Diamino-alkylamino-linked arylsulfonamide compounds with selective activity in voltage-gated sodium channels

Patent metadata

Field	Value
Publication number	US-10519147-B2
Application number	US-201616061815-A
Country	US
Kind code	B2
Filing date	Dec 15, 2016
Priority date	Dec 18, 2015
Publication date	Dec 31, 2019
Grant date	Dec 31, 2019

Abstract

Disclosed are compounds of Formula A, or a salt thereof, where Q, X, R1 and R2 are as defined herein, which compounds have properties for inhibiting Na v 1.7 ion channels found in peripheral and sympathetic neurons. Also described are pharmaceutical formulations comprising the compounds of Formula A or their salts, and methods of treating pain (acute, post-operative, neuropathic), or cough or itch disorders using the same.

First claim

What is claimed is:

1. A compound of Formula A:

or a pharmaceutically acceptable salt thereof,
wherein:
R 1 is —Cl, —Br, or —F;
R 2 is —H or —CH 3 ;
X is:
—N═; or
—C(R 3 )═, wherein R 3 is: (i) —H; (ii) —Cl; or (iii) —F; and

Q is:
(a) a moiety of the formula:

wherein one of R 5a is NH 2 and the others are —H; or
(b) a moiety of the formula:

(c) a moiety of the formula:

wherein
D 1 is a linear- or branched-alkyl, or a geminal-cycloalkyl moiety of up to 6 carbon atoms; and
R 6 is optionally present as a single substituent and is linear or branched alkyl of up to 4 carbon atoms, which is optionally substituted on one or more carbon atoms thereof with one or more —F; or

(d) R 4 —NH-D 2 -, wherein R 4 is —H, lower alkyl, or lower cycloalkyl and D 2 is a linear alkyl of at least two up to 6 carbon atoms, a branched-alkyl of up to 6 carbon atoms, or a geminal-cycloalkyl moiety of up to 8 carbon atoms.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is —CH═.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is —C(Cl)═.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is —C(F)═.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is —N═.

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Q is R 4 —NH-D 2 -, wherein R 4 is —H, lower alkyl, or lower cycloalkyl and D 2 is linear- or branched-alkyl, or a geminalcycloalkyl moiety of up to 6 carbon atoms.

7. The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein D 2 is a geminalcycloalky of the formula:

wherein m and n are 0 or 1 and m+n is at least 1.

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Q is a moiety of the formula:

wherein one of R 5a is NH 2 and the others are —H.

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Q is a moiety of the formula:

10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Q is a moiety of the formula:

wherein
D 1 is a linear- or branched-alkyl, or a geminal-cycloalkyl moiety of up to 6 carbon atoms; and
R 6 is optionally present as a single substituent and is linear or branched alkyl of up to 4 carbon atoms, which is optionally substituted on one or more carbon atoms thereof with —CF 3 .

11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Q is:

12. A compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

13. A compound which is:
5-chloro-2-fluoro-4-[(4-{[(2S)-piperidin-2-ylmethyl]amino}butyl)amino]-N-1,3-thiazol-2-ylbenzenesulfonamide;
5-chloro-2-fluoro-4-[(4-{[(2R)-piperidin-2-ylmethyl]amino}butyl)amino]-N-1,3-thiazol-2-ylbenzenesulfonamide;
5-chloro-2-fluoro-4-[(4-{[(2S)-pyrrolidin-2-ylmethyl]amino}butyl)amino]-N-1,3-thiazol-2-ylbenzenesulfonamide;
4-[(4-{[(1S,2S)-2-aminocyclohexyl]amino}butyl)amino]-5-chloro-2-fluoro-N-1,3-thiazol-2-ylbenzenesulfonamide;
4-({4-[(2-amino-1,1-dimethylethyl)amino]butyl}amino)-5-chloro-2-fluoro-N-1,3-thiazol-2-ylbenzenesulfonamide;
4-({4-[(2-aminoethyl)(methyl)amino]butyl}amino)-5-chloro-2-fluoro-N-1,3-thiazol-2-ylbenzenesulfonamide;
5-chloro-2-fluoro-4-{[4-({(1S)-1-[(2S)-pyrrolidin-2-yl]ethyl}amino)butyl]amino}-N-1,3-thiazol-2-ylbenzenesulfonamide;
4-[(4-{[(1R,2R)-2-aminocyclohexyl]amino}butyl)amino]-5-chloro-2-fluoro-N-1,3-thiazol-2-ylbenzenesulfonamide;
4-[(4-{[(1S,2R)-2-aminocyclopentyl]amino}butyl)amino]-5-chloro-2-fluoro-N-1,3-thiazol-2-ylbenzenesulfonamide;
4-[(4-{[(1R,2S)-2-aminocyclohexyl]amino}butyl)amino]-5-chloro-2-fluoro-N-1,3-thiazol-2-ylbenzenesulfonamide;
4-({4-[(2-aminoethyl)amino]butyl}amino)-5-chloro-2-fluoro-N-1,3-thiazol-2-ylbenzenesulfonamide;
5-chloro-2-fluoro-4-({4-[(3R)-pyrrolidin-3-ylamino]butyl}amino)-N-1,3-thiazol-2-ylbenzenesulfonamide;
5-chloro-2-fluoro-4-({4-[(3S)-pyrrolidin-3-ylamino]butyl}-amino)-N-1,3-thiazol-2-ylbenzenesulfonamide;
N 1 -(2-chloro-5-fluoro-4-((thiazol-2-ylmethyl)sulfonyl)phenyl)-N 4 —((S)-pyrrolidin-2-ylmethyl)pentane-1,4-diamine;
(R) N 1 -(2-chloro-5-fluoro-4-((thiazol-2-ylmethyl)sulfonyl)phenyl)-N 4 —((S)-pyrrolidin-2-ylmethyl)pentane-1,4-diamine;
(S) N-(2-chloro-5-fluoro-4-((thiazol-2-ylmethyl)sulfonyl)phenyl)-N 4 —((S)-pyrrolidin-2-ylmethyl)pentane-1,4-diamine;
4-((4-((azetidin-3-ylmethyl)amino)butyl)amino)-5-chloro-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide;
5-chloro-2-fluoro-4-[(4-{[2-(methylamino)ethyl]amino}butyl)amino]-N-1,3-thiazol-2-ylbenzenesulfonamide;
(R)-5-chloro-2-fluoro-4-((4-((pyrrolidin-2-ylmethyl)amino)butyl)amino)-N-(thiazol-2-yl)benzenesulfonamide;
2,5-difluoro-4-[(4-{[(2S)-pyrrolidin-2-ylmethyl]amino}butyl)amino]-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide;
5-chloro-2-fluoro-4-[(4-{[(2S)-pyrrolidin-2-ylmethyl]amino}butyl)amino]-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide;
5-chloro-N-(5-chloro-1,3-thiazol-2-yl)-2-fluoro-4-[(4-{[(2S)-pyrrolidin-2-ylmethyl]amino}butyl)amino]benzenesulfonamide;
5-bromo-2-fluoro-4-[(4-{[(2S)-pyrrolidin-2-ylmethyl]amino}butyl)amino]-N-1,3-thiazol-2-ylbenzenesulfonamide;
5-chloro-2-fluoro-N-(5-fluoro-1,3-thiazol-2-yl)-4-[(4-{[(2S)-pyrrolidin-2-ylmethyl]amino}butyl)amino]benzenesulfonamide;
5-chloro-2-fluoro-4-{[4-({[(2S,4S)-4-methylpyrrolidin-2-yl]methyl}amino)butyl]amino 1-N-1,3-thiazol-2-ylbenzenesulfonamide;
5-chloro-2-fluoro-4-{[4-(1[(2S,5S)-5-methylpyrrolidin-2-yl]methyl}amino)butyl]amino 1-N-1,3-thiazol-2-ylbenzenesulfonamide;
5-chloro-2-fluoro-N-1,3-thiazol-2-yl-4-{[4-(1[(2S,4S)-4-(trifluoromethyl)pyrrolidin-2-yl]methyl 1 amino)butyl]amino}benzenesulfonamide;
4-[(4-{[(1R,2R)-2-aminocyclo-pentyl]amino}butyl)amino]-5-chloro-2-fluoro-N-1,2,4-thiadiazol-5-yl-benzenesulfonamide;
4-[(4-{[(2R)-azetidin-2-ylmethyl]-amino}butyl)amino]-5-chloro-2-fluoro-N-1,2,4-thiadiazol-5-yl-benzene-sulfonamide;
4-[(4-{[(2S)-azetidin-2-ylmethyl]-amino}butyl)amino]-5-chloro-2-fluoro-N-1,2,4-thiadiazol-5-ylbenzene-sulfonamide;
4-[(4-{[(2S)-2-aminopropyl]amino}butyl)amino]-5-chloro-2-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide;
4-{[4-(azetidin-3-ylamino)butyl]-amino}-5-chloro-2-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide;
5-bromo-2-fluoro-N-(5-fluoro-1,3-thiazol-2-yl)-4-[(4-{[(2R)-piperidin-2-ylmethyl]amino}butyl)amino]benzene-sulfonamide;
4-[(4-{[(1R,2R)-2-aminocyclopentyl]-amino}butyl)a

Assignees

• Merck Sharp & Dohme
• Greshock Thomas J
• Mulhearn James
• Guo Liangqin
• Zhang Ting
• Wang Deping
• Kim Ronald M
• Layton Mark E
• Kelly Iii Michael J
• Anand Rajan
• Nantermet Philippe
• Jian Tianying
• Roecker Anthony J
• Won Walter
• Zhou Gang

Inventors

• Greshock Thomas J
• Mulhearn James
• Guo Liangqin
• Zhang Ting
• Wang Deping
• Kim Ronald M
• Layton Mark E
• Kelly Iii Michael J
• Anand Rajan
• Nantermet Philippe
• Jian Tianying
• Roecker Anthony J
• Won Walter
• Zhou Gang

Classifications

• C07D277/52

  to sulfur atoms, e.g. sulfonamides · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61P17/04

  Antipruritics · CPC title

• C07D285/135

  Nitrogen atoms · CPC title

• A61P25/02

  for peripheral neuropathies · CPC title