Bicyclo[3.1.0]hexanes and related compounds

The present invention relates to compounds of the formula I, as defined in the specification, pharmaceutical compositions containing such compounds the use of such compounds to treat neurological and psychiatric disorders.

BACKGROUND OF THE INVENTION 
The present invention relates to compounds of the formula 1, as described 
below, their pharmaceutically acceptable salts, pharmaceutical 
compositions containing them and their use in treating neurological and 
psychiatric disorders. 
The role of excitatory amino acids, such as glutamic acid and aspartic 
acid, as the predominant mediators of excitatory synaptic transmission in 
the central nervous system has been well established. Watkins & Evans, 
Ann. Rev. Pharmacol. Toxicol., 21, 165 (1981); Monaghan, Bridges, and 
Cotman, Ann. Rev. Pharmacol. Toxicol., 29, 365 (1989); Watkins, 
Krogsgaard-Larsen, and Honore, Trans. Pharm. Sci., 11, 25 (1990). These 
amino acids function in synaptic transmission primarily through excitatory 
amino acid receptors. These amino acids also participate in a variety of 
other physiological processes such as motor control, respiration, 
cardiovascular regulation, sensory perception, and cognition. 
Excitatory amino acid receptors are classified into two general types. 
Receptors that are directly coupled to the opening of cation channels in 
the cell membrane of the neurons are termed "ionotropic." This type of 
receptor has been subdivided into at least three subtypes, which are 
defined by the depolarizing actions of the selective agonists 
N-methyl-D-aspartate (NMDA), 
alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), and 
kainic acid (KA). The second general type is the G-protein or second 
messenger-linked "metabotropic" excitatory amino acid receptor. This 
second type, when activated by the agonists quisqualate, ibotenate, or 
trans-1-aminocyclopentane-1,3-dicarboxylic acid, leads to enhanced 
phosphoinosoitide hydrolysis in the postsynaptic cell. Both types of 
receptors appear not only to mediate normal synaptic transmission along 
excitatory pathways, but also participate in the modification of synaptic 
connection during development and changes in the efficiency of synaptic 
transmission throughout life. Schoepp, Bockaert, and Sladeczek. Trends in 
Pharmacol. Sci., 11, 508 (1990); McDonald and Johnson, Brain Research 
Reviews, 15, 41 (1990). 
The excessive or inappropriate stimulation of excitatory amino acid 
receptors leads to neuronal cell damage or loss by way of a mechanism 
known as excitotoxicity. This process has been suggested to mediate 
neuronal degeneration in a variety of conditions. The medical consequences 
of such neuronal degeneration makes the abatement of these degenerative 
neurological processes an important therapeutic goal. 
Excitatory amino acid excitotoxicity has been implicated in the 
pathophysiology of a number of neurological disorders. This excitotoxicity 
has been implicated in the pathophysiology of acute and chronic 
neurodegenerative conditions including stroke, cerebral ischemia, spinal 
cord trauma, head trauma, Alzheimer's Disease, Huntington's Chorea, 
amyotrophic lateral sclerosis, epilepsy, AIDS-induced dementia, perinatal 
hypoxia, hypoxia (such as conditions caused by strangulation, surgery, 
smoke inhalation, asphyxiation, drowning, choking, electrocution or drug 
or alcohol overdose), cardiac arrest, hypoglycemic neuronal damage, ocular 
damage and retinopathy, idiopathic and drug-induced Parkinson's Disease 
and cerebral deficits subsequent to cardiac bypass surgery and grafting. 
Other neurological conditions that are caused by glutamate dysfunction 
require neuromodulation. These other neurological conditions include 
muscular spasms, migraine headaches, urinary incontinence, psychosis, 
addiction withdrawal (such as alcoholism and drug addiction including 
opiate, cocaine and nicotine addiction), opiate tolerance, anxiety, 
emesis, brain edema, chronic and acute pain, convulsions, retinal 
neuropathy, tinnitus and tardive dyskinesia. The use of a neuroprotective 
agent, such as an AMPA receptor antagonist, is believed to be useful in 
treating these disorders and/or reducing the amount of neurological damage 
associated with these disorders. The excitatory amino acid receptor (EAA) 
antagonists are also believed to be useful as analgesic agents. 
The metabotropic glutamate receptors are a highly heterogeneous family of 
glutamate receptors that are linked to multiple second-messenger pathways. 
Generally, these receptors function to modulate the presynaptic release of 
glutamate, and the postsynaptic sensitivity of the neuronal cell to 
glutamate excitation. The metabotropic glutamate receptors (mGluR) have 
been pharmacologically divided into two subtypes. One group of receptors 
("Class I receptors") is positively coupled to phospholipase C, which 
causes hydrolysis of cellular phosphoinositides (PI). This first group are 
termed PI-linked metabotropic glutamate receptors. The second group of 
receptors ("Class II receptors") is negatively coupled to adenyl cyclase, 
which prevents the forskolin-stimulated accumulation of cyclic adenosine 
monophosphate (cAMP). Schoepp and Conn, Trends Pharmacol. Sci., 14, 13 
(1993). Receptors within this second group are termed cAMP-linked 
metabotropic glutamate receptors. Agonists of the cAMP-linked metabotropic 
glutamate receptors should be useful for the treatment of acute and 
chronic neurological conditions and psychiatric conditions. 
Compounds have recently been discovered that effect metabotropic glutamate 
receptors, but have no effect on ionotropic glutamate receptors. 
(1S,3R)-1-Aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD) is an 
agonist of PI-linked and cAMP-linked metabotropic glutamate receptors. 
Schoepp, Johnson, True, and Monn., Eur. J. Pharmacol., 207, 351 (1991); 
Schoepp, Johnson, and Monn, J. Neurochem., 58, 1184 (1992). 
(2S,3S,4S)-2-(carboxycyclopropyl) glycine (L-CCG-1) was recently described 
as a selective cAMP-linked metabotropic glutamate receptor agonist: 
however, at higher concentrations, this compound has activity at PI-linked 
metabotropic receptors. Nakagawa, et al., Eur J. Pharmacol., 184, 205 
(1990): Hayashi, et al., Br. J. Pharmacol., 197, 539 (1992): Schoepp et 
al., J. Neurochem., 63., 769-772 (1994). 
