1, 2, 4-benzotriazine oxides as radiosensitizers and selective cytotoxic agents

Abstract

A method of using 1,2,4-benzotriazine oxides, some of which are novel compounds, as radiosensitizers and selective cytotoxic agents is disclosed. These compounds are shown to specifically radiosensitize hypoxic tumor cells. Some are additionally disclosed to be useful as specific cytotoxic agents for these cells. They also show an unexpected ability to radiosensitize aerobic cells following or preceding a hypoxic incubation of the cells with the drug. This provides a basis for selective radiosensitization of tumors compared to normal cells. A novel method for preparing the 1,2,4-benzotriazine oxides is also disclosed.

1 - 27 . (canceled)  
     
     
         28 . A compound having the structural formula:  
       
         
           
           
               
               
           
         
         wherein X is OH, alkoxy (1-4C), NHR or NRR where each R is independently an alkyl of 1-4 carbon atoms, or acyl of 1-4 cabron atoms, or where the two R groups are alkyls linked together to form a pyrrolidino or piperidino ring or linked through an oxygen to form a morpholino ring, and the R groups may be further substituted with OH, NH 2 , alkyl (1-4C) secondary amino, dialkyl (1-4C) tertiary amino, pyrrolidino, piperidino, alkoxy (1-4C), or halogen substituents;  
         n is 1; and  
         Y 1  and Y 2  are independently either H; nitro; halogen; hydrocarbyl (1-14C) including cyclic and unsaturated hydrocarbyl, optionally substituted with 1 or 2 substituents selected from the group consisting of halogen, hydroxy, epoxy, alkoxy (1-4C), alkylthio (1-4C), primary amino (NH 2 ), lower alkyl (1-4C) secondary amino, dialkyl (1-4C) tertiary amino, dialkyl (1-4C) tertiary amino where the two alkyls are linked together to produce a morpholino, pyrrolidino or piperidino, acyloxy (1-4C), acylamido (1-4C) and thio analogs thereof, acetylaminoalkyl (1-4C), carboxy, alkoxycabonyl (1-4C), carbamyl, alkylcarbamyl (1-4C), alkylsulfonyl (1-4C) or alkylphosphonyl (1-4C), wherein the hydrocarbyl can optionally be interrupted by a single ether (—O—) linkage; or wherein Y 1  and Y 2  are independently either morpholino, pyrrolidino, piperidino, NH 2 , NHR′, NR′R′O(CO)R′, NH(CO)R′, O(SO)R′, or O(POR′)R′ in which R′ is a hydrocarbyl (1-4C) which may be substituted with OH, NH 2 , alkyl-(1-4C) secondary amino, dialkyl (1-4C) tertiary amino, morpholino, pyrrolidino, piperidino, alkoxy (1-4C), or halogen substitutents,  
         or a pharmacologically acceptable salt thereof.  
       
     
     
         29 . A compound according to  claim 28 , wherein X is OH or alkoxy.  
     
     
         30 . A compound according to  claim 28 , wherein X is NRR.  
     
     
         31 . A compound according to  claim 28 , wherein Y 1  and Y 2  are both H.  
     
     
         32 . A compound according to  claim 29 , wherein Y 1  and Y 2  are both H.  
     
     
         33 . A compound according to  claim 30 , wherein Y 1  and Y 2  are both H.  
     
     
         34 . A compound according to  claim 28 , wherein X is —NH 2 —CH 2 —(CH 2 ) m —CH 2 —NR 1 R 2  wherein m is an integer in the range of 0-4 inclusive, and R 1  and R 2  are independently selected from hydrogen or lower alkyls or together form a piperidino or pyrrolidino ring.  
     
     
         35 . A compound according to  claim 34 , wherein m is 1 or 2 and Y 1  and Y 2  are independently selected from the group consisting of H and nitro.  
     
