Method for preparing a marked purine derivative, said derivative and uses thereof

Abstract

The present invention relates to a method for preparing a 2-fluoropurine marked with the radioisotope 18 F comprising a fluorination step for a 2-nitropurine derivative. The present invention comprises a 2-fluoropurine derivative marked with the radioisotope 18 F which can be obtained by or during a method according to the invention and its various uses.

1 - 22 . (canceled) 
     
     
         23 . A method for preparing a 2-fluoropurine derivative marked with the  18 F radioisotope, the method comprising:
 a fluorination step comprising reacting an optionally protected 2-nitropurine derivative with a source of [ 18 F] marked fluoride F ions; and   a deprotection step, after said fluorination step, to obtain the 2-[ 18 F] fluoropurine derivative.   
     
     
         24 . The preparation method according to  claim 23 , wherein the 2-fluoro-purine derivative marked with the radioisotope  18 F has a formula (Ia) 
       
         
           
           
               
               
           
         
       
       in which
 R 1  represents H, an optionally substituted alkyl group, an optionally substituted aryl group, a NR 4 R 5  group; 
 R 2  represents H, an optionally substituted alkyl group, an optionally substituted aryl group, an optionally substituted furanose group, or an optionally substituted pyranose group; 
 R 3  represents H, an optionally substituted alkyl group, an optionally substituted aryl group, a halogen, a —OR 8  group or a —SR 8  group, with R 8  representing H, an optionally substituted alkyl group, an optionally substituted aryl group; and 
 R 4  and R 5  independently represent H, an electroattractive group, an optionally substituted alkyl group, an optionally substituted aryl group, an optionally substituted acyl group, an optionally substituted sulfinyl group, or an optionally substituted sulfonyl group. 
 
     
     
         25 . The method according to  claim 23 , wherein the 2-nitropurine derivative has a formula (Ib) 
       
         
           
           
               
               
           
         
         with R 1 , R 2  and R 3  being such as 
         wherein the 2-fluoro-purine derivative marked with the radioisotope  18 F has a formula (Ia) 
       
       
         
           
           
               
               
           
         
       
       in which
 R 1  represents H, an optionally substituted alkyl group, an optionally substituted aryl group, a NR 4 R 5  group; 
 R 2  represents H, an optionally substituted alkyl group, an optionally substituted aryl group, an optionally substituted furanose group, or an optionally substituted pyranose group; 
 R 3  represents H, an optionally substituted alkyl group, an optionally substituted aryl group, a halogen, a —OR 8  group or a —SR 8  group, with R 8  representing H, an optionally substituted alkyl group, an optionally substituted aryl group; and 
 R 4  and R 5  independently represent H, an electroattractive group, an optionally substituted alkyl group, an optionally substituted aryl group, an optionally substituted acyl group, an optionally substituted sulfinyl group, or an optionally substituted sulfonyl group. 
 
     
     
         26 . The method according to  claim 23 , wherein the source of [ 18 F] marked fluoride ions implemented during the fluorination step comprises said fluoride ions and a counter-ion. 
     
     
         27 . The preparation method according to  claim 23 , wherein said method further comprises the following successive steps:
 a) reacting a protected 2-nitropurine derivative with a source of [ 18 F] marked fluoride F ions to obtain a protected 2-[ 18 F] fluoropurine derivative and optionally a partially unprotected 2-[ 18 F] fluoropurine derivative; and   b) unprotecting said protected 2-[ 18 F] fluoropurine derivative and said partially unprotected 2-[ 18 F] fluoropurine derivative optionally obtained for achieving the 2-[ 18 F] [ 18 F] fluoropurine derivative.   
     
     
         28 . The preparation method according to  claim 27 , wherein said protected 2-nitropurine derivative has a formula (Ic) 
       
         
           
           
               
               
           
         
         in which R and R′ are identical or different protecting groups and R 2  and R 3  being such as 
         wherein the 2-fluoro-purine derivative marked with the radioisotope  18 F has a formula (Ia) 
       
       
         
           
           
               
               
           
         
       
       in which
 R 1  represents H, an optionally substituted alkyl group, an optionally substituted aryl group, a NR 4 R 5  group; 
 R 2  represents H, an optionally substituted alkyl group, an optionally substituted aryl group, an optionally substituted furanose group, or an optionally substituted pyranose group; 
 R 3  represents H, an optionally substituted alkyl group, an optionally substituted aryl group, a halogen, a —OR 8  group or a —SR 8  group, with R 8  representing H, an optionally substituted alkyl group, an optionally substituted aryl group; and 
 R 4  and R 5  independently represent H, an electroattractive group, an optionally substituted alkyl group, an optionally substituted aryl group, an optionally substituted acyl group, an optionally substituted sulfinyl group, or an optionally substituted sulfonyl group. 
 
