HK1036050A - Bicyclo[2.2.1]heptanes and related compounds - Google Patents

Description

Bicyclo [ 2.2.1 ] heptanes and related compounds

The present application claims the benefit of U.S. provisional application 60/078346 filed on 17/3/1998.

Background

The present invention relates to compounds of formula I, as described below, their pharmaceutically acceptable salts, pharmaceutical compositions containing them and their use in the treatment of neurological and psychiatric disorders.

The role of excitatory amino acids, such as glutamate and aspartate, as the major transmitters of excitatory synaptic transmission in the central nervous system is well established. Watkins & Evans annual review of pharmacology and toxicology (ann.rev.pharmacol.toxicol.) 21, 165 (1981); monaghan, Bridges and Cotman annual review of pharmacology and toxicology 29, 365 (1989); watkins, Krogsgaard-Larsen and Honore, Pharmacology Association, 11, 25 (1990). These amino acids exert their functions in synaptic transmission mainly through excitatory amino acid receptors. These amino acids are also involved in various other physiological processes, such as motor control, respiration, cardiovascular regulation, sensory perception and cognition.

Excitatory amino acid receptors fall into two general classes. Receptors that are directly linked to the opening of cation channels in neuronal cell membranes are called "ionotropic" receptors. Receptors of this type have been subdivided into at least three subtypes, defined by the depolarizing action of the selective agonists N-methyl-D-aspartate (NMDA), α -amino-3-hydroxy-5-methylisoxazole-4-propanoic acid (AMPA) and Kainic Acid (KA). The second general type is the G-protein or the "metabotropic (metabropic)" receptor linked to a second messenger. The second type activates the second messenger system after being activated by the agonists quisqualate, amanitic acid, trans-1-aminocyclopentane-1, 3-dicarboxylic acid or 2-amino-4-phosphonobutyric acid. A portion of these second messenger-linked receptors are coupled negatively to adenylate cyclase. Both receptors appear to mediate not only normal synaptic transmission along excitatory pathways, but also to be involved in modifying synaptic connections during development and altering synaptic transmission efficiency throughout life. Schoepp, Bockaert and Sladeczek "Trends in pharmacology science (Trends in pharmacol. sci.) 11, 508 (1990); McDonald and Johnson's review of Brain Research (Brain Research Reviews)15, 41 (1990).

Excessive or inappropriate stimulation of excitatory amino acids causes neuronal cell damage or loss, a mechanism known as excitotoxicity. This process has been suggested to mediate neuronal degeneration under a variety of conditions. The therapeutic outcome of this neuronal degeneration is the alleviation of these degenerative neurological processes as an important therapeutic target.

Excitotoxicity of excitatory amino acids has been implicated in the pathophysiology of a variety of neurological disorders. This excitotoxicity has been implicated in the pathophysiology of acute and chronic neurodegenerative states including stroke, cerebral ischemia, spinal cord injury, head trauma, alzheimer's disease, huntington's chorea, amyotrophic lateral sclerosis, epilepsy, AIDS-induced dementia, perinatal hypoxia, hypoxia (such as those caused by strangulation, surgery, smoke inhalation, asphyxia, drowning, choking, electrocution, drugs or alcohol overdose), cardiac arrest, hypoglycemic neuronal injury, eye injury and retinopathy, idiopathic and drug-induced parkinson's disease, and brain defects secondary to cardiac bypass surgery and transplantation. Other neurological states resulting from glutamate dysfunction require neuromodulation. These other neurological conditions include muscle spasms, migraine, urinary incontinence, psychosis, withdrawal from cravings (e.g., alcoholism and drug addiction, including opiate, cocaine and nicotine addiction), opiate tolerance, anxiety, emesis, cerebral edema, chronic and acute pain, convulsions, retinal neuropathy, tinnitus and tardive dyskinesia. The use of AMPA receptor antagonists and the like for neuroprotection is believed to be useful in treating these disorders and/or reducing the extent of neurological damage associated with these disorders. Excitatory amino acid receptor (EAA) antagonists are also believed to be useful as analgesics.

Metabotropic glutamate receptors are a class of highly heterotypic glutamate receptors that link multiple second messenger pathways. In general, these receptors are capable of modulating presynaptic release of glutamate and postsynaptic sensitivity of neuronal cells to glutamate excitation. Metabotropic glutamate receptors (mGluRs) have been pharmacologically divided into three subtypes. One group of receptors ("class i receptors") is actively coupled to phospholipase C, leading to cellular Phosphoinositide (PI) hydrolysis. This first group is called PI-linked metabotropic glutamate receptors. The second group of receptors ("class ii and iii receptors") couples negatively with adenylate cyclase, preventing forskolin-stimulated cyclic adenosine monophosphate (cAMP) accumulation. Schoepp and Conn, trends in pharmacology sciences, 14, 13 (1993). The group II and group III receptors are distinguished by selective activation of trans-1-aminocyclopentane-1, 3-dicarboxylic acid and 2-amino-4-phosphonobutyric acid, respectively. The receptors in this second group are called metabotropic glutamate receptors linked to cAMP. A metabotropic glutamate receptor agonist linked to cAMP should be useful in the treatment of acute and chronic neurological and psychiatric states.

Recently, compounds have been found that have an effect on metabotropic glutamate receptors, but no effect on ionized glutamate receptors. (1S, 3R) -1-aminocyclopentane-1, 3-dicarboxylic acid (1S, 3R-ACPD) is a metabotropic glutamate receptor agonist linking PI and linking cAMP. Schoepp, Johnson, True and Monn, journal of European Pharmacology 207, 351 (1991); schoepp, Johnson and Monn J. Neurochem 58, 1184 (1992). (2S, 3S, 4S) -2- (carboxycyclopropyl) glycine (L-CCG-1) has recently been described as a metabotropic glutamate receptor agonist selectively linked to cAMP; however, at high concentrations, the compounds have activity towards metabotropic receptors linked to PI. Nakagawa et al, J European Pharmacology 184, 205 (1990); hayashi et al journal of british pharmacology 197, 539 (1992); schoepp et al J. Neurochem.63, 769-772 (1994).

European patent application EP 696577a1, published 2/14/1996, relates to certain synthetic amino acids that are described as selective for the electrode-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, selective for class II metabotropic glutamate receptors.

Summary of The Invention

The present invention relates to compounds of the formula

Wherein n is 0 to 6;

x is CH₂、CH₂CH₂Or oxygen;

z is CHR²Or NR²；

R¹And R²Independently selected from hydrogen, (C)₁-C₆) Alkyl, aryl and heteroaryl, wherein the aryl is selected from phenyl and naphthyl and the heteroaryl is selected from 5-and 6-membered aromatic heterocycles containing one to four heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the aryl and heteroaryl moieties may optionally be substituted by one or more, preferably one or two, substituents independently selected from halogen (e.g. fluorine, chlorine, bromine or iodine), -S (C)₁-C₆) Alkyl, -S (O) (C)₁-C₆) Alkyl, -S (O)₂(C₁-C₆) Alkyl, optionally substituted by one to seven fluorine atoms (C)₁-C₆) Alkyl, optionally substituted by one to seven fluorine atoms (C)₁-C₆) Alkoxy, amino, nitro, cyano, carboxyl, -CO₂(C₁-C₆) Alkyl, (C)₁-C₆) Alkylamino, di [ (C)₁-C₆) Alkyl radical]Aminophenoxy, phenylamino, and thiophenyl;

with the proviso that none of the foregoing heteroaryl moieties contain one or more epoxy atoms or one or more episulfide atoms;

and pharmaceutically acceptable salts of the compounds.

Said heteroaryl group- (C)₀-C₆) Examples of heteroaryl moieties for alkyl are as follows: oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furanyl, pyrazolyl, pyrrolyl, tetrazolyl, triazolyl, thienyl, imidazolyl, pyridyl and pyrimidinyl.

The invention also relates to compounds of the formula

Wherein X and Z are as defined above for formula I, R⁷Is hydrogen, (C)₁-C₆) Alkyl or benzyl.

Compounds of formulae II, III and IV are intermediates in the synthesis of compounds of formula I.

Preferred compounds of formula I include those wherein R¹Are those which are pyridin-3-yl or pyridin-4-yl.

Other preferred compounds of formula I include those wherein R¹Are those of hydrogen, unsubstituted phenyl or phenyl substituted with one or two substituents. When R is¹When substituted phenyl, preferred substituents on said phenyl are independently selected from (C)₁-C₆) Alkyl, nitro, cyano, halogen, CF₃Quilt CF₃Substituted (C)₁-C₅) Alkyl, by CF₃Substituted (C)₁-C₅) Alkoxy and-O-CF₃。

Other preferred compounds of formula I include those wherein n is 1-6. Compounds of formula I wherein n is 1 or 2 are more preferred.

Other preferred compounds of formula I include those wherein Z is CH₂Those of (a).

Other preferred compounds of formula I include those wherein X is CH₂Those of (a).

Other preferred compounds of formula I include those wherein X and Z are both CH₂、R¹Are hydrogen and n is zero.

Other embodiments of the present invention include compounds of formula i wherein:

(a) z is NH;

(b) z is NR²，R²Is (C)₁-C₆) An alkyl group;

(c) z is NR²，R²Is phenyl;

(d) z is NR²N is zero, R¹Is phenyl or substituted phenyl;

(e) R¹and R²One is aryl or heteroaryl; or

(f)R¹And R²Are selected from the group consisting of aryl, substituted aryl, heteroaryl and substituted heteroaryl.

