piperidines, and has been extensively tested pharmacologically in animals where it has been found to be a potent and incisive neuroleptic. The drug is under clinical studies as a long-acting neuroleptic.

Supplied as
Capsules, 15 mg and 30 mg.

Manufacturer
Janssen (Belgium); McNeil Laboratories (USA)

Dosage
The usual adult dosage is 30 mg before retiring.

Proprietary Name
IMAP-7

Proprietary Name
Dalmane

References
1. JAMA 211, 2148 (1970). 2. Janssen Pharm. US pat 3.238.216. 3. The pharmacology of fluspirilene (R 6218), a potent, long-acting and injectable neuroleptic drug. P. A. J. Janssen et al. Arzneim-Forsch 20 (11), 1689-1698 (1970). 4. Clinical evaluation of fluspirilene (R 6218), A long acting injectable neuroleptic. P. Sterkmans et al. elin Trials J 6, 19-25 (1969). 5. Experience with fluspirilene (R 6218). a longacting neutoleptic. J. H. Van Epen. Psychiat Neurol Neurochir 73, 277284 (1970). 6. Clinical study of an injectable long-acting neuroleptic agent: Fluspirilene (R 6218). L. A. Onkenhout and W. Scheffer. Psychiat Neurol Neurochir 73, 285-291 (1970).

Manufacturer
Roche Lab (USA)

References
1. F. Hoffmann La Roche. Neth Appl 6,401,335. 2. Med Act (Drugs of Today), 6 (6). 216 (1970). (Review with 7 references) 3. Metabolism of flurazepam, a benzodiazepine in man and dog. M. A. Schwartz and E. Postma. J Pharm Sci 59 (12), 1800-1806 (1970).

84
7. Joint clinical study of the long-term neuroleptic drug fluspirilene. H. Immich et al. Arzneim-Forsch 20 (11), 1699-1701 (1970).

Formocortal
3-(2-Chloroethoxy)-9-fluoro-11,16,17,21-tetra hydroxy-20-oxo-pregna-3,5-diene-6carboxaldehyde, cyclic 16,17-acetal with acetone, 21-acetate

Flutiazin (USAN; Rec INN)

Flutiazinum (Lat). Flutiazina (Sp) 8-(Trifluoromethyl)phenothiazine-1-carboxylic acid

Synthesis
Prepared in two steps from 9-fluoro- -pregnen11,16,17,21-tetrol-3,20-dione-16,17-acetonide21-acetate, the last one being the reaction of 3-(2'3,5 chloroethoxy)-9-fluoro- -pregnadien11,16,17,21-tetrol-20-one-16,-17-acetonide-21acetate with dimethylformamide and phosphorus oxychloride.
4

Synthesis
Prepared by the reaction of 3-amino-4-mercaptobenzotrifluoride with potassium carbonate and 2bromo-3-nitrobenzoic acid in refluxing dimethylformamide.

Description Description
Crystals, mp 248-250 The ethyl ester melts at 95. 96 . White crystalline powder, mp 180-182 (etherpetroleum ether). UV max 217 m [=12,100] and 323 m. [=17,100] in ethanol. []D = 260 (c=1 in chloroform).

Action
Flutiazin is a new anti-inflammatory agent for veterinary use.

Action and Uses

Formocortal is a new highly active topical antiinflammatory agent, just marketed in England and Italy. The clinical indications are those of other topical anti-inflammatory steroids.

Manufacturer
Smith Kline and French Laboratories (USA)

References
1. JAMA 209, 926 (1969). 2. WHO Chron 24 (11), 530 (1970). 3. Smith Kline and French. Brit pat 1,085,926. 4. Some anti-inflammatory properties of 8trifluoromethylphenothiazine-carboxylic acid. H. Birnie et al. Med Pharmac Exp 17 (1), 51-59 (1967).

Supplied as
Cream, ointment, lotion and spray, 0.025%. Also, cream: formocortal, 0.025% and amminosidine, 0.5%.

Manufacturer
Farmitalia

Proprietary Names
Fluderma and Deflamene.

References
1. Societa Farmaceutica Italia. Brit pat 1.059.603. 2. Mad Act (Drugs of Today) 7(1). 22-23(1971). (Review)

85
9. V. Evaluation in mice. A. Kathrine Miller et al. Antimicrob Agents Chemother-1969, p 310-315 (1970). 10. Pharmacodynamics of phosphonomycin after intravenous administration in man. E. L. Foltz and H. Wallick. Antimicrob Agents Chemother-1969, p 316-321 (1970). 11 . Pharmacodynamics of Phosphonomycin aftel olal administration in man E. L. Foltz et al. Antimicrob Agents Chemother1969, p 322-326 (1970). 12. Preliminary clinical trials with phosphonomycin. W. J. Holloway et al. Antimicrob Agents Chemother1969, p 327-331 (1970) . 13. Clinical pharmacology and in vitro activity of phosphonomycin. D. G. Kestle and W. M. M. Kirby. Antimicrob Agents Chemother-1969. p 332-337 (1970). 14. Evaluation of phosphonomycin. a new cell wallactive antibiotic. H. Clark et al. Antimicrob Agents Chemother-1969, p 338-342 (1970) 15. Acute gonococcal urethritis: Failure of response to phosphonomycin therapy. P. M. Southern et al. Antimicrob Agents Chemother1969, p 343-345 (1970). 16. Activity of phosphonomycin in nasal carriers of coagulase-positive staphylococci. J. W. Smith and J. P. Sanford. Antimicrob Agents Chemother-1969, p 346-348 (1970). 17. Efficacy of phosphonomycin in treatment of urinary-tract infections. J. A. Barnett et al. Antimicrob Agents Chemother1969 p 349-351 (1970).

Fosfomycin (USAN; Prop INN) MK 955

Phosphonomycin (-)-cis-1 ,2-Epoxypropyl phosphonic acid

Production Fosfomycin is a new antibiotic produced by several species of Streptomyces. Description

The calcium salt (C3H5O4PCa.H2O) is a crystalline powder, mp up to 250 ; soluble in water (7 mg/ml); []D=3.8 (c = 7, in water).

Action
Fosfomycin appears to be a promising broad spectrum antibiotic, effective orally and parenterally against various gram-negative and grampositive bacteria. It is under clinical studies.

Manufacturer
Fosfomycin is a development of Merck Co (USA) in co-operation with Compania Espanola de Penicilina y Antibioticos SA (Spain)

Fubromegan
Diethyl (3-hydroxybutyl) methylammonium iodide, 5bromo-2-furoate 1-Methyl-3-diethylaminopropyl-5-bromofuroate methyl iodide -Methyl--(diethylamino) propyl 5-bromofuran-2carboxylate methyl iodide

References
1. JAMA 214, 1693 (1970) . 2. WHO Chron 25 (3), 134 (1971) . 3. D. Hendlin et al. Science 166, 122 (1969) . 4. Fosfomycin: isolation from fermentation sources. L. Chaiet et al. J Antibiotics 23 (7). 336-347 (1970). 5. Phosphonomycin I. Discovery and in vitro biological characterization. E. O. Stapley et al. Antimicrob Agents Chemother1969, p 284-290 (1970). 6. II. Fermentation studies. M. Jackson and E. O. Stapley. Antimicrob Agents Chemother-1969, p 291-296 (1970) . 7. III. Evaluation in vitro. D. Handlin et al. Antimicrob Agents Chemother1969, p 197-302 (1970) . 8. IV. Susceptibility testing method and survey. S. B. Zimmerman et al. Antimicrob Agents Chemother-1969, p 303-309 (1970).

Action
Fubromegan is used clinically for bronchial asthma and gastric ulcers. Recent pharmacological studies have shown the drug to have a broader profile of antiarrhythmic activity than procainamide.

86
Antiarrhythmic properties of fubromegan on various types of experimental arrhythmias. Colorless needles, which decomposeat 154-155 . UV absorption max 290 m [=5,500].

References
V. M. Samvelyan and M. V. Lvov. Farmakol Toksikol. 33 (3). 309-313 (1970).

Action
Funiculosin is a new antifungal antibiotic.

References
Jap. Med Gazz. 7 (4), 12 (1970).

Fumigachlorin
Production
From the fermentation broth of a fungus, identified as Sartorya fumigata var spinosa (Aspergillus ficheri var spinosus).

Gamolenic Acid (Rec INN)

Acidum gamolenicum (Lat). Gamolenico acido (Sp) cis,cis,cis-6,9,12-octadecatrienoic acid -Linolenic acid

Description
Colorless needles, mp 112-113 [ ]D = -77.5 (c=1, . in chloroform). UV max 238 m [E(1%, 1 cm) = 383], 273 m [E(1 %, 1 cm) = 225] and 325 m [E(1 %, 1 cm) = 217].

Action
Fumigachlorin is a new antibiotic which is principally active against filamentous fungi, but inactive against yeasts and bacteria.

Synthesis
By hydrogenation of the corresponding acetylenic 2 acid in the presence of a selective catalyst .

Toxicity
LD50 po in mice: 18.5 mg/kg; ip: 4.6 mg/kg.

Action
Gamolenic acid is an essential fatty acid.

Manufacturer
Toyo Jow Co, Ltd (Japan)

References
1. WHO Chron 24 (11), 526 (1970). 2. Roche Products Ltd. Brit pat 859,897. 3. J. M. Osbond et al. Proc Chem Soc, 221 (1960). 4. J. M. Osbond et al. J Chem Soc, 2779 (1961).

References
Fumigachlorin a new antifungal antibiotic. K. Atsumi et al. J Antibiotics 23 (4), 223-224 (1970).

GC 4072 Funiculosin
Production
Obtained from the fermentation of Penicillium funiculosum, lAM 7013 strain.

SD 7859

ENT

24969
Chlorfenvinphos Diethyl-1-(2,4-dichlorophenyl)-2-chlorovinyl phosphate

Description

87

Description
Yellow needles, mp 252-255; []D = +55 (c=0.638 in chloroform).

Action
Geldanamycin is a new antibiotic which is moderately active in vitro against protozoa, bacteria and fungi.

Description
Light amber-colored liquid with a density of 1.345 and bp 167-170 (0.5 mm). It is soluble in most organic solvents and sparingly soluble in water.

Manufacturer
The Upjohn Co (USA)

References
1 . Geldanamycin, a new antibiotic. C. DeBoer et al. J. Antibiotics 23 (9), 442-447 (1970).

Action
GC 4072 is a new organophosphate pesticide. Toxicologic studies on this compound have been undertaken in several animal species to characterize toxicity and assess safety.

Manufacturer
Allied Chemical Co (USA)

Genimycin
Production
Genimycin is a new antibiotic isolated from the fermentation materials of a soil culture, which has been isolated and classified as belonging to the germs of Actinosporangium.

References
1 . US pat 3,003.916. 2. Toxicologic studies on diethyl-1-(2.4dichlorophenyl)-2-chlorovinylphosphate. A. M. Ambrose et al. Toxicol Appl Pharmacol 17, 323-336 (1970).

Action
Genimycin possesses antifungal activity.

Toxicity
LD50 ip in mice: 17 mg/kg.

Geldanamycin
Manufacturer
Leningrad Institute for Antibiotics (USSR)

References
Genimycin, iI membero f a new group of antifungal pentaenic antibiotics. L. Va. Severinets et al. Antibiotiki 15, 5-9 (1970).

Production
It has been discovered in the culture filtrates of Streptomyces hygroscopicus var geldanus, var nova.

Germine-3-acetate GMA MK-981

88
tetradecahydro-10,13-dimethyl-3Hdicyclopropa[1,2:16,17] cyclopenta [] phenanthren3-one 4,6 6-Chloro-1,2:16,17-bis methylene- pregnadiene-3,20-dione 6-Chloro-dicyclopropa [1,2:16,17]-6-dehydroprogesterone

Synthesis
Prepared by esterification of the natural alkaloid 1 germine .

Description
Needles, mp 219-221 (ether); [ ]D = +100 (c=1.05 in pyridine).

Synthesis
The reaction of 1,2--methylene- pregnatriene3, 20-dione with trimethylsulfoxonium iodide and sodium hydride in dimethylsulfoxide, or with diazomethane in ether-methylene chloride gives an intermediate which is allowed to react with mchloroperbenzoic acid in etherethylene chloride giving an epoxide derivative which in turn reacts first with dry hydrogen chloride in anhydrous acetic acid, then with refluxing collidine, and finally with potassium hydroxide in refluxing methanol to give 64,6 chloro-1,2:16,17-bis methylene- -pregnadiene3,20-dione.
4,6,16

Action
Germine-3-acetate has been found to have typical veratrinic effects in frog and cat neuromuscular preparations but relatively little effect on the central nervous and cardiovascular systems. The neuromuscular pharmacology of the drug has been recently described. It has proved to be useful in the treatment of myastenia gravis and neuromuscular disorders.

Manufacturer
Merck (USA)

Description
Crystals, mp 231-232 (ethyl acetate). UV max 282 m [ = 17,100] in methanol.

References
1. S. M. Kupchan and C. R. Narayanan. J Am Chem Soc 81,1913-1924 (1959). 2. The neuromuscular pharmacology of germine-3acetate and germine 3.16-diacetate. F. G. Standaert and P. B. Detwiler. J Pharmacol Exp Thar 171,223-241 (1970) . 3. The effects of germine monoacetate in patients with myasthenia gravis. W. Flacke and R. P. Blume. Fed Proc 29. 194 (1970). 4. Med World News 11 (19), 23 (1970).

Action
Gestaclone is a progestogen.

Manufacturer
Schering AG (West Berlin)

References
1. JAMA 210, 713 (1969). 2. WHO Chrcn 24 (11), 530 (1970). 3. Schering AG. Brit pat 1,095,958.

Gestaclone (USAN; Rec INN) SH 1040

Gestaclonum (Lat). Gestaclona (Sp) 17-Acetyl-6-chloro1,1,2,8,9,10,11,12,13,14,15,16,16,17-

Glydanile Sodium (USAN) SH 1051

Glidanile (Prop INN). Glidanilum (Lat). Glidanilo (Sp)

89
5'-Chloro-2-[p-[(5-isobutyl-2-pyrimidinyl) sulfamoyl] phenyI]-o-acetanisidide monosodium salt

Gougeroxymycin
Production
Obtained from thefermentation culture of a streptomyces, strain MA 428 CI, which resembles Streptomyces gougeroti.

Action
Glydanile sodium is a new oral hypoglycemic drug.

Manufacturer
Schering AG (Germany)

Description
White powder, mp 103-105 .

References
1. JAMA 210, 714 (1969). 2. WHO Chron 24 (3), 129 (1970). 3. Schering AG. S African Appi 6806,929,

Action
Gougeroxymycin is a new antifungal antibiotic.

References
Jap Med Gazz 7 (4), 6-7 (1970).

Go 2825
2-(1-Piperidino)-2-(2-thenyl) ethylamine maleate

HA 966
3-Amino-1-hydroxy-2-pyrrolidinone 1-Hydroxy-3-amino-2-pyrrolidinone

Description
Colorless crystalline substance, mp 115-117 ; soluble in water at pH 6-7 and in alcohol.

Synthesis
Prepared by cyclization of -bromo, -p-tosyloxy-,or -mesyloxy--aminobutylhydroxamic acid with LiOH. Also by reaction of -chloro--aminobutyric acid methyl ester with hydroxylamine, followed by cyclization with a base.

Action
Go 2825 has been found to possess an antidepressant property. The toxicopathological effects of the compound in laboratory animals have been evaluated.

Description Crystals, mp 182-183 (ethanol). Action HA 966 possesses muscle-relaxant,

tranquillizing and anticonvulsant effects. It has been shown to produce effects similar to those ascribed to L-dopa in patients with extrapyramidal disorders.

Manufacturer
Ciba Pharmaceutical Co (USA)

References
Toxicopathologic studies of a piperidino thenyl ethylamine (ClBA Go 2825). R. Rao Rupanagudi et al. JET (2), 110-115 (1970).

Manufacturer
Organon (Holland)

90
3. Haloprogin: a topical antifungal agent. E. F. Harrison et al. Appl Microbiol19 (5), 746-750 (1970).

References
1. N. V. Organon. Belg pat 629,596 and 660,704, 2. HA 966. I Behaviour and motor effects. I. L. Bonta et al. Arch int pharmacodyn 182 (2), 391393 (1969). 3. HA 966. II Extrapyramidal aspects. I. L. Bonta et al. ibid 182 (2),394-395 (1969). 4. HA 966, III, Neurochemical aspects. F. C. Hillen et al. ibid 182 (2), 396-397 (1969). 5. HA 966 IV Clinical aspects. K. H. M. Van Der Velden. ibid 182 (2), 398 (1969).

Harpagoside

Haloprogin M 1028
3-lodo-2-propynyl-2,4,5-trichorophenyl ether 2,4,5-Trichlorophenyl--iodopropargyl ether Isolation 1,2 From the roots of Harpagophytum procumbens .

Description
Colorless hygroscopic powder, with bitter taste, mp 116-121 UV max 215.5 m (lg = 4.19), 221.5 m . (Ig = 4.12) and 276 m (Ig = 4.36).

Action Synthesis
By Seki et al as part of a series of new acetylenic compounds closely related to capillin and 1 lenamycin . In the granuloma pouch test and in the rabbit ear test for analgesic activity harpagoside has proved to produce an effect similar to phenylbutazone. In contrast to phenylbutazone no activity has been found with the following screening methods: edema of the rat paw produced by ovalbumin, formalin produced edema and formalin-induced arthritis.

Description
Crystals, mp 113-114 .

References
1. H. Licht; et al. Tetrahedron Letters 15, 835-843 (1964). 2. H. Lichti et al. Helv Chim Acta 49 (5), 1552-1580 (1966). 3. On the antiphlogistic, analgesic and spasmolytic effects of harpagosid a glycoside from the root of harpagothytum procumbens DC. O. Eichler and Ch Koch. Arzneim-Forsch 20 (1), 107-109 (1970).

Action
Haloprogin possesses potent antifungal activity both in vitro and in vivo. Its spectrum of activity also includes yeast, yeastlike fungi, and grampositive bacteria. Based on its broad spectrum of antimicrobial activity, haloprogin may prove to be a superior topical agent in the treatment of dermatophytic and monilial infections in man.

Manufacturer
Meiji Seika Kaisha Ltd (Japan)

Proprietary Name
Halotex (Mead Johnson, USA); Polik (Meiji Seika Kaisha, Japan)

Homprenorphine (BAN, Prop INN) R&S 5205-M

22-Cyclopropyl-7-((R)-1-hydroxy-1-methylpropyl)6,14-endo-ethenotetrahydrothebaine

References
1. S. Seki et al. Agr BioI Chem (Tokyo) 27, 150-151 (1963). 2. S. Seki et al. Antimicrob Agents Chemother 569572 (1963).

91

Action
Hoquizil hydrochloride is a new oral bronchodilator, which has been discovered as a metabolite of CP12,521-1 (the corresponding isobutylester). The bronchodilator effects of the drug are the result of direct relaxation of respiratory smooth muscle.

Manufacturer
Chas Pfizer and Co (USA)

Action
Homprenorphine is a new analgesic agent.

References
1. Pfizer Co, Inc. S African pat 67 06,512. 2. Hoquizil-a new 01al bronchodilator. A double blind, randomized, coded clinical study using body plethysmography. B. Scillitani et al. Acta Anaesth Scandinav Suppl 37. 299-302 (1970).

Manufacturer
Reckitt and Sons (England)

References
1. Chem Drug 194, 446 (1970). 2. WHO Chron 25 (3), 135 (1971). 3. N. Schmiedeberg. Arch Exp Path 259 (2), 154 (1968).

HS 2314
4-(3,4-Dihydro-2-phenyl-1-naphthyl)-1methylpiperidine 1-(4-Methylpiperidino)-2-phenyl-3, 4dihydronaphthalene

Hoquizil Hydrochloride (USAN) 1

4-(6,7-Dimethoxy-4-quinazolinyl)-1piperazinecarboxylic acid 2-hydroxy-2-methylpropyl ester hydrochloride

CP14,185-

Synthesis
Starting by a Grignard reaction of 2-phenyltetralone with 4-chloro-N-methyl piperidine. The free base melts at 118-119 the hydrochloride salt at 258; 262 .

Action
Sedative, tranquilizer.

Synthesis
Prepared from 4-chloro-6,7-dimethoxy-quinazoline.

Manufacturer
Merck AG (Germany)

Description
Crystals, mp 199-200 (chloroform-ethylacetate).

References
1. E. Merck AG. Neth Appl 6.413.199. 2. G. Sierra et al. Int J Neuropharmacol B (2). 153160 (1969).

92
3. Effects of different sedatives on self-ratings depending on sex and personality. P. Mikus. Arzneim-Forsch 20 (9 ). 1235-1238 (1970). 7. Preliminary clinical trials with hycanthone, a new antischistosomal agent. N. Katz et al. Arner J trop Med Hyg 17 (5), 743-746 (1968). 8. Further clinical trials with hycanthone, a new antischistosomal agent. N. Katz et al. Arner J trop Med Hyg 18 (6),924-929 (1969). 9. The uptake of tritiated hycanthone by male and female schistosoma mansoni worms and distribution of the drug in plasma and whole blood of mice following a single intramusculat injection. A. Yarinsky et al. Bull Org rnond Sante 42, 445-449 (1970).

Hycanthone Hydrochloride (USAN)

Hycantone (Rec INN) 1-[[2-(Diethylamino) ethyl] amino] 4(hydroxymethyl) thioxanthen9one

Win 24933

Production
By the fermentation of 1(2diethylaminoethylamino)4methylthioxanthen9one with Aspergillus sclerotiorum (SWRI A26) in an appropriate culture medium.

Hydrocortisone 17-Butyrate

Description
Orangeyellow microcrystals, mp 173-176 (dec). The free base melts at 92.5-95.4.

Action
Hycanthone has been reported to be schistosomicidal in the mouse, hamster and 2,3,4 5-8 monkey . The drug is under clinical trials .

Action
Hydrocortisone 17-butyrate, a simple nonfluorinated modification of hydrocortisone, shows remarkable skin penetration and offers promise as a dermatological corticosteroid.

Manufacturer
Sterling Winthrop (USA)

References
1. D. Rosi et al. (to Sterling Drug, Inc). US pat 3,312,598_ 2. D. Rosi et al. Nature 208, 1005-1006 (1965). 3. D. A. Berberian et al. Arner J trop Med Hyg 16, 487-491 (1967). 4. J. Pellegrino et al. J Parasit 53, 55-59 (1967). 5. N Katz et al. Arner J trop Med Hyg 17, 743746 (1968). 6. V. V. Clarke et al. Centr Air J Med 15, 1-6 (1969).

Manufacturer
Royal Netherlands Fermentation Industries Ltd (Netherlands)

References
1. Hydrocortisone 17-butyrate, a new corticoid with a favourable ratio of topical vs systemic activity. K. D. Jaitly et al. Third International Congress on Hormonal Steroids, abst 365. Excerpta Medica, International Congress Series No 21 0 (1970).

93
2. Clinical trial with hydrocortisone butyrate. M. K. Polano et al. Br J Derm 83, 93-97 (1970).

Hydrotalcite (Rec INN)

Hydrotalcitum (Lat). Hidrotalcita (Sp) Aluminum magnesium hydroxyde carbonate hydrate

Isolation and Synthesis Description

Synthetic mineral crystalline substance. 25-Hydroxycholecalciferol is one of the biologically active metabolites of vitamin D3, which was extracted from plasma of pigs which had been fed large amounts of regular vitamin D3. The synthesis of 25-HCC was completed by irradiation of cholesta-5,7-diene-3,25-diol.

Action
After oral ingestion, hydrotalcite produces and maintains for a long time, an optimum pH in the gastric juice.

Biological Activity
By antirachitic assay in both rats and chickens, 25HCC has proved to be 1.5 times more biologically active than cholecalciferol. When tested for its ability to stimulate calcium transport, it was not only more effective, but produced a response more rapidly than does a similar dose of vitamin D3. 25-HCC is under clinical study.

Manufacturer
Kyowa Chemical Industry Co, Ltd (Japan)

Proprietary Name
HITI

References
1. WHO Chron 24 (11), 530 (1970). 2. Jap Med Gaz 7 (4), 4 (1970). 3. Process for the preparation of hydrotalcite antacid. Kyowa Chem Industries. US pat 3,539,306.

References
1. J. W. Blunt and H. F. De luca. Biochem 8 (2), 671-674 (1969). 2. Med Act (Drugs of Today) 6 (3), 102-105 (1970). (Review with 7 references) 3. Treatment of vitamin Dresistant hypoparathyroidism with 25-hydroxycholecalciferol. Charles Y. C. Pak et al. Arch Intern Med 126 (2), 239-247 (1970). 4. 25-Hydroxycholecalciff'rol. Effet d'une dose unique chez I'enfant normal. Sonia Balsan et al. Rev Europ Etudes elin Biol15 (5), 515-521 (1970). 5. Treatment of renal osteodystrophy with 25hydroxycholecalciferol. H. F. Deluca et al. Arch Intern Med 126,896-899 (1970).

2 5-HydroxycholecaIciferol

25-Hydroxydihydrotachysterol3

94
L-255 is a spasmolytic agent. Some pharmacodynamic properties of this compound have been recently reported.

Manufacturer
Instituto Biochimico Italiano Sperimentale (IBIS)

References
1. W. Chiti et al. Farmaco (Ed Sci) 15. 809 (1960). 2. Report on some pharmacodynamic properties of 1-(2-piperidinoethyl)-4,4-bis-(p-methoxyphenyl)-2.5imidazolidinedione chlorhydrate (1255). Studies of its effect on the muscular system of duodenum. gall and urinary bladder uterus and trachea. E. Marmo and A. Annunziata. Arzneim-Forsch 20. 277-281 (1970).

Synthesis
By lithium-ammonium reduction of 25hydroxytachysterol,

Action
It is a potent bone mobilization agent. Its biological activity suggests that it may be the drug of choice in the treatment of hypoparathyroidism and other similar bone diseases.

References
25-Hydroxydihydrotachysterol: synthesis and biological activity. T. Sude et al. Fed Proc 29. 367 (1970).

Imidocarb Hydrochloride (USAN; Prop INN) 4A65

Imidocarbum (Lat). Imidocarbo (Sp) 3,3'-di-2-Imidazolin-2-ylcarbanilide dihydrochloride

L-255
1-(2-Piperidinoethyl)-4,4-bis-( p-methoxyphenyl)2,5-imidazolidinedione hydrochloride 3-(1-Piperidino )ethyl-5,5-bis (p-methoxyphenyl) hydantoine hydrochloride

Synthesis
By the reaction of m-aminophenylimidazoline with phosgene in dimethylformamide. The product 3 obtained melts at 370 (dec) .

Action
Antiprotozoal (babesicidal).

Synthesis
Prepared from 4,4-bis (p-methoxyphenyl)-2,5imidazolidinedione and -piperidinoethyl chloride in 1 the presence of sodium amide .

Manufacturer
Burroughs Wellcome (USA)

References
1. JAMA 211,2149 (1970). 2. WHO Chron 24 (9), 424 (1970). 3. Dr A Wander AG. Brit pat 1,007,334. 4. Babesicidal effect of basically substituted carbanilides. II. Imidocarb in rats and mice: toxicity and activity against Babesia rodhaini. E. Beveridge. Res Vet Sci 10 (6), 530 (1969).

Description
Crystals, mp 130 dec. UV max at about 230 and 213 m

Action

95

Indolacin
1-Cinnamoyl-2-methyl-5-methoxy-indolyl-3-acetic acid

Synthesis
Prepared in three steps from 4-aminopyridine and benzoylchloride.

Description
Crystals, mp 208-210 (ethanol).

Action
Indoramin is a new antihypertensive agent.

Synthesis
By the reaction of cinnamoyl chloride with pmethoxyphenylhydrazine hydrochloride and triethylamine in toluene at 5 to 0 and by the , reaction of the resulting intermediate hydrazine hydrochloride with levulinic acid in acetic acid at 8085 .

Manufacturer
Wyeth (England)

References
1. Chem Drug 194, 446 (1970). 2. WHO Chron 25 (3), 135 (1971). 3. Chim Ther 3, 397 (1968). 4. John Wyeth and Brother Ltd. S African Appl 6803,204.

Description
Crystals, mp 164-165 (acetone-water). The ethyl ester, mp 162-163 (acetone-water).

Action
Indolacin exhibits anti-inflammatory, antipyretic and analgesic activities.

Manufacturer
Sumitomo Chemical Co, Ltd (Japan)

Indriline Hydrochloride (Rec INN)

Indrilinum (Lat). Indrilina (Sp) N, N-Dimethyl-1-phenyl-indene-ethylamine hydrochloride 1-(2-Dimethylaminoethyl)-1-phenylindene hydrochloride

References
1. Sumitomo Chemical Co, Ltd. S African Appl 67,02,683. 2. Sogo Rinsho 19, 427 (1970) .

MJ1986

Indoramin (BAN; Prop INN) Wy 21901

3-[2-(4-Benzamido-1-piperidyl) ethyl] indole

96

Synthesis
Prepared by the reaction of sodium 3-phenylindene 2,3 with -dimethylaminoethyl chloride .

References
R. Ikan et al. Israel J Chem 8 Suppl Proc Israel Chem Soc (1970).

Description
White prisms, mp 203-204.5 .

Action
Indriline, a stimulant and antidepressant in the preclinical profile, has no antidepressant properties 4 clinically, although it shows stimulant properties .

Intrazole (USAN; Rec INN) BL-R 743

1-(p-Chlorobenzoyl)-3-(1 H-tetrazol-5-ylmethyl) indole 5-[1-(p-Chlorobenzoyl)-3-indolylmethyl] tetrazole

Manufacturer
Mead Johnson (USA)

References
1. WHO Chron 24 (11). 530 (1970). 2. C. R. Ganellin et al. Chem Ind (London) 28, 12561257 (1965). 3. S. J. Dykstra et al. J Med Chem 10 (3).418-428 (1967). 4. The clinical evaluation of four proposed antidepressants. Relationship to their animal pharmacology. L. J. Hekimian at al. Int Pharmacopsychiat 3. 65-76 (1970).

Synthesis
Prepared by treating 5-(3-indolylmethyl) tetrazole with sodium hydride and p-chlorobenzoyl chloride.

Description
Crystals, mp 233-234 .

Action

Inokosterone

Intrazole is a new non-steroid anti-inflammatory compound.

Manufacturer
Bristol Laboratories (USA)

References
1. JAMA 211,819 (1970). 2. WHO Chron 24 (3), 129 (1970). 3. Bristol Myers Co. Neth Appl 6,609,235. 4. D. R. Van Harken. Pharmacologist 11 (2), 241 (1969).

Description
Screening of Israeli plants for insect moulting hormones (ecdysones) has led to the isolation and identification of inokosterone from Achyrantes species. Insect hormones (phytoecdysones) from Israeli plants.

lOB 82
3-[Bis(2-chloroethyl)amino]-p-toluic acid 4-Methyl-3-N,N-bis(2-chloroethyl) aminobenzoic acid

97

Action Synthesis
Prepared by the reaction of ethyleneoxide with 3amino-3-methylbenzoic acid methyl ester, followed by treatment with phosphorus oxychloride, and hydrolysis of the ester group with hydrochloric acid. New cyclophosphamide cytostatic drug, which has been shown to be effective in clinic.

Manufacturer
Asta-Werke AG (Germany)

Description
lOB 82 melts at 115 (Iigroine).

References
1. WHO Chron. 24 (11), 530 (1970). 2. Results obtained with two new phosphamide derivatives. P. Drings et al. Deutsche Med. Wochenschr. 95 (10),491-497 (1970).

Action
lOB 82, a new cytostatic drug, is an alkylating agent with pronounced antitumor activity on a spectrum of 10 experimental tumors which have varying hystologic structures and degrees of sensitivity. Efficient doses of the drug have been proved to be well-tolerated by the organism.

Toxicity
LD50 ip in rats: 17.4 mg/ kg.

Ipronidazole (Rec INN)

2-lsopropyl-1-methyl-5-nitroimidazole

Manufacturer
Oncological Institute, Bucharest (Romania)

References
1. I. Niculescu-Duyaz et al. J Med Chem 11 (3). 500-3 (1968). 2. Romania, Ministry of the Chemical Industry. Rom pat 51,132, 3. 3-N,N-bis (2-chloroethylamino) p-toluic acid, a new cytostatic drug active in cancer. V. Dobre and G. Maltezeanu. Cancer Chemother Rep (part 1) 54(5), 319-323 (1970).

Synthesis
Prepared by nitration of 2-isopropylimidazole, and by methylation of the resulting nitroimidazole.

Description
White plates, mp 60

Action

Iphosphamide (Rec INN) Z4942

Ifosfamide. Ifosfamidum (Lat). Ifosfamida (Sp) 3-(2-Chloroethyl)-2-(2-chloroethylamino)-tetrahydro2H-1,3,2-oxazophosphorin-2-oxide

Ipronidazole has been reported to be highly effective and well tolerated in the prevention and therapy of turkey histomoniasis. In addition it has proved to be an effective growth promotant for turkeys.

Manufacturer
Hoffmann-La Roche Inc (USA).

References

98
1. Hoffmann-La Roche. Brit pat 1.119.636. 2. Antihistomonal activity of 1.2-disubstituted 5nitroimidazoles. M. Mitrovic et al. Antimicrobial Agents and Chemotherapy. 445-448 (1968). 3. Antihistomonal activity of ipronidazole in turkeys. M. Mitrovic and E. G. Schildknecht. Poultry Sci 49 (1). 86-92 (1970). 4. Toxicity and safety studies with the antihistomonal agent. ipronidazole in turkeys. W. L. Marusich et al. Poultry Sci 49 (1). 92-98 (1970). 5. Ipronidazole. an antihistomonal agent as a turkey growth promotant. W. L. Marusich et al. Poultry Sci 49 (1), 98-101 (1970).

References
1. E. Merck AG. Ger pat 1.159.945. 2. H. J. Karl-L. Raith. Klin Wochenschr 48 (6), 347 (1970).

Isoprinosine NPT 10381

NP 113

Acetamidobenzoate salt of inosinedimethylaminoisopropanol complex (1:3)

Isoprednidene StC 407

11,17,21-Trihydroxy-16-methylene-pregna-4,6diene-3,20-dione 6-Dehydro-16-methylene-hydrocortisone

Action
Isoprinosine is a member of a new class of drugs, inosine-alkylamino alcohol compounds, which are claimed to enhance learning and to act against viruses in animals. The drug is being used in clinical trials.

Toxicity
LD50 in the mouse, rat and cat are greater than 5 g/kg.

Manufacturer
Newport Pharmaceuticals Inc (USA)

References Synthesis
16-Methyl-16,17-oxido-4-pregnen-21-ol-3,20dione 21-acetate is heated with chloranil. The resulting 17,21-dihydroxy-16-methylenepregna-4,6diene-3,20-dione 21-acetate is hydroxylated in the 11-position in a culture of Curvularia lunata. 1. Chem Engin News 48 (22), 12 (25 May, 1970). 2. Med World News, 22 (17 April, 1970). 3. Med World News, 15 (14 August, 1970). 4. Inosine-alkylamino alcohol complexes: enhancement of avoidance learning in rats. B. Doty and P. Gordon. Fed Proc 29 (2), 684 Abs (1970). 5. Inosine-alkylamino alcohol complexes: enhancement of polyribosome function. P. Gordon. Fed Proc 29 (2), 684 Abs (1970). 6. Inosine-alkylamino alcohol complexes: anti-viral actions. E. R. Brown and P. Gordon. Fed Proc 29 (2), 684 Abs (1970). 7. The Pharmacologist 12 (2), 271 abst 389-390 (1970).

