Aryloxypropylamines as chemosensitizing agents in the treatment of cancer

Abstract

A method of treating a subject having cancer, particularly a multidrug resistance cancer, which comprises administering to the subject at least one chemotherapeutic agent and at least one 3-aryloxy-3-phenylpropylamine and pharmaceutical compositions and kits for implementing the method.

What is claimed is:  
     
         1 . A method of treating a subject suspected as having, or having a multidrug resistance cancer, the method comprising administering to the subject a chemotherapeutically effective amount of at least one chemotherapeutic agent and a chemosensitizing effective amount of at least one 3-aryloxy-3-phenylpropylamine.  
     
     
         2 . The method of  claim 1 , wherein said administering said at least one chemotherapeutic agent and said at least one 3-aryloxy-3-phenylpropylamine is performed substantially at the same time.  
     
     
         3 . The method of  claim 1 , wherein said chemosensitizing effective amount ranges between about 0.1 mg/M 2  and about 10 mg/M 2 .  
     
     
         4 . The method of  claim 1 , wherein said cancer is selected from the group consisting of leukemia, lymphoma, carcinoma and sarcoma.  
     
     
         5 . The method of  claim 1 , wherein said at least one 3-aryloxy-3-phenylpropylamine is administered orally.  
     
     
         6 . The method of  claim 1 , wherein said at least one 3-aryloxy-3-phenylpropylamine is of the formula:  
       
         
           
           
               
               
           
         
         wherein each R′ is independently hydrogen or methyl;  
         R is naphthyl or  
         
           
             
             
                 
                 
             
           
         
         R″ and R′″ are halo, trifluoromethyl, C 1 -C 4  alkyl, C 1 -C 3  alkoxy or C 3 -C 4  alkenyl; and  
         n and m are 0, 1 or 2; and acid addition salts thereof formed with pharmaceutically acceptable acids.  
       
     
     
         7 . The method of  claim 1 , wherein said at least one 3-aryloxy-3-phenylpropylamine is selected from the group consisting of 
 3-(p-isopropoxyphenoxy)-3-phenylpropylamine methanesulfonate,    N,N-dimethyl 3-(3′,4′-dimethoxyphenoxy)-3-phenylpropylamine p-hydroxybenzoate,    N,N-dimethyl 3-(alpha-naphthoxy)-3-phenylpropylamine bromide,    N,N-dimethyl 3-(beta-naphthoxy)-3-phenyl-1-methylpropylamine iodide,    3-(2′-methyl-4′,5′-dichlorophenoxy)-3-phenylpropylamine nitrate,    3-(p-t-butylphenoxy)-3-phenylpropylamine glutarate,    N-methyl 3-(2′-chloro-p-tolyloxy)-3-phenyl-1-methylpropylamine lactate,    3-(2′,4′-dichlorophenoxy)-3-phenyl-2-methylpropylamine citrate,    N,N-dimethyl 3-(m-anisyloxy)-3-phenyl-1-methylpropylamine maleate,    N-methyl 3-(p-tolyloxy)-3-phenylpropylamine sulfate,    N,N-dimethyl 3-(2′,4′-difluorophenoxy)-3-phenylpropylamine 2,4-dinitrobenzoate,    3-(o-ethylphenoxy)-3-phenylpropylamine dihydrogen phosphate,    N-methyl-(2′-chloro-4′-isopropylphenoxy)-3-phenyl-2-methylpropylamine maleate,    N,N-dimethyl 3-(2′-alkyl-4′-fluorophenoxy)-3-phenylpropylamine succinate,    N,N-dimethyl 3-(o-isopropoxyphenoxy)-3-phenyl-propylamine phenylacetate,    N,N-dimethyl 3-(o-)bromophenoxy)-3-phenyl-propylamine beta-phenylpropionate,    N-methyl 3-(p-iodophenoxy)-3-phenyl-propylamine propiolate,    N-methyl 3-(3-n-propylphenoxy)-3-phenyl-propylamine decanoate, and    N-methyl 3-(p-trifluoromethylphenoxy)-3-phenylpropylamine.    
     
