Compounds for enzyme inhibition

• US 9,657,058 B2
• Filed: 01/07/2015
• Issued: 05/23/2017
• Est. Priority Date: 06/19/2006
• Status: Active Grant

• Current Assignee: Onyx Therapeutics, Inc. (Amgen Inc.)
• Original Assignee: Onyx Therapeutics, Inc. (Amgen Inc.)
• Inventors: Sylvain, Catherine, Smyth, Mark S., Laidig, Guy J., Parlati, Francesco, Bennett, Mark K., Shenk, Kevin D., Zhou, Han-jie
• Primary Examiner(s): VAJDA, KRISTIN ANN
• Application Number:
  US14/591,351
• Publication Number:
  US 20150353601A1
• Time in Patent Office: 867 Days
• Field of Search: 5142315, 514414, 514475, 514365
• 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 immune-related disease in a patient and said patient suffers from an immune-related disease selected from the group consisting of myositis, atopic dermatitis, scleroderma, ankylosing spondylitis, dermatomyositis, and chronic granulomatous, comprising administering to the patient a compound having a structure of formula (I) or a pharmaceutically acceptable salt thereof,

2. The method of claim 1, wherein the compound of formula (I) has a structure:

3. 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 morpholino.

4. A method of treating a patient suffering from a disease selected from the group consisting of diabetic nephropathy, glomerulosclerosis, congestive heart failure, and scleroderma, comprising administering to the patient a compound having a structure of formula (I) or a pharmaceutically acceptable salt thereof,

5. The method of claim 4, wherein the compound of formula (I) has a structure:

6. The method of claim 4, wherein L is C═

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

7. A method of treating stroke in a patient, comprising administering to the patient a compound having a structure of formula (I) or a pharmaceutically acceptable salt thereof,

8. The method of claim 7, wherein the compound of formula (I) has a structure:

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

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

10. A method of treating a patient suffering from inflammation or an inflammatory disease, comprising administering to the patient a compound having a structure of formula (I) or a pharmaceutically acceptable salt thereof,

11. The method of claim 10, wherein the compound of formula (I) has a structure:

12. The method of claim 10, wherein L is C═

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

13. The method of claim 10, wherein the inflammatory disease is selected from the group consisting of bronchitis, conjunctivitis, pancreatitis, chronic cholecystitis, bronchiectasis, aortic valve stenosis, restenosis, psoriatic arthritis, fibrosis, infection, and ischemia.

14. The method of claim 10, wherein the inflammatory disease is selected from the group consisting of lupus, rheumatoid arthritis, scleroderma, ankylosing spondylitis, dermatomyositis, psoriasis, multiple sclerosis and inflammatory bowel disease.

15. The method of claim 14, wherein the inflammatory bowel disease is ulcerative colitis or Crohn'"'"'s disease.