MXPA98007227A - New atropisomeros de (5,6) -heteroarilcondensado-pirimidin-4-onas 2,3 disustitui - Google Patents

Abstract

The present invention relates to novel atropisomers of 2,3-disubstituted (5,6) -heteroaryl-condensed-pyridin-4-ones, to pharmaceutical compositions containing such compounds and to the use of such compounds to treat disorders of the central and peripheral nervous system. neurodegenerative, psychotropic and induced by drugs and alcohol

Description

NEW ATROPISOMEROS DE < 5, 6) -HETER0ARILC0NDENSAD0-PYRIMIDIN- ~ 4- ONAS 2.3 PISUSTITUIDAS The present invention relates to new atropisomers of (5 »S) -heteroar 1-condensed-p? R? Midin-4-ones 2f3 -substituted of the formula I" or is described below "to their pharmaceutically salts acceptable to pharmaceutical compositions containing them and their use in the treatment of disorders of the central nervous system and peripheral neurodegenerative psychotropic and induced by drugs and alcohol. The role of excitatory amino acids »such as glutamic acid and aspartic acid» as predominant mediators of excitatory synaptic transmission in the central nervous system »is well established» Watkins and Evans »Ann. Rev. Pharmacol. Toxicol .. 21 »165 (19B1)» Monaghan »Bridges and Cotman» Ann. Rev. Pharmacol. Toxicol. »29» 365 (19B9); Watkins »Krogsgaard-Larsen and Honore» Trans. Pharm. sc. »11» 25 (1990). These amino acids function in synaptic transmission mainly through excitatory amino acid receptors. These amino acids also participate in a variety of different physiological processes »such as motor control» breathing »cardiovascular regulation» sensory perception and cognition. Excitatory amino acid receptors are classified into two general types. The receivers that are - Dock directly into the cellular membrane of neurons for the opening of cation channels »are called" onotropic ". This type of receptor has been subdivided into at least three subtypes that are defined by the depolarizing actions of the selective agonists N-methyl-1-D-aspartate (NMDA) »a-amino-3-hydroxy-5-methyl-azole -4-Propionic (AMPA) and Cainic acid (KA). The second general type is the G protein or "metabotropic" receptor of excitatory amino acids attached to second messengers. This second type »when activated by the agonists quisqualate» ibotenate or trans-1-aminocid opentane-1 »3-dicarboxylic acid» produces an increase in the hydrolysis of phosphoinoses in the post-synaptic cell. It seems that the two types of receptors not only mediate normal synaptic transmission along the excitatory pathways, but also participate in the modification of the synaptic connection during development and change the efficiency of the synaptic transmission throughout the lifetime. Schoepp. Bockaert and Sladeczek. Trends in Pharmacol. Sci .. 11 »50B (1990); McDonald and Johnson. Brain Research Reviews. 15 »41 (1990). Excessive or inappropriate stimulation of excitatory amino acid receptors "produces injury or loss of neuronal cells by means of a mechanism known as excitotoxicity. It has been suggested that this process mediates neuronal degeneration in a variety of conditions. The medical consequences of such neuronal degeneration "make the relief of these degenerative neurological processes an important therapeutic goal. The excitotoxity of excitatory amino acids has been implicated in the pathophysiology of several neurological disorders. This excitotoxicity has been implicated in the pathophysiology of acute and chronic neurodegenerative conditions »including stroke» cerebral ischemia »spinal cord trauma» head trauma »Alzheimer's disease» Huntington's disease »lateral sclerosis to inotrophic» epilepsy »induced dementia AIDS »perinatal hiccups» hypoxia (such as conditions caused by strangulation »surgery, inhalation of smoke» asphyxia »drowning» airway obstruction »electrocution or overdose of drugs or alcohol)» cardiac arrest »neuron injury ! hypoglycemia »ocular lesion» retinopathy »idiopathic and drug-induced Parkinson's disease and brain deficits after cardiac bypass surgery and grafts. Other neurological conditions caused by glutamate dysfunction also require neuropathology. These other neurological conditions include muscle spasms, "migraines," urinary incontinence, "psychosis," withdrawal symptoms (such as the product of alcoholism and drug addiction), including opioid addiction., cocaine and nicotine) »tolerance to opiates» anxiety »emesis» cerebral edema »chronic and acute pain, seizures» retinal neuropathy »tinnitus and tardive dyskinesia. It is believed that the use of a neuroprotective agent »such as an AMPA receptor antagonist» is useful in treating these disorders and / or in reducing the dimension of the neurological lesions associated with these disorders. Antagonists of excitatory amino acid receptors (EAA) are also believed to be useful as analgesic agents. Several studies have shown that AMPA receptor antagonists are neuroprotective in models of focal and global ischemia. It has been reported that the competitive AMPA receptor antagonist NBQX (2 »3-dihydrox -6-nitro-7-sulfamoyl-l-benzoCf-3-aminoquinoline) is effective in the prevention of global and focal ischemic lesions. Sheardown and others »Science» 247. 571 (1900); Buchan and others »Neuroreport. 2 »473 (1991)» LePeillet et al., Brain Research »571» 115 (1992). It has been shown that non-competitive AMPA receptor antagonists TKYI 52466. are effective neuroprotective agents in models of rat global ischemia. LaPeillet et al. »Brain Research, 571. 115 (1992). These studies strongly suggest that neuron degeneration! Delayed cerebral ischemia involves an 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 to improve the neurological results of cerebral ischemia in humans. The present invention provides an atropisomer of formula I where v »X, Y and Z are» all of them, carbons or one of them is nitrogen and the others are carbons; each of R »R8 *» Ra »R-» and Rβ is selected »independently» from hydrogen »halogen» alkyloic, -C.sub.)) »tri-loromethyl, cyano» alkoxy (C -C.sub.be) »alkyl thio (CA-) Cß) and C (= 0) -0-alk (Cx-Cß). with the proviso that: (a) R * can not be the same as Rra when each of V »X» Y and Z is a carbon »(b) at least one of R * and Rβ must be other than hydrogen; and (c) when V. X, Y or Z is nitrogen; then RB »R" * »Ra or Ra, respectively» is absent, the ring A * is a condensed heteroaromatic ring, where said heteroaromatic ring is a 5- or 6-membered heteroaromatic ring »where said heteroaromatic ring of S members» taken together with the carbon atoms common to the two rings of the bicyclic system »has the formula 5 and where said 5-membered heteroaromatic ring» taken together with the carbon atoms common to the two rings of the bicyclic system »has the formula wherein said positions of