Pyrano[3,4-b]pyrazine kappa opioid receptor ligands for treating addiction, pruritus, pain, and inflammation

Patent metadata

Field	Value
Publication number	US-11091497-B2
Application number	US-201816769858-A
Country	US
Kind code	B2
Filing date	Dec 7, 2018
Priority date	Dec 8, 2017
Publication date	Aug 17, 2021
Grant date	Aug 17, 2021

Abstract

1-Phenylacetyl-8-aminohexahydro-2H-pyrano[3,4-b]pyrazines of formulaare disclosed. The compounds are kappa ligands and are useful to treat drug dependency, pruritus, pain, and inflammation.

First claim

The invention claimed is:

1. A compound of Formula I

wherein
R 1 is chosen from hydrogen, (C 1 -C 10 )hydrocarbyl, —C(═O)(C 1 -C 10 )hydrocarbyl, —C(═O)O(C 1 -C 10 )hydrocarbyl and —SO 2 (C 1 -C 10 )hydrocarbyl;
R 2 , R 3 , R 4 , and R 8 are chosen independently from hydrogen, halogen, (C 1 -C 4 )alkyl, fluoro(C 1 -C 4 )alkyl, nitro, —SO 3 H and —N + HR 5 R 6 ; with the provisos that (1) at least one of R 2 , R 3 , R 4 , and R 8 must be other than hydrogen; and (2) when R 2 or R 4 is fluorine, at least one of the remaining substituents on phenyl must be other than hydrogen; and
R 5 and R 6 are chosen from (C 1 -C 10 )hydrocarbyl, optionally substituted with fluoro, or, taken together with the nitrogen to which they are attached, R 5 and R 6 form a five-, six- or seven-membered non-aromatic heterocycle, which may be optionally substituted with fluoro or (C 1 -C 4 )alkyl.

2. A compound according to claim 1 wherein R 8 is hydrogen and one of R 2 , R 3 , and R 4 is hydrogen and the remaining two are chosen from hydrogen, halogen, fluoro(C 1 -C 4 )alkyl, and (C 1 -C 3 )alkyl.

3. A compound according to claim 2 wherein two of R 2 , R 3 , and R 4 are hydrogen and the remaining one is chosen from chloro, fluoro, trifluoromethyl, and methyl.

4. A compound according to claim 2 wherein R 1 is hydrogen.

5. A compound according to claim 2 wherein R 1 is chosen from (C 1 -C 7 )hydrocarbyl and —SO 2 (C 1 -C 8 )hydrocarbyl.

6. A compound according to claim 5 wherein R 1 is chosen from (C 1 -C 7 )alkyl, benzyl, and —SO 2 (C 1 -C 3 )alkyl.

7. A compound according to claim 6 wherein R 1 is —SO 2 (C 1 -C 3 )alkyl.

8. A compound according to claim 5 wherein R 1 is (C 1 -C 7 )hydrocarbyl.

9. A compound according to claim 1 wherein the ring junction of the octahydro-1H-pyrano[3,4-b]pyrazine is trans and —NR 5 R 6 is cis to its adjacent hydrogen at the ring junction.

10. A compound according to claim 1 wherein —NR 5 R 6 is

wherein R 7 is chosen from hydrogen, fluoro and (C 1 -C 3 )alkyl.

11. A compound according to claim 1 wherein:
R 1 is chosen from hydrogen, (C 1 -C 7 )hydrocarbyl, —C(═O)O(C 1 -C 3 )hydrocarbyl and —SO 2 (C 1 -C 8 )hydrocarbyl;
R 2 , R 3 , and R 4 are chosen independently from hydrogen, halogen, (C 1 -C 3 )alkyl, and fluoro(C 1 -C 3 )alkyl;
R 5 and R 6 are chosen from (C 1 -C 6 )hydrocarbyl, or, taken together with the nitrogen to which they are attached, R 5 and R 6 form a five-, six- or seven-membered non-aromatic heterocycle; and
R 8 is hydrogen.

12. A compound according to claim 11 wherein:
R 1 is chosen from hydrogen, (C 3 -C 4 )alkyl, —C(═O)O(C 1 -C 3 )hydrocarbyl, and —SO 2 (C 1 -C 8 )hydrocarbyl;
R 2 is hydrogen;
R 3 and R 4 are chosen independently from hydrogen, halogen, (C 1 -C 3 )alkyl, and fluoro(C 1 -C 3 )alkyl; and
R 5 and R 6 , taken together with the nitrogen to which they are attached, form a five-, six- or seven-membered non-aromatic heterocycle.

13. A compound according to claim 11 wherein:
R 1 is methyl or (C 1 -C 7 )hydrocarbyl.

14. A compound according to claim 11 wherein R 1 is —CH 2 R 10 and R 10 is hydrogen or (C 4 -C 6 )carbocycle.

15. A compound according to claim 11 wherein R 1 is H, R 5 is methyl and R 6 is methyl or cyclopropylmethyl.

16. A compound according to claim 11 wherein:
R 3 is fluoro(C 1 -C 3 )alkyl when R 2 and R 4 are hydrogen.

17. A compound according to claim 11 wherein:
R 5 and R 6 together with nitrogen form a pyrrolidine ring.

18. A method for activating a kappa opioid receptor, comprising contacting a kappa opioid receptor with a compound according to claim 1 .

19. A method for treating addiction, comprising administering to a patient a compound according to claim 1 .

20. A method according to claim 19 wherein said addiction is an addiction to cocaine.

Assignees

• Univ Rockefeller

Inventors

• Kreek Mary Jeanne
• Ripka Amy
• Reed Brian
• Butelman Eduardo

Classifications

• A61P25/30

  for treating abuse or dependence · CPC title

• A61P17/04

  Antipruritics · CPC title

• C07D491/04 Primary

  Ortho-condensed systems · CPC title

• A61P25/32

  Alcohol-abuse · CPC title

• C07D491/052 Primary

  the oxygen-containing ring being six-membered · CPC title