Trpv1 antagonists including dihydroxy substituent and uses thereof

Patent metadata

Field	Value
Publication number	US-2016222002-A1
Application number	US-201615018493-A
Country	US
Kind code	A1
Filing date	Feb 8, 2016
Priority date	Jun 22, 2011
Publication date	Aug 4, 2016
Grant date	—

Abstract

The disclosure relates to Compounds of Formula (I)

and pharmaceutically acceptable derivatives thereof, where R 1 , R 4 , R 8 , R 9 , and m are as defined herein, compositions comprising an effective amount of a Compound of Formula (I) or a pharmaceutically acceptable derivative thereof, and methods for treating or preventing a condition such as pain, pain associated with osteoarthritis, osteoarthritis, UI, an ulcer, IBD, and IBS, comprising administering to an animal in need thereof an effective amount of a Compound of Formula (I) or a pharmaceutically acceptable derivative thereof.

First claim

1 . A compound of formula (I):

or a pharmaceutically acceptable salt, a co-crystal, or a combination thereof, wherein:
R 1 is -halo or —CF 3 ;
R 4 is —H or —CH 3 ;
each R 8 and R 9 is independently —H, -halo, —CH 3 , —CF 3 , —OCH 3 , —OCF 3 , —OCH 2 CH 3 , —CH 2 OCH 3 , or —C(O)OR 10 ;
R 10 is —(C 1 -C 4 )alkyl;
each halo is independently —F, —Cl, —Br, or —I; and
m is the integer 0 or 1;
(1) provided that if R 4 is —H then m is 1;
(2) provided that if R 4 is —H and the carbon atom at the a position of the a-b bond is in the (S) configuration, then the methyl group bonded to the piperazine ring is a (S)-2-methyl group, a (S)-3-methyl group, or a (R)-3-methyl group;
(3) if R 4 is —H, the carbon atom at the a position of the a-b bond is in the (S) configuration, R 8 is —H, and R 9 is -halo, then the methyl group bonded to the piperazine ring is a (R)-3-methyl group;
(4) if R 4 is —H, the carbon atom at the a position of the a-b bond is in the (S) configuration, R 8 is —F, and R 9 is —F, then the methyl group bonded to the piperazine ring is a (S)-2-methyl group or a (S)-3-methyl group; and
(5) if R 4 is —CH 3 , the carbon atoms at the a and c positions of the a-b bond and the c-d bond are each in the (S) configuration, R 8 is —H, R 9 is -halo, and m is 1, then the methyl group bonded to the piperazine ring is a (S)-3-methyl group or a (R)-3-methyl group.

2 . (canceled)

3 . The compound of claim 1 or a pharmaceutically acceptable salt, a co-crystal, or a combination thereof, wherein R 1 is —F, —Cl, or —CF 3 .

4 . The compound of claim 3 or a pharmaceutically acceptable salt, a co-crystal, or a combination thereof, wherein R 1 is —F.

5 .- 6 . (canceled)

7 . The compound of claim 1 or a pharmaceutically acceptable salt, a co-crystal, or a combination thereof, wherein R 9 is —H, —F, —Cl, —Br, —CH 3 , —CF 3 , —OCH 3 , —OCF 3 , —OCH 2 CH 3 , —CH 2 OCH 3 , or —C(O)OCH 2 CH 3 .

8 . The compound of claim 1 or a pharmaceutically acceptable salt, a co-crystal, or a combination thereof, wherein R 8 is —H, —F, or —CH 3 .

9 .- 14 . (canceled)

15 . The compound of claim 1 or a pharmaceutically acceptable salt, a co-crystal, or a combination thereof, wherein m is 1 and the methyl group bonded to the piperazine ring is a (S)-2-methyl group.

16 . The compound of claim 1 or a pharmaceutically acceptable salt, a co-crystal, or a combination thereof, wherein the pharmaceutically acceptable salt, the co-crystal, or the combination thereof is a pharmaceutically acceptable salt, a hydrochlorate co-crystal, a tartrate co-crystal, a benzenesulfonate co-crystal, ap-toluenesulfonate co-crystal, or a fumarate co-crystal.

