1-Adamantyl chalcones for the treatment of proliferative disorders

Abstract

The present invention relates to the compounds of the general formula (I), a composition for and a method of treating breast cancer or other proliferative disorders in a subject using a compound of general formula [I], wherein the substituents are as defined in the specification.

1 . A compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R1 is Ad- or Ad-(L1)n-, wherein n is 0 or 1, Ad is adamantyl, and L1 is a linking group selected from the group consisting of C1-6 alkylene, C1-6 cycloalkylene, and C1-6 arylene;  
 R2 is CY1=CHR3, aryl, aryl optionally substituted by X, or HET;  
 HET is selected from the group consisting of substituted or unsubstituted pyrrolidinyl, piperadinyl, morpholinyl, piperazinyl, pyrrolyl, pyridinyl, and pyridazinyl, quinolyl and thiophenyl, wherein the substituent is X;  
 wherein X is selected from the group consisting of hydrogen, straight chain or branched C1-6 alkyl, halo, amino, C1-6 alkyl amino, C1-6 dialkyl amino, pyrrolidinyl, piperadinyl, morpholinyl, piperazinyl, C1-6 alkoxy, C1-6 aralkoxyl, aryl, C1-6 aralkyl, nitro, cyano and a phosphorus containing group;  
 Y and Y1 are independently H, C1-6 alkyl, aryl, or halo, with the proviso that when R2 is CY1=CHR3, then Y is hydrogen;  
 R3 is selected from the group consisting of aryl, aryl optionally substituted by X, or HET;  
 or a pharmaceutically acceptable salt or derivative thereof.  
 
     
     
         2 . A compound according to  claim 1 , having the formula  
       
         
           
           
               
               
           
         
       
       wherein Y is hydrogen; 
 R2 is phenyl optionally substituted by hydrogen, cyano, nitro, halo, dimethylamino, C1-4 alkyl, C1-4 alkoxy, benzyloxy, and phenyl;  
 or a pharmaceutically acceptable salt or derivative thereof.  
 
     
     
         3 . A compound according to  claim 1 , having the formula  
       
         
           
           
               
               
           
         
       
       wherein 
 R2 is phenyl substituted by X, wherein X is H, p-cyano, p-nitro, p-chloro, p-dimethylamino, p-isopropyl, p-methoxy, p-fluoro, o-bromo, p-benzyloxy, p-phenyl, p-ethyl;  
 or a pharmaceutically acceptable salt or derivative thereof.  
 
     
     
         4 . A compound according to  claim 1 , having the formula  
       
         
           
           
               
               
           
         
       
       wherein 
 X is selected from the group consisting of hydrogen, straight chain or branched C1-6 alkyl, halo, amino, C1-6 alkyl amino, C1-6 dialkyl amino, pyrrolidinyl, piperadinyl, morpholinyl, piperazinyl, C1-6 alkoxy, C1-6 aralkoxyl, aryl, C1-6 aralkyl, nitro, cyano and a phosphorus containing group;  
 or a pharmaceutically acceptable salt or derivative thereof.  
 
     
     
         5 . A compound according to  claim 1  having the formula  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or derivative thereof.  
     
     
         6 . A pharmaceutical composition comprising an anti-proliferative effective amount of a compound of  claim 1  having the formula  
       
         
           
           
               
               
           
         
       
       wherein 
 R2 is phenyl optionally substituted by hydrogen, cyano, nitro, halo, dimethylamino, C1-4 alkyl, C1-4 alkoxy, benzyloxy, and phenyl; or a pharmaceutically acceptable salt or derivative thereof, in combination with a pharmaceutically acceptable carrier.  
 
     
     
         7 . A pharmaceutical composition comprising an anti-proliferative effective amount of a compound of  claim 1  having the formula  
       
         
           
           
               
               
           
         
       
       wherein 
 R2 is phenyl substituted by X, wherein X is H, p-cyano, p-nitro, p-chloro, p-dimethylamino, p-isopropyl, p-methoxy, p-fluoro, o-bromo, p-benzyloxy, p-phenyl, p-ethyl;  
 or a pharmaceutically acceptable salt or derivative thereof in combination with a pharmaceutically acceptable carrier.  
 