Preferred compounds of formula i include, but are not limited to:

2- (endo) -amino-bicyclo [ 2.2.1 ] heptane-2- (exo) -6- (exo) -dicarboxylic acid;

(+) -2- (endo) -aminobicyclo [ 2.2.1 ] heptane-2- (exo) -6- (exo) -dicarboxylic acid;

(-) -2- (endo) -aminobicyclo [ 2.2.1 ] heptane-2- (exo) -6- (exo) -dicarboxylic acid;

2- (endo) -benzylamino-bicyclo [ 2.2.1 ] heptane-2- (exo) -6- (exo) -dicarboxylic acid; and

2- (endo) -phenethylamino-bicyclo [ 2.2.1 ] heptane-2- (exo) -6- (exo) -dicarboxylate.

Preferred compounds of formulae II, III and IV include those wherein R⁷Is hydrogen, (C)₁-C₆) Alkyl or benzyl groups. In one embodiment, the compound of formula II, III or IV includes those wherein R is⁷Is (C)₁-C₆) Tertiary alkyl groups such as tertiary butyl.

The compounds of formula I and their pharmaceutically acceptable salts are ligands for the metabotropic glutamate receptor and are useful in the treatment of various neurological and psychiatric disorders. Examples of neurological disorders which can be treated with the compounds of formula I and their pharmaceutically acceptable salts are cerebral defects secondary to heart bypass surgery and transplantation, cerebral ischaemias (e.g. stroke and cardiac arrest), spinal cord injury, head trauma, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, AIDS-induced dementia, muscle spasms, migraine, urinary incontinence, convulsions, perinatal hypoxia, hypoglycemic neuronal damage, chemical dependence and drug addiction (e.g. dependence on opiates, benzodiazepines , cocaine, nicotine or ethanol or drug addiction), symptoms of drug or alcohol withdrawal, eye damage and retinopathy, cognitive disorders, idiopathic and drug-induced parkinson's disease, emesis, cerebral edema, acute or chronic pain, sleep disorders, tourette's syndrome, attention deficit disorders and tardive dyskinesia. Examples of psychiatric disorders which can be treated with the compounds of formula i and their pharmaceutically acceptable salts are schizophrenia, anxiety and related disorders (e.g. general anxiety disorders, panic attacks and stress-related disorders such as post-traumatic stress syndrome), depression, bipolar disorders, psychosis and obsessive compulsive disorders.

The invention also relates to pharmaceutically acceptable acid addition salts of the compounds of formula I. The acids used to prepare the pharmaceutically acceptable acid addition salts of the base compounds of the invention described above are those that form non-toxic acid addition salts, i.e., salts containing pharmaceutically acceptable anions, such as 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' -methylene-bis (2-hydroxy-3-naphthoate)).

The invention also relates to pharmaceutically acceptable base addition salts of the compounds of formula I. These salts are prepared by conventional techniques. Chemical bases useful as reagents for preparing the pharmaceutically acceptable base salts of the present invention are those which form non-toxic base salts with the acidic compounds of formula i. The non-toxic base salts include those derived from pharmaceutically acceptable cations such as sodium, potassium, calcium, magnesium, and the like.

The invention also relates to a pharmaceutical composition for treating a disorder or condition in a mammal, which treatment or prevention of the disorder or condition is enabled or facilitated by modulation (i.e., increase or decrease) of glutamate neurotransmission, comprising an amount of a compound of formula i, or a pharmaceutically effective salt thereof, effective in treating the disorder or condition, and a pharmaceutically acceptable carrier.

The invention also relates to a method of treating a disorder or condition in a mammal in which treatment of the disorder or condition is effected or facilitated by modulation of glutamate neurotransmission, which comprises administering to a mammal in need of such treatment an amount of a compound of formula I, or a pharmaceutically effective salt thereof, which amount is effective in treating the disorder or condition.

The invention also relates to a pharmaceutical composition for treating a mammalian condition selected from the group consisting of stroke, cerebral ischemia, spinal cord injury, brain trauma, Alzheimer's disease, Huntington's chorea, amyotrophic lateral sclerosis, epilepsy, AIDS-induced dementia, muscle spasms, migraine, urinary incontinence, psychosis, convulsions, perinatal hypoxia, hypoxia (such as that caused by strangulation, surgery, smoke inhalation, asphyxia, drowning, choking, electrocution, drugs or alcohol overdose), cardiac arrest, hypoglycemic neuronal damage, chemical dependence and drug addiction (such as drug addiction or dependence on alcohol, opiates, benzodiazepines , nicotine, heroin or cocaine), ocular damage, retinopathy, retinal neuropathy, tinnitus, idiopathic and drug-induced Parkinson's disease, anxiety (such as post-traumatic stress syndrome), Panic disorder, generalized anxiety disorder, simple phobias and social phobias), schizophrenia, depression, bipolar disorder, obsessive-compulsive disorder, tourette's syndrome, emesis, cerebral edema, chronic and acute pain, tardive dyskinesia, and brain defects secondary to cardiac bypass surgery and transplantation, which comprises a glutamate neurotransmission modulating effective amount of a compound of formula i or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

The invention also relates to methods for treating a condition selected from the group consisting of stroke, cerebral ischemia, spinal cord injury, brain trauma, Alzheimer's disease, Huntington's chorea, amyotrophic lateral sclerosis, epilepsy, AIDS-induced dementia, muscle spasms, migraine, urinary incontinence, psychosis, convulsions, perinatal hypoxia, hypoxia (such as conditions caused by strangulation, surgery, smoke inhalation, asphyxia, drowning, choking, electrocution, drugs or alcohol overdose), cardiac arrest, hypoglycemic neuronal damage, chemical dependence and drug addiction (such as drug addiction or dependence on alcohol, opiates, benzodiazepines , nicotine, heroin or cocaine), ocular damage, retinopathy, retinal neuropathy, tinnitus, idiopathic and drug-induced Parkinson's disease, anxiety (such as post-traumatic stress syndrome), Panic disorder, generalized anxiety disorder, simple phobias and social phobias), schizophrenia, depression, bipolar disorder, obsessive-compulsive disorder, tourette's syndrome, emesis, cerebral edema, chronic and acute pain, tardive dyskinesia, and brain defects secondary to cardiac bypass surgery and transplantation, which comprises administering to a mammal in need of such treatment a glutamate neurotransmission modulating effective amount of a compound of formula i or a pharmaceutically acceptable salt thereof.

The invention also relates to a pharmaceutical composition for treating a disorder or condition in a mammal which treatment is effected or facilitated by modulation of glutamate neurotransmission, comprising a glutamate neurotransmission modulating effective amount of a compound of formula i, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

The invention also relates to a method for treating a disorder or condition in a mammal which is amenable to or facilitated by modulation of glutamate neurotransmission, which comprises administering to a mammal in need of such treatment a compound of formula I or a pharmaceutically acceptable salt thereof, in an amount effective for modulation of glutamate neurotransmission. The invention also relates to methods of treating a mammalian condition selected from the group consisting of stroke, cerebral ischemia, spinal cord injury, brain trauma, Alzheimer's disease, Huntington's chorea, amyotrophic lateral sclerosis, epilepsy, AIDS-induced dementia, muscle spasms, migraine, urinary incontinence, psychosis, convulsions, perinatal hypoxia, hypoxia (such as that caused by strangulation, surgery, smoke inhalation, asphyxia, drowning, choking, electrocution, drugs or alcohol overload), cardiac arrest, hypoglycemic neuronal damage, chemical dependence and drug addiction (such as drug addiction or dependence on alcohol, opiates, benzodiazepines , nicotine, heroin or cocaine), ocular damage, retinopathy, retinal neuropathy, tinnitus, idiopathic and drug-induced Parkinson's disease, anxiety (such as post-traumatic stress syndrome, panic disorder, Parkinson's disease, and other diseases, General anxiety disorders, simple phobias and social phobias), schizophrenia, depression, bipolar disorders, obsessive compulsive disorders, tourette's syndrome, emesis, cerebral edema, chronic and acute pain, tardive dyskinesia, and brain defects secondary to cardiac bypass surgery and transplantation, which method comprises administering to a mammal in need of such treatment an amount of a compound of formula i which is effective in treating the condition.

The invention also relates to a pharmaceutical composition for treating a mammalian condition selected from the group consisting of stroke, cerebral ischemia, spinal cord injury, brain trauma, Alzheimer's disease, Huntington's chorea, amyotrophic lateral sclerosis, epilepsy, AIDS-induced dementia, muscle spasms, migraine, urinary incontinence, psychosis, convulsions, perinatal hypoxia, hypoxia (such as that caused by strangulation, surgery, smoke inhalation, asphyxia, drowning, choking, electrocution, drugs or alcohol overdose), cardiac arrest, hypoglycemic neuronal damage, chemical dependence and drug addiction (such as drug addiction or dependence on alcohol, opiates, benzodiazepines , nicotine, heroin or cocaine), ocular damage, retinopathy, retinal neuropathy, tinnitus, idiopathic and drug-induced Parkinson's disease, anxiety (such as post-traumatic stress syndrome), Panic disorder, generalized anxiety disorder, simple phobias and social phobias), schizophrenia, depression, bipolar disorder, obsessive-compulsive disorder, tourette's syndrome, emesis, cerebral edema, chronic and acute pain, tardive dyskinesia, and brain defects secondary to cardiac bypass surgery and transplantation, which comprises an amount of a compound of formula i effective in treating the condition, and a pharmaceutically acceptable carrier.

The invention also relates to a method for treating a disorder or condition in a mammal which treatment is enabled or facilitated by modulation of glutamate neurotransmission, comprising administering to a mammal in need of such treatment:

(a) a compound of formula i or a pharmaceutically acceptable salt thereof; and

(b) a serotonin reuptake inhibitor (such as sertraline, fluoxetine, fluvoxamine, paroxetine, citalopram, fenfluramine, and fexistine) or serotonin-1A (5 HT)_1A) A receptor ligand (e.g., buspirone, fluxoxan, etc.) or a pharmaceutically acceptable salt of the inhibitor or ligand;

wherein the compound of formula I and serotonin reuptake inhibitor or 5HT are used in the method_1AThe amount of receptor ligand is such that the combination of the two active ingredients is effective to treat the condition or state.

