MXPA99000392A - Bicycle [3.1.0] hexants and related compounds - Google Patents

Abstract

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

Description

BICICLOC3.1.0] HEXANTS AND RELATED COMPOUNDS BACKGROUND OF THE INVENTION The present invention relates to compounds of formula I, as described below, to their acceptable pharmaceutical salts, to pharmaceutical compositions containing them and to their use in the treatment of entopathological and psychiatric disorders. The function of excitatory amino acids, such as aspartic acid, has been well established as the principal mediators of excitatory synaptic transmission in the central nervous system. 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 series of different philosophical processes such as motor control, respiration, cardiovascular regulation, sensory perception and consignment. The excitatory amino acid receptors are classified into two general types. The receptors that attach directly to the entrance of the cation channels in the cell membrane of the neurons are called "inotropic".

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-acid. propidnico (AMPA) and 5 caà ± nico acid (KA). The second general type is the protein G or excitatory amino acid receptor "metabotropic" attached to the second messenger. This second type, when activated by the quisqualate, ibotenate or trans-1-aminocyclopentan-1,3-carboxylic acid agonists, leads to an increased hydrolysis of the phosphoinosoitide in the postsynaptic cell. It seems that both types of receptors not only mediate normal synaptic transmission in the excitatory pathways, but also participate in the modification of the synaptic connection during development and changes in the efficacy of synaptic transmission throughout life. Schoepp, Brockaert, and Sladeczek, Trends in Phamacol Sci., 11, 508 (1990); McDonald and Johnson, Brain Research Revie s, 15, 41 (1990). fc Excessive or inappropriate stimulation of excitatory amino acid receptors leads to injury Neuronal or neuronal loss by means of a mechanism known as excitotoxicity. It has been suggested that this process induces neuronal degeneration in a series of disorders. The medical consequences of neuronal degeneration make the relief of these degenerative neurological processes a important therapeutic objective. Excitotoxicity by excitatory amino acids has been implicated in the pathophysiology of a series of neurological disorders. This excitotoxicity has been implicated in the pathophysiology of chronic and acute neurodegenerative disorders that include stroke, cerebral ischemia, spinal cord trauma, head injury, Azheimer's disease, Huntigton's chorea, amyotrophic lateral sclerosis, apilepsy, dementia. induced by AIDS, perinatal hypoxia, hypoxia (such as disorders caused by strangulation, surgery, smoke inhalation, asphyxia, drowning, drowning, electrocution or overdose of drugs or alcohol), cardiac arrest, hypoglycaemic neuronal injury, ocular injury and retinopathy, idiopathic Parkinson's disease- and drug-induced and crebral deficits after cardiac bypass and graft surgery. Other disorders neurological disorders that are caused by glutamate dysfunction require neuromodulation. These different neurological disorders include muscle spasms, migraine headaches, urinary incontinence, psychosis, addiction-abandonment disorders (such as alcoholism and drug addiction). that include opioid addiction, ***e and nicotine), opioid tolerance, anxiety, emesis, cerebral edema, acute and chronic pain, seizures, retinal neuropathy, tinnitus and tardive dyskinesia. It is believed that the use of a neuroprotective agent as an AMPA receptor antagonist is useful in the treatment of these disorders and / or e the reduction of the neurological lesion associated with these disorders. It is also believed that excitatory amino acid receptor (EAA) antagonists are useful as analgesic agents. Metabotropic glutamate receptors are a very heterogeneous family of glutamate receptors that bind to several pathways of the second messenger. In general, these receptors work by modulating the presynaptic release of glutamate, and the postsynaptic sensitivity of the neuronal cell to excite glutamate. The metabotropic glutamate receptors (mGluR) have been pharmacologically divided into two subtypes. A group of receptors ("Class I receptors") binds positively to phospholipase C, which causes the hydrolysis of cellular phosphoinositides (PI). This first group is called metabotropic glutamate receptors bound to Pl. The second group of receptors ("Class II receptors") binds negatively to adenyl cyclase, which prevents the accumulation of cyclic adenosine monophosphate byskolin ( cAMP). Schoepp and Conn. , Trends Phamacol. Sci. , 14, 13 (1993). The receptors of this second group are called metabotropic glutamate receptors attached to cAMP. Metabotropic glutamate receptor agonists linked to cAMP will be useful for the treatment of acute and chronic neurological disorders and psychiatric disorders. Recently, compounds have been discovered that act as metabotropic glutamate receptors but do not act on the ionotropic glutamate receptors. (1S, 3R) -l-aminociclopentan-l, 3-dicarboxylic acid (1S, 3R-ACPD) is an agonist of metabotropic glutamate receptors attached to Pl and joined to cAMP. Schoepp, Johnson, True an Monn., Eur. J. Phamacol. , 207, 351 (1991); Schoepp, Johnson and Monn, J. Neurochem. , 58, 1184 (1992). Recently, (2S, 3S, 4S) -2- (carboxycyclopropyl) glycine (L-CCG-1) has been described as a metabotropic glutamate receptor agonist bound to selective cAMP; However, at high concentrations, this compound has activity in the metabotropic receptors attached to Pl. Nakaga 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 696577A1, which was published on February 14, 1996, refers to certain synthetic amino acids which are described by their selectivity to negatively couple the metabotropic glutamate receptors attached to cAMP (ie, to the receptors of metabotropic glutamate of Class II). The compounds of formula I and their pharmaceutically acceptable salts are metabotropic glutamate receptor ligands that are selective for metabotropic glutamate receptors of Class II.