ring "A", "Btt," Dtt and "E" 5 can be selected "i dependently" between carbon on nitrogen "where said ring positions" F "» "G" and "J" can be select »independently» between carbon »nitrogen» oxygen or sulfur »with the proviso that: (a) if more than two" F "," G "or" J "is a heteroatom» then said 5-membered heteroaromatic ring is selected between the group consisting of (1 »2» 3) -triazole »(1» 2 »3) -thiadiazole» (1, 2 »5) -thiadiazole and (1» 2,5) -oxadiazole; and (b) if two of "F". "G" or "J" are heteroatoms "only one of said heteroatoms can be oxygen or sulfur" wherein said optionally fused heteroaromatic rings can be independently substituted, on any of the carbon or nitrogen atoms capable of forming an additional bond, with a substituent selected from hydrogen »alkyl (CA-Cß). halogen trifluoromethyl. ami o-íCHs ,,) ,, - »a! qui lamino (C -Cß) - (CHz) r) -» dial qui lamiraHCa, - Cß) - (CHß) "-» alkoxy (CX-C?). hydroxyalkyl) -C1) alkyl (Cx-Cß) »-CH» alkyl 1O (C -Cβ) -CO-0-alkynyl (Ca_-Cß) - »alkyl 10 (C.,. -C.sub.β) -0-CO-0-alkyl (C -C.sub.be) »alkyl 1o (CA-C.sub.a) -C0-0-» hydrox. -NO-g »Rxß-C (= 0) -» R3-ß-C (= 0) - »dialkyl (C1-Cß) -NC (= 0) -» cycloalkyl (C3-C ^) and R * - & -O-NH-C (= 0) - »and phenyl optionally substituted with halo» alkyl (CA-Cß) »-CN or -CFa. R * is phenyl of the formula Ph or a five- or six-membered heterocycle »wherein said 6-membered heterocycle has the formula wherein "N" is nitrogen; wherein said ring positions "K" »" L "and" M "can be selected" independently "between carbon or nitrogen» with the proviso that only one of "K" »" L "and" M "can be nitrogen where said Five-member heterocycle has the formula e wherein said ring positions "P". "Q" and "T" can be selected »i dependently» between carbon »nitrogen» oxygen or sulfur »with the proviso that only one of" P "or T, T" can be oxygen or sulfur and at least one of "P" "» «QTT and» tjn has to be a heteroatom, where said PhA is a group of the formula wherein each Riß eß »independently» hydrogen or alkyl (C -Cß) »each of Rβ» R * - ° and R * A are independently selected. between hydrogen »alkyl (Cx-C). optionally substituted with one to three halogen atoms »halo» CF3 »(C-C) alkoxy optionally substituted with one to three halogen atoms» alkyl (C -Cß) »Riß0- (CHjg) ß-» ali l? C -Cβ) -NH- (CHsí) P, - »dial qui 10 (Cx-Cß) -NH- (CH 3?) -, C Cloalkyl (C3-C ^) - NH- (CHa) P > -, H58N- (C = 0) - (CHat) F, - »alkyl lo < CX-C ") - HN- (C = 0) - (CH.,.), Dialkyl (C1-Ca) -N- (C = 0) - (CHß)? -, Cycloalkyl O (C3-C -,) - NH- (C = 0) - (CHa) _- »Riß0- (C = 0) - (_. > -» alkylO (C1-Ca) - (0 = C ) -0-a! Qui lOíC ^ -C ^ "alkyl (C1-C (B) -0- (0 = C) -0-alkyl (Cx-Cß> .alkyl (Cx-Cß) - (0 = C) -0- »alkyl lo (C -Cβ) - (Oz-O-NH-iCHz.) ..-, H (0 = O-NH- (CH2) -» alkyl (C-) Cß) - (0 = C) -N- Calkyl (C? -Cβ) 2 (CHa, ^ -, H (CO = C) -N-Calqui l? (Cx-Cß) 1 (CH ^) ^ - , hydroxy »HC (= 0) - (CH2) p-, alkyl (C -Cß) -C (= 0) -» alkyl (Cx-Cß) -0-C (= 0) - »Ra-ß- ( CHß) -0-C (= 0 >; -, amino-CHCH ^) ,, - »hydro? i-alkyl (Cx-Cß)» alkyl! or (C -Cβ) -Q-a1 ui 1 or (Cx-Cß) and cyanoi each of R ^ »Riar and Rxa» are selected »independently» from hydrogen. optionally substituted (C -Cβ) alkyl with one to three halogen atoms »halo» CF3 a1koxy (C -Cβ) optionally substituted with one to three halogen atoms »halo» CF3 »alco? i < CX-Cß) optionally substituted with one to three halogen atoms »alkylthio (Cx-Cß)» RJ- * 0- (CHsz) p > - »alkyl (C-Cß) -NH- (CHz) P > -, dialqui lo (Cx-C3) -N- (CHa) ^ - »Cycloalkyl (C3-C ^) - NH- (CHae) (, -» HßN- (C = 0) - (C _.) " - »alkyl 10 (C -Cβ) -HN- (C = 0) - (CHss) 0-» dialqui l (Cx-Cß) -N- (C = 0) - (CHa) p-. Cycloalkyl ( C3-C6) -NH- (C = 0) - (CHss) |!, - »R ** 0- (C = 0) - (CHat) β-, alkyl (C -Cβ) - (0 = C) -0-alkyl (Cx-Cß) to which (Cx-Cβ) -0- (0 = C) -0-alkyl (C -Cβ) »alkyl (Cx-Cβ) - (0 = C> -0- »alky! (C -Cß) - (0 = C) -NH- (CHa!) _, -, (.Q = -C) -UH - (. CHs_) -t- .alkyls (Cx-Cß) - (0 = ON-CalkylO (C -Cß) 2 (CHa) p- »H (0 = C) -N-Calqui l0 (C -Cß) 1 (CHa) ^ - »H (0 = C) -N-Calkyl (Cx-Cß) 3 (CHz) |!, -» hydroxy, HC (= 0) - (CHz) IS, - »alkyl (C -Cß) - C (= 0) -, alkyl 10 (C? -Cβ) -0-C (= 0) -, ñ? -es- (CH _.) F, ~ 0-C (= 0) - »ai no- ( CHa.) ß- »hydroxy-alkyl (Cx-C <B)» alkyl (Cx-Cß) -O-alkylamino (C -Cß), -CHO and cyano »each R - * is hydrogen» halogen »cyano or IO trif1uorometi 1o »Rlß is hydrogen, alkyl (Cx-Cß>» alkyl (Cx-Cß) - (C = 0) - .alkyl (Cx-Cß) -0- (C = 0) - »alkyl 10 (Cx-Cß) -NH- (C = 0) - O dia1 qui 10 (Cx-Cß) -N- (C = 0) - »R * is hydrogen» cyano »alkyls (C -Cβ> halogen) »Tri luoromethyl -CHO or alco? I (Cx-Cm); n is an integer from zero to 3, p is an integer from zero to 3» and where the broken line represents an optional double bond; pharmaceutically acceptable salts of such compounds This invention also relates to the atropisomers and their pharmaceutically acceptable salts which are defined as the atropisomers of formula I above "with the proviso that when R is hydrogen" one of RAa and R * - * is other than hydrogen The present invention also provides the pharmaceutically acceptable acid addition salts of the atropisomers of the formula I. The acids which are used to prepare the pharmaceutically acceptable acid addition salts of the aforementioned basic compounds of this invention, are those which form non-toxic acid addition salts, ie salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulphate, bisulfate, phosphate salts. acid phosphate »acetate, lactate» citrate »acid citrate» tartrate »bitartrate» succinate »maleate» fumarate »gluconate» saccharate »benzoate» methanesulfonate »ethanesulfonate» benzenesulonate »p-toluenesulfonate and pamoate Cys say» l »lt-me ilen- bis- (2-hydro? i ~ 3-na oato) 1. This invention also provides a pharmaceutical composition for the treatment of stroke »cerebral ischemia, spinal cord trauma» cephalic trauma »Alzheimer's disease» Huntington's disease » amyotrophic lateral sclerosis »epilepsy» dementia induced by AIDS »muscle spasms» migraine »urinary incontinence» psychosis »seizures» hypox perinatal »hiccups (such as the conditions caused by strangulation» surgery »inhalation of smoke, suffocation, drowning, obstruction of the respiratory tract» electrocution or overdose of drugs or alcohol). cardiac arrest »neuron injury! hypoglycemic opioid tolerance »withdrawal syndrome (such as that produced by alcoholism and drug addiction» including opiate addiction, cocaine and nicotine), eye injuries, retinopathy »retinal neuropathy. tinnitus idiopathic and drug-induced Parkinson's disease »anxiety» emesis »cerebral edema» chronic or acute pain, tardive dyskinesia or brain deficits after cardiac bypass surgery and grafts »in a mammal, comprising a pharmacologically effective amount of an atropisomer of the formula I and a pharmaceutically acceptable carrier.

