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US 2010/0168083 A1Published application
Adamantane derivatives for the treatment of the metabolic syndrome
OwnerSoren Ebdrupinventor
Life of this patent
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Abstract
Novel substituted adamantane based inhibitors, their use in therapy, pharmaceutical compositions comprising the compounds, the use of said compounds in the manufacture of medicaments, and therapeutic methods comprising the administration of said compounds are described. The present compounds modulate the activity of 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) and are accordingly useful in the treatment of diseases in which such a modulation is beneficial, such as the metabolic syndrome.
Claims23
A compound of the general formula I
- wherein
- R1 and R2 together with the nitrogen to which they are attached, are forming a saturated cyclic ring system containing from 4 to 7 carbon atoms, the ring system being substituted with -A-X;
- A is selected from the group consisting of C1-2-alkylene, C2-3-alkenylene and C2-3-alkynylene;
- X is selected from the group consisting of —OR6, —SR6, —NHR9, —S(O)R6, —S(O)2R6 and —NS(O)2R6;
- R6 is selected from the group consisting of C1-10-alkyl, C2-8-alkenyl, C2-8-alkynyl, aryl, monocyclic or bicyclic heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, each of which alkyl, alkenyl and alkynyl is optionally substituted with one or more of R7 and each of which aryl, heteroaryl, heterocyclyl and cycloalkyl is optionally substituted with one or more of R8;
- R7 is halogen, aryl, heteroaryl, arylC1-6-alkyl, heteroarylC1-6-alkyl, heteroarylaminocarbonyl, hydroxy, oxo, carboxy, C3-8-heterocyclyl, C3-10-cycloalkylamino, cyano, C1-6-alkyloxy, arylC1-6-alkyloxy, heteroarylC1-6-alkyloxy, C1-6-alkyloxycarbonylC1-6-alkyl, C2-6-alkenyloxycarbonyl, carboxyC1-6-alkyl, C1-6-alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylC1-6-alkylcarbonyl, heteroarylC1-6-alkylcarbonyl, C1-6-alkylcarboxy, arylcarboxy or arylC1-6-alkylcarboxy, each of which alkyl and alkenyl is optionally substituted with one or more hydroxy, hydroxyC1-6-alkyl, carboxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyloxy or aryloxy and each of which aryl, heteroaryl, heterocyclyl and cycloalkyl is optionally substituted with one or more hydroxy, hydroxyC1-6-alkyl, carboxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, C1-6-alkyloxy, C3-10-cycloalkyl or aryloxy;
- R8 is C1-10-alkyl, C2-8-alkenyl, C2-8-alkynyl, halogen, aryl, heteroaryl, arylC1-6-alkyl, heteroarylC1-6-alkyl, heteroarylaminocarbonyl, hydroxy, oxo, carboxy, C3-8-heterocyclyl, C3-10-cycloalkylamino, cyano, C1-6-alkyloxy, arylC1-6alkyloxy, heteroarylC1-6-alkyloxy, C1-6-alkyloxyC1-6alkyl, C1-6-alkyloxycarbonylC1-6-alkyl, C2-6-alkenyloxycarbonyl, carboxyC1-6-alkyl, C1-6alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylC1-6-alkylcarbonyl, heteroarylC1-6alkylcarbonyl, C1-6alkylcarboxy, arylcarboxy or arylC1-6-alkylcarboxy, each of which alkyl and alkenyl is optionally substituted with one or more hydroxy, hydroxyC1-6-alkyl, carboxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyloxy or aryloxy and each of which aryl, heteroaryl, heterocyclyl and cycloalkyl is optionally substituted with one or more hydroxy, hydroxyC1-6-alkyl, carboxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, C1-6-alkyloxy, C3-10-cycloalkyl or aryloxy;
- R9 is selected from the group consisting of aryl or heteroaryl, each of which is optionally substituted with one or more R8;
- R3, R4, and R5 independently are selected from the group consisting of hydrogen, hydroxy, carboxy, perhalomethyl, —CH2OH, and halogen;
- or
- a prodrug thereof, or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture or any tautomeric forms.
