Amine derivatives as potassium channel blockers

Patent metadata

Field	Value
Publication number	US-9914702-B2
Application number	US-201615366513-A
Country	US
Kind code	B2
Filing date	Dec 1, 2016
Priority date	May 16, 2011
Publication date	Mar 13, 2018
Grant date	Mar 13, 2018

Abstract

The present invention relates to compounds useful in the modulation of potassium channel activity in cells, in particular the activity of Kv1.3 channels found in T cells. The invention also relates to the use of these compounds in the treatment or prevention of autoimmune and inflammatory diseases, including multiple sclerosis, pharmaceutical compositions containing these compounds and methods for their preparation.

First claim

The invention claimed is:

1. A compound of Formula (I):

wherein
X is —CH 2 —CH 2 —,
Y is selected from an alkylene group having 2 to 6 carbon atoms optionally substituted one or two times with C 3 -C 8 -cycloalkyl or C 1 -C 3 -alkyl,
Q is O,
W is a single bond,
U is a 5-6-membered cycloalkyl, a 5-12-membered heterocycle or a 5-6-membered heteroaryl group, each of the above groups being optionally substituted with 1 to 3 substituents selected from Hal, NO 2 , CN, SO 2 , NMe 2 , C 1 -C 6 -alkyl, O—C 1 -C 6 -alkyl, —(CH 2 ) m —O—C 1 -C 6 -alkyl, —C(O)O—C 1 -C 6 -alkyl, —SO 2 — C 1 -C 6 -alkyl, —S—C 1 -C 6 -alkyl, or —C 1 -C 6 -halo-alkyl,
V is a phenyl group optionally substituted with 1 to 3 substituents selected from Hal, —C 1 -C 6 -halo-alkyl, O—C 1 -C 6 -halo-alkyl or SO 2 — C 1 -C 6 -alkyl,
T, R 1 , R 2 and R 2′ are together represented by

R 3 is —CH 3 ;
R 4 denotes H,
m is selected from 1, 2, 3 or 4,
Hal is F, Cl, Br, or I,
wherein —C(O)—Y—W— together is at least 3 atoms in length,
or a pharmaceutically acceptable salt thereof, or an enantiomeric mixture of 2 enantiomers in all ratios, and/or as a mixture of diastereoisomers in all ratios.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof wherein U is selected from pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, imidazolyl, pyrazolyl, tetrahydropyranyl, cyclohexyl, 8-azabicyclo[3.2.1]octan-3-yl, triazolyl and piperidinyl, each of the above groups being optionally substituted with 1 to 3 substituents selected from Hal, NO 2 , CN, SO 2 , NMe 2 , C 1 -C 6 -alkyl, O—C 1 -C 6 -alkyl, —(CH 2 ) m —O—C 1 -C 6 -alkyl, —C(O)O—C 1 -C 6 -alkyl, —SO 2 —C 1 -C 6 -alkyl, —S—C 1 -C 6 -alkyl, or —C 1 -C 6 -halo-alkyl.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof wherein U is selected from pyridinyl, pyridazinyl and pyrazolyl, each of the above groups being optionally substituted with 1 to 3 substituents selected from CF 3 , —SO 2 —C 1 -C 6 -alkyl, C 1 -C 6 -alkyl or Hal.

4. A pharmaceutical composition comprising a compound according to claim 1 together with a pharmaceutically acceptable vehicle.

5. A process of making compounds of Formula (I) as defined in claim 1 comprising the steps of reacting a compound of Formula 5, wherein R 1 , R 2 , R 2 ′, R 3 , R 4 , X, Q, T and U are as defined in claim 1 , with a compound of Formula 8, wherein Y, W, and V are as defined in claim 1 and wherein LG is a suitable leaving group,

or reacting a compound of Formula 7, wherein R 1 , R 2 , R 2 ′, R 3 , R 4 , Y, W, T and V are as defined in claim 1 , with a compound of Formula 9, wherein X, Q and U are as defined in claim 1 and wherein LG denotes a suitable leaving group:

6. The compound according to claim 1 , wherein the compound is selected from:

or a pharmaceutically acceptable salt thereof, or an enantiomeric mixture of 2 enantiomers in all ratios, and/or as a mixture of diastereoisomers in all ratios.

7. A pharmaceutical composition comprising a compound according to claim 6 together with a pharmaceutically acceptable vehicle.

Assignees

• Bionomics Ltd
• Merck Patent Gmbh

Inventors

• Harvey Andrew
• Bombrun Agnes
• Cooke Rachel
• Jeanclaude-Etter Isabelle
• Kuchel Nathan
• Molette Jerome
• Mould Jorgen
• Paul Dharam
• Singh Rajinder
• Donini Cristina
• Colovray Veronique
• Avery Thomas
• Crossman Julia
• Ripper Justin

Classifications

• A61P37/02

  Immunomodulators · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title