This invention also provides a treatment for stroke treatment »cerebral ischemia» spinal cord trauma »head trauma, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, epilepsy» AIDS-induced dementia »muscle spasms» migraine, urinary incontinence »Psychosis» seizures »hypoxia perinata!» Hypoxia (such as the conditions caused by strangulation surgery »smoke inhalation» asphyxia »drowning» airway obstruction »drug or alcohol electrocution or overdose» cardiac arrest »neuronal injury hypoglycemic »tolerance to opiates» withdrawal syndrome (ta!) as produced by alcoholism and drug addiction »including opiate addiction» retinal cocaine »tinnitus» idiopathic and drug-induced Parkinson's disease »anxiety» emesis, cerebral edema, chronic or acute pain, tardive dyskinesia or cerebral deficits s after cardiac bypass surgery and grafts, in a mammal "comprising administering to a mammal in need of such treatment a pharmacologically effective amount of an atropisomer of formula I or a pharmaceutically acceptable salt thereof. This invention it also provides a pharmaceutical composition for treatment of a disorder or condition "whose treatment or prevention can be accomplished or facilitated by reducing or inhibiting the neurotransmission of glutamate in a mammal" comprising an archaeologically effective amount of an atropisomer of formula I "or a pharmaceutically salt acceptable thereof "and a pharmaceutically acceptable carrier. This invention also provides a method for treating a disorder or condition "whose treatment can be performed or facilitated by reducing or inhibiting the neurotransmission of glutamate in a mammal" which comprises administering to a mammal in need of such treatment "a pharmacologically effective amount of an atropisomer of Formula I "or a pharmaceutically effective salt thereof" which is effective in the treatment of such disorder or condition. This invention also provides a pharmaceutical composition for the treatment of stroke »cerebral ischemia, spinal cord trauma, cephalic trauma, Alzheimer's disease »epilepsy, AIDS-induced dementia, muscle spasms» migraine »urinary incontinence» psychosis »seizures, perinatal hypoxia, hiccups (such as conditions caused by strangulation» surgery »smoke inhalation» choking »choking» airway obstruction »electrocution or drug or alcohol overdose >; »Cardiac arrest» neuron injury! hypoglycemic »opioid tolerance» withdrawal syndrome (such as that produced by alcoholism and addiction »including opiate addiction, cocaine and nicotine)» eye injuries »retinopathy» retinal neuropathy »tinnitus» idiopathic and induced by Parkinson's disease s »anxiety» emesis »cerebral edema, chronic or acute pain» tardive dyskinesia or brain deficits after cardiac bypass surgery and grafts in a mammal, comprising an amount effective to antagonize the AMPA receptor of an atropisomer of the formula I or a pharmaceutically acceptable salt of! same »and a pharmaceutically acceptable vehicle. This invention also provides a method for treating a condition selected from stroke: »cerebral ischemia» spinal cord trauma »head trauma» Alzheimer's disease »Huntington's disease» amyotrophic lateral sclerosis »epilepsy» dementia induced by AIDS »muscle spasms» migraine »urinary incontinence» psychosis »seizures» hypoxia perinata! »hypoxia (such as the conditions caused by strangulation» surgery »inhalation of smoke, suffocation, drowning» airway obstruction, electrocution or overdose of s or alcohol) » cardiac arrest »neuron injury! hypoglycemic »opioid tolerance» withdrawal syndrome (such as that produced by alcoholism and addiction »including addiction to opiates» cocaine and nicotine), eye injuries »retinopathy» retinal neuropathy »tinnitus» idiopathic and induced Parkinson's disease by s »anxiety» emesis, cerebral edema »chronic or acute pain» tardive dyskinesia or brain deficits after cardiac bypass surgery and grafts in a mammal, which comprises administering to a mammal requiring such treatment »an amount effective to antagonize the APMA receptor of an atropisomer of formula I »or a sa! pharmaceutically acceptable thereof. This invention also relates to a pharmaceutical composition for the treatment of a disorder or condition "whose treatment can be carried out or facilitated by reducing or inhibiting the neurotransmission of glutamate in a mammal" comprising an amount effective to antagonize the AMPA receptor of an atropisomer of Formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. This invention also relates to a method for treating a disorder or condition »which treatment can be carried out or facilitated by reducing or inhibiting the neurotransmission of glutamate in a mammal» comprising administering to a mammal in need of treatment an amount effective to antagonize the recipient of glutamate. AMPA of an atropisomer of the formula I or a pharmaceutically acceptable salt thereof. 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 may also be cyclic (eg, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl) or can be linear or branched and contain cyclic radicals. The term "treat", as used herein, refers to the reversal, alleviation and inhibition of progress, or prevention of the disorder or condition to which such term applies, or of one or more symptoms of such disorder or condition. . The term "treatment", as used herein, refers to the act of treating, as "treating" is defined in the immediately preceding phrase. The term "pharmacologically effective amount", as used herein, refers to an amount sufficient to treat the disorder or condition indicated, or an amount effective to antagonize the AMPA receptor, as the case may be. Unless otherwise indicated, the terms "halo" and "halogen," as used herein, refer to the fluorine »bromine» chlorine or iodine. Compounds of formula I in which the condensed At ring is a 6-membered aryheterocycle include compounds in which the positions A »B» D and E of the ring assume the following combinations of respective atoms: The compounds of formula I wherein the fused A ring is an aryl 5-membered heterocycle. they include compounds in which combinations of heteroatoms assume the following combinations of respective atoms: When R is heteroaryl. a person of ordinary skill in the art will understand that heteroaryl includes pyridin-2-yl-1'-3-pyrazin-4-yl, 1,4-pyrazin-2-yl, 1,3-pyrimidin-2-yl. lo, pyrrol-2-i, 1, 3-imidazole-1, 1,3-imidazol-2-yl, 1,3,4-triazole-2-ylo. 1,3-oxazol-4-lo, 1,3-oxazol-2-ylo, 1,3-thiazol-4-yl, 1,3-thiazol-2-yl, 1,2,4-o-adiazole -3-i lo. I, 2,4-o? adiazo! -5-I lo. fu -2-i what. 1,3-o? Azole-5-ylo and 1'-3'-4-oxadiazol-2-yl "substituted or unsubstituted" wherein said heteroaryl may be optionally substituted on any of the atoms capable of forming an additional bond with up to a maximum of three substituents. The compounds of the formula I can have chiral centers and therefore they can exist in different enantiomeric and diastereomeric forms. This invention relates to all optical isomers and to all stereoisomers of the compounds of formula I and mixtures thereof and to all pharmaceutical compositions and methods of treatment defined above that contain or use them, respectively. Due to the substituent in position "2" and the carbonyl group of position "4" of the pyrimidi-4-one of formula I "e! Ring attached to the nitrogen of position "3" can not rotate freely. This restricted rotation means that the compounds of formula I exist in two isomeric or atropisomeric forms. These atropisomers can be separated. This invention relates to the stereoisomers of the compounds of formula I which are atropisomers. Atropisomers are isom rich compounds that are chiral, that is, each isomer can not be superimposed on its mirror image and the isomers "once separated" rotate the polarized light in equal directions but in the opposite direction. Atropisomers are distinguished from enantiomers in that atropisomers do not possess a simple asymmetric atom. Such compounds are conformational isomers that appear when rotation through a single bond of the molecule is impeded or slowed down largely as a result of steric interactions with other parts of the molecule and substituents at the two ends of the single bond. They are asymmetrical. A detailed list of atropisomers can be found in Jerry March. Advanced Organic Chemistry. 101-102 (4 »Ed. 1992) and in O i, Top. Stereochem., 14, 1-B1 (1983). The thick lines of formula I above indicate that the bold atoms and the groups attached to them "are sterically restricted" so that they exist orthogonally above the plane of the fused ring of pyrimidin-4-one. This steric restriction is due to a rotational energy barrier that prevents free rotation around the single bond connecting the nitrogen at the "3" position of the bicyclic ring A '. which contains e! nucleus »to the six-membered aromatic ring containing V» X »Y and Z. This invention relates to all the atropisomers represented by formula I above» as well as to the opposite atropisomers of all such compounds and to all mixtures not racemic of any one or more atropisomers. AND! term "compound of formula I", a! which is referred to below, is intended to include all the atropisomers of this invention, ie, those represented by formula I above "as well as the opposed atropisomers of such compounds and all non-racemic mixtures of one or more atropiomers selected from among the represented in formula I and its opposite atropisomers. Formula I above includes compounds identical to those represented "except for the fact that one or more hydrogen or carbon atoms are replaced by isotopes thereof. Such compounds are useful as research and diagnostic tools in pharmacociological studies of metabolism and in binding assays. Specific applications in research include radio binding assays! igandos. autoradiography studies and in vivo binding studies. Examples of preferred compounds of this invention are compounds of formula I wherein Rx is above the plane of the bicyclic ring A containing the nucleus of formula I. Further examples of preferred compounds of this invention are compounds of formula I in that the ring A "is thieno» Rß is 2 »4 or 5-thiazolyl substituted with a methyl group» x is chloro or methyl, Z is carbon or nitrogen and each of V, X and Y is carbon. Other examples of preferred compounds of this invention are compounds of the formula I in which the ring A 'is thieno Rs is 2 »4 or 5-thiazolyl substituted with a methyl group» Rx is methyl or chloro »Z is nitrogen» and each of V »X and Y is carbon. Other examples of preferred compounds of this invention are compounds of formula I in which the ring A "is thieno R * is phenyl, 2-chlorophenol, 2-fluorophenyl, 2-bromsphenyl or 2-hydroxyphene, each. of Rβ »R?» »R- * and Rβ" if present, is hydrogen, and Rx is methyl or chloro Other examples of preferred compounds of this invention are compounds of formula I wherein ring A "is tieno R * is 2-pyridi! Or »each of V. X. Y and Z is carbon» each of Rs »Rß» R4 * and Rßes hydrogen »and R * - is chlorine or metho. Other examples of preferred compounds of this invention are compounds of formula I wherein e! ring A * is thieno. R * is 2-fluorophenyl, Z is nitrogen, each of V. X and Y is carbon »each of R3» R ** and RB is hydrogen »and Rx is chloro or methyl. Throughout this application »the group of the formula which appears in the formula I "and the opposite atropisomers of such a group, are collectively referred to as R * -" 7. The compounds of formula I can be prepared according to the procedures of schemes 1 and 2. In the reaction schemes and the discussion that follows »A» »A» B »D» E »F, G, J, K, L, M» Pf Q, T ».X, Y, Z» R »R *» Ra, RS Rß , R «, R-7» R », Rβ» Rxo »R". R ** »R * 3» R4"*. Rxß »Rxß» A7 »PhA» n and p. unless otherwise indicated, they are defined as indicated above for formula I.

