Patent EA-003947-B1 (EA)
Title: Benzimidazoles, production thereof and use thereof as medicaments
Inventor: RIES UWE
IPC: A61K31/415
Filed: 1999-07-01
Abstract: 1. Benzimidazoles of general formula wherein Ar denotes a phenylene or naphthylene group optionally substituted by a fluorine, chlorine or bromine atom, by a trifluoromethyl, C1-3-alkyl or C1-3alkoxy group, a thienylene, thiazolylene, pyridinylene, pyrimidinylene, pyrazinylene or pyridazinylene group optionally substituted in the carbon skeleton by a C1-3alkyl group, A denotes a C1-3alkylene group, B denotes an oxygen or sulphur atom, a methylene, carbonyl, sulphinyl or sulphonyl group, an imino group optionally substituted by a C1-3alkyl group wherein the alkyl moiety may be mono- or disubstituted by a carboxy group, Ra denotes an R1-CO-C3-C5-cycloalkyl group wherein R1 denotes a C1-3alkoxy, amino, C1-4-alkylamino or di-(C1-4-alkyl)-amino group wherein each alkyl moiety may be substituted by a carboxy group, a 4- to 7-membered cycloalkyleneimino or cycloalkenyleneimino group which may be substituted by a hydroxy group or by one or two C1-3alkyl groups, whilst an alkyl substituent may simultaneously be substituted by a hydroxy, C1-3alkoxy, carboxy, carboxy-C1-3alkoxy, carboxy-C1-3alkyl amino, N-(C1-3alkyl)-N-(carboxy-C1-3alkyl)-amino, carboxy-C1-3alkylaminocar-bonyl, N-(C1-3alkyl)-N-(carboxy-C1-3alkyl)-aminocarbonyl, carboxy-C1-3alkylaminocarbonylamino, 1-(C1-3alkyl)-3-(carboxy-C1-3alkyl)-aminocarbonylamino, 3-(C1-3alkyl)-3-(carboxy C1-3alkyl)-aminocarbonylamino or 1,3-di-(C1-3alkyl)-3-(carboxy-C1-3alkyl)-aminocarbonylamino group, a 4- to 7-membered cycloalkenyleneimino group substituted by a hydroxy group, a 5- to 7-membered cycloalkyleneimino group optionally substituted by a C1-3alkyl group, to which a phenyl ring is fused via two adjacent carbon atoms, a morpholino, piperazino, N-(C1-3alkyl)-piperazino, pyrrolino, 3,4-dehydro-piperidino or pyrrol-1-yl group, an R2-CX-C3-5-cycloalkyl group wherein R2 denotes a phenyl, naphthyl or monocyclic 5- or 6-membered heteroaryl group optionally substituted by a C1-3alkyl group, wherein the 6-membered heteroaryl group contains one, two or three nitrogen atoms and the 5-membered heteroaryl group contains an imino group optionally substituted by a C1-3alkyl group, an oxygen or sulphur atom or an imino group optionally substituted by a C1-3alkyl group and an oxygen or sulphur atom or one or two nitrogen atoms and the above mentioned alkyl substituent may be substituted by a carboxy, carboxy-C1-3alkoxy, carboxy-C1-3alkyl amino or N-(C1-3alkyl)-carboxy-C1-3alkyl amino group, and X denotes an oxygen atom, a C1-3alkylimino, C1-3alkoxyimino, C1-3alkylhydrazino, di-(C1-3alkyl)-hydrazino, C2-4-alkanoyl-hydrazino, N-(C1-3alkyl)-C2-4-alkanoylhydrazino or C1-3alkylidene group each of which may be substituted in the alkyl or alkanoyl moiety or in the alkyl and alkanoyl moieties by a carboxy group, a C1-3alkyl or C3-5-cycloalkyl group substituted by an imidazole or imidazolone group wherein the imidazole ring may be substituted by a phenyl or carboxy group and by one or two C1-3alkyl groups or by one, two or three C1-3alkyl groups, wherein the substituents may be identical or different and one of the above mentioned alkyl substituents may simultaneously be substituted by a carboxy group or may be substituted in the 2 or 3 