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

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.

BACKGROUND OF THE INVENTION 
1. Field of the Invention 
This invention is related to 4-substituted piperidine analogs, including 
hydroxypiperidine and tetrahydropyridine analogs, as well as novel 
intermediates of the 4-substituted analogs. The analogs are selectively 
active as antagonists of N-methyl-D-aspartate (NMDA) receptor subtypes. 
The invention is also directed to the use of 4-substituted piperidine 
analogs as neuroprotective agents for treating conditions such as stroke, 
cerebral ischemia, central nervous system trauma, hypoglycemia, anxiety, 
convulsions, aminoglycoside antibiotics-induced hearing loss, migraine 
headache, chronic pain, glaucoma, CMV retinitis, psychosis, urinary 
incontinence, opioid tolerance or withdrawal, or neuro-degenerative 
disorders such as lathyrism, Alzheimer's Disease, Parkinsonism and 
Huntington's Disease. 
2. Related Background Art 
Excessive excitation by neurotransmitters can cause the degeneration and 
death of neurons. It is believed that this degeneration is in part 
mediated by the excitotoxic actions of the excitatory amino acids (EAA) 
glutamate and aspartate at the N-methyl-D-Aspartate (NMDA) receptor. This 
excitotoxic action is considered responsible for the loss of neurons in 
cerebrovascular disorders such as cerebral ischemia or cerebral infarction 
resulting from a range of conditions, such as thromboembolic or 
hemorrhagic stroke, cerebral vasospasms, hypoglycemia, cardiac arrest, 
status epilepticus, perinatal asphyxia, anoxia such as from drowning, 
pulmonary surgery and cerebral trauma, as well as lathyrism, Alzheimer's 
Disease, Parkinson's Disease and Huntington's Disease. 
Various classes of substituted piperidine analogs are known. For example, 
U.S. Pat. No. 5,273,977 generically discloses tetrahydropyridine and 
hydroxy piperidine derivatives described by the formula: 
##STR1## 
wherein n is an integer of 2, 3, or 4; Z is 
##STR2## 
Ar.sup.1 and Ar.sup.2 are each independently substituted or unsubstituted 
aryl, a heteroaromatic ring, or a heteroaromatic bicylic ring. The 
tetrahydropyridines and hydroxypiperidines of this reference are indicated 
to be useful as central nervous system agents, particularly as 
dopaminergic, antipsychotic and antihypertensive agents, and for treating 
central nervous system disorders such as Parkinson Disease, Huntington 
Disease and depression. The particular 4-substituted piperidines, 
including the 4-hydroxypiperdines and tetrahydropyridines of this 
invention are not exemplified. In addition, there is no disclosure or 
suggestion of treating disorders with selective NMDA receptor subtype 
antagonists and the advantages of such treatment. 
GB 1055548 discloses 1-aryl-3-aminopropynes having the generic formula: 
##STR3## 
wherein R represents unsubstituted phenyl or phenyl substituted by methyl, 
halogen, nitro, amino, (lower alkanoyl)amino, or lower alkoxyl; and either 
A is alkyl of 1 to 4 carbon atoms and A' is alkyl of 1 to 4 carbon atoms, 
benzyl, chlorobenzyl, or dimethoxybenzyl; or A and A', together with the 
adjacent nitrogen atom, from one of the following heterocyclic rings: 
pyrrolidino, 25 morpholino, thiomorpholino, 4-phenylpiperidino, 
4-phenyl-4-hydroxypiperidino, N'-methylpiperazino, N'-benzylpiperazino, 
N'-phenylpiperazino, N'-chlorophenylpiperazino, N'-tolylpiperazino, 
N'-methoxyphenylpiperamino, N'-(.beta.-hydroxyethyl)piperazino, 
N'-(.beta.-acetoxyethyl)piperazino, 
N'-(.beta.-propionyloxyethyl)-piperazino, N'-carbethoxypiperazino, 
hexamethyleneimino, and heptamethylene-imino; provided that when R is 
phenyl, p-methoxyphenyl, o- or p-nitrophenyl, or o-aminophenyl, 
##STR4## 
does not represent dimethylamino or diethylamino; and their acid addition 
salts, especially those containing physiologically innocuous anions. The 
compounds of this reference are said to have antiulcer activity. This 
reference does not disclose or suggest the 4-substituted piperidine 
analogs of this invention or their use as selective NMDA receptor subtype 
antagonists. 
DE 3703435 discloses compounds having a piperidine ring substituted by an 
aminothiazole moiety. The compounds are said to be useful for treating 
Parkinson's Disease, schizophrenia and circulatory disorders with a 
particular effect on the dopaminergic system. This reference does not 
disclose or suggest the compositions of the present invention, let alone 
their use as selective NMDA receptor subtype antagonists. 
PCT International Publication Number WO 92/02502 generically discloses 
N-hydrocarbyl 4-substituted piperidines described by the formula: 
##STR5## 
in which 
R is C.sub.1-8 alkyl(phenyl)p, C.sub.2-8 alkenyl(phenyl)p, C.sub.2-8 
alkynyl(phenyl)p, C.sub.3-8 cycloalkyl; 
p is 0 to 2; 
n is 0 to 6; 
A is a bond, oxygen, sulphur or NR.sup.1 ; 
R.sup.1 is hydrogen, C.sub.1-8 alkyl or phenylC.sub.1-4 alkyl; 
m is 0 to 3; and 
Ar is aryl or heteroaryl, each of which may be optionally substituted; and 
salts thereof. 
This reference exemplifies 4-aryloxyalkyl piperidines. The substituted 
piperidines are said to be calcium channel blockers expected to be useful 
in the treatment of anoxia, ischemia including stroke, migraine, epilepsy, 
traumatic head injury, AIDS-related dementia, neurodegenerative disorders 
and drug addiction. The reference does not disclose or suggest the 
particular 4-substituted piperidine analogs of this invention or their use 
as selective NMDA receptor subtype antagonists for the treatment of 
disorders responsive thereto. 
PCT International Publication Number WO 93/15052 generically describes 
compounds that are said to be calcium channel antagonists broadly 
represented by the formula: 
##STR6## 
and the salts thereof, wherein W is --CH.sub.2 --, a bond, O or S; k is O, 
or when W represents --CH.sub.2 -- k may also be 2, in which case the 
dotted lines represent single bonds; 
R is C.sub.1-8 alkyl(phenyl)p, C.sub.2-8 alkenyl(phenyl)p, C.sub.2-8 
alkynyl(phenyl)p, C.sub.3-8 cycloalkyl or C.sub.1-8 alkylC.sub.3-8 
cycloalkyl, or R may also represent hydrogen when k is 2; p is 0 to 2 n is 
0 to 6; 
m is 0 to 6; and 
A is a bond, --CH.dbd.CH--, --C.tbd.C--, oxygen, sulphur or NR.sup.1 ; 
R.sup.1 is hydrogen, C.sub.1-8 alkyl or phenylC.sub.1-4 alkyl; and 
Ar is aryl or heteroaryl, each of which may be optionally substituted; 
provided that: when W is a bond the side chain is .alpha. to the ring 
nitrogen atom; when W is CH.sub.2, k is zero, the side chain is at the 3- 
or 4-position of the piperidine ring and A is a bond, oxygen, sulphur or 
NR.sup.1 then Ar is aryl substituted by phenoxy or substituted phenoxy or 
is a tricyclic heteroaryl group as hereinafter defined; and when W is 
CH.sub.2 and k is 2 the side chain --(CH.sub.2).sub.n A(CH.sub.2).sub.m Ar 
is not .alpha. to the nitrogen atom. This reference exemplifies mostly 2 
and 3 substituted piperidines. In addition, the particular group of 3 and 
4 substituted piperidines described by the reference requires A to be 
--CH.dbd.CH-- or --C.tbd.C--. This reference does not disclose or suggest 
the 4-substituted piperidine analogs of this invention. Moreover, there is 
no suggestion of employing 4-substituted piperidine analogs as selective 
NMDA receptor subtype antagonists. 
