Patent GB-1115406-A (GB)
Title: 3(aminopyrazinoyl)guanidine 4-oxide derivatives and their preparation and use
IPC: C07D241/30
Filed: 1966-06-29
Abstract: Novel compounds of Formula X <FORM:1115406/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, phenylsubstituted C1- 5 alkylthio, C1- 5 alkylsulphonyl, phenyl-substituted C1- 5 alkylsulphonyl, di-(C1- 5 alkyl)amino, morpholino, N-benzyl-N-methyl-amino, or piperidino; R1 is hydrogen, formyl, C2- 6 alkanoyl or benzoyl, R2 is hydroge or C1- 5 alkyl, R3 is hydrogen, C1- 5\t alkyl, C1- 5 hydroxyalkyl, C1- 5 haloalkyl, C1- 5 alkylamino-substituted C1- 5 alkyl, di-(C1- 5 alkyl)-amino-substituted C1- 5 alkyl, phenyl-substituted C1- 5 alkyl, halophenyl-substituted C1- 5 alkyl, (C1- 5 alkyl)-phenyl substituted C1- 5 alkyl, (C1- 5 alkoxy)-phenyl substituted C1- 5 alkyl, naphthyl-substituted C1- 5 alkyl, (octahydro-1-azoamyl)-substituted C1- 5 alkyl or pyridyl-substituted C1- 5 alkyl, R4 is hydrogen, a radical of the type defined for R3 or an aryl, heteroaryl, substituted aryl, alkylidene-amino or acyl, or, when R3 is hydrogen, a radical of the formula <FORM:1115406/C2/2> or -NR3R4 is a 1-pyrrolidinyl, piperidino, morpholino, or 4-(C1- 5 alkyl)piperazinyl group, or R2 and R3 are joined to form a cyclic structure with the nitrogen atoms to which they are respectively attached, are prepared (1) when R1 is hydrogen, by reacting a guanidine of formula H2N-C(=NR2)-NR3R4 with a C1- 5 alkyl ester of a 3-amino-6-X-pyrazinoic acid-4-oxide, (2) when R1 is formyl, C2- 6 alkanoyl or benzoyl, by reacting a guanidine of the formula given above with a 4H-pyrazino[2,3-d][1,3]-oxazin-4-one 8-oxide of formula <FORM:1115406/C2/3> wherein R5 is a hydrogen atom, or a C1- 5 alkyl or phenyl radical, or (3) when R1 is hydrogen, by hydrolysis of the corresponding 3-formyl, 3-C2- 6 alkanoyl or benzoyl derivative.  The C1- 5 alkyl 3-amino-6 X-pyrazinoate 4-oxides may be prepared by reacting the corresponding C1- 5 alkyl 3-amino-6X-pyrazinoate with m-chloroperbenzoic acid.  The 4H-pyrazino[2,3-d][1,3]oxazin-4-one 8-oxides may be obtained by reacting a 3-amino-pyrazinoic acid 4-oxide obtained by hydrolysis of the C1- 5 alkyl ester with acetic anhydride. 2-Methyl-6-dimethylamino - 4H - pyrazino[2,3-d][1,3]oxazin-4-one 8-oxide is obtained by reacting methyl 3-amino-6-chloropyrazinoate with methylamine, treating the N-methyl-3-amino-6-chloropyrazinamide obtained with m-chloroperbenzoic acid, reacting the N-methyl-3-amino-6-chloropyrazinamide 4-oxide produced with triethyl orthoformate and acetic anhydride, treating the 3-methyl-6-chloro-4(3H)pteridinone 8-oxide thus formed with dimethylamine, decomposing the 3 - methyl - 6 - dimethylamino - 4(3H) - pteridinone 8-oxide obtained with sodium hydroxide, and reacting the 3-amino-6-dimethylaminopyrazinoic acid 4-oxide produced with acetic anhydride. The 6-diethylamino, 6-morpholino, 6-N-benzyl-N-methyl-amino and 6-piperidino derivatives are similarly produced by replacing dimethylamine with the appropriate amine. 2 - Methyl - 6 - methoxy - 4H - pyrazino[2,3-d][1, 3]-oxazin-4-one 8-oxide is similarly obtained by reacting 3-methyl-6-chloro-4(3H)-pteridinone-8-oxide with sodium in methanol to give 3-methyl - 6 - methoxy - 4(3H) - pteridinone 8-oxide which is hydrolysed to 3-amino-6-methoxypyrazinoic acid 4-oxide and cyclised as described above.  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 compound and treating the 3-amino-6-chloro-pyrazinamide-4-oxide obtained with acetic anhydride and ethyl orthoformate to give 4-hydroxy-6-chloropteridine 8-oxide which is converted to the 6-benzylthio derivative, hydrolysed to 3-amino-6-benzylthiopyrazinoic acid 4-oxide and cyclized as described above.  The 6-methylsulphonyl compound is obtained by converting 4-hydroxy-6-chloropteridine 8-oxide to the 6-methylthio derivative, hydrolysing this compound and oxidizing the 3 - amino - 6 - methylthiopyrazinoic acid - 4 oxide to the 6-methylsulphonyl derivative which is cyclized as described above.ALSO:Therapeutic and veterinary compositions having diuretic and natriuretic properties which may be administered orally or parenterally contain as active ingredients one or more compounds of formula <FORM:1115406/A5-A6/1> and their pharmaceutically acceptable acid addition salts, wherein X is hydrogen, chlorine, bromide, 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, di-(C1-5 alkyl) - amino, morpholino, N - benzyl - N - methylamino, or piperidino, R1 is hydrogen, formyl C2-6 alkanoyl or benzoyl, R2 is hydrogen or C1-5 alkyl, R3 is hydrogen, C1-5 alkyl, C1-5 hydroxylalkyl, C1-5 haloalkyl, C1-5 alkylamino - substituted C1-5 alkyl, di(C1-5 alkyl) - amino - substituted C1-5 alkyl, phenyl-substituted C1-5 alkyl, halophenyl - substituted C1-5 alkyl, (C1-5 alkyl) - phenyl - substituted C1-5 alkyl, (C1-5 alkoxy) - phenyl substituted C1-5 alkyl, naphthyl - substituted C1-5 alkyl, (octahydro - 1 - azocinyl) - substituted C1-5 alkyl or pyridyl - substituted C1-5 alkyl, R4 is hydrogen, a radical of the type defined for R3, or aryl, heteroaryl, substituted aryl, alkylideneamino or acyl, or, when R3 is hydrogen, a radical of formula <FORM:1115406/A5-A6/2> or - NR3R4 is 1 - pyrrolidinyl, piperidino, morpholino, or 4 - (C1-5 alkyl) - piperazinyl, or R2 and R3 are joined to form a cyclic structure with the nitrogen atoms to which they are attached, if desired, in combination with other diuretic or therapeutic agents.