Compounds for enzyme inhibition

• US 8,609,654 B1
• Filed: 08/16/2013
• Issued: 12/17/2013
• Est. Priority Date: 06/19/2006
• Status: Active Grant

• Current Assignee: Onyx Therapeutics, Inc. (Amgen Inc.)
• Original Assignee: Onyx Therapeutics, Inc. (Amgen Inc.)
• Inventors: Shenk, Kevin D., Parlati, Francesco, Sylvain, Catherine, Smyth, Mark S., Bennett, Mark K., Laidig, Guy J., Zhou, Han-jie
• Primary Examiner(s): VAJDA, KRISTIN ANN
• Application Number:
  US13/969,138
• Publication Number:
  US 20130338057A1
• Time in Patent Office: 123 Days
• Field of Search: 514/18, 514/231.5
• US Class Current: 514/231.5
• 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 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 11/08 Bronchodilators
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 17/14 for baldness or alopecia
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• 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 25/16 Anti-Parkinson drugs
• 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 27/02 Ophthalmic agents
• 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 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 3/12 : for electrolyte homeostasis
• 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 31/18 : for HIV
• CPC Class Codes: A61P 33/00 : Antiparasitic agents
• CPC Class Codes: A61P 33/02 : Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
• 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 9/04 : Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• 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 303/32 : by aldehydo- or ketonic radicals
• CPC Class Codes: C07D 405/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07K 5/06 : Dipeptides
• 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 5/06043 : Leu-amino acid
• CPC Class Codes: C07K 5/06052 : Val-amino acid
• 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 5/06086 : with the first amino acid being basic
• CPC Class Codes: C07K 5/06113 : Asp- or Asn-amino acid
• 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 5/0812 : and aromatic or cycloaliphatic
• CPC Class Codes: C07K 5/0819 : with the first amino acid being acidic
• CPC Class Codes: C07K 5/0821 : with the first amino acid being heterocyclic, e.g. His, Pro, Trp
• 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
• 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

One aspect of the invention relates to inhibitors that preferentially inhibit immunoproteasome activity over constitutive proteasome activity. In certain embodiments, the invention relates to the treatment of immune related diseases, comprising administering a compound of the invention. In certain embodiments, the invention relates to the treatment of cancer, comprising administering a compound of the invention.

Claims

1. A method for the treatment of an ischemic condition or a reperfusion injury in a patient, comprising administering to the patient a therapeutically effective amount of a compound having a structure of formula (I) or a pharmaceutically acceptable salt thereof,

2. The method of claim 1, wherein R⁷ and R⁸ are independently selected from hydrogen and C_1-6alkyl.

3. The method of claim 2, wherein R⁷ and R⁸ are both hydrogen.

4. The method of claim 3, wherein R¹⁵ is selected from methyl, ethyl, hydroxymethyl, and 2-hydroxyethyl.

5. The method of claim 4, wherein R¹⁵ is methyl.

6. The method of claim 1, wherein R⁵ is hydrogen.

7. The method of claim 1, wherein L and Q are absent.

8. The method of claim 1, wherein R¹ is selected from —

C_1-6alkyl-B and C_1-6aralkyl.

9. The method of claim 8, wherein R¹ is selected from methyl, ethyl, isopropyl, carboxymethyl, and benzyl.

10. The method of claim 1, wherein R² is selected from C_1-6alkyl-phenyl, C_1-6alkyl-indolyl, C_1-6alkyl-thienyl, C_1-6alkyl-thiazolyl, and C_1-6alkyl-isothiazolyl.

11. The method of claim 10, wherein R² is selected from

12. The method of claim 1, wherein R³ is selected from C_1-6alkyl-phenyl and C_1-6alkyl-indolyl.

13. The method of claim 12, wherein R³ is selected from

14. The method of claim 1, wherein R⁶ is selected from heterocyclylMZAZ—

C_1-6alkyl-, heterocyclylM-, and carbocyclylM-.

15. The method of claim 14, wherein R⁶ is heterocyclylMZAZ—

C_1-6alkyl-, and heterocyclylM-.

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

O, Q is absent, M is C_1-8alkyl and R⁶ is heterocyclylM- and the heterocyclyl moiety is selected from morpholino, piperidino, piperazino, and pyrrolidino.

17. The method of claim 16, wherein L is C═

O, Q is absent, M is C_1-8alkyl and R⁶ is heterocyclylM- and the heterocyclyl moiety is morpholino.

18. The method of claim 17, wherein X is O.

19. The method of claim 18, wherein R⁵, R⁷, and R⁸ are hydrogen.

20. The method of claim 19, wherein R¹⁵ is methyl.

21. The method of claim 20, wherein R¹ is —

C_1-6alkyl-B.

22. The method of claim 21, wherein R¹ is selected from methyl, ethyl, isopropyl, carboxymethyl, and benzyl.

23. The method of claim 22, wherein R¹ is methyl.

24. The method of claim 23, wherein R² is C_1-6alkyl-phenyl.

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

26. The method of claim 1, wherein the ischemic condition or reperfusion injury is associated with inflammation.

27. The method of claim 1, wherein the ischemic condition or reperfusion injury is selected from the group consisting of:

acute coronary syndrome, arterial occlusive disease, atherosclerosis, infarctions, heart failure, pancreatitis, myocardial hypertrophy, myocardial necrosis, reduced ventricular function, stenosis, and restenosis.

28. The method of claim 27, wherein the ischemic condition or reperfusion injury is selected from the group consisting of:

arterial occlusive disease, atherosclerosis, infarctions, heart failure, and reduced ventricular function.

29. The method of claim 28, wherein the ischemic condition or reperfusion injury is selected from infarctions and heart failure.

30. A method for treating an ischemic condition or a reperfusion injury in a patient, comprising administering to the patient a therapeutically effective amount of a compound having the structure:

31. The method of claim 30, wherein the ischemic condition or reperfusion injury is associated with inflammation.

32. The method of claim 31, wherein the ischemic condition or reperfusion injury is selected from the group consisting of:

acute coronary syndrome, arterial occlusive disease, atherosclerosis, infarctions, heart failure, pancreatitis, myocardial hypertrophy, myocardial necrosis, reduced ventricular function, stenosis, and restenosis.

33. The method of claim 32, wherein the ischemic condition or reperfusion injury is selected from the group consisting of:

arterial occlusive disease, atherosclerosis, infarctions, heart failure, and reduced ventricular function.

34. The method of claim 33, wherein the ischemic condition or reperfusion injury is selected from the group consisting of:

infarctions and heart failure.

35. A method for the treatment of an infarction or heart failure in a patient, comprising administering to the patient a therapeutically effective amount of a compound having a structure of formula (I) or a pharmaceutically acceptable salt thereof,

36. The method of claim 35, wherein R⁷ and R⁸ are independently selected from hydrogen and C_1-6alkyl.

37. The method of claim 36, wherein R⁷ and R⁸ are both hydrogen.

38. The method of claim 37, wherein R¹⁵ is selected from methyl, ethyl, hydroxymethyl, and 2-hydroxyethyl.

39. The method of claim 38, wherein R¹⁵ is methyl.

40. The method of claim 35, wherein R⁵ is hydrogen.

41. The method of claim 35, wherein L and Q are absent.

42. The method of claim 35, wherein R¹ is selected from —

C_1-6alkyl-B and C_1-6aralkyl.

43. The method of claim 42, wherein R¹ is selected from methyl, ethyl, isopropyl, carboxymethyl, and benzyl.

44. The method of claim 35, wherein R² is selected from C_1-6alkyl-phenyl, C_1-6alkyl-indolyl, C_1-6alkyl-thienyl, C_1-6alkyl-thiazolyl, and C_1-6alkyl-isothiazolyl.

45. The method of claim 44, wherein R² is selected from

46. The method of claim 35, wherein R³ is selected from C_1-6alkyl-phenyl and C_1-6alkyl-indolyl.

47. The method of claim 46, wherein R³ is selected from

48. The method of claim 35, wherein R⁶ is selected from heterocyclylMZAZ—

C_1-6alkyl-, heterocyclylM-, and carbocyclylM-.

49. The method of claim 48, wherein R⁶ is heterocyclylMZAZ—

C_1-6alkyl-, and heterocyclylM-.

50. The method of claim 35, wherein L is C═

O, Q is absent, M is C_1-8alkyl and R⁶ is heterocyclylM- and the heterocyclyl moiety is selected from morpholino, piperidino, piperazino, and pyrrolidino.

51. The method of claim 50, wherein L is C═

O, Q is absent, M is C_1-8alkyl and R⁶ is heterocyclylM- and the heterocyclyl moiety is morpholino.

52. The method of claim 51, wherein X is O.

53. The method of claim 52, wherein R⁵, R⁷, and R⁸ are hydrogen.

54. The method of claim 53, wherein R¹⁵ is methyl.

55. The method of claim 54, wherein R¹ is —

C_1-6alkyl-B.

56. The method of claim 55, wherein R¹ is selected from methyl, ethyl, isopropyl, carboxymethyl, and benzyl.

57. The method of claim 56, wherein R¹ is methyl.

58. The method of claim 57, wherein R² is C_1-6alkyl-phenyl.

59. The method of claim 58, wherein R³ is C_1-6alkyl-phenyl.

60. A method for treating an infarction or heart failure in a patient, comprising administering to the patient a therapeutically effective amount of a compound having the structure: