Proteasome inhibitors

• US 8,772,536 B2
• Filed: 08/12/2013
• Issued: 07/08/2014
• Est. Priority Date: 08/06/2007
• Status: Active Grant

• Current Assignee: Takeda Pharmaceutical Company Limited
• Original Assignee: Millennium Pharmaceuticals Incorporated (Takeda Pharmaceutical Company Limited)
• Inventors: Olhava, Edward J., Danca, Mihaela Diana
• Primary Examiner(s): WITHERSPOON, SIKARL A
• Application Number:
  US13/964,769
• Publication Number:
  US 20130331595A1
• Time in Patent Office: 330 Days
• Field of Search: 562/7, 562/450, 564/8, 564/169, 558/288
• US Class Current: 562/7
• CPC Class Codes: A61K 31/198 Alpha-amino acids, e.g. alanine or edetic acid [EDTA] betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00
• CPC Class Codes: A61K 31/454 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• CPC Class Codes: A61K 31/675 having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
• CPC Class Codes: A61K 31/69 Boron compounds
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07C 233/83 of an acyclic saturated carbon skeleton
• CPC Class Codes: C07F 5/025 Boronic and borinic acid compounds
• CPC Class Codes: C07F 5/05 Cyclic compounds having at least one ring containing boron but no carbon in the ring

Abstract

The present invention provides novel compounds useful as proteasome inhibitors. The invention also provides pharmaceutical compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various diseases.

Claims

1. A process for generating a compound of Formula (v)

2. The process of claim 1, wherein the reaction of step (1) is conducted in the presence of a peptide coupling reagent.

3. The process of claim 2, wherein the peptide coupling reagent is selected from the group consisting of a carbodiimide reagent, phosphonium reagent, and uranium reagent.

4. The process of claim 3, wherein the peptide coupling reagent is selected from one or more of the group consisting of dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl-3-ethylcarbodiimide (EDC), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP), O-(1H-benzotriazol-1-yl)-N,N,N′

N′

-tetramethyluronium tetrafluoroborate (TBTU) and N-Hydroxybenzotriazole (HOBt).

5. The process of claim 1, wherein the reaction of step (3) is conducted in the presence of a peptide coupling reagent.

6. The process of claim 5, wherein the peptide coupling reagent is selected from the group consisting of a carbodiimide reagent, phosphonium reagent, and uranium reagent.

7. The process of claim 6, wherein the peptide coupling reagent is selected from one or more of the group consisting of dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl-3-ethylcarbodiimide (EDC), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP), O-(1H-benzotriazol-1-yl)-N,N,N′

N′

-tetramethyluronium tetrafluoroborate (TBTU) and N-Hydroxybenzotriazole (HOBt).

8. The process of claim 1, wherein the reaction of step (1) is conducted in the presence of a solvent comprising a polar aprotic solvent.

9. The process of claim 8, wherein the polar aprotic solvent is selected from one or more of the group consisting of dichloromethane, tetrahydrofuran, and dimethylformamide.

10. The process of claim 1, wherein the reaction of step (3) is conducted in the presence of a solvent comprising a polar aprotic solvent.

11. The process of claim 10, wherein the polar aprotic solvent is selected from one or more of the group consisting of dichloromethane, tetrahydrofuran, and dimethylformamide.

12. The process as in any one of claims 1-11, wherein PG is a protecting group selected from the group consisting of an acyl protecting group and a urethane protecting group.

13. The process of claim 12, wherein PG is a protecting group selected from the group consisting of formyl, acetyl, succinyl, methoxysuccinyl, tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), and fluorenylmethoxycarbonyl (Fmoc).

14. The process as in any one of claims 1-11, wherein X₁⁻

is CF₃CO₂⁻

.

15. The process as in any one of claims 1-11, wherein X₂⁻

is Cl⁻

.

16. The process as in any one of claims 1-11, wherein Z¹ and Z², together with the boron atom to which they are attached, form

17. The process as in any one of claims 1-11, wherein Ring A is

18. A process for generating a compound of Formula (v)

19. The process of claim 18, wherein the reaction of step (1a) is conducted in the presence of a peptide coupling reagent.

20. The process of claim 19, wherein the peptide coupling reagent is selected from the group consisting of a carbodiimide reagent, phosphonium reagent, and uranium reagent.

21. The process of claim 20, wherein the peptide coupling reagent is selected from one or more of the group consisting of dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl-3-ethylcarbodiimide (EDC), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP), O-(1H-benzotriazol-1-yl)-N,N,N′

N′

-tetramethyluronium tetrafluoroborate (TBTU) and N-Hydroxybenzotriazole (HOBt).

22. The process of claim 18, wherein the reaction of step (3a) is conducted in the presence of a peptide coupling reagent.

23. The process of claim 22, wherein the peptide coupling reagent is selected from the group consisting of a carbodiimide reagent, phosphonium reagent, and uranium reagent.

24. The process of claim 23, wherein the peptide coupling reagent is selected from one or more of the group consisting of dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl-3-ethylcarbodiimide (EDC), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP), O-(1H-benzotriazol-1-yl)-N,N,N′

N′

-tetramethyluronium tetrafluoroborate (TBTU) and N-Hydroxybenzotriazole (HOBt).

25. The process of claim 18, wherein the reaction of step (1a) is conducted in the presence of a solvent comprising a polar aprotic solvent.

26. The process of claim 25, wherein the polar aprotic solvent is selected from one or more of the group consisting of dichloromethane, tetrahydrofuran, and dimethylformamide.

27. The process of claim 18, wherein the reaction of step (3a) is conducted in the presence of a solvent comprising a polar aprotic solvent.

28. The process of claim 27, wherein the polar aprotic solvent is selected from one or more of the group consisting of dichloromethane, tetrahydrofuran, and dimethylformamide.

29. The process as in one of claims 18-28, wherein PG is a protecting group selected from the group consisting of an acyl protecting group and a urethane protecting group.

30. The process of claim 29, wherein PG is a protecting group selected from the group consisting of formyl, acetyl, succinyl, methoxysuccinyl, tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), and fluorenylmethoxycarbonyl (Fmoc).

31. The process as in any one of claims 18-28, wherein X₁⁻

is CF₃CO₂⁻

.

32. The process as in any one of claims 18-28, wherein X₂⁻

is Cl⁻

.

33. The process as in any one of claims 18-28, wherein Z¹ and Z², together with the boron atom to which they are attached, form

34. The process as in any one of claims 18-28, wherein Ring A is

35. A compound of Formula (iii)

36. A compound of Formula (iiia)

37. A compound of Formula (iv)

38. The compound of claim 37, wherein Ring A is

39. A compound of Formula (vii)

40. The compound of claim 39, wherein Ring A is

41. A compound of Formula (viia)

42. The compound of claim 41, wherein Ring A is