     
         8 . The method of  claim 1 , wherein said at least one 3-aryloxy-3-phenylpropylamine is N-methyl 3-(p-trifluoromethylphenoxy) -3-phenylpropylamine or a pharmaceutically acceptable salt thereof.  
     
     
         9 . The method of  claim 1 , wherein said at least one chemotherapeutic agent is selected from the group consisting of an alkylating agent, an antimetabolite, a natural product, a miscellaneous agent, a hormone and an antagonist.  
     
     
         10 . A method of treating a subject suspected as having, or having a multidrug resistance cancer, the method comprising administering to the subject, substantially at the same time, a chemotherapeutically effective amount of at least one chemotherapeutic agent and a chemosensitizing effective amount of at least one 3-aryloxy-3-phenylpropylamine.  
     
     
         11 . The method of  claim 10 , wherein said chemosensitizing effective amount ranges between about 0.1 mg/M 2  and about 10 mg/M 2 .  
     
     
         12 . The method of  claim 10 , wherein said cancer is selected from the group consisting of leukemia, lymphoma, carcinoma and sarcoma.  
     
     
         13 . The method of  claim 10 , wherein said at least one 3-aryloxy-3-phenylpropylamine is administered orally.  
     
     
         14 . The method of  claim 10 , wherein said at least one 3-aryloxy-3-phenylpropylamine is of the formula:  
       
         
           
           
               
               
           
         
         wherein each R′ is independently hydrogen or methyl;  
         R is naphthyl or  
         
           
             
             
                 
                 
             
           
         
         R″ and R′″ are halo, trifluoromethyl, C 1 -C 4  alkyl, C 1 -C 3  alkoxy or C 3 -C 4  alkenyl; and  
         n and m are 0, 1 or 2; and acid addition salts thereof formed with pharmaceutically acceptable acids.  
       
     
     
         15 . The method of  claim 10 , wherein said at least one 3-aryloxy-3-phenylpropylamine is selected from the group consisting of 
 3-(p-isopropoxyphenoxy)-3-phenylpropylamine methanesulfonate,    N,N-dimethyl 3-(3′,4′-dimethoxyphenoxy)-3-phenylpropylamine p-hydroxybenzoate,    N,N-dimethyl 3-(alpha-naphthoxy)-3-phenylpropylamine bromide,    N,N-dimethyl 3-(beta-naphthoxy)-3-phenyl-1-methylpropylamine iodide,    3-(2′-methyl-4′,5′-dichlorophenoxy)-3-phenylpropylamine nitrate,    3-(p-t-butylphenoxy)-3-phenylpropylamine glutarate,    N-methyl 3-(2′-chloro-p-tolyloxy)-3-phenyl-1-methylpropylamine lactate,    3-(2′,4′-dichlorophenoxy)-3-phenyl-2-methylpropylamine citrate, N,N-dimethyl 3-(m-anisyloxy)-3-phenyl-1-methylpropylamine maleate,    N-methyl 3-(p-tolyloxy)-3-phenylpropylamine sulfate, N,N-dimethyl 3-(2′,4′-difluorophenoxy)-3-phenylpropylamine 2,4-dinitrobenzoate,    3-(o-ethylphenoxy)-3-phenylpropylamine dihydrogen phosphate,    N-methyl-(2′-chloro-4′-isopropylphenoxy)-3-phenyl-2-methylpropylamine maleate,    N,N-dimethyl 3-(2′-alkyl-4′-fluorophenoxy)-3-phenylpropylamine succinate,    N,N-dimethyl 3-(o-isopropoxyphenoxy)-3-phenyl-propylamine phenyl acetate,    N,N-dimethyl 3-(o-)bromophenoxy)-3-phenyl-propylamine beta-phenylpropionate,    N-methyl 3-(p-iodophenoxy)-3-phenyl-propylamine propiolate,    N-methyl 3-(3-n-propylphenoxy)-3-phenyl-propylamine decanoate, and    N-methyl 3-(p-trifluoromethylphenoxy)-3-phenylpropylamine.    
     
     
         16 . The method of  claim 10 , wherein said at least one 3-aryloxy-3-phenylpropylamine is N-methyl 3-(p-trifluoromethylphenoxy) -3-phenylpropylamine or a pharmaceutically acceptable salt thereof.  
     
     
         17 . The method of  claim 10 , wherein said at least one chemotherapeutic agent is selected from the group consisting of an alkylating agent, an antimetabolite, a natural product, a miscellaneous agent, a hormone and an antagonist.  
     
     
         18 . A method of treating a subject suspected as having, or having a multidrug resistance cancer, the method comprising administering to the subject a chemotherapeutically effective amount of at least one chemotherapeutic agent and a chemosensitizing effective amount of at least one 3-aryloxy-3-phenylpropylamine, said chemosensitizing effective amount ranges between about 0.1 mg/M 2  and about 10 mg/M 2 .  
     
     
         19 . The method of  claim 1   8 , wherein said administering said at least one chemotherapeutic agent and said at least one 3-aryloxy-3-phenylpropylamine is performed substantially at the same.  
     
     
         20 . The method of  claim 18 , wherein said cancer is selected from the group consisting of leukemia, lymphoma, carcinoma and sarcoma.  
     
     
         21 . The method of  claim 18 , wherein said at least one 3-aryloxy-3-phenylpropylamine is administered orally.  
     
     
         22 . The method of  claim 18 , wherein said at least one 3-aryloxy-3-phenylpropylamine is of the formula:  
       
         
           
           
               
               
           
         
         wherein each R′ is independently hydrogen or methyl;  
         R is naphthyl or  
         
           
             
             
                 
                 
             
           
         
         R′ and R′″ are halo, trifluoromethyl, C 1 -C 4  alkyl, C 1 -C 3  alkoxy or C 3 -C 4  alkenyl; and  
         n and m are 0, 1 or 2; and acid addition salts thereof formed with pharmaceutically acceptable acids.  
       
     
     
         23 . The method of  claim 18 , wherein said at least one 3-aryloxy-3-phenylpropylamine is selected from the group consisting of 
 3-(p-isopropoxyphenoxy)-3-phenylpropylamine methanesulfonate,    N,N-dimethyl 3-(3′,4′-dimethoxyphenoxy)-3-phenylpropylamine p-hydroxybenzoate,    N,N-dimethyl 3-(alpha-naphthoxy)-3-phenylpropylamine bromide,    N,N-dimethyl 3-(beta-naphthoxy)-3-phenyl-1-methylpropylamine iodide,    3-(2′-methyl-4′,5′-dichlorophenoxy)-3-phenylpropylamine nitrate,    3-(p-t-butylphenoxy)-3-phenylpropylamine glutarate,    N-methyl 3-(2′-chloro-p-tolyloxy)-3-phenyl-1-methylpropylamine lactate,    3-(2′,4′-dichlorophenoxy)-3-phenyl-2-methylpropylamine citrate,    N,N-dimethyl 3-(m-anisyloxy)-3-phenyl-1-methylpropylamine maleate,    N-methyl 3-(p-tolyloxy)-3-phenylpropylamine sulfate,    N,N-dimethyl 3-(2′,4′-difluorophenoxy)-3-phenylpropylamine 2 4-dinitrobenzoate,    3-(o-ethylphenoxy)-3-phenylpropylamine dihydrogen phosphate,    N-methyl-(2′-chloro-4′-isopropylphenoxy)-3-phenyl-2-methylpropylamine maleate,    N,N-dimethyl 3-(2′-alkyl-4′-fluorophenoxy)-3-phenylpropylamine succinate,    N,N-dimethyl 3-(o-isopropoxyphenoxy)-3-phenyl-propylamine phenylacetate,    N,N-dimethyl 3-(o-)bromophenoxy)-3-phenyl-propylamine beta-phenylpropionate,    N-methyl 3-(p-iodophenoxy)-3-phenyl-propylamine propiolate,    N-methyl 3-(3-n-propylphenoxy)-3-phenyl-propylamine decanoate, and    N-methyl 3-(p-trifluoromethylphenoxy)-3-phenylpropylamine.    
     
