Substituted spiropyrido[1,2-a]pyrazine derivative and medicinal use thereof as HIV integrase inhibitor

Patent metadata

Field	Value
Publication number	US-10087178-B2
Application number	US-201314758082-A
Country	US
Kind code	B2
Filing date	Dec 27, 2013
Priority date	Dec 27, 2012
Publication date	Oct 2, 2018
Grant date	Oct 2, 2018

Abstract

Provided is a substituted spiropyrido[1,2-a]pyrazine derivative or a pharmaceutically acceptable salt thereof, which is useful as an anti-HIV agent. The present invention relates to a compound represented by the following formula [I] or [II] or a pharmaceutically acceptable salt thereof:

wherein each symbol is as defined in the specification.

First claim

We claim:

1. A compound represented by the following formula [I] or [II], or a pharmaceutically acceptable salt thereof:

wherein
R 1 is halogen atom,
R 2 is hydrogen atom, halogen atom or trifluoromethyl group,
R 3 is
(1) halogen atom,
(2) C 1-6 alkoxy group, or
(3) 2-oxopyrrolidinyl group,

when p is 2 or 3, R 3 are the same or different,
R 4 is C 1-6 alkyl group or cyclopropyl group,
R 5 is
(1) hydroxy group,
(2) C 1-6 alkoxy group,
(3) benzyloxy group,
(4) C 1-6 alkoxy C 2-6 alkyleneoxy group,
(5) carboxy group,
(6) —CO—NR 6a R 6b
wherein R 6a and R 6b are the same or different and each is
(i) hydrogen atom, or
(ii) C 1-6 alkyl group,

(7) —NR 7a COR 7b
wherein R 7a and R 7b are the same or different and each is
(i) hydrogen atom, or
(ii) C 1-6 alkyl group,

(8) methanesulfonyl group, or
(9) methanesulfonyloxy group,

R 8 is
(1) hydrogen atom,
(2) acetyl group,
(3) propionyl group,
(4) isobutyryl group,
(5) pivaloyl group,
(6) palmitoyl group,
(7) benzoyl group,
(8) 4-methylbenzoyl group,
(9) dimethylcarbamoyl group,
(10) dimethylaminomethylcarbonyl group,
(11) fumaryl group, or
(12) 3-carboxybenzoyl group,

p is an integer of 0 to 3,
q is 0 or 1, and
r is 0 or 1.

2. The compound according to claim 1 , wherein q is 1 or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1 , wherein q is 0 or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 1 , wherein p is 0 or 1, or a pharmaceutically acceptable salt thereof.

5. The compound according to any one of claims 1 to 4 , wherein r is 1, or a pharmaceutically acceptable salt thereof.

6. The compound according to any one of claims 1 to 4 , wherein r is 0, or a pharmaceutically acceptable salt thereof.

7. The compound according to any one of claims 1 to 4 , wherein R 2 is halogen atom, or a pharmaceutically acceptable salt thereof.

8. The compound according to any one of claims 1 to 4 , wherein R 4 is C 1-6 alkyl group, or a pharmaceutically acceptable salt thereof.

9. The compound according to any one of claims 1 to 4 , wherein R 5 is
(1) hydroxy group,
(2) C 1-6 alkoxy group,
(3) benzyloxy group,
(4) C 1-6 alkoxy C 2-6 alkyleneoxy group, or
(5) —CO—NR 6a R 6b
wherein R 6a and R 6b are the same or different and each is
(i) hydrogen atom, or
(ii) C 1-6 alkyl group,

or a pharmaceutically acceptable salt thereof.

10. The compound according to any one of claims 1 to 4 , wherein R 5 is
(1) hydroxy group,
(2) C 1-6 alkoxy group, or
(3) —CO—NR 6a R 6b
wherein R 6a and R 6b are the same or different and each is
(i) hydrogen atom, or
(ii) C 1-6 alkyl group,

or a pharmaceutically acceptable salt thereof.

11. A compound represented by the formula [I′] or [II′], or a pharmaceutically acceptable salt thereof:

wherein
R 1 is halogen atom,
R 2 is hydrogen atom, halogen atom or trifluoromethyl group,
R 3 is the same or different and each is
(1) halogen atom,
(2) C 1-6 alkoxy group, or
(3) 2-oxopyrrolidinyl group,

R 4 is C 1-6 alkyl group or cyclopropyl group,
R 5 is
(1) hydroxy group,
(2) C 1-6 alkoxy group,
(3) benzyloxy group,
(4) C 1-6 alkoxy C 2-6 alkyleneoxy group,
(5) carboxy group,
(6) —CO—NR 6a R 6b
wherein R 6a and R 6b are the same or different and each is
(i) hydrogen atom, or
(ii) C 1-6 alkyl group,

(7) —NR 7a COR 7b
wherein R 7a and R 7b are the same or different and each is
(i) hydrogen atom, or
(ii) C 1-6 alkyl group,

(8) methanesulfonyl group, or
(9) methanesulfonyloxy group,

p is an integer of 0 to 3,
q is 0 or 1, and
r is 0 or 1.

12. A pharmaceutical composition comprising the compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

13. An anti-HIV agent comprising the compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, as an active ingredient.

14. An HIV integrase inhibitor comprising the compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, as an active ingredient.

15. An anti-HIV agent comprising the compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, in combination with one or more other kinds of anti-HIV active substances.

16. A method for the treatment of an HIV infection in a mammal, comprising administering an effective amount of the compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, to the mammal.

17. The method according to claim 16 , further comprising administering an effective amount of one or more other kinds of anti-HIV active substances to the mammal.

18. A method for inhibiting HIV integrase in a mammal, comprising administering an effective amount of the compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof.

19. A compound represented by the formula (6), or a pharmaceutically acceptable salt thereof:

20. A compound represented by the formula (26), or a pharmaceutically acceptable salt thereof:

21. A compound represented by the formula (S20), or a pharmaceutically acceptable salt thereof:

22. A compound represented by the formula (S40), or a pharmaceutically acceptable salt thereof:

23. A compound represented by the formula (S51), or a pharmaceutically acceptable salt thereof:

24. A compound represented by the formula (S68), or a pharmaceutically acceptable salt thereof:

25. A compound represented by the formula (T13), or a pharmaceutically acceptable salt thereof:

26. A compound represented by the formula (T40), or a pharmaceutically acceptable salt thereof:

27. A compound represented by the formula (T41), or a pharmaceutically acceptable salt thereof:

28. A pharmaceutical composition comprising the compound according to any one of claims 19 - 27 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Assignees

• Japan Tobacco Inc

Inventors

• Miyazaki Susumu
• Isoshima Hirotaka
• Oshita Kengo
• Kawashita Seiji
• Nagahashi Noboru
• Terashita Masakazu

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P31/18

  for HIV · CPC title

• C07D471/10

  Spiro-condensed systems · CPC title

• C07D487/10

  Spiro-condensed systems · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title