BRIEF DESCRIPTION OF THE INVENTION wherein n is 0-6; Z is C1-C4 alkylene, oxygen, sulfur, NH or N (alkyl) C? -C6); R is hydrogen, C ^ -Cg alkyl, aryl or heteroaryl, said aryl being selected from phenyl and natfyl and said heteroaryl being selected from 5- and 6-membered aromatic heterocyclic rings containing one or four heteroatoms selected, independently, from nitrogen, oxygen and sulfur, and wherein said aryl and heteroaryl radicals may be optionally substituted by one or more substituents, preferably by one or two substituents which are independently selected from halogen (eg, fluoro, chloro, bromo) or iodine), -S0 (C ^ Cg alkyl), - SO2, -S? 2NR5Rg, C] -C- alkyl optionally substituted by one to seven fluorine atoms, C1-Cg alkoxy optionally substituted by one to three fluorine atoms , amino, nitro, cyano, carboxy, -CO2 (C? -Cg alkyl), (C ^ -Cg alkyl) amino, di (C ^ -Cg alkyl) aminophenoxy, anilino and phenylthio; R is -O (C ^ -Cg alkyl), C2 ~ Cg alkyl or phenyl; and R and R, 6 are independently selected from hydrogen, C ^ -Cg alkyl and phenyl; provided that R1 can not be hydrogen when n is zero, and provided that none of the above heteroaryl radicals can contain more than one oxygen atom in the ring or more than one sulfur atom in the ring; and the pharmaceutically acceptable salts of said compounds. Examples of heteroalyl radicals of said "heteroaryl- (Cg-Cg alkyl) are the following: oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furanyl, pyrazolyl, pyrrolyl, tetrazolyl, triazolyl, thienyl, imidazolyl, pyridinyl, and pyrimidinyl. in addition to the compounds of formula wherein R1 and Z are as defined for formula I above, and R2 and R3 are independently selected from hydrogen and C ^ -Cg alkyl, provided that only one of R2 and R3 can be hydrogen . The compounds of formula II are intermediates in the synthesis of the compounds of formula I. The prefedial compounds of formula I include those in which R is a pyrid-3-yl or pyrid-4-yl group. Other examples of preferred compounds of formula I are those in which R is attached to the bicyclic ring re-sessed in structural formula I by means of an alkyl group. Other examples of preferred compounds of formula I are those in which R is a mono- or disubstituted phenyl group in which one of the substituents is in the para position. Other examples of preferred compounds of formula I are those in which Z is CH2. Other examples of preferred compounds of formula I are those in which R is a thien-2-ylmethyl group. The compounds of formula I and their pharmaceutically acceptable salts are linked to the metabotropic glutamate receptor and are useful in the treatment of a number of neurological and psychiatric disorders. Examples of neurological disorders that can be treated with the compounds of formula I and their pharmaceutically acceptable salts are brain deficits after cardiac bypass and graft surgery, cerebral ischemia (e.g., stroke and cardiac arrest), spinal cord trauma. spinal, head trauma, Alzheimer's disease, Huntington's disease, amyotrophic lecateral sclerosis, AIDS-induced dementia, muscle spasms, migraine headache, urinary incontinence, seizures, perinatal hypoxia, hypoglycaemic neuronal injury, dependence and addictions to chemical substances (eg, dependence or addiction to opiates, benzodiazepines, ***e, nicotine or ethanol), symptoms of drug or alcohol withdrawal, ocular injury and retinopathy, cognitive disorders, idiopathic and drug-induced Parkinson's disease, emesis, cerebral edema, acute and chronic pain, sleep disorders, Tourette syndrome, trast Flattened attention and tardive dyskinesia. Examples of psychiatric disorders that can be treated with the compounds of formula I and their pharmaceutically acceptable salts are schizophrenia, anxiety and related disorders (e.g., panic attacks and stress-related disorders), depression, bipolar disorders, psychosis and disorder. obsessive compulsive. Examples of preferred specific compounds of formula I are those in which Z is CH2 and R1 is one of the following groups Another example of a preferred specific compound of formula I is the compound of formula I, wherein Z is CH2 and R1 is 3-methylbutyl. Other examples of specific compounds of 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-benylamino) -bicyclo [3, 1, 0] hexane-2,6-dicarboxylic acid; 2- (3,4-dichloro-benzylamino) -bicyclo [3.1.0] exano-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-ylbenzylamino) -bicyclo [3.1.0] hexane-2,6-dicarboxylic acid; 2- (4-piperidin-1-ylbenzylamino) -bicyclo [3.1.0] hexane-2,6-dimethoxy acid; and 2- [(6-pyrrolidin-1-yl-pyridin-3-ylmethyl) -amino] -bicyclo [3.1.0] hexane-2,6-dicarboxylic acid. The present invention also relates to pharmaceutically acceptable acid addition salts of compounds of formula I. The acids that are used to prepare the salts by addition of acids, pharmaceutically acceptable, of the above-mentioned basic compounds of this invention are those that form non-toxic salts by the addition of acids, ie, 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 [ie 1.1"- methylene-bis- (2-hydroxy-3-naphthoate)] The present invention further relates to the pharmaceutically acceptable base addition salts of the compounds of formulas I. These salts are all prepared by conventional techniques. Chemicals which are used as reagents for preparing the pharmaceutically acceptable base addition salts of this invention are those which form non-toxic base salts with the acid compounds of formula I. Such base salts include those derived from pharmacologically acceptable cations such as sodium, potassium, calcium and magnesium, etc. This invention further relates to a pharmaceutical composition for treating a disorder or condition, the treatment or prevention of which can be effected or facilitated by modulating (ie, increasing or decreasing) the neurotransmission of glutamate in a mammal, comprising an amount that is effective in the treatment of said disorder or condition of a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. This invention further relates to a method for treating a disorder or condition, the treatment or prevention of which can be effected or facilitated by modulating the neurotransmission of glutamate in a mammal, which comprises administering to a mammal in need thereof an amount which is effective in the treatment of said disorder or condition of a compound of formula I, or of a pharmaceutically acceptable salt thereof. The invention further relates to a pharmaceutical composition for treating a disorder selected from stroke, cerebral ischemia, spinal cord trauma, head trauma, Alzheimer's disease, Huntington's chorea, amyotrophic lateral sclerosis, epilepsy, AIDS-induced dementia, spasms muscle, migraine headaches, urinary incontinence, psychosis, convulsions, perinatal hypoxia, hypoxia (such as disorders caused by strangulation, surgery, smoke