position by an amino, C2-4-alkanoylamino, C1-3alkylamino, N-(C2-4-alkanoyl) C1-3alkylamino or di-(C1-3alkyl)-amino group, and the imidazolone ring may be substituted by a C1-3alkyl group, whilst the alkyl substituent may be substituted by a carboxy group or in the 2 or 3 position by an amino, C2-4-alkanoyl-amino, C1-3alkyl amino, N-(C2-4alkanoyl)-C1-3alkyl amino or di (C1-3alkyl)-amino group, and additionally a phenyl or pyridine ring may be fused to the above mentioned imidazole or imidazolone rings via two adjacent carbon atoms, an imidazolidine-2,4-dion-5-yl group which may be substituted by one or two C1-3alkyl groups, whilst at the same time an alkyl substituent may be substituted by a carboxy group, a C1-4-alkyl group which is substituted by a C1-3alkyl-Y1-C1-3alkyl, HOOC-C1-3alkyl-Y1-C1-3alkyl, tetrazolyl-C1-3alkyl-Y2, R3NR4- or R3NR4-C1-3alkyl group and by an isoxazolidinylcarbonyl group optionally substituted by a C1-3alkyl group, by a pyrrolino-carbonyl, 3,4-dehydro-piperidinocarbonyl, pyrrol-1-yl-carbonyl, carboxy, aminocarbonyl, C1-3alkylaminocarbonyl, di-(C1-3alkyl)-aminocarbonyl or 4- to 7-membered cycloalkyleneiminocarbonyl group, whilst in the above mentioned groups the cycloalkyleneimino moiety may be substituted by one or two C1-3alkyl groups and at the same time each alkyl moiety or alkyl substituent in the above mentioned C1-3alkylaminocarbonyl, di-(C1-3alkyl)-amino-carbonyl or cycloalkyleneiminocarbonyl groups may be substituted by a carboxy croup, and the remaining hydrogen atoms of the C1-4-alkyl group may be wholly or partially replaced by fluorine atoms wherein R3 denotes a hydrogen atom or a C1-3alkyl group optionally substituted by a carboxy group and R4 denotes a hydrogen atom, a C1-3alkyl-Y1-C1-3alkyl-Y2, carboxy-C1-3alkyl-Y1-C1-3alkyl-Y2, C1-3alkyl-Y2 or carboxy C1-3alkyl-Y2 group or R3 and R4 together with the nitrogen atom between them denote an 4- to 7-membered cycloalkyleneimino group optionally substituted by a carboxy, C1-3alkyl or carboxy C1-3alkyl group wherein Y1 denotes a carbon-carbon bond, an oxygen atom, a sulphenyl, sulphinyl, sulphonyl, -NH-, -NH-CO- or -NH-CO-NH-group and Y2 denotes a carbon-nitrogen bond or a carbonyl, sulphonyl, imino or -NH-CO-group, wherein the carbonyl group of the -NH-CO-group is linked to the nitrogen atom of the R3NR4 group, and the imino groups occurring in the definition of the groups Y1 and Y2 may each additionally be substituted by a C1-3alkyl or carboxy-C1-3alkyl group, a C1-3alkyl or C3-5-cycloalkyl group substituted by a R5NR6group wherein R5 denotes a hydrogen atom, a C1-3alkyl, C5-7-cycloalkyl, phenylcarbonyl, phenylsulphonyl or pyridinyl group and R6 denotes a C1-3alkyl, carboxy-C1-3alkyl or carboxy-C1-3alkylcarbonyl group, a C1-3alkyl group which is substituted by a C2-4-alkanoyl or C5-7-cycloalkanoyl group and by a C1-3alkyl group substituted by a chlorine, bromine or iodine atom, Rb denotes a hydrogen atom or a C1-3-alkyl group and Rc denotes a cyano group or an amidino group optionally substituted by one or two C1-3alkyl groups, wherein said meanings of the above mentioned residues of carboxy group may be, besides, substituted for a group transferred in vivo in a carboxy group, or a group which is negatively charged under physiological conditions; or said meanings of the above mentioned residues of amino- and imino group may