     
     
         29 . The preparation method according to  claim 27 , wherein said protected 1-[ 18 F] fluoropurine derivative has a formula (Id) 
       
         
           
           
               
               
           
         
         with R 2 , R 3 , R and R′ being such as 
         wherein said protected 2-nitropurine derivative has a formula (Ic) 
       
       
         
           
           
               
               
           
         
         in which R and R′ are identical or different protecting groups and R 2  and R 3  being such as 
         wherein the 2-fluoro-purine derivative marked with the radioisotope  18 F has a formula (Ia) 
       
       
         
           
           
               
               
           
         
       
       in which
 R 1  represents H, an optionally substituted alkyl group, an optionally substituted aryl group, a NR 4 R 5  group; 
 R 2  represents H, an optionally substituted alkyl group, an optionally substituted aryl group, an optionally substituted furanose group, or an optionally substituted pyranose group; 
 R 3  represents H, an optionally substituted alkyl group, an optionally substituted aryl group, a halogen, a —OR 8  group or a —SR 8  group, with R 8  representing H, an optionally substituted alkyl group, an optionally substituted aryl group; and 
 R 4  and R 5  independently represent H, an electroattractive group, an optionally substituted alkyl group, an optionally substituted aryl group, an optionally substituted acyl group, an optionally substituted sulfinyl group, or an optionally substituted sulfonyl group. 
 
     
     
         30 . The preparation method according to  claim 27 , wherein said partially deprotected 2-[ 18 F] fluoropurine derivative has a formula (Ie) 
       
         
           
           
               
               
           
         
         with R 2 , R 3  and R being such as 
         wherein said protected 2-nitropurine derivative has a formula (Ic) 
       
       
         
           
           
               
               
           
         
         in which R and R′ are identical or different protecting groups and R 2  and R 3  being such as 
         wherein the 2-fluoro-purine derivative marked with the radioisotope  18 F has a formula (Ia) 
       
       
         
           
           
               
               
           
         
       
       in which
 R 1  represents H, an optionally substituted alkyl group, an optionally substituted aryl group, a NR 4 R 5  group; 
 R 2  represents H, an optionally substituted alkyl group, an optionally substituted aryl group, an optionally substituted furanose group, or an optionally substituted pyranose group; 
 R 3  represents H, an optionally substituted alkyl group, an optionally substituted aryl group, a halogen, a —OR 8  group or a —SR 8  group, with R 8  representing H, an optionally substituted alkyl group, an optionally substituted aryl group; and 
 R 4  and R 5  independently represent H, an electroattractive group, an optionally substituted alkyl group, an optionally substituted aryl group, an optionally substituted acyl group, an optionally substituted sulfinyl group, or an optionally substituted sulfonyl group. 
 
     
     
         31 . The preparation method according to  claim 27 , wherein said deprotection step (b) is carried out by reacting the protected 2-[ 18 F] fluoropurine derivative such as the compound of formula (Id), and the optionally present partially unprotected 2-[ 18 F] fluoropurine derivative such as the compound of formula (Ie), with a mixture of alcohol and aqueous ammonia. 
     
     
         32 . The preparation method according to  claim 27 , wherein said deprotection step (b) is carried out in two sub-steps (b′) and (b″). 
     
     
         33 . The preparation method according to  claim 32 , wherein step (b′) involves reacting the 2-fluoropurine derivative marked with the radioisotope  18 F and protected having the formula (Id) with a nucleophilic compound to obtain a mono-hydrolyzed (or mono-deprotected) 2-fluoropurine derivative marked with the radioisotope  18 F having a formula (Ie) such as
 wherein said partially deprotected 2-[ 18 F]fluoropurine derivative has a formula (Ie)   
       
         
           
           
               
               
           
         
         with R 2 , R 3  and R being such as 
         wherein said protected 2-nitropurine derivative has a formula (Ic) 
       
       
         
           
           
               
               
           
         
         in which R and R′ are identical or different protecting groups and R 2  and R 3  being such as 
         wherein the 2-fluoro-purine derivative marked with the radioisotope  18 F has a formula (Ia) 
       
       
         
           
           
               
               
           
         
       
       in which
 R 1  represents H, an optionally substituted alkyl group, an optionally substituted aryl group, a NR 4 R 5  group; 
 R 2  represents H, an optionally substituted alkyl group, an optionally substituted aryl group, an optionally substituted furanose group, or an optionally substituted pyranose group; 
 R 3  represents H, an optionally substituted alkyl group, an optionally substituted aryl group, a halogen, a —OR 8  group or a —SR 8  group, with R 8  representing H, an optionally substituted alkyl group, an optionally substituted aryl group; and 
 R 4  and R 5  independently represent H, an electroattractive group, an optionally substituted alkyl group, an optionally substituted aryl group, an optionally substituted acyl group, an optionally substituted sulfinyl group, or an optionally substituted sulfonyl group. 
 
