IP Library › Granted Patent US 10,221,167

Granted Patent B2

US 10,221,167 · App. 15/378,465 · Granted Mar 5, 2019

Hydroxyalkylamine- and hydroxycycloalkylamine-substituted diamine-arylsulfonamide compounds with selective activity in voltage-gated sodium channels

Inventors: Thomas J. Greshock (Collegeville, PA); James Mulhearn (Elkins Park, PA); Junying Zheng (New Providence, NJ); Ronald M. Kim (Summit, NJ); Ting Zhang (Princeton Junction, NJ); Anthony J. Roecker (Harleysville, PA); Walter Won (Alpine, NJ); Philippe Nantermet (Lansdale, PA); Rajan Anand (Fanwood, NJ); Gang Zhou (Bridgewater, NJ); Deping Wang (Furlong, PA); Liangqin Guo (Edison, NJ)

Assignee: Merck Sharp & Dohme Corp.

C07D417/12 A61K31/426 A61K31/427 A61K31/433 A61K31/551 A61K45/06 C07D277/52 C07D285/08

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Quick Facts

Patent No.: US 10,221,167
App. No.: 15/378,465
Granted: Mar 5, 2019
Kind: B2

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Abstract

Disclosed are compounds of Formula A, or a salt thereof: wherein R 1 , R 2 , and E are 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 disorders, cough, and itch using the same.

Claims (173)

1. A compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula A:

wherein:

R 1 is: —Cl, —Br, or linear, branched or cyclic alkyl of up to 3 carbon atoms;

R 2 is:

(a) a moiety of the formula:

wherein, one of R 3a and R 3b is H and the other is —H, —F, CH 3 ; or

(b) a moiety of the formula:

and

E is:

(I) a moiety of Formula E 1 :

wherein:

R 6 is —H or a linear, branched or cyclic alkyl of up to 6 carbon atoms; and

B is:

(a) a moiety of the formula:

which moiety is bonded to nitrogen at one of R 7A ,

R 7B , or R 7C via —CH 2 —, or is bonded to nitrogen directly at one of R 7C , and

wherein:

m is 0, 1 or 2;

R 7A and R 7B are independently for each occurrence —H, or a linear, branched or cyclic alkyl of up to 3 carbon atoms when not selected to be bonded to the nitrogen via methylene;

R 7C when not selected to be bonded to the nitrogen directly or via methylene is independently for each occurrence: (i) —H; (ii) linear, branched, or cyclic alkyl of up to three carbon atoms; and

R 7D is: (ai) —H; or (aii) a linear, branched or cyclic alkyl of up to 5 carbon atoms; or

(b) a moiety of the formula:

wherein:

R 7h is —H or a linear, branched or cyclic alkyl of up to 3 carbon atoms; and

R 7g and R 7f are selected as follows:

(i) R 7g is a linear alkyl of 2 to 4 carbon atoms, a branched alkyl of 3 to 6 carbon atoms or cyclic alkyl of up to 6 carbon atoms and R 7f is a linear alkyl of 2 to 4 carbon atoms, or a branched or cyclic alkyl of up to 6 carbon atoms which is substituted with —OH on one carbon atom thereof that is bonded beta to, or further from, the nitrogen to which it is attached; or

(ii) R 7f is —H or a linear, branched or cyclic alkyl of up 6 carbon atoms and R 7g is —(CH 2 ) 1-2 —(HC(OH))—(CH 2 ) 1-2 ;

(II) a moiety of Formula E 2 :

wherein each R 8 is independently —H or linear, branched, or cyclic alkyl of up to 6 carbon atoms; or

(III) a moiety of Formula E 3 :

wherein:

R 9A is independently for each occurrence: (i) —H; (ii) —OH; or (iii) a linear, branched or cyclic alkyl of up to 6 carbon atoms which is optionally substituted on one carbon atom there of with an —OH;

R 10A is independently for each occurrence: (i) —H; or (ii) linear, branched or cyclic alkyl of up to 6 carbon atoms which is optionally substituted on one carbon atom thereof with an —OH;

R 11A is —H or an alkyl of 2 or 3 carbons which is optionally substituted on a beta or gamma carbon with an —OH,

with the proviso that only one —OH substituent is present among all of R 9A , R 10A , and R 11A .

2. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein E has the structure of Formula E 1 :

wherein:

R 6 is —H or a linear, branched or cyclic alkyl of up to 6 carbon atoms; and

B is:

wherein:

(a) R 7Cg is —CH 2 —CH(OH)—CH 2 — and R 7Cf is —H or a linear alkyl of 2 to 4 carbon atoms or a branched or cyclic alkyl of up to 6 carbon atoms; or

(b) R 7Cg is linear alkyl of 2 to 4 carbon atoms, branched alkyl of 3 to 6 carbon atoms or cyclic alkyl of up to 6 carbon atoms and R 7Cf is linear, branched, or cyclic alkyl of up to 6 carbon atoms that is substituted on one carbon thereof which is beta or further from the nitrogen with —OH.

3. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, having the structure of Formula AI:

wherein:

X is —N═ or —C(R C14c )═, wherein R C14c is —H, —F, or —CH 3 ;

R 14 is —Cl or —Br; and

R 15 is a moiety of Formula AIb bonded to nitrogen via methylene through one of R 15b , R 15c , or R 15d , or bonded directly to nitrogen through R 15c if present:

wherein:

m is 0 or 1;

R 15c , when present and not selected to be bonded to nitrogen is, independently: (i) —H; or (ii) linear, branched or cyclic alkyl of up to 3 carbon atoms; and

R 15b and R 15d , when not selected to be bonded to nitrogen are, independently: (i) —H; or (ii) linear, branched or cyclic alkyl of up to 3 carbon atoms.

4. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, having the structure of Formula AI:

wherein:

X is —N═ or —C(R C14c )═, wherein R C14c is —H, —F, or —CH 3 ;

R 14 is —Cl or —Br; and

R 15 is a moiety of the formula:

H 2 N—CH 2 —CH(OH)—CH 2 —.

5. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, having the structure:

wherein:

X is —N═ or —C(R C14e )═, wherein R C14e is —H, —F, or —CH 3 ;

R a14F is —Cl, —Br or —CH 3 ; and

R 8F is independently —H or linear, branched, or cyclic alkyl of up to 6 carbon atoms.

6. A composition comprising at least one compound of claim 1 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

7. A pharmaceutical composition of claim 6 comprising additionally an effective amount of at least one other pharmaceutically active ingredient which is: (i) an opioid agonist or antagonist; (ii) a calcium channel antagonist; (iii) an NMDA receptor agonist or antagonist; (iv) a COX-2 selective inhibitor; (v) an NSAID (non-steroidal anti-inflammatory drug); or (vi) paracetamol (APAP, acetaminophen), and a pharmaceutically acceptable carrier.

8. The composition of claim 6 that provides an amount of said compound of claim 1 , or a pharmaceutically acceptable salt thereof, which is sufficient to provide a therapeutic response in a subject in need of therapy for a pain disorder, cough, or acute itch or chronic itch disorder.

9. A method of treating a pain disorder, or cough, or acute itch or chronic itch disorder comprising administering to a patient in need thereof a therapeutically effective amount of the composition of claim 6 .

10. The method of claim 9 wherein said disorder is an acute pain, inflammatory pain or neuropathic pain disorder.

11. A compound, or a pharmaceutically acceptable salt thereof, which is:

4-[(4-{[(2S)-3-amino-2-hydroxypropyl]amino}butyl)amino]-5-chloro-2-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide;

4-[(4-{[3-amino-2-hydroxypropyl]amino}butyl)amino]-5-chloro-2-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide;

4-({4-[3-(aminomethyl)-3-hydroxyazetidin-1-yl]butyl}amino)-5-chloro-2-fluoro-N-(5-fluoro-1,3-thiazol-2-yl)benzenesulfonamide;

4-({4-[3-(aminomethyl)-3-hydroxyazetidin-1-yl]butyl}amino)-5-chloro-2-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide;

2-fluoro-N-(5-fluoro-1,3-thiazol-2-yl)-4-[(4-{[(3-hydroxyazetidin-3-yl)methyl]amino}butyl)amino]-5-methylbenzenesulfonamide;

5-bromo-2-fluoro-4-[(4-{[(3-hydroxyazetidin-3-yl)methyl]amino}butyl)amino]-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide;

4-[(4-{[(2R)-3-amino-2-hydroxypropyl]-amino}butyl)amino]-5-chloro-2-fluoro-N-1,2,4-thiadiazol-5-yl-benzenesulfonamide;

4-[(4-{[(2S)-3-amino-2-hydroxypropyl]-amino}butyl)amino]-5-bromo-2-fluoro-N-1,2,4-thiadiazol-5-yl-benzenesulfonamide;

4-[(4-{[(2R)-3-amino-2-hydroxypropyl]-amino}-butyl)amino]-5-bromo-2-fluoro-N-1,2,4-thiadiazol-5-yl-benzenesulfonamide;

4-[(4-{[3-amino-2-hydroxypropyl]-amino}-butyl)amino]-5-bromo-2-fluoro-N-1,2,4-thiadiazol-5-yl-benzenesulfonamide;

5-chloro-2-fluoro-4-[(4-{[(3-hydroxyazetidin-3-yl)methyl]amino}butyl)amino]-N-(4-methyl-1,3-thiazol-2-yl)-benzenesulfonamide;

