Antiviral methods using [1,8]naphthyridine derivatives

• US 6,340,690 B1
• Filed: 02/22/2000
• Issued: 01/22/2002
• Est. Priority Date: 02/22/1999
• Status: Expired due to Fees

• Current Assignee: Biochem Pharma, Incorporated (Shire plc)
• Original Assignee: Biocryst Pharmaceuticals Incorporated
• Inventors: Nguyen-Ba, Nghe, Siddiqui, Arshad, Bachand, Benoit, Levesque, Sophie
• Primary Examiner(s): DENTZ, BERNARD I
• Application Number:
  US09/507,936
• Time in Patent Office: 700 Days
• Field of Search: 514/300
• US Class Current: 514/300
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: A61P 31/22 for herpes viruses
• CPC Class Codes: C07D 471/04 Ortho-condensed systems

Abstract

The present invention is concerned with novel [1,8] naphthyridine derivatives useful for the inhibition of the hepatitis virus, more specifically the hepatitis C virus.

Claims

1. A method for the inhibition of a viral infection in a mammal, the method comprising administering to the mammal, an antiviral amount of a (1,8) naphthyridine derivative of Formula I or a pharmaceutically acceptable salt thereof;

wherein

Z₁, Z₁′

, Z₁″

, and Z₂ are independently H, halogen, carboxyl, amino, amidino, guanidino, nitro, OH, SH, CN, C_1-6 alkyl, C_2-6 alkenyl, C_2-6, alkynyl, C_1-6 alkoxy or C_1-6 heteroalkyl;

A is

X is O, NH or S;

Y is O, S, (CH₂)_n, O(CH₂)_n, or S(CH₂)_n;

with n is 0 to 6;

R₁ is independently H or C_1-6 alkyl, C_2-6 alkenyl, or C_2-6 alkynyl;

W is C_6-12 aryl, C_6-12 heteroaryl, or C_3-12 heterocycle.

2. The method of claim 1 wherein Z₁, Z₁′

, Z₁″ and

Z₂ are independently C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl which can be substituted with one or more halogen, OH, carboxy, amino, guanidino, amidino, nitro, SH or CN.

3. The method of claim 1 wherein R₁ is independently C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl which is substituted by one or more C_1-6 alkyl, C_1-6 alkoxy or C_1-6 alkylthio, halogen, amino, guanidino, amidino nitro, OH, SH or CN.

4. The method of claim 1 wherein W is C_6-12 aryl, C_6-12 heteroaryl, C_3-12 heterocycle, either of which is substituted by one or more C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 perfluoroalkyl, C_1-6 alkoxy, C_1-6 perfluoroalkoxy, C_1-6 heteroalkyl, C_1-6 perfluoroalkylthio, halogen, amino, guanidino, amidino, nitro, OH, COOH, SH or CN.

5. The method of claim 1 wherein Y is (CH₂)_n and wherein n is chosen between 0 to 6.

6. The method of claim 1 wherein X is O.

7. The method of claim 1 wherein X is S.

8. The method of claim 1 wherein X is NH.

9. The method of claim 1 wherein R₁ is H.

10. The method of claim 1 wherein Z₁, Z₁′

and Z₁″

are H.

11. The method of claim 1 wherein Z₂ is H.

12. The method of claim 1 wherein Z₁, Z₁′

, Z₁″ and

Z₂ are H.

13. The method of claim 1 wherein R₁, Z₁, Z₁′

, Z₁″ and

Z₂ are H.

14. The method of claim 1 wherein R₁, Z₁, Z₁′

, Z₁″ and

Z₂ are H and Y is (CH₂)_n wherein n is chosen between 0 to 6.

15. The method of claim 1 wherein n is 0.

16. The method of claim 1 wherein W is phenyl or pyridinyl unsubstituted or substituted with one or more C_1-6 alkoxy groups.

