MXPA98004631A - Antagonists quinazolin-4-ona del a - Google Patents

Abstract

The present invention relates to the novel quinazolin-4-one derivatives of formula I, as described in the specification, to pharmaceutical compositions containing said compounds, to the use of said compounds to treat disorders of the central nervous system and peripheral neurodegenerative, psychotropic and induced by alcohol and drugs

Description

ANTAGONISTS QUINAZQLIN- -ONA DEL AMPA BACKGROUND OF THE INVENTION The present invention relates to the in-4-one compounds of formula I, as described below, to their pharmaceutically acceptable s, to the pharmaceutical compositions containing them and to their use for treating disorders of the nervous system. central and peripheral neurodegenerati or, psychotropic and induced by alcohol and drugs. The role of excitatory amino acids, such as glutamic acid and aspartic acid co. As the main mediators of excitatory synaptic transmission in the central nervous system, it is very well established. Watkins & Evans. Ann. Rev. Pharmacol. Toxico! .. 21. 165 (1981); Monaghan, Bridges and Cot an. Ann. Rev. Pharmacol. Toxico! .. 29 »3S5 (1989); Watkins. Krogsgaard-Larsen and Honore. Trans. Pharm. Sci .. 11. 25 (1990). These amino acids act primarily in synaptic transmission through excitatory amino acid receptors. These amino acids also participate in other physiological processes, such as motor control, respiration. cardiovascular regulation. sensory perception and cognition. The receptors of the excitatory amino acids are classified into two general types. The receptors that are directly linked to the opening of cation channels in the cell membrane of neurons are called "ionotropic". This type of receptor has been subdivided into at least three subtypes. which are defined by the depolarizing actions of the selective agonists N-meti 1-D-aspartate (NMDA). a-amino-3-hydroxy-5-methyl-soxazole-4-propionic acid (AMPA) and cayic acid (KA). The second general type is the G protein or "metabotropic" excitatory amino acid receptor bound to the second messenger. This second type, when activated by quisqualate agonists. ibotenate or trans-1-aminocyclopentane-3-ticarboxylic acid? 1 ico. it produces a reinforcement of the hydrolysis of phosphoinositides in the postsynaptic cell. Both types of receptors appear not only to mediate normal synaptic transmission along the excitatory pathways, but also participate in the modification of the synaptic connection during development and in changes in the efficacy of the synaptic transmission throughout the lifetime. Schoepp. BocKaert walks Sladeczek. Trends in Pharmacol. Sci. »11» 508 (1990); McDonald and Johnson »Brain Research Reviews» 15, 41 (1990). Excessive or inappropriate stimulation of excitatory amino acid receptors results in neuronal cell damage or loss through a mechanism known as excito-oxocyty. It has been suggested that this process mediates neuronal degeneration in several disorders. The medical consequences of said neuron degeneration! it makes the healing of these degenerative neurological processes an important therapeutic goal. It has been seen that the excitotoxicity of excitatory amino acids is implicated in the pathophysiology of several neurological disorders. This excitotoxicity is implicated in the pathophysiology of acute and chronic neurodegenerative disorders, such as cerebral apoplexy. cerebral ischemia, trauma of the spinal cord. cephalic trauma, Alzheimer's disease. Huntington's disease »lateral amyotrophic sclerosis, epilepsy, AIDS-induced dementia» perinatal hypoxia. Hypoxia (such as disorders caused by strangulation, surgery, inhalation of smoke, suffocation, drowning, obstruction, electrocution or overdose of drugs or alcohol), cardiac arrest, hypoglycemic neuronal damage. ocular damage and retinopathy. idiopathic and drug-induced Parkinson's disease and brain deficits as a consequence of cardiac bypass and graft surgery. Other neurological disorders that are caused by glutamate dysfunction require neuromodel ation. These other neurological disorders are muscle spasms »migraines, urinary incontinence» psychosis, withdrawal syndrome (such as that produced by alcohol or addition to drugs such as the addition to opiates »cocaine and nicotine). tolerance to the apiaceos. anxiety. emesisi. cerebral edema. acute and chronic pain »seizures. retinal neuropathy »tinnitus and tardive dyskinesis. It is believed that the use of a neuroprotective agent. as an AMPA receptor antagonist. It is useful to treat these disorders and / or r d ^ ^ -:, -. amount of neurological damage associated with these disorders. Likewise, it is believed that excitatory amino acid receptor (EAA) antagonists are also useful as analgesic agents. Several studies have shown that AMPA receptor antagonists are neuroprotective in models of focal and global ischemia. It has been reported that the competitive antagonist of the AMPA receptor. NBOX (2,3-dihydroxy-S-nitro-7-sulfamoi IbenzoCf-Jquinoxal ina). It is effective for the prevention of focal and global ischemic damage. Sheardown et al. »Science. 247. 571 (1990); Buchan et al. Neuroreport, 2, 473 (1991); LePeillet et al .. Brain Research. 571. 115 (1992). The non-competitive AMAP receptor antagonist, GKYI 52466 »is an effective neuroprotective agent in models of global ischemia in rats. LePeillet et al .. Brain Research. 571 »115 (1992). These studies strongly suggest that the delay of neuronal degeneration in cerebral ischaemia! 861Ximpl was glutamate excitotoxicity mediated at least in part by the activation of the AMPA receptor. Therefore, AMPA receptor antagonists can be useful as neuroprotective agents and improve the neurological prognosis of cerebral ischemia in humans.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to the compounds of formula in which the dotted line represents an optional double bond; A is a benzo or thieno fused aromatic ring; B is phenyl. pyridyl or pyrimidyl; X is l \ l or CH; R1 is selected from hydrogen, (C1-C6) alkyl optionally substituted with one to three fluorine atoms. cyano. halogen Not me. nitro and (C 1 -C 6) alkoxy optionally substituted with one to three fluorine atoms; R 2 is halogen, cyano, (C 1 -C 6) alkyl optionally substituted with one to three fluorine atoms, nitro »amino, (C 1 -C 6) alkylthio, (C 1 -C 6) alkoxy optionally substituted with one to three fluorine atoms, hydroxy »HC = (= 0) -» alkyl (Cl-C6) -0-C (= 0) - or NH2-C (= 0> -; R3 and R4 is independently selected from hydrofen. C6) optionally substituted with one to three fluorine »halogen» cyano »hydroxy (C1-C6) alkoxy atoms optionally substituted with one to three fluorine atoms -C (= 0) H» -CH20R5 and -CH2NR6R7; R5 is hydrogen »(C1-C6) alkyl or -C (= 0) to qui 1 or (Cl-C6), and R6 and R7 are independently selected from hydrogen» (C1-C6) alkyl »-C (= 0) H and - C (= 0) alkyl (Cl-C-6), or R6 R7 »bound together with the nitrogen atom to which they are attached» form a saturated or unsaturated ring of four to seven elements »in which not atoms carbon of said ring, can optionally be replaced by oxygen or nitrogen (for example, a ring or morpholine, piperidine, pyrro! idina »pieperazine» azetidine »pyrrole» pyridine and oxazoline); and pharmaceutically acceptable salts of said compounds, the present invention also relates to the pharmaceutically acceptable acid addition salts of the compounds of formula I; the 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 acid addition salts, ie, the salts containing pharmacologically acceptable anions, such as the hydrochloride salts »Hydrobromide» Yodhydrate. nitrate »sulfate» bisulfate »phosphate, acid phosphate, acetate, lactate. citrate. acid citrate. tartrate »bitartrate» succinate. maleate fumarate. gluconate. saccharate. benzoate, methanesulonate. ethanesulfonate. Benconosul Fonate. p-toluenosul onate and pamoate Let's say, 1. l'-methylene-bis- (2-hydroxy-3-naphthoate) D; examples of preferred compounds of formula I are those in which R 1 is fluoro; other examples of preferred compounds of formula I are those in which ring A is benzo; Other examples of preferred compounds of formula I are those in which ring A is benzo and R 1 is fluoro; other examples of preferred compounds of formula I are those in which ring A is benzo. Rl is fluorine. R2 is chlorine and the bond represented by the continuous and dotted lines is a carbon-carbon double bond; other examples of preferred compounds of formula I are those wherein R2 is halogen. methyl or trifluoromethyl; other examples of preferred compounds of formula I are those in which R 1 is fluorine and R 2 is chlorine; other examples of preferred compounds of formula I are those in which R3 and R4 are independently selected from 2-cyano. 3-cyano »2-formyl. 3-C 1 -C 6 alkyl. 3-halogen. 2-halogen and 3-CH-2NRSR7. Other examples of preferred compounds of formula I are those in which ring A is benzo. R1 is fluorine, ring B is 2-pyridyl or phenyl and R3 is cyano. Other examples of preferred compounds of formula I are those in which ring B is phenyl or 2-pyridyl. Other, more specific embodiments of this invention are the following: (a) compounds of formula I wherein ring A is benzo; (b) compounds of formula I in which ring A is thieno; (c) compounds of formula I wherein ring B is phenyl; (d) compounds of formula I in which ring B is pyridyl or pi ri i di 1 o; (e) compounds of formula I in which the bond represented by the dashed lines is.? .-? e simple carbon-carbon lace; (f) compound of formula I in which the bond represented by the dashed and dotted lines is a carbon-carbon double bond; (g) compounds of formula I in which R3 is fluorine, cyano. hydrogen or CH2NR6R7, in 1 to which R6 and R7. together with the nitrogen atom to which they are attached, they form a ring of morpholine, pyrrole idine or piperazine. Examples of specific compounds of formula I sor: 3- (6-chloro-2-chloro-phenyl-1) -2-C2-hydroxy-2- (6-methyl-1-peridin-2-y1) -vim * 13- 3 H-quinazol in-4-one; 2-f_2-C3- (2-Chloro-phe-1) -4-oxo-3,4-dihydro-q-aiol in-2i 1) 3-1-hydroxy-vinyl} -nicotinonitrile; 2-f2-C3- (2-Chloro-pyri-3-1) -G-f1-oro-4-oxo-3,4-dih-d-uinazo! in-2-i 1 Dhidrs i-vini 1} -nicotí "noni tri! o; 2-f_2-C6-Chloro-3- (2-methyl-1-pheny1) -4-oxo-3'4-di-ro-quinazol in-2-yl 3-1-hydroxy -vini l.