Compounds and methods for the treatment of cardiovascular, inflammatory and immune disorders

• US 5,681,966 A
• Filed: 06/07/1995
• Issued: 10/28/1997
• Est. Priority Date: 06/27/1994
• Status: Expired due to Term

• Current Assignee: Millennium Pharmaceuticals Incorporated (Takeda Pharmaceutical Company Limited)
• Original Assignee: CytoMed, Inc. (Takeda Pharmaceutical Company Limited)
• Inventors: Biftu, Tesfaye, Cai, Xiong, Grewal, Gurmit, Hussoin, Sajjat, Fura, Aberra, Scannell, Ralph
• Primary Examiner(s): Raymond, Richard L.
• Assistant Examiner(s): LAMBKIN, DEBORAH C
• Application Number:
  US08/485,096
• Time in Patent Office: 874 Days
• Field of Search: 549/493, 549/487, 549/480, 549/65, 549/77, 549/68, 514/471, 514/472, 514/473, 514/445, 514/447
• US Class Current: 549/65
• CPC Class Codes: C07D 307/14 Radicals substituted by nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 471/04 Ortho-condensed systems

Abstract

Enantiomerically enriched disubstituted tetrahydrofurans, tetrahydrothiophenes, pyrrolidines and cyclopentanes are disclosed that reduce the chemotaxis and respiratory burst leading to the formation of damaging oxygen radicals of polymorphonuclear leukocytes during an inflammatory or immune response. The compounds exhibit this biological activity by acting as PAF receptor antagonists, by inhibiting the enzyme 5-lipoxygenase, or by exhibiting dual activity, i.e., by acting as both a PAF receptor antagonist and inhibitor of 5-lipoxygenase.

It has been determined that 5-lipoxygenase activity, oral availability, and stability in vivo (for example, glucuronidation rate) can vary significantly among the optical isomers of the disclosed compounds.

Claims

1. The compound of formula:

##STR46## wherein;

Ar is phenyl optionally substituted with at least one group selected from the group consisting of halo, lower alkoxy, lower aryloxy, W, cyano, or R³ ;

m is 0 or 1;

W is independently --AN(OM)C(O)N(R³)R⁴, --AN(R³)C(O)N(OM)R⁴, --AN(OM)C(O)R⁴, or --AC(O)N(OM)R⁴ ;

A is lower alkynyl wherein one or more carbons optionally can be replaced by O, N, or S;

M is hydrogen, a pharmaceutically acceptable cation, or metabolically cleavable leaving group;

X is O, S, S(O),

Y is O, S, S(O), NR⁵, or CHR⁵ ;

R¹ and R² are independently hydrogen, lower alkyl;

halo lower alkyl;

halo; and

--COOH;

R³ and R⁴ are independently hydrogen or alkyl, alkenyl, alkynyl, aralkyl, alkaryl, C_1-6 alkoxy-C_1-10 alkyl, C_1-6 or alkylthio-C_1-10 alkyl,; and

R⁵ is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, alkaryl, --AN(OM)C(O)N(R³)R⁴, --AN(R³)C(O)N(OM)R⁴, --AN(OM)C(O)R⁴, --AC(O)N(OM)R⁴,

--AS(O)xR³, --AS(O)xCH₂ C(O)R³, AS(O)xCH₂ CH(OH)R³, or --AC(O)NHR³ ;

wherein x is 0-2, or a pharmaceutically acceptable salt thereof.

2. A method for the treatment of a patient in need of immunosuppression comprising administering an effective mount of the compound of claim 1 or a pharmaceutically acceptable salt thereof.

3. A method for the treatment of inflammatory disorders in a host comprising administering an effective amount of a compound of claim 1 wherein the host is selected from a human, a mammal, an equine, a canine, and a bovine.

4. The method of claim 2, wherein the animal is selected from a human, a mammal, an equine, a canine and a bovine.

5. The method for the treatment of a cardiovascular disorder comprising administering an effective amount of the compound of claim 1, or a pharmaceutically acceptable salt thereof.

6. A method for the inhibition of 5-lipoxygenase in a patient comprising administering an effective amount of the compound of claim 1, or a pharmaceutically acceptable salt thereof.

7. The compound of claim 1 wherein Ar is selected from the group consisting of phenyl, trimethoxyphenyl, dimethoxyphenyl, fluorophenyl, and difluorophenyl.

8. The compound of claim 1 wherein Ar is selected from 4-fluorophenyl, 3,4,5-methoxyphenyl, 3,4-dimethoxyphenyl, and 3,4-difluorophenyl.

9. The compound of claim 1 wherein W is selected from --C.tbd.CCH₂ N(OH)C(O)NH₂, and --C.tbd.CCH(CH₃)N(OH)C(O)NH₂.

10. The compound of claim 1 wherein X is oxygen.

11. The compound of claim 1 wherein the substituent on Ar is halo.

12. The compound of the claim 1 wherein Ar is:

##STR47##

21. A method for the treatment of an inflammatory disorder in a host comprising administering an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

22. A method for the treatment of an inflammatory disorder in a host comprising administering an effective amount of the compound of claim 12 or a pharmaceutically acceptable salt thereof.