European Patent Application EP 696577AI, which was published on Feb. 14, 
1996, refers to certain synthetic amino acids that are described as being 
selective for the negatively coupled cAMP linked metabotropic glutamate 
receptors (i.e., Class II metabotropic glutamate receptors). 
The compounds of formula I and their pharmaceutically acceptable salts are 
metabotropic glutamate receptor ligands that are selective for Class II 
metabotropic glutamate receptors. 
SUMMARY OF THE INVENTION 
This invention relates to compounds of the formula 
##STR1## 
wherein n is 0-6; Z is (C.sub.1 -C.sub.4) alkylene, oxygen, sulfur, NH or 
N(C.sub.1 -C.sub.6)alkyl; 
R.sup.1 is hydrogen, (C.sub.1 -C.sub.6)alkyl, aryl or heteroaryl, wherein 
said aryl is selected from phenyl and naphthyl and said heteroaryl is 
selected from 5 and 6 membered aromatic heterocyclic rings that contain 
from one to four heteroatoms selected, independently, from nitrogen, 
oxygen and sulfur, and wherein said aryl and heteraryl moieties can 
optionally be substituted with one or more substituents, preferably with 
one or two substituents, that are selected, independently, from halo (es, 
fluoro, chloro, bromo or iodo), --SO(C.sub.1 -C.sub.6)alkyl, --SO.sub.2 
R.sup.4, --SO.sub.2 NR.sup.5 R.sup.6, (C.sub.1 -C.sub.6)alkyl optionally 
substituted with from one to seven fluorine atoms, (C.sub.1 
-C.sub.6)alkoxy optionally substituted with from one to seven fluorine 
atoms, amino, nitro, cyano, carboxy, --CO.sub.2 (C.sub.1 -C.sub.6)alkyl, 
(C.sub.1 -C.sub.6)alkylamino, di-[(C.sub.1 -C.sub.6)alkyl]amino phenoxy, 
anilino and phenylthio; 
R.sup.4 is --O(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkyl or phenyl; 
and 
R.sup.5 and R.sup.6 are independently selected from hydrogen, (C.sub.1 
-C.sub.6)alkyl and phenyl; 
with the proviso that R.sup.1 can not be hydrogen when n is zero, and with 
the proviso that none of the foregoing heteroaryl moieties may contain 
more than one ring oxygen atom or more than one ring sulfur atom; 
and the pharmaceutically acceptable salts of such compounds. 
Examples of the heteroaryl moieties of said heteroaryl-(C.sub.0 
-C.sub.6)alkyl are the following: oxazolyl, isoxazoyl, thiazolyl, 
isothiazolyl, furanyl, pyrazolyl, pyrrolyl, tetrazolyl, triazolyl, 
thienyl, imidazolyl, pyridinyl, and pyrimidinyl. 
This invention also relates to compounds of the formula 
##STR2## 
wherein R.sup.1 and Z are defined as for formula I above and R.sup.2 and 
R.sup.3 are selected, independently, from hydrogen and (C.sub.1 
-C.sub.6)alkyl, with the proviso that only one of R.sup.2 and R.sup.3 can 
be hydrogen. 
Compounds of the formula II are intermediates in the synthesis of compounds 
of the formula I. 
Preferred compounds of the formula I include those wherein R.sup.1 is a 
pyrid-3-yl or pyrid-4-yl group. 
Other examples of preferred compounds of the formula I are those wherein 
R.sup.1 is linked to the bicyclic ring depicted in structural formula I 
via an alkyl group. 
Other examples of preferred compounds of the formula I are those wherein 
R.sup.1 is a mono- or disubstituted phenyl group wherein one of the 
substituents is in the para position. 
Other examples of preferred compounds of the formula I are those wherein Z 
is CH.sub.2. 
Other examples of preferred compounds of the formula I are those wherein 
R.sup.1 is a thien-2-ylmethyl group. 
The compounds of formula I and their pharmaceutically acceptable salts are 
metabotropic glutamate receptor ligands and are useful in the treatment of 
a variety of neurological and psychiatric disorders. Examples of 
neurological disorders that can be treated with the compounds of formula I 
and their pharamaceutically acceptable salts are cerebral deficits 
subsequent to cardiac bypass surgery and grafting, cerebral ischemia 
(e.g., stroke and cardiac arrest), spinal cord trauma, head trauma, 
Alzheimer's Disease, Huntington's disease, amyotrophic lateral sclerosis, 
AlDS-induced dementia, muscular spasms, migrane headache, urinary 
incontinence, convulsions, perinatal hypoxia, hypoglycemic neuronal 
damage, chemical dependencies and addictions (e.g., a dependency on, or 
addiction to opiates, benzodiazepines, cocaine, nicotine or ethanol), drug 
or alcohol withdrawal symptoms, ocular damage and retinopathy, cognitive 
disorders, idiopathic and drug-induced Parkinson's Disease, emesis, brain 
edema, acute or chronic pain, sleep disorders, Tourette's syndrome, 
attention deficit disorder and tardive dyskinesia. Examples of psychiatric 
disorders that can be treated with the compounds of formula I and their 
pharamaceutically acceptable salts are schizophrenia, anxiety and related 
disorders (e.g., panic attack and stress-related disorders), depression, 
bipolar disorders, psychosis, and obsessive compulsive disorders. 
Examples of specific preferred compounds of the formula I are those wherein 
Z is CH.sub.2 and R.sup.1 is one of the following groups. 
##STR3## 
Another example of a specific preferred compound of the formula I is the 
compound of formula I wherein Z is CH.sub.2 and R.sup.1 is 3-methylbutyl. 
Other examples of specific compounds of the formula I are the following: 
2-Benzylamino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid; 
2-(4-Methoxy-benzylamino)-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid; 
2-(4-Diethylamino-benzylamino)-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid; 
2-(4-Chloro-benzylamino)-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid; 
2-(3,4-Dichloro-benzylamino)-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid; 
2-[(Pyridin-3-ylmethyl)-amino]-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid; 
2-[(Pyridin-4-ylmethyl)-amino]-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid; 
2-[(Thiophen-2-ylmethyl)-amino]-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid; 
2-(4-Pyrrolidin-1-yl-benzylamino)-bicyclo[3.1.0]hexane-2,6-dicarboxylic 
acid; 
2-(4-Piperidin-1-yl-benzylamino)-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 
and 
2-[(6-Pyrrolidin-1-yl-pyridin-3-ylmethyl)-amino]-bicyclo[3.1.0]hexane-2,6-d 
icarboxylic acid. 
The present invention also relates to the pharmaceutically acceptable acid 
addition salts of compounds of the formula I. The acids which are used to 
prepare the pharmaceutically acceptable acid addition salts of the 
aforementioned base compounds of this invention are those which form 
non-toxic acid addition salts, i.e., salts containing pharmacologically 
acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, 
nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, 
citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, 
gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, 
benzenesulfonate, p-toluenesulfonate and pamoate [i.e., 
1,1'-methylene-bis-(2-hydroxy-3-naphthoate)]salts. 
The present invention also relates to the pharmaceutically acceptable base 
addition salts of compounds of the formula I. These salts are all prepared 
by conventional techniques. The chemical bases that are used as reagents 
to prepare the pharmaceutically acceptable base salts of this invention 
are those which form non-toxic base salts with the acidic compounds of 
formula I. Such non-toxic base salts include those derived from such 
pharmacologically acceptable cations as sodium, potassium, calcium and 
magnesium, etc. 
This invention also relates to a pharmaceutical composition for treating a 
disorder or condition, the treatment or prevention of which can be 
effected or facilitated by modulating (i.e., increasing or decreasing) 
glutamate neurotransmission in a mammal, comprising an amount of a 
compound of the formula I, or a pharmaceutically effective salt thereof, 
that is effective in treating such disorder or condition and a 
pharmaceutically acceptable carrier. 
This invention also relates to a method of treating a disorder or 
condition, the treatment of which can be effected or facilitated by 
modulating glutamate neurotransmission in a mammal, comprising 
administering to a mammal in need of such treatment an amount of a 
compound of the formula I, or a pharmaceutically effective salt thereof, 
that is effective in treating such disorder or condition. 
This invention also relates to a pharmaceutical composition for treating a 
condition selected from stroke, cerebral ischemia, spinal cord trauma, 
head trauma, Alzheimer's Disease, Huntington's Chorea, amyotrophic lateral 
sclerosis, epilepsy, AIDS-induced dementia, muscular spasms, migraine 
headaches, urinary incontinence, psychosis, convulsions, perinatal 
hypoxia, hypoxia (such as conditions caused by strangulation, surgery, 
smoke inhalation, asphyxiation, drowning, choking, electrocution or drug 
or alcohol overdose), cardiac arrest, hypoglycemic neuronal damage, 
chemical dependencies and addictions (e,g., addictions to or dependencies 
on alcohol, opiates, benzodiazepines, nicotine, heroin or cocaine), ocular 
damage, retinopathy, retinal neuropathy, tinnitus, idiopathic and drug 
induced Parkinson's Disease, anxiety, panic disorder, schizophienia, 
depression, bipolar disorder, obsessive-compulsive disorder, Tourette's 
syndrome, emesis, brain edema, chronic and acute pain, tardive dyskinesia 
and cerebral deficits subsequent to cardiac bypass surgery and grafting in 
a mammal, comprising a glutamate neurotransmission modulating effective 
amount of a compound of the formula I, or a pharmaceutically salt thereof, 
and a pharmaceutically acceptable carrier. 
This invention also relates to a method for treating a condition selected 
from stroke, cerebral ischemia, spinal cord trauma, head trauma, 
Alzheimer's Disease, Huntington's Chorea, amyotrophic lateral sclerosis, 
epilepsy, AIDS-induced dementia, muscular spasms, migraine headaches, 
urinary incontinence, psychosis, convulsions, perinatal hypoxia, hypoxia 
(such as conditions caused by strangulation, surgery, smoke inhalation, 
asphyxiation, drowning, choking, electrocution or drug or alcohol 
overdose), cardiac arrest, hypoglycemic neuronal damage, chemical 
dependencies and addictions (e.g., addictions to or dependencies on 
alcohol, opiates, benzodiazepines, nicotine, heroin or cocaine), ocular 
damage, retinopathy, retinal neuropathy, tinnitus, idiopathic and drug 
induced Parkinson's Disease, anxiety, panic disorder, schizophienia, 
depression, bipolar disorder, obsessive-compulsive disorder, Tourette's 
syndrome, emesis, brain edema, chronic and acute pain, tardive dyskinesia 
and cerebral deficits subsequent to cardiac bypass surgery and grafting in 
a mammal, comprising administering to a mammal requiring such treatment a 
glutamate neurotransmission modulating effective amount of a compound of 
the formula I, or a pharmaceutically acceptable salt thereof. 
This invention also relates to a pharmaceutical composition for treating a 
disorder or condition, the treatment of which can be effected or 
facilitated by modulating glutamate neurotransmission in a mammal, 
comprising a glutamate neurotransmission modulating effective amount of a 
compound of the formula I, or a pharmaceutically acceptable salt thereof, 
and a pharmaceutically acceptable carrier. 
This invention also relates to a method for treating a disorder or 
condition, the treatment of which can be effected or facilitated by 
modulating glutamate neurotransmission in a mammal, comprising 
administering to a mammal requiring such treatment a glutamate 
neurotransmission modulating effective amount of a compound of the formula 
I or a pharmaceutically acceptable salt thereof. 
