Radiolabeled PDE10 inhibitors

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Quick Facts

Patent No.: US 8,846,000
App. No.: 13/320,816
Granted: Sep 30, 2014
Kind: B2

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Abstract

The present invention is directed to radiolabeled pyrimidinone compounds of general structural formula I which are useful as radiotracers for quantitative imaging of PDE10 in mammals.

Claims (149)

1. A radiolabeled compound which is

2-{2-[3-(4-methoxyphenyl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl]ethyl}-1H-isoindole-1,3(2H)-dione,

2-[2-(3-biphenyl-3-yl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl]-1H-isoindole-1,3(2H)-dione,

2-{2-[7-chloro-3-(4-methylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-1H-isoindole-1,3(2H)-dione,

2-{2-[3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-4-methyl-1H-isoindole-1,3(2H)-dione,

2-{2-[3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-5-methyl-1H-isoindole-1,3(2H)-dione,

2-{2-[3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-1,3-dioxoisoindoline-4-carbonitrile,

4-methoxy-2-{2-[7-methoxy-3-(3-methylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-1H-isoindole-1,3(2H)-dione,

4-methoxy-2-{2-[3-(4-methoxyphenyl)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-1H-isoindole-1,3(2H)-dione,

tert-butyl 3-{2-[3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-1H-indole-1-carboxylate,

N-biphenyl-2-yl-N′-{2-[3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}urea,

4-isopropoxy-2-{2-[3-(4-methoxyphenyl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl]ethyl}-1H-isoindole-1,3(2H)-dione,

2-(2-{3-[4-(2-fluoroethoxy)phenyl]-4-oxo-3,4-dihydroquinazolin-2-yl}ethyl)-4-isopropoxy-1H-isoindole-1,3(2H)-dione,

2-{2-[3-(1H-indol-6-yl)-7-methoxy-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-4-isopropoxy-1H-isoindole-1,3(2H)-dione,

4-isopropoxy-2-{2-[7-methoxy-3-(3-methylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-1H-isoindole-1,3(2H)-dione,

2-{2-[3-(1H-indazol-6-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl]ethyl}-4-isopropoxy-1H-isoindole-1,3(2H)-dione,

2-{2-[3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-4-pyridin-4-yl-1H-isoindole-1,3(2H)-dione,

2-{[3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]methyl}-1H-isoindole-1,3(2H)-dione,

2-{3-[3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]propyl}-1H-isoindole-1,3(2H)-dione,

2-{3-[3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-4-(2,2,2-trifluoroethoxy)-1H-isoindole-1,3(2H)-dione,

4-(cyclopropylmethoxy)-2-{2-[3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-1H-isoindole-1,3(2H)-dione,

4-(cyclobutyloxy)-2-{2-[3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-1H-isoindole-1,3(2H)-dione,

2-{2-[3-(4-methoxyphenyl)-7-methyl-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl]ethyl}-4-(2,2,2-trifluoroethoxy)-1H-isoindole-1,3(2H)-dione

4-methoxy-2-{2-[3-(1-methyl-1H-indazol-6-yl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-1H-isoindole-1,3(2H)-dione,

2-{2-(3-(4-methoxyphenyl)-7-methyl-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl]ethyl}-4-(propan-2-yloxy)-1H-isoindole-1,3(2H)-dione

2-[2-(3-cyclohexyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl]-4-(propan-2-yloxy)-1H-isoindole-1,3(2H)-dione

2-{2-[3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-1H-isoindole-1,3(2H)-dione

4-hydroxy-2-{2-[3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-1H-isoindole-1,3(2H)-dione,

4-methoxy-2-{2-[3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-1H-isoindole-1,3(2H)-dione,

2-{2-[3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-4-(1,3-oxazol-2-yl)-1H-isoindole-1,3(2H)-dione,

2-(2-{3-[4-(benzyloxy)phenyl]-4-oxo-3,4-dihydroquinazolin-2-yl}ethyl)-4-isopropoxy-1H-isoindole-1,3(2H)-dione

2-{2-[3-(4-hydroxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-4-isopropoxy-1H-isoindole-1,3(2H)-dione

4-isopropoxy-2-{2-[3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-1H-isoindole-1,3(2H)-dione,

2-methoxy-N-{2-[3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-benzamide,

2-{2-[3-(1H-indazol-6-yl)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-4-(propan-2-yloxy)-1H-isoindole-1,3(2H)-dione,

2-{2-[7-methyl-3-(1-methyl-1H-indazol-6-yl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-4-(propan-2-yloxy)-1H-isoindole-1,3(2H)-dione,

or a pharmaceutically acceptable salts thereof wherein the radiolabeled compound is radiolabeled with 11 C or 18 F.

2. A compound which is 4-isopropoxy-2-{2-[3-(4- 11 C-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-1H-isoindole-1,3(2H)-dione or a pharmaceutically acceptable salt thereof.

3. A compound which is 2-{2-[7-methyl-3-(1- 11 C-methyl-1H-indazol-6-yl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-4-(propan-2-yloxy)-1H-isoindole-1,3(2H)dione, or a pharmaceutically acceptable salt thereof.

4. A method for quantitative imaging of PDE10 in a mammal which comprises administering to a human in need of such imaging an effective amount of a radiolabeled compound selected from: