Benzopyranone compounds, compositions thereof, and methods of treatment therewith

Abstract

Benzopyranone compounds having the following structure: wherein R 1 , X, Y and n are as defined here, are disclosed. The compounds of formula (I), wherein R 1 is H, can be prepared by demethylation of the corresponding phenolic methyl ether. The compounds are useful for treating a bone-resorbing disease, cancer, arthritis or an estrogen-related condition such as breast cancer, osteoporosis, endometriosis, cardiovascular disease, hypercholesterolemia, prostatic hypertrophy, prostatic carcinomas, obesity, hot flashes, skin effects, mood swings, memory loss, and adverse reproductive effects associated with exposure to environmental chemicals or natural hormonal imbalances.

What is claimed is:  
     
         1 . A method for modulating gene expression in a cell expressing ER, comprising contacting the cell with an effective amount of a compound having the structure:  
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof,  
         wherein: 
 n is 2, 3 or 4;  
 R 1  is hydrogen, C(═O)R 2 , C(═O)OR 2 , C(═O)NHR 2 , C(═O)NR 2 R 3 , or S(═O 2 )NR 2 R 3 ;  
 R 2  and R 3  are independently C 1-8 alkyl, C 6-12 aryl, C 7-12 arylalkyl, or a five- or six-membered heterocycle containing up to two heteroatoms selected from O, NR 4  and S(O) q , wherein each of the above groups are optionally substituted with one to three substituents independently selected from R 5  and q is 0, 1 or 2;  
 R 4  is hydrogen or C 1-4  alkyl;  
 R 5  is hydrogen, halogen, hydroxy, C 1-6 alkyl, C 1-4 alkoxy, C 1-4 acyloxy, C 1-4 thio, C 1-4 alkylsulfinyl, C 1-4 alkylsulfonyl, (hydroxy)C 1-4 alkyl, C 6-12 aryl, C 7-12 aralkyl, COOH, CN, CONHOR 6 , SO 2 NHR 6 , NH 2 , C 1-4 alkylamino, C 1-4 dialkylamino, NHSO 2 R 6 , NO 2 , or a five- or six-membered heterocycle, where each occurrence of R 6  is independently C 1-6 alkyl;  
 X is hydrogen, halogen or trifluoromethyl; and  
 Y is halogen or trifluoromethyl.  
 
       
     
     
         2 . The method of  claim 1  wherein ER is ER-α or ER-β.  
     
     
         3 . The method of  claim 1  wherein the cell preferentially expresses ER-β over ER-α.  
     
     
         4 . The method of  claim 1  wherein the cell is of bone, bladder, uterus, ovary, prostate, testis, epididymis, gastrointestinal tract, kidney, breast, eye, heart, vessel wall, immune system, lung, pituitary, hippocampus or hypothalamus.  
     
     
         5 . A method of modulating ER in tissue expressing ER, comprising contacting the tissue with an effective amount of a compound having the structure:  
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof,  
         wherein: 
 n is 2, 3 or 4;  
 R 1  is hydrogen, C(═O)R 2 , C(═O)OR 2 , C(═O)NHR 2 , C(═O)NR 2 R 3 , or S(═O 2 )NR 2 R 3 ;  
 R 2  and R 3  are independently C 1-8 alkyl, C 6-12 aryl, C 7-12 arylalkyl, or a five- or six-membered heterocycle containing up to two heteroatoms selected from O, NR 4  and S(O) q , wherein each of the above groups are optionally substituted with one to three substituents independently selected from R 5  and q is 0, 1 or 2;  
 R 4  is hydrogen or C 1-4  alkyl;  
 R 5  is hydrogen, halogen, hydroxy, C 1-6 alkyl, C 1-4 alkoxy, C 1-4 acyloxy, C 1-4 thio, C 1-4 alkylsulfinyl, C 1-4 alkylsulfonyl, (hydroxy)C 1-4 alkyl, C 6-12 aryl, C 7-12 aralkyl, COOH, CN, CONHOR 6 , SO 2 NHR 6 , NH 2 , C 1-4 alkylamino, C 1-4 dialkylamino, NHSO 2 R 6 , NO 2 , or a five- or six-membered heterocycle, where each occurrence of R 6  is independently C 1-6 alkyl;  
 X is hydrogen, halogen or trifluoromethyl; and  
 Y is halogen or trifluoromethyl.  
 
       
     
     
         6 . The method of  claim 5  wherein ER is ER-α or ER-β.  
     
     
         7 . The method of  claim 5  wherein the tissue preferentially expresses ER-β over ER-α.  
     
