Therapeutic compound for pain and synthesis thereof

Patent metadata

Field	Value
Publication number	US-10766898-B2
Application number	US-201816222852-A
Country	US
Kind code	B2
Filing date	Dec 17, 2018
Priority date	Sep 4, 2015
Publication date	Sep 8, 2020
Grant date	Sep 8, 2020

Abstract

The invention provides compounds of Formula XXIII:

wherein R 1 is hydrogen, alkyl, acyl, or silyl, R 2 is hydrogen, alkyl, benzyl, acyl, or ester, and R 3 is hydrogen, alkyl, an aromatic group, azacyclic, carbocycle, aryl, cycloalkyl, heterocycloalkyl, heterocycle, heteroaryl, heteroalkyl, acyl, or ester, as well as derivatives and stereoisomers, pharmaceutically acceptable salts and derivatives thereof; and methods of making and using such compounds. The invention includes pharmaceutical compositions containing such compounds, and the use of such compounds in methods of treating conditions, diseases, or disorders.

First claim

What is claimed is:

1. A compound of Formula XXIII(A):

wherein R 2 is selected from the group consisting of hydrogen, C(O)R′ wherein R′ is CH 2 OCH 3 , or pyridine optionally substituted with halo;
wherein R 3 is selected from the group consisting of hydrogen, BOC, optionally substituted phenyl, or methylbenzodioxole; and
wherein R 4 is hydrogen, alkyl, or cycloalkyl, or a stereoisomer, pharmaceutically acceptable salt, or mixture thereof.

2. The compound of claim 1 , wherein R 4 is C 3 cycloalkyl.

3. A compound of Formula XXIII(B):

wherein R 1 is selected from the group consisting of hydrogen, benzyl, tert-butyldiphenylsilyl, or C═OR 4 , wherein R 4 is alkyl;
wherein R 3 is selected from the group consisting of hydrogen, BOC, phenyl substituted with CON(R′) 2 wherein R′ is H, or; and
wherein R 5 is hydrogen, alkyl, alkyl substituted with OCH 3 , optionally substituted pyridine, or a stereoisomer, pharmaceutically acceptable salt, or mixture, thereof.

4. The compound of claim 3 , wherein R 5 is CH 2 OCH 3 or pyridine substituted with F.

5. The compound of claim 3 , having the Formula XXIII(C):

wherein R 4 is alkyl or cycloalkyl, or a stereoisomer, pharmaceutically acceptable salt, or mixture thereof.

6. The compound of claim 5 , wherein R 4 is C 3 cyloalkyl.

7. The compound of claim 5 , having the Formula XXIII(E):

wherein R 6 is methylbenzodioxole, or phenyl substituted with CON(R′) 2 wherein R′ is H or a stereoisomer, pharmaceutically acceptable salt, or mixture thereof.

8. The compound of claim 7 , wherein R 6 is methylbenzodioxole.

9. A compound of Formula XXIII(D):

wherein R 1 is hydrogen, C═Oalkyl, or C═O cycloalkyl;
wherein R 2 is C═O optionally substituted pyridine or COCH 2 OCH 3 ; and
wherein R 6 is phenyl substituted with CON(R′) 2 wherein R′ is H, methylbenzodioxole, azacyclic, pharmaceutically acceptable salt, or mixture thereof.

10. The compound of claim 9 , wherein R 6 is methylbenzodioxol, or phenyl substituted with CON(R′) 2 wherein R′ is H.

11. A pharmaceutical composition comprising a compound of claim 1 , and a pharmaceutically acceptable carrier or diluent.

12. A method for treating pain in a subject, comprising administering to the subject an effective amount of the compound of claim 1 .

13. The method of claim 12 , wherein the compound is administered to effect localized delivery to the subject.

14. The method of claim 12 , wherein the compound is administered to effect systemic delivery to the subject.

15. The method of claim 12 , wherein the pain is chronic pain.

16. The method of claim 12 , wherein the pain is neuropathic pain.

17. A compound having the

or pharmaceutically acceptable salt, or stereoisomer thereof.

18. A method of producing a compound of

or

wherein R 1 is hydrogen, tert-butyldiphenylsiyl, or COC 3 cyloakyl;
wherein R 2 is C═O optionally substituted pyridine, or COCH 2 OCH 3 ;
wherein R 5 is fluoropyridine or CH 2 COCH 3 ; and
wherein R 3 or R 6 is hydrogen, BOC, methylbenzodioxole, or phenyl substituted with CON(R′) 2 wherein R′ is H,
or a stereoisomer, or pharmaceutically acceptable salt thereof, by reacting scopolamine or a derivative thereof.

19. A compound of Formula XVIII:

or a stereoisomer, pharmaceutically acceptable salt, or mixture thereof.

20. A pharmaceutical composition comprising a compound of claim 17 , and a pharmaceutically acceptable carrier or diluent.

21. A pharmaceutical composition comprising a compound of claim 19 , and a pharmaceutically acceptable carrier or diluent.

22. A method of producing a compound of claim 19 , wherein the method comprises reacting a compound of

23. A pharmaceutical composition comprising a compound of claim 3 , and a pharmaceutically acceptable carrier or diluent.

24. A pharmaceutical composition comprising a compound of claim 9 , and a pharmaceutically acceptable carrier or diluent.

25. A method for treating pain in a subject, comprising administering to the subject an effective amount of the compound of claim 3 .

26. The method of claim 25 , wherein the pain is neuropathic pain or chronic pain.

27. A method for treating pain in a subject, comprising administering to the subject an effective amount of the compound of claim 9 .

28. The method of claim 27 , wherein the pain is neuropathic pain or chronic pain.

Assignees

• Janssen Pharmaceutica Nv

Inventors

• Decorte Bart
• Russcher Jacob Cornelis
• Monnee Menno Cornelis Franciscus

Classifications

• C07D451/12

  acylated by aromatic or heteroaromatic carboxylic acids, e.g. cocaine · CPC title

• C07D451/10

  acylated by aliphatic or araliphatic carboxylic acids, e.g. atropine, scopolamine · CPC title

• C07D451/06

  Oxygen atoms · CPC title

• C07D451/04

  with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system · CPC title

• A61P29/02

  without antiinflammatory effect · CPC title