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

• US 5,780,503 A
• Filed: 06/07/1995
• Issued: 07/14/1998
• 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:
  US08/474,444
• Time in Patent Office: 1,133 Days
• Field of Search: 549/493, 549/487, 549/480, 514/471, 514/311, 514/472, 514/314, 514/473, 514/336, 514/445, 514/303
• US Class Current: 514/471
• 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. The method for the treatment of inflammatory disorders in a host, comprising administering an effective amount of a compound of the 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, W, cyano, or R³ but when W is -A-B, Ar is substituted at least once with -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, and is optionally substituted with halo, lower alkoxy, lower aryloxy, A-B, cyano, or R³ ;

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, or -A-B;

but when W is -A-B, Ar is substituted at least once with -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, and is optionally substituted with halo, lower alkoxy, lower aryloxy, A-B, cyano, or R³ ;

A is lower alkynyl , 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;

C_3-8 cycloaklyl, halo lower alkyl, halo; and

-COOH;

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-; 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)_n R ³, -AS(O)_n CH₂ C(O)R³, -AS(O)_n CH₂ CH(OH)R³, AC(O)NHR ³ ;

wherein n is 0-2, or

(b) the compound of (a), wherein Ar is selected form the group consisting of pyridyl, dimethoxypyridyl, quinolinyl, 3-quinolyl, furyl, imidazolyl, and thienyl;

X is selected from O, CH₂, S and NH;

R¹ and R² are hydrogen; and

W is selected from --C.tbd.CCH₂ N(OH)C(O)NH₂, and --C.tbd.CCH(CH₃)N(OH)C(O)NH₂, or a pharmaceutically acceptable salt thereof,

with the proviso that Ar is not phenyl optionally substituted with at least one group selected from the group consisting of halo, lower alkoxy, lower aryloxy, W, cyano or R³.

2. A method for the treatment of a patient in need of immunosuppression comprising administering an effective amount of compounds (a), (b), or (c) or a pharmaceutically acceptable salt thereof.

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

4. The method of claim 3, wherein the animal is selected from a human, a mammal, an equine, a canine and a bovine.

5. A method for the treatment of a cardiovascular disorder comprising administering an effective amount of compounds (a), (b), or (c), or a pharmaceutically acceptable salt thereof.

6. A method for the inhibition of 5-lipoxygenase in a patient comprising administering an effective amount of compounds (a), (b), or (c), or a pharmaceutically acceptable salt thereof.