MXPA99007991A - Atropisomers of 3-heteroaryl-4(3h)-quinazolinones for the treatment of neurodegenerative and cns-trauma related conditions - Google Patents

Abstract

The present invention relates to novel atropisomers of 3-heteroaryl-4(3H)-quinazolinones of formula (1a), and their pharmaceutically acceptable salts, and pharmaceutical compositions and methods of treating neurodegenerative and CNS-trauma related conditions.

Description

ATROPISOMEROS DE 3-HETEROARIL-4 (3H) -QUALAZZOLINONES BACKGROUND OF THE INVENTION The present invention relates to atropisomers of 3-heteroaryl-4 (3H) -quinazolinones of the formula la, described below, to their pharmaceutically acceptable salts and to pharmaceutical compositions and methods for the treatment of neurodegenerative and CNS trauma related conditions. Atropisomers are isomeric compounds that are chiral, that is, each isomer can not be superimposed on its mirror image and the isomers, once separated, rotate the polarized light in equal amounts but in opposite directions. Atropisomers differ from enantiomers in that atropisomers do not possess a single asymmetric atom. Atropisomers are conformational isomers that appear when rotation around a single bond of the molecule is impeded or greatly diminished as a result of steric interactions with other parts of the molecule and the substituents of the ends of the single bond are asymmetric. Detailed lists of atropisomers can be found in Jerry March, Advanced Organic Chemistry, 101-102 (4th ed., 1992) and in Oki, Top, Stereochem., 14, 1-81 (1983). The compounds of the invention provide the first evidence that the quinazolinone atropisomers can be separated and that the separate isomers possess different AMPA receptor antagonist activities. (AMPA receptors are subspecies of glutamate receptors, identified by their ability to bind to -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), which are receptors of post-synaptic neurotransmitters for excitatory amino acids. ) Colebrook and others, Can. J. Chem, 53, 3431-4, (1975), observed a hindered rotation around C-N bonds of aryl groups in the quinazolinones, but did not separate or suggest that the rotational isomers could be separated. U.S. Patent Application 60 / 017,738, filed May 15, 1996 and entitled "Novel 2,3-Disubstituted-4- (3H) -Quinazolnones" ("New 4- (3H) -Quinazole) 2,3-Disubstituted Nona ") and U.S. Patent Application 60 / 017,737, filed May 15, 1996 and entitled" Novel 2,3-Disubstituted- (5,6) -Heteroarylfused-Pyrimidn- " 4-ones "(" New Pirimidin-4-ones (5,6) -Heteroaryl-decondensed 2,3-Disubstituted "). the two applications incorporated herein by reference in their entirety refer to racemic quinazolines and pyrimidinones. The inventors of the present invention have discovered that, surprisingly, a quinazolinone isomer, defined by the spatial positions of the substituents due to spherical interactions, possesses all the antagonist activity of the AMPA receptor. The role of excitatory amino acids, such as glutamic acid and aspartic acid, as predominant mediators of excitatory synaptic transmission in the central nervous system, is well established. Watkins and Evans, An. 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 mainly through excitatory amino acid receptors. These amino acids also participate in a variety of different physiological processes, such as motor control, respiration, cardiovascular regulation, sensory perception and cognition. Excitatory amino acid receptors are classified into two general types. The receptors that attach directly to the cellular membrane of the neurons for the opening of cation channels are called "ionotropic". This type of receptor has been subdivided into at least three subtypes that are defined by the depolarizing actions of the selective agonists N-methyl-D-aspartate (NMDA), a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and cainic acid (KA). The second general type is the G protein or "metabotropic" receptor of excitatory amino acids attached to second messengers. This second type, when activated by the agonists quisqualate, ibotenate or trans-1-aminocyclopentane-1,3-dicarboxylic acid, produces an increase in the hydrolysis of phosphoinositide in the post-synaptic cell. It seems that the two types of receptors not only mediate normal synaptic transmission along the excitatory pathways, but also participate in the modification of the synaptic connection during development and change the efficiency of the synaptic transmission throughout the lifetime. Schoepp, Bockaert and Sladeczek. Trends in Pharmacol. Sci., 11, 508 (1990); McDonald and Johnson, Brain Research Reviews, 15, 41 (1990). Excessive or inappropriate stimulation of excitatamino acid receptors results in injury or loss of neuronal cells through a mechanism known as excitotoxicity. It has been suggested that this process mediates neuronal degeneration in a variety of conditions. The medical consequences of such neuronal degeneration make the relief of these degenerative neurological processes an important therapeutic goal. The excitotoxicity of excitatamino acids has been implicated in the pathophysiology of several neurological disorders. This exitotoxicity has been implicated in the pathophysiology of acute and chronic neurodegenerative conditions, including brain deficits after cardiac bypass surgery and grafts, stroke, cerebral ischemia, spinal cord trauma, cephalic trauma, Alzheimer's disease, chorea of Huntington, amyotrophic lateral sclerosis, epilepsy, AIDS-induced dementia, perinatal hypoxia, hypoxia (such as conditions caused by strangulation, surgery, smoke inhalation, asphyxia, choking, airway rupture, electrocution, or overdose of drug or alcohol), cardiac arrest, hypoglycaemic neuronal injury, eye injury, retinopathy and idiopathic Parkinson's disease and drug-induced. Neuromodulation also requires other neurological conditions caused by glutamate dysfunction. These other neurological conditions include muscle spasms, migraines, urinary incontinence, psychosis, withdrawal syndrome (such as that produced by alcoholism and drug addiction, including opiate addiction, cocaine and nicotine), tolerance to opiates, anxiety, emesis , cerebral edema, chronic pain, seizures, retinal neuropathy, tinnitus and tardive dyskinesia. It is believed that the use of a neuroprotective agent, such as an AMPA receptor antagonist, is useful to treat these disorders and / or to reduce the dimension of the neurological lesions associated with these disorders. Antagonists of excitatamino acid receptors (EAA) are also useful as analgesic agents. Several studies have shown that AMPA receptor antagonists are neuroprotective in models of focal and global ischemia. The competitive antagonist of the AMPA receptor NBQX (2,3-dihydroxy-6-nitro-7-sulfamoylbenzo [f-] quinoxaline) has been reported to be effective in the prevention of global and focal ischemic lesions. Sheardown et al., Science, 247, 571 (1900); Buchan et al., Neuroreport, 2, 473 (1991); LePeillet et al., Brain Research, 571, 115 (1992). It has been shown that non-competitive AMPA receptor antagonists GKYI 52466 are effective neuroprotective agents in rat global ischemia models. LaPeillet et al., Brain Research, 571, 115 (1992). These studies strongly suggest that the delayed neuronal degeneration of cerebral ischemia involves an exotoxicity of glutamate measured at least in part by the activation of the AMPA receptor. Thus, AMPA receptor antagonists may be useful as neuroprotective agents and to improve the neurological results of cerebral ischemia in humans.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to an atropisomer of the formula wherein each of "A, B and D" is nitrogen or -CH-, with the proviso that only one of "A", "B" and "D" can be nitrogen; wherein n is an integer from one to four, preferably one or two, and wherein each R5 is a substituent of any ring carbon atom containing "A, B or D", capable of supporting an additional bond , with the proviso that an R5 must be attached to a carbon atom in the ortho position with respect to the ring atom marked with an asterisk; and wherein each R5 can be independently selected from the group consisting of alkyl (CrC6), halogen, trifluoromethyl, amino- (CH2) m ", alkylamino (C1-C6) - (CH2) m '. dialkyl (C1-C6) -amino- (CH2) m-, alkoxy (C? -C6), hydroxyalkyl (C? -C6) -, alkyl (d-C? J-O-alkyl (C? -C6), -CN, hydroxy- (CH2) m-, alkyl (C? -C6) - (C = O) -O- alkyl (CrC6) -, alkyl (C6) -O- (C = O) -O-alkyl (d-Ce), alkyl ( C C6) - (0 = C) -O-, H- (C = O) - (CH2) m-, alkyl (d-C6) - (C = O) - (CH2) m-, HO- (C = O) -, alkyl (d-C6) -O- (C = O) - (CH2) m-, NH2- (C = O) - (CH2) m-, alkyl (d-C6) -NH- ( C = O) - (CH2) m ", and dialkyl (d-C6) -N- (C = O) - (CH2) m-, and dialkyl (d-C6) -N- (C = O) - ( CH2) m-, and where m is an integer from zero to four R2 is a phenyl group of the formula Ph2 or a five or six membered heterocycle, where said 6-membered heterocycle has the formula wherein "N" is nitrogen; wherein said positions of the ring "K", "L" and "M" can be independently selected from carbon and nitrogen, with the proviso that i) only one of "K", "L" and "M" can be nitrogen and ) when "K", "L" or "M" is nitrogen, then the respective R15, R16 or R17 is absent. Where said five-membered heterocycle has the formula wherein said "T" is -CH-, N, NH, O or S; where said ring positions "P" and "Q" can be independently selected from carbon, nitrogen, oxygen and sulfur; with the proviso that only one of "P", "Q" or "T" can be oxygen or sulfur and at least one of "P", "Q" or "T" must be a heteroatom; where said Ph2 is a group of the formula R is hydrogen, halo, -CN, -NO2, CF3, alkyl (d-Cß) or alkoxy (CrC6); R is hydrogen, halo, CF3, alkyl (d-Cß) optionally substituted with one to three halogen atoms, alkoxy (dC?) Optionally substituted with one to three halogen atoms, alkylthiol (C? -C6), amino- ( CH2) S-, alkyl (d-C6) -NH- (CH2) S-, dialkyl (d-C6) -N- (CH2) S-, cycloalkyl (C3-C7) -NH- (CH2) S-, H2N- (C = O) - (CH2) S- (C6-6) -NH- (C = O) - (CH2) S- dialkyl (C6) -N- (C = O) - (CH2) ) S-, cycloalkyl (C3-C7) -NHR- (C = O) - (CH2) S-, R13O- (CH2) s-, R13O- (C = O) - (CH2) S-, H (O = C) - NH- (CH2) S-, alkyl (d-C6HO = C) -NH- (CH2) s-, alkyl (CrC6) - (0 = C) -N- (CH2) S-, H ( 0 = C) -N- alkyl (C ^ Cg) alkyl (C ^ -Cg) H- (C = O) - (CH2) S-, alkyl (d-C6) - (C = O) -, hydroxy, hydroxy-alkyl (C6-6), alkyl (C6-C6) -O- alkyl (C? -C6) or -CN; R10 is hydrogen or halo; R11 and R14 are independently selected from hydrogen, halo, CF3, alkyl (d-Cß) optionally substituted with one to three halogen atoms, (d-Cß) alkoxy optionally substituted with one to three halogen atoms, alkylthiol (d) -C6), amino- (CH2) p-, alkyl (d-C6) -NH- (CH2) P-, dialquiio (d-C6) -N- (CH2) P-, cycloalkyl (C3-C7) -NH - (CH2) P-, amino- (C1-C6) alkyl -NH- (CH2) P-, (C6-C6) -NH-alkyl (d-C6) -NH- (CH2) P-, dialkyl (d -C6) -N-alkyl (d-C6) -NH- (CH2) P-, dialkyl (d-C6) -N-alkyl (C6) -N- (CH2) p-) H2N- (C = O ) -, (CH2) P-, alkyl (C6C6) alkyl (C6C6) -HN- (C = O) - (CH2) P-, dialkyl (C6C6) -N- (C = O) - (CH2) P-, cycloalkyl (C3-C7) -NH- (C = O) - (CH2) P-, R13O- (CH2) P-, R13O- (C = O) - (CH2) P-, H (O = C) -O-, H (O = C) -O- alkyl (d-C6), H (C = O) -NH- (CH2) PI alkyl (d-C6) - ( O = C) -NH- (CH2) P-, -CHO, H- (C = O) - (CH2) P-, alkyl (d-C6) - (C = O) - (CH2) P-, alkyl (C C6) - (O = C) -N- (CH2) P-, H (O = C) -N- (CH2) P-, HO-alkyl (C6) -Calkium (C6-6) alkyl (C? -C6) N- (CH2) P-alkyl (dC6) - (C = O) -O- (CH2) P-, amino-alkyl (d-C6) amino-alkyl (C? -C6) - (C = O) -O- (CH2 ) P-, alkyl (d-C6) -NH-alkyl (C C6) - (C = O) -O- (CH2) P-, dialkyl (d-C6) -N-alkyl (d-C6) - ( C = O) -O- (CH2) P-, amino-alkyl (Ci-Ce) -O- (C = O) - (CH2) P-, alkyl (d-C6) -NH- alkyl (Ci-Ce) ) -O- (C = 0) - (CH2) P-, dialkyl (C6) -N-alkyl (d-C6) -O- (C = 0) - (CH2) p-, hydroxy, hydroxy-alkyl (d-C6) -. hydroxy-alkyl (C? -C6) -NH- (CH2) p-, (C6-C6) alkyl-O-C-alkyloid), -CN, piperidine- (CH2) p-, pyrrolidine- (CH2) p-, and 3-pyrroline- (CH2) p-, wherein said piperidine, pyrrolidine and 3-pyrroline radical of said piperidine- (CH2) p- and 3-pyrroline- (CH2) P- groups, may be optionally substituted in any of the ring carbon atoms capable of supporting an additional bond, preferably with zero to two substituents, a substituent being independently selected from halo, CF3, optionally substituted (C? -C6) alkyl with one to three halogen atoms, alkoxy (C-C6) ) optionally substituted with one to three halogen atoms, alkylthiol (d-C6), amino- (CH2) P-, alkyl (d-C6) -NH- (CH2) p-, dialkyl (C? -C6) -N - (CH2) P-, cycloalkyl (C3-C7) -NH- (CH2) P-, amino-alkyl (d-C6) -NH- (CH2) p-, (C1-C6) alkyl -NH-alkyl ( d-C6) -NH- (CH2) p-, d-alkyl (d-C6) -N-alkyl (C? -C6) -NH- (CH2) p-, alkyl (C? -C6) -O- alkyl (d-C6), dialkyloid-CeJ-N-C6-alkyloid) -N- (CH2) P-, H2N- (C = 0) -CH2) P -, alkyl- (C? -C6) (d-C6) -HN- (C = 0) - (CH2) P-, dialkyl (C1-C6) -N- (C = 0) - (CH2) p -, (C3-C7) cycloalkyl -NH- (C = 0) - (CH2) P-, R13O- (CH2) P-, R13O- (C = O) - (CH2) P-, H (C = O ) -O-, H (O = C) -O-alkyl (d-C6) -H (O = C) -NH- (CH2) P-, alkyl (d-C6) - (O = C) -NH - (CH2) P-, -CHO, H- (C = O) - (CH2) P-, alkyl (C? -C6) - (C = 0) -, alkyl (d-C6) - (O = C) ) - N- (CH2) P-, H (O = C) -N- (CH2) P-, HO-alkyl (d-C6) -alkyl (CrC6) alk.lo (d-C6) N- (CH2) P -, alkyl (C? -C6) - (C = O) -O-NH- (CH) p-, aminoalkyl-alkyl (C? -C6) (d-C6) - (C = O) -O- ( CH2) p-, alkyl (d-C6) -NH-alkyl (d-C6) - (C = O) -O- (CH2) p-, dialkyl (C? -C6) -N- (C1-C6) alkyl ) - (C = O) -O- (CH2) p-, hydroxy, hydroxy-alkyl (d-C6), hydroxy-alkyl (C? -C6) -NH- (CH2) p and -CN; R 12 is hydrogen, -CN or halo; R13 is hydrogen, (C? -C6) alkyl, (C1-C6) alkyl- (C = O) -, (C? -C6) -O- (C = O) - alkyl, Ci? -Ci? -C?), Dialkyl (d-C6) -N-alkyl (d-C6) -, alkyl (d-C6) -NH- (C = O) -o dialkyl (d-C6) -N- ( C = O) -; R15 is hydrogen, -CN, (C6C6) alkyl, halo, CF3, -CHO or (C6C6) alkoxy; R16 is hydrogen, -CN, alkyl (d-C6), halo, CF3, -CHO or (C? -C6) alkoxy; R > 17 is hydrogen, -CN, alkyl (d-C6), amino-alkylene (C? -C6), alkyl-CeJ-NH-alkyloid-Ce) -, dialkyl (CrC6) -N-alkyl (C? - C6) -, halo, CF3, -CHO or alkoxy (d-C6); each p is, independently, an integer from zero to 4. s is an integer from zero to 4; where the dashed link represents an optional double bond; and pharmaceutically acceptable salts of such compounds. The present invention also relates to the pharmaceutically acceptable acid addition salts of the compounds of the formula I.

