Trpv1 antagonists including dihydroxy substituent and uses thereof

Patent metadata

Field	Value
Publication number	US-2016355499-A1
Application number	US-201615179612-A
Country	US
Kind code	A1
Filing date	Jun 10, 2016
Priority date	Apr 27, 2007
Publication date	Dec 8, 2016
Grant date	—

Abstract

The invention relates to compounds of formula IA

and pharmaceutically acceptable derivatives thereof, compositions comprising an effective amount of a compound of formula IA or a pharmaceutically acceptable derivative thereof, and methods for treating or preventing a condition such as pain, UI, an ulcer, IBD and IBS, comprising administering to an animal in need thereof an effective amount of a compound of formula IA or a pharmaceutically acceptable derivative thereof.

First claim

What is claimed:

1 . A compound of formula IA:

or a pharmaceutically acceptable salt, solvate, stereoisomer, geometric isomer or tautomer thereof, wherein
X is O, S, N—CN, N—OH, or N—OR 10 ;
W is N or C;
the dashed line denotes the presence or absence of a bond, and when the dashed line denotes the presence of a bond or W is N then R 4 is absent, otherwise R 4 is —H, —OH, —OCF 3 , -halo, —(C 1 -C 6 )alkyl, —CH 2 OH, —CH 2 Cl, —CH 2 Br, —CH 2 I, —CH 2 F, —CH(halo) 2 , —CF 3 , —OR 10 , —SR 10 , —COOH, —COOR 10 , —C(O)R 10 , —C(O)H, —OC(O)R 10 , —OC(O)NHR 10 , —NHC(O)R 13 , —CON(R 13 ) 2 , —S(O) 2 R 10 , or —NO 2 ;
R 10 is —(C 1 -C 4 )alkyl;
each R 13 is independently —H, —(C 1 -C 4 )alkyl, —(C 1 -C 4 )alkenyl, —(C 1 -C 4 )alkynyl, or -phenyl;
Ar 1 is

Ar 2 is

c is the integer 0, 1, or 2;
Y 1 , Y 2 , and Y 3 are independently C, N, or O;
wherein no more than one of Y 1 , Y 2 , or Y 3 can be O, and for each Y 1 , Y 2 , and Y 3 that is N, the N is bonded to one R 21 group, and for each Y 1 , Y 2 , and Y 3 that is C, the C is bonded to two R 20 groups, provided that there are no more than a total of two (C 1 -C 6 )alkyl groups substituted on all of Y 1 , Y 2 , and Y 3 ;
R 12a and R 12b are independently —H or —(C 1 -C 6 )alkyl;
E is ═O, ═S, ═CH(C 1 -C 5 )alkyl, ═CH(C 1 -C 5 )alkenyl, —NH(C 1 -C 6 )alkyl, or ═N—OR 20 ;
R 1 is —H, -halo, —(C 1 -C 4 )alkyl, —NO 2 , —CN, —OH, —OCH 3 , —NH 2 , —C(halo) 3 , —CH(halo) 2 , —CH 2 (halo), —OC(halo) 3 , —OCH(halo) 2 , or —OCH 2 (halo);
each R 2 is independently:
(a) -halo, —OH, —O(C 1 -C 4 )alkyl, —CN, —NO 2 , —NH 2 , —(C 1 -C 10 )alkyl, —(C 2 -C 10 )alkenyl, —(C 2 -C 10 )alkynyl, or -phenyl, or
(b) a group of formula Q;
wherein Q is

Z 1 is —H, —OR 7 , —SR 7 , —CH 2 —OR 7 , —CH 2 —SR 7 , —CH 2 —N(R 20 ) 2 , or -halo;
Z 2 is —H, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —CH 2 —OR 7 , -phenyl, or -halo;
each Z 3 is independently —H, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, or -phenyl;
Z 4 is —H, —OH, —OR 20 , —(C 1 -C 6 )alkyl, or —N(R 20 ) 2 ;
J is —OR 20 , —SR 20 , —N(R 20 ) 2 , or —CN;
provided that at least one R 2 group is a group of formula Q, and provided that when Z 1 is —OR 7 or —SR 7 , then Z 2 is not -halo;
each R 3 is independently:
(a) —H, —(C 1 -C 6 )alkyl, or —CH 2 OR 7 ; or
(b) two R 3 groups together form a (C 2 -C 6 )bridge, which is unsubstituted or substituted with 1, 2 or 3 independently selected R 8 groups, and which bridge optionally contains —HC═CH— within the (C 2 -C 6 )bridge; or
(c) two R 3 groups together form a —CH 2 —N(R a )—CH 2 — bridge, a