Description
Crystals, mp 234-236 (acetone). Ultraviolet absorption maximum at 283 m [=24,900]; []D = +81 (dioxane).

Action
ACTH inhibitor.

Manufacturer
E. Merck A.G. (Germany)

Janiemycin

99

Production
Janiemycin is a new peptide antibiotic produced by a strain of Streptomyces macroporeus isolated from soil.

JB 318
Benzilic acid, 1-ethyl-3-piperidyl ester N-Ethyl-3-piperidyl benzilate N-Ethyl-3-piperidyl diphenylglycolate

Description
Amorphous, light tan powder.

Action
Janiemycin is a bactericidal compound, active primarily against gram-positive bacteria.

Manufacturer
Squibb (USA)

References
Janiemycin a new peptide antibiotic. E. Meyers et al. J Antibiotics 23 (10), 502-507 (1970).

Synthesis
Prepared from N-ethyl-3-chloropiperidine and benzilic acid.

Description

Jatrophone

The free base boils at 194-198 (0.12-0.18 mm Hg). The hydrochloride occurs as a white crystals, mp 186-187 .

Action
The Director of the Bureau of Narcotics and Dangerous Drugs has proposed that JB 318 be listed in the category of depressant or stimulant drugs subjected to control, because of their hallucinogenic effects.

References
1. Lakeside Laboratories, Inc. US pat 2,995,492. 2. J. H. Biel et al. J Am Chem Soc 77, 2250-6 (1965). 3. Fed Reg 35 (47), 4305-4306 (1970).

Isolation
From Jatropha gossypii folia.

JB 336
Benzilic acid, 1-methyl-3-piperidyl ester N-Methyl-3-piperidyl benzilate N-Methyl-3-piperidyl diphenylglycolate

Description
Crystals, mp 152-153 [ ]D = 292 (c=1,23 in ; ethanol). UV max 285 m [=10.200]; sh 225 m.

Action
Jatrophone, a novel macrocyclic diterpenoid, is a tumor inhibitor.

References
1. S. Morris Kupchan et al. Chem Eng News 48 (30), 42 (1970). 2. S. M. Kupchan et al. J Am Chem Soc 92. 4476 (1970).

100

Synthesis
Prepared from N-methyl-3-chloropiperidine and benzilic acid.

Description
The free base boils at 175-176 (0.03 mm Hg). The hydrochloride melts at 212-213 .

Kanendomycin Sulfate NK1006

2'-Amino-2'-deoxy-kanamycin sulfate 4-O[-2',6'-Diamino-2',6'-dideoxy-Dglucopyranosyl(1')]-6-0-[-3"-amino-3"-deoxy-Dglucopyranosyl (1")]-1,3-diamino-1,2,3trideoxymyoinositol sulfate

Action
The Director of the Bureau of Narcotics and Dangerous Drugs has proposed that J B be listed in the category of depressant or stimulant drugs subjected to control, because of their hallucinogenic effects.

References
1. Lakeside Laboratories, Inc. US pat 2.995,492. 2. J . H. Siel et al. J Am Chem Soc 77. 2250-6 (1965). 3. Fed Reg 35 (47).4305-4306 (1970).

K 76
2-Methyl-3-(4-phenylpiperidino) propionohydroxamic acid hydrochloride

Action and Uses

Kanendomycin is a new broad spectrum antibiotic, recently marketed in Japan. It was isolated from the culture medium of mutant strains of Streptomyces kanamyceticus.

Dosage
Kanendomycin Sulfate is administered intramuscularly. Adults, 400 to 600 mg daily in 2 to 3 divided doses. Children, 10 to 20 mg/kg per day in two divided doses,

Supplied as
Vials, 200 mg.

Action
K 76 is a new hypotensive agent. It has been suggested that this compound produces a fall in the blood pressure by blocking sympathetic ganglia.

Manufacturer
Meiji Seika Kaisha Ltd (Japan).

References References
1. -Aminopropionohydroxamic acids and aminopropionic esters with hypotensive properties. R. T. Cautts et al. J Med Chem 12 (5). 940-941 (1969). 2. 2-Methyl-3-{4-phenylpiperidino) propionohydroxamic acid hydrochloride: a new hypotensive agent. K. K. Midha et al. Eur J Pharmacol 11. 48-55 (1970). Med Act (Drugs of Today) 6 (5), 181-182 (1970).

101

Ketamine Hydrochloride (USAN; Rec INN) 581

2-(o-Chlorophenyl)-2-methylaminocyclohexanone hydrochloride

Kethoxal (USAN) CIKetoxal(Rec INN). Ketoxalum(Lat) 3-Ethoxy-1,1-dihydroxy-2-butanone 3-Ethoxy-2-oxobutyraldehyde hydrate

Action Synthesis
The method for producing ketamine involves a rearrangement at 190 of the carbon skeleton of (ochlorophenyl)-(hydroxycyclopentyl)(N-methylimino) methane, which manifests itself in a ring expansion. The compound used in the above reaction is prepared in several steps from o-chlorobenzonitrile and the Grignard reagent prepared from cyclopentylbromide and magnesium. Kethoxal has a broad spectrum of virucidal activity (except for the picornaviruses), and it is also highly active as an inhibitor of intracellular virus multiplication in vitro a nd in vivo.

Manufacturer
The Upjohn Co (USA)

References
1. WHO Chron 24 (11), 530 (1970). 2. Antiviral studies with Kethoxal. H. E. Renis. Ann NY Acad Sci 173 (Art 1), 527-535 (1970).

Description
White crystalline powder, mp 262-263 it is freely ; soluble in water.

Action and Uses

Ketamine, an arycycloalkylamine, is a parenteral anesthetic agent with good analgesic properties.

Ketimipramine (Rec INN; USAN) G 35259

5-[3-(Dimethylamino)propyl]-5,11-dihydro-10Hdibenz[b,f] azepin-10-one

Supplied as
Solution (injection). 11.53 mg/ml (equivalent to 10 mg of ketamine base). Solution (injection) 57.67 mg/ml (equivalent to 50 mg of ketamine base).

Proprietary Names
Ketalar and Ketanest.

Manufacturer
Parke Davis

References
1. Parke Davis Co. Brit pat 1.01.4 ,060. 2. Med Act (Drugs of Today) 6 (2),44-47 (1970). (Review with 21 references)

Synthesis
Prepared by the reaction of 10-methoxy-5H-dibenz [b,f] azepine with 3-(dimethylamino) propylchloride in the presence of NaNH2 followed by the hydrolysis of the methoxy group with HCI.

Description

102
Ketimipramine melts at 87, and boils at 174 (0.005 mm). Betadrenol (Germany).

Action
Ketimipramine is a new antidepressant, closely related to imipramine; it differs from the latter only in having a 10-keto group. Ketimipramine fumarate is under clinical trials, and so far has proved to be largely free of the troublesome side effects sometimes encountered with imipramine.

Supplied as
Tablets, 40 mg.

References
1. Wilhelm Kunz et al. US pat 3,309,406; Brit pat 1.147.032. 2. H. Jacobi and R. Fontaine. Fortschr Med 85, 749 (1967). 3. E. Waterloh et al. Arzneim-Forsch 19 (2). 153-156 (1969). 4. Studies on the myocardial depressant effect of KL 255: a beta adrenergic receptor antagonist. R. G. Pendleton et al. Arch Int Pharmacodyn Ther 187 (1).75-87 (1970).

Manufacturer
J. R. Geigy AG (Switzerland)

References
1. J. R. Geigy AG. Ger pat 1.161,279. 2. Amer Druggist, 41 (Sept 21,1970).

KL 255
1-t-Butylamino-3-(6-chloro-m-tolyloxy)-2-propanol hydrochloride

Ko 592 ICI 45763

1-lsopropylamino-3-m-tolyloxy-2-propanol hydrochloride 1-(3-Methylphenoxy)-2-hydroxy-3-isopropylaminopropanehydrochloride

Synthesis
Prepared from 2-chloro-5-methylphenyl glycidylether and tert-butylamine.

Description
Crystals, mp 120-121 (ethanol/ether).

Description
Crystals, mp 224-225 .

Action
Ko 592 is a new potent and specific beta receptor antagonist, which has been recently marketed in Germany.

Action
KL 255 is a potent beta receptor antagonist both in vitro and in vivo. An analysis of the mechanism for the in vivo myocardial depressant effects of this 4 drug has been reported . It has been suggested that they are due to a blockade of endogenously released catecholamines. The drug has been recently marketed in Germany.

Supplied as
Tablets, 10 and 50 mg.

Manufacturer
C. H. Boehringer Sohn (Germany); ICI Ltd (England)

Manufacturer
Pharma Schwarz GmbH (Germany); Smith Kline and French Laboratories (USA)

Proprietary Name
Doberol (Germany).

Proprietary Name

References
1. C. H. Boehringer Sohn. Neth Appl 6.409,883.

103
2. ICI Ltd. Neth AppI 301.580; Brit pat 1.079.534; Neth AppI 6.410.522. 3. J. V. Levy and V. Richards. Proc Soc Exp Biol Med 122. 373-379 (1966). 4. Cardiopulmonary actions of 1-isopropyl-3-(3tolyloxy)-2-propanol hydrochloride: a new adrenergic beta receptor antagonist. B. R. Madan et al. Indian J Med Res 58. 246-252 (1970). 5. Effects of beta-blocking agent Ko 592 in massive doses upon catecholamines in arterial tissue and plasma and peripheral blood flow in anesthetized dogs before and after electric stimulation of sympathetic ganglia. E. N. Terry et al. J Cardiovasc Surg 11 (2). 146-150 (1970). 6. Wirkungen eines adrenergischen BetaReceptorenb/ockers (KG 592) auf die Atmung. J. Hamm et al. Klin Wschr 48 (8).457-464 (1970).

KT 125
1-(p-Methoxyphenyl)-6,8-dimethylimidazoline[1,2-f] xanthine

Action

Ko 1173
1-(2',6'-Dimethyl phenoxy)-2-aminopropane

KT 125, chemically related to KT 136, shows hypertensive action.

References
Pharmacology of 6,8-dimethylimidazoline-[1,2-fJxanthines. V. V. Viasov and I. V. Komissarov. Farmakol Toxikol 33 (5), 582 (1970).

Synthesis
Prepared by catalytic reduction of 1-(2,6dimethylphenoxy)-2-propanone oxime. The hydrochloride melts at 203-205 .

KT 136
1-Allyl-6,8-dimethylimidazoline[1,2-f]-xanthine

Action
Pharmacological studies have indicated that K 1173 is as effective as phenytoin in experimental cardiac arrhythmias.

Manufacturer
Boehringer, Ingleheim (Germany),

References
1. C. H. Boehringer Sohn. Fr pat 1,551,055. 2. The effect on experimental cardiac arrhythmias of a new anticonvulsant agent, K6 1173, and its comparison with phenytoin and procainamide. J. D. Allen et al. Br J Pharmac 39 (1), 183P (1970).

Action
KT 136 has proved to be a positive inotropic and respiratory analeptic agent

References

104
Pharmacology of 6,8-dimethylimidazoline [1,2]xanthines. V. V. Vlasov and I. V. Komissarov. Farmakol Toxikoi 33 (5), 582 (1970).

Description
Yellow crystalline material, mp 140. Soluble in chloroform, alcohol, benzene and slightly soluble in ether.

Action
Lapachol was first investigated for vitamin K effect and for antimalarial activity. Recently, lapachol has proved to exhibit high antitumor activity against the 3 Walker 256 carcinosarcoma tumor in rats . The toxicology studies conducted prior to the clinical 4 investigation have been reported . The drug is now under clinical study as a cancer chemotherapeutic 5 agent .

L 7108
2-(3,4,5-Trimethoxybenzoyl) isoxazolidine

Toxicity
LD50 po in the male mouse: 487 mg/kg; in the female: 792 mg/kg.

Manufacturer Action
Neurodepressant Chas Pfizer and Co, Inc (USA)

References
1. J Am Chem Soc 49, 857 (1936). 2. J Am Chem Soc 58.1181 (1936). 3. K. V. Rao et al. Proc Am Ass Cancer Res 8. 55 (1967). 4. Oral toxicology studies with lapachol R. K. Morrison et al. Toxicol Appl. Pharmacol 17. 111 (1970). 5. Early clinical studies with lapachol. J. B. Block et al. Fed Proc 29 (2), 684 abst (1970).

Manufacturer
Lepetit SpA (Italy)

References
Neuro and psychopharmacological profile of a new compound L 7108. E. Arrigoni-Martelli et al. VII International Congress Collegium Internationale NeuroPsychopharmacology, Prague, Czechoslovakia, Aug 11-15 (1970); abstr. 12.

Largomycin Lapachol
2-Hydroxy-3-(3-methyl-2-butenyl)-1,4naphthoquinone

Production
Largomycin is a new antibiotic isolated from the culture filtrate of Streptomyces pluricolorescens MCRL-0367. Three active components have been separated, of which largomycin FII was the most biologically active.

Description
Largomycin FII is an acidic yellow, amorphous powder. UV absorption max. 278 m (in 0,1N HCI) and 540 m (in 0,1N NaOH).

Synthesis
Lapachol is derived from the heartwood of certain Asian and South American biguoniaceous plants. 2 The synthesis was reported by Fieser and Hooker .

Action
Antitumor antibiotic.

Manufacturer

105
Tanabe Seiyaku Co, Ltd (Japan) 4. Mechanism of the antihypertensive properties of LD 2855. Rene Giudicelli and Henri Schmitt. J Pharmacol 1(3),339-358 (1970).

References
1. Studies on a new antitumor antibiotic, largomycin. 1 Taxonomy of the largomycin-producing strain and production of the antibiotic. T. Yamaguchi et al. j Antibiotics 23 (8), 369-372 (1970). 2. II. Isolation, purification and physicochemical properties. T. Yamaguchi et al. j Antibiotics 23 (8), 373-381 (1970). 3. III. Biological properties and antitumor activity of largomycin F-II. T. Yamaguchi et al. J Antibiotics 23 (8), 382-387 (1970).

Lentysine
Lentinacin meso-,-Dihydroxy-adenine-9-butyric acid meso-6-Amino-,-dihydroxy-9H-purine-9-butyric acid

LD 2855
2-Xylidino-2-oxazoline

Synthesis
Lentysine was first extracted from the mushroom lentinus edodes, and later its structure was established, and it was prepared by total synthesis starting from 2,3-O-isopropylidene-Derythronolactone.

Synthesis
Prepared by the condensation of xylidine with chloroethylisocyanate and subsequent treatment with water at 100 .

Description
Colorless needles, mp 279 [ ]D = +50 (in 0.1 N ; sodium hydroxide) and []D = +10 (in N hydrochloric acid). UV max 261 m [=14,300, in water and in 0,5 N sodium hydroxide]; 260 m [=14,000 in 0,5 N hydrochloric acid].

Description
White crystals, mp 81 insoluble in water. ;

Action
Lentysine has been shown to lower serum total cholesterol, phospholipids and triglycerides in animal experiments. It is under clinical trials.

Action
LD 2855 was reported to exert antihypertensive effects in man. Its pharmacological properties are complex and have been described recently.

Toxicity
LD50 ip in mice: 2,600 mg/kg; po in mice: 9,200 mg/kg; ip in rats: 1,600 mg/ kg and po in rats: 4,700 mg/ kg.

Manufacturer
Centre de Recherche Therapeutique (France)

References
1. Rene Giudicelli et al. Compt. rend. 247, 2494-7 (1958). 2. Henry Najer et al. Bull soc chim France, 352-359 (1959). 3. Henry Najer et al. Bull soc chim France, 1650-2 (1960).

Manufacturer
Tanabe Seiyaku Co, Ltd (Japan)

References
1. Structure and synthesis of lentysine. a new hypocholesterolemic substance. T. Kamiya et al. Tetrahedron Lett 53, 4729 (1969).

106
2. Jap Med Gaz 6(12),10 (1969). 3. Lentysine: a new hypolipemic agent from a mushroom. T. Rokujo et al. Life Sciences 9, 379-385 (1970) .

Description

Letimide Hydrochloride (USAN; Prop INN) MA 1443

3-[2-(Diethylamino)ethyI]-2H-1,3-benzoxazine2,4(3H)-dione hydrochloride

The free base melts at 60-61.5; the hydrochloride salt at 227-229 ; []D = -85.1 (c = 10, chloroform); []D = -1242 (c = 0.9 in water).

Action
Levamisole is the physiologically active I (-) isomer of the broad spectrum veterinary anthelmintic tetramisole.

Manufacturer
American Cyanamid Co (USA), Janssen (Belgium)

Proprietary Name
Tramisol (American Cyanamid Co)

Synthesis
Prepared by the reaction of diethylaminoethylsalicylamide with ethyl chloroformiate.

References
1. JAMA 212, 467 (1970). 2. A. H. M. Raeymaekers et al. Tetrahedron Lett 1467-1470 (1967). 3. American Cyanamid Co. Brit pat 1.120.406.

Description
Crystals, mp 232-233 (methanol/ether).

Action
Letimide is an analgesic agent.

Levodopa

Ro 5-4759

Manufacturer
Miles Lab Inc (USA)

3-(3,4-Dihydroxyphenyl)-L-alanine -(3.4-Dihydroxyphenyl)--alanine 2-Amino-3-(3,4-dihydroxyphenyl)propanoic acid

References
1. JAMA 213, 1326 (1970). 2. WHO Chron 25 (3), 135 (1971). 3. Miles Lab Inc. Fr pat 1,536,546.

Levamisole

R12564

L-Dopa is a natural amino a eid found in Vicia alba L. (velvet beans) and in seeds of Mucuna pruriens L.D.C. Leguminosae

L-Tetramisole
(-)-2,3,5,6-Tetrahydro-6-phenylimidazo [2,1-b]thiazole

Synthesis
Prepared from 3-(3,4-methylenedioxyphenyl)-L1 alanine methyl ester . A microbiological synthesis has recently been described which utilizes the 2 inexpensive starting material L-tyrosine .

107

Description
White crystalline powder, mp 276-278 (dec); slightly soluble in water, []D = -13.1 (c=5,12 in 1 N HCI).

Action and Uses

Lidoflazine is a coronary vasodilator. Indications angina pectoris, coronary sclerosis; prophylaxis and treatment of patients with myocardial infarction.

Action and Uses

Levodopa is an anticholinergic agent. It is used in the treatment of Parkinson's disease and syndrome.

Dosage
Initially, 60 mg three times daily.

Supplied as
Tablets and capsules 100, 250, and 500 mg.

Supplied as
Tablets, 60 mg.

Dosage
Usual initial dosage 0.5 to 1.0 g daily. Dosage should be adjusted to the needs of the individual patient as determined by clinical response and appearance of side effects.

Proprietary Name
Clinium

Manufacturer
Janssen (Germany)

Proprietary Name and Manufacturer

Larodopa (Roche) ; Dopalfher (Fher, Spain); Dopar (Endo, USA) ; Eldopal (Brocades-Steeman, Netherlands); Sobiodopa (Fanee).

References
Med Act (Drugs of Today) 6 (1), 21-24 (1970). (Review with 13 references)

References
1. S. Yamada et al. Chem Pharm Bull 10, 693 (1962). 2. Ch. J. Sih et al. J Amer Chem Soc 91 (22), 6204 (1969). 3. Med Act (Drugs of Today) 6 (4), 125-132 (1970). (Review with 27 references)

Lincomycin-2-phosphate Lidoflazine (Rec INN) R 7904

4-[4,4-bis(p-Fluorophenyl) butyl]-1-piperazine-aceto2',6'-xylidide

Synthesis Description
White or slightly yellow amorphous powder, mp 159161 practically insoluble in water, and very solu ble ; in chloroform and in glacial acetic acid. Reaction of 3,4-O-anysilidene lincomycin with trityl chloride gives 7-O-trityl-3,4-O-anisylidene lincomycin. Treatment of the latter with phosphorus oxychloride and subsequent hydrolysis gives the phosphate ester.

108

Description
White crystalline powder, mp 223-225 (dec)

Lividomycin
Production
Lividomycin is a basic antibiotic produced by Streptomyces lividus 2230 (ATCC-21178).

Action
In vivo lincomycin 2-phosphate has proved to be as active as the parent compound in mice infected with Staphylococcus. The taste of the new ester is less bitter than that of lincomycin. The stability of lincomycin-2-phosphate has been studied in aqueous solutions in order to supply basic information for the formulation in liquid dosage forms.

Action
Lividomycin has proved effective against Pseudomonas aeruginosa and tuberculosis bacilli.

Manufacturer
The Upjohn Co (USA)

Manufacturer
Kowa Co (Japan)

References
1. Synthesis and bioactivity of lincomycin 2phosphate. W. Morozowich et al. J Pharm Sci 58 (12), 14851492 (1969). 2. Hydrolysis of lincomycin-2-phosphate and clindamycin-2-phosphate. T. O. Oesterling and E. L. Lowe. J Pharm Sci 59 (2), 175-179 (1970).

References
Jap Med Gaz 7(8),12(1970).

LL-BH 872a
D-1-Hydroxy-3-(1'-cis-hexenylazoxy)-2-butanone

Lipoxamycin Sulfate
Production
From Streptomyces virginiae var lipoxae.

Production
Obtained from Streptomyces hinnulinus.

Action
Lipoxamycin is a new antifungal antibiotic.

Description
Light yellow oil, very unstable. []D = +157 1.7 (c=1.7, methanol). UV max 238 m (=9000).

Manufacturer
The Upjohn Co (USA)

Action
Antifungal antibiotic.

References
Tenth Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, Oct 1821, 1970; abstr 25.

Manufacturer
Lederle (USA)

References
1. A novel ,-unsaturated azoxy-containing antibiotic. W. J. McGahren et al. J Am Chem Soc 91, 2808 (1969).

109
3. A quantitative approach to the initial clinical trial of tricyclic antidepressants. A comparison of Leo 640 and nortriptyline. B. Siwers et aJ. Eur J Clin Pharm 3 (1), 22 (1970). 4. On the pharmacology of Leo 640, a new tricyclic anti-depressant. O. Rohte. VII Internat Congr Colleg Internationale Neuro-Psychopharmacol Prague, Czechoslovakia, Aug 11-15 (1970); abst 365.

Lopramine Hydrochloride (Prop INN) Leo 640

Lopraminum (Lat). Lopramina (Sp) 4'-Chloro-2-[[3-(10,11-dihydro-5H-dibenz [b,f] azepin-5-yl) propyl] methylamino] acetophenone hydrochloride N-Methyl-N-(4-chlorobenzoyl methyl)-3-(10,11dihydro-5 H-dibenz [b, f] azepin-5-yl)-propylamine hydrochloride

Lorazepam (USAN; Rec INN) Wy 4036

7-Chloro-5-(o-chlorophenyl)-1,3-dihydro-3-hydroxy2H-1,4-benzodiazepin-2-one

Synthesis
Prepared from N-methyl-3-(10,11-dihydro-5H-dibenz [b,f] azepin-5-yl)-propylamine and 2-bromo-4'chloroacetophenone.

Synthesis
Prepared by hydrolysis of 3-acetoxy-7-chloro-5-(ochlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2one.

Description
Crystals, mp 152-154. The free base melts at 104106.

Description
Crystals, mp 166-168 .

Action
Lopramine is a new potential antidepressant, closely related to imipramine and desipramine. It differs from the two latter in having a N-(4chlorobenzoylmethyl) group instead of a N-methyl or hydrogen respectively. Preliminary studies in man have shown promising results.

Action
Lorazepam is a new tranquilizer of the 1,4benzodiazepine series.

Manufacturer
Wyeth Laboratories (USA)

Toxicity
LD50 po in mice> 1000 mg/kg; ip: 920 mg/kg.

References
1. JAMA 209, 1213 (1969). 2. WHO Chron 24 (11), 530 (1970). 3. American Home Corp. Brit pat 1,057,492. Belg pat 621,819. 4. B. D. Berger and L. Stein. Fed Proc 28 (2), 641 (1969).

Manufacturer
AB Leo (Sweden)

References
1. WHO Chron 24 (9),425 (1970). 2. Chemistry and pharmacology of a new potential antidepressant. E. Erikson and O. Rohte. Arzneim-Forsch 20 (10), 1561-1568 (1970).

110

Lorbamate (USAN; Prop INN) Abbott 19957

Lorbamatum (Lat). Lorbamato (Sp) Cyclopropanecarbamic acid, 2-(hydroxymethyl)-2methyl-pentylester, carbamate 2-(Hydroxymethyl)-2-methylpentyl cyclopropanecarbamate carbamate (ester) 2-Methyl-2-propyl-1 ,3-propanediol carbamate cyclopropane carbamate

Synthesis
Prepared by the reaction of 2-chloro-10,11-dihydro11-oxo-dibenz [b,f] [1,4] oxazepine with phosphorus oxychloride to yield 2,11-dichloro-dibenz [b, f] [1,4] oxazepine, followed by reaction of the latter with Nmethyl piperazine.

Synthesis
Prepared in several steps from 5-methyl-5-(n) propyl-2-m-dioxanone and cyclopropylamine.

Description
Pale yellowish, grainy crystals, mp 109-111 .

Action
Loxapine is considered to be a potent psychoactive agent in laboratory animals. It has calming effects in cats, dogs and monkeys. It is closely related to the dibenzothiazepine clothiapine.

Description
Crystals, mp 72-74 (ether-pentane) .

Action
Centrally acting muscle relaxant.

Toxicity
LD50 po in mice: 47 mg/kg.

Manufacturer
Abbott Laboratories (USA)

Manufacturer
Dorsey Laboratories (USA); Lederle Laboratories (USA)

References
1. WHO Chron 24 (9), 425 (1970) . 2. JAMA 212,2247 (1970). 3. Abbott Laboratories, US pat 3,037,045.

References
1. JAMA 209, 2043 (1969). 2. WHO Chron 24 (11), 530 (1970). 3. Or. A. Wander S. A. Brit pat 1,045,903.

Loxapine (USAN; Rec INN) SUM 3170 CL 62,362 LW 3170

Loxapinum (Lat). Loxapina (Sp) 2-Chloro-11-(4-methyl-1-piperazinyl) dibenz [b,f] [1,4] oxazepine

Loxapine Succinate CL 71563

SUM 3170 LE 3170

2-Chloro-11-(4-methyl-1-piperazinyl) dibenz [b,f] [1,4] oxazepine succinate (1:1)

111
dimethylamino-1-phenyl-1-[2-(2-hydroxy-2-propyl) phenyl]-1-butanol.

Description
White crystalline powder, mp 190-191 .

Action
Lu 3-010 and Lu-5-003 (the corresponding thiophthalane derivative) are two new drugs currently under investigation for antidepressant properties.

Action
See Loxapine. The drug is rapidly absorbed from the gastrointestinal tract, well distributed in the tissue and extensively metabolized. In a preliminary clinical study it has been concluded that the drug possesses definite neuroleptic properties without significant toxicity.

Manufacturer
H. Ludbeck and Co (Denmark)

References
1. Kefalas A/S Neth Appl 6,603,606 and 6,603,603. 2. Preliminary experiences of treated depressive patients with Lu 3-010 and Lu 5-003. J. Ravn and C. Rud. Nord psykiat T 23, 253-261 (1961). 3. Further pharmacological studies of bicyclic thymoleptics. P. V. Petersen at al. Acta Pharmacal Toxicol 28, 241-248 (1970). 4. Inhibitory effect of two newer antidepressants, Lu5-003 and Lu 3-010 on serotonin uptake in human blood platelets in vitro. O. Lingjaerde. Psychopharmacologia 17, 94-99 (1970).

Toxicity
LD50 po in rats: 40 mg/kg.

Manufacturer
Lederle Laboratories (USA)

References
1. Clinical pharmacological trial of loxapine succinate. J Clin Pharmacal 10 (3), 175-181 (1970). 2. Antipsychotic properties of loxapine succinate. S. Gershon et al. Curr Ther Res 12 (5), 280-285 (1970).

Lu-5-003
N,3,3-Trimethyl-1-phenyl-1-thiophthalanpropylamine hydrochloride 1-(3-Methylaminopropyl)-1-phenyl-3,3-dimethylthiophthalane hydrochloride

Lu 3-010
N,3,3-Trimethyl-1-phenyl-1-phthalan-propylamine hydrochloride 1-(3-Methylaminopropyl)-1-phenyl-3,3dimethylphthalane hydrochloride

Description
Crystals, mp 176-177 .

Action Synthesis
Prepared in 3 steps, starting with the reaction of 1phenyl-3,3-dimethylphthalan-1-ol with LiAIH4. Also prepared in 3 steps, starting by the dehydration of 4Lu 5-003 and Lu 3-010 (the corresponding phthalane derivative) are two new drugs currently under investigation for antidepressant properties. Lu 5-003 seems to be the clinically more promising of the two compounds.

112

Manufacturer
H. Lundbeck and Co (Denmark)

Maprotiline (Rec INN) Ciba 34,276 Ba

Maprotilinum (Lat). Maprotilina (Sp) N-Methyl-9,10-ethanoanthracene-9-(10H)propylamine hydrochloride 1-(Methylaminopropyl)-dibenzo-[b,e]-bicyclo-[2,2,2] octadiene hydrochloride

References
1. Preliminary experiences of treated depressive patients with Lu 3-010 and Lu 5-003. J. Ravn and C. Rud. Nord Psykiat T 23, 253-261 (1961). 2. Further pharmacological studies of bicyclic thymoleptics. P. V. Petersen et al. Acta Pharmacol Toxicol 28, 241-248 (1970). 3. Metabolism, distribution and excretion of the thiophthalane Lu 5-003 a bicyclic thymoleptic. K. Fredricson Overo et al. Acta Pharmacol Toxicol 28, 81-96 (1970).

Macarbomycin
Production
Antibiotic isolated from the culture broth of a Streptomyces, Str phaeochromogenes C715-7 strain.

Synthesis
Prepared by the reduction of N-methyl-9,10ethanoanthracene-9(10H)-propionic acid amide with lithium aluminum hydride.

Description
Crystals, mp 230-232 (isopropanol).

Description
White powder. The ammonium salt is readily soluble in water and is dextrorotatory, []D = + 150 (c=1, in methanol).

Action
Maprotiline, a benzoctamine analog, inhibits the uptake and potentiates the action of noradrenaline and antagonizes mescaline-induced excitation in the animal. Its effect on the cortical EEG has been 3 recently studied in healthy volunteers . The results 4 of clinical trials have been reported .

Action
Macarbomycin has strong antibacterial activity in vivo and in vitro and gives good results in weight gain and feed conversion with both broilers and swine.

Manufacturer
CIBA Ltd (Switzerland)

Toxicity
LD50 iv in mice: 750 mg/kg.

References
1. WHO Chron 24 (3), 130 (1970). 2. CIBA Ltd. Neth Appl 6.516.749. 3. The effect of compound ClBA 34,276-8a on the cortical electroencephalogram of healthy persons. U. J. Jovanovic and B. Tan-Eli. Europ Neurol 4. 3956 (1970). 4. On the antidepressive effect of Ciba 34,276-8a. Observations on 562 cases. W. Gruter. Coll Intern Neuro-psycho-pharm. VII Congress Abstracts, Vol II. abst 482 (1970).

Manufacturer
Meiji Seika Kaisha, Ltd (Japan)

References
1. Macarbomycin a new antibiotic containing phosphorus. S. Takahashi et al. J Antibiotics 23 (1), 48-50 (1970). 2. Jap Mad Gaz 7(3).4(1970).

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Matchamycin
Production
Matchamycin has been isolated from a culture broth of a Streptomyces E-753.

Action
Mazindol has been found to produce moderate to marked central nervous system stimulation, appetite suppression and anti-depressant activity in mice, rats and monkeys.

Manufacturer
Sandoz Pharmaceuticals (USA)

Description
Green material, mp 150-156 (green to brown); []D = + 33 12 (c=1, in dimethylsulfoxide).

References
1. JAMA 211, 1363 (1970). 2. WHO Chron 24 (3), 130 (1970). 3. Sandoz AG. Ger Offen 1,814,540; Ger Offen 1,901,497; Ger Offen 1,930,488. 4. Fed Proc 27, Abst 1603. 2152 (1968) . 5. Curr Ther Res 11. 256 (1969). 6. American Druggist pg 32 (June 29. 1970).

Action
Matchamycin is a new antibacterial substance.

Manufacturer
Shionogi and Co, Ltd (Japan)

References
Matchamycin: a new antibiotic produced by Streptomyces E-753. A. Kinuera and H. Nishimura J Antibiotics 23 (9), 461-463 (1970).

MDA Hydrochloride
3,4-Methylenedioxy--methylphenethylamine hydrochloride 3,4-Methylenedioxyamphetamine hydrochloride 1-(3,4-Methylenedioxyphenyl)-2-aminopropane hydrochloride

Mazindal (USAN; Prop INN) 42-548

5-(p-Chlorophenyl)-2,5-dihydro-3H-imidazo [2,1-a] isoindol-5-ol 5-(p-Chlorophenyl)-5-hydroxy-2,3-dihydro-5Himidazo[2,1-a] isoindol

Description
Crystals, mp 181-182 .

Action
MDA is a mild euphoriant, which increases need for interpersonal relationships. It induces changes in vision and hearing. This drug is subjected to control.

References
1. C. Mannich and W. Jacobson. Ber 43, 189 (1910). 2. Analogs of a-methylphenethylamine (amphetamine). I. Synthesis and pharmacological activity of some methoxy and/or methyl analogs. B. T. Ho et al. J Med Chem 13 (1), 26-30 (1970). 3. JAMA 211, 830 (1970). 4. Fed Reg 35 (47) 43054306 (1970)

Synthesis
Prepared by air oxidation of 5-(p-chlorophenyl)-2,3dihydro-5H-imidazo [2,1-a] isoindol, and subsequent treatment of the resulting 5-hydroperoxy derivate with methanol.

Description
Crystals, mp 202-203 .

114
Prepared in several steps from 11-keto-6-methylprogesterone.

Meclofenamic Acid (Rec INN) CI 583

N-(2,6-Dichloro-m-tolyl) anthranilic acid

Description
White crystalline powder, mp 155-158 [ ]D = 189 . (in chloroform).

Action and Uses

Medrysone is a new corticoid which has topical antiinflammatory and antiallergic activity. It is effective in the treatment of allergic conjunctivitis, vernal conjunctivitis and apiscleritis.

Supplied as Synthesis
Several methods have been described .
1-3

5 ml sterile suspension in plastic dropper bottles.

Dosage
One drop instilled in the conjunctival sac up to every four hours.

Description
Crystals, mp 257-259 .

Action
Meclofenamic acid is an anti-inflammatory drug. It has proved to be effective in clinic.

Proprietary Name
HMS

Manufacturer
Allergan (USA)

Manufacturer
Parke Davis (USA)

References
1. The Upjohn Co. US pat 2,864,837. 2. Med Act (Drugs of Today), 6(5),183-185 (1970). (Review)

References
1. Parke Davis Co. Neth Appl 6,507,783; Ger pat 1,149,015; US pat 3,313,848; Brit pat 1,046,319. 2. Bristol-Myers Co. Neth Appl 6,604,860. 3. P. J. Juby et al. J Med Chem 11(1),111116(1968). 4. Hormones 1(4),193 (1970).

Medrysone (USAN) U 8471

11 -Hydroxy-6 -methylpregn-4-ene-3,20-dione 11 -Hydroxy-6 -methylprogesterone 6 -Methyl-11 -hydroxyprogesterone

Mefenorex Hydrochloride (Prop INN) Ro 4-5282

N-(3-Chloropropyl)--methyl-phenethylamine hydrochloride 1-Phenyl-2-(3-chloropropylamino) propane hydrochloride -Methyl--phenyl-N-(-chloropropyl) ethylamine hydrochloride

Synthesis Synthesis
Prepared from 1-phenyl-2-(3-hydroxypropylamino) propane.

