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US 2004/0023927 A1Published application
Bicyclic imidazo-5-yl-amine derivatives
AssigneeGruenenthal GmbH
InventorsMatthias Gerlach, Corinna Maul
Life of this patent
Estimating the term…
Abstract
A novel bicyclic imidazo-5-yl-amine derivative of Formula I, 1 wherein X denotes CR5, N or S, and Y in the case where X denotes S, denotes CR6 or N and in all other cases denotes N, and methods for preparation thereof are disclosed. Also disclosed are methods for treating pain using the compound of Formula I, and pharmaceutical compositions comprising the compound of Formula I.
Claims18
A bicyclic imidazo-5-yl-amine of formula I
- 6
- wherein
- R1 denotes C(CH3)3;
- (CH2)6CN;
- optionally substituted phenyl;
- C4-C8-cycloalkyl;
- CH2CH2R (R=4-morpholino);
- 1,1,3,3-tetramethylbutyl;
- or CH2Ra, wherein Ra represents hydrogen, branched or unbranched C1-C8-alkyl, optionally substituted phenyl, CO(OR′) (where R′=branched or unbranched C1-C8-alkyl), PO(OR″)2 (where R″=branched or unbranched C1-C4-alkyl) or Si(RxRyRz) (where Rx, Ry and Rz in each case independently of one another are branched or unbranched C1-C8-alkyl, C4-C8-cycloalkyl or phenyl),
- R2 denotes hydrogen;
- CORb, wherein Rb represents hydrogen, branched or unbranched C1-C8-alkyl, C3-C8-cycloalkyl, CH2CH2CO(OR′) (where R′=branched or unbranched C1-C8-alkyl), adamantyl, optionally substituted phenyl, optionally substituted 1-naphthyl, 2-naphthyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, thiazolyl or furoyl;
- CH2Rc, wherein Rc represents hydrogen, branched or unbranched C1-C8-alkyl or optionally substituted phenyl;
- CH2CH2Rd, wherein Rd represents optionally substituted phenyl;
- or CONHRe, wherein Re represents phenyl,
- R3 denotes branched or unbranched C1-C8-alkyl, C3-C8-cycloalkyl, optionally substituted phenyl, optionally substituted 1-naphthyl, 2-naphthyl, quinoline, anthracene, phenanthrene, benzothiophene, benzofurfuryl, optionally substituted pyrrole, 2-pyridyl, 3-pyridyl, 4-pyridyl, optionally substituted furfuryl or optionally substituted thiophene,
- X denotes CR5, N or S, and
- Y is N, or if X is S, then Y may also be CR6,
- R4, R5 and R6 independently of one another denote hydrogen;
- branched or unbranched C1-C8-alkyl;
- fluorine;
- chlorine;
- bromine;
- CF3;
- CN;
- NO2;
- NHRf, wherein Rf represents hydrogen, branched or unbranched C1-C8-alkyl or optionally substituted phenyl;
- SRg, wherein Rg represents hydrogen, branched or unbranched C1-C8-alkyl, phenyl, pyridine, benzyl or fluorenyl;
- ORh, wherein Rh represents branched or unbranched C1-C8-alkyl, optionally substituted phenyl or CO(OR′) (R′=branched or unbranched C1-C8-alkyl);
- CO(OR′) or CH2CO(OR′), wherein R′ in each case has the abovementioned meaning or in the case of the group CH2CO(OR′) also denotes hydrogen, or an optionally substituted phenyl group,
- wherein optionally substituted phenyl, optionally substituted 1-naphthyl, optionally substituted pyrrole, optionally substituted furfuryl, optionally substituted thiophene, and optionally substituted alkyl is optionally substituted by one or more substituents selected from the group consisting of a halogen atom, cyano group, nitro group, carboxyl group, hydroxyl group, C1-C4 alkylamido group, C1-C4 alkylamino group, pyrrolidino group, branched or unbranched C1-C6 alkyl group, C1-C4 alkyl group substituted with one or more halogen atoms, C1-C4 alkoxy group, C1-C4 alkoxy group substituted with one or more halogen atoms, and halogen substituted phenoxy group,
- or a pharmaceutically acceptable salt thereof,
- excluding compounds in which simultaneously R1 denotes C(CH3)3, R2 denotes hydrogen, R3 denotes unsubstituted phenyl, X denotes S, and Y denotes N or CR6, where R6=hydrogen or CH2—CO2-ethyl, or simultaneously R1 denotes C(CH3)3, R2 denotes hydrogen, R3 denotes unsubstituted phenyl, Y denotes NH, and X denotes N or CR5, where R5═CO2ethyl.
