MXPA97003610A

MXPA97003610A - New (5,6) -heteroaril condensate-pyrimidin-4-onas 2,3 disustitui

Info

Publication number: MXPA97003610A
Application number: MXPA/A/1997/003610A
Authority: MX
Inventors: Leo Chenard Bertrand; Leonard Elliott Mark; Mckowan Welch Willard Jr
Original assignee: Pfizer Inc
Priority date: 1996-05-15
Filing date: 1997-05-14
Publication date: 1998-10-30

Abstract

The present invention relates to: New compounds of the formula I, described above, to their pharmaceutically acceptable salts, to pharmaceutical compositions and to methods of treatment of neurodegenerative and trauma-related conditions of the S

Description

NIJFVAS f S B) -HETEROORTL CONDENSflDO-PIRiriIDIN-4-ONflS 2. 3 PISUSTITUIPflS BACKGROUND OF THE INVENTION The present invention relates to new compounds of formula I described below, to their pharmaceutically acceptable salts, to pharmaceutical compositions and to processes for the treatment of neurodegenerative and CNS trauma related conditions. The compounds of the invention are potent antagonists of the AUPA receptor. The AtIPA receptors are a subspecies of glutamate receptors, identified by their ability to bind a-amino-3-hydroxy-5-rnetyl-4-isoxazolepropionic acid (AMPA), which are involved with or post-synaptic neurotransmitter receptors for amino acids. Exciters The power of excitatory amino acids, such as glyceric acid and aspartic acid, as the predominant mediators of the excited synaptic transmission of the central nervous system, is well established. Ualtkins and Evans, Ann. Rev. Pharmacol. Tnxicol .. 21, 165 (1981); l? onaghan, Bridges and Cot an, Ann. Rev. Pharmacol. Toxicol .. 29, 365 (1989); Uatkins, Krogsgaard-Larsen and Honore, Trans. Pharm. Soi .. ll, 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. The receptors of the excitatory amino acids are classified into two general types. The receptors that are directly coupled with the opening of cation channels in the cell membrane of neurons are called "ionotropic". This type of receptor has been subdivided into at least three subtypes, which are defined by the depolarizing actions of the selective agonists N-met? LD-aspartate (NMDA), a-amino-3-h? Drox? -5-rnetil acid ? soxa;? ol ~ 4-propion? co (AMPA) and cainic acid (KA). The second general type is the G protein or "metabotropic" excitatory amino acid receptor bound to the second messenger. This second type, when activated by the agonists quisqualate, ibotenate or trans-l-aminoc? Clopentane-1,3-d? Carboxy? Co acid, produces an increase in the hydrolysis of phosphoinositide in the post-synaptic cell. Apparently, the two types of receptors not only mediate the normal synaptic transmission along the excitatory pathways, but also participate in the modification of the synaptic connection during development and in the changes of the efficiency of the synaptic transmission throughout of the life. Shoepp, Bockaert and Sladeczek. Trends in Pharmacol. Ser .. 11, 508 (1990); McDonald and ZJohnson, Bram Research Revieus. 15, 41 (1990).

