Kappa opioid agonists and uses thereof

Patent metadata

Field	Value
Publication number	US-9815824-B2
Application number	US-201414900039-A
Country	US
Kind code	B2
Filing date	Jun 27, 2014
Priority date	Jun 28, 2013
Publication date	Nov 14, 2017
Grant date	Nov 14, 2017

Abstract

Provided are compounds of Formula I; and pharmaceutically acceptable salts and solvates thereof.

The present disclosure relates to novel compounds and to their use as agonists of the kappa opioid receptor. The disclosure also relates to methods for preparation of the compounds and to pharmaceutical compositions containing such compounds. Kappa opioid agonists that exhibit full agonist properties at the kappa opioid receptor have been widely shown to be efficacious in preclinical models of pain, particularly visceral pain.

First claim

What is claimed is:

1. A compound having the structure:

wherein:
R 1 is

R 2 is hydrogen;
R 3 is hydrogen;
R 4 is —X-POLY;
R 5 is hydrogen;
R 6 is hydrogen;
X is —O— or —OC(O)NH—;
POLY is —(CH 2 CH 2 O) n —Y;
n is 1 to 30; and
Y is hydrogen or substituted or unsubstituted lower alkyl;
and pharmaceutically acceptable salts and solvates thereof.

2. A compound selected from:
2-(3, 4-dichlorophenyl)-N-{(1S)-2-[(3S)-3-(2-methoxyethoxy)pyrrolidin-1-yl]-1-phenylethyl}-N-methylacetamide;
2-(3, 4-Dichlorophenyl)-N-{(1S)-2-[(3S)-3-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)pyrrolidin-1-yl]-1-phenylethyl}-N-methylacetamide;
(3S)-1-[(2S)-2-{[(3,4-Dichlorophenyl)acetyl](methyl)amino}-2-phenylethyl]pyrrolidin-3-yl{2-[2-(2-methoxyethoxy)ethoxy]ethyl}carbamate;
(3S)-1-[(2S)-2-{[(3,4-Dichlorophenyl)acetyl](methyl)amino}-2-phenylethyl]pyrrolidin-3-yl 2,5,8,11,14-pentaoxahexadecan-16-ylcarbamate; and
2-(3,4-Dichlorophenyl)-N-methyl-N-{(1S)-2-[(3S)-3-(2,5,8,11,14-pentaoxahexadecan-16-yloxy)pyrrolidin-1-yl]-1-phenylethyl}acetamide;
and pharmaceutically acceptable salts thereof.

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

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

5. The compound of claim 1 , having the structure:

wherein:
n is 1 to 30;
R 10 is hydrogen; and
R 11 is —H, —CH 3 , or —CF 3 ;
and pharmaceutically acceptable salts and solvates 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

• C07D207/09

  Radicals substituted by nitrogen atoms, not forming part of a nitro radical · CPC title