8 more elements
A compound selected from the group consisting of
- (4-{2-[1-(Tricyclo[3.3.1.1.3.7]decanane-1-carbonyl)-piperidin-4-yl]-ethoxy}-phenyl)-acetic acid
- {4-[2-(1H-Imidazol-2-ylsulfanyl)-ethyl]-piperidin-1-yl}-tricyclo[3.3.1.1.3.7]decan-1-yl-methanone
- 4-{2-[1-(Tricyclo[3.3.1.1.3.7]decanane-1-carbonyl)-piperidin-4-yl]-ethoxy}-benzoic acid
- 4-{2-[1-(Tricyclo[3.3.1.1.3.7]decanane-1-carbonyl)-piperidin-4-yl]-methoxy}-benzoic acid
- [4-(1H-Imidazol-2-ylsulfanylmethyl)-piperidin-1-yl]-tricyclo[3.3.1.1.3.7]decan-1-yl-methanone
- [[4-(Pyridin-2-yloxymethyl)-piperidin-1-yl]-tricyclo[3.3.1.1.3.7]decan-1-yl-methanone
- {4-[2-(Pyridin-2-ylsulfanyl)-ethyl]-piperidin-1-yl}-tricyclo[3.3.1.1.3.7]decan-1-yl-methanone
- {4-[2-(Pyridin-2-yloxy)-ethyl]-piperidin-1-yl}-tricyclo[3.3.1.1,3,7]decan-1-yl-methanone
5 more elements
7-9. (canceled)
A pharmaceutical composition comprising at least one compound according to general formula I
- wherein
- R1 and R2 together with the nitrogen to which they are attached, are forming a saturated cyclic ring system containing from 4 to 7 carbon atoms, the ring system being substituted with -A-X;
- A is selected from the group consisting of C1-2-alkylene, C2-3-alkenylene and C2-3-alkynylene;
- X is selected from the group consisting of —OR6, —SR6, —NHR9, —S(O)R6, —S(O)2R6 and —NS(O)2R6;
- R6 is selected from the group consisting of C1-10-alkyl, C2-8-alkenyl, C2-8-alkynyl, aryl, monocyclic or bicyclic heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, each of which alkyl, alkenyl and alkynyl is optionally substituted with one or more of R7 and each of which aryl, heteroaryl, heterocyclyl and cycloalkyl is optionally substituted with one or more of R8;
- R7 is halogen, aryl, heteroaryl, arylC1-6-alkyl, heteroarylC1-6-alkyl, heteroarylaminocarbonyl, hydroxy, oxo, carboxy, C3-8-heterocyclyl, C3-10-cycloalkylamino, cyano, C1-6-alkyloxy, arylC1-6-alkyloxy, heteroarylC1-6-alkyloxy, C1-6-alkyloxyC1-6-alkyl, C1-6-alkyloxycarbonylC1-6-alkyl, C2-6-alkenyloxycarbonyl, carboxyC1-6-alkyl, C1-6-alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylC1-6-alkylcarbonyl, heteroarylC1-6-alkylcarbonyl, C1-6-alkylcarboxy, arylcarboxy or arylC1-6-alkylcarboxy, each of which alkyl and alkenyl is optionally substituted with one or more hydroxy, hydroxyC1-6-alkyl, carboxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyloxy or aryloxy and each of which aryl, heteroaryl, heterocyclyl and cycloalkyl is optionally substituted with one or more hydroxy, hydroxyC1-6-alkyl, carboxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, C1-6-alkyloxy, C3-10-cycloalkyl or aryloxy;
- R8 is C1-10-alkyl, C2-8-alkenyl, C2-8-alkynyl, halogen, aryl, heteroaryl, arylC1-6-alkyl, heteroarylC1-6-alkyl, heteroarylaminocarbonyl, hydroxy, oxo, carboxy, C3-8-heterocyclyl, C3-10-cycloalkylamino, cyano, C1-6-alkyloxy, arylC1-6-alkyloxy, heteroarylC1-6-alkyloxy, alkyloxyC1-6-alkyl, C1-6-alkyloxycarbonylC1-6-alkyl, C2-6-alkenyloxycarbonyl, carboxyC1-6-alkyl, C1-6-alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylC1-6-alkylcarbonyl, heteroarylC1-6-alkylcarbonyl, C1-6-alkylcarboxy, arylcarboxy or arylC1-6-alkylcarboxy, each of which alkyl and alkenyl is optionally substituted with one or more hydroxy, hydroxyC1-6-alkyl, carboxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyloxy or aryloxy and each of which aryl, heteroaryl, heterocyclyl and cycloalkyl is optionally substituted with one or more hydroxy, hydroxyC1-6-alkyl, carboxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, C1-6-alkyloxy, C3-10-cycloalkyl or aryloxy;
- R9 is selected from the group consisting of aryl or heteroaryl, each of which is optionally substituted with one or more R5;
- R3, R4, and R5 independently are selected from the group consisting of hydrogen, hydroxy, carboxy, C1-3-alkyl, perhalomethyl, —CH2OH, and halogen;
- or
- a prodrug thereof, or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture or any tautomeric forms;
- and
- one or more pharmaceutically acceptable carriers or excipients.
10 more elements
11-13. (canceled)
Dependencies are inferred from the claim text.