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US 5,631,269 AGranted
Dopamine receptor subtype ligands
AssigneeMerck Sharp & Dohme Corp.
InventorsHoward B. Broughton, Ian J. Collins, Raymond Baker, Paul D. Leeson, Michael Rowley
Life of this patent
Estimating the term…
Abstract
Compounds of formula (I) ##STR1## wherein one of X and Y represents nitrogen, and the other of X and Y represents oxygen, sulphur or N--R.sup.2 ; Q represents a substituted five- or six- membered monocyclic heteroaliphatic ring which contains one nitrogen atom as the sole heteroatom and is linked to the five-membered heteroatomic ring containing the moieties X and Y via a carbon atom; as well as substituted 1,3-dioxopropane precursors thereto, are ligands for dopamine receptor subtypes within the body and are therefore useful in the treatment of disorders of the dopamine system, in particular schizophrenia.
Claims9
A compound of formula I, or a pharmaceutically acceptable salt thereof or a prodrug thereof:
- ##STR18## wherein the broken circle represents two non-adjacent double bonds to form a pyrazole, isoxazole or isothiazole ring;
- one of X and Y represents nitrogen, and the other of X and Y represents oxygen, sulphur or N--R.sup.2 ;
- Q represents a ring of formula Qa to Qe ##STR19## R.sup.1 represents hydrogen, halogen, C.sub.1-6 alkyl, hydroxy or C.sub.1-6 alkoxy;
- R.sup.2 represents hydrogen or C.sub.1-6 alkyl;
- A represents a group of formula (i), (ii) or (iii):
- ##STR20## in which Z represents oxygen, sulphur or NH;
- R.sup.3, R.sup.4 and R.sup.5 independently represent hydrogen, hydrocarbon, a heterocyclic group, halogen, cyano, trifluoromethyl, nitro, --OR.sup.a, --SR.sup.a, --SOR.sup.a, --SO.sub.2 R.sup.a, --SO.sub.2 NR.sup.a R.sup.b, --NR.sup.a R.sup.b, --NR.sup.a COR.sup.b, --NR.sup.a CO.sub.2 R.sup.b, --COR.sup.a, --CO.sub.2 R.sup.a or --CONR.sup.a R.sup.b ;
- R.sup.a and R.sup.b independently represent hydrogen, hydrocarbon or a heterocyclic group;
- R.sup.6 represents C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-7 cycloalkyl, C.sub.3-7 cycloalkyl(C.sub.1-6)alkyl, aryl, aryl(C.sub.1-6)alkyl, aryl(C.sub.2-6)alkenyl, aryl(C.sub.2-6)alkynyl, C.sub.3-7 heterocycloalkyl, C.sub.3-7 heterocycloalkyl(C.sub.1-6)alkyl, heteroaryl or heteroaryl(C.sub.1-6)alkyl, any of which groups may be optionally substituted;
- and
- R.sup.7 represents hydrogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-7 cycloalkyl, C.sub.3-7 cycloalkyl(C.sub.1-6)alkyl, aryl, aryl(C.sub.1-6)alkyl, aryl(C.sub.2-6)alkenyl, aryl(C.sub.2-6)alkynyl, C.sub.3 -7 heterocycloalkyl, C.sub.3-7 heterocycloalkyl(C.sub.1-6)alkyl, heteroaryl or heteroaryl(C.sub.1-6)alkyl, any of which groups may be optionally substituted.
8 more elements
A compound selected from:
- 3-[1-(4-chlorobenzyl)piperidin-4-yl]-5-(4-chlorophenyl)pyrazole;
- 3-(1-benzylpiperidin-4-yl)-5-(4-chlorophenyl)pyrazole;
- 5-(4-chlorophenyl)-3-[1-(4-methylbenzyl)piperidin-4-yl]pyrazole;
- 5-(4-chlorophenyl)-3-[1-(4-methoxybenzyl)piperidin-4-yl]pyrazole;
- 5-(4-chlorophenyl)-3-[1-(prop-2-en-1-yl)piperidin-4-yl]pyrazole;
- 5-(4-chlorophenyl)-3-[1-(4-nitrobenzyl)piperidin-4-yl]pyrazole;
- 3-[1-(4-chlorobenzyl)piperidin-4-yl]-5-phenylpyrazole;
- 3-[1-(4-chlorobenzyl)piperidin-4-yl]-5-(2-thienyl)-pyrazole;
- 3-[1-(4-chlorobenzyl)piperidin-4-yl]-5-(4-isopropylphenyl)pyrazole;
