Prodrugs of Heteraromatic Compounds

• US 20120015866A1
• Filed: 12/23/2010
• Published: 01/19/2012
• Est. Priority Date: 01/07/2010
• Status: Active Grant

• Current Assignee: Alkermes Pharma Ireland Limited (Alkermes plc)
• Original Assignee: Alkermes Pharma Ireland Limited (Alkermes plc)
• Inventors: Blumberg, Laura Cook, Almarsson, Örn
• Granted Patent: US 9,107,911 B2
• Time in Patent Office: Days
• US Class Current: 514/1.3
• CPC Class Codes: A61K 31/4192 1,2,3-Triazoles
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 403/14 containing three or more hetero rings
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07K 5/0821 with the first amino acid being heterocyclic, e.g. His, Pro, Trp
• CPC Class Codes: C07K 5/0823 and Pro-amino acid; Derivatives thereof

Abstract

The present invention relates to prodrugs of parent drug compounds containing heteroaromatic NH groups.

Claims

1. A prodrug compound of Formula I;

2. The compound of claim 1, wherein R₈ is hydrogen, C₁-C₃-alkyl, —

C(O)H or —

CH(OH)CH₂OH and R₉ is hydrogen.

3. The compound of claim 2, wherein R₈ is hydrogen.

4. The compound of claim 1, wherein R₅ is selected from —

CH(R₈)—

OC(O)OR₁₀, —

CH(R₈)—

OC(O)R₁₀ and —

CH(R₈)—

OC(O)NR₁₁R₁₂.

5. The compound of claim 1, wherein R₅ is selected from —

CH(R₈)—

OPO₃MY, —

CH(R₈)—

OP(O)₂(OR₁₁)M and —

CH(R₈)—

OP(O)(OR₁₁)(OR₁₂).

6. The compound of claim 1, wherein R₁₀, or at least one of R₁₁ and R₁₂, is optionally substituted aryl, C₇-C₂₄-alkyl, C₇-C₂₄-alkenyl, or C₇-C₂₄-alkynyl.

7. The compound of claim 1, wherein R₁₀, or at least one of R₁₁ and R₁₂, is branched C₃-C₂₄-alkyl, -alkenyl or -alkynyl.

8. The compound of claim 7, wherein R₁₀, or at least one of R₁₁ and R₁₂, is a secondary or tertiary C₃-C₂₄-alkyl, -alkenyl or -alkynyl group.

9. The compound of claim 7, wherein R₁₀, or at least one of R₁₁ and R₁₂, is a β

-branched C₃-C₂₄-alkyl, -alkenyl or -alkynyl group.

10. The compound of claim 8, wherein R₁₀ is C₃-C₁₂-cycloalkyl or a group represented by one of the formulas below:

11. The compound of claim 1 wherein R₅ is selected from the groups set forth below:

12. The compound of claim 9, wherein R₁₀ is 2-methyl-C₃-C₂₃-alkyl or 2,2-dimethyl-C₃-C₂₂-alkyl.

13. A method of sustained delivery of a heteroaryl NH-containing parent drug to a subject in need thereof, said method comprising the step of administering to the subject an effective amount of a prodrug compound produced by substituting a labile, hydrophobic aldehyde-linked prodrug moiety replacing the H of NH on the heteroaryl NH nitrogen atom.

14. The method of claim 13, wherein the prodrug compound has decreased solubility under physiological conditions compared to the parent drug.

15. The method of claim 13, wherein the heteroaryl NH-containing parent drug is represented by Formula II:

16. The method of claim 15, wherein R₈ is hydrogen, C₁-C₃-alkyl, —

C(O)H or —

CH(OH)CH₂OH and R₉ is hydrogen.

17. The method of claim 16, wherein R₈ is hydrogen.

18. The method of claim 15, wherein R₅ is selected from —

CH(R₈)—

OC(O)OR₁₀, —

CH(R₈)—

OC(O)R₁₀ and —

CH(R₈)—

OC(O)NR₁₁R₁₂.

19. The method of claim 15, wherein R₅ is selected from —

CH(R₈)—

OPO₃MY, —

CH(R₈)—

OP(O)₂(OR₁₁)M and —

CH(R₈)—

OP(O)(OR₁₁)(OR₁₂).

