# US 8,541,440 B2 · Derivatives of 5-pyridinyl-1-azabicyclo[3.2.1]octane, preparation method thereof and use of same in therapeutics

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- Number: US 8,541,440 B2
- Document ID: US8541440B2
- Status: Granted
- Kind: B2
- Application number: 12/955,389
- Filed: 2010-11-29
- Published: 2011-03-31
- Granted: 2013-09-24
- Earliest claimed: 2005-08-12
- Assignees: Sanofi
- Applicants: Frederic Galli; Odile Leclerc; Alistair Lochead; Julien Vache
- Inventors: Frederic Galli; Odile Leclerc; Alistair Lochead; Julien Vache
- Web page: https://patentgrep.com/patent/US8541440B2

## CPC

- C07D 471/18: Bridged systems
- A61P 9/04: Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
- A61P 9/08: Vasodilators for multiple indications
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 9/14: Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/02: for peripheral neuropathies
- A61P 25/04: Centrally acting analgesics, e.g. opioids
- A61P 25/14: for treating abnormal movements, e.g. chorea, dyskinesia
- A61P 25/16: Anti-Parkinson drugs
- A61P 25/18: Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 25/30: for treating abuse or dependence
- A61P 25/32: Alcohol-abuse
- A61P 25/34: Tobacco-abuse
- A61P 25/36: Opioid-abuse
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The invention relates to compounds having general formula (I), wherein R is as defined herein. The invention also relates to acid addition salt, a hydrate or a solvate of compounds of formula (I). The invention further relates to the method of preparing said compounds and to the use of same in therapeutics.

## Claims

### Claim 1

A method of treating a disorder associated with dysfunction of the nicotinic receptors, comprising administering to a patient in need of said treatment a therapeutically effective amount of a compound of formula (I):
in which:
R represents a group chosen from pyrazolyl, imidazolyl, triazolyl, oxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl and tetrazolyl, said group optionally substituted with one or more groups chosen from halogen, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethoxy, trifluoromethyl, nitro, cyano, hydroxyl, amino, (C1-C6)alkylamino and di(C1-C6)alkylamino group; and wherein
the carbon-carbon bond between positions 3 and 4 of the azabicyclooctane ring is a single or a double bond;
or a pharmaceutically acceptable salt thereof;
wherein the disorder is selected from the group consisting of executive function disorders associated with Alzheimer's disease and schizophrenia.

### Claim 2 (depends on 1)

The method according to claim 1, wherein for the compound of formula (I):
R represents a group chosen from pyrazolyl, imidazolyl, triazolyl, oxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl and tetrazolyl, said group optionally substituted with one or more (C1-C6)alkyl group; and wherein
the carbon-carbon bond between positions 3 and 4 of the azabicyclooctane ring is a single or a double bond.

### Claim 3 (depends on 1)

The method according to claim 1, wherein for the compound of formula (I):
R represents a group chosen from pyrazolyl, imidazolyl, triazolyl, oxazolyl, oxadiazolyl, thiazolyl and tetrazolyl, said group optionally substituted with one or more groups chosen from halogen, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethoxy, trifluoromethyl, nitro, cyano, hydroxyl, amino, (C1-C6)alkylamino and di(C1-C6)alkylamino group; and wherein
the carbon-carbon bond between positions 3 and 4 of the azabicyclooctane ring is a single or a double bond.

### Claim 4 (depends on 1)

The method according to claim 1, wherein for the compound of formula (I):
R represents a group chosen from pyrazolyl, imidazolyl, triazolyl, oxazolyl, oxadiazolyl, thiazolyl and tetrazolyl, said group optionally substituted with one or more (C1-C6)alkyl group; and wherein
the carbon-carbon bond between positions 3 and 4 of the azabicyclooctane ring is a single or a double bond.

### Claim 5 (depends on 1)

The method according to claim 1, wherein for the compound of formula (I):
R represents a pyrazolyl group optionally substituted with one or more (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethoxy, trifluoromethyl, nitro, cyano, hydroxyl, amino, (C1-C6)alkylamino or di(C1-C6)alkylamino group; and wherein
the carbon-carbon bond between positions 3 and 4 of the azabicyclooctane ring is a single or a double bond.

### Claim 6 (depends on 1)

The method according to claim 1, wherein for the compound of formula (I):
R represents a pyrazolyl group optionally substituted with one or more (C1-C6)alkyl group; and wherein
the carbon-carbon bond between positions 3 and 4 of the azabicyclooctane ring is a single or a double bond.

### Claim 7 (depends on 1)

The method according to claim 1, wherein for the compound of formula (I):
R represents a pyrazolyl group optionally substituted with one or more (C1-C6)alkyl groups; and wherein
the carbon-carbon bond between positions 3 and 4 of the azabicyclooctane ring is a single bond.

### Claim 8 (depends on 1)

The method according to claim 1, wherein the compound is selected from the group consisting of:
5-[2-(1-methyl-1H-pyrazol-4-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]octane;
5-[2-(1H-pyrazol-4-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]octane;
5-[2-(1H-pyrazol-4-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]oct-3-ene;
5-[2-(1-methyl-1H-pyrazol-4-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]-oct-3-ene;
5-[2-(1H-imidazol-1-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]oct-3-ene
5-[2-(1H-imidazol-4-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]oct-3-ene
5-[2-(1H-imidazol-4-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]octane
5-[2-(1H-imidazol-1-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]octane
5-[2-(1H-imidazol-2-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]octane
5-[2-(3,5-dimethyl-1H-pyrazol-4-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]octane;
5-[2-(1H-1,2,4-triazol-3-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]octane;
5-[2-(5-methyl-1,2,4-oxadiazol-3-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]octane;
5-[2-(1,3-oxazol-2-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]octane;
5-[2-(thiazol-4-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]octane
5-[2-(pyrazol-3-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]octane
5-[2-(2-methylthiazol-5-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]octane
5-[2-(tetrazol-5-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]octane;
5-[2-(1-isobutyl-1H-pyrazol-4-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]octane; and
5-[2-(1-n-propyl-1H-pyrazol-4-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]octane;
or a pharmaceutically acceptable salt thereof.

### Claim 9

A method of inhibiting a nicotinic receptor, comprising administering to a patient in need of said inhibition a therapeutically effective amount of a compound of formula (I):
in which:
R represents a group chosen from pyrazolyl, imidazolyl, triazolyl, oxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl and tetrazolyl, said group optionally substituted with one or more groups chosen from halogen, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethoxy, trifluoromethyl, nitro, cyano, hydroxyl, amino, (C1-C6)alkylamino and di(C1-C6)alkylamino group; and wherein
the carbon-carbon bond between positions 3 and 4 of the azabicyclooctane ring is a single or a double bond;
or a pharmaceutically acceptable salt thereof.

### Claim 10 (depends on 9)

The method according to claim 9, wherein for the compound of formula (I):
R represents a group chosen from pyrazolyl, imidazolyl, triazolyl, oxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl and tetrazolyl, said group optionally substituted with one or more (C1-C6)alkyl group; and wherein
the carbon-carbon bond between positions 3 and 4 of the azabicyclooctane ring is a single or a double bond.

### Claim 11 (depends on 9)

The method according to claim 9, wherein for the compound of formula (I):
R represents a group chosen from pyrazolyl, imidazolyl, triazolyl, oxazolyl, oxadiazolyl, thiazolyl and tetrazolyl, said group optionally substituted with one or more groups chosen from halogen, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethoxy, trifluoromethyl, nitro, cyano, hydroxyl, amino, (C1-C6)alkylamino and di(C1-C6)alkylamino group; and wherein
the carbon-carbon bond between positions 3 and 4 of the azabicyclooctane ring is a single or a double bond.

### Claim 12 (depends on 9)

The method according to claim 9, wherein for the compound of formula (I):
R represents a group chosen from pyrazolyl, imidazolyl, triazolyl, oxazolyl, oxadiazolyl, thiazolyl and tetrazolyl, said group optionally substituted with one or more (C1-C6)alkyl group; and wherein
the carbon-carbon bond between positions 3 and 4 of the azabicyclooctane ring is a single or a double bond.

### Claim 13 (depends on 9)

The method according to claim 9, wherein for the compound of formula (I):
R represents a pyrazolyl group optionally substituted with one or more (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethoxy, trifluoromethyl, nitro, cyano, hydroxyl, amino, (C1-C6)alkylamino or di(C1-C6)alkylamino group; and wherein
the carbon-carbon bond between positions 3 and 4 of the azabicyclooctane ring is a single or a double bond.

### Claim 14 (depends on 9)

The method according to claim 9, wherein for the compound of formula (I):
R represents a pyrazolyl group optionally substituted with one or more (C1-C6)alkyl group; and wherein
the carbon-carbon bond between positions 3 and 4 of the azabicyclooctane ring is a single or a double bond.

### Claim 15 (depends on 9)

The method according to claim 9, wherein for the compound of formula (I):
R represents a pyrazolyl group optionally substituted with one or more (C1-C6)alkyl groups; and wherein
the carbon-carbon bond between positions 3 and 4 of the azabicyclooctane ring is a single bond.

### Claim 16 (depends on 9)

The method according to claim 9, wherein the compound is selected from the group consisting of:
5-[2-(1-methyl-1H-pyrazol-4-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]octane;
5-[2-(1H-pyrazol-4-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]octane;
5-[2-(1H-pyrazol-4-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]oct-3-ene;
5-[2-(1-methyl-1H-pyrazol-4-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]-oct-3-ene;
5-[2-(1H-imidazol-1-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]oct-3-ene
5-[2-(1H-imidazol-4-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]oct-3-ene
5-[2-(1H-imidazol-4-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]octane
5-[2-(1H-imidazol-1-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]octane
5-[2-(1H-imidazol-2-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]octane
5-[2-(3,5-dimethyl-1H-pyrazol-4-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]octane;
5-[2-(1H-1,2,4-triazol-3-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]octane;
5-[2-(5-methyl-1,2,4-oxadiazol-3-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]octane;
5-[2-(1,3-oxazol-2-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]octane;
5-[2-(thiazol-4-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]octane
5-[2-(pyrazol-3-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]octane
5-[2-(2-methylthiazol-5-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]octane
5-[2-(tetrazol-5-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]octane;
5-[2-(1-isobutyl-1H-pyrazol-4-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]octane; and
5-[2-(1-n-propyl-1H-pyrazol-4-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]octane;
or a pharmaceutically acceptable salt thereof.