COMPOUNDS FOR USE IN IMAGING, DIAGNOSING AND/OR TREATMENT OF DISEASES OF THE CENTRAL NERVOUS SYSTEM OR OF TUMORS
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 .