This invention also relates to a method of treating a condition selected 
from stroke, cerebral ischemia, spinal cord trauma, head trauma, 
Alzheimer's Disease, Huntington's Chorea, amyotrophic lateral sclerosis, 
epilepsy, AIDS-induced dementia, muscular spasms, migraine headaches, 
urinary incontinence, psychosis, convulsions, perinatal hypoxia, hypoxia 
(such as conditions caused by strangulation, surgery, smoke inhalation, 
asphyxiation, drowning, choking, electrocution or drug or alcohol 
overdose), cardiac arrest, hypoglycemic neuronal damage, chemical 
dependencies and addictions (e.g., addictions to or dependencies on 
alcohol, opiates, benzodiazepines, nicotine, heroin or cocdine), ocular 
damage, retinopathy, retinal neuropathy, tinnitus, idiopathic and drug 
induced Parkinson's Disease, anxiety, panic disorder schizophienia, 
depression, bipolar disorder, obsessive-compulsive disorder, Tourette's 
syndrome, emesis, brain edema, chronic and acute pain, tardive dyskinesia 
and cerebral deficits subsequent to cardiac bypass surgery and grafting in 
a mammal, comprising administering to a mammal in need of such treatment 
an amount of a compound of the formula I that is effective in treating 
such condition. 
This invention also relates to a pharmaceutical composition for treating a 
condition selected from stroke, cerebral ischemia, spinal cord trauma, 
head trauma, Alzheimer's Disease, Huntington's Chorea, amyotrophic lateral 
sclerosis, epilepsy, AIDS-induced dementia, muscular spasms, migraine 
headaches, urinary incontinence, psychosis, convulsions, perinatal 
hypoxia, hypoxia (such as conditions caused by strangulation, surgery, 
smoke inhalation, asphyxiation, drowning, choking, electrocution or drug 
or alcohol overdose), cardiac arrest, hypoglycemic neuronal damage, 
chemical dependencies and addictions (e.g., addictions to or dependencies 
on alcohol, opiates, benzodiazepines, nicotine, heroin or cocaine), ocular 
damage, retinopathy, retinal neuropathy, tinnitus, idiopathic and drug 
induced Parkinson's Disease, anxiety, panic disorder, schizophienia, 
depression, bipolar disorder, obsessive-compulsive disorder, Tourette's 
syndrome, emesis, brain edema, chronic and acute pain, tardive dyskinesia 
and cerebral deficits subsequent to cardiac bypass surgery and grafting in 
a mammal, comprising an amount of a compound of the formula I that is 
effective in treating such condition and a pharmaceutically acceptable 
carrier. 
This invention also relates to a method for treating a disorder or 
condition, the treatment of which can effected or facilitated by 
modulating glutamate neurotransmission in a mammal, comprising 
administering to a mammal requiring such treatment: 
(a) a compound of the formula I, or a pharmaceutically acceptable salt 
thereof; and 
(b) a serotonin reuptake inhibitor (e.g., sertraline, fluoxetine, 
fluvoxamine, etc.) or a serotonin-1A (5HT.sub.1A) receptor ligand (e.g., 
buspirone, flesinoxan, etc.) or a pharmaceutically acceptable salt of such 
inhibitor or ligand; 
wherein the amounts of the compound of formula I and the serotonin reuptake 
inhibitor or 5HT.sub.1A receptor ligand that are employed in such method 
are such that the combination of the two active ingredients is effective 
in treating such disorder or condition. 
This invention also relates to a pharmaceutical composition for treating a 
disorder or condition, the treatment of which can effected or facilitated 
by modulating glutamate neurotransmission in a mammal, comprising: 
(a) a compound of the formula I, or a pharmaceutically acceptable salt 
thereof; 
(b) a serotonin reuptake inhibitor (e.g., sertraline, fluoxetine, 
fluvoxamine, etc.) or a serotoin-1A (5HT.sub.1A) receptor ligand (e.g., 
buspirone, flesinoxan, etc.) or a pharmaceutically acceptable salt of such 
inhibitor or ligand; and 
(c) a pharmaceutically acceptable carrier; 
wherein the amounts of the compound of formula I and the serotonin reuptake 
inhibitor or 5HT.sub.1A receptor ligand that are contained in such 
compostion are such that the combination of the two active ingredients is 
effective in treating such disorder or condition. 
This invention also relates to a method for treating a disorder or 
condition, the treatment of which can effected or facilitated by 
modulating glutamate neurotransmission in a mammal, comprising 
administering to a mammal requiring such treatment: 
(a) a glutamate neurotransmission modulating compound, or a 
pharmaceutically acceptable salt thereof; and 
(b) a serotonin reuptake inhibitor (e.g., sertraline, fluoxetine, 
fluvoxamine, etc.) or a serotonin-1A (5HT.sub.1A) receptor ligand (e.g., 
buspirone, flesinoxan, etc.) or a pharmaceutically acceptable salt of such 
inhibitor or ligand; 
wherein the amounts of the glutamate neurotransmission modulating compound 
and the serotonin reuptake inhibitor or 5HT.sub.1A receptor ligand that 
are employed in such method are such that the combination of the two 
active ingredients is effective in treating such disorder or condition. 
This invention also relates to a pharmaceutical composition for treating a 
disorder or condition, the treatment of which can effected or facilitated 
by modulating glutamate neurotransmission in a mammal, comprising: 
(a) a glutamate neurotransmission modulating compound or a pharmaceutically 
acceptable salt thereof; 
(b) a serotonin reuptake inhibitor (e.g., sertraline, fluoxetine, 
fluvoxamine, etc.) or a serotoin-1A (5HT.sub.1A) receptor ligand (e.g., 
buspirone, flesinoxan, etc.) or a pharmaceutically acceptable salt of such 
inhibitor or ligand; and 
(c) a pharmaceutically acceptable carrier; 
wherein the amounts of the glutamate neurotransmission modulating compound 
and the serotonin reuptake inhibitor or 5HT.sub.1A receptor ligand that 
are contained in such compostion are such that the combination of the two 
active ingredients is effective in treating such disorder or condition. 