     
         24 . The method of  claim 18 , wherein said at least one 3-aryloxy-3-phenylpropylamine is N-methyl 3-(p-trifluoromethylphenoxy) -3-phenylpropylamine or a pharmaceutically acceptable salt thereof.  
     
     
         25 . The method of  claim 18 , wherein said at least one chemotherapeutic agent is selected from the group consisting of an alkylating agent, an antimetabolite, a natural product, a miscellaneous agent, a hormone and an antagonist.  
     
     
         26 . A method of selecting a chemotherapeutic agent for which 3-aryloxy-3-phenylpropylamine is a chemosensitizer comprising: 
 assaying cytotoxicity of a candidate chemotherapeutic agent in the presence and in the absence of a 3-aryloxy-3-phenylpropylamine; and    selecting a candidate chemotherapeutic agent as a chemotherapeutic agent for which 3-aryloxy-3-phenylpropylamine is a chemosensitizer when the cytotoxicity of the candidate agent is greater in the presence of 3-aryloxy-3-phenylpropylamine than in the absence of 3-aryloxy-3-phenylpropylamine.    
     
     
         27 . The method of  claim 26 , wherein said assaying is performed with multidrug resistant cells.  
     
     
         28 . The method of  claim 26 , wherein said assaying is performed using a 3-aryloxy-3-phenylpropylamine at a dose that ranges between about 1 μM and about 10 μM.  
     
     
         29 . The method of  claim 26 , wherein when said assaying is performed in the presence of a 3-aryloxy-3-phenylpropylamine, said 3-aryloxy-3-phenylpropylamine and said candidate chemotherapeutic agent are administered substantially at the same time.  
     
     
         30 . The method of  claim 26 , wherein said 3-aryloxy-3-phenylpropylamine is of the formula:  
       
         
           
           
               
               
           
         
         wherein each R′ is independently hydrogen or methyl;  
         R is naphthyl or  
         
           
             
             
                 
                 
             
           
         
         R′ and R′″ are halo, trifluoromethyl, C 1 -C 4  alkyl, C 1 -C 3  alkoxy or C 1 -C 4  alkenyl; and  
         n and m are 0, 1 or 2; and acid addition salts thereof formed with pharmaceutically acceptable acids.  
       
     
     
         31 . The method of  claim 26 , wherein said 3-aryloxy-3-phenylpropylamine is selected from the group consisting of 
 3-(p-isopropoxyphenxoy)-3-phenylpropylamine methanesulfonate,    N,N-dimethyl 3-(3′,4′-dimethoxyphenoxy)-3-phenylpropylamine p-hydroxybenzoate,    N,N-dimethyl 3-(alpha-naphthoxy)-3-phenylpropylamine bromide,    N,N-dimethyl 3-(beta-naphthoxy)-3-phenyl-1-methylpropylamine iodide,    3-(2′-methyl-4′,5′-dichlorophenoxy)-3-phenylpropylamine nitrate,    3-(p-t-butylphenoxy)-3-phenylpropylamine glutarate,    N-methyl 3-(2′-chloro-p-tolyloxy)-3-phenyl-1-methylpropylamine lactate,    3-(2′,4′-dichlorophenoxy)-3-phenyl-2-methylpropylamine citrate,    N,N-dimethyl 3-(m-anisyloxy)-3-phenyl-1-methylpropylamine maleate,    N-methyl 3-(p-tolyloxy)-3-phenylpropylamine sulfate,    N,N-dimethyl 3-(2′,4′-difluorophenoxy)-3-phenylpropylamine 2,4-dinitrobenzoate,    3-(o-ethylphenoxy)-3-phenylpropylamine dihydrogen phosphate,    N-methyl-(2′-chloro-4′-isopropylphenoxy)-3-phenyl-2-methylpropylamine maleate,    N,N-dimethyl 3-(2′-alkyl-4′-fluorophenoxy)-3-phenylpropylamine succinate,    N,N-dimethyl 3-(o-isopropoxyphenoxy)-3-phenyl-propylamine phenylacetate,    N,N-dimethyl 3-(o-)bromophenoxy)-3-phenyl-propylamine beta-phenylpropionate,    N-methyl 3-(p-iodophenoxy)-3-phenyl-propylamine propiolate,    N-methyl 3-(3-n-propylphenoxy)-3-phenyl-propylamine decanoate, and    N-methyl 3-(p-trifluoromethylphenoxy)-3-phenylpropylamine.    
     