SCHEME 1 Racemate of I ESQMEi? V VI The Scheme 1 refers to the preparation of compounds of formula I from the compound of formula V. The compounds of formula V are commercially available or can be prepared by methods well known to those of ordinary skill in the art. . The compounds of the formula V "wherein Af is 4-amino- (1" 2) -pyridazine-5-carboxylic acid "can be prepared according to the procedures described in J.Het. Chem. »14» 1099 (1977); Aust. J. Chem., 22, 1745 (1969); J. Het. Chem., 5 B45 (196B). 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 J. Het. Chem. »5» 523 (196B). The compounds of the formula V in which A 'is 2-am non-(1.2) -pyridazine-3-carboalkyl acid can be obtained according to the procedures described in J. Het Chem., 5, 523 (1968). ); and J. Org. Chem., 50 »346 (1995). The compounds of the formula V in which A 'is 5-amino- (1 »2» 3) -thiadiazole-4-carbo! ico can be prepared according to the procedures described in Chem. Berichte .. 99 »1618 (1996). The compounds of the formula V in which Ar is 4-amino- (1 »2» 5) -thiadiazole-3-carboxylic acid can be obtained according to the procedures described in J. Med. Che. »22» 944 (1979 ) and Tetrahedro Lett., 2143 (1971). The compounds of the formula V in which A "is 4-a ino- (l» 2 »5) -o? -iazole-3-carboxylic acid can be obtained according to the procedures described in Heterocycle, No. 20, 2351 (1983). The compounds of the formula V in which A * is 3-amino-thiophene-2-carboalionic acid can be prepared according to the procedures described in European Patent Publication 269,295 »published June 1, 1989. A compound of formula V can be converted to an acetamide of formula IV by reaction thereof with acetyl chloride or acetic anhydride »in the presence of a base» in a reaction-inert solvent Suitable solvents include methylene chloride , dichloroethane »tetrahydrofuran and dioxide Methylene chloride is the preferred solvent Suitable bases include trialqui lamines (eg, triethylamine and tributylamine), dimethyl inopyridine and potassium carbonate, preference is given to triethylamine. this reaction can It may vary between approximately 0 ° C and approximately 35 ° C and is preferably approximately 30 ° C. The reaction is generally carried out for approximately 1 hour to approximately 10 hours, preferably for approximately 3 hours. The acetamide of formula IV can be cyclized to form a compound of formula III by the reaction of! same 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, dicyclohexcarbodiimide and acetyl chloride. Acetic anhydride is preferred. Examples of catalysts which can be used are sodium or potassium acetate, acetic acid, p-toluene sulphonic acid and e! tri-boron luteuro eterato. Sodium acetate is the preferred catalyst. This reaction is generally carried out in a solvent inert to the dry reaction »such as dioxane» toluene »diglyme or dichloroethane. They are preferably made in dioxane. The temperature of this reaction can vary between about 80 ° C and about 110 ° C. The reaction is typically carried out for approximately 1 hour to approximately 24 hours. Preferably the reaction is carried out at 100 ° C for approximately 3 to 10 hours approximately. As an alternative, the compound of formula V can be converted directly into a compound of formula III by the reaction of! same with acetic anhydride »in the presence of an acid catalyst» in a solvent. Suitable acid catalysts include acetic acid, sulfonic acid and p-toluene sulfonic acid. Suitable solvents include acetic acid. toluene and? ileno. AND! Acetic acid is the preferred catalyst and the preferred solvent. The temperature of this reaction may vary between approximately 20 ° C and approximately 150 ° C for about 10 minutes to approximately 10 hours. Preferably the reaction is carried out at approximately 120 ° C for approximately 2 to 5 hours. The compound of the formula III »formed by any of the above processes» can then be reacted with an amine of the formula R ^^ NH ^ in? Polar protic solvent »in the presence of an acid catalyst» to form a compound of to formula II. Suitable acidic catalysts include acetic acid, p-toluene sulfonic acid and sulfuric acid. Suitable polar protic solvents include acetic acid, methane, ethanol and isopropanol. Acetic acid is the preferred catalyst and e! preferred solvent. The temperature of this reaction may vary between approximately 20 ° C and approximately 117 ° C and preferably is 117 ° C. Generally, the reaction is allowed to proceed for approximately 1 hour to approximately 24 hours. Preferably it is allowed to proceed for approximately 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- ^ H-. and a base »in a solvent inert to the reaction. Examples of suitable dehydrating agents are phosphorus trichloride or phosphorus chloride, phosphorus pentachloride and thionyl chloride, with phosphorus trichloride being preferred. Suitable bases include pyridine »lutidine» dimethylaminopyridine »triethylamine and N-methyl morpholine, with pyridine being preferred. Suitable solvents include toluene, cyclohexane, benzene and? Ileum. Toluene is the preferred solvent. Under some circumstances »when the combined reagents are liquid» the reaction can be carried out in pure form. The temperature of the reaction may vary between approximately 50 ° C and approximately 150 ° C for approximately 1 hour to approximately 24 hours. The reaction is preferably carried out at approximately 110 ° C for approximately 4 hours. The reaction of the compound of formula II with an aldehyde of the formula RCHINO »in the presence of a catalyst and a dehydrating agent» in a suitable solvent »produces the corresponding compound of formula I. The catalyst is selected from zinc chloride» aluminum chloride »Tin chloride and boron trifluoride etherate» and is preferably zinc chloride. The dehydrating agent is selected from acetic anhydride and propionic anhydride, and is preferably acetic anhydride. Suitable polar solvents include acetic acid and propionic acid. The temperature of this reaction may vary between approximately 60 ° C and approximately 100 ° C for approximately 30 minutes to approximately 24 hours. Preferably the reaction is carried out at approximately 100 ° C for approximately 3 hours. Alternatively, a compound of formula V can be converted to a compound of formula II according to the procedures illustrated in Scheme 2. The compound of formula II "thus formed" can then be converted to a compound of formula I in accordance with The procedures in Scheme 1. Referring to Scheme 2, a compound of formula V is reacted with a coupling reagent, an amine of the formula R? - ^ NH- and a base in a solvent inert to the reaction. to form a compound of the formula VI. The reagents of Are the appropriate coupling activated by the car? lica »such as dicyclohe- icarbodiimide» N-3-dimeti 1 ami nopropi 1-N »-eti 1 carbodi ida» 2-ethoxy-1-ethocarbaryl »2-dihydroquinol ina (EEDQ)» carbonyldiimidazole (CDI) and dieti ifosforí Icianuro. Suitable bases include dimethylaminopyridine (DMAP) »hi ro? And enzotriazole (HBT) and triethylamine. The dimethylaminopyridine is preferred. The coupling is carried out in an inert solvent, preferably a polar aprotic solvent such as acetonitrile, dichloromethane, dichloroethane or dimethylformamide. The preferred solvent is dichloromethane. The temperature of this reaction can generally vary between approximately 30 and about 80 ° C and preferably is from about 0 to about 25 ° C. The compound of formula VI thus formed can be converted into a compound of formula VII by reaction with acetyl chloride or acetic anhydride in the presence of a base such as a trialkyl sheet (for example, triethylamine or tributyl sheet). dimethyl laminopyridine or potassium carbonate, preferably triethyl "in a solvent such as methylene chloride. tetrahydrofuran or chloroform, preferably methylene chloride "at a temperature from about 0 ° C to about 35 ° C" for approximately 1 hour to approximately 10 hours, preferably to approximately 30 ° C for approximately 3 hours.

