4-Substituted piperidine analogs and their use as subtype selective NMDA receptor, antagonists

Abstract

Novel 4-substituted piperidine analogs, pharmaceutical compositions containing the same and the method of using 4-substituted piperidine analogs as selectively active antagonists of N-methyl-D-aspartate (NMDA) receptor subtypes for treating conditions such as stroke, cerebral ischemia, central nervous system trauma, hypoglycemia, anxiety, convulsions, aminoglycoside antibiotics-induced hearing loss, migraine headaches, glaucoma, CMV retinitis, chronic pain, opioid tolerance or withdrawals, or neurodegenerative disorders, such as lathyrism, Alzheimer's Disease, Parkinsonism and Huntington's Disease are described. Also described are novel methods for preparing 4-substituted piperidine analogs and novel intermediates of the 4-substituted piperidine analogs.

What is claimed is:  
     
         1 . A compound represented by the formula (I)  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof wherein 
 Ar 1  and Ar 2  are independently aryl or a heteroaryl group, either of which may be independently substituted by hydrogen, hydroxy, alkyl, halogen, nitro, aryl, aralkyl, amino, a halogenated alkyl group, —NHAc, —NHSO 2 Me, —N(SO 2 Me) 2 , —CONHalkyl, —SO 2 NH2, an alkylguanidine group, a lower alkyl amino group or a lower alkoxy group;  
 z is a single or double bond;  
 X is —(CHR 2 ) m —, O, S or NR 3 , wherein each R 2  is independently hydrogen, hydroxy, lower alkoxy or a lower alkyl group having 1 to 6 carbon atoms and m is 0, 1 or 2, and R 3  is hydrogen or a lower alkyl group having 1 to 6 carbon atoms, provided that when z is a double bond then X is not O, S or NR 3 ;  
 R 1  is hydrogen or hydroxy;  
 n is 0, 1 or 2;  
 Q is —CH═CH— or —C≡C—; and  
 R 4  is hydrogen or hydroxy when z is a single bond provided that (i) when n is 0, then z is a double bond and R 4  is not present, (ii) when n is 1 or 2 and Q is —C≡C— and Z is a double bond or R 4  is hydroxy, then Ar 1  is aryl substituted by halogen and (iii) when R 4  is hydroxy then R 2  is not hydroxy or lower alkoxy.  
 
     
     
         2 . A compound according to  claim 1 , wherein Q is —C≡C—.  
     
     
         3 . A compound according to  claim 2 , wherein Ar 2  is a pyridynyl or a phenyl group, either of which is unsubstituted or substituted by halogen, amino or lower alkyl amino.  
     
     
         4 . A compound according to  claim 3 , wherein Ar′ is substituted or unsubstituted phenyl.  
     
     
         5 . A compound according to  claim 4 , wherein Ar 2  is selected from the group consisting of 2-amino pyridynyl, 2-aminophenyl, 3-aminophenyl and 4-aminophenyl.  
     
     
         6 . A compound according to  claim 5 , wherein Ar 1  is a halophenyl group.  
     