17. The method of claim 1 wherein R₁, is H, Z₁, Z₁′

, Z₁″

, are H and Z₂, is H.

18. The method of claim 1 wherein Y is (CH₂)_n and n is 0.

19. The method of claim 1, wherein Y is (CH₂)_n and n is 1.

20. The method of claim 1 wherein Y is (CH₂)_n and n is 2.

21. The method of claim 1 wherein X is S, R₁ is H, Z₁, Z₁′

, Z₁″

, are H and Z₂, is H.

22. The method of claim 1 wherein X is O, R₁ is H, Z₁, Z₁′

, Z₁″

, are H and Z₂, is H.

23. The method of claim 1 wherein X is NH, R₁ is H, Z₁, Z₁′

, Z₁″

, are H and Z₂, is H.

24. The method according to claim 1 wherein said naphthyridine derivative is in the form of the (+) enantiomer, the (−

) enantiomer or mixture of the (+) and (−

) enantiomer including racemic mixture.

25. The method according to claim 1 wherein the viral infection is hepatitis or herpes.

26. The method according to claim 1 wherein the viral infection is HBV or HCV.

27. The method according to claim 1, wherein the viral infection is HCV.

28. The method according to claim 1, wherein the viral infection is HSV-1 or HSV-2.

29. The method according to claim 28 wherein the viral infection is HCV.

39. A composition useful as an antiviral agent, the composition comprising at least one [1,8] naphthyridine derivative of Formula I or a pharmaceutically acceptable salt thereof;

wherein A, Z₁, Z₁′

, Z₁″ and

Z₂ are as defined in claim 1.

40. A composition useful as an antiviral agent, the composition comprising at least one [1,8] naphthyridine derivative of Formula I or a pharmaceutically acceptable salt thereof;

wherein A, Z₁, Z₁′

, Z₁″ and

Z₂ are as defined in claim 24.

41. The composition according to claim 40, wherein the antiviral activity is anti-hepatitis or anti-herpes.

42. The composition according to claim 40, wherein said is anti-hepatitis activity is anti-HBV or anti-HCV.

43. The composition according to claim 40, wherein said anti-hepatitis activity is anti-HCV.

44. The composition according to claim 40, wherein said anti-viral activity is anti-HCV.

45. The composition according to claim 40, wherein said anti-herpes activity is anti-HSV-1 or anti-HSV-2.

30. A method for the inhibition of a viral infection in a mammal, the method comprising administering to the mammal an antiviral amount of a [1,8] naphthyridine derivative selected from the group consisting of:

[1,8] naphthyridine-2-carboxylic acid 2-methoxybenzylamide (Compound #1);

[1,8] naphthyridine-2-carboxylic acid benzylamide (Compound #2);

[1,8] naphthyridine-2-carboxylic acid 4-methoxy-benzylamide (Compound #3);

[1,8] naphthyridine-2-carboxylic acid 3-methoxy-benzylamide (Compound #4);

[1,8] naphthyridine-2-carboxylic acid 2,4,6-trimethoxy-benzylamide (Compound #5);

[1,8] naphthyridine-2-carboxylic acid 2,3-dimethoxy-benzylamide (Compound #6);

[1,8] naphthyridine-2-carboxylic acid 2,4-dimethoxy-benzylamide (Compound #7);

[1,8] naphthyridine-2-carboxylic acid 2-isopropoxy-benzylamide (Compound #8);

[1,8] naphthyridine-2-carboxylic acid [2-(2-methoxyphenyl)ethyl]-amide (Compound #11);

[1,8] naphthyridine-2-carboxylic acid (pyridin-3-ylmethyl)-amide (Compound #12);

[1,8] naphthyridine-2-carboxylic acid (pyridin-2-ylmethyl)-amide (Compound #13);

[1,8] naphthyridine-2-carboxylic acid pyridin-4-ylamide (Compound #14);

[1,8] naphthyridine-2-carboxylic acid pyridin-2-ylamide (Compound #15);