     
         8 . The method of  claim 5  wherein the tissue is of bone, bladder, uterus, ovary, prostate, testis, epididymis, gastrointestinal tract, kidney, breast, eye, heart, vessel wall, immune system, lung, pituitary, hippocampus or hypothalamus.  
     
     
         9 . A method for obtaining a compound having the structure:  
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof,  
         wherein: 
 n is 2, 3 or 4;  
 R 1  is hydrogen;  
 X is hydrogen, halogen or trifluoromethyl; and  
 Y is halogen or trifluoromethyl;  
 comprising the step of demethylating of a compound having the structure:  
                     
 
         or a pharmaceutically acceptable salt thereof,  
         wherein: 
 n is 2, 3 or 4;  
 X is hydrogen, halogen or trifluoromethyl; and  
 Y is halogen or trifluoromethyl.  
 
       
     
     
         10 . A method for activating the function of ER in a bone cell, comprising contacting a bone cell with an effective amount of a compound having the structure:  
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof,  
         wherein: 
 n is 2, 3 or 4;  
 R 1  is hydrogen, C(═O)R 2 , C(═O)OR 2 , C(═O)NHR 2 , C(═O)NR 2 R 3 , or S(═O 2 )NR 2 R 3 ;  
 R 2  and R 3  are independently C 1-8 alkyl, C 6-12 aryl, C 7-12 arylalkyl, or a five- or six-membered heterocycle containing up to two heteroatoms selected from O, NR 4  and S(O) q , wherein each of the above groups are optionally substituted with one to three substituents independently selected from R 5  and q is 0, 1 or 2;  
 R 4  is hydrogen or C 1-4  alkyl;  
 R 5  is hydrogen, halogen, hydroxy, C 1-6 alkyl, C 1-4 alkoxy, C 1-4 acyloxy, C 1-4 thio, C 1-4 alkylsulfinyl, C 1-4 alkylsulfonyl, (hydroxy)C 1-4 alkyl, C 6-12 aryl, C 7-12 aralkyl, COOH, CN, CONHOR 6 , SO 2 NHR 6 , NH 2 , C 1-4 alkylamino, C 1-4 dialkylamino, NHSO 2 R 6 , NO 2 , or a five- or six-membered heterocycle, where each occurrence of R 6  is independently C 1-6 alkyl;  
 X is hydrogen, halogen or trifluoromethyl; and  
 Y is halogen or trifluoromethyl.  
 
       
     
     
         11 . The method of  claim 10  wherein the cell is an osteosarcoma cell.  
     
     
         12 . A method for inhibiting the function of ER in a breast cancer cell, ovary cancer cell, endometrial cancer cell, uterine cancer cell, prostate cancer cell or hypothalamus cancer cell comprising contacting said cell with an effective amount of a compound having the structure:  
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof,  
         wherein: 
 n is 2, 3 or 4;  
 R 1  is hydrogen, C(═O)R 2 , C(═O)OR 2 , C(═O)NHR 2 , C(═O)NR 2 R 3 , or S(═O 2 )NR 2 R 3 ;  
 R 2  and R 3  are independently C 1-8 alkyl, C 6-12 aryl, C 7-12 arylalkyl, or a five- or six-membered heterocycle containing up to two heteroatoms selected from O, NR 4  and S(O) q , wherein each of the above groups are optionally substituted with one to three substituents independently selected from R 5  and q is 0, 1 or 2;  
 R 4  is hydrogen or C 1-4  alkyl;  
 R 5  is hydrogen, halogen, hydroxy, C 1-6 alkyl, C 1-4 alkoxy, C 1-4 acyloxy, C 1-4 thio, C 1-4 alkylsulfinyl, C 1-4 alkylsulfonyl, (hydroxy)C 1-4 alkyl, C 6-12 aryl, C 7-12 aralkyl, COOH, CN, CONHOR 6 , SO 2 NHR 6 , NH 2 , C 1-4 alkylamino, C 1-4 dialkylamino, NHSO 2 R 6 , NO 2 , or a five- or six-membered heterocycle, where each occurrence of R 6  is independently C 1-6 alkyl;  
 X is hydrogen, halogen or trifluoromethyl; and  
 Y is halogen or trifluoromethyl.  
 
