Fluorinated phenyl thiophenyl derivatives and their use for imaging serotonin transporters
View Patent ↗This invention relates to novel fluorinated phenyl thiphenyl (also named diarylsulfide) derivatives and their use in Positron Emission Tomagraphy (PET) imaging of Serotonin Transporters (SERTS). The present invention also provides diagnostic compositions comprising the novel compounds of the present invention, and a pharmaceutically acceptable carrier or diluent. The invention further provides a method of imaging SERTS, comprising introducing into a patient a detectable quantity of a labeled compound of the present invetion, or a pharmaceutically acceptable salt, ester, amide or prodrug thereof.
1. A compound of Formula I
or a pharmaceutically acceptable salt thereof, wherein,
R 1 is selected from the group consisting of hydroxy(C 1-4 )alkyl, halo(C 1-4 )alkyl, nitro, azido, halo or —NR 6 R 7 wherein,
R 6 and R 7 are each independently selected from the group consisting of hydrogen, C 1-4 alkyl, halo(C 1-4 )alkyl, halo(C 1-4 )alkanoyl and halobenzoyl,
R 2 is —NR 8 R 9 wherein,
R 8 and R 9 are each independently selected from the group consisting of hydrogen, C 1-4 alkyl, halo(C 1-4 )alkyl, halo(C 1-4 )alkanoyl and halobenzoyl,
R 3 is independently selected from the group consisting of hydrogen, halo, cyano, C 1-4 alkyl, halo(C 1-4 )alkanoyl and (C 1-4 )alkoxy,
R 4 and R 5 are each independently selected from the group consisting of hydrogen, halo, cyano, C 1-4 alkyl, halo(C 1-4 )alkanoyl and (C 1-4 )alkoxy, and
X is hydrogen or halo,
provided that:
one of R 1 , R 2 , R 3 , R 4 , R 5 or X contains 18 F, and
if R 1 is —NR 6 R 7 wherein R 6 and R 7 are both hydrogen, and
R 2 is —NR 8 R 9 wherein R 8 and R 9 are both methyl,
then
R 3 is hydrogen, halo, cyano, C 1-4 alkyl, or (C 1-4 )alkoxy, and
if R 1 is fluoromethyl,
then
R 3 and X are other than 4-iodine.
2. The compound of claim 1 , wherein
R 1 is hydroxy(C 1-4 )alkyl,
one of R 8 and R 9 is C 1-4 alkyl the other of R 8 and R 9 is C 1-4 alkyl, halo(C 1-4 )alkyl, halo(C 1-4 )alkanoyl or halobenzoyl, and
X is hydrogen or halo.
3. The compound of claim 2 , wherein
R 1 is hydroxymethyl,
one of R 8 and R 9 is methyl, the other of R 8 and R 9 is halo(C 1-4 )alkyl,
R 3 , R 4 and R 5 are hydrogen, and
X is halo.
4. The compound of claim 1 , wherein
R 1 is halo,
R 8 and R 9 are C 1-4 alkyl,
R 3 , R 4 and R 5 are each hydrogen,
X is halo.
5. The compound of claim 1 , wherein
R 1 is —NR 6 R 7 ,
R 6 and R 7 are independently selected from the group consisting of hydrogen, C 1-4 alkyl, halo(C 1-4 )alkyl, halo(C 1-4 )alkanoyl or halobenzoyl,
R 8 and R 9 are C 1-4 alkyl,
R 3 , R 4 and R 5 are each independently selected from the group consisting of hydrogen, halo and cyano, and
X is hydrogen or halo,
provided that:
if R 6 and R 7 are each hydrogen,
then
R 3 and X are both hydrogen,
or
R 3 is cyano, chloro, bromo or iodo, and
X is hydrogen or fluorine.
6. The compound of claim 5 , wherein
R 1 is —NR 6 R 7 wherein,
R 6 and R 7 are independently selected from the group consisting of hydrogen, halo(C 1-4 )alkyl, halo(C 1-4 )alkanoyl or halobenzoyl,
R 8 and R 9 are each methyl,
R 3 is halo,
R 4 and R 5 are hydrogen, and
X is hydrogen.
7. The compound of claim 6 wherein,
R 6 and R 7 are independently selected from the group consisting of halo(C 1-4 )alkyl,
halo(C 1-4 )alkanoyl or halobenzoyl.
8. The compound of claim 5 wherein,
R 6 and R 7 are hydrogen,
R 8 and R 9 are methyl,
R 4 and R 5 are each hydrogen,
R 3 is cyano, and
X is fluorine.
9. The compound of claim 5 wherein,
R 3 and X are each hydrogen,
R 6 and R 7 are hydrogen,
R 8 and R 9 are methyl,
R 4 is cyano, and
R 5 is 18 F.
10. The compound of claim 5 wherein,
R 6 and R 7 are hydrogen,
R 8 and R 9 are methyl,
R 4 and R 5 are each hydrogen,
R 3 is halo, and
X is fluorine.
11. The compound of claim 10 wherein,
R 3 is 4-chloro, and
X is 5- 18 F.
12. The compound of claim 1 , wherein
R 1 is hydroxy(C 1-4 )alkyl,
R 8 and R 9 are each C 1-4 alkyl, and
R 3 is hydrogen or C 1-4 alkyl.
13. The compound of claim 12 wherein,
R 4 and R 5 are each hydrogen.
14. The compound of claim 1 , wherein
R 1 is —NH 2 ,
one of R 8 and R 9 is hydrogen or C 1-4 alkyl, the other of R 8 and R 9 is C 1-4 alkyl, or halo(C 1-4 )alkyl,
R 3 is hydrogen or cyano,
R 4 and R 5 are hydrogen, and
X is hydrogen or halo,
provided that,
if R 8 and R 9 are each C 1-4 alkyl,
then
R 3 is other than cyano.
15. The compound of claim 14 wherein,
one of R 8 and R 9 is C 1-4 alkyl, the other of R 8 and R 9 is C 1-4 alkyl or halo(C 1-4 )alkyl.
16. The compound of claim 15 wherein,
one of R 8 and R 9 is C 1-4 alkyl, the other of R 8 and R 9 is halomethyl,
R 3 is hydrogen, C 1-4 alkyl, or cyano,
R 4 and R 5 are each hydrogen, and
X is halo.
17. The compound of claim 16 , wherein
R 8 is methyl, and
R 9 is fluoromethyl.
18. The compound of claim 15 , wherein
R 8 and R 9 are methyl,
R 4 and R 5 are each hydrogen,
R 3 is hydrogen, and
X is 4- 18 F.
19. A pharmaceutical composition comprising a compound of claim 1 , and
a pharmaceutically acceptable excipient or diluent.
20. A diagnostic composition for imaging serotonin transporters, comprising a compound of claim 1 , and
a pharmaceutically acceptable excipient or diluent.
21. A method of imaging serotonin transporters in a mammal, comprising:
a. introducing into a mammal a detectable quantity of a diagnostic composition of claim 20 ;
b. allowing sufficient time for the labeled compound to be associated with serotonin transporter; and
c. detecting the labeled compound associated with one or more serotonin transporters.