     
         7 . A compound according to  claim 1 , said compound selected from the group consisting of: 
 1-[4-(3-Aminophenyl)-3-butynyl]-4-hydroxy-4-(4-chlorophenyl)piperidine;    1-[4-(5-(2-Amino)pyridynyl)-3-butynyl]-4-hydroxy-4-(4-chlorophenyl)piperidine;    1-[4-(4-Fluorophenyl)-3-butynyl]-4-hydroxy-4-(4-chlorophenyl)piperidine;    1-[5-(3-Aminophenyl)-4-pentynyl]-4-hydroxy-4-(4-chlorophenyl)piperidine;    1-[4-(3-Aminophenyl)-3-butynyl]-4-(4-chlorophenyl)-1,2,5,6-tetrahydropyridine;    1-[4-(5-(2-Amino)pyridynyl)-3-butynyl]-4-(4-chlorophenyl)-1,2,5,6-tetrahydropyridine;    1-[4-(4-Fluorophenyl)-3-butynyl]-4-(4-chlorophenyl)-1,2,5,6-tetrahydropyridine;    1-[5-(3-Aminophenyl)-4-pentynyl]-4-(4-chlorophenyl)-1,2,5,6-tetrahydropyridine;    4-Benzyl-1-[4-(3-aminophenyl)-3-butynyl]piperidine;    4-Benzyl-1-(4-phenyl-3-butynyl)piperidine;    4-(4-Chloro)benzyl-1-[4-(3-aminophenyl)-3-butynyl]piperidine;    4-(4-Chloro)benzyl-1-[4-(4-hydroxyphenyl-3-butynyl]piperidine;    4-(4-Chloro)benzyl-1-[4-(5-(2-amino)pyridynyl)-3-butynyl]-piperidine;    1-[4-(4-Fluorophenyl)-3-butynyl]-4-(3-trifluoromethylbenzyl)-piperidine;    4-(4-Chlorobenzyl)-1-[5-(3-aminophenyl)-4-pentynyl]-piperidine;    4-Benzyl-1-[4-(3-aminophenyl)-3-butynyl]-3-hydroxypiperidine;    4-Benzyl-1-(4-phenyl-3-butynyl)-3-hydroxypiperidine;    4-(4-Chloro)benzyl-1-[4-(3-aminophenyl)-3-butynyl]3-hydroxypiperidine;    4-(4-Chloro)benzyl-1-[4-(5-(2-amino)pyridynyl)-3-butynyl]-3-hydroxypiperidine;    1-[4-(4-Fluorophenyl)-3-butynyl]-4-(3-trifluoromethylbenzyl)-3-hydroxy-piperidine;    4-(4-Chlorobenzyl)-3-hydroxy-1-[5-(3-aminophenyl)-4-pentynyl]-piperidine;    1-[4-(3-Aminophenyl)-3-butynyl]-4-phenoxy-piperidine;    1-(4-Phenyl-3-butynyl)-4-phenoxypiperidine;    1-[4-(3-Aminophenyl)-3-butynyl]-4-(4-chloro)phenoxypiperidine;    1-[4-(5-(2-Amino)pyridynyl)-4-butynyl]-4-(4-chloro)phenoxypiperidine;    1-[4-(4-Fluorophenyl)-3-butynyl]-4-(3-trifluoromethyl)phenoxypiperidine;    1-[5-(3-Aminophenyl)-4-pentynyl]-4-(4-chloro)phenoxypiperidine;    1-[4-(3-Aminophenyl)-3-butynyl]-4-(phenyl)aminopiperidine;    1-(4-Phenyl-3-butynyl)-4-(phenyl)aminopiperidine;    1-[4-(3-Aminophenyl)-3-butynyl]-4-(4-chlorophenyl)aminopiperidine;    1-[4-(5-(2-Amino)pyridynyl)-3-butynyl]-4-(4-chlorophenyl)aminopiperidine;    1-[4-(4-Fluorophenyl)-3-butynyl]-4-(3-trifluoromethylphenyl)aminopiperidine;    1-(4-(4-Amino-3-fluorophenyl)-3-butynyl)-4-(4-chlorobenzyl)piperidine;    1-[5-(3-Aminophenyl)-4-pentynyl]-4-(4-chlorophenyl)aminopiperidine;    4-Phenyl-1-(4-phenyl-3-butynyl)piperidine;    4-(3-(Trifluoromethyl)phenyl)-3-hydroxy-1-(4-phenyl-3-butynyl)piperidine;    1-(4-(4-Aminophenyl)-3-butynyl)-4-(4-chlorophenyl)-4-hydroxypiperidine;    N-n-Butyl-N′-(3-(4-(4-(4-chlorophenyl)-4-hydroxy)piperidinyl)butynyl)phenylguanidine;    4-Benzyl-1-(4-(3-methylphenyl)-3-butynyl)piperidine;    1-(4-(4-Aminophenyl)-3-butynyl)-4-benzyl-4-hydroxypiperidine;    1-(4-(4-Aminophenyl)-3-butynyl)-4-(4-chlorobenzyl)piperidine;    N-4-(1-(4-(3-Aminophenyl)butyn-3-yl)piperidinyl)-2-oxobenzimidazol;    1-(4-(2-Aminophenyl)-3-butynyl)-4-phenylpiperidine;    4-{4-[4-(4-Chloro-phenoxy)-piperidin-1-yl]-but-1-ynyl}-phenylamine;    N-{4-[4-(4-Phenoxy-piperidin-1-yl)-but-1-ynyl]-phenyl}-acetamide;    4-{4-[4-(4-Methyl-benzyl)-piperidin-1-yl]-but-1-ynyl}-phenylamine;    4-Benzyl-1-[4-(4-nitro-phenyl)-but-3-ynyl]-piperidine;    4-Benzyl-1-[4-(4-methoxy-phenyl)-but-3-ynyl]-piperidine;    4-[4-(4-Benzyl-piperidin-1-yl)-but-1-ynyl]-phenol;    4-Benzyl-1-[4-(4-fluoro-phenyl)-but-3-ynyl]-piperidine;    4-Benzyl-1-[4-(4-chloro-phenyl)-but-3-ynyl]-piperidine;    4-Benzyl-1-[4-(3-chloro-phenyl)-but-3-ynyl]-piperidine;    4-Benzyl-1-[4-(2,3-dichloro-phenyl)-but-3-ynyl]-piperidine;    4-Benzyl-1-[4-(3,4-dichloro-phenyl)-but-3-ynyl]-piperidine;    4-Benzyl-1-(4-p-tolyl-but-3-ynyl)-piperidine;    4-Benzyl-1-[4-(2,3-dimethyl-phenyl)-but-3-ynyl]-piperidine;    4-Benzyl-1-[4-(3,4-dimethyl-phenyl)-but-3-ynyl]-piperidine;    3-[4-(4-Benzyl-piperidin-1-yl)-but-1-ynyl]-phenylamine;    3-[4-(4-Benzyl-piperidin-1-yl)-but-1-ynyl]-benzylamine;    N-{4-[4-(4-Benzyl-piperidin-1-yl)-but-1-ynyl]-phenyl}-acetamide;    {4-[4-(4-Benzyl-piperidin-1-yl)-but-1-ynyl]-phenyl}-methyl-amine;    {4-[4-(4-Benzyl-piperidin-1-yl)-but-1-ynyl]-phenyl}-dimethyl-amine;    N-{4-[4-(4-Benzyl-piperidin-1-yl)-but-1-ynyl]-phenyl}-methanesulfonamide;    4-[4-(4-Benzyl-piperidin-1-yl)-but-1-ynyl]-benzamide;    N-(Methylsulfonyl)-N-[4-[4-[4-(phenylmethyl)-1-piperidinyl]-1-butynyl]phenyl]-methanesulfonamide;    4-[4-(4-Benzyl-piperidin-1-yl)-but-1-ynyl]-benzenesulfonamide;    4-[4-(4-Benzyl-piperidin-1-yl)-but-1-ynyl]-N-butyl-benzamide;    1-(4-Benzo[1,3]dioxol-5-yl-but-3-ynyl)-4-benzyl-piperidine;    4-Benzyl-1-[4-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-but-3-ynyl]-piperidine;    4-[3-(4-Benzyl-piperidin-1-yl)-prop-1-ynyl]-phenylamine;    N-{4-[3-(4-Benzyl-piperidin-1-yl)-prop-1-ynyl]-phenyl}-methanesulfonamide;    N-{4-[4-(4-Phenylsulfanyl-piperidin-1-yl)-but-1-ynyl]-phenyl}-acetamide;    5-[4-(4-Benzyl-piperidin-1-yl)-but-1-ynyl]-1H-indole;    4-{4-[4-(4-Methyl-benzyl)-piperidin-1-yl]-but-1-ynyl}-phenol;    5-[4-(4-Benzyl-piperidin-1-yl)-but-1-ynyl]-1H-indazole;    4-[4-(4-Benzyl-piperidin-1-yl)-but-1-ynyl]-2-nitro-phenylamine;    4-[4-(4-Benzyl-piperidin-1-yl)-but-1-ynyl]-benzene-1,2-diamine;    5-[4-(4-Benzyl-piperidin-1-yl)-but-1-ynyl]-1,3-dihydro-benzoimidazol-2-one;    N-{4-[4-(4-Phenylsulfanyl-piperidin-1-yl)-but-1-ynyl]-phenyl}-methanesulfonamide;    4-[3-(4-Benzyl-piperidin-1-yl)-prop-1-ynyl]-benzamide;    4-[3-(4-Benzyl-piperidin-1-yl)-prop-1-ynyl]-benzenesulfonamide;    5-[4-(4-Benzyl-piperidin-1-yl)-but-1-ynyl]-1H-indole-2,3-dione;    4-benzyl-4-hydroxy-1-4-(-3-methylphenyl)-3-butynyl)piperidine;    4-benzyl-4-hydroxy-1-(4-phenyl-3-butynyl)piperidine;    4-benzyl-4-hydroxy-1-(4-(4-aminophenyl)-3-butynyl)piperidine; and    4-(4-methylbenzyl)-4-hydroxy-1-(4-(4-aminophenyl)-3-butynyl)piperidine, and    a pharmaceutically acceptable salt thereof.    
     
