Treatment of Solid Tumours

Abstract

A cell permeable iron chelator, optionally in combination with an autophagy inhibiting agent, is used for treating a solid cancer tumour in a person. A preferred chelator is an alkyl substituted N-(1-pyridine-2-yl-methylidene)-N-(9H-1,3,4,9-tetraaza-fluoren-2-yl)-hydrazine. A preferred autophagy inhibiting agent is chloroquine. Also disclosed is a pharmaceutical composition comprising iron chelator, pharmaceutically acceptable carrier and, optionally, autophagy inhibiting agent; and a method of treating cancer by administering cancer combating-effective amount(s) of the iron chelator or the combination of iron chelator and autophagy inhibiting agent.

1 .- 14 . (canceled) 
     
     
         15 . A method for treating a solid cancer tumour in a person, comprising administering a cell permeable iron chelator, optionally in combination with an autophagy inhibiting agent, to the person. 
     
     
         16 . The method of  claim 15 , wherein the cell permeable iron chelator is N-(1-pyridine-2-yl-methylidene)-N-(9H-1,3,4,9-tetraaza-fluoren-2-yl)-hydrazine, or a pharmaceutically acceptable salt or complex or prodrug thereof of the general formula I, wherein R is H or methyl, R 1  is H or C 1 -C 4  alkyl, and R 2  is H or C 1 -C 4  alkyl 
       
         
           
           
               
               
           
         
       
     
     
         17 . The method of  claim 16 , wherein R is methyl. 
     
     
         18 . The method of  claim 16 , wherein both of R and R 1  are methyl. 
     
     
         19 . The method of  claim 16 , wherein R 1  is 6-methyl or 8-methyl. 
     
     
         20 . The method of  claim 17 , wherein R 1  is 6-methyl or 8-methyl. 
     
     
         21 . The method of  claim 16 , wherein
 R is methyl, R 1  is 8-methyl and R 2  is H; or   R is methyl, R 1  is H and R 2  is H; or   R is methyl, R 1  is 6-methyl and R 2  is H; or   R is H, R 1  is 6-methyl and R 2  is H, or   R is H, R 1  is 8-methyl and R 2  is CH 3 .   
     
     
         22 . The method of  claim 15 , wherein the cell permeable iron chelator is selected from the group consisting of deferoxamine, deferiprone, and deferasirox. 
     
     
         23 . The method of  claim 15 , wherein the autophagy inhibiting agent is administered and is chloroquine. 
     
     
         24 . The method of  claim 15 , wherein the autophagy inhibiting agent is administered and is selected from the group consisting of hydroxychloroquine, 3-methyladenine, adenosine, bafilomycin A1, 5-amino-4-imidazole carboxamide riboside, wortmannin, and viniblastine. 
     
     
         25 . Pharmaceutical composition comprising a cell permeable iron chelator N-(1-pyridine-2-yl-methylidene)-N-(9H-1,3,4,9-tetraaza-fluoren-2-yl)-hydrazine, or a pharmaceutically acceptable salt or complex or prodrug thereof of the general formula I, wherein R is H or methyl, R 1  is H or C 1 -C 4  alkyl, and R 2  is H or C 1 -C 4  alkyl 
       
         
           
           
               
               
           
         
       
       and a pharmaceutically suitable carrier. 
     
     
         26 . The composition of  claim 25 , consisting of the cell permeable iron chelator and a pharmaceutically suitable carrier. 
     
     
         27 . The composition of  claim 25 , additionally comprising an autophagy inhibiting agent, wherein the autophagy inhibiting agent is chloroquine. 
     
     
         28 . The composition of  claim 27 , additionally comprising an autophagy inhibiting agent, wherein the autophagy inhibiting agent is selected from the group consisting of hydroxychloroquine, 3-methyladenine, adenosine, bafilomycin A1, 5-amino-4-imidazole carboxamide riboside, wortmannin, and viniblastine. 
     
     
         29 . A method of treating a solid cancer tumour in a person, comprising administering to the person a pharmacologically cancer-combatting effective dose of the composition of  claim 25 . 
     
     
         30 . A method of treating a solid cancer tumour in a person, comprising separate administration to the person of pharmacologically cancer-combatting effective doses of (i) a cell permeable iron chelator N-(1-pyridine-2-yl-methylidene)-N-(9H-1,3,4,9-tetraaza-fluoren-2-yl)-hydrazine, or a pharmaceutically acceptable salt or complex or prodrug thereof of the general formula I, wherein R is H or methyl, R 1  is H or C 1 -C 4  alkyl, and R 2  is H or C 1 -C 4  alkyl 
       
         
           
           
               
               
           
         
       
       and (ii) an autophagy inhibiting agent selected from the group consisting of chloroquine, hydroxychloroquine, 3-methyladenine, adenosine, bafilomycin A1, 5-amino-4-imidazole carboxamide riboside, wortmannin, and viniblastine, in a close timely relationship. 
     
     
         31 . The method of  claim 31 , wherein the cell permeable iron chelator and the autophagy inhibiting agent are administered within an hour of one another. 
     
     
         32 . The method of  claim 31 , wherein the cell permeable iron chelator and the autophagy inhibiting agent are administered within a day of one another. 
     
     
         33 . The method of  claim 31 , wherein the cell permeable iron chelator and the autophagy inhibiting agent are administered within a week of one another. 
     
     
         34 . The method of  claim 31 , wherein the doses are in separate pharmaceutical compositions, each of which comprises a pharmaceutically suitable carrier.