Excessive or inappropriate stimulation of excitatory amino acid receptors leads to injury to neuronal cells or loss thereof by means of a mechanism known as excitotoxicity. It has been suggested that this process "edia neuronal degeneration in a variety of conditions. The medical consequences of such neuronal degeneration make the alleviation of these degenerative neurological processes an important therapeutic goal. The excitotoxicity of excitatory amino acids has been implicated in the pathophysiology of numerous neurological disorders. This excitotoxicity has been implicated in the pathophysiology of acute and chronic neurodegenerative conditions including cerebral deficits following 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, choking, suffocation, electrocution or overdose of drugs or alcohol), cardiac arrest , hypoglycemic neuronal injuries, eye lesions, retinopathy and idiopathic and drug-induced Parkinson's disease. Other neurological conditions caused by glutamate dysfunction require neuromodulation. Other neurological conditions include muscle spasms, headaches, urinary incontinence, psychosis, addiction withdrawal syndrome (such as alcoholism and addiction to drugs including opioid addiction, cocaine and nicotine), opioid tolerance, anxiety, emesis, cerebral edema, chronic pain, seizures, retinal neuropathy, tinnitus and tardive dyskinesia. The use of a neuroprotective agent, such as an AMPA receptor antagonist, is considered useful in the treatment of these disorders and / or in reducing the amount of neurological injury associated with these disorders. EAA antagonists are also useful as analgesic agents. Several studies have shown that AMPA receptor antagonists are neuroprotective in focal and global ischemia models. It has been shown that the competitive AMPA receptor antagonist NBOX (2,3-dihydroxy-6-nitro-7-sulfa oilbenzoLf-lquinoxaline) is effective in the prevention of global and focal ischemic lesions. Sheardown et a .. Science, 247, 571 (1900); Buchan = i al. , Neu oreno t. 2, 473 (1991); LePeillet e ± al, Brain Research. 571, 115 (1992). It has been shown that non-competitive AMPA receptor antagonists GKYI 52466 are effective neuroprotective agents in models of global ischemia in rats. LaPeiller yes al-, Brain Research. 571, 115 (1992). These studies strongly suggest that delayed neuronal degeneration in cerebral ischemia involves excitotoxicity of glutamate mediated, at least in part, by activation of the AMPA receptor. Thus, AMPA receptor antagonists may be useful as neuroprotective agents and improve the neurological consequences of cerebral ischemia in humans.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to a bicyclic compound of the formula wherein A is a fused heteroaromatic ring, wherein said heteroaromatic ring is a 5- or 6-membered heteroaromatic ring, wherein said 6-membered heteroatom ring, taken together with the carbon atoms common to the two rings of the bicyclic system, has the formula and where said 5-membered heteroaromatic ring, taken together with the carbon atoms of the two rings of the bicyclic system, has the formula wherein said positions of the ring "A", "B", "D" and "E" can be independently selected from carbon or nitrogen; where said ring positions "F", "G" and "3" can be independently selected from carbon, nitrogen, oxygen or sulfur, with the proviso that: i) if more than two of "F", "G" or " 3"are heteroatoms, then said 5-membered heteroarsophytic ring is selected from the group consisting of (1,2,3) -triazole, (1, 2,3) -triadiazole, (1,2,5) -triadiazole and ( l, 2,5) -oxidiazole; and ii) if two of "F", "G" or "3" are heteroatoms, one of said heteroatoms may be oxygen or sulfur; wherein said fused heteroaromatic rings may optionally be substituted independently on any of the carbon or nitrogen atoms capable of forming an additional bond with a substituent selected from hydrogen, (C -C?) alkyl, halogen, trifluoromethyl, amino- (CH2) n -, alquilaraino. { Ca.-C4 - (CHa) r? -, dialkylamino (C -C *) - (CHa ^ -, alkoxy (C-C?), Hydroxyalkyl (C-C), alkyloC-Cs.) -O-alkyl ( C -C * -CN, alkyl (C? -CA) -C (= 0) -0-alkylCi-Cß), alkyl (C3-C4Sh) -0 ~ C (= 0) -0-alkyl (C? - C "&), alkyl (C -C" -C (= 0) -0-, hydroxy, -N0a, R3-C (= 0) -, R * -0-C (= 0) -, dialkyl ( C -C?) - NC (= 0) -, cycloalkyl? C? -C?) And R * -NH-C (= 0) - and phenyl optionally substituted with halo, alkyl (C? -C "?), - CN or -CF3; R is optionally substituted phenyl of the formula Ph * or heteroaryl, wherein said heteroaryl is selected from the group consisting of pyridin-2-yl,? Iridin-3-yl, pyridin-4-yl, wherein said heteroaryl may be optionally substituted on the any of the atoms capable of forming an additional bond, with up to a maximum of three substituents, with a substituent selected from hydrogen, alkyl (C -CS), halogen, trifluoromethyl, amino- (CHs »), -, -, alkylamino ( C -C 's) - (CHi2) r? -, dialkylaminoyCx-Cßl-ÍCHzJr, -, alkoxyCx-C *), hydroxyalkyl (Cx-C *), alkyl (C? -C' s,) -O-alkyl (C? -C?), -CN, alkyl (Cx-Cs) -C (= 0) -O-alkyl (Cx-C *, alkyl (C -C *) - 0-C (= 0) -0 -alkyl (Cx-C *), alkyl (Cx-C *) -C (= 0) -0-, hydroxy, HC (= 0), alkyl (C-C) -0-C (= 0) -, NHa-C (= 0) -, alkyl (C -C?) -NH-C (= 0) - and dialkyl (C? ~ CA) -NH-C (= 0) -; wherein said Ph3- is ur. group of the formula Ra is phenyl of the formula Phz or a five or six membered heterocycle, wherein said six membered heterocycle has the formula R 16 wherein "N" is nitrogen; wherein said ring positions "K", "L" and "M" can be independently selected from carbon or nitrogen, with the proviso that only one of "K", "L" or "M" can be nitrogen; where said five-membered heterocycle has the formula wherein said positions of the ring "P", "0" and "T" can be independently selected from carbon, nitrogen, oxygen or sulfur; with the proviso that only one of "P", "0" or "T" can be oxygen or sulfur and at least one of "P", "0" or "T" must be a heteroatom; where said Ph2 is a group of the formula R3 is hydrogen or alkyl (C? -Cβ); R * is hydrogen or alkyl (C? -C?); Ra is hydrogen, alkyl (Cx-C < s), halo, CF3, alkoxy (C? -C?), Or alkylthiol (C? -C?); R * is hydrogen or halo; R "7" is hydrogen or halo; Rβ is hydrogen or halo; R ** is hydrogen, (C-C) alkyl optionally substituted with one to three halogen atoms, halo, CF3, (C? -C 's) alkoxy optionally substituted with one to three halogen atoms, alkylthiol (C? C «s), Rx30- (CHa) * > -, alkyl (C? -C *) ~ NH- (CHa) p ~, dialkyl (C? -Cs) -N- (CHa) e > -, cycloalkyl (C? -Ca) - NH ~ (CHalp-, HaN- (C = 0) - (CH5i) fa-, alkyl (Cx-C * -NH- (C = 0) - (CHa) p-, dialkyl cycloalkyl (C -Cs) -NH - (C = 0) - (CHa) "-, R * -a0- (C = 0) - (CHa) * > -, alkyl (C? -C?) - (0 = C) -O-alkyl (Cx-C *) -, alkyl (C? -CA) -0- (0 = C) -0-alkyl (C? -C ",), alkyl (C? -C *) - (0 = C) -0-, alkyl (C? -C *) - (0 = C) -NH- (CH2) r > -, H (0 = C) - NH- (CHa) *, - alkyl (C? -C?) - (0 = C) -Nalk? Ílo (C? -Cß)) - (CHa) p-, HÍ0 = C) -N (C -C * alkyl) - (CHa) p-, hydroxy, HC (= 0) - (CHa) * > -, alkyl (C? -C *) -C (= 0) -, amino- (CHa) »-, hydroxyalkyl (C? -C« -, alkyl (C? -C?) -O-alkyl (C ? -C?) - and - CN; R * -0 and Rx * are hydrogen, (Cx-C *) alkyl optionally substituted with one to three halogen atoms, halo, CFa, (C? -Cβ) alkoxy optionally substituted with one to three halogen atoms, alkylthiol (C? -C?), R a, 0- (CH2) p- / alkyl (C? ~ C "-NH- (CHa) P-, dialkyl (C? -CA) -N- (CHa) p > -, cycloalkyl (C? -C3) -NH- (CHa) p-, HaN- (C = 0) - (CHa) P > -, alkyl (Cx-) C *) -NH- (C = 0) - - (CHa) * >, cycloalkyl (C ~ Ca) - NH- (C = 0) - (CHa) * > -, R aO- (C = 0 ) -CH) r, - alkyl (C -CA) - (0 = C) -0- alkyl (C? -C?), Alkyl (C? -C?) -0- (0 = C) -0- alkyl (C? -C ", alkyl (C? -C) - (0 = C) -0-, alkyl (Cx-C *) - (0 = 0-NH- (CHa) p-, -H (0 = C) -NH- (CHa) e, -, alkyl (Cx-C *) - (0 = C) -N- (alkyl (C? -C?)) - (CHa) p> -, H ( 0 = C) -N (alkyl (C? -C?)) - (CHa) »-, hydroxy, HC (= 0) - (CHa) * > -, alkyl (C? -CA) -C (= 0) -, alkyl amino- (CHa) * > -, hydroxy-alkyl (Cx-Ce,), alkyl oxyCx-C *) -O-alkyl (C? -C?), -CHO and -CN; R is hydrogen or halo; Rxa is hydrogen or halo; R 3 is hydrogen, alkyl (Cx-C *), alkyl (C? -C 's) ~ (C = 0) -, alkyl? C? ~ C *) -0- (C = 0) -, alkyl (Cx) -C *) -NH- (C = 0) - or dialkyl IC? -C *) -N ~ (C = 0) -; R a is hydrogen, -CN, alkyl (C? -C?), Halo, CFa, -CHO or alkoxy (Cx-Cs); R * is hydrogen, -CN, alkyl (C? -C, &), halo, CFa, -CHO, or alkoxy (C? -C?); R3- "7" is hydrogen, -CN, alkyl (C? -C?), Halo, CFa, -CHO or alkoxy (C? -C 's); n is an integer from zero to 3; p is an integer from zero to 3; where the dashed link represents an optional double bond; with the condition of; when R9 is hydrogen, one of R and Rxz is other than hydrogen; 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 aforementioned base compounds of this invention are which form non-toxic acid addition salts, ie salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate salts, Acid citrate, tartrate, bitartrate, succinate, maleic acid, fumarate, gluconate, sac ato, benzoate, methanesulfonate, ethanesulfonate, benzenesul fonate, p-toluenesulfonate and parnoate. Let say, l, m-tilen-bis ~ (2-hydroxy-3) -naftoat) 1. The invention also relates to the addition salts of bases of formula I. The chemical bases which can be used as reagents for preparing pharmaceutically acceptable base salts of these compounds of formula I which are acidic in nature, are those which form salts of non-toxic bases with such compounds. Talee salts of non-toxic bases include, but are not limited to, those derived from pharmacologically acceptable cations such as alkali metal cations (eg, potassium and sodium) and alkali earth metal cations (eg, calcium and magnesium), ammonium or salts of water-soluble amine additions such as N-methygiucarnine (meglurnin), the lower alkanolarnonium salts and other salts of pharmaceutically acceptable organic amine bases. The present invention also relates to compounds of the formula I wherein the "A", "D" or "E" atom of the 6-membered heteroaromatic ring is nitrogen or the "G" or "F" heteroatoms of the heteroaroxy ring of 5 sulfur members. Preferred compounds of formula I are those in which ring A is a 5-membered heteroaromatic ring, "G" is sulfur and "F" and "D" are carbons. Other preferred compounds of formula I are those in which ring A is a 5-membered heteroaromatic ring, "F" is sulfur and "G" and "3" are carbons. Other preferred compounds of formula I in which R x is Ph, are those in which one of R s, R b, R 7 - or R b is fluoro, bromo, chloro, methyl or trifluoromethyl, preferably R s is fluoro, bromo, chloro, methyl or tri l? oronetilo. Other preferred compounds of formula I in which Rx is Pha, are those in which R is fluoro, chloro, -CN or hydroxy; or R o is -CHO, chloro, fluoro, methyl, alkyl (C? -C?) - NH- (CHa) *, -, dialkyl (C? -Os) -N- (CHa) - * > - or cyano. Other preferred compounds of formula I in which R is heteroaryl, are those in which heteroaryl is pyridin-3-yl, optionally substituted with halo, -CN, CF3 or alkyl (C? -C **? Preferably chlorine or methyl, more preferably substituted at the 2-position. Preferred compounds of formula I wherein Ra is heteroaryl, are those in which the heteroaryl is optionally substituted pyrid-2-yl, 1,3-thiazol-4-yl, 1, 3-thiazol-2-yl or fur-2-yl, preferably pyrid-2-yl optionally substituted with -CHO, chloro, fluoro methyl, alkyl (C? -C?) - NH- (CHa) * > -, dialkyl (C -CA) -N- (CHa) * > - or cyano; 1,3-thiazol-4-yl substituted with chloro, fluoro, methyl or cyano; ol, 3-thiazol-2-yl substituted in the position 4 with methyl The most preferred compounds of the formula I in which G is sulfur and F and 3 are carbons, are those in which: R and Ph and Rs is methyl, chloro, trifluoromethyl or bromine, and R2 is phenyl ,? iridin-2-yl or (l, 3) -thiazol-2-yl or (l, 3) -thiaz ol-4-yl; wherein said phenyl is Pha and R is chloro, fluoro, -CN or hydroxy; said pyridin-2-yl is optionally substituted by methyl, -CN, alkylC? -C?) - NH- (CHa) p-, dialkyl (C? -C?) - N- (CHa), »-, more preferably substituted in the 6-position with methyl or in the 3-position with -CN; said (1, 3) -thiazol-2-yl is optionally substituted in the 2-moiety with -CHa; and said (1,3) -thiazol-4-yl is optionally substituted in the 2-position with -CHa; The most preferred compounds of formula I in which F is sulfur and G and 3 are carbons, are those in which: R is Ph and Rs is methyl or chloro; and R = is Ph2 and R ** is fluoro or -CN, or? iridin-2-yl optionally substituted with methyl, -CN, alkyl (C-β) -NH- (CHa) p- or dialkyl (C? C *) - N- (CHZ) 0-. Preferred specific compounds of formula I are: 3- (2-chloro-phenyl) -2- C 2- (2-fluoro-enyl) -vinyl] -3H-thienoE3, 2-d3p? rimidin-4-on; 3- (2-methylphenyl) -2-C2-chloroenylvinyl] -3H-thienoC3,2-d3? Irimidm-4-one; 3- (2-tri luoromethyl-phenyl) -2- [2-fluoro in l-vi-nyl-3-3H-thienoC3,2-d3-pyrimidin-4-one; 3- (2-chloropyrid-3-yl) -2-C2-fluoro-phenyl) -vinyl] -3H-thienoC3, 2-d] pyrimidin-4-one; 3- (2-methylphenyl) -2-C6-carboxaldehyde-pyrid-2-yl-vi nil3-3H-thien C3, 2-d-3-pyrimidin-4-one; 3- (2-methi Ipi rid-3-yl) -2- C2-f luorophenyl) -vini 13 -3H-thienoC3,2-d3pi imidin-4-one; 3- (2-chlorophenyl) -2- (2-pyridin-2-yl-vinyl-3H-thienoT3,2-d3pi rimidin-4-one; 3- (-methyl phenyl) -2- (2-fluoro-phenyl) vi) nyl) -3H-thienor3, 2-d3-pyrimidin-4-one; 3- (2-methyl phenyl) -2-C2- (2-fluoro-phenyl) -vinyl-3H-thienoC3,2-d pyridin-4 -one; 3- (2-chloro-pyridin-3-yl) -2-C2- (2-methyl-thiazol-4-yl) -vinyl-3H-thienoC3,2-d] pyrimidin-4-one; 3- (2-rnethyl-pyridin-3-yl) -2-C2- (2-rnethyl-thiazole-4-iD-vinyl-3H-t-eneC3,2- 3-pyriridin-4-one; -chlorophenyl) -2-C2-hydroxy enyl) -vinyl-3H-thieno [3,2-d3p? rimi i n- -one; and 3- (2-chloro-enyl) -2-r2-pyrid-2-yl-vinyl-3H-thieno [3,2-d-pyrimidin-4-one. Specific compounds of this invention are: 3- (2-methylphenyl) -2-C2-brom phenyl-vinyl-3H-ienoC3,2-d3p? Rimid? N-4-na; 3- (2-chlorophenyl) -2-C2-methoxyphenyl-vinyl-3H-thienoC3, 2-d3-pyrimidin-4-one; 3- (2-chlorophenyl) -2- 4-methoxy-phenyl-vi or 1 -3H-thienoC3 2-d-pyrimidinone-3- (2-methyl phenyl) -2- [4-carbomethoxy-phenyl-vinyl] -3H-thienoC3,2-d3p-rimidin-4-one; 3- (2-methylphenyl) ) -2-i: 2 ~ pyrid-2-yl-vinyl-3H-thienoC3,2-d-pyrimidin-4-one; 3- (2-bromo-enyl) -2- [2-pyrid-2-yl-vinyl] .I-3H-thieno [3,2-d-pyrimid-n-4-one; 3- (2-methylphenyl) -2-C2-methoxyphenyl-vinyl-3-H-thienoC3,2-d3-pyrimidin-4-one; - (2-methyl phenyl) -2-C2-hydroxyphenyl-inyl-3H-thienoC3,2-d3-pyrimidin-4-one; 3- (2-methyl phenyl) -2- (2-pyridin-2-yl-vinyl) -3H-thienoC3,2-d3pirimi in-4 ~ ona; 2-C2- (2-luoro-phenyl) -vinyl -3-o-tolyl-3H-pteridin-4- .1.6 ona; 3- (2-methyl phenyl) -2- (2-pyridin-2-yl-vinyl) -3H-pteridin-4-one; 3- (2-chloro phenyl) -2- (2-fluoro-phenyl-vinyl) -3H-pteridin-4-one; 3- (2-chlorophenyl-2- (2-pyridin-2-yl-vinyl) - 3H-pteri-4-one; 2-E2- (2-fluoro-phene) -vinyl-3-3-o-tolyl-3H-pyridoE3,4-d-pyrimidin-3-phenyl (2-chloro-phenyl) ~ 2- (2-pyridin-2-yl-ethyl) -3H-thienoE3,2-d-pyrimidin-4-one; 3- (2-phenyl-phenyl) -2- (2-f-luoro-phenyl-ethyl) - 3H-thienoC 3, 2-d3 pi imi innonone: 3- (2-methyl-phenyl) -2- (2-pi ridin-2-yl-ethyl) -3H-thienoE3,2-d3pi rimidin- 4-one; 3- (2-methyl-phenyl) -2- (2-pyridin-2-yl-ethyl) -3H-thienoE3,4-dlpyrimidin-4-one; 3- (2-chloro-phenyl) -2- (2-pyridin-2-ethyl) -3H-thieno 3,4-d 3-pyrimidin-4-one; 5- (2-pyridin-2-yl-vinyl) -6-o-tolyl-3 , 6-dihydroyl, 2,33-triazole-4,5-d3-pyrimidin-7-one; 2- 2- (2-fluorophenyl) -vinyl-3-6-ethyl-3-o-tolyl-3H-thienoC3,2-d3-pyrimidin-4 -one 3- (2-chlorophenyl) -2- E 2- (2-fluorophenyl) -vinyl-5-methyl-3H-thienoE3,4-d] pyrimido-4-one; 2- 2- (2- f luo rof enyl J - vinyl3-6-methyl- (2-chlorofonyl) -3H-thienoE3,2- nipyrimidin-4-one; 3- (2-methyl phenyl) -2-E2- (2-fluor) ofhenyl) -vinyl 3-5-rnethyl-3H-t.ienoE3,4-d3-pyrimidin-4-one; 2-E2- (2-hydroxyphenyl) -vinyl-3-6-methyl-3-o-tolyl-3H-thienoE3,2-d] pyrimidin-4-one; 3- (2-chlorophenyl) -2-E2- (2-hydroxyphenyl) -vinyl-3-methyl-3H-thienoE3,4-d3-pyrimidin-4-one; 2-C2- (2-hydroxy-phenyl) -vinyl-6-rnethyl-3- (2-chloro-phenyl) -3H-thienoC3,4-d-3-pyrimido-4-alan; 3- (2-methylphenyl) -2-E2- (2-hydroxyphenyl) -vinyl-3-methyl-3H-thienoE3,4-d3-pyrimidin-4-one; 2- (2-chloro-phenyl) -vinyl-6-ethyl-3-o-tolyl-3H-thienoE3,4-d3p-rimidin-4-one; 3- (2-chlorophenyl) -2- 2- (2-chlorophenyl) -vinyl 3 -5-methyl-3H-thienoE 3, 2-d-pyrimidin-4-one; 2- E 2- (2-chloro-phenyl) -vinyl-3-6-methyl-3- (2-chloro-phenyl) -3H-thieno-3,2-di-pyrimidin -one; 3- (2-methyl phenyl) -2-E2- (2-chlorophenyl) -vinyl-5-methyl-3H-thieno 3,4-d-pyrimidin-4-one; 2- 2- (2-f luorophenyl J- vini 1 -6-met.i 1-3- (2-t rif luoromethyl enyl) -3H-thieno 3,2 -d3pi imi din-4-one; 3- ( 2-trif luoro phenyl) -2- 2- (2-fluoro phenyl) -vini 13 -5-methyl-3H-thienoE3,4-d3pyrimidin-4-onaj 2-E2- (2-fl orophenyl) -vinyl3- 6- ethyl-3- (2-chloropyridin-3-yl) -3H-thienoE3,2-d3-pyrimidin-4-one; 3- (2-met.-ilpyridin-3-yl) -2-E2- (2- fluoro) phenyl) -vinyl 3-5-rnethyl-3H-t-eneE3,4-d3p? rimidin-4-one; 2-C2- (2-hydroxy in? l) -v? n? l3-6-rnet l-3- (2-tr? fluoromet? lphenyl) -3H-thienoC3,2-d3p? ri id? n-4-one; 3- (2-tp luo-phenyl) -2- 2- (2-h? drox? nyl) -vinyl 3-5-rnethyl-3H-? enoC3,4-d3-pyrimidi-n-4-one; 2-E2- (2-hydroxyphenyl?) -vinyl-3-fi-methyl-3- (2- chloropi p m-3-? l) -3H-thieno 3,2- 3p?? mi i-n-4 -one; 3- (-methylpyridin-3? l) -2- 2- (2-hydroxyphenyl) ) -v? nil3 5-rnethyl-3H-t-ene 3,4-d3p? rirn? n-4 -one; 2- 2- (2-chloro phenyl) -vinyl 3-6-rnetyl-3- (2 -chloro-pyridin-3-? l) -3H-thieno-3-, 2- 3-pyrimidin-4-one; 3- (2-chloropyridin-3-yl) -2-E2- (2-chlorophenyl) -vini 13- 5-me? L-3H-thienor3,4-d pyrimidin-4-one; 2- 2- (2-chloro) ofhenyl) -vinyl-3-6-methyl-3- (pyridin-2-yl) ~ 3H-thieno-3, 2-d3-pyrimidin-4-one; 3- (2-methyl phenyl) -2- E 2- (-p? I in-2-yl) -vinyl3-5-met? L-3H-thienoE 3,4- 3 pyrimidine- 4 -on; 3- (2-chlorophenyl) -2-El, 3-thiazol-4-yl-vinyl-3-6-methyl-3H-thieno-3,2-d3-pyrimidin-4-one; 3- (2-methyl phenyl) -2-Cl, 3-thiazol-4-yl-vinyl 3-5-rnet? L- 3 H -thienoE3,4-d3pyrimidin-4-one; 3- (2-chlorophenyl) -2-El, 3-t-azol-2-yl-vinyl 3-6-chloro-3H-t-ene 3,2- 3-pyrimidin-4-one; 3- (2-methylphenyl) -2-E, 3-thiazol-2-yl) -vinyl-3-chloro-3H-thienoE3,2-dl-pyrimidin-4-one; 3- (2-chlorophenyl) -2-Cl, 3-thiazol-4-yl-vinyl-3-H-thienoE3, 2-d3-pyrimidin-4-one; 3- (2-methyl phenyl) -2- The, 3-thiazo.l -4 -yl-vinyl 3 -3H-t.ienoC3,2-d3p? Rimi in-4-one; 3- (1-chlorophenyl) -2- 1, 3-thiazole -2-yl-v.inyl.3-3H-thienoE3, 2-d3-pyriridin-4-one; 3- (2-methylphenyl) -2- l, 3-ti zol-2-yl • ~ vinyl-3H-thienoE3, 2-d3p? Rimidin-4-one; 3- (2-chlorophenyl) -2-C2- (2-cyanophenyl) -vinyl3-3H-thieno 3,2-d3p? Rimidin-4-one; 3- (2-methylphenyl) -2 ~ E2 ~ cyanophenyl-vinyl3-3H-t..i.enoE3,2-d3pyrirnidin-4-one; 3- (2 -trif luo ometil-phenyl) -2 -E 2 -ciano eni. I- vi nyl 3 -3H-thieno 3, 2- d pyrimidin -one, • 3- (2-chloro? Irid-3-yl) -2-E2-cyanophenyl-vinyl3-3H-ti eneE 3.2- 3 pirimi in- 4 -on; 3- (2-Rethyl-phenyl) -2-E6-cyano-pyrid-2-yl) -vinyl-3H-thienor-3, 2- 3-pyrimidin-4-one; 3- (2-methylpyrid-3-yl) -2-E2-cyanophenyl-vinyl.3 -3H-thienol3,2-d-pyrimidin-4-one; 3- (2-chlorophenyl) -2-E2-cyanopyridin-2-yl-vinyl-3-3H-thienoE3, 4-d3-pyrimidin-4-one; 3- (2-methylphenyl) -2- (2-cyanophenyl-vinyl-3-3H-thieno-3,4-d3-pyrimidin-4-one; 3- (2-methyl-phenyl) -2-E2- (2-cyanophenyl); -vinyl 3-3H-t ienoE 3, 2-d3 pyrimido-4-a, 3- (2-chlorophenyl) -2-E2-cyanopyrid-2-yl) -vinyl.3-3H-thienoE3, 2-d3pyrimidine -4-one and 3- (2-chlorophenyl) -2-E2-hydroxyphenyl-vinyl I-3H-thienoE3, 2-d3-irimidin-4-one This invention also relates to a pharmaceutical composition for treating or preventing a condition selected from cerebral deficits after cardiac bypass surgery and grafts, stroke, cerebral ischemia, spinal cord injury, head trauma, Alzheimer's disease, Huntington's disease, lateral sclerosis to iotrophic, epilepsy, dementia-induced dementia AIDS, muscle spasms, migraines, urinary incontinence, psychosis, convulsions, perinatal hypoxia, hypoxia (such as the conditions caused by strangulation, surgery, inhalation of smoke, suffocation, choking, suffocation, electrocution or over drug or alcohol dosing), cardiac arrest, hypoglycaemic neuronal lesions, opioid tolerance, addiction withdrawal syndrome (such as alcoholism and drug addiction including opioid addiction, cocaine and nicotine), eye lesions, retinopathy, neuropathy retinal, tinnitus, idiopathic and drug-induced Parkinson's disease, anxiety, emesis, cerebral edema, chronic or acute pain or tardive dyskinemia, in a mammal, comprising a quantity of compound of formula I effective in the treatment or prevention of 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 following cardiac bypass surgery and grafts, stroke, cerebral ischemia, spinal cord trauma, head trauma, Alzheiner's disease, Huntington's disease. , lateral sclerosis to iotrophic, epilepsy, AIDS-induced dementia, muscle spasms, migraines, urinary incontinence, psychosis, seizures, perinatal hypoxia, hypoxia (such as the conditions caused by strangulation, surgery, inhalation of smoke, suffocation, choking, suffocation , electrocussion or overdosage of drugs or alcohol) v cardiac arrest, hypoglycemic neuronal lesions, tolerance to opiates, withdrawal syndrome due to addiction (such as alcoholism and addiction to drugs including opioid addiction, cocaine and nicotine), eye injuries , retinopathy, retinal neuropathy, tinni us, Enfermed idiopathic and drug-induced Parkinson's disease, anxiety, emesis, cerebral edema, chronic or acute pain or tardive dyskinesia, in a mammal, which comprises administering to a mammal in need of such treatment or prevention, a quantity of a compound of formula I effective in the treatment or prevention of such a condition. This invention also relates to a pharmaceutical composition for treating or preventing a disorder, the treatment or prevention of which is facilitated by the increased neurotransmission of glutamate in a mammal, which comprises an amount of - >; compound of formula I effective in the treatment or prevention of such a condition and a pharmaceutically acceptable carrier. This invention also relates to a method of treating or preventing a disorder, the treatment or prevention of which is facilitated by the increased neurotransmission of glutamate in a mammal, which comprises administering to a mammal in need of such treatment or prevention an amount of A compound of formula I effective in the treatment or prevention < 3 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, Aizheimer's disease, Korea Huntington, lateral sclerosis to iotrophic, epilepsy, AIDS-induced dementia, muscle spasms, migraines, urinary incontinence, psychosis, seizures, perinatal hypoxia, hypoxia (such as the conditions caused by strangulation, surgery, inhalation of smoke, suffocation, choking, suffocation, electrocution or overdosage of drugs or alcohol), cardiac arrest, hypoglycaemic neuronal lesions, tolerance to opiates, withdrawal syndrome due to addiction (such as alcoholism and addiction to drugs including opioid addiction, cocaine and nicotine), eye injuries , retinopathy, retinal neuropathy, tinn itus, idiopathic and drug-induced Parkineon disease, anxiety, emesis, cerebral edema, chronic or acute pain or tardive dyskinesia, in a mammal, comprising an effective amount as antagonist of the AMPA receptor of? n composed of formula I and a pharmaceutically acceptable vehicle. 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, muscle spasms, migraines, urinary incontinence, psychosis, seizures, perinatal hypoxia, hypoxia (such as choking, surgery, inhalation of smoke, suffocation, choking, suffocation, electrocution or overdosage of drugs or alcohol), cardiac arrest, hypoglycemic neuronal lesions, tolerance to opiates, withdrawal syndrome due to addiction (such as alcoholism and addiction to drugs including opioid addiction, cocaine and nicotine), injuries ocular, retinopathy, retinal neuropathy, tin nitus, idiopathic and drug-induced Parkinson's disease, anxiety, emesis, cerebral edema, chronic or acute pain or tardive dyskinesia, in a mammal, which comprises administering to a mammal in need of such treatment or prevention an effective amount as an AMPA receptor antagonist of a compound of formula I. This invention also relates to a pharmaceutical composition for treating or preventing a disorder, the treatment of which is facilitated by the increase of neurotransmission of glutamate in a mammal, comprising an effective amount as or antagonist of the receptor. AMPA of a compound of formula I and a pharmaceutically acceptable carrier. This invention also relates to a pharmaceutical composition for treating or preventing a disorder, the treatment of which is facilitated by the increased neurotransmission of glutamate in a mammal, which comprises administering to a mammal in need of such treatment or prevention an effective amount as an antagonist. of the AMPA receptor of a compound of formula I. Unless otherwise indicated, the alkyl groups mentioned herein, as well as the alkyl radicals of other groups mentioned herein (eg, alkoxy), may be linear or branched and also they can be cyclical (for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl) or can be linear or branched and contain cyclic radicals. Compounds of the formula I in which the fused A ring is a 6-membered aryl heterocycle include compounds in which the ring positions A, B, D and E assume the following combinations of respective atoms: The compounds of the formula I wherein the fused A ring is a 5-membered aryl heterocycle, include the compounds in which the heteroatom combinations assume the following combinations of respective atoms: When R2 is heteroaryl, a person of ordinary skill in the art will understand that heteroaryl includes pyridin-2-yl, 1,3-pyrazin-4-yl ,. l, 4-pyrazin-2-yl, 1,3-pyrimidin-2-yl, pyrrol-2-yl, 1,3-imidazol-4-yl, 1,3-irnidazol-2-yl, l, 3, 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, 2,4-oxadiazol-3-yl, l, 2,4-oxadiazol-5-yl, f-r-2-yl, 1,3-oxazol-5-yl and l, 3,4-oxadiazol-2-yl , wherein said heteroaryl may be optionally substituted on any of the atoms capable of forming an additional bond, up to a maximum of three substituents.

