Patent GB-1066855-A (GB)
Title: Pyrazinoylguanidine derivatives
IPC: C07D241/30
Filed: 1963-10-24
Abstract: The invention comprises compounds of the general formula I <FORM:1066855/C2/1> in which X is a hydrogen or halogen atom, a trihalomethyl, C1- 6 alkyl, C3 to C6 cycloalkyl, mononuclear aryl, anilino, C1- 5 alkylthio, C1- 5-alkylsulphonyl, phenyl-substituted C1- 5 alkylthio or phenyl-substituted C1- 5 alkylsulphonyl; Y is a hydrogen or halogen atom or a hydroxyl, mercapto, C1- 5 alkoxy, C1- 5 alkylthio, C1- 6 alkyl, C3- 6 cycloalkyl, mononuclear aryl or 4-methyl-1-piperazinyl group or an amino group of the formula -NRR1, wherein R is a hydrogen atom or an amino, amidino, C3- 6 cycloalkyl, C1- 6 alkyl, hydroxy-substituted C1- 6 alkyl, halogen-substituted C1- 6 alkyl, (C3- 6 cycloalkyl)-(C1- 5 alkyl), phenyl-substituted C1- 5 alkyl, (C1- 5 alkyl) phen-(C1- 5 alkyl), halophenyl-substituted C1- 5 alkyl, furyl-substituted C1- 5 alkyl, pyridyl-substituted C1- 5 alkyl, C1- 5 alkylamino (C1- 5 alkyl), C2- 6 alkenyl, b -aminoethyl, phenyl, halophenyl or (C1- 5 alkyl) phenyl radical and R1 is a hydrogen atom or a C1- 6 alkyl or C2- 6 alkenyl radical or R and R1 are joined to form a C2- 6 alkylene radical, but with the proviso that Y is not hydrogen when X is hydrogen, halogen or trihalomethyl; or X and Y together form a tetramethylene, 1,3-butadienylene or 2-chloro-1,3-butadienylene radical; Z is an amino, monosubstituted amino, disubstituted amino, or heterocyclic amino radical; R2 is a hydrogen atom or a C1- 6 alkyl radical; each of R3 and R4 is a hydrogen atom or a C1- 6 alkyl, hydroxy-substituted C1- 6 alkyl, phenyl-substituted C1- 5 alkyl, halophenyl-substituted C1- 5 alkyl, (C1- 5 alkyl) phen-(C1- 5 alkyl), (C1- 5 alkoxyphenyl) substituted C1- 5 alkyl, naphthyl-substituted C1- 5 alkyl, (octahydro-1-azocinyl)-substituted C1- 5 alkyl, pyridyl-substituted C1- 5 alkyl, or phenyl radical; or R3 and R4, together with the nitrogen atom to which they are attached, represent a 1-pyrrolidinyl, piperidino, morpholino, or 4-(C1- 4 alkyl)-piperazinyl group and pharmaceutically acceptable salts thereof.  These compounds may be prepared by the following methods:  (1) reacting a substituted pyrazinoic acid ester of the Formula II <FORM:1066855/C2/2> wherein R* is a C1-alkyl radical with a guanidine of formula <FORM:1066855/C2/3> to produce a compound of Formula I;  (2) reacting a (3-amino-5,6-dichloropyrazinoyl) guanidine of the Formula III <FORM:1066855/C2/4> with an amine of formula RR1NH to produce a compound of Formula IV <FORM:1066855/C2/5> (3) reacting a C1-alkyl ester of a 3-amino-5,6-dihalopyrazinoic acid with a saturated alcohol or phenol to produce the corresponding C1-alkyl ester of 3-amino-5-alkoxy- (or aryloxy-)-6-halopyrazinoic acid and reacting the latter with a guanidine of the formula <FORM:1066855/C2/6> to produce a compound of Formula V <FORM:1066855/C2/7> (4) acylating a compound of Formula VI <FORM:1066855/C2/8> with an acid anhydride of the formula (R5CO)2O to produce a 2-alkyl-4H-pyrazino-[2,3-d][1,3]-oxazin-4-one of the Formula VII <FORM:1066855/C2/9> and reacting the latter with a guanidine of formula <FORM:1066855/C2/100> to produce a compound of the Formula VIII <FORM:1066855/C2/111> the N-acyl group of which may be removed by hydrolysis if desired, and  (5) catalytic hydrogenolysis of a compound of the Formula IX <FORM:1066855/C2/122> where R11 is an alkyl radical, to replace the chlorine atom by hydrogen, brominating the resulting 6-unsubstituted compound to introduce a 6-bromine atom, and reacting the latter with a guanidine