Pyrazinoyl-benzamidines

摘要

Compounds of the formula or a pharmaceutically acceptable salt thereof, in which formula: R is H or a halogen atom, a C1- 6-alkyl, C3- 6-cycloalkyl, trihalomethyl, phenyl (optionally substituted), phenyl-C1- 5-alkyl, C1- 5-alkylthio, phenyl-C1- 5-alkylthio, C1- 5-alkylsulphonyl or phenyl-C1- 5-alkyl sulphonyl radical; R1 is H or a C1- 5-alkyl or phenyl group; R2 is H or a R11CO-radical where R11 is H or a C1- 5-alkyl or phenyl radical; R3 is phenyl, halophenyl, C1- 5-alkyl-phenyl, C1- 5-alkoxy-phenyl or trihalomethyl-phenyl radical are prepared by reacting a benzamidine with a 4-H-pyrazino[2,3-d]-[1,3]oxazin-4-one of the formula and optionally removing the acyl group R11CO-. 2 - Methyl - 6 - chloro - 4 - H - pyrazino[2,3-d] -[1,3]-oxazin-4-one is prepared from 3-amino-6-chloropyrazinoic acid and acetic anhydride. 3-Amino-6-chloropyrazinoic acid is prepared by reacting methyl 3-aminopyrazinoate with Cl2 to give 3 - chloroamino - 6 - chloropyrazinoate and treating this with sodium bisulphite to give methyl 3 - amino - 6 - chloropyrazinoate and saponifying this. Similarly prepared are 3-amino-6-bromo- and 6-iodopyrazinoic acids. 3-Amino - 5 (or 6) - trifluoromethyl -, - methyl -, -phenyl-, p-chlorophenyl-, -benzyl-, -cyclohexyl-, and -cyclopropyl-pyrazinoic acids are prepared by reacting a 1,2-diketone or 2-oxoaldehyde with either a diaminouracil to give a lumazine which is hydrolysed or with an aminomalonamidamidine and hydrolysing the amide formed. 3 - Amino - 6 - methylthio -, - benzylthio and -methylsulphonyl-pyrazinoic acids are prepared by reacting methyl 3-amino-6-chloropyrazinoate with ammonia to form the amide, treating this with ethyl carbonate to give a pyrazino pyrimidine compound, replacing the chlorine atom by a methyl- or benzyl-thio group, splitting the fused ring system and optionally oxidizing the thio group to the sulphonyl group.ALSO:Pharmaceutical compositions comprise a compound of the formula or a pharmaceutically acceptable acid addition salt thereof wherein R is H or a halogen atom, or a C1-5-alkyl, C3-6-cyclo-alkyl, trihalomethyl, phenyl, substituted phenyl, phenyl-C1-5-alkyl, C1-5-alkylthio, phenyl-C1-5 alkylthio, C1-5 alkylsulphonyl or phenyl-C1-5 alkyl sulphonyl radical; R/sv is H or C1-5 alkyl or phenyl group; R2 is H or a R/yF-CO-, where R/yF is H, or a C1-5 alkyl or phenyl radical; R3 is phenyl, halophenyl C1-5 alkylphenyl, C1-5-alkoxyphenyl or trihalomethyl-phenyl radical and an inert carrier. The compositions, which have diuretic activity, may also contain a second diuretic compound or a compound having therapeutic activity. Examples of such additional active ingredients include hydrochlorothiazide, 4/sv-methyl - 6 - chlorspiro-[2H-1,2,4-benzothiadiazine - 3(4H)-1/sv-cyclohexane]-7-sulphonamide-1, 1-dioxide, trichloromethiazide, cyclopenthiazide, acetazolamide, dichlorophenamide, chlorthalidone, chlormerodrin, chlorazinil and spironolactone. The composition may be administered either orally or parenterally.