}. -nicotinoni tri lo »3- (2-Chloro-phenyl 1) -2-C2- (3-diethi laminomethyl 1-pheny1) -2-hydroxy-ethyl 1-6-fluoro-3H- quinazol in-4-ona »3- (2-Cl oro-feni 1) -6-fluoro-2-C2- (3-pirrol idi -1-i Imeti 1-feni 1) -2-hydroxy-eti 13- 3H-q indole in-4-one; 3- (2-chloro-p id-3-i 1) -2-C2- (3-d eti laminomethyl 1-pheny1) -2-hydroxy-eti 13-6 -f luoro-3H-quinazol in-4-one; 2-C2- (3-Diethi laminomethyl 1-eni 1) -2-hydroxy-eti 13-6-fluoro-3- (2-fluoro-fem '1) -3H-q indole in-4-one; 2-C2- (3-Diethi-laminomethyl-1-pheny1) -2-hydroxy-3-13- (2-fluoro-en-1) -3H -quinazol-4-one; 2-C2-C3- (2-C1 oro-piri d-3-i 1) -B-f1 uoro-4-o or -3,4-dihydroquinol 2-i 13-1-hydroxy-vini 1.}. -G-meti 1-nicotino-ni tri lo; 2-f_2-C3- (2-Cl oro-feni 1) -4-oxo-3 »4- dihydro-qui nazol in-2- 1 -1-hydroxy-vini 1.}. -6-methy1-nicotinone tri lo; 2- { 2-Chloro-3- (2-chloro-pheny1) -4 -oxo-3 »4-di hydro-qu nazo l in-2-i 1 -1-hydro i-ini 1} -6-meti 1-nicotinone ri lo »2-C2-L3- (2-Cl-oro-feni 1) -6-fluoro-4-oxo-3,4-di idro-quinazol in-2-i 1 -1 -hydroxy-vi i 1} -6- luoro-nicotinoni tri lo »2-. { 2-C3- (2-Cl-oro-pheny1) -6-f1-uoro-4-oxo-3'-d-hydroquinidazole in-2-i-1-hydroxy-vini 1} -4-fluoro-benzoni tri lo; 2-C2- 3- (2-Cl-oro-phenyl-1) -6-fluoro-4-oxo-3 »4-dihydro-qui-nazol n-2-i-1-l-hr i-vi i 1} -4- eti 1-benzo i tri lo; 2-C2-C3- (2-C "! Gold-phenyl-1) -4-oxo-3,4-di-hydro-thi-ene-C3, 2-d3pi imidin-2-i 13-1-hydroxy-vinyl} -6-methyl-niconitri lo »2- { 2-C3- (2-Meti 1-phenyl) -4-oxo-3» 4-dihydro-thienoC3 »2-d3p rimidin-2-i 13- 1-hydroxy-v or 1.}. -6-methy1-nicotin tri lo; 2-C2-C3- (2-chloro-pyridid-3-1) -4-oxo-3,4-dihi dro-ti enoC3 »2-d pi rimi di -2-i 1 -1-hydroxy-vini 1.} -4-methy1-benzonitri lo; 2-C-3- (2-Clcro-pheny1) -4-oxo -3,4-di-hydro-thienoC3, 2-d3-pyrimidin-2-i 13-1-hydraxy-vim * 1.}. -4-f luoro-benzoni tri lo; 2-C2- 3- (2- Fluoro-fe i 1) -4-oxo-3 »4-dihydrothi-ene ene 3.2-d3pir midin-2-i 13-1-hydroxy-vini 1.} -4-meti 1-ben? Oni tri lo; 2- { 2- 3- (2-C1 oro-feni 1) -4-oxo-3,4-di hydro-thieno 3.2-d3pi imidin-2i 13-lhidrox -vini 1.}. -benzoni tri lo; 2-C2- 3- (2-C1 oro-piri d -3-1) -4-OXO-3, -di hydro-thienoC3 »2-d pir midin-2-il -1-hydro i-vi No. 1-Benzoni tri lo This invention also relates to a pharmaceutical composition for treating a disorder selected from among cerebral apoplexy »cerebral ischemia» spinal cord trauma »head injury, Alzheimer's disease, Huntington's disease» lateral amyotrophic sclerosis »epilepsy» dementia induced by AIDS, muscle spasms, migraines, urinary incontinence, psychosis. seizures perinatal hypoxia. Hypoxia (such as disorders caused by choke surgery, inhalation of smoke, asphyxia, drowning, obstruction, electrocution or overdose of drugs or alcohol), cardiac arrest, neuron damage! hypoglycemic »tolerance to opiates» withdrawal syndrome (such as that produced by alcoholism or drug addiction such as addiction to apiods, cocaine and nicotine), eye damage, retinopathy »retinal neuropathy» tinnitus. idiopathic and drug-induced Parkinson's disease »anxiety» emesis »cerebral edema» chronic or acute pain, tardive dyskinesia and brain deficits as a consequence of cardiac bypass surgery and grafting in a mammal, which comprises an amount of a compound of formula I that is effective to treat said disorder and a pharmaceutically acceptable carrier. This invention also relates to a method for treating a disorder selected from cerebral stroke, cerebral ischemia, spinal cord trauma, head trauma, Alzheimer's disease »Huntington's disease» lateral amyotrophic sclerosis »epilepsy, AIDS-induced dementia, muscle spasm »Migraines, urinary incontinence. psychosis. convulsions »perinatal hypoxia. hypoxia (such as disorders caused by strangulation, surgery, inhalation of smoke, asphyxia, drowning, obstruction, electrocution or overdose of drugs or alcohol). cardiac arrest. neuron damage! hypoglycemic ico. tolerance to opiates, withdrawal syndrome (such as that produced by alcoholism or drug addiction such as addiction to opiates, cocaine and nicotine). ocular damage, retinopathy »neuropathy retini ana. t? nnitus. idiopathic and drug-induced Parkinson's disease, anxiety »emesis, cerebral edema» chronic or acute pain, tardive dyskinesia and brain deficits as a consequence of cardiac bypass surgery and grafting in a mammal, comprising administration to a mammal that need such treatment of an amount of a compound of formula I that is effective to treat said disorder. This invention also relates to a pharmaceutical composition for treating a disease or disorder, which treatment or prevention can be performed or facilitated by reducing or inhibiting the neurotransmission of glutamate in a mammal, comprising a quantity of a compound of formula I. or a salt pharmaceutically effective thereof, which is effective to treat said disease or disorder and a pharmaceutically acceptable carrier. This invention also relates to a method for treating a disease or disorder "whose treatment can be performed or facilitated by reducing or inhibiting the neurotransmission of glutamate in a mammal" comprising administering to a mammal in need of such treatment an amount of a compound of formula I. or a pharmaceutically effective salt thereof which is effective to treat said disease or disorder. This invention also relates to a pharmaceutical composition for treating a disorder selected from cerebral stroke »cerebral ischemia» spinal cord trauma »head trauma» Alzheimer's disease »Huntington's disease» lateral amyotrophic sclerosis »epilepsy, AIDS-induced dementia. muscle spasms, migraines. urinary incontinence. psychosis. seizures perinatal hypoxia. hypoxia (as disorders produced by strangulation, surgery, inhalation of smoke, asphyxia, drowning, obstruction, electrocution or overdose of drugs or alcohol), cardiac arrest, hypoglyceal neuronal damage. tolerance to opiates »withdrawal syndrome (such as that produced by alcoholism or drug addiction such as opioid addiction, cocaine and nicotine), eye damage, retinopathy. retinal neuropathy. tinn? tus »idiopathic and drug-induced Parkinson's disease, anxiety, emesis, cerebral edema» chronic or acute pain, tardive dyskinesia and brain deficits as a consequence of cardiac bypass surgery and grafting in a mammal, comprising the administration of an AMP receptor antagonist effective amount of a compound of formula I "or a pharmaceutically acceptable salt thereof" and a pharmaceutically acceptable carrier. This invention also relates to a method for treating a disorder selected from cerebral stroke, cerebral ischemia. spinal cord trauma »head trauma» Alzheimer's disease »Huntington's disease» lateral amyotrophic sclerosis »epilepsy, AIDS-induced dementia, muscle spasms, migraines, urinary incontinence» psychosis. seizures, perinatal hypoxia. hypoxia (as disorders produced by strangulation, surgery, smoke inhalation »asphyxia. drowning obstruction. electrocution or overdose of drugs or alcohol). cardiac arrest. Hypoglycemic neuronal damage. opioid tolerance »withdrawal syndrome (such as that produced by alcoholism or drug addiction such as opioid addiction» cocaine and nicotine). ocular damage »retinopathy» retinal neuropathy, tinnitus. idiopathic and drug-induced Parkinson's disease. anxiety, emesis »cerebral edema» chronic or acute pain, tardive dyskinesia and brain deficits as a consequence of cardiac bypass and graft surgery in a mammal comprising administration to a mammal in need of such treatment of an effective receptor antagonist amount of the AMP of a compound of formula I. or a pharmaceutically acceptable salt thereof. This invention also relates to a pharmaceutical composition for treating a disease or disorder, which treatment can be performed or facilitated by reducing or inhibiting the neurotransmission of glutamate in a mammal, comprising an AMP receptor antagonist effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof. and a pharmaceutically acceptable vehicle. This invention also relates to a method for treating a disease or disorder "whose treatment can be performed or facilitated by reducing or inhibiting the neurotransmission of glutamate in a mammal" comprising administering to a mammal in need of such treatment an effective antagonist amount of the AMP receptor of a compound of formula I "or a pharmaceutically acceptable salt thereof. Unless otherwise indicated, the alkyl groups mentioned herein as well as the alkyl moieties of other groups mentioned herein (for example alkoxy) may be linear or branched and may also be cyclic (for example, cyclopropyl. cyclobutyl, cyclopentyl or clohexyl) or can be linear or branched and cyclic. The term "treat", as used herein, refers to "reversing, alleviating or inhibiting the progress of" or the prevention of the disease or disorder to which the term is applied or one or more symptoms of said disease or disorder. . The term "treatment" as used herein refers to the act of treating "being" treated "as defined above Unless otherwise indicated" "halo" and "halogen" as used herein, refer to fluorine, bromine, chlorine and iodine. The compounds of formula I can have chiral centers. and therefore. they can exist in different enantiomeric and diastereomeric forms. This invention relates to all optical isomers and to all stereoisomers of the compounds of formula I and mixtures thereof and to all pharmaceutical compositions and methods of treatment defined above that contain or use them, respectively. Due to the substituent in position "2" and the carbonyl groups of the "4" position in the quinazo! in-4-one of formula I. the ring attached to the nitrogen in position "3" can not rotate freely. This restriction of rotation means that the compounds of formula I exist in two isomeric or atropoisomeric forms. These atropoisomers can be separated. This grant includes. for example, those stereoisomers of the compounds of formula I that are shallow atropoi. Atropoisomers are isomeric compounds that are chiral, that is, each isomer is not superimposable to its mirror image and the isomers, once separated, turn the polarized light the same, but in the opposite direction. Atropoisomers are distinguished from enantiomers in that atropoisomers do not possess a single asymmetric carbon atom. Such compounds are conformational isomers that occur when rotation around a single bond in the molecule is impeded or severely restricted as a result of steric interactions with other parts of the molecule and the substituents on both ends of the single bond are symmetric. More details on atropo-somers can be found in Jerry March »Advanced Organic Chemistry» 101-102 (4th Ed. 1992) and in Oki, Top. Stereoche., 14, 1-81 (1983). The following structure represents the atropoisomeria of the compound of formula I.

The lines in bold in the formulas indicate that the atoms in bold and the groups attached to them, are sterically hindered as to exist orthogonally above the plane of the quinazo ring! ninth. This steric restriction is due to a rotational energy barrier that impedes the rotation around the single bond that connects the nitrogen in position "3" of the canvas quinazoni ring with the aryl (phenyl or pyridyl) that contains the X group. compounds of formula I in which the bond represented by the dashed and dotted lines is a single carbon-carbon bond. they will contain at least one center that is also the one that gives rise to the atropoisome. Therefore. said compounds will exist in at least four somatic stereois forms. Formula I and the above include compounds identical to those depicted, except for the fact that one or more hydrogen atoms, "carbon or other atoms" are substituted by isotopes thereof. These compounds can be useful as research and diagnostic tools in the far acoinetic studies of metabolism and in binding assays. The formulas I and the above include compounds identical to those represented "except for the fact that one more hydrogen atom" carbon or other atoms are replaced by isotocols thereof. Said compounds are useful as research and diagnostic tools in the pharmacokinetic studies of metabolism and in binding assays. Specific applications in the research include radioactive binding assays, autoradiography studies and in vivo binding studies.

DETAILED DESCRIPTION OF THE INVENTION The compounds of formula I can be prepared according to the methods of scheme 1. In the reaction scheme and in the discussion which follows "unless otherwise indicated" rings A and B and substituents Rl to R7 they are as defined above for formula I.

SCHEME 1 III / SCHEME 2 l? Scheme 1 illustrates all the synthesis methods of the compounds of formula V. With reference to scheme 1, a compound of formula V can be converted to an acetamide of formula IV by reaction with acetyl chloride or acetic anhydride in the presence of a base. in an inert solvent for the reaction. Suitable solvents are methylene chloride, dimethoxyethane (DME), t-butyl 1-methylene ether, dichloroethane, tetrahydrofuran (THF) and dioxane. Suitable bases are the trialkine sheets, such as triethylamine, t-butyl, dimethyl-laminopyridine and potassium carbonate, preferably triethylamine. The temperature of this reaction can range from about 0 ° C to about 100 ° C, the reactions being generally carried out for about 1 hour to about 10 hours. Preferably the reaction is carried out at about 0 ° C to about 30 ° C for about 3 hours. The acetamide of formula IV can be cyclized and form a compound of formula III by reaction with a dehydrating agent, in the presence of a catalyst, in a solvent inert to the reaction. Suitable dehydrating agents are acetic anhydrides, phosphorus pentoxide, diclohexylcarbodimide and acetyl chloride. Acetic anhydride is preferred. Suitable catalysts are sodium or potassium acetate, acetic acid, p-to-ienosulic acid and boron trifluoride etherate. Sodium acetate is preferred. Suitable solvents are dioxane »toluene» diglyme and dichloroethane. The temperature of this reaction diglyme and dichloroethane. The temperature of this reaction can range from about 0 ° C to about 150 ° C. the reaction being carried out generally for about 1 hour to about 24 hours. Preferably the reaction is carried out in dioxane at about 80 ° C to about 120 ° C for about 3 to 10 hours. On the other hand, the compound of formula V can be converted directly into a compound of formula III by reacting it with acetic anhydride in the presence of an acid catalyst in a solvent inert to the reaction. Examples of acid catalysts that can be used are acetic acid, sulfuric acid, p-toluenesulfonic acid. Acetic acid is preferred. Examples of solvents that can be used are toluene and xylene. Acetic acid is also preferred as a solvent. The temperature of the reaction mixture can range from about 20 ° C to about 150 ° C. Generally, the mixture is allowed to react for about 10 minutes to about 10 hours. Preferably, the reaction is carried out at about 80 ° C to about 120 ° C for about 2 to 5 hours. The compound of formula III. formed by any of the above methods, can then be reacted with an amine of formula VIII in a polar protic solvent in the presence of an acid catalyst to form a compound of formula II. Suitable acid catalysts are acetic acid, p-toluenesulfonic acid and sulfuric acid, with preference being given to acetic acid. Suitable polar protic solvents are acetic acid, methane, ethanol and isopropanol. With acetic acid being preferred, this reaction is generally carried out at a temperature from about 20 ° C to about 150 ° C. for about 1 hour to about 24 hours, preferably from about 80 ° C to about 120 ° C for about 6 hours. On the other hand, a compound of formula IV can be converted directly into a compound of formula II by reacting it with a dehydrating agent, an amine of formula VIII, as described above, and a base in a solvent inert to the reaction. Examples of dehydrating agents that can be used are phosphorus trichloride, phosphorus oxychloride, phosphorus pentachloride and thionyl chloride, with phosphorus trichloride being preferred. Suitable bases are pyridine »di isoprop lamina» lutidine »di eti laminopyridine» triethylamine and IM-methyl 1-morphol ina. Examples of solvents that can be used are toluene »dioxane» THF »chlorobenzene» DME. cyclohexane. benzene and xylene. Preferably, pyridine is used as bast3 >; The reaction being carried out in toluene as solvent. In some circumstances, when the combined reactants are liquid, the reaction can be done without solvent. The temperature can range from about 50 ° C to about 150 ° C »leaving the reaction mixture to react generally for about 1 hour to about 24 hours, preferably the reaction is carried out at about 80 ° C to about 120 ° C. for about 1 to 8 hours. The compound of formula II can then be deprotonated with a lithium base, sodium hydride or sodium or lithium hexamethexidine (LiHDS or NaHMDS), preferably LDA or LiHMDS. in an appropriate solvent such as THF »dioxane ether or DME» preferably ether or THF, at a temperature from about -100 ° C to about 100 ° C, preferably between -80 ° C and -50 ° C. The anion thus formed reacts with an aldehyde of formula IX or an ether of formula X.

IX wherein Q is a group facilitating nucleophil addition to the carbonyl group of formula X (for example »0R6 or SR8» wherein RB is methyl, ethyl »phenyl or 2-pyridyl) to form a compound of formula I The compound of formula IX or X can be added to the solution of the anion (normal addition) or the solution of the anion can be added to the compound of formula IX or X (reverse addition). Although both methods can be used to obtain the compounds of formula I, the reverse addition is preferred. A) Yes. when sodium hydride is used as the base and the resulting anion is reacted with a compound of formula X "the preferred reaction temperature is approximately 0 ° C to approximately B0 ° C and the reactants with formulas II and X can be combine in the reaction mixture at the same time by a normal addition mode. (See J. Med. Chem. 1990. 33. 161). On the other hand, a compound of formula V can be converted into a compound of formula II according to the methods described in scheme 2. The compound of formula II thus formed can then be converted into the desired compound of formula I according to with the methods of scheme 1. Referring to scheme 2 »a compound of formula V is reacted with a coupling agent» an amine of formula VIII. as described above, and a base in an inert solvent for the reaction to form a compound of formula VI. Examples of suitable coupling reagents that activate the carboxylic functionality are diclohexy Icarbodi im da. I \ -3-d eti laminopropi 1-N'- eti 1 carbodi imi da. 2-Ethoxy-ethoxycarbonyl-1'-2-dihydroquinoline (EEDQ) »carbom" 1-diimidazole (CDI) and diethylphosphoryl trile Suitable bases are dimethyl-1-aminopyridine (DMAP) and triethylamine. dimethyl 1aminopyridine A catalyst such as hydroxybenzotriazole (HBT) can be used The coupling is carried out in an inert solvent, preferably in an aprotic solvent Appropriate solvents are acetonitrile, dichloromethane, dichloroethane and dimethylformamide The preferred solvent is dichloromethane. said reaction is generally from about -30 ° C to about 80 ° C and preferably from about 0 ° C to about 25 ° C. The compound of formula VI can be converted into a compound of formula VII by reaction with acetyl chloride or anhydride acetic acid in the presence of a base (for example, a trialkylamine such as triethylamine or tributylum, dimethyl laminopyridine or potassium carbonate) in an inert solvent for the reaction. Suitable solvents are methylene chloride. tetrahydrofuran and chloroform, preferably methylene chloride. Preferably, triethylamine is used as the base. This reaction is generally carried out at a temperature of about 0 ° C to about 50 ° C. for about 1 hour to about 10 hours, preferably at room temperature for 3 hours.

The compound of formula VII can be cyclized to a compound of formula II by reaction with tri-enylphosphine »a base» and a dialkyl azodicarboxylate in a solvent inert to the reaction. Base examples that can be used in this reaction are pyridine. triethylamine and 4-dimeti inopyridine »4-dimethi lamini-pyridine being preferred.

Suitable solvents are dimethylformamide »toluene» xylene »tetrahydrofuran and dioxane. Dioxane is preferred.

Generally, this reaction is carried out at a temperature from about 25 ° C to about 125 ° C for about 1 hour to about 24 hours, preferably at about 100 ° C for about 8 to 15 hours. The compounds of formula II can also be prepared according to the methods described in Miyashita et al., Heterocycles »42, 2. S91-S99 (1996). Unless stated otherwise, the pressure of each of the above reactions is not critical.

