Patent EA-003697-B1 (EA)
Title: Disubstituted bicyclic heterocycles, their production and use as medicaments
Inventor: HAUEL NORBERT
IPC: C07D277/64
Filed: 1998-02-16
Abstract: 1. Disubstituted bicyclic heterocycles of general formula wherein A denotes a carbonyl or sulphonyl group linked to the benzo-, pyrido- or thieno moiety of the group Het, B denotes an ethylene group, in which a methylene group, linked to the Ar moiety, may be replaced by an oxygen or sulphur atom or by -NR1 group, wherein R1 denotes a hydrogen atom or a C1-4-alkyl group, Rb denotes a hydrogen atom, a hydroxy group, alkoxycarbonyl, whilst C1-9-alkoxy, cyclohexyloxycarbonyl, phenylalkoxycarbonyl, whilst C1-3-alkoxy, benzoyl, p-alkylbenzoyl, whilst C1-3-alkyl or a pyridinoyl group, wherein ethoxy part in the 2-position of said alkoxycarbonyl group, whilst C1-9-alkoxy may be optionally substituted by an alkylsulfonyl group, whilst C1-3-alkyl, or 2-alkoxyethylene group, whilst C1-3-alkoxy, Ar denotes a 1,4-phenylene or 2,5-thienylene group optionally substituted by a chlorine atom, methyl, ethyl or methoxy-group, Het denotes 1-(C1-3-alkyl)-2,5-benzimidazolylene, 1-cyclopropyl-, 2,5-benzimidazolylen, 2,5-benzthiazolylene-, 1-(C1-3-alkyl)-2,5-indolylene-, 1-(C1-3-alkyl)-2,5-imidazo[4,5-b]pyridinylene-, 3-(C1-3-alkyl)-2,7-imidazo[1,2-a]pyridinylene-or 1-(C1-3-alkyl)-2,5-thieno[2,3-d]imidazolylene group, and R2 denotes a C1-4 alkyl group, which may be substituted by a carboxy, alkyloxycarbonyl, whilst C1-6 alkyl, benzyloxycarbonyl, alkylsufonylaminocarbonyl, whilst C1-3-alkyl or 1H-tetrazolyl 5-yl group, a C2-4-alkyl group substituted by a hydroxy, benzyloxy, carboxyalkylamino, whilst C1-3-alkyl alkoxycarbonylalkylamino, whilst C1-3-alkoxy and alkyl-N-alkyl-carboxy-alkylamino, whilst both C1-3-alkyls, or N-alkyl-alkoxycarbonylalkylamino group whilst alkoxy and C1-3-alkoxy and both alkyls, whilst in the above-mentioned groups the carbon atom in the alpha-position relative to the adjacent nitrogen atom may not be substituted, R3 denotes a C3-7-cycloalkyl group, a propargyl group, wherein the unsaturated part may not be linked directly to the nitrogen atom of the R2NR3- group, a phenyl group optionally substituted by a fluorine or chlorine atom, methyl or methoxy group, pyrazolyl, pyridinyl, pyridazolyl group optionally substituted by a methyl group, or R2 and R3 together with the nitrogen atom between them denote a 5- to 7-membered cycloalkyleneimino group, optionally substituted by a carboxymethyl or an alkoxycarbonyl group, whilst C1-4 alkoxy, onto which a phenyl ring may additionally be fused, the tautomers, the stereoisomers and the salts thereof. 2. Disubstituted bicyclic heterocycles of general formula I according to claim 1, wherein A denotes a carbonyl or sulphonyl group linked to the benzo-, pyrido- or thieno moiety of the group Het, B denotes an ethylene group, in which a methylene group, linked to the Ar moiety, may be replaced by an oxygen or sulphur atom or by -NR1 group, wherein R1 denotes a hydrogen atom or a methyl group, Rb denotes a hydrogen atom, a hydroxy group, alkoxycarbonyl whilst C1-9-alkoxy, cyclohexyloxycarbonyl, benzyloxycarbonyl. benzoyl, p-alkylbenzoyl, whilst C1-3-alkyl or a nicotinoyl group, wherein ethoxy part in the 2-position of said alkoxycarbonyl group, whilst C1-9-alkoxy may be optionally substituted by an alkylsulfonyl group, whilst C1-3-alkyl, or 2-alkoxyethylene group, whilst C1-3-alkoxy, Ar denotes a 1,4-phenylene or 2,5-thienylene group optionally substituted by a chlorine atom, methyl, ethyl or methoxy-group, Het denotes 1-methyl-2,5-benzimidazolylene, 1-cyclopropyl-, 2,5-benzimidazolylen, 2,5-benzthiazolylene-, 1-methyl-2,5-imidazo[4,5-b]pyridinylene-, 3-methyl-2,7-imidazo[1,2-a]pyridinylene-or 1-methyl-2,5-thieno[2,3-d]imidazolylene group, and R2 denotes a C1-3 alkyl group, which may be substituted by a carboxy, alkyloxycarbonyl, whilst C1-6 alkyl, benzyloxycarbonyl, methylsulfonylaminocarbonyl or 1H-tetrazolyl 5-yl group, a C2-3-alkyl group substituted by a hydroxy, benzyloxy, carboxyalkylamino, whilst C1-3-alkyl, alkoxycarbonylalkylamino, whilst C1-3-alkoxy and alkyl, N-alkyl-carboxy-alkylamino, whilst both C1-3-alkyls, or N-alkyl-alkoxycarbonylalkylamino group whilst alkoxy and C1-3-alkoxy and both alkyls, wherein in the above-mentioned groups the carbon atom in the alpha-position relative to the adjacent nitrogen atom may not be substituted, R3 denotes a propargyl group, wherein the unsaturated part may not be linked directly to the nitrogen atom of the R2NR3- group, a phenyl group optionally substituted by a fluorine or chlorine atom, methyl or methoxy group, pyridinyl group, the tautomers, the stereoisomers and the salts thereof. 