Compounds for use in imaging, diagnosing and/or treatment of diseases of the central nervous system or of tumors

Abstract

This invention relates to novel compounds suitable for labelling or already labelled by 18 F, methods of preparing such a compound, compositions comprising such compounds, kits comprising such compounds or compositions and uses of such compounds, compositions or kits for diagnostic imaging by positron emission tomography (PET).

1 . A compound of formula Ia 
       
         
           
           
               
               
           
         
       
       or formula Ib 
       
         
           
           
               
               
           
         
       
       wherein
 W is selected from the group comprising 
 —C(U 1 )(U 2 )—C≡CH and cyclopropyl, U 1  and U 2  being independently selected from hydrogen and deuterium; 
 A is selected from the group comprising substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, such as furanyl, (C 1 -C 10 )alkyl, G 4 -(C 2 -C 4 )alkynyl, G 4 -(C 1 -C 4 )alkoxy, (G 4 -(C 1 -C 4 )alkyl)aryl, (G 4 -(C 1 -C 4 )alkoxy)aryl, (G 4 -(C 1 -C 4 )alkyl)aryl, and (G 4 -(C 1 -C 4 )alkoxy)aryl, wherein preferably said heteroaryl is furanyl, 
 G 1 , G 2 , G 3  and G 4  in formula Ia and formula Ib are independently and individually, at each occurrence, selected from the group comprising hydrogen, (C 1 -C 4 )alkyl, preferably methyl, L, and —(C 1 -C 6 )alkyl-L, 
 with the proviso that exactly one of G 1 -G 4  in formula Ia are selected from L and —(C 1 -C 6 )alkyl-L, and 
 with the proviso that exactly one of G 3  and G 4  in formula Ib are selected from L and —(C 1 -C 6 )alkyl-L, 
 L being a leaving group, or L being F, preferably  18 F or  19 F, wherein, preferably, if L is  19 F, said compound contains exactly one  19 F-atom being attached to an sp 3 -hybridized carbon atom, 
 wherein n is an integer from 0 to 6, preferably 1-3, more preferably 1-2, and wherein m is an integer from 0 to 4, preferably 0 to 2, more preferably 0-1, and wherein e and f are integer from 0 to 1, with the proviso that at least one of e and f is 1, including all isomeric forms of said compound, including but not limited to enantiomers and diastereoisomers as well as racemic mixtures, 
 and any pharmaceutically acceptable salt, ester, amide, complex or prodrug thereof. 
 
     
     
         2 . The compound according to  claim 1 , wherein W is —CH 2 —C≡CH. 
     
     
         3 . The compound according to  claim 1 , wherein A is selected from the group comprising substituted or unsubstituted phenyl, substituted or unsubstituted furanyl, in particular furan-2-yl, furan-3-yl, (C 1 -C 4 )alkyl, G 4 -(C 3 -C 4 ), alkynyl, G 4 -(C 1 -C 3 )alkoxy, (G 4 -(C 1 -C 3 )alkyl)phenyl, (G 4 -(C 1 -C 3 )alkoxy)phenyl. 
     
     
         4 . The compound according to  claim 3 , wherein A is selected from the group comprising substituted or unsubstituted phenyl, substituted or unsubstituted furanyl, (G 4 -(C 1 -C 3 )alkyl)phenyl, (G 4 -(C 1 -C 3 )alkoxy)phenyl, hydroxy-phenyl, halo-phenyl, methoxy-phenyl, dimethoxy-phenyl, trifluormethyl-phenyl, and ((C 1 -C 4 )alkyl)-phenyl. 
     
     
         5 . The compound according to  claim 4 , wherein A is selected from the group comprising substituted or unsubstituted phenyl, (G 4 -(C 1 -C 3 )alkoxy)phenyl, hydroxyl-phenyl, fluorophenyl, methoxyphenyl, and methylphenyl. 
     
     
         6 . The compound according to  claim 1 , wherein G 1 , G 2 , G 3  and G 4  in formula Ia, and G 3  and G 4  in formula Ib are independently and individually, at each occurrence, selected from the group comprising hydrogen, (C 1 -C 4 )alkyl, preferably methyl, L, and —(C 1 -C 4 )alkyl-L,
 with the proviso that exactly one of G 1 -G 4  in formula Ia and exactly one of G 3 -G 4  in formula Ib are selected from L and —(C 1 -C 4 )alkyl-L.   
     
     
         7 . The compound according to  claim 6 , wherein G 1 , G 2 , G 3  and G 4  in formula Ia, and G 3  and G 4  in formula Ib are independently and individually, at each occurrence, selected from the group comprising hydrogen, methyl, L, and —(C 1 -C 2 )alkyl-L,
 with the proviso that exactly one of G 1 -G 4  in formula Ia and exactly one of G 3 -G 4  in formula Ib are selected from L and —(C 1 -C 2 )alkyl-L.   
     