     
     
         8 . A pharmaceutical composition comprising an anti-proliferative effective amount of a compound of  claim 1  having the formula  
       
         
           
           
               
               
           
         
       
       wherein HET is selected from the group consisting of pyrid-2-yl, pyrid-2-yl, pyrid-2-yl, 6-methylpyrid-2-yl, quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, and thiophen-2-yl; or a pharmaceutically acceptable salt or derivative thereof in combination with a pharmaceutically acceptable carrier.  
     
     
         9 . A pharmaceutical composition comprising an anti-proliferative effective amount of a compound of  claim 1  having the formula  
       
         
           
           
               
               
           
         
       
       wherein X is selected from the group consisting of hydrogen, straight chain or branched C1-6 alkyl, halo, amino, C1-6 alkyl amino, C1-6 dialkyl amino, pyrrolidinyl, piperadinyl, morpholinyl, piperazinyl, C1-6 alkoxy, C1-6 aralkoxyl, aryl, C1-6 aralkyl, nitro, cyano and a phosphorus containing group;  
       or a pharmaceutically acceptable salt or derivative thereof in combination with a pharmaceutically acceptable carrier.  
     
     
         10 . A pharmaceutical composition comprising an anti-proliferative effective amount of a compound of  claim 1  having the formula  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or derivative thereof in combination with a pharmaceutically acceptable carrier.  
     
     
         11 . A method for the treatment of a proliferative disorder selected from the group consisting of prostate cancer, lung cancer, pancreatic cancer, breast cancer, colon cancer, ovarian cancer, and bladder cancer, comprising administering to a host in need of such treatment an anti-proliferative effective amount of a compound according to  claim 1 , optionally in combination with a pharmaceutically acceptable carrier.  
     
     
         12 . A method for the treatment of a proliferative disorder selected from the group consisting of prostate cancer, lung cancer, pancreatic cancer, breast cancer, colon cancer, ovarian cancer, and bladder cancer, comprising administering to a host in need of such treatment an anti-proliferative effective amount of a compound according to  claim 1  having the formula  
       
         
           
           
               
               
           
         
       
       wherein R2 is phenyl optionally substituted by hydrogen, cyano, nitro, halo, dimethylamino, C1-4 alkyl, C1-4 alkoxy, benzyloxy, and phenyl;  
       or a pharmaceutically acceptable salt or derivative thereof optionally in combination with a pharmaceutically acceptable carrier.  
     
     
         13 . A method for the treatment of a proliferative disorder selected from the group consisting of prostate cancer, lung cancer, pancreatic cancer, breast cancer, colon cancer, ovarian cancer, and bladder cancer, comprising administering to a host in need of such treatment an anti-proliferative effective amount of a compound according to  claim 1  having the formula  
       
         
           
           
               
               
           
         
       
       wherein 
 R2 is phenyl substituted by X, wherein X is H, p-cyano, p-nitro, p-chloro, p-dimethylamino, p-isopropyl, p-methoxy, p-fluoro, o-bromo, p-benzyloxy, p-phenyl, p-ethyl;  
 or a pharmaceutically acceptable salt or derivative thereof optionally in combination with a pharmaceutically acceptable carrier.  
 
     
     
         14 . A method for the treatment of a proliferative disorder selected from the group consisting of prostate cancer, lung cancer, pancreatic cancer, breast cancer, colon cancer, ovarian cancer, and bladder cancer, comprising administering to a host in need of such treatment an anti-proliferative effective amount of a compound according to  claim 1  having the formula  
       
         
           
           
               
               
           
         
       
       wherein 
 HET is selected from the group consisting of pyrid-2-yl, pyrid-2-yl, pyrid-2-yl, 6-methylpyrid-2-yl, quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, and thiophen-2-yl;  
 or a pharmaceutically acceptable salt or derivative thereof optionally in combination with a pharmaceutically acceptable carrier.  
 