     
         8 . A pharmaceutical composition useful for treating disorders responsive to the selective blockade of N-methyl-D-aspartate receptor subtypes such as stroke, cerebral ischemia, central nervous systems, trauma, hypoglycemia, neurodegenerative disorders, anxiety, migraine headaches, convulsions, aminoglycoside antibiotics-induced hearing loss, chronic pain, psychosis, glaucoma, CMV retinitis, opioid tolerance or withdrawal or urinary incontinence, said compositions comprising a pharmaceutically acceptable carrier or diluent and a therapeutically effective amount of at least one compound of  claim 1 .  
     
     
         9 . A compound represented by the formula:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof wherein: 
 Ar 1  and Ar 2  are independently aryl or a heteroaryl group, either of which may be independently substituted by hydrogen, hydroxy, alkyl, halogen, nitro, aryl, aralkyl, amino, a halogenated alkyl group, —NHAC, —NHSO 2 Me, —N(SO 2 Me) 2 , —CONHalkyl, —SO 2 NH 2 , an alkylguanidine group, a lower alkyl amino group or a lower alkoxy group; and  
 Q is —CH═CH— or —C═C—, provided that when Q is —C═C— then Ar 1  is aryl substituted by halogen.  
 
     
     
         10 . A compound represented by the formula:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof wherein: 
 Ar 1  and Ar 2  are independently aryl or a heteroaryl group, either of which may be independently substituted by hydrogen, hydroxy, alkyl, halogen, nitro, aryl, aralkyl, amino, a halogenated alkyl group, —NHAc, —NHSO 2 Me, —N(SO 2 Me) 2 , —CONHalkyl, —SO 2 NH 2 , an alkylguanidine group, a lower alkyl amino group or a lower alkoxy group; and  
 Q is —CH═CH— or —C≡C—, provided that when Q is —C≡C— then Ar 1  is aryl substituted by halogen.  
 
     
     
         11 . A compound represented by the formula:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof wherein: 
 Ar 1  and Ar 2  are independently aryl or a heteroaryl group, either of which may be independently substituted by hydrogen, hydroxy, alkyl, halogen, nitro, aryl, aralkyl, amino, a halogenated alkyl group, —NHAc, —NHSO 2 Me, —N(SO 2 Me) 2 , —CONHalkyl, —SO 2 NH 2 , an alkylguanidine group, a lower alkyl amino group or a lower alkoxy group; and  
 Q is —CH═CH— or —C═C—.  
 
     
     
         12 . A compound represented by the formula:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof wherein: 
 Ar 1  and Ar 2  are independently aryl or a heteroaryl group, either of which may be independently substituted by hydrogen, hydroxy, alkyl, halogen, nitro, aryl, aralkyl, amino, a halogenated alkyl group, —NHAc, —NHSO 2 Me, —N(SO 2 Me) 2 , —CONHalkyl, —SO 2 NH 2 , an alkylguanidine group, a lower alkyl amino group or a lower alkoxy group; and  
 Q is —CH═CH— or —C≡C—.  
 
     
     
         13 . A compound represented by the formula:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof wherein: 
 Ar 1  and Ar 2  are independently aryl or a heteroaryl group, either of which may be independently substituted by hydrogen, hydroxy, alkyl, halogen, nitro, aryl, aralkyl, amino, a halogenated alkyl group, —NHAc, —NHSO 2 Me, —N(SO 2 Me) 2 , —CONHalkyl, —SO 2 NH 2 , an alkylguanidine group, a lower alkyl amino group or a lower alkoxy group; X is O or S; and  
 Q is —CH═CH— or —C≡C—.  
 
     
     
         14 . A compound represented by the formula:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof wherein: 
 Ar 1  and Ar 2  are independently aryl or a heteroaryl group, either of which may be independently substituted by hydrogen, hydroxy, alkyl, halogen, nitro, aryl, aralkyl, amino, a halogenated alkyl group, —NHAc, —NHSO 2 Me, —N(SO 2 Me) 2 , —CONHalkyl, —SO 2 NH 2 , an alkylguanidine group, a lower alkyl amino group or a lower alkoxy group; and  
 Q is —CH═CH— or —C≡C—; and  
 R 3  is hydrogen or a lower alkoxy group having 1 to 6 carbon atoms.  
 
     
     
         15 . A method for treating disorders responsive to the selective blockade of N-methyl-D-aspartate receptor subtypes in an animal suffering thereof which comprises administering in unit dosage form of at least one compound represented by the formula:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof wherein 
 Ar 1  and Ar 2  are independently aryl or a heteroaryl group, either of which may be independently substituted by hydrogen, hydroxy, alkyl, halogen, nitro, aryl, aralkyl, amino, a halogenated alkyl group, —NHAc, —NHSO 2 Me, —N(SO 2 Me) 2 , —CONHalkyl, —SO 2 NH 2 , an alkylguanidine group, a lower alkyl amino group or a lower alkoxy group;  
 z is a single or double bond;  
 X is —(CHR 2 ) m —, O, S or NR 3 , wherein each R 2  is independently hydrogen, hydroxy, lower alkoxy or a lower alkyl group having 1 to 6 carbon atoms and m is 0, 1 or 2, and R 3  is hydrogen or a lower alkyl group having 1 to 6 carbon atoms, provided that when z is a double bond then X is not O, S or NR 3 ;  
 R 1  is hydrogen or hydroxy;  
 n is 0, 1 or 2;  
 Q is —CH═CH— or —C≡C—; and  
 R 4  is hydrogen or hydroxy when z is a single bond, provided that when R 4  is hydroxy then R 2  is not hydroxy or alkoxy.  
 
     
     
         16 . A method for treating disorders responsive to the selective blockade of N-methyl-D-aspartate receptor subtypes in an animal suffering thereof which comprises administering in unit dosage form of at least one compound represented by the formula:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof wherein: 
 Ar 1  and Ar 2  are independently aryl or a heteroaryl group, either of which may be independently substituted by hydrogen, hydroxy, alkyl, halogen, nitro, aryl, aralkyl, amino, a halogenated alkyl group, —NHAc, —NHSO 2 Me, —N(SO 2 Me) 2 , —CONHalkyl, —SO 2 NH 2 , an alkylguanidine group, a lower alkyl amino group or a lower alkoxy group; and  
 Q is —CH═CH— or —C≡C—.  
 
     
     
         17 . A method for treating disorders responsive to the selective blockade of N-methyl-D-aspartate receptor subtypes in an animal suffering thereof which comprises administering in unit dosage form of at least one compound represented by the formula:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof wherein: 
 Ar 1  and Ar 2  are independently aryl or a heteroaryl group, either of which may be independently substituted by hydrogen, hydroxy, alkyl, halogen, nitro, aryl, aralkyl, amino, a halogenated alkyl group, —NHAc, —NHSO 2 Me, —N(SO 2 Me) 2 , —CONHalkyl, —SO 2 NH 2 , an alkylguanidine group, a lower alkyl amino group or a lower alkoxy group; and  
 Q is —CH═CH— or —C≡C—.  
 
     
     
         18 . A method for treating disorders responsive to the selective blockade of N-methyl-D-aspartate receptor subtypes in an animal suffering thereof which comprises administering in unit dosage form of at least one compound represented by the formula:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof wherein: 
 Ar 1  and Ar 2  are independently aryl or a heteroaryl group, either of which may be independently substituted by hydrogen, hydroxy, alkyl, halogen, nitro, aryl, aralkyl, amino, a halogenated alkyl group, —NHAc, —NHSO 2 Me, —N(SO 2 Me) 2 , —CONHalkyl, —SO 2 NH 2 , an alkylguanidine group, a lower alkyl amino group or a lower alkoxy group; and  
 Q is —CH═CH— or —C≡C—.  
 
     
     
         19 . A method for treating disorders responsive to the selective blockade of N-methyl-D-aspartate receptor subtypes in an animal suffering thereof which comprises administering in unit dosage form of at least one compound represented by the formula:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof wherein: 
 Ar 1  and Ar 2  are independently aryl or a heteroaryl group, either of which may be independently substituted by hydrogen, hydroxy, alkyl, halogen, nitro, aryl, aralkyl, amino, a halogenated alkyl group, —NHAc, —NHSO 2 Me, —N(SO 2 Me) 2 , —CONHalkyl, —SO 2 NH 2 , an alkylguanidine group, a lower alkyl amino group or a lower alkoxy group; and  
 Q is —CH═CH— or —C≡C—.  
 
     
     
         20 . A method for treating disorders responsive to the selective blockade of N-methyl-D-aspartate receptor subtypes in an animal suffering thereof which comprises administering in unit dosage form of at least one compound represented by the formula:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof wherein: 
 Ar 1  and Ar 2  are independently aryl or a heteroaryl group, either of which may be independently substituted by hydrogen, hydroxy, alkyl, halogen, nitro, aryl, aralkyl, amino, a halogenated alkyl group, —NHAc, —NHSO 2 Me, —N(SO 2 Me) 2 , —CONHalkyl, —N(SO 2 Me) 2 ), —CONHalkyl, —SO 2 NH 2 , an alkyl guanidine group, a lower alkyl amino group or a lower alkoxy group;  
 Q is —CH═CH— or —C≡C—; and  
 X is O or S.  
 
     
     
         21 . A method for treating disorders responsive to the selective blockade of N-methyl-D-aspartate receptor subtypes in an animal suffering thereof which comprises administering in unit dosage form of at least one compound represented by the formula:  
       
         
           
           
               
               
           
         
       
       a pharmaceutically acceptable salt thereof wherein: 
 Ar 1  and Ar 2  are independently aryl or a heteroaryl group, either of which may be independently substituted by hydrogen, hydroxy, alkyl, halogen, nitro, aryl, aralkyl, amino, a halogenated alkyl group, —NHAc, —NHSO 2 Me, —N(SO 2 Me) 2 , —CONHalkyl, —SO 2 NH 2 , an alkylguanidine group, a lower alkyl amino group or a lower alkoxy group;  
 Q is —CH═CH— or —C≡C—; and  
 R 3  is hydrogen or a lower alkoxy group having 1 to 6 carbon atoms.  
 
