Patent GB-1115380-A (GB)
Title: (3-aminopyrazinamido) guanidine 4-oxide derivatives and their preparation and use
IPC: C07D475/02
Filed: 1966-06-29
Abstract: Novel compounds of Formula A <FORM:1115380/C2/1> and their pharmaceutically acceptable acid addition salts, wherein X is hydrogen, chlorine bromine, trifluoromethyl, alkoxy, C1- 5 alkyl, C3- 6 cycloalkyl, mononuclear aryl, substituted mononuclear aryl, C1- 5 alkylthio, phenyl-substituted C1- 5 alkylthio, C1- 5 alkylsulphonyl, phenyl-substituted C1- 5 alkylsulphonyl, or di-(C1- 5 alkyl)-amine, R1 is hydrogen, formyl, C2- 6 alkanoyl, or benzoyl, and each of R3 and R4 is hydrogen, C1- 5 alkyl, C1- 5 hydroxyalkyl, aryl or substituted aryl, phenyl-substituted C1- 5 alkyl, C3- 6 cycloalkyl, amino or substituted amino, or R3 and R4 are joined together to form a heterocyclic ring with the nitrogen atom to which they are attached, are prepared (1) when R1 is hydrogen, by reacting an aminoguanidine with an alkyl ester of a 3-amino-6X-pyrazinoic acid 4-oxide, (2) when R1 is formyl, C2- 6 alkanoyl or benzoyl, by reacting an aminoguanidine with a 4H-pyrazino[2,3-d][1,3]oxazin-4-one 8-oxide of formula <FORM:1115380/C2/2> wherein R5 is hydrogen, C1- 5 alkyl, or phenyl, (3) when R1 is hydrogen, by hydrolysis of the corresponding compound in which R1 is a formyl, C2- 6 alkanoyl or benzoyl radical, or (4) when R1 is hydrogen, by reacting a 3-aminopyrazinoic acid hydrazide 4-oxide with a cyanamide of formula NC-N-R3R4, or with a compound of formula NH = C(SY)NR3R4 in which Y is a C1- 5 alkyl or an aralkyl radical.  The alkyl 3-amino-6X-pyrazinoate 4-oxides are obtained by treating the alkyl 3-amino-6X-pyrazinoates with m-chloroperbenzoic acid. The 3-amino-pyrazinoic acid hydrazide 4-oxides are prepared by reacting an alkyl ester of the desired acid with hydrazine.  The 4H-pyrazino-[2,3-d][1,3]oxazin-4-one-8 oxides are made by treating a 3-aminopyrazinoic acid 4-oxide obtained by hydrolysis of the corresponding ester with acetic anhydride. 2-Methyl-6-dimethyl-amino - 4H - pyrazino[2,3-d][1,3]oxazin - 4 - one 8-oxide is made by converting methyl 3-amino-6-chloropyrazinoate to its N-methylamide, oxidizing this, and treating the N-methyl-3-amino-6-chloropyrazinamide 4-oxide with triethyl ortho-formate and acetic anhydride to give 3-methyl-6 -chloro-4(3H)-pteridinone 8-oxide which is reacted with dimethylamine and the 3-methyl-6-dimethylamino - 4(3H) - pteridinone 8 - oxide obtained hydrolysed with sodium hydroxide, the 3-amino-6-dimethylaminopyrazinoic acid 4-oxide thus formed being cyclized using acetic anhydride.  The 6-methoxy derivative is obtained by treating 3-methyl-6-chloro-4(3H)-pteridinone 8-oxide with sodium in methanol, the 3 - methyl - 6 - methoxy - 4(3H) - pteridinone 8-oxide thus obtained being treated as described above to give 3-amino-6-methoxy-pyrazinoic acid 4-oxide and 2-methyl-6-methoxy-4H-pyrazino[2,3-d][1,3]oxazin - 4 - one 8 oxide. 2-Methyl - 6 - benzylthio - 4H - pyrazino[2,3-d][1,3]-oxazin-4-one 8-oxide is obtained by converting methyl 3-amino-6-chloropyrazinoate to its amide, oxidizing this, and reacting the 3-amino-6-chloropyrazinamide -4-oxide obtained with ethyl orthoformate and acetic anhydride, treating the 4-hydroxy-6-chloropteridine 8-oxide produced with benzyl mercaptan, hydrolysing the 6-benzylthio derivative obtained, and cyclizing the 3-amino-6-benzylthiopyrazinoic acid 4-oxide as described above.  The 6-methylsulphonyl derivative is similarly prepared by treating 4-hydroxy -6-chloropteridine 8-oxide with methyl mercaptan, hydrolysing the 6-methylthio derivative as described above and oxidizing the 3-amino -6-methylthiopyrazinoic acid 4-oxide obtained followed by cyclization of the 6-methyl-sulphonyl compound. Therapeutic and veterinary compositions having diuretic and natriuretic properties which can be administered orally or parenterally, contain as active ingredient one or more of the compounds of Formula A above.