29 more elements
A bicyclic imidazo-5-yl-amine selected from the group consisting of
- tert-butyl-(5-furan-2-yl-imidazo[1 ,2-b][1,2,4]triazol-6-yl)-amine,
- tert-butyl-(6-furan-2-yl-imidazo[2,1-b]thiazol-5-yl)-amine,
- (5-tert-butylamino-6-furan-2-yl-imidazo[2,1-b]thiazol-3-yl)-acetic acid,
- tert-butyl-(5-pyridin-2-yl-imidazo[1,2-b][1,2,4]triazol-6-yl)-amine,
- tert-butyl-(6-pyridin-2-yl-imidazo[2,1-b]thiazol-5-yl)-amine,
- tert-butyl-(5-pyridin-3-yl-imidazo[1,2-b][1,2,4]triazol-6-yl)-amine,
- tert-butyl-(5-pyridin-4-yl-imidazo[1,2-b][1,2,4]triazol-6-yl)-amine,
- tert-butyl-(6-cyclohexyl-imidazo[2,1-b]thiazol-5-yl)-amine,
- tert-butyl-(5-methyl-imidazo[1,2-b][1,2,4]triazol-6-yl)-amine,
- tert-butyl-(6-methyl-imidazo[2,1-b]thiazol-5-yl)-amine,
- cyclohexyl-(5-pyridin-2-yl-imidazo[1,2-b][1,2,4]triazol-6-yl)-amine,
- cyclohexyl-(6-pyridin-2-yl-imidazo[2,1-b]thiazol-5-yl)-amine,
- (5-cyclohexylamino-6-pyridin-2-yl-imidazo[2,1-b]thiazol-3-yl)-acetic acid,
- cyclohexyl-(6-pyridin-4-yl-imidazo[2,1-b]thiazol-5-yl)-amine,
- cyclohexyl-(6-cyclohexyl-imidazo[2,1-b]thiazol-5-yl)-amine,
- (6-cyclohexyl-5-cyclohexylamino-imidazo[2,1-b]thiazol-3-yl)-acetic acid,
- (5-cyclohexylamino-6-methyl-imidazo[2,1-b]thiazol-3-yl)-acetic acid,
- (2,6-dimethyl-phenyl)-(5-furan-2-yl-imidazo[1,2-b][1,2,4]triazol-6-yl)-amine,
- (2,6-dimethyl-phenyl)-(6-pyridin-2-yl-imidazo[2,1-b]thiazol-5-yl)-amine,
- (2,6-dimethyl-phenyl)-(6-pyridin-3-yl-imidazo[2,1-b]thiazol-5-yl)-amine,
- (2,6-dimethyl-phenyl)-(6-pyridin-4-yl-imidazo[2,1-b]thiazol-5-yl)-amine,
- methyl (6-cyclohexyl-imidazo[2,1-b]thiazol-5-ylamino)-acetate,
- methyl (6-methyl-imidazo[2,1-b]thiazol-5-ylamino) -acetate,
- tert-butyl-(2-phenyl-5H-imidazo[1,2-b]pyrazol-3-yl)-amine,
- 3-(5-tert-butylamino-imidazo[2,1-b]thiazol-6-yl)-phenol,
- tert-butyl-[6-(3,4-dimethoxy-phenyl)-imidazo[2,1-b]thiazol-5-yl]-amine,
- tert-butyl-[5-(2,3-dichloro-phenyl)-imidazo[1,2-b][1,2,4]triazol-6-yl]-amine,
- tert-butyl-[6-(2,3-dichloro-phenyl)-imidazo[2,1-b]thiazol-5-yl]-amine,
- tert-butyl-[5-(2,4-dichloro-phenyl)-imidazo[1,2-b][1,2,4]triazol-6-yl]-amine,
