Novel fluorescent derivatives of polyamines, method for preparing same and applications thereof as diagnosis tools in the treatment of cancerous tumors

Abstract

The invention relates to novel fluorescent derivatives of polyamines having a benzoxadiazole group, to a method for preparing the same and to the use thereof as diagnosis tools for emphasising the polyamine transport system in cancerous cells in order to adapt the treatment thereof, and thus for selecting patients carrying such tumours in order to adapt their treatment. The derivatives are of the formula (I) or a pharmaceutically acceptable salt thereof, in which: R 1 is one or more NO 2 groups in position 4 or 6, or a SO 2 Ph, SO 2 NMe 2 , SO 2 NH 2 or SO 3 H group; R 2 is hydrogen, C 1-6 alkyl, benzyl, a perfluoroalkyl group; the values of a, b, c range from 2 to 5 independently from each other and represent alkylene chains separating the amino groups, and the values of d and e can independently be 0 or 1.

1 . Method for detecting tumours expressing the polyamine transport system using as diagnostic fluorescent probe a compound of general formula 1: 
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt thereof, 
       in which: 
       R 1  represents one or two NO 2  groups at position 4 and/or 6, or a SO 2 Ph, SO 2 NMe 2 , SO 2 NH 2 , or SO 3 H group; 
       the polyamine chain can be at position 5, 6 or 7; 
       R 2  represents a hydrogen, a C 1-6  alkyl, a benzyl, or a perfluoroalkyl group; 
       the values of a, b, and c can be 2 to 5, independently of each other, and represent alkylene chains separating the amino groups; 
       the values of d and e may be 0 or 1 independently, but cannot represent value 0 at the same time. 
     
   
   
       2 . Compound of general formula 1: 
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt thereof: 
       in which: 
       R 1  represents one or two NO 2  groups at position 4 and/or 6, or a SO 2 Ph, SO 2 NMe 2 , SO 2 NH 2 , or SO 3 H group; 
       the polyamine chain can be at position 5, 6 or 7; 
       R 2  represents a hydrogen, a C 1-6  alkyl, a benzyl, or a perfluoroalkyl group; 
       the values of a, b, and c can be 2 to 5, independently of each other, and represent alkylene chains separating the amino groups; 
       the values of d and e may be 0 or 1 independently but cannot represent value 0 at the same time; 
       provided that when e=0, then R2 cannot be a hydrogen; 
       and 
       with the exception of the compound in which R 1 =4-NO 2 , R 2 ═H, a=3, b=4, c=3 and d=e=1. 
     
   
   
       3 . Compound according to  claim 2 , in which R 1 =4-NO 2 , R 2 ═C 1-6  alkyl, a=3, b=4, c=3, and d=e=1. 
   
   
       4 . Compound according to  claim 2 , in which R 1 =4-NO 2 , R 2 ═H or C 1-6  alkyl, a=0, b=4, c=3, d=0, and e=1. 
   
   
       5 . Compound according to  claim 2 , in which R 1 =4-NO 2 , R 2 ═H or C 1-6  alkyl, a=0, b=3, c=4, d=0, and e=1. 
   
   
       6 . Compound according to  claim 2 , in which R 1 =4-NO 2 , R 2 ═C 1-6  alkyl, a=4, b=0, c=0, d=1, and e=0. 
   
   
       7 . Compound according to  claim 2 , which:
 R 1 =4-NO 2 , R 2 =Methyl, a=3, b=4, c=3, and d=e=1, which corresponds to N-(3-Aminopropyl)-N′-{3-[methyl-(7-nitrobenzo[1,2,5]oxadiazol-4-yl)-amino]-propyl}-butane-1,4-diamine.   
   
   
       8 . Compound according to  claim 2 , in which: R 1 =4-NO 2 , R 2 =Methyl, a=0, b=4, c=3, d=0, and e=1, which corresponds to N-(3-Aminopropyl)-N′-methyl-N′-(7-nitrobenzo[1,2,5]oxadiazol-4-yl)-butane-1,4-diamine. 
   
   
       9 . Compound according to  claim 2 , in which: R 1 =4-NO 2 , R 2 ═H, a=0, b=4, c=3, d=0, and e=1, which corresponds to N-(3-Aminopropyl)-N′-(7-nitrobenzo[1,2,5]oxadiazol-4-yl)-butane-1,4-diamine. 
   
   
       10 . Compound according to  claim 2 , in which: R 1 =4-NO 2 , R 2 =Methyl, a=0, b=3, c=4, d=0, and e=1, which corresponds to N*1*-{3-[methyl-(7-nitrobenzo[1,2,5]oxadiazol-4-yl)-amino]-propyl}-butane-1,4-diamine. 
   
   
       11 . Compound according to  claim 2 , in which: R 1 =4-NO 2 , R 2 ═H, a=0, b=3, c=4, d=0, and e=1, which corresponds to N*1*-[3-(7-nitrobenzo[1,2,5]oxadiazol-4-yl-amino)-propyl]-butane-1,4-diamine. 
   
   
       12 . Compound according to  claim 2 , in which: R 1 =4-NO 2 , R 2 =Methyl, a=4, b=0, c=0, d=1, and e=0, which corresponds to N*1*-Methyl-N*1*-(7-nitrobenzo[1,2,5]oxadiazol-4-yl)-butane-1,4-diamine. 
   
   
       13 . Method to synthesize a compound of formula 1, comprising the following steps:
 a) Coupling a derivative of benzoxadiazole of formula 2   
     
       
         
         
             
             
         
       
       in which R 1  represents one or two nitro groups at position 4 and/or 6 or a SO 2 Ph, SO 2 NMe 2 , SO 2 NH 2 , or SO 3 H group; 
       R 3  is a halogen substituent mobile at position 7, 
       with a polyamine of formula 6 in which P is a protector group of the amine functions and in which a, b, and c lie between 2 and 5, independently of each other, and in which d and e can independently be 0 or 1; 
     
     
       
         
         
             
             
         
       
       b) Alkylating the compound derived from the coupling reaction a) with an alkyl halide in the presence of a base in an inert solvent; and 
       c) Deprotecting the compound derived from step b) in an acid medium at room temperature to obtain the compound of formula 1.