The acids which are used to prepare the pharmaceutically acceptable acid addition salts of the above-mentioned basic compounds of this invention, are those which form non-toxic acid addition salts, ie, salts containing pharmacologically acceptable anions, such as hydrochloride, hydrobromide, hydrate, nitrate, sulfate, busulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p toluenesulfonate and pamoate [i.e., 1,1 '-methylene-bis- (2-hydroxy-3-naphthoate)]. The invention also relates to base addition salts of formula I. The chemical bases which can be used as reagents for preparing pharmaceutically acceptable base salts of the compounds of formula I which are acidic in nature, are those which form non-base salts. toxic with such compounds. Such non-toxic base salts include, but are not limited to, those derived from pharmacologically acceptable cations such as alkali metal cations, (e.g., potassium and sodium) and alkaline earth metal cations (e.g. calcium and magnesium), addition salts of water-soluble ammonium or amine, such as N-methylglucamine (meglumine), the lower alkanolammonium salts and other pharmaceutically acceptable organic amine base salts. Preferred compounds of formula I are those in which R3 is hydrogen, halo or alkyl (C6C6). Other preferred compounds of the formula la are those in which "B" is nitrogen and "A" and "D" are carbon, and R5 is hydrogen, halo, -CN-CF3 or alkyl (d-C6), preferably R5 is chlorine or methyl and, more preferably, R5 is a substituent in the ortho position with respect to the carbon marked with an asterisk. Preferred compounds of the formula wherein R 2 is Ph 2, are those in which R 9 is fluoro, chloro, -CN or hydroxy; or R11 is -CHO, chloro, fluoro, methyl, alkyl (d-C6) -NH- (CH2) P-, d-alkyl (d-C6) -N- (CH2) P-, pyrrolidine- (CH2) p -, or cyano. The most preferred compounds of the formula wherein R 2 is Ph 2, are those in which R 9 is fluoro or -CN; or R11 is methyl, alkyl (dC6) -NH- (OH2) p-, or cyano. Preferred compounds of the formula wherein R 2 is heteroaryl, are those in which said heteroaryl is an optionally substituted six-membered heterocycle wherein "K", "L" and "M" are carbons (ie, pyridine) 2-yl) or "K" and "L" are carbon and "M" is nitrogen (ie, pyrimidin-2-yl), or said heteroaryl is an optionally substituted five-membered heterocycle in which "T" is nitrogen, "P" is sulfur and "Q" is carbon (ie, 1,3-thiazol-4-yl), "T" is nitrogen or sulfur, "Q" is nitrogen or sulfur and "P" is carbon ( that is, 1,3-thiazol-2-yl) or "T" is oxygen and "P" and "Q" are, each, a carbon (ie, fur-2-ilo). Preferred compounds of the formula wherein R 2 is an optionally substituted six-membered heterocycle, wherein "K", "L" and "M" are carbons (ie, pyridin-2-yl), are those in the that R14 is hydrogen, -CHO, chloro, fluoro, methyl, alkyl (C? -C6) -NH- (CH2) p-, pyrrolidine- (CH2) p- or cyano; R17 is hydrogen, -CHO, chloro, fluoro, methyl, alkyl (C? -Ce) -NH-alkyl (C? -C6), dialkyl (C? -C6) -N-alkyl (C? -C6) or cyano; or R15 or R16 are, independently, hydrogen, -CHO, chloro, fluoro, methyl or cyano. The most preferred compounds of the formula wherein R 2 is an optionally substituted six-membered heterocycle, wherein "K", "L" and "M" are carbons (ie, pyridin-2-yl), are those in which wherein R14 is hydrogen, -CHO, methyl, alkyl (CI-C6) -NH- (CH2) P-, dialkyl (C? -C6) -N- (CH2) p- or cyano. Preferred compounds of the formula wherein R 2 is an optionally substituted five-membered heterocycle wherein "T" is nitrogen, "P" is sulfur and "Q" is carbon (i.e., 1,3-thiazole-4) ilo) are those in which R14, R15 or R16 are each, independently, hydrogen, chloro, fluoro, methyl or cyano.