- 3-[1-(4-chlorobenzyl)piperidin-4-yl]-5-(4-methoxyphenyl)pyrazole;
- 5-(4-chlorophenyl)-3-(1-cyclohexylmethylpiperidin-4-yl)-pyrazole;
- 5-(4-chlorophenyl)-3-[1-(2-phenylethyl)piperidin-4-yl]-pyrazole;
- 5-(4-chlorophenyl)-3-[1-(3,4-dichlorobenzyl)piperidin-4-yl]pyrazole;
- 3-[1-(4-chlorobenzyl)piperidin-4-yl]-5-(3-chlorophenyl)pyrazole;
- 3-[1-(3-chlorobenzyl)piperidin-4-yl]-5-(4-chlorophenyl)pyrazole;
- 5-[1-(4-chlorobenzyl)piperidin-4-yl]-3-(4-chlorophenyl)-1-methylpyrazole;
- 3-[l-(4-chlorobenzyl)piperidin-4-yl]-5-(4-chlorophenyl)-1-methylpyrazole;
- 3-[1-(4-chlorobenzyl)piperidin-4-yl]-5-(2-chlorophenyl)pyrazole;
- 3-(1-benzylpiperidin-4-yl)-5-phenylpyrazole;
- 3-[1-(4-chlorobenzyl)piperidin-4-yl]-5-(4-chlorophenyl)isoxazole;
- 5-[1-(4-chlorobenzyl)piperidin-4-yl]-3-(4-chlorophenyl)isoxazole;
- 3-[1-(4-chlorobenzyl)piperidin-4-yl]-5-(2-methoxyphenyl)pyrazole;
- 5-(4-chlorophenyl)-3-[1-(2-methylbenzyl)piperidin-4-yl]-pyrazole;
- 5-(4-chlorophenyl)-3-[1-(3-nitrobenzyl)piperidin-4-yl]-pyrazole;
- 5-(4-chlorophenyl)-3-[1-(3-methylbenzyl)piperidin-4-yl]-pyrazole;
- 5-(4-chlorophenyl)-3-[1-(2-nitrobenzyl)piperidin-4-yl]-pyrazole;
- 3-[1-(4-chlorobenzyl)piperidin-4-yl]-4-methyl-5-phenylpyrazole;
- 3-[1-(2-chlorobenzyl)piperidin-4-yl]-5-(4-chlorophenyl)pyrazole;
- 5-(4-chlorophenyl)-3-(1-cyclopropylmethylpiperidin-4-yl)pyrazole;
- 3-(1-benzylpiperidin-4-yl)-5-(4-chlorophenyl)-4-methylpyrazole;
- 5-(4-chlorophenyl)-3-[1-(2-naphthylmethyl)piperidin-4-yl]pyrazole;
- 5-(4-chlorophenyl)-3-[1-(3-phenylpropyl)piperidin-4-yl]pyrazole;
- 5-(4-chlorophenyl)-3-[1-(3-methoxybenzyl)piperidin-4-yl]pyrazole;
- 3-[1-(2-phenylethyl)piperidin-4-yl]-5-(2-pyridyl)pyrazole;
- 3-(1-benzyl-4-methylpiperidin-4-yl)-5-(4-chlorophenyl)pyrazole;
- 5-(4-chlorophenyl)-3-[1-(indol-3-ylmethyl)piperidin-4-yl]pyrazole;
- 5-(4-chlorophenyl)-4-methyl-3-[1-(2-phenylethyl)piperidin-4-yl]pyrazole;
- 3-(1-benzylpiperidin-3-yl)-5-(4-chlorophenyl)pyrazole;
- 3-(1-benzylpiperidin-4-yl)-5-(2-thienyl)isoxazole;
- 5-(1-benzylpiperidin-4-yl)-3-(2-thienyl)isoxazole;
- 5-(4-chlorophenyl)-3-[1-(2-phenylethyl)piperidin-4-yl]isoxazole;
- 3-(1-benzylpiperidin-4-yl)-5-(4-chlorophenyl)isoxazole;
- 3-(4-chlorophenyl)-4-methyl-5-[1-(2-phenylethyl)piperidin-4-yl]isoxazole;
- 5-(4-chlorophenyl)-4-methyl-3-[1-(2-phenylethyl)piperidin-4-yl]isoxazole;
- 3-(1-benzylpiperidin-4-yl)-5-(4-chlorophenyl)-4-ethylpyrazole;
- 5-(1-benzylpiperidin-4-yl)-3-(4-chlorophenyl)-1,4-dimethylpyrazole;
- 3-(1-benzylpiperidin-4-yl)-5-(4-chlorophenyl)-1,4-dimethylpyrazole;
- 4-methoxy-5-phenyl-3-[1-(2-phenylethyl)piperidin-4-yl]pyrazole;
- 5-(4-chlorophenyl)-3-[1-(3-E-phenylprop-2-en-1-yl)piperidin-4-yl]pyrazole;
- 5-(4-chlorophenyl)-3-[1-(1-naphthylmethyl)piperidin-4-yl]pyrazole;
- 3-[1-(2-furylmethyl)piperidin-4-yl]-4-methyl-5-phenylpyrazole;
- 3-[1-(2-(4-methoxyphenyl)ethyl)piperidin-4-yl]-4-methyl-5-phenylpyrazole;
- 4-methyl-3-[1-(2-oxo-2-phenylethyl)piperidin-4-yl]-5-phenylpyrazole;
- 4-methyl-5-phenyl-3-[1-(2-(3-pyridyl)ethyl)piperidin-4-yl]pyrazole;
- 5-(4-chlorophenyl)-3-[1-(1,2,3,4-tetrahydronaphth-2-yl)piperidin-4-yl]pyraz ole;
- 4-chloro-5-(4-chlorophenyl)-3-[1-(2-phenylethyl)piperidin-4-yl]pyrazole;
- or a pharmaceutically acceptable salt or a prodrug thereof.
54 more elements
Dependencies are inferred from the claim text.