     
     
         22 . A method for treating disorders responsive to the selective blockade of N-methyl-D-aspartate receptor subtypes in an animal suffering thereof which comprises administering in unit dosage form of at least one compound selected from the group consisting of: 
 1-[4-(3-Aminophenyl)-3-butynyl]-4-hydroxy-4-(4-chlorophenyl)piperidine;    1-((4-Phenyl)-3-butynyl)-4-hydroxy-4-phenylpiperidine;    1-[4-(3-Aminophenyl)-3-butynyl]-4-hydroxy-4-phenylpiperidine;    1-[4-(5-(2-Amino)pyridynyl)-3-butynyl]-4-hydroxy-4-(4-chlorophenyl)piperidine;    1-[4-(4-Fluorophenyl)-3-butynyl]-4-hydroxy-4-(4-chlorophenyl)piperidine;    1-[5-(3-Aminophenyl)-4-pentynyl]-4-hydroxy-4-(4-chlorophenyl)piperidine;    1-[4-(3-Aminophenyl)-3-butynyl]-4-(4-chlorophenyl)-1,2,5,6-tetrahydropyridine;    1-((4-Phenyl)-3-butynyl)-4-phenyl-1,2,5,6-tetrahydropyridine;    1-[4-(3-Aminophenyl)-3-butynyl]-4-phenyl-1,2,5,6-tetrahydropyridine;    1-[4-(5-(2-Amino)pyridynyl)-3-butynyl]-4-(4-chlorophenyl)-1,2,5,6-tetrahydropyridine;    1-[4-(4-Fluorophenyl)-3-butynyl]-4-(4-chlorophenyl)-1,2,5,6-tetrahydropyridine;    1-[5-(3-Aminophenyl)-4-pentynyl]-4-(4-chlorophenyl)-1,2,5,6-tetrahydropyridine;    4-Benzyl-1-[4-(3-aminophenyl)-3-butynyl]piperidine;    4-Benzyl-1-(4-phenyl-3-butynyl)piperidine;    4-(4-Chloro)benzyl-1-[4-(3-aminophenyl)-3-butynyl]piperidine;    4-(4-Chloro)benzyl-1-[4-(4-hydroxyphenyl-3-butynyl]piperidine;    4-(4-Chloro)benzyl-1-[4-(5-(2-amino)pyridynyl)-3-butynyl]-piperidine;    1-[4-(4-Fluorophenyl)-3-butynyl]-4-(3-trifluoromethylbenzyl)-piperidine;    4-(4-Chlorobenzyl)-1-[5-(3-aminophenyl)-4-pentynyl]-piperidine;    4-Benzyl-1-[4-(3-aminophenyl)-3-butynyl]-3-hydroxypiperidine;    4-Benzyl-1-(4-phenyl-3-butynyl)-3-hydroxypiperidine;    4-(4-Chloro)benzyl-1-[4-(3-aminophenyl)-3-butynyl]3-hydroxypiperidine;    4-(4-Chloro)benzyl-1-[4-(5-(2-amino)pyridynyl)-3-butynyl]-3-hydroxypiperidine;    1-[4-(4-Fluorophenyl)-3-butynyl]-4-(3-trifluoromethylbenzyl)-3-hydroxy-piperidine;    4-(4-Chlorobenzyl)-3-hydroxy-1-[5-(3-aminophenyl)-4-pentynyl]-piperidine;    1-[4-(3-Aminophenyl)-3-butynyl]-4-phenoxy-piperidine;    1-(4-Phenyl-3-butynyl)-4-phenoxypiperidine;    1-[4-(3-Aminophenyl)-3-butynyl]-4-(4-chloro)phenoxypiperidine;    1-[4-(5-(2-Amino)pyridynyl)-4-butynyl]-4-(4-chloro)phenoxypiperidine;    1-[4-(4-Fluorophenyl)-3-butynyl]-4-(3-trifluoromethyl)phenoxypiperidine;    1-[5-(3-Aminophenyl)-4-pentynyl]-4-(4-chloro)phenoxypiperidine;    1-[4-(3-Aminophenyl)-3-butynyl]-4-(phenyl)aminopiperidine;    1-(4-Phenyl-3-butynyl)-4-(phenyl)aminopiperidine;    1-[4-(3-Aminophenyl)-3-butynyl]-4-(4-chlorophenyl)aminopiperidine;    1-[4-(5-(2-Amino)pyridynyl)-3-butynyl]-4-(4-chlorophenyl)aminopiperidine;    1-[4-(4-Fluorophenyl)-3-butynyl]-4-(3-trifluoromethylphenyl)aminopiperidine; and    1-[5-(3-Aminophenyl)-4-pentynyl]-4-(4-chlorophenyl)aminopiperidine;    4-Phenyl-1-(4-phenyl-3-butynyl)piperidine;    4-(3-(Trifluoromethyl)phenyl)-3-hydroxy-1-(4-phenyl-3-butynyl)piperidine;    1-(4-(4-Aminophenyl)-3-butynyl)-4-(4-chlorophenyl)-4-hydroxypiperidine;    N-n-Butyl-N′-(3-(4-(4-(4-chlorophenyl)-4-hydroxy)piperidinyl)butynyl)phenylguanidine;    4-Benzyl-1-(4-(3-methylphenyl)-3-butynyl)piperidine;    1-(4-(4-Aminophenyl)-3-butynyl)-4-benzylpiperidine;    4-Benzyl-4-hydroxy-1-(4-phenyl-3-butynyl)piperidine;    