Preferred compounds of the formula wherein R 2 is an optionally substituted five-membered heterocycle wherein "T" is nitrogen or sulfur, "Q" is sulfur or nitrogen and "P" is carbon (i.e., 1, 3- thiazol-2-yl), are those in which R 14 or R 15 are independently hydrogen, chloro, fluoro, methyl or cyano Examples of the preferred specific compounds of formula la include: (S) -6-fluoro-2- [2 - (2-fluoro-phenyl) -vinyl] -3- (2-methyl-pyridin-3-yl) -3H-quinazolin-4-one; (S) -2-. { 2- [6-fluoro-3- (2-methyl-pyridin-3-yl) -4-oxo-3,4-dihydro-quinazolin-2-yl] -vinyl} -benzonitrile; (S) -2-. { 2- [6-fluoro-3- (2-methylpyridin-3-yl) -4-oxo-3,4-ihydroquinazolin-2-yl] -vinyl} -benzonitrile; (S) -2-. { 2- [3- (2-chloro-pyridin-3-yl) -6-fIuoro-4-oxo-3,4-dihydroquinazolin-2-yl] -vinyl} -benzonitrile; (S) -2-. { 2- [6-fIuoro-3- (2-methyl-pyridin-3-yl) -4-oxo-3,4-dihydro-quinazolin-2-yl] -vinyl} -4-methyl-benzonitrile; (S) -2-. { 2- [3- (2-Methyl-pyridin-3-yl) -4-oxo-3,4-dihydro-quinazolin-2-yl] -vinyl} -benzonitrile; (S) 6-Fluoro-3- (2-methyl-pyridin-3-yl) -2- [2- (thiazol-4-yl) -v] nyl] -3H-quinazolin-4-one; (S) 6-Fluoro-3- (2-methyl-pyridin-3-yl) -2- [2- (2-methyl-thiazol-4-yl) -vinyl] -3H-quinazolin-4- ona; (S) -6-fluoro-3- (2-methyl-pyridin-3-yl) -2- [2- (4-methy1-thiazol-2-yl) -vinyl] -3H-quinazolin- 4-one. (S) -2- [2- (5-Diethylaminomethyl-2-fluoro-phenyl) -vinyl] -6-fluoro-3- (2-methyl-pyridin-3-yl) -3H-quinazole-4- ona; and (S) -6-fluoro-2- [2- (2-fluoro-5-pyrrolidin-1-ylmethyl-phenyl) -vinyl] -3- (2-methyl-pyridin-3-yl) -3H-quinazolin-4-one. Other compounds of the invention include: (S) -3- (2-chloro-pyridin-3-yl) -2- [2- (2-fluoro-phenyl) -vinyl] -3H-quinazolin-4-one; (S) -3- (2-Chloro-pyridin-3-yl) -6-fluoro-2- [2- (6-methyl-phenyl-2-yl) -vinyl] -3H-quinazolin-4-one; (S) -3- (2-Chloro-pyridin-3-yl) -6-fluoro-2- [2- (fluoro-phenyl) -vinyl] -3H-quinazolin-4-one; (S) -6-chloro-2- [2- (2-fluoro-phenyl) -vinyl] -3- (2-methyl-pyridin-3-yl) -3H-quinazolin-4-one; (S) -6-chloro-2- [2- (2-fluoro-pheny] -vinyl] -3- (3-methyl-1-oxy-pyrid-4-yl) - 3 H -quinazolin-4-one; (S) -3-. { 2- (3- (2-Chloro-pyridin-3-yl) -6-fluoro-4-oxo-3,4-dihydro-quinazolin-2-yl) -vinyl} - benzaldehyde; (S) -3-. { 2- [3- (2-Chloro-pyridin-3-yl) -4-oxo-3,4-dihydroquinazolin-2-yl] -vinyl} -benzaldehyde; (S) -3- (2-chloro-pyridin-3-yl) -2-. { 2 [3 (1, 4-dioxa-8-aza-spiro [4.5] dec-8-methylmethyl) -vinyl} -6-fluoro-3H-quinazolin-4-one; (S) -3- (2-chloro-pyridin-3-yl) -6-fluoro-2-. { 2- [3 (4-pyrrolidin-1-yl-piperidin-1-ylmethyl) -phenyl] -vinyl} -3H-quinazolin-4-one; (S) -2-. { 2- [3- (2-Chloro-pyridin-3-yl-6-fluoro-4-oxo-3,4-dihydro-quinazolin-2-yl] -vinyl] -benzonitrile; (S) -2- {.2- [3- (2-Chloro-pyridin-3-yl) -4-oxo-3,4-dihydro-quinazolin-2-yl] -vinyl} -benzonitrile; (S) -2- [2- (2-fluoro-pheny] -vinyl] -3- (2-methyl-pyridin-3-yl) -3H-quinazolin-4-one; (S) -3- (2-chloro-pyridine; -3-yl) -6-fluoro-2- [2-hydroxy-phenyl) -vinyl] -3H-quinazolin-4-one; (S) -6-fluoro-3- (2-methyl-pyridin-3-yl) -2- [2- (2-methyl-thiazol-4-yl) -ethyl] -3H-quinazolin-4- ona; (S) -6-fluoro-3- (2-chloro-pyridin-3-yl) -2- [2- (2-dimethylamino-methylthiazol-4-yl) -vinyl] -3H-quinazolin-4-one; (S) -2- [2- (5-Diethylaminomethyl-2-fluoro-phenyl) -vinyl] -6-fluoro-3- (4-methyl-pyridin-3-yl) -3H-quinazolin-4- ona; (S) -4-Diethylaminomethyl-2-. { 2- [6-fluoro-3- (4-methy1-pyridin-3-yl) -4-oxo-3,4-dihydro-quinazolin-2-yl] -vinyl} -benzonitrile; (S) -2- [2 (5-Diethylaminomethyl-2-fluoro-phenyl) -vinyl] -6-fluoro-3- (3-methyl-pyrazin-2-yl) -3H-quinazolin-4-one; (S) -6-fluoro-3- (2-methyl-pyridn-3-yl) -2- [2- (2-d-methylamino-methylthiazol-4-yl) -vinyl] -3H- quinazolin-4-one; (S) -6-fluoro-3- (2-methyl-pyridin-3-yl) -2- [2- (2-methyl-oxazol-4-yl) -vinyl] -3H-quinazolin-4-one; (S) -6-fluoro-3- (2-chloro-pyridin-3-yl) -2- [2- (2-thiazol-4-yl) -vinyl] -3H-quinazolin-4-one; (S) -6-fluoro-3- (4-methyl-pyridin-3-yl) -2- [2- (4-methyl-thiazol-2-yl) -vinyl] -3H-quinazolin-4-one; (S) -3- (2-Chloro-pyridin-3-yl) -6-fluoro-2- [2- (2-hydroxy-phenyl) -vinyl] -3H-quinazolin-4-one; and (S) -6-fIuoro-2- [2- (2-fluoro-5-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -3- (2-methyl-pyridin-3-yl) -3H-quinazolin - -ona This invention also relates to a pharmaceutical composition for treating or preventing a condition selected from brain deficits subsequent to cardiac bypass surgery and grafts, stroke, cerebral ischemia, spinal cord trauma, brain trauma, Alzheimer's disease, Korea. Huntington, amyotrophic lateral sclerosis, epilepsy, AIDS-induced dementia, perinatal hypoxia, hypoxia (such as conditions caused by strangulation, surgery, inhalation of smoke, suffocation, drowning, airway obstruction, electrocution or overdose of drugs or alcohol), cardiac arrest, hypoglycemic neuronal injury, opioid tolerance, withdrawal syndrome (such as that produced by alcoholism and drug addiction, including opiate addiction, cocaine and nicotine), idiopathic and drug-induced Parkinson's disease or cerebral edema, muscle spasms, migraines, incontinence urinary tract, psychosis, seizures, chronic or acute pain, eye lesions, retinopathy, retinal neuropathy, tinnitus, anxiety, emesis and tardive dyskinesia, in a mammal, comprising an amount of a compound of the formula effective to treat or prevent such a condition , and a pharmaceutically acceptable vehicle. This invention also relates to a method for treating or preventing a condition selected from brain deficits subsequent to cardiac bypass surgery and grafts, stroke, cerebral ischemia, spinal cord trauma, head trauma, Alzheimer's disease, Huntington's disease. , amyotrophic lateral sclerosis, epilepsy, AIDS-induced dementia, perinatal hypoxia, hypoxia (such as conditions caused by strangulation, surgery, inhalation of smoke, suffocation, drowning, airway obstruction, electrocution or overdose of drugs or alcohol ), cardiac arrest, hypoglycaemic neuronal injury, opioid tolerance, withdrawal syndrome (such as that produced by alcoholism and drug addiction, including opiate addiction, cocaine and nicotine), idiopathic and drug-induced Parkinson's disease or edema cerebral, muscle spasms, migraines, urinary incontinence, psych osis, seizures, chronic or acute pain, ocular lesions, retinopathy, retinal neuropathy, tinnitus, anxiety, emesis and tardive dyskinesia, in a mammal, which comprises administering to a mammal in need of such treatment or prevention, an amount of a compound of formula effective in the treatment or prevention of such a condition. This invention also relates to a pharmaceutical composition for treating or preventing a condition selected from brain deficits subsequent to cardiac bypass surgery and grafts, stroke, cerebral ischemia, spinal cord trauma, head trauma, Alzheimer's disease, Korea. Huntington, amyotrophic lateral sclerosis, epilepsy, AIDS-induced dementia, perinatal hypoxia, hypoxia (such as conditions caused by strangulation, airway obstruction, electrocution or drug or alcohol overdose), cardiac arrest, hypoglycaemic neuronal injury, opioid tolerance, withdrawal syndrome (such as that produced by alcoholism and drug addiction, including opiate addiction, cocaine and nicotine), idiopathic and drug-induced Parkinson's disease or cerebral edema, muscle spasms, migraines, urinary incontinence, psychosis, convulsions, chronic or acute pain, eye lesions, retinopathy, retinal neuropathy, tinnitus, anxiety, emesis and tardive dyskinesia, in a mammal, comprising an effective amount to antagonize the AMPA receptor of a compound of formula la and a pharmaceutically acceptable carrier. This invention also relates to a method for treating or preventing a condition selected from brain deficits subsequent to cardiac bypass surgery and grafts, stroke, cerebral ischemia, spinal cord trauma, head trauma, Alzheimer's disease, Huntington's disease. , amyotrophic lateral sclerosis, epilepsy, AIDS-induced dementia, perinatal hypoxia, hypoxia (such as conditions caused by strangulation, surgery, inhalation of smoke, asphyxia, drowning, airway obstruction, electrocution or overdose of drugs or alcohol ), cardiac arrest, hypoglycemic neuronal injury, opioid tolerance, withdrawal syndrome (such as that produced by alcoholism and by addition to drugs, including opiate addiction, cocaine and nicotine), idiopathic and drug-induced Parkinson's disease or edema cerebral; muscle spasms, migraines, urinary incontinence, psychosis, seizures, chronic or acute pain, ocular lesions, retinopathy, retinal neuropathy, tinnitus, anxiety, emesis and tardive dyskinesia, in a mammal, which comprises administering to a mammal that requires such treatment or prevention , an effective amount for antogonizing the AMPA receptor of a compound of formula la. The compounds of this invention include all stereoisomers and all optical isomers of the compounds of the formula la (for example, the R and S enantiomers), as well as racemic, diastereomeric mixtures and other mixtures of such isomers. The compounds of this invention may contain double bonds similar to those of olefins. When such bonds are present, the compounds of the invention exist in the cis and trans configurations and as mixtures thereof.

Unless otherwise indicated, the alkyl groups mentioned herein, as well as the alkyl radicals of other groups mentioned herein (e.g., alkoxy), may be linear or branched and may also be cyclic (e.g., cyclopropyl) , cyclobutyl, cyclopentyl or cyclohexyl) or can be linear or branched and contain cyclic radicals. Unless otherwise indicated, halo or halogen refers to fluoro, bromo, chloro or iodo. The thick lines of the formulas la and Ib, shown below, indicate that the bold atoms and the groups attached to them are sterically restricted, so that they exist orthogonally above the plane of the quinazolinone ring or orthogonally below the of the quinazolinone ring. This spherical restriction is due to a rotational energy barrier that prevents free rotation around the single bond connecting the quinazolinone ring with the ring containing "A, B and D". This rotational energy barrier is the result of the inability of a substituent R5, in ortho position with respect to the carbon marked with an asterisk, to rotate around the quinazoline nucleus. In the compounds of formula la, the "A and B" atoms and substituents thereof are sterically restricted such that they exist orthogonally above the plane of the quinazolinone ring when the ring is with the vinyl group to the right of the quinazolinone ring. The compounds of formula la are denoted by the stereochemistry (S). In the compounds of formula Ib shown below, the atoms "A, B and D" are sterically restricted, so that they exist orthogonally above the plane of the quinazolinone ring when the vinyl group is to the left of the quinazolinone ring. The compounds of the formula Ib are denoted by the stereochemistry (R). The compounds of formula possess substantially all of the AMPA receptor antagonist activity, while the compounds of formula Ib essentially lack the antagonist activity of the AMPA receptor.

DETAILED DESCRIPTION OF THE INVENTION The compounds of formula I can be prepared according to the procedures of Scheme 1. In the reaction Scheme and in the discussion that follows, A, B, D, K, L, M, P, Q, T, R2, R3, R5, R9, R10, R11, R12, R13, R14, R15, R16, R17, Ph2, n, m, pys, unless otherwise indicated, are as defined above for formula la.

SCHEME 1 the Ib SCHEME 2 V VI Vile Scheme 1 refers to the preparation of compounds of formula la or Ib, from compounds of formula V. Compounds of formula V are commercially available or can be prepared by procedures well known to persons of ordinary skill in the art. The technique. A compound of the formula V can be converted to an acetamide of the formula IV by reaction with acetyl chloride or acetic anhydride, in the presence of a base, in a reaction-inert solvent. Suitable solvents include methylene chloride, dichloroethane, tetrahydrofuran and dioxane, preferably methylene chloride. Suitable bases include trialkylamines such as triethylamine and tributylamine, dimethylaminopyridine and potassium carbonate, preferably triethylamine. The temperature of the aforesaid reaction is in the range of about 0 ° C to about 35 ° C, for about 1 hour to about 10 hours, preferably at about 25 ° C for about 3 hours. The acetamide of formula IV is cyclized to obtain a compound of formula III, by reaction with a dehydrating agent, in the presence of a catalyst, in a dry solvent inert to the reaction. Suitable dehydrating agents include acetic anhydride, phosphorus pentoxide, dicyclohexylcarbodiimide and acetyl chloride, preferably acetic anhydride. Suitable catalysts include sodium or potassium acetate, acetic acid, p-toluene sulfonic acid or boron trifluoride etherate, preferably sodium acetate. Suitable solvents include dioxane, toluene, diglyme or dichloroethane, preferably dioxane, toluene, diglyme or dichloroethane, preferably dioxane. The temperature of the aforesaid reaction is in the range of about 80 ° C to about 110 ° C, for about 1 hour to about 24 hours, preferably a temperature of about 100 ° C is used for about 3 to 10 hours. Alternatively, the compound of formula V can be converted directly to a compound of formula III by reaction with acetic anhydride in the presence of an acid catalyst in a solvent. Suitable acidic catalysts include acetic acid, sulfuric acid or p-toluene sulfonic acid, preferably acetic acid. Suitable solvents include acetic acid, toluene or xylene, preferably acetic acid. The temperature of the above reaction is from about 20 ° C to about 150 ° C, for about 10 minutes to about 10 hours, preferably a temperature of about 120 ° C is used for about 2 to 5 hours. The compound of formula III, formed by any of the above processes, is reacted with an amine of the formula VIII in a polar protic solvent, in the presence of an acid catalyst, to form a compound of formula II. Suitable acidic catalysts include acetic acid, p-toluene sulfonic acid or sulfuric acid, preferably acetic acid. Suitable polar protic solvents include acetic acid, methanol, ethanol or isopropanol, preferably acetic acid. The temperature of the reaction mentioned above is from about 1 hour to about 24 hours, preferably a temperature of about 17-17 ° C is used for about 6 hours. Alternatively, a compound of formula IV can be converted directly to a compound of formula II by reaction with a dehydrating agent, an amine of formula VIII and a base, in a reaction-inert solvent. Suitable dehydrating agents include phosphorus trichloride, phosphorus oxychloride, phosphorus pentachloride or thionyl chloride, preferably phosphorus trichloride. Suitable bases include pyridine, lutidine, dimethylaminopyridine, triethylamine or N-methyl morpholine, preferably pyridine. Suitable solvents include toluene, cyclohexane, benzene or xylene, preferably toluene. Under some circumstances, when the mixture of reagents is a liquid, the reaction can be carried out in the pure state. The temperature of the above reaction is from about 50 ° C to about 150 ° C, for from about 1 hour to about 24 hours, preferably a temperature of about 110 ° C is used for about 4 hours. The compound of formula II is reacted with an aldehyde of formula R CHO in the presence of a catalyst and a dehydrating agent, in a suitable solvent, to form a compound of formula I, wherein the broken line is a double bond. Suitable catalysts include zinc chloride, sodium acetate, aluminum chloride, tin chloride or boron trifluoride etherate, preferably zinc chloride or sodium acetate. Suitable dehydrating agents include acetic anhydride, methanesulfonic anhydride, trifluoroacetic anhydride or propionic anhydride, preferably acetic anhydride. Suitable polar solvents include acetic acid, dioxane, dimethoxyethane or propionic acid.

