Phosphate-bearing prodrugs of sulfonyl hydrazines as hypoxia-selective antineoplastic agents

Abstract

Novel phosphate-bearing prodrugs of sulfonyl hydrazines have the formula presented below. Methods of treatment of cancer are claimed. The aforementioned prodrugs include enantiomers, stereoisomers and tautomers thereof, as well as pharmaceutically acceptable salts or solvates and metabolites from all stages. The aforementioned prodrugs are preferentially activated in hypoxic tumors and can be given either alone, or in combination with other anticancer agents or with phototheraphy or radiotherapy. where R is C 1 -C 10 alkyl or haloalkyl; R′ and R″ are each independently C 1 -C 10 alkyl; and R 1 is C 1 -C 10 alkyl, or a pharmaceutically acceptable salt, solvate, polymorph or metabolite thereof.

1 - 52 . (canceled) 
     
     
         53 . A method of treating cancer in a patient in need of therapy comprising administering to said patient an effective amount of a compound according to the chemical structure: 
       
         
           
           
               
               
           
         
       
       where R is C 1 -C 10  alkyl or haloalkyl;
 R′ and R″ are each independently C 1 -C 10  alkyl; 
 R 1  is C 1 -C 10  alkyl, 
 
       or a pharmaceutically acceptable salt, enantiomer or solvate thereof. 
     
     
         54 . The method according to  claim 53  wherein R is a CH 2 CH 2 Cl group and R′ and R″ are CH 3 , or a pharmaceutically acceptable salt or enantiomer thereof. 
     
     
         55 . The method according to  claim 53  wherein R is CH 3 , CH 2 CH 3  or a C 2 -C 3  haloalkyl or a pharmaceutically acceptable salt or enantiomer thereof. 
     
     
         56 . The method according to  claim 53  wherein R′ and R″ are C 1 -C 3  alkyl or a pharmaceutically acceptable salt or enantiomer thereof. 
     
     
         57 . The method according to  claim 53  wherein R is a C 2 -C 5  haloalkyl group and R′ and R″ are C 1 -C 3  alkyl, or a pharmaceutically acceptable salt or enantiomer thereof. 
     
     
         58 . The method according to  claim 53  wherein R 1  is CH 3 , R is a C 2 -C 5  haloalkyl group and R′ and R″ are C 1 -C 3  alkyl, or a pharmaceutically acceptable salt or enantiomer thereof. 
     
     
         59 . The method according to  claim 53  wherein R 1  is CH 3 . 
     
     
         60 . The method according to  claim 54  wherein R 1  is CH 3 . 
     
     
         61 . The method according to  claim 55  wherein R 1  is CH 3 . 
     
     
         62 . The method according to  claim 56  wherein R 1  is CH 3 . 
     
     
         63 . The method according to  claim 57  wherein R 1  is CH 3 . 
     
     
         64 . The method according to  claim 53  wherein said compound is according to the chemical structure: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         65 . The method according to  claim 53  wherein said compound is according to the chemical structure: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         66 . The method according to  claim 53  wherein said cancer is stomach cancer, colon cancer, rectal cancer, liver cancer, pancreatic cancer, lung cancer, breast cancer, cervical cancer, uterine cancer, corpus uterine cancer, ovarian cancer, prostate cancer, testicular cancer, bladder cancer, renal cancer, skin cancer, brain/CNS cancer, head and neck cancer, throat cancer, Hodgkins disease, non-Hodgkins disease, multiple myeloma, acute lymphocytic leukemia, acute mylogenous leukemia, Ewings Sarcoma, choriocarcinoma, rhabdomyosarcoma, Wilms' tumor, neuroblastoma, hairy cell leukemia, mouth/pharynx cancer, esophageal, cancer of the larynx, melanoma or lymphoma. 
     
     
         67 . The method according to  claim 54  wherein said cancer is stomach cancer, colon cancer, rectal cancer, liver cancer, pancreatic cancer, lung cancer, breast cancer, cervical cancer, uterine cancer, corpus uterine cancer, ovarian cancer, prostate cancer, testicular cancer, bladder cancer, renal cancer, skin cancer, brain/CNS cancer, head and neck cancer, throat cancer, Hodgkins disease, non-Hodgkins disease, multiple myeloma, acute lymphocytic leukemia, acute mylogenous leukemia, Ewings Sarcoma, choriocarcinoma, rhabdomyosarcoma, Wilms' tumor, neuroblastoma, hairy cell leukemia, mouth/pharynx cancer, esophageal, cancer of the larynx, melanoma or lymphoma. 
     
