Agonists of the mu opioid receptor

Patent metadata

Field	Value
Publication number	US-10125129-B2
Application number	US-201715498725-A
Country	US
Kind code	B2
Filing date	Apr 27, 2017
Priority date	Apr 27, 2016
Publication date	Nov 13, 2018
Grant date	Nov 13, 2018

Abstract

The present technology is directed to compounds, compositions, and methods related to non-morphinan-like mu opioid receptor agonists. Compounds of the present technology demonstrate remarkable potency and selectivity for the mu opioid receptor over the kappa opioid receptor, while also exhibiting a significant reduction (or, essentially, absence) of the negative side effects of many morphine-derived compounds.

First claim

What is claimed is:

1. A compound of Formula I:

or a pharmaceutically acceptable salt and/or solvate thereof, wherein
R 1 is

 —CH 2 Ph, —CH 2 CH 2 Ph, —CH═CH-Ph, or heteroaryl; and
R 2 , R 3 , and R 4 are each independently H, halo, OH, nitro, unsubstituted C 1 -C 3 alkyl, or unsubstituted C 1 -C 3 alkoxy.

2. The compound of claim 1 , wherein R 1 is

—CH═CH-Ph, or heteroaryl.

3. The compound of claim 1 , wherein R 2 , R 3 , and R 4 are each independently H, halo, OH, nitro, unsubstituted C 1 -C 3 n-alkyl, or unsubstituted C 1 -C 3 n-alkoxy.

4. The compound of claim 1 , wherein R 2 is H, halo, or unsubstituted C 1 -C 3 alkyl.

5. The compound of claim 1 , wherein heteroaryl is furanyl, thiophenyl, pyridinyl, pyrimidinyl, 4-thiazolyl, or 4-oxazolyl.

6. The compound of claim 1 , wherein heteroaryl is furanyl, thiophenyl, pyrimidinyl, 4-thiazolyl, 4-oxazolyl, 4-pyridinyl, or

wherein one of X 1 and X 2 is N and the remaining X 1 or X 2 is CH; and R 6 is H, OH, or C 1 -C 3 alkoxy.

7. The compound of claim 1 , wherein heteroaryl is unsubstituted 2-furanyl, unsubstituted 2-benzofuranyl, unsubstituted 3-furanyl, unsubstituted 2-thiophenyl, unsubstituted 3-thiophenyl, unsubstituted 5-pyrimidinyl, unsubstituted 4-thiazolyl, unsubstituted 4-oxazolyl, unsubstituted 4-pyridinyl, or

wherein one of X 1 and X 2 is N and the remaining X 1 or X 2 is CH; and R 6 is H, OH, or C 1 -C 3 alkoxy.

8. The compound of claim 1 , wherein
R 1 is

 —CH 2 Ph, —CH 2 CH 2 Ph, —CH═CH-Ph, furanyl, thiophenyl, pyrimidinyl, 4-thiazolyl, 4-oxazolyl, 4-pyridinyl, or

 wherein one of X 1 and X 2 is N and the remaining X 1 or X 2 is CH; and R 6 is H, OH, or C 1 -C 3 alkoxy; and
R 2 , R 3 , and R 4 are each independently H, halo, OH, nitro, unsubstituted C 1 -C 3 n-alkyl, or unsubstituted C 1 -C 3 n-alkoxy.

9. The compound of claim 1 , wherein
R 1 is

 —CH 2 Ph, —CH 2 CH 2 Ph, —CH═CH-Ph, unsubstituted 2-furanyl, unsubstituted 2-benzofuranyl, unsubstituted 3-furanyl, unsubstituted 2-thiophenyl, unsubstituted 3-thiophenyl, unsubstituted 5-pyrimidinyl, unsubstituted 4-thiazolyl, unsubstituted 4-oxazolyl, unsubstituted 4-pyridinyl, or

 wherein one of X 1 and X 2 is N and the remaining X 1 or X 2 is CH; and R 6 is H, OH, or C 1 -C 3 alkoxy; and
R 2 , R 3 , and R 4 are each independently H, halo, OH, nitro, unsubstituted C 1 -C 3 n-alkyl, or unsubstituted C 1 -C 3 n-alkoxy.

10. The compound of claim 1 , wherein
R 1 is

 —CH═CH-Ph, unsubstituted 2-furanyl, unsubstituted 2-benzofuranyl, unsubstituted 3-furanyl, unsubstituted 2-thiophenyl, unsubstituted 3-thiophenyl, unsubstituted 5-pyrimidinyl, unsubstituted 4-thiazolyl, unsubstituted 4-oxazolyl, unsubstituted 4-pyridinyl, or

 wherein one of X 1 and X 2 is N and the remaining X 1 or X 2 is CH; and R 6 is H, OH, or C 1 -C 3 alkoxy; and
R 2 , R 3 , and R 4 are each independently H, halo, OH, nitro, unsubstituted C 1 -C 3 n-alkyl, or unsubstituted C 1 -C 3 n-alkoxy.

11. The compound of claim 1 , wherein the compound is

12. A composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.

13. A composition comprising the compound of claim 8 and a pharmaceutically acceptable carrier.

14. A composition comprising the compound of claim 10 and a pharmaceutically acceptable carrier.

15. A pharmaceutical composition comprising an effective amount of the compound of claim 1 for treating pain in a subject, and a pharmaceutically acceptable carrier.

16. A pharmaceutical composition comprising an effective amount of the compound of claim 8 for treating pain in a subject, and a pharmaceutically acceptable carrier.

17. A method comprising administering an effective amount of a compound of claim 1 to a subject in need thereof.

18. The method of claim 17 , wherein the subject is suffering from at least one of acute pain and chronic pain.

19. A method of binding the mu opioid receptor, the method comprising contacting a mu opioid receptor with a compound of claim 1 .

20. The method of claim 19 , wherein the contacting comprises a cell not within a patient.

Assignees

• Univ Kansas

Inventors

• Prisinzano Thomas E
• Riley Andrew P
• Groer Chad E

Classifications

• G01N33/9486

  Analgesics, e.g. opiates, aspirine · CPC title

• C07D401/14

  containing three or more hetero rings · CPC title

• C07D413/14

  containing three or more hetero rings · CPC title

• C07D411/14

  containing three or more hetero rings · CPC title

• G01N33/5041

  involving analysis of members of signalling pathways · CPC title