Phenylindole derivatives as 5-ht2a receptor ligands
First Claim
Patent Images
1. A compound of formula I, or a salt thereof:
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whereinA and B independently represent hydrogen, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, C1-6 alkyl or C1-6 alkoxy;
X and Y independently represent hydrogen, halogen, trifluoromethyl, trifluoromethoxy, C1-6 alkyl, C1-6 alkoxy or phenyl; and
Q is selected from the structures of formula Qa to Qm;
in which the asterisk denotes the point of attachment to the remainder of the molecule;
Z represents oxygen, sulphur or N—
R1;
R1 and R2 independently represent hydrogen, or C1-6 alkyl, aryl(C1-6)alkyl or C3-7 heterocycloalkyl(C1-6)alkyl, any of which groups may be optionally substituted by one or more substituents; and
R3 represents hydrogen, halogen, C1-6 alkyl, hydroxy or C1-6 alkoxy;
provided that at least one of R1, R2 and R3 is other than hydrogen.
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Abstract
Compounds according to Formula (I) or a salt thereof are selective antagonists of the human 5-HT2A receptor useful for treatment of adverse conditions of the central nervous system:
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Citations
8 Claims
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1. A compound of formula I, or a salt thereof:
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wherein A and B independently represent hydrogen, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, C1-6 alkyl or C1-6 alkoxy;
X and Y independently represent hydrogen, halogen, trifluoromethyl, trifluoromethoxy, C1-6 alkyl, C1-6 alkoxy or phenyl; and
Q is selected from the structures of formula Qa to Qm;
in which the asterisk denotes the point of attachment to the remainder of the molecule;
Z represents oxygen, sulphur or N—
R1;
R1 and R2 independently represent hydrogen, or C1-6 alkyl, aryl(C1-6)alkyl or C3-7 heterocycloalkyl(C1-6)alkyl, any of which groups may be optionally substituted by one or more substituents; and
R3 represents hydrogen, halogen, C1-6 alkyl, hydroxy or C1-6 alkoxy;
provided that at least one of R1, R2 and R3 is other than hydrogen.- View Dependent Claims (2, 3, 5, 6, 7, 8)
wherein Z1 represents oxygen, N—
R1 or CH—
R3.
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5. A process for the preparation of a compound as claimed in claim 1, which comprises:
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(A) attachment of the requisite substituent to a precursor compound of formula III;
wherein A, B, X and Y are as defined in claim 1, and Q1 corresponds to a moiety of formula Q as defined in claim 1 in which R1 and R2 independently represent hydrogen;
or(B) reducing a compound of formula V;
wherein A, B, X, Y and Q are as defined in claim 1;
or(C) reducing a compound of formula VI;
wherein A, B, X and Y are as defined in claim 1, and Q2 corresponds to a moiety of formula Q as defined in claim 1 in which R1 and R2 independently represent a benzyloxycarbonyl group;
or(D) reacting a compound of formula X or an acid adition salt thereof with a compound of formula XI;
wherein A, B, X, Y and Q are as defined in claim 1; and
(E) subsequently, where required, converting a compound of formula I initially obtained into a further compound of formula I by conventional methods.
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6. A pharmaceutical composition comprising a compound of formula I as defined in claim 1 or a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable carrier.
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7. A composition as claimed in claim 6 further comprising another anti-schizophrenic medicament.
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8. A method for the treatment of a psychotic disorder which comprises administering to a patient in need of such treatment an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.
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4. A compound selected from:
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3-(1-methylpiperidin-3-ylmethyl)-2-phenyl-1H-indole;
3-(1-methylpyrrolidin-3-ylmethyl)-2-phenyl-1H-indole;
3-(1-methylpyrrolidin-2(R)-ylmethyl)-2-phenyl-1H-indole;
3-(1-methylpyrrolidin-2(S)-ylmethyl)-2-phenyl-1H-indole;
2-methyl-3-(2-phenyl-1H-indol-3-ylmethyl)-2-azabicyclo [2.2.2]octane;
3-(2-methyl-2-azabicyclo[2.2.1]hept-3-ylmethyl)-2-phenyl-1H-indole;
3-(1,5-dimethyl-cis-pyrrolidin-2-ylmethyl)-2-phenyl-1H-indole;
3-(1,4-dimethylpiperazin-2(S)-ylmethyl)-2-phenyl-1H-indole;
7-chloro-3-(1,4-dimethylpiperazin-2(S)-ylmethyl)-2-phenyl-1H-indole;
3-(4-methylmorpholin-3-ylmethyl)-2-phenyl-1H-indole;
3-[1-(2-phenylethyl)piperidin-3-ylmethyl]-2-phenyl-1H-indole;
3-(1-benzylpyrrolidin-2-ylmethyl)-2-phenyl-1H-indole;
3-[1-(2-phenylethyl)pyrrolidin-2-ylmethyl]-2-phenyl-1H-indole;
2-phenyl-3-[1-(3-phenylpropyl)pyrrolidin-2(R)-ylmethyl]-1H-indole;
3-(1-benzylpyrrolidin-3-ylmethyl)-2-phenyl-1H-indole;
3-[1-(2-phenylethyl)pyrrolidin-3-ylmethyl]-2-phenyl-1H-indole;
3-(1-methylpiperidin-2(R)-ylmethyl)-2-phenyl-1H-indole;
3-(1-methylpiperidin-2(S)-ylmethyl)-2-phenyl-1H-indole;
3-(1-methylazepin-2(R)-ylmethyl)-2-phenyl-1H-indole;
3-(1-methylazepin-2(S)-ylmethyl)-2-phenyl-1H-indole;
3-(1-ethylpiperidin-2-ylmethyl)-2-phenyl-1H-indole;
3-[1-(2-methoxyethyl)piperidin-2-ylmethyl]-2-phenyl-1H-indole;
3-(1-benzylpiperidin-2-ylmethyl)-2-phenyl-1H-indole;
3-[1-(2-phenylethyl)piperidin-2-ylmethyl]-2-phenyl-1H-indole;
2-(3-fluorophenyl)-6-fluoro-3-(4-methylpiperazin-2(S)-ylmethyl)-1H-indole;
2-(3-fluorophenyl)-6-fluoro-3-(1-methylpiperazin-2(S)-ylmethyl)-1H-indole; and
salts thereof.
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Specification