The invention also relates to a pharmaceutical composition for treating a disorder or condition in a mammal, which treatment of the disorder or condition can be effected or facilitated by modulation of glutamate neurotransmission, the pharmaceutical composition comprising:

(a) a compound of formula I or a pharmaceutically acceptable salt thereof;

(b) a serotonin reuptake inhibitor (such as sertraline, fluoxetine, fluvoxamine, paroxetine, citalopram, fenfluramine, and fexistine) or serotonin-1A (5 HT)_1A) A receptor ligand (e.g., buspirone, fluxoxan, etc.) or a pharmaceutically acceptable salt of the inhibitor or ligand; and

(c) a pharmaceutically acceptable carrier;

wherein a compound of formula I and a serotonin reuptake inhibitor or 5HT are contained in the composition_1AThe amount of receptor ligand is such that the combination of the two active ingredients is effective to treat the condition or state.

The invention also relates to a method for treating a disorder or condition in a mammal which treatment is enabled or facilitated by modulation of glutamate neurotransmission, comprising administering to a mammal in need of such treatment:

(a) a glutamate neurotransmission modulating compound or a pharmaceutically acceptable salt thereof; and

(b) a serotonin reuptake inhibitor (such as sertraline, fluoxetine, fluvoxamine, paroxetine, citalopram, fenfluramine, and fexistine) or serotonin-1A (5 HT)_1A) A receptor ligand (e.g., buspirone, fluxoxan, etc.) or a pharmaceutically acceptable salt of the inhibitor or ligand;

wherein the glutamate neurotransmission modulating compound and the serotonin reuptake inhibitor or 5HT inhibitor are used in the method_1AThe amount of receptor ligand is such that the combination of the two active ingredients is effective to treat the condition or state.

The invention also relates to a pharmaceutical composition for treating a disorder or condition in a mammal, which treatment of the disorder or condition can be effected or facilitated by modulation of glutamate neurotransmission, the pharmaceutical composition comprising:

(a) a glutamate neurotransmission modulating compound or a pharmaceutically acceptable salt thereof;

(b) a serotonin reuptake inhibitor (such as sertraline, fluoxetine, fluvoxamine, paroxetine, citalopram, fenfluramine, and fexistine) or serotonin-1A (5 HT)_1A) A receptor ligand (e.g., buspirone, fluxoxan, etc.) or a pharmaceutically acceptable salt of the inhibitor or ligand; and

(c) a pharmaceutically acceptable carrier;

wherein the glutamate neurotransmission modulating compound and the serotonin reuptake inhibitor or 5HT inhibitor are comprised in the composition_1AThe amount of receptor ligand is such that the combination of the two active ingredients is effective to treat the condition or state.

The invention also relates to methods for treating a disorder or condition selected from stroke, cerebral ischemia, spinal cord injury, brain trauma, Alzheimer's disease, Huntington's chorea, amyotrophic lateral sclerosis, epilepsy, AIDS-induced dementia, muscle spasms, migraine, urinary incontinence, psychosis, convulsions, perinatal hypoxia, hypoxia (such as that caused by strangulation, surgery, smoke inhalation, asphyxia, drowning, choking, electrocution, drugs or alcohol overdose), cardiac arrest, hypoglycemic neuronal damage, chemical dependence and drug addiction (such as drug addiction or dependence on alcohol, opiates, benzodiazepines , nicotine, heroin or cocaine), ocular damage, retinopathy, retinal neuropathy, tinnitus, idiopathic and drug-induced Parkinson's disease, anxiety (such as post-traumatic stress syndrome, post-anxiety disorders, cerebral ischemia, post-menopausal withdrawal, and post-menopausal withdrawal symptoms, and post-traumatic withdrawal, and post-traumatic, Panic disorder, generalized anxiety disorder, simple phobias and social phobias), schizophrenia, depression, bipolar disorder, obsessive-compulsive disorder, tourette's syndrome, emesis, cerebral edema, chronic and acute pain, tardive dyskinesia, and brain defects secondary to cardiac bypass surgery and transplantation, which comprises administering to a mammal in need of such treatment:

(a) a compound of formula i or a pharmaceutically acceptable salt thereof; and

(b) a serotonin reuptake inhibitor (such as sertraline, fluoxetine, fluvoxamine, paroxetine, citalopram, fenfluramine, and fexistine) or serotonin-1A (5 HT)_1A) A receptor ligand (e.g., buspirone, fluxoxan, etc.) or a pharmaceutically acceptable salt of the inhibitor or ligand;

wherein the compound of formula I and serotonin reuptake inhibitor or 5HT are used in the method_1AThe amount of receptor ligand is such that the combination of the two active ingredients is effective to treat the condition or state.

The invention also relates to a pharmaceutical composition for treating a disorder or condition in a mammal selected from stroke, cerebral ischemia, spinal cord injury, brain trauma, Alzheimer's disease, Huntington's chorea, amyotrophic lateral sclerosis, epilepsy, AIDS-induced dementia, muscle spasms, migraine, urinary incontinence, psychosis, convulsions, perinatal hypoxia, hypoxia (e.g., conditions resulting from strangulation, surgery, smoke inhalation, asphyxia, drowning, choking, electrocution, drugs or alcohol overdose), cardiac arrest, hypoglycemic neuronal damage, chemical dependence and drug dependence (e.g., drug or dependence on alcohol, opiates, benzodiazepines , nicotine, heroin or cocaine), ocular damage, retinopathy, retinal neuropathy, tinnitus, idiopathic and drug-induced Parkinson's disease, anxiety (e.g., post-traumatic stress syndrome, post-operative stress, surgery, stress, apnea, drowning, choking, electrocution, drug or alcohol overdose), cardiac arrest, hypoglycemic, Panic disorder, generalized anxiety disorder, simple phobias and social phobias), schizophrenia, depression, bipolar disorder, obsessive-compulsive disorder, tourette's syndrome, emesis, cerebral edema, chronic and acute pain, tardive dyskinesia, and brain defects secondary to cardiac bypass surgery and transplantation, comprising:

(a) a compound of formula i or a pharmaceutically acceptable salt thereof;

(b) a serotonin reuptake inhibitor (such as sertraline, fluoxetine, fluvoxamine, paroxetine, citalopram, fenfluramine, and fexistine) or serotonin-1A (5 HT)_1A) A receptor ligand (e.g., buspirone, fluxoxan, etc.) or a pharmaceutically acceptable salt of the inhibitor or ligand; and

(c) a pharmaceutically acceptable carrier;

wherein a compound of formula I and a serotonin reuptake inhibitor or 5HT are contained in the composition_1AThe amount of receptor ligand is such that the combination of the two active ingredients is effective to treat the condition or state.

Unless otherwise indicated, the alkyl groups referred to herein, as well as the alkyl portions of other groups referred to herein (e.g., alkoxy groups), may be straight or branched chain (e.g., t-butyl), they may also be cyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), or straight or branched chain and contain cyclic moieties.

The verb "treat" and its conjugations is used herein to mean to reverse, alleviate, inhibit the development of, or prevent the development of a disorder or condition to which the term applies, or one or more symptoms of the disorder or condition. The term "treatment" as used herein refers to the act of "treating" as just defined.

The terms "halo" and "halogen" as used herein, unless otherwise indicated, refer to fluoro, bromo, chloro or iodo.

The compounds of formula i may have chiral centers and may therefore exist in different enantiomeric and diastereomeric forms. The present invention relates to all optical isomers and all other stereoisomers of the compounds of formula i, to all racemic and other mixtures thereof, to all pharmaceutical compositions and methods of treatment containing or using such isomers or mixtures, as defined above.

The invention also includes isotopically-labelled compounds, which are identical to those recited in formula i, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in practice. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as²H、²H、¹³C、¹⁴C、¹⁵N、¹⁸O、¹⁷O、³¹P、³²P、³⁵S、¹⁸F and³⁶and (4) Cl. Compounds of the invention and pharmaceutically acceptable salts of said compounds containing the aforementioned isotopes and/or other isotopes of other atoms are within the scope of the invention. Certain isotopically-labelled compounds of the present invention, e.g. having incorporated therein³H and¹⁴those of radioactive isotopes, such as C, are useful in drug and/or substrate tissue distribution assays. Tritium-containing, i.e. readily preparable and capable of detection³H and carbon-14, i.e.¹⁴Isotopes of C are particularly preferred. Furthermore, substitution with heavy isotopes such as deuterium, i.e., 2H, may be preferred in some circumstances due to their greater metabolic stability which may afford certain therapeutic advantages such as increased in vivo half-life or reduced dosage requirements. Isotopically-labelled compounds of formula I of the present invention can generally be prepared by carrying out the procedures disclosed in the schemes and/or in the examples and preparations below, using only readily available isotopically-labelled reagentsThe agent replaces a non-isotopically labeled agent.

Detailed description of the invention

The compounds of formula I can be prepared according to the procedure of scheme 1. In the reaction schemes and discussion that follows, unless otherwise indicated, n, X, Z, R¹、R²And R⁷And the structural formulae I, II, III and IV are as defined above.

Scheme 1

Scheme 1 continues

Scheme 2

Scheme 1 illustrates where n is zero, R¹Preparation of all compounds of formula I which are hydrogen. Such compounds are referred to in scheme 1 and hereinafter as compounds of formula IA. The diene of formula VI is reacted with a dienophile of formula VII using well known Diels Alder reactions according to scheme 1 (see organic reaction 1948, pp.1-173, volume IV). The reaction may be carried out in the absence of a solvent, or in any of a variety of solvents, including water, diethyl ether, tetrahydrofuran, benzene, toluene, and dichloroethane. The reaction may be carried out at atmospheric pressure or in a sealed vessel at 1-10 atmospheres. The reaction time varies depending on the particular Diels Alder (Diels Alder) reaction. The reaction may begin with the mixing of the reagents or may take several days to complete the reaction. At Z is NR²In the case of starting materials of the formula VII, starting materials can be prepared from the corresponding aldehydes in which Z is oxygen and the formula NH₂R²The amine of (a) is generated in situ, and the reaction can be carried out in water (tetrahedron Kupffer 1990, 31, 2603; journal of American society of chemistry 1985, 107, 1768-1769; Japanese society of chemistry 1992, 65, 61).

