Inhibition of 5-lipoxygenase products

• US 4,686,231 A
• Filed: 04/28/1986
• Issued: 08/11/1987
• Est. Priority Date: 12/12/1985
• Status: Expired due to Fees

• Current Assignee: Smithkline Beecham Corporation (Smithkline Beecham PLC)
• Original Assignee: Smithkline Beecham Corporation (Smithkline Beecham PLC)
• Inventors: Bender, Paul E., Hanna, Nabil, Sarau, Henry M., Griswold, Don E.
• Primary Examiner(s): Jiles, Henry R.
• Assistant Examiner(s): WHITTENBAUGH, ROBERT
• Application Number:
  US06/856,927
• Time in Patent Office: 470 Days
• Field of Search: 548/315, 548/337, 546/256, 546/278, 514/333, 514/341, 514/398, 514/400, 514/396
• US Class Current: 514/333
• CPC Class Codes: C07D 233/88 Nitrogen atoms, e.g. allantoin
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond

Abstract

Novel compounds, compositions and pharmaceutical a method of inhibiting the 5-lipoxygenase pathway in an animal in need thereof which comprising administering an effective, 5-lipoxygenase pathway inhibiting amount of a 4,5-diaryl-2(substituted)-imidazole or a pharmaceutically acceptable salt thereof.

Claims

1. A compound of the formula ##STR32## wherein:

X¹ is NHCN or NH₂ ;

R¹ and R are independently selected from 4-pyridyl or monosubstituted phenyl wherein said substituent is selected from halo or C_1-4 alkoxy; and

Y¹ is H or CN provided that when X¹ is NH₂, Y¹ is CN when X¹ is NHCN, Y¹ is H;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 wherein Y¹ is H, X¹ is NHCN and R and R¹ are both 4-methoxyphenyl.

3. The compound of claim 1 wherein Y¹ is H, X¹ is NHCN and R and R¹ are both 4-fluorophenyl;

or wherein Y¹ is CN, X¹ is NH₂ and R and R¹ are both 4-fluorophenyl.

4. A pharmaceutical composition having 5-lipoxygenase inhibitory activity comprising an effective, non-toxic 5-lipoxygenase pathway inhibiting amount of a compound of the formula ##STR33## wherein:

X¹ is NHCN or NH₂ ;

R¹ and R are independently selected from 4-pyridyl or monosubstituted phenyl wherein said substituent is selected from halo or C_1-4 alkoxy; and

Y¹ is H or CN provided that when X¹ is NH₂, Y¹ is CN and when X¹ is NHCN, Y¹ is H;

or a pharmaceutically acceptable salt or thereof, and a pharmaceutically acceptable carrier or diluent.

5. The composition of claim 4 wherein Y¹ is H, X¹ is NHCN and R and R¹ are both 4-methoxyphenyl.

6. The composition of claim 4 wherein Y¹ is H, X¹ is NHCN and R and R¹ are 4-fluorophenyl;

or wherein Y¹ is CN, X¹ is NH₂ and R and R¹ are both 4-fluorophenyl.

7. The composition of claim 4 wherein the composition is in a dosage unit form adapted for parenteral administration.

8. The composition of claim 7 wherein the composition comprises the compound in an amount of from about 25 mg to about 200 mg.

9. The composition of claim 4 wherein the composition is in a dosage unit form adapted for administration of inhalation.

10. The composition of claim 4 wherein the composition is in a dosage unit form adapted for topical administration.

11. A method for treating rheumatoid arthritis in an animal in need thereof which comprises administering to such animal an effective, non-toxic 5-lipoxygenase pathway inhibiting amount of a compound of the formula ##STR34## wherein:

X¹ is NHCN or NH₂ ;

R¹ and R are independently selected from 4-pyridyl or monosubstituted phenyl wherein said substituent is selected from halo or C_1-4 alkoxy; and

Y¹ is H or CN provided that when X¹ is NH₂, Y¹ is CN and when X¹ is NHCN, Y¹ is H;

or a pharmaceutically acceptable salt thereof.