The temperature of the aforesaid reaction is from about 60 ° C to about 100 ° C, for from about 30 minutes to about 24 hours, preferably a temperature of about 100 ° C is used for about 3 hours. Compounds of formula I in which the dashed line represents a single carbon-carbon bond can be prepared by hydrogenation of the corresponding compounds in which the dashed line represents a carbon-carbon double bond, using conventional techniques that are well known for those skilled in the art. For example, the reduction of the double bond can be done with hydrogen gas (H2), using catalysts such as palladium on carbon (Pd / C), palladium on barium sulfate (Pd / BaSO4), platinum on carbon (Pt / C) or tris (triphenylphosphine) rhodium chloride (Wilkinson catalyst), in an appropriate solvent such as methanol, ethanol, THF, dioxane or ethyl acetate, at a pressure of about 1 to about 5 atmospheres and at a temperature from about 10 ° C to about 60 ° C, as described in Catalytic Hydroqenation in Orqanic Svnsthesis, Paul Rylander, Academic Press Inc., San Diego, 1979, p. 31-63. The following conditions are preferred; Pd on carbon, ethyl acetate at 25 ° C and a hydrogen gas pressure of 15-20 psi (103.421-137.895 kPa). This procedure also provides the introduction of hydrogen isotopes (ie, deuterium, tritium) replacing 1H2 with 2H2 or 3H2 in the above procedure. The compounds of the formula I can be separated into compounds of the formula la and Ib by high pressure liquid chromatography (HPLC) using a chiral HPLC column and eluting with an appropriate solvent. A person of ordinary skill in the art will understand that many types of instruments can be used, columns and eluents, to separate the individual atropisomers. Suitable HPLC instruments include LC SpiderLing®, Waters 4000®, Hewlett Packard 1050® and Analytical Grade Thermo Separation Productions HPLC. Suitable HPLCs are configured according to procedures well known to those of ordinary skill in the art. Such a configuration invariably includes a pump, an injection hole and a detector. Suitable chiral columns can be purchased pre-filled or filled by a person of ordinary skill in the art. Suitable chiral columns include chiral columns OA, OD, OG, AD and AS, which can be purchased from Chiral Technologies Inc., 730 Springdale Drive, PO Box 564, Exton, PA 19341. A person of ordinary skill in the art will appreciate that in order to separate the isomers of the invention, many other chiral columns purchased from other vendors may be suitable.

The filling material can also be purchased with different sizes of the beads. The beads suitable for the preparative separations have a size of 20 micrometers in diameter. The beads suitable for analytical separation have a size of approximately 10 micrometers in diameter. Compounds of the formula in which a basic group is present can also be resolved by treatment with an enantiomerically pure acid in a suitable solvent to form separable diastereomeric salts. Suitable enantiomerically pure acids include camphorsulfonic acid, tartaric acid (and derivatives thereof), mandelic acid and lactic acid. Suitable solvents include alcohols, such as ethanol, methanol and butanol, toluene, cyclohexane, ether and acetone. Alternatively, a compound of formula V can be converted to a compound of formula II according to the procedures described in scheme 2. The compound of formula II thus formed can be converted to a compound of formula I according to the procedures of the scheme I. Referring to scheme 2, a compound of formula V is reacted with a coupling reagent, an amine of formula VIII and a base, in a reaction-inert solvent, to form a compound of formula VI. Examples of suitable coupling reagents that activate the carboxylic functionality are dicyclohexylcarbodiimide, N-3-dimethylaminopropyl-N'-ethylcarbodiimide, 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ), carbonyl diimidazole (CD1) and diethylphosphorylnide. Suitable bases include dimethylaminopyridine (DMAP), hydroxybenzotriazole (HBT) or triethylamine, preferably dimethylaminopyridine. The coupling is carried out in an inert solvent, preferably in an aprotic solvent. Suitable solvents include acetonitrile, dichloromethane, dichloroethane and dimethylformamide. The preferred solvent is dichloromethane. The temperature of the above reaction is generally from about -30 to about 80 ° C, preferably from about 0 to about 25 ° C. The compound of the formula VI is converted to a compound of the formula VII by reaction with acetyl chloride or acetic anhydride, in the presence of a base, in a reaction-inert solvent. Suitable solvents include methylene chloride, tetrahydrofuran and chloroform, preferably methylene chloride. Suitable bases include trialkylamines such as triethylamine and tributylamine, dimethylaminopyridine and potassium carbonate, preferably triethylamine. The temperature of the above reaction is in the range of about 0 ° C to about 35 ° C, for about 1 hour to about 10 hours, preferably a temperature of about 30 ° C is used for about 3 hours. The compound of formula VII is cyclized to obtain a compound of formula II, by reaction with triphenylphosphine, a phase, and a dialkyl azodicarboxylate, in solvent inert to the reaction. Suitable bases include pyridine, triethylamine and 4-dimethylaminopyridine, preferably 4-dimethylaminopyridine. Suitable solvents include dimethylformamide, tetrahydrofuran and dioxane, preferably dioxane. The temperature of the above reaction is in the range of about 25 ° C to about 125 ° C, for about 1 hour to about 24 hours, preferably a temperature of about 100 ° C is used for about 8 to 15 hours. The compound of formula II can be converted into a compound of formula I according to the procedure described in scheme 1. Compounds of formula II can also be obtained according to the procedures described in Miyashita, and others., Heterocycles, 42, 2, 691-699 (1996). In scheme 3, the compound of formula II is converted into the corresponding compound of formula VIII by reaction with a base, such as lithium diisopropylamide, in a polar aprotic solvent such as tetrahydrofuran. The solution is stirred at room temperature between about -100 ° C and about 0 ° C, preferably at -78 ° C for a period of time between about 15 minutes and about 1 hour, preferably about 30 minutes. The anionic product thus formed is reacted with a tetrahydrofuran solution of an aldehyde of the formula R 2 CHO. The aldehyde solution can be added to the anion solution (normal addition or the anion solution can be added to the aldehyde solution (reverse addition).

Although the two methods can be used to produce compounds of formula VIII, reverse addition is preferred. The resulting reaction mixture is stirred for a period of time between about 15 minutes and about 1 hour, preferably about 30 minutes, at a temperature between about -100 ° C, preferably -78 ° C, and then it is allowed to warm to the room temperature. In reaction 2 of scheme 3, the compound of formula VIII is converted to the corresponding compound of formula I by reaction of VIII with a dehydrating agent, such as trifluoroacetic anhydride, in a dry, reaction-inert solvent, such as dioxane, toluene, diglyme or dichloroethane, preferably dioxane. The reaction mixture is stirred at a temperature between about 0 ° C and about 50 ° C, preferably at room temperature, for a period of time between about 1 hour and about 14 hours, preferably about 12 hours.

The compounds of formula I, in which the dashed line represents a single carbon-carbon bond, can be prepared by hydrogenation of the corresponding compounds in which the dotted line represents a carbon-carbon double bond, using conventional techniques that are well known to those skilled in the art.

For example, the reduction of the double bond can be done with hydrogen gas (H2), using catalysts such as palladium on carbon (Pd / C), palladium on barium sulfate (Pd / BaSO4), platinum on carbon (Pt / C or tris (triphenylphosphine) rhodium chloride (Wilkinson's catallizer), in an appropriate solvent such as methanol, ethanol, THF dioxane or ethyl acetate, at a pressure of about 1 to about 5 atmospheres and at a temperature of about 10 ° C to about 60 ° C, as described in Catalytic Hydrogenation in Organic Svnthesis, Paul Rylander, Academic Press Inc., San Diego, 1979, p. 31-63. The following conditions are preferred: Pd on carbon, ethyl acetate at 25 ° C and hydrogen gas pressure of 15-20 psi (103, 421-137, 895 kPa). This method also provides for the introduction of hydrogen isotopes (ie, deuterium, tritium) by replacing 1H2 with 2H2 or 3H2 in the above procedure. When R2 is heteroaryl, a person of ordinary skill in the art will understand that the heteroaryl is selected from the group consisting of pyridin-2-yl, 1,3-pyrazin-4-yl, 1,4-pyrazin-3-yl, 1,3-pyrazin-2-yl, pyrrol-2-yl, 1,3-imidazol-4-yl, 1,3-imidazol-2-yl, 1,4-triazol-2-yl, 1 3-oxazol-4-yl, 1,3-oxazol-2-yl, 1,3-thiazol-4-yl, 1,3-thiazol-2-yl, 1, 2-oxadiazol-3-yl, 1 , 2,4-oxadiazol-5-yl, fur-2-yl, 1,3-oxazol-5-yl and 1,3,4-oxadiazol-2-yl, wherein said heteroaryl may be optionally substituted in any of the atoms capable of forming an additional bond, with a maximum of up to three substituents. Unless otherwise indicated, the pressure of each of the above reactions is not critical. Generally, the reactions will be carried out at a pressure of about one to about three atmospheres, preferably at ambient pressure (about one atmosphere). The compounds of the formula which are basic in nature can form a wide variety of different salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable to be administered to animals, it is often desirable in practice to initially isolate a compound of formula I from a reaction sample as a pharmaceutically unacceptable salt, then simply convert the latter into the compound of free base by treatment with an alkaline reagent and subsequently converting the free base to a pharmaceutically acceptable acid addition salt. The acid addition salts of the basic compounds of this invention are readily prepared by treating the base compound with a substantially equivalent amount of the chosen organic or mineral acid., in an aqueous solvent medium or in a suitable organic solvent such as methanol or ethanol. After careful evaporation of 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, hydroiodide, nitrate, sulfate or bisulfate, phosphate or phosphate acid, acetate, lactate, citrate or citrate acid, tartrate or bitartrate, succinate, maleate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate and pamoate [ie 1, 1'-methylene-bis- (2-hydroxy-3-naphthoate)]. The compounds of formula which are acidic in nature, are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include the alkali metal or alkaline earth metal salts and, in particular, the sodium and potassium salts. All these salts are prepared by conventional techniques. The chemical bases that are used as reagents for preparing the pharmaceutically acceptable base salts of this invention are those that form non-toxic base salts with the acidic compounds of the formula described herein. These non-toxic base salts include those derived from pharmacologically acceptable cations such as sodium, potassium, calcium, magnesium, etc. These salts can be easily prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations and, subsequently, evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, they can be prepared by mixing lower alkanolic solutions of the acidic compounds and the desired alkali metal alkoxide and then evaporating the resulting solution to dryness, in the same manner as indicated above. In any case, stoichiometric amounts of reagents are preferably employed to ensure that the reaction is complete and that maximum yields of the desired final product are obtained. The compounds of the formula la and the pharmaceutically acceptable salts thereof (hereinafter also referred to as "the active compounds of the invention") are useful for the treatment of neurodegenerative and CNS trauma related conditions and are potent agonists and antagonists of the CNS. AMPA receiver. Therefore, the active compounds of the invention can be used in the treatment or prevention of brain deficits subsequent to cardiac bypass surgery and grafts, stroke, cerebral ischemia, spinal cord trauma, head trauma, Alzheimer's disease, Correa of Huntington, amyotrophic lateral sclerosis, epilepsy, AIDS-induced dementia, perinatal hypoxia, hypoxia (such as conditions caused by strangulation, surgery, inhalation of smoke, suffocation, drowning, airway obstruction, electrocution or drug overdose or of alcohol), cardiac arrest, hypoglycaemic neuronal injury, opioid tolerance, withdrawal syndrome (such as that produced by alcoholism and drug addiction, including opiate addiction, cocaine and nicotine), Idiopathic and drug-induced cerebral palsy or cerebral edema; muscle spasms, migraines, urinary incontinence, psychosis, seizures, chronic or acute pain, eye injuries, retinopathy, retinal neuropathy, tinnitus, anxiety, emesis and tardive dyskinesia. The in vitro and in vivo activity of the compounds of the invention with respect to the antagonism of the Areceptor can be determined by methods available to a person of ordinary skill in the art. A method for determining the activity of the compounds of the invention is by the inhibition of pentylenetetrazole (PTZ) -induced attacks. 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 Areceptor. A specific procedure to determine the inhibition of the pentylenetetrazole (PTZ) -induced attacks is as follows. The activity of the compounds of the invention with respect to the inhibition of pentylenetetrazole (PTZ) -induced attacks in mice can be determined according to the following procedure. This essay examines the ability of compounds to block attacks and death produced by PTZ. The measures taken are latency for clonic and tonic attacks and death. The Dl50 values are determined based on percent protection.

