Novel 2-phenylpiperazine derivatives

• US 20030166616A1
• Filed: 02/20/2003
• Published: 09/04/2003
• Est. Priority Date: 02/22/2002
• Status: Active Grant

• Current Assignee: Nippon Zoki Pharmaceutical Co., Ltd.
• Original Assignee: Nippon Zoki Pharmaceutical Co., Ltd.
• Inventors: Ogino, Takashi, Furukawa, Kazuhito, Higashiura, Kunihiko, Konishi, Yukari
• Granted Patent: US 6,906,074 B2
• Time in Patent Office: Days
• US Class Current: 514/85
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: C07D 241/04 having no double bonds between ring members or between ring members and non-ring members
• CPC Class Codes: C07D 241/08 with oxygen atoms directly attached to ring carbon atoms
• CPC Class Codes: C07D 401/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 403/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 403/06 linked by a carbon chain containing only aliphatic carbon atoms

Abstract

Excellent tachykinin receptor antagonistic activity is provided by 2-phenylpiperazine derivatives. The piperazine derivatives exhibit a strong inhibitory action against a tachykinin-induced increase of vascular permeability in in vivo tests. Moreover, the derivatives show a preferred transfer into blood, a long half-life in blood in pharmacokinetic tests of oral administration to rats or guinea pigs, and are very stable in blood plasma of various animals. Consequently, a piperazine derivative of the present invention is very useful as a tachykinin antagonist.

Claims

1. A 2-phenylpiperazine derivative represented by the following formula (I) or a pharmaceutically acceptable salt, hydrate, or complex thereof, said 2-phenylpiperazine derivative being represented by the formula (I):

2. A 2-phenylpiperazine derivative according to claim 1 wherein X₁ is oxygen.

3. A 2-phenylpiperazine derivative according to claim 2 wherein X₂ is oxygen.

4. A 2-phenylpiperazine derivative according to claim 3 wherein X₃ is two hydrogen atoms.

5. A 2-phenylpiperazine derivative according to claim 4 wherein n is an integer of 1.

6. A 2-phenylpiperazine derivative according to claim 5 wherein R₁ is methyl.

7. A 2-phenylpiperazine derivative according to claim 6 wherein R₂ is triazolonylmethyl.

8. A 2-phenylpiperazine derivative according to claim 7 wherein R₃ is hydrogen.

9. A 2-phenylpiperazine derivative according to claim 8 wherein R₄ is substituted at the m-position.

10. A 2-phenylpiperazine derivative according to claim 9 wherein R₄ is trifluoromethyl.

11. A 2-phenylpiperazine derivative according to claim 10 wherein R₅ is substituted at the m-position.

12. A 2-phenylpiperazine derivative according to claim 11 wherein R₅ is trifluoromethyl.

13. A 2-phenylpiperazine derivative according to claim 1 wherein R₂ is lower alkyl which is substituted with oxo.

14. A 2-phenylpiperazine derivative according to claim 13 wherein R₂ is lower alkyl which is substituted with both an oxo and a triazolonyl substituent.

16. A pharmaceutical composition comprising at least one 2-phenylpiperazine derivative or a pharmaceutically acceptable salt, hydrate, or complex thereof according to claim 1 in a pharmaceutically effective amount, and a pharmaceutically acceptable carrier.

17. A pharmaceutical composition according to claim 16 wherein X₁ is oxygen.

18. A pharmaceutical composition according to claim 16 wherein said at least one 2-phenylpiperazine derivative comprises (5S,6S)-6-(3,5-Bis(trifluoromethyl)benzyloxymethyl)-1-methyl-4-(5-oxo-4,5-dihydro-1H-(1,2,4)triazol-3-ylmethyl)-5-phenylpiperazin-2-one.

19. A method for the treatment of a disease or condition associated with at least one tachykinin comprising administering to a patient known to be in need of such treatment, or known to be in need of suppression of said at least one tachykinin, a pharmaceutically effective amount of at least one 2-phenylpiperazine derivative or a pharmaceutically acceptable salt, hydrate, or complex thereof according to claim 1.

20. A method as claimed in claim 19 wherein said disease or condition is selected from the group.consisting of diseases of the digestive system, nervous system and respiratory system, inflammation, allergy, carcinoid syndrome, chronic pain, headache, Crohn disease, depression and vomiting.

21. A method as claimed in claim 19 wherein said at least one tachykinin comprises at least one member selected from the group consisting of Substance P (SP), neurokinin A (NKA) and neurokinin B (NKB).

22. A method for the treatment of a disease or condition associated with at least one tachykinin comprising determining the serum tachykinin value of a patient and administering to a patient in need of such treatment a pharmaceutically effective amount of at least one 2-phenylpiperazine derivative or a pharmaceutically acceptable salt, hydrate, or complex thereof according to claim 1 to substantially suppress the serum tachykinin value.

23. A method as claimed in claim 22 wherein said at least one tachykinin comprises at least one member selected from the group consisting of Substance P (SP), neurokinin A (NKA) and neurokinin B (NKB).

15. (5S,6S)-6-(3,5-Bis(trifluoromethyl)benzyloxymethyl)-1-methyl-4-(5-oxo-4,5-dihydro-1H-(1,2,4)triazol-3-ylmethyl)-5-phenylpiperazin-2-one.