     
         68 . The method according to  claim 55  wherein said cancer is stomach cancer, colon cancer, rectal cancer, liver cancer, pancreatic cancer, lung cancer, breast cancer, cervical cancer, uterine cancer, corpus uterine cancer, ovarian cancer, prostate cancer, testicular cancer, bladder cancer, renal cancer, skin cancer, brain/CNS cancer, head and neck cancer, throat cancer, Hodgkins disease, non-Hodgkins disease, multiple myeloma, acute lymphocytic leukemia, acute mylogenous leukemia, Ewings Sarcoma, choriocarcinoma, rhabdomyosarcoma, Wilms' tumor, neuroblastoma, hairy cell leukemia, mouth/pharynx cancer, esophageal, cancer of the larynx, melanoma or lymphoma. 
     
     
         69 . The method according to  claim 56  wherein said cancer is stomach cancer, colon cancer, rectal cancer, liver cancer, pancreatic cancer, lung cancer, breast cancer, cervical cancer, uterine cancer, corpus uterine cancer, ovarian cancer, prostate cancer, testicular cancer, bladder cancer, renal cancer, skin cancer, brain/CNS cancer, head and neck cancer, throat cancer, Hodgkins disease, non-Hodgkins disease, multiple myeloma, acute lymphocytic leukemia, acute mylogenous leukemia, Ewings Sarcoma, choriocarcinoma, rhabdomyosarcoma, Wilms' tumor, neuroblastoma, hairy cell leukemia, mouth/pharynx cancer, esophageal, cancer of the larynx, melanoma or lymphoma. 
     
     
         70 . The method according to  claim 57  wherein said cancer is stomach cancer, colon cancer, rectal cancer, liver cancer, pancreatic cancer, lung cancer, breast cancer, cervical cancer, uterine cancer, corpus uterine cancer, ovarian cancer, prostate cancer, testicular cancer, bladder cancer, renal cancer, skin cancer, brain/CNS cancer, head and neck cancer, throat cancer, Hodgkins disease, non-Hodgkins disease, multiple myeloma, acute lymphocytic leukemia, acute mylogenous leukemia, Ewings Sarcoma, choriocarcinoma, rhabdomyosarcoma, Wilms' tumor, neuroblastoma, hairy cell leukemia, mouth/pharynx cancer, esophageal, cancer of the larynx, melanoma or lymphoma. 
     
     
         71 . The method according to  claim 64  wherein said cancer is stomach cancer, colon cancer, rectal cancer, liver cancer, pancreatic cancer, lung cancer, breast cancer, cervical cancer, uterine cancer, corpus uterine cancer, ovarian cancer, prostate cancer, testicular cancer, bladder cancer, renal cancer, skin cancer, brain/CNS cancer, head and neck cancer, throat cancer, Hodgkins disease, non-Hodgkins disease, multiple myeloma, acute lymphocytic leukemia, acute mylogenous leukemia, Ewings Sarcoma, choriocarcinoma, rhabdomyosarcoma, Wilms' tumor, neuroblastoma, hairy cell leukemia, mouth/pharynx cancer, esophageal, cancer of the larynx, melanoma or lymphoma. 
     
     
         72 . The method according to  claim 65  wherein said cancer is stomach cancer, colon cancer, rectal cancer, liver cancer, pancreatic cancer, lung cancer, breast cancer, cervical cancer, uterine cancer, corpus uterine cancer, ovarian cancer, prostate cancer, testicular cancer, bladder cancer, renal cancer, skin cancer, brain/CNS cancer, head and neck cancer, throat cancer, Hodgkins disease, non-Hodgkins disease, multiple myeloma, acute lymphocytic leukemia, acute mylogenous leukemia, Ewings Sarcoma, choriocarcinoma, rhabdomyosarcoma, Wilms' tumor, neuroblastoma, hairy cell leukemia, mouth/pharynx cancer, esophageal, cancer of the larynx, melanoma or lymphoma.