# US 2013/0158050 A1 · Piperidine derivatives

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- Number: US 2013/0158050 A1
- Document ID: US20130158050A1
- Status: Published application
- Kind: A1
- Application number: 13/766,840
- Filed: 2013-02-14
- Published: 2013-06-20
- Earliest claimed: 2009-01-27
- Assignees: Hoffmann-La Roche Inc.
- Inventors: Sabine Kolczewski; Emmanuel Pinard; Henri Stalder
- Web page: https://patentgrep.com/patent/US20130158050A1

## CPC

- C07D 407/04: directly linked by a ring-member-to-ring-member bond
- A61K 31/451: having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
- 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 25/18: 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 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 211/56: Nitrogen atoms (nitro radicals C07D211/38)
- C07D 213/56: Amides
- C07D 221/20: Spiro-condensed ring systems
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 405/04: directly linked by a ring-member-to-ring-member bond
- C07D 417/10: linked by a carbon chain containing aromatic rings
- 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

The present invention relates to a compound of formula I wherein R1, R2, and Ar are as defined herein or to a pharmaceutically acceptable acid addition salt, to a racemic mixture, or to its corresponding enantiomer and/or optical isomer thereof. These compounds and their pharmaceutical compositions are useful in the treatment of neurological and neuropsychiatric disorders.

## Claims

### Claim 1

A compound of formula I
wherein
R1 is hydrogen, lower alkyl, CD3, —(CH2)n—CHO, —(CH2)n—O-lower alkyl, —(CH2)n—OH, —(CH2)n-cycloalkyl or heterocycloalkyl;
R2 is hydrogen, halogen, hydroxy, lower alkyl, di-lower alkyl, —OCH2—O-lower alkyl, or lower alkoxy; or the piperidin ring together with R2 forms 4-aza-spiro[2.5]oct-6-yl;
Ar is phenyl optionally substituted by one, two or three substituents selected from halogen, lower alkyl, lower alkyl substituted by halogen, lower alkoxy substituted by halogen, cycloalkyl, lower alkoxy, S-lower alkyl, heteroaryl, heterocycloalkyl, and phenyl optionally substituted by R′,
R′ is lower alkyl, lower alkoxy, lower alkoxy substituted by halogen, or heteroaryl;
R is phenyl optionally substituted by one or two R′; and
n is 0, 1 2 or 3;
or a pharmaceutically acceptable acid addition salt, racemic mixture, enantiomer, or optical isomer thereof.

### Claim 2 (depends on 1)

A compound of claim 1, wherein R1 is lower alkyl.

### Claim 3 (depends on 2)

A compound of claim 2, wherein the phenyl group for Ar is substituted by at least two CF3 groups.

### Claim 4 (depends on 3)

A compound of claim 3, selected from the group consisting of
rac-2-fluoro-N-(1-methyl-3-phenyl-piperidin-3-yl)-4,6-bis-trifluoromethyl-benzamide;
rac-2-methoxy-N-(1-methyl-3-phenyl-piperidin-3-yl)-4,6-bis-trifluoromethyl-benzamide;
rac-2-ethyl-N-(1-methyl-3-phenyl-piperidin-3-yl)-4,6-bis-trifluoromethyl-benzamide;
rac-N-[3-(4-fluoro-phenyl)-1-methyl-piperidin-3-yl]-2-methoxy-4,6-bis-trifluoromethyl-benzamide; and
2-methoxy-N—((R)-1-methyl-3-phenyl-piperidin-3-yl)-4,6-bis-trifluoromethyl-benzamide.

### Claim 5 (depends on 1)

A compound of claim 1, wherein the phenyl group for Ar is substituted by at least one CF3 group.

### Claim 6 (depends on 5)

A compound of claim 5, selected from the group consisting of
rac-2-ethyl-N-(1-methyl-3-phenyl-piperidin-3-yl)-4-trifluoromethyl-benzamide;
rac-2-bromo-6-methoxy-N-(1-methyl-3-phenyl-piperidin-3-yl)-4-trifluoromethyl-benzamide;
rac-N-(1,2-dimethyl-3-phenyl-piperidin-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide;
rac-2-cyclopropyl-N-(1-methyl-3-phenyl-piperidin-3-yl)-4-trifluoromethyl-benzamide;
rac-2-methoxy-N-(1-methyl-3-phenyl-piperidin-3-yl)-6-methylsulfanyl-4-trifluoromethyl-benzamide;
rac-N-(1-methyl-3-phenyl-piperidin-3-yl)-2-methylsulfanyl-4-trifluoromethyl-benzamide;
rac-N-[3-(4-fluoro-phenyl)-1-methyl-piperidin-3-yl]-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide;
rac-N-[3-(4-chloro-phenyl)-1-methyl-piperidin-3-yl]-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide;
2-methoxy-N-((S)-1-methyl-3-phenyl-piperidin-3-yl)-6-methylsulfanyl-4-trifluoromethyl-benzamide;
2-methoxy-N—((R)-1-methyl-3-phenyl-piperidin-3-yl)-6-methylsulfanyl-4-trifluoromethyl-benzamide; and
rac-2-difluoromethoxy-N-(1-methyl-3-phenyl-piperidin-3-yl)-4-trifluoromethyl-benzamide.