As subjects for these experiments, male mice serve CD-1 from Charles River, weighing 14-16 g after arrival and 25-35 g at the time of testing. The mice are enclosed, 13 per cage, under conventional laboratory conditions, in a light cycle L: O / 7 a.m .: 7 p.m. for at least 7 days before experimentation. Food and water are available ad libitum until the time of the trial. All compounds are administered in a volume of 10 ml / kg. The vehicles of the drug will depend on the solubility of the compound, but the selection will typically be made using saline, distilled water or E: D: S / 5: 5: 90 (5% emulfor, 5% DMSO and 90% solution salina) as an injection vehicle. The mice are administered the test compounds or the 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 receive an injection of PTZ (i.p., 120 mg / kg) and place them in individual plexiglass cages. The measures taken during this five-minute test period are: (1) latepcia for clone attacks, (2) latency for tonic attacks, and (3) latency for death. The treatment groups are coed with the vehicle-treated group by Kruskal-Wailis Anova and Mann-Whitney U (Statview) assays. The protection percentage for each group is calculated (number of subjects that do not show attack or death as indicated by a score of 300 secs.) In each measurement. The Dl50 values are determined by probit analysis (Biostat).

Another method for determining the activity of the compounds is to determine the effect of the compounds on motor coordination in mice. This activity can be determined according to the following procedure. As subjects for these experiments, male mice serve CD-1 from Charles River, weighing 14-16 g after arrival and 23-35 g at the time of testing. The mice are enclosed, 13 per cage, under conventional laboratory conditions in a light cycle L: O / 7 a.m .: 7 p.m. for at least 7 days before the experimentation. Food and water are available ad libitum until the time of the trial. All compounds are administered in a volume of 10 ml / kg. The vehicles of the drug will depend on the solubility of the compound, but typically the selection will be made using saline, distilled water or E: D: S / 5: 5: 90 (5% emulfor, 5% DMSO and 90% solution salina) as an injection vehicle. The apparatus used in these studies consists of a group of five 13.34 x 13.34 cm wire mesh panels suspended on 11.43 cm steel rods connected to a 165.1 cm rod that is elevated 38. 1 cm above the laboratory table. These wire mesh boxes can be reversed. The mice are administered the test compounds or the 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 placed on top of the wire mesh frames and these move abruptly so that the mice are suspended downwards. During the one minute test, the mice receive an evaluation of 0 if they fall from the screen, of 1 if they stay caught in the reverse position or of 2 if they climb to the top. The treatment groups are compared with vehicle-treated groups with the Kruskal-Wailis and Mann-Whitney U (Statview) trials. Next, a specific procedure for determining the blocking of 45 Ca2 + uptake induced by the activation of the AMPA receptor is described.

Primary Neuronal Cultures Primary cultures of neurons from rat brain granules are prepared as described by Parks, TN, Artman, LD, Alasti, N., and Nemeth, EF, Modualtion of N-Methyl-D-Aspartate Receptor-Mediated Increases In Cvtosolic Calcium In Cultured Rat Cerebellar Granule Cells, Brain Res. 552, 13-22 (1992). According to this procedure, the cerebellums of 8-day-old CD rats are removed, cut into 1-mm pieces and incubated for 15 minutes at 37 ° C in Tyrode's solution without calcium or magnesium, containing 0.1 % of trypsin. The tissue is then ground using a fine-tipped Pasteur pipette. The cell suspension is introduced into 96-well tissue culture plates, coated with poly-D-lysine, at 10 5 cells per well. The medium consists of Minimum Essential Medium (MEM), with Earle salts, thermally inactivated 10% Fetal Bovine Serum, 2 mM L-glutamine, 21 mM glucose, Penicillin-Streptomycin (100 units per ml) and 25 mM KCl. After 24 hours, the medium is replaced with fresh medium containing 10 μM cytosine arabinoside to inhibit cell division.

Crops should be used at 6-8 DIV. 45Ca2 + training induced by AMPA receptor activation The effects of drugs on 45Ca2 + uptake induced by AMPA receptor activation can be examined in cultures of rat cerebellar granule cells. Cultures are preincubated in 96-well plates, for approximately 3 hours, in medium without serum, and then for 10 minutes in a balanced salt solution without Mg2 + (in mM: NaCl 120, KCL 120, KCl 5, NaH2PO4 0.33, CaCl2 1.8, glucose 22.0 and HEPES 10.0 to pH 7.4) containing 0.5 mM DTT, 10 μM glycine and drugs at a final concentration of 2X. The reaction is started by the rapid addition of an equal volume of the balanced salt solution containing 100 μM of the AMPA receptor agonist kainic acid and 45Ca2 + (final specific activity 250 Ci / mmol). After 10 minutes at 25 ° C, the reaction is stopped by aspirating the solution containing 45Ca2 + and washing the cells 5 times in an ice-cold balanced salt solution containing no added calcium and containing 0.5 mM EDTA. The cells are then lysed by overnight incubation in Triton-X100 ai 0.1% and then the radioactivity in the lysate is determined. All the compounds of the invention that were tested, had IC50 values less than 500 nM. 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, intranasal, parenteral (e.g., intravenous, intramuscular or subcutaneous) or rectal administration, or in a form suitable for administration by inhalation or insufflation. For oral administration, the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl hypromellose).; 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 they may be presented as a dry product to be reconstituted with water or other suitable vehicle before use. Such liquid preparations can be prepared by conventional means with pharmaceutically acceptable additives, such 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, oil esters or ethyl alcohol); and preservatives (e.g., methyl or propyl p-hydroxybenzoate or sorbic acid). For buccal administration, the composition may take the form of tablets or dragees formulated in a conventional manner. For transdermal administration, the composition may take the form of patches, creams, ointments or iontophoresis, formulated in a conventional manner as described in the patents of the United States of America.

United States 5,004,610 or 5,364,630, issued on April 2, 1991 and June 15, November 1994, respectively. The active compounds of the invention can be formulated for parenteral administration by injection, including conventional catheterization or infusion techniques. Formulations for injection may be presented in a unit dosage form, for example, in ampules or multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredient may be in powder form to be reconstituted 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, which contain, for example, conventional suppository bases such as cocoa butter and other glycerides. For intranasal administration or administration by inhalation, the active compounds of the invention are conveniently supplied in the form of a solution or suspension from a container with a spray pump that is tightened or pumped by the patient, or in the form of a spray presentation. of aerosol from a pressurized container or a nebulizer, with the use of a suitable propellant, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by arranging a valve to release a measured quantity. The pressurized container or nebulizer may contain a solution or suspension of the active compound. Capsules and cartridges (made, for example, with gelatin) for use in an inhaler or insufflator, can be formulated so as to contain a powder mixture of a compound of the invention and a suitable powder base such as lactose or starch. A proposed dose of the active compounds of the invention for oral, parenteral or buccal administration to an average adult human, for the treatment of the aforementioned conditions (eg, apoplectic attack), is 0.01 to 20 mg / kg of the active ingredient per dosage unit, which could be administered, for example, from 1 to 4 times a day. Aerosol formulations for the treatment of the above-mentioned conditions (for example, apoplectic attack) in an average adult human being are preferably arranged 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 with an aerosol will be within the range of 100 μg to 10 mg. The administration can be carried out several times a day, for example, 2, 3, 4 or 8 times, for example, 1, 2 or 3 doses each time. The following examples illustrate the preparation of the compounds of the present invention. Commercial reagents were used without further purification. The melting points are uncorrected. All NMR data were recorded at 250, 300 or 400 MHz in deuteriochloroform, unless otherwise specified, reported in parts per million (d) and refer to the deuterium stabilization signal of the solvent in the sample. All non-aqueous reactions were carried out in dry glass containers, with dry solvents, under an inert atmosphere, for reasons of convenience and to maximize yields. Unless otherwise indicated, all reactions were shaken with a magnetic stir bar. Unless otherwise indicated, all mass spectra were performed using chemical impact conditions. The ambient temperature refers to a temperature of 20 to 25 ° C.

EXAMPLE 1 MESYLATE OF (S)-β-FLUORO-3- (2-METHYL-PYRIDIN-3-IL) -2-r2- (2-METHYL-TZAZOL-4-IL) -VINlL1-3H-QUINAZOLIN-4- ONA AND MESILATE OF (R) -6- FLUORO-3- (2-METHYL-PLRIDIN-3-IL-2-r2- (2-METHYL-TIAZOL-4-IL) -VINIL1-3H-QUINAZOLIN-4-ONA Racemic 6-fluoro-3- (2-methyl-pyridin-3-yl) -2- [2- (2-methyl-thiazol-4-yl) -vinyl] -3H-quinazolin-4-one was dissolved. (0.090 g) in 0.1% diethylamine in isopropanol (60 ml) (final concentration 1.5 mg / ml), the solution was applied to a preparative HPLC column (5 x 50 cm Chiralcel AD) and eluted with 85/15 / 0.1 of heptane / isopropanol / diethylamine at a flow rate of 100 ml / min. The eluent was monitored with ultraviolet detection at 265 nM. Two fractions were collected, the first component was centered around an elution time of 60 minutes and the second component around an elution time of 75 minutes. The total time of the cycle for the test was 90 minutes. The eluents of 4 cycles were combined with an elution time of 60 minutes and the mixture was concentrated to give a brown oily solid. The solid was triturated with ether / hexane to yield 0.175 g of a tan powder. This powder was completely dissolved in ethyl acetate (15 ml) stirred magnetically and treated with 1 N methanesulfonic acid in ethyl acetate (0.462 ml, 0.462 mmol). Immediately the precipitation of a salt began. The mixture was stirred for 6 hours, after which the product was collected, rinsed with ethyl acetate and dried to yield 0.144 g of (+) - 6-fluoro-3- (2-methyl-pyridine) mesylate. 3-yl) -2- [2- (2-methyl-thiazol-4-yl) -vinyl] -3H-quinazolin-4-one in the form of a light yellow solid. Melting point 145-146 ° C (The melted material was equilibrated and resolidified.The continued heating produced a second melting range of 210-225 ° C). The product also had: NMR (methane ^) d 9.02 (dd, J = 1.5, 6Hz, 1 H), 8.69 (dd, J = 1.5, 8.3 Hz, 1 H), 8.17 (dd, J = 6, 8.2 Hz , 1 H), 8.01 (d, J = 15 Hz, 1 H), 7.92-7.85 (M, 2H), 7.76 (s, 1 H), 7.72 (dt, J = 3, 8.7 Hz, 1H), 6.58 (d, J = 15 Hz, 1 H), 2.68 (s, 3 H), 2.67 (s, 3 H), 2.63 (s, 3 H); [Ó] D = + 18.9 ° (c = 0.18 in methanol). The eluents of the same four cycles were concentrated with an elution time of 75 minutes and the mixture was converted to the mesylate salt, in the same way, to yield 0.144 g of (-) - 6-fluoro-3- mesylate. 2-methyl-pyridin-3-yl) -2- [2- (2-methyl-thiazol-4-yl) -vinyl] -3H-quinazolin-4-one in the form of a light yellow solid having: [O ] D = -18.3 ° (c = 0.175 in methane). All other physical characteristics were identical to those of the atropisomer.

EXAMPLE 2-7 Examples 2-7 were prepared according to procedures analogous to those of the example.

TABLE 1 EXAMPLE 8-9 All experimental conditions of analytical HPLC separations described below were performed with a Hewlett Packard model 1050 HPLC. The dimensions of the analytical columns were 4.6 mm x 25 cm and the particle size of the stationary phase was 10 microns. All the samples were dissolved in methanol.

(S) -3- (2-CHLORO-PIRiDIN-3-IL) -6-FLUORO-2-r 2 -fl-FUORO-PHENYL) -VINYL-3H-QUINAZOLIN-4-ONA (S) -6-FLUORO-3- (2-METHYL-PIRIDIN-3-IL) -2-r2- (2-METHYL-TIAZOL-4-IL-VINYL1-3H-QUINAZOLIN-4-ONA PREPARATION 1 3- (2-Chlorophenyl) -2-r2- (6-diethylamomethylpyridin-2-yl) -vinyl-6-fluoro-3H-quinazolin-4-one Procedure A 6-Fluoro-2-methylquinoxalin-4-one A solution of 12.95 g (70.0 mmoles) of 2-nitro-5-fluorobenzoic acid in 200 ml of glacial acetic acid and 20 ml of acetic anhydride was treated with 0.625 g of 10% palladium on carbon and reduced to an initial pressure of 54.5 psi (375.764 kPa). The hydrogen uptake was complete after two hours. The catalyst was removed by filtration and the filtrate was heated to reflux for two hours, after which TLC (1: 1 hexane / ethyl acetate) indicated that the reaction was complete. The reaction mixture was evaporated to a semi-crystalline mass which was dissolved in a minimum amount of 2-propanol and stirred in an ice bath for one hour. The crystalline solid was filtered off, washed with a minimum amount of cooled 2-propanol and dried in air to give 5.79 g (46%) of the desired product as a brown solid, m.p. 127.5-128.5 ° C. Slothouwer, J.H., Red. Trav. Chim. Pays-Bas. 33, 336 (1914) describes a synthesis of 5-fluoro-2-nitrobenzoic acid.

Procedure B 3- (2-Chlorophenol) -6-fluoro-2-methyl-4- (3H) -quinazolinone.

A solution of 2.50 g (14.0 mmol) of 6-fluoro-2-methylquinoxalin-4-one and 1.96 g (15.4 mmol) of 2-chloroaniline in about 20 ml of glacial acetic acid was heated to reflux under a nitrogen atmosphere. for 6 hours. The majority of the solvent was evaporated from the cooled reaction mixture and the residues were taken up in ethanol and cooled. After 6 days in the refrigerator, the crystals formed were separated by filtration, washed with a minimum amount of cooled ethanol and air dried to give 1.79 g (44%) of the product, m.p. 137-138 ° C.

Procedure C 6- (2-r3 (2-Chlorophenip-6-fluoro-4-oxo-3,4-dithiazolin-2-yl-vinyl) pyridine-2-carbaldehyde A catalytic amount (approximately 100 mg) of anhydrous zinc chloride was added to a solution of 576 mg (2.0 mmol) of 3- (2-chlorophenyl) -6-fluoro-2-methyl-4 (3H) -quinazolinone and 270 mg (2.0 mmoles) of 2,6-pyridinedicarboxaldehyde in 20-25 ml of dioxane and 1.0 ml of acetic anhydride. The reaction mixture was heated to reflux under a nitrogen atmosphere for 3 hours, until TLC indicated that the starting materials had been consumed. The cooled reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The combined extracts were dried with brine and magnesium sulfate, treated with decolorizing carbon, filtered and the solvent removed to give the desired product. This was taken up in 2: 1 ether / pentane and the crystals were filtered to give 266 mg of the product, 33%, m.p. 247-248 ° C. Papadopoulos, and others, J.Org. Chem. 31, 616 (1966) describe a synthesis of pyridine-2,6-dicarboxaldehyde.

Procedure D 3- (2-Chlorophenyl) -2-r2- (6-diethylaminomethylpyridin-2-yl) -v-nil-6-fluoro-3H-quinazolin-4-one A solution of 65 mg (0.16 mmol) of 6-. { 2- [3- (2-chlorophen? 'I) -6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl) -vinyl) pyridine-2-carbaldehyde in 10 ml of methylene chloride, at Room temperature, under a nitrogen atmosphere, was treated with 3 drops of diethylamine and 73 mg (0.34 mmoles) of sodium triacetoxyborohydride. After stirring for 2.5 hours at room temperature, the solvent was evaporated, the residues were partitioned between dilute hydrochloric acid and ether and stirred for 30 minutes. The ether layer was separated, the aqueous layer was extracted again with ether and the ether extracts were discarded. The aqueous acid solution at a pH of about 14 with 10% sodium hydroxide (cooling with an ice bath) and then extracted twice with ether. The combined ether extracts were dried with brine and with magnesium sulfate and the solvent was evaporated. After an attempt to form the mesylate salt, the treated free base, in ethyl acetate, was treated with 7.5 mg (0.06 mmol) of maleic acid dissolved in a little ethyl acetate. In the resulting solutions, crystals were formed which were filtered and washed with ethyl acetate to give 22 mg of the monomaleate salt, (24%), m.p. 170.5-171.5 ° C.

PREPARATION 2-19 The preparations 2-19 were made according to procedures analogous to those of the preparation.

TABLE 1 PREPARATION 18 NMR: (CDCl 3) d 2.44 (3H, s), 6.83 (1H, D, J = 13), 7.04 (1H, d, J, 7.13 (1H, d, J = 10), 7.50-7.58 (3H, m ), 7.78-7.84 (2H, m), 7.92 (1H, m), (1H, d, J = 10), 8.61 (1H, m).

PREPARATION 19 NMR: (CDCl 3) d 2.09 (3H, s), 6.45 (1 H, D, J = 15), 7.03-7.18 (3H, m), 7.31-7.40 (2H, m), 7.75 (2H, s), 8.14 (1 H, d, J = 15), 8.22-8.71 (3H, m).

PREPARATION 20 6-Fluoro-3- (2-methyl-pyridin-3-yl) -2-r2- (2-methyl-thiazol-4-yl) -vinin-3H-quinazolin-4-one and its salt mesylate In a round-bottomed flask with open flame, anhydrous zinc chloride (2.7 g, 20 mmol) was fused with nitrogen purge. The reaction vessel was allowed to return to room temperature and then dioxane (150 ml) was added: To this mixture were added 6-fluoro-2-methyl-3- (2-methyl-pyridin-3-yl) -3H -quinazolin-4-one (2.6 g, 10 mmol), acetic anhydride (2.8 ml, 30 mmol) and 2-methylthiazole-4-carboxaldehyde (3.7 g, 30 mmol). The reaction was refluxed for 2 hours, then cooled to room temperature and diluted with water. Sodium carbonate was added until mixture was made basic. After the mixture was basic, it was extracted repeatedly with chloroform. The combined chloroform layers were washed with water and brine and finally dried over sodium sulfate and concentrated to a dark residue. This residue was treated with methanol and concentrated (azeotropically distilling all residual chloroform from the residue). This process was repeated until a brown solid formed. The solid was triturated with ether (twice), filtered and dried to produce 3J g (82%) of 6-fluoro-3- (2-methyl-pyridin-3-yl) -2- [2- (2-methyl-thiazol-4-yl) -vinyl] -3H-quinazolin-4 -one in the form of a solid chestnut. Fusion Point: 223-224 ° C. NMR d 8.70 (dd, J = 1.5, 5 Hz, 1 H), 7. 90 (dd, partially obscured, J = 3 Hz, 1 H), 7.89 (d, J = 15 Hz, 1 H), 7.78 (dd, J = 5.9 Hz, 1 H), 7.54 (m, 2H), 7.39 (d, J = 5.8 Hz, 1 H), 7.23 (s, 1 H), 6.57 (d, J = 15 Hz, 1 H), 2.61 (s, 3H), 2.36 (s, 3H). Analysis calculated for C20H15FN4OSO.5 H2O: C, 62.06; H, 4.13; N, 14.58. Found: C, 62.39; H, 3.96; N, 14.33. A sample was dissolved in ethyl acetate and treated with 1 N methanesulfonic acid in ethyl acetate to form the mesylate salt. The precipitate was collected, rinsed with ethyl acetate and dried to produce 6-fluoro-3- (2-methyl-pyridn-3-yl) -2- [2- (2-methyl-thiazole-4-mesylate. il) -vinyl] -3H-quinazolin-4-one in the form of a light yellow solid. Fusion Point: 230-231 ° C. NMR (methanold4) d 9.01 (dd, J = 1.2, 5.8 Hz, 1 H), 8.65 (dd, J = 1.3, 8.2 Hz, 1 H), 8.15 (dd, J = 5.9, 8.2 Hz, 1 H), 8.00 (d, J = 15 Hz, 1 H), 7.88 (m, sim., 2H), 7.71 (m, 2H), 6.56 (d, J) = 15 Hz, 1H), 2.68 (s, 3H), 2.65 (s, 3H), 2.62 (s, 3H). Analysis calculated for C20H15FN4OS CH3SO3H.O.75 H2O: C, 51.69; H, 4.20; N, 11.48. Found: C, 51.80; H, 4.18; N, 11.35.

PREPARATION 21 The compounds indicated in Table 1 were obtained essentially by procedures analogous to those exemplified for preparation 64.

PREPARATION 27 2-Dimethylaminomethylthiazole-4-carboxaldehyde To a suspension of 2-dimethylaminothioacetamide hydrochloride (7.7 g, 50 mmol) in ethanol (100 ml), ethyl bromopyruvate (6.3 ml) was added. The mixture was refluxed for 6 hours and then cooled to room temperature. Additional ethyl bromopyruvate (3.2 ml for a total of 75 mmol) was added and the reaction was heated at reflux for a further 2.5 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between water and ethyl acetate and brought to pH 10 with the addition of solid potassium carbonate. The phases were separated and the aqueous layer was extracted with ethyl acetate. The combined organic phase was washed with water and brine, then dried over sodium sulfate and concentrated to yield an amber oil. This oil was purified by flash chromatography on silica gel (120 g). The elution was carried out as follows: 2% methane / chloroform, 200 ml, fronts; methanol to % / chloroform, 75 ml, nothing; 750 ml, 10.7 g, (100%) of ethyl 2-dlmetllaminomethylthiazole-4-carboxylate in the form of a light yellow oil having: NMR d 8.07 (d, J = 1.4 Hz, 1 H), 4.3 (q, J = 7 Hz, 2H), 3.73 (s, 2H), 2.8 (s, 6H), 1.31 (t, J = 7 Hz, 3H). The material was suitable for use without further purification. To a mixture of lithium aluminum hydride. (4.5 g, 119 mmol) in ice-cold tetrahydrofuran (100 ml) was added dropwise, during 40 minutes, ethyl 2-dimethylaminomethylthiazole-4-carboxylate (8.5 g, 39.7 mmoles in 40 ml of tetrahydrofuran), maintaining an internal temperature of 5-10 ° C. The mixture was stirred at this temperature range for 90 minutes. The reaction was carefully quenched with saturated aqueous ammonium chloride (30 ml). The resulting gray suspension was stirred for 15 minutes and filtered through celite. The layer was washed well with ethyl acetate.

The filtrate was washed with brine and dried over sodium sulfate. The concentration of this organic solution gave 4.2 g, (62%) of 2-dimethylaminomethyl-4-hydroxymethylthiazole in the form of an amber oil having an NMR of 7.12 (s, 1 H), 4.71 (s, 2 H), 3.73 ( s, 2H), 2.50 (s, 1 H), 2.32 (s, 6H).

The material was used without further purification. A solution of 2-dimethylaminomethyl-4-hydroxyethylthiazole (4.2 g, 27.3 mmol) in methylene chloride (200 ml) was treated with Dess-Martin reagent (14.5 g, 34.1 mmol). The mixture was stirred at room temperature for 24 hours. More Dess-Martin reagent (2.9 g) was added and the mixture was stirred for a further 4 hours. The reaction was stopped by the addition of saturated aqueous sodium thiosulfate. (100 ml) and the pH of the resulting mixture was adjusted to 10 by the addition of solid potassium carbonate. The mixture of two phases of filtered. The phases were separated from the filtrate and the aqueous layer was extracted with methylene chloride. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated to yield a yellow solid. This solid was purified by flash chromatography on silica gel (50 x 130 mm) eluting first with chloroform (200 ml) and then with 2% methanol / chloroform, and collecting 25 ml fractions. Fractions 51-80 were combined and concentrated to leave 2.9 g of a milky yellow oil. This oil was triturated with 50% ethereal chloroform and a solid was removed by filtration. The filtrate was concentrated to yield 2.6 g, (62%) of 2-dimethylaminomethyl-thiazole-4-carboxaldehyde as a yellow oil having: NMR d 9.95 (s, 1 H), 8.14 (s, 1 H), 3.81 (s, 2H), 2.36 (s, 6H). This product was used without further purification.