Usually. The reactions will be carried out at a pressure of approximately one to approximately three atmospheres. preferably at ambient pressure (approximately one atmosphere). The compounds of formula I which are basic in nature are capable of forming * - a wide range of different salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate a compound of formula I from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter into the free base compound by treatment. with an alkaline reagent and subsequently converting the free base to a pharmaceutically acceptable acid addition salt, and then simply converting the latter to the free base compound by treatment with an alkaline reagent and subsequently converting the free base to an acid addition salt. pharmaceutically acceptable. The acid addition salts of the 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 an appropriate organic solvent, such as methanol or ethanol. By carefully evaporating the solvent, the desired solid salt is obtained. The acids which are used to prepare the pharmaceutically acceptable acid addition salts of the basic compounds of this invention are those which form non-toxic acid addition salts, ie salts containing pharmacologically acceptable anions, such as the hydrochloride salts, hydrobromide »iodohydrate, nitrate, bisulfate sulfate, phosphate or acid phosphate. acetate, lactate »citrate or acid citrate» tartrate or bitartrate, succinate. maleate fumarate. gluconate. saccharate. benzoate. methanesulfonate and pato Cés say. 1. l'-methylene-bis- (2-hydroxy-3-naphthoate). The compounds of formula I and the pharmaceutically acceptable salts thereof (hereinafter referred to as "active compounds of the invention") are useful for treating neurodegenerative »psychotropic and drug-induced and alcohol-induced deficits being potent antagonists of the AMPA receptor. The active compounds of the invention can therefore be used for the treatment or prevention of cerebral stroke »cerebral ischemia» spinal cord trauma »head trauma» Alzheimer's disease »Huntington's disease» lateral amyotrophic sclerosis »epilepsy, AIDS-induced dementia »Muscle spasms» migraines »urinary incontinence. psychosis. seizures, perinatal hypoxia. hypoxia (as disorders caused by strangulation, surgery »inhalation of smoke, asphyxia» drowning, obstruction, electrocution or overdose of drugs or alcohol), cardiac arrest »hypoglycemic neuronal damage. opioid tolerance »withdrawal syndrome (such as that produced by alcoholism or drug addiction such as opioid addiction, cocaine and nicotine), eye damage, retinopathy» retinal neuropathy. tinnitus idiopathic and drug-induced Parkinson's disease, anxiety »emesis, cerebral edema, chronic pain or here. delayed dyskinesia and cerebral deficits as a consequence of surgical intervention by cardiac bypass and graft.

The in vitro and in vivo activity of the compounds of the invention with respect to the antagonism of the AMPA receptor can be determined by methods available to the person skilled in the art. A method for determining the activity of the compounds of the invention is by inhibiting seizures induced by PTZ lenstrazole PTZ. Another method for determining the activity of the compounds of the invention is by blocking the uptake of 45Ca2 + induced by the activation of the AMPA receptor. A specific method to determine inhibition e the seizures induced by the lentetrazol pent (PTZ) is the following. The activity of the compounds of the invention with respect to the inhibition of seizures induced by penti lentetrazole (PTZ) in mice can be determined according to the following procedure. This test examines the ability of compounds to block seizures and death produced by PTZ. The measurements taken are latency to clonic and tonic seizures and death. The DI50 are determined based on the percentage of protection. For these experiments, CD-1 male mice from Charles River are used. with a weight of 14-16 g at the time of arrival and 25-35 g at the time of the trial. The mice are housed in a number of 13 per cage under standard laboratory conditions. with a brightness cycle L / 0/7 a.m.:7 p.m. for at least 7 days before the experiment. Access to food and drink is ad libitum until the time of rehearsal. All compounds are administered, -, a volume of 10 ml / kg. The vehicles of the drug will depend on the solubility of the compound. Saline, distilled water or E: D: S / 5: 5: 90 (E ulfor 5? 4, DMSO 5% and saline 90%) as an injectable vehicle is used during the experiments. The mice are given the test compounds or vehicle (i.p. »s.c.» or p.o.) and placed in plexiglass cages in groups of five. At a predetermined time after these injections, the mice are injected with PTZ (i.p., 120 mg / kg) and placed in individual prexigllas cages. The measurements taken during this five-minute test period are: (i) latency to clonic seizures »(2) latency to tonic seizures» and (3) latency to death. The treatment groups are compared with the group treated with the vehicle by means of the Kruskal-Wal 1 is ANOVA test and the Mann-Whitney U test (Statview). The protection percentage for each group (number of subjects that do not show seizures or death, as indicated by a score of 300 sec) is calculated for each of the measurements. The ID50 are determined by prohibit analysis (Biostat). Another method for determining the activity of the compounds is to determine the effect of the compounds on motor coordination in the mice. This activity can be determined by the following procedure. For these experiments CD-1 male mice from Charles River are used with a weight of 14-16 g at the time of arrival and 25-35 g at the time of the test. The mice are housed in a number of 13 per cage under standard laboratory conditions, with a brightness cycle L / 0/7 a.m.:7 p.m. for at least 7 days before the experiment. Access to food and drink is ad libitum until the time of rehearsal. All compounds are administered in a volume of ml / kg. The vehicles of the drug will depend on the solubility of the compound, using during the experiments generally saline, distilled water or E: D: S / 5: 5: 90 (Emulfor 5%, DMSO 5% and saline 905-í) as vehicle injectable The apparatus used in these studies consists of a group of five 13.34 x 13.34 cm metal mesh squares suspended on 11.43 cm steel bars connected to a 165.1 cm bar. which rises 38.1 cm above the laboratory work table. These metal mesh squares can be put inside out. The mice are given the test compounds or vehicle (i.p. »s.c.» or p.o.) and placed in plexiglass cages in groups of five. At a certain time after these injections, the mice are placed on an upper area of the metal mesh squares and pushed so that they are suspended upside down. During the one-minute test »the mice are classified as 0 if they fall off the grid» 1 if they stay down or 2 if they go up to the top. The treatment groups are compared with the group treated with the vehicle using the Kruskal-Wal 1 s ANOVA test and the Mann-Whitney U test (Statview). A specific method to determine the blockade of the uptake of 45Ca2 + induced by the activation of the AMPA receptor is described below.

NEURONAL PRIMARY CROPS Primary cultures of rat brain granulosa neurons are prepared, as described by Parks »T.N.» Art an »L.D.» Alasti »N., and Nemeth, E.F.

Modulation of IM-Methi 1-D-Aspartate Receptor-Mediated Increases in Citosol i c Calcium in Cultured Rat Cerebellar Granule Cells.

Brain Res. 552. 13-22 (1991). According to this method, the cerebellums of 8-day old CD rats are excised, crushed into 1 mm chunk and incubated for 15 minutes at 37 ° C in a Tyrode solution without calcium or magnesium and containing 0.1 Ji of trypsin. . This tissue is then ground using a fine-hole Pasteur pipette. The cell suspension is placed in 96-well tissue culture plates coated with pol -D-1 isine. at a ratio of 1085 cells per well. The medium consists of minimal stage medium (MEM) »with Earle salts» fetal bovine serum inactivated by heat 13%. 2 mM L-glutamine, 21 mM glucose »penicillin-streptomycin (100 units per ml) and 25 M KCl. After 24 H» the medium is replaced by fresh medium containing 10 μM cytosine arabinoside to inhibit cell division. Crops should be used at 6-8 DIV.