Cyclization of the compound of formula VII by reaction with triphenylphosphine, a base and a dialkyl azodicarboxylate in a reaction-inert solvent produces the corresponding compound of formula II. Suitable bases for use in this reaction include pyridine »triethylamine and 4-dimethylaminopyridine. Preferred is 4-dimethyl laminopyridine. Examples of solvents that can be used include dimethyl Iformamide, tetrahydrofuran and dioxide, with e! gave? The temperature of the reaction may vary between about 25 ° C and about 125 ° C for approximately 1 hour to approximately 24 hours. Preferably the reaction is carried out at approximately 100 ° C for approximately 8 to 15 hours. The resulting compound of formula II can then be converted into e! corresponding compound of formula I according to e! 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). The compounds prepared by the procedures of Schemes 1 and 2 are racemic mixtures of atropisomers. To obtain pure individual atropisomers, the racemic mixtures have to be separated. This separation can be achieved by high performance liquid chromatography using a chiral column. Examples of suitable chiral columns include Chiral pak AD and Chiral cel OA »OB» OC »OD and OK. but other chiral columns can also be used. With the appropriate chiral column, individual atropisomers will elute with different retention times. The collection and concentration of the eluent of the individual atropisomers will produce the pure atropisomeros. Alternatively, for racemic mixtures of atropisomers containing an acidic or basic radical, the chiral resolution can be achieved by forming diatereomeric salts with optically pure acids (for example, tartaric acid) when the racemate contains a basic radical or with optically pure bases ( for example, to oc-methyl encyl amine) when it contains an acid radical. Repeated recrystallization of these diastereomeric salts will allow obtaining the pure individual atropisomer. The pure individual atropisomer can be used directly in the form of a salt or can be neutralized to obtain the atropisomer in the form of udder base or 1-ibre acid. For the atropisomers that can form racemic mixtures after heating, it is possible to effect a chiral resolution by performing the recrystallization of the aforementioned diastereomeric salt at a temperature at which the atropisomers interconvert rapidly. Under such conditions »all racemic material can be channeled to the desired atropisomer as it crystallizes from the solution. This procedure is preferred for the resolution of the above chiral salts, since it provides yields that are 100% approved. 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 approximately one to three atmospheres, preferably at ambient pressure (approximately one atmosphere). The compounds of the formula I which are basic in nature can form 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, it is often desirable in practice to initially isolate a compound of formula I from the reaction mixture as a pharmaceutically unacceptable salt, then simply convert the latter to e. compound of free base by treatment with an alkaline reagent and subsequently converting the free base to a pharmaceutically acceptable acid addition salt. The acid addition salts of the basic compounds of this invention are readily prepared by treating the base compound with a substantially equivalent amount of the chosen organic or mineral acid in an aqueous solvent medium or in a suitable organic solvent such as methanol or ethanol. . After careful evaporation of the solvent, the desired solid salt is obtained. The acids which are used prepare the pharmaceutically acceptable acid addition salts of the basic compounds of this invention, are those that form addition salts of non-toxic acids, ie, salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, iodohydrate salts. nitrate »sulfate or bisulfate» acid phosphate »acetate» lactate »citrate or acid citrate» tartrate or bitartrate »succinate» meleate »fumarate» gluconate »saccharate» benzoate »methanesulfonate and patoate Cs say» 1 »1t-methylen-bis- (2-hydro? I-3-naphthoate) 3. The compounds of the formula I and the pharmaceutically acceptable salts of Cough themselves (hereinafter also referred to as the active compounds of the invention) are useful for the treatment of neurodegenerative »psychotropic deficits and induced by drugs and alcohol and are potent antagonists of the AMPA receptor. Therefore, the active compounds of the invention can be used in e! treatment or prevention of stroke »cerebral ischemia, spinal cord trauma» cephalic trauma, Alzheimer's disease »Huntington's disease» amyotrophic lateral sclerosis »epilepsy» AIDS-induced dementia »muscle spasms» migraine »urinary incontinence» psychosis »Seizures» perinatal hypoxia »hiccups (such as lax conditions caused by strangulation» surgery »smoke inhalation asphyxia» drowning »airway obstruction» drug or alcohol electrocution or overdose »heart failure» injury neuronal hypoglycemic »opioid tolerance» withdrawal syndrome (such as that produced by alcoholism and drug addiction »including opiate addiction» cocaine and nicotine), eye injuries »retinopathy» retinal neuropathy »tinnitus» Idiopathic and induced Parkinson's disease by drugs »anxiety» emesis »cerebral edema» chronic or acute pain »discin It is late or brain deficits after cardiac bypass surgery and grafts. The "live vitro" 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 the inhibition of attacks induced by penti lentetrazole (PTZ). Another method for determining the activity of the compounds of the invention is by blocking the uptake of ^ Ca2 * inducibility by the activation of the AMPA receptor. A specific procedure to determine the inhibition of the attacks induced by the penti lentetrazol (PTZ) is the following. The activity of the compounds of the invention with respect to the inhibition of the attacks induced by the penti lentetrazole (PTZ) in mice, can be determined according to the following procedure. This essay examines the ability of compounds to block attacks and death produced by PTZ. The measures taken are latency for clonic and tonic attacks and death. The DIßo values are determined based on percentage protection.