inhalation, asphyxia, drowning, drowning, electrocution or drug or alcohol overdose), cardiac arrest, neuronal injury hypoglycemic, dependencies and addictions to chemical substances (for example, addictions or dependancies of alcohol, opiates, benzodiazepinas, nicotine, heroin or ***e), eye injury, retinopathy, retinal neuropathy, tinnitus, idiopathic or drug-induced Parkinson's disease, anxiety, panic disorders, schizophrenia, of pressure, bipolar disorder, obsessive-compulsive disorder, Tourette's syndrome, emesis, cerebral edema, chronic and acute pain, tardive dyskinesia and brain deficits after cardiac bypass and graft surgery in a mammal, comprising a quantity 5 of a compound of formula I, or a pharmaceutically acceptable salt thereof, effective to modulate the neurotransmission of glutamate, and a pharmaceutically acceptable carrier. This invention also relates to a method for treating a disorder selected from an accident cerebrovascular, cerebral ischemia, spinal cord trauma * spinal ß, head trauma, Alzheimer's disease, chorea Huntington, amyotrophic lateral sclerosis, epilepsy, AIDS-induced dementia, muscle spasms, migraine headaches, urinary incontinence, psychosis, seizures, hypoxia perinatal, hypoxia (such as disorders caused by strangulation, surgery, smoke inhalation, suffocation, drowning, drowning, overdosing or overdosing of drugs or alcohol), cardiac arrest, hypoglycaemic neuronal injury, dependence and addictions to chemical substances (for example, addictions or dependencies of alcohol, opiates, benzodiazepines, nicotine, heroin or ***e), eye injury, retinopathy, retinal neuropathy, tinnitus, idiopathic or drug-induced Parkinson's disease, anxiety, panic disorders, schizophrenia, depression, disorder bipolar disorder, obsessive-compulsive disorder, Tourette syndrome, emesis, cerebral edema, chronic and acute pain, tardive dyskinesia and brain deficits after cardiac bypass and graft surgery in a mammal, which comprises administering to a breastfed person in need of such treatment an amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, effective to modulate the neurotransmission of glutamate. This invention further relates to a pharmaceutical composition for treating a disorder or condition, the treatment of which can be effected or facilitated by modulating the neurotransmission of glutamate in a mammal, comprising an amount that is effective to modulate the neurotransmission of glutamate of a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, • This invention further relates to a method for treating a disorder or condition, the treatment of which can be effected or facilitated by modulating the neurotransmission of glutamate in a mammal, which comprises administering to a mammal in need of such treatment an amount that is effective to modulate the neurotransmission of glutamate of a compound of formula I, or of a pharmaceutically acceptable salt thereof. This invention further relates to a method for treating a disorder selected from stroke, cerebral ischemia, spinal cord trauma, head trauma, Alzheimer's disease, Huntington's chorea, amyotrophic lateral sclerosis, epilepsy, AIDS-induced dementia, muscle spasms. , migraine headaches, urinary incontinence, psychosis, seizures, perinatal hypoxia, hypoxia (such as disorders caused by strangulation, surgery, smoke inhalation, choking, drowning, electrocution or drug or alcohol overdose), cardiac arrest, hypoglycemic nerve injury, dependencies and addictions to chemical substances (for example, additions or dependencies of alcohol, opiates, benzodiazapines, nicotine, heroin or ***e), eye injury, retinopathy, retinal neuropathy, tinnitus, idiopathic or drug-induced Parkinson's disease, anxiety, panic, schizophrenia, depressive depression non-bipolar disorder, obsessive-compulsive disorder, Tourette syndrome, emesis, cerebral edema, chronic and acute pain, tardive dyskinesia and brain deficits after cardiac bypass and graft surgery in a mammal, which comprises administering to a mammal in need of such treatment an amount of a compound of formula I that is effective to treat said disorder. The invention further relates to a pharmaceutical composition for treating a disorder selected from stroke, cerebral ischemia, spinal cord trauma, head trauma, Alzheimer's disease, Huntington's chorea, amyotrophic lateral sclerosis, epilepsy, AIDS-induced dementia, spasms muscle, migraine, urinary incontinence, psychosis, seizures, perinatal hypoxia, hypoxia (such as disorders caused by strangulation, surgery, smoke inhalation, suffocation, drowning, drowning, electrocution or overdose of drugs or alcohol), cardiac arrest, hypoglycemic neronal injury, dependencies and addictions to chemical substances (for example, additions or dependence on alcohol, opiates, benzodiazepines, nicotine , heroin or ***e), eye injury, retinopathy, retinal neuropathy, tinnitus, idiopathic or drug-induced Parkinson's disease, anxiety, panic disorders, schizophrenia, depression, bipolar disorder, obsessive-compulsive disorder, Tourette syndrome, emesis, edema cerebral, chronic and acute pain, tardive dyskinesia and cerebral deficits after cardiac bypass and graft surgery in a mammal, comprising an amount of a compound of formula I, which is effective to treat said disorder and a pharmaceutically acceptable carrier. This invention further relates to a method for treating a disorder or condition, the treatment of which can be effected or facilitated by modulating the neurotransmission of glutamate in a mammal, 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) an inhibitor of serotonin reuptake (eg, setralin, fluoxetine, fluvoxamine, etc.) or a serotonin-1A receptor ligand (dHTj - (eg, buspirone, flesinoxane, etc.) or a pharmaceutically acceptable salt of said inhibitor or ligand, wherein the amounts of the compound of formula I and of inhibitor of serotonin reuptake or 5HT receptor ligand? _ ^ which are employed in said process are such that the combination of the two ingredients This invention is further directed to a pharmaceutical composition for treating a disorder or condition, the treatment of which can be effected or facilitated by modulating the glutamate nerotransmission in a mammal, comprising: (a) a compound of formula I, or a pharmaceutically acceptable salt thereof, (b) an inhibitor of serotonin retention (eg, sertraline, fluoxetine, fluvoxamine, etc.) or a ligand of the serotonin-1A receptor (5HT? _ ^) (eg, buspirone, flesinoxane, etc.) or a pharmaceutically acceptable salt of said inhibitor or ligand; and (c) a pharmaceutically acceptable carrier; wherein the amounts of the compound of formula I and of the serotonin reuptake inhibitor or 5HT receptor ligand that are contained in said composition are such that the combination of the two active ingredients is effective in treating said disorder or condition. This invention further