Back to results
US 2010/0267738 A1Published application
Novel amide and amidine derivatives and uses thereof
AssigneeAbbott Laboratories
InventorsSridhar Peddi, Meena V. Patel, Jeffrey J. Rohde
Life of this patent
Estimating the term…
Abstract
The present invention relates to inhibitors of 11-β-hydroxysteroid dehydrogenase type 1 enzyme and their use in treatment of non-insulin dependent type 2 diabetes, insulin resistance, obesity, lipid disorders, metabolic syndrome, central nervous system disorders, and diseases and conditions that are related to excessive glucocorticoids.
Claims20
A compound of formula (I):
- wherein
- L is —(CH2)n—, or —(CR38R39)m—X—(CR38R39)n— or —(CR38R39)m—X—(CR38R39)n—Y—;
- m is independently at each occurrence 0, 1, or 2;
- n is independently at each occurrence 0, 1, or 2;
- R1 is cycloalkyl or heterocycle;
- R2 is hydrogen, alkyl, or aryl;
- R1 and R2 together with the atoms to which they are attached form a heterocycle;
- or R2 and R3 together with the atoms to which they are attached form a heterocycle;
- R3 and R4 are independently hydrogen, alkyl or cycloalkyl;
- or R3 and R4 together with the atom to which they are attached form a cycloalkyl, heterocycle, heteroaryl, or aryl;
- R5 is hydrogen, alkyl, amino, aryl, cycloalkyl, heteroaryl, or heterocycle provided R5 is other than amino when L is —(CR38R39)m—X—(CR38R39)n—Y—;
- or R4 and R5 together with the atoms to which they are attached form a cycloalkyl or heterocycle;
- X is —O—, —S—, —S(O)—, —S(O)2—, —NR36—, or —CR36R37—;
- Y is O or Ne;
- R36 and R37 are independently at each occurrence hydrogen or alkyl;
- or R36 and R2 together with the atoms to which they are attached form a heterocycle;
- R38, R39 and R40 are independently at each occurrence hydrogen or alkyl;
- W is N—CN, N—OR6, N—R6, or S;
- and
- R6 is hydrogen, alkyl or aryl;
- or
- a pharmaceutically acceptable salt, ester, amide, N-oxide or prodrug thereof.
19 more elements
The compound selected from the group consisting of
- {4-[(4-methylphenyl)sulfonyl]piperazin-1-yl}(4-nitrophenyl)methylenecyanamide;
- N′-cyano-N-{1-[(1-cyanocyclopropyl)methyl]piperidin-4-yl}-N-cyclopropyl-4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)benzenecarboximidamide;
- [4-[{(cyanoimino)[4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl]methyl}(cyclopropyl)amino]-1-(4-fluorophenyl)cyclohexyl]methyl carbamate;
- N′-cyano-N-cyclopropyl-N-[4-(2-hydroxyethyl)cyclohexyl]-4-isopropylbenzenecarboximidamide[5-(4-methylphenyl)isoxazol-4-yl] (3-pyridin-3-ylpyrrolidin-1-yl)methylenecyanamide;
- 4-[4-[(1-adamantylamino)(cyanoimino)methyl]-5-(1-methylcyclopropyl)-1H-pyrazol-1-yl]benzoic acid;
