USRE24505E - Antithyroid compounds - Google Patents
Antithyroid compounds Download PDFInfo
- Publication number
- USRE24505E USRE24505E US RE24505 E USRE24505 E US RE24505E
- Authority
- US
- United States
- Prior art keywords
- methyl
- compounds
- antithyroid
- compound
- mercaptoglyoxaline
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title description 18
- 230000003208 anti-thyroid Effects 0.000 title description 10
- 239000003200 antithyroid agent Substances 0.000 description 20
- 239000000047 product Substances 0.000 description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- 238000000034 method Methods 0.000 description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
- 239000000126 substance Substances 0.000 description 12
- 239000007795 chemical reaction product Substances 0.000 description 8
- 238000001816 cooling Methods 0.000 description 8
- 238000002844 melting Methods 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- RAXXELZNTBOGNW-UHFFFAOYSA-N Imidazole Chemical compound C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 4
- 125000002877 alkyl aryl group Chemical group 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-M chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- YGYAWVDWMABLBF-UHFFFAOYSA-N phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Inorganic materials [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 4
- 230000003389 potentiating Effects 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 4
- 101700031589 BEX3 Proteins 0.000 description 2
- HSDAJNMJOMSNEV-UHFFFAOYSA-N Benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 2
- ZEMGGZBWXRYJHK-UHFFFAOYSA-N Thiouracil Chemical compound O=C1C=CNC(=S)N1 ZEMGGZBWXRYJHK-UHFFFAOYSA-N 0.000 description 2
- 125000005083 alkoxyalkoxy group Chemical group 0.000 description 2
- 125000003282 alkyl amino group Chemical group 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 125000002102 aryl alkyloxo group Chemical group 0.000 description 2
- 125000005418 aryl aryl group Chemical group 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 239000002178 crystalline material Substances 0.000 description 2
- 235000021185 dessert Nutrition 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940079593 drugs Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 125000004494 ethyl ester group Chemical group 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- FFLYUXVZEPLMCL-UHFFFAOYSA-N ethylchloranuidyl formate Chemical compound CC[Cl-]OC=O FFLYUXVZEPLMCL-UHFFFAOYSA-N 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- UAVOCTDYPKOULU-UHFFFAOYSA-N methylchloranuidyl formate Chemical group C[Cl-]OC=O UAVOCTDYPKOULU-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 201000002674 obstructive nephropathy Diseases 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 230000002035 prolonged Effects 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 239000010802 sludge Substances 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 229950000329 thiouracil Drugs 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
Definitions
- This invention comprises new anti-thyroid compounds. It is known that 1-methyl-2-mercaptoglyoxaline is a cry potent anti-thyroid agent. Its activity is much reater than thiouracil, the drug in most common use.
- the new compounds of the present invention [have re formula] have one of the two following formulae:
- R is an alkyl, aryl or alkaryl group and R is [1 alkoxy, alkylamino or aralkyloxy group, or mercaptolyoxaline residue.
- the compounds may be produced from Z-mercapto- .yoxalines having a substituent group R on the l-nitrogen :om, according to the following reaction.
- Example 2 Preparation of 1-methyl-[2Il3-carbonmethoxy[thioglyoxaline]-2-thioglyoxalone
- the procedure of Example 1 is followed but substituting methyl chloroformate for the ethyl ester.
- the product recrystallised from ethanol, has a melting point of 135 (3. Found: '0, 41.7; H, 4.4. 0,11,0,N,s requires (a): mol of I-methyl-2-mercaptoglyoxaline is dissolved in the minimum amount of pyridine at 0 C. 0.1 mol of carbobenzcxy chloride is added dropwise with stirring. The solution is then stirred for /z1 hour at room-temperature and placed in a vacuum desiccator over concentrated H SO /KOH.
- Example 5. --Preparation of di-(l-methyl-Z-glyoxalinyl) dithiolcarbonate dihydrochloride 0.01 mol. of 1-methyl-2-mercaptoglyoxaline is dissolved in 30 ml. dry benzene and 0.01 mol. phosgene dissolved in toluene is added slowly with cooling. The reddish coloured precipitate is filtered off and recrystallised from alcohol containing a small amount of water. Colourless needles M. P. 167 C. Found: C, 32.3; H, 4.1%. C9H12ON4S2C121'I20 requires C, H, 4.07%.
- a new anti-thyroid compound a substance selected from the group consisting of l-methyl-2-carbethoxy thioglyoxaline, I-methyI-Z-carbomethoxy thioglyoxaline,
Description
United States Patent 015 ice 24,505 ANTITHYROID COMPOUNDS Claude Rimiugton, Deansway, London, Alexander Lawson, Southgate, London, Charles E. Searle, Englefield 5 Matter enclosed in heavy brackets II] appears in the rriginal patent but forms no part of this reissue specifiatiou; matteroprinted in italics indicates the additions nade by reissue.
This invention comprises new anti-thyroid compounds. It is known that 1-methyl-2-mercaptoglyoxaline is a cry potent anti-thyroid agent. Its activity is much reater than thiouracil, the drug in most common use. The new compounds of the present invention [have re formula] have one of the two following formulae:
CH=CH CH CH N 3 1 N.R R.CON(3) (1)N.R
l which R is an alkyl, aryl or alkaryl group and R is [1 alkoxy, alkylamino or aralkyloxy group, or mercaptolyoxaline residue.
These compounds are no less potent than l-methyl-Z- lercaptoglyoxaline and have the advantage of being relavely tasteless and of having a more prolonged action. 1 these respects, the compounds hereinafter described l the examples are particularly valuable. They exhibit J evidence of toxicity.
The compounds may be produced from Z-mercapto- .yoxalines having a substituent group R on the l-nitrogen :om, according to the following reaction.
The R-substituted Z-mercaptoglyoxalines themselves ample 1.Preparation of 1-methyl-[2]3-carbethoxy [thioglyoxaline]-2-1hioglyoxalone 3.1 mol. of 1-methyl-2-mercaptoglyoxaline is dissolved Reissued July 22, 1958 in the minimum quantity of pyridine at 0 C. 0.1 mol. of ethyl chloroformate is added dropwise with stirring. More pyridine is added, if necessary, to keep the mixture semi-fluid. The sludge is then placed in an ice-box for 30 minutes. The crystals are filtered 0E and washed firstly with a little ethanol and secondly with ethanol and water. The product is crystallised from the solvent to give colourless needless having a melting point of 122-3 C. Found: C, 45.7; H, 5.4. C H O N S requires C, 43.2, H, 5.4%.
Example 2.-Preparation of 1-methyl-[2Il3-carbonmethoxy[thioglyoxaline]-2-thioglyoxalone The procedure of Example 1 is followed but substituting methyl chloroformate for the ethyl ester. The product, recrystallised from ethanol, has a melting point of 135 (3. Found: '0, 41.7; H, 4.4. 0,11,0,N,s requires (a): mol of I-methyl-2-mercaptoglyoxaline is dissolved in the minimum amount of pyridine at 0 C. 0.1 mol of carbobenzcxy chloride is added dropwise with stirring. The solution is then stirred for /z1 hour at room-temperature and placed in a vacuum desiccator over concentrated H SO /KOH.
The sticky oil is rubbed under petroleum-ether and the solvent poured off.- This is repeated twice. oil is then rubbed under water which causes it to crystallise slowly. The white crystalline material is filtered off. On recrystallisation from benzene/petroleum-ether (60- C.) the product is obtained in white needles having a melting point of 9l92 C. (b) 0.1 mol of l-methyl- Z-mercaptoglyoxaline is dissolved in 50 ml. of 4 N-caustic soda at 0 C. 0.1 mol. ofcarbobenzoxy chloride is added slowly. After the addition, the mixture is stirred at 0 C. for l530 minutes. The reaction mixture is then placed in an icebox for V2 hour, the White solid filtered off and washed firstly with water and secondly with petroleumether. The solid is crystallised from benzene/petroleumether to give white needles having a melting point of 91- 92 C. Found: C, 58.3; H, 4.9. C H O N S requires C, 58.1;H, 4.9%.
Example 4.Preparation of l-methyl-[2]3-hippuroyl [thioglyoxaline]-2-thiogly0xalone Example 5.--Preparation of di-(l-methyl-Z-glyoxalinyl) dithiolcarbonate dihydrochloride 0.01 mol. of 1-methyl-2-mercaptoglyoxaline is dissolved in 30 ml. dry benzene and 0.01 mol. phosgene dissolved in toluene is added slowly with cooling. The reddish coloured precipitate is filtered off and recrystallised from alcohol containing a small amount of water. Colourless needles M. P. 167 C. Found: C, 32.3; H, 4.1%. C9H12ON4S2C121'I20 requires C, H, 4.07%.
We claim:
[1. As a new anti-thyroid compound, a substance selected from the group consisting of l-methyl-2-carbethoxy thioglyoxaline, I-methyI-Z-carbomethoxy thioglyoxaline,
The thick I-methyl-Z-carbobenzoxy thioglyoxaline, l-methyl-Z-hippuroyl-thioglyoxaline and di-(l-methyl-2-glyoxa1inyl) dithiolcarbonate dihydrochloride] [2. As a new anti-thyroid compound, the substance 1- methyl-Z-carbethoxythioglyoxaline] [3. As a new anti-thyroid compound,vthe substance 1- methyl-Z-carbomethoxythioglyoxalinc.]
[4. As a new anti-thyroid compound, the substance 1- methyl-Z-carbobenzoxythioglyoxaline] [5. As a new anti-thyroid compound, the substance 1- methyl-2-hippurylthioglyoxaline.]
[6. As a new anti-thyroid compound, the substance di- (l-methyl-Z-glyoxalinyl) dithiolcarbonate dihydrochloo ride] '7. The product resulting from the process of producing antithyroid compounds by reacting Z-mercapto glyoxaline having a substituent methyl nadical R on the 1- nitrogen atom with a compound selected from the group consisting of ClCOCl and ClCOR' where R is selected from the group consisting of lower alkyl, benzyl, and mercaptoglyoxalinyl radicals, in the presence of a tertiary base.
- 8. The product resulting from the process of producing an antithyroid cdmpound by reacting l-methylmeroaptoglyoxaline with ethyl chloroformnte while cool- '4 ing in the presence .of a tertiary base and recovering the reaction product produced.
9. The product resulting from the process of producing an antithyroid compound by reacting while cooling 1- methyl-Z-mercaptoglyoxaline with methyl chloroformzzte in the presence of a tertiary base and recovering the reaction product formed.
10. The product resulting from the process of producing an antithyroid compound by reacting while cooling 1- methyl-2-mercaptoglyoxaline with carbobenzoxy chloride in the presence of a tertiary base and recovering the reaction product formed.
.11. The product resulting from the process of producing an antithyroid compound by reacting while cooling 1- methyl-Z-mercaptoglyoxaline with phosgene, in the presence of a tertiary base and recovering the reaction product formed Dessert Aug. 15, 1950 Jones Feb 12, 1952
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