Alcohol derivatives as KV7 potassium channel openers

Patent metadata

Field	Value
Publication number	US-11548849-B2
Application number	US-202016943872-A
Country	US
Kind code	B2
Filing date	Jul 30, 2020
Priority date	Aug 2, 2019
Publication date	Jan 10, 2023
Grant date	Jan 10, 2023

Abstract

The present invention provides novel compounds (e.g., compounds of Formula I) 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 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 substituents selected from the group consisting of C 1 -C 3 alkyl, F, CHF 2 and 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 ; and
R3 is C 1 -C 3 alkyl, CH 2 O—C 1-3 alkyl, or CH 2 O-cyclopropyl, wherein said C 1 -C 3 alkyl or CH 2 O—C 1 -C 3 alkyl is substituted with C≡N or C 3 -C 5 cycloalkyl; and
R4 is selected from the group consisting of OCF 3 , or OCHF 2;
or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R4 is OCF 3 .

3. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R3 is selected from the group consisting of CH 2 —O— cyclopropyl and CH 2 —C≡N.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R1 is C 3 -C 4 cycloalkyl optionally substituted with 1 or 2 C 1 -C 3 alkyl, F, CHF 2 or CF 3 .

5. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R1 and R2 combine to form cyclobutyl optionally substituted with 1 or 2 F and R4 is OCF 3 or OCHF 2 .

6. The compound of claim 1 , wherein the compound is selected from the group consisting of:
(S)—N—((R)-2-cyclopropoxy-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide;
(S)—N—((S)-2-cyano-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide;
(S)—N—((S)-3-cyano-1-(3-(trifluoromethoxy)phenyl)propyl)-3-hydroxy-4,4-dimethylpentanamide;
(R)—N-(2-cyclopropoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)-2-(3,3-difluoro-1-hydroxycyclobutyl)acetamide;
(R)—N-(2-cyclopropoxy-1-(3-(difluoromethoxy)phenyl)ethyl)-2-(3,3-difluoro-1-hydroxycyclobutyl)acetamide;
and
(S)—N-(2-cyano-1-(3-(trifluoromethoxy)phenyl)ethyl)-2-(3,3-difluoro-1-hydroxycyclobutyl)acetamide,
or a pharmaceutically acceptable salt thereof.

7. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

8. A method for the manufacture of a pharmaceutical composition comprising combining a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable excipient.

9. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R4 is OCHF 2 .

Assignees

• H Lundbeck As

Inventors

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

Classifications

• C07C2601/08

  the ring being saturated · CPC title

• C07C2601/04

  with a four-membered ring · CPC title

• C07C2601/02

  with a three-membered ring · CPC title

• C07C235/26

  the carbon skeleton being saturated and containing rings · CPC title

• C07C255/44

  at least one of the singly-bound nitrogen atoms being acylated · CPC title