Crystalline tripeptide epoxy ketone protease inhibitors

• US 8,604,215 B2
• Filed: 03/22/2010
• Issued: 12/10/2013
• Est. Priority Date: 03/20/2009
• Status: Expired due to Fees

• Current Assignee: Onyx Therapeutics, Inc. (Amgen Inc.)
• Original Assignee: Onyx Therapeutics, Inc. (Amgen Inc.)
• Inventors: Phiasivongsa, Pasit, Sehl, Louis C.
• Primary Examiner(s): Chu, Yong
• Assistant Examiner(s): Cheng, Karen
• Application Number:
  US13/257,887
• Publication Number:
  US 20120088903A1
• Time in Patent Office: 1,359 Days
• Field of Search: 548/200
• US Class Current: 548/200
• CPC Class Codes: A61K 31/427 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 33/00 Antiparasitic agents
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• 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: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 417/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07K 1/026 by fragment condensation in solution
• CPC Class Codes: C07K 5/0802 : with the first amino acid being neutral
• CPC Class Codes: C07K 5/0821 : with the first amino acid being heterocyclic, e.g. His, Pro, Trp
• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The invention relates to crystalline tripeptide keto epoxide compounds, methods of their preparation, and related pharmaceutical compositions. In addition, the compounds provided herein are immunoproteasome inhibitors and are useful, for example, in the treatment of cancer and autoimmune disease. In some cases, a compound provided herein is a compound of Formula (II):

Claims

1. A method for preparing a crystalline compound of Formula (II)

2. A method of claim 1, wherein the organic solvent is selected from acetonitrile, ethyl acetate, heptanes, hexanes, isopropyl acetate, methanol, methylethyl ketone, tetrahydrofuran, toluene and water, or any combination thereof.

3. A method of claim 2, wherein the organic solvent is selected from acetonitrile, heptanes, hexanes, methanol, tetrahydrofuran, and toluene.

4. A method of claim 3, wherein the organic solvent is selected from hexanes, tetrahydrofuran and toluene.

5. A method of claim 1, wherein bringing the solution to supersaturation comprises addition of an anti-solvent, allowing the solution to cool, reducing the volume of the solution, or any combination thereof.

6. A method of claim 5, wherein bringing the solution to supersaturation comprises adding an anti-solvent, cooling the solution to ambient temperature, and reducing the volume of the solution.

7. A method of claim 5, wherein the anti-solvent is added slowly.

8. A method of claim 5, wherein the anti-solvent is selected from hexanes, toluene and water.

9. A method of claim 5, wherein the volume reduction is performed by evaporation.

10. A method of claim 1, further comprising seeding the solution.

11. A method of claim 10, further comprising washing the crystals.

12. A method of claim 11, wherein the washing comprises washing with a liquid selected from anti-solvent, acetonitrile, heptanes, hexanes, methanol, tetrahydrofuran, toluene, water, or a combination thereof.

13. A method of claim 12, wherein washing comprises washing with a combination of an anti-solvent and the organic solvent.

14. A method of claim 13, wherein the anti-solvent is hexanes or heptanes.

15. A method of claim 1, wherein isolating the crystals comprises filtering the crystals.

16. A method of claim 1, further comprising drying the crystals under reduced pressure.

17. A crystalline compound having a structure of Formula (II)

18. A crystalline compound of claim 17, having a melting point of about 140 to about 155°

C.

19. A crystalline compound of claim 18, having a melting point of about 145 to about 150°

C.

20. A method for the preparation of a crystalline compound of Formula (II),