relates to a method for treating a disorder or condition and treatment can be performed or facilitated by modulating the neurotransmission of glutamate in a mammal, which comprises administering to a mammal in need of such treatment, • (a) a compound that modulates the glutamate neurotransmission, or a pharmaceutically acceptable salt thereof; and (b) a serotonin reuptake inhibitor (e.g., sertraline, fluoxetine, fluvoxamine, etc.) or a serotonin receptor ligand-A (5HT-] _ ^) (e.g., buspirone, flesinoxane, etc.). .) or a pharmaceutically acceptable salt of said inhibitor or ligand; wherein the amounts of the compound that modulates the neurotransmission of glutamate and of the serotonin reuptake inhibitor or 5HT receptor ligand ^ which are employed in said method are such that the combination of the two active ingredients is effective in treating said disorder or condition This invention further relates to a pharmaceutical composition for treating a disorder or condition whose treatment can be effected or facilitated by modulating the neurotransmission of glutamate in a mammal, comprising; (a) a compound that modulates the neurotransmission of glutamate, or a pharmaceutically acceptable salt thereof; (b) a serotonin reuptake inhibitor (e.g., sertraline, fluoxetine, fluvoxamine, etc.) or a serotonin-A (5HT) j- receptor ligand (e.g., buspirone, flesionoxane, etc.) or a pharmaceutically acceptable salt of said inhibitor or ligand, and (c) a pharmaceutically acceptable carrier, wherein the amounts of the compound that modulates the neurotransmission of glutamate and of the inhibitor of the reuptake of serotonin or ligand of the SHTIA receptor that are contained in said The present invention also relates to a method for treating a disorder selected from stroke, cerebral ischemia, spinal cord trauma, head trauma, etc. The present invention also relates to a method for treating a disorder selected from stroke, cerebral ischemia, spinal cord trauma, head trauma, etc. Alzheimer's disease, Huntington's chorea, amyotrophic lateral sclerosis, epilepsy, AIDS-induced dementia, moss spasms, migra headaches monosaccharides, urinary incontinence, psychosis, convulsions, perinatal hypoxia, hypoxia (such as those caused by strangulation disorders, surgery, smoke inhalation, suffocation, drowning, drowning, electrocution or overdose of drugs or alcohol), cardiac arrest, hypoglycemic neuronal injury, dependencies and addictions to chemical substances (for example, addictions or dependence on alcohol, opiates, benzodiazepines, nicotine, heroin or ***e), ocular injury, retinopathy, retinal neuropathy, tinnitus, idiopathic or drug-induced Parkinson's disease, anxiety, panic disorders, schizophrenia, depression, bipolar disorder, obsessive-compulsive disorder, Tourette syndrome, emesis, cerebral edema, chronic and acute pain , tardive dyskinesia and brain deficits after cardiac bypass and graft surgery in a mammal, 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 (eg, sertraline, fluoxetine, fluvoxamine, etc.) or a serotonin receptor ligand-A (5HT.) _ (eg, buspirone, flesinoxane, etc.). .) or a pharmaceutically acceptable salt of said inhibitor or ligand; wherein the amounts of the compound of formula I and of the serotonin reuptake inhibitor or 5HT receptor ligand; and ^ which are employed in said method are such that the combination of the two active ingredients is effective in treating said disorder or condition . The invention further relates to a pharmaceutical composition for treating a disorder selected from stroke, cerebral ischemia, spinal cord trauma, head trauma, Alzheimer's disease, Huntington's cores, amyotrophic lateral sclerosis, epilepsy, AIDS-induced dementia, spasms muscle, migraine headaches, urinary incontinence, psychosis, convulsions, perinatal hypoxia, hypoxia (such as disorders caused by strangulation, surgery, smoke inhalation, asphyxiation, drowning, drowning, electrocution or drug or alcohol overdose), cardiac arrest, neuronal injury hypoglycemic, dependencies and addictions to chemical substances (for example, addictions or dependence on alcohol, opiates, benzodiazepines, nicotine, heroin or ***e), eye injury, retinopathy, retinal neuropathy, tinnitus, idiopathic or drug-induced Parkinson's disease, anxiety, panic disorders, schizophrenia, dep resuscitation, bipolar disorder, obsessive-compulsive disorder, Tourette's syndrome, emesis, cerebral edema, chronic and acute pain, tardive dyskinesia and brain deficits after cardiac bypass and graft surgery in a mammal, comprising: (a) a compound of formula I, or a pharmaceutically acceptable salt thereof; (b) a serotonin reuptake inhibitor (eg, sertraline, fluoxetine, fluvoxamine, etc.) or a ligand for the serotonin-1A receptor (5HTj- (eg, buspirone, flesinoxane, etc.) or a salt pharmaceutically acceptable of said inhibitor or ligand, and (c) a pharmaceutically acceptable carrier, wherein the amounts of the compound of formula I and of the serotonin reuptake inhibitor or SHT receptor receptor ligand which are contained in said composition are such that the combination of the two active ingredients is effective in treating said disorder or condition, unless otherwise indicated, the alkyl groups recited herein, as well as the alkyl radicals of other groups mentioned herein (e.g. alkoxy), can be linear or branched and can also be cyclic (for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl) or be linear or branched and contain radicals cyclic. The term "treating", as used herein, refers to reversing, alleviating, inhibiting the progress or preventing the disorder or condition to which the term is applied, or one or more symptoms of said disorder or condition. The term "Treatment", as used herein, refers to the ^ act to treat, being "treat" as defined above. Unless otherwise indicated, "halo" and "halogen", as used herein, refers to fluorine, bromine, chlorine or iodine. The compounds of formula I can have chiral centers and therefore exist in different enantiomeric and diastereomeric forms. This invention relates to all The optical isomers and the rest of the stereoisomers of the compounds of the formula I, and all the racemic and Another type thereof, and to the pharmaceutical compositions and methods of treatment defined above that contain or employ such isomers or mixtures. Formula I above includes compounds identical to those represented, except for the fact that one has been replaced or more hydrogen or carbon atoms for their isotopes. Such compounds are useful with diagnostic tools in pharmacokinetic studies of metabolism and in binding assays. Specific applications in the 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 procedures of scheme 1. Unless otherwise indicated, in the following reaction and description scheme, n, Z, R1, R2, R3, R4, R5, and R6 and structural formulas I and II are as defined above.

