Patent ES-341317-A1 (ES)
Title: Novel Pyrazinamides and their Preparation
IPC: C07D241/26
Filed: 1967-06-02
Abstract: Novel 3-aminopyrazinamides of the general formula wherein X is hydrogen, chloro, bromo, iodo, trifluoromethyl, C 1-5 alkyl, C 3-6 cycloalkyl, phenyl, chlorophenyl, bromophenyl, C 1-5 alkylthio, phenyl-C 1-6 alkylthio, C 1-5 alkylsulphonyl, phenyl-C 1-5 alkylsulphonyl, C 1-5 alkoxy, C 1- 5 alkylamino, di-C 1-5 alkylamino, phenyl-C 1-5 alkylamino, (C 1-5 alkyl) - (phenyl - C 1-5 alkyl)- amino, 1-piperidinyl or 1-pyrrolidinyl Y is hydrogen, hydroxy, mercapto, C 1-5 alkoxy, C 1-5 alkyl-thio, C 1-5 alkyl, halo-substituted C 1-5 alkyl, C 3-6 cycloalkyl, phenyl, 1-pyrrolidinyl, hexahydro - 1 - azepinyl, 4 - C 1-5 alkyl- 1-piperazinyl, or -NR5R6 where R6 is hydrogen or C 1-5 alkyl and R5 is hydrogen, amino, C 1-5 alkylamino, di - (C 1-5 alkyl) - amino, C 1-5 alkoxy, phenyl, halophenyl, C 1-6 alkyl, C 2-6 unsaturated alkyl, C 3-6 cycloalkyl, (C 3-6 cycloalkyl)-C 1-5 alkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, amino - C 1-6 alkyl, (C 1-5 alkyl) - amino - (C 1-6 alkyl), di - (C 1-5 alkyl) - amino - (C 1-6 alkyl), phenyl - C 1-6 alkyl, halophenyl - C 1-6 alkyl, (C 1-5 alkyl) - phenyl - C 1-6 alkyl, furyl- C 1-6 alkyl, pyridyl-C 1-6 alkyl, (CH 2 ) n N-C 1- 6 alkyl, where n is 4, 5 or 6, (1-pyrrolidinyl)-C 1-6 alkyl, (hexahydro - 1 - azepinyl) - C 1-6 alkyl) or (C 1-6 alkanoyl)-(C 1-6 alkyl) R is aminoethyl, (C 1-5 alkyl) aminoethyl, di-(C 1-5 alkyl) aminoethyl, morpholinoethyl, 1 - pyrrolidinylethyl, 1 - piperidinylethyl, hexahydro - 1 - azepinylethyl, octahydro - 1 - azocinylethyl, 4- (C 1-5 alkyl) - 1 - piperazinylpropyl, 2 -, 3 - or 4 - pyridylmethyl, 1 - (C 1-5 alkyl) - 2 - pyrrolidinylmethyl or 1-(C 1-5 alkyl)-3-pyrrolidinyl R 1 is hydrogen or C 1-5 alkyl R2 is hydrogen, C 1-5 alkyl, C 1-5 alkoxy) - (C 1-5 alkyl), di- (C 1-5 alkyl) - amino - (C 1-5 alkyl), 1 - pyrrolidinyl, 1 - piperidinyl, hexahydro - 1 - azepinyl, octahydro - 1 - azocinyl, morpholino, piperazinyl, furyl - (C 1-5 alkyl), phenyl - (C 1-5 alkyl), halophenyl - (C 1-5 alkyl), (C 1-5 alkyl) - phenyl - (C 1-5 alkyl), (C 1-5 alkoxy) - phenyl - (C 1-5 alkyl), C 1-6 alkanoyl, phenyl-C 1-6 alkanoyl, cyclopentyl or cyclohexyl, or R1 and R2 are C 1-5 alkylene joined together directly to form a 5-membered ring with the nitrogen atom to which they are attached or joined together either directly or through a nitrogen or oxygen atom to form a 6-membered ring with the nitrogen atom to which they are attached and pharmaceutically acceptable acid addition salts thereof are prepared by reaction of an alkyl 3-aminopyrazinoate of the general formula wherein Alk is C 1-5 alkyl, with an amine of the general formula H 2 NR or by reaction of a 4H - pyrazino - [2,3 - d][1,3] - oxazin - 4 - one of the general formula wherein R10 is hydrogen, alkyl or aralkyl, with an amine of the general formula NH 2 R, followed optionally by acid hydrolysis of the resulting 3-acylamino derivative of the first general formula above, followed optionally by conversion of the product to a pharmaceutically acceptable acid addition salt thereof. 1-Ethyl-3-pyrrolidine is prepared by reaction of 1-ethyl-3-hydroxypyrrolidine with thionyl chloride, followed by treatment of the resulting 1-ethyl-3-chloropyrrolidine with ammonia. Methyl - 3 - amino - 5 - trifluoromethyl - pyrazinoate is prepared by reaction of 1,1,1-trifluoromethyl, 3,3-dibromoacetone and aminomalonamidamidine dihydrochloride, hydrolysis of the resulting 3-amino-5-trifluoromethyl-pyrazinamide (some 3 - amino - 6 - trifluoromethylpyrazinamide is also formed) and esterification of the obtained 3 - amino - 5 - trifluoromethyl - pyrazinoic acid with methanol. Ethyl 3-amino- 6-trifluoromethyl-pyrazinoate is prepared from 3 - amino - 6 - trifluoromethyl - pyrazinamide by treatment successively with triethyloxonium fluoroborate, potassium carbonate and diethyl ether. Methyl 3-benzylamino-6-chloropyrazinoate is prepared by reaction of methyl 3-bromo- 6 - chloropyrazinoate with benzylamine. Methyl 3 - p - chlorobenzylamino - 6 - chloropyrazinoate is prepared by reaction of methyl 3 - bromo - 6 - chloro - pyrazinoate with pchlorobenzylamine. Methyl 3-p-methoxybenzylamino-6-chloropyrazinoate is prepared by reaction of methyl 3-bromo-6-chloropyrazinoate with p - methoxybenzylamine. Methyl 3-(2- furfurylamino) - 6 - chloropyrazinoate is prepared by reaction of methyl 3-bromo-6-chloropyrazinoate with furfurylamine. Methyl 3-(2- methoxyethylamino) - 5 - ethylamino - 6 - chloropyrazinoate is prepared by bromination of methyl 3 - amino - 5 - ethylamino - 6 - chloropyrazinoate, followed by reaction of the resulting methyl 3 - bromo - 5 - ethylamino - 6-chloropyrazinoate with methoxyethylamine 2 - Methyl - 6 - benzylsulphonyl - 4H - pyrazino - [2,3-d][1,3[-oxazin-4-one is prepared by oxidizing 3 - amino - 6 - benzylmercapto - pyrazinoic acid with potassium permanganate and then treating with acetic anhydride. Pharmaceutical compositions having diuretic and/or saluretic activity comprise, as active ingredient, a 3-aminopyrazinamide of the first general formula above or a pharmaceutically acceptable acid addition salt thereof, together with a pharmaceutical carrier or diluent, and may be administered orally or parenterally.