of the formula <FORM:1066855/C2/133> to produce a compound of the Formula X <FORM:1066855/C2/144> The intermediate 3-aminopyrazinoic acid esters may be produced by the methods represented by the following reaction schemes: <FORM:1066855/C2/155> <FORM:1066855/C2/166> <FORM:1066855/C2/177> <FORM:1066855/C2/188> <FORM:1066855/C2/199> where R in steps (b) and (c) represents a C1- 5 alkyl radical; <FORM:1066855/C2/200> <FORM:1066855/C2/211> The compounds of Formula VI may be prepared by hydrolysis of the corresponding esters or amides or, for those compounds having a 6-RS or 6-RSO2 group, the method represented by the reaction scheme <FORM:1066855/C2/222> where R is a C1 alkyl or a phenyl-substituted C1 alkyl radical.  The compounds of Formula III may be prepared by reacting a pyrazinoic acid ester of formula <FORM:1066855/C2/233> where R11 is an alkyl radical, with a guanidine of the formula <FORM:1066855/C2/244>ALSO:Pyrazinoylguanidines of the general formula I <FORM:1066855/A5-A6/1> in which X is a hydrogen a halogen atom, a trihalo-methyl, C1-6 alkyl, C3-6 cycloalkyl, mononuclear aryl, anilino, C1-5 alkylthio, C1-5 alkylsulphonyl, phenyl-substituted C1-5 alkylthio, or phenyl-substituted C1-5 alkylsulphonyl; 7 is a hydrogen or halogen atom or a hydroxyl, mercapto, C1-5 alkoxy, C1-5 alkylthio, C1-6 alkyl, C3-6 cycloalkyl, mononuclear aryl or 4-methyl-1-piperazinyl group or an amino group of the formula -NRR1, where R is a hydrogen atom or an amino, amidino, C3-6 cycloalkyl, C1-6 alkyl, hydroxy-substituted C1-6 alkyl,, halogen-substituted C1-6 alkyl, (C3-6 cycloalkyl)-(C1-5 alkyl), phenyl-substituted C1-5 alkyl, (C1-5 alkyl) phen (C1-5 alkyl), halophenyl substituted C1-5 alkyl, furyl-substituted C1-5 alkyl, pyridyl substituted C1-5 alkyl, C1-5 alkylamino (C1-5 alkyl), C2-6 alkenyl, b -aminoethyl, phenyl, halophenyl or (C1-5 alkyl) phenyl radical and R1 is a hydrogen atom or a C1-6 alkyl or C2-6 alkenyl radical or R and R1 are joined to form a C2-6 alkylene radical, but with the proviso that 7 is not hydrogen when X is hydrogen, halogen or trihalomethyl; or X and Y together form a tetramethylene, 1,3-butadienylene or 2-chloro-1,3-butadienylene radical; Z is an amino, mono-substituted amino, disubstituted amino or heterocyclic amino radical; R2 is a hydrogen atom or a C1-6 alkyl radical; each of R3 and R4 is a hydrogen atom or a C1-6 alkyl, hydroxy-substituted C1-6 alkyl, phenyl-substituted C1-5 alkyl, halophenyl-substituted C1-5 alkyl, (C1-5 alkyl) phen (C1-5 alkyl), (C1-5 alkoxyphenyl) substituted C1-5 alkyl, naphthyl-substituted C1-5 alkyl, (octahydro-1-azocinyl)-substituted C1-5 alkyl, pyridyl-substituted C1-5 alkyl, or phenyl radical; or R3 and R4, together with the nitrogen atom to which they are attached, represent a 1-pyrrolidinyl, piperidino, morpholino, or 4-(C1-4 alkyl)-piperazinyl group and pharmaceutically acceptable salts thereof are employed as duiretic and/or saluretic agents in, for example, pills, tablets, capsules, elixirs, injectable preparations.  Other therapeutic agents may be present in the pharmaceutical compositions and when said known therapeutic agents administered alone enhance the elimination of potassium and sodium ions the co-administration of the guaridine of the formula I.  Specified known diuretics employed in said pharmaceutical compositions are hydrochlorothiazide; 4\sv-methyl-6-chloro-spiro-[2H-1,2,4-benzothiadiazide-3(4H) -1\sv-cyclohexane] - 7 - sulphonamide-1,1-dioxide; trichloromethiazide; cyclopenthiazide; acetazolamide; dichlorophenamide; chlorthalidone; chlormerodrin; chlorazinil; or spironolactone.