3. Disubstituted bicyclic heterocycles of general formula I according to claim 1, wherein A denotes a carbonyl group linked to the benzo or thieno moiety of the group Het, B denotes an ethylene group in which the methylene group linked to the group Ar may be replaced by an oxygen or sulphur atom or by an -NR1- group, wherein R1 denotes a hydrogen atom or a methyl group, Rb denotes a hydrogen atom, a hydroxy group, alkoxycarbonyl whilst C1-9-alkoxy, cyclohexyloxycarbonyl, benzyloxycarbonyl, benzoyl, p-alkylbenzoyl, whilst C1-3-alkyl or a nicotinoyl group, wherein ethoxy part in the 2-position of said alkoxycarbonyl group, whilst C1-9-alkoxy may be optionally substituted by an methylsulfonyl group or 2-ethoxyethyl group, Ar denotes a 1,4-phenylene or 2,5-thienylene group optionally substituted by a methoxy-group, Het denotes 1-methyl-2,5-benzimidazolylene or 1-methyl-2,5-thieno[2,3-d]imidazolylene group, and R2 denotes a C1-3 alkyl group, which may be substituted by a carboxy, alkyloxycarbonyl, whilst C1-6 alkyl, benzyloxycarbonyl, methylsulfonylaminocarbonyl or 1H-tetrazolyl 5-yl group, a C2-3-alkyl group substituted by a hydroxy-, benzyloxy, carboxyalkylamino, whilst C1-3-alkyl, alkoxycarbonylalkylamino, whilst C1-3-alkoxy and alkyl, N-alkyl-carboxy-alkylamino, whilst both C1-3-alkyls, or N-alkyl-alkoxycarbonylalkylamino group whilst alkoxy and C1-3-alkoxy and both alkyls, wherein in the above-mentioned groups the carbon atom in the alpha-position relative to the adjacent nitrogen atom may not be substituted, R3 denotes a phenyl group optionally substituted by a fluorine atom, 2-pyridinyl group, the tautomers, the stereoisomers and the salts thereof. 4. The following compounds of general formula I: (a) 2-[N-(4-amidinophenyl)-aminomethyl]-benzthiazole-5-carboxylic acid-N-phenyl-N-(2-carboxyethyl)-amide, (b) 2-[N-(4-midinophenyl)-N-methyl-aminomethyl] -benzthiazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide, (c) 1-methyl-2-[N-(4-amidinophenyl) -aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide, (d) 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-hydroxycarbonylpropyl)-amide, (e) 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(hydroxycarbonylmethyl)-amide, (f) 1-methyl-2-[2-(2-amidinothiophen-5-yl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)-amide, (g) 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)- amide, (h) 1-methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)-amide, (i) 1-methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide, (j) 1-methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-[2-(1H-tetrazol-5-yl)ethyl]-amide, (k) 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-[2-(1H-tetrazol-5-yl) ethyl]-amide, (l) 1-methyl-2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)-amide, (m) 1-methyl-2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-pyridyl)-N-(2-hydroxycarbonylethyl)-amide, (n) 1-methyl-2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide, (o) 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-[(N-hydroxycarbonylethyl-N-methyl)-2-aminoethyl]-amide, (p) 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-fluorophenyl)-N-(2-hydroxycarbonylethyl)-amide, (q) 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl] -benzimidazol-5-yl-carboxylic acid-N-(4-fluorophenyl)-N- (2-hydroxycarbonylethyl)-amide, (r) 1-methyl-2-[N-(4-amidino-2-methoxy-phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide, (s) 1-methyl-2-[N-(4-amidino-2-methoxy-phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)-amide, (t) 1-methyl-2-[N-(4-amidinophenyl)aminomethyl]-indol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide and (u) 1-methyl-2-[N-(4-amidinophenyl)aminomethyl] -thieno[2.3-d]imidazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide, the tautomers, stereoisomers and the salts thereof. 5. 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbony 1 ethyl)-amide and the salts thereof. 6. 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylmethyl)-amide and the salts thereof. 7. 1-methyl-2-[N-(4-amidino-2-methoxy-phenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)-amide and the salts thereof. 8. 1-methyl-2-[N-[4-(N-n-hexyloxycarbonylamidino)phenyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonylethyl)-amide and the salts thereof. 9. Physiologically acceptable salts of the compounds according to claims 1 to 8. 10. Pharmaceutical compositions containing a compound according to at least one of claims 1 to 8 or the salt thereof according to claim 9, optionally together with one or more inert carriers and/or dil