 bridge, or a

 bridge;
R a is —H, —(C 1 -C 6 )alkyl, —(C 3 -C 8 )cycloalkyl, —CH 2 —C(O)—R c , —(CH 2 )—C(O)—OR c , —(CH 2 )—C(O)—N(R c ) 2 , —(CH 2 ) 2 —O—R c , —(CH 2 ) 2 —S(O) 2 —N(R c ) 2 , or —(CH 2 ) 2 —N(R c )S(O) 2 —R c ;
R b is:
(a) —H, —(C 1 -C 6 )alkyl, —(C 3 -C 8 )cycloalkyl, -(3- to 7-membered)heterocycle, —N(R c ) 2 , —N(R c )—(C 3 -C 8 )cycloalkyl, or —N(R c )-(3- to 7-membered)heterocycle; or
(b) -phenyl, -(5- or 6-membered)heteroaryl, —N(R c )-phenyl, or —N(R c )-(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with 1, 2 or 3 independently selected R 7 groups;
each R c is independently —H or —(C 1 -C 4 )alkyl;
each R 7 is independently —H, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 3 -C 8 )cycloalkyl, —(C 5 -C 8 )cycloalkenyl, -phenyl, —(C 1 -C 6 )haloalkyl, —(C 1 -C 6 )hydroxyalkyl, —(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, —(C 1 -C 6 )alkyl-N(R 20 ) 2 , or —CON(R 20 ) 2 ;
each R 8 and R 9 is independently:
(a) —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 3 -C 8 )cycloalkyl, —(C 5 -C 8 )cycloalkenyl, or -phenyl, each of which is unsubstituted or substituted with 1 or 2 —OH groups; or
(b) —H, —CH 2 C(halo) 3 , —C(halo) 3 , —CH(halo) 2 , —CH 2 (halo), —OC(halo) 3 , —OCH(halo) 2 , —OCH 2 (halo), —SC(halo) 3 , —SCH(halo) 2 , —SCH 2 (halo), —CN, —O—CN, —OH, -halo, —N 3 , —NO 2 , —CH═NR 7 , —N(R 7 ) 2 , —NR 7 OH, —OR 7 , —C(O)R 7 , —C(O)OR 7 , —OC(O)R 7 , —OC(O)OR 7 , —SR 7 , —S(O)R 7 , or —S(O) 2 R 7 ;
each R 11 is independently —CN, —OH, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, -halo, —N 3 , —NO 2 , —N(R 7 ) 2 , —CH═NR 7 , —NR 7 OH, —OR 7 , —C(O)R 7 , —C(O)OR 7 , —OC(O)R 7 , or —OC(O)OR 7 ;
each R 14 is independently —H, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 3 -C 8 )cycloalkyl, —(C 5 -C 8 )cycloalkenyl, —(C 1 -C 6 )alkoxy-(C 1 -C 6 )alkyl, -phenyl, —C(halo) 3 , —CH(halo) 2 , —CH 2 (halo), -(3- to 7-membered)heterocycle, —(C 1 -C 6 )haloalkyl, —(C 2 -C 6 )haloalkenyl, —(C 2 -C 6 )haloalkynyl, —(C 2 -C 6 )hydroxyalkenyl, —(C 2 -C 6 )hydroxyalkynyl, —(C 1 -C 6 )alkoxy(C 2 -C 6 )alkyl, —(C 1 -C 6 )alkoxy(C 2 -C 6 )alkenyl, —(C 1 -C 6 )alkoxy(C 2 -C 6 )alkynyl, —(C 1 -C 6 )alkoxy(C 3 -C 8 )cycloalkyl, —CN, —OH, -halo, —OC(halo) 3 , —N 3 , —NO 2 , —CH═NR 7 , —N(R 7 ) 2 , —NR 7 OH, —OR 7 , —SR 7 , —O(CH 2 ) b OR 7 , —O(CH 2 ) b SR 7 , —O(CH 2 ) b N(R 7 ) 2 , —N(R 7 )(CH 2 ) b OR 7 , —N(R 7 )(CH 2 ) b SR 7 , —N(R 7 )(CH 2 ) b N(R 7 ) 2 , —N(R 7 )COR 7 , —C(O)R 7 , —C(O)OR 7 , —OC(O)R 7 , —OC(O)OR 7 , —S(O)R 7 , —S(O) 2 R 7 , —S(O) 2 N(R 7 ) 2 , —SO 2 C(halo) 3 , —SO 2 (3- to 7-membered)heterocycle, —CON(R 7 ) 2 , —(C 1 -C 5 )alkyl-C═NOR 7 , —(C 1 -C 5 )alkyl-C(O)—N(R 7 ) 2 , —(C 1 -C 6 )alkyl-NHSO 2 N(R 7 ) 2 , or —(C 1 -C 6 )alkyl-C(═NH)—N(R 7 ) 2 ;
each R 20 is independently —H, —(C 1 -C 6 )alkyl, or —(C 3 -C 8 )cycloalkyl;
each R 21 is independently —H, —(C 1 -C 6 )alkyl,

each halo is independently —F, —Cl, —Br, or —I;
n is the integer 1, 2, or 3;
p is the integer 1 or 2;
each b is independently 1 or 2;
q is the integer 0, 1, 2, 3, or 4;
r is the integer 0, 1, 2, 3, 4, 5, or 6;
s is the integer 0, 1, 2, 3, 4, or 5;
t is the integer 0, 1, 2, or 3; and
m is the integer 0, 1, or 2.

2 . The compound of claim 1 or a pharmaceutically acceptable salt, solvate, stereoisomer, geometric isomer or tautomer thereof, wherein X is O.

3 . A compound of formula II:

or a pharmaceutically acceptable salt, solvate, stereoisomer, geometric isomer or tautomer thereof, wherein
X is O, S, N—CN, N—OH, or N—OR 10 ;
W is N or C;
the dashed line denotes the presence or absence of a bond, and when the dashed line denotes the presence of a bond or W is N then R 4 is absent, otherwise R 4 is —H, —OH, —OCF 3 , -halo, —(C 1 -C 6 )alkyl, —CH 2 OH, —CH 2 Cl, —CH 2 Br, —CH 2 I, —CH 2 F, —CH(halo) 2 , —CF 3 , —OR 10 , —SR 10 , —COOH, —COOR 10 , —C(O)R 10 , —C(O)H, —OC(O)R 10 , —OC(O)NHR 10 , —NHC(O)R 13 , —CON(R 13 ) 2 , —S(O) 2 R 10 , or —NO 2 ;
R 10 is —(

Assignees

• Purdue Pharma Lp

Inventors

• Tafesse Laykea

Classifications

• A61P43/00

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

• A61P29/00

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

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• A61P25/04

  Centrally acting analgesics, e.g. opioids · CPC title

• A61P1/00

  Drugs for disorders of the alimentary tract or the digestive system · CPC title