SCHEME 1 SCHEME 2 lll I (R * 1 = renil substituted with 0-3 EWG) (Ri = renilo with other different substituents) SCHEME 3 (R1-heteroaryl substituted with 0-3 EWG) (R1 = heteroaryl with other substituents) Scheme 1 illustrates the preparation of compounds of formula I in which there is an alkyl bond of R with the amino nitrogen of formula I. With reference to scheme 1, a compound of formula III is reacted with the appropriate aldehyde of formula R1 (CH2) mCHO, wherein m is equal to n-1, forming a compound of formula IIA. The above reductive amination formulation can be carried out using conventional procedures well known to those skilled 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 source of chemical hydrogen such as formic acid or ammonium formate) and a metal catalyst such as platinum, palladium or rhodium. , zinc, and hydrochloric acid, boron / dimethyl sulfide or hydrochloric acid, borane / dimethyl sulfide or formic acid, at a temperature of about -60 ° C to about 50 ° C. Suitable inert reaction 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 ° C and the reducing agent is sodium triacetoxyborohydride. The compounds of formula IIA formed in the above reaction can be converted to the corresponding desired compounds of formula I by subjecting them to hydrolysis with acid or base, using procedures well known to those skilled in the art. Suitable acids for use in the basic hydrolysis of compounds of formula IIA including alkali metal hydroxides and barium hydroxide. The reaction temperature for the acid and basic hydrolysis reactions may vary from about 0 ° C to about 100 ° C. Preferably, these reactions are carried out at the reflux temperature of the reaction mixture. The compounds of formula I, wherein R is aryl or heteroaryl and n is zero, can be formed from the corresponding compounds of formula IIA, as illustrated in schemes 2 and 3, respectively. The compounds of formula IIA in which R is aryl can be formed, as illustrated in scheme 2, with a compound, of formula R- X, wherein X is a leaving group such as halogen, triflate, mesylate or tosylate . This reaction is generally carried out in a solvent such as ethanol, N, N-dimethylformamide (DMF), N, N, -dimethylacetamide, acetonitrile, nitromethane, dioxane or dichloroethane, preferably DMF, at a temperature of about 0 ° C. at about 160 ° C, preferably at about reflux temperature. Scheme 2 specifically represents the synthesis of the compounds of formula I in which R 1 is an unsubstituted phenyl group or a phenyl group having from 0 to 3 electron extractor groups (EWG) as substituents. Examples of EWG include, but are not limited to, nitro, (C-alkyl); _-Cg) -SO-, (C ^ -Cg alkyl) -SOI2-, (alkyl CL-Cg) -0-C (= 0) -, (C1-C6 alkyl) 2-NC (= 0) -, cyano, S02R4 and S02NR5R6. Analogously, compounds of formula I in which R is heteroaryl and n is zero can be prepared as illustrated in scheme 3. With reference to scheme 3, a compound of formula III is reacted with a heteroaromatic compound of formula V wherein ring A is a heterocycle containing a nitrogen and X is a leaving group, as defined above, which is ortho to a ring nitrogen. The intermediate of formula IIA that is formed in the above reaction can be subsequently hydrolyzed, under the conditions described above, to provide the final desired compound of formula I. Examples of compounds of formula V are the following: R4 The presence in the above heteroaryl groups of additional EWGs further activates them. The compounds in which R1 is another aryl or heteroaryl group can be synthesized analogously starting from the appropriate compound of formula R X. Additional compounds of formula I in which R is aryl or substituted heteroaryl, can be obtained from compounds of formula IIA in which R1 is a nitroaryl or nitroheteroaryl group, using chemical procedures of well known syntheses. For example, following procedures • ^ like those described by Jerry March, Advanced Organic Chemistry, 4th edition, pages 721-725 and 1216-1217, the nitro group can be reduced in an amine. The newly formed amine can be replaced by other substituents by diazotization and subsequent reaction as summarized in the previous reference.

For example, compounds of formula I in which R is an aryl or heteroaryl group can be prepared in this way • substituted by amino, mercapto, halogen, cyano or phenyl. The starting materials of formula IV and others compounds of formula R X are commercially available, are known in the literature or can be readily obtained from commercially available or known compounds using methods that are known in the art. The starting materials of formula III are known in the literature (see, for example, European patent application 696577A1, cited above). or The compounds of formula II in which one of the R? and R is hydrogen can be prepared by partial hydrolysis of the corresponding compounds of formula IIA. Unless stated otherwise, the pressure in each of the above reactions is not critical. In general, the reactions will be carried out at a pressure of approximately 101330 Pa, preferably at ambient pressure (approximately 101330 Pa). The preparation of other compounds of formula I not specifically described in the above experimental section can be carried out using combinations of reactions described above that will be apparent to those skilled in the art. The compounds of formula I which are basic in nature can form a wide variety of different salts with various inorganic or organic acids. Acids which are used to prepare the pharmaceutically acceptable acid addition salts of the aforementioned basic compounds of this invention are those which form non-toxic salts by addition of acids, i.e. salts containing pharmacologically acceptable anions, such as hydrochloride, bromohydrate, hydroiodide, nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate, citrate or citrate acid, tartrate or bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate and pamoate [ie 1, 1"-methylene-bis- (2-hydroxy-3-naphthoate)].