PREPARATION 28 2-Methyloxazole-4-carboxaldehyde Ethyl 2-methyloxaxoline-4-carboxylate was prepared according to the published procedure (Heterocycles, 1976, 4, 1688).

To a room temperature solution of ethyl 2-methyloxaxoine-4-carboxylate (6.28 g, 40 mmol) in benzene (300 ml), copper (I) bromide (6.31 g, 44 mmol) was added and then acetate copper (II) (7.99 g, 44 mmol). To this mixture was added dropwise, for 15 minutes, tertiary butyl perbenzoate (11.4 ml, 60 mmol) and the reaction warmed slightly to the touch. The black mixture was refluxed for 24 hours, cooled to room temperature and filtered through a pad of celite (rinsed with ether). The filtrate was washed with aqueous ammonium chloride, water and brine, then dried over sodium sulfate and concentrated. The brown residue was purified by flash chromatography on silica gel (80 g) eluting with 40% ethyl acetate / hexane. After 100 ml of fronts, 20 ml fractions were collected. Reactions 11-22 were collected and concentrated to yield 4.27 g (69%) of ethyl 2-methyloxazole-4-carboxylate in the form of a yellow oil having: NMR d 8.04 (s, 1 H), 4.32 (q , J = 7 Hz, 2H), 2.46 (s, 3H), 1.33 (t, J = 7 Hz, 3H). This material was used without further purification. A solution of ethyl 2-methyloxazole-4-carboxylate (0.31 g, 2.0 mmol) in tetrahydrofuran was cooled to -65 ° C and diisobutylaluminium hydride (4.1 ml of a 1 N solution) was added dropwise over 15 minutes. in toluene, 4.1 mmol). The solution was allowed to warm to room temperature and was stirred for 15 minutes. The reaction was cooled to 5 ° C and carefully quenched by the addition of methanol (2 mL). The reaction mixture was returned to room temperature and water (0.18 ml) was added followed by sodium fluoride (1.68 g). This mixture was stirred for 30 minutes, then dried with magnesium sulfate and filtered. The filtrate was concentrated and azeotropically distilled with chloroform to yield 0.215 g. (96%) of 4-hydroxymethyl-2-methyloxazole in the form of a clear oil having: NMR d 7.45 (s, 1 H), 4.52 (d, J = 6 Hz, 2H), 3.41 (s a, 1 H), 2.42 (s, 3H). A solution of 4-hydroxymethyl-2-methyloxazole (0.79 g, 6.99 mmol) in methylene chloride (25 ml) was treated with Dess-Martin reagent (8.9 g, 20.97 mmol) and stirred for 24 hours. The reaction was stopped by the addition of saturated aqueous sodium thiosulfate and stirred for 30 minutes. The mixture was filtered. The filtrate was extracted repeatedly with methylene chloride. The combined organic layers were washed with saturated aqueous bicarbonate (twice), water and brine. The organic phase was dried over sodium sulfate and concentrated to an oily white solid. This residue was triturated with ether and filtered. The filtrate was concentrated to yield 0.541 g (69%) of 2-methyloxazole-4-carboxaldehyde as a light yellow solid having: NMR d 9.88 (s, 1 H), 8.15 (s, 1 H), 2.52 ( s, 3H).

PREPARATION 29 The compounds indicated in Table 1 were obtained by procedures essentially the same as those exemplified for Preparation 28. fifteen PREPARATION 34 6-Fluoro-3- (2-methyl-pyridin-3-yl) -2-r2- (2-methylo-thiazol-4-yl) -etin-3H-quinazolin-4-one To a suspension of 10% palladium on carbon (0.15 g) in methanol (12 ml), 6-fluoro-3- (2-methyl-pyridin-3-yl) -2- [2- (2- methyl-thiazol-4-yl) -vinyl] -3H-qulnazolin-4-one (0.075 g, 0.198 mmoies) and ammonium formate (1.2 g, 19 mmol). The mixture was heated to reflux overnight, cooled and filtered through celite. The layer was washed with methanol. The filtrate was concentrated. The residue was partitioned between chloroform and water. The phases were separated and the aqueous layer was extracted with chloroform. The combined organic phase was washed with water and brine, dried over magnesium sulfate and concentrated to yield 0.035 g (47%) of 6-fluoro-3- (2-methyl-pyridin-3-yl) -2- [ 2- (2-methyl-thiazol-4-l) -ethyl] -3H-qulnazolin-4-one as a white solid. Melting point 151-153 ° C; NMR d 8.62 (dd, J = 1.5, 5 Hz, 1 H), 7. 86 (dd, J = 3, 8.5 Hz, 1 H), 7.73 (dd, J = 5.9 Hz, 1 H), 7.49 (dt, J = 3.8 Hz, 1 H), 7.41 (dd, J = 1.5, 8 Hz, 1 H), 7.30 (dd, J = 5.8 Hz, 1 H), 6.70 (s, 1 H), 3.19 (m, 2H), 2.67 (m, 2H), 2.59 (s, 3H), 2.28 (s, 3H).

Claims (19)

NOVELTY OF THE INVENTION CLAIMS

1. - An atropisomer of the formula the wherein each of "A, B and D" is nitrogen or -CH-, with the proviso that only one of "A", "B" and "D" can be nitrogen; wherein n is an integer of one to four carbon atoms of the ring containing "A, B or D", capable of supporting an additional bond, with the proviso that an R5 has to be attached to a carbon atom in ortho position with respect to the ring atom marked with an asterisk; and wherein each R5 can be independently selected from the group consisting of alkyl (CrC6), halogen, trifluoromethyl, amino- (CH2) m-alkylamino (C6C6) - (CH2) m-. dialkyl (C Ce) -amino- (CH 2) m. (C? -C6) alkoxy, hydroxyalkyl (C? -C6) -, (C? -C6) -O-alkyl (C? -C6), -CN, hydroxy- (CH2) m-, alkyl (C1-6) C6) - (C = O) -O-alkyl (C Ce) -, alkyl (C? -C6) -O- (C = O) -O-alkyl (d-Ce), alkyl (CrC6HC = O) - O-, H- (C = O) - (CH2) m, alkyl (C1-Ce) - (C = OHCH2) m-, HO- (C = O) -, (C1-C6) alkyl -O- ( C = O) - (CH2) m-, alkyl (d-CeJ-NH- ^ OMCHa and dialkyl (C? -C6) -N- (CH2) m; and where m is an integer from zero to four. is a phenyl group of the formula Ph2 or a five- or six-membered heterocycle, wherein said 6-membered heterocycle has the formula wherein "N" is nitrogen; wherein said positions of the ring "K", "L", and "M" can be independently selected from carbon and nitrogen, with the proviso that i) only one of "K", "L" and "M" can be nitrogen and ii) when "K", "L" or "M" is nitrogen, then the respective R15, R16 or R17 is absent; where said five-membered heterocycle has the formula wherein said "T" is -CH-, N, NH, O or S; wherein said positions of the ring "P" and "Q" can be independently selected from carbon, nitrogen, oxygen and sulfur; with the proviso that only one of "P", "Q" or "T" can be oxygen or sulfur and at least one of "P", "Q" or "T" must be a heteroatom; where said Ph2 is a group of the formula

R3 is hydrogen, halo, -CN, -NO2, CF3, alkyl (d-C6) or alkoxy (d-C6); R9 is hydrogen, halo, CF3, (C? -C6) alkyl optionally substituted with one to three halogen atoms, alkylthol (d-Cß), amino- (CH2) S-. alkyl (C? -C6) -NH- (CH2) S-, dialkyl (d-C6) -N- (CH2) S-, cycloalkyl (C3-C7) -NH- (CH2) S-, H2N- (C = O) - (CH2) S- (d-C6) alkyl -NH- (C = O) - (CH2) s-, dialkyl (C? -C6) -N- (C = O) - (CH2) S -, (C3-C7) cycloalkyl -NH- (C = O) - (CH2) s-, R13O- (CH2) S-, R13O- (C = O) - (CH2) S-, H (C = O ) -NH- (CH2) s-, alkyl (d-C6) - (C = O) -NH- (CH2) S-, alkyl (C Ce) - (C = O) -N- (CH2) S- , H (C = O) -N- (CH2) s- (C? -C6) alkyl (d-Ce) H- (C = O) - (CH2) s-, (d-C6) alkyl- ( C = O) -, hydroxy, hydroxy-alkyl (d-Ce), alkyl (C? -C6) -O-alkyl (d-C6) or -CN; R10 is hydrogen or halo; R 1 and R 14 are independently selected from hydrogen, halo, CF 3, alkyl (d-Cß) optionally substituted with one to three halogen atoms, alkoxyl (d-Cß) optionally substituted with one to three halogen atoms, alkylthiol ( C1-C6), amino- (CH2) P-, alkyl (d-Ce) -NH- (CH2) s-, diacyl (d-C6) -N- (CH2) p-, cycloalkyl (C3-C7) - NH- (CH2) p-, amino-alkyl (d-CeJ-NH-YCHajp-, alkyl (d-C6) -NH- alkyl (d-C6) -NH- - (CH2) P-, dlalqullo (C C6 ) -N-alkyl (d-C6) -NH- (CH2) P, dialkyl (d-C6) -N-alkyl (d-C6) -N- (CH2) p-, H2N- (C = O) - I (d-C6) alkyl (CH2) P-, (d-C6) alkyl-NH- (C = O) - (CH2) p-, dialkyl (d-C6) -N- (C = O) - ( CH2) P-, cycloalkyl (C3-C7) -NH- (C = O) - (CH2) p-, R13O- (CH2) p-, R13O- (C = O) - (CH2) P-, H ( C = O) -O-, H (C = 0) -0-alkyl (d-C6), H (C = O) -NH- (CH2) P-, alkyl (d-C6) - (C = O ) -NH- (CH2) p-, - CHO, H- (C = O) - (CH2) p-, alkyl (Ci-Ce) - (C = 0) -N- (CH2) p-, H ( C = O) -N- (CH2) p-, HO-alkyl (C? -C6) -II alkyl (CrC6) alkyl (C? -C6) N- (CH2) P-, (C1-C6) alkyl- (C = O) -O- (CH2) p-, amino-alkyl (d-) aikyl (d-Cß) -C6) - (C = O) -O- (CH2) p-, (C? -C6) alkyl -NH- (C1-C6) alkyl- (C = O) -O- ( CH2) p-, dialkyl (d-C6) -N-alkyl (C? -C6) - (C = O) -O- (CH2) p-, alkyl (C? -C6) -NH- alkyl (d- C6) -O- (C = O) - (CH2) p-, dialkyl (d-C6) -N-alkyl (d-C6) -O- (C = O) - (CH2) p-, hydroxy, hydroxy -alkyl (d-C6) -, hydroxy-1-a1-NH- (CH2) p-, alkyl (d-C6) -O-alkyl (C? -C6), -CN, piperidine- (CH2, p-, pyrrolidine (CH2) P -, and 3-pyrroline- (CH2) p-, where said piperidine, pyrrolidine and 3-pyrroline radicals of said piperidine- (CH2) p-, pyrrolidine- (CH2) p-, and 3-pyrroline- (CH2) groups p-, they may be optionally substituted on any of the ring carbon atoms capable of supporting an additional bond, preferably with zero to two substituents, a substituent being independently selected from halo, CF3, alkyl (d-Cß) optionally substituted with each other three halogen atoms, alkoxy (d-Cß) optionally substituted with one to three halogen atoms, alkylthiol (dd.), amino (CH2) P-, alkyl (C? -d >);) -NH- (CH2) P-.dialkyl (d-C6) -N- (CH2) p-, cycloalkyl (C3-C7) -NH- (CH2) P-, amino-alkyl (d-C6) -NH- (CH2) p-, alkyl (C? -Cβ) -NH-alkyl (d-C6) -NH- (CH2) P-, dialkyl