     
         32 . The method of  claim 26 , wherein said 3-aryloxy-3-phenylpropylamine is N-methyl 3-(p-trifluoromethylphenoxy)-3-phenylpropylamine or a pharmaceutically acceptable salt thereof.  
     
     
         33 . The method of  claim 26 , wherein said chemotherapeutic agent is selected from the group consisting of an alkylating agent, an antimetabolite, a natural product, a miscellaneous agent, a hormone and an antagonist.  
     
     
         34 . A pharmaceutical composition comprising as a chemotherapeutically active ingredient at least one chemotherapeutic agent and as a chemosensitization active ingredient at least one 3-aryloxy-3-phenylpropylamine.  
     
     
         35 . The pharmaceutical composition of  claim 34 , packaged in a packaging material and identified in print in or on said packaging material, for use in the treatment of a multidrug resistance cancer.  
     
     
         36 . The pharmaceutical composition of  claim 34 , wherein said at least one 3-aryloxy-3-phenylpropylamine is of the formula:  
       
         
           
           
               
               
           
         
         wherein each R′ is independently hydrogen or methyl;  
         R is naphthyl or  
         
           
             
             
                 
                 
             
           
         
         R′ and R′″ are halo, trifluoromethyl, C 1 -C 4  alkyl, C 1 -C 3  alkoxy or C 3 -C 4  alkenyl; and  
         n and m are 0, 1 or 2; and acid addition salts thereof formed with pharmaceutically acceptable acids.  
       
     
     
         37 . The pharmaceutical composition of  claim 34 , wherein said at least one 3-aryloxy-3-phenylpropylamine is selected from the group consisting of 
 3-(p-isopropoxyphenxoy)-3-phenylpropylamine methanesulfonate,    N,N-dimethyl 3-(3′,4′-dimethoxyphenoxy)-3-phenylpropylamine p-hydroxybenzoate,    N,N-dimethyl 3-(alpha-naphthoxy)-3-phenylpropylamine bromide,    N,N-dimethyl 3-(beta-naphthoxy)-3-phenyl-1-methylpropylamine iodide,    3-(2′-methyl-4′,5′-dichlorophenoxy)-3-phenylpropylamine nitrate,    3-(p-t-butylphenoxy)-3-phenylpropylamine glutarate,    N-methyl 3-(2′-chloro-p-tolyloxy)-3-phenyl-1-methylpropylamine lactate,    3-(2′,4′-dichlorophenoxy)-3-phenyl-2-methylpropylamine citrate,    N,N-dimethyl 3-(m-anisyloxy)-3-phenyl-1-methylpropylamine maleate,    N-methyl 3-(p-tolyloxy)-3-phenylpropylamine sulfate,    N,N-dimethyl 3-(2′,4′-difluorophenoxy)-3-phenylpropylamine 2,4-dinitrobenzoate,    3-(o-ethylphenoxy)-3-phenylpropylamine dihydrogen phosphate,    N-methyl-(2′-chloro-4′-isopropylphenoxy)-3-phenyl-2-methylpropylamine maleate,    N,N-dimethyl 3-(2′-alkyl-4′-fluorophenoxy)-3-phenylpropylamine succinate,    N,N-dimethyl 3-(o-isopropoxyphenoxy)-3-phenyl-propylamine phenyl acetate,    N,N-dimethyl 3-(o-)bromophenoxy)-3-phenyl-propylamine beta-phenylpropionate,    N-methyl 3-(p-iodophenoxy)-3-phenyl-propylamine propiolate,    N-methyl 3-(3-n-propylphenoxy)-3-phenyl-propylamine decanoate, and    N-methyl 3-(p-trifluoromethylphenoxy)-3-phenylpropylamine.    
     