Although such salts must be pharmaceutically acceptable for administration to animals, it is sometimes desirable in practice to initially isolate from the reaction mixture a compound of formula I in pharmaceutically acceptable salt form and then simply convert the latter into the compound in free base form by treatment with an alkaline reagent and subsequently converting the free base to a salt by the addition of a pharmaceutically acceptable acid. The acid addition salts of the active basic compounds of this invention are readily prepared by treating the basic compound with a substantially equivalent amount of the chosen mineral or organic acid, in an aqueous solvent medium or in a suitable organic medium, such as methanol or ethanol. After careful evaporation of the solvent, the solid salt is easily obtained desired. The compounds of formula I which are acidic in nature can form base salts with various cations • pharmacologically acceptable. These salts are all prepared by conventional techniques. The chemical bases that are used as reagents for preparing 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 pharmacologically acceptable cations such as sodium, potassium, calcium and magnesium, etc. These signals can be easily 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, these can also be prepared by mixing lower alkane solutions of the acidic compounds and the desired alkali metal alkoxide, and then evaporating the resulting solution to dryness in the same manner as above. In any case, stoichiometric amounts of the reagents are preferably employed in order to ensure that the reaction has been completed and to obtain the maximum yields of the desired final product. The compounds of formula I and the pharmaceutically acceptable salts thereof (hereinafter collectively referred to as "the active compounds of the invention") are useful for the treatment of neurodegenerative, psychotropic and drug-induced or alcohol-induced deficits, and are potent antagonists of metabotropic glutamate receptor ligands. Thus, the active compounds of the invention can 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, dementia induced by AIDS, muscle spasms, migraine headaches, urinary incontinence, psychosis, convulsions, perinatal hypoxia, hypoxia (such as disorders caused by strangulation, surgery, inhalation of smoke, suffocation, drowning, drowning, electrocution or overdose of drugs or alcohol), cardiac arrest , hypoglycaemic neuronal injury, dependencies and addictions to chemical substances (for example, addictions or dependencies of alcohol, opiates, benzodiazepines, nicotine, heroin or ***e), eye injury, retinopathy, retinal neuropathy, tinnitus, idiopathic Parkinson's disease or indicated by drugs , anxiety, emesis, cerebral edema, chronic and acute pain, dis delayed kinesis and brain deficits after cardiac bypass surgery e 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 to use geneticin (G418, Gibco, 500-700 μg / ml) and analyzed by 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 TTG TTG AGT ACG CCA-3') Positive clones were reproduced until confluence and responses to cAMP were measured in the presence of 10 μM 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 Dulbeco Modified Eagle's Medium (DMEM) (Gibco catalog number 11960- 044), containing 10% dialyzed fetal bovine serum, 1% proline, 0.11 mg / ml sodium pyruvate, 0.5 mg / ml Geneticin, 2 mM l-glutamine and penicillin / streptomycin.The cells were harvested using a solution of ethylenediaminetetraacetic acid (EDTA) ) 5 mM and then centrifuged at 800 rpm in a refrigerated centrifuge at 4 ° C. The resulting pellet was resuspended in a phosphate-buffered saline solution containing 30 mM HEPES (Gibco, cathin, 15630-080), 5 mM magnesium chloride (MgCl2), 3-isobutyl-1-methylxanthine (IBMX) 300 μM and 0.1% dextrose. The cell suspension was added in 200 μl aliquots to flat bottom polypropylene tubes which were then placed in a water bath heated at 37 ° C for 22 minutes. Without a compound tested to determine its antagonist activity, it is reduced to pre-incubate with the cells in the bath during the first 11 minutes. At the end of 11 minutes, 5 μM forskolin plus a known concentration of a test compound was added, and the incubation was prolonged for another 11 minutes. If a compound was tested for agonist activity, the cells were shaken in the bath for the initial 11 minutes and then 5 μM forskolin plus a known concentration of agonist was added for the remaining 11 minutes of incubation. In any case, the reaction was interrupted with 25 μl of 6N precoric acid (PCA), and each tube was immediately transferred to an ice 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. The aliquots (25 μl) were assayed in a commercial competitive binding assay kit (Amersham TRK.432). Samples were then collected on GF / B filters coated with 0.5% PEI using a 96-well Skatron harvester. The samples were quantified using a Betaplate 1205 liquid scintillation counter. The CPMs (counts per minute) of the Betaplace reader were converted to cAMP pinoles / mg protein / minute of incubation with forskolin using an Excel spreadsheet. The EC50 and IC50 can be calculated from a linear regression of the concentration-response data. The following procedure can be used to determine the agonist activity of the therapeutic agents of this invention as metabotropic glutamate receptor agonists. Chinese hamster ovary (CHO) cells transfected stably with the rat metabotropic glutamate receptor, mGluR2 in DMEM, were confluenced.

(Gibco catalog number 11960-044), which contained 10% dialyzed fetal bovine serum, 15% proline, 0.11 mg / ml sodium pyruvate, 0.5 mg / ml Geneticin, 2 mM l-glutamine and penicillin / streptomycin. The cells were harvested using a 5 mM EDTA solution and homogenized with 10 strokes in a hand-held Teflon glass homogenizer, then 50 volumes of a phosphate buffered saline (PBS) solution were added and the solution was centrifuged. 18,000 rpm for 10 minutes at 4 ° C. The pellet was re-homogenized and resuspended in assay buffer (100 mM HEPES, 1 mM EGTA, pH 7.5) at a concentration that will result in approximately 0.009 mg protein / well. A reaction mixture containing 6 mM MgCl 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 of creatine phosphokinase (final concentrations in the assay) just before starting the experiment. 20 μl of the test compound, 20 μl of forskolin (final 5 μm), 20 μl of reaction mixture and 40 μl of tissue in sequential order are added to a 96-well polypropaline plate. The plate is incubated at 37 ° C in a water bath heated for 15 minutes. The reaction is stopped with the addition of 50 μl of 40 mM EDTA. The plate is then transferred to ice and stirred for 10-15 minutes before extracting a 25 μl aliquot for analysis with a commercial competitive binding assay kit (Amersham TRK.432). After an incubation of 2-18 hours in a refrigerator, samples are collected on GF / B filters coated in 0.5% polyethyleneimine (PEI) using a Skatron 96-well collector. Samples are quantified using a Betaplace 1205 liquid scintillation counter.

