Patented Mar.

2, 1954 2,671,088
UNITED
REISSUED
STATES PATENT OFFICE 2,671,088
ANTYROD COMPOUNDS
July 22, 1958 Claude Rimington, New Barnet, Alexander Laws
son, Southgate, London, Charles Edmund
Re 2k, 505 Searle, Wandsworth Common, London, and
Harold Victor Morley, Denmark Hill, London,
England, assignors to National Research De
velopment Corporation, London, England, a
British corporation
No Drawing. Application March 24, 1952,
Serial No. 28,308
Claims priority, application Great Britain
April 2, 1951
6 Claims. (C. 260-309)
1. 2
This invention comprises new anti-thyroid at 0° C. 0.1 mol. of ethylchloroformate is added
compounds. dropwise with stirring. More pyridine is added,
It is known that 1-methyl-2-mercaptogly if necessary, to keep the mixture semi-fluid. The
oxaline is a very potent anti-thyroid agent. Its sludge is then placed in an ice-box for 30 minutes.
activity is much greater than thiouracil, the drug The crystals are filtered off and washed firstly
in most Common use. with a little ethanol and secondly with ethanol
The new compounds of the present invention and water. The product is crystallised from the
have the formula: solvent to give colourless needles having a melt
CC ing point of 122-3° C. Found: C, 45.7; H, 5.4.
() (5) O CH10O2N2S requires C, 45.2, H, 5.4%.
Eacample 2-Preparation of 1-methyl-2-carbo
N(3) (1)NR methocythioglyoacaline
Ng/ The procedure of Example i is followed but
S.C.O.R. s substituting methyl chloroformate for the ethyl
in which R is an alkyl, ary or alkaryl group and ester. The product, recrystallised from ethanol,
R is an alkoxy, alkylamino or aralkyloxy group, has a melting point of 135° C. Found: C, 41.7;
Or mercaptoglyoxaline residue. H, 4.4, C6HsO2N2S requires C, 41.8; H, 4.6%.
These compounds are no less potent than Eacample 3-Preparation of 1-methyl-2-carbo
1-methyl-2-mercaptoglyoxaline and have the ad 20 benzoacylthioglyoacaline
vantage of being relatively tasteless and of hav
a more prolonged action. In these respects, the (a) 0.1 mol of 1-methyl-2-mercaptoglyoxaline
compounds hereinafter described in the examples is dissolved in the minimum amount of pyridine
are particularly valuable. They exhibit no evi at 0° C. 0.1 mol of carbobenzoxy chloride is
dence of toxicity. 2. added dropwise with stirring. The solution is
The compounds may be produced from 2-mer then stirred for A2-1 hour at room-temperature
captoglyoxalines having a substituent group R. and placed in a vacuum desiccator over concen
on the 1-nitrogen atom, according to the follow trated H2SO4/KOH. .
ing reaction. The sticky oil is rubbed under petroleunether
CH=CH CBCE and the solvent poured off. This is repeated
30 twice. The thick oil is then rubbed under water
N NR
-- ClCOR -
N/
which causes it to crystallise slowly. The white
C crystalline material is filtered off. On recrystal
th S.C.O.R. lisation from benzene/petroleum-ether (60
80' C.) the product is obtained in white needles
The R-substituted 2-mercaptoglyoxalines 35 having a melting point of 91-92 C. (b) 0.1 mol
themselves are prepared by either of the two foll of 1-methyl-2-mercaptoglyoxaline is dissolved in
lowing methods which are already known. 50 ml. of 4 N-caustic soda at 0° C. 0.1 mol. of
(a) By the reaction of bronoacetal under Carbobenzoxy chloride is added slowly. After the
pressure with an amine (e. g. methylamine, allyl addition, the mixture is stirred at 0°C. for 15-30
amine, benzylamine, antine, or cinnamylamine) 40 minutes. The reaction mixture is then placed in
followed by ring closure with an alkali thio an ice-box for A hour, the white solid filtered
cyanate in acid Solution, or (b) by the reaction off and washed firstly with water and secondly
in alcoholic solution of aminoacetal with an or with petroleum-ether. The solid is crystallised
ganic isothiocyanate (e. g. methylisothiocyanate, from benzene/petroleum-ether to give white
allylisothiocyanate, benzylisothiocyanate, or 45 needles having a melting point of 91-92° C.
phenylisothiocyanate) followed, if necessary, by Found: C, 58.3; H, 4.9. C12H12O2NS requires
treatment of the so formed substituted thiourea C, 58.1; H, 4.9%. w
with acid to effect ring closure. Eacample 4-Preparation of 1-methyl-2-hippur
t The following examples are given in illustra ylthioglyoacaline
O 50
cample 1-Preparation of 1-methyl-2-carbeth 0.01 mol. of 1-methyl-2-mercaptoglyoxaline is
Oathioglyoacaline dissolved in 10 ml. B-picoline at room tempera
ture and 0.01 mol. 2-phenyloxazol-5-one added
0.1 mol. of 1-methyl-2-mercaptoglyoxaline is slowly. The mixture is allowed to stand at room
dissolved in the minimum quantity of pyridine 55 temperature for 24 hrs., and then is poured into
 2,671,088
3 4.
ice water with stirring. The small crystals ap thioglyoxane and di-(1-methyl-2-glyoxaliny)
pearing are then removed by filtration and re dithiolcarbonate dihydrochloride.
crystallised several times from ethyl acetate in 2. As a new anti-thyroid compound, the sub
which they are rather sparingly soluble. This stance 1-methyl-2-carbethoxythioglyoxaline.
gives a colourless microcrystalline product, M. P. 5 3. As a new anti-thyroid compound, the sub
175° C. Found C, 56.4; H, 4.9; N, 15.3%. stance 1-methyl-2-carbomethoxythioglyoxaline,
C3H13ONS requires C, 56.9; H, 4.7; N, 15.3%. 4. As a new anti-thyroid compound, the sub
Eacample 5-Preparation of dis (1-methyl-2-gly stance 1-methyl-2-carbobenzoxythioglyoxaline.
Ocalinyl) dithiocarbonate dihydrochloride 5. As a new anti-thyroid compound, the sub
O stance 1-methyl-2-hippurylthioglyoxaline,
0.01 mol. of 1-methyl-2-mercaptoglyoxaline is 6. As a new anti-thyroid compound, the sub
dissolved in 30 ml, dry benzene and 0.01 mo, stance di - (1-methyl-2-glyoxaliny) dithiolcar
phosgene dissolved in toluene is added slowly with bonate dihydrochloride.
cooling. The reddish coloured precipitate is fl CLAUDERMINGTON.
tered off and recrystallised from alcohol con 5 ALEXANDER, LAWSON.
taining a small amount of water. Colourless CHARLES EDMUND SEARLE.
needles M. P. 167° C. Found: C, 32.3; H, 4.1%. HAROLD VICTOR MORLEY.
CHONASC.HO requires C, 31.4; H, 4.07%.
We cairn: w References Cited in the file of this patent
1. As a new anti-thyroid compound, a sub 20 UNITED STATES PATENTS
stance Selected from the group consisting of
1-methyl-2-carbethoxythioglyoxaline, 1-methyl Number Name Date
2 - carbomethoxythioglyoxaline, 1-methyl-2-car 2,519,310 Dessert ------------ Aug. 15, 1950
bobenzoxythioglyoxaline, 1 - methyl-2-hippury 2,585,388 Jones -------------- Feb. 12, 1952