Uptake of ^ a »* induced by AMPA receptor activation The effects of drugs on the uptake of * * βaa * induced by AMPA receptor activation can be examined in rat cerebellum granule cell cultures. Cultures in 96-well plates are preincubated for about 3 hours in a serum-free medium and then for 10 min in a balanced salt solution without Mg2 * (in mM: ClIMa 120, KCl 5, NaHjjPO, 0.33, CaCl 2 1, 8. glucose 22 and HEPES 10.0 to pH 7.4) containing 0.5 mM DTT, 10 μM glycine and drugs with a final concentration of 2x. The reaction begins with the rapid addition of an equal volume of balanced salt solution containing 100 μM of the AMPA receptor agonist »caycus acid and" β Caz- * "(final specific activity 250 Ci / mmol). After 10 minutes at 25 ° C the reaction is stopped by aspirating the solution containing ^ ßCa2 * and washing the 5x cells in a balanced salt solution cooled with ice and to which no calcium and 0.5mM EDTA have been added. The cells are then lysed by incubating them overnight in Triton-X 100 O 4 and the radioactivity in the lysate is then determined. All the compounds of the invention that were tested had C 1 or less than 5 μM. The compositions of the present invention may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers. Thus »the active compounds of the invention can be formulated for oral» oral administration, transdermal (for example, patch), intranasal. parenteral, for example, intravenous, intramuscular or subcutaneous) or rectal or in a form suitable for administration by inhalation or insufflation. For oral administration, the pharmaceutical compositions can be in the form, for example, of tablets or capsules prepared by conventional methods with pharmaceutically acceptable excipients, such as binders, for example, pregelatinized maize starch. poly inylpyrrolidone or hydro? ipropi 1 methylcellulose); charges B for example »lactose» microcrystalline cellulose or calcium phosphate); lubricants 8 for example »magnesium stearate» talc or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents 8 for example. sodium lauryl sulfate. The tablets may be coated by methods well known in the art, liquid preparations for oral administration may have the form of. for example, solutions, syrups or suspensions, or they may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Said liquid preparations can be prepared by conventional methods with pharmaceutically acceptable additives, as suspending agents (for example, sorbitol syrup, methylcellulose or hydrogenated edible fats); emulsifying agents - for example, lecithin or gum arabic); non-aqueous vehicles 8 for example, almond oil, oily esters or ethyl alcohol); and preservatives (for example, methyl or propyl p-hydroxybenzoates or sorbic acid). For the oral administration. the composition may be in the form of tablets or tablets formulated in conventional manner. The active compounds of the intervention can be formulated for parenteral administration by injection "including conventional catheterization techniques or infusion. The formulations for injection may be presented in unit dosage forms "for example" in ampoules or in multi-dose containers »with a preservative, the compositions may take the form of suspensions» solutions or emulsions in oily or aqueous vehicles and may contain agents for the formulation , as suspending, stabilizing and / or dispersing agents. On the other hand, the active ingredient may be in powder form for reconstitution with an appropriate vehicle, for example, pyrogen-free water, before use.

The active compounds of the invention can also be formulated for 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 in a spray container that is tightened or pumped by the patient or as an aerosol spray presentation in a pressurized container or nebulizer, using a suitable propellant, for example »Dichlorodi luoromethane» trichlorotrifluoromethane »dichlorotetrafluoroethane» carbon dioxide or other appropriate gas: In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to dispense a measured quantity. The pressurized container or nebulizer may contain a solution or suspension of the active composition. Capsules and cartridges (made, for example, of gelatin) for use in an inhaler or insufflator can be formulated containing a powder mixture of a compound of the invention and an appropriate powder base such as lactose or starch. A proposed dose of the active compounds of the invention for oral, parenteral or buccal administration in an adult adult for the treatment of the above-mentioned disorders (e.g., cerebral stroke) is 0.01 to 50 mg / kg of the ingredient active per unit dose »which can be administered» for example, 4 times a day. Aerosol formulations for the treatment of the above-mentioned disorders (eg cerebral stroke) in an adult adult are preferably established so that each measured dose or "puff" of aerosol contains from 20 μg to 1000 μg of the compound of the invention . The average daily dose of an aerosol will be within the range of 100 μg to 10 mg. The administration can be several times a day, for example »2» 3 »4 or 8 times» administering each time »for example» 1 »2 or 3 doses. The following examples illustrate the preparation of the compounds of the present invention. The commercial reagents were used without further purification. Melting points are given without correction. All NMR data were recorded at 250 »300 or 400 MHz in deuterochlorofor or" unless otherwise specified "and are given in parts per million (μ) and refer to the deuterium stabilization signal in a sample of solvent, all non-aqueous reactions were performed in dry glass containers with dry solvents in an inert atmosphere for convenience and to maximize yields. All reactions were shaken with a magnetic stir bar "unless otherwise indicated, all mass spectra were obtained, unless otherwise indicated, using chemical impact conditions. The ambient temperature refers to 20-25 ° C. Melting points are given without correction.

EXAMPLE 1 3- (2-Chloro-1) -β-f1uoro-2- (2-hydroxy-2-P ridin-Z-i 1-vini 1) - 3 H -guinazo 1 in-4-one A solution of diisopropylane (0.061 ml, 0.47 mmol) in tetrahydrofuran (2.7 ml) was cooled to -78 ° C and butyl lithium (0.134 ml »0» 34 mmol »2.5 N in he? years). The solution was stirred 20 min and then a solution of 3-1 (2-chloro-phenyl-1) -6-fluoro-2-methyl-3H-quinazole in-4-one (0.10 g »0.35) was added dropwise. mmol) in tetrahydrofuran (0 »7 ml). The solution turned a deep red color and was stirred for 30 min. In a separate vessel, an ethyl picoloulate solution (0.491 ml. 3.6 mmol) in tetrahydrofuran (2 ml) was prepared and cooled to -78 ° C. The cold red anionic solution was added to the cold ethyl picolinate solution via a cannula for a period of two minutes. The resulting mixture was stirred 30 minutes at -78 ° C and then allowed to warm to room temperature. The reaction with ethyl acetate. The combined extracts were washed with water and brine, dried over magnesium sulfate and concentrated. The residue was triturated with ether / hexane and the yellow solid that formed was collected and dried to give 0.054 g (4054) of 3- (2-cl-oro-phenyl-1) -6-fluoro-2- (2-idrox -2 -pi ridi n-2-il-vini 1) -3H-quinazole n-4-one »which gave: mp >; 250 ° C AH NMR (DMS0dft?) Or 8.45 (d, J = 5 Hz, 1H), 7.97 (d, J = 7 Hz »1H), 7.90 (td J = 1.B Hz . 1 HOUR). 7, B8-7.5B (m, 7H), 7 »35 (m, sim 1H)» 5.80 (s »1H). Analysis calculated for: C-eiHi3 IF? M302 .: C, 64.05; H. 3.33; N, 10.67. Found: C, 64.16; H, 3.71; l \ l »10.72.

EXAMPLE 2 2-f2-C6-F1uoro-3- (2-met-1-pyridin-3-1) -4-oxo-3t-dih? roguinazole n-2- l 3-1-hydrox -v nor n-benzoni tri lo A solution of diisopropylamide (0.046 ml, 0.47 mmole) in tetrahydrofuran (2.7 ml) was cooled to -78 ° C and butyllithium (0.13 ml, 0.32 mmole, 2.5 l in hexanes) was added dropwise. . The solution was stirred 10 min and then a solution of 6-fluoro-2-methy1-3- (2-methyl-1-pyridin-3-yl) -3H-quinazol in-4-one (0.10) was added dropwise. g. 0.37 mmol) in tetrahydrofuran (0.7 ml). The solution turned a deep red color and was stirred for 30 min. In a separate vessel, a solution of methyl 2-cyanobenzoate (0.50 g »3.1 mmol) in tetrahydrofuran (10 ml) was prepared and cooled to -78 ° C. The red and cold anionic solution was added to the solution of cold methyl 2-cyanobenzoate by cannula for 30 seconds. The resulting mixture was stirred 30 minutes at -78 ° C and then quenched with saturated aqueous bicarbonate and warmed to room temperature. The mixture was diluted with water and extracted repeatedly with ethyl acetate. The combined extracts were washed with water and brine, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel (20 x 100 mm). with elution proceeding as follows: 10% ethyl acetate / hexane (50 ml), nothing; ethyl acetate 205 I / hexane (50 ml). recovered without weighing 3- (2-methyl-pyridin-3-yl) -6-fluoro-2-methyl-3H-quinazole i-4-one; 30% ethyl acetate / hexane (50 ml). nothing; 40% ethyl acetate / hexane (50 ml). recovered without weighing the methyl 2-cyanobenzoate; ethyl acetate 5054 / hexane (50 ml), impurity without weighing; ethyl acetate 60? i / hexane (50 ml), mixture of impurity and the desired product; ethyl acetate / hexane (50 ml), the product. The fractions containing the product were combined and concentrated. The residue was triturated with ethyl acetate / ether and the yellow solid which formed was collected and dried to give 0.017 g (10%) of 2-C2-C6-f1-3- (2-methyl-1-pyridini) -3-i 1) -4-oxo-3,4-dihydro-qui nazol in-2-i 1 -1-hydroxy-vini 1} -benzonitrile »which gave: p.f. > 213-215 ° C AH NMR? 8.70 (d, J = 4 Hz. 1H), 7.85 (dd, J = 3.8 Hz, 1H), 7.67 (d.J = 7 Hz, 1H). 7.60 (d, J = 9 Hz), 7.58-7.38 (m, 6H), 4.94 (s, 1H), 2.44 (s, 3H). Analysis calculated for Ca3HlßFN.0s, -0.25 Ha0: 68.57; H »3.88! N, 13.91. Found: C, 6B »52» 68.91; H, 4.13, 4.21; N. 13.25 »13.28.

