Crystalline peptide epoxy ketone protease inhibitors and the synthesis of amino acid keto-epoxides

• US 8,921,583 B2
• Filed: 02/01/2013
• Issued: 12/30/2014
• Est. Priority Date: 10/04/2007
• Status: Active Grant

• Current Assignee: Onyx Therapeutics, Inc. (Amgen Inc.)
• Original Assignee: Onyx Therapeutics, Inc. (Amgen Inc.)
• Inventors: Phiasivongsa, Pasit, Sehl, Louis C., Fuller, William Dean, Laidig, Guy J.
• Primary Examiner(s): Bradley, Christina
• Application Number:
  US13/757,113
• Publication Number:
  US 20130150289A1
• Time in Patent Office: 697 Days
• Field of Search: None
• US Class Current: 549/512
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• 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 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 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 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• 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: A62C 3/004 for freezing warehouses and storages
• CPC Class Codes: A62C 35/60 wet, i.e. containing extinguishing material even when not in use
• CPC Class Codes: A62C 35/62 dry, i.e. empty of extinguishing material when not in use
• CPC Class Codes: A62C 35/68 Details, e.g. of pipes or valve systems valves in general F16K
• CPC Class Codes: A62C 37/11 heat-sensitive
• CPC Class Codes: A62C 37/14 : with frangible vessels
• CPC Class Codes: C07C 51/412 : by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
• CPC Class Codes: C07C 53/18 : containing fluorine
• CPC Class Codes: C07D 301/00 : Preparation of oxiranes
• CPC Class Codes: C07D 301/03 : by oxidation of unsaturated compounds, or of mixtures of unsaturated and saturated compounds
• CPC Class Codes: C07D 303/36 : with hydrocarbon radicals, substituted by nitrogen atoms nitro, nitroso radicals C07D303/08
• CPC Class Codes: C07K 1/1075 : by covalent attachment of amino acids or peptide residues
• CPC Class Codes: C07K 1/306 : by crystallization
• CPC Class Codes: C07K 5/0812 : and aromatic or cycloaliphatic
• CPC Class Codes: C07K 5/1008 : the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
• CPC Class Codes: C07K 5/1016 : and aromatic or cycloaliphatic

Abstract

The invention relates to crystalline peptide keto epoxide compounds, methods of their preparation, and related pharmaceutical compositions. This invention also relates to methods for the preparation of amino acid keto-epoxides. Specifically, allylic ketones are stereoselectively converted to the desired keto epoxides.

Claims

1. A method for the preparation of a crystalline compound of Formula (III),

2. A method of claim 1, wherein PG is selected from Boc and Cbz and X is trifluoroacetate.

3. A method of claim 1, wherein the organic solvent is selected from dichloromethane, ethyl acetate, isopropyl acetate, isobutyl acetate, butyl acetate, propyl acetate, diethyl ether, methyl tert-butyl ether (MTBE), or any combination thereof.

4. A method of claim 3, wherein the organic solvent is selected from dichloromethane, ethyl acetate, MTBE, or any combination thereof.

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 or lower, and reducing the volume of the solution.

7. A method of claim 5, wherein the anti-solvent is hexanes or heptanes.

8. A method of claim 1, further comprising washing the crystals.

9. A method of claim 8, wherein the washing comprises washing with a liquid selected from anti-solvent, dichloromethane, ethyl acetate, isopropyl acetate, isobutyl acetate, butyl acetate, propyl acetate, diethyl ether, and methyl tert-butyl ether, or any combination thereof.

10. A method of claim 9, wherein washing comprises washing with anti-solvent.

11. A method of claim 10, wherein the anti-solvent is hexanes or heptanes.

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

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

14. A crystalline compound having a structure of Formula (III)

15. A crystalline compound of claim 14, having a DSC thermogram substantially as shown in FIG. 9.

16. A crystalline compound of claim 14, having an XRPD pattern substantially as shown in FIG. 10.