Kappa opioid agonists and uses thereof

Patent metadata

Field	Value
Publication number	US-2016145245-A1
Application number	US-201414900039-A
Country	US
Kind code	A1
Filing date	Jun 27, 2014
Priority date	Jun 28, 2013
Publication date	May 26, 2016
Grant date	—

Abstract

Provided are compounds of Formula I; and pharmaceutically acceptable salts and solvates thereof. The compounds of Formula I described herein relate to and/or have application(s) in (among others) the fields of drug discovery, pharmacotherapy, physiology, organic chemistry and polymer chemistry.

First claim

What is claimed is:

1 . A compound selected from Formula I:

wherein:
R 1 is selected from optionally substituted aryl, optionally substituted amino, and optionally substituted aryloxy;
R 2 is selected from hydrogen, optionally substituted aryl, and X-POLY;
R 3 is selected from hydrogen and an optionally substituted alkyl;
R 4 is selected from an optionally substituted aryl;
R 5 is selected from hydrogen, optionally substituted alkyl, and X-POLY;
R 6 is selected from hydrogen and an optionally substituted alkyl; or
R 5 and R 6 may be taken together to form an optionally substituted heterocyclyl; provided at least one of R 1 , R 2 , R 4 , R 5 , and R 6 are an X-POLY group or are substituted with an ˜X-POLY group, wherein X is an optional linker and POLY is a water soluble, non-peptidic oligomer; and
provided that when R 1 is phenyl, R 2 is phenyl, R 3 is methyl, R 4 is phenyl, and R 5 and R 6 are taken together to form a pyrrolidinyl group, the pyrrolidinyl group is not substituted with ˜X-POLY;
and pharmaceutically acceptable salts and solvates thereof.

2 . The compound of claim 1 , wherein R 1 is an optionally substituted phenyl.

3 . The compound of any one of the proceeding claims, wherein R 1 is selected from phenyl, phenyl substituted with 1 to 3 halogens, and phenyl substituted with X-POLY.

4 . The compound of any one of the proceeding claims, wherein R 1 is optionally substituted amino.

5 . The compound of any one of the proceeding claims, wherein R 1 is amino substituted with an optionally substituted aryl.

6 . The compound of any one of the proceeding claims, wherein R 1 is amino substituted with an optionally substituted phenyl.

7 . The compound of any one of the proceeding claims, wherein R 1 is amino substituted with a phenyl group.

8 . The compound of any one of the proceeding claims, wherein R 2 is hydrogen.

9 . The compound of any one of the proceeding claims, wherein R 2 is X-POLY.

10 . The compound of any one of the proceeding claims, wherein R 2 is an optionally substituted aryl.

11 . The compound of any one of the proceeding claims, wherein R 2 is an optionally substituted phenyl.

12 . The compound of any one of the proceeding claims, wherein R 2 is phenyl.

13 . The compound of any one of the proceeding claims, wherein R 3 is hydrogen.

14 . The compound of any one of the proceeding claims, wherein R 3 is an optionally substituted lower alkyl.

15 . The compound of any one of the proceeding claims, wherein R 3 is methyl.

16 . The compound of any one of the proceeding claims, wherein R 4 is selected from an optionally substituted phenyl.

17 . The compound of any one of the proceeding claims, wherein R 4 is selected from phenyl and phenyl substituted with ˜X-POLY.

18 . The compound of any one of the proceeding claims, wherein R 5 is hydrogen.

19 . The compound of any one of the proceeding claims, wherein R 5 is an optionally substituted alkyl.

20 . The compound of any one of the proceeding claims, wherein R 5 is an optionally substituted lower alkyl.

21 . The compound of any one of the proceeding claims, wherein R 5 is a lower alkyl or a lower alkyl substituted with a lower alkoxy group.

22 . The compound of any one of the proceeding claims, wherein R 5 is ˜X-POLY.

23 . The compound of any one of the proceeding claims, wherein R 6 is hydrogen.

