Pharmaceutical composition for inhibiting the growth of cancers

Abstract

A pharmaceutical composition that inhibits the growth of tumors and cancers in mammals that comprises a 1H-1,2,4-triazole derivative along with a safe and effective amount of a chemotherapeutic agent. Potentiators can be used to enhance the effectiveness of the drugs. The triazoles and potentiators compounds can also be used to treat viral infections.

What is claimed is:  
     
         1 . A pharmaceutical composition for treating cancers comprising a pharmaceutically acceptable carrier and a safe and effective amount of a chemotherapeutic agent and a safe and effective amount of a triazole or the formula:  
       
         
           
           
               
               
           
         
       
       wherein Z is an alkylene selected from the group consisting of CH 2 -CH 2 -,-CH 2 -CH 2 -CH 2 -, -CH(CH 3 )-CH(CH 3 )- and -CH 2 -CH(alkyl) wherein said alkyl has from 1 to about 10 carbon atoms; and Ar is a member selected from the group consisting of phenyl, substituted phenyl, thienyl, halothienyl, naphthyl and fluorenyl.  
     
     
         2 . A pharmaceutical composition according to    claim 1    comprising a pharmaceutically acceptable carrier and a safe and effective amount of a 1H-1,2,4-triazole selected from the group consisting of: 
 1-[2-(2,4-dichlorophenyl)-1,3-dioxolan-2-ylmethyl]-1H-1,2,4-triazole;  
 1-[2-(2,4-dichlorophenyl)4-methyl-1,3-dioxolan-2-ylmethyl]-1H-1,2,4-triazole,  
 1-[2-(2,4-dichlorophenyl)4-ethyl-1,3-dioxolan-2-ylmethyl]-1H-1,2,4-triazole,  
 1-[2-(2,4-dichlorophenyl)-4-propyl-1,3-dioxolan-2-ylmethyl]-1H-1,2,4-triazole,  
 1-[2-(2,4-dichlorophenyl)-4-pentyl-1,3-dioxolan-2-ylmethyl]-1H-1,2,4-triazole, and the therapeutically active acid addition salts thereof.  
 
     
     
         3 . A pharmaceutical composition according to    claim 1    for inhibiting the growth of tumors.  
     
     
         4 . A pharmaceutical composition according to    claim 3    wherein said pharmaceutical acceptable acid addition salts are selected from the group consisting of chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formates, tartrates, maleates, malates, citrates, benzoates, salicylates, ascorbates and mixtures thereof.  
     
     
         5 . A pharmaceutical composition according to    claim 2    wherein said chemotherapeutic agent is selected from the group consisting of DNA-interactive Agents. Antimetabolites. Tubulin-Interactive Agents. Hormonal agents, Asparaginase or hydroxyurea  
     
     
         6 . A pharmaceutical composition according to    claim 5    wherein said chemotherapeutic agent is selected from the group consisting of Asparaginase, hydroxyurea, Cisplatin, Cyclophosphamide, Altretamine, Bleomycin, Dactinomycin, Doxorubicin, Etoposide, Teniposide and Plcamydin.  
     
     
         7 . A pharmaceutical composition according to    claim 5    wherein said chemotherapeutic agent is selected from the group consisting of Methotrexate, Fluorouracil, Fluorodeoxyuridine, CB3717, Azacitidine, Cytarabine, Floxuridine, Mercaptopurine, 6-Tioguanine, Fludarabine, Pentostatin, Cyctrabine, and Fludarabine.  
     
     
         8 . A pharmaceutical composition according to    claim 1    which further comprises a potentiator.  
     
     
         9 . A method of treating cancer in warm blooded mammals comprising administering a safe and effective amount of a chemotherapeutic agent and a safe and effective amount of a 1H-1,2,4-triazole derivative of the formula:  
       
         
           
           
               
               
           
         
       
       wherein Z is an alkylene selected from the group consisting of CH 2 -CH 2 -,-CH 2 -CH 2 -CH 2 -, -CH(CH 3 )-CH(CH 3 )- and -CH 2 -CH(alkyl) wherein said alkyl has from 1 to about 10 carbon atoms; and Ar is a member selected from the group consisting of phenyl, substituted phenyl, thienyl, halothienyl, naphthyl and fluorenyl.  
     
     
         10 . A method according to    claim 9    wherein from about 2 mg/kg body weight to about 400 mg/kg of said 1H-1,2,4-triazole is administered and from 0.5 mg/kg body weight to about 40 mg/kg body weight of said chemotherapeutic agent is administered.  
     