### Claim 7 (depends on 5)

A compound of claim 5, selected from the group consisting of
rac-N-[3-(3-chloro-phenyl)-1-methyl-piperidin-3-yl]-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide;
rac-2-methoxy-N-[3-(4-methoxy-phenyl)-1-methyl-piperidin-3-yl]-6-methylsulfanyl-4-trifluoromethyl-benzamide;
rac-N-(5-fluoro-1-methyl-3-phenyl-piperidin-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide;
rac-N-(1-isopropyl-3-phenyl-piperidin-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide;
2-cyclopropyl-N—((S)-1-methyl-3-phenyl-piperidin-3-yl)-4-trifluoromethyl-benzamide;
2-cyclopropyl-N—((R)-1-methyl-3-phenyl-piperidin-3-yl)-4-trifluoromethyl-benzamide;
rac-2-cyclobutyl-N-(1-methyl-3-phenyl-piperidin-3-yl)-4-trifluoromethyl-benzamide;
rac-N-[3-(2,4-difluoro-phenyl)-1-methyl-piperidin-3-yl]-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide;
rac-N-[3-(2-fluoro-phenyl)-1-methyl-piperidin-3-yl]-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide;
rac-N-[3-(2,5-difluoro-phenyl)-1-methyl-piperidin-3-yl]-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide; and
rac-2-isopropyl-N-(1-methyl-3-phenyl-piperidin-3-yl)-4-trifluoromethyl-benzamide.

### Claim 8 (depends on 5)

A compound of claim 5, selected from the group consisting of
2-methoxy-N-((3RS,5SR)-5-methoxy-1-methyl-3-phenyl-piperidin-3-yl)-6-methylsulfanyl-4-trifluoromethyl-benzamide;
2-cyclopropyl-N-((3RS,5SR)-5-methoxy-1-methyl-3-phenyl-piperidin-3-yl)-4-trifluoromethyl-benzamide;
2-ethyl-N-((3RS,5SR)-5-methoxy-1-methyl-3-phenyl-piperidin-3-yl)-4-trifluoromethyl-benzamide;
rac-2,6-dimethoxy-N-(1-methyl-3-phenyl-piperidin-3-yl)-4-trifluoromethyl-benzamide;
2-cyclopropyl-N-((3RS,5SR)-1,5-dimethyl-3-phenyl-piperidin-3-yl)-4-trifluoromethyl-benzamide;
rac-2-cyclopropyl-4-trifluoromethyl-N-(1,5,5-trimethyl-3-phenyl-piperidin-3-yl)-benzamide; and
rac-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-N-(1,6,6-trimethyl-3-phenyl-piperidin-3-yl)-benzamide.

### Claim 9 (depends on 5)

A compound of claim 5, selected from the group consisting of
N-((3RS,5SR)-1,5-dimethyl-3-phenyl-piperidin-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide;
2-methoxy-N-((3RS,5SR)-5-methoxymethoxy-1-methyl-3-phenyl-piperidin-3-yl)-6-methylsulfanyl-4-trifluoromethyl-benzamide;
rac-N-[3-(3-bromo-phenyl)-1-methyl-piperidin-3-yl]-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide;
rac-N-[3-(2-chloro-4-fluoro-phenyl)-1-methyl-piperidin-3-yl]-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide;
rac-2-methoxy-6-methylsulfanyl-N-[1-methyl-3-(3-trifluoromethyl-phenyl)-piperidin-3-yl]-4-trifluoromethyl-benzamide;
rac-2-methoxy-N-[3-(3-methoxy-phenyl)-1-methyl-piperidin-3-yl]-6-methylsulfanyl-4-trifluoromethyl-benzamide;
rac-N-[3-(3-fluoro-phenyl)-1-methyl-piperidin-3-yl]-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide;
rac-N-[3-(3-chloro-4-fluoro-phenyl)-1-methyl-piperidin-3-yl]-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide;
rac-N-[3-(3,4-difluoro-phenyl)-1-methyl-piperidin-3-yl]-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide; and
rac-2-methoxy-6-methylsulfanyl-N-(1-methyl-3-m-tolyl-piperidin-3-yl)-4-trifluoromethyl-benzamide.

