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

• US 5,792,776 A
• Filed: 06/27/1994
• Issued: 08/11/1998
• 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, Hussoin, Sajjat, Scannell, Ralph
• Primary Examiner(s): Lambkin, Deborah C.
• Application Number:
  US08/265,656
• Time in Patent Office: 1,506 Days
• Field of Search: 549/496, 549/493, 549/475, 549/472, 549/484, 549/488, 549/487, 549/77, 549/73, 549/72, 549/62, 549/67, 549/64, 549/66, 549/65, 514/471, 514/445, 514/446, 514/448, 514/438, 514/423, 514/617, 514/613, 514/618, 514/619, 514/575, 514/303, 548/530, 548/304.7, 564/189, 564/182, 564/161-163, 564/168, 562/621, 546/118
• US Class Current: 514/303
• 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

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.

A method to treat disorders mediated by PAF and/or leukotrienes is also disclosed, that includes administering an effective amount of one or more of the above-identified compounds or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier.

Claims

1. A compound of formula:

##STR25## wherein;

Ar is an aryl or heteroaryl group that is optionally substituted with at least one group selected from the group consisting of halo, lower alkoxy, lower aryloxy, --C(O)N(OM)R⁴, A--B, cyano, or R³ ;

but when W is --A--B, Ar is substituted at least once with --C(O)N(OM)R⁴, and is optionally substituted with halo, lower alkoxy, lower aryloxy, A--B, cyano, or R³ ;

W is independently --C(O)N(OM)R⁴, or --A--B;

but when W is --A--B, Ar is substituted at least once with --C(O)N(OM)R⁴, and is optionally substituted with halo, lower alkoxy, lower aryloxy, A--B, cyano, or R³ ;

A is lower alkyl, lower alkenyl, lower alkynyl, alkaryl or aralkyl groups, wherein one or more carbons optionally can be replaced by O, N, or S;

(with valence completed with hydrogen or oxygen as necessary), provided --A-- does not form two adjacent heteroatoms;

B is selected from the group consisting of pyridylimidazole and benzimidazole, either of which is optionally substituted with R₃ ;

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

X is O, S, S(O), NR⁵, or CHR⁵ ;

R¹ and R² are independently hydrogen, lower alkyl;

halo lower alkyl, halo; and

--COOH; and

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

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)_n R³, --AS(O)_n CH₂ C(O)R³, --AS(O)_n CH₂ CH(OH)R³, --AC(O)NHR³ ; and

wherein n is 0-2,

or pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein Ar is selected from the group consisting of phenyl, trimethoxyphenyl, dimethoxyphenyl, fluorophenyl, difluorophenyl, pyridyl, dimethoxypyridyl, quinolinyl, furyl, imidazolyl, and thienyl.

3. The compound of claim 1, wherein Ar is selected from the group consisting of 4-fluorophenyl, 3,4,5-trimethoxyphenyl, 3,4-dimethoxyphenyl, 2,3-dimethoxypyridyl, 3,4-difluorophenyl, 3-quinolinyl,

wherein:

R¹ and R² are hydrogen.

4. A pharmaceutical composition comprising an effective amount of the compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

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

6. The method of claim 5, wherein the animal is selected from a human, a mammal, an equine, a canine and a bovine.

7. The compound of claim 1 wherein X is O.

8. The compound of claim 1, wherein the aryl group has a halogen substituent.

9. The compound of claim 1 wherein W is --A--B .

10. The compound of claim 9, wherein R³ or R⁴ are hydrogen.

11. The compound of claim 1, wherein R¹ and R² are hydrogen.

12. The compound of claim 1, wherein A is selected from the group consisting of acetylenyl, propynyl, and --C.tbd.C--CH(alkyl)-.

13. The compound of claim 1, wherein A is lower alkyl-.

14. The compound of claim 1 wherein X is S.

15. The compound of claim 1 wherein the aryl group has a fluorine substituent.

16. The compound of claim 1, wherein W is --C(O)N(OM)R⁴.

17. The compound of claim 1, wherein A is lower alkenyl.

18. The compound of claim 1, wherein A is lower alkynyl.

19. The compound of claim 1, wherein B is benzimidazole.

20. The method of claim 5, wherein the compound has a W substituent that is --A--B.

29. A method for the treatment of inflammatory disorders in a host comprising administering an effective amount of a compound of any of claims 7-10, or 12-19, or a pharmaceutically acceptable salt thereof.

21. A compound of formula:

##STR26## wherein;

Ar is an aryl or heteroaryl group any of which is substituted at least once with --C(O)N(OM)R⁴, and is optionally substituted with halo, lower alkoxy, lower aryloxy, A--B, cyano, or R³ ;

A is lower alkyl, lower alkenyl, lower alkynyl, alkaryl or aralkyl groups, wherein one or more carbons optionally can be replaced by O, N, or S;

(with valence completed with hydrogen or oxygen as necessary), provided --A-- does not form two adjacent heteroatoms;

B is selected from the group consisting of pyridylimidazole and benzimidazole, either of which is optionally substituted with R₃ ;

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

X is O, S, S(O);

R¹ and R² are independently hydrogen, lower alkyl;

halo lower alkyl;

halo; and

--COOH; and

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

or pharmaceutically acceptable salt thereof.

22. The compound of claim 21 wherein --A--B is ##STR27## and wherein Ar is aryl or heteroaryl, any of which group is substituted at least once with--C(O)N(OM)R⁴, and is optionally substituted with halo, alkoxy, aryloxy, or cyano.

23. The compound of claim 21, wherein --A--B is ##STR28## and wherein Ar is aryl or heteroaryl substituted at least once --C(O)N(OM)R⁴.

24. A pharmaceutical composition comprising an effective amount of the compound of claim 21 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

25. A pharmaceutical composition comprising an effective amount of the compound of claim 23 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

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

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

28. A method for the treatment of inflammatory disorders in a host comprising administering an effective amount of a compound of claim 23 or a pharmaceutically acceptable salt thereof.

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