Patent ES-267445-A1 (ES)
Title: N-phenylpiperazinyl derivatives of benzimidazole
IPC: C07D235/26
Filed: 1961-05-17
Abstract: The invention comprises phenylpiperazine derivatives of the formula:- <FORM:0971043/C1/1> wherein X is a straight, saturated hydrocarbon chain of two, three or four carbon atoms, which when the chain contains four carbon atoms may be substituted by an oxo group on the carbon atom adjacent to the phenyl group, R1 is a hydrogen atom or an o-halogen or p-fluorine atom, or a m-alkyl group, or an alkoxy or cyano group in the ortho position, R2 is a hydrogen or an o- or p-fluorine or o-chlorine atom or a m-alkyl group, Q is a straight, saturated or ethylenically unsaturated hydrocarbon group containing up to three carbon atoms optionally substituted by an alkyl, hydroxyalkyl, alkoxyalkyl, phenyl, aralkyl, acylamido or trifluoromethyl group or by two groups on the same carbon atom selected from alkyl, hydroxyalkyl, and alkoxyalkyl groups, or by two groups each on a different carbon atom selected from alkyl, hydroxyalkyl, alkoxyalkyl and acylamido groups, and/or by one or two oxo or thiono groups, one of R3 and R4 is a hydrogen atom, or an alkyl group and the other represents a hydrogen atom or an alkyl or aralkyl group or-when Q represents an unsaturated group-one or both of R3 and R4 may represent single bonds, and acid addition salts thereof together with processes for their preparation (a) by reacting a phenylpiperazine of the Formula II- <FORM:0971043/C1/2> with a compound of formula:- <FORM:0971043/C1/3> (b) by reacting a compound of formula:- <FORM:0971043/C1/4> with a heterocyclic compound of formula:- <FORM:0971043/C1/5> (wherein one of Z and Z1 represents hydrogen and the other represents a grouping -CH2CH2.Y, Y being the acid residue of a reactive ester) (c) by reducing a nitrile or aldehyde of general formulae:- <FORM:0971043/C1/6> <FORM:0971043/C1/7> (wherein T represents -CH2-, -(CH2)2-, -(CH2)3- or -(CH2)2-CO-) in the presence of a phenyl piperazine of Formula II (d) (when Q is a >CR group, R being a hydrogen atom or an alkyl group containing up to 6 carbon atoms, and one of R3 and R4 is a single bond and the other is a hydrogen atom or an alkyl or aralkyl group) (i) by reduction of a compound of the general formula:- <FORM:0971043/C1/8> (wherein R6 is a hydrogen atom or an alkyl or aralkyl group), or (ii) by heating a compound of the formula:- <FORM:0971043/C1/9> (wherein one of R10 and R11 is hydrogen or an acyl group and the other represents an acyl group, and R8 is hydrogen or an alkyl or aralkyl group) alone or in the presence of a mineral acid or caustic alkali (e) (when Q is >CR7, R7 being hydrogen, or an alkyl, hydroxyalkyl, alkoxyalkyl, phenyl, aralkyl, acylamido or trifluoromethyl group, and one of R3 and R4 is a single bond and the other is hydrogen or an alkyl or aralkyl group) by reacting a compound of the Formula III- <FORM:0971043/C1/100> (wherein one of R8 and R81 is hydrogen or an alkyl or aralkyl group and the other is hydrogen) with an acid R7COOH or a derivative thereof (halide, anhydride, ester, amide, lactone, nitrile, aldehyde or ketone) or with guanidine (f) (when Q is -CH2-, -(CH2)2-, or -(CH2)3-, or such a group substituted by an alkyl, hydroxyalkyl, alkoxyalkyl, phenyl, or aralkyl group, and optionally by a further alkyl, hydroxyalkyl, or alkoxyalkyl group, and R3 and R4 are hydrogen atoms) by reacting a diester Y-(CH2)n-Y (wherein Y is a reactive ester residue and n is 1, 2, or 3) or such a diester substituted as aforesaid for Q on one or two