DETAILED DESCRIPTION OF THE INVENTION The compounds of formula I can be prepared according to the procedures of schemes 1 and 2. In the reaction Scheme and in the discussion shown below, A, B, D, E, F, G, 3, K, L, M, P, 0, T, R, R2, R3,, Ra, R *, R7, Rβ, R9, R o, R, R 2, R a, R *, R a, R *, R ^, Ph , Ph2, n, ro and p, unless otherwise indicated, are as defined above for formula 1.

SCHEME 1 SCHEME 7 II Scheme 1 refers to the preparation of compounds of formula I from compounds of formula V. Compounds of formula V are commercially available or can be prepared by methods well known to persons of ordinary skill in the art. technique. The compounds of the formula V, wherein "A" is 4-amino- (1, 2) -pyridazine-5-carboxylic acid can be prepared according to the procedures described in 3. Het. Chem. 1, 1099 (1977); flust 3. Chem. 2ZJ 1745 (1969); and 3. Het. Chem. _5, 845 (1968). The compounds of the formula V in which "A" is 4-amino- (1, 2) -pyridazine-3-carboxylic acid can be obtained according to the procedures described in 3. Het. Chern .. E 523 (1968). The compounds of the formula V in which "A" is 2-amino- (1, 2) -pyridazine-3-carboxylic acid can be obtained according to the procedures described in 3. Het. Chern..5. 523 (1968); and 3. Org. chem .. 50. 346 (1995). The compounds of formula V, wherein "A" is 5-amino- (1,2,3) -thiadiazole-4-carboxylic acid can be prepared according to the procedures described in Chem. Berichte. 99. 1618 (1966). The compounds of the formula V in which "A" is 4-amino- (1, 2,5) -thiadiazole-3-carboxylic acid can be obtained according to the procedures described in 3. Med. Chem .. 22. 944 (1979) and Tetrahedron i < ? tt -. 2143 (1971). The compounds of the formula V in which "A" is 4-amino- (1, 2,5) -oxadiazole-3-carboxylic acid can be obtained according to the methods described in Heterocycles. £ L 2351 (1983). The compounds of the formula V, wherein "A" is 3-amino-thiophene-2-carboxylic acid can be prepared according to the process described in the European Patent Publication 269,295 published June 1, 1988. A compound of the formula V can be converted to an acetamide of the formula IV by reaction of acetyl chloride or acetic anhydride in the presence of a base, in a solvent inert to the reaction. Suitable solvents include methylene chloride, dichloroethane, tetrahydrofuran and dioxane, preferably ethylene 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 30 ° 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 solvent inert to the dry 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. The temperature of the reaction mentioned above is in the range of about 80 ° C to about 110 ° C, for about 1 hour to about 24 hours, preferably at about 100 ° C 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 aforesaid reaction is from about 20 ° C to about 150 ° C, from about 10 minutes to about 10 hours, preferably at about 120 ° C 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 RXNH »in a polar protic solvent in the presence of an acid catalyst to form a compound of the formula II. Suitable acid catalysts include acetic acid, p-toluene sulphonic 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 20 ° C to about 117 ° C, for about 1 hour to about 24 hours, preferably at about 117 ° C for about 6 hours. Alternatively, a compound of the formula IV can be converted directly to a compound of the formula II by reaction with a dehydrating agent, an amine of the formula R NH =. and a base, in a solvent inert to the reaction. 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 liquid, the reaction can be carried out without solvents. The temperature of the above reaction is from about 50 ° C to about 150 ° C, for about 1 hour to about 24 hours, preferably at about 110 ° C for about 4 hours. The compound of the formula II is made with an aldehyde of the formula R 2 CHO in the presence of a catalyst and a dehydrating agent in a suitable solvent to form a compound of the formula I. Suitable catalysts include zinc chloride, aluminum chloride, tin chloride or boron trifluoride etherate, preferably zinc chloride. Suitable dehydrating agents include acetic anhydride or propionic anhydride, preferably acetic anhydride. Suitable polar solvents include acetic acid or propionic acid. The temperature of the reaction mentioned above is from about 60 ° C to about 100 ° C, from about 30 minutes to about 24 hours, preferably at about 100 ° C for about 3 hours. 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 into a compound of formula I in accordance with The procedures of Scheme 1. Referring to Scheme 2, a compound of formula V is reacted with a coupling reagent, an amine of the formula R ^ -NHa and a baee, in a reaction-inert solvent, to form a compound of the formula VI. Examples of suitable coupling reagents that activate the carboxylic functionality are dicyclohexylcarbodiimide, N-3-dimethylaminopropy.IN- '-ethylcarbodi-ida, 2-ethoxy-l-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ), carbonyl di-idazole (CDl). ) and diethylphosphoryl cyanide. 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, dichloethane and dimethyl formate. 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 formula VI is converted to a compound of formula VII by reaction with acetyl chloride or acetic anhydride in the presence of a base, in a solvent inert to the reaction. Suitable solvents include methylene chloride? tetrahydrofuran and chloroform, preferably roethylene chloride. Suitable bases include trialkylates such as triethylaniline and tributylamine, direthylaminopyridine 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 at about 30 ° C for about 3 hours. The compound of the formula VII is cyclized to obtain a compound of the formula II by reaction with triphenyl phosphine, a base and a dialkyl azodicarboxylate in a reaction-inert solvent. Suitable bases include pyridine, triethylamine and 4-dimethylaminopyridine, preferably 4-dimethylaminopi idine. 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 at about 100 ° C for a period of about 8 15 hours. The compound of formula II can be converted to 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, et al. Heterocycles. 42, 2, 691-699 (1996). 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 formula I which are basic in nature, are capable of forming a wide variety of different salts with various inorganic and organic acids. Although such salts have to be pharmaceutically acceptable to be administered to animals, in practice, it is often desirable to initially isolate a compound of formula I from the reaction mixture in the form of a pharmaceutically unacceptable salt and then simply convert the latter into the compound free bae by treatment with an alkaline reagent, and subsequently converting the free base to a pharmaceutically acceptable acid addition salt. The addition salts of the base compounds of this invention are readily prepared by treating the base compound with a substantially equivalent amount of the chosen mineral or organic 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 base compounds of this invention, are those which form non-toxic acid addition salts, ie salts which contain pharmacologically acceptable anions, such as the hydrochloride, hydroiodide, nitrate, sulfate or bisulfate, acid phosphate, acetate, lactate, citrate or citrate acid, tartrate or bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, lysine and pamoate [ that is, 1, 1-ethylene-bie- (2-hydroxy-3-naphthoate) 3. Compounds of the formula I which are acidic in nature, can form 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 which are used as reactants for preparing the pharmaceutically acceptable base salts of this invention are those which form non-toxic base salts with the acidic compounds described herein of formula I. These non-toxic base salts include those obtained at 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 then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, they can also be prepared by mixing together lower alkanolic solutions of the acidic compounds and the alkali metal alkoxide, and then evaporating the resulting solution to dryness in the same manner as indicated above. In any case, stoichiometric amounts are preferably employed to ensure completion of the reaction with a maximum yield of the desired final product. The compounds of the formula I and the pharmaceutically acceptable salts thereof (hereinafter referred to as 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 AMPA receptor. Therefore, the active compounds of the invention can be used in the treatment or prevention of cerebral deficits subsequent to cardiac bypass surgery and grafts, stroke, cerebral ischemia, spinal cord trauma, head trauma, Alzheimer's disease, Korea of Huntington, later-to-iotrophic sclerosis, epilepsy, AIDS-induced dementia, muscular spasms, headaches, urinary incontinence, psychosis, convulsions, perinatal hypoxia, hypoxia (such as the conditions caused by strangulation, surgery, smoke inhalation , asphyxia, choking, suffocation, electrocution or overdose of drugs or alcohol) cardiac arrest, hypoglycemic neuronal lesions, tolerance to opiates, withdrawal syndrome due to addiction (such as alcoholism and addiction to drugs including opiate addiction, cocaine and nicotine ), eye injuries, retinopathy, retinal neuropathy, tinnitus, Sickness of Idiopathic and drug induced insonson pair, anxiety, emesis, cerebral edema, chronic or acute pain or tardive dyskinesia. The in vitro and in vivo activity of the compounds of the invention with respect to antagonism of the AMPA receptor 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 inhibiting penile ileototetrazole (PTZ) -induced attacks. Another method for determining the activity of the compounds of the invention is by blocking the uptake of aCa2 * induced by the activation of the AMPA receptor. Then, a specific procedure is shown to determine the inhibition of pentylenetetrazole (PTZ) -induced attacks. The activity of the compounds of the invention for 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 prevent attacks and deaths caused by PTZ. The measures taken are latency for clinical and tonic attacks and for death. The DIßo values are determined based on the percentage of protection. As subjects for this experiment, CD-1 male mice from Charles River, weighing 14-16 g after arrival and 25-35 g at the time of testing, are used. The mice are enclosed, 13 per cage, under conventional laboratory conditions, in a light cycle L: 0/7 a.m .: 7 p. . 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 drug vehicles will depend on the compound's solubility, 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 a five-minute test period are: (1) latency for clone attacks, (2) latency for tonic attacks, and (3) latency for death. The treatment groups are compared to the vehicle-treated group by Kr? Skal-Uallis Anova and Mann-Uhitney U (Statview) assays. The percentage of protection 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 measure. The values of DIaa 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. Co, or subjects for this experiment, serve Charles River CD-1 male mice, weighing 14-16 g after arrival and 23-35 g at the time of testing. The mice are enclosed, 13 per cage, >Conventional laboratory conditions in a light cycle L: 0/7 a.m .: 7 p. . for at least 7 days before the experimentation. Food and water are available ad libitu until the moment of the eneayo. 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: 0: 5/5: 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 squares suspended on 11.43 cm steel rods connected to a 165.1 cm rod that is 38.1 cm high above the table. laboratory. These wire mesh squares can be inverted. The mice are administered test compounds or vehicle (i.p., s.c. or p.o.) and placed in plexiglas cages in groups of five. At a predetermined time after these injections, the mice are placed on top of the wire mesh squares and they move abruptly so that the mice are suspended downward. 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. Treatment groups are compared to vehicle-treated groups with the Kruskal-? Allis and Mann-Uhitney U (Statview) trials.

Next, we describe a specific procedure to determine the blockade of aCa2 + uptake induced by the activation of the AMPA receptor. Primary Neuronal Cultures Primary cultures of rat cerebellar granule neurons are prepared as described by Parks, T. N. , Artrnan, L D., Alaeti, N., and Nemeth, E. f. , Poflula ion Of N "ethvl-D-Asoar te Recentor-Mediate IncreaSQS lO Cv QSQliC Calcium In CJ3? U ?? < 3 Ra Cerefrgllar granule C = JLls, Brain Res. 552. 13-22 (1992). According to this procedure, the 8-day-old CD ratse cerebellum is removed, cut into pieces of 1 mm and these are incubated for 15 minutes at 37 ° C in Tyrode solution without calcium and 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 a cells per well. The medium consists of Minimum Essential Medium (MEM), with Earle salts, thermally inactivated 10% Fetal Bovine serum, 2 M L-glutamine, 21 M glucose, penicillin-Streptomycin (100 units per ml) and 25 M KCl. After 24 hours, the medium is replaced by a new medium containing cytosine arabinoside IQuM to inhibit cell division. Crops should be used at 6-8 DIV. Cap ón- «te ^ a2 * intimid by receptor activation of ñMPfl The effects of drugs on uptake of * aCa2 + 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 5, NaHaPO * 0.33, CaCla 1.8, glucose 22.0 and HEPES 10.0 to pH 7.4) containing 0.5 nM DTT, 10 μM glycine and drugs at a final concentration of 2X. The reaction is started by a rapid addition of an equal volume of the balanced salt solution containing 100 μM of the AMPA receptor agonist kainic acid and * aCa2 + (final specific activity 250 Ci / mmol). After 10 minutes at 25 ° C, the reaction is stopped by aspirating the solution containing * aCa2 + 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 0.1% triton-X100 and then the radioactivity in the lysate is determined. All compounds of the invention that were tested had Clao values of less than 5 μM. 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, intranaeal, parental (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, polyvinylprirrolidone or hydroxypropylmethylcellulose); fillers (for example, lactose, microcrystalline cellulose or calcium phosphate); lubricant (eg, magnesium stearate, talc or silica); diggings (for example, potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate). The tablets can be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or may be presented as a dry product to be constituted 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 (eg, 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 (for example, 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. The active compounds of the invention can be formulated for parenteral administration by injection, including conventional catheterization or infusion techniques. Formulations for injection may preertain in a unit dosage form, for example, in ampoules or multi-dose containers, with added preservative. The compositions may take such forms as suspeneions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as stabilizing and / or dispersing suspending agents. Alternatively, the active ingredient may be in powder form for reconstitution with a suitable vehicle, e.g., sterile, pyrogen-free water, before use. The active compounds of the invention may also be formulated in rectal compositions such as suppositories or enemas. retention containing, for example, conventional s? positorioe bases such as cocoa butter and other glyceride. 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 spray pump that is tightened or pumped by the patient, or in the form of a presentation of spraying aerosol from a pressurized container or a nebulizer, with the use of a suitable propellant, for example, dichlorodifluoromethane, trichloro-fluoromethane, 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 or nebulizing vessel 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 or an average adult human being, for the treatment of the aforementioned disorders (for example, apoplectic attack), is 0.01 to 50 mg / kg of the active ingredient per dosage unit that could be administered, for example, 1 to 4 times per 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, giving for example, 1, 2 or 3 doses each time. The following Examples illustrate the preparation of the compounds of the following invention. Commercial reagents were used without further purification. The melting points are uncorrected. The NMR data are presented in parts per million (d) and refer to the deuterium stabilization signal of the solvent in the sample. Unless otherwise indicated, all mass spectra were performed under chemical impact conditions. The ambient temperature refers to 20-25 ° C.

AXIS? PLQ I 3-t2-neil-phenyl-2-C2-C2-fluoro-phenyl-vinyl] -3H-thienoE3.2-d] pyrimidin-4-one Anhydrous zinc chloride (7.0 g, 51.4 mmol) was melted with A purge of nitrogen in a round bottom flask with an open flame. The reaction vessel was allowed to return to room temperature and then dioxane (100 ntl) was added. To this mixture was added 2-methyl-3- (2-methylphenyl) -3H-thieno C3,2-d] pyrimidin-4-one (7.0 g, 27.34 mmol, preparation 2), acetic anhydride (7.7 ml, 82.0 mmol) ) and 2-fluorobenzaldehyde (8.6 ml, 10.2 mmol). The reaction was refluxed for 14 hours, cooled to room temperature and partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate and the combined organic layer was filtered to obtain a small amount of product which had precipitated. The filtrate was washed with water and brine, dried over magnesium sulfate and concentrated to leave a mustard-colored solid. This material was added to the product that had previously been collected and the combined material was subjected to flash chromatography on silica gel (60 x 185) eluting with 25-40% ethyl acetate / hexane to yield 5.06 g (51%) of 3- (2-Roethyl-phenyl) -2-C2- (2-fluoro-phenyl) -vinyl] -3H-thienoC3,2-d] pyrimidin-4-one in the form of a light yellow solid. P.f: 220-221 ° C; NMR 6 8.03 (d, 3 = 15.8 Hz, 1H), 7.82 (d, 3 = 5.2 Hz, 1H), 7.45-7.37 (m, 4H), 7.25-7.10 (m, 3H), 7.07-6.99 (, 2H ), 6.44 (d, 3 = 15.9 Hz, 1H), 2.11 (s, 3H). Analysis calculated for Ca H sFNa0S: C, 68.75; H, 4.23; N, 7.64. Found: C, 68.89; H, 4.16; N, 7.72.

EXAMPLE 2 3- (2-Chloro-phenyl) -7-T7- i 2- f Iom-feni 1, -vi, or 11-3H-thienoC3 .2-dlpyrimidin-4-one To a mixture of molten zinc chloride (0.35 g, 2.56 mmole) and dioxane (15 ml), 2-methyl-3- (2-chlorophenyl) -3H-thieno C3,2-d] pyrimidin-4-one (0.344 g, 1.24 mmol, preparation 3) and acetic anhydride (0.35 ml, 3.73 mmol) was added 2-fluorobenzaldehyde (0.39 ml, 3.73 vials). The reaction was heated to r-efflux for 30 hours, cooled to room temperature and diluted with ethyl acetate and water. The two-phase mixture was treated with sodium bicarbonate until the aqueous layer became basic. The phases were filtered to remove an insoluble residue and then separated. The aqueous layer was extracted with ethyl acetate and the combined organic layer was washed with water and brine, dried over sodium eulfate and concentrated to leave a brown residue. This material was taken up in ethyl acetate and diluted with hexane to form a precipitate (0.153 g, 32%) of 3- (2-chloro-phenyl) -2-C2-fluoro-phenyl) -vinyl] -3H-thienoC3 , 2-d] pyrimidin-4-one, in the form of a yellow solid. P.f: 215-216 ° C; NMR d 8.05 (d, 3 = 15.5 Hz, 1H), 7.84 (d, 3 = 5.2 Hz, 1H), 7.65-7.61 (m, 1H), 7.51-7.40 (m, 2H), 7.39-7.36 (m, 1H), 7.29-7.22 (m, 2H), 7.08-7.00 (m? 2H, 6.42 (d, 3 = 15.5 Hz, 1H) Analysis calculated for CaoH to CINaOS: C, 62.75; H, 3.14; N, 7.32, Found: C, 62.45; H, 3.14; N, 7.40.

EXAMPLE 3 3- (2-Methyl-phenyl) -2-r2-nirid-α-yl-vinyl-1-3H-tαne. - dlDiimidin-4-one To a mixture of fused zinc chloride (2.13 g, 15.6 mmol) and dioxane (75 ml), 2-methyl-3- (2-methylphenyl) -3H-thienot3, 2-d3pi rimidin-4 -one (2.0 g, 7.81 vials, preparation 2) and acetic anhydride (2.2 ml, 23.4 mmoles) was added 2-pyridine carboxaldehyde (2.2 ml, 23.4 mmolee). The reaction was refluxed for 1.5 hours, cooled to room temperature and diluted with aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate and the organic extracts were washed with water and brine, dried over sodium sulfate and concentrated to leave a dark residue. This material was subjected to flash chromatography on silica gel (45 x 125 nm). Elution with 20% ethyl acetate / hexane removed a non-weighed impurity. Continued elution with 40% ethyl acetate / hexane gave a yellow sticky foam. The foam was triturated with 5% ethyl acetate / hexane to yield 1.9 g (70%) of 3- (2-ethyl-phenyl) -2-i: 2-pyrid-2-yl-vinyl] -3H- thienoC3,2-dlpyrimidin-4-one in the form of a yellow solid. P.f: 203 ° C; NMR d 8.47 (d, 3 = 3 Hz, 1H), 7.92 (d, 3 = 14.7 Hz, 1H), 7.82 (d, 3 = 4 Hz, LH), 7.60 (t, 3 = 8.5 Hz, 1H), 7.43-7.37 (m, 4H), 7.26-7.12 (, 3H), 6.89 (d, 3 = 14.7 Hz, 1H), 2.10 (s 3H). Analysis calculated for CaoH aNgOS: C, 69.36; H, 4.62; N, 12.14. Found: C, 69.10; H, 4.50; N, 12.19.

AXIS? PLQ All the compounds of Table 1 were obtained essentially by the same procedure as exemplified in Examples 1-3.

Table 1 2-methylthiazole-2-methylpyrid-3-yl pf215 ° C 4-rt RMN δ 8.67 (da.J-4.2 Hz, 1 H), 7.88-7.83 (m, 2 H), 7 , 56 (d, J - 7.5 Hz. 1 H) .7.38 (, 2 H), 7.20 (8.1 H), 6.67 (d, J - 14.8 HZ.1 H), 2.59 (ß, 3 H) .2.37 (8.3H). 2- etii-1 .3-2-methylphenyl pf246-247 ° C thiazo? -4- or R Ní 7.89 (d, J-15 Hz, 1H), 7.77 (m, 1H), 7, 43 (m, 4H), 7.25 (ß, 1H), 7.19 (8, 1H), 6.62 (d, J = 14.9 Hz, 1H), 2.61 (ß, 3H). 2.11 (83H).

EPLAM 5 The compounds of Table 2 were prepared substantially by the same methodology described in Examples 1-3, with the exception that the products of Preparations 15 and 17 were employed in the reactions.

TABLE 2 R1 Physical Data 2-fluorophenyl 2-methylphenium p.f. 196 ° C NMR d 8.31 (d, J = 3.2 Hz, 1 H), 7.94 (d, J - 15.9 Hz, 1 H), 7.62 (d, J - 3.3 Hz. 1 H), 7.43-7.33 (m, 3 H), 7.23-7.16 (m, 3 H), 7.05-6.86 (m, 2 H). 6.38 (d, J = -16.1 Hz, 1 H), 2.12 (8. 3 H) Analysis calculated for C 21 H 19 FN, 0 S: C, 69.61; H, 4.14; N, 7.73.Incontr .: C, 69.11; H, 4.10; N, 7.35.

EXAMPLE 6 2-E2- (2-Fluoro-phenyl) -vinyl-3-3-o-t-Phenyl-3H-periodin-Qna A mixture of molten zinc chloride (0.17 g, 1.25 mmol) was heated at reflux overnight. dioxane (15 rnl), 2-methyl-3-C2-ethyl-phenyl) -3H-pteridin-4-one (0.174 g, 0.69 mmole, preparation 8) and 2-fluorobenzaldehyde (0.22 ml, 2.07 mmole) and acetic anhydride (0.195 ml, 2.07 mmol). The reaction was cooled and concentrated. The residual material was partitioned between saturated aqueous sodium bicarbonate and methylene chloride. The layers were carefully shaken and separated. The organic layer was washed with brine, dried and concentrated. The residue was subjected to flash chromatography on silica gel (0.75 x 4 inches) by eluting as follows: 50% ethyl acetate / hexane (300 ml. ) , development; 60% ethyl acetate / hexane (400 ml). 2-C2- (2-fluorophenyl) -vinill-3-o-tolyl-3H-pteridin-4-one (0.137 g, 55%) was isolated as a yellow crystalline solid. A sample was crystallized from ethyl acetate. P.f > 250 ° C; RflN d 8.98 (d, 3 = 2 Hz, 1H), 8.80 (d, 3 = 2 Hz, 1H), 8.36 (d, J = 15.5 Hz, 1H), 7.54-7.40 (m, 3H), 7.35-7.20 (m, 3H), 7.15-6.98 (m, 2H), 6.49 (d, 3 = 15 Hz, 1H), 2.15 (s, 3H). Analysis calculated for Cs,: t.H; LaFNU0: C, 70.38; H, 4.22; N, 15.63. Found: C, 70.07; H, 4.21; N, 15.78.

E3E11PLQ 7 The compounds of Table 3 were prepared following substantially the same procedure of Example 6 starting from the product of preparation 8 or preparation 11.

TABLE 4 50 E3EI1PLQ 8 2-C2- (2-Fluoro-phenyl) -vinyl] -3-ot? LI-3H-DÍrÍd? C3.4- d3pirimidin-4-one The title compound was prepared according to the procedures of Examples 1- 3 from the product of the preparation 20. Pf 211-211.5 ° C; NMR d 9.26 (s, 1H), 8.70 (d, 3 = 5 Hz.lh), 8.18 (d, 3 = 15.5 Hz, 1H), 8.08 (d, 3 = 4.5 Hz, 1H), 7.54-7.48 (, 3H), 7.46-7.15 (, 3H), 7.13-7.00 (m, 2H), 6.47 (d, 3 = 15.5 Hz, 1H), 2.13 (s, 3H). Analysis calculated for Csss¡H? «IFNaO • 0.125 Ha0: C, 73.47; H, 4.55; N, 11.68. Found: C, 73.35; H, 4.49; N, 11.66.

