Patent GB-1083902-A (GB)
Title: Pyrazinoyl guanidines
IPC: C07D475/02
Filed: 1964-10-06
Abstract: The invention comprise compounds of the formula <FORM:1083902/C2/1> (a) in which R is a mononuclear-aryl-substituted C1- 5 alkyl, (alkoxyphenyl substituted C1- 5 alkyl) amino, (4-piperidylmethyl) amino, trifluoromethylamino or anilino radical, R2 is hydrogen or a C1- 5 alkyl radical, and each of R3 and R4 is hydrogen or a C1- 5 alkyl, hydroxy - C1- 5-alkyl, phenylsubstituted C1- 5 alkyl, halophenyl - substituted C1- 5 alkyl, (C1- 5) phen (C1- 5 alkyl), (C1- 5 alkoxy)-phenyl - substituted C1- 5 alkyl, naphthyl-C1- 5 alkyl, pyridyl - C1- 5 alkyl, or phenyl radical (provided not both R3 and R4 are phenyl) or -NR3R4 represent a 1-pyrrolidinyl, piperidino, morpholino or 4-(C1- 5 alkyl)-1-piperazinyl residue, and Z is an amino, monosubstituted amino, di-substituted amino or heterocyclic amino radical, or (b) R is hydroxyl or a C1- 5 alkyl, cycloalkyl, (C1- 5 alkyl)-cycloalkyl, C1- 5 alkoxy, phenyl, phenyl-C1- 5 alkyl, (C1- 5 alkyl) phen (C1- 5 alkyl,) or a (C1- 5 alkoxyl) phen (C1- 5 alkyl) radical or an amino radical -NR1R11 where R1 is hydrogen or a C1- 5 alkyl radical and R11 is hydrogen, amino, amidino, C1- 5 alkoxy, C1- 5 alkyl, C1- 5 hydroxyalkyl, C1- 5 haloalkyl, C3- 6 cycloalkyl-substituted C1- 5 alkyl, phenyl-C1- 5 alkyl, furyl-C1- 5 alkyl, (C1- 5 alkyl) phen (C1- 5 alkyl), pyridyl - C1- 5 alkyl, C1- 5 alkylamino (C1- 5 alkyl), phenyl or a (C1- 5 alkyl) phenyl radical, or R1 and R11 together represent a C2- 6 alkylene radical, two of R2, R3 and R4 are both methyl and the other is hydrogen, or R2 and R4 are both hydrogen and R3 is a methyl, 2-hydroxyethyl, phenyl, benzyl or 4-methoxybenzyl radical, provided that if R is hydroxy or a C1- 5 alkyl, C3- 6 cycloalkyl, C1- 5 alkoxy or -NR1R11, then R3 is not a phenyl radical, and Z is amino, monosubstituted amino, disubstituted amino or a heterocyclic amino radical and the acid addition salts thereof. The compounds are prepared by reacting a pyrazinoic acid ester of the formula <FORM:1083902/C2/2> wherein R0 is a C1- 6 alkyl radical, with guanidine of the formula <FORM:1083902/C2/3> The guanidines possess pharmaceutical properties (see Division A5).  The pyrazinoate starting materials are made by esterification of the free acid, or by dechlorination of the corresponding 6-chloropyrazinoate, which, in turn, is prepared from the 5,6-dichloro-pyrazinoate by introducing various value of R into the 5-position, e.g. by reaction with a sodium mercaptide to give the 5-alkylthio-6-chloropyrazinoate, e.g. the 5-methylthio-compound which is converted to the 5-methyl-sulphinyl compound with hydrogen peroxide, followed by treatment with acetic acid to give the 5-hydroxy compound.  The guanidine starting materials of the Formula (II) in which R2 and R3 are hydrogen are prepared by reacting the corresponding amine NH2R4 with 2-methyl-2-pseudo-thiuronium sulphate.ALSO:Pharmaceutical compositions comprise one or more of the guanidines of the following formula, or an acid addition salt thereof <FORM:1083902/A5-A6/1> where (a) R is a mono-nuclear aryl substituted C1-5 alkyl, (alkoxyphenyl C1-5 alkyl) amino, (4-piperidylmethyl) amino, trifluoromethyl amino or anilino radical, R2 is hydrogen or a C1-5 alkyl radical, each of R3 and R4 is hydrogen or a C1-5 alkyl, C1-5 hydroxyalkyl, phenyl-C1-5 alkyl, halophenyl-C1-5 alkyl, (C1-5 alkyl) phen (C1-5 alkyl)-, (C1-5 alkoxy) phenyl-C1-5 alkyl, naphthyl-C1-5 alkyl, pyridyl-C1-5 alkyl or phenyl radical (provided not both R3 and R4 are phenyl) or -NR3R4 represents a 1-pyrrolidinyl, piperidino, morpholino or 4-(C1-5 alkyl)-1-piperazinyl residue; and Z is an amino, mono- or disubstituted amino or heterocyclic amino radical; (b) R is a hydroxy, C1-5 alkyl, cycloalkyl, (C1-5 alkyl)-cycloalkyl, C1-5 alkoxy, phenyl, phenyl-C1-5 alkyl, (C1-5 alkyl) phen (C1-5 alkyl), (C1-5 alkoxy)-phen (C1-5 alkyl) or an amino radical -NR\svR\yF where R\sv is hydrogen or a C1-5 alkyl radical and R\yF is hydrogen or an amino, amidino, C1-5 alkoxy, C1-5 alkyl, C1-5 hydroxyalkyl, C1-5 haloalkyl, (C3-6 cycloalkyl)-C1-5 alkyl, phenyl-C1-5 alkyl, furyl-C1-5 alkyl, (C1-5 alkyl) phen (C1-5 alkyl), pyridyl-C1-5 alkyl, (C1-5 alkylamino)-C1-5 alkyl, phenyl or a (C1-5 alkyl) phenyl radical or R\sv and R\yF together represent a C2-6 alkylene radical; and 2 of R2, R3 and R4 are both methyl and the other hydrogen, or R2 and R4 are both hydrogen and R3 is a methyl, 2-hydroxyethyl, phenyl, benzyl or 4-methoxybenzyl radical (provided that if R is a hydroxy, C1-5 alkyl, C3-6 cycloalkyl, C1-5 alkoxy or -NR\sv R\yF radical, R3 is not a phenyl radical; and Z is an amino, mono- or di-substituted amino or heterocyclic amino radical.  The compositions possess diuretic and natriuretic properties and are used in the treatment of ocdema and hypertension.  The compositions may take the form of pills, tablets, capsules, elixirs or injectable preparations and may contain other therapeutic agents, particularly diuretic agents, e.g. 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, chorthalidone, chlormerodin, chlorazinil or spironolactone, steroids and hypotensive agents.  Examples 11 and 12 relate to dry filled capsules.