Antifungal agents

• US 20080009504A1
• Filed: 03/29/2007
• Published: 01/10/2008
• Est. Priority Date: 04/03/2006
• Status: Active Grant

• Current Assignee: Scynexis Incorporated
• Original Assignee: Merck Sharp & Dohme Corporation (Merck & Co., Inc.)
• Inventors: Balkovec, James, Greenlee, Mark, Bouffard, Frances, Liu, Hao, Dropinski, James, Meng, Dongfang, Fan, Weiming, Tse, Bruno, Mamai, Ahmed, Li, Keqaing, Peel, Michael
• Granted Patent: US 7,863,465 B2
• Time in Patent Office: Days
• US Class Current: 514/254.11
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/10 Antimycotics
• CPC Class Codes: C07J 71/0005 Oxygen-containing hetero ring

Abstract

The present invention relates to novel enfumafungin derivatives of formula I and pharmaceutically acceptable salts thereof, their synthesis, and their use as inhibitors of (1,3)-β-D-glucan synthase. The present compounds and pharmaceutically acceptable salts thereof, as well as pharmaceutical compositions comprising the present compounds and pharmaceutically acceptable salts thereof, are useful for treating or preventing antifungal infections and associated diseases and conditions.

Claims

1. A compound of Formula I:

2. The compound of claim 1, wherein R³ is C(O)R¹⁴.

3. The compound of claim 2, wherein R¹⁴ is OH or OR¹⁵.

4. The compound of claim 2, wherein the compound is of Formula II:

5. The compound of claim 1, wherein X is O.

6. The compound of claim 1, wherein X is H₂.

7. The compound of claim 1, wherein R¹ is OC(O)C₁-C₁₂ alkyl, unsubstituted or substituted with 1 or 2 substituents selected from OR⁰, N(R⁰)₂, and CO₂R⁰.

8. The compound of claim 1, wherein R¹ is OC(O)NHC₁-C₆ alkyl, unsubstituted or substituted with phenyl.

9. The compound of claim 1, wherein R² is CH₂CHR⁵(CH₂)_mNR⁶R⁷, CH₂CR⁸R⁹(CH₂)_mNR⁶R⁷, or CHR¹³CHR⁵(CH₂)_mNR⁶R⁷.

10. The compound of claim 9, wherein the compound is of Formula III-1, III-2, III-3 or III-4:

11. The compound of claim 9, wherein the compound is of Formula IV-1, IV-2, IV-3 or IV-4:

12. The compound of claim 9, wherein the compound is of Formula V-1 or Formula V-3:

13. The compound of claim 11 having Formula IV-1 wherein

R¹³ is —

CR³;

m is 0;

R⁸ is selected from the group consisting of —

CH₃, CH₂CH₃, CH₂OCH(CH₃)₂, and CH(CH₃)₂;

R⁹ is selected from the group consisting of CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH(CH₃)(CH₂CH₃), CH₂CH₂CH₂CH₃, CH₂OCH₃, CH₂CH₂OCH₃, CH₂CH₂OCH₂CH₃, cyclohexyl, (R)CH(CH₃)₂, and (S)CH(CH₃)₂;

R⁶ is H, —

CH₃, CH₂CH₃, CH₂CF₃, CH₂CH₂CH₃, CH₂CH₂OCH₃, cyclobutyl, CH₂-cyclopropyl, CH(CH₃)₂, CH₂CH₂CH₂CH₃, CH(CH₃)(CH₂CH₃), cyclopentyl, and cyclohexyl; and

R⁷ is H, —

CH₃, CH₂CH₃, CH(CH₃)₂, and CH₂CH₂CH₃.

14. The compound of claim 11 having Formula IV-1 wherein R¹³ is —

CH₃, m is 0, R⁸ is —

CH₃, and R⁹ is —

CH(CH₃)₂.

15. The compound of claim 14 wherein R⁶ is H or —

CH₃ and R⁷ is H or —

CH₃.

16. The compound of claim 15, wherein the compound is of Formula IV-1a:

17. The compound of claim 16 wherein R⁶ is H or —

CH₃, and R⁷ is —

CH₃.

18. The compound of claim 16 wherein R⁶ is —

CH₃, and R⁷ is —

CH₃.

19. The compound of claim 15, wherein the compound is of Formula IV-1b:

20. The compound of claim 19 wherein R⁶ is H or —

CH₃, and R⁷ is —

CH₃.

21. The compound of claim 20 wherein R⁶ is —

CH₃, and R⁷ is —

CH₃.

22. The compound of claim 10, wherein m is 0.

23. The compound of claim 11, wherein m is 0.

24. The compound of any one of claims 10-12, wherein R¹³ is methyl.

25. The compound of claim 23, wherein both R⁸ and R⁹ are C₁-C₃ alkyl;

or R⁸ and R⁹ are taken together to form a 3- to 6-membered saturated ring having 0-1 heteroatom selected from N, O or S.