This invention also relates to a method for treating a disorder or 
condition, selected from stroke, cerebral ischemia, spinal cord trauma, 
head trauma, Alzheimer's Disease, Huntington's Chorea, amyotrophic lateral 
sclerosis, epilepsy, AIDS-induced dementia, muscular spasms, migraine 
headaches, urinary incontinence, psychosis, convulsions, perinatal 
hypoxia, hypoxia (such as conditions caused by strangulation, surgery, 
smoke inhalation, asphyxiation, drowning, choking, electrocution or drug 
or alcohol overdose), cardiac arrest, hypoglycemic neuronal damage, 
chemical dependencies and addictions (e.g., addictions to or dependencies 
on alcohol, opiates, benzodiazepines, nicotine, heroin or cocaine), ocular 
damage, retinopathy, retinal neuropathy, tinnitus, idiopathic and drug 
induced Parkinson's Disease, anxiety, panic disorder, schizophienia, 
depression, bipolar disorder, obsessive-compulsive disorder, Tourette's 
syndrome, emesis, brain edema, chronic and acute pain, tardive dyskinesia 
and cerebral deficits subsequent to cardiac bypass surgery and grafting in 
a mammal, comprising administering to a mammal requiring such treatment: 
(a) a compound of the formula I, or a pharmaceutically acceptable salt 
thereof; and 
(b) a serotonin reuptake inhibitor (e.g., sertraline, fluoxetine, 
fluvoxamine, etc.) or a serotonin-1A (5HT.sub.1A) receptor ligand (e.g., 
buspirone, flesinoxan, etc.) or a pharmaceutically acceptable salt of such 
inhibitor or ligand; 
wherein the amounts of the compound of formula I and the serotonin reuptake 
inhibitor or 5HT.sub.1A receptor ligand that are employed in such method 
are such that the combination of the two active ingredients is effective 
in treating such disorder or condition. 
This invention also relates to a pharmaceutical composition for treating a 
disorder or condition selected from stroke, cerebral ischemia, spinal cord 
trauma, head trauma, Alzheimer's Disease, Huntington's Chorea, amyotrophic 
lateral sclerosis, epilepsy, AIDS-induced dementia, muscular spasms, 
migraine headaches, urinary incontinence, psychosis, convulsions, 
perinatal hypoxia, hypoxia (such as conditions caused by strangulation, 
surgery, smoke inhalation, asphyxiation, drowning, choking, electrocution 
or drug or alcohol overdose), cardiac arrest, hypoglycemic neuronal 
damage, chemical dependencies and addictions (e.g., addictions to or 
dependencies on alcohol, opiates, benzodiazepines, nicotine, heroin or 
cocaine), ocular damage, retinopathy, retinal neuropathy, tinnitus, 
idiopathic and drug induced Parkinson's Disease, anxiety, panic disorder, 
schizophienia, depression, bipolar disorder, obsessive-compulsive 
disorder, Tourette's syndrome, emesis, brain edema, chronic and acute 
pain, tardive dyskinesia and cerebral deficits subsequent to cardiac 
bypass surgery and grafting in a mammal, comprising: 
(a) a compound of the formula I, or a pharmaceutically acceptable salt 
thereof; and 
(b) a serotonin reuptake inhibitor (e.g., sertraline, fluoxetine, 
fluvoxamine, etc.) or a serotoin-1A (5HT.sub.1A) receptor ligand (e.g., 
buspirone, flesinoxan, etc.) or a pharmaceutically acceptable salt of such 
inhibitor or ligand; and 
(c) a pharmaceutically acceptable carrier; 
wherein the amounts of the compound of formula I and the serotonin reuptake 
inhibitor or 5HT.sub.1A receptor ligand that are contained in such 
composition are such that the combination of the two active ingredients is 
effective in treating such disorder or condition. 
Unless otherwise indicated, the alkyl groups referred to herein, as well as 
the alkyl moieties of other groups referred to herein (e.g., alkoxy), may 
be linear or branched, and they may also be cyclic (e.g., cyclopropyl, 
cyclobutyl, cyclopentyl, or cyclohexyl) or be linear or branched and 
contain cyclic moieties. 
The term "treating" as used herein, refers to reversing, alleviating, 
inhibiting the progress of, or preventing the disorder or condition to 
which such term applies, or one or more symptoms of such disorder or 
condition. The term "treatment", as used herein, refers to the act of 
treating, as "treating" is defined immediately above. 
Unless otherwise indicated, "halo" and "halogen", as used herein, refer to 
fluorine, bromine, chlorine or iodine. 
Compounds of the formula I may have chiral centers and therefore may exist 
in different enantiomeric and diastereomic forms. This invention relates 
to all optical isomers and all other stereoisomers of compounds of the 
formula I, and to all racemic and other mixtures thereof, and to all 
pharmaceutical compositions and methods of treatment defined above that 
contain or employ such isomers or mixtures. 
Formula I above includes compounds identical to those depicted but for the 
fact that one or more hydrogen or carbon atoms are replaced by isotopes 
thereof. Such compounds are useful as research and diagnostic tools in 
metabolism pharmokinetic studies and in binding assays. Specific 
applications in research include radioligand binding assays, 
autoradiography studies and in vivo binding studies. 
DETAILED DESCRIPTION OF THE INVENTION 
The compounds of formula I can be prepared according to the methods of 
Scheme 1. In the reaction Scheme and discussion that follow, unless 
otherwise indicated, n, Z, R.sup.1, R.sup.2, R.sup.3 R.sup.4, R.sup.5 and 
R.sup.6 and structural formulas I and II are defined as above. 
##STR4## 
Scheme 1 illustrates the preparation of all compounds of the formula I in 
which there is an alkyl linkage of R.sup.1 to the amino nitrogen of 
formula I. 
Referring to Scheme I, a compound of the formula III is reacted with the 
appropriate aldehyde of the formula R.sup.1 (CH.sub.2).sub.m CHO, wherein 
m is equal to n-1, to form a compound of the formula IIA. 
The above reductive amination reaction can be carried out using standard 
methods well known to those of skill in the art. This reaction is 
typically carried out in the presence of a reducing agent such as sodium 
cyanoborohydride, sodium triacetoxyborohydride, sodium borohydride, 
hydrogen (or a chemical hydrogen source such as formic acid or ammonium 
formate) and a metal catalyst such as platinum, palladium or rhodium, zinc 
and hydrochloric acid, borane dimethylsulfide or formic acid, at a 
temperature from about -60.degree. C. to about 50.degree. C. Suitable 
reaction inert solvents for this reaction include lower alcohols (e.g., 
methanol, ethanol and isopropanol), dioxane, methylene chloride, 
dichloroethane, acetic acid and tetrahydrofuran (THF). Preferably, the 
solvent is methylene chloride or dichloroethane, the temperature is about 
25.degree. C., and the reducing agent is sodium triacetoxyborohydride. 
The compounds of formula IIA formed in the above reaction can be converted 
onto the corresponding desired compounds of the formula I by subjecting 
them to acid or base hydrolysis, using methods well known to those of 
skill in the art. Suitable acids for the use in acid hydrolysis compound 
of the formula IIA include mineral acids such as hydrofluoric acid, 
sulfuric acid, hydrochloric acid and hydrobromic acid. Suitable bases for 
use in base hydrolysis of compounds of the formula IIA include alkali 
metal hydroxides and barium hydroxide. The reaction temperature for the 
acid and base hydrolysis reactions can range from about 0.degree. C. to 
about 100.degree. C. Preferably, these reactions are carried out at about 
the reflux temperature of the reaction mixture. 
Compounds of the formula I, wherein R.sup.1 is aryl or heteroaryl and n is 
zero can be formed from the corresponding compounds of the formula IIA, as 
illustrated in Schemes 2 and 3, respectively. Compounds of the formula IIA 
wherein R.sup.1 is aryl can be formed, as illustrated in Scheme 2, by 
reacting the corresponding compounds of the formula III, as depicted in 
Scheme 2, with a compound of the formula R.sup.1 X, wherein X is a leaving 
group such as halo, triflate, mesylate or tosylate. This reaction is 
generally carried out in a solvent such as ethanol, N,N-dimethylformamide 
(DMF), N,N-dimethylacetamide, acetonitrile, nitromethene, dioxane or 
dichloroethane, preferably DMF, at a temperature from about 0.degree. C. 
to about 160.degree. C., preferably at about the reflux temperature. 
Scheme 2 specifically depicts the synthesis of compounds of the formula I 
wherein R.sup.1 is an unsubstituted phenyl group or a phenyl group having 
from 0 to 3 electron withdrawing groups (EWG'S) as substituents. Examples 
of EWG's include, but are not limited to, nitro, (C.sub.1 
-C.sub.6)alkyl-SO--, (C.sub.1 -C.sub.6)alkyl-SO.sub.2 --, (C.sub.1 
-C.sub.6)alkyl-O--C(.dbd.O)--, [(C.sub.1 -C.sub.6)alkyl)].sub.2 
NC(.dbd.O)--, cyano, --SO.sub.2 R.sup.4 and SO.sub.2 NR.sup.5 R.sup.6. 
In an analogous fashion, compounds of the formula I wherein R.sup.1 is 
heteroaryl and n is zero may be prepared as illustrated in Scheme 3. 
Referring to Scheme 3, a compound of the formula III is reacted with a 
heteroaromatic compound of the formula V wherein ring A is a nitrogen 
containing heterocycle and X is a leaving group, as defined above, which 
is ortho to a ring nitrogen. The intermediate of the formula IIA that is 
formed in the foregoning reaction can be further hydrolyzed, under the 
conditions described above, to yeild the desired final product of formula 
I. Examples of compounds of the formula V are the following: 
##STR5## 
The presence on the above heteroaryl groups of additional EWG's further 
activates them. 
Compounds wherein R.sup.1 is another aryl or heteroaryl group can be 
synthesized in an analogous fashion starting with the appropriate compound 
of the formula R.sup.1 X. 
Additional compounds of the formula I wherein R.sup.1 is substituted aryl 
or heteroaryl may be obtained from compounds of the formula IIA wherein 
R.sup.1 is a nitroaryl or nitroheteroraryl group, by employing well known 
synthetic chemical methods. For example, following procedures such as 
those described by Jerry March, Advanced Organic Chemistry, 4th edition 
pp721-725 and 1216-1217, the nitro group can be reduced to an amine. The 
newly formed amine can be replaced with other substituents by 
diazotization and further reaction as summarized in the above reference. 
For example, compounds of the formula I wherein R.sup.1 is an aryl or 
heteroaryl group substituted with amino, mercapto, halo, cyano, or phenyl 
can be prepared in this manner. 
The starting materials of formula IV and other compounds of the formula 
R.sup.1 X are either commerically available, known in the literature, or 
readily obtainable from commercially available or known compounds using 
methods that are known in the art. 
The starting materials of the formula III are known in the literature. 
(See, e.g., European Patent Application 696577A1, referred to above). 
Compounds of the formula II wherein one of R.sup.2 and R.sup.3 is hydrogen 
can be prepared by partial hydrolysis of the corresponding compounds of 
formula IIA. 
Unless indicated otherwise, the pressure of each of the above reactions is 
not critical. Generally, the reactions will be conducted at a pressure of 
about one to about three atmospheres, preferably at ambient pressure 
(about one atmosphere). 
The preparation of other compounds of the formula I not specifically 
described in the foregoing experimental section can be accomplished using 
combinations of the reactions described above that will be apparent to 
those skilled in the art. 
The compounds of the formula I that are basic in nature are capable of 
forming a wide variety of different salts with various inorganic and 
organic acids. The acid that can be used to prepare the pharmaceutically 
acceptable acid addition salts of the base compounds of this invention are 
those which form non-toxic acid addition salts, i.e., salts containing 
pharmacologically acceptable anions, such as hydrochloride, hydrobromide, 
hydroiodide, nitrate, sulfate or bisulfate, phosphate or acid phosphate, 
acetate, lactate, citrate or acid citrate, tartrate or bitartrate, 
succinate, maleate, fumarate, gluconate, saccharate, benzoate, 
methanesulfonate and pamoate [i.e., 
1,1'-methylene-bis-(2-hydroxy-3-naphthoate)] salts. Although such salts 
must be pharmaceutically acceptable for administration to animals, it is 
often desirable in practice to initially isolate a compound of the formula 
I from the reaction mixture as a pharmaceutically unacceptable salt and 
then simply convert the latter back to the free base compound by treatment 
with an alkaline reagent, and subsequently convert the free base to a 
pharmaceutically acceptable acid addition salt. The acid addition salts of 
the base compounds of this invention are readily prepared by treating the 
base compound with a substantially equivalent amount of the chosen mineral 
or organic acid in an aqueous solvent medium or in a suitable organic 
solvent such as methanol or ethanol. Upon careful evaporation of the 
solvent, the desired solid salt is obtained. 