20. The method of claim 15, wherein R₁₀, or at least one of R₁₁ and R₁₂, is optionally substituted aryl, C₇-C₂₄-alkyl, C₇-C₂₄-alkenyl, or C₇-C₂₄-alkynyl.

21. The method of claim 15, wherein R₁₀, or at least one of R₁₁ and R₁₂, is branched C₃-C₂₄-alkyl, -alkenyl or -alkynyl.

22. The method of claim 21, wherein R₁₀, or at least one of R₁₁ and R₁₂, is a secondary or tertiary C₃-C₂₄-alkyl, -alkenyl or -alkynyl group.

23. The method of claim 21, wherein R₁₀, or at least one of R₁₁ and R₁₂, is a β

-branched C₃-C₂₄-alkyl, -alkenyl or -alkynyl group.

24. The method of claim 22, wherein R₁₀ is C₃-C₁₂-cycloalkyl or a group represented by one of the formulas below:

25. The method of claim 22, wherein R₁₀ is 2-methyl-C₃-C₂₃-alkyl or 2,2-dimethyl-C₃-C₂₂-alkyl.

26. The method of claim 15 wherein R₅ is selected from the groups set forth below:

27. The method of claim 15, wherein the heteroaromatic NH-containing parent drug comprises a pyrrole group, an imidazole group, a 1,2,3- or 1,2,4-triazole group, a tetrazole group, a benzimidazole group, an indole group or a pyrazole group.

28. A method of producing a prodrug of a parent heteroaromatic NH-containing drug compound, wherein the prodrug has decreased solubility under physiological conditions and sustained activity upon dosing compared to the parent drug compound, said method comprising the step of modifying the parent drug by substituting a labile, hydrophobic aldehyde-linked prodrug moiety on the heteroaromatic NH nitrogen atom.

29. The method of claim 28, wherein parent heteroaromatic NH-containing drug compound is represented by Formula II,

30. The method of claim 29, wherein the step of modifying the parent drug by substituting a labile, hydrophobic aldehyde-linked prodrug moiety on the heteroaromatic NH nitrogen atom comprises reacting the parent drug with an aldehyde of the formula HCR₈, and an acid of the formula R₁₀C(O)OH.

31. The method of claim 29, wherein R₈ is hydrogen, C₁-C₃-alkyl, —

C(O)H or —

CH(OH)CH₂OH and R₉ is hydrogen.

32. The method of claim 31, wherein R₈ is hydrogen.

33. The method of claim 29, wherein R₅ is selected from —

CH(R₈)—

OC(O)OR₁₀, —

CH(R₈)—

OC(O)R₁₀ and —

CH(R₈)—

OC(O)NR₁₁R₁₂.

34. The method of claim 29, wherein R₅ is selected from —

CH(R₈)—

OPO₃MY, —

CH(R₈)—

OP(O)₂(OR₁₁)M and —

CH(R₈)—

OP(O)(OR₁₁)(OR₁₂).

35. The method of claim 29, wherein R₁₀, or at least one of R₁₁ and R₁₂, is optionally substituted aryl, C₇-C₂₄-alkyl, C₇-C₂₄-alkenyl, or C₇-C₂₄-alkynyl.

36. The method of claim 29, wherein R₁₀, or at least one of R₁₁ and R₁₂, is branched C₃-C₂₄-alkyl, -alkenyl or -alkynyl.

37. The method of claim 36, wherein R₁₀, or at least one of R₁₁ and R₁₂, is a secondary or tertiary C₃-C₂₄-alkyl, -alkenyl or -alkynyl group.

38. The method of claim 36, wherein R₁₀, or at least one of R₁₁ and R₁₂, is a β

-branched C₃-C₂₄-alkyl, -alkenyl or -alkynyl group.

39. The method of claim 37, wherein R₁₀ is C₃-C₁₂-cycloalkyl or a group represented by one of the formulas below:

40. The method of claim 29, wherein R₅ is selected from the groups set forth below:

41. The method of claim 38, wherein R₁₀ is 2-methyl-C₃-C₂₃-alkyl or 2,2-dimethyl-C₃-C₂₂-alkyl.

42. The method of claim 29, wherein the heteroaromatic NH-containing parent drug comprises a pyrrole group, an imidazole group, a 1,2,3- or 1,2,4-triazole group, a tetrazole group, a benzimidazole group, an indole group or a pyrazole group.