E3EMPL0 9 D-3- (2-Chloro-phenyl) -2- (2-DÍridin-2-yl-ethyl) -3H-ylsinoCa. 2-d3-pyrimidin-4-one hydrochloride It was heated at reflux for 4 hours to a mixture of 3- (2-Chloro-phenyl) -2-C2-pyri-2-yl-vinyl-3-3H-thienoC3,2-d3-pyrimid-din-4-one (0.12 g, 0.33 mmol), ethanol, 10 ml), formic acid ( 0.55 ml, 14.8 mmol) and 10% palladium on carbon (0.12 g), cooled and diluted with ethanol and water. The mixture was filtered through Celite * (trademark) and the bed was washed with ethyl acetate and water. The filtrate was treated with saturated aqueous sodium bicarbonate and the phases were separated. The aqueous layer was extracted with ethyl acetate and the combined organic phase was washed with water and brine.The mixture was dried over sodium sulfate and concentrated to yield 0.094 g of 3- (2-chloro-phenyl) -2- (2-pyridin-2-l-ethyl) -3H-thienoC3,2-d] pyrirnidin-4. -one in the form of a brown film. The material was dissolved in dioxane (3 ml) and treated with saturated ether of hydrogen chloride. The solid was collected and weighed 0.094 g. The solid was taken up in water, concentrated, dried azeotropically by suspending the product in chloroform and concentrating three times to produce 3- (2-chloro-phenyl) -2- (2-pi idin-2-hydrochloride. il-ethyl) -3H-thienoC3,2-dlpyrimidin-4-one (0.038 g, 31%) as a yellow solid. P.f 136 ° C; Analysis calculated for C ^ H ^ ClNaOS • HCl • 1.5 Ha0: C, 52.13; H, 4.11; N, 9.15. Found: C, 51.96; H, 3.78; N, 9.27.

The compounds of Table 4 were prepared following the procedure of Example 9.

TABLE 3 fl2 Physical data pyric-2-yl 2-methylphenyl p.f. > 250ßC NMR 6 9.00 (d.J. "2 Hz. 1 H). 6.83 (d, J = 2 Hz, 1 H), 8.51 | wide intermesh collection, J = 3.6 Hz, 1 H), 8.29 (d, J - 15 Hz. 1 H), 7.68 (dt, J - 2, 7.5 Hz, 1 H), 7.56-7.40 (m, 3 H), 7.35 (d, J "7.5 Hz, 1 H), 7.26-7.18 (m, 2 H). 7.01 (d, J-15 HZ, 1 H), 2.18 (ß, 3 H) Analysis calculated for CMH, sN.sub.SO: C, 70.37; H, 4.43; N, 20.62. Found: C, 69.97; H, 4.43; N. 20.78. 2-fluorophen? Io 2-chlorophenyl p.f. 228-230 ° C NMR d 8.98 (d, J-2 Hz, 1 H). 8.81 (d, J - 2 Hz, 1 H), 8.35 (d, J - 15.5 Hz, 1 H), 7.71-7.63 (m, 1 H), 7.55 ( m sim, 2 H), 7.48-7.40 (m, 1 H). 7.37-7.26 (m.2 H), 7.13-6.95 (m, 2 H), 6.47 (dd, J «1, 15.5 Hz, 1 H). Analysis calculated for C ^^ CIF ^ O'O.S H, 0: C, 61.94; H, 3.38; N, 14.46. Found: C, 62.17; H, 3.32; N, 14.54. pipc-2-yl 2-chlorofenib p.f. 231-232 ° C NMR 6 8.98 (d, J-2 Hz, 1 H). 8.81 (d, J = 2 Hz. 1 H). I51 < 8 (m Sim. 1 H), 8.28 (d, J-15 Hz, 1 H). 7.72-7.62 (m, 2 H), 7.55 (m sim, 2 H), 7.46-7.40 (m, 1 H), 7.34 (d, J-7.5) Hz, 1 H), 7.19 (m 1 H), 6.98 (d, J = 16 Hz, 1 H) Analysis calculated for C, tH12CJN50 - 0.5 H, 0: C, 61.55; H, 3.53; N, 18.89. Found: C, 61.67; H, 3.38; N, 19.13.

EXAMPLE 11 The compounds of Table 5 were prepared following the procedure of Example 9.

TABLE 5 EXAMPLE 12 -C2-Pyridin-2-yl-vinyl) -Bo-olyl-3.6-di idrp-C1.2.3] riazoloh, 5-d] pyrim «Jin-7-pna fl a mixture of molten zinc chloride ( 0.551 g, 4.04 mmol) and dioxane (20 ml), was added 5-methyl-6-o-tolyl-3,6-dihydro- [1,3,3-triazoloC4,5-d3-pyrimidin-7-one (0.488 g, 2.02 rnols), 2-pyridinecarboxaldehyde (0.58 ml, 6.06 mmoles) and acetic anhydride (0.57 rnl, 6.06 mmoles). The mixture was heated at 70 ° C for 6 hours, cooled and quenched with saturated sodium bicarbonate. The mixture was stirred overnight at room temperature. The dioxane was removed under reduced pressure and the resulting black liquid was extracted with methylene chloride. The organic fae was dried over magnesium sulfate, treated with activated carbon, filtered and found. The residue (1.5 g) was subjected to flash chromatography on silica gel (50 g). Elution with 50% and 60% ethyl acetate / hexane gave 5- (2-pyridin-2-yl-vinyl) -6-o-tolyl-3,6-dihydro-IIl, 2,3] triazolo- C4,5-d3-pyrimidin-7-one (0.023 g, 3.5%). NMR 5 9.06, (d, 3 = 7.3 Hz, 1H), 8.70 μm, 2H), 7.60 (t, 3 = 7.8 Hz, 1H), 7.50 (t, 3 - 7.7 Hz, 1H), 7.23-7.00 (rn , 4H), 6.80 (t, 3 = 8.2 Hz, 1H), 6.59 (t, 3 = 8 Hz, 1H), 2.28 (s, 3H); MS m / e = 330. The product was treated with hydrogen chloride (HCl) in dioxane to form the hydrochloride salt having a melting point (mp) of 80-85 ° C.

Preparation 1 3-Acetamidothiophene-2-carboxylic acid or a solution of methyl 3-aminothiophene-2-carboxylate (10 g and 0.0637 mol) and triethylamine (10.3 g, 0.102 mol) in methyl chloride was added dropwise acetyl chloride (8.0 g, 0.102 mol in 10 ml of methylene chloride).

The reaction was stirred for 3 hours at room temperature.

The mixture was quenched with water and the phases were separated. The aqueous layer was extracted twice with methylene chloride and the combined organic phase was washed with water and brine, dried over sodium sulfate and concentrated to yield 14.0 g of a yellow solid product which was suitable for the reaction without further purification. RrtN or 8.10 (d, 3 = 5.4 Hz, 1H), 7.43 (d, 3 = 5.4 HZ, 1H), 3.86 (S, 1H), 2.20 (s, 3H); Eli m / e = 199. The product was added to 200 ml of 10% methanolic potassium hydroxide and heated to 60-65 ° C for 4 h. The reaction was concentrated and the residue was taken up in water. The aqueous solution was extracted with ether and then made acidic with hydrochloric acid N (HCl). The precipitate was filtered, washed well with water and dried in air to yield 9.5 g (80%) of 3-aceta-idothiophene-2-carboxylic acid in the form of a solid chestnut. P.f. 212-213 ° C; NMR (DMSO d6) & 7.82 (d, 3 = 5.4 Hz, 1H), 7.72 (d, 3 = 5.4 Hz, 1H), 2.06 (s, 3H).

Preparation 2 2-Riethyl-3- (2-ethyl-ethyl) -3H-thienor3.2-d3D-rhamidin-4-one a mixture of 3-acetamidothiophene-2-carboxylic acid (15.1 g, 75.67 mmol) and sodium acetate (6.45 g) , 78. 6 mmoles) in dioxane (200 rolls), acetic anhydride (71 ml, 75.7 moles) was added. The reaction was heated to reflux for 2 hours, it was cooled to room temperature and divided between chloroform and water. The phases were prepared and the aqueous layer was extracted with chloroform. The combined organic phase was washed with water brine, dried over magnesium sulfate and concentrated to leave 15.1 g of 2-methyl-thienoC3,2-d] Cl, 33 oxazin-4-one as a brown oil which solidified slowly. NMR 5 7.78 (d, 3 = 6.5 Hz, 1H), 7.14 (d, 3 = 6.5 Hz, 1H), 2.40 (s, 3H); ? M m / e = 167. The material was used without further purification. 2-Methyl-thienoC3,2-d3Cl, 3] oxazin-4-one (12.7 g, 76 mmol) and o-tol? Idine (16.2 ml, 152 mmol) in acetic acid (175 ml) were combined and heated to reflux for 3 hours. The reaction was concentrated and the residue was partitioned between ethyl acetate and water. The two-phase mixture was treated with sodium bicarbonate until the aqueous layer became basic and the phases were then separated. The aqueous phase was extracted with ethyl acetate and the combined organic layer was washed with water brine, dried over sodium sulfate and concentrated to leave a black oil. This residue was purified by flash chromatography on silica gel (60 X 200 nm). Elution with 20% ethyl acetate / hexane gave 16.2 g of impure product and 3 g of a cyclic diamide biproduct. The impure product was chromatographed a second time as indicated above but eluted with 10% ethyl acetate and 15% / nexane. In this way, 9.2 g (47%) of 2-methyl-3- (2-methylphenyl) -3H-thienoC3,2-d] pyrimidin-4-one was isolated as a light yellow solid.

NMR 3 7.70 (D, 3 = 5.3 Hz, 1H), '7.39-7.30 (m, 3H), 7.29 (d, 3 = 5.3 Hz, 1H), 7.13 (d, 3 = 7.8 Hz, 1H), 2.15 ( s, 3H), 2.10 (s, 3H).

Preparation 3 2-Metho 1-3-f-chloro-phenyl) -3H-thienor-3-2-dlDiimidin-4-one 2-methylo-thienoC3,2-d3 [l, 33-oxazin-4-one (1.67 g. mmoles) and o-chloroaniline (2.1 ml, 20 mmol) in acetic acid (20 ml) and heated to reflux for 4.5 h. The reaction was partitioned between ethyl acetate and water.

The two-phase mixture was treated with sodium bicarbonate until the aqueous layer became basic and the phases were then evaporated. The aqueous phase was extracted with ethyl acetate and the combined organic layer was washed with water and brine, dried over sodium sulfate and concentrated to leave a brown oil.

This residue was purified by flash chromatography on silica gel (30 X 50 mm). Elution with 1.0% and 20% ethyl acetate / hexane gave 1.42 g (51%) of 2-methyl-3- (2-chlorophenyl) -3H-thienoC3,2-d3-pyrimidin-4-one q? E it was isolated in the form of a brown solid which solidified upon standing. P.f. 118-121ßC; RT1N d 7.78 (d, 3 = 5.3 Hz, 1H), 7.57 (m, 1H), 7.46-7.43 (m, 2H), 7.33-7.29 (, 2H), 2.20 (s, 3H); MS m / e = 276.

Preparation 4 2-Methyl-3- (2-chloroDrid-3-yl) -3H-thymsoC3.2-d3Drimidin-4-one with a mixture of pyridine (4 ml), 3-amino-2-chloropyridine, γ.514 g, 4 mmoles) and 3-acetamidothiophene-2-carboxylic acid '0.374 g, 4 rnmoles), phosphorus trichloride (0.02 ml, 2.3, mmoles) was added. The reaction was heated at 105 ° C for 3 hours, cooled to room temperature and partitioned between ethyl acetate and water. The phases were prepared and the aqueous layer was extracted with ethyl acetate. The combined organic phase was washed with water brine, dried over sodium sulfate and concentrated to obtain a greenish brown oil. This residue was subjected to flash chromatography on silica gel (20 X 120 mm) eluting with 20-40% ethyl acetate / hexane to yield 0.350 g (63%) of 2-methyl-3- (2-chloropyrid-3-). il) -3H-thieno [3,2-d3-pyrirnidin-4-one in the form of a yellow foam. NMR 5 8.58-8.56 (rn, 1H), 7.83 (d, 3 = 5.2 Hz, lH), 7.74-7.71 (, 1H), 7.50-7.46 (m, 1H), 7.33 (d, 3 = 5.3 Hz, 1H ), 2.24 (s, 3H); MS m / e = 277.

Preparation 5 2-Riethyl-3- (2-bromophenyl) -3H-thymnoC3.2-dlDiimidin-4-one fl a mixture of pyrimidine (6 ml), 2-bromoaniline (1.03 g 6"moles) and 3-acetamidothiophene-2-carboxylic acid (0.555 g, 3 mannols), phosphorus trichloride (0.03 rnl, 3. 45 mmoles). The reaction was heated at 105 ° C for 4 hours, cooled to room temperature and partitioned between chloroform and water (an insoluble precipitate was removed by filtration). The phases were prepared and the aqueous layer was extracted with chloroform. The combined organic layer was washed with water brine, dried over magnesium sulfate and concentrated to obtain a pale yellow film. This residue was subjected to flash chromatography on silica gel (30 x 125 nm) eluting with 15-25% ethyl acetate / hexane to yield 0.411 g (47%) of 2-methyl-3- (2-bromo-phenyl) -3H -tienoC3, 2-d3pirimidin-4-one in the form of a yellow foam. NMR d 7.76-7.55 (m, 2H), 7.44 (t, 3 = 7.2 Hz, 1H), 7.39-7.05 (m, 3H), 2.10 (s, 3H); MS m / e = 320 and 322.

Preparation 6 o-Toluamide of 3-aminoDyrazine-2-carboxylic acid A mixture of 3-aminopyrazine carboxylic acid (5.0 g, 35.94 pwoles), methylene chloride (110 ml), 4-di-ethylaminopi-idine (10.98 g 89.85 mrnols), o-toluidine (4.22 ml, 39.53 mmol) and l- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (8.27 g, 43.13 mmol) was stirred overnight at room temperature. The solvent was removed and the residue was diluted with ethyl acetate. This organic phase was extracted with 1H-di-lithium chloride (LiCl), water and brine, dried over calcium sulfate and concentrated. The residue was subjected to flash chromatography on silica gel C2.75 x 4 inches) (6.985 x 10.16 was) by elution as follows: hexane (300 ml), nothing; 20% ethyl acetate / hexane (500 nl), o-toluidine recovered not weighed; 20% ethyl acetate (1000 ml) and 30% ethyl acetate / hexane (2000 ml) to obtain 4.79 g (58%) of 3-aminopyrazine-2-carboxylic acid o-toluamide as a solid crystalline yellow. P.f. 135-137 ° C; NMR 6 9.80 (sa, 1H), 8.22 (d, 3 = 2.5 Hz, 1H), 8.11 (d, 3 = 8.0 Hz, 1H), 7.87 (d, 3 = 2.5 Hz, 1H), 7.33-7.23 (n , 2H), 7.10 (dt, 3 = 1, 7.5 Hz, 1H), 2.39 (e, 3H).

