# US 9,434,724 B2 · Quinuclidines for modulating alpha 7 activity

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- Number: US 9,434,724 B2
- Document ID: US9434724B2
- Status: Granted
- Kind: B2
- Application number: 14/794,497
- Filed: 2015-07-08
- Published: 2016-01-14
- Granted: 2016-09-06
- Earliest claimed: 2014-07-11
- Assignees: Alpharmagen, LLC
- Applicants: Alpharmagen, LLC
- Inventors: Geoffrey M. Bilcer; Raymond Ng
- Web page: https://patentgrep.com/patent/US9434724B2

## CPC

- C07D 453/02: containing not further condensed quinuclidine ring systems
- A61K 31/439: the ring forming part of a bridged ring system, e.g. quinuclidine (8-azabicyclo [3.2.1] octanes A61K31/46)
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 25/00: Drugs for disorders of the nervous system
- 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 25/22: Anxiolytics
- A61P 25/24: Antidepressants
- 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 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 519/00: Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Provided are substituted quinuclidine compounds, pharmaceutical compositions comprising such compounds, and methods of modulating α7 nicotinic acetylcholine receptors and treating neurological disorders using such compounds.

## Claims

### Claim 1

A compound having the formula (I):
wherein
R1 is C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, or bromo, wherein the C1-C6 alkyl, C1-C6 alkoxy, or C3-C6 cycloalkyl is unsubstituted or substituted with 1 to 5 halo substituents;
R2 and R3 are each independently hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, halo, cyano, —NRaRb, —NHC(O)Rc, —ORd, or —OC(O)Re;
Ra, Rb, and Rc are each independently hydrogen, unsubstituted C1-C6 alkyl, or unsubstituted C3-C6 cycloalkyl;
Rd is hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl, wherein the C1-C6 alkyl or C3-C6 cycloalkyl is unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of hydroxyl, C1-C6 alkoxy, and halo; and
Re is unsubstituted C1-C6 alkyl or unsubstituted C3-C6 cycloalkyl;
provided that 1) at least one of R2 and R3 is hydrogen, and 2) when R1 is C1-C6 alkoxy, R2 is other than hydrogen,
or a salt thereof.

### Claim 2 (depends on 1)

The compound of claim 1, or a salt thereof, wherein R1 is C1-C6 alkyl or C3-C6 cycloalkyl, wherein the C1-C6 alkyl or C3-C6 cycloalkyl is unsubstituted or substituted with 1 to 5 halo substituents.

### Claim 3 (depends on 1)

The compound of claim 1, or a salt thereof, wherein R1 is unsubstituted C1-C6 alkyl.

### Claim 4 (depends on 1)

The compound of claim 1, or a salt thereof, wherein R1 is —CH3.

### Claim 5 (depends on 1)

The compound of claim 1, or a salt thereof, wherein R1 is C1-C6 alkoxy, which is unsubstituted or substituted with 1 to 5 halo substituents.

### Claim 6 (depends on 1)

The compound of claim 1, or a salt thereof, wherein R1 is —OCH3.

### Claim 7 (depends on 1)

The compound of claim 1, or a salt thereof, wherein R1 is bromo.

### Claim 8 (depends on 1)

The compound of claim 1, or a salt thereof, wherein R2 is hydrogen.

### Claim 9 (depends on 1)

The compound of claim 1, or a salt thereof, wherein R2 is C1-C6 alkyl or C3-C6 cycloalkyl.

### Claim 10 (depends on 1)

The compound of claim 1, or a salt thereof, wherein R2 is —CH3.

### Claim 11 (depends on 1)

The compound of claim 1, or a salt thereof, wherein R2 is halo.

### Claim 12 (depends on 1)

The compound of claim 1, or a salt thereof, wherein R2 is fluoro or chloro.

### Claim 13 (depends on 1)

The compound of claim 1, or a salt thereof, wherein R2 is cyano.

### Claim 14 (depends on 1)

The compound of claim 1, or a salt thereof, wherein R2 is —ORd, and Rd is hydrogen or unsubstituted C1-C6 alkyl.

### Claim 15 (depends on 14)

The compound of claim 14, or a salt thereof, wherein Rd is —CH3.

### Claim 16 (depends on 1)

The compound of claim 1, or a salt thereof, wherein R2 is ORd, and Rd is C1-C6 alkyl substituted with C1-C6 alkoxy.

### Claim 17 (depends on 1)

The compound of claim 1, or a salt thereof, wherein R3 is hydrogen.

### Claim 18 (depends on 1)

The compound of claim 1, or a salt thereof, wherein R3 is C1-C6 alkyl or C3-C6 cycloalkyl.

### Claim 19 (depends on 1)

The compound of claim 1, or a salt thereof, wherein R3 is —CH3.

### Claim 20 (depends on 1)

The compound of claim 1, or a salt thereof, wherein R3 is halo.

### Claim 21 (depends on 1)

The compound of claim 1, or a salt thereof, wherein R3 is fluoro or chloro.

### Claim 22 (depends on 1)

The compound of claim 1, or a salt thereof, wherein R3 is cyano.

### Claim 23 (depends on 1)

The compound of claim 1, or a salt thereof, wherein R3 is —ORd, and Rd is hydrogen or unsubstituted C1-C6 alkyl.

### Claim 24 (depends on 23)

The compound of claim 23, or a salt thereof, wherein Rd is —CH3.

### Claim 25 (depends on 1)

The compound of claim 1, wherein
R1 is C1-C4 alkyl, C1-C4 alkoxy, C3-C4 cycloalkyl, or bromo, wherein the C1-C4 alkyl is unsubstituted or substituted with 1 to 5 fluoro substituents;
R2 and R3 are each independently hydrogen, C1-C6 alkyl, fluoro, chloro, cyano, —NHC(O)Rc, —ORd, or —OC(O)Re;
Rc is hydrogen or unsubstituted C1-C6 alkyl;
Rd is hydrogen or C1-C6 alkyl, wherein the C1-C6 alkyl is unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of hydroxyl, C1-C6 alkoxy, and halo; and
Re is unsubstituted C1-C6 alkyl;
provided that 1) at least one of R2 and R3 is hydrogen, and 2) when R1 is C1-C4 alkoxy, R2 is other than hydrogen,
or a salt thereof.

### Claim 26 (depends on 1)

The compound of claim 1, or a salt thereof, wherein the compound is selected from the group consisting of:
Compound
No.
Structure
21
24
34
37
40
41
42
43
44
47
48
49
50
53
54
60
61
67
68
70
75
80
83
88
89
91
92
93
94
95

### Claim 27

A compound, or a salt thereof, selected from the group consisting of:
Compound
No.
Structure
35
38
46
62
63
64
65
71
74
77
82

### Claim 28 (depends on 1)

A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

### Claim 29 (depends on 1)

A method for modulating an α7-nicotinic acetylcholine receptor (α7 NAChR), comprising contacting the α7 NAChR with an effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.

### Claim 30 (depends on 27)

A pharmaceutical composition comprising a compound of claim 27, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

### Claim 31 (depends on 27)

A method for modulating an α7-nicotinic acetylcholine receptor (α7 NAChR), comprising contacting the α7 NAChR with an effective amount of a compound of claim 27, or a pharmaceutically acceptable salt thereof.

### Claim 32 (depends on 26)

A pharmaceutical composition comprising a compound of claim 26, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

### Claim 33 (depends on 26)

A method for modulating an α7-nicotinic acetylcholine receptor (α7 NAChR), comprising contacting the α7 NAChR with an effective amount of a compound of claim 26, or a pharmaceutically acceptable salt thereof.