Compositions and methods for modulating inflammatory and degenerative disorder

Abstract

The disclosure provides compounds and method useful for modulating gp130 biological activity. The disclosure also provides methods and compositions for treating disease and disorders associated with gp130 activity, particularly those associated with inflammation.

What is claimed is: 
     
         1 . A pharmaceutical composition comprising a compound of Formula I 
       
         
           
           
               
               
           
         
         wherein, 
         X is 
       
       
         
           
           
               
               
           
         
         Y is 
       
       
         
           
           
               
               
           
         
         Z is 
       
       
         
           
           
               
               
           
         
         Y 1-3  are C, Z is O, Z 2  is N or C, Z 3  is N or C, Z 4  is C, v is 0 or 1, R 1  is H and R 3 -R 7  are independently selected from H, D, (C 1 -C 3 ) alkyl, (C 1 -C 3 ) alkenyl, halo, cyano, hydroxyl, nitro, thiol or amino;
 wherein the compound is present in an amount effective to treat inflammation, reduce joint pain or prevent joint degeneration. 
 
       
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein the compound is 
       
         
           
           
               
               
           
         
       
     
     
         3 . The pharmaceutical composition of  claim 1 , wherein the compound is selected from the following: 
       
         
           
           
               
               
           
         
       
     
     
         4 . The pharmaceutical composition of  claim 1 , formulated to be effective upon single administration. 
     
     
         5 . The pharmaceutical composition of  claim 1 , further comprising microspheres, wherein the composition is formulated for slow release delivery. 
     
     
         6 . The pharmaceutical composition of  claim 1 , formulated to be effective upon administration to a human subject suffering from osteoarthritis. 
     
     
         7 . The pharmaceutical composition of  claim 1 , formulated for administration by intra-articular injection. 
     
     
         8 . The pharmaceutical composition of  claim 1 , wherein the compound is present in an amount effective to (i) lower activity of an inflammatory indicator selected from NF-kB and pSRC kinase, and (ii) prevent activation of gp130 in an articular chondrocyte, synovial cells or immune cells. 
     
     
         9 . The pharmaceutical composition of  claim 1 , further comprising an additional therapeutic compound selected from the group consisting of alkylating agents, cancer immunotherapy monoclonal antibodies, anti-metabolites, mitotic inhibitors, antitumor antibiotics, topoisomerase inhibitors, photosensitizers, tyrosine kinase inhibitors, anti-cancer agents, chemotherapeutic agents, anti-migraine treatments, anti-tussives, mucolytics, decongestants, anti-allergic non-steroidals, expectorants, antihistamine treatments, anti-retroviral agents, CYP3A inhibitors, CYP3A inducers, protease inhibitors, adrenergic agonists, anticholinergics, mast cell stabilizers, xanthines, leukotriene antagonists, glucocorticoid treatments, antibacterial agents, antifungal agents, sepsis treatments, steroidals, local or general anesthetics, NSAIDS, NRIs, DARIs, SNRIs, sedatives, NDRIs, SNDRIs, monoamine oxidase inhibitors, hypothalamic phoshpholipids, antiemetics, ECE inhibitors, opioids, thromboxane receptor antagonists, potassium channel openers, thrombin inhibitors, growth factor inhibitors, anti-platelet agents, P2Y (AC) antagonists, anticoagulants, low molecular weight heparins, Factor Via inhibitors, Factor Xa inhibitors, renin inhibitors, NEP inhibitors, vasopepsidase inhibitors, squalene synthetase inhibitors, anti-atherosclerotic agents, MTP inhibitors, calcium channel blockers, potassium channel activators, alpha-muscarinic agents, beta-muscarinic agents, anti-arrhythmic agents, diuretics, thrombolytic agents, anti-diabetic agents, mineralocorticoid receptor antagonists, growth hormone secretagogues, aP2 inhibitors, phophodiesterase inhibitors, anti-inflammatories, antiproliferatives, antibiotics, farnesyl-protein transferase inhibitors, hormonal agents, plant-derived products, epipodophyllotoxins, taxanes, prenyl-protein transferase inhibitors, anti-TNF antibodies and soluble TNF receptors, Cyclooxygenase-2 inhibitors, and miscellaneous agents. 
     
     
         10 . A pharmaceutical composition formulated for intra-articular administration to a mammalian subject in need thereof comprising a therapeutically effective amount of a compound comprising the structure of Formula I. 
     
     
         11 . The pharmaceutical composition of  claim 10 , wherein the compound is 
       
         
           
           
               
               
           
         
       
     
     
         12 . The pharmaceutical composition of  claim 10 , where in the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         13 . The pharmaceutical composition of  claim 10 , wherein the composition is administered to a knee articular joint or a hip articular joint. 
     
     
         14 . The pharmaceutical composition of  claim 10 , wherein the composition is administered to a knee articular joint of a human subject suffering from a cartilage degenerative disease, a joint surface injury, or joint pain arising from arthritis. 
     
     
         15 . A pharmaceutical composition comprising a therapeutically effective amount of a compound comprising the structure of Formula I, wherein the pharmaceutical composition is effective to treat inflammation, pain and joint degeneration associated with osteoarthritis at a concentration less than about 10 mg/kg of body weight. 
     
     
         16 . The pharmaceutical composition of  claim 15 , wherein the compound is 
       
         
           
           
               
               
           
         
       
     
     
         17 . The pharmaceutical composition of  claim 15 , wherein the compound is selected from the group consisting of: