4-SUBSTIUTED PIPERODINE ANALOGS AND THEIR USE AS SUBTYPE SELECTIVE NMDA RECEPTOR ANTAGONISTS

摘要

1. A compound represented by the formula (I) or a pharmaceutically acceptable salt thereof wherein Ar<1> and Ar<2> are independently phenyl, naphthyl, piperidinyl, quinolinyl, quinoxalinyl, benzamidazolyl, benzoxazolyl, indolyl, thiophenyl group, either of which may be independently substituted by one or two groups, selected from C1-C6 alkyl, hydroxy, halogen, nitro, cyano, carboxaldehyde, C1-C6 alkoxy carbonylmethyl, hydroxy C1-C6 alkyl, amino, a C1-C6 alkyl amino group, di- C1-C6 alkyl amino, z is a single or double bond; X is -(CHR<3>)m-, O, S or NR<4>, wherein each R<3> is independently hydrogen, hydroxy or an alkyl group having 1 to 6 carbon atoms, R<4> is hydrogen or an alkyl group having 1 to 6 carbon atoms and m is 0, 1 or 2, provided that when z is a double bond then X is not O or NR<4>; R<1> is independently hydrogen or hydroxy; each R<2> is independently hydrogen, hydroxy or a C1-C6 alkyl group having 1 to 6 carbon atoms; n is 0, 1, 2, 3 or 4; Y is O, S, NR<4> or a single bond; and R<5> is hydrogen or hydroxy when z is a single bond, provided that: (i) R<2> cannot be hydroxy in an α position to Ar<2>; (ii) if X is a single bond, z is a double bond or R<5> is hydroxy and Ar<2> is phenyl then Y cannot be O; (iii) if Y is O, n is 3 or 4, R<2> is exclusively hydrogen, z is a single bond, R<1> and R<5> are hydrogen and Ar<2> is phenyl, or halogen, methoxy or trifluoromethyl substituted phenyl then X cannot be methylene or ethylene; (iv) if X is - -(CHR<3>)m-, m is 2 and R<3> is exclusively hydrogen then Ar<1> cannot be imidazolyl substituted; (v) if Y is O, n is 2, 3 or 4, R<2> is hydrogen or hydroxy, z is a single bond, R<1> and R<5> are hydrogen and Ar<2> is phenyl, or NO2, CN, 1-imidazoyl, or 1,2,4-triazol-1-yl substituted phenyl then X cannot be methylene, hydroxymethylene, or O; (vi) if Y is O or S, R<1> and R<5> are hydrogen and R<2> is hydroxy then X is not methylene or a single bond; or (vii) if Y is a single bond, R<2> is exclusively hydrogen and Ar<2> is phenyl then either R<1> or R<5> must be hydroxy 2. A compound according to claim 1, wherein Y is O or a single bond. 3. A compound according to claim 2, wherein Ar<2> is phenyl, naphthyl, piperidinyl, quinolinyl, quinoxalinyl, benzamidazolyl, benzoxazolyl, indolyl, thiophenyl group. 4. A compound according to claim 2, wherein R<1> or R<5> is hydroxy 5. A compound according to claim 1, said compound selected from the group consisting of: 4-Phenoxy-1-[(4-fluorophenoxy)propyl]piperidine; 1-(3-Phenoxypropyl)-4-phenylpiperidine; 1-(2-Phenoxyethyl)-4-phenylpiperidine; 1-(4-Phenoxybutyl)-4-phenylpiperidine; 1-(4-(3-(Trifluoromethyl)phenoxy)butyl)-4phenylpiperidine; 1-(2-(4-Aminophenoxy)ethyl)-4-benzylpiperidine; 3-((2-(4-Benzylpiperidin-1-yl)ethyl)oxy) - benzaldehyde; 3-((2-(4-Benzylpiperidin-1-yl)ethyl)oxy)benzaldehyde, oxime; 4-Benzyl-1-(2-(3-(ethoxycarbonylmethyl) phenoxy) ethyl) piperidine; 4-Benzyl-1-(2-(3-(2-hydroxyethyl)phenoxy) ethyl)piperidine; 1-(2-(3-(Aminocarbonylmethyl)phenoxy)ethyl)-4benzylpiperidine; 4-Benzyl-1-(2-(3-(hydrazinocarbonylmethyl)phenoxy)ethyl)piperidine; 4-Benzyl-1-(1-methyl-2-phenoxyethyl)piperidine; 4-(4-Chlorobenzyl)-1-(2-(4-fluorophenoxy)ethyl)piperidine; 4-(4-Chlorobenzyl)-1-(2-(4-chlorophenoxyethyl)piperidine; 1-(2-(4-Aminophenoxy)ethyl)-4-(4-chlorobenzyl)piperidine; 4-(4-Chlorobenzyl)-1-(2-(3-(2-hydroxyethyl)phenoxy)-ethyl)piperidine; 4-(4-Fluorobenzyl)-1-(2-(4-fluorophenoxy)ethyl)piperidine; 4-(4-Fluorobenzyl)-1-(2-(4-chlorophenoxy)ethyl)piperidine; 1-(2-(4-Fluorophenoxy)ethyl)-4-(4-methoxybenzyl) piperidine; 1-(2-(4-Fluorophenoxy)ethyl)-4-(4-nitrobenzyl)piperidine; 4-Benzyl-1-(1-methyl-3-phenoxypropyl)piperidine; 1-(2-Phenoxyethyl)-4-phenylpiperidine; 3-Hydroxy-1-(2-phenoxyethyl)-4-(3trifluoromethylphenyl)piperidine; 3-Hydroxy-1-(3-phenoxypropyl)-4-(3trifluoromethylphenyl)piperidine; 4-Benzyl-1-[2-(6-quinolinoxy)ethyl)]piperidine; 4-Benzyl-1-[2-(8-quinolinoxy)ethyl]piperidine; 4-Benzyl-1-[2-(2-amino-3-nitrophenoxy)ethyl]piperidine; 4-Benzyl-1-[2-(2,3-diaminophenoxy)ethyl]piperidine; 4-Benzyl-1-[2-(2,3-dioxoquinoxalin-5-oxy)ethyl]piperidine; 4-Benzyl-1-[2-(2-oxobenzimidazol-4-oxy)ethyl]piperidine; 4-Benzyl-1-[2-(4-amino-3-nitrophenoxy) ethyl) piperidine; 4-Benzyl-1-[2-(3,4-diaminophenoxy)ethyl]piperidine; 4-Benzyl-1-[2-(2,3-dioxoquinoxalin-6-oxy)ethyl]piperidine; 4-Benzyl-1-[2-(2-oxobenzimidazol-5-oxy)ethyl]piperidine; 4-Benzyl-1-[2-(2-aminophenoxy)ethyl]piperidine; 4-Benzyl-1-[2-(3-aminophenoxy)ethyl]piperidine; 4-Benzyl-1-[2-(4-aminophenoxy)ethyl]piperidine; 4-[2- (4-Benzylpiperidinoethoxy) quinazoline; 4-[2-(4-Benzylpiperidino)ethoxy]pyrazolo-[3,4- d]pyrimidine; 1-[2-(4-Benzylpiperidino)-ethyl]-4 hydroxypyrazolo[3,4-d]pyrimidine; 4-Benzyl-1-[2-(2-methoxyphenoxy)ethyl]piperidine; 4-Benzyl-1-[2-(3-methoxyphenoxy)ethyl]-piperidine; 4-Benzyl-1-[2-(4-methoxyphenoxy)ethyl]piperidine; 4-Benzyl-1-[2-(3,4-bisacetamidophenoxy)ethyl]piperidine; 4-Benzyl-1-[2-(2-methylbenzimidazol-6 