- N′-cyano-N-cyclohexyl-2-[(2-phenylethyl)thio]pyridine-3-carboximidamide;
- 4-[5-[(2-adamantylamino)(cyanoimino)methyl]-6-(propylthio)pyridin-2-yl]morpholine-2-carboxylic acid;
- N′-cyano-N-cyclopropyl-N-(4-cyclopropyl-4-hydroxycyclohexyl)-4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)benzenecarboximidamide;
- 2-[2-(4-fluorophenyl)-6-hydroxy-2-adamantyl]-1-(3-hydroxyazetidin-1-yl)ethylidenecyanamide;
- 2-{1-[2-(2-adamantylamino)-2-(cyanoimino)ethyl]cyclopentyl}-N-isobutylacetamide;
- 2-{4-[(2-fluorophenyl)sulfonyl]-1,4-diazepan-1-yl}-1-octahydroquinolin-1(2H)-ylethylidenecyanamide;
- 1-cyclohexyl-3-[(3,5-dichloro-4′-{[4-(2-fluoro ethyl)piperazin-1-yl]carbonyl}-1,1′-biphenyl-4-yl)methyl]pyrrolidin-2-ylidenecyanamide;
- 3-[(3,5-dichloro-4′-{[4-(trifluoromethyl)piperidin-1-yl]carbonyl}-1,1′-biphenyl-4-yl)methyl]-1-piperidin-1-ylpyrrolidin-2-ylidenecyanamide;
- 3-cyclohexyl-1-[(3,5-dichloro-4′-{[4-(2-fluoro ethyl)piperazin-1-yl]carbonyl}-1,1′-biphenyl-4-yl)methyl]pyrrolidin-2-ylidenecyanamide;
- 3-[(3,5-dichloro-4′-{[4-(trifluoromethyl)piperidin-1-yl]carbonyl}-1,1′-biphenyl-4-yl)methyl]-1-(4,4-difluorocyclohexyl)pyrrolidin-2-ylidenecyanamide;
- 3-[(3,5-dichloro-4′-fluoro-1,1′-biphenyl-4-yl)methyl]-1-(4,4-difluorocyclohexyl)pyrrolidin-2-ylidenecyanamide;
- 3-[(3,5-dichloro-4′-{[4-(trifluoromethyl)piperidin-1-yl]carbonyl}-1,1′-biphenyl-4-yl)methyl]-1-(4-hydroxypiperidin-1-yl)pyrrolidin-2-ylidenecyanamide;
- methyl 4-{2-(cyanoimino)-3-[(3,5-dichloro-4′-{[4-(trifluoromethyl)piperidin-1-yl]carbonyl}-1,1′-biphenyl-4-yl)methyl]pyrrolidin-1-yl}piperidine-1-carboxylate;
- 2-[(3,5-dichloro-4′-{[4-(trifluoromethyl)piperidin-1-yl]carbonyl}-1,1′-biphenyl-4-yl)methyl]-2-azaspiro[4.5]dec-1-ylidenecyanamide;
- 3-[(3,5-dichloro-4′-{[4-(trifluoromethyl)piperidin-1-yl]carbonyl}-1,1′-biphenyl-4-yl)methyl]-1-(4,5,6,7-tetrahydro-1H-benzimidazol-6-yl)pyrrolidin-2-ylidenecyanamide;
- 3-[(3,5-dichloro-4′-fluoro-1,1′-biphenyl-4-yl)methyl]-1-(4,5,6,7-tetrahydro-2H-indazol-5-yl)pyrrolidin-2-ylidenecyanamide;
- N-2-adamantyl-2′-tert-butyl-N-cyano-2′H-1,3′-bipyrazole-4′-carboximidamide;
- 2-(4-bromo-2-fluorophenyl)-2-hydroxy-1-(3-oxo-1′H,3H-spiro[2-benzofuran-1,3′-pyrrolidin]-1′-yl)ethylidenecyanamide;
- N′-cyano-N-(1-{[4-(2,5-dimethylphenyl)piperazin-1-yl]carbonyl}piperidin-3-yl)-4-hydroxyadamantane-1-carboximidamide;
- 1-{3-[1-(4-chlorophenyl)cyclopropyl]-1-oxa-2,7-diazaspiro[4.4]non-2-en-7-yl}ethylidenecyanamide;
- 7-(2-chlorophenyl)-1-isobutyl-1,7-diazaspiro[4.4]non-6-ylidenecyanamide;
- 8-(3-chloropyridin-2-yl)-2-cyclohexyl-2,8-diazaspiro[4.5]dec-1-ylidenecyanamide;