     
         36 . A compound having the structural formula:  
       
         
           
           
               
               
           
         
         X is NH 2 ;  
         n is 1; and  
         Y 1  and Y 2  are chosen such that one but not both may be hydrogen and one or both may independently be either nitro, saturated or unsaturated hydrocarbyl of 7-14C, or unsaturated hydrocarbyl of 2-6C, optionally substituted with 1 or 2 substituents selected from the group consisting of halogen, hydroxy, epoxy, alkoxy (1-4C), alkylthio (1-4C), primary amino (NH 2 ), lower alkyl (1-4C) secondary amino, dialkyl (1-4C) tertiary amino, dialkyl (1-4C) tertiary amino where the two alkyls are linked together to produce a morpholino, pyrrolidino or piperidino, acyloxy (1-4C), acylamido (1-4C) and thio analogs thereof, acetylaminoalkyl (1-4C), carboxy, alkoxycabonyl (1-4C), carbamyl, alkylcarbamyl (1-4C), alkylsulfonyl (1-4C) or alkylphosphonyl (1-4C), wherein the hydrocarbyl can optionally be interrupted by a single ether (—O—) linkage; or wherein Y 1  and Y 2  are independently either morpholino, pyrrolidino, piperidino, NH 2 , NHR′, NR′R′O(CO)R′, NH(CO)R′, O(SO)R′, or O(POR′)R′ in which R′ is a hydrocarbyl (1-4C) which may be substituted with OH, NH 2 , alkyl-(1-4C) secondary amino, dialkyl (1-4C) tertiary amino, morpholino, pyrrolidino, piperidino, alkoxy (1-4C), or halogen substitutents,  
         or a pharmacologically acceptable salt thereof.  
       
     
     
         37 . A compound according to  claim 36 , wherein Y 1  is H and Y 2  is saturated or unsaturated hydrocarbyl of 7-14C.  
     
     
         38 . A compound according to  claim 36 , wherein Y 1  is H and Y 2  is unsaturated hydrocarbyl of 2-6C.  
     
     
         39 . A compound according to  claim 36 , wherein Y 1  is H and Y 2  is nitro.  
     
     
         40 . A compound having the structural formula:  
       
         
           
           
               
               
           
         
         X is hydrogen or hydrocarbyl (2-4C) optionally substituted with OH, NH 2 , alkoxy (1-4C) or halogen substituents;  
         n is 1; and  
         Y 1  and Y 2  are independently either H; nitro; halogen; hydrocarbyl (1-14C) including cyclic and unsaturated hydrocarbyl, optionally substituted with 1 or 2 substituents selected from the group consisting of halogen, hydroxy, epoxy, alkoxy (1-4C), alkylthio (1-4C), primary amino (NH 2 ), lower alkyl (1-4C) secondary amino, dialkyl (1-4C) tertiary amino, dialkyl (1-4C) tertiary amino where the two alkyls are linked together to produce a morpholino, pyrrolidino or piperidino, acyloxy (1-4C), acylamido (1-4C) and thio analogs thereof, acetylaminoalkyl (1-4C), carboxy, alkoxycabonyl (1-4C), carbamyl, alkylcarbamyl (1-4C), alkylsulfonyl (1-4C) or alkylphosphonyl (1-4C), wherein the hydrocarbyl can optionally be interrupted by a single ether (—O—) linkage; or wherein Y 1  and Y 2  are independently either morpholino, pyrrolidino, piperidino, NH 2 , NHR′, NR′R′O(CO)R′, NH(CO)R′, O(SO)R′, or O(POR′)R′ in which R′ is a hydrocarbyl (1-4C) which may be substituted with OH, NH 2 , alkyl-(1-4C) secondary amino, dialkyl (1-4C) tertiary amino, morpholino, pyrrolidino, piperidino, alkoxy (1-4C), or halogen substitutents,  
         or a pharmacologically acceptable salt thereof.  
       
     
     
         41 . A compound according to  claim 40 , wherein X is H.  
     
     
         42 . A compound according to  claim 40 , wherein X is hydrocarbyl (2-4C).  
     
     
         43 . A compound according to  claim 40 , wherein Y 1  and Y 2  are both H.  
     
     
         44 . A compound according to  claim 41 , wherein Y 1  and Y 2  are both H.  
     
     
         45 . A compound according to  claim 42 , wherein Y 1  and Y 2  are both H.  
     
     
         46 - 53 . (canceled)