The CPMs of the Betaplace reader are converted into cAMP / well pmoles using an Excel spreadsheet. The agonist compounds are identified by percentage reduction of the forskolin signal, also in Excel. The EC50 are calculated by linear regression of the concentration-response data. The compositions of the present invention can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers. Thus, the active compounds of the invention can 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 as binding agents (e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (for example, lactose, microcrystalline cellulose or calcium phosphate); lubricants (for example, magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate). The tablets can 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 may be presented as a dry product for reconstruction with water or other suitable vehicle before use. Such liquid preparations can be prepared by conventional means with pharmaceutically acceptable additives as suspending agents (for example, sorbitol syrup, hypromellose or hydrogenated edible fats); emulsifying agents (for example, lecithin or gum arabic); non-aqueous vehicles (e.g., almond oil, oily esters or ethyl alcohol); and preservatives (for example, methyl or propyl-p-hydroxybenzoates or sorbic acid). For buccal administration, the composition may take the form of tablets or tablets formulated in the conventional manner. The active compounds of the invention can be formulated for parenteral administration by injection, including the use of conventional catheterization or infusion techniques. Formulations for injection may be presented in unit dosage form, for example, in ampules or multi-dose containers, to which a preservative is added. The compositions may take such forms as 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 the form of a powder for reconstitution with a suitable vehicle, eg, sterile pyrogen-free water, before use. The active compounds of the invention can also be formulated in rectal compositions such as suppositories or retention enemas, for example, 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 administered in the form of a solution or suspension from a powdered container provided with a pump that is compressed or pumped by the patient, or as a spray presentation of aerosol from a pressurized container or a nebulizer, using a suitable propellant, for example, dichloridifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the unit dose can be determined by providing the container with a valve to release a measured quantity. The pressure pack or nebulizer may contain a solution or suspension of the active compound. Capsules or cartridges (made, for example, in gelatin) for use in an inhaler or insufflator can be formulated containing a powder mixture of a compound of the invention and a suitable powder base such as lactose or starch. A proposed dose of active compounds of the invention for oral, parenteral or buccal administration to an average adult human for the treatment of the above-mentioned disorders (e.g., stroke), ranges from 0.01 to 50 mg / kg of active ingredient per unit dose to be administered for example, from 1 to 4 times a day. Aerosol formulations for the treatment of the above-mentioned disorders (e.g., cerebrovascular accidents), in the average human adult are preferably arranged so that each metered dose or "application" of aerosol contains from 20 mg to 1000 mg of the compound of the invention. The total daily dose with an aerosol will vary in the range of 100 mg to 10 mg. The administration can be several times a day, for example, 2, 3, 4 or 8 times a day, applying for example, 1, 2 or 3 doses each time. The following examples illustrate the preparation of the compounds of the present invention. The commercial reagents were used without further purification. The melting points are uncorrected. All NMR data were recorded at 250, 300 or 400 MHz in deuterochloroform, unless otherwise indicated and reported in parts per million (Ü) taking as reference the deuterium stabilization signal for the sample solvent . All non-aqueous reactions were carried out in dry glass apparatus with dry solvents and under an inert atmosphere for reasons of convenience and to maximize yields. If not stated otherwise, all reactions were shaken with a magnetic stir bar. If not stated otherwise, all mass spectra were obtained using chemical impact conditions. Ambient temperature refers to 20-25 ° C. The melting points are uncorrected. The HPLC conditions are as follows: (a) Column: Waters Symmetry C18, 3.0 x 150 mm, part. No. WAT046980, lot No. T71961R 87. Solvent system: Isocratic, 5 mM ammonium acetate buffer at 75% unadjusted / 25% acetonitrile. Flow rate: 0.8 ml / minute. Run time: 10 minutes Injection volume: 20 μl Detection wavelength: 206.4 nm (b) Column: Waters Symmetry C18, 4.6 x 250 mm, part. No. WAT054275, lot No. T71141U 02. Solvent system: Isocratic, 5 mM ammonium acetate buffer 5% unadjusted / 9% acetonitrile. Flow rate: 0.8 ml / minute. Execution time: 10 minutes Injection volume: 20 μl Detection wavelength: 203.9 nm (c) Column: Waters Spherisorb Phenyl 4.6 x 250 mm Solvent system: Isocratic Flow rate: 1.0 ml / minute. Run time: 10 minutes Injection volume: 15 μl Detection wavelength: 203.9 nm EXAMPLE 1 A. Sodium triacetoxyborohydride (0.0403 g, 0.19 mmol) was added to a mixture of 2-aminobicyclo [3.1.0] hexane-2,6-dicarboxylic acid diethyl ester (0.0092 g, 0.038 mmol) and 0.046 mmol of benzaldehyde in dichloromethane (0.92). ml) in a 1.0 ml screw cap vial and the mixture was stirred at room temperature overnight. Activity 1 alumina B (50-200 mesh, 0.10 g) was added, and the mixture was stirred for another 30 minutes before filtering through alumina B of activity 1 (0.5 g). The alumina was washed with 2 ml of 5% methanol / dichloromethane. An aliquot of the filtrate was analyzed by HPLC to determine the unreacted 2-aminobicyclo [3.1.0] hexane-2,6-dicarboxylate diethyl ether. If this starting material was present, the mixture is not brought to step 2. The solution was concentrated at 50 ° C (4826 mm Hg) to provide an oil intermediate. B. The intermediate from step 1 was combined with 6N HCl (0.50 ml) in a 1 ml screw cap vial and stirred at 100 ° C overnight. An aliquot was extracted for HPLC analysis. If the HPLC analysis indicates that the intermediate from step 1 has been consumed, the reaction is cooled to room temperature and loaded onto a cation exchange resin (Burdick and Jackson SCS, 0.50 g which had previously been washed with water until which eluent had a pH about 4.5). The product eluted with 2 ml of water. Eluent concentration at 70 ° C (4826 mm Hg) gave the off-white solid product. The product was characterized by the HPLC retention time and the molecular ion mass spectrum. The following compounds of formula I were prepared using an analogous procedure. •

Claims (9)

1. NOVELTY OF THE INVENTION
3. A compound of formula wherein n is 0-6; Z is C ^ - ^ alkylene, oxygen, sulfur, NH or Nalkyl C] _- Cg); R1 is hydrogen, C1-C4 alkyl, aryl or heteroaryl, said aryl being selected from phenyl and naphthyl and said heteroaryl being selected from 5- and 6-membered aromatic heterocyclic rings containing from one to four heteroatoms selected, independently, from nitrogen, oxygen and sulfur, and wherein said aryl and heteroaryl radicals may be optionally substituted by one or more substituents, preferably by one or two substituents which are independently selected from halogen (eg, fluoro, chloro, bromo or iodo) , -S0 (CI-Q alkyl), -S02R4, -S02NR5R6, C ^ -Cg optionally substituted by one to seven fluorine atoms, C? -Cg alkoxy optionally substituted by one to seven fluorine, amino, nitro, cyano atoms , carboxy, -CO2 (Cj_-C? alkyl), (C ^ -Cg alkyl) amino, di (C ^ -Cg alkyl) aminophenoxy, anilino and phenylthio; R is -O (C ^ -Cg alkyl), C ^ -Cg alkyl or phenyl; and R and R are independently selected from hydrogen, C] _- Cg alkyl and phenyl; provided that R can not be hydrogen when n is zero, and provided that none of the above heteroaryl radicals can contain more than one oxygen atom in the ring or more than one sulfur atom in the ring; or a pharmaceutically acceptable salt thereof. 2. - A compound according to claim 1, wherein
4. Z is CH2. 3. A compound according to claim 1 or claim 2, wherein R is a disubstituted phenyl group having substituents in the meta and para positions. 4. A compound according to claim 1, 2 or 3, wherein R2 is a monosubstituted or disubstituted phenyl group in which a substituent is in the para position.