31. A method for the inhibition of 5-lipoxygenase in a host in need thereof comprising administering an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

32. A method for the inhibition of 5-lipoxygenase in a host in need thereof comprising administering an effective amount of the compound of claim 12 or a pharmaceutically acceptable salt thereof.

41. A method for the treatment of a cardiovascular disorder in a host comprising administering an effective mount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

42. A method for the treatment era cardiovascular disorder in a host comprising administering an effective amount of the compound of claim 12 or a pharmaceutically acceptable salt thereof.

13. A compound of the formula:

##STR48##

23. A method for the treatment of an inflammatory disorder in a host comprising administering an effective mount of the compound of claim 13 or a pharmaceutically acceptable salt thereof.

33. A method for the inhibition of 5-lipoxygenase in a host in need thereof comprising administering an effective amount of the compound of claim 13 or a pharmaceutically acceptable salt thereof.

43. A method for the treatment of a cardiovascular disorder in a host comprising administering an effective amount of the compound of claim 13 or a pharmaceutically acceptable salt thereof.

14. A compound of the formula:

##STR49##

24. A method for the treatment of an inflammatory disorder in a host comprising administering an effective mount of the compound of claim 14 or a pharmaceutically acceptable salt thereof.

34. A method for the inhibition of 5-lipoxygenase in a host in need thereof comprising administering an effective amount of a compound of claim 14 or a pharmaceutically acceptable salt thereof.

44. A method for the treatment of a cardiovascular disorder in a host comprising administering an effective amount of the compound of claim 14 or a pharmaceutically acceptable salt thereof.

15. A compound of the formula:

##STR50##

25. A method for the treatment of an inflammatory disorder in a host comprising administering an effective amount of the compound of claim 15 or a pharmaceutically acceptable salt thereof.

35. A method for the inhibition of 5-lipoxygenase in a host comprising administering an effective mount of the compound of claim 15 or a pharmaceutically acceptable salt thereof.

45. A method for the treatment of a cardiovascular disorder in a host comprising administering an effective amount of the compound of claim 15 or a pharmaceutically acceptable salt thereof.

16. A compound of the formula:

##STR51##

26. A method for the treatment of an inflammatory disorder in a host comprising administering an effective amount of the compound of claim 16 or a pharmaceutically acceptable salt thereof.

36. A method for the inhibition of 5-lipoxygenase in a host in need thereof comprising administering an effective amount of a compound of claim 16 or a pharmaceutically acceptable salt thereof.

46. A method for the treatment of a cardiovascular disorder in a host comprising administering an effective amount of the compound of claim 16 or a pharmaceutically acceptable salt thereof.

17. A compound of the formula:

##STR52##

27. A method for the treatment of an inflammatory disorder in a host comprising administering an effective amount of the compound of claim 17 or a pharmaceutically acceptable salt thereof.

37. A method for the inhibition of 5-lipoxygenase in a host in need thereof comprising administering an effective amount of a compound of claim 17 or a pharmaceutically acceptable salt thereof.

47. A method for the treatment of a cardiovascular disorder in a host comprising administering an effective amount of the compound of claim 17 or a pharmaceutically acceptable salt thereof.

18. A compound of the formula:

##STR53##

28. A method for the treatment of an inflammatory disorder in a host comprising administering an effective amount of the compound of claim 18 or a pharmaceutically acceptable salt thereof.

38. A method for the inhibition of 5-lipoxygenase in a host in need thereof comprising administering an effective amount of a compound of claim 18 or a pharmaceutically acceptable salt thereof.

48. A method for the treatment of a cardiovascular disorder in a host comprising administering an effective amount of the compound of claim 18 or a pharmaceutically acceptable salt thereof.

19. A compound of the formula:

##STR54##

29. A method for the treatment of an inflammatory disorder in a host comprising administering an effective amount of the compound of claim 19 or a pharmaceutically acceptable salt thereof.

39. A method for the inhibition of 5-lipoxygenase in a host in need thereof comprising administering an effective amount of a compound of claim 19 or a pharmaceutically acceptable salt thereof.

49. A method for the treatment of a cardiovascular disorder in a host comprising administering an effective amount of the compound of claim 19 or a pharmaceutically acceptable salt thereof.

20. A compound of the formula:

##STR55##

30. A method for the treatment of an inflammatory disorder in a host comprising administering an effective amount of the compound of claim 20 or a pharmaceutically acceptable salt thereof.

40. A method for the inhibition of 5-lipoxygenase in a host in need thereof comprising administering an effective amount of a compound of claim 20 or a pharmaceutically acceptable salt thereof.

50. A method for the treatment of a cardiovascular disorder in a host comprising administering an effective amount of the compound of claim 20 or a pharmaceutically acceptable salt thereof.