Using an aqueous acid, e.g. hydrochloric acid (HCl), hydrobromic acid (HBr) or sulfuric acid(H₂SO₄) Alternatively, R in formula VIII can be substituted by an aqueous hydroxide⁷Diels Alder reaction products other than H hydrolyze to the free acid. A diluent such as tetrahydrofuran, methanol, ethanol or isopropanol may be added. The hydrolysis may be carried out at a temperature of about 0 ℃ to about 150 ℃, preferably at a temperature of about room temperature to about 65 ℃.

The resulting compound of formula IX is further subjected to iodolactonization with iodine and a base (J. org. chem., 1976, 41, 1229) to yield the corresponding compound of formula X. The reaction is generally carried out in a solvent, such as water, methanol, diethyl ether or tetrahydrofuran, or a mixture of two or more of the foregoing solvents, the base typically being an alkali metal bicarbonate. The reaction is generally carried out at a temperature of from about 0 ℃ to about 50 ℃, preferably from about 30 minutes to about 48 hours, typically from about 8 to 24 hours, at about ambient temperature.

The iodolactone intermediate of formula X is then reacted with a base, typically an alkali metal hydroxide, in water, methanol or ethanol, or a mixture of two or more of these solvents, according to the procedure of Bastiaansen (J. org. chem. 1995, 60, 4240) to give the corresponding intermediate of formula XI.

The compound of formula XI is then esterified according to standard conditions well known in the art (e.g. with diazomethane or trimethylsilyldiazomethane, or with trimethylsilylchloride and an alcohol, or with an acid such as hydrochloric acid or sulfuric acid and an alcohol, or with a chloroformate such as methyl, ethyl or benzyl chloroformate).

The resulting ketone of copper ester of formula XII may be protected as a ketal by treatment with ethylene glycol or an orthoformate ester, such as trimethyl orthoformate, under dehydration conditions such as molecular sieves or azeotropic removal of water, to produce a protected intermediate of formula XIII. A catalyst, such as trimethylsilyl chloride, or an acid, such as p-toluenesulfonic acid, sulfuric acid or benzenesulfonic acid, or pyridinium tosylate, may be used to promote the reaction. The reaction temperature may range from about ambient temperature to about the reflux temperature of the solvent. Suitable solvents include aprotic solvents such as toluene, benzene, tetrahydrofuran, dimethoxyethane, dichloromethane, and dichloroethane. Ketoesters (XII) or ketoacetal (XIII) are treated with a base such as sodium methoxide or sodium ethoxide in an alcoholic solvent at about ambient to about solvent reflux temperature for about 6 hours to about 5 days to maintain the ester predominantly in the exo-equilibrium state. Deketalization with an acid such as hydrochloric acid, sulfuric acid, oxalic acid or acetic acid in water alone or in admixture with methanol, tetrahydrofuran or diethyl ether affords an intermediate of formula XV.

The compound of formula XV is further reacted under Buhel hydantoin forming conditions (see journal of Organic Chemistry 1982, 47, 4081 and references cited herein; Vogel's textbook of Practical Organic Chemistry 4 th edition 1978, p.876) to give a hydantoin intermediate of formula XI. Such conditions include, for example, reaction with an alkali metal cyanide and ammonium carbonate in water, methanol or ethanol at a temperature of from about ambient to about 150 c, at a pressure of from about ambient to about 150psi, for a period of from about 30 minutes to about 48 hours. The hydantoin obtained is generally hydrolyzed with an inorganic acid or aqueous alkali metal hydroxide or aqueous barium hydroxide at a temperature of from about 50 ℃ to about 150 ℃ to give the desired final product of formula IA.

Alternatively, the compound of formula XV may be reacted under Steckel synthesis conditions (JerryMarch, Advanced Organic Chemistry, 4 th edition 1992, p.965; Vogel, A Practical handbook of Organic Chemistry, 4 th edition 1978, p.546) to produce an alpha amino nitrile intermediate of formula III. Such conditions include, for example, the use of (a) ammonia and hydrogen cyanide, (b) ammonium cyanide, (c) an alkali metal cyanide and ammonium chloride, or (d) trimethylsilyl cyanide, in an alcoholic solvent, such as methanol or ethanol, optionally with the addition of an acid, such as acetic acid, at a temperature of about 20 ℃ to about 100 ℃ for about 0.5 to about 24 hours, typically at a temperature between about 40 ℃ and 80 ℃ for about 1-8 hours. The hydrolysis of this intermediate is carried out as described above for the hydrolysis of hydantoin to give the desired final product of formula IA.

As depicted in scheme 2, the compounds of formula IA can be esterified to the corresponding diesters of formula IVA using standard conditions as described above. The resulting diester containing a free amino group can be further functionalized at the amino group using standard reductive amination procedures to yield the corresponding compounds of formulas IVB (n is not zero), IVC (n is zero, R)¹Is aryl) and IVD (n is zero, R¹Is heteroaryl) compound. When R is¹When attached to the amino nitrogen of formula I through an alkyl group, i.e. n is not zero, reacting a compound of formula IVA with the appropriate compound of formula R¹(CH²)_mCHO aldehyde reaction, where m is equal to n-1 (i.e., m is 1 less than n) to produce a compound of formula IVB. The reductive amination reaction described above can be carried out using standard procedures well known to those skilled in the art. The reaction is typically carried out in the presence of a reducing agent, such as sodium cyanoborohydride, sodium triacetoxyborohydride, sodium borohydride, hydrogen (or a source of chemical hydrogen, such as formic acid or ammonium formate), and a metal catalyst, such as platinum, palladium or rhodium, zinc with hydrochloric acid, borane dimethyl sulfide or formic acid at a temperature of from about-60 ℃ to about 50 ℃. Reaction inert solvents suitable for this reaction include lower alcohols (e.g., methanol, ethanol, and isopropanol), dioxane, dichloromethane, dichloroethane, acetic acid, and Tetrahydrofuran (THF). Preferably, the solvent is dichloromethane or dichloroethane, the temperature is about 25 ℃, and the reducing agent is sodium triacetoxyborohydride.

Compounds of formulae IVC and IVD are equal to compounds of formula IVB, but n is zero, R¹Are each aryl or heteroaryl. These compounds can also be formed from the corresponding compounds of formula IVA. This is achieved by reacting the corresponding compounds of the formula IVA with the formula R¹The compound of X wherein X is a leaving group such as halo, triflate, mesylate or tosylate. The reaction is generally carried out in a solvent such as ethanol, N-Dimethylformamide (DMF), N-dimethylacetamide, methanol, ethanol, at a temperature of about 0 ℃ to about 160 ℃, preferably about 80 ℃ to about 150 ℃Acetonitrile, nitromethane (nitromethane), dioxane or dichloroethane, preferably DMF.

In a similar manner, compounds of formula ivd may be prepared by reaction of a corresponding compound of formula iva with a heteroaromatic compound of formula AX, wherein a is a nitrogen-containing heterocycle, X is a leaving group as defined above, and is ortho to a ring nitrogen atom. Examples of compounds of formula AX are as follows:

the electron withdrawing groups present on the above heteroaryl groups, such as esters, nitriles, sulfones, and nitro groups, further activate them.

The compounds of formulae IVB, IVC and IVD formed in the above-described reactions can be converted into the corresponding desired compounds of formulae IB, IC and ID by acid or base hydrolysis using methods well known to those skilled in the art. Suitable acids for acid hydrolysis of the compounds of formula ivb include inorganic acids such as hydrofluoric, sulfuric, hydrochloric and hydrobromic acids. Suitable bases for the alkaline hydrolysis of the compound of formula ivb include alkali metal hydroxides and barium hydroxide. The reaction temperature for the acid and base hydrolysis reactions may be from about 0 ℃ to about 100 ℃. Preferably, these reactions are carried out at about the reflux temperature of the reaction mixture.

From which R may be derived by well-known chemical synthesis methods¹A compound of formula IC or ID, each of which is nitroaryl or nitroheteroaryl, to give a compound of formula wherein R is¹Further compounds of formula ic or id which are substituted aryl or heteroaryl, respectively. For example, the nitro group may be reduced to an amine in accordance with procedures such as those described in Jerry March, advanced organic Chemistry, 4 th edition, pp.721-725 and 1216-1217. The newly formed amine may be substituted with other substituents by diazotization and further reactions as summarized in the above references. For example, in this way one can prepare compounds in which R is¹Compounds of formula I are aryl or heteroaryl substituted with amino, mercapto, halo, cyano or phenyl.

Starting materials of the formulae VI and VII and R¹The X and AX feedstocks are commercialAre available, known in the literature, or may be obtained from commercially available or known compounds using methods known in the art.

Unless otherwise indicated, the pressure of each reaction described above is not critical. Generally, the reaction will be carried out at about one to about three atmospheres, preferably ambient pressure (about one atmosphere).

Other compounds of formula i not specifically described in the preceding experimental section may be prepared using combinations of the above reactions, and such combinations will be apparent to those skilled in the art.

The basic compounds of formula I are capable of forming a wide variety of different salts with various inorganic and organic acids. Acids which may be used to prepare pharmaceutically acceptable acid addition salts of the base compounds of the present invention are those which form non-toxic acid addition salts, i.e., salts containing pharmaceutically acceptable anions, such as the 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 salts (i.e., 1' -methylene-bis (2-hydroxy-3-naphthoate)). Although these salts must be pharmaceutically acceptable for administration to animals, it is often practical to isolate the pharmaceutically unacceptable salt of the compound of formula i from the reaction mixture and then simply convert the latter back to the free base compound by treatment with a basic agent, followed by conversion of the free base to a pharmaceutically acceptable acid addition salt. The acid addition salts of the base compounds of the present invention are readily prepared by treating the base compound with a substantially equivalent amount of the selected inorganic or organic acid in an aqueous solvent medium or in a suitable organic solvent, such as methanol or ethanol. Careful evaporation of the solvent gave the desired solid salt.

Acidic compounds of formula I are capable of forming base salts with various pharmaceutically acceptable cations. These salts are prepared by conventional techniques. The chemical bases used as reagents for preparing the pharmaceutically acceptable base salts of the present 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 pharmaceutically acceptable cations such as sodium, potassium, calcium, magnesium, and the like. These salts can be readily prepared by treating the corresponding acidic compound with an aqueous solution containing the desired pharmaceutically acceptable cation and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, they may be prepared by mixing a lower alkanol solution of the acidic compound together with the desired alkali metal alkoxide and then evaporating the resulting solution to dryness in the same manner as described above. In both cases, it is preferred to use stoichiometric amounts of the reagents in order to ensure complete reaction and maximum yield of the desired end product.

The compounds of formula (I) and their pharmaceutically acceptable salts (hereinafter also referred to collectively as "active compounds of the invention") are useful in the treatment of neurodegenerative, psychiatric and drug or alcohol-induced shortages and are potent metabotropic glutamate receptor ligand antagonists. The active compounds of the invention are therefore useful for the treatment or prophylaxis of stroke, cerebral ischemia, spinal cord injury, brain trauma, Alzheimer's disease, Huntington's chorea, amyotrophic lateral sclerosis, epilepsy, AIDS-induced dementia, muscle spasms, migraine, urinary incontinence, psychoses, convulsions, perinatal hypoxia, hypoxia (e.g., conditions caused by strangulation, surgery, smoke inhalation, asphyxia, drowning, choking, electrocution, drugs, or alcohol overdose), cardiac arrest, hypoglycemic neuronal damage, chemical dependence and drug addiction (e.g., drug addiction or dependence on alcohol, opiates, benzodiazepines , nicotine, heroin, or cocaine), ocular damage, retinopathy, retinal neuropathy, tinnitus, idiopathic and drug-induced Parkinson's disease, anxiety, vomiting, cerebral edema, chronic and acute pain, tardive dyskinesia, and brain defects secondary to heart bypass surgery and transplantation.

The following procedures can be used to determine the activity of the therapeutic agents of the present invention as agonists and antagonists of metabotropic glutamate receptors.

Chinese Hamster Ovary (CHO) cells were transfected with cDNA (mGluR2 and pcDNA3) using the calcium phosphate method. Positive clones were selected with geneicin (G418, Gibco, 500-. Positive clones were grown to confluence and cAMP response was measured in the presence of 10 μ M forskolin. The pooled clones were frozen and stored in liquid nitrogen.

Chinese Hamster Ovary (CHO) cells stably transfected with rat metabotropic glutamate receptor mGluR2 were grown to confluence in Dulbecco's Modified Eagle Medium (DMEM) (Gibco Cat # 11960-. The cells were harvested with a 5mM ethylenediaminetetraacetic acid (EDTA) solution and then spun at 800rpm under refrigerated centrifugation conditions at 4 ℃. The remaining pellet was resuspended in phosphate buffered saline solution containing 30mM HEPES (Gibco Cat #15630-₂) 300 μ M3-isobutyl-1-methylxanthine (IBMX) and 0.1% glucose. The cell suspension was added in 200. mu.l aliquots to flat-bottomed polypropylene tubes, which were then placed in a 37 ℃ hot water bath for 22 minutes. If the test compound has antagonistic activity, it is preincubated with cells in a water bath for 11 minutes. At the end of 11 minutes, 5 μ M forskolin plus known concentrations of test compound was added and incubation continued for an additional 11 minutes. If agonist activity of the compound is to be tested, the cells are shaken in a water bath for the first 11 minutes, then 5 μ M forskolin plus known concentration of agonist is added and the remaining 11 minutes of incubation are performed. In both cases, the reaction was terminated with 25. mu.l of 6N perchloric acid (PCA), and each tube was immediately transferred to an ice-water bath. Potassium hydroxide (KOH) was added, the pH of each sample was adjusted to about 8.0, and Tris, pH 7.4, was added for stabilization. Aliquots (25 μ l) were assayed in a commercial competitive binding kit (Amersham TRK 432). Samples were then collected on GF/B filters coated with 0.5% PEI using a 96-well Skatron collectorOn the machine. The samples were quantified using a 1205Betaplate liquid scintillation counter.

CPM obtained from a Betaplate reader was converted to picomolar (pmol) cAMP/mg protein/min incubation with forskolin using an Excel checkerboard comparison table. Calculation of EC from Linear regression of concentration response data₅₀And IC₅₀。

The following procedures can be used to determine the agonistic activity of the therapeutic agents of the present invention as agonists to metabotropic glutamate receptors.

Chinese Hamster Ovary (CHO) cells stably transfected with rat to the 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, 2mM 1-glutamine and penicillin/streptomycin. Cells were harvested with 5mM EDTA solution, homogenized for 10 strokes with a glass-polytetrafluoroethylene hand-held homogenizer, then 50 volumes of Phosphate Buffered Saline (PBS) were added and the solution spun at 18000rpm for 10 minutes at 4 ℃. The pellet was again homogenized and resuspended in test buffer (100mM HEPES, 1mM EGTA, pH 7.5) at a concentration of approximately 0.009 mg protein/well. The reaction mixture was prepared just before the start of the experiment and contained 6mM MgCl₂0.5 mM Adenosine Triphosphate (ATP), 0.5 mM 3-isobutyl-1-methylxanthine (IBMX), 0.1 mM Guanosine Triphosphate (GTP), 10mM creatine phosphate, 0.31 mg/ml creatine phosphokinase (final concentration in the assay). Mu.l of test compound, 20. mu.l of forskolin (final concentration of 5. mu.M), 20. mu.l of reaction mixture and 40. mu.l of tissue were added in this order to a 96-well polypropylene (polypropaline) culture dish. The dishes were incubated for 15 minutes in a 37 ℃ hot water bath. The reaction was stopped by adding 50. mu.l of 40mM EDTA. The plates were then transferred to ice, shaken for 10-15 minutes, and 25 μ l aliquots were then taken for analysis in a commercial competitive binding kit (Amersham TRK 432). After incubation in the refrigerator for 2-18 hours, samples were collected on GF/B filters coated with 0.5% Polyethyleneimine (PEI) using a 96-well Skatron collector. Scintillation counting with 1205Betaplate liquidThe device quantifies the sample.

CPM from Betaplate reader was converted to picomolar cAMP per well using an Excel checkerboard comparison table. The percent reduction in forskolin was used to determine the agonist compounds. Calculation of EC from Linear regression of concentration response data₅₀。

The compositions of the present invention may be formulated in conventional manner using one or more pharmaceutically acceptable carriers. Thus, the active compounds of the present 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, for example, be in the form of tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., pregelatinized corn starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (such as lactose, microcrystalline cellulose or calcium phosphate); lubricants (such as magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate). 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 methods 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); a non-aqueous carrier (such as almond oil, oily esters or ethyl alcohol); and preservatives (such as methyl or propyl paraben or sorbic acid).

For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.

The active compounds of the present invention may be formulated for parenteral administration by injection, including by use of conventional catheterization techniques or infusion. Injectable preparations may be in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may, for example, take the form of suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

The active compounds of the present 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 suitably delivered in the form of a solution or suspension from a pump spray container which is squeezed or injected by the patient or, alternatively, is suitably delivered as an aerosol from a pressurised container or a nebuliser, using 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 releasing a metered dose valve. The pressure vessel or nebulizer may contain a solution or suspension of the active compound. Capsules and cartridges (made, for example, from gelatin) suitable 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.

The recommended dose of the active compounds according to the invention for oral, parenteral or buccal administration to normal adults for the treatment of the above-mentioned states (e.g. stroke) is 0.01 to 50 mg/kg of active ingredient per unit dose, which can be administered, for example, 1 to 4 times per day.

Aerosols for the treatment of the above-mentioned conditions (e.g. stroke) in a typical adult preferably contain from 20mg to 1000mg of a compound of the invention in each metered dose or "puff volume" thereof. The total daily dose of the aerosol will be in the range 100mg to 10 mg. Administration may be divided several times per day, e.g. 2, 3, 4 or 8 times, each time e.g. 1, 2 or 3 doses.

The following examples illustrate the preparation of the compounds of the present invention. Commercial reagents were used without further purification. The melting points are not calibrated. Unless otherwise specified, all NMR data are recorded in deuterated chloroform at 250, 300, or 400MHz, expressed in parts per million (δ), and referenced to the deuterium lock signal of the sample solvent. All reactions without water were carried out in dry glassware under an inert atmosphere with anhydrous solvents for convenience and to maximize yield. All reactions were stirred with a magnetic stir bar unless otherwise stated. Unless otherwise stated, all mass spectra were obtained using chemical impingement conditions. Ambient or room temperature means 20-25 ℃.

The following examples 1-4 are examples of compounds of formula I. These examples are provided only for illustrating the inventive content. They are not intended to, and should not be construed to, limit the invention as set forth in the claims and described in detail herein.