JMPLO 3 2-fZ-C3- (2-Chloro-pyr-din-3-1) -6- 1 -ooro-4-oxo-3,4-dihydro-uinazol -2- l 3-1-h rox? -vn n-benzon tr lo Two identical reactions were carried out simultaneously. A solution of diisopropylamina (0.120 ml »0.91 mmoles) in tetrahydrofuran (5.4 ml) was cooled to 78 ° C and butyllithium (0.26 ml» 0.65 mmole, 2.5 N in hexanes) was added dropwise. The solution was stirred 10 min and then a solution of 3- (2-chloro-pyridin-3-yl) -6-fluoro-2-met l-3H-quinazole i, γ-4-one was added dropwise. (0.204 g, 0.70 mmol) in tetrahydrofuran (5 ml). The solution turned a deep red color and was stirred for 30 min. In a separate vessel, a solution of methyl 2-cyanobenzoate (1.02 g, 6.33 mmoles) in tetrahydrofuran (15 ml) was prepared and cooled to -78 ° C. The red and cold anionic solution was added to the cold methyl 2-cyanobenzoate solution by cannula for 20 seconds. The resulting mixture was stirred 1 hour at -78 ° C and then quenched with saturated aqueous bicarbonate and warmed to room temperature. The mixture was diluted with water and extracted repeatedly with ethyl acetate. The combined extracts were washed with water and brine, dried over magnesium sulfate and concentrated. The residues of the two simultaneous reactions were combined and subjected to flash chromatography on silica gel (40 x 220 mm), with elution proceeding as follows: 10% ethyl acetate / hexane (50 ml), nothing; 20% ethyl acetate / hexane (250 ml), natia; 30% ethyl acetate / hexane (50 ml), impurities without weighing; 40% ethyl acetate / hexane (250 ml), recovered without weighing 3- (2-chloro-pyridin-3-y1) -6-fluoro-2-methyl-3H-quinazol-4-one; 50% ethyl acetate / hexane (250 ml), nothing; 60% ethyl acetate / hexane (250 ml). desired product (tic Rf = 0 »3 with ethyl acetate 5054 hexane on silica gel). The fractions containing the product were combined and concentrated. The residue was triturated with ether and the pale yellow solid that formed was collected and dried to give 0.093 g (37%) of 2-C2-6-f1-oro-3- (2-methyl-1-pyridin-3-y1) ) -4-oxo-3,4-dihydro-quinazol in-2-i 1 -1-hydroxyvinyl} -benzonitrile »which gave: p.f. > 217-218 ° C AH NMR or 8.60 (dd, J = 3.5 Hz »1H). 7.B5 (dd J = 3.8 Hz »1H)» 7 »81 (d, J = 2.8 Hz, 1H), 7.67 (d, J = 7Hz, 1H), 7.58-7 , 42 (m, 6H), 4.98 (S, 1H). Analysis calculated for C-eiH a! ClFN ^ O:?: C, 63 > 09; H, 2.89; N »13.38. Found: C. 62, 9 ?; H. 2.81; N. 13.01. The title compounds of Examples 4-10 of the following table were prepared following substantially the same procedures employed in Examples 1-3 above.

EJE-M 0 ?? N Two diastereomers of 3- (2-chloro-fem'l) -6-fluoro-2-C2- < 2- • fluoro-feni 1) -2-h drox -e? 1] -3H-gui azo1i - -one A solution of diisopropyl sheet (0.60 ml, 4.57 mmol) in tetrahydrofuran (27 ml) was cooled to -78 ° C, butyl lithium (1.30 ml, 3.25 mmol, 2.5 N in hexanes) was added dropwise. The solution was stirred 10 min and then a solution of 3- (2-chloro-phenyl-1) -6-fluoro-2-methyl-3H-quinazol-4-one (1. 04 g. 3 × 60 mmol) in tetrahydrofuran (7 ml). The solution turned a deep red color and was stirred for 30 min. In a separate vessel, a solution of 2-fluorobenzaldehyde (0 »575 ml» 6 »33 mmol) in tetrahydrofuran (20 ml) was prepared and cooled to -78 ° C. The red and cold anionic solution was added to the cold 2-fluorobenzaldehyde solution via a cannula for 30 seconds. The resulting mixture was stirred 1 hour at -78 ° C and then quenched with saturated aqueous bicarbonate and warmed to room temperature. The mixture was concentrated and the residue was diluted with water (50 ml), ethyl acetate (10 ml) and saturated aqueous sodium bisulfite (50 ml). This mixture was stirred 1 hour and then extracted repeatedly with ethyl acetate. The combined extracts were washed with water and brine, dried over magnesium sulfate and concentrated. The residues from the two simultaneous reactions were combined and subjected to flash chromatography on silica gel (45 x 150 mm). with elution proceeding as follows: 20% ethyl acetate / hexane (500 ml), nothing; 30% ethyl acetate / hexane (500 ml) and 40% ethyl acetate / hexane (500 ml), two diastereomers of 3- (2-chloro-phenyl-1) -6-fluoro-2-C2- (2-fluoropheni) 1) -2-hydroxy-ethyl-1 D-3H-qui nazol in-4-one. both as viscous oils. The fastest eluting diastereomer weighed 0.231 g (17%): H NMR or 7.92 (dd J = 3, 8.5 Hz, 1 H), 7.77 (dd J = 5.9 HZ, 1 H) , 7.60 (dd, J = 1 »5» 7.5 Hz »1 H)» 7 »57 -7» 55 (m »1 H), 7» 53 (dd, J = 3.8 Hz »1 H) »7» 4B - 7.42 (sim m, 2 H) »7» 36 - 7 »31 (m 1 H), 7.24 - 7» 18 (m 1 H), 7.12 (t J = 7.5 Hz. 1 H), 6. 6 - 6.90 (m, 1 H), 5 »65 (s a.1 H), 5, 55 (dt. J = 2» 5 »9 Hz» 1 H). 2.70 (dd J = 2.5, 17 Hz), 2.61 (dd J = 9, 17 Hz »1 H). The slowest eluting diastereomer weighed 0 »283 g (21%): H NMR or 7.91 (dd, J = 3, 9 Hz, 1 H), 7.76 (dd J = 5.9 Hz, 1 H) , 7.58 (dd, J = 1.5, 8 Hz. 1 H). 7.54 (dd, J = 3.9 Hz, 1 H) »7» 51 (dd, J = 1.5.? HZ.1 H), 7.44 (td, J = 2.8 Hz, 1 H). 7.39 (td, J = 1, 5, 8 Hz, 1 H), 7.23-7.17 (m, 1 H). 7.13-7.07 (m, 2 H). 6.98 - 6.91 (m, 1 H), 5.61 (S a, 1 H), 5.57 (dd, j = 4.8 HZ, 1 H), 2, 72 - 2.60 (m, 2 H).