Preparation 7 O-Toluamide of 3-acetamido-Drazrazine-2-carboxylic acid A mixture of 3-aminopyrazine-2-carboxylic acid o-toluamide (1.0 g 4.39 mmol) and acetic anhydride (12 ml) was heated at reflux for 2 hours. The solvent was removed and the residue was triturated with hot ethyl acetate. The ethyl acetate suspension was cooled and the product was collected and rinsed with ether to yield 0.893 g (76%) of 3-acetamidopyrazine-2-carboxylic acid o-toluamide. NMR & 11.88 (s a, 1H), 10.0 (s a, 1H?, 8.65 (d, 3 = 2.5 Hz, 1H), 8.28 (d 3 = 2.5, Hz, 1H) 8.04 (d, 3 = 8 Hz, 1H), 7.38-7.24 (m, 2H), 7.20-7.11 (, 1H), 2.39 (s, 3H) ), 2.38 (s, 3H). The material was used without further purification.

Preparation 8 2-Phtethyl-3- (2-methyl-enyl) -3H-pteridin-4-one? A mixture of 3-acetamidopyrazine-2-carboxylic acid o-toluamide (1.0 g, 3.70 mmol), tri-phen. il osfina (2.91 g, 11.1 mmol) and 4-dimethylamino pyridine (0.045 g, approximately 10% by mole) in dioxane (45 ml), diethyl azodicarboxylate (1.75 ml, 11.1 mmol) was added dropwise by syringe. The reaction was refluxed overnight, cooled to room temperature and concentrated. The residue was partitioned between rnetylene chloride and water. The phases were prepared and the organic layer was washed with brine, dried and concentrated. The residue was subjected to flash chromatography on silica gel (2.25 x 4 inches, (5.715 x 10.16 cm) introduced in hexane) by eluting as follows: ethyl acetate -80% / hexane, pre-development; 85% ethyl acetate / hexane (1000 ml), to obtain 0.71 g (76%) of 2-methyl-3- (2-methyl-phenyl-3H-pteridin-4-one) which was suitable for use without additional purification A mixture was crystallized from ethyl acetate, mp 186-187 ° C, NMR &8.98 (d, 3 = 2 Hz, 1H), 8.83 Cd, 3 = 2 Hz, 1H), 7.51-7.35 (m , 3H), 7.18 (d, 3 = 7 Hz, 1H), 2.30 (S, 3H), 2.16 (s, 3H).

PREPARATION 9 - Cyclophosphamide in 3-aminopyrazine-2-carboxylic acid A mixture of 3-aminopyrazine carboxylic acid (7.0 g, 50.32 mmol), methylene chloride (60 ml) was stirred overnight at room temperature. ), dimethylformamide (40 nmol), 4-dimethylaminopyridine (15.37 g, 126 mmol), 2-chloroaniline (5.82 ml, 55.35 mmol) and l- (3-dimethylamino-ropil) -3-ethylcarbodiimide hydrochloride (11.58 g, 60.38 mmol). The solvent was removed and the residue was mixed with ethyl acetate and lithium chloride IN. The precipitate that formed was filtered and rinsed with 1N lithium chloride, ethyl acetate and ether, and then air dried to yield 6.22 g (50%) of 3-aminopyrazine-2-chlorophenylamide. -carboxylic in the form of yellow hairy crystals. P.f. 177-179 ° C; NMR 6 10.47 (s a, 1H), 8.52 (dd, 3 = 1.5, 8.5 Hz, 1H), 8.23 (d, 3 = 2.5 Hz, 1H), 7.92 (d, 3 = 2.5 Hz, 1H), 7.43 (do, 3 = 1.5, 8 Hz, 1H), 7.33 ( dt, 3 = 1.5, 7.5 Hz, 1H), 7.09 (dt, 3 = 1.5, 7.5 Hz, 1H).

Preparation 10 2-Chlorophonylamide of 3-acetamidopyrA? Ina-2-carhoxyl A mixture of 2-chlorophenyl 3-aminopyrazine-2-carboxylic acid (4.0 g, 16.1 mmol) and acetic anhydride (25 ml) was heated at reflux for 2 hours. The solvent was removed and the residue was partitioned between methylene chloride and saturated aqueous sodium bicarbonate. The phases were separated and the organic layer was washed with water and brine, dried and concentrated. The residue was subjected to flash chromatography on silica gel (2.25 x 4 inches) (6.985 x 10.16 cm) by elution as follows: hexane (200 nl) and 25% ethyl acetate / hexane (500 ml) , pre-development; 40% ethyl acetate / hexane (700 ml, 0.69 g of an unidentified material); 40% ethyl acetate / hexane (200 ml) and 60% ethyl acetate / hexane (500 ml) v 0.836 g (18%) 2-chlorophenylamide 3-acetamidopyrazine 2-carboxylic acid. P.f. 194-196 ° C; NMR d 11.70 (s s, 1H), 10.65 (s a, 1H), 8.66 (d, 3 = 2.5, Hz, 1H), 8.49 (dd, 3 = 1.5, 10 Hz, 1H), 7.36 (dt, 3 = 1.5, 9 Hz, 1H), 7.14 (dt, 3 = 1.5, 7.5, Hz, 1H), 2.42 (s, 3H). The material was used without further purification.

Preparation 11 2-Hethyl-3-C2-chloro-phenyl-1-H-pteridin-4-one a 2-chlorophenylaride mixture of 3-acetamidopyrazine na-2-carboxylic acid (0.816 g, 2.81 mmol), tri-phenyl phosphine (2.21 g, 8.43 mmol) and 4-dimethylaminopyridine (0.034 g, 0.28 mmol) in dioxane (35 mL) was added diethyl azodicarbixilate (1.33 mL, 8.43 mmol), dropwise, by syringe. The reaction was heated to reflux overnight, cooled to room temperature and concentrated. The residue was partitioned between rnetylene chloride and water. The phases were separated and the organic layer was washed with brine, dried and concentrated. The residue was subjected to flash chromatography on silica gel (1.5 x 5 inches, (3.81 x 12.7 cm) introduced in hexane) by elution as follows: 20% ethyl acetate / hexane (250 nl), pre-development; 40% ethyl acetate / hexane (1600 ml), triphenylphosphine oxide not weighed; 60% ethyl acetate / hexane (500 ml) and 75% ethyl acetate / hexane (500 ml), nothing; 80% ethyl acetate / hexane (1000 ml), 0.62 g (81%) of 2-methyl-3- (2-chlorophenyl) -3H-? teridin-4-one in the form of a brown foam which was suitable for use without further purification. A sample was ground with hexane. P.f. 74-80 ° C; NMR d 8.98 (d, 3 = 2Hz, 1H), 8.84 (d, 3 = 2 Hz, 1H), 7.70-7.63 (rn.1H), 7.53 f sim, 2H), 7.42-7.33 (rn, 1H), 2.34 (s, 3H).

Preparation 12 methyl 3-phytamidothiophene-4-carboxylate A mixture of ethyl 3-aminothiophene-4-carboxylate d-m ethyl hydrochloride (3. 1 g, 16 mmol) and triethyl laminate (6.7 ml) was stirred for 30 minutes. 48 mmol) in methylene chloride (75 ml) and then cooled on wet ice. Acetiyl chloride (1.4 ml, 19. 2 mmol) was added and the reaction was warmed to room temperature and stirred for one hour. The reaction was quenched with water and diluted with methylene chloride. The phases were separated and the aqueous layer was extracted with methylene chloride. The combined organic layer was washed with water, dried over magnesium sulfate and concentrated to yield 2. 85 g (91%) of methyl 3-acetamidothiophene-4-carboxylate in the form of a brown oil which solidified upon standing. The product was suitable for use without further purification. NMR d 7.98 (d, 2H), 3.87 (e, 3H), 2.18 (s, 3H).

Preparation 13 3-Acetamidothiophene-4-carboxylic acid Methyl 3-acetamidothiophene-4-carboxylate (10.0 g, 50.25 mmol) was added to a 5% methanolic potassium hydroxide solution (100 ml). The mixture was refluxed for 2 hours, cooled and concentrated. The residue was dissolved in water and the acidity was adjusted to pH 1 by the addition of hydrochloric acid IN (HCl). The precipitate was collected, washed with water and dried in air to yield 8.66 g (93%) of 3-acetamidothiophene-4-carboxylic acid. P.f. 206 ° C; NMR d 8.29 (D, 1H), 7.88 (d, 1H), 2.11 (s, 3H). The product was used without purification.

Preparation 14 2-Phtethyl-thienoC3.4-d3 [: i.3loxa2Ín-4-one A mixture of 3-acetaside thiopheno-4-carcic acid (1.6 g, 8.65 mmol) was refluxed overnight. ), dioxane (40 m), acetic anhydride (10.2 ml, 86.5 mmole) and sodium d-acetate (0.75 g, 9.08 mmole). The reaction was cooled and concentrated. The residue was partitioned between ethyl acetate and water. The phases were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water and brine, dried over sodium sulfate and concentrated to yield 1.39 g (96%) of 2-methyl-thienot.3,4-dHl, 3] oxazin-4-one as a solid chestnut NMR 6 8.34 (d? 3 = 3.4 Hz, 1H), 7.40 (d, 3 = 3.4, Hz, 1H), 2.38 (s, 3H). The product was suitable for use without purification.

Preparation 15 2-fTethyl-3-o-Qlil-3H-tienQC3 -d] pyrim << Jin - * - ona fl a suspension of 2-methyl-thienoC3,4-d3Cl, 3] oxazin "4-one (1.0 g, 5.99 mmoles) and acetic acid (15 ml), o-toluidine (1.2 ml, 10.78 mmoles) The mixture was refluxed for 3 hours, cooled and concentrated, the residue was partitioned between ethyl acetate and water and the aqueous phase made basic by the careful addition of saturated aqueous sodium bicarbonate. The aqueous layer was extracted with ethyl acetate.The combined organic layer was washed with water brine, dried over sodium sulfate and concentrated to obtain a black oil.The oil was subjected to flash chromatography on silica gel (30 × 100 mm) eluting with 20% ethyl acetate / hexane The product fractions were combined to yield 0.303 g of 2-methyl-3-otolyl-3H-thienoC3,4-d]? Irimidin-4-one in the form of a brown oil that solidified after resting, Mp 122-123 248 ° C, NMR d 8.25 (d, 3 = 3.2 Hz, 1H), 7.47 (d, 3 = 3.3 Hz, LH), 7.37- 7.32 (m, 3H), 7.12 (d, 3 = 6.8 Hz, 1H), 2.13 (e, 3H), 2.10 fs, 3H). The mixed fractions were chromatographed a second time. The product fractions of this purification were combined, concentrated and the residues were triturated with 10% ethyl acetate / hexane to yield 0.447 g more of product. In this way 0.75 g (49%) of product was obtained. The last fractions of the chromatography contained a non-cyclised diamine byproduct that could be cyclized according to the preparation procedure.

Preparation 16 2-Chlorine in lide of 3-ace amidothiophene-4-carboxylic acid a suspension of 2-methyl-thieno C3,4-d] Cl, 3] oxazin-4-one (1.3 g, 7.78 mmoles) and acid acetic acid (15 rnl), was added 2-chloroaniline (1.64 ml, 15.57 mmol). The mixture was refluxed for 4 hours, cooled and concentrated. The residue was partitioned between ethyl acetate and water and the aqueous phase made basic by the careful addition of saturated aqueous sodium bicarbonate. The phases were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over sodium sulfate and concentrated to a black oil. The oil was subjected to flash chromatography on silica gel (30 x 100 rnm) eluting with 10% ethyl acetate / hexane. The first component that eluted from the column, 0.363 g of white solid, was identified as 3-acetamidot-ofeno-4-carboxylic acid 2-chlorophenylamide. NMR 6 8.33 (d, 3 = 9.7 Hz, 1H), 8.28 (d, 3 = 3.4 Hz, 1H), 8.23 (sa, 1H), 7.78 id, 3 = 3.3 Hz, 1H), 7.44-7.41 (m, 1H), 7.30-7.24 (m, 1H), 7.14-7.11 (m, 1H), 2.19 (s, 3H); EM m / e = 294. The continued elution gave 0.273 g of an unidentified white solid which had an NMR d 8.36 (d, 3 = 8.3 Hz, 1H), 7.56 (sa, 1H), 7.35-7.33 (, 1H), 7.28-7.22 ( rn ,. 1H), 7.04-6.99 (rn, 1H), 2.22 (e, 3H).

Preparation 17 2-Hetl 1-3- (2-chloro-eni) -3H-thienor3.4-d] pyrimidin-4-one It was heated to reflux for 8 hours, with azeotropic removal of water (Dean-Star section) , a mixture of 3-acetamidothiophene-4-carboxylic acid 2-chlorophenylamide (0.36 g, 1.23 mmoles), toluene (15 rnl) and phosphorus oxychloride (0.35 ml, 3.7 mmol). The reaction was cooled and partitioned between ethyl acetate and water. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic layer was washed with water brine, dried over sodium sulfate and concentrated. The residue was subjected to flash chromatography on silica gel (20 x 85 mm) eluting with 10% ethyl acetate / hexane. After a non-peeled precursor, 2-methyl-3- (2-chlorophenyl) -3H-thienoC3,4-dyrimidin-4-one was isolated as a white solid.

NMR 3 8.28-8.26 (m, 1H), 7.56-7.55 (m, 1H), 7.49-7.40 (rn, 3H), 7.31 Cm, 1H), 2.10 (s, 3H); EM rn / e = 277.

PREPARATION 18 3-Aminopyridine-4-carboxylic acid fl ice-cooled mixture of 3,4-pyridinedicarboximide (5.2 g 35.11 rnols) in 10% sodium hydroxide (85 ml), bromine (1.84 ml, 35.8 mmoles). The resulting solution was heated at 80 ° C for 1 hour, cooled in ice and the acidity carefully adjusted to pH 5.5 with acetic acid. The precipitate was collected, washed well with water and air dried to yield 3-aminopyridine-4-carboxylic acid (2.74 g 57%). NMR (DMSO d6) d 8.20 (s, 1H), 7.72 (d, 3 = 5 Hz, 1H), 7.45 (d, 3 = 5 Hz, 1H). The material was used without purification.

Preparation 19 2-Phtethyl-3-oxa-l. 7-diaza-naphthalen-4-one A mixture of 3-aminopyridine-4-carboxylic acid (3.38 g, 24.5 mmol), acetic anhydride (15 g) was refluxed for 4 hours. ml) and sulfuric acid (3 drops). The reaction was cooled and carefully quenched with solid sodium bicarbonate. The mixture was filtered through Celite * (trademark). The filtrate was extracted with ethyl acetate. This organic phase was washed with brine, dried over magnesium sulfate and concentrated to give 2-methyl-3-oxa-l, 7-diaza-naphthalen-4-one (1.95 g, 49%) as a crystalline material. brown. NMR 6 9.00 (s, 1H), 8.78 (d, 3 = 5 Hz, 1H), 7.96 (d, 3 = 5 Hz, 1H), 2.52 (s, 3H). The product was suitable for use without further purification.