Co or subjects for these experiments »male CD-l 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: o / 7 a.m .: 7 p.m. for at least 7 days before the experimentation. The food and e! Water are available ad libitum until the time of! test. All compounds are administered in a volume of 10 ml / kg. The vehicles of the drug will depend on the solubility of the compound. but the evaluation will typically be performed using saline solution »distilled water or E: D: S / 5: 5: 90 (5JÍ of emulsifier» 5% of DMSO and 9054 of saline) as injection vehicle. The mice are administered the test compounds or vehicle (i.p. »s.c. or p.o.) and placed in plexiglass cages in groups of five. At a predetermined time after these injections, the mice receive an injection of PTZ (i.p., 120 mg / kg) and are placed in individual cells of pellets. The measures taken during this five-minute test period are: (1) latency for clone attacks »(2) 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 Kruskal-all is Anova and Mann-Whitney U (Statview) trials. The protection percentage for each group is calculated (number of subjects that do not show attack or death as indicated by a score of 300 sec.) In each measurement. The DIßo values are determined by probit analysis (Biostat). Another method to determine the activity of the compounds is to determine effect of the compounds on motor coordination in mice. This activity can be determined according to the following procedure. As subjects for these experiments, CD-1 male mice from Charles River are used, weighing 14-16 g after arrival and 23-35 g at the time of testing. The mice are enclosed, 13 per cage, under conventional laboratory conditions in a light cycle L: 0/7 a.m .: 7 p.m. for at least 7 days before the experimentation. Food and water are available ad libitum haßta at the time of the trial. All compounds are administered in a volume of 10 ml / kg. The vehicles of the drug will depend on the solubility of the compound, but typically the evaluation will be made using saline, distilled water or E: D: S / 5: 5: 90 (5 '? Emulsifier, 5% DMSO and 90% saline) as the injection vehicle. The apparatus used in these studies consists of a group of five squares of wire mesh of 13.34? 13.34 cm suspended on steel rods of 11.43 cm connected with a rod of 165.1 cm that is elevated 38.1 cm above the laboratory table. These wire mesh squares can be inverted. The test compounds or vehicle (i.p. »s.c. or p.o.) are administered to the mice and placed in cages of ple? Iglás 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. While e! 1-minute test »mice receive an evaluation of O if they fall from the screen» of 1 if they stay caught in the reverse position or 2 if they climb to the top. The treatment groups are compared with the vehicle-treated groups with the Kruskal-Wal lis and Mann-Whitney U-tests (Statview). The following describes a specific procedure to determine the blockade of the uptake of - * ßCaa - * - induced by the activation of! AMPA receiver.

PRIMARY NEURAL CROPS Primary cultures of neurons from rat brain granules are prepared as described by Parks »T.N.» Artman »L.D.» Alasti »N.» and Nemeth »E.F.» Modulation of N-Methyl-D-Aspartate Receptor-Mediated Increases In Cytosolic Calcium In Cultured Rat Cerebeur Granule Cells »Brain Res. : »13-22 (1992). According to this procedure, the cerebellums of 8-day-old CD rats are removed and cut into 1-mm pieces and incubated for 15 minutes at 37 ° C in calcium-magnesium-free Tyrode solution containing a 0.154 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 i-D-1 isine» at 10 * 8 cells per well. AND! medium consists of Minimum Essential Medium (MEM), with Earle salts »Thermally inactivated Fetal Bovine Serum to 10JÍ» L-glutamine 2 M »glucose 21 M» Penici 1 ina-Streptomycin (100 units per ml) and 25 M KCl of 24 hours »e! medium is replaced by fresh medium containing 10 mM cytosine arabinoside to inhibit cell division. Crops should be used at 6-8 DIV.

CAPTATION OF - «« Ca ** - INDUCED BY ACTIVATION OF THE AMPA RECEIVER The effects of the drugs on the uptake of "Ca2 * induced by the activation of the AMPA receptor can be erased 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 *** "(in M: NaC! 120, KCl 5, aH ^ PO ^ O, 33 »CaCla 1.8» glucose 22, O and HEPES 10 »0 at pH 7.4) containing 0.5 M DTT, 10 μM glycine, and drugs at a fine concentration of 2 × The reaction is started by the addition of an equal volume of the balanced salt solution containing 100 mM of the AMPA receptor agonist kainic acid and - * ßCaß * (final specific activity 250 Ci / mmol) After 10 minutes at 25 ° C the reaction is interrupted aspirating a solution containing - «« Ca- -t- and washing the cells 5 times in a balanced salt solution 5 and cooled with ice containing no added calcium and containing 0 * 5 mM EDTA. they are used by overnight incubation in Triton-XlOO to 0.1J4 and then the radioactivity in the lysate is determined. All the compounds of the invention that were tested had IO Cl values of less than 500 mM. 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 administration.

Oral »transdermal (for example» patches) »intranasal» parenteral (for example »intravenous» intramuscular or subcutaneous) or rectal »or in a form suitable for admi- stration by inhalation or insufflation. _. For oral administration, the pharmaceutical compositions can take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (eg, pregelatinized maize starch, polyvinylpyrrolidone or hydro? Ipropy). 1 hypromellose); fillers (for example, lactose, microcrystalline cellulose or calcium phosphate) lubricants (for example, magnesium stearate, talc or silica); disintegrants (for example, potato starch or sodium starch glycolate) or wetting agents (for example sodium lauryl sulphate). 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 reconstituted with water or other suitable vehicle before! use. Such liquid preparations can be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (for example sorbitol syrup, hypromellose or hydrogenated edible fats); emulsifying agents (for example, lecithin or gum arabic); non-aqueous vehicles (for example »almond oil» esters of oils or ethyl alcohol); and preservatives (for example, methyl or propyl p-hydroxy-benzoate or sorbic acid). For oral administration »the composition can take the form of tablets or lozenges 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 be presented in a unit dosage form "for example" in ampules or multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredient may be in the form of a powder to be reconstituted with a suitable vehicle, eg, sterile, pyrogen-free water, before! use. The active compounds of the invention can also be formulated in rectal compositions such as suppositories or retention enemas containing "for example, conventional suppository bases such as cocoa butter and other glycerides. For intranasal administration! or administration by inhalation; the active compounds of the invention are conveniently supplied in the form of a solution or suspension from a container with a spray pump that is tightened or pumped by the patient, or in the form of an aerosol spray presentation from a patient. pressurized container or a nebulizer, with the use of a suitable propellant, for example, chlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by arranging a valve to release a measured quantity. The pressurized container or nebulizer may contain a solution or suspension of the active compound. Capsules and cartridges (manufactured) »for example» with gelatin) for use in an inhaler or insufflator. they may 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 administration "parenterally or buccally to an average adult human" for the treatment of the aforementioned conditions (for example, apoltic attack). it is 0.01 to 50 mg / kg of the active ingredient per dosage unit »which could be administered» for example »from 1 to 4 times a day. Aerosol formulations for the treatment of the aforementioned 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 mg to 1000 g of! Composite of the invention. The average daily dose with an aerosol will be within! range of 100 mg to 10 mg. The administration can be done several times a! day »for example» 2 »3» 4 u B times »giving for example» 1 »2 or 3 doses each time. The following Examples illustrate the preparation of the compounds of the present invention. Commercial reagents were used without further purification. The melting points are uncorrected. All NMR data were recorded at 250 »300 or 400 MHz in deuteriochloroform" unless otherwise specified "are presented in parts per million (d) and are referenced to the signal! of deuterium stabilization in the solvent of the sample. All non-aqueous reactions were carried out in dry glass containers, with dry solvents, under an inert atmosphere »for reasons of convenience and to optimize yields. Unless otherwise indicated, all reactions were shaken with a magnetic stir bar. Unless otherwise indicated, all mass spectra were performed using chemical impact conditions. The ambient temperature refers to a temperature of 20 to 25 ° C. The melting points are uncorrected.

AXIS X 3- (2-Met l- en l) -2-C2- (2-luoro-enyl) -vinyl33H-thienoC3.2- flJ jrimjdin-4-png.

