Macrocyclic therapeutic agents, methods of manufacture, 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 1 or formula 2: 
       
         
           
           
               
               
           
         
       
       wherein
 each X is independently S or O; 
 each Y is independently H or optionally substituted alkyl; 
 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 1  and R 2  is independently H or optionally substituted alkyl; 
 each R 3  is independently H, optionally substituted alkyl, or —C(O)alkyl; and 
 each R 4  is H or optionally substituted alkyl. 
 
     
     
         2 . The compound of  claim 1 , according to formula 3 or formula 4: 
       
         
           
           
               
               
           
         
       
       wherein:
 each n is independently 0, 1, 2, 3, or 4; and 
 each R 5  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 , according to formula 15: 
       
         
           
           
               
               
           
         
       
       wherein the variables are as defined in  claim 1 . 
     
     
         6 . The compound of  claim 1  that is: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         7 .- 18 . (canceled) 
     
     
         19 . A method of treating a subject suffering from or susceptible to a cell proliferation related disorder or disease, comprising administering to said subject an effective amount of a compound of  claim 1 , such that said subject is treated for said disorder. 
     
     
         20 . The method of  claim 19 , wherein the receptor tyrosine kinase is IGF1R-β, PDGFR-β, HER2/neu, c-Met, or an FGFR or VEGFR. 
     
     
         21 . The method of  claim 19 , wherein the disorder is cancer, solid tumor, or metastatic tumor. 
     
     
         22 . The method of  claim 19 , wherein the disorder is an angiogenesis disorder. 
     
     
         23 . The method of  claim 19 , wherein the disorder is solid tumor. 
     
     
         24 . The method of  claim 19 , wherein the subject is a mammal. 
     
     
         25 . The method of  claim 19 , wherein the subject is a primate or human. 
     
     
         26 .- 29 . (canceled) 
     
     
         30 . The method of  claim 19 , wherein the compound is administered intravenously, intramuscularly, subcutaneously, intracerebroventricularly, orally or topically. 
     
     
         31 . The method of  claim 19 , wherein the compound is administered alone or in combination with one or more other therapeutics. 
     
     
         32 . The method of  claim 31 , wherein the additional therapeutic agent is an anti-cancer agent, chemotherapeutic agent, an anti-angiogenesis agent, cytotoxic agent, or an anti-proliferation agent. 
     
     
         33 .- 37 . (canceled) 
     
     
         38 . A pharmaceutical composition comprising a compound of any one of  claims 1 - 6  and a pharmaceutically acceptable carrier. 
     
     
         39 . (canceled) 
     
     
         40 . A process to prepare a compound of formula 16 or formula 17: 
       
         
           
           
               
               
           
         
       
       wherein the process comprises the step of reacting a compound of formula 18, 
       
         
           
           
               
               
           
         
       
       with a compound of formula 19, 
       
         
           
           
               
               
           
         
       
       to afford a compound of formula 20, 
       
         
           
           
               
               
           
         
         wherein 
         each X is independently S or O; 
         each R 1  is optionally substituted alkyl; 
         each R 2  is H; 
         each R 3  is independently H, optionally substituted alkyl, or —C(O)alkyl; 
         each R 6  is independently H, optionally substituted alkyl, or —C(O)alkyl; 
         each R 7  and R 8  are independently H or optionally substituted alkyl; and 
         each R 9  is independently H, optionally substituted alkyl, or optionally substituted aralkyl. 
       
     
     
         41 .- 57 . (canceled)