     
         8 . The compound according to  claim 7 , wherein G 1 , G 2 , G 3  and G 4  in formula Ia, and G 3  and G 4  in formula Ib are independently and individually, at each occurrence, selected from the group comprising hydrogen, methyl, L, and -methyl-L,
 with the proviso that exactly one of G 1 -G 4  in formula Ia and exactly one of G 3 -G 4  in formula Ib are selected from L and -methyl-L.   
     
     
         9 . The compound according to  claim 1 , wherein L is a leaving group selected from the group comprising halo, in particular chloro, bromo, iodo, mesyloxy, tosyloxy, trifluormethylsulfonyloxy, nona-fluorobutylsulfonyloxy, (4-bromo-phenyl)sulfonyloxy, (4-nitro-phenyl)sulfonyloxy, (2-nitro-phenyl)sulfonyloxy, (4-isopropyl-phenyl)sulfonyloxy, (2,4,6-tri-isopropyl-phenyl)sulfonyloxy, (2,4,6-trimethyl-phenyl)sulfonyloxy, (4-tertbutyl-phenyl)sulfonyloxy, and (4-methoxy-phenyl)sulfonyloxy. 
     
     
         10 . The compound according to  claim 9 , wherein L is selected from the group comprising chloro, bromo, mesyloxy, tosyloxy, trifluormethylsulfonyloxy, (4-bromo-phenyl)sulfonyloxy, (4-nitro-phenyl)sulfonyloxy, (4-isopropyl-phenyl)sulfonyloxy, and (2,4,6-tri-isopropyl-phenyl)sulfonyloxy. 
     
     
         11 . A compound according to  claim 1  which is 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         12 . A compound according to  claim 1  wherein L is not F. 
     
     
         13 . A compound according to  claim 1 , wherein L is  18 F, or wherein the mesyloxy-group, chloro-group and tosyloxy-group in any of the compounds, is replaced by  18 F. 
     
     
         14 . A compound according to  claim 1 , wherein L is  19 F, or wherein a mesyloxy-group, chloro-group and tosyloxy-group in any of the compounds of  claim 1  is replaced by  19 F. 
     
     
         15 . A method of synthesis of a compound as defined in  claim 1  wherein L is  18 F or  19 F, in which a compound according to  claim 1  where L is not F, is reacted with an F-fluorinating agent, wherein F═ 18 F or  19 F. 
     
     
         16 . The method according to  claim 15 , wherein said F-fluorinating agent is a compound comprising F-anions, preferably a compound selected from the group comprising 4, 7, 13, 16, 21, 24-hexaoxa-1,10-diazabicyclo[8.8.8]-hexacosane K F, i.e. crownether salt Kryptofix KF, KF, HF, KH F 2 , CsF, NaF and tetraalkylammonium salts of F, such as [ 18 F]tetrabutylammonium fluoride, and wherein F═ 18 F or  19 F. 
     
     
         17 . A method of synthesis of a compound as defined in  claim 1  wherein L is  18 F or  19 F, in which a compound according to  claim 1  where L is not F, is reacted with an F-fluorinating agent, wherein F═ 18 F or  19 F, comprising the steps:
 F-fluorinating a compound of formula V   
       
         
           
           
               
               
           
         
         with an F-fluorinating agent to yield a compound of formula IV, 
       
       
         
           
           
               
               
           
         
         substituting said compound of formula IV with a compound of formula VI 
       
       
         
           
           
               
               
           
         
         wherein F is  18 F or  19 F, 
         a is an integer from 0 to 4, preferably from 0 to 2, more preferably from 0 to 1, 
         B is a leaving group, preferably halo, in particular chloro, bromo, iodo, mesyloxy, tosyloxy, trifluormethylsulfonyloxy, nona-fluorobutylsulfonyloxy, (4-bromo-phenyl)sulfonyloxy, (4-nitro-phenyl)sulfonyloxy, (2-nitro-phenyl)sulfonyloxy, (4-isopropyl-phenyl)sulfonyloxy, (2,4,6-tri-isopropyl-phenyl)sulfonyloxy, (2,4,6-trimethyl-phenyl)sulfonyloxy, (4-tertbutyl-phenyl)sulfonyloxy, and (4-methoxy-phenyl)sulfonyloxy, 
         and wherein W 2  is W as defined in any of  claims 1 - 2 , 
         wherein A 2  is selected from the group comprising R 12 —O-aryl, R 12 -O-heteroaryl, aryl, heteroaryl, such as furanyl, (C 1 -C 10 )alkyl, (C 2 -C 4 )alkynyl, (C 1 -C 4 )alkoxy, ((C 1 -C 4 )alkoxy)aryl, ((C 1 -C 4 )alkyl)aryl, 
         wherein R 9  and R 10  are independently and individually, at each occurrence, selected from the group comprising (C 1 -C 6 )alkyl and hydrogen, 
         wherein R 11  is selected from the group comprising (C 1 -C 6 ) alkyl and R 12 , 
         wherein R 12  is hydrogen, 
         wherein d is an integer from 0 to 4, preferably from 0-2, more preferably from 0-1, and wherein said F-fluorinating agent is as defined in  claim 16 , 
         and wherein F═ 18 F or  19 F, 
         with the proviso that compounds of formula VI contain exactly one R 12 . 
       
