Novel [f-18]- labelled l-glutamic acid and l-glutamine derivatives (i), use thereof and method for their production

Abstract

What is described are the compounds and the synthesis of [F-18]-labelled L-glutamic acid, [F-18]-labelled L-glutamate, their derivatives of the formula (I) and their use.

1 ) Compounds of the general formula I 
       
         
           
           
               
               
           
         
         in which 
         A represents
 a) hydroxyl, 
 b) branched or straight-chain C 1 -C 5  alkoxy, 
 c) branched or straight-chain hydroxy C 1 -C 5  alkoxy, 
 d) branched or straight-chain O—C 1 -C 5  alkyl-(O—C 1 -C 4  alkyl) n -O—C 1 -C 4  alkyl, 
 e) N(C 1 -C 5  alkyl) 2 , 
 f) NH 2 , 
 g) N(H)-L, 
 h) O-L or 
 i) O—Z, 
 
         G represents
 a) hydroxyl, 
 b) O—Z, 
 b) branched or straight-chain O—C 1 -C 5  alkyl, 
 c) branched or straight-chain O—C 2 -C 5  alkenyl, 
 d) branched or straight-chain O—C 1 -C 5  alkyl-(O—C 1 -C 4  alkyl) n -O—C 1 -C 4  alkyl, 
 e) branched or straight-chain O—C 2 -C 5  alkynyl or 
 f) triphenylmethoxy, 
 
         R 1  and R 2  represent
 a) hydrogen, 
 b) branched or straight-chain  18 F—C 1 -C 5  alkoxy, 
 c) branched or straight-chain  18 F—C 1 -C 5  alkyl, 
 d) branched or straight-chain  18 F—C 2 -C 5  alkenyl, 
 e) branched or straight-chain  18 F—C 2 -C 5  alkynyl, 
 f) hydroxyl, 
 g) branched or straight-chain C 1 -C 5  alkyl or 
 h) branched or straight-chain C 1 -C 5  alkoxy, 
 alkyl being optionally interrupted by one or more O, S or N, 
 with the proviso that one of the substituents R 1  or R 2  contains exactly one  18 F isotope and the respective other substituent contains no  18 F isotope, with the proviso that R 1  is not hydrogen, 
 
         L represents
 a) branched or straight-chain C 1 -C 5  alkyl, 
 b) branched or straight-chain C 2 -C 5  alkenyl, 
 c) branched or straight-chain C 1 -C 5  alkyl-(O—C 1 -C 4  alkyl) n -O—C 1 -C 4  alkyl or 
 d) branched or straight-chain C 2 -C 5  alkynyl, 
 
         Z represents a metal cation equivalent, and 
         where n=0, 1, 2 or 3. 
       
     
     
         2 . Compounds according to any of  claim 1 , characterized in that R 1  is selected from the group consisting of  18 F-methoxy,  18 F-ethoxy,  18 F-propoxy,  18 F-ethyl and  18 F-propyl, and R 2  is hydrogen. 
     
     
         3 . Compound according to  claim 1 , selected from the group of compounds of the formulae: 
       
         
           
           
               
               
           
         
       
     
     
         4 ) Compounds of the general formula (II): 
       
         
           
           
               
               
           
         
         in which 
         A′ represents
 a) hydroxyl, 
 b) branched or straight-chain C 1 -C 5  alkoxy, 
 c) branched or straight-chain hydroxy C 1 -C 5  alkoxy, 
 d) branched or straight-chain O—C 1 -C 5  alkyl-(O—C 1 -C 4  alkyl) n -O—C 1 -C 4    
 alkyl, 
 e) N(C 1 -C 5  alkyl) 2 , 
 f) NH 2 , 
 g) N(H)-L′, 
 h) O-L′, 
 
         G′ represents
 a) hydroxyl, 
 b) O—Z′, 
 c) branched or straight-chain O—C 1 -C 5  alkyl, 
 d) branched or straight-chain O—C 2 -C 5  alkenyl, 
 e) branched or straight-chain O—C 1 -C 5  alkyl-(O—C 1 -C 4  alkyl) n -O—C 1 -C 4  alkyl, 
 f) branched or straight-chain O—C 2 -C 5  alkynyl or 
 g) triphenylmethoxy, 
 