EP 0235463 discloses N-substituted-arylalkyl and arylalkylene 
aminoheterocyclics as coronary vasodilators, antihypertensives, 
antiarrhythmic, antiallergy, antihistamic and antisecretory agents. 
4-substituted N-alkene and alkyne piperidine analogs of this invention, as 
well as their NMDA antagonistic activity, are not disclosed or suggested. 
U.S. Pat. No. 5,169,855 generically discloses disubstituted piperidine 
ether derivatives for use as antipsychotic agents selective for sigma 
receptors. Similarly, PCT International Publication No. WO 92/18127 and 
PCT International Publication No. WO 91/06297 generically disclose 
N-phthalimidoalkyl piperidines which are useful as antipsychotic agents 
and which are selective for sigma receptors. However, the 4-substituted 
piperidine analogs of this invention are not disclosed by these references 
and there is no mention of NMDA receptor activity. 
Numerous references have disclosed additional piperidine derivatives 
substituted at the 4 and 3 position for use in a variety of treatments. 
Such references include, for example, U.S. Pat. No. 3,255,196 (3 and 
4-substituted piperidines that are active antitussives and possess 
analgesic, antiemetic and local anaesthetic properties); U.S. Pat. No. 
5,202,346 (4-substituted piperidines that are Class III antiarrhythmic 
agents); PCT International Publication No. WO 88/02365 (3 and 
4-substituted piperidines that may be useful for treatment of mental 
disorders accompanying cerebrovascular disease); BE 860701 (4-substituted 
piperidines for use as vasodilators and .beta.-adrenergic inhibitors); FR 
2681319 (4-substituted piperidines for use as neuroprotectors and 
anticonvulsants); and DE 2939292 (4-substituted piperidines for use as 
antiallergenic and antiinflammatory agents). None of these references 
disclose or suggest the 4-substituted piperidine analogs of the present 
invention or their use as selective NMDA receptor subtype antagonists. 
Excitatory amino acid receptor antagonists that block NMDA receptors are 
recognized for usefulness in the treatment of disorders. NMDA receptors 
are intimately involved in the phenomenon of excitotoxicity, which may be 
a critical determinant of outcome of several neurological disorders. 
Disorders known to be responsive to blockade of the NMDA receptor include 
acute cerebral ischemia (stroke or cerebral trauma, for example), muscular 
spasm, convulsive disorders, neuropathic pain and anxiety, and may be a 
significant causal factor in chronic neurodegenerative disorders such as 
Parkinson's disease [T. Klockgether, L. Turski, Ann. Neurol. 34, 585-593 
(1993)], human immunodeficiency virus (HIV) related neuronal injury, 
amyotrophic lateral sclerosis (ALS), Alzheimer's disease [P. T. Francis, 
N. R. Sims, A. W. Procter, D. M. Bowen, J. Neurochem. 60 (5), 1589-1604 
(1993)] and Huntington's disease. [See S. Lipton, TINS 16 (12), 527-532 
(1993); S. A. Lipton, P. A. Rosenberg, New Eng. J. Med. 330 (9), 613-622 
(1994); and C. F. Bigge, Biochem. Pharmacol. 45, 1547-1561 (1993) and 
references cited therein.]. NMDA receptor antagonists may also be used to 
prevent tolerance to opiate analgesia or to help control withdrawal 
symptoms from addictive drugs (Eur. Pat. Appl. 488,959A). 
Expression cloning of the first NMDA receptor subunit, NMDAR1 (NR1) in 
Nakanishi's lab in 1991 provided an initial view of the molecular 
structure of the NMDA receptor [Nature 354, 31-37 (1991)]. There are 
several other structurally related subunits (NMDAR2A through NMDAR2D) that 
join NR1 in heteromeric assemblies to form the functional ion channel 
complex of the receptor [Annu. Rev. Neurosci. 17, 31-108 (1994)]. The 
molecular heterogeneity of NMDA receptors implies a future potential for 
agents with subtype selective pharmacology. 
Many of the properties of native NMDA receptors are seen in recombinant 
homomeric NR1 receptors. These properties are altered by the NR2 subunits. 
Recombinant NMDA receptors expressed in Xenopus oocytes have been studied 
by voltage-clamp recording, as has developmental and regional expression 
of the mRNAs encoding NMDA receptor subunits. Electrophysiological assays 
were utilized to characterize the actions of compounds at NMDA receptors 
expressed in Xenopus oocytes. The compounds were assayed at three subunit 
combinations of cloned rat NMDA receptors, corresponding to four putative 
NMDA receptor subtypes [Moriyoshi, et al. Nature 1991, 354, 31-37; Monyer 
et al, Science 1992, 256, 1217-1221; Kutsuwada et al, Nature 1992, 358, 
36-41; Sugihara et al, Biochem. Biophys Res. Commun. 1992, 185, 826-832]. 
An object of this invention is to provide novel 4-substituted piperidine 
analogs which function as subtype-selective NMDA receptor antagonists. 
A further object of this invention is to provide a pharmaceutical 
composition containing an effective amount of the 4-substituted piperidine 
analogs to treat cerebrovascular disorders responsive to the selective 
blockade of NMDA receptor subtypes. 
Another object of this invention is to provide a method of treating 
disorders responsive to the subtype-selective NMDA receptor antagonists in 
an animal by administering a pharmaceutically effective amount of 
4-substituted piperidine analogs. 
Yet another object of this invention is to provide novel methods of 
preparing 4-substituted piperidine analogs. 
A further object of this invention is directed to novel intermediates of 
the 4-substituted piperidine analogs of this invention. 
SUMMARY OF THE INVENTION 
This invention relates to novel 4-substituted piperidine analogs 
represented by the formula (I): 
##STR7## 
or a pharmaceutically acceptable salt thereof wherein 
Ar.sup.1 and Ar.sup.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.sub.2 Me, --N(SO.sub.2 Me).sub.2, --CONHalkyl, --SO.sub.2 NH.sub.2, 
an alkylguanidine group, a lower alkyl amino group or a lower alkoxy 
group; 
z is a single or double bond; 
X is --(CHR.sup.2).sub.m --, O, S or NR.sup.3, wherein each R.sup.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.sup.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.sup.3 ; 
R.sup.1 is hydrogen or hydroxy; 
n is 0, 1 or 2; 
Q is --CH.dbd.CH-- or --C.tbd.C--; and 
R.sup.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.sup.4 is not 
present, (ii) when n is 1 or 2 and Q is --C.tbd.--C-- and z is a double 
bond or R.sup.4 is hydroxy, then Ar.sup.1 is aryl substituted by halogen 
and (iii) when R.sup.4 is hydroxy then R.sup.2 is not hydroxy or lower 
alkoxy. 
The compounds of the present invention may exist as optical isomers and the 
inventive compounds include both the racemic mixtures of such optical 
isomers as well as the individual enantiomers. 
Examples of pharmaceutically acceptable addition salts include inorganic 
and organic acid addition salts such as the hydrochloride, hydrobromide, 
phosphate, sulphate, citrate, lactate, tartrate, maleate, fumarate, 
mandelate, oxalate, and the acetate. 
Halogen is fluorine, chlorine, bromine, or iodine; fluorine, chlorine, and 
bromine are preferred groups. 
Alkyl means a straight or branched chain of from one to six carbon atoms or 
cyclic alkyl of from three to seven carbon atoms including, but not 
limited to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, 
pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. 
Aryl means a monocyclic or bicyclic carbocyclic aromatic ring system which 
can be substituted or unsubstituted, for example, but not limited to 
phenyl, naphthyl or the like. 
Heteroaryl means a monocyclic or bicyclic carbocyclic aromatic ring system 
substituted by one or more hetero atoms, which can be the same or 
different, and includes, for example, thienyl, benzo[b]thienyl, 
naphtho[2,3[b]thienyl, thianthrenyl, furyl, pyranyl, isobenzofuranyl, 
chromenyl, xanthenyl, phenoxanthiinyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, 
pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, 
isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, 4H-quinolizinyl, 
isoquinolyl, quinolyl, phthalzinyl, naphthyridinyl, quinozalinyl, 
cinnolinyl, pteridinyl, 5aH-carbozolyl, carbozolyl, .beta.-carbolinyl, 
phenanthridinyl, acrindinyl, perimidinyl, phenanthrolinyl, phenazinyl, 
isothiazolyl, phenothiazinyl, isoxazolyl, furazanyl, phenoxazinyl, 
quinoxalinyl, 2,3-dioxoquinoxalinyl, benzimidazolyl, 2-oxobenzimidazolyl, 
2-oxindolyl and 2-thiobenzimidazolyl groups. 
Aralkyl means any of the alkyl groups defined herein substituted by any of 
the aryl groups as defined herein. 
Halogenated alkyl means any of the alkyl groups defined herein substituted 
by one or more halogen groups as defined herein. 
Alkylguanidine means a guanidine substituted by one of the alkyl groups 
defined herein. 
Lower alkyl amino means any of the alkyl groups defined herein substituted 
by an amino group. 
Lower alkoxy means an alkoxy group containing an alkyl group as defined 
herein. 
The instant invention is also related to a pharmaceutical composition 
containing the compound defined by formula I in an amount effective to 
treat cerebrovascular disorders responsive to the selective blockade of 
NMDA receptor subtypes and a pharmaceutically acceptable carrier. 
Exemplary disorders responsive to such treatment include cerebral ischemia 
caused by cerebral trauma, stroke, hypoglycemia, heart attack, and 
surgery; anxiety, psychosis and schizophrenia; glaucoma; CMV retinitis; 
urinary incontinence; opioid tolerance or withdrawal; and chronic 
neurodegenerative disorders such as Huntington's disease, ALS, 
Parkinsonism and Alzheimer's disease. The pharmaceutical composition of 
this invention may also be employed as an analgesic or for the treatment 
of epilepsy or migraine headaches. 
The invention is also related to a method for preparing the compound of 
formula (I) comprising the steps of: 
(a) reacting, in the presence of a base, a compound of formula VII 
##STR8## 
wherein Ar.sup.1, X, R.sup.1, R.sup.4 and z are as previously described, 
with a compound of formula IX 
EQU L--CH.sub.2 --(CH.sub.2).sub.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 
##STR9## 
wherein Ar.sup.1, X, R.sup.1, R.sup.4, z, n and Q are as previously 
described; and 
(b) reacting the compound of formula X with Ar.sup.2 Y, wherein Ar.sup.2 is 
as previously defined and Y is a transmetalation group, such as for 
example, Br, I, B(OH).sub.2 or HgCl, in the presence of a palladium 
catalyst to afford the compound of formula I. The leaving group L is 
preferably selected from the group consisting of para-toluenesulfonate, 
halogen, triflate and the like. Para-toluenesulfonate is most preferred. 
The transmetalation group is a group capable of transmetalating with 
palladium. 
The base used in step (a) of the above described process is generally 
present in at least an amount equivalent to the tosylate of formula IX to 
ensure that the tosic acid evolved during the reaction is quenched. Such 
bases include, for example, triethylamine, potassium carbonate or the 
like. The reaction of step (a) is conducted in a polar aprotic solvent, 
such as, for example, tetrahydrofuran, dimethylformamide, acetonitrile or 
the like. The reaction generally may be conducted at temperature between 
ambient temperature and 100.degree. C., although the temperature is 
typically not critical. 
The reaction of step (b) is conducted typically in the presence of a 
palladium catalyst such as PdCl.sub.2 (PPh.sub.3).sub.2, i.e., 
bis(triphenyl-phosphine)palladium(II)chloride and a base such as, for 
example, triethylamine. The reaction of this step is generally run at a 
temperature from about 60 to about 100.degree. C. in a polar solvent such 
as tetrahydrofuran, methanol, acetonitrile, t-butylamine or the like. The 
resulting product may be purified by means well known to those of ordinary 
skill in the art. 
Yet another method of this invention for preparing the compound of formula 
(I) comprises the steps of: (a) reacting, in the presence of a palladium 
catalyst, a compound of formula XI 
EQU P--O--CH.sub.2 --(CH.sub.2).sub.n --QH XI 
wherein P is a general protecting group, and n and Q are as previously 
described, with Ar.sup.2 Y, wherein Ar.sup.2 is as previously defined and 
Y is a transmetalating group, such as for example Br, I, B(OH).sub.2 or 
HgCl, to afford a compound represented by formula XII 
EQU P--O--CH.sub.2 --(CH.sub.2).sub.n --Q--Ar.sup.2 XII 
wherein P, n, Q and Ar.sub.2 are as previously described; 
(b) deprotecting the compound of formula XII to give a compound represented 
by formula XIII 
EQU HO--CH.sub.2 --(CH.sub.2).sub.n --Q--Ar.sup.2 XIII 
wherein n, Q and Ar.sup.2 are as previously described; 
(c) reacting the compound of formula XIII with an activating compound such 
as tosylates e.g., tosylchloride, mesylates triflates, 
diethylazadicarboxylates or the like in the presence of base, to give the 
compound represented by formula XIV 
EQU A--CH.sub.2 --(CH.sub.2).sub.n --Q--Ar.sup.2 XIV 
wherein A is an activating group such as, for example, a 
para-toluenesulfonate group, and n, Q and Ar.sup.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 
##STR10## 
wherein Ar.sup.1, X, R.sup.1, R.sup.4 and z are as previously described, 
to give the compound of formula I. 
The general protecting group P of this method of the invention is, for 
example, selected from the group consisting t-butyldimethylsilyl, 
methoxymethyl, tetrahydropyranyl, trimethylsilyl and the like, with the 
silyl protecting groups preferred. The palladium catalyst employed in step 
(a) of this method may be, for example, PdCl.sub.2 (PPh.sub.3).sub.2. 
Generally this step of the reaction is conducted in the presence of a 
base, such as triethylamine, at a temperature range of 60-100.degree. C. 
in a polar solvent, such as tetrahydrofuran, methanol, acetonitrile, 
t-butylamine or the like. 
Step (d) of this method is also performed in the presence of a base, such 
as triethylamine or potassium carbonate, to ensure that the tosic acid 
evolved during the reaction is quenched. This reaction step (d) is 
performed in an aprotic polar solvent, such as tetrahydrofuran, 
dimethylformamide, acetonitrile or the like at a temperature typically 
between ambient temperature and about 100.degree. C. The resulting product 
may be purified by means well known to one of ordinary skill in the art. 
This invention is further directed to novel intermediates which may be 
prepared during the preparation of the 4-substituted piperidine analogs of 
this invention. These novel intermediates also possess NMDA subtype 
selective activity. 
