Diaryldiazepine Prodrugs for the Treatment of Neurological and Psychological Disorders

• US 20110166128A1
• Filed: 12/23/2010
• Published: 07/07/2011
• Est. Priority Date: 01/07/2010
• Status: Abandoned Application

• Current Assignee: Alkermes Pharma Ireland Limited (Alkermes plc)
• Original Assignee: Alkermes Pharma Ireland Limited (Alkermes plc)
• Inventors: Blumberg, Laura Cook, Remenar, Julius F.
• Application Number:
  US12/978,240
• Publication Number:
  US 20110166128A1
• Time in Patent Office: Days
• US Class Current: 514/220
• CPC Class Codes: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: C07D 403/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 495/04 Ortho-condensed systems

Abstract

The present invention provides prodrug compounds of diaryldiazepine drug compounds.

Claims

1. A compound of Formula I or Formula II,

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

C(R₈)(R₉)—

OC(O)OR₁₀, —

C(R₈)(R₉)—

OC(O)R₁₀, and —

C(R₈)(R₉)—

OC(O)NR₁₁R₁₂.

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

C(R₈)(R₉)—

OPO₃²⁻

, —

C(R₈)(R₉)—

OPO₃MY, and —

C(R₈)(R₉)—

OP(O)(OR₉)(OR₁₀).

4. The compound of claim 2 wherein R₉ is hydrogen and R₈ is selected from the group consisting of hydrogen and C₁-C₃-alkyl.

5. The compound of claim 2 wherein R₁₀ is C₈-C₂₄-alkyl.

6. The compound of claim 3 wherein R₅ is —

C(R₈)(R₉)—

OPO₃MY and M and Y together are Ca²⁺.

7. A compound of claim 1 represented by Formula VII, Formula VIII, Formula IX or Formula X:

8. 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.

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

CH(R₈)—

OPO₃²⁻

, —

CH(R₈)—

OPO₃MY, and —

CH(R₈)—

OP(O)(OR₁₁)(OR₁₂).

10. The compound of claim 8 wherein R₈ is selected from the group consisting of hydrogen and C₁-C₃-alkyl.

11. The compound of claim 8 wherein R₁₀ is C₈-C₂₄-alkyl.

12. The compound of claim 9 wherein R₅ is —

CH(R₈)—

OPO₃MY and M and Y together are Ca²⁺.

13. The compound of claim 1 wherein R₅ is selected from the structures set forth below.

31. The compound of claim 14 wherein R₅ is selected from the structures set forth below.

33. A method of treating a neurological or psychiatric disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of claim 1.

34. The method according to claim 33 wherein said disorder is schizophrenia.

35. The method according to claim 33 wherein the disorder is bipolar disorder.

36. The compound of claim 9 wherein R₈ is s selected from the group consisting of hydrogen and C₁-C₃-alkyl.

39. The method according to claim 3 wherein said disorder is schizophrenia.

14. A compound of Formula III or Formula IV:

15. The compound of claim 14 wherein Ring A is benzo or thieno.

16. The compound of claim 14 wherein each of R₁, R₂, R₃ and R₄ is hydrogen.

17. The compound of claim 14 wherein R₁, R₃ and R₄ are each hydrogen, and R₂ is chlorine.

18. The compound of claim 14 wherein Ring A is optionally substituted thieno and each of R₁ to R₄ is hydrogen.

19. The compound of claim 14 wherein Ring A is benzo, R₂ is chlorine and R₁, R₃ and R₄ are each hydrogen.

20. The compound of claim 14 wherein R₅ is selected from —

CH(R₈)—

OC(O)OR₁₀, —

CH(R₈)—

OC(O)R₁₀ and —

CH(R₈)—

OC(O)NR₉R₁₀.

21. The compound of claim 14 wherein R₅ is selected from —

CH(R₈)—

OPO₃MY, and —

CH(R₈)—

OP(O)(OR₉)(OR₁₀).

22. The compound of claim 20 wherein R₈ is selected from the group consisting of hydrogen and C₁-C₃-alkyl.

23. The compound of claim 20 wherein R₁₀ is C₈-C₂₄-alkyl.

24. The compound of claim 14 wherein R₅ is —

C(R₈)(R₉)—

OPO₃MY wherein M and Y together are Ca²⁺.

25. A compound of claim 14 represented by Formula V or Formula VI,

26. The compound of claim 25 wherein R₅ is selected from —

C(R₈)(R₉)—

OC(O)OR₁₀, —

C(R₈)(R₉)—

OC(O)R₁₀ and —

C(R₈)(R₉)—

OC(O)NR₁₁R₁₂.

27. The compound of claim 25 wherein R₅ is selected from —

C(R₈)(R₉)—

OPO₃²⁻

, —

C(R₈)(R₉)—

OPO₃MY, and —

C(R₈)(R₉)—

OP(O)(OR₁₁)(OR₁₂).

28. The compound of claim 26 wherein R₈ is selected from the group consisting of hydrogen and C₁-C₃-alkyl.

29. The compound of claim 26 wherein R₁₀ is C₈-C₂₄-alkyl.

30. The compound of claim 27 wherein R₅ is —

C(R₈)(R₉)—

OPO₃MY and M and Y together are Ca²⁺.

37. The compound of claim 27 wherein R₈ is selected from the group consisting of hydrogen and C₁-C₃-alkyl.

38. A method of treating a neurological or psychiatric disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of claim 14.

40. The method according to claim 38 wherein the disorder is bipolar disorder.

32. A method of producing a prodrug of a parent drug, wherein said prodrug has pH-independent solubility properties and wherein the parent drug is represented by the formula below,