         R 1  and R 2  represent
 a) hydrogen, 
 b) branched or straight-chain  18 F—C 1 -C 5  alkoxy, 
 c) branched or straight-chain  18 F—C 1 -C 5  alkyl, 
 d) branched or straight-chain  18 F—C 2 -C 5  alkenyl, 
 e) branched or straight-chain  18 F—C 2 -C 5  alkynyl, 
 f) hydroxyl, 
 g) branched or straight-chain C 1 -C 5  alkyl or 
 h) branched or straight-chain C 1 -C 5  alkoxy, 
 alkyl being optionally interrupted by one or more O, S or N, 
 with the proviso that exactly one of the substituents R 1  or R 2  contains exactly one  18 F isotope and the respective other substituent contains no  18 F isotope, with the proviso that R 1  is not hydrogen, 
 
         Q represents
 a) N(H)-tert-butoxycarbonyl, 
 b) N(H)-allyloxycarbonyl, 
 c) N(H)-benzyloxycarbonyl, 
 d) N(H)-ethoxycarbonyl, 
 e) N(H)-methoxycarbonyl, 
 f) N(H)-propoxycarbonyl, 
 e) N(H)-2,2,2-trichloroethoxycarbonyl, 
 f) N(H)-1,1-dimethylpropynyl, 
 g) N(H)-1-methyl-1-phenylethoxycarbonyl, 
 h) N(H)-1-methyl-1-(4-biphenylyl)ethoxycarbonyl, 
 i) N(H)-cyclobutylcarbonyl, 
 j) N(H)-1-methylcyclobutylcarbonyl, 
 k) N(H)-vinylcarbonyl, 
 l) N(H)-allylcarbonyl, 
 m) N(H)-adamantylcarbonyl, 
 n) N(H)-diphenylmethylcarbonyl, 
 o) N(H)-cinnamylcarbonyl, 
 p) N(H)-formyl, 
 q) N(H)-benzoyl, 
 r) N(H)-trityl, 
 s) N(H)-p-methoxydiphenylmethyl, 
 t) N(H)-di(p-methoxyphenyl)phenylmethyl, 
 
       
       
         
           
           
               
               
           
         
         
            or 
           v) N-(tert-butoxycarbonyl) 2 , 
         
         L′represents
 a) branched or straight-chain C 1 -C 5  alkyl, 
 b) branched or straight-chain C 2 -C 5  alkenyl, 
 c) branched or straight-chain C 1 -C 5  alkyl-(O—C 1 -C 4  alkyl) n O—C 1 -C 4  alkyl or 
 d) branched or straight-chain C 2 -C 5  alkynyl, 
 
         X′ and X″ independently of one another represent
 a) branched or straight-chain C 1 -C 5  alkyl, 
 b) substituted or unsubstituted aryl, 
 c) substituted or unsubstituted aralkyl or 
 d) substituted or unsubstituted heteroaryl, 
 
         Z′ represents a metal cation equivalent, and 
         where n=0, 1, 2 or 3. 
       
     
     
         5 ) Compounds according to  claim 4 , characterized in that R 1  is selected from the group consisting of  18 F-ethoxy,  18 F-propoxy,  18 F-ethyl, and  18 F-propyl, and R 2  is hydrogen. 
     
     
         6 ) Compound according to  claim 4 , characterized in that Q is selected from the group consisting of N(H)-tert-butoxycarbonyl, N(H)-benzyloxycarbonyl and 
       
         
           
           
               
               
           
         
         in which 
         X′ and X″ independently of one another represent
 a) branched or straight-chain C 1 -C 5  alkyl, 
 b) substituted or unsubstituted aryl, 
 c) substituted or unsubstituted aralkyl or 
 d) substituted or unsubstituted heteroaryl. 
 
       
     
     
         7 ) Process for preparing compounds of the general formula (I) which comprises
 removing one or more protective groups present in a compound of the formula (II) according to  claim 4 .   
     
