2-phenylpiperazine derivatives

• US 6,906,074 B2
• Filed: 02/20/2003
• Issued: 06/14/2005
• Est. Priority Date: 02/22/2002
• Status: Expired due to Fees

• Current Assignee: Nippon Zoki Pharmaceutical Co., Ltd.
• Original Assignee: Nippon Zoki Pharmaceutical Co., Ltd.
• Inventors: Konishi, Yukari, Ogino, Takashi, Furukawa, Kazuhito, Higashiura, Kunihiko
• Primary Examiner(s): McKenzie, Thomas C.
• Application Number:
  US10/370,918
• Publication Number:
  US 20030166616A1
• Time in Patent Office: 845 Days
• Field of Search: 514/253.01, 514/254.01, 514/254.05, 514/255.02, 514/255.03, 544/337, 544/360, 544/366, 544/372, 544/384, 544/389, 544/390, 544/391, 544/403
• US Class Current: 514/253.01
• 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

A 2-phenylpiperazine derivative represented by the formula (I) or a pharmaceutically acceptable salt, hydrate, or complex thereof:
wherein each of X₁ and X₃ is oxygen or two hydrogen atoms, X₂ O, NH, NCH₃, or CH₂, n is an integer of 0 or 1, R₁ is hydrogen or lower alkyl and R₂ is hydrogen, cyano, tetrazolyl, aminotriazolyl , mesyl, t-butoxycarbonyl, or a lower alkyl which may be optionally substituted, R₃ is hydrogen, halogen, lower alkyl or lower alkoxy, each of R₄ and R₅ is hydrogen, lower alkoxy or trifluoromethyl, and a broken line indicates a single or double bond. The derivative may be used as a tachykinin antagonist in the treatment of diseases of the digestive system, nervous system and respiratory system, inflammation, allergy, carcinoid syndrome, chronic pain, headache, Crohn disease, depression and vomiting.

Claims

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

wherein each of X₁ and X₃ is oxygen or two hydrogen atoms, X₂ is O, NH, NCH₃, or CH₂, n is an integer of 0 or 1, R₁ is hydrogen or lower alkyl and R₂ is hydrogen, cyano, tetrazolyl, aminotriazolyl, mesyl, t-butoxycarbonyl, or lower alkyl, wherein when R₂ is lower alkyl, the lower alkyl may be optionally substituted with a substituent selected from the following substituents (a) to (j) and/or oxo,

(a) triazolonyl,

(b) tetrazolyl,

(c) dimethylaminomethyltriazolyl;

(d) phosphotriazolonyl,

(e) pyridyl,

(f) dimethylamino,

(g) cyano,

(h) pyrrolidino,

(i) amino,

(j) phenyl,

R₃ is hydrogen, halogen, lower alkyl or lower alkoxy, each of R₄ and R₅ is hydrogen, lower alkoxy or trifluoromethyl, and a broken line indicates a single or double bond.

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, 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.

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.