     
     
         15 . A method for the treatment of a proliferative disorder selected from the group consisting of prostate cancer, lung cancer, pancreatic cancer, breast cancer, colon cancer, ovarian cancer, and bladder cancer, comprising administering to a host in need of such treatment an anti-proliferative effective amount of a compound according to  claim 1  having the formula  
       
         
           
           
               
               
           
         
       
       wherein 
 X is selected from the group consisting of hydrogen, straight chain or branched C1-6 alkyl, halo, amino, C1-6 alkyl amino, C1-6 dialkyl amino, pyrrolidinyl, piperadinyl, morpholinyl, piperazinyl, C1-6 alkoxy, C1-6 aralkoxyl, aryl, C1-6 aralkyl, nitro, cyano and a phosphorus containing group;  
 or a pharmaceutically acceptable salt or derivative thereof optionally in combination with a pharmaceutically acceptable carrier.  
 
     
     
         16 . A method for the treatment of a proliferative disorder selected from the group consisting of prostate cancer, lung cancer, pancreatic cancer, breast cancer, colon cancer, ovarian cancer, and bladder cancer comprising administering to a host in need of such treatment an anti-proliferative effective amount of a compound according to  claim 1  having the formula  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or derivative thereof optionally in combination with a pharmaceutically acceptable carrier.  
     
     
         17 . A method for the treatment of breast cancer comprising administering to a host in need of such treatment an anti-proliferative effective amount of a compound according to  claim 1  having the formula  
       
         
           
           
               
               
           
         
       
       wherein R2 is phenyl optionally substituted by hydrogen, cyano, nitro, halo, dimethylamino, C1-4 alkyl, C1-4 alkoxy, benzyloxy, and phenyl;  
       or a pharmaceutically acceptable salt or derivative thereof in combination with at least one other chemotherapeutic agent selected from the group consisting of tamoxifen, toremifene, idoxifene, droloxifene, TAT-59, LY117018, raloxifene, genistein, doxyrubicin, Taxol, Taxotere, aredia, arimidex, navilbine, busulfan, cisplatin, cyclophosphamide (Cytoxan), dacarbazine, ifosfamide, mechlorethamine (Mustargen), melphalan, carmustine, lomustine, 5-fluorouracil, methotrexate, gemcitabine, cytarabine (Ara-C), fludarabine, bleomycin, dactinomycin, daunorubicin, idarubicin, paclitaxel, docetaxel, etoposide, vinblastine, vincristine, vinorelbine, prednisone, dexamethasone, and herceptin, optionally in combination with a pharmaceutically acceptable carrier.  
     
     
         18 . A method for the treatment of breast cancer comprising administering to a host in need of such treatment an effective amount of a compound according to  claim 1  having the formula  
       
         
           
           
               
               
           
         
       
       wherein 
 R2 is phenyl substituted by X, wherein X is H, p-cyano, p-nitro, p-chloro, p-dimethylamino, p-isopropyl, p-methoxy, p-fluoro, o-bromo, p-benzyloxy, p-phenyl, p-ethyl; or a pharmaceutically acceptable salt or derivative thereof in combination with at least one other chemotherapeutic agent selected from the group consisting of tamoxifen, toremifene, idoxifene, droloxifene, TAT-59, LY117018, raloxifene, genistein, doxyrubicin, Taxol, Taxotere, aredia, arimidex, navilbine, busulfan, cisplatin, cyclophosphamide (Cytoxan), dacarbazine, ifosfamide, mechlorethamine (Mustargen), melphalan, carmustine, lomustine, 5-fluorouracil, methotrexate, gemcitabine, cytarabine (Ara-C), fludarabine, bleomycin, dactinomycin, daunorubicin, idarubicin, paclitaxel, docetaxel, etoposide, vinblastine, vincristine, vinorelbine, prednisone, dexamethasone, and herceptin, optionally in combination with a pharmaceutically acceptable carrier.  
 