be, besides, substituted by a group deprotected in vivo; wherein under the group transferred in vivo in carboxy group is understood, for example, a carboxy group esterified with alcohol, in which an alcohol moiety denotes preferably a C1-6alkanol, a phenyl-C1-3alkanoyl, a C3-9cycloalkanol, wherein C5-8may be optionally substituted with one or two C1-3alkyl groups, a C5-8cycloalkanol, in which methylene group in 3 or 4 positions is substituted by an oxygen atom or optionally substituted imino group by a C1-3alkyl, a phenyl-C1-3alkyl, a phenyl-C1-3alkoxycarbonyl or a C2-6alkanoyl group, and a cycloalkanoyl fragment may be additionally substituted by one or two phenyl-C1-3alkyl groups, C4-7cycloalkanoyl, a C1-3alkenol, phenyl-C1-3cycloalkenol, C1-3alkenol, phenyl-C3-5alkenol, C3-5alkynol or phenyl-C3-5alkynol, provided that the bond is absent between an oxygen atom and a carbon atom, carrying either double or triple bond, C3-8cycloalkyl-C1-3alkanol, bicycloalkanol having totally 8 to 10 carbon atoms, which in a bicycloalkyl moiety may be optionally substituted by one or two C1-6alkyl groups, 1,3-dihydro-3-oxo-1-isobenzfuranolor alcohol of the formula Rd-CO-O-(ReCRf)-OH, wherein Rd denotes C1-8alkyl, C5-7cycloalkyl, phenyl or phenyl-C1-3alkyl group, Re denotes a hydrogen atom, C1-3alkyl, C5-7cycloalkyl or a phenyl group and Rf denotes a hydrogen atom or C1-3alkyl group; under negatively charged under physiological conditions group are meant such groups as tetrazole-5-yl, fhenylcarbonylaminocarbonyl, trifluormethylcarbonylaminocarbonyl-, C1-6alkylsulfonylamino, phenylsulfonylamino, benzylsulfonylamino-, trifluormethylsulfonylamino-, C1-6alkylsulfonylaminocarbonyl, phenylsulfonylaminocarbonyl, benzylsulfonylaminocarbonyl or perfluoro-C1-6alkylsulfonylaminocarbonyl group, and under deprotected in vivo from imino- or amino group such as a hydroxy group, an acyl group are meant, such as a single- or double-substituted by a fluorine, chlorine or bromine atoms, benzoyl group by a C1-3alkyl- or a C1-3alkoxy group, wherein the substituents may be identical or different, pyridinoyl group or a C1-6alkanoyl group such as formyl, acetyl, propionyl, butanoyl, pentanoyl or other hexanoyl group a 3,3,3-trichlorpropionyl or an allyloxycarbonyl group, a C1-16alkoxycarbonyl or a C1-16alkylcarbonyloxy group, in which hydrogen atoms are fully or partially substituted by fluoro or chloro atoms, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, pentoxycarbonyl, hexoxycarbonyl, octyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl, undecyloxycarbonyl, dodecyloxycarbonyl, hexadecyloxycarbonyl, methylcarbonyloxy, ethylcarbonyloxy-, 2,2,2-tri-chlorethylcarbonyloxy, propylcarbonyloxy, isopropylcarbonyloxy, butylcarbonyloxy, tert-butylcarbonyloxy, pentylcarbo-nyloxy, hexylcarbonyloxy, octylcarbonyloxy, nonylcarbonyloxy, decylcarbonyloxy, undecylcarbonyloxy, dodecylcarbonyloxy or hexadecylcarbonyloxy group, a phenyl-C1-6-alkoxycarbonyl group, such as a benzyloxycarbonyl, phenylethoxycarbonyl or phenylpropoxycarbonyl group, a 3-amino-propionyl-group, in which amino group is a mono- or double substituted C1-6alkyl or C3-7cycloalkyl groups, and substituents may be identical or different, C1-3alkylsulfonyl, C2-4alkoxycarbonyl, C1-3alkoxy-C2-4alkoxy-C2-4alkoxycarbonyl, Rd-CO-O-(RdCRf)-O-CO-, C1-6alkyl-CO-NH-(RgCRh)-O-CO- or C1-6alkyl-C