(C? -C6) -N-alkyl (d-C6) -NH- (CH2) P-, alkyl (C? -C6) -O-alkyl (Ci-Ce), dialkyl (C? -C6) -N - alkyl (C? -C6) -N- (CH2) P-, H2N- (C = O) - (CH2) P-, alkyl I alkyl (C? -C6) (C? -C6) -HN- ( C = 0) - (CH2) p-, dialkyl (C1-C6) -N- (C = O) - (CH2) p-, cycloalkyl (C3-C7) -NH- (C = O) - (CH2) p-, R13O- (C = O) - (CH2) p-, H (C = O) -O-, H (C = O) -O-alkyl (d-C6) -, H (C = O) -NH- (CH2) p-, alkyl (d-C6) - (C = O) -NH- (CH2) P-, CHO, H- (C = O) - (CH2) P-, alkyl (d-) C6) - (C = O) -alkyl (d-C6HC = O) -N- (CH2) P-, H (C = O) -N- (CH2) p-, HO-alkyl (d-C6) - alkyl (d-C6) alkyl (d-II alkyl (d-Cß) alkyl (CrC6) N- (CH2) P-, alkyl (d-C6) - (C = O) -O-NH- (CH2) p -, aminoalkyl-alkyl alkyl (d-C6) (C? -C6) - (C = O) -O- (CH2) p-, alkyl (C? -C6) -NJ-alkyl (d-C6) - (C = O) - O- (CH2) p-, dialkyl (C? -C6) -N-alkyl (d-C6) - (C = O) -O- (CH2) p-, hydroxy, hydroxy-alkyl (d-C6), hydroxy-alkyl (C? -C6) -NH_ (CH2) p-, and -CN; R 12 is hydrogen, -CN or halo;

R13 is hydrogen, alkyl (d-C6), alkyl (C1-C6) - (C = O) -, alkyl (C? -C6) -O- (C = O) -, alkyl (d-C6) -NH -alkyl (C C6), dialkyl (C? -C6) -N-alkyl (d- C6) -, alkyl (C6) -NH- (C = O) - or dialkyl (C? -C6) -N- (C = O) -; R15 is hydrogen,

-CN, alkyl (C C6), halo, CF3, -CHO or alkoxy (d-C6); R16 is hydrogen, -CN, alkyl (d-C6), halo, CF3, -CHO or alkoxy (d-C6); R17 is hydrogen, -CN, alkyl (d-C6), amino-alkyl (d-C6), alkyl (d-C6) -NH-alkyl (C? -C6), dialkyl (Cr

C6) -N- (d-C6) alkyl-, halo, CF3, -CHO or alkoxy (d-C6); each p is, independently, an integer from zero to 4 s is an integer from zero to 4; where the dashed link represents an optional double bond; and pharmaceutically acceptable salts of such compounds. 2. A compound according to claim 1, wherein R3 is hydrogen, halo or alkyl (d-C6). 3. A compound according to claim 1, wherein "B" is nitrogen, "A" and "D" are carbons and R5 is hydrogen, halo, -CN, CF3 or alkyl (d-C6). 4. A compound according to claim 1, wherein R5 is chloro or methyl. 5. A compound according to claim 3, wherein n is one and R5 is a substltuent in the ortho position with respect to the carbon marked with an asterisk. 6. A compound according to claim 1, wherein R2 is Ph2 and R9 is fluoro, chloro, -CN or hydroxy; or R10 is -CHO, chloro, fluoro, methyl, alkyl (d-C6) -NH- (CH2) P-, dialkyl (d-C6) -N- (CH2) p-, or cyano.

7. - A compound according to claim 2, wherein R2 and Ph2 and R9 is fluoro, chloro, -CN or hydroxy; or R10 is -CHO, chloro, fluoro, methyl, alkyl (C? -C6) -NH- (CH2) P-, dialkyl (C? -C6) -N- (CH2) p-, or cyano.

8. A compound according to claim 1, wherein R2 is heteroaryl and said heteroaryl is an optionally substituted six-membered heterocycle, wherein "K", "L" and "M" are carbons or "K" and "L" are carbon and "M" is nitrogen, or said heteroaryl is an optionally substituted five-membered heterocycle wherein "T" is nitrogen, "P" is sulfur and "Q" is carbon, "T" is nitrogen or sulfur, "Q" is nitrogen or sulfur and "P" is carbon or "T" is oxygen and "P" and "Q" are, each, a carbon.

9. A compound according to claim 2, wherein R2 is heteroaryl and said heteroaryl is an optionally substituted six-membered heterocycle, wherein "K", "L" and "M" are carbons or "K" and "L" are carbon and "M" is nitrogen, or said heteroaryl is an optionally substituted five-membered heterocycle wherein "T" is nitrogen, "P" is sulfur and "Q" is carbon, "T" is nitrogen or sulfur, "Q" is nitrogen or sulfur and "P" is carbon or "T" is oxygen and "P" and "Q" are, each, a carbon.

10. A compound according to claim 3, wherein R2 is heteroaryl and said heteroaryl is an optionally substituted six-membered heterocycle, wherein "K", "L" and "M" are carbon or "K" and "L" are carbon and "M" is nitrogen, or heteroaryl is an optionally substituted five-membered heterocycle wherein "T" is nitrogen, "P" is sulfur and "Q" is carbon, "T" is nitrogen or sulfur, "Q" is nitrogen or sulfur and "P" is carbon or "T" is oxygen and "P" and "Q" are, each, a carbon.

11. A compound according to claim 1, wherein R2 is an optionally substituted six-membered heterocycle, wherein "K", "L" and "M" are carbons; R 14 is hydrogen, -CHO, chloro, fluoro, methyl, alkyl (C? -C6) -NH- (CH2) P-, d-alkyl (d-C6) -N- (CH2) p- or cyano; R17 is hydrogen, -CHO, chloro, fluoro, methyl, alkyl (d-C6) -NH-alkyl (C? -C6), dialkyl (C? -C6) -N-alkyl (C? -C6) or cyano; or R15 or R16 are, independently, hydrogen, -CHO, chloro, fluoro, methyl pyrrolidine- (CH2) p or cyano.

12. A compound according to claim 1, wherein R2 is an optionally substituted six-membered heterocycle, wherein "K", "L" and "M" are carbons; R14 is hydrogen, -CHO, methyl, alkyl (d-C6) -NH- (CH2) P-, dialkyl (d-C6) -N- (CH2) p-pyrrolidine- (CH2) p- or cyano.

13. A compound according to claim 1, wherein R2 is an optionally substituted five-membered heterocycle wherein "T" is nitrogen, "P" is sulfur and "Q" is carbon; and R14, R15 or R16 are each, independently, hydrogen, chloro, fluoro, methyl or cyano.

14. A compound according to claim 1, wherein R2 is an optionally substituted five-membered heterocycle wherein "T" is nitrogen or sulfur, "Q" is sulfur or nitrogen and "P" is carbon; and R14 or R15 are, independently, hydrogen, chloro, fluoro, methyl or cyano.

15. - A compound according to claim 1, said compound being selected from the group consisting of: (S) -6-fluoro-2- [2- (2-fluoro-phenyl) -vinyl] -3- (2-methyl) -pyridin-3-yl) -3H-quinazolin-4-one; (S) -2-. { 2- [6-fluoro-3- (2-methyl-pyridin-3-yl) -4-oxo-3,4-dihydro-quinazolin-2-yl] -vinyl} -benzonitrile; (S) -2-. { 2- [6-fluoro-3- (2-methylpyridin-3-yl) -4-oxo-3,4-dihydroquinazolin-2-yl] -vinyl} -benzonitrile; (S) -2-. { 2- [3- (2-Chloro-pyridin-3-yl) -6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl] -vinyl} -benzonitrile; (S) -2-. { 2- [6-fluoro-3- (2-methy1-pyridin-3-yl) -4-oxo-3,4-dihydro-quinazolin-2-yl] -vinyl} -4-methyl-benzonitrile; (S) -2- [2- (5-Diethylaminomethyl-2-fluoro-phenyl) -vinyl] -6-fluoro-3- (2-methyl-pyridin-3-yl) -3H-quinazolin-4-one; and (S) -6-fluoro-2- [2- (2-fluoro-5-pyrrolidin-1-ylmethyl-phenyl) -vinyl] -3- (2-methyl-pyridin-3-yl) -3H-quinazolin -4-one.

16. A pharmaceutical composition for treating or preventing a condition selected from brain deficits after cardiac bypass surgery and grafts, stroke, cerebral ischemia, spinal cord trauma, cephalic trauma, Alzheimer's disease, Huntington's disease, sclerosis lateral amyotrophic, epilepsy, AIDS-induced dementia, perinatal hypoxia, hypoxia (such as conditions caused by strangulation, surgery, inhalation of smoke, suffocation, drowning, airway obstruction, electrocution or overdose of drugs or alcohol), cardiac arrest, hypoglycemic neuronal injury, opioid tolerance, withdrawal syndrome (such as that produced by alcoholism and drug addiction, including opioid addiction, cocaine and nicotine), idiopathic and drug-induced Parkinson's disease or cerebral edema; muscle spasms, migraines, urinary incontinence, psychosis, seizures, chronic or acute pain, ocular lesions, retinopathy, retinal neuropathy, tinnitus, anxiety, emesis and tardive dyskinesia, in a mammal, comprising a quantity of a compound according to the claim 1 effective to treat or prevent such a condition, and a pharmaceutically acceptable vehicle.

17. The use of a compound according to claim 1 for the manufacture of a medicament for treating or preventing a condition selected from brain deficits subsequent to cardiac bypass surgery and grafts, stroke, cerebral ischemia, marrow trauma spinal cord, head trauma, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, epilepsy, AIDS-induced dementia, perinatal hypoxia, hypoxia (such as conditions caused by strangulation, surgery, smoke inhalation, asphyxia, drowning, obstruction of the respiratory tract, electrocution or overdose of drugs or alcohol), cardiac arrest, hypoglycaemic neuronal injury, opioid tolerance, withdrawal syndrome (such as that produced by alcoholism and drug addiction, including opiate addiction, cocaine and nicotine ), idiopathic and drug-induced Parkinson's disease or cerebral edema; muscle spasms, migraines, urinary incontinence, psychosis, seizures, chronic or acute pain, ocular lesions, retinopathy, retinal neuropathy, tinnitus, anxiety, emesis and tardive dyskinesia, in a mammal.

18. - A pharmaceutical composition for treating or preventing a condition selected from brain deficits after cardiac bypass surgery and grafts, stroke, cerebral ischemia, spinal cord trauma, head trauma, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis , epilepsy, dementia induced by AIDS, perinatal hypoxia, hypoxia (such as conditions caused by strangulation, surgery, inhalation of smoke, suffocation, drowning, airway obstruction, electrocution or overdose of drugs or alcohol), cardiac arrest, hypoglycaemic neuronal injury, tolerance to opioids, withdrawal syndrome (such as that produced by alcoholism and drug addiction, including opioid addiction, cocaine and nicotine), Idiopathic and drug-induced cerebral palsy or cerebral edema; muscle spasms, migraines, urinary incontinence, psychosis, seizures, chronic or acute pain, ocular lesions, retinopathy, retinal neuropathy, tinnitus, anxiety, emesis and tardive dyskinesia, in a mammal, comprising an effective amount to antagonize the AMPA receptor of a compound according to claim 1, and a pharmaceutically acceptable carrier.

19. The use of an effective amount for antagonizing the AMPA receptor of a compound according to claim 1 for the manufacture of a medicament for treating or preventing a condition selected from brain deficits subsequent to cardiac bypass surgery and grafts, apoplectic attack, cerebral ischemia, spinal cord trauma, head trauma, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, epilepsy, AIDS-induced dementia, perinatal hypoxia, hypoxia (such as conditions caused by strangulation, surgery, inhalation of smoke, suffocation, drowning, obstruction of the respiratory tract, electrocution or overdose of drugs or alcohol), cardiac arrest, hypoglycaemic neuronal injury, opioid tolerance, withdrawal syndrome (such as that produced by alcoholism and drug addiction) , including opiate addiction, cocaine and nicotine), idiopathic Parkinson's disease and induced by drugs or cerebral edema; muscle spasms, migraines, urinary incontinence, psychosis, seizures, chronic or acute pain, ocular lesions, retinopathy, retinal neuropathy, tinnitus, anxiety, emesis and tardive dyskinesia, in a mammal.