SEPARATION OF ANTRQPOISOMER BY HPLCA The separation by HPLC of the shallow atropoi 2-. { C3- (2-c 1 oro-feni 1) -6-f luoro-4-oxo-3, 4-dihydro-qui nazol i -2-i 1 D-l-h idrox i-vi ni l} ~ 6-methyl-1-nicotinone tri is described below.

Claims (6)

1. NOVELTY OF THE INVENTION CLAIMS A compound of formula wherein the dotted line represents an optional double bond; A is a benzo or thieno fused aromatic ring; B is phenyl. piri di lo or pyrimidyl; X is? M or CH; R1 is selected from hydrogen, C ^ -C ^ alkyl) optionally substituted by one to three fluorine atoms, cyano »halogen» amino »nitro, and (C ^ -C0) alkoxy optionally substituted by one to three fluorine atoms; R3 is halogen »cyano» alkyl (Cx-Cß) optionally substituted with one to three fluorine atoms, nitro »amino. alkylthio (C -C?), alkoxy (Cx-Cß> optionally substituted by one to three fluorine atoms, hydroxy, HC = (= 0) - (C1-C) alkyl) -0-C (= 0) - or NH2-C (= 0) -; R3 and R- »are independently selected from" hydrogen "alkyl (C -Cβ) optionally substituted by one to three fluorine atoms» halogen »cyano» hydroxy alkoxy (optionally substituted CX-Cß) with one to three fluorine atoms, -Ci =) H »-CH_.ORß and -CHseNR, sR" 7; Rβ is hydrogen »alkyl (Cx-Cß) or -C (= 0) alkyi (Ca_-Cß) and Rβ and R "7 are independently selected from hydrogen" C ^ -C ^ alkyl) and -C (= 0) alkyl (C., -C.sub.S); or Rß and R-7. joined together with the nitrogen atom to which they are attached form a saturated or unsaturated ring of seven elements, in which one of the carbon atoms of said ring, can optionally be replaced by oxygen or nitrogen; and the pharmaceutically acceptable salts of said compounds.
2. 2. A compound according to claim 1, wherein ring A is benzo.
3. 3. A compound according to claim 1 or claim 2, wherein ring B is phenyl or 2-pyridyl.
4. 4. A compound according to claim 1, 2 or 3. wherein Rx is hydrogen or halogen and Rz is halogen or alkyl (Ca.-C ,.).
5. 5. A compound according to claim 1. 2 or 3. wherein R is fluoro and R * is chloro or methyl.
6. 6. A compound according to any one of claims 1-5. in which the bond represented by a continuous line and a dotted line is a carbon-carbon double bond. A compound according to claim 1. wherein said compound is selected from the group consisting of: 3- (2-chloro-phenyl) -6-f luoro-2-C2-hydroxy-2- ( 2-methyl-thiazol-4-yl) -vini 13-3H-quinazol in-4-one; 3- (2-chloro-phenyl) -6-fluoro-2-C2-hydro i-2- (6-methyl-1-pyridin-2-yl) -vini 13-3H-quinazole in-4-one; 2-C2-C3- (2-Cl-oro-pheny1) -6-f-luoro-4-oxo-3,4-dihydro-quinazol in-2-i 11-1-hydroxy-vini 1} -6-methy1-nicotinonitrile; 2-C2-C3- (2-Chloro-phenyl-1) -6-fluoro-4-oxo-3,4-dihydro-quinazole in-2-i 1 D-l-hydroxy-vini 13-nicotinone tri lo; 2-C2-C3- (2-Cl-oro-phen-1) -6-f1-uoro-4-oxo-3,4-dihydro-qui-nazoyl-n-2-i-D-l-hydroxy-vini 1} -benzoni tri lo; 2-C2-C3- (2-Chlora-pyridin-3-yl) -6-f-luoro-4-oxo-3,4-dihydro-qui-nazol-2-yl 3-1-hydroxy-vinyl-nicotinonitri the; 2-. { 2-C3- (2-Cl-oro-pyridin-3-y1) -6-fluoro-4-oxo-3,4-dihydro-qui-nazol in-2-yl-1-hydroxy-vini 1} -6-meti 1-nicotinonitri lo; 3- (2-Cl-oro-pheny1) -6-fluoro-2- (2-hydroxy-2-pyridin-2-y1-vini 1) -3H-qui a? Ol in-4-one; 2-C2-C6-fluoro-3- (2-methyl-1-pyridin-3-y1-vin 1) -4-oxo-3,4-dihydro-qui-nazole in-2-i 11-1-hydroxy-vim "1-benzoni trilo; 2-C2-C3- (2-Chloro-pyridin-3-y1) -6-fluoro-oxo-3,4-dihydro-qui nazole i n-2-i 1 ll -hydroxy-vi ni 1.} - benzonitrile; and 3- (2-Cl-oro-pheny1) -6-fluoro-2-C2- (2-fluorofeni 1) -2-idro i-eti 13-3H- quinazole in-4-one 8.- A pharmaceutical composition for treating a disorder selected from cerebral stroke, cerebral ischemia, spinal cord trauma, cephalic trauma, Alzheimer's disease, Huntington's disease, lateral amyotrophic sclerosis, AIDS-induced dementia Muscle spasms, migraines, urinary incontinence, psychosis, seizures, perinatal hypoxia, cardiac arrest, hypoglycaemic neuron damage, opioid tolerance and withdrawal syndrome, eye damage and retinopathy, idiopathic Parkinson's disease and drug induced, anxiety »emesis, cerebral edema. chronic acute pain, tardive dyskinesia and cerebral deficits as a consequence of cardiac bypass surgery and grafting in a mammal, comprising an effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier. 9. A pharmaceutical composition for treating a disease or disorder, whose treatment or prevention can be carried out or facilitated by reducing or inhibiting the neurotransmission of glutamate in a mammal, comprising an effective amount of a compound according to claim 1. and a pharmaceutically vehicle that is effective to treat said disease or disorder and a pharmaceutically acceptable carrier. 10. The use of an effective amount of a compound according to claim 1. to prepare a composition for treating a disorder selected from cerebral stroke, cerebral ischemia, spinal cord trauma, head trauma, Alzheimer's disease, Korea Huntington, amyotrophic lateral sclerosis, AIDS-induced dementia, muscle spasms, migraines »urinary incontinence» psychosis »seizures. periratal hipcxia. cardiac arrest »hypoglycemic neuronal damage, opioid tolerance and withdrawal syndrome, eye damage and retinopathy» idiopathic and drug-induced Parkinson's disease, anxiety »emesis. cerebral edema. acute or chronic pain »tardive dyskinesia and cerebral deficits as a consequence of cardiac bypass surgery and grafting of a mammal. 11. The use of an effective amount of a compound according to claim 1. to prepare a composition. treat a disease or disorder. whose treatment can be carried out or facilitated by reducing or inhibiting the neurotransmission of glutamate in a mammal. 12. A pharmaceutical composition for treating a disorder selected between cerebral apoplexy. crebral ischemia trauma of the spinal cord. cephalic traumatism. Alzheimer's disease »Huntington's disease» lateral amyotrophic sclerosis »AIDS-induced dementia» muscle spasms »migraines» urinary incontinence »psychoses» seizures »perinatal hypoxia» cardiac arrest »neuron damage! hypoglycemic, tolerance to opiates and withdrawal syndrome, eye damage and retinopathy, idiopathic and drug-induced Parkinson's disease, anxiety, emesis, cerebral edema »acute or chronic pain» tardive dyskinesia and cerebral deficits as a consequence of bypass surgery cardiac and graft of a mammal "comprising admixing an effective AMP receptor antagonist amount of a compound according to claim 1 and a pharmaceutically acceptable carrier. 13. A pharmaceutical composition for treating a disease or disorder "whose treatment or prevention can be performed or facilitated by reducing or inhibiting the neurotransmission of glutamate in a mammal, comprising an AMP receptor antagonist effective amount of a compound in accordance with claim 1 and a pharmaceutically acceptable carrier.