12. The method of claim 11 wherein Y¹ is H, X¹ is NHCN and R and R¹ are both 4-methoxyphenyl.

13. The method of claim 11 wherein Y¹ is H, X¹ is NHCN and R and R¹ are both 4-fluorophenyl;

or wherein Y is CN, X is NH₂ and R and R¹ are both 4-fluorophenyl.

14. The method of claim 11 wherein the compound is administered parenterally.

15. The method of claim 14 wherein the amount of compound administered in a dosage unit is from about 25 mg to about 200 mg.

16. The method of claim 14 wherein the amount of compound administered per day is from about 50 mg to about 1000 mg.

17. The method of claim 14 wherein the compound is administered by inhalation.

18. The method of claim 17 wherein the amount of compound administered is from about 10 mg to about 200 mg per day.

19. The method of claim 14 wherein the compound is administered topically.

20. The method of claim 19 wherein the amount of compound administered per dose is 1 μ

g to 1000 μ

g.

21. A method of treating a 5-lipoxygenase pathway mediated disease in an animal in need thereof, provided that such animal is in need of treatment of a 5-lipoxygenase pathway mediated disease other than, or in addition to, rheumatoid arthritis, which comprises administering to such animal an effective, non-toxic 5-lipoxygenase pathway inhibiting amount of a compound of the formula, ##STR35## wherein:

X is S, S(0)_n R², NHCN, NH₂, polyhalo C_1-4 alkyl, or 4-halophenyl;

n is 0, 1 or 2;

R² is selected from H, C_1-6 alkyl, or mono- or polyhalo C_1-4 alkyl;

R and R¹ are independently selected from pyridyl or mono substituted phenyl wherein said substituent is selected from halo or C_1-4 alkoxy;

provided that when R and/or R¹ are pyridyl, R² is other than C_1-6 alkyl, tetrahaloethyl or C_1-4 perhaloalkyl; and

Y is H, CN, or C_1-4 alkyl provided that when X is NH₂, Y is CN and when X is NHCN, Y is H;

or a pharmaceutically acceptable salt thereof.

22. The method of claim 21 wherein the compound is administered parenterally.

23. The method of claim 22 wherein the amount of compound administered in a dosage unit is from amount 50 mg to about 500 mg.

24. The method of claim 22 wherein the amount of compound administered per day is from about 50 mg to about 1000 mg.

25. The method of claim 21 wherein the compound is administered by inhalation.

26. The method of claim 25 wherein the amount of compound administered is from about 10 mg to about 200 mg per day.

27. The method of claim 21 wherein the compound is administered topically.

28. The method of claim 27 wherein the amount of compound administered per dose is 1 μ

g to 1000 μ

g.

29. The method of claim 21 wherein R and R¹ are both 4-methoxyphenyl, X is 3--CH₃ and Y is CH₃.

30. The method of claim 21 wherein R and R¹ are both 4-fluorophenyl, X is SO₂ CF₂ CF₂ H and Y is H.

31. The method of claim 21 wherein R and R¹ are both 4-methoxyphenyl, X is 3--CH₂ CH₃ and Y is CH₂ CH₃.

32. The method of claim 21 wherein R and R¹ are both 4-methoxyphenyl, X is NHCN and Y is H.

33. The method of claim 21 wherein R and R¹ are both 4-fluorophenyl, X is NHCN and Y is H;

or wherein R and R¹ are both 4-fluorophenyl, X is NH₂ and Y is CN.

34. The method of claim 21 wherein R and R¹ are both 4-methoxyphenyl, X is trifluoromethyl and Y is H.

35. The method of claim 21 wherein R and R¹ are both 4-fluorophenyl, X is 4-fluorophenyl and Y is H.

36. The method of claim 21 wherein R is 4-pyridyl, R¹ is 4-fluorophenyl, X is S and Y is H.

37. The method of claim 21 wherein R is 4-pyridyl, R¹ is 4-fluorophenyl, X is SCF₂ CF₂ H and Y is H.