     
         38 . The pharmaceutical composition of  claim 34 , wherein said at least one 3-aryloxy-3-phenylpropylamine is N-methyl 3-(p-trifluoromethylphenoxy)-3-phenylpropylamine or a pharmaceutically acceptable salt thereof.  
     
     
         39 . The pharmaceutical composition of  claim 34 , wherein said at least one chemotherapeutic agent is selected from the group consisting of an alkylating agent, an antimetabolite, a natural product, a miscellaneous agent, a hormone and an antagonist.  
     
     
         40 . A pharmaceutical kit comprising as a chemotherapeutically active ingredient at least one chemotherapeutic agent and as a chemosensitization active ingredient at least one 3-aryloxy-3-phenylpropylamine, wherein said at least one chemotherapeutic agent and said at least one 3-aryloxy-3-phenylpropylamine are individually packaged within the pharmaceutical kit.  
     
     
         41 . The pharmaceutical kit of  claim 40 , identified in print for use in the treatment of a multidrug resistance cancer.  
     
     
         42 . The pharmaceutical kit of  claim 40 , wherein said at least one 3-aryloxy-3-phenylpropylamine is of the formula:  
       
         
           
           
               
               
           
         
         wherein each R′ is independently hydrogen or methyl;  
         R is naphthyl or  
         
           
             
             
                 
                 
             
           
         
         R′ and R′″ are halo, trifluoromethyl, C 1 -C 4  alkyl, C 1 -C 3  alkoxy or C 3 -C 4  alkenyl; and  
         n and m are 0, 1 or 2; and acid addition salts thereof formed with pharmaceutically acceptable acids.  
       
     
     
         43 . The pharmaceutical kit of  claim 40 , wherein said at least one 3-aryloxy-3-phenylpropylamine is selected from the group consisting of 
 3-(p-isopropoxyphenxoy)-3-phenylpropylamine methanesulfonate,    N,N-dimethyl 3-(3′,4′-dimethoxyphenoxy)-3-phenylpropylamine p-hydroxybenzoate,    N,N-dimethyl 3-(alpha-naphthoxy)-3-phenylpropylamine bromide,    N,N-dimethyl 3-(beta-naphthoxy)-3-phenyl-1-methylpropylamine iodide,    3-(2′-methyl-4′,5′-dichlorophenoxy)-3-phenylpropylamine nitrate,    3-(p-t-butylphenoxy)-3-phenylpropylamine glutarate,    N-methyl 3-(2′-chloro-p-tolyloxy)-3-phenyl-1-methylpropylamine lactate,    3-(2′,4′-dichlorophenoxy)-3-phenyl-2-methylpropylamine citrate,    N,N-dimethyl 3-(m-anisyloxy)-3-phenyl-1-methylpropylamine maleate,    N-methyl 3-(p-tolyloxy)-3-phenylpropylamine sulfate,    N,N-dimethyl 3-(2′,4′-difluorophenoxy)-3-phenylpropylamine 2,4-dinitrobenzoate,    3-(o-ethylphenoxy)-3-phenylpropylamine dihydrogen phosphate,    N-methyl-(2′-chloro-4′-isopropylphenoxy)-3-phenyl-2-methylpropylamine maleate,    N,N-dimethyl 3-(2′-alkyl-4′-fluorophenoxy)-3-phenylpropylamine succinate,    N,N-dimethyl 3-(o-isopropoxyphenoxy)-3-phenyl-propylamine phenylacetate,    N,N-dimethyl 3-(o-)bromophenoxy)-3-phenyl-propylamine beta-phenylpropionate,    N-methyl 3-(p-iodophenoxy)-3-phenyl-propylamine propiolate,    N-methyl 3-(3-n-propylphenoxy)-3-phenyl-propylamine decanoate, and    N-methyl 3-(p-trifluoromethylphenoxy)-3-phenylpropylamine.    
     
     
         44 . The pharmaceutical kit of  claim 40 , wherein said at least one 3-aryloxy-3-phenylpropylamine is N-methyl 3-(p-trifluoromethylphenoxy) -3-phenylpropylamine or a pharmaceutically acceptable salt thereof.  
     
     
         45 . The pharmaceutical kit of  claim 40 , wherein said at least one chemotherapeutic agent is selected from the group consisting of an alkylating agent, an antimetabolite, a natural product, a miscellaneous agent, a hormone and an antagonist.  
     
     
         46 . A pharmaceutical composition comprising as an active ingredient at least one 3-aryloxy-3-phenylpropylamine the pharmaceutical composition being packaged and indicated for use in chemosensitization, in combination with a chemotherapeutic agent and/or in a medical condition for which chemosensitization is beneficial.  
     
     
         47 . The pharmaceutical composition of  claim 46 , wherein said at least one 3-aryloxy-3-phenylpropylamine is of the formula:  
       
         
           
           
               
               
           
         
         wherein each R′ is independently hydrogen or methyl;  
         R is naphthyl or  
         
           
             
             
                 
                 
             
           
         
         R′ and R′″ are halo, trifluoromethyl, C 1 -C 4  alkyl, C 1 -C 3  alkoxy or C 3 -C 4  alkenyl; and  
         n and m are 0, 1 or 2; and acid addition salts thereof formed with pharmaceutically acceptable acids.  
       
     
     
         48 . The pharmaceutical composition of  claim 46 , wherein said at least one 3-aryloxy-3-phenylpropylamine is selected from the group consisting of: 
 3-(p-isopropoxyphenxoy)-3-phenylpropylamine methanesulfonate,    N,N-dimethyl 3-(3′,4′-dimethoxyphenoxy)-3-phenylpropylamine p-hydroxybenzoate,    N,N-dimethyl 3-(alpha-naphthoxy)-3-phenylpropylamine bromide,    N,N-dimethyl 3-(beta-naphthoxy)-3-phenyl-1-methylpropylamine iodide,    3-(2′-methyl-4′,5′-dichlorophenoxy)-3-phenylpropylamine nitrate,    3-(p-t-butylphenoxy)-3-phenylpropylamine glutarate,    N-methyl 3-(2′-chloro-p-tolyloxy)-3-phenyl-1-methylpropylamine lactate,    3-(2′,4′-dichlorophenoxy)-3-phenyl-2-methylpropylamine citrate,    N,N-dimethyl 3-( n-anisyloxy)-3-phenyl-1-methylpropylamine maleate,    N-methyl 3-(p-tolyloxy)-3-phenylpropylamine sulfate,    N,N-dimethyl 3-( 2′,4′-difluorophenoxy)-3-phenylpropylamine 2,4-dinitrobenzoate,    3-(o-ethylphenoxy)-3-phenylpropylamine dihydrogen phosphate,    N-methyl -(2′-chloro-4′-isopropyl phenoxy)-3-phenyl-2-methylpropylamine maleate,    N,N-dimethyl 3-(2′-alkyl-4′-fluorophenoxy)-3-phenylpropylamine succinate,    N,N-dimethyl 3-(o-isopropoxyphenoxy)-3-phenyl-propylamine phenylacetate,    N,N-dimethyl 3-(o-)bromophenoxy)-3-phenyl-propylamine beta-phenylpropionate,    N-methyl 3-(p-iodophenoxy)-3-phenyl-propylamine propiolate,    N-methyl 3-(3-n-propylphenoxy)-3-phenyl-propylamine decanoate, and N-methyl 3-(p-trifluoromethylphenoxy)-3-phenylpropylamine.    
     
     
         49 . The pharmaceutical composition of  claim 46 , wherein said at least one 3-aryloxy-3-phenylpropylamine is N-methyl 3-(p-trifluoromethylphenoxy)-3-phenylpropylamine or a pharmaceutically acceptable salt thereof.  
     
     
         50 . The pharmaceutical composition of  claim 46 , wherein said at least one chemotherapeutic agent is selected from the group consisting of an alkylating agent, an antimetabolite, a natural product, a miscellaneous agent, a hormone and an antagonist.