     
     
         18 . The method according to  claim 17 , wherein B is selected from the group comprising iodo, bromo, chloro, mesyloxy, tosyloxy, trifluormethylsulfonyloxy, and nona-fluorobutylsulfonyloxy. 
     
     
         19 . The method according to  claim 17 , wherein A 2  is selected from the group comprising R 12 —O-phenyl, phenyl, furanyl, (C 1 -C 4 )alkyl, (C 3 -C 4 )alkynyl, (C 1 -C 3 ) alkoxy and substituted phenyl, more preferably from the group comprising R 12 —O-phenyl, phenyl, furanyl, ((C 1 -C 3 )alkoxy)phenyl, hydroxyphenyl, halo-phenyl, methoxy-phenyl, dimethoxy-phenyl, trifluormethyl-phenyl and ((C 1 -C 4 )alkyl)phenyl, even more preferably from the group comprising R 12 —O-phenyl, phenyl, furanyl, hydroxyphenyl, fluoro-phenyl, methoxy-phenyl, and methyl-phenyl. 
     
     
         20 . The method according to  claim 17 , wherein R 9  and R 10  are independently and individually, at each occurrence, selected from the group comprising (C 1 -C 4 )alkyl and hydrogen, preferably from the group comprising methyl and hydrogen. 
     
     
         21 . The method according to  claim 17 , wherein R 11  is selected from the group comprising (C 1 -C 4 )alkyl and R 12 , preferably from the group comprising methyl and R 12 . 
     
     
         22 . A composition comprising a compound according to  claim 1 , and a pharmaceutically acceptable carrier or diluent. 
     
     
         23 . The composition comprising a compound according to  claim 13  and a pharmaceutically acceptable carrier or diluent. 
     
     
         24 . The composition comprising a compound according to  claim 14  and a pharmaceutically acceptable carrier or diluent. 
     
     
         25 . The composition comprising a compound according to  claim 12  and a pharmaceutically acceptable carrier or diluent. 
     
     
         26 . A compound according to  claim 1 , for use as a pharmaceutical or diagnostic agent or imaging agent. 
     
     
         27 . A method of using a compound according to  claim 1 , for the manufacture of a medicament for the treatment and/or diagnosis and/or imaging of diseases of the central nervous system (CNS). 
     
     
         28 . A compound according to  claim 13  for use as a diagnostic agent or imaging agent, in particular for diseases of the central nervous system. 
     
     
         29 . A kit comprising a sealed vial containing a predetermined quantity of a compound according to
 a)  claim 12  or   b) formula V and VI,   
       
         
           
           
               
               
           
         
         wherein 
         a is an integer from 0 to 4, preferably from 0 to 2, more preferably from 0 to 1, 
         B is a leaving group, preferably halo, in particular chloro, bromo, iodo, mesyloxy, tosyloxy, trifluormethylsulfonyloxy, nona-fluorobutylsulfonyloxy, (4-bromo-phenyl)sulfonyloxy, (4-nitro-phenyl)sulfonyloxy, (2-nitro-phenyl)sulfonyloxy, (4-isopropyl-phenyl)sulfonyloxy, (2,4,6-tri-isopropyl-phenyl)sulfonyloxy, (2,4,6-trimethyl-phenyl)sulfonyloxy, (4-tertbutyl-phenyl)sulfonyloxy, and (4-methoxy-phenyl)sulfonyloxy, 
         W 2  is —C(U 1 )(U 2 )—C≡CH and cyclopropyl, U 1  and U 2  being independently selected from hydrogen and deuterium; 
         A 2  is selected from the group comprising R 12 —O-aryl, R 12 —O-heteroaryl, aryl, heteroaryl, such as furanyl, (C 1 -C 10 )alkyl, (C 2 -C 4 )alkynyl, (C 1 -C 4 )alkoxy, ((C 1 -C 4 )alkoxy)aryl, ((C 1 -C 4 )alkyl)aryl, R 9  and R 10  are independently and individually, at each occurrence, selected from the group comprising (C 1 -C 6 )alkyl and hydrogen, 
         R 11  is selected from the group comprising (C 1 -C 6 ) alkyl and R 12 , 
         R 12  is hydrogen, 
         d is an integer from 0 to 4, preferably from 0-2, more preferably from 0-1, 
         with the proviso that compounds of formula VI contain exactly one R 12 . 
       
     
     
         30 . A method for detecting the presence of monoamine oxidase in a patient's body, preferably for imaging a disease of the central nervous system in a patient, comprising:
 introducing into a patient's body a detectable amount of a compound according to  claim 13 ,   and detecting said compound or said composition by positron emission tomography (PET).   
     
     
         31 . A method of treatment of a disease of the central nervous system comprising the step of introducing into a patient a suitable quantity of a compound according to  claim 1 .