# US 8,569,334 B2 · P2X7R antagonists and their use

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- Number: US 8,569,334 B2
- Document ID: US8569334B2
- Status: Granted
- Kind: B2
- Application number: 13/549,077
- Filed: 2012-07-13
- Published: 2012-11-29
- Granted: 2013-10-29
- Earliest claimed: 2008-03-25
- Assignees: Affectis Pharmaceuticals AG
- Applicants: Michael Bös
- Inventors: Michael Bös
- Web page: https://patentgrep.com/patent/US8569334B2

## CPC

- C07D 209/42: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 19/10: for osteoporosis
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- 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 25/16: 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 27/04: Artificial tears; Irrigation solutions
- A61P 27/06: Antiglaucoma agents or miotics
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- C07D 231/56: Benzopyrazoles; Hydrogenated benzopyrazoles
- C07D 403/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 471/04: Ortho-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present application is directed to novel P2X7R antagonists that are indol-3-carboxamide or azaindole-3-carboxamide compounds, pharmaceutical compositions comprising the same and their use for the prophylactic or therapeutic treatment of diseases mediated by P2X7R activity.

## Claims

### Claim 1

A compound of the general formula:
wherein,
R1 is a mono- or bicycloalkylalkyl group;
R2 is selected from straight or branched C1-C5 alkyl which may optionally substituted with —OH, C1-C5 alkoxy, NH2—, N(Ra)2—,NHRa—, CN—, CF3, halogen, piperidino, morpholino, pyrrolidino, 5H-tetrazolylpropyl, methylcarbamoyl, dimethylcarbamoyl, or ethylmethylcarbamoyl, wherein Ra is hydrogen or C1-C5 alkyl;
R3, R4, R5, R6, are at each occurrence independently selected from hydrogen, halogen, methyl, hydroxy, methoxy, cyano, or trifluoromethyl; and
a, b, c, and d are carbon and x is nitrogen, or
a, c, d, and x are carbon and b is nitrogen, or
a, b, d, and x are carbon and c is nitrogen, or
b, c, d, and x are carbon and a is nitrogen;
or a pharmaceutically acceptable salt or solvate thereof.

### Claim 2 (depends on 1)

A compound according to claim 1, wherein R1 is a mono- or bicycloalkylalkyl group selected from cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, cycloheptylmethyl, cycloheptylethyl, bicyclo[2.2.2]octan-1-ylmethyl and bicyclo[2.2.2]octan-1-ylethyl.

### Claim 3 (depends on 1)

A compound according to claim 1, wherein R2 is C1-C5 alkyl or C2-C5 hydroxyalkyl.

### Claim 4 (depends on 1)

A compound according to claim 1, wherein at least two of R3, R4, R5, R6 are hydrogen.

### Claim 5

A compound selected from the group consisting of
4-chloro-N-(cycloheptylmethyl)- 1-methyl-1H-indazole-3-carboxamide,
4-bromo-N-(cycloheptylmethyl)-1-methyl-1H-indazole-3-carboxamide,
N-(bicyclo [2.2.2]octan-1-ylmethyl)-4-chloro-1-methyl-1H-indazole-3-carboxamide,
N-(bicyclo [2.2.2]octan-1-ylmethyl)-4-bromo-1-methyl-1H-indazole-3-carboxamide,
4-chloro-N-(cycloheptylmethyl)-1-methyl-1H-pyrrolo [2,3-b]pyridine-3-carboxamide),
4-bromo-N-(cycloheptylmethyl)-1-methyl-1H-pyrrolo [2,3-b]pyridine-3-carboxamide,
N-(bicyclo [2.2.2]octan-1-ylmethyl)-4-chloro-1-methyl-1H-pyrrolo [2,3-b]pyridine-3carboxamide,
N-(bicyclo [2.2.2]octan-1-ylmethyl)-4-bromo-1-methyl-1H-pyrrolo [2,3-b]pyridine-3carboxamide,
4-chloro-N-(cycloheptylmethyl)-1-methyl-1H-pyrrolo [3,2-c]pyridine-3-carboxamide,
4-bromo-N-(cycloheptylmethyl)-1-methyl-1H-pyrrolo [3,2-c]pyridine-3-carboxamide),
N-(bicyclo [2.2.2]octan-1-ylmethyl)-4-chloro-1-methyl-1H-pyrrolo [3,2-c]pyridine-3carboxamide,
N-(bicyclo [2.2.2]octan-1-ylmethyl)-4-bromo-1-methyl-1H-pyrrolo [3,2-c]pyridine-3carboxamide,
4-chloro-N-(cycloheptylmethyl)-1-methyl-1H-pyrrolo [2,3-c]pyridine-3-carboxamide,
4-bromo-N-(cycloheptylmethyl)-1-methyl-1H-pyrrolo [2,3-c]pyridine-3-carboxamide,
N-(bicyclo [2.2.2]octan-1-ylmethyl)-4-chloro-1-methyl-1H-pyrrolo [2,3-c]pyridine-3carboxamide, and
N-(bicyclo [2.2.2]octan-1-ylmethyl)-4-bromo-1-methyl-1H-pyrrolo [2,3-c]pyridine-3carboxamide.

### Claim 6 (depends on 1)

A pharmaceutical composition comprising a compound according to claim 1.

### Claim 7 (depends on 6)

A pharmaceutical composition according to claim 6, further comprising an additional active compound in separate or unit dosage form for simultaneous or sequential administration.

### Claim 8 (depends on 1)

A method for treating depression, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1.

### Claim 9 (depends on 1)

A method for inhibiting P2X7R activity in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1.

### Claim 10 (depends on 1)

A method for treating inflammation, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1.

### Claim 11 (depends on 1)

A method for treating pain, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1.