Preparation 2Q 2-Methyl-3-o-tolyl-3H-pyrido [3,4-d3-pyrimidin-4-one 2-Methyl-3-oxa-l, 7-diaza-naphthalen-4-one (1.95 g, 12.0 mmol) was dissolved ) in acetic acid (30 ml) and o-toluidine (1.92 ml, 18 mmol) was added. The reaction was refluxed for 7 hours, cooled and concentrated. The residue was taken up in ethyl acetate and extracted with water, aqueous sodium bicarbonate and brine. The organic layer was dried over magnesium sulfate and concentrated. The residue was subjected to flash chromatography on silica gel (2 x 4 inches (5.08 x 10.16 cm), introduced in hexane) by eluting as follows: 10% ethyl acetate / hexane (500 ml); 25% ethyl acetate / hexane (800 ml); 25% ethyl acetate / hexane (200 ml) and 40% ethyl acetate / hexane (200 nl), 2-methyl-3-oxa-l, 7-diaza-naphthalen-4-one recovered not weighed; 40% ethyl acetate / hexane (300 ml), mixed fraction not weighed; 40% ethyl acetate / hexane (3000 ml), to obtain 2-methyl-3-o-tolyl-3H-pyridoC3,4-d3-pyrimidin-4-one (2.47 g, 81%) as a solid whitish NMR S 9.15 (s, 1H), 8.70 (d, 3 = 5 Hz, 1H). 8.05 (d, 3 = 5 Hz, 1H), 7.46-7.35 (m, eH), 7. 16 (d, 3 = 7 Hz, 1H), 2.23 (s, 3H), 2.13 fe, 3H). This product was suitable for use without additional puri fi cation.

Preparation 21 Q-Toluamide with cyanoacetic acid A mixture of o-toluidine (5.0 ml, 47 mmol), rnetylene chloride (15 ml) was stirred at room temperature overnight., cyanoacetic acid (8.0 g, 94 mmol), 1-hydroxybenzotpazole (12.7 g 94 mmol), 4-dimethylaminopyridine (5 crystals, catalytic amount) and l- (3-dimethylamino-ropil) -3-ethylcarbodiimide hydrochloride (16. 2 g, 94 rnmoles). The reaction was concentrated and the residual pale yellow oil was partitioned between ethyl acetate and water. The phases were separated and the organic layer was washed with sodium bicarbonate and concentrated to 5.2 g of an off-white solid. This solid was crystallized from methylene chloride in two cultures to produce o-toluamide of cyanoacetic acid (4.71 g, 57%) as white crystals. P.f. 129-130 ° C; NMR d 9.66 (s, 1H), 8.00-7.07 (rn, 6H), 3.92 (s, 2H), 2.20 Cs, 3H).

Preparation 22 o-Toluamide of S-amino-1-henyl-1,2-triazole-4-carboxylic acid A mixture of sodium (0.598 g 26 mmol) and ethanol (50 ml) was stirred until all of the sodium had reacted In the form of sodium ethoxide, this solution was added o-toluamide of cyanoacetic acid (2.32 g, 13 mmol). The mixture became homogeneous and yellow in a short time and then a yellow solid precipitated. At this time benzyl azide (1.73 g 13 mmol) was added and the reaction was stirred at room temperature for 17 hours. The mixture was concentrated and the yellow solid residue was suspended in water and acidified to pH 4 by the addition of acetic acid. The suspension was stirred for 30 minutes and the bright red solid which formed was collected and dried (5.2 g). The solid was subjected to flash chromatography on silica gel (100 g) eluting with 0.05% ammonium hydroxide / 1% methanol / methylene chloride to yield 3.5 g of an impure product in two fractions. This crude product was crystallized from 16% methanol / isopropyl ether to produce 5-amino-1-benzyl-1, 2,3-triazole-4-carboxylic acid o-toluamide (1.52 g, 38%) in the form of a pale orange solid. P.f. 14Q-144 ° C; NMR d 8.54 IS, 1H), 8.00 (d, 3 = 7.9 Hz, 1H), 7.43-7.22 (m, 7H), 7.07 (t, 3 = 7.5 Hz, 1H), 5.41 (s, 2H), 4.86 (e, 2H), 2.37 (s, 3H). The concentration of the mother water produced 0.818 g more of product.

Preparation 23 l-Bßncyl-S- »ethyl-6-o-tolyl-3.6-dihydro-Cl .2.33tria2? LC, 5-d3 Pyrimidin-7-one A mixture of sodium (1.14 g 49.5 mmol) and ethanol was stirred. (100 ml) until the sodium had reacted to form sodium ethoxide, and this solution was added 5-amino-1-benzyl-l, 2,3-triazole-4-carboxylic acid o-toluamide (7.6 g, 24.7 mroles) and ethyl acetate (50 ml). The reaction was refluxed for 48 hours, cooled and concentrated to obtain an orange solid. This solid was partitioned between water and methylene chloride. The phases were separated and the organic layer was dried over magnesium sulfate. The concentration of this organic phase produced 0.5 g of product. The aqueous layer of the extraction was acidified to pH 6.5 with acetic acid and extracted with chloro forwo (2 x 100 ml). Methanol (20 ml) was added to the chloroform to help maintain the product without precipitation. This organic phase was dried over magnesium sulfate and concentrated to give 6.93 g of white crystals. The products were combined to yield 7.43 g (90%) of 1-benzyl-1-5-methyl-6-o-tolyl-3,6-dihydro-1,2-triazole-4,5-d-pyrimidine. -7-ona. P.f. 178-180 ° C; NMR (DMSO d6) d 9.86 (s, 1H), 7.49-7.09 (m, 6H), 5.49 Cs, 2H), 2.24 Cs, 3H), 2.05 Cs a, 3H).

Preparation 2 S- 'ethyl-β-o-tolyl-3-γ-dihydro-ri.2.33tria2? Ir4.S-d3 pyrimidin-7-one Hydrogenated in an apparatus Para? A mixture of 1-benzyl -5- methyl-6-o-toli 1-3, 6-dihydro-p, 2,33-triazole C 4,5-d3-pyrimidin-7-one C4.0 g, 12.07 mmol), acetic acid (150 ml), ethanol (25 ml) and palladium hydroxide on carbon (4.0 g). After 5 hours, the catalyst was removed by filtration and replaced by fresh palladium hydroxide on carbon (4.0 g). The hydrogenation was continued for a further 48 hours. The reaction was filtered and the filtrate was concentrated to yield 5-methyl-6-o-tolyl-3,6-dihi roCl, 2,33-triazole-E4,5-d-pyrimidin-7-one (0.588 g, 17%) as a white powder. NMR & 9.31 (s, 1H), 7.85 (m, 1H), 7.30-6.95 (m, 3H), 1.88 (s, 6H). The product was used without further purification.

Preparation 25 4-Fethyl-2-yl-2-carfroxalide A solution of 4-rnetylthiazole CO.9.1 ml, 10.0 mmol) in tetrahydrofuran C20 ml was cooled to -78 ° C and added dropwise, over 15 minutes , butyllithium (6.0 ml, 15 rnols, 2.5 molar solution in hexane). The light yellow solution was stirred 1 h at -78 ° C and transformed into a slurry. Dimethylformamide (1.2 ml, 15 mmol) was added to the reaction via syringe for 5 minutes. The reaction was stirred for a further 2 h at -79 ° C, then allowed to warm to 0 ° C and poured into wet ice. The acidity of the mixture was adjusted to pH 4 with 1N HCl and extracted with ether. The combined ether extracts were washed with brine, dried over sodium sulfate and concentrated to yield 4-methylthiazole-2-carboxaldehyde 0.734 g, 57%) as a brown oil. NMR d 9.88 (S, 1H), 7.29 (m, 1H), 2.50 (s, 3H3.) The material was used without further purification.

Preparation 26 2-pe iltiazQl-4-carPoxalde í < A solution of ethyl 2-methylthiazole-4-carboxylate (1.0 g, 5.8 mmol) in tetrahydrofuran (35 ml) was cooled to -50 ° C and added dropwise via a syringe, for 15 minutes, hydr. of diisobutyl onium (12 ml, 11.97 mmol, 1 molar solution in tetrahydrofuran). The solution was stirred for 30 minutes at -50 ° C, then allowed to warm to room temperature for 3 h. The reaction was cooled on wet ice and carefully quenched with 10 rnl of 5 OZ methane / tetrahydrofuran. The reaction was treated with sodium tartrate and aqueous potassium saturated in half (Rochelle salt) and the mixture was filtered. The filter cake was washed intensely with ether and water. The whole filtrate was combined and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over sodium sulfate and concentrated to obtain 4-hydroxymethyl-2-methylthiazole (0.57 g, 76%) in the form of a chestnut oil. NMR d 6.97 (s, 1H), 4.54 (s, 2H), 4.43 (s a, 1H), 2. 63 (2, 3H1) This material was used without further purification.A room temperature solution of 4-hydroxymethyl-2-ethylthiazole (10 g, 7.75 mmol) and dichloromethane (50 ml) was treated with Dess Martin periodinane (4.12). g, 9.69 mmol) at one time The mixture was allowed to stir overnight, more periodinane (1.2 g) was added and the reaction was allowed to stir for further hours.The reaction was poured into 50 ml of aqueous sodium thiosulfate. The organic layer was washed with saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate and concentrated to yield 0.901 g (92%) of 2-methylthiazole-4-carboxaldehyde. in the form of a whitish waxy eolid having: NMR d 9.96 (s, 1H), 8.03 (sv 1H), 2.77 (e, 3H) The product was suitable for use without further purification.

Preparation 27 2-Pimethylaminemethylthia-2-Chl-4-carfr-xal4e-4-a4-2-dimethylaminothioaceta hydrochloride (7.7 g, 50 mmol) in ethanol (100 ml) was added ethyl acetate solution, 6.3 ml). The mixture was heated to r efflux for 6 hours and then cooled to room temperature. Methyl ethyl bromopyruvate (3.2 ml for a total of 75 moles) was added and the reaction was heated to reflux for 2.5 more 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). Elution proceeded as follows: 2% methanol / chloroform, 200 ml, pre-development; 102 methanol / chloroform, 75 ml, nothing; 750 ml, 10.7 g (100%) of ethyl 2-dirnethylaminomethylthiazole-4-carboxylate in the form of a clear yellow oil. The material was suitable for use without further purification. NMR & 8.07 (d, 3 = 1.4 Hz, 1H), 4.32 (q, 3 = 7 Hz, 2H), 3.73 (S, 2H), 2.28 (s, 6H), 1.31 (t, 3 = 7 Hz, 3H ). 0 a mixture of lithium aluminum hydride (4.5 g, 119 mmol) in ice-cold tetrahydrofuran (100 mL) was added ethyl 2-dimethylaminomethylthiazole-4-carboxylate (8.5 g, 39.7 mmol in 40 mL of tetrahydrofuran). ) Drop by drop, for 40 minutes, 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 harmonic chloride (30 ml). The resulting gray suspension was stirred for 15 minutes and filtered through celite. The cake 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-dimethylaram- ine-methyl-4-hydroxymethylthiazole in the form of an amber oil. The material was used without further purification. NMR or 7.12 Cs, 1H), 4.71 (s, 2H3, 3.73 Cs, 2H), 2.50 (s a? 1H), 2.32 (s, 6H). A solution of 2-dimethylaminomethyl-4-hydroxymethylthiazole (4.2 g, 27.3 mmol) in methylene chloride (200 nmol) 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 4 more hours. The reaction was quenched by the addition of saturated aqueous sodium thiosulfate (100 ml) and the pH of the resulting mixture adjusted to pH 10 by the addition of solid potassium carbonate. The two phase mixture was 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. The solid was purified by flash chromatography on silica gel (50 x 130 rnm) eluting first with chloroform (200 ml) and then with 2% methanol / chloroform to collect 25 ml fractions. The fractions 51-30 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-dirnethylaminomethyl-thiazole-4-carboxaldehyde as a yellow oil. This product was used without further purification. NMR d 9.95 (s, 1H), 8.14 (s, 1H), 3.81 (s, 2H1, 2.36 (s, 6H).

Claims

NOVELTY PE Lfl INVENTION REVINDICßCTONES

1. - A bicyclic compound of the formula wherein a fused heteroaromatic ring, wherein said heteroaromatic ring is a 5- or 6-membered heteroaromatic ring, wherein said 6-membered heteroaromatic ring, taken together with the carbon atoms common to the two rings of the bicyclic system, has the formula and where said 5-membered heteroaromatic ring, together with the carbon atoms of the two rings of the bicyclic sevenma, has the formula where said ring positions "fl", "B", "D" and, rE "can be independently selected from carbon or nitrogen, where said ring positions" F ",, rG", and "3" can be independently selected from carbon , nitrogen, oxygen or sulfur, with the proviso that: i) if more than two of "F", "G", and "3" are heteroatoms, then said 5-membered heteroaromatic ring is selected from the group consisting of ( 1,2,3) -triazole, Cl, 2,3) -thiadiazole, 1,2,5) -thiadiazole and 1, 2,5) -oxadiazole; and ii) if two of "F", "6", or "3" are heteroatoms, one of said heteroatoms may be oxygen or sulfur; wherein said fused heteroaromatic rings may optionally be independently substituted at any of the carbon or nitrogen atoms capable of forming an additional bond with a substituent selected from hydrogen, alkyl (C ^ -C *, halogen trifluoromethyl, amino- (CHa) ^ -, alkylamino (C -Cß) - (CHa) rt-, dialkylamino (C -Cß) - (CHa) r? -, alkoxy (Ca.-Cß,), hydroxyalkyl fC -C «, alkyl (C -C * ) -O-alkyl (C -C ", CN, alkyl (C -C *) - C - (= 0) -0-alkyloxyCi-Cß.), Alkyl (C -Cβ) -0-C (= 0) -0-, hydroxy, -N0a R3-C (= 0) -, R * -0-C (= 0) -, dialkyl (Cx-C *) -NC (= 0) -, cycloalkyl (Cx-) C, s) and R * -NH-C (= 0) - and phenyl optionally substituted with halo, fC-β alkyl), -CN or -CFa; Ra is substituted phenyl of the formula Ph or heteroaryl, wherein said heteroaryl is selected from the group consisting of pyridin-2-yl, pyridin-3-yl,? Iridin-4-yl, wherein said heteroaryl may be optionally substituted in any of atoms capable of forming an additional bond, with up to a maximum of three substituents, with a s? stit? selected from hydrogen, alkyl (C -C "), halogen, trifluoromethyl, to ino- (CHs.) r , -, alkylamino (C -C?) - (CH; a) n-, dialkylamino (C -C?) - (CHa) ,, -, alkoxy (CX-CA), hydroxyalkyl (Ci-C *), alkyl (C -C?) - 0-alkylC-C *), CN, alkyl (Cx-C 's -C (= 0) -O-alkyl (C -C?), Alkyl (CX-C?) - 0-C (= 0) -O-alkyl (C -C?), Alkyl (C -C?) - C (= 0) -0-hydroxy, H-CC = 0), alkyl (C -C < 6) -C - (= 0) -, -H0-C (= 0) -, alkyl (C -C "s.) -0-C (= 0) -, NHa-C (= 0) -, alkyl (C * .- CA) ~ NH-C (= 01- and dialkyl (C -CA) -NH-C (= 0) -, where said Ph is a group of the formula