5-chloro-2-fluoro-4-[(4-{[(3-hydroxyazetidin-3-yl)methyl]amino}butyl)amino]-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide;

5-chloro-2-fluoro-4-[(4-{[(3R,4R)-4-hydroxypyrrolidin-3-yl]amino}butyl)amino]-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide;

5-chloro-2-fluoro-4-{[4-({3-[(2-hydroxyethyl)amino]propyl}amino)butyl]amino}-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide;

5-chloro-2-fluoro-4-{[4-({2-[(2-hydroxyethyl)amino]ethyl}amino)butyl]amino}-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide;

4-({4-[(3-amino-2-hydroxypropyl)amino]butyl}amino)-5-chloro-2-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide;

5-chloro-2-fluoro-N-(5-fluoro-1,3-thiazol-2-yl)-4-[(4-{[(3-hydroxyazetidin-3-yl)-methyl]amino}butyl)amino]benzenesulfonamide;

5-chloro-2-fluoro-4-[(4-{[(3S,4 S)-4-hydroxypyrrolidin-3-yl]amino}butyl)amino]-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide;

5-chloro-2-fluoro-N-(5-fluoro-1,3-thiazol-2-yl)-4-{[4-({2-[(2-hydroxy-1,1-dimethylethyl)-amino]-1,1-dimethylethyl}amino)butyl]amino)}benzenesulfonamide;

5-chloro-2-fluoro-N-(5-fluoro-1,3-thiazol-2-yl)-4-{[4-({2-[(2-hydroxyethyl)amino]-ethyl}amino)butyl]amino}benzenesulfonamide;

4-({4-[(3-amino-2-hydroxypropyl)amino]butyl}amino)-5-chloro-2-fluoro-N-(5-fluoro-1,3-thiazol-2-yl)benzenesulfonamide;

5-chloro-2-fluoro-4-({4-[7-(hydroxymethyl)-1,4-diazepan-1-yl]butyl}amino)-N-1,3-thiazol-2-ylbenzenesulfonamide;

5-chloro-2-fluoro-4-({4-[2-(2-hydroxyethyl)-1,4-diazepan-1-yl]butyl}amino)-N-1,3-thiazol-2-ylbenzenesulfonamide;

5-chloro-2-fluoro-4-({4-[2-(hydroxymethyl)-1,4-diazepan-1-yl]butyl}amino)-N-1,3-thiazol-2-ylbenzenesulfonamide;

5-chloro-2-fluoro-4-{[4-(6-hydroxy-6-methyl-1,4-diazepan-1-yl)butyl]amino}-N-1,3-thiazol-2-ylbenzenesulfonamide;

5-chloro-2-fluoro-4-({4-[4-(2-hydroxyethyl)-1,4-diazepan-1-yl]butyl}amino)-N-1,3-thiazol-2-ylbenzenesulfonamide;

5-chloro-2-fluoro-N-(5-fluoro-1,3-thiazol-2-yl)-4-[(4-{[(3S,4S)-4-hydroxypyrrolidin-3-yl]amino}butyl)amino]benzenesulfonamide;

4-[(4-{[(2R)-3-amino-2-hydroxypropyl]amino}butyl)amino]-5-chloro-2-fluoro-N-(5-fluoro-1,3-thiazol-2-yl)benzenesulfonamide;

4-[(4-{[(2S)-3-amino-2-hydroxypropyl]amino}butyl)amino]-5-chloro-2-fluoro-N-(5-fluoro-1,3-thiazol-2-yl)benzenesulfonamide;

4-[(4-{[3-amino-2-hydroxypropyl]amino}butyl)amino]-5-chloro-2-fluoro-N-(5-fluoro-1,3-thiazol-2-yl)benzenesulfonamide;

5-chloro-2-fluoro-4-[(4-{[(3R,4 S)-4-hydroxypyrrolidin-3-yl]amino}butyl)amino]-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide;

5-chloro-2-fluoro-N-(5-fluoro-1,3-thiazol-2-yl)-4-[(4-{[(3R,4R)-4-hydroxypyrrolidin-3-yl]amino}butyl)amino]benzenesulfonamide;

5-chloro-2-fluoro-N-(5-fluoro-1,3-thiazol-2-yl)-4-{[4-({[(2 S,4 S)-4-hydroxypyrrolidin-2-yl]methyl}amino)butyl]amino}benzenesulfonamide;

5-chloro-2-fluoro-N-(5-fluoro-1,3-thiazol-2-yl)-4-{[4-({[(2 S,4R)-4-hydroxypyrrolidin-2-yl]methyl}amino)butyl]amino}benzenesulfonamide;

5-chloro-2-fluoro-N-(5-fluoro-1,3-thiazol-2-yl)-4-{[4-({[(2R,4R)-4-hydroxypyrrolidin-2-yl]methyl}amino)butyl]amino}benzenesulfonamide;

5-chloro-2-fluoro-N-(5-fluoro-1,3-thiazol-2-yl)-4-{[4-({[(2R,4 S)-4-hydroxypyrrolidin-2-yl]methyl}amino)butyl]amino}benzenesulfonamide;

5-bromo-2-fluoro-N-(5-fluoro-1,3-thiazol-2-yl)-4-[(4-{[(3-hydroxyazetidin-3-yl)methyl]amino}butyl)amino]benzenesulfonamide;

5-chloro-2-fluoro-4-[(4-{[(3R,4R)-4-hydroxypyrrolidin-3-yl]amino}butyl)amino]-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide;

4-({4-[(3-amino-2-hydroxypropyl)amino]butyl}amino)-5-chloro-2-fluoro-N-1,3-thiazol-2-ylbenzenesulfonamide;

5-chloro-2-fluoro-4-[(4-{[(3-hydroxyazetidin-3-yl)methyl]amino}butyl)amino]-N-1,3-thiazol-2-ylbenzenesulfonamide;

4-[(4-{[(2R)-3-amino-2-hydroxypropyl]amino}butyl)amino]-5-chloro-2-fluoro-N-1,3-thiazol-2-ylbenzenesulfonamide;

4-[(4-{[(2S)-3-amino-2-hydroxypropyl]amino}butyl)amino]-5-chloro-2-fluoro-N-1,3-thiazol-2-ylbenzenesulfonamide;

4-[(4-{[3-amino-2-hydroxypropyl]amino}butyl)amino]-5-chloro-2-fluoro-N-1,3-thiazol-2-ylbenzenesulfonamide;

5-chloro-2-fluoro-4-[(4-{[(3R,4R)-4-hydroxypyrrolidin-3-yl]amino}butyl)amino]-N-1,3-thiazol-2-ylbenzenesulfonamide;

4-[(4-{[(1S)-3-amino-1-(hydroxymethyl)propyl]amino}butyl)amino]-5-chloro-2-fluoro-N-1,3-thiazol-2-ylbenzenesulfonamide;

4-[(4-{[(1S)-3-amino-1-(hydroxymethyl)propyl]amino}butyl)amino]-5-chloro-2-fluoro-N-(5-fluoro-1,3-thiazol-2-yl)benzenesulfonamide;

4-[(4-{[(1S)-3-amino-1-(hydroxymethyl)propyl]amino}butyl)amino]-5-chloro-2-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide;

4-[(4-{[(1S)-2-amino-1-(hydroxymethyl)ethyl]amino}butyl)amino]-5-chloro-2-fluoro-N-1,3-thiazol-2-ylbenzenesulfonamide;

4-[(4-{[(1S)-2-amino-1-(hydroxymethyl)ethyl]amino}butyl)amino]-5-chloro-2-fluoro-N-(5-fluoro-1,3-thiazol-2-yl)benzenesulfonamide;

4-[(4-{[(1S)-2-amino-1-(hydroxymethyl)ethyl]amino}butyl)amino]-5-chloro-2-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide;

5-chloro-2-fluoro-4-[(4-{[(3S,4S)-4-hydroxypyrrolidin-3-yl]amino}butyl)amino]-N-1,3-thiazol-2-ylbenzenesulfonamide;

4-[(4-{[(1R)-2-amino-1-(hydroxymethyl)ethyl]amino}butyl)amino]-5-chloro-2-fluoro-N-1,3-thiazol-2-ylbenzenesulfonamide;

4-[(4-{[(1R)-2-amino-1-(hydroxymethyl)ethyl]amino}butyl)amino]-5-chloro-2-fluoro-N-(5-fluoro-1,3-thiazol-2-yl)benzenesulfonamide;

5-bromo-2-fluoro-4-((4-(6-hydroxy-1,4-diazepan-1-yl)butyl)amino)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;

5-bromo-2-fluoro-4-((4-(((3S,4S)-4-hydroxypyrrolidin-3-yl)amino)butyl)amino)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;

5-bromo-2-fluoro-4-((4-(((3R,4R)-4-hydroxypyrrolidin-3-yl)amino)butyl)amino)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;

4-((4-(3-(aminomethyl)-3-hydroxyazetidin-1-yl)butyl)amino)-5-bromo-2-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;

4-[(4-{[(1R)-2-amino-1-(hydroxymethyl)ethyl]amino}butyl)amino]-5-chloro-2-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide; or

5-chloro-2-fluoro-4-[(4-{[(4-hydroxy-4-methylpyrrolidin-2-yl)methyl]amino}butyl)-amino]-N-1,3-thiazol-2-ylbenzenesulfonamide.

12. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt of any thereof.

13. A composition comprising at least one compound of claim 12 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

14. A compound of the Formula: