 Novel 2,3 disubstituted-4(3h)-quinazolinones
专利摘要:
PURPOSE: A 2,3 disubstituted-4(3H)-quinazolinones compound is provided to treat a tolerance to opium, an uneasiness, and vomiting and to reduce the damage of nerve system being related to the disorders. CONSTITUTION: The present invention relates to novel 2,3 disubstituted-4(3H)-quinazolinones compounds of formula (I), and their pharmaceutically acceptable salts, and pharmaceutical compositions and methods of treating neurodegenerative and CNS-trauma related conditions. 公开号:KR20000011054A 申请号:KR1019980709205 申请日:1997-02-17 公开日:2000-02-25 发明作者:마크 레오나드 엘리옷트；윌라드 맥코완 쥬니어 웰치 申请人:스피겔 알렌 제이；화이자 인코포레이티드； IPC主号:
专利说明:
Novel 2,3-Disubstituted-4 (3-H) -quinazolinones Compounds of the invention are effective AMPA receptor antagonists. AMPA receptors are a subspecies of glutamate receptors, identified by their ability to bind α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and postsynaptic to excitatory amino acids It is included as a neurotransmitter receptor. The role of stimulating amino acids such as glutamic acid and aspartic acid is well established as the main mediator of stimulating synaptic transmission in the central nervous system. Watkins and Evans, Ann. Rev. Pharmacol. Toxicol., 21, 165 (1981), Monaghan, Bridges and Cotman, Ann. Rev. Pharmacol. Toxicol., 29, 365 (1989), Watkins, Krogsgaard-Larsen and Honore, Trans. Pharm. Sci., 11, 25 (1990). These amino acids function primarily in synaptic transmission via stimulatory amino acid receptors. These amino acids and their receptors also function in various other physiological processes such as motor control, respiration, cardiovascular control, sensory perception, and perception. Stimulating amino acid receptors fall into two general forms. The receptor that directly binds to the opening of the cation channel in the cell membrane of neurons is called "ionotropic". Receptors of this type include N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and carboxylic acid (KA), which are selective agents It is divided into three or more subforms defined by the polarization action of. The second general form is a G-protein or messenger-linked "metabotropic" stimulatory amino acid receptor. This second form prevents phosphoinosoltide hydrolysis in postsynaptic cells when activated by the agonist quisculate, ibothenate or trans-1-aminocyclopentane-1,3-dicarboxylic acid. Increase. Both receptors appear to act not only to mediate normal synaptic transmission along the stimulation pathway, but also to alter synaptic connections during the evolution and evolution of the efficacy of synaptic transmission throughout life. Seechopp, Bockaert and Sladeczek, Trends in Pharmacol. Sci., 11, 508 (1990), McDonald and Johnson, Brain Research Reviews, 15, 41 (1990). Excessive or inappropriate stimulation of the stimulatory amino acid receptors damages or loses nerve cells by a mechanism known as excitatory toxicity. This process has been suggested to mediate neuronal degeneration in various situations. Due to the medical consequences of these neurodegenerations, reducing these degenerative nervous system processes has become an important therapeutic goal. Stimulating amino acid excitatory toxicity is involved in the pathophysiology of many nervous system disorders. Excitatory toxicity may include cardiac defects, seizures, cerebral ischemia, spinal cord trauma, head trauma, Alzheimer's disease, Huntington's chorea, amyotrophic lateral sclerosis, epilepsy, AIDS dementia, hypoxia at birth, and hypoxia (e.g. , Fluid, surgery, inhalation of cigarette smoke, asphyxiation, drowning, choking, electroporation, or overdose of drugs or alcohol, heart failure, hypoglycemic nerve damage, eye damage, retinal disorders, idiopathic And pathophysiology of acute and chronic neurodegenerative conditions, including drug Parkinson's disease. Other nervous system conditions caused by glutamate dysfunction require neural coordination. Other nervous system conditions include muscle spasms, migraine headaches, urinary incontinence, psychosis, stop addiction (eg alcoholism and drug addiction, including opiates, cocaine and nicotine addiction), opiate resistance, anxiety, vomiting, brain edema, chronic pain, cramps, Retinal neuropathy, tinnitus, or delayed dyskinesia. The use of neuroprotective agents, such as AMPA receptor antagonists, appears to be useful for treating the disorder and / or reducing the amount of neurological damage associated with the disorder. EAA antagonists are also useful as anesthetics. Several studies have shown that AMPA receptors are neuroprotective in focal ischemia and overall ischemia models. NBQX (2,3-dihydroxy-6-nitro-7-sulfamoylbenzo [f-] quinoxaline), a competitive AMPA receptor antagonist, has been reported to be effective in preventing total ischemia and lesional ischemic damage. Sheardown et al. (Science, 247, 571 (1900)), Buchan et al. (Neuroreport, 2, 473 (1991)), Le Peillet et al., Brain Research, et al. 571, 115 (1992). The uncompetitive AMPA receptor antagonist GKYI 52466 has been reported to be an effective neuroprotective agent in the rat ischemic model. See Leave et al., Brain Research, 571, 115 (1992). These studies strongly suggest that delayed neurodegeneration of cerebral ischemia includes glutamate excitatory toxicity mediated at least in part by AMPA receptor activity. Thus, AMPA receptor antagonists prove to be useful as neuroprotective agents and enhance the neurological consequences of human cerebral ischemia. Summary of the Invention The present invention relates to bicyclic compounds of formula (I) and pharmaceutically acceptable salts thereof: Where R 1 is optionally substituted phenyl of the formula Ph 1 or heteroaryl selected from the group consisting of pyridin-2-yl, pyridin-3-yl and pyridin-4-yl, wherein the heteroaryl is capable of forming further bonds Hydrogen on any ring carbon atom, (C 1 -C 6 ) alkyl, halogen, trifluoromethyl, amino- (CH 2 ) n- , (C 1 -C 6 ) alkylamino- (CH 2 ) n- , Di (C 1 -C 6 ) alkyl-amino- (CH 2 ) n- , (C 1 -C 6 ) alkoxy, hydroxy (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkyl-O- (C 1 -C 6) alkyl, -CN, (C 1 -C 6 ) alkyl, -COO- (C 1 -C 6) alkyl -, (C 1 -C 6) alkyl, -O-COO- (C 1 - C 6 ) alkyl-, (C 1 -C 6 ) alkyl-COO-, hydroxy, HC (═O)-, (C 1 -C 6 ) alkyl-C (= 0)-(CH 2 ) n- , HO-C (= 0)-(CH 2 ) n- , (C 1 -C 6 ) alkyl-OC (= 0)-(CH 2 ) n- , NH 2 -C (= 0)-(CH 2 ) n -, (C 1 -C 6 ) alkyl, -NH-C (= O) - (CH 2) n - , and di (C 1 -C 6) alkyl, -NH-C (= O) - (CH 2) n Optionally substituted up to 3 per ring with a substituent selected from the group consisting of Can be] Ph 1 is a chemical formula Is the flag of, R 2 is phenyl of the formula Ph 2 or a 5 or 6 membered heterocycle, The six-membered heterocycle is represented by the formula Wherein "N" is nitrogen and ring positions "K", "L" and "M" may be independently selected from the group consisting of carbon and nitrogen, provided i) "K", "L" or " Only one of M "may be nitrogen and ii) each of R 15 , R 16 or R 17 is absent when" K "," L "or" M "is nitrogen), The 5-membered heterocycle is represented by the formula Wherein “T” is —CH—, N, NH, O or S, and ring positions “P” and “Q” may be independently selected from the group consisting of carbon, nitrogen, oxygen and sulfur, provided that “P” "Only one of", "Q" or "T" may be oxygen or sulfur and at least one of "P", "Q" or "T" must be heteroatom, and The Ph 2 is the following formula With R 3 is hydrogen, halo, —CN, —NO 2 , CF 3 , (C 1 -C 6 ) alkyl or (C 1 -C 6 ) alkoxy, R 5 is hydrogen, (C 1 -C 6 ) alkyl, halo, CF 3 , (C 1 -C 6 ) alkoxy or (C 1 -C 6 ) alkylthiol, R 6 is hydrogen or halo, R 7 is hydrogen or halo, R 8 is hydrogen or halo, R 9 is hydrogen, halo, CF 3 , (C 1 -C 6 ) alkyl optionally substituted with 1 to 3 halogen atoms, (C 1 -C 6 ) alkoxy optionally substituted with 1 to 3 halogen atoms, (C 1- C 6 ) alkylthiol, amino- (CH 2 ) s- , (C 1 -C 6 ) alkyl-NH- (CH 2 ) s- , di (C 1 -C 6 ) alkyl-N- (CH 2 ) s -, (C 3 -C 7 ) cycloalkyl-NH- (CH 2 ) s- , H 2 N- (C═O)-(CH 2 ) s- , (C 1 -C 6 ) alkyl-HN- ( C═O) — (CH 2 ) s- , di (C 1 -C 6 ) alkyl-N- (C═O)-(CH 2 ) s- , (C 3 -C 7 ) cycloalkyl-NH- ( C = O)-(CH 2 ) s- , R 13 O- (CH 2 ) s- , R 13 O- (C = O)-(CH 2 ) s- , H (O = C) -NH- ( CH 2 ) s- , (C 1 -C 6 ) alkyl- (O = C) -NH- (CH 2 ) s- , (C 1 -C 6 ) alkyl- (C═O)-, hydroxy, hydroxy- (C 1 -C 6 ) alkyl-, (C 1 -C 6 ) alkyl-O- (C 1 -C 6 ) Alkyl- and -CN, R 10 and R 14 are independently hydrogen, halo, CF 3 , (C 1 -C 6 ) alkyl optionally substituted with 1 to 3 halogen atoms, (C 1 -C 6 ) alkoxy optionally substituted with 1 to 3 halogen atoms , (C 1 -C 6 ) alkylthiol, amino- (CH 2 ) p- , (C 1 -C 6 ) alkyl-NH- (CH 2 ) p- , di (C 1 -C 6 ) alkyl-N- (CH 2 ) p- , (C 3 -C 7 ) cycloalkyl-NH- (CH 2 ) p- , amino- (C 1 -C 6 ) alkyl-NH- (CH 2 ) p- , (C 1- C 6 ) alkyl-NH- (C 1 -C 6 ) alkyl-NH- (CH 2 ) p- , di (C 1 -C 6 ) alkyl-N- (C 1 -C 6 ) alkyl-NH- (CH 2 ) p- , (C 1 -C 6 ) alkyl-HN- (C═O)-(CH 2 ) p- , di (C 1 -C 6 ) alkyl-N- (C═O)-(CH 2 ) p- , ( C 3 -C 7 ) cycloalkyl-NH- (C═O)-(CH 2 ) p- , R 13 O- (CH 2 ) p- , R 13 O- (C = O)-(CH 2 ) p -, H (O = C) -O-, H (O = C) -O- (C 1 -C 6) alkyl -, H (O = C) -NH- (CH 2) p -, (C 1 -C 6 ) alkyl- (O = C) -NH- (CH 2 ) p- , -CHO, H- (C = O)-(CH 2 ) p- , Amino - (C 1 -C 6) alkyl, - (C = O) -O- ( CH 2) p -, (C 1 -C 6) alkyl, -NH- (C 1 -C 6) alkyl, - (C = O ) -O- (CH 2 ) p- , di (C 1 -C 6 ) alkyl-N- (C 1 -C 6 ) alkyl- (C = O) -O- (CH 2 ) p- , amino- ( C 1 -C 6 ) alkyl-O- (C═O) -O- (CH 2 ) p- , (C 1 -C 6 ) alkyl-NH- (C 1 -C 6 ) alkyl-O- (C = O)-(CH 2 ) p- , di (C 1 -C 6 ) alkyl-N- (C 1 -C 6 ) alkyl-O- (C = O)-(CH 2 ) p- , hydroxy, hydroxide Hydroxy- (C 1 -C 6 ) alkyl, hydroxy- (C 1 -C 6 ) alkyl-NH- (CH 2 ) p- , (C 1 -C 6 ) alkyl-O- (C 1 -C 6 ) Alkyl-, -CN, piperidine- (CH 2 ) p- , pyrrolidine- (CH 2 ) p -and 3-pyrroline- (CH 2 ) p- , wherein piperi Piperidine, pyrrolidine and 3-pyrroline of the din- (CH 2 ) p- , pyrrolidine- (CH 2 ) p -and 3-pyrroline- (CH 2 ) p -residues halo, CF 3, 1 to 3 of halogen atoms, optionally substituted (C 1 -C 6) alkyl, one to three halogen atoms, form a (C 1 -C 6) substituted on any ring carbon atom capable of supporting an alkoxyl , (C 1 -C 6) alkylthio, amino, - (CH 2) p -, (C 1 -C 6) alkyl, -NH- (CH 2) p -, di (C 1 -C 6) alkyl, -N- (CH 2 ) p- , (C 3 -C 7 ) cycloalkyl-NH- (CH 2 ) p- , amino- (C 1 -C 6 ) alkyl-NH- (CH 2 ) p- , (C 1- C 6 ) alkyl-NH- (C 1 -C 6 ) alkyl-NH- (CH 2 ) p- , di (C 1 -C 6 ) alkyl-N- (C 1 -C 6 ) al H 2 N- (C═O)-(CH 2 ) p- , (C 1 -C 6 ) alkyl-HN- (C═O)-(CH 2 ) p- , di (C 1 -C 6 ) alkyl -N- (C = O)-(CH 2 ) p- , (C 3 -C 7 ) cycloalkyl-NH- (C = O)-(CH 2 ) p- , R 13 O- (CH 2 ) p R 13 O— (C═O) — (CH 2 ) p −, H (O═C) —O—, H (O═C) —O— (C 1 -C 6 ) alkyl-, H ( O = C) -NH- (CH 2 ) p- , (C 1 -C 6 ) alkyl- (O = C) -NH- (CH 2 ) p- , -CHO, H- (C = O)-( CH 2) p -, (C 1 -C 6) alkyl, - (C = O) -, (C 1 -C 6 ) alkyl- (C═O) -O-NH- (CH 2 ) p- , amino- (C 1 -C 6 ) alkyl- (C = 0) -O- (CH 2 ) p -, (C 1 -C 6) alkyl, -NH- (C 1 -C 6) alkyl, - (C = O) -O- ( CH 2) p -, di (C 1 -C 6) alkyl, -N- ( C 1 -C 6 ) alkyl- (C═O) -O- (CH 2 ) p- , hydroxy, hydroxy- (C 1 -C 6 ) alkyl-, hydroxy- (C 1 -C 6 ) alkyl Optionally substituted with a substituent independently selected from the group consisting of -NH- (CH 2 ) p -and -CN, R 11 is hydrogen or halo, R 12 is hydrogen, —CN or halo, R 13 is hydrogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkyl- (C═O)-, (C 1 -C 6 ) alkyl-O- (C═O)-, (C 1- C 6 ) alkyl-NH- (C═O)-or di (C 1 -C 6 ) alkyl-N- (C═O)-, R 15 is hydrogen, —CN, (C 1 -C 6 ) alkyl, halo, CF 3 , —CHO or (C 1 -C 6 ) alkoxy, R 16 is hydrogen, —CN, (C 1 -C 6 ) alkyl, halo, CF 3 , —CHO or (C 1 -C 6 ) alkoxy, R 17 is hydrogen, —CN, (C 1 -C 6 ) alkyl, amino- (C 1 -C 6 ) alkyl-, (C 1 -C 6 ) alkyl-NH- (C 1 -C 6 ) alkyl-, Di (C 1 -C 6 ) alkyl-N- (C 1 -C 6 ) alkyl-, halo, CF 3 , -CHO or (C 1 -C 6 ) alkoxy, n is an integer from 0 to 3, Each p is independently an integer from 0 to 3, s is an integer from 0 to 4, Dotted line represents any double bond, but i) when R 9 is hydrogen, one of R 11 and R 12 is not hydrogen; ii) when R 1 is unsubstituted phenyl and R 3 is hydrogen, (a) R 2 cannot be unsubstituted phenyl, thienyl or furyl, or (b) R 9 and R 11 are hydrogen or R 9 or When R 12 cannot be Cl or hydroxy or (c) R 9 and R 12 are hydrogen, R 10 or R 11 cannot be chloro, iii) when R 3 is hydrogen, R 6 , R 7 and R 8 are hydrogen and R 5 is chloro or methyl, (a) R 2 may not be unsubstituted phenyl, thienyl or furyl or (b) R 10 or R 11 may not be chloro or (c) R 9 or R 12 may not be hydroxy, methyl or methoxy, iv) when R 3 is hydrogen or chloro, R 5 is methyl, R 6 , R 7 and R 8 are hydrogen and K, L and M are carbon, then (a) one of R 14 to R 17 is hydrogen Or (b) R 17 is not hydrogen or methyl, v) when R 1 is unsubstituted pyridin-2-yl and R 3 is hydrogen, bromo or iodine, then R 2 cannot be unsubstituted phenyl, vi) when R 7 is chloro, R 5 , R 6 and R 8 are hydrogen, and R 3 is hydrogen, (a) R 2 may not be unsubstituted phenyl, pyridyl, thienyl or furyl (b ) R 9 or R 12 may not be hydroxy when R 10 and R 11 are hydrogen, vii) when R 2 is unsubstituted phenyl, R 6 , R 7 and R 8 are hydrogen, and R 3 is hydrogen, R 5 cannot be —CO 2 H, viii) when R 2 is unsubstituted pyridin-2-yl, R 5 and R 7 are hydrogen, and R 3 is hydrogen, then R 6 or R 8 must not be chloro, ix) If R 2 is unsubstituted phenyl, R 3 is hydrogen, and R 5 and R 7 are hydrogen, then R 6 or R 8 must not be chloro. The invention also relates to pharmaceutically acceptable acid addition salts of compounds of formula (I). Acids used to prepare pharmaceutically acceptable acid addition salts of the aforementioned basic compounds of the present invention are non-toxic acid addition salts, ie salts containing pharmaceutically acceptable anions such as hydrochloride, hydrobromide, hydroiodide , Nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, malate, fumarate, gluconate, saccharide, benzoate , Salts of methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [ie, 1,1'-methylene-bis- (2-hydroxy-3-naphthoate)] It is. The present invention also relates to base addition salts of formula (I). Chemical bases that can be used as reagents to prepare pharmaceutically acceptable base salts of compounds of formula (I) that are acidic in nature are those that form non-toxic base salts with the compounds. Such non-toxic base salts include alkali metal cations (eg potassium and sodium), alkaline earth metal cations (eg calcium and magnesium), ammonium or water soluble amine addition salts (eg N-methylglucamine (meglumine)), lower levels Alkanolammonium and other base salts of pharmaceutically acceptable organic amines. Preferred compounds of formula (I) are those wherein R 3 is fluoro or chloro. Preferred compounds of formula I, wherein R 1 is Ph 1 , wherein one of R 5 , R 6 , R 7 or R 8 is fluoro, bromo, chloro, methyl or trifluoromethyl, preferably R 5 is fluoro Or bromo, chloro, methyl or trifluoromethyl. Most preferred compounds of formula (I) wherein R 1 is Ph 1 are those compounds wherein R 5 is chloro or methyl. Preferred compounds of formula (I) wherein R 1 is heteroaryl, most preferably, heteroaryl is optionally substituted with halo, —CN, CF 3 or (C 1 -C 6 ) alkyl, more preferably with chloro or methyl Preferably pyridin-3-yl substituted at the 2-position. Preferred compounds of formula (I) wherein R 2 is Ph 2 are those wherein R 9 is fluoro, chloro, -CN or hydroxy or R 10 is -CHO, chloro, fluoro, methyl, (C 1 -C 6 ) alkyl-NH -(CH 2 ) p- , di (C 1 -C 6 ) alkyl-N- (CH 2 ) p -or cyano. Most preferred compounds of formula (I) wherein R 2 is Ph 2 , are those wherein R 9 is fluoro or —CN or R 10 is methyl, (C 1 -C 6 ) alkyl-NH— (CH 2 ) p −, di (C 1) -C 6 ) alkyl-N- (CH 2 ) p -or cyanoin. Preferred compounds of formula (I) wherein R 2 is heteroaryl, wherein said heteroaryl is "K", "L" and "M" are carbon (ie pyridin-2-yl) or "K" and "L" are carbon Optionally substituted 6-membered heterocycle where M "is nitrogen (ie pyrimidin-2-yl) or said heteroaryl is" T "is nitrogen and" P "is sulfur and" Q "is carbon (ie 1 , 3-thiazol-4-yl) "T" is nitrogen or sulfur and "Q" is nitrogen or sulfur and "P" is carbon (ie 1,3-thiazol-2-yl) or "T" is Oxygen and “P” and “Q” are each carbon (ie, fur-2-yl). Preferred compounds of formula (I) wherein R 2 is optionally substituted 6-membered heterocycle (ie pyridin-2-yl) in which "K", "L" and "M" are carbon, are those in which R 14 is hydrogen, -CHO, chloro, Fluoro, methyl, (C 1 -C 6 ) alkyl-NH- (CH 2 ) p- , di (C 1 -C 6 ) alkyl-N- (CH 2 ) p -or cyano or R 17 is hydrogen , -CHO, chloro, fluoro, methyl, (C 1 -C 6 ) alkyl-NH- (C 1 -C 6 ) alkyl-, di (C 1 -C 6 ) alkyl-N- (C 1 -C 6 Alkyl- or cyano, or R 15 and R 16 are independently hydrogen, -CHO, chloro, fluoro, methyl or cyano. R 2 is "K", "L" and "M" are carbon in the 6 membered heterocycle optionally substituted (i.e., pyridine-2-yl), the most preferred compounds of formula I R 14 is hydrogen, -CHO, methyl , (C 1 -C 6 ) alkyl-NH- (CH 2 ) p- , di (C 1 -C 6 ) alkyl-N- (CH 2 ) p -or cyano. A preferred compound of formula (I) wherein R 2 is “T” is nitrogen, “P” is sulfur and “Q” is carbon (ie 1,3-thiazol-2-yl) is an optionally substituted 5 membered heterocycle wherein R is 14 , R 15 or R 16 are each independently hydrogen, chloro, fluoro, methyl or cyano. Preferred Formula I, wherein R 2 is “T” is nitrogen or sulfur and “Q” is sulfur or nitrogen and “P” is carbon (ie 1,3-thiazol-2-yl) optionally substituted 5-membered heterocycle Is a compound wherein R 14 or R 15 is independently hydrogen, chloro, fluoro, methyl or cyano. Specific preferred compounds of the invention are as follows: 3- (2-chloro-phenyl) -2- [2- (5-diethylaminomethyl-2-fluoro-phenyl) -vinyl] -6-fluoro-3H-quinazolin-4-one; 3- (2-chloro-phenyl) -2- [2- (6-diethylaminomethyl-pyridin-2-yl) -vinyl] -6-fluoro-3H-quinazolin-4-one; 3- (2-Chloro-phenyl) -2- [2- (4-diethylaminomethyl-pyridin-2-yl) -vinyl] -6-fluoro-3H-quinazolin-4-one; 3- (2-chloro-phenyl) -2- [2- (6-ethylaminomethyl-pyridin-2-yl) -vinyl] -6-fluoro-3H-quinazolin-4-one; 3- (2-Bromo-phenyl) -2- [2- (6-diethylaminomethyl-pyridin-2-yl) -vinyl] -6-fluoro-3H-quinazolin-4-one; 3- (2-Chloro-phenyl) -6-fluoro-2- [2- (6-methoxymethyl-pyridin-2-yl) -vinyl] -3 H-quinazolin-4-one; 6-fluoro-3- (2-methyl-pyridin-3-yl) -2- [2- (2-methyl-thiazol-4-yl) -vinyl] -3H-quinazolin-4-one; 3- (2-Chloro-phenyl) -6-fluoro-2- [2- (4-methyl-pyrimidin-2-yl) -vinyl] -3 H-quinazolin-4-one; 3- (2-Chloro-phenyl) -6-fluoro-2- {2- [6- (isopropylamino-methyl) -pyridin-2-yl] -ethyl} -3 H-quinazolin-4-one; And 2- [2- (5-Diethylaminomethyl-2-fluoro-phenyl) -vinyl] -6-fluoro-3- (2-methyl-pyridin-3-yl) -3H-quinazolin-4- On. Other specific compounds of the present invention are as follows: 6-fluoro-3- (3-methyl-pyrazin-2-yl) -2- (2-pyridin-2-yl-vinyl) -3H-quinazolin-4-one; 6-fluoro-3- (4-methyl-pyridin-3-yl) -2- (2-pyridin-2-yl-vinyl) -3H-quinazolin-4-one; 3- (2-chloro-phenyl) -6-fluoro-2- (2-pyridin-2-yl-vinyl) -3H-quinazolin-4-one; 3- (2-bromo-phenyl) -2- (2-pyridin-2-yl-vinyl) -3H-quinazolin-4-one; 6-chloro-2- (2-pyridin-2-yl-vinyl) -3-o-tolyl-3H-quinazolin-4-one; 3- (2-Chloro-phenyl) -2- [2- (6-methyl-pyridin-2-yl) -vinyl] -3 H-quinazolin-4-one; 6-chloro-2- [2- (6-methyl-pyridin-2-yl) -vinyl] -3-o-tolyl-3H-quinazolin-4-one; 3- (2-chloro-phenyl) -6-fluoro-2- (2-pyridin-2-yl-ethyl) -3H-quinazolin-4-one; 6- {2- [3- (2-Chloro-phenyl) -6-fluoro-4-oxo-3,4-dihydro-quinazolin-2-yl] -vinyl} -pyridine-2-carbaldehyde; 3- (2-Chloro-phenyl) -6-fluoro-2- [2- (6-methylaminomethyl-pyridin-2-yl) -vinyl] -3 H-quinazolin-4-one; N- (6- {2- [3- (2-Chloro-phenyl) -6-fluoro-4-oxo-3,4-dihydro-quinazolin-2-yl] -vinyl} -pyridine-2- Monomethyl) -N-methyl-acetamide; 6- {2- [3- (2-Chloro-phenyl) -6-fluoro-4-oxo-3,4-dihydro-quinazolin-2-yl] -vinyl} -pyridine-2-carbonitrile; 3- (2-fluoro-phenyl) -2- (2-pyridin-2-yl-vinyl) -3H-quinazolin-4-one; 3- (2-Bromo-phenyl) -6-fluoro-2- (2-pyridin-2-yl-vinyl) -3H-quinazolin-4-one; 3- (4-bromo-2-chloro-phenyl) -6-fluoro-2- (2-pyridin-2-yl-vinyl) -3H-quinazolin-4-one; 3- (2-Chloro-phenyl) -2- [2- (6-diethylaminomethyl-pyridin-2-yl) -vinyl] -3 H-quinazolin-4-one N- (6- {2- [3- (2-Chloro-phenyl) -6-fluoro-4-oxo-3,4-dihydro-quinazolin-2-yl] -vinyl} -pyridine-2- Monomethyl) -N-ethyl-acetamide; 3- (2-Chloro-phenyl) -6-fluoro-2- [2- (6-fluoromethyl-pyridin-2-yl) -vinyl] -3 H-quinazolin-4-one; 3- (2-Chloro-phenyl) -6-fluoro-2- [2- (6-pyrrolidin-1-ylmethyl-pyridin-2-yl) -ethyl] -3 H-quinazolin-4-one ; 3- (2-Chloro-phenyl) -2- [2- (6-{[ethyl- (2-hydroxy-ethyl) -amino] -methyl} -pyridin-2-yl) -vinyl] -6-fluor Rho-3H-quinazolin-4-one; 3- (2-Chloro-phenyl) -6-fluoro-2- {2- [6- (isopropylamino-methyl) -pyridin-2-yl) -vinyl} -3 H-quinazolin-4-one; 3- (2-Chloro-phenyl) -6-fluoro-2- {2- [6- (2-methyl-piperidin-1-ylmethyl) -pyridin-2-yl] -vinyl} -3H- Quinazolin-4-ones; 3- (2-chloro-phenyl) -2- [2- (6-ethoxymethyl-pyridin-2-yl) -vinyl] -6-fluoro-3H-quinazolin-4-one; 3- (2-Chloro-phenyl) -2- {2- [6- (2,5-dihydro-pyrrol-1-ylmethyl) -pyridin-2-yl] -vinyl} -6-fluoro-3H -Quinazolin-4-ones; 3- (2-Chloro-phenyl) -6-fluoro-2- {2- [6- (4-methyl-piperidin-1-ylmethyl) -pyridin-2-yl] -vinyl} -3H- Quinazolin-4-ones; 6-bromo-2- [2- (6-methyl-pyridin-2-yl) -vinyl] -3-o-tolyl-3H-quinazolin-4-one; 6-bromo-2- (2-pyridin-2-yl-vinyl) -3-o-tolyl-3H-quinazolin-4-one; 6-fluoro-3- (2-fluoro-phenyl) -2- (2-pyridin-2-yl-vinyl) -3H-quinazolin-4-one; 1-benzyl-5- (2-methyl- [1,3] -dioxolan-2-yl) -2-oxo-2,3-dihydro-1H-indole-3-carboxylic acid (3-phenylcarbamoyl- Phenyl) -amide; 3- (2-chloro-phenyl) -6-methyl-2- (2-pyridin-2-yl-vinyl) -3H-quinazolin-4-one; 3- (2-chloro-phenyl) -2- [2- (6-dimethylaminomethyl-pyridin-2-yl) -vinyl] -6-fluoro-3H-quinazolin-4-one; 6-fluoro-3- (2-fluoro-phenyl) -2- [2- (6-methyl-pyridin-2-yl) -vinyl] -3H-quinazolin-4-one; 3- (2-Chloro-phenyl) -2- [2- (6-{[(2-dimethylamino-ethyl) -methyl-amino] -methyl} -pyridin-2-yl) -vinyl] -6-fluoro Rho-3H-quinazolin-4-one; 3- (2-Chloro-phenyl) -6-fluoro-2- [2- (6-hydroxymethyl-pyridin-2-yl) -vinyl] -3 H-quinazolin-4-one; Acetic acid 6- {2- [3- (2-chloro-phenyl) -6-fluoro-4-oxo-3,4-dihydro-quinazolin-2-yl] -vinyl} -pyridin-2-ylmethyl ester; 6- {2- [3- (2-Bromo-phenyl) -6-fluoro-4-oxo-3,4-dihydro-quinazolin-2-yl] -vinyl} -pyridine-2-carbaldehyde ; 3- (2-Bromo-phenyl) -2- [2- (6-diethylaminomethyl-pyridin-2-yl) -vinyl] -3 H-quinazolin-4-one; Acetic acid 6- {2- [3- (2-bromo-phenyl) -6-fluoro-4-oxo-3,4-dihydro-quinazolin-2-yl] -vinyl} -pyridin-2-yl Methyl esters; Diethylamino acetic acid 6- {2- [3- (2-chloro-phenyl) -6-fluoro-4-oxo-3,4-dihydro-quinazolin-2-yl] -vinyl} -pyridine-2 Monomethyl ester; 3- (2-chloro-phenyl) -2- [2- (6-difluoromethyl-pyridin-2-yl) -vinyl] -6-fluoro-3H-quinazolin-4-one; 3- (2-Chloro-phenyl) -6-fluoro-2- [2- (6-methoxy-pyridin-2-yl) -vinyl] -3 H-quinazolin-4-one; 2- {2- [3- (2-Chloro-phenyl) -6-fluoro-4-oxo-3,4-dihydro-quinazolin-2-yl] -vinyl} -6-methyl-nicotinonitrile ; 2- {2- [3- (2-Chloro-phenyl) -6-fluoro-4-oxo-3,4-dihydro-quinazolin-2-yl] -ethyl} -6-methyl-nicotinonitrile ; 3- (2-chloro-phenyl) -6-fluoro-2- (2-pyrimidin-2-yl-ethyl) -3H-quinazolin-4-one; 3- (2-chloro-phenyl) -2- [2- (4,6-dimethyl-pyrimidin-2-yl) -vinyl] -6-fluoro-3H-quinazolin-4-one; 2- {2- [3- (2-Chloro-phenyl) -6-fluoro-4-oxo-3,4-dihydro-quinazolin-2-yl] -vinyl} -nicotinonitrile; 3- (2-Chloro-phenyl) -6-fluoro-2- (2- {6-[(3-methyl-butylamino) -methyl] -pyridin-2-yl} -ethyl) -3H-quinazoline -4-one; 2- {2- [3- (2-Chloro-phenyl) -6-fluoro-4-oxo-3,4-dihydro-quinazolin-2-yl] -ethyl} -nicotinonitrile; 3- (2-Chloro-pyridin-3-yl) -6-fluoro-2- [2- (2-hydroxy-phenyl) -vinyl] -3 H-quinazolin-4-one; 2- {2- [6-Fluoro-3- (2-methyl-pyridin-3-yl) -4-oxo-3,4-dihydro-quinazolin-2-yl] -vinyl} -4-methyl -Benzonitrile; 2- [2- (6-Chloro-4-oxo-3-o-tolyl-3,4-dihydro-quinazolin-2-yl) -vinyl] -benzonitrile; 2- (2- [3- (2-Chloro-phenyl) -6-fluoro-4-oxo-3,4-dihydro-quinazolin-2-yl] -vinyl} -4-methyl-benzonitrile; 3- (2-Bromo-phenyl) -6-fluoro-2- [2- (6-hydroxymethyl-pyridin-2-yl) -vinyl] -3 H-quinazolin-4-one; And 3- (2-Chloro-phenyl) -6-fluoro-2- [2- (6-pyrrolidin-l-ylmethyl-pyridin-2-yl) -vinyl] -3 H-quinazolin-4one. The invention also provides for brain defects, seizures, cerebral ischemia, spinal cord trauma, head trauma, Alzheimer's disease, Huntington's chorea, atrophic lateral sclerosis, epilepsy, AIDS dementia, muscle spasm, Migraines, urinary incontinence, psychosis, convulsions, hypoxia at delivery, hypoxia (e.g., fluid, surgery, tobacco smoke inhalation, asphyxiation, drowning, choking, electroporation, or a condition caused by drug or alcohol overdose) ), Heart failure, hypoglycemic nerve damage, opiate tolerance, stop addiction (e.g. alcoholism, and drug addiction, including opiates, cocaine and nicotine addiction), eye damage, retinal disorders, retinal neuropathy, tinnitus, idiopathic and drug parkinson An amount of Formula I effective to treat or prevent a condition selected from the group consisting of disease, anxiety, vomiting, brain edema, chronic or acute pain, and delayed dyskinesia. , It relates to the status to a pharmaceutical composition for the treatment or prevention comprising the compound and a pharmaceutically acceptable carrier. The invention also provides for brain defects, seizures, cerebral ischemia, spinal cord trauma, head trauma, Alzheimer's disease, Huntington's chorea, atrophic lateral sclerosis, epilepsy, AIDS dementia, muscle spasm, Migraines, urinary incontinence, psychosis, convulsions, hypoxia at delivery, hypoxia (e.g., fluid, surgery, tobacco smoke inhalation, asphyxiation, drowning, choking, electroporation, or a condition caused by drug or alcohol overdose) ), Heart failure, hypoglycemic nerve damage, opiate tolerance, stop addiction (e.g. alcoholism, and drug addiction, including opiates, cocaine and nicotine addiction), eye damage, retinal disorders, retinal neuropathy, tinnitus, idiopathic and drug parkinson Formulation of Formula I in an amount effective to treat or prevent a condition selected from the group consisting of disease, anxiety, vomiting, brain edema, chronic or acute pain, and delayed dyskinesia It relates to the water, the treatment or prevention of the condition comprising administering to a mammal in need of such treatment or prevention. The invention also provides for brain defects, seizures, cerebral ischemia, spinal cord trauma, head trauma, Alzheimer's disease, Huntington's chorea, atrophic lateral sclerosis, epilepsy, AIDS dementia, muscle spasm, Migraines, urinary incontinence, psychosis, convulsions, hypoxia at delivery, hypoxia (e.g., fluid, surgery, tobacco smoke inhalation, asphyxiation, drowning, choking, electroporation, or a condition caused by drug or alcohol overdose) ), Heart failure, hypoglycemic nerve damage, opiate tolerance, stop addiction (e.g. alcoholism, and drug addiction, including opiates, cocaine and nicotine addiction), eye damage, retinal disorders, retinal neuropathy, tinnitus, idiopathic and drug parkinson An amount of AMPA receptor antagonist effective amount for treating or preventing a condition selected from the group consisting of disease, anxiety, vomiting, brain edema, chronic or acute pain, and delayed dyskinesia. It relates to a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier. The invention also provides for brain defects, seizures, cerebral ischemia, spinal cord trauma, head trauma, Alzheimer's disease, Huntington's chorea, atrophic lateral sclerosis, epilepsy, AIDS dementia, muscle spasm, Migraines, urinary incontinence, psychosis, convulsions, hypoxia at delivery, hypoxia (e.g., fluid, surgery, tobacco smoke inhalation, asphyxiation, drowning, choking, electroporation, or a condition caused by drug or alcohol overdose) ), Heart failure, hypoglycemic nerve damage, opiate tolerance, stop addiction (e.g. alcoholism, and drug addiction, including opiates, cocaine and nicotine addiction), eye damage, retinal disorders, retinal neuropathy, tinnitus, idiopathic and drug parkinson AMPA receptors in mammals in need of treatment or prevention of a condition selected from the group consisting of disease, anxiety, vomiting, brain edema, chronic or acute pain, and delayed dyskinesia Relates to a method of treating or preventing the condition, comprising administering a compound of formula (I) wherein the effective amount. Compounds of the present invention include all stereoisomers of Formula I and all optical isomers (ie, R and S enantiomers) as well as racemic, diastereoisomers and other mixtures of these isomers. The compounds of the present invention may contain olefinic double bonds. When such a bond is present, the compounds of the present invention may exist in cis form, trans form and mixtures thereof. Unless stated otherwise, the alkyl moieties mentioned herein as well as the alkyl moieties (eg alkoxy) of other groups mentioned herein may be linear or branched and may also be cyclic (eg cyclopropyl, cyclobutyl, cyclopentyl or Cyclohexyl), linear or branched and may contain cyclic moieties. Unless stated otherwise, halo and halogen refer to fluorine, bromine, chlorine or iodine. The present invention relates to novel compounds of formula (I), pharmaceutically acceptable salts thereof, pharmaceutical compositions and methods of treating neurodegeneration and CNS-trauma related conditions. Compounds of formula (I) may be prepared according to the method of Scheme 1. Unless stated otherwise in the schemes and discussions below, K, L, M, P, Q, T, R 1 , R 2 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , Ph 1 , Ph 2 , n, m and p are as defined above in formula (I). Scheme 1 relates to a process for the preparation of compounds of formula (I) from compounds of formula (V). Compounds of formula (V) are either commercially available or can be prepared by methods well known to those skilled in the art. The compound of formula V can be converted to acetamide of formula IV by reaction with acetyl chloride or acetic anhydride in the presence of a base in a reaction inert solvent. Suitable solvents are methylene chloride, dichloroethane, tetrahydrofuran and dioxane, preferably methylene chloride. Suitable bases are trialkylamines such as triethylamine and tributylamine, dimethylaminopyridine and potassium carbonate, preferably triethylamine. The temperature of the aforementioned reactions ranges from about 0 to about 35 ° C. for about 1 to about 10 hours, preferably about 30 ° C. for about 3 hours. Acetamide of formula IV may be cyclized to a compound of formula III by reaction with a dehydrating agent in the presence of a catalyst in anhydrous reaction inert solvent. Suitable dehydrating agents are acetic anhydride, phosphorus pentoxide, dicyclohexylcarbodiimide and acetyl chloride, preferably acetic anhydride. Suitable catalysts include sodium acetate, potassium acetate, acetic acid, p-toluene sulfonic acid or boron trifluoride etherate, preferably sodium acetate. Suitable solvents are dioxane, toluene, diglyme or dichloroethane, preferably dioxane. The temperature of the above-mentioned reaction ranges from about 80 to about 110 ° C. for about 1 to about 24 hours, preferably about 100 ° C. for about 3 to 10 hours. Alternatively, the compound of formula V can be converted directly to the compound of formula III by reaction with acetic anhydride in the presence of an acid catalyst in a solvent. Suitable acid catalysts are acetic acid, sulfuric acid or p-toluene sulfonic acid, preferably acetic acid. Suitable solvents are acetic acid, toluene or xylene, preferably acetic acid. The temperature of the aforementioned reaction is from about 20 to about 150 ° C. for about 10 minutes to about 10 hours, preferably about 120 ° C. for about 2 to 5 hours. The compound of formula III formed by one of the above methods is reacted with an amine of formula R 1 NH 2 in a polar protic solvent in the presence of an acid catalyst to form a compound of formula II. Suitable acid catalysts include acetic acid, p-toluene sulfonic acid or sulfuric acid, preferably acetic acid. Suitable polar protic solvents are acetic acid, methanol, ethanol or isopropanol, preferably acetic acid. The temperature of the aforementioned reaction is about 20 to about 117 ° C. for about 1 to about 24 hours, preferably about 117 ° C. for about 6 hours. Alternatively, the compound of formula IV can be converted directly to the compound of formula II by reaction with a dehydrating agent, an amine of formula R 1 NH 2 and a base in a reaction inert solvent. Suitable dehydrating agents are phosphorus trichloride, oxychloride phosphorus, phosphorus pentachloride or thionyl chloride, preferably phosphorus trichloride. Suitable bases are pyridine, lutidine, dimethylaminopyridine, triethylamine or N-methyl morpholine, preferably pyridine. Suitable solvents are toluene, cyclohexane, benzene or xylene, preferably toluene. Suitable solvents are toluene, cyclohexane, benzene or xylene, preferably toluene. In some cases the reaction can be carried out in anhydrous state if the bound reactant is a liquid. The temperature of the aforementioned reaction is about 50 to about 150 ° C. for about 1 to about 24 hours, preferably about 110 ° C. for about 4 hours. The compound of formula II is reacted with an aldehyde of formula R 2 CHO in the presence of a catalyst and a dehydrating agent in a suitable solvent to form a compound of formula I. Suitable catalysts are zinc chloride, sodium acetate, aluminum chloride, tin chloride or trifluoride etherate boron, preferably zinc chloride or sodium acetate. Suitable dehydrating agents are acetic anhydride, methane sulfonic anhydride, trifluoroacetic anhydride or propionic anhydride, preferably acetic anhydride. Suitable polar solvents are acetic acid, dioxane, dimethoxyethane or propionic acid. The temperature of the aforementioned reaction is about 60 to about 100 ° C. for about 30 minutes to about 24 hours, preferably about 100 ° C. for about 3 hours. Compounds of formula (I) in which the dotted line represents a carbon-carbon single bond can be prepared by hydrogenating the corresponding compound in which the dotted line represents a carbon-carbon double bond using standard techniques well known to those skilled in the art. For example, the reduction of the double bond can be achieved by using palladium on carbon (Pd / C), palladium on barium sulfate (Pd / BaSO 4 ), platinum on carbon (Pt / C) in a suitable solvent such as methanol, ethanol, THF, dioxane or ethyl acetate. ) Or a catalyst such as tris (triphenylphosphine) rhodium chloride (Wilkinson catalyst) at a temperature of about 1 to about 5 atmospheres and about 10 to about 60 ° C. Catalytic Hydrogenation in Organic Synthesis, Paul Rylander, Academic Press Inc., San Diego, 1979, pp. 31-63, can be carried out using hydrogen gas (H 2 ). Palladium on carbon, methanol at 25 ° C. and hydrogen gas pressure at 50 psi are preferred. This method also introduces hydrogen isotopes (ie deuterium, tritium) by replacing 1 H 2 with 2 H 2 or 3 H 2 in the procedure. Alternatively, the compound of formula V can be converted to the compound of formula II according to the method described in Scheme 2. The compound of formula II thus formed may be converted to the compound of formula I according to the method of Scheme 1. In Scheme 2, the compound of formula V is reacted with a coupling agent, an amine of formula R 1 NH 2 and a base in a reaction inert solvent to form a compound of formula VI. Examples of suitable coupling agents that activate carboxyl functional groups are dicyclohexylcarbodiimide, N-3-dimethylaminopropyl-N'-ethylcarbodiimide, 2-ethoxy-1-ethoxycarbonyl-1,2- Dihydroquinoline (EEDQ), carbonyl diimidazole (CDI) and diethylphosphoryl cyanamide. Suitable bases are dimethylaminopyridine (DMAP), hydroxybenzotriazole (HBT) or triethylamine, preferably dimethylaminopyridine. The coupling reaction is carried out in an inert solvent, preferably in an aprotic solvent. Suitable solvents include acetonitrile, dichloromethane, dichloroethane and dimethylformamide. Preferred solvent is dichloromethane. The temperature of the above-mentioned reaction is generally about -30 to about 80 ° C, preferably about 0 to about 25 ° C. Compounds of formula VI are converted to compounds of formula VII by reaction with acetyl chloride or acetic anhydride in the presence of a base in a reaction inert solvent. Suitable solvents are methylene chloride, tetrahydrofuran and chloroform, preferably methylene chloride. Suitable bases are trialkylamines such as triethylamine and tributylamine, dimethylaminopyridine and potassium carbonate, preferably triethylamine. The temperature of the aforementioned reaction is about 0 to about 35 ° C. for about 1 to about 10 hours, preferably about 30 ° C. for about 3 hours. Compounds of formula (VII) are cyclized to compounds of formula (II) by reaction with triphenylphosphine, base and dialkyl azodicarboxylates in a reaction inert solvent. Suitable bases include pyridine, triethylamine and 4-dimethylaminopyridine, preferably 4-dimethylaminopyridine. Suitable solvents are dimethylformamide, tetrahydrofuran and dioxane, preferably dioxane. The temperature of the aforementioned reaction is about 25 to about 125 ° C. for about 1 to about 24 hours, preferably about 100 ° C. for about 8 to about 15 hours. The compound of formula II can be converted to the compound of formula I according to the method described in Scheme 1. Compounds of formula (II) can be prepared according to the methods described in Miyasita et al., Heterocycles, 42, 2, 691-699 (1996). Unless otherwise stated, the pressure of each of the reactions is not critical. Generally, the reaction is carried out at about 1 to about 3 atmospheres, preferably at ambient pressure (about 1 atmosphere). If R 2 is heteroaryl, those of ordinary skill in the art will appreciate that heteroaryl is pyridin-2-yl, 1,3-pyrazin-4-yl, 1,4-pyrazin-3-yl, 1,3-pyrazine-2 -Yl, pyrrole-2-yl, 1,3-imidazol-4-yl, 1,3-imidazol-2-yl, 1,3,4-triazol-2-yl, 1,3-oxazole -4-yl, 1,3-oxazol-2-yl, 1,3-thiazol-4-yl, 1,3-thiazol-2-yl, 1,2,4-oxadiazole-3- Selected from the group consisting of 1, 1,2,4-oxadiazol-5-yl, fur-2-yl, 1,3-oxazol-5-yl and 1,3,4-oxadiazol-2-yl Wherein the heteroaryl may be optionally substituted with up to three substituents at any atom capable of forming additional bonds. Compounds of formula (I), which are inherently basic, can form a wide variety of different salts with various inorganic and organic acids. Such salts should be pharmaceutically acceptable for animal administration, but in practice the compounds of formula (I) are initially isolated from the reaction mixture as pharmaceutically acceptable salts and then the pharmaceutically acceptable salts are treated with an alkaline reagent to free base. It is often desirable to convert back to and then convert the free base to a pharmaceutically acceptable acid addition salt. Acid addition salts of the base compounds of the present invention are readily prepared by treating the base compound with an almost equal amount of selected inorganic or organic acid in an aqueous solvent medium or a suitable organic solvent such as methanol or ethanol. Careful evaporation of the solvent yields the desired solid salt. Acids used to prepare pharmaceutically acceptable acid addition salts of the basic compounds of the present invention are non-toxic acid addition salts, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate , Acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, malate, fumarate, gluconate, saccharide, benzoate, methanesulfonate and pamoate [i.e., 1,1 Acids forming salts containing pharmacologically acceptable anions, such as salts of '-methylene-bis- (2-hydroxy-3-naphthoate)'. Compounds of formula (I) which are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts are alkali metal or alkaline earth metal salts, in particular sodium and potassium salts. These salts are all prepared by conventional techniques. The chemical base used as a reagent for preparing the pharmaceutically acceptable base salt of the present invention is to form a nontoxic base salt with the acidic compound of formula (I) described herein. These non-toxic base salts include those derived from pharmaceutically acceptable cations such as sodium, potassium, calcium and magnesium and the like. These salts can be readily prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, these salts can be prepared by mixing the lower alkanol-based solution of the acidic compound with the desired alkali metal alkoxide together and then evaporating the resulting solution to dry in the same manner as before. In either case, it is desirable to use stoichiometric amounts of the reagents in order to complete the reaction in order to maximize the yield in the desired final product. Compounds of formula (I) and their pharmaceutically acceptable salts (hereinafter also referred to as active compounds of the present invention) are useful AMPA receptor antagonists for the treatment of neurodegeneration and CNS-trauma related conditions. Therefore, the active compounds of the present invention are brain defects, seizures, cerebral ischemia, spinal cord trauma, head trauma, Alzheimer's disease, Huntington's chorea, atrophic lateral sclerosis, epilepsy, AIDS dementia, muscle spasm after bypass surgery and transplantation of the heart , Migraine, urinary incontinence, psychosis, convulsions, hypoxia at birth, hypoxia (eg, fluid, surgery, tobacco inhalation, asphyxiation, drowning, choking, death penalty, or drug or alcohol overdose) Condition), heart failure, hypoglycemic nerve damage, opiate tolerance, stop addiction (e.g. alcoholism, and drug addiction, including opiates, cocaine and nicotine addiction), eye damage, retinal disorders, retinal neuropathy, tinnitus, idiopathic and pharmacologic It can be used to treat or prevent Parkinson's disease, anxiety, vomiting, brain edema, chronic or acute pain, or delayed dyskinesia. In vitro and in vivo activity of the compounds of the present invention against AMPA receptor antagonists can be determined by methods available to those of ordinary skill in the art. One method of determining the activity of a compound of the present invention is by inhibition of pentylenetetrazole (PTZ) -induced seizures. Another method of determining the activity of the compounds of the present invention is by blocking AMPA receptor activity-induced 45 Ca 2+ uptake. One specific method of determining the activity of a compound of the present invention for inhibiting pentylenetetrazole (PTZ) -induced seizures in mice can be determined according to the following procedure. This assay studies the compound's ability to block sudden seizures and death caused by PTZ. Latency to myogenic and tonic sudden seizures, and death are measured. ID 50 is determined based on% protection. Male River CD-1 mice from Charles River, weighed from 14 to 16 g on arrival and weighed from 25 to 35 g on test, were tested in this experiment. Mice are trapped 13 per cage under standard laboratory conditions at L: D / 7 a.m.:7 p.m. (ie photoperiod 7 days or more prior to experiment). Food and water may be taken arbitrarily until the test date. All compounds are administered in an amount of 10 ml / kg. The drug vehicle depends on the solubility of the compound but is screened using saline, distilled water or E: D: S / 5: 5: 90 (5% emulphor, 5% DMSO and 90% saline) as injection vehicle This is typically done. Mice are administered a test compound or vehicle (intraperitoneally, subcutaneously or orally) and placed in five groups of plastic glass cages. After a certain time after injection, mice were injected with PTZ (intraperitoneal, 120 mg / kg) and placed in individual plastic glass cages. During the 5-minute test period, (1) the incubation period until the epileptic seizure, (2) the incubation period until the tonic sudden attack, and (3) the incubation period until death. Treatment groups were compared to vehicle treatment groups by Kruskal-Wallis Anova and Mann-Whitney U test (Statview). The percentage of protection is calculated for each group at each measurement (number of specimens that did not show a sudden seizure or death as indicated by 300 points). ID 50 is determined by probit analysis (biostatistics). Another method of determining the activity of the compound is to determine the effect of the compound on the movement coordinates of the mouse. This activity can be determined according to the following procedure. The Higgs River Mountain male CD-1 mice weighed between 14 and 16 g on arrival and weighed between 25 and 35 g on test were used as specimens of this experiment. Mice are trapped 13 per cage under standard laboratory conditions at L: D / 7 a.m.:7 p.m. (ie photoperiod 7 days or more prior to experiment). Food and water may be taken arbitrarily until the test date. All compounds are administered in an amount of 10 ml / kg. The drug vehicle depends on the solubility of the compound, but screening using brine, distilled water or E: D: S / 5: 5: 90 (5% emulsion, 5% DMSO and 90% saline) as the injection vehicle is typically Is carried out. The device used in this study consists of a group of five 13.34 x 13.34 cm wire mesh square cylinders hanging from a 11.43 cm steel bar connected to a 165.1 cm bar 38.1 cm high on a lab bench. Mice are administered a test compound or vehicle (intraperitoneally, subcutaneously or orally) and placed in five groups of plastic glass cages. After a certain time after injection, the mouse is placed on the top surface of the wire mesh square tube and turned upside down to hang upside down. During the one-minute test period, the mouse is graded as 0 if it falls off the screen, as 1 if it is upside down and upside down, and 2 if it is up. Treatment groups were compared to vehicle treatment groups by the Kruskal-Wallis Anova and Mann-Whitney U tests (Statview). One specific method for determining the blocking of AMPA receptor activation-induced 45 Ca 2+ uptake is described below. Primary culture of neurons Primary cultures of rat brain granule neurons in rats were described by Parks, TN, Artman, LD, Alasti, N., and Nemeth, EF. -Methyl-D-Aspartate Receptor-Mediated Increases In Cytosolic Calcium In Cultured Rat Cerebellar Granule Cells, Brain Res. 552, 13-22 (1991). According to this method, the brain is removed from 8-day-old CD rats, sliced into 1 mm specimens, and incubated at 37 ° C. for 15 minutes in a Tyrode solution containing 0.1% trypsin and no calcium-magnesium. This tissue is ground using a fine perforated Pasteur pipette. The cell suspension is placed on a 96 well tissue culture plate coated with poly-D-lysine to 10 5 cells per well. The medium is minimal essential medium (MEM), salt of Earle, 10% heat inactivated fetal calf serum, 2 mM L-glutamine, 21 mM glucose, penicylene streptomycin (100 units per ml) and Consisting of 25 mM KCl. After 24 hours, the medium was changed to a fresh medium containing 10 μM cytosine arabinoside to inhibit cell differentiation. Cultures should be used at 6-8 DIV. AMPA receptor activity-induced 45 Ca 2+ uptake The effect of the drug on AMPA receptor activity-induced 45 Ca 2+ uptake can be examined in rat brain granule cell culture. Cultures of 96 well plates were pre-incubated for approximately 3 hours in a serum-free medium, followed by equilibrium salts containing 0.5 mM DTT, 10 uM glycine and 2 times the final concentration of drug and no Mg 2+ . The solution was pre-incubated for 10 min in 120 mM NaCl, 5 mM KCl, 0.33 mM NaH 2 PO 4 , 1.8 mM CaCl 2 , 22.0 mM glucose and 10.0 mM HEPES at pH 7.4. The reaction was initiated by rapid addition of the same amount of equilibrium salt solution (final specific activity of 250 Ci / mmol) containing 100 μM of AMPA receptor agonist carboxylic acid and 45 Ca 2+ . After 10 minutes at 25 ° C., the reaction was stopped by aspirating 45 Ca 2+ -containing solution and washing 5 times the cells in an ice cold balanced salt solution containing 0.5 mM EDTA without adding calcium. Cells were then digested by incubation overnight at 0.1% Triton X-100 and radioactivity in the digest was determined. All of the compounds of the present invention tested had an IC 50 of less than 5 μM. The compositions of the present invention may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers. Thus, the active compounds of the present invention may be formulated for oral, buccal, nasal, parenteral (eg intravenous, intramuscular or subcutaneous), transdermal or rectal administration or suitable for inhalation or inhalational administration. It may be formulated in a form. In the case of oral administration, the pharmaceutical composition may comprise, for example, a binder (e.g., pregelatinized corn starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose), a filler (e.g. lactose, microcrystalline cellulose or calcium phosphate), Conventional methods using pharmaceutically acceptable excipients such as lubricants (e.g. magnesium stearate, talc or silica), disintegrants (e.g. potato starch or sodium starch glycolate) or wetting agents (e.g. sodium lauryl sulfate) It may have a form such as tablet or capsule. Tablets may be coated by methods well known in the art. Liquid preparations for oral administration may, for example, be in the form of solutions, syrups or suspensions, or may be present as anhydrous products to be composed with water or other suitable vehicle before use. Such liquid preparations may include suspension agents (e.g. sorbitol syrup, methyl cellulose or hydrogenated edible fats), emulsifiers (e.g. lecithin or acacia), non-aqueous vehicles (e.g. almond oil, oily esters or ethyl alcohol) and preservatives (e.g. methyl Or pharmaceutically acceptable additives such as propyl p-hydroxybenzoate or sorbic acid). For oral administration, the compositions may have the form of tablets or lozenges formulated in conventional manner. The active compounds of the present invention can be formulated for parenteral administration by injection, including using conventional catheter techniques or infusion. Injectable preparations may be present in unit dosage form, eg, in ampoules or in multiple-dose containers, with the addition of a preservative. The composition may be in the form of a suspension, solution or emulsion in an oily or aqueous vehicle and may contain formulated agents such as suspensions, stabilizers and / or dispersants. Alternatively, the active ingredient may be in powder form to be reconstituted with a suitable vehicle, such as pyrogen-free sterile water, before use. The active compounds of the present invention may also be formulated in rectal compositions such as suppositories or residual enemas, eg, containing syntactic suppository bases such as cocoa butter or other glycerides. In the case of intranasal administration or inhalation administration, the active compounds of the present invention are conveniently delivered in the form of solutions or suspensions from pump spray vessels pressed or pumped by the patient or suitable propellants (e.g. dichlorodifluoromethane, trichloro Fluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas) to conveniently deliver the aerosol spray from a pressurized vessel or nebulizer. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount. Pressurized vessels or nebulizers may contain a solution or suspension of the active compound. Capsules or cartridges (eg, made from gelatin) for use inhalation or insufflation may be formulated to contain a compound of the invention and a powder mix of a suitable powder base such as lactose or starch. The recommended dosage of the active compounds of the invention for oral, parenteral or oral administration to the average adult for the treatment of the above mentioned conditions (e.g. seizures) is from 0.01 to 50 mg / kg of active ingredient per unit dose, It may be administered, for example, 1 to 4 times a day. Aerosol formulations for the treatment of the above-mentioned conditions (eg seizures) of the average adult are preferably arranged such that each metered dose or “inhalation” of the aerosol contains 20 to 1000 μg of the compound of the invention. When using aerosol the overall daily dose is in the range of 100 μg to 10 mg. Multiple, such as two, three, four or eight doses may be administered per day, with one, two or three doses provided each time. The following examples illustrate the preparation of the compounds of the present invention. Commercially available drugs were used without further purification. Melting point was not corrected. NMR data were recorded in parts per million (δ) and cited deuterium fixation signals from the sample solvent. Unless stated otherwise, all mass spectrometers were performed using chemical impact conditions. An ambient temperature or room temperature means 20-25 degreeC. Example 1 3- (2-Chloro-phenyl) -6-fluoro-2- (2-pyridin-2-yl-ethyl) -3 H-quinazolin-4-one hydrochloride 1.00 g (2.65 mmol) of 3- (2-chloro-phenyl) -6-fluoro-2- (2-pyridin-2-yl-vinyl) -3H-quinazolin-4-one in about 100 mL of ethyl acetate The solution was treated with 0.5 g of 10% Pd / C and the resulting mixture was hydrogenated at about 2 cm Hg for 2 hours, at which time absorption of hydrogen was stopped. The catalyst was filtered off using a supercel (filter) and ethyl acetate was removed by evaporation. The residue was dissolved in diethyl ether and treated with a solution excess of HCl gas in diethyl ether. The product precipitated immediately, which was stirred for 3 hours, then separated by filtration and dried over anhydrous nitrogen vapor. The product contained 1.15 g (100) of 3- (2-chloro-phenyl) -6-fluoro-2- (2-pyridin-2-yl-ethyl) -3H-quinazolin-4-one hydrochloride as a colorless white solid. %). Example 2 3- (2-Chlorophenyl) -2- [2- (6-diethylaminomethylpyridin-2-yl) -vinyl-6-fluoro-3H-quinazolin-4-one Method A 6-fluoro-2-methylquinoxalin-4-one A solution of 12.95 g (70.0 mmol) 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 palladium on 10% carbon and reduced at an initial pressure of 54.5 psi. Hydrogen uptake was completed after 2 hours. The catalyst was removed by filtration and the filtrate was heated at reflux for 2 hours, followed by thin layer chromatography (1: 1 hexanes / ethyl acetate) indicating that the reaction was complete. The reaction mixture was evaporated to a semicrystalline mass, which was triturated in a minimum amount of 2-propanol and stirred in an ice bath for 1 hour. The crystalline solid was separated by filtration, washed with a minimum amount of cold 2-propanol and air dried to yield 5.79 g (46%) of the desired product as a brown solid. Melting point: 127.5 to 128.5 ° C. Synthesis of 5-fluoro-2-nitrobenzoic acid is described in Slothouwer, J. H., Recl. Trav. Chim. Pays-Bays. 33. 336 (1914). Method B 3- (2-Chlorophenyl) -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 at reflux for 6 hours under a nitrogen atmosphere. . Most solvent was evaporated from the cooled reaction mixture and the residue was placed in ethanol and refrigerated. After 6 days of refrigeration, the crystals formed were filtered, washed with a minimum amount of cold ethanol and air dried to yield 1.79 g (44%) of product. Melting point: 137-138 ° C. Method C 6- (2- [3- (2-chlorophenyl) -6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl-vinyl) pyridine-2-carbaldehyde Anhydrous zinc chloride catalyst amount (about 100 mg) was 576 mg of 3- (2-chlorophenyl) -6-fluoro-2-methyl-4 (3H) -quinazolinone in 20-25 ml of dioxane and 1.0 ml of acetic anhydride. (2.0 mmol) and 270 mg (2.0 mmol) of 2,6-pyridinedicarboxaldehyde were added to the solution. The reaction mixture was heated at reflux for 3 hours under a nitrogen atmosphere until thin layer chromatography indicated the starting material was exhausted. The cooled reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The extracts were combined, dried over brine and magnesium sulfate, treated with decolorized carbon, filtered and the solvent removed to afford the desired product. This was taken in a 2: 1 ether / pentane and the crystals were filtered to give 266 mg (33%) of product. Melting point: 247-248 degreeC. Synthesis of pyridine-2,6-dicarboxaldehyde is described by Papadopoulos et al. Org. Chem., 31. 615, (1966). Method D 3- (2-Chlorophenyl) -2- [2- (6-diethylaminomethylpyridin-2-yl) -vinyl-6-fluoro-3H-quinazolin-4-one 6- {2- [3- (2-chlorophenyl) -6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl) -vinyl) pyridine-2-carb in 10 ml methylene chloride A solution of 65 mg (0.16 mmol) of aldehyde was treated with 3 drops of diethylamine and 73 mg (0.34 mmol) of sodium triacetoxyborohydride under nitrogen atmosphere at room temperature. After stirring for 2 hours and 30 minutes at room temperature, the solvent was evaporated and the residue was partitioned between dilute hydrochloric acid and ether and stirred for 30 minutes. The ether layer was separated and the aqueous layer was extracted once more with ether. Ether extracts were discarded. The pH of the acidic aqueous solution was adjusted to 14 using 10% sodium hydroxide (ice bath cooling) and then extracted twice with ether. The ether based extracts were combined, dried over brine and magnesium sulfate, and the solvent was evaporated. After forming the mesylate salt, the free base reconstituted in ethyl acetate was treated with 7.5 mg (0.06 mmol) maleic acid dissolved in a small amount of ethyl acetate. Crystals formed from the resulting solution were filtered and washed with ethyl acetate to give 22 mg (24%) of the monomaleate salt. Melting point: 170.5 to 171.5 ° C. Examples 3 to 69 Examples 3 to 69 were prepared by a similar method to that of Example 2. Example 63 Example 64 Example 65 Example 66 Example 67 Example 68 Example 69 Example 70 6-fluoro-3- (2-methyl-pyridin-3-yl) -2- [2- (2-methyl-thiazol-4-yl) -vinyl] -3H-quinazolin-4-one mesylate Anhydrous zinc chloride (2.7 g, 20 mmol) was melted by nitrogen purge in a round bottom flask using an open flame. The reaction vessel was returned to ambient temperature and then dioxane (150 mL) was added. To this mixture was 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) was added. The reaction was refluxed for 2 hours, cooled to ambient temperature and diluted with water. Sodium carbonate was added until the mixture became basic. The mixture was extracted repeatedly with chloroform. The combined chloroform layers were washed with water and brine and finally dried over sodium sulfate and concentrated to leave a dark residue. This residue was treated with methanol and concentrated (effectively azeotropically distilling residual chloroform from the residue) and the process was repeated to leave a brown solid. The solid was triturated twice with ether, filtered and dried to give 6-fluoro-3- (2-methyl-pyridin-3-yl) -2- [2- (2-methyl-thiazol-4-yl)- 3.1 g (82%) of vinyl] -3H-quinazolin-4-one was obtained as a tan solid. Melting point: 223 to 224 ° C; NMRδ8.70 (dd, J = 1.5, 5 Hz, 1H), 7.90 (dd is partially unclear, J = 3 Hz, 1H), 7.89 (d, J = 15 Hz, 1H), 7.78 (dd, J = 5.9 kPa, 1H), 7.54 (m, 2H), 7.39 (dd, J = 5, 8 kPa, 1H), 7.23 (s, 1H), 6.57 (d, J = 15 kPa, 1H), 2.61 (s , 3H), 2.36 (s, 3H), C 20 H 15 FN 4 OS 0.5 H 2 O requires C: 62.06; H, 4.13; N, 14.58; Found; C, 62.39; H, 3.96; N, 14.33. The sample was placed in ethyl acetate and treated with 1N methanesulfonic acid in ethyl acetate to form mesylate salts. The precipitate was collected, washed with ethyl acetate and dried to give 6-fluoro-3- (2-methyl-pyridin-3-yl) -2- [2- (2-methyl-thiazol-4-yl) -vinyl ] -3H-quinazolin-4-one mesylate was obtained as a light yellow solid. Melting point: 230 to 231 ° C .; NMR (Methanol d4 ) δ9.01 (dd, J = 1.2, 5.8kPa, 1H), 8.65 (dd, J = 1.3, 8.2kPa, 1H), 8.15 (dd, J = 5.9, 8.2kPa, 1H), 8.00 (d, J = 15 Hz, 1H), 7.88 (sym m, 2H), 7.71 (m, 2H), 6.56 (d, J = 15 Hz, 1H), 2.68 (s, 3H), 2.65 (s, 3H ), 2.62 (s, 3H), C 20 H 15 FN 4 OS CH 3 SO 3 H 0.75H 2 O requires C: 51.69; H, 4. 20; N, 11.48; Found; C, 51.80; H, 4.18; N, 11.35. Example 71 6-fluoro-2- [2- (2-methyl-thiazol-4-yl) -vinyl] -3- (2-methyl-phenyl) -3H-quinazolin-4-one Anhydrous zinc chloride (0.136 g, 1.0 mmol) was melted by nitrogen purge in a round bottom flask using an open flame. The reaction vessel was returned to ambient temperature and then dioxane (10 mL) was added. To this mixture was added 6-fluoro-2-methyl-3- (2-methyl-phenyl) -3H-quinazolin-4-one (0.134 g, 0.5 mmol), acetic anhydride (0.141 mL, 1.5 mmol) and 2- Methylthiazole-4-carboxaldehyde (0.191 g, 1.5 mmol) was added. The reaction was refluxed for 3.5 hours, cooled to ambient temperature and diluted with water. The mixture was extracted repeatedly with chloroform. The combined chloroform layers were washed with water and brine and finally dried over sodium sulfate and concentrated to leave a dark residue. The residue was triturated with ether, filtered and dried to give 6-fluoro-2- [2- (2-methyl-thiazol-4-yl) -vinyl] -3- (2-methyl-phenyl) -3H- 0.04 g (21%) of quinazolin-4-one was obtained as a tan solid. Example 72 3- (2-Chloro-phenyl) -6-fluoro-2- [2- (2-methyl-thiazol-4-yl) -vinyl] -3 H-quinazolin-4-one Anhydrous zinc chloride (0.133 g, 0.98 mmol) was melted by nitrogen purge in a round bottom flask using an open flame. The reaction vessel was returned to ambient temperature and then dioxane (7 mL) was added. To this mixture was added 3- (2-chloro-phenyl) -6-fluoro-2-methyl-3H-quinazolin-4-one (0.14 g, 0.49 mmol), acetic anhydride (0.138 mL, 1.46 mmol) and 2- Methylthiazole-4-carboxaldehyde (0.185 g, 1.46 mmol in 4 mL of dioxane) was added. The reaction was refluxed for 4 hours, cooled to ambient temperature and diluted with water. The mixture was extracted repeatedly with chloroform. The combined chloroform layers were washed with water and brine and finally dried over sodium sulfate and concentrated to leave a dark residue. The residue was triturated with ether, filtered and dried to give 3- (2-chloro-phenyl) -6-fluoro-2- [2- (2-methyl-thiazol-4-yl) -vinyl] -3H- 0.16 g (57%) of quinazolin-4-one was obtained as a tan solid. Example 73 2- [2- (2-dimethylaminomethyl-thiazol-4-yl) -vinyl] -6-fluoro-3- (2-fluoro-phenyl) -3 H-quinazolin-4-one Anhydrous zinc chloride (0.106 g, 0.78 mmol) was melted by nitrogen purge in a round bottom flask using an open flame. The reaction vessel was returned to ambient temperature and then dioxane (6 mL) was added. To this mixture was added 6-fluoro-3- (2-fluoro-phenyl) -2-methyl-3H-quinazolin-4-one (0.108 g, 0.39 mmol), acetic anhydride (0.111 mL, 1.18 mmol) and 2 -Dimethylaminomethylthiazole-4-carboxaldehyde (0.280 g, 1.18 mmol in 4 mL dioxane) was added. The reaction was refluxed for 4 hours, cooled to ambient temperature and diluted with water. Sodium carbonate was added until the mixture became basic. The mixture was extracted repeatedly with chloroform. The chloroform layers were combined and washed with aqueous bisulfite, water and brine and finally dried over sodium sulfate and concentrated to leave a dark colored residue. The residue was triturated with ether, filtered and dried to give 2- [2- (2-dimethylaminomethyl-thiazol-4-yl) -vinyl] -6-fluoro-3- (2-fluoro-phenyl) 0.051 g (31%) of -3H-quinazolin-4-one was obtained as a tan solid. Example 74 3- (2-Bromo-phenyl) -6-fluoro-2- [2- (2-methyl-thiazol-4-yl) -vinyl] -3 H-quinazolin-4-one Anhydrous zinc chloride (0.150 g, 1.1 mmol) was melted by nitrogen purge in a round bottom flask using an open flame. The reaction vessel was returned to ambient temperature and then dioxane (5 mL) was added. To this mixture was added 3- (2-bromo-phenyl) -6-fluoro-2-methyl-3H-quinazolin-4-one (0.182 g, 0.55 mmol), acetic anhydride (0.156 mL, 1.65 mmol) and 2 -Methylthiazole-4-carboxaldehyde (0.209 g, 1.65 mmol in 3 ml dioxane) was added. The reaction was refluxed for 3 hours, cooled to ambient temperature and diluted with water. The mixture was extracted repeatedly with chloroform. The combined chloroform layers were washed with water and brine and finally dried over magnesium sulfate and concentrated to leave a dark colored residue. This residue was triturated with ether, filtered and dried to give 3- (2-bromo-phenyl) -6-fluoro-2- [2- (2-methyl-thiazol-4-yl) -vinyl] -3H 0.116 g (52%) of -quinazolin-4-one was obtained as a tan solid. Example 75 3- (2-Chloro-phenyl) -2- [2- (2-methyl-thiazol-4-yl) -vinyl] -3 H-quinazolin-4-one Anhydrous zinc chloride (0.136 g, 1.0 mmol) was melted by nitrogen purge in a round bottom flask using an open flame. The reaction vessel was returned to ambient temperature and then dioxane (10 mL) was added. To this mixture was added 3- (2-chloro-phenyl) -2-methyl-3H-quinazolin-4-one (0.135 g, 0.50 mmol), acetic anhydride (0.141 mL, 1.5 mmol) and 2-methylthiazole-4 Carboxaldehyde (0.191 g, 1.5 mmol) was added. The reaction was refluxed for 3 hours, cooled to ambient temperature and diluted with water. The mixture was extracted repeatedly with chloroform. The combined chloroform layers were washed with water and brine, finally dried over sodium sulfate and concentrated to leave a waxy tan solid. The residue was triturated with ether, filtered and dried to give 3- (2-chloro-phenyl) -2- [2- (2-methyl-thiazol-4-yl) -vinyl] -3 H-quinazolin-4- 0.139 g (73%) was obtained as a tan solid. Examples 76-94 Compounds of Tables 2A-2G were prepared by essentially the same procedure as the methods of Examples 70-75. Examples 95-113 The compounds of Tables 3A-3D were prepared essentially the same as the procedure illustrated in Example 2.
