# US 2010/0168083 A1 · Adamantane derivatives for the treatment of the metabolic syndrome

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- Number: US 2010/0168083 A1
- Document ID: US20100168083A1
- Status: Published application
- Kind: A1
- Application number: 12/293,709
- Filed: 2007-03-20
- Published: 2010-07-01
- Earliest claimed: 2006-03-21
- Inventors: Soren Ebdrup
- Web page: https://patentgrep.com/patent/US20100168083A1

## CPC

- C07D 401/12: linked by a chain containing hetero atoms as chain links
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 3/06: Antihyperlipidemics
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 9/12: Antihypertensives
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 211/20: with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
- C07D 211/22: by oxygen atoms
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## 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.

## Claims

### Claim 1

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.

### Claim 2 (depends on 1)

The compound according to claim 1, wherein the compound has the general formula II
wherein A, X, R3, R4, and R5 are as defined in claim 1.

### Claim 3 (depends on 1)

The compound according to claim 1, wherein the compound has the general formula IIa
wherein A, X, R3, R4, and R5 are as defined in claim 1.

### Claim 4 (depends on 1)

The compound according to claim 1, wherein the compound has the general formula IIb
wherein A, X, R3, R4, and R5 are as defined in claim 1.

### Claim 5 (depends on 1)

The compound according to claim 1, wherein the compound has the general formula IIc
wherein A, X, R3, R4, and R5 are as defined above.

### Claim 6

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

### Claim at position 7

7-9. (canceled)

### Claim 10

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.

### Claim at position 9

11-13. (canceled)

### Claim 14 (depends on 1)

A method for the treatment, prevention and/or prophylaxis of any conditions, disorders or diseases wherein a modulation or an inhibition of the activity of 1113-HSD1 is beneficial, the method comprising administering to a subject in need thereof an effective amount of a compound according claim 1.

### Claim 15 (depends on 14)

The method according to claim 14, wherein the condition, disorder or disease is a condition, disorder or disease that is influenced by intracellular glucocorticoid levels.

### Claim 16 (depends on 14)

The method according to claim 14, wherein the conditions, disorders or diseases selected from the group consisting of the metabolic syndrome, insulin resistance, dyslipidemia, hypertension and obesity.

### Claim 17 (depends on 10)

The pharmaceutical composition according to claim 10 which is for oral, nasal, buccal, transdermal, pulmonal or parenteral administration.

### Claim 18 (depends on 10)

The pharmaceutical composition according to claim 10 in unit dosage form, comprising from 0.05 mg to 2000 mg/day, from 0.1 mg to 1000 mg or from 0.5 mg to 500 mg per day of the compound according to anyone of the clauses 1-32.

### Claim 19 (depends on 1)

The compound according to claim 1, wherein R1 and R2 together with the nitrogen to which they are attached, form a saturated cyclic ring system containing 5 or 6 carbon atoms.

### Claim 20 (depends on 1)

The compound according to claim 1, wherein R1 and R2 together with the nitrogen to which they are attached, form a saturated cyclic ring system containing 6 to 8 carbon atoms, in which ring system 1 or 2 carbon atoms are in the form of a bridge.

### Claim 21 (depends on 1)

The compound according to claim 1, wherein R1 and R2 together with the nitrogen to which they are attached, are forming a saturated cyclic ring system selected from the group consisting of

### Claim 22 (depends on 2)

The compound according to claim 2, wherein A is ethylene or methylene.

### Claim 23 (depends on 2)

The compound according to claim 2, wherein X is selected from the group consisting of —OR6, —SR6, and —NHR9.

### Claim 24 (depends on 2)

The compound according to claim 2, wherein R3, R4, and R5 independently are selected from the group consisting of hydrogen, methyl, halogen, —CH2OH and trifluormethyl.

### Claim 25 (depends on 2)

The compound according to claim 2, wherein R6 is selected from the group consisting of C1-10-alkyl, C2-8-alkenyl, and C2-8-alkynyl, each of which alkyl, alkenyl and alkynyl is optionally substituted with one or more of R7.

### Claim 26 (depends on 2)

The compound according to claim 2, wherein R6 is selected from the group consisting of aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, each of which aryl, heteroaryl, heterocyclyl and cycloalkyl being optionally substituted with one or more of R8.

### Claim 27 (depends on 2)

The compound according to claim 2, wherein R6 is imidazolyl which is optionally substituted with one or more of R8.