- 5-{4-[1-(cyanoimino)-2-(4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]dec-7-yl]-3-fluorophenyl}-N,N-dimethylpyridine-2-carboxamide;
- 2-(2-acetylphenyl)-N′-cyano-N-cyclooctyl-1,3-thiazole-4-carboximidamide;
- (5-cyclopropyl-1-piperidin-4-yl-1H-pyrazol-4-yl) {3-[2-(trifluoromethyl)phenyl]pyrrolidin-1-yl}methylenecyanamide;
- 2-[4-(2-{[(4-chlorophenyl)(cyanoimino)methyl]amino}ethyl)phenoxy]-2-methylpropanoic acid;
- 1′-{[2-(trifluoromethyl)phenoxy]acetyl}Spiro[indole-3,4′-piperidin]-2(1H)-ylidenecyanamide;
- 1-{4-[(2-adamantylamino)(cyanoimino)methyl]phenyl}piperidine-4-carboxylic acid;
- N-(1-{4-[3-azabicyclo[3.2.2]non-3-yl(cyanoimino)methyl]phenyl}pyrrolidin-3-yl)-N-methyl-1-phenylmethanesulfonamide;
- 1-adamantyl {4-[2-(1H-imidazol-2-ylthio)ethyl]piperidin-1-yl}methylenecyanamide;
- N-2-adamantyl-N-cyano-4-(2-oxa-5-azabicyclo[2.2.1]hept-5-yl)benzene carboximidamide;
- N-{4-[(cyanoimino)(1,3,3-trimethyl-6-azabicyclo[3.2.1]oct-6-yl)methyl]benzyl}-1,1,1-trifluoro-N-isopropylmethanesulfonamide;
- 1-acetyl-N-(2-{5-[(cyanoimino)(1,3,3-trimethyl-6-azabicyclo[3.2.1]oct-6-yl)methyl]-1H-benzimidazol-1-yl}ethyl)piperidine-4-carboxamide;
- ethyl 3-{4-[(cyanoimino)(1,3,3-trimethyl-6-azabicyclo[3.2.1]oct-6-yl)methyl]-1H-indol-1-yl}propanoate;
- N-1-adamantyl-N-cyano-1-(thien-2-ylsulfonyl)piperidine-4-carboximidamide;
- N′-cyano-4-(2,4-dichlorophenoxy)-N-[4-(hydroxymethyl)-2-adamantyl]butanimidamide;
- 4-[(5-chloropyridin-2-yl)oxy]-N′-cyano-N-[4-(hydroxymethyl)cyclohexyl]-N-methylbenzenecarboximidamide;
- N-2-adamantyl-N-cyano-2-[cyclohexyl(methyl)amino]ethanimidamide;
- N-2-adamantyl-N-cyano-1-methyl-5-(2-phenylethoxy)-1H-pyrazole-4-carboximidamide;
- 2,4-dichloro-N-[1-({[5-{(cyanoimino)[(5-hydroxy-2-adamantyl)amino]methyl}-4-(cyclopentylthio)isoxazol-3-yl]oxy}methyl)cyclopropyl]benzamide;
- 4-[((cyanoimino) {1-[3-cyano-3-methylbut-1-enyl]-5-isobutoxy-1H-pyrazol-4-yl}methyl)amino]-1-adamantyl carbamate;
- 2-(5-hydroxy-2-adamantyl)-3-oxo-2,3-dihydro-1H-isoindol-1-ylidene cyanamide and 2-(6-hydroxy-2-adamantyl)-3-oxo-2,3-dihydro-1H-isoindol-1-ylidene cyanamide;
- N′-cyano-N-(5-hydroxy-2-adamantyl)-4-[(pyridin-2-ylsulfonyl)methoxy]benzenecarboximidamide;
- N′-cyano-3-(cyclohexylmethoxy)-N-[5-(hydroxymethyl)-2-adamantyl]benzenecarboximidamide;
- N′-cyano-N-(3-hydroxy-1-adamantyl)-4-[methylsulfonyl)methoxy]benzenecarboximidamide;
- N′-cyano-N-(5-hydroxy-2-adamantyl)-N-methyl-3-(2-phenylethoxy)benzenecarboximidamide;
- and
- (3-hydroxy-8-azabicyclo[3.2.1]oct-8-yl)(9-methyl-9H-carbazol-3-yl)methylenecyanamide;
- and
- 1-(4-{[2-(4-chlorophenoxy)phenyl]amino}piperidin-1-yl)ethylidenecyanamide.
52 more elements
Dependencies are inferred from the claim text.