Hydroxypyrrolidine-substituted arylsulfonamide compounds with selective activity in voltage-gated sodium channels

Patent metadata

Field	Value
Publication number	US-12427159-B2
Application number	US-202017615769-A
Country	US
Kind code	B2
Filing date	Jun 8, 2020
Priority date	Jun 11, 2019
Publication date	Sep 30, 2025
Grant date	Sep 30, 2025

Abstract

Disclosed are compounds of Formula A, or a salt thereof: Wherein “A 1 ”, R 1 , R 2 , R 3 , R 6 , and R 7 are as defined herein, which compounds have properties for blocking Nav 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 and neuropathic pain disorders using the same.

First claim

We claim:

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

wherein:
B 1 is —(CR 4 R 5 ) m —,
wherein:
“m” is 1 or 2;
R 4 and R 5 are independently for each occurrence: (i) —H; (ii) a cyclic-, branched-, or linear-alkenyl moiety of up to 6 carbon atoms; (iii) a cyclic-, branched- or linear-alkyl moiety of up to 6 carbon atoms, which alkyl moiety is optionally substituted by one or more substituents which are independently:
(a) an aryl moiety of up to 10 carbon atoms which aromatic moiety is optionally substituted with up to 3 substituents which are independently for each occurrence: (1) cyclic-, branched-, or linear-alkyl moiety of up to 4 carbon atoms which is optionally substituted with —N(R 1a ) 2 , wherein “R 1a ” is independently for each occurrence: H; or linear-, branched, or cyclic-alkyl of up to 4 carbon atoms; (2) branched-, or linear-alkoxy moiety of up to 4 carbon atoms; (3) halogen; (4) —CN; or (v) —N(R 2a ) 2 , wherein “R 2a ” is independently for each occurrence: H; or linear-, branched, or cyclic-alkyl of up to 4 carbon atoms;
(b) a heteroaryl moiety, with up to 5 carbon atoms and at least one ring atom which is N, O, or S, which heteroaryl moiety is optionally substituted with up to 3 substituents which are, independently: (1) cyclic-, branched-, or linear-alkyl moiety of up to 4 carbon atoms which is optionally substituted with —N(R 3a ) 2 , wherein “R 3a ” is independently for each occurrence: H; or linear-, branched, or cyclic-alkyl of up to 4 carbon atoms; (2) branched-, or linear-alkoxy moiety of up to 4 carbon atoms; (3) halogen; (4) —CN; or (v) —N(R 4a ) 2 , wherein “R 4a ” is independently for each occurrence: H; or linear-, branched, or cyclic-alkyl of up to 4 carbon atoms
(c) halogen;
(d) —CN; or
(e) —N(R 5a ) 2 , wherein “R 5a ” is independently for each occurrence: (1) H; (2) linear-, branched, or cyclic-alkyl of up to 4 carbon atoms;

A 1 is —(CR 10 R 11 ) n —, wherein:
“n” is 1, 2, or 3;
in at least one occurrence one of R 10 or R 11 is selected to be —OH; and
the remaining occurrences of R 10 and R 11 are independently for each occurrence:
(a) hydrogen;
(b) halogen;
(c) —OH;
(d) —N(R 1e ) 2 , wherein “R 1e ” is, independently for each occurrence, (i) —H; or (ii) lower alkyl;
(e) a branched-, cyclic- or linear-alkyl moiety of up to 6 carbon atoms which is optionally substituted with one or more substituents which are, independently for each occurrence:
(i) halogen;
(ii) —N(R 2e ) 2 , wherein “R 2e ” is, independently for each occurrence: (1) —H; or (2) lower alkyl;
(iii)-OH;
(iv) an aryl moiety which is optionally substituted with one or more, independently, cyclic-, branched-, or linear-alkoxy moiety of up to 4 carbon atoms; or
(v) a heteroaryl moiety with up to 5 carbon atoms and at least one heteroatom, and which heteroaryl moiety may be optionally substituted with one or more cyclic-, branched-, or linear-alkoxy moiety with up to 6 carbon atoms;

(f) an aryl moiety which is optionally substituted with one or more substituents which are independently:
(i) a cyclic-, branched-, or linear-alkyoxy moiety of up to 4 carbon atoms; or
(ii) —OH; or

(g a heteroaryl moiety, with up to 5 carbon atoms and at least one heteroatom, wherein said heteroaryl moiety is optionally substituted with one or more substituents which are independently: (i) —CN; (ii) —OH; (iii) halogen, that is —F or —Br; (iv) cyclic-, branched-, or linear-alkyl of up to 6 carbon atoms, which alkyl moiety is optionally substituted with: —OH; —CN; halogen; or —N(R 13e ) 2 , wherein “R 13e ” is, independently for each occurrence: —H or lower alkyl; or (iv) cyclic-, branched-, or linear-alkoxy of up to 6 carbon atoms,
with the proviso that if “R 10 ” and “R 11 ” are selected to provide more than one occurrence of —OH, then the selection is made to preclude both germinal —OH and —OH depending from two adjacent carbon atoms;

R 6 is:
(c) a branched-, cyclic- or linear-alkyl of up to 6 carbon atoms which is substituted with one or more substituents which are, independently for each occurrence:
(ii) N(R 2b ) 2 , wherein “R 2b ” is, independently for each occurrence, —H or lower alkyl;
(v) an aryl moiety, with up to 6 ring carbon atoms, wherein the aryl ring of said moiety is optionally substituted with up to 3 substituents which are independently for each occurrence: (1) —CN; (2) —OH; (3) halogen; (4) cyclic-, branched-, or linear-alkyl of up to 4 carbon atoms, which alkyl moiety is optionally substituted with: —OH; —CN; halogen; or N(R 3b ) 2 , wherein “R 3b ” is, independently for each occurrence, —H or lower alkyl; (5) —N(R 4b ) 2 , wherein “R 4b ” is, independently for each occurrence, —H or lower alkyl; (6) cyclic-, branched-, or linear-alkoxy of up to 4 carbon atoms; (7) alkyl-thiol-moiety of up to 4 carbon atoms; (8) alkyl-sulfonyl moiety of up to 4 carbon atoms; or (9) a heterocycle moiety with up to 5 carbon atoms and one or more heteroatoms which are N, O, or S;
(vi) a heteroaryl moiety with up to 4 carbon atoms and at least one heteroatom, wherein said heteroaryl moiety is optionally substituted with one or more substituents which are independently: (a) —CN; (b) —OH; (c) halogen; (d) cyclic-, branched-, or linear-alkyl of up to 4 carbon atoms, which alkyl moiety is optionally substituted with: —OH; —CN; halogen; or N(R 5b ) 2 , wherein “R 5b ” is, independently for each occurrence, —H or lower alkyl; or (e) cyclic-, branched-, or linear-alkoxy of up to 4 carbon atoms;

(d) an aryl moiety, with up to 6 ring carbon atoms, wherein the aryl ring of said moiety is optionally substituted with up to 3 substituents which are independently for each occurrence: (1) —CN; (2) —OH; (3) halogen; (4) cyclic-, branched-, or linear-alkyl of up to 4 carbon atoms, which alkyl moiety is optionally substituted with: —OH; —CN; halogen; or N(R 1c ) 2 , wherein “R 1c ” is, independently for each occurrence, —H or lower alkyl; (5) —N(R 2c ) 2 , wherein “R 2c ” is, independently for each occurrence, —H or lower alkyl; (6) cyclic-, branched-, or linear-alkoxy of up to 4 carbon atoms; (7) alkyl-thiol-moiety of up to 4 carbon atoms; (8) alkyl-sulfonyl moiety of up to 4 carbon atoms; or (9) a heterocycle moiety with up to 5 carbon atoms and one or more heteroatoms which are N, O, or S;
(e) a heteroaryl moiety with up to 4 carbon atoms and at least one heteroatom, wherein said heteroaryl moiety is optionally substituted with one or more substituents which are independently: (a) —CN; (b) —OH; (c) halogen; (d) cyclic-, branched-, or linear-alkyl of up to 4 carbon atoms, which alkyl moiety is optionally substituted with: —OH; —CN; halogen; or N(R 3c ) 2 , wherein “R 3c ” is, independently for each occurrence, —H or lower alkyl; or (e) cyclic-, branched-, or linear-alkoxy of up to 4 carbon atoms; or
(f) a heterocycle moiety, with up to 5 carbon atoms and one or more heteroatoms which are N, O, or S,

R 7 is:
(a) —H;
(b) A cyclic-, branched-, or linear-alkyl moiety of up to 7 carbon atoms which is optionally substituted with one or more moieties which are, independently:
(i) halogen;
(ii) N(R 1d ) 2 , wherein “R 1d ” is, independently for each occurrence, —H or lower alkyl;
(iii) lower alkyl;
(iv) lower alkoxy;
(v) an aryl moiety, with up to 6 ring carbon atoms, wherein the aryl ring of said moiety is optionally substituted with up to 3 substituents which are independently for each occurrence: (1) —CN; (2) —OH; (3) halogen; (4) cyclic-, branched-, or linear-alkyl of up to 4 carbon atoms, which alkyl moiety is optionally substituted with: —OH; —CN; halogen; or N(R 2d ) 2 , wherein “R 2d ” is, independently for each occurrence, —H or lower alkyl; (5) —N(R 3d ) 2 , wherein “R 3d ” is, independently for each occurrence, —H or l

Assignees

• Merck Sharp & Dohme Llc
• Roecker Anthony J
• Layton Mark E
• Wang Deping
• Wang Xiu
• Peng Xuanjia

Inventors

• Roecker Anthony J
• Layton Mark E
• Wang Deping
• Wang Xiu
• Peng Xuanjia

Classifications

• C07D417/14

  containing three or more hetero rings · CPC title

• C07D417/12

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

• A61P17/04

  Antipruritics · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61K31/427

  not condensed and containing further heterocyclic rings · CPC title