PRODRUGS OF A PIPERIDINYL DERIVATIVE AS MODULATORS OF CHEMOKINE RECEPTOR ACTIVITY

• US 20110082113A1
• Filed: 10/04/2010
• Published: 04/07/2011
• Est. Priority Date: 10/07/2009
• Status: Active Grant

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Nair, Satheesh, Wu, Hong, Santella, Joseph B., Duncia, John V., Warrier, Jayakumar S., Carter, Percy H., Hynes, John, Cornelius, Lyndon A.M., Dhar, T.G. Murali
• Granted Patent: US 8,410,139 B2
• Time in Patent Office: Days
• US Class Current: 514/89
• 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 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/06 Antipsoriatics
• 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 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• 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 31/18 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 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 9/00 Drugs for disorders of the cardiovascular system
• 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 211/52 : having an aryl radical as the second substituent in position 4
• CPC Class Codes: C07D 211/60 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07F 9/59 : Hydrogenated pyridine rings

Abstract

The present application describes prodrugs of the compound of formula (I):

or stereoisomers or pharmaceutically acceptable salts thereof. In addition, methods of treating and preventing inflammatory diseases such as asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis using the prodrug compounds of the invention are disclosed.

Claims

1. A compound of the formula

3. A pharmaceutical composition comprised of a pharmaceutically acceptable carrier and a therapeutically effective amount of one or more of the compounds of claim 1.

5. A method for modulation of chemokine or chemokine receptor activity comprising administering to a patient in need thereof a therapeutically effective amount of one or more of the compounds of claim 1.

6. The method of claim 5, wherein the chemokine or chemokine receptor activity is CCR-1 or CCR-1 receptor activity.

7. A method for treating a disorder comprising administering to a patient in need thereof a therapeutically effective amount of one or more of the compounds of claim 1;

wherein said disorder is selected from osteoarthritis, aneurysm, fever, cardiovascular effects, Crohn'"'"'s disease, congestive heart failure, autoimmune diseases, HIV-infection, HIV-associated dementia, psoriasis, idiopathic pulmonary fibrosis, transplant arteriosclerosis, physically- or chemically-induced brain trauma, neuropathic pain, inflammatory bowel disease, alveolitis, ulcerative colitis, systemic lupus erythematosus, nephrotoxic serum nephritis, glomerulonephritis, asthma, multiple sclerosis, atherosclerosis, rheumatoid arthritis, restenosis, organ transplantation, multiple myeloma, colorectal cancer, hepatocellular cancer and other cancers.

8. A method for treating inflammatory diseases comprising administering to a patient in need thereof a therapeutically effective amount of one or more of the compounds of claim 1.

9. A method for preparing a medicament for the treatment of osteoarthritis, aneurysm, fever, cardiovascular effects, Crohn'"'"'s disease, congestive heart failure, autoimmune diseases, HIV-infection, HIV-associated dementia, psoriasis, idiopathic pulmonary fibrosis, transplant arteriosclerosis, physically- or chemically-induced brain trauma, neuropathic pain, inflammatory bowel disease, alveolitis, ulcerative colitis, systemic lupus erythematosus, nephrotoxic serum nephritis, glomerulonephritis, asthma, multiple sclerosis, atherosclerosis, and rheumatoid arthritis comprising formulating one or more of the compounds of claim 1.

10. A method for treating a patient in need of therapy comprising administering to said patient in need thereof a therapeutically effective amount of one or more of the compounds of claim 1.

11. A method for treating a disorder comprising administering to a patient in need thereof a therapeutically effective amount of a composition of claim 3, wherein said disorder is selected from osteoarthritis, aneurysm, fever, cardiovascular effects, Crohn'"'"'s disease, congestive heart failure, autoimmune diseases, HIV-infection, HIV-associated dementia, psoriasis, idiopathic pulmonary fibrosis, transplant arteriosclerosis, physically- or chemically-induced brain trauma, neuropathic pain, inflammatory bowel disease, alveolitis, ulcerative colitis, systemic lupus erythematosus, nephrotoxic serum nephritis, glomerulonephritis, asthma, multiple sclerosis, atherosclerosis, rheumatoid arthritis, restenosis, organ transplantation, multiple myeloma, colorectal cancer, hepatocellular cancer and other cancers.

12. A method for treating inflammatory diseases comprising administering to a patient in need thereof a therapeutically effective amount of a composition of claim 3.

13. A method for preparing a medicament for the treatment of osteoarthritis, aneurysm, fever, cardiovascular effects, Crohn'"'"'s disease, congestive heart failure, autoimmune diseases, HIV-infection, HIV-associated dementia, psoriasis, idiopathic pulmonary fibrosis, transplant arteriosclerosis, physically- or chemically-induced brain trauma, neuropathic pain, inflammatory bowel disease, alveolitis, ulcerative colitis, systemic lupus erythematosus, nephrotoxic serum nephritis, glomerulonephritis, asthma, multiple sclerosis, atherosclerosis, and rheumatoid arthritis comprising formulating a composition of claim 3 into a useful pharmaceutical dosage-form.

14. A method for treating a patient in need of therapy comprising administering to said patient in need thereof a therapeutically effective amount of a composition of claim 3.

2. A compound of the formula

4. A pharmaceutical composition comprised of a pharmaceutically acceptable carrier and a therapeutically effective amount of one or more of the compounds of claim 2.