Macrocyclic therapeutic agents and methods of treatment

Abstract

The instant invention describes macrocyclic compounds having therapeutic activity, and the mechanism and methods of treating disorders such as autoimmune diseases, inflammation, and cancer, tumors and cell proliferation related disorders.

1 . A compound of formula I′: 
       
         
           
           
               
               
           
         
         wherein 
         Each X is independently S or O; 
         Each Y is independently H or Me; 
         Each R is independently alkyl optionally substituted with OH, OMe, SH, SMe, optionally substituted phenyl, NH 2 , NH-alkyl, or N(alkyl)(alkyl); or each R is independently the side chain of a naturally-occurring or non-natural amino acid (including, e.g., phenylalanine, tyrosine, tryptophan, histidine, serine, methionine, and the like); 
         or wherein each Y and R and the adjacent atoms attached to them (nitrogen and carbon, respectively) can combine to form a heterocyclic ring; 
         Each R 2  is independently H, alkyl, or —C(O)alkyl. 
       
     
     
         2 . The compound of  claim 1 , having formula II: 
       
         
           
           
               
               
           
         
         wherein: 
         n is 0, 1, 2, 3, or 4; 
         each R 1  is independently OH, SH, thioalkoxy, alkoxy, halo, NH 2 , NH-alkyl, or N(alkyl)(alkyl). 
       
     
     
         3 . The compound of  claim 1 , of any of formulae: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein the variables are as defined in  claim 1 . 
       
     
     
         4 . The compound of  claim 1 , wherein X is S. 
     
     
         5 . The compound of  claim 2 , having formula 
       
         
           
           
               
               
           
         
       
     
     
         6 . The compound of  claim 1  that is: 
       
         
           
           
               
               
           
         
       
     
     
         7 . A method of modulating the activity of cell proliferation in a subject, comprising identifying a subject in need of inhibition of cotranslational translocation of proteins destined for the secretory pathway with a compound identified as an inhibitor of cotranslational translocation of proteins destined for the secretory pathway, and administering to said subject in need thereof, an effective amount of a compound of  claim 1 , in an amount and under conditions sufficient to modulate cell proliferation. 
     
     
         8 . The method of  claim 7 , wherein the cell is a cancer cell. 
     
     
         9 . The method of  claim 7 , wherein the cell is a tumor cell. 
     
     
         10 . The method of  claim 7  wherein the modulation is inhibition. 
     
     
         11 . The method of  claim 7 , wherein the compound downregulates the level of endoplasmic reticulum (ER) proteins. 
     
     
         12 . The method of  claim 7 , wherein the compound downregulates a FGFR or VEGFR. 
     
     
         13 . A method of treating a subject suffering from or susceptible to a cell proliferation related disorder or disease, wherein the subject has been identified as in need of treatment for a cell proliferation related disorder or disease by downregulation of a receptor tyrosine kinase, comprising administering to said subject in need thereof, an effective amount of a compound of  claim 1 , such that said subject is treated for said disorder. 
     
     
         14 . The method of  claim 12 , wherein the receptor tyrosine kinase is IGF1R-β, PDGFR-β, HER2/neu, c-Met, or an FGFR or VEGFR. 
     
     
         15 . The method of  claim 12 , wherein the disorder is cancer, solid tumor, or metastatic tumor. 
     
     
         16 . The method of  claim 12 , wherein the disorder is an angiogenesis disorder. 
     
     
         17 . The method of  claim 12 , wherein the disorder is solid tumor. 
     
     
         18 . (canceled) 
     
     
         19 . (canceled) 
     
     
         20 . (canceled) 
     
     
         21 . (canceled) 
     
     
         22 . (canceled) 
     
     
         23 . (canceled) 
     
     
         24 . (canceled) 
     
     
         25 . The method of  claim 6  or  10 , wherein the compound is administered alone or in combination with one or more other therapeutics. 
     
     
         26 . The method of claim  2524 , wherein the additional therapeutic agent is an anti-cancer agent, chemotherapeutic agent, an anti-angiogenesis agent, cytotoxic agent, or an anti-proliferation agent. 
     
     
         27 . A method of treating a subject suffering from or susceptible to a disease or disorder, comprising administering to said subject in need thereof, an effective amount of a compound or pharmaceutical composition thereof of any of the formulae herein, such that said subject is treated for said disease or disorder. 
     
     
         28 . The method of  claim 26 , wherein the compound is a compound of  claim 1 . 
     
     
         29 . The method of  claim 27 , wherein the disease or disorder is cervical, ovarian, bladder, pancreatic, or brain cancer. 
     
     
         30 . The method of  claim 27 , wherein the disease or disorder is Hashimoto's thyroiditis, Pernicious anemia, Addison's disease, Type I diabetes, Rheumatoid arthritis, Systemic lupus erythematosus, Dermatomyositis, Sjogren syndrome, Lupus erythematosus, Multiple sclerosis, Myasthenia gravis, Reactive arthritis, Grave's disease, Celiac disease—sprue, or cystic fibrosis. 
     
     
         31 . (canceled) 
     
     
         32 . (canceled)