115
Meglucycline is a new highly soluble Mannich base of tetracycline.

Description
Crystals, mp 128-130 .

Action and Uses

Mefenorex exerts an appetite-depressant effect. For use in the management of obesity.

Manufacturer Laboratorios Prodes SA (Spain) References

1. WHO Chron 24 (11). 531 (1970). 2. Prodes SA. Sp pat 355.262. 3. G. Barrenechea et al. Simposium Quimica Medica Farmaceutica Barcelona Sept 28-30 (1970).

Dosage
40 mg one or two times daily.

Supplied as
Tablets, 40 mg.

Proprietary Name
Pondinil

Memotine Hydrochloride (USAN) UK 2371

3.4-Dihydro-1-[(p-methoxy-phenoxy)-methyl] isoquinoline hydrochloride

Manufacturer Roche (Fance) References

1. F. Hoffmann La Roche and Co. Ger pat 1,210,873. 2. Med Act (Drugs of Today), 6(4),133-135(1970). (Review with 8 references).

Meglucycline (Rec INN)

Meglucyclinum (Lat). Megluciclina (Sp) 2-Deoxy-2-[[[4-(dimethylamino)1,4,4a,5,5a,6,11,12a-octahydro-3,6,10,12,12apentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamido] methyl] amino]--D-glucopyranose

Synthesis
Prepared by cyclodehydration of N-(pmethoxyphenoxyacetyl)--phenylethylamine with phosphorus pentoxide.

Description
Crystals. mp 187

Action
Memotine is an antiviral agent closely related to famotine. It has been reported that the oral administration of the drug to volunteers reduced by half the incidence of virus infection and of clinical illness after intranasal instillation of living influenza 2 B virus . Recent experiments failed to show protection of volunteers challenged with influenza 3,4 A2/Hong Kong/1968 .

Synthesis
Prepared by reacting 2-amino-2-deoxyglucose with formaldehyde and tetracycline in an aqueousorganic medium.

Manufacturer
Chas Pfizer and Co. Inc (USA)

Description
Yellow powder, mp 143 (dec).

References
1. Pfizer Corp. Neth Appl 6.516.328. 2. Prophylaxis of influenza with a synthetic isoquinoline.

Action

116
A. S. Beare et al. Lancet 1. 843 (1968). 3. Studies of isoquinoline derivatives (UK 2371 and UK 2054) in respiratory infections of volunteers, using influenza viruses, a parainfluenza virus and a rhinovitrus. Sylvia E. Reed et al. Ann NY Acad Sci 173. 760-769 (1970). 4. A trial of chemoprophylaxis of natural influenza infection with UK 2371. J. E. Stark et al. Thorax 25. 649-655 (1970) . Prepared by reaction of phenol and ethyl oxide with a substance produced by isomerization and reduction of terpene oil.

Action
Menphegol is a newly developed non-ionic surface active spermicide. It is available in the form of effervescent vaginal tablets.

Manufacturer
Eisai Co, Ltd (Japan)

Proprietary Name

Menitrazepam (Rec INN) CB 4875

Menitrazepamum (Lat) 5-(1-Cyclohexen-1-yl)-1,3-dihydro-1-methyl-7-nitro2H-1,4-benzodiazepin-2-one

Neo Sampoon

References
Jap Med Gaz 7 (4).4(1970).

Mepiprazole Dihydrochloride (BAN; Prop INN)

Mepiprazolum (Lat) 1-(m-Chlorophenyl)-4-[2-(5-methylpyrazol-3-yl) ethyl] piperazine dihydrochloride

H 4007

Action
Muscle relaxant. It is structurally related to tetrazepam; it differs from the latter in having a 7nitro group instead of a 7-chloro.

Manufacturer
Clin Byla (France)

References
1. Pharm J 203, 753 (1969). 2. WHO Chronicle 24 (11), 531 (1970).

Synthesis
Prepared by the reaction of 3-(2-chloroethyl)-5methylpyrazol with N-(3-chlorophenyl) piperazine. Also by the reaction of 3-chlorophenyl bis-(2chloroethyl) amine with 3-(2-aminoethyl)-5methylpyrazol.

Menphegol
p-Menthanyl-phenyl polyoxyethylene ether

Description
Crystals, mp 238-240 (ethanol); the trisulfate, mp 198-200 .

Synthesis

Action

117
Mepiprazole dihydrochloride is a new psychotropic drug. Serentil (Sandoz, US); Inofal (Sandoz, Germany)

References
1. WHO Chron 24 (9), 426 (1970). 2. Chem Drug 193, 228 (1970). 3. E Merck AG. Brit pat 1,124,710.

References
1. Renz et al. US pat 3.084,161. 2. Med Act (Drugs of Today) 6 (6). 219 (1970). (Review with 9 references).

Mesoridazine (USAN) TPS-23

10-[2-(1-Methyl-2-piperidyl}ethylj-2-(methylsulfinyl) phenothiazine

Metampicillin Sodium (Rec INN)

Metampicillinum (Lat). Metampicilina (Sp) 3,3-Dimethyl-6-[2-(methylenamino)-2phenylacetamido]-7-oxo-4-thia-1-azabicyclo (3.2.0) heptane-2-carboxylic acid sodium salt 6-[D(-)--Methylenaminophenylacetamido] penicillanic acid sodium salt

Synthesis
Prepared from 2-(methylsulfinyl) phenothiazine and 2-(1-methyl-2-piperidyl)-1-chloroethane.

Synthesis
A solution of equimolecular amounts of ampicillin and sodium bicarbonate is treated at 50 with formaldehyde solution. The resulting solution is filtered and then lyophilized.

Description
The free base is an oily product. The tartrate melts at 115-120 (foam formation) and sisters above 80 .

Description
White powder, freely soluble in water.

Action and Uses

Mesoridazine is a new major tranquilizer drug, chemically and pharmacologically related to thioridazine. Mesoridazine is useful in the following disease states: alcoholism-acute and chronic; schizophrenia; behavioral problems in mental defficiency and chronic brain syndrome; psychoneurotic manifestations.

Action and Uses

Metampicillin is an analogue of the ampicillin, with a methylenamino -substituent. It shows a broad spectrum of activity against gram-positive and gramnegative bacteria, similar to that of ampicillin, but it is claimed to have the advantage of being relatively stable against staphylococcal penicillinase.

Dosage
By oral route, 50-400 mg daily. Intramuscularly, 25200 mg daily.

Dosage
Adults, 250 mg orally every 6 hours, or 250 mg intramuscularly every 8-12 hours. Children 25-40 mg/kg daily.

Supplied as
Tablets, 10, 25, 50, 100 mg mesoridazine (as the besylate). Ampules, 25 mg/ml mesoridazine (as the besylate).

Supplied as
Capsules, 250 mg. Vials, 150 mg and 250 mg.

Proprietary Name and Manufacturer

Proprietary Name

118
Suvipen

Manufacturer
Midy (France, Italy)

References
1. Soc Et Res Appl Sci Med ERASME. Brit pat 1.081,093. 2. M. Londe. Presse Med. 78, 805 (1970). 3. Med Act (Drugs of Today) 6 (3), 84-87 (1970). (Review with 6 references).

Methasquin
N-[p-[[(2,4-Diamino-5-methyl-6-quinazolinyl) methyl] amino] benzoyl] aspartic acid L-form

Synthesis

Metazamide (USAN; Rec INN) GPA 878

Metazamidum (Lat) 1-(p-Methoxyphenyl)-5-methyl-4-imidazolin-2-one

Prepared by hydrolysis of the corresponding diethyl ester.

Description
Insoluble in water, soluble in alkaline solutions; mp 269-271 (dec).

Action
Antitumor qgent. It inhibits folate reductase.

Manufacturer
Parke Davis

Synthesis
Prepared from p-anisidine, formaldehyde and isonitrosoacetoacetate in several steps, the last being the decarboxylation of 1-(p-methoxyphenyl)-4carboxy-5-methyl-2-imidazolone by treatment with quinoline and copper powder.

References
1. Parke, Davis and Co. Brit pat 1,104,576 and US pat 3,471,498. 2. Quinazoline antifolates: biologic activities. Dorris J Hutchinson. Cancer Chemother Rep 52(7), (pI.1) 697-705 (1968). 3. Folate reductase of the amethopterin-resistant Streptococcus faecium var durans/Ak /. Inhibition by amethopterin and methasquin a new quinazoline antifolate. M. Alberta et al. Mol Pharmacol 6(4), 323 (1970).

Description
Glittering needles, mp 195-196 (methanol). Ultraviolet absorption max at 240 m =6580, in methanol).

Action
Anti-inflammatory

Manufacturer
Geigy Chemical Corp (USA)

Methoxyellipticine Lactate ICI180

9-Methoxyellipticine Lactate 9-Methoxy-5,11-dimethyl-6H-pyrido [4,3-b] carbazole lactate

References
1. Geigy Chemical Corp. US pat 3,303,199. 2. The biological disposition of GPA 878, an antiinflammatory imidazolone derivative. S. B. Zak et al. Fed Proc 29, 677 (1970) .

119

Description
Methoxyellipticine lactate is an alkaloid extracted from the leaves of Ochrosia borbonica. Yellow crystals, mp 295 UV max 245 m [Ig = . 4.34], 275 m [Ig = 4.53], 290 m [Ig = 4.64], 340 m [Ig = 3.71], 400 m [Ig = 3.56]. It is soluble in water.

Action
Methoxyellipticine has proved to possess experimental antitumor activity. Recently it has shown to be capable of inducing apparently complete remissions in patients with acute myeloblastic leukaemia.

Methylcobalamin differs in chemical structure from cyanocobalamin in that a methyl group is attached to the cobalt in place of a cyanide group.

Synthesis and Isolation

Methylcobalamin is prepared by reduction of cyanocobalamin with zinc followed by an alkylation with methyl bromide, methyl sulfate or diazomethane, or also, by reduction of hydroxocobalamin with sodium borohydride followed 1-6 by an alkylation with methyl iodide . The isolation 7 of methylcobalamin from a microorganism and 8 liver have been reported.

Toxicity
LD50 sc in mice: 150 mg/kg.

Manufacturer Roger Bellon Lab (Fr) References

1. L. K. Dalton et al. Aust J Chem 20 (12), 2715-27 (1967). 2. J. Poisson et al. Ann Pharm Fr 25, 523-4 (1967). 3. G. H. Svoboda et al. J Pharm Sci 57 (10). 1720-5 (1968). 4. Methoxy-9-ellipticine lactate. I. Experimental study (oncostatic and immunosuppressive actions; preclinical pharmacology). J. Le Men et al. Rev Europ Etudes Clin Biol 15 (5), 554-538 (1970). 5. II. Analysis in vitro of the mechanism of action. E. Garcfa-Giralt and A. Macieira-Coelho ibid. 15 (5). 539-541 (1970). 6. III. Clinical screening: its action in acute myeloblastic leukaemia. G. Mathe et al. ibid. 15 (5), 541-545 (1970).

Description
Red crystalline powder; sparingly soluble in water, insoluble in acetone, ether and benzene. In aqueous solution absorbancy peak at about 520 m (characteristic of cobamide compounds containing a benzimidazolyl group); in acid solution the absorbancy peak is shifted to about 460 m. In -4 aqueous solution the values of .10 , at 268, 343 6 and 525 m are respectively 2.27, 1.20 and 0.76 .

Action
Methylcobalamin participates in several enzymic reactions, including transmethylation and other reactions of methyl or carboxymethyl groups. From recent experimental studies in partially hepatectomized rats it has been assumed that 9 methylcobalamin can accelerate liver regeneration . Methylcobalamin appears to be a major component of vitamin B12 in normal human plasma and to occur 10 in the human liver as well . It has proved to have a therapeutic effect in vitamin B12 deificiency in parenteral doses of 4 to 6.5 g. It has been assayed 11 clinically; in the treatment of diabetic neuropathy .

Methylcobalamin
Cobinamide Co methyl deriv. phosphate 3'-ester with 5,6-dimethyl-1--D-ribofuranosyl benzimidazole inner salt 5,6-Dimethylbenzimidazolylmethylcobamide

References
1. E. L. Smith et al. Nature 194, 1175 (1962). 2. E. L. Smith and L. Mervyn. Biochem J 86, 2p (1963).

120
3. H. P. C. Kogenkamp and T. G. Oikawa. J Biol Chem 239,1911 (1964). 4. Hoffmann-La Roche and Co-A. G. Belg pat 631,589. 5. Glaxo Group Ltd. Brit pat 963,373. 6. W. A. Johnson at al. J Chem Soc 4146 (1963). 7. K. Lindstrand. Acta Chem Scand 19 (7), 1762-3 (1965). 8. K. Lindstrand. ibid 19 (7), 1785-7 (1965). 9. T. Koizumi et al. Experientia 26 (3), 282 (1970). 10. K. G. Stahlberg. Scand J Haematol Suppl No 1 (1967). 11. Shinryo to Shinyaku 6, 1959 (1969). 12. Med Act (Drugs of Today) 6 (3), 106-112 (19770). (Review with 16 references). centraux, Geneve-1970; Med Hyg (933), 1500 (1970). 5. Therapeutique substitutive des syndromes de Parkinson. G. Gauthier et al. Press Med 79 (3), 91 (1971).

-Methyldopahydrazine MK458
-Hydrazino-3,4-dihydroxy--methylhydrocinnamic acid (3,4-Dihydroxyphenyl)--hydrazino--methyl propionic acid

3-O-Methyldopa 3-OMD
3-(4-Hydroxy-3-methoxyphenyl) alanine

Synthesis
By the reaction of the potassium bisulphate adduct of 1-(3-methoxy-4-hydroxyphenyl)-2-propanone or of 1-(3,4-dimethoxyphenyl)-2-propanone with hydrazine hydrate and potassium cyanide. The hydrazino nitrile so obtained, upon hydrolysis with acid, yields the corresponding hydrazino amide salt and the treatment of this amide with strong hydrobromic acid finishes the hydrolysis to the free acid and dealkylates the ring methoxyl groups.

Synthesis
Prepared by hydrolysis of N-benzoyl-4-hydroxy-31 methoxyphenylalanine with dil hydrochloric acid , or by hydrolysis of 5-(4-hydroxy-3-methoxybenzyl) 2 hydantoin with barium hydroxide .

Description
Crystals, mp 209-210 (dec).

Description
Crystals, mp 255-256 dec. Very soluble in hot water, in hydrochloric acid and ammonium hydroxide.

Action
-Methyldopahydrazine is a peripheral decarboxylase inhibitor, which has been shown to potentiate the behavioural and biochemical effects of peripherally administered I-dopa in animals. Preliminary clinical experience has suggested that the drug may well facilitate the administration of Idopa to psychiatric and neurological patients heretofore unable to tolerate high doses of I-dopa because of peripheral side-effects.

Action
3-O-Methyldopa is a metabolite of dopa. It is under clinical study as an antiparkinson drug.

References
1. Bloch, Zeitschrift fr physiologische chemie 98, 236. 2. Johnson at al. J Am Chem Soc 35, 1613. 14 3. Metabolic fate of 1-dopa- C in cerebrospinal fluids and blood plasma of humans. A. Pletscher et al (Hoffmann-La Roche). Brain Res 4 (1), 106-109 (1967) . 4. A. Pletscher et al. Communication on IV Symposium of Bel-Air: Monoamines et noyaux gris

Manufacturer
Merck Sharp and Dohme (USA)

References
1. Merck Co Inc. Fr pat M 1553; Brit pat 940,596; Ger pat 1,173,487. 2. M. Sletzinger et al. J Med Chem 6, 101-103 (1963).

121
3. Dopa effects on motility in mice; Potentiation by MK 485 and dexchlorpheniramine. U. Stromberg. Psychopharmac (Berl) 18, 58-67 (1970). 4. Administration of a peripheral descarboxylase inhibitor with I-dopa to depressed patients. F. K. Goodwin et al. Lancet i, 908-911 (1970). 5. Effect of I-dopa alone and in combination with an extra cerebral decarboxylase inhibitor on blood pressure and some cardiovascular reflexes. A. M. Watanabe et al. Clin Pharmac Ther 11 (5), 740-746 (Sept-Oct 1970). 2. G. D. W. Duncan et al. Exptl Biol Med 116 (3), 800-802 (1964) . 3. Biological properties of 17-ethinyl-7-methyl-19nortestosterone. B. B. Pharris. Contraception 1(2), 87-100 (1970).

N-Methyl-N-(-phenylethyl)1,2,3,4-tetrahydro-6-methoxy-4,4dimethyl-2-naphthylamine hydrochloride

7 -Methylnorethindrone U 13,851
17-Hydroxy-7-methyl-19-nor-17-pregn-4-en-20yn-3-one 7-Methyl-19-nor-17-ethinyt-4-androsten-17-ol-3one 17-Ethinyl-7-methyl-19-nortestosterone

Synthesis
Prepared in three steps from 6-methoxy-4,41 dimethyl-2-tetralone .

Description
Colorless needles, mp 208 .

Action Synthesis
Prepared by the condensation of 7-methyl-19-nor4-androstene-3,17-dione with pyrrolidine and the reaction of the resulting 3-pyrrolidinyl enamine with sodium acetylide. This compound has been investigated for its cardioactive properties, and has proved to be a myocardial depressant and potent antifibrillatory agent in mice and guinea pigs.

References Description
Crystals, mp 197-199.5 UV max 240.5 m ; 1. A. R. Martin el al. J Pharm Sci 58, 340 (1969). 2. A new myocardial depressant and antifibrillatory agent. W. E. Johnson et al. Life Sci 9 (Pt 1), 471-476 (1970).

Action
7-Methylnorethindrone exhibits both estrogenic and progestogenic properties in several biological test systems, and has been found to be 10 to 40 times as potent as norethindrone in comparative assays.

Manufacturer
The Upjohn Co (USA)

Metiapine (USAN; Rec INN)

Metiapinum (Lat). Metiapina (Sp) 2-Methyl-11-(4-methyl-1-piperazinyl)dibenzo[b,f] [1.4]thiazepine

References
1. Upjohn Co. US pat 3,341,557; Belg pat 610.385 ; Neth AppI 6,604,702.

122
2-Methyl-3-( -imidazolin-2-ylmethyl) benzo [b] thiophene hydrochloride
2

Synthesis
Prepared by the reaction of 2-methyl-10,11-dihydro11-oxo-dibenzo[b, f] [1,4] thiazepine with phosphorus oxychloride and by reaction of the resulting 11-chloro derivate with Nmethylpiperazine.

Synthesis
Prepared from (2-methylbenzo[b]thien-3-yl) acetonitrile.

Description
Crystals, mp 248-250 (alcohol/ether). The free base melts at 156-157 (cyclohexane/petroleumether).

Description
Crystals, mp 99-107 (petroleum ether).

Action
Metiapine has been shown to have pharmacological properties consistent with those of potent neuroleptics. It is under clinical study.

Action
Vasoconstrictor-nasal decongestant.

Manufacturer
Lakeside Laboratories (USA)

Manufacturer
The Wm S Merrell Co (USA); Dr A Wander AG (Switzerland)

References
1. WHO Chron 24 (11), 531 (1970). 2. JAMA 211, 1362 (1970). 3. E. Merck AG. Fr pat M. 1614.

References
1. WHO Chron 24 (11), 531 (1970). 2. JAMA 208, 1400 (1969). 3. J. Schmutz et al. Helv Chim Acta 50 (1), 245-254 (1967). 4. J. Schmutz et al. Chim Ther 2 (6), 424-429 (1967). 5. Metiapine: Neuroleptic and peripheral autonomic attributes. H. J. Ketteler and W. L. Kuhn. Fed Proc 29, 620 Abs (1970). 6. Metiapine: a new antipsychotic agent. D. M. Galiant et al. Curr Ther Res 12 (12), 794-797 (1970).

Metolazone (USAN; Rec INN) SR 720-22

Metolazonum (Lat). Metolazona (Sp) 7-Chloro-1,2,3,4-tetrahydro-2-methyl-4-oxo-3-otolyl-6-quinazolinesulfonamide 2-Methyl-3-(o-tolyl)-6-sulfamyl-7-chloro-1,2,3,4tetrahydro-4-quinazolinone

Metizoline Hydrochloride (USAN; Rec INN) EX 10-781

Metizolinum (Lat). Metizolina (Sp) The former USAN for this compound was benazoline. 2-[(2-Methylbenzo[b]thien-3-yl)methyl]-2-imidazoline monohydrochloride

Synthesis

123
Sulfamation of N-acetyl-5-chloro-2-methylaniline with chlorosulfonic acid and concentrated NH4OH, followed by an oxidation with KMnO4, in water at 83 gives an anthranilic acid derivative, which is allowed to react with o-toluidine and phosphorus trichloride in refluxing toluene to give a product which is finally reduced with sodium borohydride in diglyme.

Description
Crystals, mp 170-171 UV max about 263 m . [E(1%,1 cm) about 600] in 0,1N HCI.

Action as Uses
Metopimazine is a new potent antiemetic agent. In experimental studies in dogs, it was found to be 100 times more active than chlorpromazine. For use in the treatment of nausea and vomiting produced by certain drugs; radiation sickness; nausea and vomiting associated with certain hepato-digestive disorders; postanesthetic and postoperative nausea and vomiting.

Description
Colorless crystals, mp 253-259 (95% ethanol).

Action
Metolazone is a new diuretic agent.

Manufacturer
Strasenburgh Laboratories (USA)

Dosage
Orally or rectally, 5 to 15 mg daily. Parenterally, 10 to 20 mg daily.

Proprietary Name
Zaroxolyn

Supplied as
Sugar coated tablets, 2.5 mg; suppositories, 5 mg; solution (injection) 10 mg/ml.

References
1. Wallace and Tiernan Inc. US pat 3,360,518. 2. The study of metalazone, a new diuretic, in human body fluids using thin layer separation, liquid 14 chromatographic measurements and C-counting techniques. O. N. Hinsvark and A. I. Cohen. Fed Proc 29(2),276 Abs (1970). 3. Human pharmacokinetics studies with 14 Zaroxolyn, a new type of diuretic agent. K. N. Modi et al. Fed Proc 29 (2), 27 Abs (1970).

Proprietary Name
Vogalene

Manufacturer Theraplix (France) References

1. Societe des Usines-Chimiques Rhone Poulenc. Ger pat 1.092.476. 2. Med Act (Drugs of Today) 6 (4). 135-138 (1970). (Review with 9 references).

Metopimazine (BAN; USAN) PP 9965 2167 Th Metrifonate

O,O-Dimethyl-1-hydroxy-2,2,2trichloroethylphosphonate 1-[3-[2-(Methylsulfonyl) phenothiazin-10-yl] propyl] isonipecotamide 10-[3-(4-Carbamoyl piperidino)-propyl]-2(methanesulfonyl) phenothiazine

Synthesis
Prepared from chloral and dimethyl phosphite.

Synthesis
Prepared from 3-methylsulfonyl-10-[3-(chloropropyl)] phenothiazine.

Description
Crystals which melt at 83-84 .

Action

124
Metrifonate has been found effective against Schistosoma hematobium, the parasite that causes juvenile urinary schistosomiasis in tropical countries. The compound was originally used as an insecticide and anthelmintic, known generically as trichlorfon.

Mianserin Hydrochloride (USAN) Org GB 94

1,2,3,4,10,14b-Hexahydro-2-methyldibenzo [c, f] pyrazino [1,2-a] azepine hydrochloride 2-Methyl-1 ,2,3,4,10,14b-hexahydro-2Hpyrazino[1,2-f] morphanthridine hydrochloride

Manufacturer
Farbenfabriken Bayer AG (Ger)

References
Farbenfabriken Bayer AG US pat 2,701,225

Metrifudil (Rec INN)

Metrifudilum (Lat). Metrifudilo (Sp) N-(-Methylbenzyl) adenosine 6-(o-Methylbenzylamino)-9-D-ribofuranosyl-9Hpurine

Synthesis
Prepared in several steps from benzylaniline, the last being the reduction of the respective 2,3diketopiperazine with diborane in tetrahydrofurane.

Description
Crystals, mp 282-284 (ethanol).

Action
Mianserin has proved to have an antiserotonin potency of the same order as cyproheptadine.

Manufacturer
NV Organon (The Netherlands)

Synthesis
Prepared from triacetyl-6-chloropurine-(-Driboside) and 2-methyl-benzylamine.

References
A novel type of substituted piperazine with high antiserotonin potency. W. J. van der Burg. J Med Chem 13 (1),35-39 (1970).

Description
Crystals, mp 157-158 .

Action
Metrifudil is a member of a family of N'aralkyladenosine derivatives, which have an action on the blood vessels and circulation.

MICA
5-Methoxyindole-2-carboxylic acid

References
1. WHO Chron 24 (11), 531 (1970). 2. C. F. Boehringer and Soehne GmbH. South African Appl. 67 7414.

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Description Synthesis
Prepared by saponification of ethyl 5methoxyindole-2-carboxylate. Crystals, mp 170.5 (isopropanol-diisopropylether). Two optical isomers have been described; (+) miconazole nitrate, mp 135.3, []D = +59 (c=1, in methanol) and (-) miconazole nitrate, mp 135 [ ]D , = -58 (c=1, in methanol).

Description
Crystals, mp 199.5-200 .

Action
It has been reported that, in vitro, low concentrations of miconazole nitrate are fungistatic against Phycomycetes, Ascomycetes, and Adelomycetes (eg, Saprolegnia; Candida, Cryptococcus, Aspergillus, dermatophytes; Phialophora, Spororichum, fungicidal against Trichophyton mentagrophytes and Microsporum canis, and bacterial against gram-positive cocci and bacilli. In guinea-pigs, doses administered topically and orally cure skin lesions caused by T mentagrophytes, canis, and C albicans. The results of a recent controlled, double-blind trial have shown the high effectiveness and excellent tolerance of miconazole nitrate in the topical treatment of chronic tinea pedis.

Action
MICA is a hypoglycemic agent which has been found to be effective both in normal and alloxaninduced diabetic rats.

Manufacturer
Lederle Laboratories (USA)

References
1. G. Pappalardo et al. Gazz Chim Ital 88, 574-590 (1958). 2. Method of inducing hypoglucemia with a substituted indole. S. Gordon et al. (to American Cyanamid Co). USA pat 3,332,846. 3. Indole-2-carboxylic acids. a new class of hypoglycemic compounds. N. Bauman et al. Biochem Pharmacol 18, 12411243 (1969).

Manufacturer
Janssen Pharmaceutica (Belgium)

References
1. JAMA 212, 467 (1970). 2. WHO Chron 24 (11), 531 (1970). 3. Janssen Pharmaceutica N. V. Ger Offen 1,940,388. 4. Treatment of long term tinea pedis with miconazole. Jo P. Brugmans et al. Arch Derm 102, 428432 (1970).

Miconazole Nitrate (USAN; Rec INN) R14889

Miconazolum (Lat). Miconazolo (Sp) 1-[2,4-Dichloro--[(2,4-dichlorobenzyl) oxy] phenethyl] imidazole mononitrate

Mitocromin
Antibiotic composed of an equilibrium mixture of two components A and B. It is related to daunomycin

Production
It is produced by two unidentified species of Streptomyces.

Description
Bright red amorphous powder, mp 170-175 .

Action
Mitocromin, a new member of the family of anthracycline antibiotics, exhibits antitumor activity.

Synthesis
Prepared in several steps from 2,4dichloroacetophenone, the last being the reaction of -(2,4-dichlorophenyl) imidazole-1-ethanol with 2,4dichlorobenzylchloride.

Manufacturer
Chas Pfizer and Co (USA)

References

126
1. Mitocromin: an antibiotic with antitumor activity. Wen Chin Liu et al. J Antibiotics 22 (12), 608-611 (1969) 2. Jap Med Gaz 7 (7), 15 (1970).

Mitomalcin
Action

NSC 113233

Synthesis
Prepared from 2,2-dichloro-1-(ochlorophenyl)ethanol with chlorobenzene in presence of sulfuric acid.

Mitomalcin is a new proteinaceous antileukemic antibiotic, of unknown structure. isolated from cultures of Streptomyces mafayensis.

Description
Crystals, mp 76-78 .

References
1. T. J. McBride et al. Proc Soc Exp Bioi Med 130, 1188-1190 (1969). 2. Toxicology studies with mitomalcin in dogs. R. K. Morrison et al. Cancer Chemother Rep 54 (4), 217-223 (1970).

Action
Antineoplastic; treatment of adrenal neoplasms.

Manufacturer
Calbiochem (USA)

Proprietary Name
Lysodren

References

Mitosper (USAN; Prop INN) A-35595C

Mitosperum (Lat). Mitospero (Sp)

1. JAMA 212, 1361 (1970). 2. Haller et al. J Arn. Chem Soc 67, 1600 (1945).

Action
Mitosper is an antineoplastic antibiotic obtained from cultures of an Aspergillus of the glaucus group.

MJ 1978
N-[[2-(o-Methoxyphenyl)-1-piperazinyl] ethyl]-1,1cyclopentanediacetimide 8-[2-(4-o-Methoxyphenyl-1-piperazinyl) ethyl]-8azaspiro[4,5] decane-7,9-dione

References
1. JAMA 212, 2246 (1970). 2. WHO Chron 24 (9), 426 (1970).

Mitotane (USAN; Rec INN) CB 313

Mitotanum(Lat); Mitotano(Sp) 1,1-Dichloro-2-(o-chlorophenyl)-2-(p-chlorophenyl) ethane o, p'-DOD

Synthesis
Prepared by the reaction of 3,3tetramethyleneglutaric anhydride with 1-(2aminoethyl)-4-(o-methoxyphenyl)piperazine. Also, by the condensation of 8-(2-chloroethyl)-8azaspiro[4, 5]-decane-7,9-dione with 1-(omethoxyphenyl)piperazine.

127
2. Therapeutic efficacy of new nitroimidazoles for experimental trichomoniasis; amebiasis and trypanosomiasis. A. C. Cuckler at al. Amer J Trop Med Hyg 19, 916 (1970). 3. A new drug (MK 910) in the therapy of intestinal and hepatic amebiasis. First results of clinical trial. M. V. Chari and B. N. Gadiyar. Amer J Trop Med Hyg 19, 927 (1970).

Description
The free base boils at 220-240 (0.35 mm Hg) and the dihydrochloride melts at 196.5-198.5 (dec).

Action
MJ 1978 has been found to have psychotropic and antiemetic properties consistent with those of major tranquilizers.

Manufacturer
Mead Johnson Laboratories (USA)

References
1. Mead Johnson and Co. US pat 3,398,151. 2. Shin Hayao et al. J Org Chem 26, 3415 (1961). 3. The pharmacology of MJ 1978. a novel azaspirodecanedione and potential tranquillizing agent. L. E. Allen et al. The Pharmacologist 11, 247 (1969).

MMDA Hydrochloride
5-Methoxy-3,4-methylenedioxy-methylphenethylamine hydrochloride 5-Methoxy-3,4-methylenedioxyamphetamine hydrochloride 1-(5-Methoxy-3,4-methylenedioxyphenyl)-2aminopropane hydrochloride

MK 910
2-(p-Fluorophenyl)-1-methyl-5-nitro-imidazole

Action
MMDA is a new amphetamine derivative. It is subjected to control because of its hallucinogenic effects.

References
Fed Reg 35 (47), 4305-4306 (1970).

Synthesis
Prepared in four steps from p-fluorobenzonitrile.

Description
Crystals, mp 187-188 (chloroform).

Moenomycin
Action
Moenomycin, a new antibiotic isolated from Streptomyces bambergiensis, is a mixture of several very chemically similar components, which are particularly characterized by their phosphorus content.

Action
M K 910 is a new amebicidal, which has proved to be effective in clinic.

Manufacturer
Merck Sharp and Dohme (USA)

References
1. Merck Co, Inc. Belg pat 660,836.

Manufacturer
Farbwerke Hoechst AG (Germany)

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2. On the distribution and metabolism of neuroleptic drugs. II. Pharmacokinetics of moperone. J. J. P. Heykants et al. Arzneim-Forsch 20 (9), 1238-1242 (1970).

References
1. R. Tschesche et al. Tetrahedron Letters 3, 141144 (1969). 2. Moenomycin VII. Isolation and properties of further components of the antibiotic moenomycin. U. Schacht and G. Huber. J Antibiotics 22 (12), 597602 (1970).

Moquizone (Rec INN) Rec 14-0127 Moperone (Rec INN) R 1658

Moperonum (Lat). Moperona (Sp) Methylperidol p-Fluoro-4-(4'-hydroxy-4'-p-tolylpiperidino) butyrophenone 1-[-(p-Fluorobenzoyl) propyl]-4-(p-tolyl) piperidine4-ol 1-Morpholinoacetyl-3-phenyl-2,3-dihydro-4(1H)quinazolinone

Description
Moquizone is soluble in water, mp 210-214 The . free base melts at 135-137 .

Synthesis
Prepared by condensing -chloro-pfluorophenylbutyrophenone with 4-(ptolyl)piperidine-4-ol.

Action
Moquizone is a member of a family of 1-aminoacyl2,3-dihydro-4-quinazolinone derivatives, which possess choleretic and arrhythmia-preventing 1 activity . The toxicologic studies on mequizone have 2 been reported .

Description
Crystals, mp 118-119.5 The hydrochloride melts at . 216-218 .

Toxicity
LD50 po in mice: 1.155 mg/kg; iv 237 mg/kg.

Action
Moperone is a highly potent and specific neuroleptic drug, closely related to haloperidol -the prototype of the neuroleptics of the butyrophenone series. The distribution and metabolism of the drug in the brain, liver and blood has been recently studied in rats.

Manufacturer
Recordati (Italy)

References
1. G. Bonola et al. J Med Chem 11.1136-1139 (1968). 2. Toxicologic investigations on moquizone. I. Setnikar and V. De Fina. Toxicol Appl Pharmacol 16, 571-584 (1970).

Manufacturer
Janssen Pharmaceutica (Belgium)

Proprietary Name
Luvatrena

References
1. P. A. J. Janssen. Brit pat 881,893; J Med Pharm Chem 1,281 (1959).

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Morantel Tartrate (USAN) CP-12,009-18

trans-1,4,5,6-Tetrahydro-1-methyl-2-[2-(3-methyl-2thienyl) vinyl] pyrimidine tartrate (1:1)

Morphethylbutyne Hydrochloride
2-Methyl-2-phenoxypropionic acid, 2morpholinoethyl ester hydrochloride 2-Phenoxy-isobutyric acid, 2-morpholine-ethyl ester hydrochloride

Synthesis
By the condensation of 3-methyl-thiophene-2carboxaldehyde with 1,2-dimethyl-1,4,5,6tetrahydropyrimidine in methyl formate and subsequent reaction with tartaric acid in isopropanol.

Synthesis
Prepared from a-phenoxyisobutyl chloride and 21 morpholinoethanol .

Description
Crystals, mp 143-145 The free base, bp 127-130 . .

Description
White, odorless, non-staining crystalline solid. It is readily soluble in water.

Action
Morphethylbutyne is a new non-narcotic antitussive agent.

Action
Morantel tartrate, the 3-methyl analogue of pyrantel, is an anthelmintic which has proved more potent than pyrantel in mice and dogs. The anthelmintic activity of morantel has been demonstrated in controlled laboratory trials involving 3 natural and experimental infections in sheep . Field 4,5 trials in sheep have also been reported .

Manufacturer
Instituto Farmacologico Serono (Italy)

References
1. E. Marchetti et al. Farmaco. Ed Sci. 20 (10), 696706 (1965). 2. Clinical trials on a new antitussive agent. M. Serembe and M. Barbetti. Farmaco Ed Pract, 24, 700-706 (1969). 3. Distribution and metabolic fate of morphethylbutyne in rats. E. Marchetti and G. Bergesi. Arch Int Pharmacodyn 184 (2), 245-251 (1970).

Manufacturer
Chas Pfizer and Co, Inc (USA)

References
1. JAMA 208, 1399 (1969). 2. Chas Pfizer Co, Inc. S African Appl 68,0516. 3. Controlled laboratory trials in sheep with the anthelmintic morantel. R. L. Cornwell and R. M. Jones. Br Vet J 126, 142 (1970). 4. Field trials in sheep with the anthelmintic morantel tartlate I. Prophylaxis of Nematodirus infection in lambs. R. L. Cornwell and R. M. Jones. Vet Rec 86, 430433 (1970). 5. Field trials in sheep with the anthelmintic morantel tartrate. R. L. Cornwell and R. M. Jones. Vet Rec 86, 465469 (1970).

Moxestrol (Prop INN) R-2858

11-Methoxy-19-nor-17-pregna-1,3,5(10)-trien-20yne-3,17-diol 11-Methoxy-17-ethynylestra-1,3,5(10)-triene3,17-diol 17-Ethynyl-11-methoxyestradiol

130
Yellow needle-shaped crystals, mp above 300.

Action
Multhiomycin is an antibiotic which only exhibits inhibitory activity against gram-positive bacteria.

References Synthesis
The reaction of 4,9-estradiene-11-ol-3,17-dione with methanol and p-toluenesulfonic acid in methylene chloride gives the corresponding 11methoxy derivative, which is refluxed with palladium hydroxide in methanol to give an aromatized monoketonic intermediate. This is treated with potassium acetylide in terc-amyl alcohol-dioxane to give 17-ethynyl-11-methoxy-1,3,5(10)-estratriene3,17-diol. 1. A new antibiotic multhiomycin. T. Tanaka et al. J. Antibiotics 23 (5), 231-237 (1970).

Mycophenolic Acid (USAN; Prop INN) Lilly 68618

(E)-6-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-5phthalanyl)-4-methyl-4-hexenoic acid

Description
Crystals, mp 280 (ethyl acetate). []D = +29 (c=0,6 in ethanol). UV max 280 m [E(1 %,1 cm) = 58.4] and 286 m [E(1 %, 1 cm) = 53.2]; sh 218, 221 and 229 m.

Action
Moxestrol exhibits pronounced estrogenic activity. It has been found to be more potent than estradiol and ethinylestradiol. It is under clinical study.

Manufacturer
Roussel Uclaf (France)

References
1. WHO Chron 24 (9), 426 (1970). 2 .Roussel-UCLAF. S African 67 03,381. 3. Controle par la eytologie vaginale des ettets dans la post-menopause d'un nouvel oestrogene, Ie 17ethinyl-11-methoxy-oestradiol. J. H. Soutoul et al. C R Soc Fr Gynecol 39 (6), 695704 (1969). 4. R-2858, a highly potent estrogenic compound. D. Bourquin et al. Third Int Congr Horm Steroids, Hamburg 7-12 Sept 1970, abs 312. Excerpta Medica International Congress Series No 210.

Production
Antibiotic isolated from the fermentation broth of Penicillium brevicompactum.

Description
Needles, mp 141 (hot water); freely soluble in alcohol and almost insoluble in water.

Action
Mycophenolic acid is an antibiotic substance which exhibits anti-tumor and immunosuppressive activity.

Manufacturer
Eli Lilly and Co (USA); ICI (UK)

Multhiomycin
Multhiomycin is a new antibiotic obtained from the mycelium of Streptomyces antibioticus 8446-CC.

References
1. JAMA 212, 2247 (1970). 2. WHO Chron 24 (9), 413 (1970). 3. Imperial Chemical Industries Ltd. Brit pat 1,158,387; 1,157,099. 4. J. H. Birkinshaw et al. Biochem J 43, 21 q-223 (1948).

Description

131
5. J. H. Birkinshaw et al. Biochem J 50, 630-634 (1952). 6. W. R. Logan et al. J Chem Soc 1946-1951 (1957). 7. Imperial Chemical Industries Ltd. Brit pat 1,157,100 (Pharmaceutical compositions). 2-Methyl-2-[p-(1,2,3,4-tetrahydro-1naphthyl)phenoxy]propionic acid

Myxin Cupric Complex

6-Methoxy-1-phenazinol-5,10-dioxide cupric complex 1-Hydroxy-6-methoxyphenazin-5,10-dioxide cupric complex

Synthesis
Prepared by reacting 1-(4-hydroxyphenyl)-1,2,3,4tetrahydronaphthalene with sodium and 2bromoisobutyric acid ethyl ester, followed by saponification of the resulting compound.

Description
Crystals, mp 131-132 (ether-hexane).

Action
Nafenopin has been found to be effective in lowering plasma cholesterol and triglycerides in the experimental animal. It has also been shown to be a potent hypolipidaemic agent in man.

Synthesis
Prepared from myxin and cupric acetate.

Manufacturer
CIBA Pharmaceutical Co (USA) Hoechst AG (Germany)

Action
Myxin cupric complex has proved to show a high degree of therapeutic activity against gram-positive and gram-negative bacteria, yeats and dermatophytes in cutaneous infections of laboratory animals.

References
1. JAMA 212, 467 (1970). 2. WHO Chron 24 (9), 426 (1970). 3. CIBA Ltd. Neth Appl 6A13.268. 4. R. Hess and W. L. Bencze. Experientia 24, 410 (196B). 5. G. Hartmann and G. Foster. J Atheroscler Res 10. 235-246 (1969). 6. Effects of SU-13437 on serum lipids in hyperlipoproteinemic patients. P. Weiss etal. Clin Pharmacal Thel 11 (1). 90-96 (1970). 7. Metabolism of SU-13434-a new hypolipidemic drug in man. J. R. Bianchine et al. Clin Pharmacol Ther 11 (6), 97-105 (1970). 8. Effect of a hypolipidaemic drug (CH 13A37) on plasma and tissue lipids, and on the intravenous fat tolerance in man. J. Boberg et al. Atherosclerosis 11. 353-360 (1970). 9. On the effect of the hypolipidaemic phenyl ether CH 13,437 on the liver metabolism of the rat. U. Schacht and E. Granzer, Biochem Pharmacol 19, 2963-2971 (1970). 10. Lipid effects of a phenolic ether (Su-13437) in the rat: Comparison with CPIB.

Manufacturer
Roche Laboratories (USA)

References
1. Hoffman La Roche. Ger Offen 1.931.466. 2. Tenth Interscience Conference on Antimicrobial Agents and Chemotherapy. Chicago Oct 18-21 (1970); abs 19.

Nafenopin (USAN; Prop INN) SU 13437 CH 13437

Nafenopinum (Lat). Nafenopino (Sp)

132
M. M. Best and C. H. Duncan. Atherosclerosis 12 (2), 188 (1970). 11. A. clinical trial with a new hypolipidemic agent (CH-13437). Arteaga et al. Rev Med Chile 98 (9), 111 (1970).

17-(Cyclobutylmethyl)-4,5-epoxymorphinane3,6,14-triol

Nafomine Malate (USAN; Prop INN)

Nafominum (Lat). Nafomina (Sp) 2-Methyl-1-naphthalenemethoxamine malate O-[(2-Methyl-1-naphthyl)-methyl]-hydroxylamine malate

Synthesis
Prepared from 14-hydroxydihydronormorphinone .
1,2

Description
Crystals, mp 229-231 .

Action
Analgesic-narcotic antagonist.

Manufacturer Synthesis
From 1-chloromethylnaphthalene. The hydrochloride melts at 198-199 (methanolacetonitrile). Endo Laboratories (USA)

References
1. Endo Laboratories. Brit pat 1,119,270. 2. Endo Laboratories. US pat 3.332,950. 3. A double blind controiled study on the pharmacologic effects of nalbuphine. H. W. Elliot at al. J Med 1(2), 74 (1970).

Action
Nafomine malate is a centrally acting muscle relaxant.

Toxicity
DL50 ip in mice: 500 mg/kg; po in mice: 1.210 mg/kg.

Nandrolone Laurate
17-Hydroxyestr-4-en-3-one 17-dodecanoate 19-Nortestosterone dodecanoate Norandrostenolone dodecanoate

Manufacturer
The Wm S. Merrell Co (USA)

References
1.JAMA 212.1360 (1970). 2. WHO Chron 24 (3), 132 (1970). 3. Richardson-Merrell Inc. Belg pat 654.632.

Nalbuphine (Rec INN; USAN) EN 2234A

Nalbuphinum (Lat). Nalbufina (Sp)

Action
Nandrolone laurate is a new long-acting anabolic agent. In a clinical study on patients with very poor physical condition, the administration of 100 mg of

133
the drug, once a month, for several months has proved to be effective.

References
1 . Instituto De Angeli. Neth Appl 6,405,327. 2. S. Casadio et al. J Med Chem 8 (5), 594-8 (1965). 3. Double blind trial of naphthypramide (DA-992) in osteoarthritis. E. Camarri et al. Curr Ther Res 12 (1), 1-9 (1970).

Manufacturer
Organon NV (Netherlands and France)

Proprietary Name
Clinibolin

References
Le laurate de nandrolone. nouvel anabolisant a action prolongee. A. Tsougranis. Immex 7 (2). 289-292 (1970).

Naproxen (USAN; Prop INN)

(+)-6-Methoxy--methyl-2-naphthaleneacetic acid (+)-2-(6'-Methoxy-2'-naphthyl)-propionic acid

Naphthypramide
Naftipramide

DA 992

-[2-(Dimethylamino) ethyl]--isopropyl-1naphthaleneacetamide -Isopropyl--(2-dimethylaminoethyl)-1-naphthyl acetamide

Synthesis
Prepared by treating diethyl 6-methoxy-2naphthalenemalonate with sodium hydride and methyliodide, followed by hydrolysis and decarboxylation.

Action
Naproxen is a new anti-inflammatory, analgesic and antipyretic agent.

Manufacturer
Syntex Laboratories, Inc (USA)

Synthesis
Prepared by hydrolysis of -isopropyl--(2dimethylaminoethyl)-1-naphthylacetonitrile.

References
1. WHO Chron 25 (3), 138 (1971). 2. Syntex Corp. S African Appl 6,707,597. 3. MNPA, a potent anti-inflammatory and analgesic agent. W. H. Rooks. Fed Proc 29, 420 (1970).

Description
Colorless crystals, mp 134 (ethanol/water = 3/7); 134-135 (ligroin).

Action
Naphthypramide is a new anti-inflammatory and antipyretic compound, also showing analgesic activity. It has shown to be effective and well tolerated in clinic.

Naproxol (USAN; Prop INN) RS 4034

(-)-6-Methoxy--methyl-2-naphthaleneethanol (-)- (6-Methoxy-2-naphthyl)--methylethanol

Manufacturer
Instituto De Angeli (Italy)

134

Description
mp 109-110 [ ]D = +42.6 in ethanol and +55 in ; chloroform.

Action
Broad spectrum antibiotic.

Synthesis
Prepared by reduction of -methyl-6-methoxy-2naphthalene acetic acid with lithium aluminum hydride or diborane. The optical isomer may be prepared by decomposition of the cinchonidine salt of naproxol monophthalate and subsequent saponification.

Manufacturer
Takeda Chemical Industries (Japan)

References
Jap Mad Gaz 7 (2), 6 (1970).

Action
Naproxol exhibits anti-inflammatory, antipyretic and analgesic activity.

Naringenine
Naringetol. Salipurpol 4',5,7-Trihydroxyflavonone

Manufacturer
Syntex Laboratories Inc (USA)

References
1. JAMA 213, 2248 (1970). 2. WHO Chron 25 (3), 138 (1971). 3. Syntex Corp. S African Appl 693229.

Synthesis
Prepared by hydrolysis of naringine, which is the glycoside,

Narbomycin B 62159B

Description
Needles, mp 251; UV absorption maxima at 226 and 292 m.

Action
Naringenine reduces capillary permeability.

Toxicity
LD50 ip in mice: 355 mg/kg.

References
1. Asahina. Ber 61,1514 (1928). 2. Rosenmund. Ber 61, 2608 (1928). 3. Zemplen. Ber 75, 648 (1942). 4. Effect of naringenine on the capillary fragility and permeability. Y. M. Khadzhai. Farmakol Toksikol 33, 313-316 (1970).

Production
From the culture filtrate of Streptomyces fradiae strain B 62159 two antibiotics have been recently isolated, which have been found to be identical to pikromycin and narbomycin respectively.

135

References

NC 1140
3-Trifluoromethyl-s-triazolo [3, 4] isoquinoline

M. E. Goldberg. Arch Int Pharmllcodyn Ther 186 (2), 287-297 (1970).

NC 3539
3-Methyl-8,9-dimethoxy-s-triazolo [3,4] isoquinoline

Action
NC 1140 is a substituted isoquinoline, which has been found to possess anti-inflammatory, analgesic and antipyretic activity in the rat. Its absorption, distribution and excretion has been studied in the dog, rat and monkey.

Action
It has been proved that NC-3539 specifically inhibits the aggressive response in both mousekilling (muricidal) and septal-Iesioned rats at doses below those which produce evidence of neurotoxicity. Pharmacologic activity of a new class of agents which selectively inhibit aggressive behavior in rats. .

Manufacturer
Neisler Laboratories, Inc (USA)

References
The absorption, distribution and excretion of 3trifluoromethyl-s-triazolo (3, 4) isoquinoline. M. J . Bartek et al. Toxicol Appl Pharmacol 17, 4152 (1970).

References
M. E. Goldberg. Arch In! Pharmacodyn Ther 186, (2). 287-297 (1970).

NC 7197 NC-3266
8, 9-Dimethoxy-s-triazolo [3,4] isoquinoline 2-(3-Ethylsulfinylpropyl)-1,2,3,4tetrahydroisoquinoline hydrochloride

Action
It has been proved that NC-3266 specifically inhibits the aggressive response in both mousekilling (muricidal) and septal-Iesioned rats at doses below those which produce evidence of neurotoxicity. Pharmacologic activity of a new class of agents which selectively inhibit aggressive behavior in rats.

Action
The cardiovascular effects of NC 7197 have been recently described. It has been suggested that the drug is a competitive -adrenergic blocking agent. It appears to produce its cardiac effects through indirect adrenergic mechanisms.

Manufacturer

136
Warner-Lambert

Negamycin
Antibiotic isolated from culture filtrates of three strains of Streptomyces

References
Cardiovascular effects of NC 7197. P. J. Privitera et al. Fed Proc 29 (2), 274 (1970).

Description
Colorless powder, mp 110-112 (dec).

Action

Nefopam Hydrochloride (Prop INN; USAN)

3,4,5,6-Tetrahydro-5-methyl-1-phenyl-1H-2.5benzoxazocine hydrochloride

Antibiotic of low toxicity and effective in vivo against gram-positive and gram-negative bacteria.

Toxicity
LD50 iv in mice: 400-500 mg/kg.

References
1. A new antibiotic, negamycin. M. Hamada et al. J. Antibiotics 23 (3), 170-171 (1970). 2, Mechanism of action of negamycin in Escherichia coli K 12. I. Inhibition of initiation of protein synthesis. S. Mizuno et al. J Antibiotics 23 (12), 581 (1970).

Synthesis
Prepared by the reduction of N-(2-hydroxyethyl)-Nmethyl-o-benzoylbenzamide with lithiumaluminum hydride in refluxing tetrahydrofurane and the reaction of the resulting alcohol with ptoluenesulfonic acid in refluxing benzene.

Description
Crystals. mp 238-242 .

Neopluramycin

Action
Muscle relaxant.

Manufacturer
Riker Laboratories Inc (USA)

Production
It has been isolated from the cultured broth of a strain of Streptomyces pluricolorescens.

References
1. WHO Chron 25 (3). 138 (1971). 2. Drug Trade News. p 26 (February 8. 1971). 3. B. J . Baltes (to Rexal Drug and Chemical Co) . US pat 3.487.153 .

Description
Orange crystals, mp 180-184 (dec). [ ]D = +362 (c=1.05, chloroform).

Action
Neopluramycin is a new antibiotic, which inhibits growth of gram-positive bacteria and shows experimental cytostatic activity, Isolation and characterization of a new antibiotic, neopluramycin.

137

References
S. Kondo et al. J Antibiotics 23 (7), 354-359 (1970).

Action
Nifungin is an antifungal antibiotic obtained from cultures of Aspergillus giganteus.

References
1. JAMA 212, 2246 (1970). 2. WHO Chron 24 (9), 427 (1970).

NF
1-(p--Pyrrolidinoethoxyphenyl)-2-phenylnaphto [2, 1-b] furan

Nifuratrone (USAN; Prop INN) WSM 10,166

Nifuratronum (Lat). Nifuratrona (Sp) N-(2-Hydroxyethyl)--(5-nitro-2-furyl) nitrone

Description
Crystals, mp 81 The hydrochloride salt melts at . 211 .

Action
NF is a new oral antifertility agent. Its biologic properties have been described in detail. The compound has a favorable therapeutic index.

Synthesis
By reacting 5-nitrofurfural with N-(2-hydroxyethyl) hydroxylamine hydrochloride.

Manufacturer
Central Drug Research Institute, Lucknow (India)

Description
Yellow needles, mp 151-152 Very soluble in water. .

References
1. Antifertility agents IV. 2,3-diphenylbenzo-and 5,6polymethylenebenzofurans, 2diphenylnaphthofurans, and some related compounds. H. P. S. Chawla et aL J Med Chem 13 (1), 54-59 (1970). 2. Biological properties of 2-phenyl-3-p-(pyrrolidinoethoxy)-phenyl (2:1,-b) naphthofuran-a new oral antifertility agent. V. P. Kamboj at al. Contraception 1 (1), 29-45 (1970) .

Action
Antimicrobial; active against a wide spectrum of gram-positive and gram-negative bacteria; effective in clinic.

Manufacturer
Dainippon Pharmaceutical Co, Ltd (Japan); Hess and Clark [Div Richardson Merrell (USA) 1

References
1. JAMA 211,2149 (1970). 2. WHO Chron 24 (9), 427 (1970). 3. Dainippon Pharmaceutical Co, Ltd. Brit pat 1,105,007. 4. The Pharmacologist 12 (2), 220 (Fall) 1970; abs. 115. 5. Tenth Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, III., Oct. 18-21 (1970); Abstr 49-51.

Nifungin (USAN; Prop INN) A18894

Nifunginum (Lat). Nifungina (Sp)

138
Tetrahydro-3-methyl-4-[(5-nitrofurfurylidene) amino]2H-1,4-thiazine 1,1-dioxide 4-[(5-Nitrofurfurylidene) amino]-3-methylthiomorpholino-1,1-dioxide

Nifurpirinol (Rec INN) P 7138

Nifurpirinolum (Lat) Furpyrinol 6-[2-(5-Nitro-2-furyl) vinyl]-2-pyridinemethanol 6-Hydroxymethyl-2-[2-(5-nitro-2-furyl) vinyl] pyridine

Synthesis
Prepared in several steps from 2-mercaptoethanol and propyleneoxide; the last being the condensation of 4-amino-3-methyl-tetrahydro-1,4-thiazine-1,1dioxide with 5-nitrofurfural.

Synthesis
Prepared by treating 5-nitrofurfural with 2-methyl-6acetoxy-methylpyridine, and hydrolyzing the resulting 2-[2-(5-nitro-2-furyl)vinyl]-5acetoxymethylpyridine with sulphuric acid. Also, by reacting 2-[2-(5-nitro-2-furyl)vinyl]-6-methylpyridine N-oxide with acetic anhydride.

Description
Orange, crystals, mp 182 (dil. acetic acid).

Action
Antitrypanosomal.

Description
Crystals, mp 170-171 (acetone).

Manufacturer
Bayer (Germany)

Action
New chemotherapeutic agent against fish diseases.

Proprietary Name
Lampit.

Toxicity
LD50 ip and po in mice > 2000 mg/kg.

References
1. WHO Chron 23, 204 (1969). 2. Farbenfabriken Bayer A. G. Ger pat 1,170,957. 3. Manuf Chem 41 (1), 72 (1970). 4. Nouveau medicament contre la maladie alge de Changas. Med Hyg (922), 1052 (1970).

Manufacturer
Dainippon Pharmaceutical Co, Ltd (Japan)

References
1. WHO Chron 24 (11), 531 (1970)_ 2. Dainippon Pharmaceutical Co, Ltd. Brit pat 1,053,730. 3. Abst. Internal Cong. Chemother (Tokyo) 6:385 (Aug 1969).

Nimorazole (Prop INN)

Nitrimidazine 4-[2-(5-Nitroimidazol-1-yl) ethyl]-morpholine N--Morpholinoethyl-5-nitroimidazole

Nifurtimox (Prop INN) Bay 2502

Nifurtimoxum (Lat)

139

Nisobamate (USAN; Rec INN) W 1015

Nisobamatum (Lat); Nisobamato (Sp) 2-Hydroxymethyl-2,3-dimethylpentyl carbamate isopropylcarbamate 2-sec-Butyl-2-methyl-1,3-propanediol carbamate isopropylcarbamate

Synthesis
From 5-nitroimidazol sodium salt and 1 chloroethylmorpholine . Also, from 1-(2'-ptoluensulfonyloxyethyl)-5-nitroimidazole and 2 morpholine .

Description
Yellow crystalline powder, mp 110-111 ;109-110 ,
1 2

Action and Uses

Nimorazole is a new topical and oral antitrichomonal agent. For use in the systemic treatment of infections by Trichomonas vagina/is and management of associated conditions.

Synthesis
Prepared by reacting N-isopropyl-2-methyl-2-secbutyl-3-hydroxypropyl carbamate with cyanic acid as a carbamating agent.

Dosage
500 mg daily (250 mg after breakfast and 250 mg after evening meal) for an average of six consecutive days.

Description
Crystalline solid, mp 78-80 .

Action
Tranquillizer, sedative and hypnotic.

Supplied as
Tablets, 250 mg.

Toxicity
LD50 ip in mice: 555 mg/kg.

Proprietary Name
Noxogin.

Manufacturer
Carter Wallace (USA)

Manufacturer
Carlo Erba (England) .

References
1. JAMA 207,1508 (1969). 2. Cron OMS 23 (10), 534 (1969). 3. Carter Products Inc. Brit pat 889.641.

References
1. Carlo Erba S. p. A. US pat 3,399,193, 2. Merck Co, Inc. Neth Appl 6,609,552 and 6,609,553 3. Med Act (Drugs of Today), 6 (5), 185-187 (1970). (Review with 6 references).

Nitrofungin
2-Chloro-4-nitrophenol

140
shown the drug to be an effective and safe drug in stimulating linear growth in stunted children.

Manufactuter
Wyeth Laboratories (USA)

Proprietary Name
Genabol

Action
Nitrofungin is an antimycotic agent. In a recent study it has been found that the compound is degraded to four metabolites only on using resistant strains; sensitive strains lacked this property.

References
1. H. Smith et al. J Chem Soc 4472 (1964). 2. Efficacy of norbolethone in stimulating linear growth in stunted children. A. N. Gogate. Curr Ther Res 12 (6), 323-332 (1970).

References
Microbial degradation of the antifungal agent 2chloro-4-nitrophenol (nitrofungin). A. Capek et al. Folia Microbiol 15, 350-353 (1970).

Norethisterone Enanthate
Norethindrone enanthate 17-Hydroxy-19-nor-17-pregn-4-en-20-yn-3-one heptanoic acid ester

Norbolethone (USAN) Wy 3475

Norboletone (Rec INN). Norboletonum (Lat) dl-13-Ethyl-17-hydroxy-18,19-dinor-17-pregn-4-en3-one dl-13, 17-Diethyl-17-hydroxygon-4-en-3-one

Action
The clinical and biochemical observations of a trial with norethisterone enanthate have been reported. 200 mg of the drug were administered intramuscularly to 10 normal fertile women every twelve weeks over a period of 9 months. No pregnancy was observed.

Synthesis
Prepared by treatment of 13,17-diethyl-3methoxygona-2,5(10)-dien-17-ol with aq hydrochloric acid. Also from 13,17-diethyl-17hydroxygon-5(10)-en-3-one and methanolic HCl.

Manufacturer
Schering AG (Germany)

References
Clinical and biochemical observations under treatment with the depotcontraceptive agent norethisterone enanthate. R. Petry et al. Third International Congress on Hormonal Steroids. Hamburg 7-12 Sept 1970. abstr 462. Excerpta Medica. International Congress Series No 210.

Description
Crystals, mp 144-145 UV max 241 m [ =16.500]. .

Action
Norbolethone is a new totally synthetic anabolic steroid of the gonone series. A recent trial has

141

d-Norgestrel
d-13-Ethyl-17-hydroxy-18,19-dinor-17-pregn-4-en20-yn-3-one

Noxiptiline Hydrochloride (Rec INN) BAY 1521

Noxiptilinum (Lat). Noxiptilina (Sp) 10,11-Dihydro-5H-dibenzo [a,d] cyclohepten-5-one, O-[2-(dimethylamino) ethyl] oxime hydrochloride 5-(2-Dimethylaminoethoxyimino)-5H-dibenzo [a,d] cyclohepta-1,4-diene hydrochloride

Description
White crystalline powder. UV max 241 m [E(1 %, 1 cm) =549] in methanol. Norgestrel is a racemate, that is, a mixture of equal parts of the d and I optical enantiomers.

Synthesis
Prepared by the reaction of 10,11-dihydro-5Hdibenzo [a,d] cyclohepten-5-one with hydroxylamine, and the reaction of the resulting ketoxime with -chloroethyldimethylamine in presence of sodium ethylate. It may also be prepared by the reaction of 10,11-dihydro5Hdibenzo [a,d] cyclohepten-5-one with 1-3 dimethylamino-ethoxyamine dihydrochloride .

Action
Experimental studie shave shown that I norgestrel lacks anti estrogenic and progestational properties, and that the d-enantiomer has twice the potency of the racemate. The results of a clinical trial have proved that the combination d-norgestrel (0.25 mg)ethinylestradiol (0.5 mg) is of equal contraceptive efficiency to the standard combination, norgestrel racemate (0.50 mg)-ethinyl estradiol (0.05 mg). The drug has just been marketed in Switzerland.

Description
White crystalline powder, mp 189-191 .

Proprietary Name
Stediril-d

Action and Uses

Noxiptiline, a tricyclic oxyimino ether, is a new antidepressive drug. It is used in the treatment of mental depression.

Supplied as
Scored tablets with 0.25 mg of d-norgestrel and 0.05 mg ethinylestradiol

Dosage
Intramuscularly: 25 to 50 mg 2-3 times daily. Orally: for initiating treatment, 25 to 50 mg 2-3 times daily. This dosage may be increased to 300 mg if necessary. The usual maintenance dosage is: 100 to 200 mg daily in endogenous depressions and 25 to 100 mg in other types of depressions.

Manufacturer
Wyeth (USA)

References
1. Biological effects of racemic and resolved 13ethyl-4-gonen-3-ones. R. A. Edgren et al. Steroids 2, 731 (1963). 2. Biological effects of synthetic gonanes. R. A. Edgren et al. Recent Progress in Hormone Research 22, 305 (1966). 3. d-Norgestrel combined with ethinyl oestradiol as an oral contraceptive. W. G. McBride. Curr Ther Res 12 (4), 177-185 (1970).

Supplied as
Tablets 28.1 and 56.2 mg (equivalent respectively to 25 and 50 mg of noxiptiline base). Solution (injection) 50 mg/2 ml.

Proprietary Names
Agedal (Bayer AG, Germany).

Manufacturer
Bayer AG (Germany)

142

References
1. H. Eugelhard. Ger pat 1,198,353, 2. B. B. Wylie at al. J Pharm Sc 54 (9), 1373-1376 (1965). 3. G. Aichinger et al. Arzneim-Forsch 19 (5a), 838845 (1968). 4. Med Act (Drugs of Today) 6 (2), 58-60 (1970). (Review with 20 references). 5. Su alcuni aspetti tossicologici e farmacodinamici di un nuovo derivato triciclico ad azione antidepressiva: [5-(dimetilaminoetiloximino5Hdibenzo-[a.d)-cicloepta-1,4-diene) cloridrato) (BAY 1521). E. Marmo. II Farmaco (Ed Prac) 25 (9). 519-567 (1970).

Description
Yellow crystals, decompose at about 270

Action
This compound has proved to be effective in retarding the growth of the Sarcoma 180 tumor and in regressing large Sarcoma 180 tumors in mice. In a recent study it has shown to inhibit the development of both Dunning leukemia and the intramuscular Walker 256 tumor in rat.

References
1. Platinum compounds: a new class of potent antitumor agents. B. Rosenberg et al. Nature 222, 385-386 (1969). 2. Inhibition of Dunning ascitic leukemia and Walker 256 carcinosarcoma with cisdiamminedichloroplatinum (NSC-119875). R. J. Kociba et al. Cancer Chemother Rep 54 (5), 325-328 (1970).

NSC1026
1-Aminocyclopentanecarboxylic acid

Octoclothepin
Description
White crystalline solid with a solubility of 5 g/100 ml of water. 8-Chloro-10-(4-methylpiperazino)-10,11dihydrodibenzo [b,f] thiepin

Action
NSC 1026 is a synthetic amino acid, which has shown antitumor activity. The results of a recent clinical study suggest that the drug may be specific in its therapeutic effect upon leiomyosarcoma.

References
1. R. B. Ross et al. J Med Pharm Chem 3, 1-23 (1961). 2. L. Berlinguet et al. Nature 194, 1082-1083 (1962). 3. Phase II study of NSC 1026 in patients with cancer. J. B. Aust at al. Cancer Chemother Rep 54 (4), 237241 (1970).

Synthesis
In several steps from p-chlorothiophenol and o1,2 iodophenylacetic acid .

Description
Crystals, mp 99-101 (aq ethanol). UV max 211 m [E(1%, 1 cm) = 707] and 265 m [E (1 %, 1 cm) = 336].

Action

NSC-119875
cis-Diamminedichloroplatinum Pt(NH2)2 Cl2

Octoclothepin is a new neuroleptic agent. Clinical trials have revealed that the drug exhibits a remarkable antipsychotic effect.

Manufacturer

143
Spofa (Czechoslovakia) NV Organon (Netherlands)

Proprietary Name
Clotepin.

References
1. A new ganglion-stimulating compound: 2-imino-l, 3-diaza-4-carboxyethylcycloheptane hydrochloride (OG 30). P. R. Saxena. Europ J Pharmacol 7,159-169 (1969). 2. Ganglion-blocking neuromuscular-blocking and other actions of 2-imino-4-ethyloxycarbonyl-1,3diazacycloheptane hydrochloride (OG 30) a ganglionic stimulant. P. R. Saxena. Europ J Pharmacol 11, 75-83 (1970). 3. Pharmacological properties of some analogues of 2-imino-4-ethyloxycalbonyl-1,3-diazacycloheptane hydrochloride (OG 30), a ganglionic stimulant. P. R. Saxena et al. Arch Intern Pharmacodyn Therap 185 (1). 159-173 (1970).

References
1. J. O. Jilek et al. Coll Czechoslav Chem Commun 33, 1831 (1968). 2. M. Protiva et al. Farmaco, Ed Sci, 20, 721 (1965). 3. J. Metysova and J. Metys. Activ Nerv Super 9, 424 (1967). 4. The fate of octoclothepin in the animal organism. A. Franc et al. Biochem Pharmacol19, 1443-1448 (1970). 5. Experience with octoclothepin in manic syndromes. K. Nahunek et al. Scripta Med 42, 6-7 (1969). 6. Further clinical experience with octoclothepine. K. Nahunek et al. Act Nerv Super 12 (3), 239 (1970). 7. Effects of octoclothepin and chlorpromazine evaluated by a standardized interview. O. Vinar et al. Act Nerv Super 12 (3), 241 (1970). 8. Our experiences with octoclothepin. J. Molean et al. Act Nerv Super 12 (3),243 (1970).

Orgotein (USAN)
Ormetein Mainly -helical partly divalent-metal (Mg, Cu, Zn) chelated water soluble protein of fairly low molecular weight (ca 34,000)

OG 30
2-lmino-4-ethyloxycarbonyl-1,3-diaza-cycloheptane hydrochloride

Production
From bovine liver in a multi-step process.

Action
Orgotein is a novel modified protein, which exhibits considerable anti-inflammatory potency in several animal models of induced inflammation.

Manufacturer
Beta Labs and Diagnostic Data, Inc (USA)

Proprietary Name
Ontosein.

Description
Crystals, mp 131-132; []D = -74.50 (c=1.04, in water).

References
1. JAMA 208, 1399 (1969). 2. Safety evaluation of orgotein. a novel antiinflammatory protein. S. Carson et al. Fed Proc 29 (2), abs 978 (1970).

Action
OG 30 is a ganglionic stimulant. It has been found to act on the nicotinic receptors of the ganglion cells.

Toxicity
LD50 ip in mice: 58 mg/kg.

Ormetoprim (Prop INN)

Ormetoprimum (Lat). Ormetoprina (Sp)

Manufacturer

144
2,4-Diamino-5-(methylveratryl) pyrimidine

Synthesis
By reacting I-ornithine with I-aspartic acid .
1

Description Synthesis
Prepared from 2,4-chloro-5(methylveratryl)pyrimidine. Crystals, mp 215-217 (dec); []D = + 7.10 (38% in water).

Action
Ornithine aspartate has proved to have a protective effect in the acute ammonia intoxication and carbon 2 tetrachloride poisoning in rats . Recently, the protective effect of this compound has been studied in conditions in which the organism of the animals would have been submitted to 3 exhaustion of muscular and cardiac strength .

Description
Crystals, mp 230

Action
Ormetropim, chemically related to trimethoprim, is used with sulfadiazine in the treatment of infections in dogs.

Manufacturer
Merz Co (Germany)

Supplied as
Film coated tablets containing ormetoprim, 20 mg and sulfadiazine 10 mg. Also, ormetoprim 80 mg and sulfadiazine 400 mg.

References
1. Tanabe Seiyaku Co, Ltd. Brit pat 965,637, 2. A. Shioya et al. Jap J Pharmac 14,201 (1964). 3. Protection by ornithine aspartate of the effects of physical exercise. L. Cutinelli et al. Arzneim-Forsch 20 (8), 1064-1067 (1970).

Manufacturer
Burroughs Wellcome (England)

Proprietary Name
Trivetrin.

References
1. WHO Chron 23 (4) (1969). 2. F. Hoffmann-La Roche and Co A-G. Neth Appl 6,514,472. 3. F. Hoffmann-La Roche and Co A-G, Neth Appl 6,514,743. 4. Vet Rec 87, xiv (Aug 29, 1970) (advt).

Ornithine-8-vasopressin POR-8

Ornithine Aspartate
I-Ornithine I-aspartate Ornithine-8-vasopressin is a synthetic derivative of vasopressin.

Action
Ornithine-8-vasopressin is a new haemostatic agent. A double blind trial has shown that the drug

145
is very effective and significantly better than noradrenalin. possesses sedative, analgesic, antihistaminic, antiemetic and weak spasmolytic effects. For use in the treatment of a variety of mental disorders including acute schizophrenia, mania, chronic psychosis, delirium, and certain anxious and delirant forms of melancholia.