Compounds of the formula that are acidic in nature are capable of forming 
base salts with various pharmacologically acceptable cations. These salts 
are all prepared by conventional techniques. The chemical bases that are 
used as reagents to prepare the pharmaceutically acceptable base salts of 
this invention are those which form non-toxic base salts with the acidic 
compounds of formula I. Such non-toxic base salts include those derived 
from such pharmacologically acceptable cations as sodium, potassium, 
calcium and magnesium, etc. These salts can easily be prepared by treating 
the corresponding acidic compounds with an aqueous solution containing the 
desired pharmacologically acceptable cations, and then evaporating the 
resulting solution to dryness, preferably under reduced pressure. 
Alternatively, they may also be prepared by mixing lower alkanolic 
solutions of the acidic compounds and the desired alkali metal alkoxide 
together, and then evaporating the resulting solution to dryness in the 
same manner as before. In either case, stoichiometric quantities of 
reagents are preferably employed in order to ensure completeness of 
reaction and maximum yields of the desired final product. 
The compounds of the formula I and the pharmaceutically acceptable salts 
thereof (hereinafter, also referred to, collectively, as "the active 
compounds of the invention") are useful for the treatment of 
neurodegenerative, psychotropic and drug or alcohol induced deficits and 
are potent metabotropic glutamate receptor ligands antagonists. The active 
compounds of the invention may therefore be used in the treatment or 
prevention of stroke, cerebral ischemia, spinal cord trauma, head trauma, 
Alzheimer's Disease, Huntington's Chorea, amyotrophic lateral sclerosis, 
epilepsy, AIDS-induced dementia, muscular spasms, migraine headaches, 
urinary incontinence, psychosis, convulsions, perinatal hypoxia, hypoxia 
(such as conditions caused by strangulation, surgery, smoke inhalation, 
asphyxiation, drowning, choking, electrocution or drug or alcohol 
overdose), cardiac arrest, hypoglycemic neuronal damage, chemical 
dependencies and addictions (e.g., addictions to or dependencies on 
alcohol, opiates, benzodiazepines, nicotine, heroin or cocaine), ocular 
damage, retinopathy, retinal neuropathy, tinnitus, idiopathic and drug 
induced Parkinson's Disease, anxiety, emesis, brain edema, chronic and 
acute pain, tardive dyskinesia and cerebral deficits subsequent to cardiac 
bypass surgery and grafting. 
The following procedure can be used to determine the activity of the 
therapeutic agents of this invention as agonists and as antagonists of 
metabotropic glutamate receptors. 
Chinese hamster ovary (CHO) cells were transfected with cDNA (mGluR2 and 
pcDNA3) using a calcium-phosphate method. Positive clones were selected 
for using geneticin (G418, Gibco, 500-700 .mu.g/ml), and analyzed with 
RT-PCR for the presence of mGluR2 mRNA (primers for mGluR2: 5'-AAG TGC CCG 
GAG AAC TTC AAC GAA-3' AND 5'-AAA GCG ACG ACG TTG TTG AGT CCA-3'). 
Positive clones were grown to confluency and cAMP responses were measured 
in the presence of 10 .mu.M forskolin. Confluent clones were frozen and 
stored in liquid nitrogen. 
Chinese hamster ovary (CHO) cells stably transfected with the rat 
metabotropic glutamate receptor, mGluR2, were grown to confluence in 
Dulbecco's Modified Eagle Medium (DMEM) (Gibco catalog # 11960-044), 
containing 10% dialysed fetal bovine serum, 1% proline, 0.11 mg/ml sodium 
pyruvate, 0.5 mg/ml Geneticin, 2 mM I-glutamine, and 
penicillin/streptomycin. Cells were harvested using a 5 mM 
ethylenediaminetetraacetic acid (EDTA) solution, and then spun down at 800 
rpm in a 4.degree. C. refrigerated centrifuge. The remaining pellet was 
resuspended in a phosphate-buffered saline solution containing 30 mM HEPES 
(Giboo, catino.15630-080) 5 mM magnesium chloride (MgCl.sub.2), 300 .mu.M 
3-Isobutyl-I-methylxanthine (IBMX), and 0.1% dextrose. The cell suspension 
was added in 200 .mu.l aliquots to flat bottomed polypropylene tubes that 
were then placed in a 37.degree. C. heated water bath for 22 minutes. If a 
compound was being tested for antagonist activity, it was allowed to 
preincubate with the cells in the bath during the first 11 minutes. At the 
end of the 11 minutes, 5 .mu.M forskolin plus a known concentration of an 
the test compound were added, and the incubation was continued for another 
11 minutes. If a compound was being tested for agonist activity, the cells 
were allowed to shake in the bath for the initial 11 minutes, and then 5 
.mu.M forskolin plus a known concentration of agonist were added for the 
remaining 11 minute incubation. In either case, the reaction was stopped 
with 25 .mu.l of 6N perchloric acid (PCA), and each tube was transferred 
immediately to an ice water bath. The pH of each sample was adjusted to 
approximately 8.0 with the addition of potassium hydroxide (KOH), and 
stabilized with the addition of Tris, pH 7.4. Aliquots (25 .mu.l) were 
assayed in a commercial competitive binding kit (Amersham TRK.432). The 
samples were then harvested onto GF/B filters coated in 0.5% PEI using a 
96-well Skatron harvester. Samples were quantified using a 1205 Betaplate 
liquid scintillation counter. 
CPMs from the Betaplate reader were converted to pmoles cAMP/mg 
protein/minute of incubation with forskolin using an Excel spreadsheet. 
EC.sub.50 's and IC.sub.50 's can be calculated from linear regression of 
the concentration response data. 
The following proceeding can be used to determine the agonist activity of 
the therapeutic agents of this invention as agonists of metabotropic 
glutamate receptors. 