In a round-bottomed flask with open flame, anhydrous zinc chloride (7.0 g, 51.4 mol) was melted with a nitrogen purge. It was left to e! The reaction vessel was returned to room temperature and then dioene (100 ml) was added. To this mixture was added 2-methyl 1-3- (2-methyl Ifeni 1) -3H-thienoC3 »2- d3piri din-4-one (7. O g» 27.34 mol »preparation 2). acetic anhydride (7.7 ml »82.0 moles) and 2-fluorobenzaldehyde (8.6 ml, 10.2 moles). The reaction was refluxed for 14 hours, cooled to room temperature and partitioned between ethyl acetate and water. The aqueous phase was washed with ethyl acetate and the combined organic layer was filtered to obtain a small amount of the 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 assembled material was subjected to flash chromatography on silica gel (60? 185 mm) »eluting with 25-40J4 ethyl acetate / water to produce 5.06 g (51 %) of 3- (2-methy1-pheny!) -2-C2- (2-luoro-phenyl) -vinyl 3 -3H-thienoC3 »2-d-Dyrimidin-4-one as a light yellow solid. p.f. 220-221 ° C; a-H NMR δ 8.03 (d J "15.8 Hz, 1H). 7.82 (d, J = 5 »2 HZ, 1H). 7.45-7.37 (m, 4H), 7.25-7.10 (m, 3H), 7 »07-6.99 (m, 2H), 6.44 (d, J = 15.9 Hz. 1 HOUR). 2.11 (s, 3H). Analysis calculated for CßxH ßF a.OS: c, 68.76; H, 4.23 »N» 7.64. Found: C »68» S9; H »4.16; N. 7.72. 3- (2-Chloro-phen l) -2-C2- (2- ^ luro in l) -v ^ •. ^ - 3H- ^ • e oC2.2- d3Pirimidin-4-one To a mixture of molten zinc chloride (O.35 g 2.56 mol) and dioxane (15 ml) «2-methy1-3- (2-chlorophenyl) -3-H-thienoC3» 2-d3-pyrimidin-4-one (0.344 g »1.24 mol» preparation 3) and acetic anhydride (O.35 ml »3.73 moles)» 2-fluorobenzaldehyde (0.39 ml »3.73 moles) was added. The reaction was refluxed for 30 hours, cooled to room temperature and eluted with ethyl acetate and water. The mixture of the two phases was treated with aqueous 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 sulfate 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 32J4) of 3- (2-chloro-phenyl) -2-C2- (2-fluoro-phenyl) -vini 13- 3H-ThienoC3 »2-d3-pyrimidi-4-one» in the form of a yellow solid. p.f. 215-216 ° C; * H NMR or 8 »05 (d» J = 15.5 Hz »1H), 7.84 (d, J = 5.2 Hz, 1H), 7.65-7.61 (m, lH), 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.J = 15.5 Hz 1H). Analysis calculated for ^^ 3 .- ^ 01 NßOS: C. 62.75; H »3.14» N, 7.32. Found: C, 62.45; H »3.14; N. 7.40.

EWEMP Q 3 3- (2 ~ Meti1-enyl) -2-C2-Pir? D-2-yl-vinyl3-3H-thienoC3.2-- d3Pi m idin-4-one To a mixture of molten zinc chloride (2.13 g »15.6 mol) and dioxide (75 ml), 2-methyl 1-3- (2-met? I eni 1) -3H-thienoC3» 2-d3pyrimidin-4 -one (2.Og »7.81 moles» preparation 2) and acetic anhydride (2.2 rol »23.4 moles) was added 2-pyridine carboxaldehyde (2.2 ml» 23.4 moles). 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 mm). Elution with 20? 4 ethyl acetate / hexans »separated a non-weighed impurity. Continued elution with ethyl acetate at 40? 4 / well? Gave a sticky yellow foam. The foam was triturated with ethyl acetate a! 5J4 / Helene to yield 1.9 g (7054) of 3- (2-methyl-phenyl-2-C2-pyrid-2-yl-vinyl-3H-thienoC3.2-d3-pyrimidin-4-one in the form of a yellow solid, mp 203 ° C0; AH NMR or 8.47 (d, J = 3 Hz »1H) 7.92 (d, J = 14.7 Hz »1H). 7.82 (d, J = 4 Hz 1H), 7.82 (d, J ß 4 Hz »1H>» 7 »60 (t» J = 8.5 HZ 1H), 7.43-7.37 (m »4H), 7.26-7.12 (m.H3H), 6.89 (d.J = 14.7 Hz 1H), 2.10 (s» 3H) Analysis calculated for C3OHx? N30S: C »69» 36 »H» 4.62 »N, 12» 14. Found: C »69» 10; H, 4.50? N. 12 »19 EJEHP Q 4 All the compounds of Table 1 were prepared essentially by procedures similar to those shown in Examples 1-3.

TABLE 1 IO -20 25 TABLE 1 (CONTINUED) TABLE 1 (CONTINUATION) 15 -twenty TABLE 1. { CONTINUATION) The compounds of Table 2 were prepared substantially by the process ig equal to that described in Examples 1-3, with the exception that the products of preparations 15 and 17 were used in the reactions.

TABLE 2 IO fifteen '20 EXAMPLE 6 2-C2- (2-Fluoro-phen!) -vini 1 -3-o-tol i 1-3H-Pter d-4-one A mixture of molten zinc chloride (0.17 g, 1.25 mmol), dioxide (15 ml), 2-methyl-3 - (2-methyl-1-pheny1) -3H-pteridin-4-one (0.174 g, 0.69 mmol, preparation 8) and 2-fluorobenzaldehyde (0.22 mL, 2.07 mmol) and acetic anhydride (0.195 mL, 2.07 mmol) was heated to reflux overnight. The reaction was cooled and concentrated. AND! Residual material was partitioned between saturated aqueous sodium bicarbonate and methyl 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 4 inches) with elution being carried out as follows: 50% ethyl acetate / hexane (300 ml), precursor; ethyl acetate a! 6054 / year (400 ml). 2-C2- (2-Fluoro-phenyl) viny! 3-3-o-to! il-3H-pte id -4-one (0.137 g, 55? 4) in the form of a yellow crystalline eolide. A sample was recrystallized from ethyl acetate. P.f. > 250 ° C; = »- H RMÑ or 8.98 (d, J = 2 Hz, 1H), 8.80 (d, J = 2 Hz, 1H), 8.36 (d, J as 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, J = 15 Hz, 1H >, 2.15 (S. 3H) Analysis calculated for CßxHxßFN ^ 0: C, 70.38 »H» 4.22; N »15.63 Found: C, 70.07; H, 4.21; N »15.78.

The compounds of Table 3 were prepared substantially by a procedure equal to that shown in Example 6 »starting from the product of preparation 8 or preparation 11.

TABLE 3 fifteen *twenty EXAMPLE 8 2-C2- (2-Fluoro-phenyl) -v? Nü3-3-o-to1-3H-pyr? DoC3 »4- d3Pi imidin-4-one The title compound was prepared according to the procedures of Examples 1-3, from the product of preparation 20. P.F. 211-211.5 ° C; * H NMR or 9.26 (S, 1H), 8.70 (d, J = 5 Hz, 1H), 8.18 (d, J - 15.5 Hz »1H)» 8.08 (d, J - 4) , 5 Hz, 1H), 7.54-7.48 (m, 3H), 7.46-7.15 (m, 3H), 7.13-7.00 (m, 2H), 6.47 ( d, J = 15.5 Hz, 1H), 2.13 (s, 3H). Analysis calculated for CaatHxßFN30-0, 125 H ^ O: C, 73.475 H, 4.55; N, 11.68. Found: C, 73.35; H, 4.49; N, 11.66.

EXAM Q 9 3- (2-Chloro-phenyl) -2-pyridin-2-yl-etp-3H-thienoC3.2-d3-pyrimidin-4-one hydrochloride A mixture of 3- (2-chloro-phenyl) -2-C2-pyrid-2-yl-vini 13-3H-thienoC3,2-d3-pyrimidin-4-one (0.12 g »0, 33 mmol), ethane ! (10 ml), formic acid (0.55 ml, 14.8 mmol) and palladium 10J4 on carbon (0.12 g) was heated to reflux for 4 hours, cooled and diluted with ethanol and water. The mixture was filtered through Ceüte * (trademark) and the pad was rinsed with ethyl acetate and water. The filtrate was treated with saturated aqueous sodium bicarbonate and the β-phase separated. The aqueous layer was washed with ethyl acetate and the combined organic phase was washed with water and brine, dried over sodium sulfate and concentrated to yield 0.094 g of 3- (2-chloro-phenyl-1) -2- ( 2-pyridin-2-y1-eti 1) -3H-thienoC3,2-d3-pyrimidin-4-one in the form of a brown film. The material was dissolved in dioxide (3 ml) and treated with ether saturated with hydrogen chloride. The solid was collected and weighed 0.094 g. The solid was taken up in water, concentrated and dried azeotropically by suspending the product in chloroform and concentrating it three times to produce 3- (2-chloro-phenyl-1) -2- (2-pyridin-2-y1-hydrochloride. eti 1) -3H-thienoC3,2-d3-pyrimidin-4-one (0.038 g, 3154) as a yellow solid. P.f. 136 ° C. Analysis calculated for CxßHx ^ ClN3OS • HCl -1.5 Hß0: C, 52.13; H, 4.11; N, 9.15. Found: C, 51.96; H, 3.78; N, 9.27.

