Alcohol derivatives as KV7 potassium channel openers

Patent metadata

Field	Value
Publication number	US-11434199-B2
Application number	US-202016781106-A
Country	US
Kind code	B2
Filing date	Feb 4, 2020
Priority date	Feb 20, 2018
Publication date	Sep 6, 2022
Grant date	Sep 6, 2022

Abstract

The present invention provides novel compounds which activate the Kv7 potassium channels. Separate aspects of the invention are directed to pharmaceutical compositions comprising said compounds and uses of the compounds to treat disorders responsive to the activation of Kv7 potassium channels.

First claim

The invention claimed is:

1. A method of treating a patient in need thereof suffering from epilepsy, bipolar disorder, migraine or schizophrenia comprising administering to the patient a therapeutically effective amount of a compound of Formula (I):

wherein
R1 is selected from the group consisting of C 1 -C 6 alkyl, CF 3 , CH 2 CF 3 , CF 2 CHF 2 , and C 3 -C 8 cycloalkyl, wherein said C 3 -C 8 cycloalkyl may be substituted with 1 or 2 F, CHF 2 or CF 3 , and R2 is H, C 1 -C 6 alkyl or CF 3 ;
or
R1 and R2 combine to form C 3 -C 5 cycloalkyl optionally substituted with 1 or 2 F, CHF 2 or CF 3 ;
R3 is C 1 -C 3 alkyl or CH 2 O—C 1-3 alkyl, wherein said C 1 -C 3 alkyl or CH 2 O—C 1-3 alkyl may optionally substituted with 1 or 2 F; and
R4 is selected from the group consisting of CF 3 , OCF 3 , OCH 2 CF 3 and OCHF 2 .

2. The method of claim 1 , wherein R4 is is OCF 3 or OCHF 2 .

3. The method of claim 1 , wherein R2 is H or CH 3 .

4. The method of claim 1 , wherein R3 is CH 2 O—C 1-3 alkyl.

5. The method of claim 1 , wherein R1 is C 3 -C 4 cycloalkyl optionally substituted with 1 or 2 F, CHF 2 or CF 3 .

6. The method of claim 1 , wherein R1 is t-butyl and R2 is H and R4 is OCF 3 , OCH 2 CF 3 , OCHF 2 or CF 3 .

7. The method of claim 1 , wherein R1 and R2 combine to form cyclobutyl optionally substituted with 1 or 2 F and R4 is OCF 3 , OCH 2 CF 3 , OCHF 2 or CF 3 .

