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

• US 5,750,565 A
• Filed: 05/31/1995
• Issued: 05/12/1998
• Est. Priority Date: 05/25/1995
• Status: Expired due to Term

• Current Assignee: Millennium Pharmaceuticals Incorporated (Takeda Pharmaceutical Company Limited)
• Original Assignee: CytoMed, Inc. (Takeda Pharmaceutical Company Limited)
• Inventors: Cai, Xiong, Qian, Changgeng, Fura, Aberra
• Primary Examiner(s): Robinson, Allen J.
• Assistant Examiner(s): LAMBKIN, DEBORAH C
• Application Number:
  US08/454,600
• Time in Patent Office: 1,077 Days
• Field of Search: 514/473, 514/472, 514/445, 514/446, 514/447, 514/448, 514/598, 514/617, 514/645, 514/575
• US Class Current: 514/473
• 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

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. 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. A method for the treatment of inflammatory disorders in a host comprising administering an effective amount of a compound of formula:

##STR30## wherein;

Ar is an aryl or heteroaryl group that is optionally substituted with halo, lower alkoxy, lower aryloxy, W, cyano, or R³ ;

m is 0 or 1;

n is 1-6;

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

A is lower alkylene, lower alkenylene, lower alkynylene, alklarylene or aryl alkylene, or a hetero derivative thereof, wherein one or more carbons optionally can be replaced by O, N, or S;

(with valence completed with hydrogen or oxygen as necessary), however, --Y--A--, --A--, and --AW-- should not include two adjacent heteroatoms;

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

X is O, S, S(O), S(O)₂, NR³, or CHR⁵ ;

Y is O, S, S(O), S(O)₂, NR³, or CHR⁵ ;

Z is O, S, S(O), S(O)₂, NR³ ;

R¹ and R² are independently hydrogen, lower alkyl, cyclopropylmethyl, ethyl, isopropyl, butyl, pentyl hexyl, and C_3-8 cycloalkyl, for example, cyclopentyl;

halo lower alkyl, halo;

or --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-;

R⁵ is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, arylalkyl, alkylaryl, --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, or --AC(O)NHR³,

wherein x is 0-2.

3. The method of claim 1, wherein Ar is 4-fluorophenyl.

4. The method of claim 1, wherein Z is O.

5. The method of claim 1, wherein Z is S.

6. The method of claim 1, wherein --(Y)_m W is selected from the group consisting of:

##STR31##

7. The method of claim 1, wherein, --(Y)_m W is selected from the group consisting of:

##STR32##

8. The method of claim 1, 2, 3, 4, 5, 6, or 7, wherein the compound is administered in at least 97% enantiomerically enriched form.

9. A method of claim 1, wherein the compound is selected from the group consisting of 2S,5S-trans-2-(4-fluorophenoxymethyl)-5-(4-protected-oxy-1-butynyl)tetrahydrofuran and 2S,5R-cis-2-(4-fluorophenoxymethyl)-5(4-protected-oxy-1-butynyl)tetrahydrofuran.

10. The method of claim 1 wherein the compound is selected from the group consisting of 2S,5R-trans-2-(4-fluorophenoxymethyl)-5-(4-N-hydroxyureidyl-1-butyl)tetrahydrofuran, 2S,5S-trans-2-(4-fluorophenoxymethyl)-5(4-hydroxyureidyl-1-butynyl)tetrahydrofuran, 2R,5S-trans-2-(4-fluorophenoxymethyl)-5-(4-N-hydroxyureidyl-1-butyl)tetrahydrofuran, 2S,5R-trans-2-(4-fluorophenoxymethyl)-5(4-hydroxyureidyl-1-butyl)tetrahydrofuran.

11. The method of claim 1, wherein the compound is 2S,5S-trans-2-(4-fluorophenoxymethyl)-5-(4-hydroxyureidyl-1-butynyl)tetrahydrofuran.

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

13. The method of claim 1, wherein the animal is a human.

14. The method of claim 1, wherein the host is selected from the group consisting of a mammal, an equine, a canine and a bovine.

15. A method for the treatment of a cardiovascular disorder comprising administering an effective amount of the compound described in claim 1 or a pharmaceutically acceptable salt thereof.

16. A method for the treatment of a patient in need of immunosuppression comprising administering an effective amount of the compound described in claim 11 or a pharmaceutically acceptable salt thereof.

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

18. A method for the treatment of a cardiovascular disorder comprising administering an effective amount of the compound described in claim 11 or a pharmaceutically acceptable salt thereof.

19. A method for the treatment of a cardiovascular disorder comprising administering an effective amount of the compound described in claim 1 or a pharmaceutically acceptable salt thereof.

20. The method of claim 1, wherein the inflammatory disorder is asthma.

21. The method of claim 11, wherein the inflammatory disorder is asthma.

22. The method of claim 1, wherein the inflammatory disorder is psoriasis.

23. The method of claim 11, wherein the inflammatory disorder is psoriasis.

24. The method of claim 1, wherein the inflammatory disorder is adult respiratory distress syndrome.

25. The method of claim 11, wherein the inflammatory disorder is adult respiratory distress syndrome.

26. The method of claim 1, wherein the inflammatory disorder is atopic dermatitis.

27. The method of claim 11, wherein the inflammatory disorder is atopic dermatitis.

28. The method of claim 1, wherein the inflammatory disorder is contact dermatitis.

29. The method of claim 11, wherein the inflammatory disorder is contact dermatitis.

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