Oxa spiro derivative, preparation method therefor, and applications thereof in medicines

• US 10,442,793 B2
• Filed: 09/30/2016
• Issued: 10/15/2019
• Est. Priority Date: 10/15/2015
• Status: Active Grant

• Current Assignee: Jiangsu Hengrui Medicine Company Limited, Shanghai Hengrui Pharmaceutical Co., Ltd. (Jiangsu Hengrui Pharmaceuticals Co., Ltd.)
• Original Assignee: Jiangsu Hengrui Medicine Company Limited
• Inventors: Li, Xin, Feng, Binqiang, Chen, Yang, Liu, Tao, He, Feng, He, Mingxun, Tao, Weikang, Sun, Piaoyang
• Primary Examiner(s): Carter, Kendra D
• Application Number:
  US15/766,985
• Publication Number:
  US 20180297988A1
• Time in Patent Office: 1,110 Days
• CPC Class Codes: A61K 31/4436 containing a heterocyclic ring having sulfur as a ring hetero atom
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: C07D 405/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• CPC Class Codes: C07D 409/14 containing three or more hetero rings

Abstract

The present invention relates to an oxa spiro derivative, a preparation method therefor, and applications thereof in medicines. Particularly, the present invention relates to an oxa spiro derivative represented by formula (I), a preparation method therefor, and a pharmaceutical composition comprising the derivative, applications thereof as an MOR receptor agonist, and applications in the preparation of drugs for treating and/or preventing pains and pains-related diseases. Substituent groups in the formula (I) are same as definitions in the specification.

Claims

1. A compound of formula (I):

2. The compound according to claim 1, wherein ring A is selected from the group consisting of 5 to 6 membered heterocyclyl and 5 to 6 membered cycloalkyl.

3. The compound according to claim 1, wherein R is pyridyl.

4. The compound according to claim 1, being a compound of formula (II):

5. The compound according to claim 1, wherein R¹ is hydrogen or halogen.

6. The compound according to claim 1, wherein R² is selected from the group consisting of hydrogen, alkyl, oxo, alkoxy, hydroxy, halogen and —

OR³, wherein the alkyl and alkoxy are each optionally substituted by one or more groups selected from the group consisting of deuterium, alkyl, halogen, hydroxy, amino, alkoxycarbonyl, nitro, cyano, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; and

R³ is selected from the group consisting of hydrogen, alkyl and cycloalkyl, wherein the alkyl is optionally substituted by halogen or cycloalkyl.

7. The compound according to claim 4, being a compound of formula (IV):

9. A process for preparing the compound of formula (I) according to claim 1, comprising:

10. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to claim 1, and one or more pharmaceutically acceptable carriers, diluents or excipients.

11. The compound according to claim 6, wherein R² is alkyl, wherein the alkyl is optionally substituted by alkoxy, cycloalkyl or haloalkyl;

and R³ is hydrogen, alkyl, haloalkyl or cycloalkyl.

12. A method of treating pain in a subject, the method comprising administering to the subject the pharmaceutical composition of claim 10.

13. The method according to claim 12, wherein the pain is selected from the group consisting of postoperative pain, pain induced by a cancer, neuropathic pain, traumatic pain and inflammatory pain.

14. The method according to claim 13, wherein the cancer is selected from the group consisting of breast cancer, endometrial cancer, cervical cancer, skin cancer, prostate cancer, ovarian cancer, fallopian tube tumor, ovarian tumor, hemophilia and leukemia.

15. A method of agonizing a MOR receptor in a subject, the method comprising administering to the subject the pharmaceutical composition of claim 10.

8. A compound selected from the group consisting of:

16. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to claim 8, and one or more pharmaceutically acceptable carriers, diluents or excipients.

17. A method of treating pain in a subject, the method comprising administering to the subject the pharmaceutical composition of claim 16.

18. The compound according to claim 8, wherein the compound is

19. The compound according to claim 8, wherein the compound is selected from the group consisting of:

20. The compound according to claim 8, wherein the compound is selected from the group consisting of:

21. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to claim 18, and one or more pharmaceutically acceptable carriers, diluents or excipients.

22. A method of treating pain in a subject, the method comprising administering to the subject the pharmaceutical composition of claim 21.

23. The method according to claim 22, wherein the pain is selected from the group consisting of postoperative pain, pain induced by a cancer, neuropathic pain, traumatic pain and inflammatory pain.

24. The method according to claim 23, wherein the cancer is selected from the group consisting of breast cancer, endometrial cancer, cervical cancer, skin cancer, prostate cancer, ovarian cancer, fallopian tube tumor, ovarian tumor, hemophilia and leukemia.