Radiolabeled PDE10A ligands
View Patent ↗Compounds of formula (I) are disclosed Compounds of formula (I) are useful in treating conditions and disorders prevented by or ameliorated by PDE10A ligands. Radiolabeled compounds of formula (I) are also useful as diagnostic tools as PDE10A positron emission tomography ligands. Also disclosed are pharmaceutical compositions comprising compound of formula (I), methods for using such compounds and compositions, and a process for preparing compounds within the scope of formula (I).
1. A radiolabeled compound of formula (I),
or a pharmaceutically acceptable salt thereof, wherein
R is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and C 3 -C 8 cycloalkyl;
HetAr is a heteroaryl group selected from the group consisting of
Z 1 and Z 8 are each CR 2 ;
Z 13 is O; and
R 1 and R 2 are each independently selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, and C 3 -C 8 cycloalkyl;
wherein each of the carbon atoms of each alkyl group is substituted with hydrogen or with 0, 1, or 2 substituents selected from acyl, acyloxy, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxyimino, alkoxysulfonyl, alkylcarbonyl, alkylsulfonyl, amido, carboxy, cyano, cycloalkyl, fluoroalkoxy, formyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, nitro, oxo, alkylthio, —NR A R B , (NR A R B )carbonyl, (NR A R B )sulfonyl, —OS(O) 2 -alkyl, and —OS(O) 2 — aryl; wherein R A and R B are independently selected from hydrogen, alkyl, acyl, cycloalkyl, and formyl;
wherein each of the carbon atoms of each cycloalkyl group is substituted with 0, 1, or 2 substituents selected from acyl, acyloxy, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxyimino, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylsulfonyl, alkynyl, amido, carboxy, cyano, cycloalkyl, fluoroalkoxy, formyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, nitro, alkylthio, —NR A R B , (NR A R B )carbonyl, —SO 2 N(R 14a )(R 14b ), and N(R 14a )SO 2 (R 14b ); wherein R A and R B are independently selected from hydrogen, alkyl, acyl, cycloalkyl, and formyl; and wherein R 14a and R 14b are each independently hydrogen, alkyl, or cycloalkyl.
2. The compound of claim 1 , wherein R comprises a radiolabel.
3. The compound of claim 1 , wherein HetAr comprises a radiolabel.
4. The compound of claim 1 , wherein HetAr is
5. The compound of claim 4 , wherein R is C 1 -C 6 alkyl.
6. The compound of claim 5 , selected from the group consisting of:
2-((4-(1-[ 11 C]methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)-1,5-naphthyridine; and
2-((4-(1-(2-[ 18 F]fluoroethyl)-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)-1,5-naphthyridine.
7. The compound of claim 1 , wherein HetAr is
8. The compound of claim 7 , wherein
Z 1 is CH;
R 1 is C 1 -C 6 alkyl; and
R is C 1 -C 6 alkyl.
9. The compound of claim 7 , selected from the group consisting of:
3-methyl-2-((4-(1-[ 11 C]methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)quinazolin-4(3H)-one;
2-((4-(1-(2-[ 18 F]fluoroethyl)-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)-3-methylquinazolin-4(3H)-one;
3-[ 11 C]methyl-2-((4-(1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)quinazolin-4(3H)-one; and
3-(2-[ 18 F]fluoroethyl)-2-((4-(1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)quinazolin-4(3H)-one.
10. The compound of claim 1 , wherein HetAr is
11. The compound of claim 10 , wherein
Z 8 is CH;
and
R is C 1 -C 6 alkyl.
12. The compound of claim 10 , selected from the group consisting of:
2-((4-(1-[ 11 C]methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)benzo[d]oxazole; and
2-((4-(1-(2-[ 18 F]fluoroethyl)-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)benzo[d]oxazole.
13. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) according to claim 1 , or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier.
14. A method for imaging PDE10A in a mammal comprising administering to a subject an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
15. The method of claim 14 , wherein the compound is selected from the group consisting of:
2-((4-(1-[ 11 C]methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)-1,5-naphthyridine;
2-((4-(1-(2-[ 18 F]fluoroethyl)-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)-1,5-naphthyridine;
3-methyl-2-((4-(1-[ 11 C]methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)quinazolin-4(3H)-one;
2-((4-(1-(2-[ 18 F]fluoroethyl)-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)-3-methylquinazolin-4(3H)-one;
3-[ 11 C]methyl-2-((4-(1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)quinazolin-4(3H)-one;
3-(2-[ 18 F]fluoroethyl)-2-((4-(1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)quinazolin-4(3H)-one;
2-((4-(1-[ 11 C]methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)benzo[d]oxazole; and
2-((4-(1-(2-[ 18 F]fluoroethyl)-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)benzo[d]oxazole.
16. The method of claim 15 , wherein the compound is selected from the group consisting of:
2-((4-(1-[ 11 C]methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)-1,5-naphthyridine;
2-((4-(1-(2-[ 18 F]fluoroethyl)-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)-1,5-naphthyridine; and
2-((4-(1-(2-[ 18 F]fluoroethyl)-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)benzo[d]oxazole.
17. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
2-((4-(1-[ 11 C]methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)-1,5-naphthyridine;
2-((4-(1-(2-[ 18 F]fluoroethyl)-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)-1,5-naphthyridine;
3-methyl-2-((4-(1-[ 11 C]methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)quinazolin-4(3H)-one;
2-((4-(1-(2-[ 18 F]fluoroethyl)-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)-3-methylquinazolin-4(3H)-one;
3-[ 11 C]methyl-2-((4-(1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)quinazolin-4(3H)-one;
3-(2-[ 18 F]fluoroethyl)-2-((4-(1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)quinazolin-4(3H)-one;
2-((4-(1-[ 11 C]methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)benzo[d]oxazole; and
2-((4-(1-(2-[ 18 F]fluoroethyl)-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)benzo[d]oxazole.