TRPV1 antagonists including dihydroxy substituent and uses thereof

Patent metadata

Field	Value
Publication number	US-9365563-B2
Application number	US-201414498724-A
Country	US
Kind code	B2
Filing date	Sep 26, 2014
Priority date	Apr 27, 2007
Publication date	Jun 14, 2016
Grant date	Jun 14, 2016

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 1- ;

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 —O 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 1 , 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 D , —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 7 (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 T , —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 —O 5 )alkyl-C═NOR 7 , —(C 1 —O 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 ;
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 7 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

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

• A61P25/04

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

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• A61P13/00

  Drugs for disorders of the urinary system · CPC title