oxy)ethyllpiperidine; 4-Benzyl-1-[2-(2-methylbenzimidazol-5oxy)ethyl]piperidine; 4-Benzyl-1-[2-(3-trifluoromethylphenoxy)ethyl]piperidine; 4-(4-Chlorobenzyl)-1-[2-(2-nitrophenoxy)ethyl]piperidine; 4-(4-Chlorobenzyl)-1-[2-(2-aminophenoxy)ethyl] piperidine; 4-(4-Chlorobenzyl)-1-[2-(2-amino-3-nitrophenoxy) ethyl]piperidine; 4-(4-Chlorobenzyl)-1-[2-(2,3diaminophenoxy)ethyl]piperidine; 4-(4-Chlorobenzyl)-1-[2-(2-oxobenzimidazol-4oxy)ethyl]piperidine; 4-(4-Chlorobenzyl)-1-[2-(4-amino-3-nitrophenoxy) ethyl] piperidine; 4-(4-Chlorobenzyl)-1-[2-(3,4-diaminophenoxy)ethyl]piperidine; 4-(4-Chlorobenzyl)-1-[2-(2-oxobenzimidazol-5-oxy) ethyl]piperidine; 4-(4-Fluorobenzyl)-1-[2-(2-oxobenzimidazol-5-oxy) ethyl]piperidine; 4-(4-Chlorophenyl)-4-hydroxyl-1-(3phenylpropyl)piperidine; 4-(4-Chlorophenyl)-4-hydroxyl-l-(4phenylbutyl)piperidine; 3-Hydroxy-1-(4-phenylbutyl)-4-(3- trifluoromethylphenyl) piperidine; 4-Benzyl-4-hydroxy-1-(2-phenylethyl)piperidine; 1,4-Dibenzyl-4-hydroxypiperidine; 1-Benzyl-4-(4-fluorobenzyl)-4-hydroxypiperidine; 4-(4-Fluorobenzyl)-1-[2-(4-fluorophenyl)ethyl]-4hydroxypiperidine; 4-(2-Keto-l-benzimidazolinyl)-1-(3-phenoxypropyl)piperidine; 4-Benzyl-4-hydroxy-1-(2-phenoxyethyl)piperidine; 4-Benzyl-4-hydroxy-1-(3-phenylpropyl)piperidine; 4-Benzyl-4-hydroxy-1-(3-phenoxypropyl)piperidine; 4-Benzyl-1-[(2-hydroxy-4-phenyl)butyl]piperidine; 3-Hydroxy-4-(3-trifluoromethylphenyl)-1-[3-(3aminophenoxy) propyl] piperidine; 3-Hydroxy-4-(4-fluorophenyl)-1-[3-(3-amino-1naphthayloxy)propyl]piperidine; 4-Benzyl-1-(2-(4-hydroxyphenoxy)ethyl)piperidine; 4-(4-Chlorobenzyl)-1-(2-(4-hydroxyphenoxy)ethyl) piperidine; 4-(4-Fluorobenzyl)-1-(2-(4-hydroxyphenoxy)ethyl) piperidine; 4-(4-Hydroxybenzyl)-1-(2-(4-fluorophenoxy)ethyl) piperidine; 4-Benzyl-1-(3-(4-hydroxyphenyl)propyl)piperidine; 4-[4-Chlorobenzyl)-1-(3-(4-hydroxyphenyl)propyl) piperidine; 4-Benzyl-1-(2-(4-hydroxyphenyl)ethyl)piperidine; 4-(3-Fluorobenzyl)-1-(2-(4-hydroxyphenoxy)ethyl) piperidine; 4-(3-Fluorobenzyl)-1-(2-(4-fluorophenoxy)ethyl) piperidine; 4-(4-Methylbenzyl)-1-(2-(4-hydroxyphenoxy)ethyl) piperidine; 4-(4-Ethylbenzyl)-1-(2-(4-hydroxyphenoxy)ethyl) piperidine; 4-(4-Methoxybenzyl)-1-(2-(4-hydroxyphenoxy)ethyl) piperidine; 4-(3,4-Difluorobenzyl)-1-(2-(4-hydroxyphenoxy) ethyl)piperidine; 4-(4-Fluorobenzyl)-4-hydroxy-1-(2-(4hydroxyphenoxy)ethyl)piperidine; 4-(2-Fluorobenzyl)-1-(2-(4-hydroxyphenoxy)ethyl) piperidine; 4-(4-Trifluoromethylbenzyl)-1-(2-(4hydroxyphenoxy)ethyl)piperidine; 4-(4-Isopropylbenzyl)-1-(2-(4-hydroxyphenoxy) ethyl)piperidine; 