     
         11 . A method according to    claim 10    wherein said 1H-1,2,4-triazole is administered orally or enterically, intravenously, peritoneally, parenterally or by injection into the tumor  
     
     
         12 . A method according to    claim 9    wherein said 1H-1,2,4-triazole is administered in a solid form, liquid form or as a liposome  
     
     
         13 . A method according to    claim 9    wherein said 1H-1,2,4-triazole is selected from the group consisting of: 
 1-[2-(2,4-dichlorophenyl)-1,3-dioxolan-2-ylmethyl]-1H-1,2,4-triazole,  
 1-[2-(2,4-dichlorophenyl)-4-methyl-1,3-dioxolan-2-ylmethyl]-1H-1,2,4-triazole,  
 1-[2(2,4-dichlorophenyl)4-ethyl-1,3-dioxolan-2-ylmethyl]-1H-1,2,4-triazole,  
 1-[2(2,4-dichlorophenyl)4-propyl-1,3-dioxolan-2-ylmethyl]-1H-1,2,4-triazole,  
 1-[2-(2,4-dichlorophenyl)-4-pentyl-1,3-dioxolan-2-ylmethyl]-1H-1,2,4-triazole, and the therapeutically active acid addition salts thereof.  
 
     
     
         14 . A method according to    claim 13    wherein said pharmaceutically acceptable acid addition salts are selected from the group consisting of chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formates, tartrates, maleates, malates, citrates, benzoates, salicylates, ascorbates and mixtures thereof.  
     
     
         15 . A method according to    claim 9    wherein said chemotherapeutic agent is selected from the group consisting of DNA-interactive Agents, Antimetabolites, Tubulin-Interactive Agents, Hormonal agents Asparaginase or hydroxyurea  
     
     
         16 . A method according to    claim 15    wherein said chemotherapeutic agent is selected from the group consisting of Asparaginase, hydroxyurea, Cisplatin, Cyclophosphamide, Altretamine, Bleomycin; Dactinomycin, Doxorubicin, Etoposide, Teniposide and Plcamydin.  
     
     
         17 . A method according to    claim 15    wherein said chemotherapeutic agent is selected from the group consisting of Methotrexate, Fluorouracil, Fluorodeoxyuridine, CB3717, Azacitidine, Cytarabine, Floxuridine, Mercaptopurine, 6-Thioguanine, Fludarabine, Pentostatin, Cyctrabine, and Fludarabine.  
     
     
         18 . A unit dosage composition for treating cancer and viral infections in animals or humans comprising a pharmaceutically acceptable carrier and a safe and effective amount of: (1) a 1H-1,2,4-triazole of the formula:  
       
         
           
           
               
               
           
         
       
       wherein Z is an alkylene selected from the group consisting of CH 2 -CH 2 -,-CH 2 -CH 2 -CH 2 -, -CH(CH 3 )-CH(CH 3 )- and -CH 2 -CH(alkyl) wherein said alkyl has from 1 to about 10 carbon atoms and Ar is a member selected from the group consisting of phenyl, substituted phenyl, thienyl, halothienyl, naphthyl and fluorenyl. (2) a chemotherapeutic agent, and (3) a potentiator  
     
     
         19 . A unit dosage composition according to    claim 18    wherein said 1H-1,2,4-triazole is selected from the group consisting of: 
 1-[2-(2,4-dichlorophenyl)-1,3-dioxolan-2-ylmethyl]-1H-1,2,4-triazole;  
 1-[2-(2,4-dichlorophenyl)4-methyl-1,3-dioxolan-2-ylmethyl]-1H-1,2,4-triazole,  
 1-[2-(2,4-dichlorophenyl)-4-ethyl-1,3-dioxolan-2-ylmethyl]-1H-1,2,4-triazole,  
 1-[2-(2,4-dichlorophenyl)-4-propyl-1,3-dioxolan-2-ylmethyl]-1H-1,2,4-triazole,  
 1-[2-(2,4-dichlorophenyl)4-pentyl-1,3-dioxolan-2-ylmethyl]-1H-1,2,4-triazole, and the therapeutically active acid addition salts thereof.  
 
     
     
         20 . A method of treating viral infections in warm blooded mammals comprising administering a safe and effective amount of a 1H-1,2,4-triazole derivative of the formula:  
       
         
           
           
               
               
           
         
       
       wherein Z is an alkylene selected from the group consisting of CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 -, -CH(CH 3 )-CH(CH 3 )- and -CH 2 -CH(alkyl) wherein said alkyl has from 1 to about 10 carbon atoms; and Ar is a member selected from the group consisting of phenyl, substituted phenyl, thienyl, halothienyl, naphthyl and fluorenyl and a potentiator.  
     
     
         21 . A method according to    claim 20    wherein said potentiator is procodazole.