Orally bioavailable caffeic acid related anticancer drugs

Abstract

The present invention concerns compounds and their use to treat cell proliferative diseases such as cancer. Compounds of the present invention display significant potency as inhibitors of Jak2/STAT3 pathways and downstream targets and inhibit the growth and survival of cancerous cell lines.

1 . A method of treating a cell proliferative disease comprising administering to a patient an effective amount of a compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
         wherein R 1  is —H or cyano and R 2  is heteroatom-substituted or heteroatom-unsubstituted C 3 -C 7 -cycloalkyl; 
       
       
         
           
           
               
               
           
         
         wherein X 1  is halo and R 3  is heteroatom-substituted or heteroatom-unsubstituted C 3 -C 7 -cycloalkyl, C 6 -C 10 -aryl, or C 7 -C 10 -aralkyl; 
       
       
         
           
           
               
               
           
         
         wherein X 2  is halo and R 4  is hydroxy or heteroatom-substituted or heteroatom-unsubstituted C 1 -C 10 -acyloxy; 
       
       
         
           
           
               
               
           
         
         wherein:
 X 3  is halo or heteroatom-substituted or heteroatom-unsubstituted C 1 -C 10 -alkyl or C 1 -C 10 -alkoxy, 
 R 5  is —H or cyano, and 
 R 6  is heteroatom-substituted or heteroatom-unsubstituted C 1 -C 10 -alkyl, C 3 -C 7 -cycloalkyl, C 1 -C 10 -acyloxy, C 6 -C 10 -aryl, or C 7 -C 10 -aralkyl; 
 
       
       
         
           
           
               
               
           
         
         wherein:
 X 4  is halo or heteroatom-substituted or heteroatom-unsubstituted C 1 -C 10 -alkyl or C 1 -C 10 -alkoxy, 
 R 7  is —H or cyano, and 
 R 8  is heteroatom-substituted or heteroatom-unsubstituted C 1 -C 10 -alkyl, C 3 -C 7 -cycloalkyl, C 1 -C 10 -acyloxy, C 6 -C 10 -aryl, or C 7 -C 10 -aralkyl; 
 
       
       
         
           
           
               
               
           
         
         wherein:
 X 5  is heteroatom-substituted or heteroatom-unsubstituted C 1 -C 10 -alkyl or C 1 -C 10 -alkoxy, 
 R 9  is —H or cyano, and 
 R 10  is heteroatom-substituted or heteroatom-unsubstituted C 1 -C 10 -alkyl, C 3 -C 7 -cycloalkyl, C 1 -C 10 -acyloxy, C 6 -C 10 -aryl, or C 7 -C 10 -aralkyl; 
 
       
       
         
           
           
               
               
           
         
         wherein:
 A is —C(O)— or —S(O 2 )—, and 
 X 6  is halo or heteroatom-substituted or heteroatom-unsubstituted C 1 -C 10 -alkyl or C 1 -C 10 -alkoxy, 
 R 11  is heteroatom-substituted or heteroatom-unsubstituted C 1 -C 10 -alkyl, C 3 -C 7 -cycloalkyl, C 1 -C 10 -acyloxy, C 6 -C 10 -aryl, or C 7 -C 10 -aralkyl; 
 
       
       
         
           
           
               
               
           
         
         wherein:
 R 12  is cyclododecyl, imidazoyl, or cyclohexenyl, 
 R 13  is —H or heteroatom-substituted or heteroatom-unsubstituted C 1 -C 10 -alkyl, C 3 -C 7 -cycloalkyl, C 1 -C 10 -acyloxy, C 6 -C 10 -aryl, or C 7 -C 10 -aralkyl; and 
 
       
       
         
           
           
               
               
           
         
         wherein:
 X 7  is halo or heteroatom-substituted or heteroatom-unsubstituted C 1 -C 10 -alkyl or C 1 -C 10 -alkoxy, 
 R 14  is 
 
       
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt of any of the above formulas. 
     
     
         2 . The method of  claim 1 , wherein R 2  is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. 
     
     
         3 . The method of  claim 1 , wherein R 3  is selected from the group consisting of phenyl, benzyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. 
     
     
         4 . The method of  claim 1 , wherein X 1  or X 2  is selected from the group consisting of —F, —Cl, —Br and —I. 
     
     
         5 . The method of  claim 1 , wherein R 4  is selected from a group consisting of hydroxy, acetoxy and 2,2-dimethylpropionyloxy. 
     
     
         6 . The method of  claim 1 , wherein X 3  or X 4  is selected from the group consisting of methoxy, —F, —Cl, —Br and —I. 
     
     
         7 . The method of  claim 1 , wherein R 6  or R 8  is selected from the group consisting of methyl and cyclopropyl. 
     
     
         8 . The method of  claim 1 , wherein X 5  is selected from a group consisting of methyl and acetoxymethyl. 
     
     
         9 . The method of  claim 1 , wherein A is —S(O 2 )—. 
     
     
         10 . (canceled) 
     
     
         11 . The method of  claim 1 , wherein the compound has the formula: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or is a pharmaceutically acceptable salt of any of the above formulas. 
       
     
     
         12 .- 44 . (canceled) 
     
     
         45 . The method of  claim 1 , wherein the compound has the formula: 
       
         
           
           
               
               
           
         
         or is a pharmaceutically acceptable salt thereof. 
       
     
     
         46 .- 86 . (canceled) 
     
     
         87 . The method of  claim 1 , wherein the subject is a mammal. 
     
     
         88 . The method of  claim 87 , wherein the mammal is a human. 
     
     
         89 . (canceled) 
     
     
         90 . The method of  claim 1 , wherein the cell proliferative disease is cancer. 
     
     
         91 . The method of  claim 90 , wherein the cancer is melanoma, non-small cell lung, small cell lung, lung, hepatocarcinoma, retinoblastoma, astrocytoma, glioblastoma, leukemia, blood, brain, skin, eye, tongue, gum, neuroblastoma, head, neck, breast, pancreatic, renal, bone, testicular, ovarian, mesothelioma, cervical, gastrointestinal, lymphoma, colon, or bladder. 
     
     
         92 . The method of  claim 1 , wherein the cell proliferative disease is rheumatoid arthritis, inflammatory bowel disease, osteoarthritis, leiomyomas, adenomas, lipomas, hemangiomas, fibromas, vascular occlusion, restenosis, arthrosclerosis, a pre-neoplastic lesion, carcinoma in situ, oral hairy leukoplakia, or psoriasis. 
     
     
         93 . The method of  claim 1 , wherein STAT3 activation is reduced in a cell of the subject. 
     
     
         94 . The method of  claim 1 , wherein c-myc expression is reduced in a cell of the subject. 
     
     
         95 .- 97 . (canceled)