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

Patent metadata

Field	Value
Publication number	US-10968210-B2
Application number	US-201716345913-A
Country	US
Kind code	B2
Filing date	Nov 13, 2017
Priority date	Nov 17, 2016
Publication date	Apr 6, 2021
Grant date	Apr 6, 2021

Abstract

Disclosed are compounds of Formula A, or a salt thereof: Formula (A), wherein: Het, Q and R 1A to R 4A are defined herein, which compounds have properties for blocking 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 cough, itch, acute pain and neuropathic pain disorders using the same.

First claim

What is claimed is:

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

wherein:
Het 1 is a five or six member heteroaryl moiety comprising up to 5 carbon atoms and one or more heteroatoms selected from N and S, which is optionally substituted on any ring carbon thereof by a halogen or methyl, which methyl may optionally be fluorine substituted, but is not selected to be a moiety of the following formula:

wherein X is —N═ or —C(R 18A )═, wherein R 18A is H, —Cl or —F;

R 1A to R 4A are independently —F, —Cl, —Br, —CN, —H, or a linear, branched or cyclic alkyl of up to 4 carbon atoms which may optionally be substituted on any carbon thereof with one or more fluorine, with the proviso that at least one of R 1A to R 4A is not —H and at least two of R 1A to R 4A are selected to be —H;
Q 1 is
(a) a moiety of the formula A 1 -NH—X 1 —, wherein:
X 1 is:
(i) alkyl of three or four carbon atoms which is optionally substituted on one or more carbon atoms thereof with halogen, benzyl, aryl, or a linear or branched alkyl of up to 4 carbon atoms; or
(ii) a moiety of the formula:

 and

A 1 is:
(i) R 1b —CHR 2b —, wherein
R 2b is: (ai)-aryl; (aii)—CH 3 ; (aiii)—H; or (aiv) halogen; and
R 1b is:
(ai) a moiety of the formula:

 wherein n 1 is 0 or 1;
(aii) a moiety of the formula:
R 3b NH—CH 2 —(CHR 4b ) 0-3 —,

wherein:
 (ai) R 3b is —H; linear or branched alkyl of up to 4 carbon, or a moiety of the formula:

 wherein the moiety is bonded via a carbon beta or gamma to the oxygen; and
 (aii) R 4b is —H or —F;
(aiii) a moiety of the formula:

wherein:
 n 2 is 1 or 2; and
 R 5b is up to two optional substituents bonded to one or more available ring carbon atoms which are independently for each occurrence: —F; —O-aryl; aryl; —CN; —O—CH 3 ; or

 wherein R 6b is an optional substituent bonded to an available ring carbon atom which, if present, is halogen or —O—CH 3 ; or
(aiv) aryl, which is substituted on one ring carbon atom thereof with —CH 2 NH 2 ;

(ii) a moiety of the formula:

 wherein R 8b is —H or aryl;
(iii) a moiety of the formula: or

 wherein n 3 is 1 or 2 and m 3 is 0 or 1;
(iv) adamantyl bonded to the nitrogen via any available carbon atom;

(b) a moiety of the formula:

wherein R 1c is a moiety of the formula:

wherein:
n 4 is 1 or 2; and
R 2c is up to two optional substituents which are independently for each occurrence: —F; —O-aryl; aryl; —CN; —O—CH 3 ; or

 wherein R 3c is an optional substituent bonded to an available ring carbon atom which, if present, is —O—CH 3 ; or

(c) a moiety of the formula A 2 -X 2 —, wherein:
X 2 is a linear or branched alkyl of three or four carbon atoms; and
A 2 is:
(i) a moiety of the formula:

wherein:
n 5 =1-4;
R 1d is —H or —CH 2 NH 2 ; and
R 2d and R 3d are selected as follows:
 if R 1d is selected to be —CH 2 —NH 2 , then for all occurrences, R 2d and R 3d are —H; or if R 1d is —H, then at least one of R 2d or R 3d is: (ai) —CH 2 —NH 2 ; (aii) —NH—CH 3 ; or (aiii) —NH 2 , and the others of R 2d and R 3d are independently for each occurrence: (ai)—H; (ii) linear-, branched, or cyclic alkyl of up to 6 carbon atoms; or (aiii) aryl;

(ii) a moiety of the formula:

wherein:
n 6 is 0 or 1;
if n 6 =0, then A 3 is —(CH 2 ) 2 —;
if n 6 =1, then A 3 is a bond between the two ring carbon atoms;

(iii) a moiety of the formula:

wherein:
p=1-3;
q 7 and m 7 are independently=0 or 1;
n 7 =1 or 2;

(iv) a moiety of the formula:

wherein:
m 8 and q 8 are independently 1, 2 or 3;
n 8 and p 8 are independently 0 or 1; and
m+n≤4; or

(v) a moiety of the formula:

Wherein: (i) both R 1e are —H; or (ii) both R 1e taken together form a bridge of the formula —(CH 2 ) 1-3 .

2. A compound according to claim 1 of the structure of Formula A 2 , or a pharmaceutically acceptable salt thereof:

wherein:
Het 2 is a five or six member heteroaryl moiety comprising up to five carbon atoms and one or more heteroatoms selected from N and S, which is optionally substituted on any ring carbon thereof by a halogen or methyl, which methyl may optionally be fluorine substituted;
R 1A2 to R 4A2 are independently —F, —Cl, —Br, —CN, —H, or a linear, branched or cyclic alkyl of up to 4 carbon atoms which may optionally be substituted on any carbon thereof with one or more fluorine, with the provisos that: (i) at least one of R 1A2 to R 4A2 is not —H; (ii) at least two of R 1A to R 4A are selected to be —H; and (iii) if R 1A2 is selected to be —F, R 2A2 is not selected to be —F, —Cl or —Br;
Q 2 is
(a) a moiety of the formula A 1b -NH—X 1b —, wherein:
X 1b is:
(i) alkyl of three or four carbon atoms which is optionally substituted on one or more carbon atoms thereof with halogen, benzyl, aryl, or linear or branched alkyl of up to 4 carbon atoms; or
(ii) a

Assignees

• Merck Sharp & Dohme
• Greshock Thomas J
• Mulhearn James
• Roecker Anthony J
• Jian Tianying
• Zhou Gang
• Guo Liangqin
• Won Walter
• Zhang Ting
• Anand Rajan
• Stelmach John E
• Wang Deping
• Kim Ronald M
• Layton Mark E
• Burgey Christopher S
• Nantermet Philippe G

Inventors

• Greshock Thomas J
• Mulhearn James
• Roecker Anthony J
• Jian Tianying
• Zhou Gang
• Guo Liangqin
• Won Walter
• Zhang Ting
• Anand Rajan
• Stelmach John E
• Wang Deping
• Kim Ronald M
• Layton Mark E
• Burgey Christopher S
• Nantermet Philippe G

Classifications

• A61K45/06 Primary

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

• C07D417/12 Primary

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title

• C07D417/14

  containing three or more hetero rings · CPC title

• C07D487/08

  Bridged systems · CPC title