Chinese hamster ovary (CHO) cells stably transfected with the rat 
metabotropic glutamate receptor, mGluR2, were grown to confluence in DMEM 
(Gibco catalog # 11960-044), containing 10% dialyzed fetal bovine serum, 
1% proline, 0.11 mg/ml sodium pyruvate, 0.5 mg/ml Geneticin, 2 mM 
I-glutamine, and penicillin/streptomycin. Cells are harvested using a 5 mM 
EDTA solution, and homogenized for 10 strokes with a glass-teflon hand 
held homogenizer, then 50 volumes of a phosphate buffered saline solution 
(PBS) are added and the solution is spun at 18,000 RPM for 10 minutes at 
4.degree. C. The pellet is rehomogenized and resuspended in assay buffer 
(100 mM HEPES, 1 mM EGTA, pH 7.5) at a concentration that will result in 
approx. 0.009 mg protein/well. A reaction mix containing 6 mM MgCl.sub.2, 
0.5 mM adenosine triphosphate (ATP), 0.5 mM 3-isobutyl-1-methylxanthine 
(IBMX), 0.1 mM guanosine triphosphate (GTP), 10 mM phosphocreatine, 0.31 
mg/ml creatine phosphokinase (final concentrations in assay) is prepared 
just prior to the initiation of the experiment. 20 .mu.l of test compound, 
20 .mu.l of forskolin (5 .mu.M final), 20 .mu.l of reaction mix, and 40 
.mu.l of tissue are added in consecutive order to a 96-well polypropaline 
plate. The plate is incubated at 37.degree. C. in a heated water bath for 
15 minutes. The reaction is stopped with the addition of 50 .mu.l of 40 mM 
EDTA. The plate is then transferred to ice and shaken for 10-15 minutes 
before a 25 .mu.l aliquot is removed for analysis in a commercial 
competitive binding kit (Amersham TRK.432). After a 2-18 hour incubation 
in the refrigerator, the samples are harvested onto GF/B filters coated in 
0.5% polyethylenimine (PEI) using a 96-well Skatron harvester. Samples 
were quantified using a 1205 Betaplate liquid scintillation counter. 
CPMs from the Betaplate reader are converted to pmoles cAMP/well using an 
Excel spreadsheet. Agonist compounds are identified by percent reduction 
of the forskolin signal, also in Excel. EC.sub.50 's are calculated from 
linear regression of the concentration response data. 
The compositions of the present invention may be formulated in a 
conventional manner using one or more pharmaceutically acceptable 
carriers. Thus, the active compounds of the invention may be formulated 
for oral, buccal, transdermal (e.g., patch), intranasal, parenteral (e.g., 
intravenous, intramuscular or subcutaneous) or rectal administration or in 
a form suitable for administration by inhalation or insufflation. 
For oral administration, the pharmaceutical compositions may take the form 
of, for example, tablets or capsules prepared by conventional means with 
pharmaceutically acceptable excipients such as binding agents (e.g., 
pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl 
methylcellulose); fillers (e.g., lactose, microcrystalline cellulose or 
calcium phosphate); lubricants (e.g., magnesium stearate, talc or silica); 
disintegrants (e.g., potato starch or sodium starch glycollate); or 
wetting agents (e.g., sodium lauryl sulphate). The tablets may be coated 
by methods well known in the art. Liquid preparations for oral 
administration may take the form of, for example, solutions, syrups or 
suspensions, or they may be presented as a dry product for constitution 
with water or other suitable vehicle before use. Such liquid preparations 
may be prepared by conventional means with pharmaceutically acceptable 
additives such as suspending agents (e.g., sorbitol syrup, methyl 
cellulose or hydrogenated edible fats); emulsifying agents (e.g., lecithin 
or acacia); non-aqueous vehicles (e.g., almond oil, oily esters or ethyl 
alcohol); and preservatives (e.g., methyl or propyl p-hydroxybenzoates or 
sorbic acid). 
For buccal administration the composition may take the form of tablets or 
lozenges formulated in conventional manner. 
The active compounds of the invention may be formulated for parenteral 
administration by injection, including using conventional catheterization 
techniques or infusion. Formulations for injection may be presented in 
unit dosage form, e.g., in ampules or in multi-dose containers, with an 
added preservative. The compositions may take such forms as suspensions, 
solutions or emulsions in oily or aqueous vehicles, and may contain 
formulating agents such as suspending, stabilizing and/or dispersing 
agents. Alternatively, the active ingredient may be in powder form for 
reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, 
before use. 
The active compounds of the invention may also be formulated in rectal 
compositions such as suppositories or retention enemas, e.g., containing 
conventional suppository bases such as cocoa butter or other glycerides. 
For intranasal administration or administration by inhalation, the active 
compounds of the invention are conveniently delivered in the form of a 
solution or suspension from a pump spray container that is squeezed or 
pumped by the patient or as an aerosol spray presentation from a 
pressurized container or a nebulizer, with the use of a suitable 
propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, 
dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the 
case of a pressurized aerosol, the dosage unit may be determined by 
providing a valve to deliver a metered amount. The pressurized container 
or nebulizer may contain a solution or suspension of the active compound. 
Capsules and cartridges (made, for example, from gelatin) for use in an 
inhaler or insufflator may be formulated containing a powder mix of a 
compound of the invention and a suitable powder base such as lactose or 
starch. 
A proposed dose of the active compounds of the invention for oral, 
parenteral or buccal administration to the average adult human for the 
treatment of the conditions referred to above (e.g., stroke) is 0.01 to 50 
mg/kg of the active ingredient per unit dose which could be administered, 
for example, 1 to 4 times per day. 
Aerosol formulations for treatment of the conditions referred to above 
(e.g., stroke) in the average adult human are preferably arranged so that 
each metered dose or "puff" of aerosol contains 20 mg to 1000 mg of the 
compound of the invention. The overall daily dose with an aerosol will be 
within the range 100 mg to 10 mg. Administration may be several times 
daily, for example 2, 3, 4 or 8 times, giving for example, 1, 2 or 3 doses 
each time.