权利要求:
Claims (22) [1" claim-type="Currently amended] A compound of formula (I) and pharmaceutically acceptable salts thereof: Formula I Where R 1 is optionally substituted phenyl of the formula Ph 1 or heteroaryl selected from the group consisting of pyridin-2-yl, pyridin-3-yl and pyridin-4-yl, wherein the heteroaryl is capable of forming further bonds Hydrogen on any ring carbon atom, (C 1 -C 6 ) alkyl, halogen, trifluoromethyl, amino- (CH 2 ) n- , (C 1 -C 6 ) alkylamino- (CH 2 ) n- , Di (C 1 -C 6 ) alkyl-amino- (CH 2 ) n- , (C 1 -C 6 ) alkoxy, hydroxy (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkyl-O- (C 1 -C 6) alkyl, -CN, (C 1 -C 6 ) alkyl, -COO- (C 1 -C 6) alkyl -, (C 1 -C 6) alkyl, -O-COO- (C 1 - C 6 ) alkyl-, (C 1 -C 6 ) alkyl-COO-, hydroxy, HC (═O)-, (C 1 -C 6 ) alkyl-C (= 0)-(CH 2 ) n- , HO-C (= 0)-(CH 2 ) n- , (C 1 -C 6 ) alkyl-OC (= 0)-(CH 2 ) n- , NH 2 -C (= 0)-(CH 2 ) n -, (C 1 -C 6 ) alkyl, -NH-C (= O) - (CH 2) n - , and di (C 1 -C 6) alkyl, -NH-C (= O) - (CH 2) n Optionally substituted up to 3 per ring with a substituent selected from the group consisting of Can be] Ph 1 is a chemical formula Is the flag of, R 2 is phenyl of the formula Ph 2 or a 5 or 6 membered heterocycle, The six-membered heterocycle is represented by the formula Wherein "N" is nitrogen and ring positions "K", "L" and "M" may be independently selected from the group consisting of carbon and nitrogen, provided i) "K", "L" or " Only one of M "may be nitrogen and ii) each of R 15 , R 16 or R 17 is absent when" K "," L "or" M "is nitrogen), The 5-membered heterocycle is represented by the formula Wherein “T” is —CH—, N, NH, O or S, and ring positions “P” and “Q” may be independently selected from the group consisting of carbon, nitrogen, oxygen and sulfur, provided that “P” "Only one of", "Q" or "T" may be oxygen or sulfur and at least one of "P", "Q" or "T" must be heteroatom, and The Ph 2 is the following formula With R 3 is hydrogen, halo, —CN, —NO 2 , CF 3 , (C 1 -C 6 ) alkyl or (C 1 -C 6 ) alkoxy, R 5 is hydrogen, (C 1 -C 6 ) alkyl, halo, CF 3 , (C 1 -C 6 ) alkoxy or (C 1 -C 6 ) alkylthiol, R 6 is hydrogen or halo, R 7 is hydrogen or halo, R 8 is hydrogen or halo, R 9 is hydrogen, halo, CF 3 , (C 1 -C 6 ) alkyl optionally substituted with 1 to 3 halogen atoms, (C 1 -C 6 ) alkoxy optionally substituted with 1 to 3 halogen atoms, (C 1- C 6 ) alkylthiol, amino- (CH 2 ) s- , (C 1 -C 6 ) alkyl-NH- (CH 2 ) s- , di (C 1 -C 6 ) alkyl-N- (CH 2 ) s -, (C 3 -C 7 ) cycloalkyl-NH- (CH 2 ) s- , H 2 N- (C═O)-(CH 2 ) s- , (C 1 -C 6 ) alkyl-HN- ( C═O) — (CH 2 ) s- , di (C 1 -C 6 ) alkyl-N- (C═O)-(CH 2 ) s- , (C 3 -C 7 ) cycloalkyl-NH- ( C = O)-(CH 2 ) s- , R 13 O- (CH 2 ) s- , R 13 O- (C = O)-(CH 2 ) s- , H (O = C) -NH- ( CH 2 ) s- , (C 1 -C 6 ) alkyl- (O = C) -NH- (CH 2 ) s- , (C 1 -C 6 ) alkyl- (C═O)-, hydroxy, hydroxy- (C 1 -C 6 ) alkyl-, (C 1 -C 6 ) alkyl-O- (C 1 -C 6 ) Alkyl- and -CN, R 10 and R 14 are independently hydrogen, halo, CF 3 , (C 1 -C 6 ) alkyl optionally substituted with 1 to 3 halogen atoms, (C 1 -C 6 ) alkoxy optionally substituted with 1 to 3 halogen atoms , (C 1 -C 6 ) alkylthiol, amino- (CH 2 ) p- , (C 1 -C 6 ) alkyl-NH- (CH 2 ) p- , di (C 1 -C 6 ) alkyl-N- (CH 2 ) p- , (C 3 -C 7 ) cycloalkyl-NH- (CH 2 ) p- , amino- (C 1 -C 6 ) alkyl-NH- (CH 2 ) p- , (C 1- C 6 ) alkyl-NH- (C 1 -C 6 ) alkyl-NH- (CH 2 ) p- , di (C 1 -C 6 ) alkyl-N- (C 1 -C 6 ) alkyl-NH- (CH 2 ) p- , (C 1 -C 6 ) alkyl-HN- (C═O)-(CH 2 ) p- , di (C 1 -C 6 ) alkyl-N- (C═O)-(CH 2 ) p- , ( C 3 -C 7 ) cycloalkyl-NH- (C═O)-(CH 2 ) p- , R 13 O- (CH 2 ) p- , R 13 O- (C = O)-(CH 2 ) p -, H (O = C) -O-, H (O = C) -O- (C 1 -C 6) alkyl -, H (O = C) -NH- (CH 2) p -, (C 1 -C 6 ) alkyl- (O = C) -NH- (CH 2 ) p- , -CHO, H- (C = O)-(CH 2 ) p- , Amino - (C 1 -C 6) alkyl, - (C = O) -O- ( CH 2) p -, (C 1 -C 6) alkyl, -NH- (C 1 -C 6) alkyl, - (C = O ) -O- (CH 2 ) p- , di (C 1 -C 6 ) alkyl-N- (C 1 -C 6 ) alkyl- (C = O) -O- (CH 2 ) p- , amino- ( C 1 -C 6 ) alkyl-O- (C═O) -O- (CH 2 ) p- , (C 1 -C 6 ) alkyl-NH- (C 1 -C 6 ) alkyl-O- (C = O)-(CH 2 ) p- , di (C 1 -C 6 ) alkyl-N- (C 1 -C 6 ) alkyl-O- (C = O)-(CH 2 ) p- , hydroxy, hydroxide Hydroxy- (C 1 -C 6 ) alkyl, hydroxy- (C 1 -C 6 ) alkyl-NH- (CH 2 ) p- , (C 1 -C 6 ) alkyl-O- (C 1 -C 6 ) Alkyl-, -CN, piperidine- (CH 2 ) p- , pyrrolidine- (CH 2 ) p -and 3-pyrroline- (CH 2 ) p- , wherein piperi Piperidine, pyrrolidine and 3-pyrroline of the dean- (CH 2 ) p- , pyrrolidine- (CH 2 ) p -and 3-pyrroline- (CH 2 ) p -residues an optionally halo, CF 3, 1 to 3 halogen atoms substituted on any ring carbon atom capable of supporting (C 1 -C 6) alkyl, one to three halogen atoms, optionally substituted (C 1 -C 6) Al When, (C 1 -C 6) alkylthio, amino, - (CH 2) p -, (C 1 -C 6) alkyl, -NH- (CH 2) p -, di (C 1 -C 6) alkyl, -N -(CH 2 ) p- , (C 3 -C 7 ) cycloalkyl-NH- (CH 2 ) p- , amino- (C 1 -C 6 ) alkyl-NH- (CH 2 ) p- , (C 1 -C 6 ) alkyl-NH- (C 1 -C 6 ) alkyl-NH- (CH 2 ) p- , di (C 1 -C 6 ) alkyl-N- (C 1 -C 6 ) al H 2 N- (C═O)-(CH 2 ) p- , (C 1 -C 6 ) alkyl-HN- (C═O)-(CH 2 ) p- , di (C 1 -C 6 ) alkyl -N- (C = O)-(CH 2 ) p- , (C 3 -C 7 ) cycloalkyl-NH- (C = O)-(CH 2 ) p- , R 13 O- (CH 2 ) p R 13 O— (C═O) — (CH 2 ) p −, H (O═C) —O—, H (O═C) —O— (C 1 -C 6 ) alkyl-, H ( O = C) -NH- (CH 2 ) p- , (C 1 -C 6 ) alkyl- (O = C) -NH- (CH 2 ) p- , -CHO, H- (C = O)-( CH 2) p -, (C 1 -C 6) alkyl, - (C = O) -, (C 1 -C 6 ) alkyl- (C═O) -O-NH- (CH 2 ) p- , amino- (C 1 -C 6 ) alkyl- (C = 0) -O- (CH 2 ) p -, (C 1 -C 6) alkyl, -NH- (C 1 -C 6) alkyl, - (C = O) -O- ( CH 2) p -, di (C 1 -C 6) alkyl, -N- ( C 1 -C 6 ) alkyl- (C═O) -O- (CH 2 ) p- , hydroxy, hydroxy- (C 1 -C 6 ) alkyl-, hydroxy- (C 1 -C 6 ) alkyl Optionally substituted with a substituent independently selected from the group consisting of -NH- (CH 2 ) p -and -CN, R 11 is hydrogen or halo, R 12 is hydrogen, —CN or halo, R 13 is hydrogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkyl- (C═O)-, (C 1 -C 6 ) alkyl-O- (C═O)-, (C 1- C 6 ) alkyl-NH- (C═O)-or di (C 1 -C 6 ) alkyl-N- (C═O)-, R 15 is hydrogen, —CN, (C 1 -C 6 ) alkyl, halo, CF 3 , —CHO or (C 1 -C 6 ) alkoxy, R 16 is hydrogen, —CN, (C 1 -C 6 ) alkyl, halo, CF 3 , —CHO or (C 1 -C 6 ) alkoxy, R 17 is hydrogen, —CN, (C 1 -C 6 ) alkyl, amino- (C 1 -C 6 ) alkyl-, (C 1 -C 6 ) alkyl-NH- (C 1 -C 6 ) alkyl-, Di (C 1 -C 6 ) alkyl-N- (C 1 -C 6 ) alkyl-, halo, CF 3 , -CHO or (C 1 -C 6 ) alkoxy, n is an integer from 0 to 3, Each p is independently an integer from 0 to 4, s is an integer from 0 to 4, Dotted line represents any double bond, but i) when R 9 is hydrogen, one of R 11 and R 12 is not hydrogen; ii) when R 1 is unsubstituted phenyl and R 3 is hydrogen, (a) R 2 cannot be unsubstituted phenyl, thienyl or furyl, or (b) R 9 and R 11 are hydrogen or R 9 or When R 12 cannot be Cl or hydroxy or (c) R 9 and R 12 are hydrogen, then R 10 or R 11 cannot be chloro, iii) when R 3 is hydrogen, R 6 , R 7 and R 8 are hydrogen and R 5 is chloro or methyl, (a) R 2 may not be unsubstituted phenyl, thienyl or furyl or (b) R 10 or R 11 may not be chloro or (c) R 9 or R 12 may not be hydroxy, methyl or methoxy, iv) when R 3 is hydrogen or chloro, R 5 is methyl, R 6 , R 7 and R 8 are hydrogen and K, L and M are carbon, then (a) one of R 14 to R 17 is hydrogen Or (b) R 17 is not hydrogen or methyl, v) when R 1 is unsubstituted pyridin-2-yl and R 3 is hydrogen, bromo or iodine, then R 2 cannot be unsubstituted phenyl, vi) when R 7 is chloro, R 5 , R 6 and R 8 are hydrogen, and R 3 is hydrogen, (a) R 2 may not be unsubstituted phenyl, pyridyl, thienyl or furyl (b ) R 9 or R 12 may not be hydroxy when R 10 and R 11 are hydrogen, vii) when R 2 is unsubstituted phenyl, R 6 , R 7 and R 8 are hydrogen, and R 3 is hydrogen, R 5 cannot be —CO 2 H, viii) when R 2 is unsubstituted pyridin-2-yl, R 5 and R 7 are hydrogen, and R 3 is hydrogen, then R 6 or R 8 must not be chloro, ix) If R 2 is unsubstituted phenyl, R 3 is hydrogen, and R 5 and R 7 are hydrogen, then R 6 or R 8 must not be chloro. [2" claim-type="Currently amended] The method of claim 1, R 3 is fluoro. [3" claim-type="Currently amended] The method of claim 1, R 1 is Ph 1 and one of R 5 , R 6 , R 7 or R 8 is fluoro, bromo, chloro, methyl or trifluoromethyl. [4" claim-type="Currently amended] The method of claim 1, R 1 is Ph 1 and R 5 is fluoro, bromo, chloro, methyl or trifluoromethyl. [5" claim-type="Currently amended] The method of claim 2, R 1 is Ph 1 and R 5 is fluoro, bromo, chloro, methyl or trifluoromethyl. [6" claim-type="Currently amended] The method of claim 1, R 2 is Ph 2 and R 9 is fluoro, chloro, -CN or hydroxy or R 10 is -CHO, chloro, fluoro, methyl, (C 1 -C 6 ) alkyl-NH- (CH 2 ) p- , di (C 1 -C 6 ) alkyl-N- (CH 2 ) p -or cyano. [7" claim-type="Currently amended] The method of claim 2, R 2 is Ph 2 and R 9 is fluoro, chloro, -CN or hydroxy or R 10 is -CHO, chloro, fluoro, methyl, (C 1 -C 6 ) alkyl-NH- (CH 2 ) p- , di (C 1 -C 6 ) alkyl-N- (CH 2 ) p -or cyano. [8" claim-type="Currently amended] The method of claim 1, R 1 is heteroaryl optionally substituted with halo, —CN, CF 3 or (C 1 -C 6 ) alkyl. [9" claim-type="Currently amended] The method of claim 2, R 1 is heteroaryl optionally substituted with halo, —CN, CF 3 or (C 1 -C 6 ) alkyl. [10" claim-type="Currently amended] The method of claim 6, R 1 is heteroaryl optionally substituted with halo, —CN, CF 3 or (C 1 -C 6 ) alkyl. [11" claim-type="Currently amended] The method of claim 1, R 1 is pyridin-3-yl optionally substituted with chloro or methyl. [12" claim-type="Currently amended] The method of claim 1, R 1 is pyridin-3-yl substituted with chloro or methyl at the 2-position of the pyridine ring. [13" claim-type="Currently amended] The method of claim 1, An optionally substituted 6 membered heterocycle (ie, pyrimidin-2-yl) wherein R 2 is “K”, “L” and “M” is carbon or “K” and “L” are carbon and “M” is nitrogen ) Or "T" is nitrogen, "P" is sulfur, "Q" is carbon, "T" is nitrogen or sulfur, "Q" is nitrogen or sulfur, "P" is carbon or "T" is oxygen and "P" And "Q" are heteroaryl, each of which is an optionally substituted 5-membered heterocycle, which is carbon. [14" claim-type="Currently amended] The method of claim 1, R 2 is “K”, “L” and “M” is carbon and R 14 is hydrogen, —CHO, chloro, fluoro, methyl, (C 1 -C 6 ) alkyl-NH— (CH 2 ) p − , Di (C 1 -C 6 ) alkyl-N- (CH 2 ) p -or cyano or R 17 is hydrogen, -CHO, chloro, fluoro, methyl, (C 1 -C 6 ) alkyl-NH- ( C 1 -C 6 ) alkyl-, di (C 1 -C 6 ) alkyl-N- (C 1 -C 6 ) alkyl- or cyano or R 15 or R 16 is independently hydrogen, —CHO, chloro, A compound that is an optionally substituted 6 membered heterocycle that is fluoro, methyl or cyano. [15" claim-type="Currently amended] The method of claim 1, R 2 is “K”, “L” and “M” is carbon and R 14 is hydrogen, —CHO, methyl, (C 1 -C 6 ) alkyl-NH— (CH 2 ) p −, di (C 1 -C 6 ) alkyl-N- (CH 2 ) p -or cyano which is an optionally substituted 6 membered heterocycle. [16" claim-type="Currently amended] The method of claim 1, An optionally substituted 5-membered wherein R 2 is “T” is nitrogen, “P” is sulfur, “Q” is carbon and R 14 , R 15 or R 16 are each independently hydrogen, chloro, fluoro, methyl or cyano Heterocycle compound. [17" claim-type="Currently amended] The method of claim 1, An optionally substituted 5-membered wherein R 2 is “T” is nitrogen or sulfur, “Q” is sulfur or nitrogen, “P” is carbon and R 14 or R 15 is independently hydrogen, chloro, fluoro, methyl or cyano Heterocycle compound. [18" claim-type="Currently amended] The method of claim 1, A compound selected from the group consisting of: 3- (2-chloro-phenyl) -2- [2- (5-diethylaminomethyl-2-fluoro-phenyl) -vinyl] -6-fluoro-3H-quinazolin-4-one; 3- (2-chloro-phenyl) -2- [2- (6-diethylaminomethyl-pyridin-2-yl) -vinyl] -6-fluoro-3H-quinazolin-4-one; 3- (2-Chloro-phenyl) -2- [2- (4-diethylaminomethyl-pyridin-2-yl) -vinyl] -6-fluoro-3H-quinazolin-4-one; 3- (2-chloro-phenyl) -2- [2- (6-ethylaminomethyl-pyridin-2-yl) -vinyl] -6-fluoro-3H-quinazolin-4-one; 3- (2-Bromo-phenyl) -2- [2- (6-diethylaminomethyl-pyridin-2-yl) -vinyl] -6-fluoro-3H-quinazolin-4-one; 3- (2-Chloro-phenyl) -6-fluoro-2- [2- (6-methoxymethyl-pyridin-2-yl) -vinyl] -3 H-quinazolin-4-one; 6-fluoro-3- (2-methyl-pyridin-3-yl) -2- [2- (2-methyl-thiazol-4-yl) -vinyl] -3H-quinazolin-4-one; 3- (2-Chloro-phenyl) -6-fluoro-2- [2- (4-methyl-pyrimidin-2-yl) -vinyl] -3 H-quinazolin-4-one; 3- (2-Chloro-phenyl) -6-fluoro-2- {2- [6- (isopropylamino-methyl) -pyridin-2-yl] -ethyl} -3 H-quinazolin-4-one; And 2- [2- (5-Diethylaminomethyl-2-fluoro-phenyl) -vinyl] -6-fluoro-3- (2-methyl-pyridin-3-yl) -3H-quinazolin-4- On. [19" claim-type="Currently amended] Bypass surgery of the heart of mammals and brain defects after transplantation, seizures, cerebral ischemia, spinal cord trauma, head trauma, Alzheimer's disease, Huntington's chorea, muscular dystrophy, AIDS dementia, muscle cramps, migraine, Urinary incontinence, psychosis, convulsions, hypoxia at birth, heart failure, hypoglycemic nerve damage, opioid tolerance and indulgence, eye damage, retinal disorders, idiopathic and drug parkinson's disease, anxiety, vomiting, brain edema, chronic pain, delayed exercise A pharmaceutical composition for treating or preventing said condition comprising an amount of the compound according to claim 1 and a pharmaceutically acceptable carrier effective for treating or preventing a condition selected from the group consisting of abnormalities and anesthesia. [20" claim-type="Currently amended] Brain defects, seizures, cerebral ischemia, spinal cord trauma, head trauma, Alzheimer's disease, Huntington's chorea, amyotrophic lateral sclerosis, AIDS dementia, muscle spasms, migraine, urinary incontinence, psychosis , Convulsions, hypoxia at birth, heart failure, hypoglycemic nerve damage, opioid tolerance and addiction, eye damage, retinal disorders, idiopathic and drug Parkinson's disease, anxiety, vomiting, brain edema, chronic pain, delayed dyskinesia and anesthesia A method of treating or preventing a condition comprising administering to a mammal in need thereof said compound according to claim 1 in an amount effective to treat or prevent a condition selected from the group consisting of: [21" claim-type="Currently amended] Brain defects, seizures, cerebral ischemia, spinal cord trauma, head trauma, Alzheimer's disease, Huntington's chorea, amyotrophic lateral sclerosis, AIDS dementia, muscle spasms, migraine, urinary incontinence, psychosis , Convulsions, hypoxia at birth, heart failure, hypoglycemic nerve damage, opioid tolerance and addiction, eye damage, retinal disorders, idiopathic and drug Parkinson's disease, anxiety, vomiting, brain edema, chronic pain, delayed dyskinesia and anesthesia A pharmaceutical composition comprising an AMPA receptor antagonist effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier for treating or preventing a condition selected from the group consisting of: [22" claim-type="Currently amended] Brain defects, seizures, cerebral ischemia, spinal cord trauma, head trauma, Alzheimer's disease, Huntington's chorea, amyotrophic lateral sclerosis, AIDS dementia, muscle spasms, migraine, urinary incontinence, psychosis , Convulsions, hypoxia at birth, heart failure, hypoglycemic nerve damage, opioid tolerance and addiction, eye damage, retinal disorders, idiopathic and drug Parkinson's disease, anxiety, vomiting, brain edema, chronic pain, delayed dyskinesia and anesthesia A method of treating or preventing a condition comprising administering an AMPA receptor antagonist effective amount of a compound according to claim 1 to a mammal in need of treating or preventing a condition selected from the group consisting of:
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同族专利:
公开号 | 公开日 HK1019607A1|2003-11-07| JP3241388B2|2001-12-25| SK284108B6|2004-09-08| CN1103772C|2003-03-26| PL330042A1|1999-04-26| AT242232T|2003-06-15| TR199802296T2|1999-02-22| GT199700049A|1998-10-21| IS4881A|1998-10-27| AU1554997A|1997-12-05| HU9902148A3|2002-11-28| HRP970261A2|2000-12-31| MA26430A1|2004-12-20| CN1218464A|1999-06-02| KR100375155B1|2003-08-19| AR007118A1|1999-10-13| NO985293L|1999-01-13| CA2252907C|2005-05-17| CZ352698A3|1999-11-17| AU730503B2|2001-03-08| ES2198546T3|2004-02-01| PT901487E|2003-08-29| EP0901487A1|1999-03-17| BR9709085A|1999-08-03| AP1148A|2003-02-28| AP9701003A0|1997-07-31| WO1997043276A1|1997-11-20| EA199800923A1|1999-06-24| DE69722613T2|2004-05-13| DE69722613D1|2003-07-10| NO985293D0|1998-11-13| CZ295565B6|2005-08-17| JPH11514663A|1999-12-14| IL126589A|2003-06-24| TW539675B|2003-07-01| CA2252907A1|1997-11-20| BG102999A|1999-09-30| TNSN97087A1|2005-03-15| HN1997000052A|1997-06-26| EA002905B1|2002-10-31| YU19197A|1999-09-27| HRP970261B1|2003-06-30| OA10918A|2001-10-25| IL126589D0|1999-08-17| ID17149A|1997-12-04| DK901487T3| SK152098A3|2000-05-16| US6303615B1|2001-10-16| EP0901487B9|2004-09-29| ZA9704156B|1998-11-16| HU9902148A2|2000-04-28| DK0901487T3|2003-08-25| CN1420114A|2003-05-28| EP0901487B1|2003-06-04| DZ2237A1|2002-12-03| SI0901487T1|2003-10-31|
引用文献:
公开号 | 申请日 | 公开日 | 申请人 | 专利标题
法律状态:
1996-05-15|Priority to US1773896P 1996-05-15|Priority to US60/017,738 1997-02-17|Application filed by 스피겔 알렌 제이, 화이자 인코포레이티드 2000-02-25|Publication of KR20000011054A 2003-08-19|Application granted 2003-08-19|Publication of KR100375155B1
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