- tert-butyl-[6-(2,4-dichloro-phenyl)-imidazo[2,1-b]thiazol-5-yl]-amine,
- tert-butyl-[5-(2-methoxy-phenyl)-imidazo[1,2-b][1,2,4]triazol-6-yl]-amine,
- tert-butyl-[6-(2-methoxy-phenyl)-imidazo[2,1-b]thiazol-5-yl]-amine,
- [5-tert-butylamino-6-(2-methoxy-phenyl)-imidazo[2,1-b]thiazol-3-yl]-acetic acid,
- tert-butyl-(5-o-tolyl-imidazo[1,2-b][1,2,4]triazol-6-yl)-amine,
- tert-butyl-(6-o-tolyl-imidazo[2,1-b]thiazol-5-yl)-amine,
- tert-butyl-[5-(2,3-dimethoxy-phenyl)-imidazo[1,2-b][1,2,4]triazol-6-yl]-amine,
- tert-butyl-[6-(2,3-dimethoxy-phenyl)-imidazo[2,1-b]thiazol-5-yl]-amine,
- tert-butyl-(6-p-tolyl-imidazo[2,1-b]thiazol-5-yl) -amine,
- (5-tert-butylamino-6-methyl-imidazo[2,1-b]thiazol-3-yl)-acetic acid,
- N-tert-butyl-N-(6-phenyl-imidazo[2,1-b]thiazol-5-yl)-acetamide,
- N-tert-butyl-N-(6-o-tolyl-imidazo[2,1-b]thiazol-5-yl)-acetamide,
- butyl-[6-(4 -tert-butyl-phenyl)-2-methyl-imidazo[2,1-b]thiazol-5-yl]amine,
- tert-butyl-[5-(2-fluorophenyl)-imidazo[1,2-b][1,2,4]triazol-6-yl]-amine,
- tert-butyl-[6-(2-fluorophenyl)-imidazo[2,1-b]thiazol-5-yl]-amine,
- tert-butyl-(5-naphthalen-1-yl-imidazo[1,2-b][1,2,4]triazol-6-yl)-amine,
- cyclohexyl-(5-naphthalen-1-yl-imidazo[1,2-b][1,2,4]triazol-6-yl)-amine,
- [5-(2-bromophenyl)-imidazo[1,2-b][1,2,4]triazol-6-yl]-(1,1,3,3-tetramethyl-butyl) -amine,
- N-[4-(6-cyclohexylamino-imidazo[1,2-b][1,2,4]triazol-5-yl)-phenyl)-acetamide,
- tert-butyl-[5-(2,5-dimethyl-phenyl)-imidazo[1,2-b][1,2,4]triazol-6-yl]-amine,
- cyclohexyl-[6-(2,4-dimethyl-phenyl)-imidazo[2,1-b]thiazol-5-yl]-amine,
- cyclohexyl-[6-(2,5-dimethylphenyl)-imidazo[2,1-b]thiazol-5-yl]-amine,
- N-tert-butyl-N-(6-p-tolyl-imidazo[2,1-b]thiazol-5-yl)-acetamide,
- [5-(2,4-dimethyl-phenyl)-imidazo[1,2-b][1,2,4]triazol-6-yl]-(1,1,3,3-tetramethyl-butyl)-amine,
- [5-(2,5-dimethyl-phenyl)-imidazo[1,2-b][1,2,4]triazol-6-yl]-(1,1,3,3-tetramethyl-butyl)-amine,
- N-butyl-N-[5-(2-chloro-6-fluorophenyl)-imidazo [1,2-b][1,2,4]triazol-6-yl]-acetamide and
- N-butyl-N-[6-(4-tert-butyl-phenyl)-2-methyl-imidazo[2,1-b]thiazol-5-yl]-acetamide
- or a pharmaceutically acceptable salt thereof.