5. 5. A compound according to claim 1 or claim 2, wherein R1 (CH2) n is one of the following groups:
6. 6. - A pharmaceutical composition for treating (a) a disorder or condition that can be treated by modulating the nuetrotransmission of glutamate in a mammal; or (b) a disorder or condition selected from stroke, cerebral ischemia, spinal cord trauma, head trauma, Alzheimer's disease, Huntington's chorea, amyotrophic lateral sclerosis, AIDS-induced dementia, muscle spasms, migraine headaches, urinary incontinence , psychosis, seizures, perinatal hypoxia, hypoxia, cardiac arrest, hypoglycaemic neural injury, dependencies and addictions to chemical substances, ocular injury and retinopathy, idiopathic or drug-induced Parkinson's disease, anxiety, panic disorders, schizophrenia, depression, bipolar disorder , obsessive-compulsive disorder, Tourette syndrome, emesis, cerebral edema, chronic and acute pain, tardive dyskinesia and cerebral deficits after cardiac bypass or graft surgery in a mammal, comprising an amount of a compound according to claim 1, effective to treat such disorder or condition, and a vehicle pharmaceutically acceptable.
7. 7. A method for treating: (a) a disorder or condition that can be treated by modulating the nuetrotransmission of glutamate in a mammal; or (b) a disorder or condition selected from stroke, cerebral ischemia, spinal cord trauma, head trauma, Alzheimer's disease, Huntington's chorea, amyotrophic lateral sclerosis, AIDS-induced dementia, muscle spasms, migraine headaches, urinary incontinence , psychosis, seizures, perinatal hypoxia, hypoxia, cardiac arrest, hypoglycaemic neural injury, dependencies and addictions to chemical substances, ocular injury and retinopathy, idiopathic or drug-induced Parkinson's disease, anxiety, panic disorders, schizophrenia, depression, bipolar disorder , obsessive-compulsive disorder, Tourette syndrome, emesis, cerebral edema, chronic and acute pain, tardive dyskinesia and cerebral deficits after cardiac bypass or graft surgery in a mammal, comprising an amount of a compound according to claim 1, effective to treat such disorder or condition.
8. 8. A pharmaceutical composition for treating: (a) a disorder or condition that can be treated by modulating the nuetrotransmission of glutamate in a mammal; or (b) a disorder or condition selected from stroke, cerebral ischemia, spinal cord trauma, head trauma, Alzheimer's disease, Huntington's chorea, amyotrophic lateral sclerosis, AIDS-induced dementia, muscle spasms, migraine headaches, urinary incontinence , psychosis, seizures, perinatal hypoxia, hypoxia, cardiac arrest, hypoglycaemic neural injury, dependencies and addictions to chemical substances, ocular injury and retinopathy, idiopathic or drug-induced Parkinson's disease, anxiety, panic disorders, schizophrenia, depression, bipolar disorder , obsessive-compulsive disorder, Tourette syndrome, emesis, cerebral edema, chronic and acute pain, tardive dyskinesia and brain deficits after cardiac bypass or graft surgery in a mammal, comprising (a) a compound of claim 1 or a pharmaceutically acceptable salt thereof; (b) an inhibitor of the reception of serotonin or a ligand of the 5W receptor? . 'A pharmaceutically acceptable salt of said inhibitor or ligand; and (c) a pharmaceutically acceptable carrier; wherein the compound according to claim 1 and the ligand of the SHT ^ receptor or serotonin reuptake inhibitor which are contained in said composition are present in such amounts that the combination of the two active ingredients is effective in treating said disorder or condition .
9. 9. A method for treating: (a) a disorder or condition that can be treated by modulating the nuetrotransmission of glutamate in a mammal; or (b) a disorder or condition selected from stroke, cerebral ischemia, spinal cord trauma, head trauma, Alzheimer's disease, Huntington's chorea, amyotrophic lateral sclerosis, AIDS-induced dementia, muscle spasms, migraine headaches, urinary incontinence , psychosis, seizures, perinatal hypoxia, hypoxia, cardiac arrest, hypoglycaemic neural injury, dependencies and addictions to chemical substances, ocular injury and retinopathy, idiopathic or drug-induced Parkinson's disease, anxiety, panic disorders, schizophrenia, depression, bipolar disorder , obsessive-compulsive disorder, Tourette syndrome, emesis, cerebral edema, chronic and acute pain, tardive dyskinesia and brain deficits after cardiac bypass or graft surgery in a mammal, which comprises administering to a mammal in need of such treatment; (a) a compound of claim 1 or a pharmaceutically acceptable salt thereof; and (b) an inhibitor of the reception of serotonin or a ligand of the 5HT? receptor, or a pharmaceutically acceptable salt of said inhibitor or ligand; wherein the amounts of the compound according to claim 1 and the ligand of the 5HT1A receptor or serotonin reuptake inhibitor that are employed in said method are such that the combination of the two active ingredients is effective in treating said disorder or condition.