Example 1

2- (endo) -amino-bicyclo [ 2.2.1 ] heptane-2- (exo), 6- (exo) -dicarboxylic acid

A. Bicyclo [ 2.2.1 ] heptan-2-one-6-carboxylic acid methyl ester hydantoin (85: 15 mixture of internal: external hydantoin nitrogen)

To bicyclo [ 2.2.1]To a mixture of methyl hept-2-one-6-exo-carboxylate (0.557 g, 3.31 mmol, journal of organic chemistry 1995, 60, 4240-one 4245) and ammonium carbonate (1.6 g, 16.65 mmol) in water (9ml) and methanol (9ml) was added potassium cyanide (0.456 g, 7 mmol). The mixture was heated to 41.5 ℃ and stirred overnight. The mixture was diluted with water and extracted repeatedly with ethyl acetate. The combined organic phases were washed with water, dried over magnesium sulfate and concentrated to give a white solid. The solid was subjected to silica gel flash chromatography (40X 80mm) and eluted as follows: 112ml of 50% ethyl acetate/hexane, none; 42ml, unidentified impurities; 322ml, none; 322ml, 0.299 g title productSubstance, white solid:¹H NMR(CDCl₃) (mainly diastereomers with internal hydantoin nitrogens)

δ10．60(s，1H)，8．23(s，1H)，3．55(s，3H)，2．81(q，J=4．5Hz，1H)，2．42(s，1H)，2．26(s，1H)，2．04(d，J=10．1Hz，1H)，1．92(dt，J=3．5，12．25Hz，1H)，1．84-1．76(m，1H)，1．60-1．52(m，1H)，1．30(d，J=10．1Hz，1H)，1．20(d，J=12．7Hz，1H)。

B.2- (endo) -amino-bicyclo [ 2.2.1 ] heptane-2, 6-di (exo) carboxylic acid

Bicyclo [ 2.2.1 ] is]A mixture of heptan-2-one-6-exo-carboxylic acid methyl ester hydantoin (0.10 g, 0.41 mmol) in 6N hydrochloric acid (10ml) was refluxed for 24 hours, cooled and left at ambient temperature for 72 hours. The reaction was concentrated in vacuo to a white solid. The solid was dissolved in water with the aid of 2 drops of 6N hydrochloric acid and loaded onto a Dowex 50 x 8100 ion exchange column (7ml resin by elution with water until eluent pH = 4). The column was eluted with water until a pH of 4.5 was reached. Elution was continued with 1N ammonium hydroxide. The ninhydrin positive fractions were combined and hydrolyzed to give 0.032 g of the product as a white solid:¹H NMR(D₂O)δ2．53(s，1H)，2．30-2．22(m，1H)，2．20-2．16(brs，1H)，2．12-2．04(m，1H)，1．75(d，J=11．8Hz，1H)，1．72-1．64(m，1H)，1．52-1．44(m，1H)，1．28-1．20(m，1H)，1．08(dd，J=2．7，13．5Hz，1H)，APCl MS m／e=200．2(P+1)。

example 2

(+) -2- (inner) -amino-bicyclo [ 2.2.1 ] heptane-2- (outer), 6- (outer) -dicarboxylic acid hydrochloride and (-) -2- (inner) -amino-bicyclo [ 2.2.1 ] heptane-2- (outer), 6- (outer) -dicarboxylic acid hydrochloride

A. Bicyclo [ 2.2.1 ] heptan-2-one-6-carboxylic acid hydantoins

Bicyclo [ 2.2.1 ] is]A solution of heptan-2-one-6-exo-carboxymethylhydantoin (1.02 g, 4.28 mmol) in 6N hydrochloric acid (20ml) was refluxed for 1 hour. After cooling to the ambient temperature, the mixture was cooled,the product precipitated as a white solid. The solid was collected and air dried to give 0.776 g of the title product:¹H NMR(D₂o) delta 2.65 (brs, 1H), 2.56 (s, 1H), 2.25 (s, 1H), 2.02-1.83 (m, 2H), 1.82-1.72 (m, 1H), 1.58-1.46 (variation t, 1H), 1.34-1.19 (variation t, 2H).

B. Resolution of bicyclo [ 2.2.1 ] heptan-2-one-6-exo-carboxylic hydantoin

Bicyclo [ 2.2.1 ] is]Heptan-2-one-6-carboxylic acid hydantoin (0.776 g) was mixed with methanol (20ml), and (S) - (-) - α -methylbenzylamine (0.470 ml) was added. The mixture was stirred at ambient temperature for 2 hours. During this time, the solution became homogeneous and then a white precipitate was formed. The precipitate (0.50 g) was collected and recrystallized twice from methanol. The recrystallized salt was treated with 1N hydrochloric acid and extracted repeatedly with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated to give 0.120 g of bicyclo [ 2.2.1](-) enantiomer of hydantoin of hept-2-one-6-carboxylate having NMR spectrum identical to that of racemate, [ alpha ]]_D= 36.11 ° (c = 0.925 methanol). Chiral HPLC analysis (chiralcel OG column, 95/5 hexane/ethanol with 0.1% trifluoroacetic acid solvent, flow rate 1 ml/min, 214nM UV detection) showed the compound to be 100% enantiomerically pure with a retention time of 14.50 min.

The mother liquors from the above salt resolution were combined and treated with 1N hydrochloric acid. Repeated extraction with ethyl acetate to recover bicyclo [ 2.2.1 ] enriched in the (+) enantiomer]Heptan-2-one-6-carboxylic acid hydantoin. This material was treated with (R) - (+) - α -methylbenzylamine as above to give 0.066 g of (+) -bicyclo [ 2.2.1]Hepta-2-one-6-carboxylic hydantoin, as a white solid: [ alpha ] to]_D= 32.77 ° (c = 0.900 methanol). Chiral HPLC according to the above method showed that the sample had 98.1% enantiomeric excess with a retention time of 17.56 min.

C. (+) -2- (endo) -amino-bicyclo [ 2.2.1 ] heptane-2- (exo), 6- (exo) -dicarboxylic acid hydrochloride

(+) -bicyclo [ 2.2.1]Hepta-2-one-6-Carboxylic hydantoin (0.098 g, 0.4 mmol) and 6N hydrochloric acid (hydrochloric acid: (hydrochloric acid) (hydrochloric acid))20ml) were mixed and refluxed for 48 hours. The mixture was concentrated in vacuo to give 0.095 g of the title product: [ alpha ] to]_D= 20.31 ° (c = 1.07 methanol).

D. (-) -2- (endo) -amino-bicyclo [ 2.2.1) hydrochloride]Heptane-2- (exo), 6- (exo) -dicarboxylic acid (-) -bicyclo [ 2.2.1 ] using the same hydrolysis procedure described above]Conversion of hepta-2-one-6-carboxylic hydantoin to the (-) title product: [ alpha ] to]_D= 24.06 ° (c = 0.575 methanol).

Example 3

2- (endo) -benzylamino-bicyclo [ 2.2.1 ] heptane-2- (exo) -6- (exo) -dicarboxylic acid

A.2- (endo) -benzylamino-bicyclo [ 2.2.1 ] heptane-2- (exo) -6- (exo) -dicarboxylic acid dimethyl ester

Reacting 2- (endo) -amino-bicyclo [ 2.2.1]A mixture of dimethyl heptane-2- (exo) -6- (exo) -dicarboxylate (0.25 g, 1.1 mmol) (see preparation 1 below), dichloromethane (10ml), benzaldehyde (0.134 ml) and sodium triacetoxyborohydride (1.2 g, 5.5 mmol) was stirred for 16 h. The reaction was quenched with 0.5N HCl (20ml) and stirred for 30 min. The phases were separated and the organic layer was washed with saturated aqueous bicarbonate, water and brine. The organic layer was dried over magnesium sulfate and concentrated to give 0.225 g of a colorless oil. The oil was subjected to silica gel chromatography (using a Flash 40s column from Biotage (Charlottesville, Virginia, USA; the Flash 40s column contains KP sil) and eluted as follows: 10% ethyl acetate/hexane 100ml, none; 100ml, 0.043 g 2- (endo) -benzylamino-bicyclo [ 2.2.1]Heptane-2- (exo) -6- (exo) -dicarboxylic acid dimethyl ester, a colorless oil: NMR (CDCl)₃)δ7．31-7．29(m，5h)，3．73(s，3H)，3．66(s，3H)，3．51(ABq，δv_1-3=40Hz，J=13Hz，2H)，3．32，(dd，J=5，9Hz，1H)，2．95(s，1H)，2．28(br s，1H)，2．21-2．15(m，1H)，1．97-1．90(m，1H)，1．88(s，1H)，1．59-1．54(m，1H)，1．45(ABq，δv_1-3=24Hz，J=11Hz，2H)，1．10(dd，J=3，13Hz，1H)。

B. Hydrolysis of ester groups

Reacting 2- (endo) -benzylamino-bicyclo [ 2.2.1 ] obtained as described in the preceding paragraph (A)]A mixture of dimethyl heptane-2- (exo) -6- (exo) -dicarboxylate (0.04 g, 0.126 mmol) and 6N HCl (5ml) was heated to 80 ℃ overnight. Additional 6N HCl (5ml) was added and the reaction heated at 103 ℃ for 24 h. The mixture was cooled and concentrated. NMR of the residue showed that mono-hydrolysis had occurred. The residue was mixed with water (5ml) and ethanol (5ml) and LiOH (0.15 g, 6.2 mmol) was added. The mixture was heated at 65 ℃ for 16 hours. The reaction was concentrated and most of the residual solids were dissolved in ethanol. Residual solids were removed from the ethanol solution by filtration through celite. The ethanol filtrate was concentrated to give 0.242 g of an incompletely white solid. The solid was dissolved in 1N HCl (1ml) and loaded onto AG50w-x8 ion exchange resin (0.15 g, previously washed with water until the pH rose to 4.5). The mixture was stirred over the weekend. An SCX column (0.5 g, strong cation exchange type, from Burdick and jackson (muskaegon, Michigan, USA) (catalog #9094)) was washed with water until the pH of the eluate was 4.5. The ion exchange resin and its associated solution were loaded onto an SCX column and eluted as follows: 3ml of water, unknown; 30ml of water, none; 28ml of 1N ammonium hydroxide, 0.02 g of the title product of this example, as a white solid: NMR (D)₂O)δ7．23-7．15(m，5H)，3．32(ABq，δv_{1- 3}=20Hz，J=12Hz，2H)，2．63(s，1H)，2．55(dd，J=5，9．5Hz，1H)，2．03(s，1h)，1．87-1．81(brd，1H)，1．58-1．51(m，1H)，1．41(t，J=10．5Hz，1H)，1．26(m，2H)，0．88(d，J=11．5Hz，1H)；APCl MS，p+1=290．2。