17 . The compound of claim 1 or a pharmaceutically acceptable salt, a co-crystal, or a combination thereof, wherein the pharmaceutically acceptable salt, the co-crystal, or the combination thereof is a hydrochloride salt, a sodium salt, a potassium salt, ap-toluenesulfonic acid salt, a fumaric acid-salt, or a fumarate co-crystal.

18 . The compound of claim 1 or a pharmaceutically acceptable salt, a co-crystal, or a combination thereof, wherein the pharmaceutically acceptable salt, the co-crystal, or the combination thereof is a fumaric acid-salt, a fumarate co-crystal, or a combination thereof.

19 .- 21 . (canceled)

22 . A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt, a co-crystal, or a combination thereof and a pharmaceutically acceptable carrier or excipient.

23 . A method for treating pain, pain associated with osteoarthritis, osteoarthritis, urinary incontinence, an ulcer, inflammatory-bowel disease, or irritable-bowel syndrome in an animal, comprising administering to an animal in need thereof, an effective amount of the compound of claim 1 or a pharmaceutically acceptable salt, a co-crystal, or a combination thereof.

24 . A method of inhibiting TRPV1 function in a cell comprising contacting a cell capable of expressing TRPV1 with an effective amount of the compound of claim 1 or a pharmaceutically acceptable salt, a co-crystal, or a combination thereof.

25 .- 28 . (canceled)

29 . The compound of claim 1 , wherein said compound is a compound of formula (II):

or a pharmaceutically acceptable salt, a co-crystal, or a combination thereof, wherein:
R 8 is —H, —F, or —CH 3 ; and
R 9 is —H, -halo, —CH 3 , —CF 3 , —OCH 3 , —OCF 3 , —OCH 2 CH 3 , —CH 2 OCH 3 , or —C(O)OCH 2 CH 3 .

30 .- 32 . (canceled)

33 . The compound of claim 29 or a pharmaceutically acceptable salt, a co-crystal, or a combination thereof, wherein R 4 is —H and the carbon atom at the a position of the a-b bond is in the (S) configuration.

34 .- 35 . (canceled)

36 . The compound of claim 29 or a pharmaceutically acceptable salt, a co-crystal, or a combination thereof, wherein R 9 is —H.

37 . The compound of claim 29 or a pharmaceutically acceptable salt, a co-crystal, or a combination thereof, wherein R 8 is —F.

38 .- 52 . (canceled)

53 . The compound of claim 1 or a pharmaceutically acceptable salt, a co-crystal, or a combination thereof, wherein said compound is

54 .- 78 . (canceled)

79 . A co-crystal of (a) a compound which is

and (b) fumaric acid, wherein said co-crystal is characterized by a CP/MAS 13 C NMR spectrum comprising peaks with a chemical shift of 171.5±0.2 ppm, 170.3±0.2 ppm, and 135.6±0.2 ppm when measured by the CP/MAS 13 C NMR procedure described in Example 10.

80 . The co-crystal of claim 79 , wherein said co-crystal is characterized by a CP/MAS 13 C NMR spectrum further comprising a peak with a chemical shift of 72.2±0.2 ppm when measured by the CP/MAS 13 C NMR procedure described in Example 10.

81 . The co-crystal of claim 79 , wherein said co-crystal is characterized by a CP/MAS 13 C NMR spectrum further comprising peaks with a chemical shift of 72.2±0.2 ppm and 15.1±0.2 ppm when measured by the CP/MAS 13 C NMR procedure described in Example 10.

82 . The co-crystal of claim 79 , wherein the molar ratio of the compound to fumaric acid is from about 1.0:0.4 to about 1.0:0.7.

83 . A co-crystal of (a) a compound which is

and (b) fumaric acid, wherein said co-crystal is characterized by an x-ray powder diffraction pattern comprising a peak at each of 6.5, 12.5, 16.8, and 25.3 degrees 2θ±0.2° when measured using CuKα radiation.

84 . The co-crystal of claim 83 , wherein said co-crystal is characterized by an x-ray powder diffraction pattern further comprising peaks at 8.6, 14.0, and 18.7 degrees 2θ±0.20 when measured using CuKα rad

Assignees

• Purdue Pharma Lp
• Shionogi & Co

Inventors

• Ando Shigeru
• Kurose Noriyuki
• Tafesse Laykea

Classifications

• A61P43/00

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

• A61P25/04

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

• A61P25/02

  for peripheral neuropathies · 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