### Claim 10 (depends on 5)

A compound of claim 5, selected from the group consisting of
rac-N-[3-(4-fluoro-3-methyl-phenyl)-1-methyl-piperidin-3-yl]-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide;
rac-N-[3-(3,5-difluoro-phenyl)-1-methyl-piperidin-3-yl]-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide;
rac-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-N-(1,5,5-trimethyl-3-phenyl-piperidin-3-yl)-benzamide;
rac-2-ethyl-3-methyl-N-(1-methyl-3-phenyl-piperidin-3-yl)-4-trifluoromethyl-benzamide;
rac-N-(1-tert-butyl-3-phenyl-piperidin-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide;
rac-2-methoxy-N-(4-methyl-6-phenyl-4-aza-spiro[2.5]oct-6-yl)-6-methylsulfanyl-4-trifluoromethyl-benzamide;
N-((3R,5S) or (3S,5R)-5-hydroxy-1-methyl-3-phenyl-piperidin-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide;
2-methoxy-N-((3R,5S) or (3S,5R)-5-methoxy-1-methyl-3-phenyl-piperidin-3-yl)-6-methylsulfanyl-4-trifluoromethyl-benzamide;
2-methoxy-N-((3S,5R) or (3R,5S)-5-methoxy-1-methyl-3-phenyl-piperidin-3-yl)-6-methylsulfanyl-4-trifluoromethyl-benzamide; and
N—[(R or S)-3-(2-fluoro-phenyl)-1-methyl-piperidin-3-yl]-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide.

### Claim 11 (depends on 5)

A compound of claim 5, selected from the group consisting of
N—[(R or S)-3-(2,5-difluoro-phenyl)-1-methyl-piperidin-3-yl]-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide;
2-ethyl-N—((R or S)-1-methyl-3-phenyl-piperidin-3-yl)-4-trifluoromethyl-benzamide;
2-methoxy-6-methylsulfanyl-4-trifluoromethyl-N-((S or R)-1,5,5-trimethyl-3-phenyl-piperidin-3-yl)-benzamide;
N-((3 S,6S) or (3R,6R)-1,6-dimethyl-3-phenyl-piperidin-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide;
N-((3R,6R) or (3S,6S)-1,6-dimethyl-3-phenyl-piperidin-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide;
N-((3R,6S) or (3S,6R)-1,6-dimethyl-3-phenyl-piperidin-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide;
N-((3S,5R) or (3R,5S)-1,5-dimethyl-3-phenyl-piperidin-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide;
N-((3R,5S) or (3S,5R)-1,5-dimethyl-3-phenyl-piperidin-3-yl)-2-ethyl-4-trifluoromethyl-benzamide;
2-ethyl-N-((3R,5S) or (3S,5R)-5-methoxy-1-methyl-3-phenyl-piperidin-3-yl)-4-trifluoromethyl-benzamide;
2-cyclopropyl-N-((3R,5S) or (3S,5R)-5-methoxy-1-methyl-3-phenyl-piperidin-3-yl)-4-trifluoromethyl-benzamide; and
2,6-Dimethoxy-N—(R or (S)-1-methyl-3-phenyl-piperidin-3-yl)-4-trifluoromethyl-benzamide.

### Claim 12 (depends on 1)

A compound of claim 1, wherein R1 is cycloalkyl or heterocycloalkyl.

### Claim 13 (depends on 12)

A compound of claim 12, selected from the group consisting of
rac-N-(1-cyclopentyl-3-phenyl-piperidin-3-yl)-2-methoxy-4,6-bis-trifluoromethyl-benzamide;
rac-N-(1-cyclopropylmethyl-3-phenyl-piperidin-3-yl)-2-methoxy-4,6-bis-trifluoromethyl-benzamide; and
rac-2-methoxy-N-[3-phenyl-1-(tetrahydro-pyran-4-yl)-piperidin-3-yl]-4,6-bis-trifluoromethyl-benzamide.

### Claim 14 (depends on 1)

A compound of claim 1, wherein R1 is hydrogen.

### Claim 15 (depends on 14)

A compound of claim 14, wherein the compound is
rac-2-cyclopropyl-N-(3-phenyl-piperidin-3-yl)-4-trifluoromethyl-benzamide.

### Claim 16 (depends on 1)

A compound of claim 1, wherein R2 is halogen.

### Claim 17 (depends on 16)

A compound of claim 16, wherein the compound is
rac-N-(5-fluoro-1-methyl-3-phenyl-piperidin-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide.

### Claim 18

A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I
wherein
R1 is hydrogen, lower alkyl, CD3, —(CH2)n—CHO, —(CH2)n—O-lower alkyl, —(CH2)n—OH, —(CH2)n-cycloalkyl or heterocycloalkyl;
R2 is hydrogen, halogen, hydroxy, lower alkyl, di-lower alkyl, —OCH2—O-lower alkyl, or lower alkoxy; or the piperidin ring together with R2 forms 4-aza-spiro[2.5]oct-6-yl;
Ar is phenyl optionally substituted by one, two or three substituents selected from halogen, lower alkyl, lower alkyl substituted by halogen, lower alkoxy substituted by halogen, cycloalkyl, lower alkoxy, S-lower alkyl, heteroaryl, heterocycloalkyl, and phenyl optionally substituted by R′,
R′ is lower alkyl, lower alkoxy, lower alkoxy substituted by halogen, or heteroaryl;
R is phenyl optionally substituted by one or two R′; and
n is 0, 1 2 or 3;
or a pharmaceutically acceptable acid addition salt, racemic mixture, enantiomer, or optical isomer thereof and a pharmaceutically acceptable carrier.