Compounds for enzyme inhibition

• US 9,205,126 B2
• Filed: 09/26/2013
• Issued: 12/08/2015
• Est. Priority Date: 11/09/2005
• Status: Active Grant

• Current Assignee: Onyx Therapeutics, Inc. (Amgen Inc.)
• Original Assignee: Onyx Therapeutics, Inc. (Amgen Inc.)
• Inventors: Zhou, Han-jie, Sun, Congcong M., Shenk, Kevin D., Laidig, Guy J.
• Primary Examiner(s): Wang, Shengjun
• Application Number:
  US14/038,626
• Publication Number:
  US 20140050737A1
• Time in Patent Office: 803 Days
• Field of Search: 514/365, 514/171, 514/235.5, 514/359, 514/372, 514/374, 514/378, 514/396, 514/406, 514/444, 514/461, 514/64, 514/19.2, 514/19.6, 514/21.9
• US Class Current: 1/1
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/69 Boron compounds
• 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: A61K 38/06 Tripeptides
• CPC Class Codes: A61K 38/55 Protease inhibitors
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• 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 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 31/12 Antivirals
• CPC Class Codes: A61P 31/18 for HIV
• 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 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 5/06026 the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
• CPC Class Codes: C07K 5/06034 the side chain containing 2 to 4 carbon atoms
• CPC Class Codes: C07K 5/0606 the side chain containing heteroatoms not provided for by C07K5/06086 - C07K5/06139, e.g. Ser, Met, Cys, Thr
• CPC Class Codes: C07K 5/06078 : and aromatic or cycloaliphatic
• CPC Class Codes: C07K 5/06139 : with the first amino acid being heterocyclic
• CPC Class Codes: C07K 5/08 : Tripeptides
• CPC Class Codes: C07K 5/0806 : the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
• CPC Class Codes: C07K 5/0808 : the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
• CPC Class Codes: C07K 5/081 : the side chain containing O or S as heteroatoms, e.g. Cys, Ser
• CPC Class Codes: C07K 5/0812 : and aromatic or cycloaliphatic
• CPC Class Codes: C07K 5/0821 : with the first amino acid being heterocyclic, e.g. His, Pro, Trp
• CPC Class Codes: C07K 5/1024 : with the first amino acid being heterocyclic

Abstract

Peptide-based compounds including heteroatom-containing, three-membered rings efficiently and selectively inhibit specific activities of N-terminal nucleophile (Ntn) hydrolases associated with the proteasome. The peptide-based compounds include an epoxide or aziridine, and functionalization at the N-terminus. Among other therapeutic utilities, the peptide-based compounds are expected to display anti-inflammatory properties and inhibition of cell proliferation. Oral administration of these peptide-based proteasome inhibitors is possible due to their bioavailability profiles.

Claims

1. A method for the treatment of a heme-related malignancy in a patient, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition comprising a compound having a structure of formula (I):

2. The method of claim 1, wherein the steroid is selected from the group consisting of:

21-acetoxypregnenolone, alclometasone, algestone, amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, clocortolone, cloprednol, corticosterone, cortisone, cortivazol, deflazacort, desonide, desoximetasone, dexamethasone, diflorasone, ditlucortolone, difuprednate, enoxolone, fluazacort, flucloronide, flumethasone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluocortolone, fluorometholone, fluperolone acetate, fluprednidene acetate, fluprednisolone, flurandrenolide, fluticasone propionate, fonnocortal, halcinonide, halobetasol propionate, halometasone, hydrocortisone, loteprednol etabonate, mazipredone, medrysone, meprednisone, methylprednisolone, mometasone furoate, paramethasone, prednicarbate, prednisolone, prednisolone 25-diethylaminoacetate, prednisolone sodium phosphate, prednisone, prednival, prednylidene, rimexolone, tixocortol, triamcinolone, triamcinolone acetonide, triamcinolone benetonide, triamcinolone hexacetonide, and salts thereof.

3. The method of claim 2, wherein the steroid is dexamethasone.

4. The method of claim 1, wherein the immunotherapeutic agent is selected from the group consisting of MDR modulators, rapamycin, mycophenylate mofetil, cyclophosomide, cyclosporine, thalidomide, and monoclonal antibodies.

5. The method of claim 1, wherein Z is absent.

6. The method of claim 1, wherein R⁴, R⁶, and R⁷ are independently selected from hydrogen and methyl.

7. The method of claim 1, wherein L is C═

O.

8. The method of claim 1, wherein R¹, R², and R³ are independently selected from hydrogen, C_1-6alkyl, C_1-6 alkenyl, C_1-6 alkynyl, C_1-6 hydroxyalkyl, C_1-6 alkoxyalkyl, C_1-6 aralkyl, C_1-6heterocycloalkyl, C_1-6heteroaralkyl, and C_1-6 carbocyclolalkyl.

9. The method of claim 8, wherein any of R¹, R², and R³ are independently C_1-6 alkyl.

10. The method of claim 9, wherein any of R¹, R², and R³ are independently selected from methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and isobutyl.

11. The method of claim 8, wherein any of R¹, R², and R³ are independently propargyl.

12. The method of claim 8, wherein any of R¹, R², and R³ are independently C_1-6hydroxyalkyl.

13. The method of claim 12, wherein any of R¹, R², and R³ are independently selected from hydroxymethyl and hydroxyethyl.

14. The method of claim 8, wherein any of R¹, R², and R³ are independently C_1-6 alkoxyalkyl.

15. The method of claim 14, wherein any of R¹, R², and R³ are independently selected from methoxymethyl and methoxyethyl.

16. The method of claim 8, wherein any of R¹, R², and R³ are independently C_1-6heteroaralkyl.

17. The method of claim 16, wherein any of R¹, R², and R³ are independently selected from imidazolylmethyl, pyrazolylmethyl, and thiazolylmethyl, and pyridylmethyl.

18. The method of claim 8, wherein any of R¹, R², and R³ are independently cyclohexylmethyl.

19. The method of claim 1, wherein R¹, R², and R³ are all different.

20. The method of claim 1, wherein at least one of R¹ and R² is selected from C_1-6hydroxyalkyl and C_1-6 alkoxyalkyl.

21. The method of claim 20, wherein at least one of R¹ and R² is C_1-6 alkoxyalkyl.

22. The method of claim 21, wherein at least one of R¹ and R² is selected from methoxymethyl and methoxyethyl.

23. The method of claim 22, wherein R³ is selected from C_1-6 alkyl and C_1-6 aralkyl.

24. The method of claim 23, wherein R³ is C_1-6 alkyl.

25. The method of claim 24, wherein R³ is selected from methyl, ethyl, isopropyl, sec-butyl, and isobutyl.

26. The method of claim 25, wherein R³ is isobutyl.

27. The method of claim 23, wherein R³ is C_1-6 aralkyl.

28. The method of claim 27, wherein R³ is phenylmethyl.

29. The method of claim 1, wherein R⁵ is selected from isoxazole, furan, or thiophene.

30. The method of claim 29, wherein R⁵ is furan or thiophene.

31. The method of claim 2, wherein R³ is thiazole.

32. The method of claim 1, wherein the compound is selected from:

33. The method of claim 1, wherein the pharmaceutical composition is orally bioavailable.

34. The method of claim 1, wherein the heme-related malignancy is multiple myeloma.

35. A method for treating a heme-related malignancy in a patient comprising administering to the patient a pharmaceutical composition comprising a compound having the structure:

36. The method of claim 35, wherein the steroid is selected from the group consisting of:

21-acetoxypregnenolone, alclometasone, algestone, amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, clocortolone, cloprednol, corticosterone, cortisone, cortivazol, deflazacort, desonide, desoximetasone, dexamethasone, diflorasone, ditlucortolone, difuprednate, enoxolone, fluazacort, flucloronide, flumethasone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluocortolone, fluorometholone, fluperolone acetate, fluprednidene acetate, fluprednisolone, flurandrenolide, fluticasone propionate, fonnocortal, halcinonide, halobetasol propionate, halometasone, hydrocortisone, loteprednol etabonate, mazipredone, medrysone, meprednisone, methylprednisolone, mometasone furoate, paramethasone, prednicarbate, prednisolone, prednisolone 25-diethylaminoacetate, prednisolone sodium phosphate, prednisone, prednival, prednylidene, rimexolone, tixocortol, triamcinolone, triamcinolone acetonide, triamcinolone benetonide, triamcinolone hexacetonide, and salts thereof.

37. The method of claim 36, wherein the steroid is dexamethasone.

38. The method of claim 35, wherein the immunotherapeutic agent is selected from the group consisting of MDR modulators, rapamycin, mycophenylate mofetil, cyclophosomide, cyclosporine, thalidomide, and monoclonal antibodies.

39. The method of claim 35, wherein the pharmaceutical composition is orally bioavailable.

40. The method of claim 35, wherein the heme-related malignancy is multiple myeloma.