R * is disubstituted phenyl of the formula Ph2 or a five or six membered heterocycle, wherein said 6 membered heterocycle has the formula wherein "N" is nitrogen; where said ring positions "K", "L" and UPI "can be independently selected from carbon or nitrogen, with the proviso that only one of" K "," L "or" M "can be nitrogen; Five-member heterocycle has the formula wherein said positions of the ring "P", "0" and "T" can be independently selected from carbon, nitrogen, oxygen or sulfur; with the proviso that only one of "P", "rQ" or "T" can be oxygen or sulfur and at least one of "P", "0" or "T" must be a heteroatom, where said Ph2 is A disubstituted group of the formula

Ra is hydrogen or alkyl (C -C?); R * is hydrogen or alkyl (C -C?); Ra is hydrogen, alkyl (Cx-C < s), halo, CF3, alkoxy (C -C, s) or alkylthiol (C ~ C?); R * is hydrogen or halo; R? it is hydrogen or halo; Rβ is hydrogen or halo; R * is hydrogen, (Cx-C3) alkyl optionally substituted with one to three halogen atoms, halo, CF3, (C ~ C, s) alkoxy optionally substituted with one to three halogen atoms, alkylthiol (C -C) ?), R a0- (CH2) P-, alkyl? (C -C?) -NH- (CHa) *, -, dialkyloylCa.-C *) -N ~ (CH2) p-, cycloalkyl (C) -Ca) -NH- (CHa) p >; -, HaN- (C = 0) - (CH2) P-, alkyl (Cx-C *) -NH- (C = 0) - (CHa) ^ -, dialkyl (Cx-C?) -N - (C = 0) - (CHss) ^ -, cycloalkyl (C -Ca) -NH- (C = 0) - (CH2) p.-, RX3 »0- (C = 0) - (CHa) * > -, alkyl (C -C?) - (0 = C) -0-alkyl (C -C < 5,) -, alkylCx-C *) -0- (0 = C) -0- alkyl (C-) C 's>, alkyl (C -C "s.) - (0 = C) -0-, alkylC ^ C * - (0 = C) -NH- CCHa) P-, H (0 = C) -NH- (CHa ^ -, alkyl (C -Cβ) - (0 = C) -N? Alkyl CC -CA)) -CCHa) p-, H (0 = C) -Nalkyl C -C?) ) - (CHa) * > -, hydroxy, HC (= 0) - (CH2) P-, alkylCi-C *) -C (= 0) -, alkyl (C -C * l -0- CC = 0) -, R ^ -ÍCHa) , - - 0-C (= 0) -, to ino-ÍCHsjJp-, hydroxy-alkyl (C -C < ß.) -, alkyl (C ~ Cß) -0-alkyl (Cx-C?) - and -CN; Rxo and R * are hydrogen, (Cx-C?) Alkyl optionally substituted with one to three halogen atoms, halo, CFa, (C -Cβ) alkoxy optionally substituted with one to three halogen atoms, alkyltiolCCx-Cß) , Rxa0- (CHa), -, alkyl (C -CA) -NH- (CHa) *, -, dialkyl (C-C4S) -N- (CHa), »-, cycloalkyl (C -3) -NH- (CHa) p, -, HaN-CC = 0) - (CHa) r > -, alkylene (C -C?) -NH- (C = 0) -CCHa) p-, dialkyl (C -C *) -N- (C = 0) - (CHa) », cycloalkyl (C ~) Cs) -NH- (C = 0) - (CHa) P-, R a0- (C = 0) (CHa) p-, alkyl (C -C?) ~ (0 = C) -O- alkyl (C -C?), Alkyl (Cx-C?) -O- (0 = C) -O-alkylene (C? C?), Alkyl (C -C?) - (0 = C) -O-, alkyl (C -C) - (0 = C) -NH- CCHa) *, -, -H (0 = C) -NH- (CHa) ^ -, alkyl (Cx-Cß) - (0 = C) -N- (alkyl (C -C < s)) - (CHs >) ß-, H (0 = C) -N (alkylene (C -C < s)) - (CH2 ) * > - hydroxy, H-C (= 0) - (CHa) * > -, alkyl (Cx-C?) -C (= 0) -, alkylene (Cx-C?) -0-C (= 0) -, R * - (CHa) P-0-C (= 0) ) -, amino- (CHa) * »-, hydroxy-alkaryl (C -CA), alkyl-Cs-Cs) -0-alkyl (Cx-C *), -CHO and -CN; R is hydrogen or halo; R 2 is hydrogen or halo; R s * is hydrogen, alkyl (C -C?), Alkyl (C -C?) - (C = 0) -, alkyl? (C -C?) -O- (C = 0) -, alkyl? ( Cx-CA) -NH- (C = 0) - or dialkylCCi-C *) -N- (C = 03-; Rxs is hydrogen, -CN, alkyl (Cx-C «s), halo, CF3, -CHO or alkoxy (Cx-C *; Rx * is hydrogen, -OJ, alkyl iloCCx-C?), halo, CFa, -CHO or alkoxy (C -C *); R * -7"is hydrogen ^ -CN, alkyl (C -C?), halo, CFa, -CHO or alkoxy (CX-C?); n is an integer from zero to 3; p is an integer from zero to 3, where the dashed link represents a optional double bond, with the proviso that when R9 is hydrogen, one of Rx and Rz is other than hydrogen, and the pharmaceutically acceptable saltse of such compounds 2. A compound according to claim 1, in that the atom "fí", "Dn or" E "of the heteroaromatic ring of 6 members is nitrogen or the heteroatoms" 6"or" F "of the 5-membered heteroaromatic ring are sulfur 3.- A compound according to the claim 1, in which the fl ring is a hßtero ring aromatic of 5 members, "G" is sulfur and "F" and "3" are carbons.

4. - A compound according to claim 1, wherein ring fl is a 5-membered heteroaromatic ring, "F" is azu fre and "G" and "3" are carbons.

5. A compound according to claim 1, wherein R is Ph and one of Rs, R ?, ^ or Rβ is fluoro, bromo, chloro, methyl or trifluorometiuo.

6. The compound according to claim 1, wherein R is Ph and Rs is fluoro, bromo, chloro, methyl or trifluoromethyl.

7. A compound according to claim 2, wherein Rx is Ph and Rs is fluoro, bromo, chloro, methyl or trifluororoethyl.

8. A compound according to claim 3, wherein R is Ph and Ra is fl? Gold, bromine, chlorine, methyl or trifluoromethyl.

9. A compound according to claim 4, wherein Rx is Ph and Ra is fluoro, bromo, chloro, methyl or tri-fluoro-ethyl.

10. A compound according to claim 1, wherein R2 is Ph2 and R ** is fluoro, chloro, hydroxy or cyano.

11. A compound according to claim 2, wherein R2 is Ph2 and R * is fluoro, chloro, hydroxy or cyano.

12. A compound according to claim 3, wherein R2 is Ph2 and R9 is fluoro, chloro, hydroxy or cyano.

13. A compound according to claim 4, wherein R2 is Ph2 and R * is fl? Gold, chlorine, hydroxy or cyano.

14. - A compound according to claim 6, wherein R2 is Ph2 and R9 is fluoro, chloro, hydroxy or cyano.

15. A compound according to claim 7, wherein R2 ee Ph2 and R9 are fluoro ,. chlorine, hydroxy or cyano.

16. A compound according to claim 9, wherein R2 is Ph2 and R is fluoro, chloro, hydroxy or cyano,

17. A compound according to claim 1, wherein Rx is pyridin- 3-yl optionally substituted with halo, -CN, CF3 or alkyl (C x -Cß).

18. A compound according to claim 2, wherein R is pyridin-3-yl optionally substituted with halo, -CN, CFa or alkyl (C? -C "s).

19. A compound according to claim 3, wherein R is pyridin-3-yl optionally substituted with halo, -CN, CF3 or alkyl (C -Cß).

20. A compound according to claim 4, wherein R is pyridin-3-yl optionally substituted with halo, -CN, CF3 or alkyl (Cx-Cß).

21. A compound according to claim 14, wherein R is pyridin-3-yl optionally substituted with halo, -CN, CF3 or alkyl (CX-C?).

22. A compound according to claim 1, wherein R2 is pyrid-2-yl, I, 3-thiazol-4-yl, 1,3-thiazol-2-yl or fur-2-yl. optionally substituted.

23. - A compound according to claim 2, wherein R2 is pyridin-2-yl, 1,3-thiazole-4-yl, 1,3-thiazol-2-yl or fur-2- ilo optionally substituted.

24. A compound according to claim 3, wherein R2 is optionally substituted pyrid-2-yl, 1,3-thiazol-4-yl, 1,3-thiazol-2-yl or fur-2-yl. .

25. A compound according to claim 4, wherein R2 is pyrid-2-yl, 1,3-thiazol-4-yl, 1,3-thiazol-2-yl or fur-2-yl. optionally substituted.

26. A compound according to claim 9, wherein R2 is optionally substituted pyrid-2-yl, 1,3-thiazol-4-yl, 1,3-thiazol-2-yl or fur-2-yl. .

27. A compound according to claim 17, wherein R2 is pyrid-2-yl, 1,3-thiazol-4-yl, 1,3-thiazol-2-yl or fur-2- ilo optionally substituted.

28. A compound according to claim 1, wherein said compound is: 3- (2-rnethylphenyl) -2-C2- (2-fluorO-phenyl) -vinyl] -3H-thienoC3,2-d] pyridimidin-4-one: 3- (2-chlorophenyl) -2-C2- (2-fluoro-phenyl) -vinyl3-3H-thienoC3,2-d.lpyridimidin-4-one: 3- (2-methylphenyl-2 -112-pyrid-2-vini13-3H-thienoC3,2-d] pyridimidin-4-one: 3- C2-methylphenyl) -2- Z 2-chlorophenyl-vinyl-3H-thienoC3,2-d] pyridimidine- 4-one: 3- (2-trifluoromethyl-phenyl) -2-C2-fluorophenyl-vini 11-3H-thienoC3, 2-d3pyridimidin-4-one: 3- (2-chloro-? Iridin-3-yl) - 2-C2- (2-methyl-thiazol-4-yl) -vinyl] -3'-thienoC3,2-d3-pyridimidin-4-one: 3- (2-methyl-? Iridin-3-yl) -2-C2 - (2-methyl-thiazol-4-yl) -vinyl3-3H-thienoC3,2-d] pyridimidin-4-one: 3- (2-chlorophenyl) -2-C2-pyrid-2-yl-vinyl3-3H -tienoí: 3, 2-dlpyridimidin-4-one: 3-C2-chlorophenyl) -2-C2-hydrroxyphen? -vinyl3-3H-thienoC3,2-d] pyridimidin-4-one: 29.- A pharmaceutical composition for treating or preventing a condition selected from cerebral deficits after cardiac bypass surgery and grafts, stroke, cerebral ischemia, spinal cord trauma, head trauma, Alzheimer's disease, Huntington's disease, arninotrophic lateral sclerosis, epilepsy, dementia induced by the AIDS, muscle spasms, headaches, urinary incontinence, psychosis, convulsions, perinatal hypoxia, hypoxia, cardiac arrest, hypoglycemic neuronal lesions, opioid tolerance, withdrawal syndrome, ocular lesions, retinopathy, retinal neuropathy, tinnitus, Parsson's disease and idiopathic drug-induced, anxiety, emesis, cerebral edema, chronic or acute pain or late dyscenesia, in a mammal, comprising a quantity of a compound according to the claim 1 effective in the treatment or prevention of such a condition and a pharmaceutically acceptable carrier. 30. The use of a compound according to claim 1 in the preparation of compositions for treating or preventing the condition selected from brain deficits subsequent to cardiac bypass surgery and grafts, stroke, cerebral ischemia, spinal trauma. spinal, head injury, Alzheimer's disease, Huntington's disease, lateral sclerosis to iotrophic, epilepsy, AIDS-induced dementia, muscle spasms, migraine, urinary incontinence ,. psychosis, seizures, perinatal hypoxia, hypoxia, cardiac arrest, hypoglycemia neuronal lesions, opioid tolerance, withdrawal syndrome, ocular lesions, retinopathy, retinal neuropathy, tinnitus, idiopathic and drug-induced Parkinson's disease, anxiety, eie, edema chronic or acute pain or tardive dyskinesia, in a mammal in need of such treatment or prevention. 31. A pharmaceutical composition for treating or preventing a disorder, whose treatment or prevention is facilitated by the increase of neurotransmission of glutamate in a mammal, which comprises a quantity of a compound according to claim 1 effective in the treatment or prevention of such a condition and a pharmaceutically acceptable vehicle. 32. The use of a compound according to claim 1 in the preparation of compositions for treating or preventing a disorder, the treatment or prevention of which is facilitated by the increase in glutamate necrotransmission in a mammal in need of treatment. such treatment or prevention. 33.- A pharmaceutical composition for treating or preventing a condition selected between cerebral deficits subsequent to surgery of cardiac deviation and grafts, apoplectic attack, cerebral ischemia, spinal cord trauma, cephalic traumatism. Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, epilepsy, AIDS-induced dementia, muscle spasms, migraines, urinary incontinence, psychosis, seizures, perinatal hypoxia, hypoxia, cardiac arrest, hypoglycemic neuronal lesions, opioid tolerance, syndrome of abstinence, eye injury, retinopathy, retinal neuropathy, tinnitus, idiopathic and drug-induced Parkinson's disease, anxiety, emesis, cerebral edema chronic or acute pain or tardive dyskinemia, in a mammal, comprising an effective amount as an AMPA receptor antagonist of a composition according to claim 1 and a pharmaceutically acceptable carrier. 34. The use of an effective amount as an AMPA receptor antagonist of a compound according to claim 1 in the preparation of compositions for treating or preventing a condition selected among brain deficiencies subsequent to cardiac bypass surgery and grafts, apoplectic attack , cerebral ischemia, spinal cord trauma, cephalic trauma, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, epilepsy, AIDS-induced dementia, muscle spasms, headaches, urinary incontinence, psychosis, seizures, perinatal hypoxia, hypoxia, cardiac arrest, hypoglycemic neural lesions, opioid tolerance, withdrawal syndrome, ocular lesions, retinopathy, retinal neuropathy, tinnitus, idiopathic and drug-induced Parkinson's disease, anxiety, emesis, cerebral edema, chronic or acute pain or tardive dyskinesia, in a mammal in need of such treatment or prevention. 35.- A pharmaceutical composition for treating or preventing a disorder, whose treatment or prevention is facilitated by the increase of neurotransmission of glutamate in a mammal, comprising an effective amount as AMPA receptor antagonist of a compound according to claim 1 and a pharmaceutically acceptable vehicle. 36.- The use of an AMPA receptor antagonist effective amount of a compound according to claim 1 in the preparation of compositions for treating or preventing a disorder, whose treatment or prevention is facilitated by the increase of neurotransmission of glutamate in a mammal in need of such treatment or prevention.