DAA-PYRIDINE AS PERIPHERAL BENZODIAZEPINE RECEPTOR LIGAND FOR DIAGNOSTIC IMAGING AND PHARMACEUTICAL TREATMENT
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 therapy and diagnostic imaging by positron emission tomography (PET).
1 . A compound of formula I
wherein
R 1 and R 2 are independently and individually, at each occurrence, selected from the group consisting of (G 3 )aryl, substituted (G 3 )aryl, (G 3 -(C 1 -C 8 )alkyl)aryl, (G 3 -(C 1 -C 8 )alkoxy)aryl, (G 3 -(C 2 -C 8 )alkynyl)aryl, (G 3 -(C 2 -C 8 )alkenyl)aryl, substituted (G 3 -(C 1 -C 8 )alkyl)aryl, substituted (G 3 -(C 1 -C 8 )alkoxy)aryl, substituted (G 3 -(C 2 -C 8 )alkynyl)aryl and substituted (G 3 -(C 2 -C 8 )alkenyl)aryl;
G 1 , G 2 and G 3 are independently and individually, at each occurrence, selected from the group consisting of hydrogen and L,
with the proviso that compounds of formula I contain exactly one L;
L is selected from the group consisting of R 3 , [ 18 F]fluoro and [ 19 F]fluoro;
R 3 is a leaving group;
wherein n is an integer from 0 to 6;
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 R 3 is selected from the group consisting of —I + (aryl)(X − ), —I + (heteroaryl)(X − ), nitro, —N + (Me) 3 (X − ), halo, in particular chloro, bromo and iodo, mesyloxy, tosyloxy, trifluoromethylsulfonyloxy, 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.
3 . The compound according to claim 2 , wherein X − is selected from the group consisting of anion of an inorganic acid and anion of an organic acid.
4 . The compound according to any of claims 3 , wherein X − is selected from the group consisting of CF 3 S(O) 2 O − , C 4 F 9 S(O) 2 O − , CF 3 COO − , H 3 CCOO − , iodide anion, bromide anion, chloride anion, perchlorate anion (ClO 4 − ), and phosphate anion.
5 . A compound according to claim 1 which is selected from the group of compounds consisting of
6 . A compound of claim 1 the formula
7 . A compound of claim 1 of the formula
8 . The compound according to claim 1 , wherein L is [ 18 F]fluoro or [ 19 F]fluoro.
9 . The compound according to claim 1 wherein the mesyloxy-group and the tosyloxy-group is replaced by [ 18 F]fluoro or [ 19 F]fluoro.
10 . A method of synthesis of a compound as defined in claim 8 , in which a compound is reacted with an F-fluorinating agent, wherein F= 18 F or 19 F.
11 . The method according to claim 10 , wherein said F-fluorinating agent is a compound consisting of F-anions, preferably a compound selected from the group consisting of 4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]-hexacosane K F, i.e. crownether salt Kryptofix KF, KF, HF, KHF 2 , CsF, NaF and tetraalkylammonium salts of F, such as N(butyl) 4 F (tetrabutylammonium fluoride), and wherein F= 18 F or 19 F.
12 . A compound of formula VI
wherein
R 10 is selected from the group consisting of (C 1 -C 6 )alkyl and hydrogen;
R 16 is selected from the group consisting of hydrogen, halo, trifluoromethyl, (C 1 -C 5 )alkyl, (C 2 -C 5 )alkynyl), (C 2 -C 5 )alkenyl and (C 1 -C 5 )alkoxy;
A 3 and A 4 are the same or different and of the structure (R 12 )(R 4 )(R 5 )phenyl;
R 12 is selected from the group consisting of R 13 and hydrogen;
R 13 is hydroxy,
with the proviso that compounds of formula VI contain exactly one R 13 ;
R 4 and R 5 are independently and individually, at each occurrence, selected from the group consisting of hydrogen, halo, trifluoromethyl, (C 1 -C 5 )alkyl, (C 2 -C 5 )alkynyl), (C 2 -C 5 )alkenyl and (C 1 -C 5 )alkoxy;
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.
13 . A method of synthesis of a compound as defined in claim 10 consisting of 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 in Formula IV is [ 18 F]fluoro or [ 19 F]fluoro,
a is an integer from 0 to 5,
B is a leaving group,
R 10 is selected from the group consisting of (C 1 -C 6 )alkyl and hydrogen;
R 16 is selected from the group consisting of hydrogen, halo, trifluoromethyl, (C 1 -C 5 )alkyl, (C 2 -C 5 )alkynyl), (C 2 -C 5 )alkenyl and (C 1 -C 5 )alkoxy;
A 3 and A 4 are the same or different and of the structure R 12 )(R 4 )(R 5 )phenyl;
R 12 is selected from the group consisting of R 13 and hydrogen;
R 13 is hydroxy,
with the proviso that compounds of formula VI contain exactly one R 13 ;
R 4 and R 5 are independently and individually, at each occurrence, selected from the group consisting of hydrogen, halo, trifluoromethyl, (C 1 -C 5 )alkyl, (C 2 -C 5 )alkynyl), (C 2 -C 5 )alkenyl and (C 1 -C 5 )alkoxy;
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
and
wherein F= 18 F or 19 F,
with the proviso that compounds of formula VI contain exactly one R 12 , that is hydroxyl.
14 . The method according to claim 13 , wherein B is selected from the group consisting of iodo, bromo, chloro, mesyloxy, tosyloxy, trifluoromethylsulfonyloxy, and nona-fluorobutylsulfonyloxy.
15 . A composition consisting of a compound according to claim 1 and a pharmaceutically acceptable carrier or diluent.
16 . A compound according claim 1 as a pharmaceutical or diagnostic agent or imaging agent.
17 . A compound according to claim 8 for use as a diagnostic agent or imaging agent, in particular for diseases of the central nervous system.
18 . A kit consisting of a sealed vial containing a predetermined quantity of a compound according to claim 1 .
19 . A method for detecting the presence of peripheral benzodiazepine receptor (translocator protein) in a patient's body, consisting of:
introducing into a patient's body a detectable amount of a compound according to claim 8 .
20 . A compound selected from the group consisting of compounds having the following structures
21 . A compound of claim 20 having the structure
22 . A compound of claim 20 having the structure
23 . A pharmaceutical or diagnostic composition comprising a compound as defined by claim 20 .
24 . A kit, containing a sealed vial comprising a compound as defined by claim 20 .
25 . A kit consisting of a sealed vial containing a predetermined quantity of a compound according to claim 5 .
26 . A kit consisting of a sealed vial containing a predetermined quantity of a compound according to claim 12 .