     
     
         34 . The preparation method according to  claim 33 , wherein the nucleophilic compound is chosen from among the compounds comprising at least an nitrogen atom carrying a free doublet included in an aromatic, unsaturated, or saturated ring, said ring preferably comprising between 3 and 8 atoms; the primary or secondary amines such as the 2-phenylethylamine; a hydrazine or hydrazone derivative; an amide; a sulfonamide; a urea derivative; a heterocyclic derivative being nitrogenous and/or sulfurated, an alcohol, and a phenol derivative. 
     
     
         35 . The preparation method according to  claim 32 , wherein said step (b″) is a deprotection whose purpose is to eliminate the remaining protecting groups. 
     
     
         36 . The method of preparation according to  claim 27 , wherein said deprotection step (b) is followed by a hydrolysis step. 
     
     
         37 . The method of preparation according to  claim 35 , wherein said deprotection step (b″) is followed by a hydrolysis step. 
     
     
         38 . The method for preparing a mono-hydrolyzed (or mono-deprotected) 2-fluoropurine derivative marked with the radioisotope  18 F having a formula (Ie) such as defined in  claim 30 , wherein a protected 2-[ 18 F] fluoropurine derivative marked with the radioisotope  18 F having a formula (Id) such as
 wherein said protected 2-[ 18 F] fluoropurine derivative has a formula (Id)   
       
         
           
           
               
               
           
         
         with R 2 , R 3 , R and R′ being such as 
         wherein said protected 2-nitropurine derivative has a formula (Ic) 
       
       
         
           
           
               
               
           
         
         in which R and R′ are identical or different protecting groups and R 2  and R 3  being such as 
         wherein the 2-fluoro-purine derivative marked with the radioisotope  18 F has a formula (Ia) 
       
       
         
           
           
               
               
           
         
       
       in which
 R 1  represents H, an optionally substituted alkyl group, an optionally substituted aryl group, a NR 4 R 5  group; 
 R 2  represents H, an optionally substituted alkyl group, an optionally substituted aryl group, an optionally substituted furanose group, or an optionally substituted pyranose group; 
 R 3  represents H, an optionally substituted alkyl group, an optionally substituted aryl group, a halogen, a —OR 8  group or a —SR 8  group, with R 8  representing H, an optionally substituted alkyl group, an optionally substituted aryl group; 
 R 4  and R 5  independently represent H, an electroattractive group, an optionally substituted alkyl group, an optionally substituted aryl group, an optionally substituted acyl group, an optionally substituted sulfinyl group, or an optionally substituted sulfonyl group is subjected to a treatment; 
 wherein step (b′) involves reacting the 2-fluoropurine derivative marked with the radioisotope  18 F and protected having the formula (Id) with a nucleophilic compound to obtain a mono-hydrolyzed (or mono-deprotected) 2-fluoropurine derivative marked with the radioisotope  18 F having a formula (Ie); 
 wherein said partially deprotected 2-[ 18 F]fluoropurine derivative has a formula (Ie) 
 
       
         
           
           
               
               
           
         
         with R 2 , R 3  and R being such as 
         wherein said protected 2-nitropurine derivative has a formula (Ic) 
       
       
         
           
           
               
               
           
         
         in which R and R′ are identical or different protecting groups and R 2  and R 3  being such as 
         wherein the 2-fluoro-purine derivative marked with the radioisotope  18 F has a formula (Ia) 
       
       
         
           
           
               
               
           
         
       
       in which
 R 1  represents H, an optionally substituted alkyl group, an optionally substituted aryl group, a NR 4 R 5  group; 
 R 2  represents H, an optionally substituted alkyl group, an optionally substituted aryl group, an optionally substituted furanose group, or an optionally substituted pyranose group; 
 R 3  represents H, an optionally substituted alkyl group, an optionally substituted aryl group, a halogen, a —OR 8  group or a —SR 8  group, with R 8  representing H, an optionally substituted alkyl group, an optionally substituted aryl group; 
 R 4  and R 5  independently represent H, an electroattractive group, an optionally substituted alkyl group, an optionally substituted aryl group, an optionally substituted acyl group, an optionally substituted sulfinyl group, or an optionally substituted sulfonyl group; and 
 wherein the nucleophilic compound is chosen from among the compounds comprising at least an nitrogen atom carrying a free doublet included in an aromatic, unsaturated, or saturated ring, said ring preferably comprising between 3 and 8 atoms; the primary or secondary amines such as the 2-phenylethylamine; a hydrazine or hydrazone derivative; an amide; a sulfonamide; a urea derivative; a heterocyclic derivative, being nitrogenous and/or sulfurated, an alcohol, and a phenol derivative. 
 