54 more elements
A process for the preparation of a bicyclic imidazo-5-yl-amine of Formula Ia,
- 7
- the process being three-component reaction and comprising reacting an amidine of Formula II
- 8
- with an aldehyde of Formula III
- 9
- and an isonitrile of Formula IV
- R1—N+≡C. IV
- in the presence of 20% perchloric acid,
- wherein in all formulae,
- R1 denotes C(CH3)3, (CH2)6CN, optionally substituted phenyl, C4-C8-cycloalkyl, CH2CH2R (R=4-morpholino), 1,1,3,3-tetramethylbutyl or CH2Ra, wherein Ra represents hydrogen, branched or unbranched C1-C8-alkyl, optionally substituted phenyl, CO(OR′) (where R′=branched or unbranched C1-C8-alkyl), PO(OR″)2 (where R″=branched or unbranched C1-C4-alkyl) or Si(RxRyRz) (where Rx, Ry and Rz in each case independently of one another are branched or unbranched C1-C8-alkyl, C4-C8-cycloalkyl or phenyl),
- R3 denotes branched or unbranched C1-C8-alkyl, C3-C8-cycloalkyl, optionally substituted phenyl, optionally substituted 1-naphthyl, 2-naphthyl, quinoline, anthracene, phenanthrene, benzothiophene, benzofurfuryl, optionally substituted pyrrole, 2-pyridyl, 3-pyridyl, 4-pyridyl, optionally substituted furfuryl or optionally substituted thiophene,
- X denotes CR5, N or S,
- Y is N, or if X is S, then Y may also be CR6,
- R4, R5 and R6 independently of one another denote hydrogen;
- branched or unbranched C1-C8-alkyl;
- fluorine;
- chlorine;
- bromine;
- CF3;
- CN;
- NO2;
- NHRf, wherein Rf represents hydrogen, branched or unbranched C1-C8-alkyl or optionally substituted phenyl;
- SRg, wherein Rg represents hydrogen, branched or unbranched C1-C8-alkyl, phenyl, pyridine, benzyl or fluorenyl;
- ORh, wherein Rh represents branched or unbranched C1-C8-alkyl, optionally substituted phenyl or CO(OR′) (R′=branched or unbranched C1-C8-alkyl);
- CO(OR′) or CH2CO(OR′), wherein R′ in each case has the abovementioned meaning or in the case of the group CH2CO(OR′) also denotes hydrogen, or an optionally substituted phenyl group,
- wherein optionally substituted phenyl, optionally substituted 1-naphthyl, optionally substituted pyrrole, optionally substituted furfuryl, optionally substituted thiophene, and optionally substituted alkyl is optionally substituted by one or more substituents selected from the group consisting of a halogen atom, cyano group, nitro group, carboxyl group, hydroxyl group, C1-C4 alkylamido group, C1-C4 alkylamino group, pyrrolidino group, branched or unbranched C1-C6 alkyl group, C1-C4 alkyl group substituted with one or more halogen atoms, C1-C4 alkoxy group, C1-C4 alkoxy group substituted with one or more halogen atoms, and halogen substituted phenoxy group,
- excluding compounds wherein R1 denotes C(CH3)3, R3 denotes unsubstituted phenyl, X denotes S, and Y denotes N or CR6, where R6 =hydrogen or CH2—CO2-ethyl, or wherein R1 denotes C(CH3)3, R3 denotes unsubstituted phenyl, Y denotes NH, and X denotes N or CR5, where R5═CO2ethyl,
24 more elements
Dependencies are inferred from the claim text.