Quinoline derivatives

• US 6,077,851 A
• Filed: 04/22/1999
• Issued: 06/20/2000
• Est. Priority Date: 04/27/1998
• Status: Expired due to Term

• Current Assignee: Active Biotech AB
• Original Assignee: Active Biotech AB
• Inventors: Jonsson, Stig, Hedlund, Gunnar, Fex, Tomas, Bjork, Anders
• Primary Examiner(s): Huang, Evelyn Mei
• Application Number:
  US09/296,519
• Time in Patent Office: 425 Days
• Field of Search: 514/312, 546/155
• US Class Current: 514/312
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: C07D 215/22 attached in position 2 or 4

Abstract

The invention relates to compounds of general formula (I) ##STR1## wherein R is selected from ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec.-butyl and allyl; R₄ is selected from hydrogen and pharmaceutically acceptable inorganic and organic cations; R₅ is selected from methyl, ethyl, n-propyl, iso-propyl, methoxy, ethoxy, chloro, bromo, CF₃, and OCH_x F_y ; wherein x=0-2, y=1-3 with the proviso that x+y=3; R₆ is hydrogen; or R₅ and R₆ taken together are methylenedioxy; and any tautomer hereof. The invention also relates to pharmaceutical compositions containing a compound of the general formula (I) together with a pharmaceutically acceptable carrier. Included are also processes for the preparation of the compounds of formula (I), as well as methods of treating mammals suffering from diseases resulting from autoimmunity and pathological inflammation by administering a compound having the formula (I) to said mammal.

Claims

1. A compound of formula (I) ##STR8## wherein R is ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl or allyl;

R₄ is hydrogen or a pharmaceutically acceptable organic or inorganic cation;

R₅ is methyl, ethyl, n-propyl, iso-propyl, methoxy, ethoxy, chloro, bromo, CF₃, or OCH_x F_y ;

wherein

x=0-2

y=1-3 with the proviso that

x+y=3;

R₆ is hydrogen;

or

R₅ and R₆ taken together are methylenedioxy;

or any tautomer thereof.

2. The compound according to claim 1 wherein the pharmaceutically acceptable inorganic cations are derived from sodium, potassium and calcium, and the organic cations are derived from monoethanolamine, diethanolamine, dimethylaminoethanol, and morpholine.

3. The compound according to claim 1 wherein R₅ is methyl, ethyl, methoxy, chloro, or bromo.

4. The compound according to claim 3 wherein R is ethyl or n-propyl.

5. The compound according to claim 4 wherein R₄ is selected from hydrogen and sodium.

6. The compound according to claim 1, N-ethyl-N-phenyl-1,2-dihydro-4-hydroxy-5-methyl-1-methyl-2-oxo-quinoline-3-carboxamide.

7. The compound according to claim 1, N-ethyl-N-phenyl-1,2-dihydro-4-hydroxy-5-ethyl-1-methyl-2-oxo-quinoline-3-carboxamide.

8. The compound according to claim 1, N-ethyl-N-phenyl-1,2-dihydro-4-hydroxy-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide.

9. The compound according to claim 1, N-ethyl-N-phenyl-1,2-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxo-quinoline-3-carboxamide or its sodium salt.

10. The compound according to claim 1, N-ethyl-N-phenyl-1,2-dihydro-4-hydroxy-5-bromo-1-methyl-2-oxo-quinoline-3-carboxamide.

11. The compound according to claim 1, N-ethyl-N-phenyl-1,2-dihydro-4-hydroxy-5,6-methylenedioxy-1-methyl-2-oxo-quinoline-3-carboxamide.

12. A pharmaceutical composition comprising as active ingredient a compound having the formula (I) according to claim 1 together with a pharmaceutically acceptable carrier.

13. The pharmaceutical composition according to claim 12 in a dosage form sufficient to provide a daily dose of said compound of 0.0005 mg/kg to about 10 mg/kg body weight.

31. The compound according to claim 2, wherein R₅ is methyl, ethyl, methoxy, chloro or bromo.

32. The compound according to claim 2 wherein R is ethyl or n-propyl.

33. The compound according to claim 2 wherein R₄ is hydrogen or sodium.

34. The composition of claim 12, wherein said dosage form is sufficient to provide a daily dose of 0.005 to 1 mg/kg of body weight.

14. A process for manufacturing of a compound of formula (I) by

(A) reacting an ester derivative of the quinolne carboxylic acid of formula (II), ##STR9## with an aniline of formula (III) in a solvent;

or (B) reacting an isatoic anhydride of formula (IV), with an N-alkyl-N-phenylcarbamoyl acetic acid alkyl ester of formula (V), ##STR10## using a strong base, in a solvent;

or (C) reacting a quinoline caxboxylic acid of formula (VI) with an aniline of formula (III), ##STR11## using a coupling reagent, in the presence of triethylamine and a solvent.

40. A process according to claim 14 wherein in reaction (A) said ester derivative of formula II is the methyl or ethyl ester, and the solvent is toluene, xylene;

in reaction (B) said acidic acid alkyl ester of formula V is the methyl or ethyl ester, the strong base is sodium hydride and said solvent is N,N-dimethyl acetamide;

or

in reaction (C) said coupling reagent is a carbodiimide or thionyl chloride, and said solvent is dichloromethane.

15. A method of treating a mammal suffering from a disease resulting from autoimmunity or pathological inflammation comprising administering to said mammal an effective amount of a compound having the formula (I) ##STR12## wherein R is ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl or allyl;

R₄ is hydrogen or a pharmaceutically acceptable inorganic or organic cation;

R₅ is methyl, ethyl, n-propyl, iso-propyl, methoxy, ethoxy, chloro, bromo, CF₃, or OCH_x F_y ;

wherein

x=0-2,

y=1-3 with the proviso that

x+y=3;

R₆ is hydrogen;

or

R₅ and R₆ taken together are methylenedioxy;

or any tautomer thereof.

16. A method according to claim 15 wherein the pharmaceutically acceptable inorganic cations are derived from sodium, potassium and calcium, and the organic cations are derived from monoethanolamine, diethanolamine, dimethylaminoethanol, and morpholine.

17. The method according to claim 15 wherein R₅ is methyl, ethyl, methoxy, chloro or bromo.

18. The method according to claim 16 wherein R is ethyl or n-propyl.

19. The method according to claim 17 wherein R4 is hydrogen or sodium.

20. The method according to claim 15 wherein the compound as administered is N-ethyl-N-phenyl-1,2-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxo-quinoline-3-carboxamide or its sodium salt.

21. The method according to claim 15 of treating a mammal suffering from multiple sclerosis (MS).

22. The method according to claim 15 of treating a mammal suffering from insulin-dependent diabetes mellitus (IDDM).

23. The method according to claim 15 of treating a mammal suffering from systemic lupus erythematosus (SLE).

24. The method according to claim 15 of treating a mammal suffering from rheumatoid arthritis (RA).

25. The method according to claim 15 of treating a mammal suffering from inflammatory bowel disease (IBD).

26. The method according to claim 15 of treating a mammal suffering from psoriasis.

27. The method according to claim 15 of treating a mammal suffering from inflammatory respiratory disorder.

28. The method according to claim 15 of treating a mammal suffering from atherosclerosis.

29. The method according to claim 17 of treating a mammal suffering from stroke.

30. The method according to claim 17 of treating a mammal suffering from Alzheimer'"'"'s disease.

35. The method according to claim 27 wherein said disorder is asthma.

36. The method according to claim 16 of treating a mammal suffering from multiple sclerosis, insulin-dependent diabetes mellitus, systemic lupus erythematosus, rheumatoid arthritis and inflammatory bowel disease, psoriasis, inflammatory respiratory disorder, atherosclerosis, stroke or Alzheimer'"'"'s disease.

37. The method according to claim 17 of treating a mammal suffering from multiple sclerosis, insulin-dependent diabetes mellitus, systemic lupus erythematosus, rheumatoid arthritis and inflammatory bowel disease, psoriasis, inflammatory respiratory disorder, atherosclerosis, stroke or Alzheimer'"'"'s disease.

38. The method according to claim 18 of treating a mammal suffering from multiple sclerosis, insulin-dependent diabetes mellitus, systemic lupus erythematosus rheumatoid arthritis and inflammatory bowel disease, psoriasis, inflammatory respiratory disorder, atherosclerosis, stroke or Alzheimer'"'"'s disease.

39. The method according to claim 21 of treating a mammal suffering from multiple sclerosis, insulin-dependent diabetes mellitus, systemic lupus erythematosus, rheumatoid arthritis and inflammatory bowel disease, psoriasis, inflammatory respiratory disorder, atherosclerosis, stroke or Alzheimer'"'"'s disease.