Compounds for Enzyme Inhibition

• US 20090203698A1
• Filed: 11/09/2006
• Published: 08/13/2009
• Est. Priority Date: 11/09/2005
• Status: Active Grant

• Current Assignee: Onyx Therapeutics, Inc. (Amgen Inc.)
• Original Assignee: Proteolix, Inc. (Amgen Inc.)
• Inventors: Laidjg, Guy J., Sun, Congcong M., Zhou, Han-Jie, Shenk, Kevin D.
• Granted Patent: US 8,716,322 B2
• Time in Patent Office: Days
• US Class Current: 514/236.800
• 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 compound having a structure of formula (I) or a pharmaceutically acceptable salt thereof:

wherein

L is selected from C═

O, C═

S, and SO₂;

X is selected from O, S, NH, and N—

C_1-6alkyl;

Z is absent, C_1-6alkyl, or C_1-6alkoxy;

R¹, R², and R³ are each independently selected from hydrogen, C_1-6alkyl, C_1-6alkenyl, C_1-6alkynyl, C_1-6hydroxyalkyl, C_1-6alkoxyalkyl, aryl, C_1-6aralkyl, heteroaryl, heterocyclyl, C_1-6heterocycloalkyl, C_1-6heteroaralkyl, carbocyclyl, and C_1-6carbocyclolalkyl;

R⁴ is selected from hydrogen, C_1-6aralkyl, and C_1-6alkyl;

R⁵ is heteroaryl; and

R⁶ and R⁷ are independently selected from hydrogen, C_1-6alkyl, and C_1-6aralkyl.

2. A compound of claim 1, wherein Z is absent.

3. A compound of claim 1 or 2, wherein R⁴, R⁶, and R⁷ are independently selected from hydrogen and methyl.

4. A compound of claim 1 or 2, wherein L is C═

O.

5. A compound of claim 1 or 2, wherein L is SO₂.

6. A compound of any one of claims 1 to 5, wherein R¹, R², and R³ are independently selected from hydrogen, C_1-6alkyl, C_1-6alkenyl, C_1-6alkynyl, C_1-6hydroxyalkyl, C_1-6alkoxyalkyl, C_1-6aralkyl, C_1-6heterocycloalkyl, C_1-6heteroaralkyl, and C_1-6carbocyclolalkyl.

7. A compound of claim 6, wherein any of R¹, R², and R³ are independently C_1-6alkyl.

8. A compound of claim 7, wherein any of R¹, R², and R³ are independently selected from methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and isobutyl.

9. A compound of claim 6 wherein any of R¹, R², and R³ are independently propargyl.

10. A compound of claim 6, wherein any of R¹, R², and R³ are independently C_1-6hydroxyalkyl.

11. A compound of claim 10, wherein any of R¹, R², and R³ are independently selected from hydroxymethyl and hydroxyethyl.

12. A compound of claim 6, wherein any of R¹, R², and R³ are independently C_1-6alkoxyalkyl.

13. A compound of claim 12, wherein any of R¹, R², and R³ are independently selected from methoxymethyl and methoxyethyl.

14. A compound of claim 6, wherein any of R¹, R², and R³ are independently C_1-6heteroaralkyl.

15. A compound of claim 14, wherein any of R¹, R², and R³ are independently selected from imidazolylmethyl, pyrazolylmethyl, and thiazolylmethyl, and pyridylmethyl.

16. A compound of claim 6, wherein any of R¹, R², and R³ are independently cyclohexylmethyl.

17. A compound of any one of claims 1 to 16, wherein R¹, R², and R³ are all different.

18. A compound of any one of claims 1 to 5, wherein at least one of R¹ and R² is selected from C_1-6hydroxyalkyl and C_1-6alkoxyalkyl.

19. A compound of claim 18, wherein at least one of R¹ and R² is C_1-6alkoxyalkyl.

20. A compound of claim 19, wherein at least one of R¹ and R² is selected from methoxymethyl and methoxyethyl.

21. A compound of any one of claims 1 to 5 or 18 to 20, wherein R³ is selected from C_1-6alkyl and C_1-6aralkyl.

22. A compound of claim 21, wherein R³ is C_1-6alkyl.

23. A compound of claim 22, wherein R³ is selected from methyl, ethyl, isopropyl, sec-butyl, and isobutyl.

24. A compound of claim 23, wherein R³ is isobutyl.

25. A compound of claim 21, wherein R³ is C_1-6aralkyl.

26. A compound of claim 25, wherein R³ is phenylmethyl.

27. A compound of any one of claims 1 to 26, wherein R⁵ is 5- or 6-membered heteroaryl.

28. A compound of claim 27, wherein R⁵ is selected from isoxazole, isothiazole, furan, thiophene, oxazole, thiazole, pyrazole, or imidazole.

29. A compound of claim 28, wherein R⁵ is selected from isoxazole, furan, or thiophene.

30. A compound of claim 29, wherein R⁵ is furan or thiophene.

31. A compound of claim 30, wherein R⁵ is unsubstituted furan-3-yl or thien-2-yl.

32. A compound of claim 29, wherein R¹ is isoxazol-3-yl or isoxazol-5-yl.

33. A compound of claim 32, wherein R⁵ is isoxazol-3-yl that has a substituent at the 5-position.

34. A compound of claim 32, wherein R⁵ is isoxazol-5-yl that has a substituent at the 3-position.

35. A compound of claim 33 or 34, wherein the substituent is selected from C_1-6alkyl, C_1-6alkoxy, C_1-6alkoxyalkyl, C_1-6hydroxyalkyl, carboxylic acid, aminocarboxylate, C_1-6alkylaminocarboxylate, (C_1-6alkyl)₂aminocarboxylate, C_1-6alkylcarboxylate, C_1-6heteroaralkyl, C_1-6aralkyl, C_1-6heterocycloalkyl, and C_1-6carbocycloalkyl.

36. A compound of claim 35, wherein the substituent is selected from methyl, ethyl, isopropyl, and cyclopropylmethyl.

37. A compound of claim 35, wherein the substituent is selected from C_1-6heteroaralkyl and C_1-6heterocycloalkyl.

38. A compound of claim 37, wherein the substituent is 1,2,4-triazol-5-ylmethyl.

39. A compound of claim 37, wherein the substituent is azetidin-1-ylmethyl.

40. A compound of claim 37, wherein the substituent is

wherein W is O, NR, or CH₂, and R is H or C_1-6alkyl.

41. A compound of claim 40, wherein W is O.

42. A compound of claim 37, wherein the substituent is selected from C_1-6alkoxy and C_1-6alkoxyalkyl.

43. A compound of claim 42, wherein the substituent is selected from methoxy, ethoxy, methoxymethy, and methoxyethyl.

44. A compound of claim 37, wherein the substituent is selected from carboxylic acid, aminocarboxylate, C_1-6alkylaminocarboxylate, (C_1-6alkyl)₂aminocarboxylate, or C_1-6alkylcarboxylate.

45. A compound of claim 44, wherein the substituent is methyl carboxylate.

47. A pharmaceutical composition comprising a compound of any one of claims 1 to 46 and a pharmaceutically acceptable diluent or carrier.

48. A pharmaceutical composition of claim 47, which is orally bioavailable.

49. A method for the treatment of inflammation, comprising administering a therapeutically effective amount of a pharmaceutical composition of claim 48.

50. A method for inhibiting or reducing HIV infection, comprising administering a therapeutically effective amount of a pharmaceutical composition of claim 48.

51. A method for the treatment of neurodegenerative disease, comprising administering a therapeutically effective amount of a pharmaceutical composition of claim 48.

52. A method for the treatment of muscle-wasting diseases, comprising administering a therapeutically effective amount of a pharmaceutical composition of claim 48.

53. A method for the treatment of cancer, comprising administering a therapeutically effective amount of a pharmaceutical composition of claim 48.

54. A method for the treatment of chronic infectious diseases, comprising administering a therapeutically effective amount of a pharmaceutical composition of claim 48.

55. A method for the treatment of a hyperproliferative condition, comprising administering a therapeutically effective amount of a pharmaceutical composition of claim 48.

56. A method for the treatment of muscle disuse, comprising administering a therapeutically effective amount of a pharmaceutical composition of claim 35.

57. A method for the treatment of immune-related conditions, comprising administering a therapeutically effective amount of a pharmaceutical composition of claim 48.

58. A method for affecting the level of viral gene expression in a subject, comprising administering a therapeutically effective amount of a pharmaceutical composition of claim 48.

59. A method for altering the variety of antigenic peptides produced by the proteasome in an organism, comprising administering therapeutically effective amount of a pharmaceutical composition of claim 48.

46. A compound selected from