4-Benzyl-4-hydroxy-1-(4-(3-methylphenyl)-3-butynyl)piperidine;    1-(4-(4-Aminophenyl)-3-butynyl)-4-benzyl-4-hydroxypiperidine;    1-(4-(4-Aminophenyl)-3-butynyl)-4-(4-chlorobenzyl)piperidine;    1-(4-(4-Amino-3-fluorophenyl)-3-butynyl)-4-(4-chlorobenzyl)piperidine;    N-4-(1-(4-(3-Aminophenyl)butyn-3-yl)piperidinyl)-2-oxobenzimidazol;    1-(4-(2-Aminophenyl)-3-butynyl)-4-phenylpiperidine;    4-{4-[4-(4-Chloro-phenoxy)-piperidin-1-yl]-but-1-ynyl}-phenylamine;    N-{4-[4-(4-Phenoxy-piperidin-1-yl)-but-1-ynyl]-phenyl}-acetamide;    4-{4-[4-(4-Methyl-benzyl)-piperidin-1-yl]-but-1-ynyl}-phenylamine;    4-Benzyl-1-[4-(4-nitro-phenyl)-but-3-ynyl]-piperidine;    4-Benzyl-1-[4-(4-methoxy-phenyl)-but-3-ynyl]-piperidine;    4-[4-(4-Benzyl-piperidin-1-yl)-but-1-ynyl]-phenol;    4-Benzyl-1-[4-(4-fluoro-phenyl)-but-3-ynyl]-piperidine;    4-Benzyl-1-[4-(4-chloro-phenyl)-but-3-ynyl]-piperidine;    4-Benzyl-1-[4-(3-chloro-phenyl)-but-3-ynyl]-piperidine;    4-Benzyl-1-[4-(2,3-dichloro-phenyl)-but-3-ynyl]-piperidine;    4-Benzyl-1-[4-(3,4-dichloro-phenyl)-but-3-ynyl]-piperidine;    4-Benzyl-1-(4-p-tolyl-but-3-ynyl)-piperidine;    4-Benzyl-1-[4-(2,3-dimethyl-phenyl)-but-3-ynyl]-piperidine;    4-Benzyl-1-[4-(3,4-dimethyl-phenyl)-but-3-ynyl]-piperidine;    3-[4-(4-Benzyl-piperidin-1-yl)-but-1-ynyl]-phenylamine;    3-[4-(4-Benzyl-piperidin-1-yl)-but-1-ynyl]-benzylamine;    N-{4-[4-(4-Benzyl-piperidin-1-yl)-but-1-ynyl]-phenyl}-acetamide;    {4-[4-(4-Benzyl-piperidin-1-yl)-but-1-ynyl]-phenyl}-methyl-amine;    {4-[4-(4-Benzyl-piperidin-1-yl)-but-1-ynyl]-phenyl}-dimethyl-amine;    N-{4-[4-(4-Benzyl-piperidin-1-yl)-but-1-ynyl]-phenyl}-methanesulfonamide;    4-[4-(4-Benzyl-piperidin-1-yl)-but-1-ynyl]-benzamide;    N-(Methylsulfonyl)-N-[4-[4-[4-(phenylmethyl)-1-piperidinyl]-1-butynyl]phenyl]-methanesulfonamide;    4-[4-(4-Benzyl-piperidin-1-yl)-but-1-ynyl]-benzenesulfonamide;    4-[4-(4-Benzyl-piperidin-1-yl)-but-1-ynyl]-N-butyl-benzamide;    1-(4-Benzo[1,3]dioxol-5-yl-but-3-ynyl)-4-benzyl-piperidine;    4-Benzyl-1-[4-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-but-3-ynyl]-piperidine;    4-[3-(4-Benzyl-piperidin-1-yl)-prop-1-ynyl]-phenylamine;    N-{4-[3-(4-Benzyl-piperidin-1-yl)-prop-1-ynyl]-phenyl}-methanesulfonamide;    N-{4-[4-(4-Phenylsulfanyl-piperidin-1-yl)-but-1-ynyl]-phenyl}-acetamide;    5-[4-(4-Benzyl-piperidin-1-yl)-but-1-ynyl]-1H-indole;    4-{4-[4-(4-Methyl-benzyl)-piperidin-1-yl]-but-1-ynyl}-phenol;    5-[4-(4-Benzyl-piperidin-1-yl)-but-1-ynyl]-1H-indazole;    4-[4-(4-Benzyl-piperidin-1-yl)-but-1-ynyl]-2-nitro-phenylamine;    4-[4-(4-Benzyl-piperidin-1-yl)-but-1-ynyl]-benzene-1,2-diamine;    5-[4-(4-Benzyl-piperidin-1-yl)-but-1-ynyl]-1,3-dihydro-benzoimidazol-2-one;    N-{4-[4-(4-Phenylsulfanyl-piperidin-1-yl)-but-1-ynyl]-phenyl}-methanesulfonamide;    4-[3-(4-Benzyl-piperidin-1-yl)-prop-1-ynyl]-benzamide;    4-[3-(4-Benzyl-piperidin-1-yl)-prop-1-ynyl]-benzenesulfonamide;    5-[4-(4-Benzyl-piperidin-1-yl)-but-1-ynyl]-1H-indole-2,3-dione;    4-benzyl-4-hydroxy-1-(4-3-methylphenyl)-3-butynyl)piperidine;    4-benzyl-4-hydroxy-1-(4-phenyl-3-butynyl)piperidine;    4-benzyl-4-hydroxy-1-(4-(4-aminophenyl)-3-butynyl)piperidine; and    4-(4-methylbenzyl)-4-hydroxy-1-(4-(4-aminophenyl)-3-butynyl)piperidine, and    a pharmaceutically acceptable salt thereof.    
     
     
         23 . A method for preparing the compound represented by formula I:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof wherein 
 Ar 1  and Ar 2  are independently aryl or a heteroaryl group, either of which may be independently substituted by hydrogen, hydroxy, alkyl, halogen, nitro, aryl, aralkyl, amino, a halogenated alkyl group, —NHAc, —NHSO 2 Me, —N(SO 2 Me) 2 , —CONHalkyl, —SO 2 NH 2 , an alkylguanidine group, a lower alkyl amino group or a lower alkoxy group;  
 z is a single or double bond;  
 X is —(CHR 2 ) m —, O, S or NR 3 , wherein each R 2  is independently hydrogen, hydroxy, lower alkoxy or a lower alkyl group having 1 to 6 carbon atoms and m is 0, 1 or 2, and R 3  is hydrogen or a lower alkyl group having 1 to 6 carbon atoms, provided that when z is a double bond then X is not O, S or NR 3 ;  
 R 1  is hydrogen or hydroxy;  
 n is 0, 1 or 2;  
 Q is —CH═C— or —C≡C—; and  
 R 4  is hydrogen or hydroxy when z is a single bond, provided that when R 4  is hydroxy then R 2  is not hydroxy or lower alkoxy, said method comprising the steps of: 
 (a) reacting, in the presence of a base, a compound of formula VII  
                     
  wherein Ar 1 , X, R 1 , R 4  and z are as previously described, with a compound of formula IX  
 L—CH 2 —(CH 2 ) n —Q—H  IX  
  wherein n and Q are as previously described and L is a leaving group to afford a compound of formula X  
                     
  wherein Ar 1 , X, R 1 , R 4 , z, n and Q are as previously described; and  
 (b) reacting the compound of formula X with Ar 2 Y, wherein Ar 2  is as previously defined and Y is a transmetalation group, in the presence of a palladium catalyst to afford the compound of formula I.  
 
 
     
     
         24 . A method according to  claim 23 , wherein said transmetalation group is selected from the group consisting of Br, I, B(OH) 2  and HgCl.  
     
     
         25 . A method for preparing the compound represented by formula I:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof wherein 
 Ar 1  and Ar 2  are independently aryl or a heteroaryl group, either of which may be independently substituted by hydrogen, hydroxy, alkyl, halogen, nitro, aryl, aralkyl, amino, a halogenated alkyl group, —NHAc, —NHSO 2 Me, —N(SO 2 Me) 2 , —CONHalkyl, —SO 2 NH2, an alkylguanidine group, a lower alkyl amino group or a lower alkoxy group;  
 z is a single or double bond;  
 X is —(CHR 2 ) m —, O, S or NR 3 , wherein each R 2  is independently hydrogen, hydroxy, lower alkoxy or a lower alkyl group having 1 to 6 carbon atoms and m is 0, 1 or 2, and R 3  is hydrogen or a lower alkyl group having 1 to 6 carbon atoms, provided that when z is a double bond then X is not O, S or NR 3;    
 R 1  is hydrogen or hydroxy;  
 n is 0, 1 or 2;  
 Q is —CH═CH— or —C≡C—; and  
 R 4  is hydrogen or hydroxy when z is a single bond, provided that when R 4  is hydroxy then R 2  is not hydroxy or lower alkoxy, said method comprising the steps of: 
 (a) reacting, in the presence of a palladium catalyst, a compound of formula XI  
 P—O—CH 2 —(CH 2 ) n —QH  XI  
  wherein P is a general protecting group, and n and Q are as previously described, with Ar 2 Y, wherein Ar 2  is as previously defined and Y is a transmetalation group, to afford a compound represented by formula XII  
 HO—CH 2 —(CH 2 ) n —Q—Ar 2   XII  
  wherein P, n, Q and Ar 2  are as previously described;  
 (b) deprotecting the compound of formula XII to give a compound represented by formula XIII  
 HO—CH 2 —(CH 2 ) n —Q—Ar 2   XIII  
  wherein n, Q and Ar 2  are as previously described;  
 (c) reacting the compound of formula XIII with an activating compound, in the presence of base, to give the compound represented by formula XIV  
 A—CH 2 —(CH 2 ) n —Q—Ar 2   XIV  
  wherein A is an activating group, and n, Q and Ar 2  are as previously described; and  
 (d) reacting, in the presence of a base, the compound of formula XIV with the compound of formula VII  
                     
  wherein Ar 1 , X, R 1 , R 4  and z are as previously described, to give the compound of formula I.  
 
 
     
     
         26 . A method according to  claim 25 , wherein said transmetalation group is selected from the group consisting of Br, I, B(OH) 2  and HgCl.  
     
     
         27 . A method according to  claim 26 , wherein said activating compound is selected from the group consisting of tosylates, triflates, mesylates and diethylazadicarboxylate.  
     
     
         28 . A compound represented by the formula (X)  
       
         
           
           
               
               
           
         
       
       or a salt thereof, wherein 
 Ar 1  is aryl or a heteroaryl group, either of which may be independently substituted by hydrogen, hydroxy, alkyl, halogen, nitro, aryl, aralkyl, amino, a halogenated alkyl group, —NHAc, —NHSO 2 Me, —N(SO 2 Me) 2 , —CONHalkyl, —SO 2 NH 2 , a lower alkyl amino group or a lower alkoxy group;  
 z is a single or double bond;  
 X is —(CHR 2 ) m —, O, S or NR 3 , wherein each R 2  is independently hydrogen, hydroxy, lower alkoxy or a lower alkyl group having 1 to 6 carbon atoms and m is 0, 1 or 2, and R 3  is hydrogen or a lower alkyl group, provided that when z is a double bond then X is not O, S or NR 2;    
 Q is —CH═CH— or —C≡C—;  
 R 1  is hydrogen or hydroxy; and  
 R 4  is hydrogen or hydroxy when z is a single bond, provided that (i) when X is —(CHR 2 ) m —, m is 0 and Q is —C≡C— then z is not a double bond and (ii) when R 4  is hydroxy then R 2  is not hydroxy or lower alkoxy.  
 
