3,4-methylenedioxy-substituted chalcones as therapeutic agents

Abstract

The present invention pertains to the use of a compounds for the manufacture of a medicament for use in the treatment of a proliferative condition, wherein the compounds have the following formula: wherein: each of R B2 , R B3 , R B4 , and R B5 is independently —H, —OH, or —OMe; each of R 1 and R 2 is independently: —H, optionally substituted C 1-4 alkyl, or optionally substituted C 5-20 aryl; R A3 is —H, —OH, —OC(═O)R E , —OS(═O) 2 OH, or —OP(═O)(OH) 2 ; R E is: —H, optionally substituted C 1-6 alkyl, optionally substituted C 3-20 heterocyclyl, or optionally substituted C 5-20 aryl; or a pharmaceutically acceptable salt, solvate, amide, ester, ether, chemically protected form, or prodrug thereof. The present invention also pertains to such compounds, pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, for both diagnosis and treatment of, for example, proliferative conditions, such as cancer, and inflammatory conditions.

1 . A method of treating a proliferative condition characterized by cells which express CYP1B1 in a patient comprising administering to said patient a therapeutically-effective amount of a compound having the formula: 
     
       
         
         
             
             
         
       
       wherein: 
       each of R B2 , R B3 , R B4 , and R B5  is independently —H, —OH, or —OMe; 
       each of R 1  and R 2  is independently:
 —H, 
 optionally substituted C 1-4 alkyl, or 
 optionally substituted C 5-20 aryl; 
 
       R A3  is —H, —OH, —OC(═O)R E , —OS(═O) 2 OH, or —OP(═O)(OH) 2 ; and 
       R E  is:
 —H, 
 optionally substituted C 1-6 alkyl, 
 optionally substituted C 3-20 heterocyclyl, or 
 optionally substituted C 5-20 aryl; 
 
       or a pharmaceutically acceptable salt, solvate, amide, ester, ether, chemically protected form, or prodrug thereof. 
     
   
   
       2 . The method according to  claim 1 , wherein:
 one of R B2 , R B3 , R B4 , and R B5  is —OH or —OMe; and   the others are —H.   
   
   
       3 . The method according to  claim 1 , wherein:
 two of R B2 , R B3 , R B4 , and R B5  is —OH or —OMe; and   the others are —H.   
   
   
       4 . The method according to  claim 1 , wherein:
 three of R B2 , R B3 , R B4 , and R B5  is —OH or —OMe; and   the other is —H.   
   
   
       5 . The method according to  claim 1 , wherein the compound is selected from: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       6 . The method according to  claim 1 , wherein the proliferative condition is characterized by cells which express CYP1B1, wherein the corresponding normal cells do not express CYP1B1. 
   
   
       7 . The method according to  claim 1 , wherein the proliferative condition is cancer. 
   
   
       8 . The method according to  claim 1 , wherein the proliferative condition is a solid tumour. 
   
   
       9 . The method according to  claim 8 , wherein the proliferative condition is a solid tumour, and is a cancer of the lung, colon, breast, ovarian, prostate, liver, pancreas, brain, or skin. 
   
   
       10 . The method according to  claim 9 , wherein the proliferative condition is a solid tumour, and is a cancer of the breast. 
   
   
       11 . The method according to  claim 1 , wherein said proliferative condition is treated prophylactically. 
   
   
       12 . A method of treating an inflammatory condition in a patient comprising administering to said patient a therapeutically-effective amount of a compound having the formula: 
     
       
         
         
             
             
         
       
       wherein: 
       each of R B2 , R B3 , R B4 , and R B5  is independently —H, —OH, or —OMe; 
       each of R 1  and R 2  is independently:
 —H, 
 optionally substituted C 1-4 alkyl, or 
 optionally substituted C 5-20 aryl; 
 
       R A3  is —H, —OH, OC(═O)R E , —OS(═O) 2 OH, or —OP(═O)(OH) 2 ; 
       R E  is;
 —H, 
 optionally substituted C 1-6 alkyl, 
 optionally substituted C 3-20 heterocyclyl, or 
 optionally substituted C 5-20 aryl; 
 
       or a pharmaceutically acceptable salt, solvate, amide, ester, ether, chemically protected form, or prodrug thereof. 
     
   
   
       13 . The method according to  claim 12 , wherein the inflammatory condition is rheumatoid arthritis, rheumatic fever, osteoarthritis, inflammatory bowel disease, psoriasis, or bronchial asthma. 
   
   
       14 . A compound having the formula: 
     
       
         
         
             
             
         
       
       wherein: 
       each of R B2 , R B3 , R B4 , and R B5  is independently —H, —OH, or —OMe; 
       each of R 1  and R 2  is independently:
 —H, 
 optionally substituted C 1-4 alkyl, or 
 optionally substituted C 5-20 aryl; 
 
       R A3  is —H 2 ; 
       R E  is:
 —H, 
 optionally substituted C 1-6 alkyl, 
 optionally substituted C 3-20 heterocyclyl, or 
 optionally substituted C 5-20 aryl; 
 
       or a pharmaceutically acceptable salt, solvate, amide, ester, ether, chemically protected form, or prodrug thereof, for use in a method of diagnosis of the human or animal body. 
     
   
   
       15 . The compound according to  claim 14 , wherein the diagnosis is for the presence of tumour cells expressing the CYP1B1 enzyme. 
   
   
       16 . A method of diagnosis of a patient for the presence of tumour cells expressing the CYP1B1 enzyme, comprising;
 (a) administering to the patient a compound according to  claim 1 , wherein R A3  is —H;   (b) determining the amount of the corresponding hydroxylated metabolite, wherein R A3  is —OH, which is subsequently produced; and,   (c) correlating the amount with the presence or absence of the tumour cells in the patient.   
   
   
       17 . A compound according to  claim 1 ,
 with the proviso that:   if: R A3  is —H and R B2  is —H and R B3  is —OMe and R B4  is —OMe;   then; R B5  is not —OMe.   
   
   
       18 . A compound according to  claim 1 ,
 with the proviso that;   if: R B2  is —H and R B3  is —OMe and R B4  is —OMe;   then: R B5  is not —OMe.   
   
   
       19 . A composition comprising a compound according to  claim 17  or  18  and a pharmaceutically acceptable carrier. 
   
   
       20 . A method of treating cancer, wherein the cancer cells express the enzyme CYP1B and the cancer is selected from lung, colon, breast, ovarian, prostate, liver, brain, and skin, by administering a solvate, amide, ester, ether, chemically protected form, or prodrug of a compound having the formula: 
     
       
         
         
             
             
         
       
       wherein R A3  is —H or —OH.