Manufacturer
Sandoz (Switzerland)

References
1. R. L. Huguenin et at Helv Chim Acta 46 (5), 166976 (1963). 2. Sandoz Ltd. Fr pat 1,396,607. 3. Olin Mathieson Chemical Corp. Fr pat 1,430,140. 4. Ornithine-8-vasopressin, a new vasoconstrictor used for haemostasis during operation for genital prolapse. O Vagn Nielsen and N. Valentin. Acta Obstet Gynec Scand 49, 45-48 (1970).

Dosage
Oxaflumazine is administered orally and parenterally. The sedative dose ranges from 150 to 400 mg daily. For the treatment of patients with psychosis, dosage ranges from 200 to 500 mg daily.

Proprietary Name
Oxaflumine.

Manufacturer
Diamant (France)

References

Oxaflumazine Disuccinate (Rec INN)

10-[3-[4-(2-m-Dioxan-2-ylethyl)-1-piperazinyl] propyl]-2-(trifluromethyl)-phenothiazine disuccinate

1. Societe Industrielle pour la Fabrication des Antibiotiques. Neth Appl 6,508,319. 2. R. Ratouis et al. Bull Soc Chim Fr 9, 2963-5 (1966) . 3. Med Act (Drugs of Today). 6 (3). 87-90 (1970). (Review with 4 (references).

Oxazinomycin

Synthesis
By the reaction of 10-(3-chloropropyl)-2(trifluoromethyl) phenothiazine with 4-(2-m-dioxan-2ylethyl) piperazine.

Description
White crystalline powder, mp 1380 ; slightly soluble in water and soluble in methanol. UV max 259.5 m [E(1 %, 1 cm) = 462] and 310 m [E(1 %, 1 cm) = 51].

Production
Oxazinomycin is an antibiotic which has been isolated from the culture filtrate of Streptomyces tanesashiensis.

Action and Uses

Oxaflumazine is a new major neuroleptic agent with an action similar to that of trifluorophenazine and fluphenazine. In addition to its main pharmacological action, oxaflumazine also

Description
White crystalline compound, mp 164-166 (dec); []D = +19,7 (c=1, water). UV max 231-232 m [E(1%, 1 cm)=168] in water.

146

Action
Oxazinomycin is active against gram positive bacteria and exhibits antitumor activity against Ehrlich mouse ascites carcinoma in vivo.

Registered Names
Trasicor.

Manufacturer
Ciba

Toxicity
LD50 iv in mice: 100-120 mg/kg; ip in mice: 10-20 mg/kg.

References
1. ICI Ltd. Neth Appl 6,607,921. 2. CIBA Ltd. Belg pat 669,402. 3. M. Wilhelm et al. Experientia 23 (8), 651-2 (1967). 4. Med Act (Drugs of Today) 6 (1), 25-29 (1970). (Review with 17 references). 5. Oxprenolol-Proceedings of a conference held at Hertford College, Oxford, on April 17, 1970. Postgrad Med J 46 (541, Suppl) (1970).

Manufacturer
Sankyo Co, Ltd (Japan)

References
Oxazinomycin. a new antibiotic. T. Haneishi et al. 174th meeting held July 27. 1970 under the sponsorship of the Japan Antibiotic Research Association (Tokyo).

Oxylidine Hydrochloride Oxprenolol Hydrochloride (Rec INN) Ciba 39089 Ba

1-(o-Allyloxyphenoxy)-3-isopropylamino-2-propanol 3-Quinuclidinol, benzoate (ester) hydrochloride 3-Benzoylhydroxyquinuclidine hydrochloride 1-Azabicyclo [2.2.2]-3-octanol benzoate (ester) hydrochloride

Synthesis
By condensing pyrocatechol monoallyl ether with epichlorhydrin, and subsequent reaction with isopropylamine. Also by reacting 3-(oallyloxyphenoxy)-2-hydroxy-1-chloropropane with 1,2,3 isopropylamine .

Synthesis
By reduction of 3-quinuclidinone to yield 3quinuclidinol, and subsequent reaction with 1 benzoylchloride .

Description
Crystals, mp 238-240 The free base boils at 148. 150 (0.3 mmHg).

Description
White crystalline powder, mp 107-109 the free ; base melts at 75-80 Freely soluble in water, . practically insoluble in ether.

Action
Oxylidine has proved to be useful in the treatment of diseases of the central nervous system and hypertensive diseases. The study of the antiarrhythmic activity of oxylidine has been recently reported.

Action and Uses

Oxprenolol is a new potent adrenergic betareceptor blocking agent.

Dosage
Cardiac Arrhythmias - Initially 40-60 mg orally daily, which may be increased to 80 mg if necessary. Angina - Initially 60 mg orally daily which may be increased gradually to 120 mg if necessary.

Manufacturer
All Union Chemo-pharmaceutical Research Institute (USSR)

References

147
1. E. E. Mikhlina et al. Zhur Obshchei Khim 30,163171 (1960). 2. M. D. Mashkovskii et al. Farmakol Toksikol 25. 32-37 (1962). 3. Antiarrhythmic activity of oxylidine. K. A. Zaitse va and M. D. Mashkovsky. Farmakol Toksikol 33. 305-309 (1970) .

Palmidrol
Palmitoylethanolamide N-(2-Hydroxyethyl) hexadecanamide N-(2-Hydroxyethyl) palmitamide

PEA

P-1961
4-Amino-1,2,3,4-tetrahydro-1-phenylquinoline hydrochloride

Synthesis
Prepared by refluxing ethanolamine with palmitic 1 acid .

Description
Crystals, mp 98-99 Insoluble in water at room . temperature.

Action
Palmidrol is a naturally occurring substance, isolated from soybean lecithin, egg yolk and peanut 2 meal and animal tissues. Antianaphylactic, antiinflammatory effects and an increase of nonspecific resistance to upper respiratory infection have been found after palmidrol treatment. The drug seems also to have moderate stimulating effects, anti4 alcvhol activity and extremely low neurotoxicity .

Synthesis
Prepared in three steps from diphenylamine Npropionic acid, the last one being the reduction of 2,3-dihydro-1-phenyl-4-(1 H)-quinolinone oxime 1.2.

Description
Crystals, mp 221-224 (water). The maleate, mp 170-174 and the free base, bp 110-130 (0.001 , mm).

References
1. E. T. Rooe et al. J Am Chem Soc 74, 3442-3443 (1952). 2. F. A. Kuehl at al. J Am Chem Soc 79, 5577-5578 (1957). 3. Cesk Fysiol 18 (3-4), 346 (1970). 4. Effects of palmitoylethanolamide on the central nervous system. H. Raskova at al. CINP VII Congress Abstracts Vol II. abstr 356 (1970).

Action
Pharmacological studies have proved that P-1961 shows centrally stimulating and sedating properties. Arousal effects without locomotor component are dominant in the activity profile.

Manufacturer
Chemischen Fabrik Promonta GmbH (Germany)

References
1. Chemische Fabrik Promonta GmbH. Brit pat 1.077,974; Ger pat 1,233,402. 2. O. Hromatka et al. Monatsch Chem 97, 1011 (1966). 3. Pharmacological study on 1-phenyl-4-amino1,2,3.4-tetrahydroquinoline. P. Marquardt. Arzneim-Forsch 20 (10), 1497-1500 (1970) .

Panidazole (BAN)
4-[2-(2-Methyl-5-nitroimidazol-1-yl) ethyl] pyridine 2-Methyl-5-nitro-1-[2-(4-pyridil) ethyl] imidazole

148
disturbances, such as pain, vomiting and meteorisms.

Synthesis
Prepared by the reaction of imidazole with 4vinylpyridine, and by the nitration of the resulting 1[2-(4-pyridyl) ethyl] imidazole.

Dosage
1 to 1.5 mg daily.

Description
Crystals, mp 108-111 .

Supplied as
Tablets, 0.5 mg.

Action
Panidazole is a new amebicidaI.

Registered Names
Vagopax.

References
1. Chem Drug 193, 228 (1970). 2. Ward Blenkinsop and Co, Ltd. Neth Appl 6.606,335.

Manufacturer
Lab Cetrane (France)

References
1. S. B. Coan et al. J Am Chem Soc 78, 3701-3 (1956). 2. Schering Corporation. Brit pat 788,126. 3. Med Act (Drugs of Today), 6 (3), 92-94 (1970). (Review with 12 references).

Parapenzolate Bromide (Prop INN) SCH 3444

4-Hydroxy-1,1-dimethylpiperidinium bromide benzilate 4-Benziloyloxy-1,1-dimethylpiperidinium bromide N-Methyl-4-piperidylbenzilate methobromide

PC 796
5,5-Diphenyl-1-(phenylsulfonyl) hydantoin

Synthesis
It is prepared by transhalogenation of N-methyl-4piperidyl benzilate methiodide with silver bromide, or alternatively by bubbling methyl bromide through a benzene solution of N-methyl-4-piperidylbenzilate. The latter is prepared from N-methyl-4-piperidinol hydrochloride and diphenylchloroacetylchloride.

Synthesis
Prepared by rearrangement of 5,5-diphenyl-3(phenylsulfonyl) hydantoin.

Description
White crystalline powder, mp 237-238 the free : base melts a 162.5-163 It is soluble in water. .

Description
White odorless crystals, mp 222-223 It is insolub le . in water and soluble in alkaline aqueous solution.

Action and Uses

Parapenzolate bromide is a new potent anticholinergic. For use in the treatment of peptic ulcers (gastric and duodenal), gastritis, spastic colitis, colopathies and functional digestive

Action
PC 796 shows anti-inflammatory, analgesic and antipyretic activity.

149
Jap Med Gazz 7 (4), 6 (1970).

Manufacturer
Dainippon Pharmaceutical Co, Ltd (Japan)

References
1. Dainippon Pharmaceutical Co. Ltd. Jap pat 6815.186; US pat 3,534,022 2. Pharmacological studies of a new antiinflammatory drug, 1-phenylsulfonyl-5.5diphenylhydantoin (PC-796) in experimental animals. H. Nakamura et al. Arzneim-Forsch 20 (8), 10321046 (1970).

Pendecamaine (Prop INN; USAN)

Pendecamainum (Lat). Pendecamaina (Sp) (Carboxymethyl)-dimethyl-(3-palmitamidopropyl) ammonium hydroxide inner salt

Pecilocine (Rec INN)

Pecilocin (BAN); Variotin N-(8'-R-Hydroxy-6'-methyl-trans-trans-trans-dodeca2',4',6'trienoyl)-2-pyrrolidone

Action
Surfactant and antibacterial compound.

Manufacturer
Th Goldschmidt (Germany)

Proprietary Name
Tego-Betaines.

Production
Isolated from Paecilomyces varioti banier var antibioticus.

References
1. WHO Chron 24 (9). 428 (1970) . 2. Chem Drug 193. 228 (1970) .

Description
Neutral oil with ester-like odor.

Action
Pecilocine is an antifungal antibiotic marketed in Japan and Denmark as an antitrichophytosis drug. The stereochemical configuration of the antibiotic has been recently elucidated by examining nuclear Overhauser effect.

Penfluridol (Prop INN; USAN) R 16341

Penfluridolum (Lat) 4-(4-Chloro-,,-trifluoro-m-tolyl)-1-[4,4-bis-(pfluorophenyl) butyl]-4-piperidinol

Manufacturer
Nippon Kayaku Co (Japan) and Leo Pharmaceutical Co (Denmark and England)

References
1. S. Takeuchi et al. J. Antibiotics 12A, 109, 195 (1959); 17 A, 267 (1964). 2. S. Takeuchi et al. Tetrahedron Lett 5197 (1966). 3. Absolute structure of Variotin.

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Synthesis
Prepared from 4,4'-dicyanodiphenoxypentane.

Description
Hygroscopic crystals, mp about 180

Action
Pentamidine isethionate has been used in the tropics for 30 years in the chemoprophylaxis and treatment of African trypanosomiasis and the treatment of leishmaniasis. The results of a recent study indicate that pentamidine, if given early enough in the course of P. carinii pneumonia, is an effective agent. Since pentamidine is a toxic drug, all efforts should be made to obtain histologic confirmation of P. carinii infection before starting therapy.

Description
White microcrystalline powder, mp 105-107 ,only slightly soluble in water or in diluted solutions of hydrochloric acid (less than 0.5mg/ml).

Action
Penfluridol is a new member of the potent and longacting series of diphenylbutyl piperidine neuroleptics of which pimozide is the prototype.

Manufacturer
May and Baker Ltd (England)

Proprietary Name
Lomidine.

Manufacturer
Janssen Pharmaceutica (Belgium)

References
1. May and Baker, Ltd. US pat 2.410.796. 2. Pentamidine isethianate in the treatment of Pneumacystis carinii pneumonia. Karl A. Wester et al. Ann Intern Med 73 (5), 695-702 (1970).

References
1. WHO Chron. 24 (9), 429 (1970). 2. JAMA 215,1313 (1971). 3. The pharmacology of Penfluridol (R 16341) a new potent and orally long-acting neuroleptic drug. P. A. J. Janssen et al. Eur J Pharmacol 11, 139-154 (1970). 4. Maintenance therapy of chronic psychotic patients with a weekly oral dose of R 16341. A controlled double-blind study. F. Baro et al. J Clin Pharmacol 10 (5) 330-341 (1970).

Pentapiperide Methylsulfate (USAN; Rec INN)

4-Hydroxy-1-methylpiperidinium methylsulfate dl-3methyl-2-phenyl-valerate

Pentamidine Isethionate MB 800 RP 2512

p,p'-(Pentamethylenedioxy)dibenzamidine bis-(hydroxyethanesulfonate)

Synthesis

151
Pentapiperide is prepared by the reaction of 3methyl-2-phenyl valerie acid chloride with 1-methyl4-piperidinol.

Description
Colorless needles, which melt at 228-229 ]D = .[ 90 (c = 0,228% in methanol). It is soluble in methanol and in ethanol.

Description
White crystalline powder, mp 110-112 Very soluble . in water and soluble in alcohol. The hydrochloride melts at 85-86 .

Action
Pepstatin is a remarkable inhibitor of pepsin activity in the gastric juice. It is under clinical study and has been shown to be effective in the treatment of peptic ulcer .

Action and Uses

Pentapiperide methylsulfate is a new anticholinergic drug, which is useful as adjunctive therapy in the management of peptic ulcer.

Toxicity
LD50 ip in rats: 875 mg/kg.

Dosage
10 or 20 mg 3 to 4 times daily .

Manufacturer
Banyu Pharmaceutical Co (Japan)

Supplied as
Tablets 10 mg.

References
1. Jap Med Gaz 7 (6), 1 (1970). 2. Pepstatin, a new pepsin inhibitor produced by actinomycetes. H. Umezawa et al. J Antibiotics 23 (5), 259-262 (1970). 3. The structure of pepstatin. H. Morishima et al. J Antibiotics 23 (5), 263-265 (1970).

Proprietary Name
Quilene.

Manufacturer
Warner-Chilcott Laboratories (USA)

References
1. Cilag Ltd. Brit pat 781,382. 2. Med Act (Drugs of Today) 6 (2). 61-63 (1970). (Review with 4 references).

Perhexiline Hydrochloride (USAN; Rec INN)

Perhexilene (FDA official name)
1

Pepstatin
iso-Valeryl-L-valyl-L-valyl-4-amino-3-hydroxy-6methyl-heptanoyl-L-alanyl-4-amino-3-hydroxy-6methylheptanoic acid

2-(2,2-Dicyclohexylethyl) piperidine hydrochloride 1,1-Dicyclohexyl-2-(2-piperidyl)ethane hydrochloride

Synthesis Production
Pepstatin is obtained from the culture filtrates of four new strains of actinomycetes, including Streptomyces testaceus sp and Streptomyces argenteofus var toyonakensis. Perhexiline can be prepared by hydrogenation of the corresponding pyridyl ethylene derivative or by hydrogenation of the corresponding 2 piperidylethylene compound .

Description

152
Perhexiline hydrochloride is a white crystalline powder, which melts at 243-246 and is slightly , soluble in water and physiologic saline. The acid maleate salt melts at 188.5-191 .

Action
Perhexiline is a new synthetic cardio-vascular agent with interesting effects in both animals and man. It has been shown to reduce exerciseinduced 3,6 tachycardia in man and to reduce frequency 4 and/or severity of anginal attacks . The effects of the drug on the coronary, and peripheral circulation as well as the possible mechanisms of inducing this activity, have been 5 recently reported .

Synthesis
Prepared from 2-methoxy-10-(3-chloro-21 methylpropyl) phenothiazine and 4-piperidinol . Also from 3-methoxy-1 0-(3-p-tolylsulfonyloxy-22 methylpropyl) phenothiazine and 4-piperidinol .

Manufacturer
The Wm. S. Merrell Co (USA)

Description
Crystals, mp 137-138

Proprietary Name
Pexid.

Action and Uses

Perimetazine is a new neuroleptic agent. It is used for its tranquilizing action in the treatment of neuroses and psychoses in which anxiety, tension and agitation are predominant. Perimetazine exerts an analgesic effect and is useful for the relief of pain of various types. Like chlorpromazine and other phenothiazine derivatives, it exerts an antiemetic effect and may be used for the control of nausea and vomiting.

References
1. Fed Reg 35 (179), 14450-14451 (Sep 15, 1970). 2. Richardson-Merrell Inc. Brit pat 1.025,578. 3. C. A. Bunde et al. Fed Proc 28, 672 (1969). 4. Y. W. Cho et al. Fed Proc 28, 671 (1969). 5. Cardiovascular pharmacology of perhexiline. W. J. Hudak et al. J Pharmacol Exp Ther 123, 287295 (1970). 6. Clinical evaluation of perhexiline maleate. T. Winsor. Clin Pharmacol Ther 11 (1), 85-89 (1970). 7. Effects of perhexiline maleate on exerciseinduced tachycardia. I. L. Grupp et al J Clin Pharmacol 10 (5), 312-315 (1970). 8. Systemic and coronary hemodynamic effects of perhexiline. G. G. Rowe et al. Arch Int Pharmacodyn 187, 377393 (1970).

Supplied as
Tablets, 5, 25 and 100 mg; solution (injection), 10 mg/ml; suppositories, 5 mg.

Dosage
Orally: In psychotic conditions, 100 to 250 mg daily. In neuroses, 10 to 100 mg daily.

Registered Name
Leptryl.

Manufacturer
Roger Bellon (France)

Perimetazine (Rec INN) AN 1317 RP 9159

1-[3-(2-Methoxyphenothiazin-10-yl)-2-methylpropyl]4-piperidinol 10-[3-(4-Hydroxypiperidino)-2-methylpropyl]-2methoxyphenothiazine

References
1. Rhone-Poulenc S. A. Brit pat 904,210. 2. Rhone-Poulenc S. A. Ger pat 1,154,117. 3. Med Act (Drugs of Today) 6 (4), 139-142 (1970). (Revie w with 11 references).

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Perlapine (Rec INN) HF 2333

6-(4-Methyl-1-piperazinyl) morphanthridine 6-(4-Methylpiperazin-1-yl)-11H-dibenz [b,e] azepine

Synthesis
Prepared from diphenylcarbamyl chloride and diethylaminoethanethiol.

Description Synthesis
In three steps from o-aminodiphenylmethane and 3,7 phosgene . By cyclization of either o-[4-methyl-14 piperazinyl) carboxamido] diphenylmethane or 2aminodiphenylmethane-2'-thiocarboxylic acid 45 methylpiperazide . Also by the reaction of 6aminomorphanthridine with sodium amide and 6 methyl-bis(-chloroethyl)amine . Crystals mp 48-49 The hydrochloride melts at 180. 181 .

Action and Uses

Antispasmodic in clinical practice (component of Spasmo-Dolviran-Bayer, Ger). Recent experiments in dogs and rabbits indicate that it is effective in a variety of experimental cardiac arrhythmias. Phencarbamide also exhibits local anesthetic properties.

Description
Yellow prismatic crystals, mp 138-138.5

Manufacturer Action
Perlapine is a new hypnotic agent. Farbenfabriken Bayer AG (Ger)

References Manufacturer
Wander (Switzerland) 1. Farbanfabriken Bayer AG, Brit pat 871,774 (1961). 2. A study of the antiarrhythmic and focal anaesthetic actions of phencarbamide. B. R. Madan at al. Arch Intern Pharmacodyn 185 (1), 53-65 (1970).

References
1. WHO Chron 24 (11), 532 (1970). 2. Chem Drug 193, 228 (1970). 3. Dr. A. Wander AG. Brit pat 1,006,156. 4. ibid. Swiss pat 436,305. 5. ibid. Swiss pat 436,306, 6. ibid. Swiss pat 436,307. 7. F. Hunziker et al. Helv Chim Acta 49, 1433 (1966). 8. G. Stille. Arzneim-Forsch 16 (2), 255-256 (1966). 9. J. Schmutz et al. Chim Ther 2 (6), 424429 (1967).

Phentonium Bromide (IAN) Z 326

8-(p-Phenylphenacyl) hyoscyaminium bromide N-(4'-Phenyl)phenacyl-1-hyoscyaminium bromide

Phencarbamide
Diphenylthiocarbamic acid S-[2-(diethylamino) ethyl] ester S-[2-(Diethylamino) ethyl] diphenylthiocarbamate

154

Production
From the culture filtrate of Streptomyces fradiae strain B 62159 two antibiotics have been recently isolated, which have been found to be identical to pikromycin and narbomycin respectively.

Description
mp 164; []D = +12.7 in ethanol.

Synthesis
Prepared from p-phenylphenacyl bromide and 1hyoscyamine.

Action
Broad spectrum antibiotic.

Manufacturer Description
Crystals, mp 193-194 . Takeda Chemical Industries (Japan)

References Action
Phentonium is a quaternary derivative of 1hyoscyamine which shows a rather high parasympathetic blocking activity with a negligible ganglion blocking and antimuscarinic activity. Jap Med Gaz 7 (2), 6 (1970).

Manufacturer
Zambon SpA (Italy)

Pimaricin

References
1. Whitefin Holding SA. Brit pat 1,026,640; Neth Appl 6,513,839. 2. UM Teotino et al. Chimie Therap 3, 453-457 (1968). 3. D. Della Bella et al. Chimie Therap 3, 458-462 (1968). 4. Human pharmacology of phentonium. a new autonomic drug. F. Azzollini et al. Curr Ther Res 12 (11), 734-754 (1970).

Production

Pikromycin
Amaromycin

B 62159A

From the culture filtrate of Streptomyces natalensis

Description
Crystals, dec at about 200 .

Action
Pimaricin is a tetraene antibiotic effective against Candida strains and Trychophyton sp. The results of a comparative study have shown that pimaricin can supplement or replace fungicidin (nystatin) at least in selected cases, especially where fungicidinresistance has developed.

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3. Un nouveau beta-bloquant, Ie LB-46 (Visken): Controles ctrocardiographiques de son action therapeutique chez les angineux. R. Saner. Therapie 25, 393-401 (1970) . 4. Haemodynamics of the new beta-adrenergic antagonist LB 46 in man. M .. H. Frick et al. Pharmac Clin 2, 134-137 (1970). 5. Klinisch Untersuchungen mit ''einem neuen Betarezeptorenblocker aus der Indolreihe (LB 46). H. Sterz. Wien Klin Wschr 82 (50), 894-899 (1970). 6. Die Behandlung der Angina pectoris mit einem neuen -Rezeptoren Blocker, dem Preparat LB-46 (4-[2-Hydroxy-3-iso-propylaminopropoxy]-indol). R. P. Saner. Schwaiz Med Wschr 100 (4), 174-179 (1970). 7. Klinisch-pharmakologische Untersuchungen mit einer neuen betarezeptoren-blockierenden Substanz (LB 46, Visken). G. Judmaier et al. Wien Klin Wschr 82 (50), 891-893 (1970). 8. A potent -adrenoreceptor blocking drug: 4-(2hydroxy-3-isopropylaminopropoxy) indole. G. E. Moore and S. R. O'Doneli. J Pharm Pharmac 22 (3), 180-188 (1970).

References
1. A. P. Struyk et al. Antibiotics Annual 878 (1957/58). 2. Preliminary report. Comparative study of pimaricin and fungicidin activity in vitro. M. Hejzlar and V. Vymola. J Hyg Epidemiol Microbiol Imn 14, 211-213 (1970).

Pindolol (USAN; Prop INN) LB 46

1-(Indol-4-yloxy)-3-(isopropylamino )-2-propanol 4-(2-Hydroxy-3-isopropylaminopropoxy) indol

Piperacetazine Hydrochloride
Synthesis
Prepared by the reaction of 4-hydroxyindol with epichlorhydrin, followed by treatment with isopropylamine.

(USAN)
10 [3-[4-(2-Hydroxyethyl)piperidino]-propyl] phenothiazin-2-ylmethyl ketone .

Description
Crystals, mp 171-173 .

Action
Pindolol is a new beta-adrenergic antagonist, which has recently been marketed in Germany and Switzerland.

Manufacturer
Sandoz

Synthesis
Prepared by the reaction of phenothiazin-2-yl methyl ketone with 1-bromo-3-chloropropane and subsequent reaction of the resulting 10(chloropropyl) phenothiazin-2-yl methyl ketone with 4-(2-hydroxyethyl) piperidine.

Proprietary Name
Visken (Germany); Viskene (Switzerland).

Supplied as
Tablets, 1 and 5 mg.

Description
White crystalline powder. Soluble in water, insoluble in ether and in benzene; mp 100-110 (with preliminary softening at 90 to 100).

References
1. Sandoz Ltd. Neth Appl 6,601,040. 2. K. Saameli. Helv physiol pharmacol Acta 25, 219221; 432-433 (1967).

Action and Uses

Piperacetazine is a new highly potent phenothiazine derivative, possessing tranquilizing and sedative properties. It is used in the control of hyperactivity,

156
agitation and anxiety states associated with acute and chronic schizophrenic reactions in adult patients.

Dosage
Orally, 10-20 mg 3 to 4 times daily. Parenterally, 10 mg once daily.

Dosage
Initially, 10 mg 2-4 times daily. Maintenance dosage, up to 160 mg daily in divided doses.

Supplied as
Tablets, 10 mg. Ampules 10 mg.

Supplied as
Tablets, 10 and 25 mg.

Manufacturer
Nippon Shinyaku Co, Ltd (Japan)

Proprietary Name
Quide.

Proprietary Name
Panpuron.

Manufacturer
Dow Chemical (USA)

References
1. Nippon Shinyaku Co, Ltd. Brit pat 1,148,858. 2. Jap Med Gazz 7 (11), 7 (1970). 3. Med Act (Drugs of Today) 7 (1), 25-26 (1971). (Review).

References
1. G. D. Searle. Brit pat 861,807. 2. Med Act (Drugs of Today) 6 (2). 64-66 (1970). (Review).

Pipoxolan Hydrochloride Pipethanate Ethobromide

Benzilic acid, 2-piperidinoethyl ester ethobromide 2-(1-Piperidino) ethyl benzylate ethobromide

(USAN)

BR-18

5,5-Diphenyl-2-(2-piperidinoethyl)-1,3-dioxalan-4one hydrochloride

Synthesis
Prepared by treating pipethanate with 1 ethylbromide .

Synthesis
By the reaction of -chloropropionaIdehyde diethyl acetal with benzilic acid, 2-(-chloroethyl)-5,5diphenyl-1,3-dioxalan-4-one is obtained. The latter 1,2 reacts with piperidine to give pipoxolan .

Description
White crystalline powder, with a bitter taste, mp 218220 Soluble in methanol, slightly soluble in ethan ol . and in water, and practically insoluble in ether and in benzene.

Description
White, odorless, crystalline powder, mp 207-209 i t ; is soluble in water.

Action and Uses

Pipethanate ethobromide is a quaternary parasympatholytic agent. It is used for the management of gastroduodenal ulcers and other gastrointestinal disorders associated with hypermotility and spasm. It is also used in the treatment of spasm of the biliary and urinary tracts.

Action and Uses

Pipoxolan is a new spasmolytic agent. For use in the treatment of gastrointestinal, genitourinary and biliary spasm.

157
considerably decreases the blood reservoir contained in the mesenteric vessels. Piribedil has proved to produce remarkable clinical results in the treatment of artheriopathies of the limbs.

Dosage
The usual dose for adults is 10 mg either orally or rectally three times daily. Children 10 mg up to twice daily.

Supplied as
Tablets, 10 mg. Suppositories, 10 mg.

Dosage
60-80 mg daily.

Proprietary Name
Rowapraxin.

Supplied as
Tablets, 20 mg.

Manufacturer
Rowa-Wagner (Germany)

Proprietary Name
Trivastal.

Bibliografia/Bibliography
1. M. Pailer et al. Monatsch Chem 99 (3), 891-901 (1968). 2. Rowa Wager K. G. Neth Appl 6,613,801; Brit pat 1.109,959. 3. Med Act (Drugs of Today) 6 (3), 94-97 (1970). (Review with 8 references).

Manufacturer
Lab Servier (France)

References
1. WHO Chron 24 (11), 532 (1970). 2. Science Union et Cie-Societe Francaise de Recherche Medicale. Neth Appl 6.413,349, 3. Med Act (Drugs of Today) 6 (1), 29-32 (1970). (Review with 5 references). 4. Preliminary results in the treatment of peripheral arteriopathies with a new pharmacologic substance (ET 495). R. J. Royer. Bibl Cardial 26, 174-179 (1970).

Piribedil (Rec INN) ET 495

2-(4-Piperonyl-1-piperazinyl)-pyrimidine 1-(2-Pyrimidyl)-4-(3,4-methylenedioxybenzyl)piperazine

Piromidic Acid PD 93
8-Ethyl-5,8-dihydro-5-oxo-2-(1-pyrrolidinyl)-pyrido [2,3-d] pyrimidine-6-carboxylic acid

Synthesis
Prepared from N-(3,4-methylenedioxybenzyl) 2 piperazine and 2-chloropyrimidine .

Description
White crystalline powder, mp 97-98 (ethanol). It i s insoluble in water and soluble in chloroform.

Action and Uses

It has been demonstrated experimentally that piribedil acts as a vasodilator, decreasing peripheral vascular resistance, as long as the sympathetic system remains intact. In addition, it decreases the action potentials of the sympathetic fibers. It has a direct vasoconstrictor effect on the smooth muscle fibers in the blood vessels when the sympathetic tonus is decreased or abolished. Lastly, it

Synthesis
Prepared by heating 5,8-dihydro-6-ethoxycarbonyl8-ethyl-2-methylthio-5-oxopyrido [2,3-d] pyrimidine with pyrrolidine.

Description
Crystals, mp 314-316 .

158

Action
Piromidic acid is a new anti-infective agent, which has been found active primarily against gramnegative bacteria and staphylococci.

Proprietary Name
Pondocillin (for the hydrochloride).

References
1. WHO Chron 24 (11). 532 (1970). 2. JAMA 213. 1325 (1970). 3. Chem Drug 193. 228 (1970). 4. Tenth Interscience Conference on Antimicrobial Agents and Chemotherapy. Chicago (USA), Oct 18-21 (1970); abs 121. 5. Acyloxymethyl esters of ampicillin. W. V. Daehne et al. J Med Chem 13 (4), 607-612 (1970).

Toxicity
LD50 po in rats and mice: 4000 mg/kg.

Manufacturer
Dainippon Pharmaceutical Co, Ltd (Japan)

References
1. Dainippon Pharmaceutical Co, Ltd. Jap pat 67 25,912. 2. Tenth Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, Oct. 18-21 (1970); abst 46.

Pizotyline (USAN) BC105

Pizotifen (Rec INN)

Pivampicillin (Rec INN; BAN; USAN) VD 923

Pivampicillinum (Lat). Pivampicilina (Sp) D-6-(2-Amino-2-phenylacetamido)-3.3-dimethyl-7oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-carboxylic acid hydroxymethyl ester pivalate ester

4-(9,10-Dihydro-4H-benzo [4,5] cyclohepta [1,2-b] thien-4-ylidene)-1-methylpiperidine

Synthesis Synthesis
Prepared from pivaloyloxymethyl 6-aminopenicillinate. By the reaction of 9,10-dihydro-4H-benzo(4,5)cyclohepta-(1,2-b)-thiophene-(4)-one with 1-methyl4-pyperidyl magnesium chloride and subsequent treatment of the resulting alcohol with hydrochloric 3 acid .

Description
Pivampicillin hydrochloride hemihydrate melts at 155-156 [ ]D = 200 (c=1. H2O). ;

Description
Crystals, mp 261-263 (dec).

Action
Pivampicillin is an acyloxymethyl ester of ampicillin. In experimental mouse infections oral pivampicillin has proved to be superior to the parent antibiotic. Studies in human volunteers have revealed that pivampicillin is much better absorbed than ampicillin.

Action
Anabolic, antidepressant and migraine prophylactic.

Manufacturer
Sandoz

Manufacturer
Leo Pharmaceutical Products (Denmark)

References
1. JAMA 212. 467 (1970).

159
2. WHO Chron 24 (11), 532 (1970). 3. Sandoz S. A. Belg pat 636,717. 4. An antiaminic drug, BC 705, in the prophylaxis of migraine. F. Sicuteri et al. Int Arch Allergy Appl Immunol 31 (1),78-93 (1967). 5. The influence of maturation on the acute toxicity to rats of the serotonin antagonists pizotyline (BC-705) and cyproheptadine. R. E. Bagdon and J. Dorado. Pharmacologist 12 (2), 531 (1970). 6. Protein metabolic effects of a non-steroidal anabolic agent. A. A. Albanese et al. Nutr Rep Int 2 (1), 29-41 (1970)

Action
Polihexanide is a polymeric biguanidine bactericide. It has been shown to possess a similar mode of action on vegetative bacteria to that of chlorhexidine, but has certain advantages over the latter, e.g. greater speed of kill, less inactivation by non-ionic surface active agents and greater physical compatibility and activity in the presence of cations and anions commonly present in hard waters.

Manufacturer

Polignate Sodium (USAN) AHR 24388

Sodium lignosulfonate The structure has not been fully defined but consists of a sulfonated polymer whose subunit is similar in structure to the subunit of coniferyl alcohol polymer. The individual polymer units are considered to be three-dimensional structures with molecular weights in the range of several thousand.

Imperial Chemical Industries Ltd (England)

References
1. WHO Chron 24 (9), 429 (1970). 2. Brit pat 702,268. 3. A. Davies et al. J Appl Bact 31 (4), 44B (196B) . 4. Evaluation of teat dipping formulations containing a germicidal polymeric biguanide. S. F. Forse et al. Vet Record 86, 506-511 (1970).

Action
Polignate sodium is a new anti-ulcer (pepsin inhibitor) agent.

Poloxalene
Polyoxypropylenepolyoxyethylene glycol non ionic block polymer

Manufacturer
A. H. Robins Co (USA)

References
JAMA 214, 1693 (1970).

Description
Hydroxyl number: 35.7-39.4; cloud point (10 per cent solution): 42-46 .

Polihexanide (Prop INN)

Polihexanidum (Lat). Polihexanido (Sp) Poly (iminoimidocarbonyliminoimidocarbonyliminohexamethylene monohydrochloride)

Action
The new animal drug application proposing the safe and effective use of poloxalene as a drench in cattle has been approved.

Manufacturer
Norden Laboratories Inc (USA)

References
Federal Register 35 (92), 7378 (1970).

160

Manufacturer
Ethicon Co (USA)

Proprietary Name

Polyglycolic Acid (USAN)

Poly (oxycarbonyl methylene)

Ethicon PTFE Paste for Injection (component of)

References
1. JAMA 209. 407 (1969). 2. Polytef injection for nasal deformity. J. J. Schell. Arch Otolaryng 92. 554559 (1970).

Synthesis
By polymerization of glycolic acid.

Practolol (USAN; Prop INN) ICI 50,172 AY 21,011

4-[2-Hydroxy-3-(isopropylamino) propoxy]acetanilide 1-(4-Acetamido-phenoxy)-3-isopropylamino-2propanol

Action
Polyglycolic acid is a surgical suture material.

Manufacturer
Lederle (USA)

Proprietary Name
Dexon.

References
1. JAMA 213. 1326 (1970). 2. The use of a new absorbable suture material (polyglycolic acid) in general surgery. A. R. Anscombe et al. Brit J Surg 57 (12), 921 (1970).

Synthesis
Prepared from 4-acetamidophenoxy-2, 3epoxypropane and isopropylamine. The free base melts at 134-136 and the , hydrochloride at 140-142 .

Action and Uses

Polytef (USAN)
Poly(tetrafluoroethylene)

Teflon

Practolol is a cardioselective beta-blocking agent. For use in the treatment of angina pectoris and control of cardiac arrhythmias.

Supplied as
Tablets 100 mg; ampoules 10 mg/5 ml.

Dosage
Angina pectoris: Orally 200 to 600 mg daily. Cardiac arrhythmias: 200 mg daily.

Action
Polytef is a prosthetic agent, for vocal cord rehabilitation and plastic and reconstructive surgery.

Proprietary Name
Eraldin.

Manufacturer

161
Imperial Chemical Industries Ltd (England)

References
1. Imperial Chemical Industries Ltd. Brit pat 1,078,852. 2. Med Act (Drugs of Today), 6 (5), 188-191 (1970). (Review with 14 references). 3. Coronary and hemodynamic effects of myocardioselective -receptor blockade by ICI 50172 in the closed chest dog. W. D. Bussmann et al. Am Heart J 79, 347-360 (1970). 4. Influence of propranolol and ICI 50.172 on the cardiovascular actions of catecholamines as modified by ergotamine. W. Osswald et al. J Pharmacol Exp Ther 174, 315322 (1970) .

Pramiverine (BAN; Rec INN) HSp 2986

Pramiverinum (Lat). Pramiverina (Sp) N-lsopropyl-4,4-diphenylcyclohexylamine 1-lsopropylamino-4,4-diphenylcyclohexane

Prajmalium Bitartrate GT 1012

Prajmalii bitartras (Lat). Prajmalio bitartrato (Sp) N-Propylajmalinium hydrogen tartrate

Synthesis
Prepared by the reaction of isopropylamine with 4,4diphenylcyclohexylchloride, or 4,4diphenylcyclohexanol, or 3,3-diphenylcyclohexen-6one, followed by hydrogenation.

Description
The free base boils at 164-165 (0.05 mm); the hydrochloride melts at 230 (ethanol).

Action Synthesis
By treating N-(n-propyl)-ajmaliniumbromide with sodium bicarbonate the crude free aldehyde is obtained, which is subsequently treated with tartaric acid. The product melts at 149-152 dec. Pramiverine is a new spasmolytic agent with relatively little effect on salivary secretion.

Manufacturer
Merck, Darmstadt (Germany)

Action
Antiarrhythmic agent.

References
1. Chem Drug 193, 228 (1970). 2. E. Merck AG. Neth Appi 6,515,046. 3. H. Diamant et al. Arzneim-Forsch 18 (9), 1137 (1968).

References
1. WHO Chron 24 (11), 532 (1970). 2. Dr. Karl Thomae GmbH. Ger pat 1,196,207. 3. Treatment of cardiac arrhythmias with Npropylajmaline bitartrate. R. Wegehaupt and W. Hager: Deutsche Med Wochenschr 95, 938-942 (1970). 4. On the pharmacology of N-propylajmaline bromide. E. J. Gendenshtein. Farmakol Toksikol 33 (3), 303305 (1970).

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Prazosin Hydrochloride (Rec INN) CP-12,199-1

Synthesis
Prednazoline is prepared from 21prednisolonephosphoric acid and fenoxazolin base in alcohol. 4-Amino-2-[4-(2-furoyl)-1-piperazinyl]-6,7dimethoxy-quinazoline Hydrochloride 1-(4-Amino-6,7-dimethoxy-2-quinazolinyl)-4-(2furoyl)-piperazine Hydrochloride

Description
Prednazoline occurs as a white crystalline powder, mp 140-190 Soluble in methanol, ethanol, and in . water in the presence of an equimolecular quantity of sodium bicarbonate.

Action and Uses

Prednazoline, a salt of 21-prednisolonephosphoric acid with fenoxazolin, causes anti-inflammatory and anti-allergic effects when applied topically to the nasal mucosa. It is used in the treatment of nasal congestion of allergic and inflammatory origin, rhinitis, rhinosinusitis, rhinopharingitis, sinusitis.

Action
Laboratory and human trials has suggested that prazosin can be an effective anti-hypertensive agent when given orally.
3 4,5

Supplied as
Nebulizer 25 mg/10 ml.

Manufacturer
Pfizer Laboratories (USA)

Proprietary Name
Deturgylone (Dausse, France).

References
1. WHO Chron 24 (11), 532 (1970). 2. Pfizer, Chas and Co, Inc. Brit pat 1.156,973. 3. A. Schriabine et al. Experientia 24 (11), 11501151 (1968). 4. D. W. Richardson et al. Circulation 38, 164 (1968). 5. Prazosin hydrochloride (CP-12,199-1), an oral anti-hypertensive agent: preliminary clinical observations in ambulatory patients. B. M. Cohen. J Clin Pharmac 10 (6), 408-417 (1970).

References
1. Nouveau medicament vasoconstricteur et antiinflammatoire. Lab Dausse Fr pat M 4,111. 2. Med Act (Drugs of Today) 7 (1), 26-28 (1971). (Review with 5 references).

Proadifen Hydrochloride (USAN; Rec INN) Prednazoline (Rec INN)

Fenoxazolin prednisolone phosphate 11,17,21-Trihydroxy-21-(dihydrogenphosphate)pregna-1,4-dien-3,20-dione compound with 2-[(ocumenyloxy) methyl]-2-imidazoline

SKF

525-A
2-(Diethylaminoethyl) 2,2-diphenylvalerate hydrochloride -Diethylaminoethyl diphenylpropyl acetate hydrochloride

163

Synthesis
Prepared by the reaction of 2,2-diphenylvaleric acid chloride with 2-diethylaminoethanol.

Description
Needles, mp 122-123 (acetone-ether)

Probucol (USAN; Prop INN) DH 581

Probucolum (Lat) Bis-(3,5-di-tert-butyl-4-hydroxy-phenyl) mercaptole acetone 4,4'-(Isopropylidenedithio)-bis-(2,6-di-tertbutylphenol)

Action
Proadifen hydrochloride has been commonly described as having little or no pharmacologic effect of its own. The drug has proved to inhibit numerous reactions catalyzed by the microsomal enzyme 2 system . It can antagonize as well as potentiate 3 neuromuscular blocking agents ; can inhibit contractions of vascular smooth muscle induced by potassium without significantly affecting those due 4 to norepinephrine . 5 It has a protective effect on CCI4 toxicity , prevents 6 the embryopathic effects of 7-OHM-12-MBA , and has unespecific effect on the gastrointestinal 7 absorption of drugs in rats . It shows antiarrhythmic activity on several experimentally induced 9 arrhythmias in the anesthetized dog .

Manufacturer
Smith Kline and French Laboratories (USA)

References
1. P. N. Craig et al. J Am Chem Soc 73, 1339-1341 (1951). 2. The Pharmacological Basis of Therapeutics. Ed by L S Goodman and A Gilman, 3rd edition p 34. The MacMillan Co 1965. 3. Sites of action of SKF 525-A in nerve and muscle. G. Suarez-Kurtz and C. Paul Bianchi. J Pharmacol Exptl Ther 172 (1), 33-43 (1970). 4. Selective blockade of potassium-induced contractions of aortic strips by -diethylaminoethyldiphenylpropylacetate (SKF 525A). S. Kalsner et al. J Pharmacol Exptl Ther 174 (3), 500-508 (1970). 5. The effect of SKF 525A on the distribution of carbon tetrachloride in rats. C. Marchand et al. J Pharmacol Exp Ther 174 (2), 232-238 (1970). 6. Protection from the embryopathic effects of 7hydroxymethyl-12-methylbenz() anthracene by 2methyl-1,2-bis-(3-pyridyl}-1-propanone (metopirone, Ciba) and -diethylaminoethyldiphenyl-n-propyl acetate (SKF 525-A). C. C Bird et al. Brit J Cancer 24 (3), 548-553 (1970). 7. The effect of SKF 525-A on drug concentration in the blood. S. McLean and C. Marchand. Life Sci 9 (Part 1),1075-1080 (1970). 8. Effect of SKF 525-A on biliary function. Influence of body temperature. W. G. Levine. Life Sci 9 (Part I), 437-442 (1970). 9. Antiarrhythmic effects of proadifen hydrochloride (SKF 525-A). A. P. Viana and W. Osswald. Arzneim-Forsch 20 (6), 851-853 (1970).

Synthesis
Prepared by acid-catalyzed condensation of 4mercapto-2,6-di-t-butylphenol with acetone.

Description
Crystals, mp 125-127 .

Action
Probucol is a new cholesterol-lowering agent found to be effective and safe in mice, rats, dogs and monkeys. It goes into clinical test.

Manufacturer
The Dow Chemical Co (USA)

References
1. WHO Chron 24 (9),429 (1970). 2. JAMA 212, 1360 (1970). 3. J. W. Barnhan et al. Fed Proc 28, 268 (1969). 4. J. W. Barnhan et al. J Med Chem 13 (4), 722-725 (1970). 5. J. W. Drake et al. Metabolism 18, 916-925 (1969). 6. Hypocholesterolemic effect of probucol. J. W. Barnhart et al. Amer J Clin Nutr 23 (9), 12291233 (1970).

164

Propionylpromazine hydrochloride CB
Propiopromazine Hydrochloride 1-[10-[3-(Dimethylamino) propyl] phenothiazin-2-yl]1-propanone hydrochloride

1497

Description
White, odorless, crystalline powder.

Action
Propoxyphene dibudinate is a new antitussive drug.

Manufacturer
Ravensberg Chem Fab (Germany)

Description
Crystals, mp 69-70 .

Proprietary Name
Sotorni.

Action
Propiomazine hydrochloride has been recently approved in the USA for oral administration to dogs as a tranquilizer.

References
1. WHO Chron 25 (3), 148 (1971). 2. Z Therapie 8 (2), 99 (1970).

Manufacturer
Diamond Laboratories (USA)

Propiretary Name
Tranvet.

Proxifezone (Prop INN) PM 6

(+)-4-(Dimethylamino)-3-methyl-1,2-diphenyl-2butanol-propionate (ester) compound with 4-butyl1,2-diphenyl-3,5-pyrazolidinedione (1:1) Dextropropoxyphene compound with phenylbutazone

Supplied as
Chewable tablets, 10 or 20 mg.

References
1. Etablissements Clin-Byla. Fr Add 71,342. 2. Fed Register 35 (228), 17995 (1970).

Propoxyphene Dibudinate
Probunafon 4-(Dimethylamino)-3-methyl-1,2-diphenyl-2-butanol propionate 2,6-di-tert-butyl-1,5-naphthalene disulfonate Dibudinate is a shorter nonproprietary name for 2,6di-tert-butyl-1,5-naphthalene disulfonate.

Description
White crystalline powder, mp 82-84 UV max 265 . m.

165

Action and Uses

Proxifezone, a dextropropoxyphene compound with phenylbutazone, has recently been marketed in France. It exercises analgesic, anti-inflammatory and antipyretic actions. It is used chiefly for the treatment of rheumatoid conditions.

Synthesis
Pyrantel is prepared by the reaction of 2thienylacrylamide with 1,3-propanesultone and the reaction of the resulting compound with N-methyl1 trimethylendiamine . Also from thiophene-2carboxaldehyde and 1,2-dimethyl-1,4,5,62 tetrahydropyrimidine .

Supplied as
Tablets, containing proxifezone 100 mg and creosotamide (myorelaxant) 300 mg. Suppositories, containing proxifezone 300 mg, creosotamide 600 mg and sodium ascorbate 50 mg.

Description
Pale yellow solid, soluble in water.

Action and Uses

Pyrantel is a new highly active anthelmintic compound which exhibits a broad spectrum of activity against both adult and immature worm infections of domestic animals. The drug acts on the neuromuscular system of the parasites. Pyrantel tartrate is used to treat infestations with Strongyloides spp., Oxyuris spp., Parascaris spp., Strongylides and Trichostrongylus axei.

Dosage
The initial dosage is 2 to 4 tablets daily. The maintenance dosage is 1 to 2 tablets daily. Rectally, 1 to 2 suppositories daily.

Manufacturer
Laboratories Midy (France)

Proprietary Name
Midalgyl.

Supplied as
Water soluble powder with 6.25% of pyrantel tartrate.

References
1. WHO Chron 24 (9), 430 (1970). 2. A new antirrheumatic drug: Midalgyl. J . Laurent and W. Kopp. Press Med 78 (48). 2145 (1970). 3. Propiedades fisico-quimicas de un nuevo analgsico. N. Sans-A. Alsina, Simposium Quimica Medico Farmaceutica. Barcelona. Septiembre 1970. Quimica e Industria 17 (1), 119-122 (1971) . 4. Med Act (Drugs of Today) 7 (1). 29-31 (1971). (Review).

Proprietary Name
Pyrequan.

Manufacturer Pfizer GmbH (Germany) References

1. Pfizer Ltd. Brit pat 1,045,838. 2. Pfizer Ltd. Brit pat 1,108,207. 3. Med Act (Drugs of Today), 6 (2), 71-74 (1970). (Review with 9 references).

Pyrantel Tartrate (USAN) CP-10423-18

1,4,5,6-Tetrahydro-1-methyl-2-[2-(2-thienyl) vinyl] pyrimidine tartrate (1:1)

Pyrazinobutazone
Phenylbutazone piperazine salt

166

Description
White powder, with a bitter taste; mp 140-141 the n , solidifies and remelts at about 180 Soluble in . methanol, ethanol and slightly soluble in water.

Synthesis
Prepared by the bromination of pmethylvalerophenone, followed by the treatment with pyrrolidine. Also by hydrogenation of 1-p-tolyl2-pyrrolidino-4-penten-1-one.

Action and Uses

Pyrazinobutazone has proved to be a defined chemical compound and its structure has been established by spectral methods. It is claimed to show the anti-inflammatory, analgesic and antipyretic properties of phenyl butazone, but with lower toxicity and less ulcerogenic effects. It is used with the same indications as phenylbutazone.

Description
Crystals, mp 178 .

Action
Pyrovalerone is a psychostimulant. Both in 2 3,4,5 pharmacological and in clinical experiments , it differs markedly from amphetamine. The 6 metabolism of the drug has been recently reported .

Dosage
Orally, 600 to 900 mg daily. Rectally, 425 to 900 mg daily.

Manufacturer
Dorsey (USA); Dr A. Wander SA (Switzerland)

Supplied as
Gelules, 300 mg. Suppositories, 425 mg.

Proprietary Name
Centroton.

Manufacturer
Laboratories Francais de Therapeutique (France)

References
1. W. Heffe. Helv Chim Acta 47, 1289 (1964). 2. G. Stille et al. Arzneim-Forsch 13, 871 (1963). 3. H. Heimann and K. Vetter. Schweiz Med Wochenschr 95, 306 (1965). 4. A. R. Holliday at al. Psychopharmacologia 6, 192 (1964). 5. H. Heimann and G. Lukacs. ibid 8, 79 (1965). 6. The metabolism of pyrovalerone hydrochloride. W. Michaelis et al. J Med Chem 13 (3), 497-503 (1970).

Proprietary Name
Carudol.

References
1. Etude sur la structure et les proprietes physicochimiques du pyrazinobutazone. J . Hue. et al. Cahier Medicaux Lyonnais (24), 21112119 (1970). 2. Med Act (Drugs of Today) 7 (1), 31-33 (1971) . (Review).

Pyrovalerone Hydrochloride (USAN; Rec INN) F1983

4'-Methyl-2-(1-pyrrolidinyl) valerophenone hydrochloride

Quinestrol (Rec INN) W 3566

3-(Cyclopentyloxy)-19-nor-17-pregna-1,3,5(10}trien-20-yn-17-ol 17-Ethynylestradiol 3-cyclopentyl ether

Synthesis

167
Prepared by the reaction of 17-ethynylestradiol with cyclopentyl bromide and potassium carbonate in refluxing ethanol. Also, by the reaction of estrone cyclopentyl ether with potassium acetylide.

Description
Crystals, mp 107-108 [ ]D = +5 (c=0.5 in ; dioxane).

Action
Quinestrol is an estrogen which has prolonged activity in animals and in man, as a result of storage in and subsequent release from body fat. The 2 combinations quinestrol-quingestanol and quinestrol-6-dehydro-retroprogesterone 3 (Duphaston) have been studied as a one dose a month oral contraceptive. The duration of the effect of quinestrol when administered to humans by 4 injection as compared to the oral route has been explored.

Synthesis
By treating 17-ethinyl-19-nortestosterone 3,17diacetate with cyclopentanol in the presence of p1 toluenesulfonic acid and also by treating 3methoxy-17-ethinyl-19-norandrosta-2,5(10)dien17-ol 17-acetate with cyclopentanol in the 2 presence of pyridine hydrochloride .

Description
Crystals, mp 182-184 (dioxane); [ ]D = -215 (in dioxane).

Manufacturer
Warner-Lambert (USA)

Proprietary Name
Estrovis.

Action
Quingestanol acetate is the 3-cyclopentyl enol ether derivative of norethindrone acetate and has the same biological profile as norethindrone acetate but 3,4 is twice as potent . The results of the use of this progestagen, taken routinely by fertile, married women in a single dose less than 24 hours after 5 coitus, have been reported . A combination of quingestanol acetate and quinestrol taken by mouth once every four weeks has proved to be effective as a contraceptive.

References
1. A. Ercoli. US pat 3,159,343 and 3,231,567. 2. Once-a-month oral contraceptive: quinestrol and quingestanol. B. Rubio and E. Berman. Obst Gynec 35 (6), 933936 (1970). 3. A trial of a one dose a month oral contraceptive. D. Claman. Arner J Obstet Gynec 107 (3), 461-464 (1970). 4. Duration of estrogenic effect following oral and intramuscular quinestrol administration. F. Brambilla and G. Bruno. Curr Ther Res 12 (8), 493-501 (1970).

Manufacturer
Warner-Lambert (USA)

References
1. F. Vismara SA. US pat 3,159,620; Ger pat 1,159,940. 2. F. Vismara SA. Ger pat 1,228,608. 3. T. Giannina et al. Proc Soc exp Biol Med 131. 781-789 (1969). 4. T. Mischler et al. Proc Soc exp Biol Med 132, 323-327 (1969). 5. A new postcoital oral contraceptive. B. Rubio et al. Contraception 1 (5), 303-314 (1970). 6. Once-a-month oral contraceptive: quinestrol and quingestanol. B. Rubio and E. Berman. Obstet Gynec 35 (6), 933936 (1970).

Quingestanol Acetate (Rec INN) W4540

3-(Cyclopentyloxy)-19-nor-17-pregna-3,5-dien-20yn-17-ol, acetate 3-Cyclopentylenol ether of 17-ethinyl-19nortestosterone acetate Norethindrone acetate-3-cyclopentyl enol ether

168

R 2323
13-Ethyl-17-hydroxy-18,19-dinor-17-pregna4,9,11-trien-20-yn-3-one

Synthesis
Several methods have been described .
1

Synthesis
Prepared by the reaction of aqueous 40% formaldehyde, 1-phenyl-2,3-dimethyl-4isopropylamino-5-pyrazolone, and nicotinamide in hot ethanol.

Description
Crystals, mp 154 (ethyl acetate); [ ]D = 84.6 (c=0.41, in methanol). UV max 239-240 m (=5,920) and 344 m (=29,850) in ethanol.

Description
White needles, mp 162-162.5 UV max 260 m in . 0.1 N HCI. It is readily soluble in methanol, chloroform, and slightly soluble in ether.

Action
R 2323 is a new contraceptive compound which has been found to be characterized mainly by its marked and efficient activity following post coitum administration. It acts as an anti-deciduogenic and anti-inplantationagent in non-oestrogenic doses. Preliminary clinical trials have shown that oral administration of the drug once weekly affords efficient protection without inhibiting ovulation.

Action
Ra 101 has antipyretic, analgesic, antiphlogistic, and mild sedative effects.

Manufacturer
R. Ravasini and Co (Italy)

Manufacturer
Roussel-UCLAF (France)

References
1. F. Banci and E. Tubaro. US pat 3,420,839. 2. Pharmacology of a nicotinamidomethylaminopyrazolone (Ra 201). E. Tubaro and F. Banci. Arzneim-Forsch 20 (8), 1019-1023 (1970).

References
1. Roussel-Uclaf. Neth Appl 6,607,609; Brit pat 1,069,709; Fr pat 1.479,352 and 1,503,984. 2. R 2323-an original contraceptive compound. E. Sakiz and G. Azadian-Boulanger. Third International Congress on Hormonal Steroids, Hamburg 7-12 Sept 1970; Abstr 86 [Excerpta Medica, International Congress Series No. 210].

RA233
2,6-Bis-(diethanolamino)-4-piperidino-pyrimido-[5Ad] pyrimidine

Ra 101
1-Phenyl-2,3-dimethyI-4-(N-nicotinamido-methyl-Nisopropyl) amino-pyrazolin-5-one

Action
RA 233, an analog of dipyridamole, is a potent inhibitor of experimental arterial thrombosis as measured by the arteriovenous Teflon microshunt technique in rats. Platelet retention by a column of

169
glass beads (platelet adhesiveness) is almost completely inhibited in blood samples drawn from rats during RA 233 infusion. These effects were associated with severe hypolension, but hypotension is not required for the antithrombogenic effect of RA 233. Wen-Chih Liu et al. J Antibiotics 23 (9). 437-441 (1970).

Manufacturer
Karl Thomae GmbH (Germany)

References
1. Effect of RA-233 on platelet function in vitro. AA Hassanein et al. Brit Med J 2, 83-86 (1970). 2. Prevention of experimental arterial thrombosis and platelet adhesiveness by 2,6-bis(diethanolamino)-4-piperidinopyrimido-[5,4-d]pyrimidine (RA 233). Paul Didisheim and C. A. Owen. Mayo Clin Proc 45, 695-699 (1970).

Rafoxanide (USAN; Rec INN) MK 990

3'-Chloro-4'-(p-chlorophenoxy)-3,5diiodosalicylanilide

Rabelomycin
3,4-Dihydro-3,6,8-trihydroxy-3-methylbenz [] anthracene-1,7,12(2H)-trione

Synthesis
a) By the reaction of 2-hydroxy-3,5diiodobenzonitrile with 3-chloro-4-(p-chlorophenoxy) 3 benzenediazonium fluoroborate . b) By the reaction of 3-chloro-4-(p-chlorophenoxy) aniline with salicylic acid in the presence of phosphorus trichloride, and subsequent reaction 4 with iodine monochloride . c) By the reaction of p-nitrophenol with 3, 4dichloroaniline, and subsequent reaction with 3,5diiodosalicylic acid. The resulting nitro derivative is first reduced to the amino-derivative, then diazotated in the presence of cupric chloride and 5 finally treated with hydrochloric acid .

Production
Rabelomycin, a new antibiotic, is produced by a strain of Streptomyces olivaceus ATCC 21,549

Description
Crystals, mp 168-170 (benzene) 5 also reported .
3,4

; mp 175-177

Description
Yellow needles, mp 193 (dec).

Action
Anthelmintic. It is used for the treatment of fascioliasis.

Action
Rabelomycin is active against gram-positive microorganisms.

Supplied as
Veterinary drench: rafoxanide, 2.27% w/v.

Manufacturer
Squibb (USA)

Manufacturer
Merck Sharp and Dohme

References
Isolation characterization, and structure of rabelomycin a new antibiotic.

Proprietary Name
Flukanide.

170
Prepared from 2,6-dihydroxybenzoic acid phenylester and 4-bromoaniline.

References
1. JAMA 212, 2247 (1970). 2. WHO Chron 24 (11), 459 (1970). 3. Merck Co, Inc. Ger Offen 1,808,679. 4. Merck Co, Inc. Ger Offen 1,810,821. 5. Merck Co, Inc. Ger Offen 1,810,819.

Description
Crystals, mp 229-230 .

Action
Resorantel is a new drug active against tapeworms in sheep and other rumiants.

Ranatensin
It is a decapeptide isolated from the skin of the frog, Rana pipiens with the amino acid sequence:

Manufacturer
Farbwerke Hoechst AG (Germany)

Proprietary Name
Terenol.

Pyr-Val-Pro-Glu-Trp-Ala-Val-GIy-HisPhe-Met-NH2 Action
Experimental studies have shown that the spectrum of action of ranatensin on blood pressure of various animals and the various isolated smooth muscle preparations is unlike that of any other vasoactive peptide. Ranatensin raises blood pressure in the dog and rabbit, but lowers it in the monkey.

References
1. WHO Chron 24 (11), 532 (1970). 2. Farbwerke Hoechst A. G. Brit pat 1,124,613. 3. H. Lemaire et al. J Pharm Sci 50, 831-7 (1961). 4. Deut Tierarztl Wochenschr 77 (5), 104-107 (1970).

References
1. Isolation and structure of a new vasoactive polypeptide. T. Nakajima et al. Fed Proc 29, 282 (1970). 2. Pharmacology of ranatensin. R. G. Geller et al. Fed Proc 29, 282 (1970). 3. The action of ranatensin, a new polypeptide from amphibian skin on the blood pressure of experimental animals. R. G. Geller et al. Br J Pharmacal 40, 605-616 (1970).

Riboflavin-Tryptophan Complex
The complex consists of equimolecular amounts of riboflavine and tryptophan

Resorantel (Rec INN)

Resorantelum (Lat) 4'-Bromo-resorcylanilide 4'-Bromo-2,6-dihydroxybenzanilide

Synthesis
Prepared from riboflavine and tryptofan in acid solution [n-butanol and 12N HCl (7:3), in presence of small amounts of carbon tetrachloride].

Description
Brownish crystals, mp 169.2 The solubility of the . complex, calculated as riboflavine, is five times greater than that of riboflavine.

Synthesis

171
2. Studies on antibiotic SF 733, a new antibiotic. I. Taxonomy, isolation and characterization. T. Shomura et al. J Antibiotics 23, 155-161 (1970). 3. Jap pat 70 17,150, June 13, 1970.

Action
From the nutritional point of view this complex presents the advantage of increasing the solubility of riboflavine, and also its stability against photolysis. It has been suggested that it can be used in patients with vitamin B, defficiency.

References
Preparation and properties of crystalline riboflavintryptophan complex. H. Mitsuda, H. Tsuge and F. Kawai. J Vitaminol 16 (3), 119-224 (1970).

RJ 64
3-(4-Pyridyl)-5-(2-chlorophenyl)-1,2,4-oxadiazole

Ribostamycin SF733 Vistamycin

O--D-Ribofuranosyl-(1-> 5)-O-[-2,6-diamino-2,6dideoxy-D-glucopyranosyl-(1-> 4)]-2deoxystreptamine

Description
White crystalline powder, mp 105-106.5 Freely . soluble in chloroform and poorly soluble in water.

Action
RJ 64 is a new centrally acting muscle relaxant. Its action is similar to that of chlorzoxazone.

Manufacturer
Chinoin (Hungary)

References Production
It is produced in culture liquids of Streptomyces ribosidicus SF-733 strain, and extracted and purified by an ion-exchange resin process. It has also been synthesized from neamine. Pharmacology of a new centrally acting muscle relaxant (RJ-64). G. P. Leszkovszky and L. Tardos. Arzneim-Forsch 20 (11), 1778-1783 (1970).

Description
Colorless needles, mp 192-195 (dec); [ ]D = +42 (c=1, water).

Ro 7-0207
-(Chloromethyl)-2-methyl-5-nitroimidazole-1ethanol 1-(3-Chloro-2-hydroxypropyl)-2-methyl-5nitroimidazole

Action
Ribostamycin is a broad spectrum antibiotic. Studies in humans so far have shown same to possess good therapeutic effects and few adverse reactions.

Manufacturer
Meiji Seika Kaisha (Japan)

References
1. Jap Med Gazz 7 (3), 12 (1970).

172

Synthesis
Prepared by the reaction of 2-methyl4(5)nitroimidazole with bis-(3-chloro-2hydroxypropyl) sulfate to yield 1-(2,3-epoxypropyl)2-methyl-5-nitroimidazole, and by the reaction of this nitroimidazole with hydrochloric acid.

Description
Crystals, mp 234-235 (isopropyl ether). [ ]D = +138.7 (c = 0.88, chloroform). UV max 299 m [=16,800] in methanol.

Action
Ro 7-2133 is a new progestational steroid, which has been reported to be 3 to 10 times more potent than its 4-deschloro analogue, chlormadinone 1 acetate . Some data on the endocrine profile of this 2 steroid has been recently reported .

Description
Crystals, mp 77-78 (toluene).

Action
Ro 7-0207 is a potentially potent antiparasitic substance whose range of usefulness may extend from helminthiasis, trichomoniasis, and amebiasis in their several forms, to possibly other infections produced by obligately anaerobic microorganisms.

Manufacturer
Hoffmann-La Roche

References
1. R. Wiechert. Experientia 24, 767 (1968). 2. Endocrine profile of a new progestational steroid. A. Boris et al. Acta Endocr. 63. 476-488 (1970) .

Manufacturer
Hoffmann-La Roche Inc (USA)

References
1. F. Hoffmann-La Roche Co, AG. Neth Appl 6,606,853. 2. E. Grunberg el al. Anlimicrob Ag Chemother, 513 (1968). 3. -Chloromethyl-2-methyl-5-nitro-1imidazoleethanol (Ro 7-0207), a substance exhibiting antiparasitic activity against amebae, trichomonads, and pinworms. E. Grunberg et al. Proc Soc Exp Biol Med 133, 490492 (1970).

Robenidine Hydrochloride (Prop INN)

Robenzidene hydrochloride 1,3-Bis [(p-chlorobenzylidene)amino] guanidine hydrochloride

Ro 7-2133
4,6-Dichloro-17-hydroxy-pregna-4,6-diene-3,20dione, acetate

Synthesis
Prepared from 1,3-diaminoguanidine nitrate and pchlorobenzaldehyde.

Description Synthesis
Prepared from 6-chloro-17-hydroxy-pregna-4,6diene-3,20-dione acetate by treatment with lithium chloride, N-chlorosuccinimide and hydrochloric-satd dioxane. After working up the mixture is treated with pyridine. White crystalline powder, mp 289-290 (dec). The nitrate salt melts at 198 (dec).

Action
Robenidine is a new poultry anticoccidial agent, highly effective in preventing chicken coccidiosis

173
caused by all eight most common pathogenic Eimeria species.

References
1. Chem Drug 194, 446 (1970). 2. Colgate-Palmolive Co. Brit pat 1,000,895. 3. Lakeside Lab Inc. Fr Addn 87,352. 4. J. J. McMonigle. Diss Abstr B28 (7), 2979 (1968).

Manufacturer
Lederle Laboratories (USA).

References
1. WHO Chron 25 (3), 142 (1971). 2. Robenzidene: a new poultry anticoccidial agent. S. Kantor et al. Science 168, 373-374 (1970). 3. Efficacy evaluations of, obenzidene for control of coccidiosis in chickens. W. M. Reid et al. Avian Diseases 14 (4), 788-797 (1970).

Salsolinol
1-Methyl-1,2,3,4-tetrahydroisoquinoline

Rolicypram (BAN) EX 4883

Rolicyprine 5-0xo-N-(trans-2-phenylcyclopropyl)-L-2pyrrolidinecarboxamide

Synthesis
Prepared by the reaction of Nchloroacetylphenethylamine with phosphorus pentoxide, and by the reduction of the resulting 1chloromethyl-3,4-dihydroisoquinoline with zinc/hydrochloric acid. The free base, bp 119 (19 mm); the hydrochloride, mp 178 .

Action
Salsolinol, a pharmacologically active alkaloid, is formed endogenously by brain tissue from dopamine as substrate in presence of ethanol or its metabolite acetaldehyde. It has been suggested that tetrahydroisoquinoline alkaloids could possibly be responsible for some of the effects either produced by ethanol or associated with alcoholism.

Synthesis
By the condensation of D-trans-2phenylcyclopropylamine with L-5-oxopyrrolidine-2carboxylic acid via the dicyclohexylcarbodiimide 2,3 method .

References
1. R. A. Robinson (to G. D. Searly). J Org Chem 16, 1911-1920 (1951). 2. Formation of an alkaloid derivative of dopamine with ethanol or acetaldehyde. Y. Yamanaka. Fed Proc 29 (2), 680 (1970).

Description
Crystals, mp 144-147 [ lD =+ 104.28 ; (dimethylformamide).

Action
Antidepressant agent.

Manufacturer
Lakeside

Sandoz 42-348
1-Methyl-4-piperidyl bis-(p-chloro-phenoxy) acetate

Proprietary Name
Cypromin.

174
Sch 9122 hydrochloride, a compound structurally related to diethylstilbestrol, has been reported to have significant hypocholesterolemic activity on prolonged administration to male rats. It has been shown that at oral doses which lowered serum cholesterol by as much as 30%, the drug did not 2 produce estrogenic effects .

Toxicity
LD50 : po in mice: 1632 mg/kg; iv: 94.5 mg/kg.

Action
Sandoz 42-348 is a new experimental compound which appears to be a highly active hypolipidemic drug; it has been found to be 9 times more active than clofibrate in animal tests. The drug is undergoing clinical testing.

Manufacturer
Schering Corp (USA)

References
1. Hypocholesteremic agents, I. Substituted stilbazoles and dihydrostilbazoles. F. J. Villani et al. J Med Chem 13 (3), 359366 (1970). 2. Effects of Sch 9122 HCl, a hypocholesterolemic compound, on mammary tissue, libido, and fertility of male rats. M. Steinberg and A. S. Watnick. Proc Soc Exp Biol Med 134 (3), 696-699 (1970).

Manufacturer
Sandoz Pharmaceuticals (USA)

References
1. Am Drug, pg 36-37 (July 28. 1969). 2. Fed Proc 27 (2), abstr 146-147 (1968). 3. A. R. Timms et al. Biochem Pharmacol 18 (8), 1861-1871 (1969). 4. R. M. Welch et al. Fed Proc 29 (2), abstr 683 (1970) . 5. Effect of clofibrate and 1-methyl-4-piperidyl bis(pchlorophenoxy) acetate (Sandoz 42-348) on steroId and drug metabolism by rat liver microsomes. R. A. Salvador et al. Life Sci 9 (Pt 2), 397-407 (1970).

Sch 9122 Hydrochloride

2-(p-Anisyl)-3-(2-pyridyl) pentane hydrochloride

Sclerothricin Hydrochloride
Sclerothricin is a new strongly basic antibiotic obtained from the culture filtrate of Streptomyces sclerogranulatus

Description
White amorphous powder, mp 214 (dec).

Action
The antibiotic is active against Gram-positive and Gram-negative bacteria and some fungi. Sclerothricin a new basic antibiotic.

Synthesis
Prepared by hydrogenation of the corresponding 1 stibazol .

References
Y. Kana at al. J. Antibiotics 22 (12), 583-589 (1969).

Description
Crystals, mp 170-171 (ethanol/ether); the free bas e melts at 50-51 (hexane).