carbon atoms (i) with a compound of the Formula IV:- <FORM:0971043/C1/111> or (ii) with a compound of the formula:- <FORM:0971043/C1/122> (wherein R1 is a hydrocarbon radical) in the presence of an acid binding agent, and removing the -SO2R1 groups by hydrolysis (g) (when Q is >C=S and one of R3 and R4 is hydrogen and the other is hydrogen or an alkyl or aralkyl group) by heating a compound of Formula III with an alkali metal alkyl xanthate, carbon disulphide, thiourea or thiophosgene (h) (when Q is -CO-, -CO.CO-, or -CO-CR7R71-CO-group, R71 being hydrogen, or an alkyl, hydroxy-alkyl or alkoxyalkyl group, R3 is hydrogen or an alkyl or aralkyl group and R4 is hydrogen) by reacting a compound of Formula III with a reactive derivative of carbonic, oxalic, or malonic acid, or with oxalic or malonic acid or a C-substituted derivative thereof where Q is -CO-CO- or -CO-CR7R71-CO- (i) (when Q is -CO-CHR7-, R3 is hydrogen, or an alkyl or aralkyl group and R4 is hydrogen) by reacting a compound of Formula III with a haloacetyl halide Hal-CO-CHR7-Hal (j) (when Q is -CR9-CR91-, R9 being hydroge or an alkyl, hydroxyalkyl, alkoxyalkyl, phenyl, aralkyl or trifluoromethyl group and R91 being hydrogen or an alkyl, hydroxyalkyl or alkoxy-alkyl group, and R3 and R4 are single bonds) by reacting a compound of Formula IV with an a ,a 1-dicarbonyl compound R9-CO-CO-R91 (k) (when Q is -CO-, and one of R3 and R4 is a single bond and the other is a hydrogen atom, or Q is -CH2CO- or -CH2CH2CO- and R3 and R4 are both hydrogen) by heating a compound of formula:- <FORM:0971043/C1/133> (wherein Z is a single bond or -CH2- or -CH2-CH2-, and R1 is a hydrocarbon group) (l) (when X is a straight, saturated hydrocarbon chain of 2, 3 or 4 carbon atoms) by reducing a compound of the formula:- <FORM:0971043/C1/144> (wherein M is oxygen or sulphur, X1 is a straight, saturated hydrocarbon chain of one to three carbons) by known methods (m) (when X is -(CH2)4-) by reacting a compound of Formula II with a compound of formula:- <FORM:0971043/C1/155> and reducing the double bond in the product. The invention is illustrated by 14 detailed examples. The novel compounds possess pharmacological and pyschotropic properties and may be administered parenterally or preferably orally e.g. as tablets, pills, dispersible powders, granules, emulsions, solutions, suspensions, syrups and elixirs. Specific tablet and injectable formulations are given containing 2,4-dioxo-2,3,4, 5-tetrahydro-7-21-(4-o-chlorophenylpiperazin-1-yl) ethyl-1, 5-benzodiazepine and 2-methyl-5-21-(4-o-chloro-phenylpiperazin-1-yl) ethylbenzimidazole dihydrochloride as the respective active ingredients. Specification 971,041 is referred to.ALSO:Substituted benzimidazole p-derivatives of N-phenyl piperazines of formula: <FORM:0971043/C6-C7/1> wherein X is a chain of two, three or four carbon atoms, which, when the chain contains four carbon atoms may be substituted by an oxo group on the carbon atom adjacent to the phenyl group, R1 is hydrogen or an o-halo or p-fluoro atom, or a m-alkyl group or an alkoxy or cyano group in the o-position, R2 is a hydrogen or an o- or p-fluoro atom or o-chloro atom, or a m-alkyl group, Q is a <FORM:0971043/C6-C7/2> group (wherein R is a hydrogen atom or an alkyl group of up to six carbon atoms) and one of R3 and R4 is a single bond and the other is a hydrogen atom or an alkyl or aralkyl group, are prepared by the electrolytic reduction in acetic acid solution of a compound of formula : <FORM:0971043/C6-C7/3> (R6 is hydrogen or an alkyl or aralkyl group).