     
     
         39 . A method for preparing, by direct fluorination, a partially unprotected 2-[ 18 F]fluoropurine derivative having a formula (Ie) such as
 wherein said partially deprotected 2-[ 18 F]fluoropurine derivative has a formula (Ie)   
       
         
           
           
               
               
           
         
         with R 2 , R 3  and R being such as 
         wherein said protected 2-nitropurine derivative has a formula (Ic) 
       
       
         
           
           
               
               
           
         
         in which R and R′ are identical or different protecting groups and R 2  and R 3  being such as 
         wherein the 2-fluoro-purine derivative marked with the radioisotope  18 F has a formula (Ia) 
       
       
         
           
           
               
               
           
         
       
       in which
 R 1  represents H, an optionally substituted alkyl group, an optionally substituted aryl group, a NR 4 R 5  group; 
 R 2  represents H, an optionally substituted alkyl group, an optionally substituted aryl group, an optionally substituted furanose group, or an optionally substituted pyranose group; 
 R 3  represents H, an optionally substituted alkyl group, an optionally substituted aryl group, a halogen, a —OR 8  group or a —SR 8  group, with R 8  representing H, an optionally substituted alkyl group, an optionally substituted aryl group; 
 R 4  and R 5  independently represent H, an electroattractive group, an optionally substituted alkyl group, an optionally substituted aryl group, an optionally substituted acyl group, an optionally substituted sulfinyl group, or an optionally substituted sulfonyl group from a protected 2-nitropurine derivative having a formula (Ic); 
 wherein said protected 2-nitropurine derivative has a formula (Ic) 
 
       
         
           
           
               
               
           
         
         in which R and R′ are identical or different protecting groups and R 2  and R 3  being such as 
         wherein the 2-fluoro-purine derivative marked with the radioisotope  18 F has a formula (Ia) 
       
       
         
           
           
               
               
           
         
       
       in which
 R 1  represents H, an optionally substituted alkyl group, an optionally substituted aryl group, a NR 4 R 5  group; 
 R 2  represents H, an optionally substituted alkyl group, an optionally substituted aryl group, an optionally substituted furanose group, or an optionally substituted pyranose group; 
 R 3  represents H, an optionally substituted alkyl group, an optionally substituted aryl group, a halogen, a —OR 8  group or a —SR 8  group, with R 8  representing H, an optionally substituted alkyl group, an optionally substituted aryl group; 
 R 4  and R 5  independently represent H, an electroattractive group, an optionally substituted alkyl group, an optionally substituted aryl group, an optionally substituted acyl group, an optionally substituted sulfinyl group, or an optionally substituted sulfonyl group, 
 the method comprising reacting a protected 2-nitropurine derivative having a formula (Ic) such as disclosed in claim  6  with a source of [ 18 F] marked fluoride F ions comprising said [ 18 F] marked fluoride F ions and counter-ions in the form of K 2 SO 4  salt. 
 
     
     
         40 . A compound that can be prepared or obtained during a method according to  claim 23 , said compound having the formula (A) 
       
         
           
           
               
               
           
         
         in which R 6  and R 7  are independently H or a protecting group, 
         or a salt of the latter. 
       
     
     
         41 . The compound according to  claim 40 , further comprising a mono-, di- or tri-phosphate group, in the 5 position of the ribose. 
     
     
         42 . A pharmaceutical or diagnostic composition, comprising at least one compound according to  claim 40  in an acceptable pharmaceutical vehicle. 
     
     
         43 . A pharmaceutical or diagnostic composition, comprising at least one compound according to  claim 41  in an acceptable pharmaceutical vehicle. 
     
     
         44 . A method for performing PET imaging studies in a subject comprising administering to the subject a compound according to  claim 40  and detecting said compound. 
     
     
         45 . A method for performing PET imaging studies in a subject comprising administering to the subject a compound according to  claim 41  and detecting said compound. 
     
     
         46 . The method according to  claim 44 , wherein PET imaging studies are applied to the fields of neurobiology, cardiology, oncology, and to the fields of chronic lymphoid leukemia and related illnesses. 
     
     
         47 . The method according to  claim 45 , wherein PET imaging studies are applied to the fields of neurobiology, cardiology, oncology, and to the fields of chronic lymphoid leukemia and related illnesses. 
     
     
         48 . A method for evaluating the treatment of the chronic lymphoid leukemia in a subject comprising administering to the subject a compound according to  claim 40  and detecting said compound. 
     
     
         49 . A method for evaluating the treatment of the chronic lymphoid leukemia in a subject comprising administering to the subject a compound according to  claim 41  and detecting said compound. 
     
     
         50 . A method for in vivo mapping malignant hematopoietic cells in a subject comprising administering to the subject a compound according to  claim 40  and detecting said compound. 
     
     
         51 . A method for in vivo mapping malignant hematopoietic cells in a subject comprising administering to the subject a compound according to  claim 41  and detecting said compound.