     
         8 ) Process for preparing compounds of the general formula (II) which comprises
 reacting a compound of the formula (III) according to  claim 12  with F-18 fluoride.   
     
     
         9 ) Compounds according to any of  claim 1  for use as medicaments. 
     
     
         10 ) Compounds according to  claim 1  for use for imaging in tumour disorders. 
     
     
         11 ) Use of compounds according to any of  claim 1  for preparing a medicament for imaging in tumour disorders. 
     
     
         12 ) Compounds of the formula (III) 
       
         
           
           
               
               
           
         
         in which 
         A″ represents
 a) branched or straight-chain C 1 -C 5  alkoxy, 
 b) branched or straight-chain hydroxy C 1 -C 5  alkoxy, 
 c) branched or straight-chain O—C 1 -C 5  alkyl-(O—C 1 -C 4  alkyl) n -O—C 1 -C 4  alkyl, 
 d) N(C 1 -C 5  alkyl) 2 , 
 e) NH 2 , 
 f) N(H)—U′ 
 g) N(H)-L″, or 
 h) O-L″, 
 
         G″ represents
 a) O—Z″, 
 b) branched or straight-chain O—C 1 -C 5  alkyl, 
 c) branched or straight-chain O—C 2 -C 5  alkenyl, 
 d) branched or straight-chain O—C 1 -C 5  alkyl-(O—C 1 -C 4  alkyl) n -O—C 1 -C 4  alkyl, 
 e) branched or straight-chain O—C 2 -C 5  alkynyl or 
 f) triphenylmethoxy, 
 
         R 3  and R 4  represent
 a) hydrogen, 
 b) branched or straight-chain E-C 1 -C 5  alkoxy, 
 c) branched or straight-chain E-C 1 -C 5  alkyl, 
 d) branched or straight-chain E-C 2 -C 5  alkenyl, 
 e) branched or straight-chain E-C 2 -C 5  alkynyl, 
 f) hydroxyl, 
 g) branched or straight-chain C 1 -C 5  alkyl or 
 h) branched or straight-chain C 1 -C 5  alkoxy, 
 alkyl being optionally interrupted by one or more O, S or N, 
 with the proviso that exactly one of the substituents R 3  or R 4  contains an E and the respective other substituent contains no E, with the proviso that R 3  is not hydrogen, 
 
         E represents a leaving group, 
         Q′ represents
 a) N(H)-tert-butoxycarbonyl 
 b) N(H)-allyloxycarbonyl, 
 c) N(H)-benzyloxycarbonyl, 
 d) N(H)-ethoxycarbonyl, 
 e) N(H)-methoxycarbonyl, 
 f) N(H)-propoxycarbonyl, 
 g) N(H)-2,2,2-trichloroethoxycarbonyl, 
 h) N(H)-1,1-dimethylpropynyl, 
 i) N(H)-1-methyl-1-phenylethoxycarbonyl, 
 j) N(H)-1-methyl-1-(4-biphenylyl)ethoxycarbonyl, 
 k) N(H)-cyclobutylcarbonyl, 
 l) N(H)-1-methylcyclobutylcarbonyl, 
 m) N(H)-vinylcarbonyl, 
 n) N(H)-allylcarbonyl, 
 o) N(H)-adamantylcarbonyl, 
 p) N(H)-diphenylmethylcarbonyl, 
 q) N(H)-cinnamylcarbonyl, 
 r) N(H)-formyl, 
 s) N(H)-benzoyl, 
 t) N(H)-trityl, 
 u) N(H)-p-methoxydiphenylmethyl, 
 v) N(H)-di(p-methoxyphenyl)phenylmethyl, 
 
       
       
         
           
           
               
               
           
         
         
            or 
           x) N-(tert-butoxycarbonyl) 2 , 
         
         L″ represents
 a) branched or straight-chain C 1 -C 5  alkyl, 
 b) branched or straight-chain C 2 -C 5  alkenyl, 
 c) branched or straight-chain C 1 -C 5  alkyl-(O—C 1 -C 4  alkyl) n -O—C 1 -C 4  alkyl or 
 d) branched or straight-chain C 2 -C 5  alkynyl, 
 
         X′ and X″ independently of one another represent
 a) branched or straight-chain C 1 -C 5  alkyl, 
 b) substituted or unsubstituted aryl, 
 c) substituted or unsubstituted alkylaryl or 
 d) substituted or unsubstituted heteroaryl, 
 
         Z″ represents a metal cation equivalent, and 
         where n=0, 1, 2 or 3. 
       
