Combination chemotherapy compositions and methods

Abstract

This invention relates to combination therapies involving anticancer chemotherapeutic agents and isoflavones or analogues thereof. The invention flier relates to compounds, compositions, methods and therapeutic uses involving, containing, comprising, including and/or for preparing platinum-isoflavonoid complexes suitable for use in the combination therapies of the invention.

1 . A method of increasing the sensitivity of melanoma cells or a melanoma to a chemotherapeutic agent by contacting said cells or melanoma with an isoflavonoid compound of formula (I):  
       
         
           
           
               
               
           
         
       
       in which 
 R 1 , R 2  and Z are independently hydrogen, hydroxy, OR 9 , OC(O)R 10 , OS(O)R 10 , CHO, C(O)R 10 , COOH, CO 2 R 10 , CONR 3 R 4 , alkyl, haloalkyl, arylalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkylaryl, alkoxyaryl, thio, alkylthio, amino, alkylamino, dialkylamino, nitro or halo, or  
 R 2  is as previously defined, and R 1  and Z taken together with the carbon atoms to which they are attached form a five-membered ring selected from  
                     
 or  
 R 1  is as previously defined, and R 2  and Z taken together with the carbon atoms to which they are attached form a five-membered ring selected from  
                     
 and  
 W is R 1 , A is hydrogen, hydroxy, NR 3 R 4  or thio, and B is selected from  
                     
 W is R 1 , and A and B taken together with the carbon atoms to which they are attached form a six-membered ring selected from  
                     
 W, A and B taken together with the groups to which they are associated are selected from  
                     
 W and A taken together with the groups to which they are associated are selected from  
                     
 and B is selected from  
                     
 wherein  
 R 3  is hydrogen, alkyl, arylalkyl, alkenyl, aryl, an amino acid, C(O)R 11  where R 11  is hydrogen, alkyl, aryl, arylalkyl or an amino acid, or CO 2 R 12  where R 12  is hydrogen, alkyl, haloalkyl, aryl or arylalkyl,  
 R 4  is hydrogen, alkyl or aryl, or  
 R 3  and R 4  taken together with the nitrogen to which they are attached comprise pyrrolidinyl or piperidinyl,  
 R 5  is hydrogen, C(O)R 11  where R 11  is as previously defined, or CO 2 R 12  where R 12  is as previously defined,  
 R 6  is hydrogen, hydroxy, alkyl, aryl, amino, thio, NR 3 R 4 , COR 11  where R 11  is as previously defined, CO 2 R 12  where R 12  is as previously defined or CONR 3 R 4 , R 7  is hydrogen, C(O)R 11  where R 11  is as previously defined, alkyl, haloalkyl, alkenyl, aryl, arylalkyl or Si(R 13 ) 3  where each R 13  is independently hydrogen, alkyl or aryl,  
 R 8  is hydrogen, hydroxy, alkoxy or alkyl,  
 R 9  is alkyl, haloalkyl, aryl, arylalkyl, C(O)R 11  where R 11  is as previously defined, or Si(R 13 ) 3  where R 13  is as previously defined,  
 R 10  is hydrogen, alkyl, haloalkyl, amino, aryl, arylalkyl, an amino acid, alkylamino or dialkylamino,  
 the drawing “- - -” represents either a single bond or a double bond,  
 T is independently hydrogen, alkyl or aryl,  
 X is O, NR 4 or S, and  
 Y is  
                     
 wherein  
 R 14 , R 15  and R 16  are independently hydrogen, hydroxy, OR 9 , OC(O)R 10 , OS(O)R 10 , CHO, C(O)R 10 , COOH, CO 2 R 10 , CONR 3 R 4 , alkyl, haloalkyl, arylalkyl, alkenyl, alkynyl, aryl, heteroaryl, thio, alkylthio, amino, alkylamino, dialkylamino, nitro or halo, or any two of R 14 , R 15  and R 16  are fused together to form a cyclic alkyl, aromatic or heteroaromatic structure,  
 and pharmaceutically acceptable salts thereof  
 
     
     
         2 . The method of  claim 1  wherein the melanoma cells or melanoma display resistance to the chemotherapeutic agent.  
     
     
         3 . The method of  claim 2 , wherein the sensitivity of the melanoma cells or melanoma to the chemotherapeutic agent is restored as a result of the treatment.  
     
     
         4 . The method of  claim 1 , wherein the compound of formula (I) is administered to a subject in need of such treatment  
     
     
         5 . The method of  claim 1  wherein the chemotherapeutic agent is selected from carboplatin, cisplatin, paclitaxel, docatexel, gemcitabine, and topotecan.  
     
     
         6 . The method of  claim 5  wherein the chemotherapeutic agent is carboplatin.  
     
     
         7 . The method of  claim 1  wherein the compound of formula (I) is dehydroequol.  
     
     
         8 . A method for the treatment or prevention of melanoma in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) as defined in  claim 1  and a chemotherapeutic agent.  
     
     
         9 . The method of  claim 8  wherein the compound of formula (I) is administered prior to the chemotherapeutic agent.  
     
     
         10 . The method of  claim 8  wherein the compound of formula (I) and the chemotherapeutic agent are administered simultaneously.  
     
     
         11 . The method of  claim 8  wherein the therapy follows observed resistance in the melanoma cells or melanoma to a chemotherapeutic agent.  
     
     
         12 . The method of  claim 8  wherein the chemotherapeutic agent is selected from carboplatin, cisplatin, paclitaxel, docataxel, gemcitabine and topotecan.  
     
     
         13 . The method of  claim 12  wherein the chemotherapeutic agent is carboplatin.  
     
     
         14 . The method of  claim 8  wherein the compound of formula (I) is dehydroequol.  
     
     
         15 . Combination therapy for the treatment or prevention of melanoma comprising administering to a subject a therapeutically effective amount of a compound of formula (I) as defined in  claim 1  and a chemotherapeutic agent.  
     
     
         16 . A pharmaceutical composition for the treatment or prevention of melanoma, the composition comprising at least one isoflavonoid compound of formula (I) and at least one chemotherapeutic agent.  
     
     
         17 . The composition of  claim 16  wherein the chemotherapeutic agent is selected from: carboplatin, cisplatin, paclitaxel, docatexel, gemcitabine and topotecan.  
     
     
         18 . The composition of  claim 16  wherein the compound of formula (I) is dehydroequol.