     
     
         19 . A method for the treatment of breast cancer comprising administering to a host in need of such treatment effective amount of a compound according to  claim 1  having the formula  
       
         
           
           
               
               
           
         
       
       wherein 
 HET is selected from the group consisting of pyrid-2-yl, pyrid-2-yl, pyrid-2-yl, 6-methylpyrid-2-yl, quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, and thiophen-2-yl;  
 or a pharmaceutically acceptable salt or derivative thereof in combination with at least one other chemotherapeutic agent selected from the group consisting of tamoxifen, toremifene, idoxifene, droloxifene, TAT-59, LY117018, raloxifene, genistein, doxyrubicin, Taxol, Taxotere, aredia, arimidex, navilbine, busulfan, cisplatin, cyclophosphamide (Cytoxan), dacarbazine, ifosfamide, mechlorethamine (Mustargen), melphalan, carmustine, lomustine, 5-fluorouracil, methotrexate, gemcitabine, cytarabine (Ara-C), fludarabine, bleomycin, dactinomycin, daunorubicin, idarubicin, paclitaxel, docetaxel, etoposide, vinblastine, vincristine, vinorelbine, prednisone, dexamethasone, and herceptin, optionally in combination with a pharmaceutically acceptable carrier.  
 
     
     
         20 . A method for the treatment of breast cancer comprising administering to a host in need of such treatment an effective amount of a compound according to  claim 1  having the formula  
       
         
           
           
               
               
           
         
       
       wherein 
 X is selected from the group consisting of hydrogen, straight chain or branched C1-6 alkyl, halo, amino, C1-6 alkyl amino, C1-6 dialkyl amino, pyrrolidinyl, piperadinyl, morpholinyl, piperazinyl, C1-6 alkoxy, C1-6 aralkoxyl, aryl, C1-6 aralkyl, nitro, cyano and a phosphorus containing group;  
 or a pharmaceutically acceptable salt or derivative thereof in combination with at least one other chemotherapeutic agent selected from the group consisting of tamoxifen, toremifene, idoxifene, droloxifene, TAT-59, LY117018, raloxifene, genistein, doxyrubicin, Taxol, Taxotere, aredia, arimidex, navilbine, busulfan, cisplatin, cyclophosphamide (Cytoxan), dacarbazine, ifosfamide, mechlorethamine (Mustargen), melphalan, carmustine, lomustine, 5-fluorouracil, methotrexate, gemcitabine, cytarabine (Ara-C), fludarabine, bleomycin, dactinomycin, daunorubicin, idarubicin, paclitaxel, docetaxel, etoposide, vinblastine, vincristine, vinorelbine, prednisone, dexamethasone, and herceptin, optionally in combination with a pharmaceutically acceptable carrier.  
 
     
     
         21 . A method for the treatment of breast cancer comprising administering to a host in need of such treatment an effective amount of a compound according to  claim 1  having the formula  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or derivative thereof in combination with at least one other chemotherapeutic agent selected from the group consisting of tamoxifen, toremifene, idoxifene, droloxifene, TAT-59, LY117018, raloxifene, genistein, doxyrubicin, Taxol, Taxotere, aredia, arimidex, navilbine, busulfan, cisplatin, cyclophosphamide (Cytoxan), dacarbazine, ifosfamide, mechlorethamine (Mustargen), melphalan, carmustine, lomustine, 5-fluorouracil, methotrexate, gemcitabine, cytarabine (Ara-C), fludarabine, bleomycin, dactinomycin, daunorubicin, idarubicin, paclitaxel, docetaxel, etoposide, vinblastine, vincristine, vinorelbine, prednisone, dexamethasone, and herceptin, optionally in combination with a pharmaceutically acceptable carrier.