     
     
         13 ) Use of compounds of the formula (IV) for preparing compounds of the formula (I) or (II): 
       
         
           
           
               
               
           
         
         in which 
         G′″ represents
 a) branched or straight-chain O—C 1 -C 5  alkyl, 
 b) branched or straight-chain O—C 2 -C 5  alkenyl, 
 c) branched or straight-chain O—C 1 -C 5  alkyl-(O—C 1 -C 4  alkyl)-O—C 1 -C 4  alkyl, 
 d) branched or straight-chain O—C 2 -C 5  alkynyl or 
 e) triphenylmethoxy, 
 
         R 5  and R 6  represent
 a) hydrogen, 
 b) hydroxyl, 
 c) branched or straight-chain C 1 -C 5  alkyl, 
 d) branched or straight-chain C 1 -C 5  alkoxy or 
 e) R 7 -E′, 
 with the proviso that exactly one of the substituents R 5  or R 6  contains an E′ and the respective other substituent contains no E′, with the proviso that R 5  is not hydrogen, 
 
         E′ represents a leaving group, 
         R 7  represents
 a) branched or straight-chain C 1 -C 5  alkoxy, 
 b) branched or straight-chain C 1 -C 5  alkyl, 
 c) branched or straight-chain C 2 -C 5  alkenyl or 
 d) branched or straight-chain C 2 -C 5  alkynyl, 
 
         Q′″ represents
 a) N-tert-butoxycarbonyl 
 b) N-allyloxycarbonyl, 
 c) N-benzyloxycarbonyl, 
 d) N-ethoxycarbonyl, 
 e) N-methoxycarbonyl, 
 f) N-propoxycarbonyl, 
 g) N-2,2,2-trichloroethoxycarbonyl, 
 h) hydrogen, 
 i) N-1-methyl-1-phenylethoxycarbonyl, 
 j) N-1-methyl-1-(4-biphenyl)-pethoxycarbonyl, 
 k) N-cyclobutylcarbonyl, 
 l) N-1-methylcyclobutylcarbonyl, 
 m) N-vinylcarbonyl, 
 n) N-allylcarbonyl, 
 o) N-adamantylcarbonyl, 
 p) N-diphenylmethylcarbonyl, 
 q) N-cinnamylcarbonyl, 
 r) N-formyl, 
 s) N-benzoyl, 
 t) N(H)-trityl, 
 u) N(H)-p-methoxyphenyldiphenylmethyl, 
 v) N(H)-di(n-methoxyphenyl)phenylmethyl, 
 
       
       
         
           
           
               
               
           
         
         
            or 
           x) N-(tert-butoxycarbonyl) 2 , 
         
         X′ and X″ independently of one another represent
 a) branched or straight-chain C 1 -C 5  alkyl, 
 b) substituted or unsubstituted aryl, 
 c) substituted or unsubstituted alkylaryl or 
 d) substituted or unsubstituted heteroaryl, and 
 
         where n=0, 1, 2 or 3. 
       
     
     
         14 ) Imaging kit, comprising compounds of the general formula III or IV. 
     
     
         15 ) Pharmaceutical composition, comprising compounds of the general formula I, II, III or IV and suitable pharmaceutical carrier substances. 
     
     
         16 ) Compounds according to  claim 1 , and compounds of the general formula IV, characterized in that the compounds are suitable for imaging in a dosage range of 37-600 MBq. 
     
     
         17 ) Compounds according to  claim 16 , characterized in that the compounds are particularly suitable in a dosage range of 150 MBq-370 MBq.