26. The compound of claim 25, wherein R⁸ is methyl and R⁹ is methyl, ethyl or propyl;

or R⁸ and R⁹ are taken together to form a cyclobutyl.

27. The compound of claim 23 or 25, wherein both R⁶ and R⁷ are H.

28. The compound of claim 23 or 25, wherein R⁶ and R⁷ are independently unsubstituted C₁-C₆-alkyl.

29. The compound of claim 28, wherein R⁶ and R⁷ are independently methyl or ethyl, or R⁶ is H and R⁷ is propyl.

30. The compound of claim 10 or 12, wherein m is 1.

31. The compound of claim 11, wherein m is 1.

32. The compound of claim 1 selected from the group consisting of:

(1S,2R,3R,4aR,6aS,7R,8R,10aR,10bR,12aR)-3-(acetyloxy)-2-[(2S)-2-amino-2,3-dimethylbutyloxy]-8-[(1R)-1,2-dimethyl propyl]-1,6a,8,10a-tetramethyl-6-oxo-1,3,4,6,6a,7,8,9,10,10a,10b,11,12,12a-tetradecahydro-2H-1,4a-(methanooxymethano)chrysene-7-carboxylic acid,

(1S,2R,3R,4aR,6aS,7R,8R,10aR,10bR,12aR)-3-(acetyloxy)-2-[(2S)-2-methylamino-2,3-dimethylbutyloxy]-8-[(1R)-1,2-dimethyl propyl]-1,6a,8,10a-tetramethyl-6-oxo-1,3,4,6,6a,7,8,9,10,10a,10b,11,12,12a-tetradecahydro-2H-1,4a-(methanooxymethano)chrysene-7-carboxylic acid,

(1S,2R,3R,4aR,6aS,7R,8R,10aR,10bR,12aR)-3-(acetyloxy)-2-[(2S)-2-dimethylamino-2,3-dimethylbutyloxy]-8-[(1R)-1,2-dimethyl propyl]-1,6a,8,10a-tetramethyl-6-oxo-1,3,4,6,6a,7,8,9,10,10a,10b,11,12,12a-tetradecahydro-2H-1,4a-(methanooxymethano)chrysene-7-carboxylic acid,

(1S,2R,3R,4aR,6aS,7R,8R,10aR,10bR,12aR)-3-acetoxy-2-[[(2R)-2-amino-2,3-dimethylbutyl]oxy]-8-[(1R)-1,2-dimethylpropyl]-1,6a,8,10a-tetramethyl-6-oxo-1,3,4,6,6a,7,8,9,10,10a,10b,11,12,12a-tetradecahydro-2H-1,4a-(methanooxymethano)chrysene-7-carboxylic acid,

(1S,2R,3R,4aR,6aS,7R,8R,10aR,10bR,12aR)-3-acetoxy-2-[[(2R)-2-methylamino-2,3-dimethylbutyl]oxy]-8-[(1R)-1,2-dimethylpropyl]-1,6a,8,10a-tetramethyl-6-oxo-1,3,4,6,6a,7,8,9,10,10a,10b,11,12,12a-tetradecahydro-2H-1,4a-(methanooxymethano)chrysene-7-carboxylic acid, and

(1S,2R,3R,4aR,6aS,7R,8R,10aR,10bR,12aR)-3-acetoxy-2-[[(2R)-2-dimethylamino-2,3-dimethylbutyl]oxy]-8-[(1R)-1,2-dimethylpropyl]-1,6a,8,10a-tetramethyl-6-oxo-1,3,4,6,6a,7,8,9,10,10a,10b,11,12,12a-tetradecahydro-2H-1,4a-(methanooxymethano)chrysene-7-carboxylic acid,

and pharmaceutically acceptable salts thereof.

33. A compound of claim 32 or a pharmaceutically acceptable salt thereof which is:

(1S,2R,3R,4aR,6aS,7R,8R,10aR,10bR,12aR)-3-(acetyloxy)-2-[(2S)-2-dimethylamino-2,3-dimethylbutyloxy]-8-[(1R)-1,2-dimethyl propyl]-1,6a,8,10a-tetramethyl-6-oxo-1,3,4,6,6a,7,8,9,10,10a,10b,11,12,12a-tetradecahydro-2H-1,4a-(methanooxymethano)chrysene-7-carboxylic acid,

34. The compound of claim 1, wherein the compound is selected from Tables A-H and J-M and 3a.

35. A composition comprising a compound of claim 1 and a carrier, adjuvant, or vehicle.

36. The method of treating a fungal infection in a mammal, comprising administering to said mammal an effective amount of a compound of claim 1.

37. The method of claim 36, wherein said fungal infection is caused by Cryptococcus spp., Candida spp. or Aspergillus spp. fungi.