24 . The compound of any one of the proceeding claims, wherein R 6 is an optionally substituted alkyl.

25 . The compound of any one of the proceeding claims, wherein R 6 is an optionally substituted lower alkyl;

26 . The compound of any one of the proceeding claims, wherein R 6 is a lower alkyl or a lower alkyl substituted with a lower alkoxy group.

27 . A compound of any one of the proceeding claims, wherein R 5 and R 6 are taken together to form an optionally substituted heterocyclyl.

28 . A compound of any one of the proceeding claims, wherein R 5 and R 6 are taken together to form an optionally substituted piperidinyl or an optionally substituted pyrrolidinyl.

29 . A compound of any one of the proceeding claims, wherein R 5 and R 6 are taken together to form an optionally substituted pyrrolidinyl.

30 . A compound of any one of the proceeding claims, wherein R 5 and R 6 are taken together to form a pyrrolidinyl substituted with a group selected from hydroxyl and X-POLY.

31 . The compound of any one of the proceeding claims, wherein X is selected from a covalent bond, —C(O)—NH—; —C(O)—NH—CH 2 —; —C(O)—NH—CH 2 CH 2 —; —O—C(O)NH—, —C(O)—NH—; —O—; —NH—C(O)—; —NH—C(O)—CH 2 —; —NHC(O)CH 2 O—, —NH—C(O)—CH 2 CH 2 —; —NH—; and —NHS(O) 2 —.

32 . The compound of any one of the proceeding claims, wherein POLY is a poly(alkylene oxide) oligomer.

33 . The compound of any one of the proceeding claims, wherein POLY is a poly(ethylene oxide) oligomer.

34 . The compound of any one of the proceeding claims, wherein POLY is end-capped with an end-capping group selected from the group consisting of a hydroxyl group, a lower alkoxy group, and a trifluoromethoxy group.

35 . The compound of any one of the proceeding claims wherein POLY is made of 1 to 30 monomers.

36 . A compound of any one of the proceeding claims, wherein the compound has the structure:

wherein X is selected from O, —O—C(O)N—, and a covalent bond and POLY is (CH 2 CH 2 O) n —Y, wherein n is 1 to 30, and Y is selected from hydrogen, lower alkyl and trifluoromethoxy.

37 . A compound of any one of the proceeding claims, wherein the compound has the structure:

wherein X is selected from O, —O—C(O)N—, and a covalent bond; and POLY is ˜(CH 2 CH 2 O) n —Y, wherein n is 1 to 30, and Y is selected from hydrogen, lower alkyl and trifluoromethoxy.

38 . A compound of any one of claims 1 to 35 , wherein the compound has the structure:

wherein X is —NHC(O)CH 2 O—, NH—, —O—, and NHS(O) 2 — and POLY is ˜(CH 2 CH 2 O) n —Y, wherein n is 1 to 30, and Y is selected from hydrogen, lower alkyl and trifluoromethoxy.

39 . A compound of any one of claims 1 to 35 and 38 , wherein the compound has the structure:

wherein X is —NHC(O)CH 2 O—, NH—, —O—, and NHS(O) 2 — and POLY is (CH 2 CH 2 O) n —Y, wherein n is 1 to 30, and Y is selected from hydrogen, lower alkyl and trifluoromethoxy.

40 . A compound of any one of claims 1 to 35 , wherein the compound has the structure:

wherein X is O or a covalent bond and POLY is ˜(CH 2 CH 2 O) n —Y; wherein n is 1 to 30, and Y is selected fr

Assignees

• Nektar Therapeutics

Inventors

• Anand Neel K
• Duarte Franco J
• Zhang Wen
• Ren Zhongxu

Classifications

• A61P25/04

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

• A61P1/06

  Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia · CPC title

• C07D213/56

  Amides · CPC title

• C07D213/61

  Halogen atoms or nitro radicals · CPC title

• C07D295/125

  with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings · CPC title