Example 4

2- (endo) -phenethylamino-bicyclo [ 2.2.1 ] heptane-2- (exo) -6- (exo) -dicarboxylic acid

Essentially the same procedure as described in example 3 above was followed, but the LiOH hydrolysis was performed directly (without the acid partial hydrolysis step) from 2- (endo) -amino-bicyclo [ 2.2.1]Preparation of the title of this example from heptane-2- (exo) -6- (exo) -dicarboxylic acid dimethyl ester (0.015 g, 0.066 mmol), dichloromethane (2ml), phenylacetaldehyde (0.01 ml, 0.08 mmol) and sodium triacetoxyborohydride (0.07 g, 0.33 mmol)The title compound. The title compound of this example: NMR (D)₂O)δ7．19-7．11(m，5H)，2．70-2．44(m，5H)，2．38(dd，J=5，9Hz，1H)，2．05- 2．01(m，1H)，1．82(ddd，J=3，5，13Hz，1H)，1．58-1．51(m，1H)，1．41(t，J=10．5Hz，1H)，1．24-1．16(m，2H)，0．85(dd，J=2，11．5Hz，1H)；APCl MS，p+1=304．1。

Preparation example 1

Hydrochloric acid 2- (endo) -amino-bicyclo [ 2.2.1]Heptane-2- (exo) -6- (exo) -dicarboxylic acid dimethyl ester 2- (endo) -amino-bicyclo [ 2.2.1]Heptane-2- (exo) -6- (exo) -dicarboxylic acid (0.010 g, 0.05 mmol) was dissolved in methanol (5ml) and the solution was saturated with HCl gas. The mixture was heated to reflux overnight. The reaction was cooled and concentrated to give the title compound of this preparation as a white solid: NMR (CD)₃OD)δ3．84(s，3H)，3．68(s，3H)，2．90(s，1H)，2．74-2．62(m，1H)，2．54-2．40(m，2H)，2．06-1．96(m，1H)，1．88(d，J=11Hz，1H)，1．84-1．74(m，1H)，1．52(dd，J=4．5，11Hz，1H)，1．34(dd，J=1．9，13．5Hz，1H)。

Preparation example 2

2- (endo) -amino-bicyclo [ 2.2.1]Diethyl heptane-2- (exo) -dicarboxylate the compounds of this preparation are also useful in the preparation of compounds of formula I. Reacting 2- (endo) -amino-bicyclo [ 2.2.1]Heptane-2- (exo) -6- (exo) -dicarboxylic acid (0.392 g, 1.96 mmol) was dissolved in ethanol (15ml) and the solution was saturated with HCl gas. The mixture was heated to reflux overnight. The solution was concentrated and the residue was treated with saturated aqueous sodium bicarbonate. The aqueous mixture was further treated with sodium carbonate to bring the pH to 10. The aqueous layer was extracted repeatedly with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated to give the title compound of this preparation as a pale yellow oil: NMR (CDCL)₃)δ4．20-4．05(m，4H)，3．30(dd，J=5，8．5Hz，1H)，2．69(s，1H)，2．37(ddd，J=3，4．8 13Hz，1H)，2．27(s，1H)，1．94-1．86(m，1H)，1．95-1．75(brs，2H)，1．55(t，J=11Hz，1H)，1．42(ABq，δv_1-3=23Hz，J=11Hz，2H)，1．27-1．21(m，6H)，0．91(dd，J=2，13Hz，1H)。

Claims (27)

1. A compound of the formula

Wherein n is 0 to 6;

x is CH₂、CH₂CH₂Or oxygen;

z is CHR²Or NR²；

R¹And R²Independently selected from hydrogen, (C)₁-C₆) Alkyl, aryl and heteroaryl, wherein the aryl is selected from phenyl and naphthyl and the heteroaryl is selected from the group consisting of mono-to tetra-substituted arylA 5 and 6 membered heteroaromatic ring of heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein said aryl and heteroaryl moieties may be optionally substituted by one or more substituents independently selected from halo, -S (C)₁-C₆) Alkyl, -S (O) (C)₁-C₆) Alkyl, -S (O)₂(C₁-C₆) Alkyl, optionally substituted by one to seven fluorine atoms (C)₁-C₆) Alkyl, optionally substituted by one to seven fluorine atoms (C)₁-C₆) Alkoxy, amino, nitro, cyano, carboxyl, -CO₂(C₁-C₆) Alkyl, (C)₁-C₆) Alkylamino, di [ (C)₁-C₆) Alkyl radical]Aminophenoxy, phenylamino, and thiophenyl;

with the proviso that none of said heteroaryl moieties contain more than one epoxy atom or more than one episulfide atom;

or a pharmaceutically acceptable salt of the compound.

2. The compound according to claim 1, wherein Z is CH₂。

3. A compound according to claim 1, wherein R¹Selected from the group consisting of hydrogen, unsubstituted phenyl and phenyl substituted with one or two substituents.

4. A compound according to claim 1, wherein n is zero, 1 or 2.

5. The compound according to claim 1, wherein X is CH₂。

6. A compound according to claim 1 selected from

2- (endo) -amino-bicyclo [ 2.2.1 ] heptane-2- (exo) -6- (exo) -dicarboxylic acid;

(+) -2- (endo) -aminobicyclo [ 2.2.1 ] heptane-2- (exo) -6- (exo) -dicarboxylic acid;

(-) -2- (endo) -aminobicyclo [ 2.2.1 ] heptane-2- (exo) -6- (exo) -dicarboxylic acid;

2- (endo) -benzylamino-bicyclo [ 2.2.1 ] heptane-2- (exo) -6- (exo) -dicarboxylic acid; and

2- (endo) -phenethylamino-bicyclo [ 2.2.1 ] heptane-2- (exo) -6- (exo) -dicarboxylic acid.

7. A pharmaceutical composition for treating a disorder or condition in a mammal selected from stroke, cerebral ischemia, spinal cord injury, brain trauma, alzheimer's disease, huntington's chorea, amyotrophic lateral sclerosis, AIDS-induced dementia, muscle spasms, migraine, urinary incontinence, psychosis, convulsions, perinatal hypoxia, cardiac arrest, hypoglycemic neuronal damage, chemical dependencies and drug addiction, eye injury and retinopathy, idiopathic and drug-induced parkinson's disease, anxiety, including panic disorder, generalized anxiety disorder, post-traumatic stress syndrome, simple phobia, and social phobia; schizophrenia, depression, bipolar disorders, obsessive-compulsive disorders, tourette's syndrome, emesis, cerebral edema, chronic and acute pain, tardive dyskinesia, and brain defects secondary to cardiac bypass surgery and transplantation, which comprises a compound according to claim 1 in an amount effective to treat the disorder or condition, and a pharmaceutically acceptable carrier.

8. A pharmaceutical composition for treating a disorder or condition in a mammal, which treatment or prevention of the disorder or condition is enabled or facilitated by modulation of glutamate neurotransmission, comprising a compound according to claim 1 in an amount effective to treat the disorder or condition, and a pharmaceutically acceptable carrier.

9. A method for treating a disorder or condition in a mammal selected from stroke, cerebral ischemia, spinal cord injury, brain trauma, alzheimer's disease, huntington's chorea, amyotrophic lateral sclerosis, AIDS-induced dementia, muscle spasms, migraine, urinary incontinence, psychosis, convulsions, perinatal hypoxia, cardiac arrest, hypoglycemic neuronal damage, chemical dependencies and drug addiction, eye damage and retinopathy, idiopathic and drug-induced parkinson's disease, anxiety including panic disorder, generalized anxiety disorder, post-traumatic stress syndrome, simple phobia, and social phobia; schizophrenia, depression, bipolar disorders, obsessive-compulsive disorders, tourette's syndrome, emesis, cerebral edema, chronic and acute pain, tardive dyskinesia, and brain defects secondary to cardiac bypass surgery and transplantation, which method comprises administering to a mammal in need of such treatment an amount of a compound according to claim 1 effective to treat this condition.

10. A method for the treatment of a disorder or condition in a mammal in which treatment of the disorder or condition is effected or facilitated by modulation of glutamate neurotransmission, which method comprises administering to a mammal in need of such treatment an amount of a compound according to claim 1 effective to treat the condition.

11. A pharmaceutical composition for treating a disorder or condition in a mammal selected from stroke, cerebral ischemia, spinal cord injury, brain trauma, alzheimer's disease, huntington's chorea, amyotrophic lateral sclerosis, AIDS-induced dementia, muscle spasms, migraine, urinary incontinence, psychosis, convulsions, perinatal hypoxia, cardiac arrest, hypoglycemic neuronal damage, chemical dependencies and drug addiction, eye injury and retinopathy, idiopathic and drug-induced parkinson's disease, anxiety, including panic disorder, generalized anxiety disorder, post-traumatic stress syndrome, simple phobia, and social phobia; schizophrenia, depression, bipolar disorders, obsessive-compulsive disorders, tourette's syndrome, emesis, cerebral edema, chronic and acute pain, tardive dyskinesia, and brain defects secondary to cardiac bypass surgery and transplantation, which comprises a metabotropic glutamate neurotransmission modulating effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier.