8. The method of claim 1 , wherein the compound is selected from the group consisting of:
(S)-3-hydroxy-4,4-dimethyl-N-[(1S)-1-[3-(trifluoromethoxy)phenyl]ethyl]pentanamide,
R)-3-hydroxy-4,4-dimethyl-N-[(1S)-1-[3-(trifluoromethoxy)phenyl]ethyl]pentanamide,
(S)-3-hydroxy-4,4-dimethyl-N—((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl) ethyl)pentanamide,
(R)-3-hydroxy-4,4-dimethyl-N—((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl) ethyl)pentanamide,
(S)—N—((S)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide,
(R)—N—((S)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide,
(S)-3-hydroxy-4,4-dimethyl-N—((S)-1-(3-(trifluoromethyl)phenyl)ethyl)pentanamide
(R)-3-hydroxy-4,4-dimethyl-N—((S)-1-(3-(trifluoromethyl)phenyl)ethyl)pentanamide,
(S)-3-hydroxy-4,4-dimethyl-N—((S)-1-(3-(trifluoromethoxy)phenyl)propyl)pentanamide,
(R)-3-hydroxy-4,4-dimethyl-N—((S)-1-(3-(trifluoromethoxy)phenyl)propyl)pentanamide,
(S)-3-(3,3-difluorocyclobutyl)-3-hydroxy-N—((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)propanamide,
(R)-3-(3,3-difluorocyclobutyl)-3-hydroxy-N—((S)-1-(3-(trifluoro methoxy)phenyl)ethyl)propanamide,
(S)-3-hydroxy-4-methyl-N—((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)pentanamide,
(R)-3-hydroxy-4-methyl-N—((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)pentanamide,
(S)-3-(1-(difluoromethyl)cyclopropyl)-3-hydroxy-N—((S)-1-(3-(trifluoro-methoxy)phenyl)ethyl)propanamide,
(R)-3-(1-(difluoromethyl)cyclopropyl)-3-hydroxy-N—((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)propanamide,
(R)-3-hydroxy-N—((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-(1-(trifluoromethyl)cyclopropyl)propanamide,
(S)-3-hydroxy-N—((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-(1-(trifluoromethyl)cyclopropyl)propanamide,
(S)-3-hydroxy-4-methyl-N—((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanamide,
(R)-3-hydroxy-4-methyl-N—((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)pentan amide,
N—((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-(R)-hydroxy-4,4-dimethylpentanamide,
N—((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy) phenyl)ethyl)-3-(S)-hydroxy-4,4-dimethylpentanamide,
(S)-3-hydroxy-N—((R)-2-methoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)-4,4-dimethylpentanamide, (R)-3-hydroxy-N—((R)-2-methoxy-1-(3-(trifluoromethoxy) phenyl)ethyl)-4,4-dimethylpentanamide,
(S)-2-(3,3-difluoro-1-hydroxycyclobutyl)-N-(1-(3-(trifluoromethoxy)phenyl)ethyl)acetamide,
(S)-2-(1-hydroxycyclobutyl)-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)acetamide,
(3R)-3-hydroxy-4-methyl-N-[(1S)-1-[3-(2,2,2-trifluoroethoxy)phenyl]ethyl]-3-(trifluoromethyl)pentanamide,
(3S)-3-hydroxy-4-methyl-N-[(1S)-1-[3-(2,2,2-trifluoroethoxy)phenyl]ethyl]-3-(trifluoromethyl)pentanamide,
4,4,4-Trifluoro-3-hydroxy-N-[(1S)-1-[3-(trifluoromethoxy)phenyl]ethyl]-3-(trifluoromethyl)butanamide,
(R)-4,4,5,5-tetrafluoro-3-hydroxy-3-methyl-N—((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanamide,
(S)-4,4,5,5-tetrafluoro-3-hydroxy-3-methyl-N—((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanamide,
(R)-5,5,5-trifluoro-3-hydroxy-3-methyl-N—((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanamide,
(S)-5,5,5-trifluoro-3-hydroxy-3-methyl-N—((S)-1-(3-(trifluoro methoxy)phenyl)ethyl)pentanamide,
(R)-3-(1-fluorocyclopropyl)-3-hydroxy-N—((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)butanamide,
(S)-3-(1-fluorocyclopropyl)-3-hydroxy-N—((S)-1-(3-(trifluoro-methoxy)phenyl)ethyl)butanamide,
(R)-2-(1-hydroxycyclopentyl)-N-(2-methoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)acetamide,
(R)-3-cyclopropyl-3-hydroxy-N—((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)butanamide,
(S)-3-cyclopropyl-3-hydroxy-N—((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)butanamide,
(R)-4,4,4-trifluoro-3-hydroxy-3-methyl-N—((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)butanamide, and
(S)-4,4,4-trifluoro-3-hydroxy-3-methyl-N—((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)butanamide.

9. The method of claim 1 , wherein the patient is suffering from epilepsy.

10. The method of claim 1 , wherein the patient is suffering from bipolar disorder.

11. The method of claim 1 , wherein the patient is suffering from migraine.

12. The method of claim 1 , wherein the patient is suffering from schizophrenia.

Assignees

• H Lundbeck As

Inventors

• Rottlander Mario
• Sams Anette Graven
• Wang Xiaofang
• Das Debasis
• Hong Jian
• Chen Shu Hui

Classifications

• A61P25/18

  Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia · CPC title

• A61P25/22

  Anxiolytics · CPC title

• C07C235/26

  the carbon skeleton being saturated and containing rings · CPC title

• C07C235/08

  having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms · CPC title

• A61P25/08

  Antiepileptics; Anticonvulsants · CPC title