Patent GB-1067473-A (GB)
Title: Pyrazinamidoguanidines
IPC: C07D241/30
Filed: 1963-10-15
Abstract: The invention comprises (3-aminopyrazinamido) guanidines of the formula <FORM:1067473/C2/1> wherein R is a hydrogen or halogen atom or a trihalomethyl radical; R1 is a hydrogen atom or an amino radical of the formula <FORM:1067473/C2/2> wherein R5 is a hydrogen atom, C1- 5 alkyl, or a C2- 5 alkynyl radical, and R6 is a hydrogen atom a C1- 5 alkoxy radical; a C1- 5 alkyl radical or a cycloalkyl radical having a 3- to 6-membered ring, said alkyl or cycloalkyl being either unsubstituted or containing one or more hydroxyl, halogen, C3- 6 cycloalkyl, aryl, heterocyclic or amino or substituted amino substituents; C2- 5 alkenyl; phenyl; halophenyl; or (C1- 5 alkyl) phenyl; or R5 and R6 are linked together to form, with the nitrogen atom to which they are attached, a 1-pyrrolidinyl, piperidino, 4-methyl-1 - piperazinyl, hexahydro - 1 - azepinyl or octahydro - 1 - azocinyl radical; R3 and R4 are similar or dissimilar and each represents a hydrogen atom or a phenyl; (C1- 5 alkyl) phenyl; halophenyl; amino; di-(C1- 5 alkyl) amino; C1- 5 alkyl or C3- 6 cycloalkyl, said alky or cycloalkyl being unsubstituted or bearing one or more of the substituents hydroxy, halogen, aryl, amino or substituted amino radical; or NR3R4 represents a heterocyclic radical; and R2 is a hydrogen atom or, when R1 is hydrogen and R is halogen, a C2- 6 alkanoyl radical, and pharmaceutically acceptable salts thereof, and (3 - amino - 5 - trifluoromethylpyrazinamido) guanidine hydrochloride.  Those compounds wherein R2 is hydrogen may be prepared by (a) mixing together under anhydrous conditions the compounds <FORM:1067473/C2/3> and <FORM:1067473/C2/4> or (b) reacting under anhydrous conditions the compounds <FORM:1067473/C2/5> and <FORM:1067473/C2/6> wherein Y is a C1- 5 alkyl or an aralkyl radical. Other pyrazinoic acid esters having 3-amino-5-R1-6R-substituents may be employed in process (a) in place of the methyl ester and methods for the preparation of said esters, including the methyl ester, are described.  The hydrazide reactant employed in process (b) may be prepared by heating the corresponding pyrazinoic acid methyl ester with hydrazine.  Those compounds of the invention wherein R2 is C2- 6 alkanoyl may be prepared by mixing a solution of 2 (C1- 5 alkyl) - 6 - halo - 4H - pyrazino [2,3-d] [1,3] oxazin-4-one, see Specification 1,067,474, in boiling ethyl acetate and the solution obtained on (a) dissolving sodium metal in boiling ethyl alcohol, (b) adding the solution so obtained to a solution of aminoguanidine hydrochloride in ethyl alcohol and (c) removing the sodium chloride so precipitated. The alkanoyl compounds so obtained may be hydrolysed to the corresponding amino compound. (3 - Amino - 6 - chloropyrazinamido) guanidine may be prepared by reacting 3-amino-6-chloropyrazinoic acid hydrazide with cyanamide. (3 - Amino - 5 - trifluoromethyl pyrazinamido) guanidine hydrochloride is prepared by reacting methyl - 3 - amino - 5 - trifluoromethyl pyrazinoate with aminoguanidine hydrochloride. (3 - Amino - 5 - dimethylamino - 6 - chloro - pyrazinamido) guanidine may be prepared by reacting (3 - amino - 5,6 - dichloropyrazinamido) guanidine hydrochloride with dimethylamine in the presence of dimethylformamide.  The preparations of aminoguanidine hydrochloride (Ex. 1); 1-amino-3-(2-hydroxyethyl) guanidine hydriodide (Ex. 8); 3-amino-6-chloropyrazinoic acid (Ex. 4); methyl-3-chloroamino - 6 - chloropyrazinoate (Ex. 1); methyl - 3 - amino - 5,6 - dichloropyrazinoate (Ex. 16); 2 - methyl - 6 - chloro - 4H - pyrazino-[2,3 - d][1,3] - oxazine - 4 - one (Ex. 4); 3-amino - 5 - trifluoromethyl pyrazinamide (Ex. 12); 3 - amino - 5 - trifluoromethylpyrazinoic acid and the methyl ester thereof (Ex. 12); and 1,1 - dimethyl - 2 - benzyl - 2 - thiopseudourea hydrochloride (Ex. 9) are also described in the Specification.ALSO:(3-amino pyrazinamido) guanidines of the formula <FORM:1067473/A5-A6/1> wherein R is a hydrogen or halogen atom or a trihalomethyl radical; R1 is a hydrogen atom or an amino radical of the formula <FORM:1067473/A5-A6/2> , wherein R5 is a hydrogen atom, C1-5 alkyl or a C2-5 alkenyl radical and R6 is a hydrogen atom; a C1-5 alkoxy radical; a C1-5 alkyl radical or a cycloalkyl radical having a 3 to 6 membered ring, said alkyl or cycloalkyl being either unsubstituted or containing one or more hydroxyl, halogen, C3-6 cycloalkyl, aryl, heterocyclic or amino or substituted amino substituents; C2-5 alkenyl; phenyl; halophenyl; or (C1-5 alkyl) phenyl; or R5 and R6 are linked together to form, together with the nitrogen atom to which they are attached, a 1-pyrrolidinyl, piperidino, 4-methyl-1-piperazinyl, hexahydro-1- azepinyl or octahydro-1- azocinyl radical; R3 and R4 are similar or dissimilar and each represents a hydrogen atom or a phenyl; (C1-5 alkyl) phenyl; halophenyl; amino; di(C1-5 alkyl) amino; C1-5 alkyl or C3-6 cycloalkyl, said alkyl or cycloalkyl being unsubstituted or bearing one or more of the substituents hydroxy, halogen, aryl, amino or substituted amino; or NR3R4 represents a heterocyclic radical; and R2 is a hydrogen atom or, when R1 is hydrogen and R is halogen, a C2-6 alkanoyl radical, and pharmaceutically acceptable salts thereof are employed as diuretic and/or saluretic agents in, for example, pills, tablets, capsules or injectable preparations.  Other therapeutic agents may be present in the pharmaceutical compositions and where said known therapeutic agents alone enhance the elimination of potassium and sodium ions the co-administration of the (3-aminopyrazinamido) guanidines reduces the excretion of potassium ions.