     
     
         29 . A compound according to  claim 28 , said compound selected from the group consisting of 
 1-(3-Butynyl)-4-hydroxy-4-phenylpiperidine;    1-(3-Butynyl)-4-hydroxy-4-((4-chloro)phenyl)piperidine;    1-(3-Butynyl)-4-hydroxy-4-((3-trifluoromethyl)phenyl)piperidine;    4-Hydroxy-4-phenyl-1-(2-propynyl)piperidine;    4-Hydroxy-1-(4-pentynyl)-4-phenylpiperidine;    1-(3-Butynyl)-4-(4-chloro)phenyl-1,2,5,6-tetrahydropyridine;    1-(3-Butynyl)-4-(4-trifluoromethyl)phenyl-1,2,5,6-tetrahydropyridine;    4-(4-Chloro)phenyl-1-(2-propynyl)-1,2,5,6-tetrahydropyridine;    4-(4-Chloro)phenyl-1-(4-pentynyl)-1,2,5,6-tetrahydropyridine;    4-Benzyl-1-(3-butynyl)piperidine;    4-(4-Chloro)benzyl-1-(3-butynyl)piperidine;    4-(3-Trifluoromethyl)benzyl-1-(3-butynyl)piperidine;    4-(4-Chloro)benzyl-1-(2-propynyl)piperidine;    4-(4-Chloro)benzyl-1-(4-pentynyl)piperidine;    4-Benzyl-1-(3-butynyl)-3-hydroxy-piperidine;    4-(4-Chloro)benzyl-1-(3-butynyl)-3-hydroxy-piperidine;    4-(3-Trifluoromethyl)benzyl-1-(3-butynyl)-3-hydroxy-piperidine;    4-(4-Chloro)benzyl-3-hydroxy-1-(2-propynyl)piperidine;    4-(4-Chloro)benzyl-3-hydroxy-1-(4-pentynyl)piperidine;    1-(3-Butynyl)-4-phenoxypiperidine;    1-(3-Butynyl)-4-(4-chloro)phenoxypiperidine;    1-(3-Butynyl)-4-(3-trifluoromethyl)phenoxypiperidine;    4-(4-Chloro)phenoxy-1-(2-propynyl)piperidine;    1-(4-Pentynyl) 4 -(4-chloro)phenoxypiperidine;    1-(3-Butynyl)-4-(phenyl)aminopiperidine;    1-(3-Butynyl)-4-((4-chloro)phenyl)aminopiperidine;    1-(3-Butynyl)-4-((3-trifluoromethyl)phenyl)aminopiperidine;    4-((4-Chloro)phenyl)amino-1-(2-propynyl)piperidine;    1-(4-Pentynyl) 4 -((4-chloro)phenyl)aminopiperidine;    1-(But-3-ynyl)-4-(4-chlorobenzyl)piperidine;    4-Benzyl-1-(but-3-yn-1-yl)-4-hydroxypiperidine; 4-4(4-Methylbenzyl)-4-hydroxy-1-(but-3-yn-1-yl)piperidine;    and a salt thereof.    
     
     
         30 . A method for treating disorders responsive to the selective blockade of N-methyl-D-aspartate receptor subtypes in an animal suffering thereof which comprises administering in unit dosage form of at least one compound represented by the formula (X):  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein 
 Ar 1  is aryl or a heteroaryl group, either of which may be independently substituted by hydrogen, hydroxy, alkyl, halogen, nitro, aryl, aralkyl, amino, a halogenated alkyl group, —NHAc, —NHSO 2 Me, —N(SO 2 Me) 2 , —CONHalkyl, —SO 2 NH 2 , a lower alkyl amino group or a lower alkoxy group;  
 z is a single or double bond;  
 X is —(CHR 2 ) m , O, S or NR 3  wherein each R 2  is independently hydrogen, hydroxy, lower alkoxy or a lower alkyl group having 1 to 6 carbon atoms and m is 0, 1 or 2, and R 3  is hydrogen or a lower alkyl group having 1 to 6 carbon atoms, provided that when z is a double bond then X is not O, S or NR 2 ;  
 Q is —CH═CH— or —C≡C—;  
 R 1  is hydrogen or hydroxy; and R 4  is hydrogen or hydroxy when z is a single bond, provided that (i) when X is —(CHR 2 ) m —, m is 0 and Q is —C≡C— then z is not a double bond and (ii) when R 4  is hydroxy then R 2  is not hydroxy or lower alkoxy.  
 
     
     
         31 . The method according to any one of claims  15 - 22  and  30 , wherein said disorder is stroke, cerebral ischemia, central nervous system trauma or hypoglycemia.  
     
     
         32 . The method according to any one of claims  15 - 22  and  30 , wherein said disorder is anxiety, convulsions or chronic pain.  
     
     
         33 . The method according to any one of claims  15 - 22  and  30 , wherein said disorder is a aminoglycoside antibiotics-induced hearing loss.  
     
     
         34 . The method according to any one of claims  15 - 22  and  30 , wherein said disorder is Parkinson's disease.  
     
     
         35 . The method according to any one of claims  15 - 22  and  30 , wherein said disorder is a migraine headache.  
     
     
         36 . The method according to any one of claims  15 - 22  and  30 , wherein said disorder is glaucoma or CMV retinitis.  
     
     
         37 . The method according to any one of claims  15 - 22  and  30 , wherein said disorder is a psychosis.  
     
     
         38 . The method according to any one of claims  15 - 22  and  30 , wherein said disorder is urinary incontinence.  
     
     
         39 . The method according to any one of claims  15 - 22  and  30 , wherein said disorder is opioid tolerance or withdrawal.  
     
     
         40 . The method according to any one of claims  15 - 22  and  30 , wherein said disorder is aminoglycoside antibiotics-induced hearing loss.