[1,8] naphthyridine-2-carboxylic acid 2-fluoro-benzylamide (Compound #16);

[1,8] naphthyridine-2-carboxylic acid 2-chloro-benzylamide (Compound #17);

[1,8] naphthyridine-2-carboxylic acid 2-trifluoromethoxy-benzylamide (Compound #18);

[1,8] naphthyridine-2-carboxylic acid (3-nitrophenyl)-amide (Compound #19);

[1,8] naphthyridine-2-carboxylic acid benzyloxyamide (Compound #21);

[1,8] naphthyridine-2-carboxylic acid thiazol-2-ylamide (Compound #22);

[1,8] naphthyridine-2-carboxylic acid benzothiazol-2-ylamide (Compound #23);

[1,8] naphthyridine-2-carboxylic acid (2-fluoro-phenyl)-amide (Compound #24);

[1,8] naphthyridine-2-carboxylic acid (2-methoxy-benzyl)-methyl-amide (Compound #25);

[1,8] naphthyridine-2-carboxylic acid 2-methoxy-benzylamide (Compound #26);

(2-methoxy-benzyl)-[1,8] naphthyridine-2-carboxamidine trifluoroacetate (Compound #27);

[1,8] naphthyridine-2-carboxylic acid phenyl-amide (Compound #28);

[1,8] naphthyridine-2-carboxylic acid pyridin-3-yl-amide (Compound #29);

[1,8] naphthyridine-2-carboxylic acid (phenyl-3-trifluoromethyl)-amide (Compound #30); and

[1,8] naphthyridine-2-carboxylic acid (phenylmethyl-3-trifluoromethyl) (Compound #31).

31. The method according to claim 30 wherein said naphthyridine derivative is in the form of the (+) enantiomer, the (−

) enantiomer or mixture of the (+) and (−

) enantiomer including racemic mixture.

33. The method of claim 30 wherein said [1,8] naphthyridine derivative is selected from the group consisting of:

[1,8] naphthyridine-2-carboxylic acid 2-methoxybenzylamide (Compound #1);

[1,8] naphthyridine-2-carboxylic acid benzylamide (Compound #2);

[1,8] naphthyridine-2-carboxylic acid 4-methoxy-benzylamide (Compound #3);

[1,8] naphthyridine-2-carboxylic acid 3-methoxy-benzylamide (Compound #4);

[1,8] naphthyridine-2-carboxylic acid 2,4,6-trimethoxy-benzylamide (Compound #5);

[1,8] naphthyridine-2-carboxylic acid (pyridin-3-ylmethyl)-amide (Compound #12);

[1,8] naphthyridine-2-carboxylic acid 2-fluoro-benzylamide (Compound #16);

[1,8] naphthyridine-2-carboxylic acid 2-chloro-benzylamide (Compound #17); and

(2-methoxy-benzyl)-[1,8]naphthyridine-2-carboxamidine trifluoroacetate (Compound #27).

34. The method according to claim 33 wherein said naphthyridine derivative is in the form of the (+) enantiomer, the (−

) enantiomer or mixture of the (+) and (−

) enantiomer including racemic mixture.

35. The method according to claim 30 wherein the viral infection is hepatitis or herpes.

36. The method according to claim 30 wherein the viral infection is HBV or HCV.

37. The method according to claim 30, wherein the viral infection is HCV.

38. The method according to claim 30, wherein the viral infection is HSV-1 or HSV-2.

32. A method for the inhibition of a viral infection in a mammal, the method comprising administering to the mammal an antiviral amount of a [1,8] naphthyridine derivative selected from the group consisting of

(+)-[1,8] naphthyridine-2-carboxylic acid 2-sec-butoxy-benzylamide (Compound #9);

and

(−

)-[1,8] naphthyridine-2-carboxylic acid 2-sec-butoxy-benzylamide (Compound #10).