4-(4-t-Butylbenzyl)-1-(2-(4-hydroxyphenoxy) ethyl)piperidine; 4-(2-Fluoro-4-methylbenzyl)-1-(2-(4hydroxyphenoxy)ethyl)piperidine; 4-((5,6,7,8-Tetrahydro-2-naphthyl)methyl)-1-(2-(4hydroxyphenoxy)ethyl)piperidine; 4-((2-Naphthyl)methyl)-1-(2-(4-hydroxyphenoxy) ethyl)piperidine; 4-Benzyl-1-(2-(N-methylanilino)ethyl)piperidine; 4-Benzyl-l-(2- (thiophenoxy) ethyl)piperidine; 4-(4-Chlorobenzyl)-1-(2-(2-chloro-4-(2- hydroxyethyl)phenoxy)ethyl)piperidine; 4-(2,6-Difluorobenzyl)-1-(2-(4-hydroxyphenoxy) ethyl)piperidine; 4-(2-Fluoro-4-methylbenzyl)-1-(2-(4-hydroxy-3methylphenoxy)ethyl)piperidine; 4-Benzyl-1-(2-(3,4-methylenedioxyphenoxy) ethyl)piperidine; 4-(2-Fluoro-4-methylbenzyl)-1-(2-(3-fluoro-4hydroxyphenoxy)ethyl)piperidine; 4-(4-Fluorobenzyl)-1(2-(3-fluoro-4-hydroxyphenoxy)ethyl)piperidine; 4-(4-Methylbenzyl)-l-(2-(3-fluoro-4- hydroxyphenoxy) ethyl) piperidine; 4-(4-Fluorobenzyl)-1(2-(4-hydroxy-3-methylphenoxy)ethyl)piperidine; 4-(4-Methylbenzyl)-1-(2-(4-hydroxy-3-methylphenoxy)ethyl)piperidine; 4-Hydroxy-4-(4-methylbenzyl)-1-(2-(4hydroxyphenoxy)ethyl)piperidine; 4-Hydroxy-4-(4-methylbenzyl)-1-(2-(4-hydroxy-3methylphenoxy)ethyl)piperidine; 4-Benzyl-1-(2-(2-hydroxyphenoxy)ethyl)piperidine; 4-Benzyl-1-(2-(3-hydroxyphenoxy)ethyl)piperidine; 4-(4-Fluorobenzyl)-1-(2-(2-hydroxyphenoxy)ethyl) piperidine; 4-(4-Fluorobenzyl)-1-(2-(3-hydroxyphenoxy)ethyl) piperidine; 4-(4-Methylbenzyl)-1-(2-(2-hydroxyphenoxy)ethyl) piperidine; 4-(4-Methylbenzyl)-1-(2-(3-hydroxyphenoxy)ethyl) piperidine; 4-Benzyl-1-(2-(N-methyl-4-hydroxyanilino)ethyl) piperidine; 4-Benzyl-4-hydroxy-1-(2-(4-hydroxyphenoxy)ethyl) piperidine; 4-(4-Fluorobenzyl)-1-(2-(4-hydroxythiophenoxy) ethyl)piperidine; 4-(4-Hydroxyphenyl)-1-(4-phenylbutyl)piperidine; 4-Benzyl-1-(3-(2-oxobenzimidazol-5-oxy)propyl) piperidine; 4-Benzyl-l-(2-(2-thioxobenzimidazol-5-oxy) ethyl)piperidine; 4-Benzyl-1-(2-(2-iminobenzimidazol-5-oxy)ethyl) piperidine; 4-(4-Methylbenzyl)-1-(2-(2-thioxobenzimidazol-5oxy)ethyl)piperidine; 4-(4-Fluorobenzyl)-1-(2-(2-thioxobenzimidazol-5oxy)ethyl)piperidine; 4-(4-Chlorobenzyl)-1-(2-(2-thioxobenzimidazol-5oxy)ethyl)piperidine; 4-Benzyl-1-(2-(2-oxobenzoxazol-5-oxy)ethyl) piperidine; 4-Benzyl-l-(2-(2-oxobenzoxazol-6-oxy)ethyl) piperidine; 4-Benzyl-1-(2- (2-hydroxynaphth-6-oxy)ethyl) piperidine; 4-Benzyl-1-(2-(3-hydroxynaphth-6-oxy)ethyl) piperidine; 4-(4-Fluorobenzyl)-1-(2-(2-hydroxynaphth-6oxy)ethyl)piperidine; 4-(4-Methylbenzyl)-1-(2-(2-hydroxynaphth-6oxy)ethyl)piperidine; 4-Benzyl-1-(2-(3-m