Inhibitors of sox18 protein activity for treating angiogenesis and/or lymphangiogenesis-related diseases

Abstract

Disclosed are compounds of a formula provided herein that show efficacy in the inhibition of SOX18 protein activity, and in particular with respect to the ability of SOX18 to bind DNA and/or particular protein partners. Further, methods of treating angiogenesis- and/or lymphangiogenesis-related diseases, disorders or conditions, such as cancer metastasis and vascular cancers, are provided herein.

1 . A compound of formula (I), or a pharmaceutically acceptable salt, solvate or prodrug thereof: 
       
         
           
           
               
               
           
         
       
       wherein,
 R 1  is selected from the group consisting of OH and OR 6  wherein R 6  is C 1 -C 4  alkyl; 
 R 2  is selected from the group consisting of H, COOR 7 , and C(O)NR 8 R 9  wherein R 7 , R 8  and R 9  are independently selected from H and C 1 -C 4  alkyl; 
 R 3  is L-A wherein L is a linker selected from C 2 -C 8  alkyl, C 2 -C 8  alkenyl and C 2 -C 8  alkoxyalkyl and A is selected from optionally substituted phenyl and optionally substituted napthyl; 
 R 4  is selected from the group consisting of H, OR 10 , halo and C 1 -C 4  alkyl wherein R 10  is selected from H and C 1 -C 4  alkyl; and 
 R 5  is selected from the group consisting of H and OR 11 , halo and C 1 -C 4  alkyl wherein R 11  is selected from H and C 1 -C 4  alkyl, 
 wherein, the compound is for use in the inhibition of a SOX18 activity. 
 
     
     
         2 . The compound of  claim 1 , wherein;
 R 1  is selected from the group consisting of OH and OMe;   R 2  is selected from the group consisting of H, COOH, COOMe and   
       
         
           
           
               
               
           
         
         R 4  is selected from the group consisting of H, OH, OMe, Cl and Me; and 
         R 5  is selected from the group consisting of H, OH and OMe. 
       
     
     
         3 - 5 . (canceled) 
     
     
         6 . The compound of  claim 1 , wherein R 4  and R 5  are H. 
     
     
         7 . The compound of  claim 1 , wherein L is a linker selected from C 2 -C 6  alkyl, C 2 -C 6  alkenyl and C 2 -C 6  alkoxyalkyl. 
     
     
         8 . The compound of  claim 1 , wherein R 3  is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         wherein, the broken line indicates the attachment from that adjacent atom to the ring of formula I and the structures shown include E/Z isomers thereof. 
       
     
     
         9 . The compound of  claim 1 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         10 .- 11 . (canceled) 
     
     
         12 . A pharmaceutical composition comprising the compound of  claim 1 , or a pharmaceutically acceptable salt, solvate or prodrug thereof, and a pharmaceutically acceptable carrier, diluent and/or excipient. 
     
     
         13 . A method of treatment or prevention of an angiogenesis- and/or lymphangiogenesis-related disease, disorder or condition in a subject including the step of administering to the subject an effective amount of the compound of  claim 1 , or a pharmaceutically effective salt, solvate or prodrug thereof, or the pharmaceutical composition of  claim 12 , to thereby treat or prevent the angiogenesis- and/or lymphangiogenesis-related disease, disorder or condition. 
     
     
         14 . (canceled) 
     
     
         15 . The method of  claim 13 , wherein the angiogenesis- and/or lymphangiogenesis-related disease, disorder or condition is or comprises:
 (i) an opthalmic disease, disorder or condition, or   (ii) an opthalmic disease, disorder or condition selected from the group consisting of age-related macular degeneration, diabetic retinopathy, ischemic retinopathy, retinopathy of prematurity, neovascular glaucoma, iritis rubeosis, corneal neovascularization, cyclitis, sickle cell retinopathy, pterygium, vascular response during corneal injury and any combination thereof.   
     
     
         16 . (canceled) 
     
     
         17 . The method of  claim 13 , wherein the angiogenesis- and/or lymphangiogenesis-related disease, disorder or condition is or comprises:
 (i) a cancer, or   (ii) a cancer selected from the group consisting of prostate cancer, lung cancer, breast cancer, bladder cancer, renal cancer, colon cancer, gastric cancer, pancreatic cancer, ovarian cancer, melanoma, hepatoma, hepatocellular carcinoma, sarcoma, leukemia, lymphoma, a vascular neoplasm and any combination thereof.   
     
     
         18 .- 19 . (canceled) 
     
     
         20 . The method of  claim 13 , wherein the angiogenesis- and/or lymphangiogenesis-related disease, disorder or condition is or comprises:
 (i) a renal disease, disorder or condition, or   (ii) a renal disease, disorder or condition selected from the group consisting of chronic renal transplant dysfunction, primary renal fibrotic disorders, proteinuria, diabetic nephropathy, renal inflammation and any combination thereof.   
     
     
         21 . (canceled) 
     
     
         22 . A method of inhibiting or preventing metastasis of a cancer in a subject including the step of administering to the subject an effective amount of the compound of  claim 1 , or a pharmaceutically effective salt, solvate or prodrug thereof, or the pharmaceutical composition of  claim 12 , to thereby inhibit or prevent metastasis of the cancer. 
     
     
         23 . A method of inhibiting, preventing or reducing a SOX18 activity in a subject comprising the step of administering to the subject an effective amount of the compound of  claim 1 , or a pharmaceutically effective salt, solvate or prodrug thereof, or the pharmaceutical composition of  claim 12 , to thereby inhibit, prevent or reduce the SOX18 activity in the subject. 
     
     
         24 . The method of  claim 23 , wherein the SOX18 activity includes contacting and/or binding to a DNA sequence and/or a protein. 
     
     
         25 . (canceled)