The novel intermediate compounds are represented by the formula (X): 
##STR11## 
or a salt thereof, wherein 
Ar.sup.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.sub.2 Me, 
--N(SO.sub.2 Me).sub.2, --CONHalkyl, --SO.sub.2 NH.sub.2, a lower alkyl 
amino group or a lower alkoxy group; 
z is a single or double bond; 
X is --(CHR.sup.2).sub.m --, O, S or NR.sup.3, wherein each R.sup.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.sup.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.sup.2 ; 
Q is --CH.dbd.CH-- or --C.tbd.C--; 
R.sup.1 is hydrogen or hydroxy; and 
R.sup.4 is hydrogen or hydroxy when z is a single bond, provided that (i) 
when X is --(CHR.sup.2).sub.m --, m is 0 and Q is --C.tbd.C-- then z is 
not a double bond and (ii) when R.sup.4 is hydroxy then R.sup.2 is not 
hydroxy or lower alkoxy. 
The invention further relates to 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 
at least one compound represented by the formula (I): 
##STR12## 
or a pharmaceutically acceptable salt thereof wherein Ar.sup.1 and 
Ar.sup.2 are independently aryl or a heteroaryl group, either of which may 
be independently substituted by hydrogen, alkyl, halogen, hydroxy, nitro, 
aryl, aralkyl, amino, a halogenated alkyl group, --NHAc, --NHSO.sub.2 Me, 
--N(SO.sub.2 Me).sub.2, --CONHalkyl, --SO.sub.2 NH.sub.2, an 
alkylguanidine group, a lower alkyl amino group or a lower alkoxy group; 
z is a single or double bond; 
X is --(CHR.sup.2).sub.m --, O, S or NR.sup.3, wherein R.sup.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.sup.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.sup.3 ; 
R.sup.1 is hydrogen or hydroxy; 
n is 0, 1 or 2; 
Q is --CH.dbd.CH-- or --C.tbd.C--; and 
R.sup.4 is hydrogen or hydroxy when z is a single bond, provided that when 
R.sup.4 is hydroxy then R.sup.2 is not hydroxy or lower alkoxy. The 
invention also relates to a method for treating disorders responsive to 
the selective blockade of N-methyl-D-aspartate receptor subtypes in an 
animal suffering thereof comprising administering in unit dosage form at 
least one intermediate compound represented by the formula (X). 
DETAILED DESCRIPTION OF THE INVENTION 
The novel 4-substituted piperidine analogs of this invention are 
represented by previously defined formula (I). Generally, Q is preferably 
--C.tbd.C--. In addition, Ar.sup.2 is preferably a pyridynyl or a phenyl 
group unsubstituted or substituted by halogen, amino or a lower alkyl 
amino group. Preferably Ar.sup.1 is phenyl, more preferably phenyl 
substituted by a halogen group and most preferably 4-chlorophenyl. 
Preferred embodiments of the novel 4-substituted piperidine analogs of this 
invention are represented by formula (II-VII). In particular, a first 
embodiment is represented by formula (II) as follows: 
##STR13## 
or a pharmaceutically acceptable salt thereof wherein: 
Ar.sup.1 and Ar.sup.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.sub.2 Me, --N(SO.sub.2 Me).sub.2, --CONHalkyl, --SO.sub.2 NH.sub.2, 
an alkylguanidine group, a lower alkyl amino group or a lower alkoxy 
group; and 
Q is --CH.dbd.C-- or --C.tbd.C--, provided that when Q is --C.tbd.C-- then 
Ar.sup.1 is aryl substituted by halogen. Preferably, when Q is --C.tbd.C-- 
then Ar.sup.2 is substituted by amino. 
Another embodiment of the novel 4-substituted piperidines of this invention 
is represented by formula (III) as follows: 
##STR14## 
or a pharmaceutically acceptable salt thereof wherein; 
Ar.sup.1 and Ar.sup.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.sub.2 Me, --N(SO.sub.2 Me).sub.2, --CONHalkyl, --SO.sub.2 NH.sub.2, 
an alkylguanidine group, a lower alkyl amino group or a lower alkoxy 
group; and 
Q is --CH.dbd.CH-- or --C.tbd.C--, provided that when Q is --C.tbd.C-- then 
Ar.sup.1 is aryl substituted by halogen. Preferably, when Q is --C.tbd.C-- 
then Ar.sup.2 is substituted by an amino or hydroxy group. 
Three additional embodiments of the novel 4-substituted piperidines of this 
invention are represented by formula (IV-VI) as follows: 
##STR15## 
or a pharmaceutically acceptable salt thereof, 
##STR16## 
or a pharmaceutically acceptable salt thereof, or 
##STR17## 
or a pharmaceutically acceptable salt thereof, wherein: 
Ar.sup.1 and Ar.sup.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.sub.2 Me, --N(SO.sub.2 Me).sub.2, --CONHalkyl, --SO.sub.2 NH.sub.2, 
an alkylguanidine group, a lower alkyl amino group or a lower alkoxy 
group; and 
Q is --CH.dbd.CH-- or --C.tbd.C--. For formula (VI) X is O or S. 
Yet another embodiment of the invention is represented by the formula 
(VII): 
##STR18## 
or a pharmaceutically acceptable salt thereof wherein: 
Ar.sup.1 and Ar.sup.2 are independently aryl or a heteroaryl group, either 
of which may be independently substituted by hydrogen, alkyl, halogen, 
nitro, aryl, aralkyl, amino, a halogenated alkyl group, --NHAc, 
--NHSO.sub.2 Me, --N(SO.sub.2 Me).sub.2, --CONHalkyl, --SO.sub.2 NH.sub.2, 
an alkylguanidine group, a lower alkyl amino group or a lower alkoxy 
group; and 
Q is --CH.dbd.CH- or --C.tbd.C--; and 
R.sup.3 is hydrogen or a lower alkoxy group having 1 to 6 carbon atoms. 
Exemplary preferred compounds of formula I include, without limitation: 
** 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)piperid 
ine; 
* 1-[4-(4-fluorophenyl)-3-butynyl]-4-hydroxy-4-(4-chlorophenyl)piperidine; 
* 1-[5-(3-aminophenyl)-4-pentynyl]-4-hydroxy-4-(4-hlorophenyl)piperidine; 
** 
1-[4-(3-aminophenyl)-3-butynyl]-4-(4-chlorophenyl)-1,2,5,6-tetrahydropyrid 
ine; 
** 
1-[4-(5-(2-amino)pyridynyl)-3-butynyl]-4-(4-chlorophenyl)-1,2,5,6-tetrahyd 
ropyridine; 
* 
1-[4-(4-fluorophenyl)-3-butynyl]-4-(4-chlorophenyl)-1,2,5,6-tetrahydropyri 
dine; 
* 
1-[5-(3-aminophenyl)-4-pentynyl]-4-(4-chlorophenyl)-1,2,5,6-tetrahydropyri 
dine; 
* 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]pipridine 
** 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-hydroxypiperid 
ine; 
* 
1-[4-(4-fluorophenyl)-3-butynyl]-4-(3-trifluoromethylbenzyl)-3-hydroxy-pip 
eridine; 
* 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)aminopiperidin 
e; 
* 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)phenyl 
guanidine; 
** 4-benzyl-1-(4-(3-methylphenyl)-3-butynyl)piperidine; 
** 1-(4-(4-aminophenyl)-3-butynyl)-4-benzylpiperidine; 
** 1-(4-(4-aminophenyl)-3-butynyl)-4-(4- chlorobenzyl)piperidine; 
** 1-(4-(4-amino-3-fluorophenyl)-3-butynyl)-4-(4-chlorobenzyl)piperdine; 
N-4-(1-(4-(3-aminophenyl)butyn-3-yl)piperidinyl)-2-oxobenzimidazol; 
** 1-(4-(2-aminophenyl)-3-butynyl)-4-phenylpiperidine; and 
* 1-[5-(3-aminophenyl)-4-pentynyl]-4-(4-chlorophenyl)aminopiperidine; 
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-l-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]pheny 
l]-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}-methanesulfon 
amide; 
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-l-(4-(4-aminophenyl)-3-butynyl)piperidine; and 
4-(4-methylbenzyl)-4-hydroxy-1-(4-(4-aminophenyl)-3-butynyl)piperidine. 
Of the above-listed exemplary compounds, the more preferred compounds are 
designated * and the most preferred are designated **. 
The invention is also directed to a method for treating disorders 
responsive to the selective blockade of NMDA receptor subtypes in animals 
suffering thereof. Particular preferred embodiments of the 4-substituted 
piperidine analogs for use in the method of this invention are represented 
by previously defined formula (IV-VII), as well as formula (II-III) 
wherein Q may be selected from --CH.dbd.CH-- and --C.tbd.C-- without 
restriction. 
Exemplary preferred compounds that may be employed in the method of this 
invention include, without limitation: 
** 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)piperid 
ine; 
* 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-tetrahydropyrid 
ine; 
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-tetrahyd 
ropyridine; 
* 
1-[4-(4-Fluorophenyl)-3-butynyl]-4-(4-chlorophenyl)-1,2,5,6-tetrahydropyri 
dine; 
* 
1-[5-(3-Aminophenyl)-4-pentynyl]-4-(4-chlorophenyl)-1,2,5,6-tetrahydropyri 
dine; 
* 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-hydroxypiperid 
ine; 
* 
1-[4-(4-Fluorophenyl)-3-butynyl]-4-(3-trifluoromethylbenzyl)-3-hydroxy-pip 
eridine; 
* 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)aminopiperidin 
e; 
* 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)phenyl 
guanidine; 
** 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; 
* 1-[5-(3-Aminophenyl)-4-pentynyl]-4-(4-chlorophenyl)aminopiperidine; 
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]pheny 
l]-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}-methanesulfon 
amide; 
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. 
Of the above-listed exemplary compounds, the more preferred compounds for 
use in the method of this invention are designated * and the most 
preferred are designated **. 
The compounds of this invention may be prepared using methods well known to 
those skilled in the art such as disclosed in U.S. Pat. No. 5,273,977, the 
disclosure of which is incorporated by reference herein, or by the novel 
methods of this invention. Exemplary reaction schemes I and II illustrate 
preparations of the compounds of this invention having alkyne 
functionality. The starting materials employed in Schemes I and II are 
readily available or can be prepared by known methods. 
##STR19## 
The methods set forth herein, may also be employed to prepare novel 
intermediates of this invention. The preferred novel intermediates 
include: 
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-(But-3-ynyl)-4-(4-chlorobenzyl)piperidine; 
4-Benzyl-1-(but-3-yn-1-yl)-4-hydroxypiperdine; 
4-(4-Methylbenzyl)-4-hydroxy-1-(but-3-yn-1-yl)piperidine; and 
1-(4-Pentynyl)4-((4-chloro)phenyl)aminopiperidine. 
The compounds of the present invention are useful in treating or preventing 
neuronal loss, neurodegenerative diseases and chronic pain. They are also 
useful as anticonvulsants and for inducing anesthesia, as well as for 
treating epilepsy and psychosis. The therapeutic and side effect profiles 
of subtype-selective NMDA receptor antagonists and agonists should be 
markedly different from the more non-subtype-selective NMDA receptor 
inhibitors. The subtype-selective analogs of the present invention are 
expected to exhibit little or no untoward side effects caused by 
non-specific binding with other receptors, particularly, the PCP and 
glutamate bindings sites associated with the NMDA receptor. In addition, 
selectivity for different NMDA receptor subtypes will reduce side effects 
such as sedation that are common to non-subtype-selective NMDA receptor 
antagonists. The compounds of the present invention are effective in 
treating or preventing the adverse consequences of the hyperactivity of 
excitatory amino acids, e.g. those which are involved in the NMDA receptor 
system, by preventing the ligand-gated cation channels from opening and 
allowing excessive influx of Ca.sup.++ into neurons, as occurs during 
ischemia. 
Neurodegenerative diseases which may be treated with the compounds of the 
present invention include those selected from the group consisting of 
Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, 
Parkinson's disease and Down's syndrome. 
The compounds of the present invention find particular utility in the 
treatment or prevention of neuronal loss associated with multiple strokes 
which give rise to dementia. After a patient has been diagnosed as 
suffering from a stroke, the compounds of the present invention may be 
administered to ameliorate the immediate ischemia and prevent further 
neuronal damage that may occur from recurrent strokes. 
Moreover, the compounds of the present invention are able to cross the 
blood/brain barrier which makes them particularly useful for treating or 
preventing conditions involving the central nervous system. 
The compounds of the invention find particular utility in treating or 
preventing the adverse neurological consequences of surgery. For example, 
coronary bypass surgery requires the use of heart-lung machines which tend 
to introduce air bubbles into the circulatory system which may lodge in 
the brain. The presence of such air bubbles robs neuronal tissue of 
oxygen, resulting in anoxia and ischemia. Pre- or post-surgical 
administration of the compounds of the present invention will treat or 
prevent the resulting ischemia. In a preferred embodiment, the compounds 
of the invention are administered to patients undergoing cardiopulmonary 
bypass surgery or carotid endarterectomy surgery. 
The compounds of the present invention also find utility in treating or 
preventing chronic pain. Such chronic pain may be the result of surgery, 
trauma, headache, arthritis, pain from terminal cancer or degenerative 
diseases. The compounds of the present invention also find particular 
utility in the treatment of phantom pain that results from amputation of 
an extremity. In addition to treatment of pain, the compounds of the 
invention are also expected to be useful in inducing anesthesia, either 
general or local anesthesia, for example, during surgery. 
The selective NMDA receptor subtype antagonists, agonists and modulators 
may be tested for in vivo anticonvulsant activity after intraperitoneal or 
intravenous injection using a number of anticonvulsant tests in mice 
(audiogenic seizure model in DBA-2 mice, pentylenetetrazol-induced 
seizures in mice, maximum electroshock seizure test (MES) or NMDA-induced 
death). The compounds may also be tested in drug discrimination tests in 
rats trained to discriminate PCP from saline. It is expected that most of 
the compounds of the present invention will not generalize to PCP at any 
dose. In addition, it is also expected that none of the compounds will 
produce a behavioral excitation in locomotor activity tests in the rodent. 
It is expected that such results will suggest that the selective NMDA 
receptor subtype antagonists and agonists of the present invention do not 
show the PCP-like behavioral side effects that are common to NMDA channel 
blockers such as MK-801 and PCP, or to competitive NMDA antagonists such 
as CGS 19755. 
The subtype-selective NMDA receptor antagonists and agonists are also 
expected to show potent activity in vivo after intraperitoneal or 
intravenous injection suggesting that these compounds can penetrate the 
blood/brain barrier. 
Elevated levels of glutamate has been associated with glaucoma. In 
addition, it has been disclosed that glaucoma management, particularly 
protection of retinal ganglion cells, can be achieved by administering to 
a patient a compound capable of reducing glutamate-induced excitotoxicity 
in a concentration effective to reduce the excitotoxicity. See W094/13275. 
Thus, the compounds of the present invention, which are expected to cross 
the blood-retina barrier, are also expected to be useful in the treatment 
of glaucoma. Preferably, the invention is directed to the treatment of 
patients which have primary open-angle glaucoma, chronic closed-angle 
glaucoma, pseudo doexfoliation, or other types of glaucoma or ocular 
hypertension. Preferably, the compound is administered over an extended 
period (e.g. at least six months and preferably at least one year), 
regardless of the changes in the patient's intraocular pressure over the 
period of administration. The compounds of the present invention are also 
useful in treating CMV retinitis, particularly in combination with 
antiviral agents. CMV afflicts the ganglion cell layer which may result in 
higher levels of glutamate. Thus, NMDA receptor antagonists could block 
retinitis by blocking the toxicity effect of high levels of glutamate. 
Aminoglycoside antibiotics have been used successfully in the treatment of 
serious Gram-negative bacterial infections. However, prolonged treatment 
with these antibiotics will result in the destruction of sensory hearing 
cells of the inner ear and consequently, induce permanent loss of hearing. 
A recent study of Basile, et al. (Nature Medicine, 2: 1338-1344, 1996) 
indicated that aminoglycosides produce a polyamine-like enhancement of 
glutamate excitotoxicity through their interaction with the NMDA receptor. 
Thus, compounds of the present invention with NMDA receptor antagonist 
activity will be useful in preventing aminoglycoside antibiotics-induced 
hearing loss by antagonizing their interaction with the receptor. 
The compounds of the present invention are useful in treating headaches, in 
particular, migraine headaches. During migraine attack, a sensory 
disturbance with unique changes of brain blood flow will result in the 
development of characteristic migraine auras. Since this unique phenomena 
has been replicated in animal experiments with cortical-spreading 
depression (CSD) of Leao, A. A. P. J., Neurophysiol. 7:359-390 (1944), CSD 
is considered an important phenomena in the pathophysiology of migraine 
with aura (Tepley et al., In: Biomagnetism, eds. S. Williamson, L. 
Kaufmann, pp. 327-330, Plenum Press, New York (1990)). The CSD is 
associated with the propagation (2.about.6 mm/s) of transient changes in 
electrical activity which relate to the failure of ion homoestatis in the 
brain, efflux of excitatory amino acids from the neurons and increased 
energy metabolism (Lauritzen, M., Acta Neurol. Scand. 76 (Suppl. 113):4-40 
(1987)). It has been demonstrated that the initiation of CSD in a variety 
of animals, including humans, involved the release of glutamate and could 
be triggered by NMDA (Curtis et al., Nature 191:1010-1011 (1961); and 
Lauritzen et al., Brain Res. 475:317-327 (1988)). Subtype selective NMDA 
antagonists will be therapeutically useful for migraine headache because 
of their expected low side effects, their ability to cross the blood brain 
barrier and their systemic bioavailability. 
Bladder activity is controlled by parasympathetic preganglionic neurons in 
the sacral spinal cord (DeGroat et al., J. Auton. Nerv. Sys. 
3:135-160(1981)). In humans, it has been shown that the highest density of 
NMDA receptors in the spinal cord are located at the sacral level, 
including those areas that putatively contain bladder parasympathetic 
preganglionic neurons (Shaw et al., Brain Research 539:164-168 (1991)). 
Because NMDA receptors are excitatory in nature, pharmacological blockade 
of these receptors would suppress bladder activity. It has been shown that 
the noncompetitive NMDA receptor antagonist MK801 increased the frequency 
of micturition in rat (Vera and Nadelhaft, Neuroscience Letters 
134:135-138(1991)). In addition, competitive NMDA receptor antagonists 
have also been shown to produce a dose-dependent inhibition of bladder and 
of urethral sphincter activity (U.S. Pat. No. 5,192,751). Thus, it is 
anticipated that subtype-selective NMDA receptor antagonists will be 
effective in the treatment of urinary incontinence mediated by their 
modulation on the receptor channel activity. 
Non-competitive NMDA receptor antagonist MK801 has been shown to be 
effective in a variety of animal models of anxiety which are highly 
predictive of human anxiety (Clineschmidt, B. V. et al., Drug Dev. Res. 
2:147-163 (1982)). In addition, NMDA receptor glycine site antagonists are 
shown to be effective in the rat potentiated startle test (Anthony, E. W., 
Eur. J. Pharmacol. 250:317-324 (1993)) as well as several other animal 
anxiolytic models (Winslow, J. et al, Eur. J. Pharmacol. 190:11-22 (1990); 
Dunn, R. et al., Eur. J. Pharmacol. 214:207-214 (1992); and Kehne, J. H. 
et al, Eur. J. Pharmacol. 193:282-292 (1981)). 
Glycine site antagonists, (+) HA-966 and 5,7-dichlorokynurenic acid were 
found to selectively antagonize d-amphetamine induced stimulation when 
injected into rat nucleus accumbens but not in striatum (Hutson, P. H. et 
al., Br. J. Pharmacol. 103:2037-2044 (1991)). Interestingly, (+) HA-966 
was also found to block PCP and MK801-induced behavioral arousal (Bristow, 
L. J. et al., Br. J. Pharmacol. 108:1156-1163 (1993)). These findings 
suggest that a potential use of NMDA receptor channel modulators, but not 
channel blockers, as atypical neuroleptics. 
It has been shown that in an animal model of Parkinson's disease--MPP.sup.+ 
or methamphetamine-induced damage to dopaminergic neurons--can be 
inhibited by NMDA receptor antagonists (Rojas et al., Drug Dev. Res. 
29:222-226 (1993); and Sonsalla et al, Science 243;398-400 (1989)). In 
addition, NMDA receptor antagonists have been shown to inhibit 
haloperidol-induced catalepsy (Schmidt, W. J. et al., Amino Acids 
1:225-237 (1991)), increase activity in rodents depleted of monoamines 
(Carlsson et al., Trends Neurosci. 13:272-276 (1990)) and increase 
ipsilateral rotation after unilateral substantia nigra lesion in rats 
(Snell, L. D. et al., J. Pharmacol. Exp. Ther. 235:50-57 (1985)). These 
are also experimental animal models of Parkinson's disease. In animal 
studies, the antiparkinsonian agent amantadine and memantine showed 
antiparkinsonian-like activity in animals at plasma levels leading to NMDA 
receptor antagonism (Danysz, W. et al., J. Neural Trans. 7:155-166, 
(1994)). Thus, it is possible that these antiparkinsonian agents act 
therapeutically through antagonism of an NMDA receptor. Therefore, the 
balance of NMDA receptor activity maybe important for the regulation of 
extrapyramidal function relating to the appearance of parkinsonian 
symptoms. 
It is well known to use opiates, e.g., morphine, in the medical field to 
alleviate pain. (As used herein, the term "opiates" is intended to mean 
any preparation or derivative of opium, especially the alkaloids naturally 
contained therein, of which there are about twenty, e.g., morphine, 
noscapine, codeine, papaverine, and thebaine, and their derivatives.) 
Unfortunately, with continued use, the body builds up a tolerance for the 
opiate, and, thus, for continued relief, the patient must be subjected to 
progressively larger doses. Tolerance develops after both acute and 
chronic morphine administration (Kornetsky et al., Science 162:1011-1012 
(1968); Way et al., J. Pharmacol. Exp Ther. 167:1-8 (1969); Huidobro et 
al., J. Pharmacol. Exp Ther. 198:318-329 (1976); Lutfy et al., J. 
Pharmacol. Exp Ther. 256:575-580 (1991)). This, in itself, can be 
detrimental to the patient's health. Furthermore, a time can come when the 
tolerance is substantially complete and the pain killing properties of the 
drug are no longer effective. Additionally, administration of higher doses 
of morphine may lead to respiratory depression, causing the patient to 
stop breathing. Seeking alternative drugs to produce analgesia without 
development of tolerance or as an adjunct therapy to block tolerance 
without interference with analgesia is an active area of research. 
Recent studies have suggested a modulatory role for the NMDA receptor in 
morphine tolerance. (Trujillo et al., Science 251:85-87 (1991); Marek et 
al., Brain Res. 547:77-81 (1991); Tiseo et al., J. Pharmacol. Exp Ther. 
264:1090-1096 (1993); Lutfy et al., Brain Res. 616:83-88 (1993); Herman et 
al., Neuropsychopharmacology 12:269-294 (1995).) Further, it has been 
reported that NMDA receptor antagonists are useful for inhibiting opioid 
tolerance and some of the symptoms of opioid withdrawal. Thus, the present 
invention is also directed to the administration of the compounds 
described herein to inhibit opiate tolerance and to treat or ameliorate 
the symptoms of opiate withdrawal by blocking the glycine co-agonist site 
associated with the NMDA receptor. 
Thus, the present invention is directed to compounds having high affinity 
to a particular NMDA receptor subunit (subtype) and low affinity to other 
sites such as dopamine and other catecholamine receptors. According to the 
present invention, those compounds having high binding to a particular 
NMDA subunit exhibit an IC.sub.50 of about 100 .mu.M or less in an NMDA 
subunit binding assay (see Table 1). Preferably, the compounds of the 
present invention exhibit a selective subunit IC.sub.50 of 10 .mu.M or 
less. More preferably, the compounds of the present invention exhibit a 
selective subunit IC.sub.50 of about 1.0 .mu.M or less, more preferably 
about 0.1 .mu.M or less. 
Compositions within the scope of this invention include all compositions 
wherein the compounds of the present invention are contained in an amount 
which is effective to achieve its intended purpose. While individual needs 
vary, determination of optimal ranges of effective amounts of each 
component is within the skill of the art. Typically, the compounds may be 
administered to mammals, e.g. humans, orally at a dose of 0.0025 to 50 
mg/kg, or an equivalent amount of the pharmaceutically acceptable salt 
thereof, per day of the body weight of the mammal being treated for 
anxiety disorders, e.g., generalized anxiety disorder, phobic disorders, 
obsessional compulsive disorder, panic disorder and post traumatic stress 
disorders or for schizophrenia or other psychoses. Preferably, about 0.01 
to about 10 mg/kg is orally administered to treat or prevent such 
disorders. For intramuscular injection, the dose is generally about 
one-half of the oral dose. For example, for treatment or prevention of 
anxiety, a suitable intramuscular dose would be about 0.0025 to about 15 
mg/kg, and most preferably, from about 0.01 to about 10 mg/kg. 
In the method of treatment or prevention of neuronal loss in ischemia, 
brain and spinal cord trauma, hypoxia, hypoglycemia, and surgery, to treat 
or prevent glaucoma or urinary incontinence, as well as for the treatment 
of Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's 
disease, Parkinson's disease and Down's Syndrome, or in a method of 
treating a disease in which the pathophysiology of the disorder involves 
hyperactivity of the excitatory amino acids or NMDA receptor-ion channel 
related neurotoxicity, the pharmaceutical compositions of the invention 
may comprise the compounds of the present invention at a unit dose level 
of about 0.01 to about 50 mg/kg of body weight, or an equivalent amount of 
the pharmaceutically acceptable salt thereof, on a regimen of 1-4 times 
per day. When used to treat chronic pain, migraine headache, to induce 
anesthesia, to treat or prevent opiate tolerance or to treat opiate 
withdrawal, the compounds of the invention may be administered at a unit 
dosage level of from about 0.01 to about 50 mg/kg of body weight, or an 
equivalent amount of the pharmaceutically acceptable salt thereof, on a 
regimen of 1-4 times per day. Of course, it is understood that the exact 
treatment level will depend upon the case history of the animal, e.g., 
human being, that is treated. The precise treatment level can be 
determined by one of ordinary skill in the art without undue 
experimentation. 
The unit oral dose may comprise from about 0.01 to about 50 mg, preferably 
about 0.1 to about 10 mg of the compound. The unit dose may be 
administered one or more times daily as one or more tablets each 
containing from about 0.1 to about 10, conveniently about 0.25 to 50 mg of 
the compound or its solvates. 
In addition to administering the compound as a raw chemical, the compounds 
of the invention may be administered as part of a pharmaceutical 
preparation containing suitable pharmaceutically acceptable carriers 
comprising excipients and auxiliaries which facilitate processing of the 
compounds into preparations which can be used pharmaceutically. 
Preferably, the preparations, particularly those preparations which can be 
administered orally and which can be used for the preferred type of 
administration, such as tablets, dragees, and capsules, and also 
preparations which can be administered rectally, such as suppositories, as 
well as suitable solutions for administration by injection or orally, 
contain from about 0.01 to 99 percent, preferably from about 0.25 to 75 
percent of active compound(s), together with the excipient. 
Also included within the scope of the present invention are the non-toxic 
pharmaceutically acceptable salts of the compounds of the present 
invention. Acid addition salts are formed by mixing a solution of the 
particular subtype-selective NMDA receptor antagonist or agonist of the 
present invention with a solution of a pharmaceutically acceptable 
non-toxic acid such as hydrochloric acid, fumaric acid, maleic acid, 
succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, 
phosphoric acid, oxalic acid, and the like. 
The pharmaceutical compositions of the invention may be administered to any 
animal which may experience the beneficial effects of the compounds of the 
invention. Foremost among such animals are mammals, e.g., humans, although 
the invention is not intended to be so limited. 
The pharmaceutical compositions of the present invention may be 
administered by any means that achieve their intended purpose. For 
example, administration may be by parenteral, subcutaneous, intravenous, 
intramuscular, intraperitoneal, transdermal, or buccal routes. 
Alternatively, or concurrently, administration may be by the oral route. 
The dosage administered will be dependent upon the age, health, and weight 
of the recipient, kind of concurrent treatment, if any, frequency of 
treatment, and the nature of the effect desired. 
The pharmaceutical preparations of the present invention are manufactured 
in a manner which is itself known, for example, by means of conventional 
mixing, granulating, dragee-making, dissolving, or lyophilizing processes. 
Thus, pharmaceutical preparations for oral use can be obtained by 
combining the active compounds with solid excipients, optionally grinding 
the resulting mixture and processing the mixture of granules, after adding 
suitable auxiliaries, if desired or necessary, to obtain tablets or dragee 
cores. 
Suitable excipients are, in particular, fillers such as saccharides, for 
example lactose or sucrose, mannitol or sorbitol, cellulose preparations 
and/or calcium phosphates, for example tricalcium phosphate or calcium 
hydrogen phosphate, as well as binders such as starch paste, using, for 
example, maize starch, wheat starch, rice starch, potato starch, gelatin, 
tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium 
carboxymethylcellulose, and/or polyvinyl pyrrolidone. If desired, 
disintegrating agents may be added such as the above-mentioned starches 
and also carboxymethyl-starch, cross-linked polyvinyl pyrrolidone, agar, 
or alginic acid or a salt thereof, such as sodium alginate. Auxiliaries 
include, without limitation, flow-regulating agents and lubricants, for 
example, silica, talc, stearic acid or salts thereof, such as magnesium 
stearate or calcium stearate, and/or polyethylene glycol. Dragee cores are 
provided with suitable coatings which, if desired, are resistant to 
gastric juices. For this purpose, concentrated saccharide solutions may be 
used, which may optionally contain gum arabic, talc, polyvinyl 
pyrrolidone, polyethylene glycol and/or titanium dioxide, lacquer 
solutions and suitable organic solvents or solvent mixtures. In order to 
produce coatings resistant to gastric juices, solutions of suitable 
cellulose preparations such as acetyl-cellulose phthalate or 
hydroxypropymethyl-cellulose phthalate, are used. Dye stuffs or pigments 
may be added to the tablets or dragee coatings, for example, for 
identification or in order to characterize combinations of active compound 
doses. 
Other pharmaceutical preparations which can be used orally include push-fit 
capsules made of gelatin, as well as soft, sealed capsules made of gelatin 
and a plasticizer such as glycerol or sorbitol. The push-fit capsules can 
contain the active compounds in the form of granules which may be mixed 
with fillers such as lactose, binders such as starches, and/or lubricants 
such as talc or magnesium stearate and, optionally, stabilizers. In soft 
capsules, the active compounds are preferably dissolved or suspended in 
suitable liquids, such as fatty oils, or liquid paraffin. In addition, 
stabilizers may be added. 
Possible pharmaceutical preparations which can be used rectally include, 
for example, suppositories, which consist of a combination of one or more 
of the active compounds with a suppository base. Suitable suppository 
bases are, for example, natural or synthetic triglycerides, or paraffin 
hydrocarbons. In addition, it is also possible to use gelatin rectal 
capsules which consist of a combination of the active compounds with a 
base. Possible base materials include, for example, liquid triglycerides, 
polyethylene glycols, or paraffin hydrocarbons. 
Suitable formulations for parenteral administration include aqueous 
solutions of the active compounds in water-soluble form, for example, 
water-soluble salts and alkaline solutions. In addition, suspensions of 
the active compounds as appropriate oily injection suspensions may be 
administered. Suitable lipophilic solvents or vehicles include fatty oils, 
for example, sesame oil, or synthetic fatty acid esters, for example, 
ethyl oleate or triglycerides or polyethylene glycol-400 (the compounds 
are soluble in PEG-400). Aqueous injection suspensions may contain 
substances which increase the viscosity of the suspension include, for 
example, sodium carboxymethyl cellulose, sorbitol, and/or dextran. 
Optionally, the suspension may also contain stabilizers. 
The characterization of NMDA subunit binding sites in vitro has been 
difficult because of the lack of selective drug ligands. Thus, the 
compounds of the present invention may be used to characterize the NMDA 
subunits and their distribution. Particularly preferred selective NMDA 
receptor subtype antagonists and agonists of the present invention which 
may be used for this purpose are isotopically radiolabelled derivatives, 
e.g., where one or more of the atoms are replaced with .sup.3 H, .sup.11 
C, .sup.14 C, .sup.15 N, or .sup.18 F. 
Electrophysiological Assays at NMDA Receptor Subunits 
Preparation of RNA. cDNA clones encoding the NR1A, NR2A, NR2B, NR2C and 
NR2D rat NMDA receptor subtypes were provided by Dr. P. H. Seeburg (see, 
Moriyoshi et al., Nature (Lond.) 354:31-37 (1991); Kutsuwada et al., 
Nature (Lond.) 358:36-41 (1992) Monyer et al., Science (Washington. D.C.) 
256:1217-1221 (1992); Ikeda et al., FEBS Lett. 313:34-38 (1992); Ishii et 
al., J. Biol. Chem. 268:2836-2843 (1993) for details of these clones or 
their mouse homologs). The clones were transformed into appropriate host 
bacteria and plasmid preparations were made with conventional DNA 
purification techniques. A sample of each clone was linearized by 
restriction enzyme digestion and cRNA was synthesized with T3 RNA 
polymerase. The cRNA was diluted to 400 ng/.mu.l and stored in 1 .mu.l 
aliquots at --80.degree. C. until injection. 
The Xenopus oocyte expression system. Mature female Xenopus laevis were 
anaesthetized (20-40 min) using 0.15% 3-aminobenzoic acid ethyl ester 
(MS-222) and 2-4 ovarian lobes were surgically removed. Oocytes at 
developmental stages IV-VI (Dumont, J. N., J. Morphol. 136:153-180 
(1972)), were dissected from the ovary still surrounded by enveloping 
ovarian tissues. Follicle-enclosed oocytes were micro-injected with 1:1 
mixtures of cRNA:NR1A+NR2A, 2B, 2C or 2D; injecting .about.2, 5, or 20 ng 
of RNA encoding each receptor subunit. NR1A encoding cRNA was injected 
alone at .about.20 ng. Oocytes were stored in Barth's medium containing 
(in mM):NaCl, 88; KCl, 1; CaCl.sub.2, 0.41; Ca(NO.sub.3).sub.2, 0.33; 
MgSO.sub.4, 0.82 NaHCO.sub.3, 2.4; HEPES 5, pH 7.4, with 0.1 mg/ml 
gentamicin sulphate. While oocytes were still surrounded by enveloping 
ovarian tissues the Barth's medium was supplemented with 0.1% bovine 
serum. Oocytes were defolliculated 1-2 days following injections by 
treatment with collagenase (0.5 mg/ml Sigma Type I for 0.5-1 hr) (Miledi 
and Woodward, J. Physiol. (Lond.) 416:601-621 (1989)) and subsequently 
stored in serum-free medium. 
Electrical recordings were made using a conventional two-electrode voltage 
clamp (Dagan TEV-200) over periods ranging between 3-21 days following 
injection. (Woodward et al., Mol. Pharmacol. 41: 89-103 (1992)). Oocytes 
were placed in a 0.1 ml recording chamber continuously perfused (5-15 ml 
min.sup.-1) with frog Ringer's solution containing (in mM):NaCl, 115; KCl, 
2; CaCl.sub.2, 1.8; HEPES, 5; pH 7.4. Drugs were applied by bath 
perfusion. Using oocytes expressing different subunit combinations of NMDA 
receptor, NMDA currents were activated by co-application of glutamate (100 
.mu.M) and glycine (1-100 .mu.M). Inhibitory potency of the novel 
antagonists was assessed on responses elicited by fixed concentrations of 
glutamate and glycine, by measuring reductions in current induced by 
progressively increasing concentrations of antagonist. 
Concentration-inhibition curves were fit with equation 1. 
EQU I/I.sub.control =1/(1+([antagonist]/10.sup.-pIC50).sup.n) Eq. 1 
in which I.sub.control is the current evoked by agonists alone, pIC.sub.50 
=-log IC.sub.50, IC.sub.50 is the concentration of antagonist that 
produces half maximal inhibition, and n is the slope factor. (De Lean et 
al., Am. J. Physiol. 235:E97-102 (1978)). For incomplete curves analysis 
by fitting was unreliable and IC.sub.50 values were calculated by simple 
regression over linear portions of the curves (Origin: Microcal Software). 
Maximal Electroshock-induced Seizures. Seizures were induced by application 
of current (50 mA, 60 pulses/sec, 0.8 sec pulse width, 1 sec duration, 
d.c.) through saline-coated corneal electrodes using a Ugo Basile ECT 
device (Model 7801). Mice were restrained by gripping the loose skin on 
their dorsal surface, electrodes were held lightly against the two cornea, 
then current was applied and mice were observed for a period of up to 30 
sec for the occurrence of a tonic hindlimb extensor response. A tonic 
seizure was defined as a hindlimb extension in excess of 90 degrees from 
the plane of the body. Results were treated in a quantal manner. 
The examples which follow are intended as an illustration of certain 
preferred embodiments of the invention, and no limitation of the invention 
is implied.