Kappa opioid agonists and uses thereof

Patent metadata

Field	Value
Publication number	US-10407416-B2
Application number	US-201715719376-A
Country	US
Kind code	B2
Filing date	Sep 28, 2017
Priority date	Jun 28, 2013
Publication date	Sep 10, 2019
Grant date	Sep 10, 2019

Abstract

Provided are compounds of Formula I:

and pharmaceutically acceptable salts and solvates thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are as described herein. The compounds of Formula I are agonists of the kappa opioid receptor and 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 according to Formula I:

wherein:
R 1 is an optionally substituted phenyl;
R 2 is hydrogen or phenyl;
R 3 is selected from hydrogen and an optionally substituted lower alkyl;
R 4 is a phenyl substituted with —X-POLY;
R 5 and R 6 together with the nitrogen to which they are attached form an optionally substituted pyrrolidinyl or azetidinyl ring;

X is an optional linker selected from a covalent bond; —C(O)NH—; —C(O)NHCH 2 —; —C(O)NHCH 2 CH 2 —; —OC(O)NH—; —C(O)NH—; —O—; —NHC(O)—; —NHC(O)CH 2 —; —NHC(O)CH 2 O—; —NHC(O)CH 2 CH 2 —; —NH—; or —NHS(O) 2 —; and
POLY is a poly(alkylene oxide) oligomer comprising 2 to 10 alkylene oxide monomers;

or pharmaceutically acceptable salts and solvates thereof.

2. The compound of claim 1 , wherein R 1 is substituted with 1, 2, or 3 halogen atoms.

3. The compound of claim 1 , wherein R 3 is methyl.

4. The compound of claim 1 , wherein R 5 and R 6 are taken together to form an optionally substituted pyrrolidinyl.

5. The compound claim 1 , wherein the poly(alkylene oxide) oligomer is a poly(ethylene oxide) oligomer.

6. The compound of claim 1 , wherein POLY is end-capped with a hydroxyl group, a lower alkoxy group, or a trifluoromethoxy group.

7. The compound of claim 1 according to the following formula:

wherein:
POLY is —(CH 2 CH 2 O) n —Y;
n is an integer from 2 to 10; and
Y is hydrogen, methyl, or trifluoromethoxy;

or pharmaceutically acceptable salts and solvates thereof.

8. The compound of claim 7 according to the following formula:

or pharmaceutically acceptable salts and solvates thereof.

9. The compound of claim 1 according to the following formula:

wherein:
POLY is —(CH 2 CH 2 O) n —Y;
n is an integer from 42 to 10; and
Y is hydrogen, methyl, or trifluoromethoxy;

or pharmaceutically acceptable salts and solvates thereof.

10. The compound of claim 9 according to the following formula:

or pharmaceutically acceptable salts and solvates thereof.

11. The compound of claim 1 according to any of the following formulas:

or pharmaceutically acceptable salts and solvates thereof.

12. A pharmaceutical composition comprising a compound of claim 1 and at least one pharmaceutically acceptable excipient.

13. A method of treating pain or inflammation comprising administering a compound of claim 1 to a patient in need thereof.

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

• C07D205/04

  having no double bonds between ring members or between ring members and non-ring members · 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

• C07D401/12

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