12. A pharmaceutical composition for treating a disorder or condition in a mammal which treatment or prevention of the disorder or condition is enabled or facilitated by modulation of glutamate neurotransmission, comprising a compound according to claim 1 in an amount effective to modulate metabotropic glutamate neurotransmission and a pharmaceutically acceptable carrier.

13. A method for treating a disorder or condition in a mammal selected from stroke, cerebral ischemia, spinal cord injury, brain trauma, alzheimer's disease, huntington's chorea, amyotrophic lateral sclerosis, AIDS-induced dementia, muscle spasms, migraine, urinary incontinence, psychosis, convulsions, perinatal hypoxia, cardiac arrest, hypoglycemic neuronal damage, chemical dependencies and drug addiction, eye damage and retinopathy, idiopathic and drug-induced parkinson's disease, anxiety including panic disorder, generalized anxiety disorder, post-traumatic stress syndrome, simple phobia, and social phobia; schizophrenia, depression, bipolar disorders, obsessive-compulsive disorders, tourette's syndrome, emesis, cerebral edema, chronic and acute pain, tardive dyskinesia, and brain defects secondary to cardiac bypass surgery and transplantation, which method comprises administering to a mammal in need of such treatment an amount of a compound according to claim 1 effective to modulate metabotropic glutamate neurotransmission.

14. A method for the treatment of a disorder or condition in a mammal in which treatment or prevention of the disorder or condition is enabled or facilitated by reduction or inhibition of glutamate neurotransmission, which method comprises administering to a mammal in need of such treatment an amount of a compound according to claim 1 effective to modulate metabolic glutamate neurotransmission.

15. A pharmaceutical composition for treating a disorder or condition in a mammal, which treatment of the disorder or condition is enabled or facilitated by modulation of glutamate neurotransmission, comprising:

(a) a compound of formula i or a pharmaceutically acceptable salt thereof;

(b) a serotonin reuptake inhibitor or serotonin-1A (5 HT)_1A) A receptor ligand, or a pharmaceutically acceptable salt of the inhibitor or ligand; and

(c) a pharmaceutically acceptable carrier;

wherein a compound of formula I and a serotonin reuptake inhibitor or 5HT are contained in the composition_1AThe amount of receptor ligand is such that the combination of the two active ingredients is effective to treat the condition or state.

16. The pharmaceutical composition according to claim 15, wherein (b) is a serotonin reuptake inhibitor selected from the group consisting of sertraline, fluoxetine, fluvoxamine, paroxetine, citalopram, fenfluramine and non-moxidectin.

17. A method for treating a disorder or condition in a mammal which treatment is enabled or facilitated by modulation of glutamate neurotransmission, which method comprises administering to a mammal in need of such treatment:

(a) a compound of formula i or a pharmaceutically acceptable salt thereof; and

(b) a serotonin reuptake inhibitor or serotonin-1A (5 HT)_1A) A receptor ligand, or a pharmaceutically acceptable salt of the inhibitor or ligand;

wherein the compound of formula I and serotonin reuptake inhibitor or 5HT are used in the method_1AThe amount of receptor ligand is such that the combination of the two active ingredients is effective to treat the condition or state.

18. The method according to claim 17, wherein (b) is a serotonin reuptake inhibitor selected from the group consisting of sertraline, fluoxetine, fluvoxamine, paroxetine, citalopram, fenfluramine and non-moxidectin.

19. A pharmaceutical composition for treating a mammalian condition selected from the group consisting of stroke, cerebral ischemia, spinal cord injury, brain trauma, alzheimer's disease, huntington's chorea, amyotrophic lateral sclerosis, AIDS-induced dementia, muscle spasms, migraine, urinary incontinence, psychosis, convulsions, perinatal hypoxia, cardiac arrest, hypoglycemic neuronal damage, chemical dependencies and drug addiction, eye damage and retinopathy, idiopathic and drug-induced parkinson's disease, anxiety including panic disorders, generalized anxiety disorders, post-traumatic stress response syndrome, simple phobias, and social phobia; schizophrenia, depression, bipolar disorders, obsessive-compulsive disorders, Tourette's syndrome, emesis, cerebral edema, chronic and acute pain, tardive dyskinesia, and brain defects secondary to cardiac bypass surgery and transplantation, the pharmaceutical composition comprising:

(a) a compound according to claim 1 or a pharmaceutically acceptable salt thereof;

(b) serotonin reuptake inhibitor or 5HT_1AA receptor ligand, or a pharmaceutically acceptable salt of the inhibitor or ligand; and

(c) a pharmaceutically acceptable carrier;

wherein a compound according to claim 1 and 5HT are comprised in the composition_1AThe amount of receptor ligand or serotonin reuptake inhibitor is such that the combination of the two active ingredients is effective in treating the condition.

20. The pharmaceutical composition according to claim 19, wherein (b) is a serotonin reuptake inhibitor selected from the group consisting of sertraline, fluoxetine, fluvoxamine, paroxetine, citalopram, fenfluramine and non-moxidectin.

21. A method for treating a mammalian condition selected from the group consisting of stroke, cerebral ischemia, spinal cord injury, brain trauma, alzheimer's disease, huntington's chorea, amyotrophic lateral sclerosis, AIDS-induced dementia, muscle spasms, migraine, urinary incontinence, psychosis, convulsions, perinatal hypoxia, cardiac arrest, hypoglycemic neuronal damage, chemical dependence and drug addiction, eye damage and retinopathy, idiopathic and drug-induced parkinson's disease, anxiety including panic disorders, generalized anxiety disorders, post-traumatic stress response syndrome, simple phobias, and social phobia; schizophrenia, depression, bipolar disorders, obsessive-compulsive disorders, Tourette's syndrome, emesis, cerebral edema, chronic and acute pain, tardive dyskinesia, and brain defects secondary to cardiac bypass surgery and transplantation, which method comprises administering to a mammal in need of such treatment:

(a) a compound according to claim 1 or a pharmaceutically acceptable salt thereof; and

(b) serotonin reuptake inhibitor or 5HT_1AA receptor ligand, or a pharmaceutically acceptable salt of the inhibitor or ligand;

wherein a compound according to claim 1 and 5HT are used in the method_1AThe amount of receptor ligand or serotonin reuptake inhibitor is such that the combination of the two active ingredients is effective in treating the condition.

22. The method according to claim 21, wherein (b) is a serotonin reuptake inhibitor selected from the group consisting of sertraline, fluoxetine, fluvoxamine, paroxetine, citalopram, fenfluramine and non-moxidectin.

23. A pharmaceutical composition for treating a disorder or condition in a mammal, which treatment of the disorder or condition is enabled or facilitated by modulation of glutamate neurotransmission, comprising:

(a) a glutamate neurotransmission modulating compound or a pharmaceutically acceptable salt thereof;

(b) a serotonin reuptake inhibitor or serotonin-1A (5 HT)_1A) A receptor ligand, or a pharmaceutically acceptable salt of the inhibitor or ligand; and

(c) a pharmaceutically acceptable carrier;

wherein the glutamate neurotransmission modulating compound and the serotonin reuptake inhibitor or 5HT inhibitor are comprised in the composition_1AThe amount of receptor ligand is such that the combination of the two active ingredients is effective to treat the condition or state.

24. The pharmaceutical composition according to claim 23, wherein (b) is a serotonin reuptake inhibitor selected from the group consisting of sertraline, fluoxetine, fluvoxamine, paroxetine, citalopram, fenfluramine and non-moxidectin.

25. A method for treating a disorder or condition in a mammal which treatment is enabled or facilitated by modulation of glutamate neurotransmission, which method comprises administering to a mammal in need of such treatment:

(a) a glutamate neurotransmission modulating compound or a pharmaceutically acceptable salt thereof; and

(b) a serotonin reuptake inhibitor or serotonin-1A (5 HT)_1A) A receptor ligand, or a pharmaceutically acceptable salt of the inhibitor or ligand;

wherein the glutamate neurotransmission modulating compound and the serotonin reuptake inhibitor or 5HT inhibitor are used in the method_1AThe amount of receptor ligand is such that the combination of the two active ingredients is effective to treat the condition or state.

26. The method according to claim 25, wherein (b) is a serotonin reuptake inhibitor selected from the group consisting of sertraline, fluoxetine, fluvoxamine, paroxetine, citalopram, fenfluramine and non-moxidectin.

27. A compound of the formula

Wherein n is 0 to 6;

x is CH₂、CH₂CH₂Or oxygen;

z is CHR²Or NR²；

R¹And R²Independently selected from hydrogen, (C)₁-C₆) Alkyl, aryl and heteroaryl, wherein the aryl is selected from phenyl and naphthyl, the heteroaryl is selected from 5-and 6-membered aromatic heterocycles containing one to four heteroatoms, the heteroatoms being independentlySelected from nitrogen, oxygen and sulfur, wherein said aryl and heteroaryl moieties may be optionally substituted with one or more substituents independently selected from halo, -S (C)₁-C₆) Alkyl, -S (O) (C)₁-C₆) Alkyl, -S (O)₂(C₁-C₆) Alkyl, optionally substituted by one to seven fluorine atoms (C)₁-C₆) Alkyl, optionally substituted by one to seven fluorine atoms (C)₁-C₆) Alkoxy, amino, nitro, cyano, carboxyl, -CO₂(C₁-C₆) Alkyl, (C)₁-C₆) Alkylamino, di [ (C)₁-C₆) Alkyl radical]Aminophenoxy, phenylamino, and thiophenyl;

R⁷is hydrogen, (C)₁-C₆) Alkyl or benzyl, with the proviso that none of the heteroaryl moieties contain more than one epoxy atom or more than one episulfide atom.