       
     
     
         13 . A method for inhibiting the expression of IL-6, comprising contacting a cell capable of expressing ER and IL-6 with an effective amount of a compound having the structure:  
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof,  
         wherein: 
 n is 2, 3 or 4;  
 R 1  is hydrogen, C(═O)R 2 , C(═O)OR 2 , C(═O)NHR 2 , C(═O)NR 2 R 3 , or S(═O 2 )NR 2 R 3 ;  
 R 2  and R 3  are independently C 1-8 alkyl, C 6-12 aryl, C 7-12 arylalkyl, or a five- or six-membered heterocycle containing up to two heteroatoms selected from O, NR 4  and S(O) q , wherein each of the above groups are optionally substituted with one to three substituents independently selected from R 5  and q is 0, 1 or 2;  
 R 4  is hydrogen or C 4  alkyl;  
 R 5  is hydrogen, halogen, hydroxy, C 1-6 alkyl, C 1-4 alkoxy, C 1-4 acyloxy, C 1-4 thio, C 1-4 alkylsulfinyl, C 1-4 alkylsulfonyl, (hydroxy)C 1-4 alkyl, C 6-12 aryl, C 7-12 aralkyl, COOH, CN, CONHOR 6 , SO 2 NHR 6 , NH 2 , C 1-4 alkylamino, C 1-4 dialkylamino, NHSO 2 R 6 , NO 2 , or a five- or six-membered heterocycle, where each occurrence of R 6  is independently C 1-6 alkyl;  
 X is hydrogen, halogen or trifluoromethyl; and  
 Y is halogen or trifluoromethyl.  
 
       
     
     
         14 . The method of  claim 13  wherein the cell is a bone cell.  
     
     
         15 . A method for inhibiting the growth of a cancer or neoplastic cell comprising contacting a cancer or neoplastic cell capable of expressing ER with an effective amount of a compound having the structure:  
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof,  
         wherein: 
 n is 2, 3 or 4;  
 R 1  is hydrogen, C(═O)R 2 , C(═O)OR 2 , C(═O)NHR 2 , C(═O)NR 2 R 3 , or S(═O 2 )NR 2 R 3 ;  
 R 2  and R 3  are independently C 1-8 alkyl, C 6-12 aryl, C 7-12 arylalkyl, or a five- or six-membered heterocycle containing up to two heteroatoms selected from O, NR 4  and S(O) q , wherein each of the above groups are optionally substituted with one to three substituents independently selected from R 5  and q is 0, 1 or 2;  
 R 4  is hydrogen or C 1-4  alkyl;  
 R 5  is hydrogen, halogen, hydroxy, C 1-6 alkyl, C 1-4 alkoxy, C 1-4 acyloxy, C 1-4 thio, C 1-4 alkylsulfinyl, C 1-4 alkylsulfonyl, (hydroxy)C 1-4 alkyl, C 6-12 aryl, C 7-12 aralkyl, COOH, CN, CONHOR 6 , SO 2 NHR 6 , NH 2 , C 1-4 alkylamino, C 1-4 dialkylamino, NHSO 2 R 6 , NO 2 , or a five- or six-membered heterocycle, where each occurrence of R 6  is independently C 1-6 alkyl;  
 X is hydrogen, halogen or trifluoromethyl; and  
 Y is halogen or trifluoromethyl.  
 
       
     
     
         16 . A method for reducing a patient's serum level comprising administering to a patient in need thereof an effective amount of a compound having the structure:  
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof,  
         wherein: 
 n is 2, 3 or 4;  
 R 1  is hydrogen, C(═O)R 2 , C(═O)OR 2 , C(═O)NHR 2 , C(═O)NR 2 R 3 , or S(═O 2 )NR 2 R 3 ;  
 R 2  and R 3  are independently C 1-8 alkyl, C 6-12 aryl, C 7-12 arylalkyl, or a five- or six-membered heterocycle containing up to two heteroatoms selected from O, NR 4  and S(O) q , wherein each of the above groups are optionally substituted with one to three substituents independently selected from R 5  and q is 0, 1 or 2;  
 R 4  is hydrogen or C 1-4 alkyl;  
 R 5  is hydrogen, halogen, hydroxy, C 1-6 alkyl, C 1-4 alkoxy, C 1-4 acyloxy, C 1-4 thio, C 1-4 alkylsulfinyl, C 1-4 alkylsulfonyl, (hydroxy)C 1-4 alkyl, C 6-12 aryl, C 7-12 aralkyl, COOH, CN, CONHOR 6 , SO 2 NHR 6 , NH 2 , C 1-4 alkylamino, C 1-4 dialkylamino, NHSO 2 R 6 , NO 2 , or a five- or six-membered heterocycle, where each occurrence of R 6  is independently C 1-6 alkyl;  
 X is hydrogen, halogen or trifluoromethyl; and  
 Y is halogen or trifluoromethyl.