Action

175

Scopafungin (USAN) U 29479

Production
An unspecified substance from Streptomyces hygroscopicus.

Manufacturer
Simes SpA (Italy)

References
1. Imperial Chemical Industries Ltd. Neth Appl 6.301.580. 2. Carl D. Lundsford et al. J Am Chem Soc 82. 116671 (1960). 3. -Adrenergic blocking drugs. III. 1-Aryloxy-and 1arylamino-3-amino-2-propanols. G. Ferrari et al. Boll Chim Farm 107 (4).234-48 (1968). 4. Pharmacological actions of SD16. a new blocking agent. R. Ferrini et al. Arzneim-Forsch 20 (8), 1074-79 (1970).

Action
Scopafungin is a new antibiotic with antifungal and antibacterial activity.

Manufacturer
The Upjohn Co (USA)

References
JAMA 212, 466 (1970).

SDDS
2-Sulfamoyl-4,4'-diaminodiphenylsulfone

SD 1601
1-lsopropylamino-3-(o-methoxyphenoxy)-2-propanol

Description
White crystalline powder, mp 236-242 It is slight ly . soluble in acetone, sparingly soluble in ethanol and chloroform, and practically insoluble in water.

Action
SDDS was first reported to be effective against 1 Toxoplasma . After thelapeutic experiments on 2,3 acute toxoplasmosis in swine both in artificially and naturally infected animals, it is now widely used in Japan as a potent therapeutic agent against toxoplasmosis in pigs. The prophylactic effects of the drug on toxoplasma infection in pigs have been 4 recently reported .

Synthesis
Prepared by the reaction of o-methoxyphenol with epichlorhydrine, and by the reaction of the resulting 3-(o-methoxyphenoxy)-1-chloro-2-propanol with isopropylamine. The free base melts at 82-83 and the hydrochloride at 110-112 .

Manufacturer
Tanabe Seiyaku Co, Ltd (Japan)

Action
SD 1601 is a new -blocking agent. from the results of a recent pharmacological study it has been concluded that the drug has a slightly greater blocking activity than propanolol, and at the same time that its specific side effects, such as myocardial and neurodepressant actions, are much less evident than in propanolol.

References
1. S. Ohshima et al. Jap J Parasitol 16, 331-338 (1967). 2. S. Ohshima et al. J Jap Vet Med Ass 22, 239-244 (1969). 3. K. Shimizu et al. Jap J Vet Sci 30, 183-195 (1968).

176
4. Toxicology and pharmacology of 2-sulfamoyl-4-4'diaminodiphenylsulfone (SDDS). S. Sakuma et al. Pharmacometrics 2, 184-195 (1968). 5. Prophylactic effect of SDDS on experimental infection with Toxoplasma in pigs. S. Ohsima et al. Am J Trop Med Hyg 19 (3), 422426 (1970).

Silver Allantoinate
Synthesis
By the action of silver nitrate in aqueous solution upon a saturated solution of allantoin at elevated temperatures.

Siccanin (Prop INN)

(13aS)-1,2,3,4,4a,5,6,6a,11,13b-Decahydro4,4,6a,9-tetramethyl-13H-benzo[afuro[2, 3, 4-mnjxanthen-l1-ol .

Action
Silver allantoinate has proved to have highly effective antibacterial properties when tested in vitro. The effectiveness of silver allantoinate as an inhibitor of the cutaneous bacterial flora of the hands of operating room personnel has been studied. Silver allantoinate as an inhibitor of cutaneous bacteria upon the hands of operating room personnel.

References
W. F. Ballinger et al. Ann Surg 171 (6), 836-842 (1970).

Production
It is obtained from the mycelium of Helminthosporium siccans, BH 34 strain.

Description
Colorless needles, mp 139-140 [ ]D = -136 (c = 2, , chloroform).

Simfibrate (Rec INN) CLAY 503

Simfibratum (Lat). Simfibrato (Sp) 2-(p-Chlorophenoxy)-2-methylpropionic acid trimethylene ester 1,3-Propanediol bis (2-p-chlorophenoxyisobutyrate)

Action
Siccanin is a new antifungal antibiotic.

Toxicity
LD50 ip in mice: 1,590-1,720 mg/kg.

Manufacturer
Sankyo Co, Ltd (Japan)

References
1. WHO Chron 25 (3), 143 (1971). 2. Jap Med Gazz 7 (4), 6 (1970) . 3. Siccanin. a new antifungal antibiotic I. In vitro studies. M. Arai et al. Antimicrob Agents Chemother-1969, p 247-252 (1970) . 4. II. In vivo studies. S. Sugawara. Antimicrob Agents Chemother-1969, p 253256 (1970).

Action
Simfibrate is a new anticholesterol agent. Experimental studies have proved that it shows an hypolipidemic activity more durable in rats. and more potent in rats and cholesterol-fed mice than clofibrate in continued administration.

177
3. Cardiovascular action of mesoionic compounds. 3-substituted sydnonimines. K. Kikuchi at al. Jap J Pharmac 20 (1), 23-43 (1970). 4. Hypotensive action of N-ethoxycarbonyl-3morpholinosydnonimine. SIN 10. K. Kikuchi et al. Jap J Pharmac 20 (1). 102-115 (1970). 5. Coronary collateral vasodilator action of Nethoxycarbonyl-3-orpholinosydnonimine (SIN-10) in heart with chronic coronary insufficiency in dogs. M. Hirata and K. Kikuchi. Jap J Pharmac 20 (2), 187-193 (1970). 6. Metabolic fate of 5-ethoxycarbonyl-3morpholinosydnonimine (SIN-10) 1. Absorption. excretion and tissue distribution in rats and mice. S. Tanayama, et al. Jap J Pharmac 20 (3), 413-423 (1970).

Toxicity
LD50 po in mice (male): 3500 mg/kg; in rats (male): 8000 mg/kg.

Manufacturer
Yoshitomi Pharmaceutical Industries Ltd (Japan)

References
1. WHO Chron 24 (11). 532 (1970). 2. Studies on anti-atherosclerotic agents. II Experimental studies of 1,3-propanediol bis (2-pchlorophenoxyisobutyrate) (CLY-503) for antiatherosclerotic agents. M. Nakanishi at al. Yakugaku Zasshi 90 (8). 926932 (1970).

SIN 10
N-Ethoxycarbonyl-3-morpholinosydnonimine

Sodium Hexafluorostannate
Na2SnF6 Action
From the results of a recent study it seems that topical treatment of dentine with a hexafluorostannate solution has a definite caries inhibiting effect.

Synthesis
SIN 10 is one of sydnonimine derivatives with 1 mesoionic ring synthesized by Masuda et al .

References
The caries inhibiting effect of topically applied hexafluorostannate on dentine and enamel. F. R. von Der Fehr. Caries Research 4, 269-282 (1970) .

Description
White, crystalline powder, mp 140-141 It is solub le . in water.

Action
SIN 10 has proved to show a sustained hypotensive effect in rabbit, dog, cat and rat. It has been suggested that the drug exerts its effect not by affecting peripheral resistance vessels, but by mainly effecting capacitance vessels. The absorption, excretion and tissue distribution of 14 C labelled SIN 10 in mice have been reported.

Sodium Tyropanoate
Sodium 3-butyramido--ethyl-2,4,6triiodohydrocinnamate

Manufacturer
Takeda Chemical Industries (Japan)

References
1. K. Masuda et al. Pharmacometrics 2. 280 (1968). 2. F. Takenaka et al. Pharmacometrics 2. 298 (1968).

178
Chugai Pharmaceutical Co (Japan)

Synthesis
Prepared by the reaction of iopanoic acid with butyric anhydride, and subsequent conversion of the acid so obtained to the sodium salt.

References
Studies on piperazine compounds V. Effects of 7-[2Hydroxy3-[4-(p-chlorobenzyl)-piperazino] propyl] theophilline on circulatory system. Y. Shiraki et al. Yakugaku Zasshi 90 (7), 785-795 (1970).

Description
Colorless solid, mp 208-210 Tyropanoic acid . occurs as very pale tan prisms, mp 182-184 UV ; max 237m [=33,900] in 95% ethanol.

Action
Sodium tyropanoate is a new oral cholacystographic agent.

Spiclomazine Hydrochloride (Prop INN) APY 606

8-[3-(2-Chloro-10-phenothiazinyl) propyl]-1-thia-4,8diazaspiro[4,5] decane-3-one hydrochloride

Manufacturer
Sterling-Winthrop (USA)

Proprietary Name
Bilopaque

References
Sodium tyropanoate, a new oral cholecystographic agent. J. O. Hoppe et al. J Med Chem 13 (5),997-999 (1970).

Description
White crystalline powder, mp 267

SP 1131
7-[2-Hydroxy-3-[4-(p-chlorobenzyl) piperazino] propyl] theophylline

Action
Spiclomazine exhibits a potent spasmolytic action with a low toxicity. It may prove to be a new type agent having a psychotropic activity in clinical use.

Manufacturer
Yoshitomi Pharmaceutical Industries Ltd (Japan)

References
1. WHO Chron 25 (3), 143 (1971) 2. Pharmacological effects of APY 606. M. Nakanishi et al. Yakugaku Zasshi 90 (7), 800807 (1970). 3. Metabolic fate of APY 606. Excretion and metabolism in rats. M Nakanishi et al. Yakugaku Zasshi 90 (7), 808-812 (1970).

Description
White crystalline powder, mp 156-157 It is very . slightly soluble in water.

Action
SP 1131 is a coronary dilator. The action of this compound on the circulatory system, using aminophylline as the control agent, has been studied in dogs and rats.

Manufacturer

179

Spirgetine Sulfate LD 3598

[2-(6-Azaspiro [2,5] oct-6-yl) ethyl] guanidine sulfate N--Guanidinoethyl-6-azaspiro [2,5] octane sulfate

SQ 18571
7-Chloro-2-(p-chlorostyryl)-4-[[4-(diethylamino-1methyl butyl] amino] quinoline dihydrochloride

Synthesis
Prepared from N-(-aminoethyl)-6-azaspiro [2,5] octane.

Synthesis
Prepared by condensation of p-chlorobenzaldehyde with 7-chloro-2-methyl-4-[[4-{diethylamino)-1methylbutyljamino] quinoline.

Description
White crystalline powder, mp 275-277 Soluble in . water.

Action and Uses

Spirgetine, a derivative of guanidine, is related in chemical structure and pharmacological action to guanethidine. Thus the major effect of the drug is inhibition of responses to sympathetic adrenergic nerve activity. Spirgetine is used for the treatment of moderate to severe (including malignant) hypertension.

Description
Crystals. mp 260-261

Action
SQ 18571 is a long-lasting antituberculous agent. It differs from aminoquinol in having a p-chlorostyryl group instead of an o-chlorostyryl group. In the treatment of murine tuberculosis the intragastric potency of SQ 18571 has proved to be twice that of aminoquinol and about 20% that of isoniazide.

Dosage
Treatment should begin with small doses which may be increased depending upon the patient's response. The average maintenance dose is 5 to 7.5 mg daily.

Manufacturer
Squibb (USA)

Supplied as
Tablets: 2.5 mg and paraflutizide 5 mg.

References
1. M. V. Rubtsov et al. J Med Pharm Chem 2, 113131 (1960). 2. Long-lasting antituberculous activity of derivatives of 2-styrylquinoline. F. Pansy at al. Arner Rev Resp Dis 101 (5). 770-772 (1970).

Registered Name
Divimax.

Manufacturer
Dausse (France)

References
1. Dausse S A. Fr pat M 3013. 2. H. Najer et al. Bull Soc Chim Fr, 2572-2581 (1964). 3. Mad Act (Drugs of Today), 6 (4), 142-144 (1970). (Review with 5 references).

St 600
2-(5-Fluoro-o-toluidino)-2-imidazoline 2-(5' .Fluoro-2'-methyl)anilino-1,3-diaza-2cyclopentene

180
this isothiourea with methyliodide and subsequent condensation with ethylenediamine.

Description
The free base melts at 159-161 and the , hydrochloride at 220 .

Action Synthesis
Prepared by the reaction of 2-methyl-5-fluoroaniline hydrochloride with ammonium thiocyanate to yield N-(2-methyl-5-fluorophenyl) isothiourea, and by methylation of this isothiourea with methyl iodide and subsequent condensation with ethylenediamine. St 608 is a clonidine-like hypotensive. It shows a better hypotensive behavioural effect ratio than clonidine.

Manufacturer
Boehringer Ingelheim (Germany)

Description
The free base melts at 119-121 the hydrochloride, ; mp 169-170 .

References
1. C. H. Boehringer Sohn. Neth Appl 6,613,829. 2. A comparison of the behavioural effects of some hypotensive imidazoline derivatives in rats. R. Laverty. Eur J Pharmacol 9 (2), 163 (1970).

Action
St 600 is a clonidine-like hypotensive but with relatively less behavioural effect.

Manufacturer
Boehringer Ingelheim (Germany)

Strontium Carbonate
SrCO3 Description
White, odorless, tasteless powder.

References
1. C. H. Boehringer Sohn. Neth Appl 6,613,829. 2. A comparison of the behavioural effects of some hypotensive imidazoline derivatives in rats. R. Laverty. Eur J Pharmacol 9 (2), 163 (1970) .

Action
Strontium carbonate has been reported as successful in clinical trials as a tranquilizer and antianxiety agent. It appears to be less toxic than lithium carbonate.

St 608
2-(2-Chloro-m-toluidino)-2-imidazoline 2-(2'-Chlaro-3'-methyl)anilino-1,3-diaza-2cyclopentene

References
American Druggist pg 4 (Sept. 21, 1970).

Strophanthidin Arabinoside
Strophanthidin 3 -I-arabinoside

Synthesis
Prepared by the reaction of 2-chloro-3-methylaniline with ammonium thiocyanate to yield N-(2-chiaro-3methyl phenyl) isothiourea, and by methylation of

181

Action
It has been shown that metyrapone is converted to a reduced metabolite by rat adrenal, kidney and 1 liver in vitro . This metabolite (SU 5236) has proved to be nearly as effective an inhibitor of 17hydroxylation in the rat adrenal cortex as metyrapone itself.

Manufacturer
CIBA Pharmaceuticals (USA)

References
1. I. Kraulis et al. Canad J Biochem 46, 463 (1968). 2. A comparison of the effects produced by metyrapone and its reduced metabolite on the adrenal 11-hydroxylase system in the rat. H. D. Colby and A. C. Brownie. Steroids 16 (4). 401413 (1970).

Synthesis
Prepared by the saponification of the triacetylderivate with barium methoxide.

Description
Long needles, mp at about 210 (dec) after preliminary sistering. []D = 31 (c=1.1 in alcohol).

Su-19789 B
2-[p-Methoxy--(1-piperidyl)-benzyl] cyclohexanol cyclohexane sulfamate

Action
The results of a recent clinical study have indicated that the semisynthetic glycoside. strophanthidin arabinoside, can serve as a substitute for ouabain for rapid digitalization by the intravenous route.

References
1. F. C. Uhle et al. J Org Chem 8. 162 (1943). 2. Comparison of a partially synthetic glycoside strophanthidin-arabinoside with ouabain and digitalis in patients with auricular fibrillation. H. Gold et al. J Clin Pharmac 10(3), 145-152 (1970)

Action
It has been shown to be a unique stimulant in that it produces an increase in spontaneous motor activity with little, if any, concomitant effect on other parameters. The major sites of action suggested for this compound are the spinal cord and the neuromuscular junction.

SU-5236
2-Methyl-1,2-bis (3-pyridyl)-1-propanol

Manufacturer
Ciba Pharmaceutical Co (USA)

References
1. Pharmacological properties of Su-19789B, a unique central nervous system stimulant. H. I. Chemov et al. Arch int Pharmacodyn 184, 3444 (1970).

182

Substance 86
4-Bromo-6-tert-butyl-6-methyl-2H-pyran2,3,5(4H,6H)-trione

Synthesis
Prepared by mixing aqueous solutions of sucrose hydrogen sulfate salts with solutions of aluminum salts.

Description
White powder, insoluble in water.

Action
Prevention and treatment of peptic ulcerative disease.

Manufacturer Synthesis
Prepared by bromination of 6-tert-butyl-6-methyl-2H1,2 pyran-2,3,5(4H,6H)-trione . Chugai (Japan)

Proprietary Name
Ulcerlmin.

Description
Crystals, mp 167-168 .

References
1. WHO Chronicle 24 (11), 532 (1970). 2. Pharm J 203, 754 (1969). 3. Chugai Pharmaceutical Co. Fr pat 1,500,571. 4. Jap Med News 57, 6 (1968).

Action
The compound is thought to act on the cell membrane preventing aggregation of platelets and red blood cells.

References
1. Technion Research and Development Foundation Ltd. Fr pat M4126. 2. M. Cais et al. US pat 3,393,204. 3. Prevention by an antiadhesive drug of thrombosis by blood cell aggregation. H. I. Bicher and A. Beemer. Angiology 21, 431-441 (1970).

Sulfacytine (USAN)
Sulfacitine (Prop..lNN). Sulfacitinum (Lat). Sulfacitina (Sp) , N'-(1-Ethyl-1,2-dihydro-2-oxo-4-pyrimidinyl) sulfanilamide N-Sulfanilyl-1-ethylcytosine

Sucralfate (Rec INN)

Sucralfatum (Lat). Sucralfato (Sp) Surcrose hydrogen sulfate basic aluminum salt

Synthesis
Prepared in several steps from 1-ethyl-uracil, the last being the reduction of 1-ethyl-N(pnitrophenylsulfonyl) cytosine. Also prepared from 1-ethyl-N-(N-acetylsulfanilyl) cytosine.

183
T. Yoshinaga et al. Arzneim-Forsch 20 (9), 12061210 (1970).

Description
Sulfacytine is highly soluble (1 mg/ml, pH;5) and melts at 167-168 (methanol); ultraviolet absorptio n max. 298 m [E(1%, 1 cm); 705] and 263 m [E(1 %, 1 cm) ; 542] in methanol. Sulfacytine monohydrate melts at 104 .

Action
Tests in vivo have proved sulfacytine to be a quickly absorbed,quickly excreted (short acting) antibacterial sulfa drug, potentially and especially suitable for the treatment of urinary tract infections.

Sulfomycin
Sulfur-containing peptide antibiotic. It consists of three main componets

Production Manufacturer
Parke Davis and Co (USA) In the culture liquid and mycelium of Streptomyces viridochromogenes var sulfomycini.

References
1. WHO Chron 24 (3), 135 (1970). 2. N-Sulfanilyl-l-alky/cytosines. A new highly active class of soluble, short-acting sulfanilamides. L. Doub et al. J Med Chem 13 (2), 242-246 (1970). 3. Parke Davis and Co. Neth Appl 6,610,815.

Description
Colorless amorphous powder.

Action
Sulfomycin is a new antibacterial antibiotic.

Manufacturer
Tanabe Seiyaku Co, Ltd (Japan)

References

Sulfamonomethoxine (USAN) DJ1550

N'-(6-Methoxy-4-pyrimidinyl)sulfanilamide monohydrate 4-Methoxy-6-sulfanilamidopyrimidine monohydrate

1. Jap Med Gaz 7 (3). 10-11 (1970). 2. Jap pat 70 06,880.

Sulpiride (Rec INN)

Sulpiridum (Lat). Sulpirida (Sp) N-[(1-Ethyl-2-pyrrolidinyl)methylj-2-methoxy-5sulfamoylbenzamide

Action
In a recent clinical study sulfamonomethoxine has been shown to be effective not only on chloroquinesensitive malaria, but also on chloroquine-resistant malaria.

Manufacturer
Daiichi Seiyaku Co, Ltd (Japan)

Action
Pharmacological studies have shown that sulpiride is a powerful antagonist of apomorphine emesis in dog. The drug is used as antipsychotic and also in the treatment of gastro-duodenal ulcers, vertigo and digestive migraines.

References
1. Studies on the antimalarial property of sulfamonomethoxine and on its effect on the chloroquine-resistant malaria.

184
257.5, and 263.5 m. The spectrum is similar to that of atropine.

Manufacturer
Laboratoires Delagrange (France)

Proprietary Name
Dogmatil.

Dosage
The oral dose is 15 to 30 mg two to three times daily. The rectal dose is 25 to 75 mg daily.

Supplied as
Gelules, 50 mg. Tablets, 200 mg. Solution (injection), 100 mg/2 ml.

Supplied as
Tablets, 15 mg. Suppositories, 25 mg.

References
1. J. Besancon et al. C R Acad Sci (Paris) 265, 1253-1254 (1967). 2. M. Thominet et al. Fr pat 1,472,025. 3. G. et B. Vidal. Vie Med 50 (42), 5525 (1969). 4. J. Puech et al. Immex 6 (8-9), 1105 (1969). 5. M. Legre. Therapeutique 45 (10). 1003 (1969). 6. J. Collard. Sem Hop 45 (48), 3028 (1969). 7. Traitement de la pousee ulcereuse par Ie sulpiride. J. Ristelhuober. Gaz Med Fr 77 (1). 120 (1970). 8. Effect du sulpiride sur Ietat psychique de 40 malades mentaux. J. Carriere. J Med Chir Prat 141 (1), 9 (1970). 9. Treatment of gastro-duodenal ulcers by sulpiride. C. Couinaud et al. Ann Gastroenterol Hepatol 7 (1). 85-87 (1970).

Proprietary Name
Sultropan

Manufacturer
Biotherax (France)

References
1. J. P. M. Raudnitz et H. Wahl. Fr pat M4,097. 2. Med Act (Drugs of Today) 6 (3), 97-100 (1970). (Review with 4 references).

Suncillin Sodium (USAN; Prop INN) Sultroponium (Rec INN) A 118

3-Hydroxy-8-(3-sulfopropyl)-1H, 5Htropaniumhydroxide () tropate, inner salt ' 8-(3-Sulfopropyl) atropine

BL-P 1462

3,3-Dimethyl-7-oxo-6-[2-phenyl-D-2-(sulfoamino) acetamido]-4-thia-1-azabicyclo [3,2,0] heptane-2carboxylic acid disodium salt 6-(D--Sulfoaminophenylacetamido) penicillanic acid, disodium salt

Synthesis
Prepared by the treatment of 6-(D-aminophenylacetamido) penicillanic acid with trimethylamine-sulfur trioxide complex.

Synthesis
Prepared by reaction of atropine with propane 1,3sultone in acetone.

Description
White powder; mp 219-230 (dec).

Action
Suncillin sodium is a new semisynthetic penicillin with anti-pseudomonal activity. It has been shown to be effective in clinic.

Description
White crystalline powder, mp about 2200 (dec). Freely soluble in water, insoluble in alcohol, acetone and ether; soluble in hot alcohol. UV max 251.5,

185
M. Daly et al. Br J Pharmac 35, 283-294 (1969). 3. Investigations into the site of action of taloximine; a new respiratory stimulant molecule. J. A. Pearson and J. P. Griffin. Experientia 25, 716717 (1969). 4. Human pharmacology of taloximina. J. P. Griffin and P. Turner. Br J Pharmac 39, 249P (1970).

Manufacturer
Bristol Laboratories (USA)

References
1. Bristol Myers Company. US pat 3,381,001. 2. Antipseudomonal activity of sulfoaminopenicillins. K. E. Price et al. Applied Microbiol 17, 881-887 (1969). 3. In vitro studies of a new semisynthetic penicillin. G. P. Bodey et al. Applied Microbicl 18, 76-79 (1969). 4. Preliminary studies of BL-P 1462 in the treatment of pseudomonas infections. G. P. Bodey and V. Rodriguez. Curr Ther Res 12 (6), 363-368 (1970). 5. Abstr Intersc Conf Antimicr 10, 43 . (1970).

TAT-3
N-(2-Picolyl)-N-phenyl-N-(2-piperidinoethyl) amine hydrochloride

Taloximine (Rec INN)

Taloximinum (Lat). Taloximina (Sp) 1-Hydroxyimino-4-(2-dimethylamino) ethoxy-1,2dihydrophthalazine monohydrochloride monohydrate 4-[2-(Dimethylamino)ethoxy]-1(2H)phthalazinoxime hydrochloride monohydrate

Synthesis
Prepared by the reaction of N-(2-pyridylmethyl)aniline with 2-piperidinoethyl chloride and sodium amide in refluxing toluene.

Description
Colorless crystals, mp 183-185 (dec). The free base, bp 195-196 (4 mm).

Action
TAT-3 is a non-narcotic antitussive. It has proved to show an antitussive effect equal to or slightly more potent than codeine phosphate in dogs and lower toxicity than codeine in mice.

References Action
Taloximine has proved to show respiratory stimulant 2,3 and bronchodilator properties in animals . The results of studies of the drug in man have been 4 described . 1. Takeda Chemical Industries Ltd. Fr pat 1,511.398. 2. Pharmacology of TAT-3, a new antitussive agent. Y. Kass et al. Arzneim-Forsch 19, 1916-1927 (1969). 3. On the sites of antitussive action of TAT-3. Y. Kass et al. Arzneim-Forsch 20 (1), 37-43 (1970).

Manufacturer
Riker (England)

References
1. Brit pat 1,094,044, 2. Taloximine, a new respiratory stimulant with bronchodilator properties.

186

Taurine N-Carbodithioate TDT

(2-Sulfoethyl) dithiocarbamic acid N-Dithiocarboxytaurine

Action
TCMF is a potent general anesthetic when administered by inhalation to man. This compound produces circulatory depression and irritation of the mucous membranes and offers no advantage over those agents currently in common use.

References
1. C. G. Miller and C. Wolf. US pat 2.803.665. 2. The anesthetic properties of 1.1-difluoro-2.2trichloroethyl methylether. F. G. Rudo et al. Analg Anesth 49 (2). 251-256 (1970).

Description
The disodium salt melts at 240-243 .

Action
Taurine N-carbodithioate has proved to protect the liver of rats from the toxic action of carbon tetrachloride. It has been concluded that the observed effect may not be due to TOT itself but be due to its metabolites or degradation products, and that the action site of TOT would be located at the early stage of the pathoquietic process of CCI4 liver injury.

Tebrofen Tebrophen
Bis-(3,5-dibromo-2,4-dihydroxyphenyl)

Manufacturer
Oainippon Pharmaceutical Co, Ltd (Japan)

References
1. Dainippon Pharmaceutical Co, Ltd. Brit pat 1,094,076. 2. Effect of sodium taurine N-carbodithioate on acute experimental hepatic injury induced in rats by carbon tetrachloride. T. Karasawa et al. Jap J Pharmac 20 (2), 229-236 (1970).

Action and Uses

For use in the treatment of herpes keratitis and odenoviral keratoconjuntivitis.

Manufacturer
VNIKhFI (USSR)

Preparations
Ophthalmic ointment, 0.1 or 0.25%.

TCMF
1.1-Difluoro-2.2.2-trichloroethyl methyl ether

References
A new antiviral preparation. A. N. Grinev et al. Khimiko Farm Zh 4 (9), 61 (1970).

d-Tembetarine Chloride
Description
Nonflammable liquid. bp 124 .

187

Description Action and Uses

White crystalline powder, mp 119-121 . Temazepam is a new 1,4-benzodiazepine compound which is structurally and pharmacologically related to chlordiazepoxide and diazepam. Temazepam is a metabolite of diazepam. It differs chemically from the latter only in having a 3-hydroxy group. It is indicated for the management and control of anxiety, tension agitation, irritability and related symptoms.

Isolation
Alkaloid isolated from the bark of Zanthoxylum 1 martinicense DC .

Dosage
10 to 60 mg daily.

Action
Pharmacological studies have shown that dtembetarine chloride causes a significant fall in blood pressure in intact anesthetized cats and dogs, and that it shows ganglion-blocking activity.

Supplied as
Capsules, 5 and 10 mg.

Proprietary Name
Levanxol.

Toxicity
LD50 ip in mice: 638.2 mg/kg.

Manufacturer
C. Erba (Italy)

References
1. J. Tomko et al. Lloydia 30, 231 (1967). 2. A pharmacological study of the alkaloids Icanadine methochloride and d-tembetarine chloride. D. G. Patel et al. LIoydia 33 (1), 36-42 (1970) ..

References
1. American Home Prod Corp. Brit pat 1,022,642; Brit pat 1,022,645; Brit pat 1,057,492. 2. S. C. Bell et al. J Org Chem 27, 1691 (1962). 3. Med Act (Drugs of Today) 6 (6),223 (1970), (Review with 12 references).

Temazepam (USAN) WY 3917

7-Chloro-1,3-dihydro-3-hydroxy-1-methyl-5-phenyl2H-1,4-benzodiazepin-2-one

Temekhin Temechin
2,2,6,6-Tetramethylquinuclidine hydrobromide

Synthesis Synthesis
Prepared by reaction of 7-chloro-3-hydroxy-5phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one and dimethyl sulphate in presence of sodium hydroxide. Also, by hydrolysis of 3-acetoxy-7-chloro1,3-dihydro-1-methyl-5-phenyl-2H-1,4benzodiazepin-2-one with sodium hydroxide. 2,2,6,6-Tetramethylpiperidin-4-one is converted in several steps to 2,2,6,6-tetramethyl-4-(bromoethyl) piperidine. By cyclization of the latter temekhin is obtained.

Description
Crystals, mp 270-272 .

188

Action
Temekhin is a new antihypertensive ganglionic blocking agent. It has been approved for clinical use in USSR.

Tesicam (USAN; Prop INN) CP 13,608

4'-Chloro-1,2,3,4-tetrahydro-1,3-dioxo-4isoquinolinecarboxanilide 4'-Chloro-1,4-(2H,4H)-dioxoisoquinoline-4carboxanilide

References
The synthesis of a new ganglionic-blocking agent. E. S. Nikitskaya et al. Khim Farm Zh 4 (10), 59 (1970).

Terbutaline (USAN; Rec INN) KWD 2019

Terbutalinum (Lat). Terbutalina (Sp) -[(tert-Butylamino) methyl]-3,5-dihydroxybenzyl alcohol

Description
mp 243-245 (dec); pKa=4.6. Practically insoluble in water.

Action
Tesicam exhibits anti-inflammatory and uricosuric activity with an extended plasma half-life.

Action
The results obtained from the pharmacological studies indicate that terbutaline is a potent, bronchospasmolytic agent with an effect predominantly on the tracheal and bronchial muscles. It has an action of long duration.

Manufacturer
Pfizer Inc (USA)

References
1. JAMA 213 (13), 2248 (1970). 2. WHO Chron 25 (3), 145 (1971). 3. Chas Pfizer Co, Inc. S African Appl 68 03.465, 4. Dioxoisoquinoline4-carboxanilides, a new class of non-steroidal anti-inflammatory agents. S. B. Kadin and E. H. Wiseman. Nature 222, 275276 (1969). 5. Dioxoisoquinoline-4-carboxanilides, novel nonsteroidal anti-inflammatory agents with a speciesspecific effect on basal metabolism. E. H. Wiseman et al. J Pharmac Exp Ther 172 (1), 138-153 (1970).

Manufacturer
Draco (Sweden); Astra Pharmaceutical Products (USA)

Proprietary Name
Bronchodil (marketed by Draco, Sweden).

References
1. WHO Chron 24 (11), 533 (1970). 2. JAMA 212, 1360 (1970). 3. Belg pat 704,932. 4. J. Bergman et al. Experientia 25, 899 (1969). 5. Effect of bronchodilator drugs on the peak expiratory rate of asthmatic patients. Oral orciprenaline and terbutaline. M. J. Mattila and A. Maittari. Ann Med Exp Fenn 47,298-302 (1969) .

189

Tetracasactrin (BAN) ClBA 30920 Ba

Tetracosactride (Rec INN) Synthetic beta 1-24 corticotrophin

Tetracycline Cyclohexylsulfamate
Tetracycline cyclamate

H-Ser-Tyr-Ser-Met-Glu-H is-Phe-ArgTry-Gly-Lys-ProVal-Gly-Lys-LysAtg-Arg-Pro-Val-Lys-Val-Tyr-Pro-OH Synthesis

The synthesis of tetracosactrin, a 24-aminoacid polypeptide, was made possible by using N'-tbutoxycarbonyl-L-Iysine and -butyl-L-glutamate as 1 intermediates .

Synthesis
An ethanolic solution of tetracycline is added at 45 to an ethanolic solution of cyclohexylsulfamic acid. By addition of ether, tetracycline 1 cyclohexylsulfamate precipitates .

Action and Uses

Tetracosactrin is a tetracosapeptide incorporating the aminoacid residues 1-24 of ACTH. It retains the biological activity of the latter and in a similar manner stimulates the adrenal cortex to produce adrenocortical hormones. Tetracosactrin depot a preparation of tetracosactrin absorbed on zinc hydroxide or zinc phosphate, has been recently introduced in the pharmaceutical market. Absorption after parenteral administration is delayed, its action is thus maintained with less frequent administration. Indications: nearly all conditions for which corticosteroids are prescribed: collagen disease, allergic reactions, skin diseases, except where adrenal function is impaired.

Description
Yellow powder, mp at about 220 (dec); very soluble in water. UV max 220, 268 and 355 m.

Action and Uses

Tetracycline cyclohexylsulfamate is a new pleasant tasting salt of tetracycline. It is used for the same indications as other tetracycline preparations.

Dosage
Intramuscularly: Adults, 1 mg daily. Intervals between injections may be increased to 2 or 3 days.

Supplied as
Capsules, 250 mg (expressed in terms of tetracycline hydrochloride) with 220 mg sodium hexametaphosphate.

Supplied as
Tetracosactrin with zinc hydroxide in aqueous suspension in two strengths: 0.5 mg/ml and 1 mg/ml. Tetracosactrin zinc phosphate complex 1 mg/ml and 2 mg/2 ml.

Dosage
Adults, 4-6 capsules daily given in two to three divided doses. In more severe cases 8 capsules daily.

Proprietary Names and Manufacturers

Cortrosyn [Organon (England); Endopancrine (France)]. Synacthen (Ciba, England)

Proprietary Name
Sifacycline.

Manufacturer
Diamant (France)

References
1. H. Kappeler and R. Schwyzer. Helv Chim Acta 44,11361141 (1961); 46,1550 (1963). 2. Med Act (Drugs of Today) 6 (2), 66-71(1970). (Review with 13 references).

References
1. SIFA. Fr pat M 3004. 2. Med Act (Drugs of Today) 6 (1). 32-34 (1970). (Review).

190

Tetrazepam (Prop INN) CB-4261

7-Chloro-5-(1-cyclohexen-1-yl)-1,3-dihydro-1methyl-2H-1,4-benzodiazepin-2-one

Th 1165a
3,5-Dihydroxy--[[(p-hydroxy--methylphenethyl) amino] methylbenzyl alcohol 1-(3,5-Dihydroxyphenyl)-1-hydroxy-2-[(4hydroxyphenyl) isopropylamino] ethane 1-(p-Hydroxyphenyl)-2-[[-hydroxy--(3',5'dihydroxyphenyl)] ethyl] aminopropane

Synthesis
Prepared in several steps from 3,5-diacetoxy-bromo-acetophenone and 1-(p-methoxyphenyl)-2benzylaminopropane; the last being the hydrogenation of 1-(p-hydroxyphenyl)-2-[N-(3,5dihydroxybenzoyl) methyl] aminopropane. The hydrochloride, mp 182-183 the hydrobromide, ; mp 232-233 .

Synthesis
Tetrazepam, a new 1,4-benzodiazepine derivative, is structurally related to diazepam. It differs from the latter in having a 5-cyclohexenyl group instead of a 5-phenyl group. Prepared from 7-chloro-5-(1-cyclohexen-1-yl)-1,3dihydro-2H-1,4-benzodiazepin-2-one.

Action
Th 1165, a hydroxyphenyl derivative of orciprenaline, is a beta-adrenergic substance. It has proved to be useful in the resuscitation of patients with cardiac arrest and effective in the treatment of status asthmaticus and acute respiratory insufficiency.

Description
Yellow-brown crystalline powder, mp 144 UV max . 227 m (=28,500) in ethanol.

Action and Uses

Tetrazepam is a new myorelaxant drug. Indications: certain types of hemiplegias; spasmodic paraplegias; lumbago, sciatica, tetanus contractures; functional rehabilitation.

Manufacturer
C. H. Boehringer Sohn, Ingelheim (Germany)

References
1. C. H. Boehringer Sohn. Belg pat 640,433. 2. Hemodynamic studies with the p-hydroxyphenyl derivative of orciprenaline. P. Lichtlen et al. Arzneim-Forsch 19 (2), 147-149 (1969). 3. Airway resistance und intrathoracic gas volume after the inhalation of a hydroxyphenyl derivative of orciprenaline (Th 1165a). D. Nolte. Respiration 27, 396-405 (1970). 4. Spirographischer und atemmechanischer Wirkungsvergleich zwischen Orciprenalin (Alupent) und dem Hydroxyphenyl-Derivat Th 1165a. J. Hamm und H. Wusthofen. Klin Wschr 48 (7),415418 (1970). 5. Beziehungen zwischen Atemregulation und peripherem Atmungsapparat untersucht mittels CO2-Antwortkurven vor und nach bronchospasmolytischer Therapie. J. Hamm. Klin Wschr 48 (7), 418-426 (1970). 6. A selective -adrenoreceptor stimulant (Th 1165a) related to orciprenaline. S. R. O'Donneil. Eur J Pharmac 12 (1), 35 (1970).

Dosage
Orally, 150 to 400 mg daily.

Registered Name
Myolastan.

Manufacturer
Clin Byla (France)

References
1. Clin Byla Neth pat 6,600,095; Fr pat 978,360. 2. S. C. Bell et al. J Org Chem 27, 562 (1962). 3. Med Act (Drugs of Today) 6 (4), 145-150 (1970) . (Review with 12 references) .

191
White fluffy powder, []D = -10.40 (c=0.5, 1 N acetic acid).

Action

Thiophanate
1,2-Bis-(ethoxycarbonylthioureido) benzene

4-Threonine-oxytocin is an analogue of oxytocin in which the glutamine residue in the four position is replaced by a threonine residue. This analogue is about twice as active as oxytocin in rat uterus assays in vitro and in vivo and about three times as active in fowl vasodepressor assays than oxytocin itself, and possesses specifically weaker vasopressor and antidiuretic activities than oxytocin.

References
1. Solid-phase synthesis of 4-threonine-oxytocin. A more potent and specific oxytocic agent than oxytocin. M. Manning et al. Biochem 9 (20), 3925-3929 (1970). 2. 4-Threonine-oxytocin: a more active and specific oxytocic agent than oxytocin. M. Manning and W. H. Sawyer. Nature 227 (5259), 715-716 (1970). 3. 4-Threonine analogues of neurohypophysial hormones with selectively enhanced oxytocin-like activities. W. H. Sawyer and M. Manning. J Endocr 49,151165 (1971).

Synthesis
By reacting ethyl chloroformate with potassium thiocyanate, and subsequent reaction with ophenylendiamine.

Description
Colorless crystals, mp 195 (dec).

Action
Fungicide.

Manufacturer
Nippon Soda (Japan)

References
1. Japan Soda Co, Ltd. Ger Offen 1,806,123. 2. Oyo Yakuri (Pharmacometrics) 4 (1970).

Thyrotropin-Releasing Hormone
Pyroglutamylhistidylproline amide pGlu-His-Pro-NH2

4-Threonine Oxytocin

Synthesis
The key intermediate required for the synthesis of 4threonine-oxytocin is the protected nonapeptide, Nbenzyloxycarbonyl-5-benzyl-L-cysteinyl-O-benzyl-Ltyrosyl-L-isoleucyl-O-benzyl-L-threonyl-Lasparaginyl-S-benzyl-L-cysteinyl-L-prolyl-L-Ieucylglycinamide. This protected nona peptide is 1 synthesized by the solid phase method .

Action
Two teams of US investigators have recently succeeded in determining the structure of TRH. It is understood that Dr Rolf Studer et al (HoffmannLa Roche, Switzerland) have achieved the total synthesis of this hormone.

Description

References
Chem Engineer News 48 (52), 39 (Dec 14, 1970).

192

Tibolone (USAN; Rec INN) Org OD14

27-Hydroxy-7-methyl-19-nor-17-pregn-5(10)-en20-yn-3-one 17-Ethinyl-17-hydroxy-7-methyl-5-(10)-estren-3one

Synthesis
Prepared from 2-chloromercapto-4chlorobenzoylchloride and aqueous ammonia. From 4,4'-dichloro-2,2'-dithiosalicylic acid diamide and sodium hydroxide. From 4,4'-dichloro-2,2'dithiosalicylic acid diamide and a solution of bromine in CCI4.

Description
White crystals, mp 271.273 .

Action and Uses

Bacteriostat and fungistat.

Synthesis
Prepared by the reaction of potassium acetylide with 4 7-methyl- -3,17,19-trioxoandrostene in liquid 3 ammonia . Also by the reaction of lithium acetylideethylenediamine with 3-methoxy-7-methyl-17-oxo2,5(10) -19-norandrostadiene in dimethylsulfoxide 4 and toluene .

Supplied as
Powder, 0.5%; ointment. 0.5% and lotion, 0.1 %.

Manufacturer
Dr A Wander (Switzerland). Dorsey Lab (USA)

Proprietary Name
Landromil.

Description
Crystals, mp 168-169 [ ]D = +105 ; (c=0.539).

References
1. JAMA 212,466 (1970). 2. WHO Chron 24 (11), 533 (1970). 3. Dr A Wander AG. Ger pat 1,135.468, 4. R. Fischer et al. ArzneimForsch 14 (12), 13011306 (1964). 5. H. Hurni et al. ArznaimForsch 14 (12), 13061309 (1964). 6. R. Ponci at al. Farmaco, Ed Sci, 22 (12), 989998 (1967). 7. T. Vitali et al. Farmaco, Ed Sci, 23 (11), 10751080 (1968). 8. Med Act (Drugs of Today) 5 (3), 86 (1969).

Action
Tibolone is an anabolic agent.

Manufacturer Organon References

1. JAMA 209, 1212 (1970). 2. WHO Chron 24 (11), 533 (1970). 3. N. V. Organon. Fr pat 1.527,563. 4. G. Anner and P. Wieland (to Ciba Corp). US pat 3,432,528. 5. P. Wieland et al. Helv Chim Acta 50 (6), 14531461 (1967).

Ticlatone (USAN; Rec JNN) FER1443

6-Chloro-1,2-benzisothiazolin-3-one

193

Tilidine Hydrochloride Semihydrate (USAN; Prop INN) W 5759A 1261C

dl-trans-2-(Dimethylamino)-1-phenyl-3-cyclohexene1-carboxylic acid ethyl ester hydrochloride semihydrate

GO

Tilorone (USAN; Prop INN) DEAE-F

Tiloronum (Lat). Tilorona (Sp) Bis-DEAE-fluorenone 2,7-Bis [2-(diethylamino) ethoxy] fluoren-9-one

Action Synthesis
Prepared from atropic acid ethyl ester and 1dimethylamino-1,3-butadiene. Tilorone dihydrochloride is a compound that has a broad spectrum of antiviral activity in vivo following oral administration in mice. The compound, stimulates the production of an antiviral protein with properties characteristic of interferon.

Description
White crystalline powder, mp 128 Very soluble in . water. The hydrochloride melts at 162 .

Manufacturer
Wm S Merrell (USA)

Action and Uses

Tilidine hydrochloride is a new potent analgesic agent, recently marketed in Germany. It is useful for the relief of pain associated with surgery, trauma, labor, colic and cancer.

References
1. WHO Chron 24 (9), 432 (1970). 2. Science 169, 1213 (1970). 3. Antiviral activity of bis-deae-ffuorenone. an oral interferon-inducer. R. F. Krueger and S. Yoshimura. Fed Proc 29, 635 (1970). 4. Bis-deae-fluorenone, an oral inducer of interferon. G. D. Mayer and B. A. Fink. Fed Proc 29, 635 (1970). 5. Effects of an oral interferon-inducer on the hematopopoietic and reticuloendothelial systems. M. W. Rohovsky et al. Toxicol Appl Pharmacol 17, 556-558 (1970).

Dosage
Adults: Orally, up to 51.45 mg four times daily; rectally, up to 77.18 mg four times daily; parenterally up to 51.45 mg four times daily. 51.45 mg of tilidine hydrochloride semi hydrate is equivalent to 50 mg of tilidine hydrochloride.

Supplied as
Solution (injection), 51 .45 mg/ml. Drops, 102.9 mg/ml. Capsules, 51.45 mg. Suppositories, 77.18 mg.

Proprietary Name
Valoron.

Tinidazole (USAN) CP-12,574

1-[2-(Ethylsulfonyl) ethyI]-2-methyl-5-nitroimidazole Ethyl [2-(2-methyl-5-nitro-l-imidazolyl) ethyI] sulfone

Manufacturer
Giidecke AG (Germany) Wamer-Lambert (USA)

References
1. Warner-Lambert. Brit pat 1.120,186. 2. Med Act (Drugs of Today) 7 (1). 3336 (1971). (Review with 7 references) .

194

Tinoridine (Prop INN) Y 3642

Ethyl 2-amino-6-benzyl-4,5,6,7-tetrahydrothieno [2,3-c] pyridine-3-carboxylate 2-Amino-3-ethoxycarbonyl-6-benzyl-4,5,6,7tetrahydrothieno [2,3-c] pyridine

Synthesis
Prepared by the reaction of 2-methyl-5nitroimidazole with ethylsulfonylethyl p1,2 toluenesulfonate .

Description
Colorless crystals. mp 127-128 (benzene).

Action
Tinidazole is a potent. orally effective agent against trichomoniasis and amebiasis.

Action
This compound exhibits potent analgesic, antipyretic and anti-inflammatory effects with low toxicity.

Toxicity
LD50 po in mice > 3600 mg/kg; ip in mouse or rat > 2000 mg/kg.

Toxicity
LD50 po in rats> 10,200 mg/kg; ip 1,250 mg/kg.

Manufacturer
Chas Pfizer Co (USA)

Manufacturer
Yoshitomi Pharmaceutical Industries Ltd (Japan)

Proprietary Name
Fasigyn.

References
1. WHO Chron 25 (3), 145 (1971). 2. Studies on anti-inflammatory agents. I. Some biological activities of thienopyridine derivatives. M. Nakanishi et al. Yakugaku Zasshi 90 (3), 272276 (1970). 3. II. Analgesic and anti-edematous activities of Y3642. M. Nakanishi et al. Yakugaku Zasshi 90 (3), 277283 (1970). 4. III. Effect of Y-3642 on pyretic reaction, vascular permeability and granuloma formation in experimental animals. M. Nakanishi et al. Yakugaku Zasshi 90 (3), 284290 (1970). 5. IV. On the appearance of physical dependence and analgesic activity of Y-3642 by repeated administration. M. Nakanishi et al. Yakugaku Zasshi 90 (3), 291296 (1970). 14 6. V. Distribution of C-Y-3642 in mice. H. Imamura et al. Yakugaku Zasshi 90 (3), 296-301 (1970). 14 7. VI. Absorption, excretion and metabolism of ( CY-3642) in mice. H. Imamura et al. Yakugaku Zasshi 90 (3), 302-307 (1970). 8. VII. Absorption, distribution excretion and 14 metabolism of C-Y-3642 in rats. H. Imamura et al. Yakugaku Zasshi 90 (3), 317-323 (1970).

References
1. JAMA 211. 819 (1970). 2. K. Butler (to Chas Pfizer Co. Inc). US pat 3.376.311. 3. Alkylation of 2-methyl-5-nitroimidazole. Some potent antiprotozoal agents. M. W. Miller et al. J Med Chem 13 (5). 849-852 (1970). 4. Tinidazole. a potent new antiprotozoal agent. M. W. Miller et al. Antimicrob Ag Chemother-1969. p 257-260 (1970). 5. Tinidazole. a new anti protozoal agent: effect on Trichomonas and other protozoa. H. L. Howes et al. Antimicrob Ag Chemother 1969. p 261-266 (1970). 6. Tinidazole and metronidazole pharmacokinetics in man and mouse. J. A. Taylor et al. Antimicrob Ag Chemother 1969. p 267-270 (1970).

195
9. VIII. Activity of (Y-3642) on central nervous system, respiration and cardiovascular system and the isolated organ. M. Nakanishi et al. Yakugaku Zasshi 90 (3), 329334 (1970). 10. IX. Effect of (Y-3642) on heat-induced hemolysis. M. Nakanishi et al. Yakugaku Zasshi 90 (5), 548551 (1970). 11. X. Stabilization of rat liver lysosome by Y-3642. M. Nakanishi et al. Yakugaku Zasshi 90 (5), 557563 (1970). 12. XI. Inhibitory effects of Y-3642 On platelet aggregation. M. Nakanishi et al. Yakugaku Zasshi 90 (5), 564569 (1970) . 13. XII. Metabolites of Y-3642 in human urine. E. Matsui et al. Yakugaku Zasshi 90 (9), 1156-1159 (1970). 35 14. XI/I. Distribution of S-Y-3642. H. Imamura et al. Yakugaku Zasshi 90 (9), 11261134 (1970). 15. Pharmacological investigations of 2-amino-3ethoxycarbonyl-6-benzyl-4,5,6,7-tetrahydrothieno[2,3-]-pyridine. M. Nakanishi at al. Arzneim-Forsch 20 (8), 998-1003 (1970). 16. Pharmacological investigations of 2-amino-3ethoxycarbonyl-6-benzyl-4,5,6,7-tetrahydrothieno[2,3-c]-pyridine. M. Nakanishi at al Arzneim-Forsch 20 (8), 10041009 (1970). Tiprenolol base melts at 87.5-90.5 (ligroin). The hydrochloride melts at 125-127 (alcohol-ether).

Action
Tiprenolol is a -adrenergic blocker. It differs chemically from alprenolol in having an o-methylthio group instead of an o-allyl group.

Manufacturer
N. V. Phillips-Duphar (Netherlands)

References
1. WHO Chron. 24 (11), 533 (1970). 2. JAMA 213,1326 (1970). 3. N.V. Phillips Gloeilampenfabrieken. Neth Appl 6,504,268. 4. Med Klin 63, 1939 (1968).

TMA Hydrochloride
3,4,5-Trimethoxy--methylphenethylamine hydrochloride 3,4,5-Trimethoxyamphetamine hydrochloride 1-(3,4,5-Trimethoxyphenyl)-2-aminopropane hydrochloride

Tiprenolol (Rec INN, USAN) DU 21445

1-(lsopropylamino)-3-[O-(methylthio) phenoxy]-2propanol 1-(2-Methylthiophenoxy)-2-hydroxy-3isopropylaminopropane

Synthesis
Prepared by reduction of 1-(3,4,5trimethoxyphenyl)--nitropropene.

Description
Crystals, mp 216-217 ,

Action
TMA is a new amphetamine derivative. It is subjected to control because of its hallucinogenic effects.

Synthesis
Tiprenolol is prepared by treating 2-(methylthio) phenol with epichlorhydrine, and reacting the resulting compound with isopropylamine.

References
1. A. T. Shulgin. Experientia 20, 366 (1964). 2. Analogs of -methylphenethylamine (amphetamine). 1. Synthesis and pharmacological activity of some methoxy and/or methyl analogs. B. T. Ho et al. J Med Chem 13 (1), 26-30 (1970). 3. Fed Reg 35 (47), 4305-4306 (1970) .

Description

196

Tramadol Hydrochloride (USAN; Prop INN) 26,225A -Tocopherylquinone

-Tocoquinone (3-Hydroxy-3,7,11,15-tetramethylhexadecyl) trimethyl-pbenzoquinone ()-trans-2-[(Dimethylamino)-methyl]-1-(mmethoxyphenyl) cyclohexanol hydrochloride

Synthesis Synthesis
By oxidation of -tocopherol. The reaction of m-methoxyphenyl magnesium bromide with 2-dimethylaminoethyl-cyclohexanone in tetrahydrofurane at room temperature gives 1-(mmethoxyphenyl)-2-dimethylaminomethylcyclohexanol. This product can be separated into two isomers by crystallization of the hydrochloride in moist dioxane: isomer hydrochloride, mp 162-3 and isomer hydrochloride, mp 175-7 (moist dioxane). The free base, bp 138-140 (0.6 mm).

Description
Yellow-orange oil; insoluble in water and soluble in organic solvents.

Action and Uses -Tocopherylquinone has been

marketed in France and is claimed to show myotrophic activity.

Action
Tramodol is an analgesic agent, It has appeared to be effective in clinical investigation, but with gastrointestinal and psychological side effects.

Dosage
300 mg daily, in three divided doses.

Manufacturer
The Upjohn Co (USA); Chemie Grunenthal (Germany)

Preparations
Solution (oral) 100 mg per ampoule.

References
1. JAMA 209, 925 (1969). 2. Clinical investigation of tramadol hydrochloride. J. S. Finch and T. J. DeKornfeld. Pharmacologist 12 (2), 231 (1970).

Registered Name
Eutrophyl.

Manufacturer
Medial-Riker (France)

References
1. Ch. D. Robeson and D. R. Nelan. US pat 2,856,414. 2. Sogespar SA. Fr pat Addn 75.631. 3. Med Act (Drugs of Today) 6 (1), 3437 (1970). (Review with 8 references).

Trazodone Hydrochloride (USAN; Rec INN) 1161

2-[3-[4-(m-Chlorophenyl)-1-piperazinyl] propyl]-striazolo [4,3-] pyridin-3(2H)-one hydrochloride

AF

197

Description
Crystals, mp 180-182 (ethanol). UV max 351-352 m (=45,000) in methanol.

Synthesis
Prepared by the reaction of s-triazolo [4,3-] pyridine-3-one with sodium hydride and 1-(3chloropropyl)-4-(m-chlorophenyl) piperazine.

Action
Keratolytic.

Description
Crystals, mp 223 (alcohol); the free base melts at 86-87.

Manufacturer
Hoffmann La Roche

References
1. JAMA 211, 1363 (1970). 2. WHO Chron 25 (11), 147 (1971). 3. BASF. Ger pat 1,025,869; 1,046.612; 1.050.763; 1,068,702. US pat 3,006,939.

Action
Trazodone hydrochloride is a central nervous system stimulant. In a controlled clinical study the drug has proved to exert an anti-depressive effect.

Manufacturer
Angelini Francesco (Italy)

References
1. JAMA 211,1362 (1970). 2. WHO Chron 24 (11). 533 (1970). 3. Aziende Chimiche Riunite Francesco Angelini. Brit pat 1,117,068; US pat 3.381.009. 4. Controlled clinical study af trazodane, a new antidepressant drug. M. De Gregorio and A. Dionisio. VII International Congress Collegium Internationale Neuro Psychopharmacologicum, Prague, Aug 11-15 (1970); abs 107.

Tretoquinol Hydrochloride (Prop INN) 110 Trimetoquinol

1-(3,4,5-Trimethoxybenzyl)-6,4-dihydroxy-1,2,3,4tetrahydroisoquinoline hydrochloride

AQ

Tretinoin (USAN; Prop INN)

all trans-Retinoic acid [3,7-Dimethyl-9-(2,6,6-trimethyl-1-cyclohexen-1-yl)2,4,6,8-nonatetraenoic acid]

Action
Trimetoquinol is a new bronchodilator agent, which has been found to be 5 to 10 times more potent than isoproterenol, but with less cardiovascular action. The circulatory effects of the drug have been compared recently with those of isoproterenol and salbutamol.

198
chloride or aldactone supplementation, as the latter 6 two do, to prevent hypokalemia .

Manufacturer
Tanabe Seiyaku (Japan) May and Baker (England)

Proprietary Name
Inolin (Tanabe Seiyaku).

Manufacturer
Lederle Laboratories (USA)

Supplied as
Tablets, 3 mg. Solution (injection) 1 mg. Inhalation 5 mg/ml.

References
1. JAMA 209, 2044 (1969). 2. WHO Chron 24 (3), 138 (1970). 3. D. Evans and C H. Cashin. J Med Chem 10, 428431 (1967). 4. J. B. Cummings et al. Pharmacologist 10, 162 (1968). 5. Renal mechanisms of the natriuretic and antiphosphaturic effects of triflocin-a new diuretic. Z. S. Agus and M. Goldberg. J Lab Clin Med 76 (2), 280-292 (1970). 6. Triflocin: a new potassium sparing diuretic. F. Steigmann et al. Fed Proc 29, 481 (1970).

References
1. Sato at al. Jap J Pharmacal 17. 153-163 (1967). 2. Med Act (Drugs of Today) 5 (3). 109 (1969). 3. A comparison of the cardiovascular actions of AQ 110 with those of isoprenaline and salbutamol. F. Fogelman and H. F. Grundy. Br J Pharmac 38. 416-432 (1970).

Triflocin (USAN; Prop INN) CL 65,562

Triflocinum (Lat). Triflocino (Sp) 4-(,,,-Trifluoro-m-toluidino) nicotinic acid 4-(m-Trifluoromethylanilino) nicotinic acid

Triflumidate (USAN; Rec INN) MBR 4223 BA 4223

Triflumidatum (Lat). Triflumidato (Sp) Ethyl m-benzoyl-N-[(trifluoromethyl) sulfonyl] carbanilate N-Ethoxycarbonyl-3-benzoyltrifluoromethanesulfonanilide

Synthesis
Prepared by the reaction of 4-chloronicotinic acid 3 with m-trifluoromethylaniline .

Synthesis
3-Aminobenzophenone is treated with trifluoromethanesulfonic anhydride to give 3benzoyl-1,1,1-trifluoromethanesulfonanilide. Formation of the sodium salt of the latter with sodium hydroxide followed by reaction with ethyl chloroformate gave triflumidate.

Description
Crystals, mp 205-206 (aqueous ethanol).

Action
Triflocin, a nicotinic acid derivative, is a structurally new diuretic agent. It is non-sulfhydryl reactive, and 4 does not inhibit carbonic anhydrase in vitro . It has proved to be an orally effective natriuretic agent in man, active in the ascending limb of the loop of 5 Henle . Triflocin while less potent than furosemide and ethacrynic acid, did not require potassium

Description
Crystals, mp 131.5-132.5 it is highly insoluble i n ; water.

Action
Triflumidate is a new anti-inflammatory agent. It has proved to be approximately equipotent with

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phenylbutazone in the carrageenin rat paw edema test and in the adjuvant arthritis test. 2. K. Pelz et al. Coll Czech Chem Commun 34 (12), 3936-3943 (1969).

Toxicity
LD50 po in mice: greater than 2000 mg/kg.

Manufacturer
Minnesota Mining and Mfg, Co (USA)

Trimebutine Hydrochloride
3.4.5-Trimethoxybenzoic acid, -(dimelhylamino)-ethylphenethylester hydrochloride 3.4.5-Trimethoxybenzoic acid, 2-phenyl-2dimethylamino-n-butylester hydrochloride

References
1. Anti-inflammatory agents. I. Benzoylfluoroalkanesulfonanilides. J. Kenneth Harrington et al. J Med Chem 13 (1), 137 (1970). 2. The metabolism of MBR-4223 (triflumidate), a new nonsteroidal anti-inflammatory agent, in man and laboratory animals. S. F. Chang et al. Fed Proc 29 (2), 678 Abs, 2433 (1970).

Synthesis

Trifluthepin
8-Trifluoromethyl-10-(4-methylpiperazino)-10-11dihydrodibenzo-[b,f] thiepine

Prepared by reacting 2-phenyl-2-dimethylamino-nbutanol with 3,4,5-trimethoxybenzoic acid chloride.

Description Action and Uses

Crystals, mp 184 Trimebutine exhibits a local antispasmodic activity on the digestive tract. It also possesses analgesic and local anaesthetic properties. It is used in the treatment of nausea and vomiting, abdominal pain, flatulence in the course of esophagitis, gastritis and duodenitis, colitis, and biliary dyskinesia.

Dosage
300 to 400 mg daily.

Supplied as Synthesis
Prepared from 8-trifluoromethyl-10-chlaro-10-11dihydrodibenzo [b,f] thiepine. Trifluthepin maleate melts at 137-138 (acetone/ether). Tablets, 100 mg. Suppositories, 100 mg. Vials 50 mg (as trimebutine maleate).

Manufacturer
Laboratories Jouveinal (France)

Action
Tritluthepin, a trifluoromethyl analogue of octoclothepin, is a very potent neuroleptic. This potency is manifested mainly in the cataleptic test in rats, in which trifluthepin is 3 to 4 times stronger than octoclothepin. Its central sedative activity is somewhat lower than that of octociothepin.

Proprietary Name
Debridat.

References
1. Lab. Jouveinal. Fr pat 1.344.455. 2. Med Act (Drugs of Today) 7 (1), 37-38 (1971). (Review).

References
1. SPOFA United Pharmaceutical Works. Fr pat 1,566,933.

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Trophosphamide (Rec INN) Trofosfamide Z4828

Trofosfamidum (Lat). Trofosfamido (Sp) 3-(2-Chloroethyl)-2-[bis-(2-chloroethyl) amino]-1tetrahydro-2H-1,3,2-oxazophosphorin-2-oxide

Action
U 5897 is an effective male rat chemosterilant. Sterility results from a lesion in the initial segment of the caput epididymidis.

Manufacturer
The Upjohn Co (USA)

References
1. Organic Synthesis 1. 294 (1941). 2. Beilstein 1, III, 2150. 3. Male antifertility compounds: V-5897 as a rat chemosterilant. R. J. Ericsson. J Reprod Fert 22, 213-222 (1970). 4. Male antifertility compounds: Structure and activity relationships of V-5897, V-15, 646 and related substances. R. J. Ericsson and G. A. Youngdale. J Reprod Fert 21,263-266 (1970). 5. Male antifertility compounds: Biological properties of V-5897 and V-15,646. R. J. Ericsson and V. F. Baker. J Reprod Fert 21,267-273 (1970). 6. Male antifertility compounds; Efficacy of V-5897 in primates (Macaca Mulatta). K. T. Kirton et al. J Reprod Fert 21, 275-278 (1970). 7. Antifertility activity of 3-chloro-1,2-propanediol (V5897) on male rats. E. Samojlik and M. C. Chang. Biology of Reproduction 2, 299-304 (1970). 8. Induction of temporary infertility in rams with an orally administered chlorohydrin. J. L. Kreider and R. H. Dutl. J Animal Sci 31 (1), 9598 (1970).

Action
New cyclophosphamide cytostatic drug, which has been shown to be well tolerated and effective in clinic.

Manufacturer
Asta-Werke AG (Ger)

References
1. WHO Chron 24 (11). 533 (1970). 2. Results obtained with two new phosphamide derivatives. P. Drings at al. Deutsche Med Wochenschr 95 (10).491-497 (1970).

U-5897
3-Chloro-1,2-propanediol -Chlorohydrin

U 14,624
1-Phenyl-3-(2-thiazolyl)-2-thiourea

Synthesis
Prepared from glycerol and hydrochloric acid gas.

Synthesis
Prepared from 2-aminothiazole and phenyl sulfocyanate.

Description
Liquid, bp 119 (14 mm); d4 = 1,3214 and nD = 1,4809. Miscible with water, ethanol, ether and acetone.
20 20

Description
Crystals, mp 178.5 .

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2. 1-lsopropylamino-3-(4-indanoxy)-2-propanol HCl: A potent -adrenoceptor antagonist. B. levy and M. Wasserman. Br J Pharmac 39 (1), 139-14B (1970).

Action
U 14,624 is a dopamine -hydroxylase inhibitor. It has proved to decrease brain norepinephrine and to increase brain dopamine in both mice and rats.

Toxicity
LD50 ip in mice: 680 mg/kg.

Manufacturer
The Upjohn Co (USA)

V 111
p-Bromo-desoxyephedrine p-Bromo-methamphetamine

References
1. T. Uno and S. Akihama. Yakugaku Zasshi 80, 1015-1020 (1960). 2. In vivo inhibition of dopamine -hydroxylase by U14.624. G. A. Johnson et al. J Pharmacal Exp Ther 171, 8087 (1970). 3. Behavioral and brain catecholamine depleting actions of U-14,624, an inhibitor of dopamine hydroxylase. P. F. von Voigtlander and K. E. Moore. Proc Soc Exp Biol Med 133, 817-820 (1970).

Action
V 111 is a new psychotomimetic agent. A detailed pharmacological analysis of the central actions of this compound in comparison with LSD has been reported.

USVC 6524
1-(4-lndanyloxy)-3-(isopropylamino)-2-propanol hydrochloride

Manufacturer
Chinoin (Hungary)

References
1. Pharmacological studies on para-bromomethamphetamine (V-111) and LSD. J. Knoll et al. Acta Physiol Acad Sci Hung 37 (1-2), 151-170 (1970). 2. Inhibition of the effects of LSD and p-bromomethamphetamine (V-111) by pchlorophenylalanine. J. Knoll and E. S. Vizi. Pharmacol Res Commun 2 (1), 67-70 (1970).

Synthesis
Prepared by the reaction of 1-(4-indanyloxy)-3chloro-2-propanol with isopropylamine. The free base melts at 105 and the hydrochloride at 153 , .

Action
USVC has proved to be a -adrenoceptor antagonist of considerable potency with relatively weak cardiac depressant properties. It differs structurally from propranolol in that it possesses an indane rather than a naphthyl group.

Verticillin A
Production
Obtained from cultures of Verticiflium sp.

References
1. Imperial Chemical Industries ltd. Belg pat 641.417.

202
P. J. Cambar and D. M. Aviado. Arch int Pharmacodyn 183, 107-126 (1970).

Description
Pale yellow amorphous powder, mp 203-214 (dec) (tetrahydrofuran).

Action
Verticillin A is a new antibiotic which has been found active against gram-positive bacteria and mycobacteria but not against gram-negative bacteria and fungi. It also exhibits antitumor effects.

Wy 8678
[(2,6-Dichlorobenzylidene )amino] guanidine acetate

Toxicity
LD50 ip in mice 7.6 mg/kg.

Manufacturer
Shionogi Co, Ltd (Japan)

References
Venicillin A a new antibiotic from Verticillium sp. K. Katagiri et al. J Antibiot 23 (8), 42022 (1970).

Synthesis
Prepared by the reaction of 2,6dichlorobenzaldehyde with either aminoguanidine hydroiodide, or aminoguanidine and p-toluensulfonic 1 acid . The free base melts at 227-229.

WR 4809
1-Methyl-4-[4-(7-chloro-4-quinolylamino) benzoyl] piperazine acetate

Action
Wy 8678 is an antihypertensive agent. It has been found to lower blood pressure and heart rate in unanesthetized hypertensive animals. The general cardiovascular actions of the compound have been described.

Manufacturer
Wyeth Laboratories Inc (USA)

References
1. Shell Internationale Research Maatschappij NV. Brit pat 1.019,120; Ger Offen 1,802.364. 2. 2,6-Dichlorobenzylidene amino guanidine acetate (Wy 8678). A new hypotensive agent. T. Baum et al. Experientia (Basel) 25. 1066 (1969). 3. Actions of the antihypertensive agent 2,6dichlorobenzylidene aminoguanidine acetate (Wy8678) on the cardiac conduction system. T. Baum et al. Arch Int Pharmacodyn Ther 183 (1),75-84 (1970). 4. General pharmacologic actions of the antihypertensive agent 2,6-dichlorobenzylidene aminoguanidine acetate (Wy-8678). T. Baum et al. J Pharmacol Exp Ther 171 (2). 276287 (1970).

Action
New antimalarial agent. Pharmacological studies have shown that WR 4809 is capable of blocking both alpha and beta adrenergic receptors.

Toxicity
LD50 iv in rats: 101 mg/kg.

Manufacturer
Walter Reed Army Institute of Research (USA)

References
Pharmacology of new antimalarial drugs. A piperazine which exerts an unusual type of adrenergic blockade.

203

Xipranolol (Rec INN) BS 7977D

Xipranololum (Lat) 1-(Di-2,6-xylylmethoxy)-3-(isopropylamino)-2propanol hydrochloride

Action
The antibiotic is active against bacteria and fungi.

Manufacturer
Tanabe Seiyaku Co, ltd (Japan)

References
Antibiotic YC 73 of pseudomonas origin. I production isolation and properties. Y. Egawa et al. J Antibiotics 23 (6), 467-470 (1970).

Synthesis
Prepared in two steps from di-(2,6-xylyl)methylchloride, the last one being the reaction of 1,2-epoxy-3-(di-2,6-xylylmethoxy)propane with isopropylamine.

Zeranol (USAN; Rec INN) P1496 MK-188 THFES

Zeranolum (Lat) The trivial designation, zearalanol, has been used to identify this compound 1-Resorcylic acid-(6,10-dihydroxyundecyl)-p-Iactone (3S,7X)-3,4,5,6,7,8,9,11,12-Decahydro7,14,16-trihydroxy-3-methyl-1H-2benzoxacyclotetradecin-1-one (6X,10)-6,10-Dihydroxyundecyl--resorcylic acid-Iactone

Description
Crystals, mp 189-191 (acetone).

Action
Xipranolol is a potent antiarrhythmic agent, devoid of beta adrenoreceptor blocking activity.

Manufacturer
NV Brocades-Stheeman (Netherlands)

References
1. WHO Chron 24 (11), 534 (1970). 2. Brocades-Stheeman. Neth Appl 6712697 6,712,697. 3. J. De Vries et al. Arzneim-Forsch 18 (9), 1200-3 (1968). 4. Antiarrhythmic activity of BS-7977-D in the dog heart lung preparation. Atul R. Laddu. Eur J Pharmacol 9 (2), 129-135 (1970).

Synthesis
Prepared by hydrogenation of zearalenone using reduction conditions sufficient to reduce only the olefinic bond and the ketone group to add four 3 hydrogen atoms . Zearalenone has also been named as the fermentation estrogenic substance (FES) since a convenient method for producing it is by cultivating on a suitable nutrient medium, the 4 organism Gibberella zeae . Zearalenone has also 5 been synthesized . The reduction of the ketone group of zearalen one introduces a second asymetric carbon atom and makes diastereoisomers possible.

YC 73
Antibiotic isolated from the culture broth of a pseudomona

Description
There are two diasterioisomers of zeranol, one having a mp 146-148 and a specific rotation []D of about 390 in methanol and another having a mp of

Description
Dark green needles, mp 199 (dec).

204
178-180 and a specific rotation []D of about 460 in methanol.

Action
Veterinary anabolic.

Manufacturer
Commercial Solvents Corp (USA)

References
1. JAMA 210, 1454 (1969). 2. WHO Chron 24 (3), 139 (1970) . 3. Commercial Solvents Corp. Brit pat 1,107,738. 4. Nature 196, 1318 (1962). 5. Merck Co. US pat 3,551,455 and 3.551,454 (1970). 6. Chem Eng News 47, 22 (1 Dec 1969). 7. An anabolic agent for rumiants. R. G. Brown. J Amer Vet Med Ass 157 (11). 15371539 (1970).

Zorbamycin (USAN) U 30604

Production An unspecified substance from Streptomyces ikiniensis variant. Action
Zorbamycin is a new antibacterial antibiotic.

Manufacturer
The Upjohn Co (USA)

References
JAMA 212, 467 (1970).