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

TABLE 4 EXAMPLE 11 The compounds of Table 5 were prepared following the procedure of Example 9.

HP ppo 5 fifteen •twenty AX PLO -2 5- (2-Pyridin-2-yl-vin l) -6-o-tolyl-3,6-dihydric, 2 »33tr azoloC4» 5-d3Pir roiditt-7-one A mixture of molten zinc chloride (0.551 g »4» 04 mmoles) and dioxide (20 ml) was added 5-methi 1-6-o-tol-3,6-dihydro-Cl, 2,33-triazo-1-C4, 5-d3-pyrimidin-7-one (0.488 g »2.02 mmol)» 2-pyridinecarbo aldehyde (0.58 ml »6.06 mmole) and acetic anhydride (0.57 ml, 6.06 mmole). The mixture was heated to 70 ° C for 6 hours »cooled and quenched with saturated sodium bicarbonate. This 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 phase was dried over magnesium sulfate, treated with activated charcoal, filtered and concentrated. The residue (1.5 g) was subjected to flash chromatography on silica gel (50 g). Elution with ethyl acetate a! 5054 and 6054 / year gave 5- (2-? Ir din-2-i 1-vini!) -6-o-to1 i 1-3 »5-dihydro-Cl» 2 »33triazoloC4» 5-d3pyrimidin- 7-one (0.023 g »3.554). AH NMR at 9 »06 (d» J = 7.3 Hz, 1H), 8.70 (m, 2H), 7.60 (t, J = 7.8 Hz, 1H), 7 »50 (t J = 7.7 Hz, 1H), 7.32-7.00 (m, 4H), 6.80 (t, J = 8.2 HZ, 1H), 6.59 (t, J = 8 Hz, 1H), 2.28 (s, 3H); MS m / e O 330. The product was treated with hydrogen chloride (HCl) in dioxide to form the hydrochloride salt having a melting point (m.p.) of 80-85 ° C.

PREPARATION 1 Acido 3-acetami otiofeno-2-carbox l po To a solution of methyl 3-ai-otiofen-2-carbohydrate (10 g »0.0637 mol) and triethylamine (10.3 g» 0.102 mol) in methylene chloride was added dropwise acetyl chloride (8.0 g) »0.102 moles 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 yellow solid product which was suitable for the reaction without further purification. AH NMR or 8 »10 (d, J = 5.4 Hz, 1H), 7.43 (d, J = 5.4 Hz, 1H), 3.86 (S, 1H), 2.20 (s, 3H); MS m / e = 199. The product was added to 200 ml of potassium hydroxide methane! ico to 1054 and heated to 60-65 ° C for 4 hours. The reaction was concentrated and e! residue was collected in water. The aqueous solution was extracted with ether and then made acidic with 6 N hydrochloric acid (HCl). The precipitate was filtered, washed well with water and dried in air to yield 9.5 g (80%) of 3-acetamidothiophene-2-carboxylic acid in the form of a tan solid. P.f. 212-213 ° C; * H NMR (DMSO d ,,,) or 7.82 (d, J = 5.4 HZ »1H)» 7 »72 (d.J = 5.4 Hz, 1H), 2.06 (S, 3H ).

PREPA ACIÓ g 2-meti1-3- (2-methylphenyl) -3H-thienoC3 »2-d3piriroidin-4-one To a mixture of 3-acetamidothiophene-2-carboxylic acid (15.1 g »75.67 mmol) and sodium acetate (6.45 g» 78.6 mmol) in dioxide (200 ml) was added acetic anhydride (71 ml »75.7 mmoles) . The reaction was refluxed for 2 hours, cooled to room temperature and partitioned between chloroform and water. The phases were separated and the aqueous layer was brought with chloroform. The combined organic phase was washed with water and brine, dried over magnesium sulfate and concentrated to leave 15.1 g of 2-methyl-1-thieno C3,2-d3Cl, 33o? Azin-4-one as a brown oil which It solidified slowly. AH NMR? 7.78 (d, J = 6.5 Hz, 1H), 7.14 (d, J = 6.5 Hz, 1H), 2.40 (s, 3H); MS m / e = 167. The material was used without further purification. 2-Met l-thienoE3 »2-d3Cl» 33o? Azin-4-one (12.7 g »76 mmol) and o-toluidine (16.2 ml, 152 mmol) in acetic acid (175 ml) were combined and the mixture heated 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 then the phases were separated. The aqueous phase was extracted with ethyl acetate and the combined organic layer was washed with water and ßaluera. it was placed over magnesium sulfate and concentrated to leave a black oil. This residue was purified by flash chromatography on silica gel (60 >; < 200 mm). Elution with ethyl acetate a! 2054 / hexane gave 16.2 g of an impure product and 3 g of non-cyclized by-product by-product. The impure product was chromatographed a second time as indicated above but with an elution of 1054 ethyl acetate and 1554 / hexane. Thus. In this way, 9.2 g (4754) of 2-methyl Ifeni 1) -2H-thienoC3,2-d3-pyrimidin-4-one was isolated as a light yellow solid. ^ H NMR < S 7.70 (d, J = 5.3 HZ, 1H), 7.39-7.30 (m, 3H), 7.29 (d, J »5.3 Hz, 1H), 7.13 (d, J = 7.8 Hz »1H). 2 »15 (s, 3H), 2.10 (s, 3H).

PREPARATION 3 2-Methyl-3- < 2-chlorophen I) -3H-thienoC3.2- < 33Pirimidin-4-one 2-Methyl-1-thienoC3,2-doxazin-4-one (1.67 g, 10 mmol) and o-chloroan-1-one (2.1 ml, 20 mmol) in acetic acid (20 ml) were combined and the mixture heated refluxed for 4.5 hours. The reaction was partitioned between ethyl acetate and water. The mixture of the two phases was treated with sodium bicarbonate until the aqueous layer became basic and then the phases were separated. The aqueous phase was washed 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 (30-150 mm). Elution with ethyl acetate at 1054 and 2054 / year gave 1.42 g (5154) of 2-methyl 1-3- (2-chlorophenyl) -3H-thienoC3 »l-d3-pyrimid-4-one. which was isolated in the form of a brown oil that solidified brings a period of rest. P.F .. 118-121 ° C; AH NMR or 7.78 (d.J = 5 »3 Hz. 1H), 7.57 (m, 1H), 7.46-7.43 (m, 2H), 7.33-7.29 (m, 2H ), 2.20 (s, 3H > MS m / e = 276.

PRE ACIÓ 4 2-methyl-3- (2-c1oropir? D -3- l) -3H-thienoC3,2-d3Pir midi -4-one To a mixture of pyridine (4 ml), 3-amino-2-chloropyridine (0.514 g, 4 mmol) and 3-acetamido isphene-2-carboalicylic acid (0.370 g, 4 mmol), trichloride was added. of phosphorus (0.02 ml, 2.3 mmol). The reaction was heated at 105 ° C for 3 hours, cooled to room temperature and partitioned between ethyl acetate and water. The phases were separated and the aqueous layer was brought with ethyl acetate. The combined organic phase was washed with water and brine, dried over sodium sulfate and concentrated until a greenish-brown oil was obtained. This residue was subjected to flash chromatography on silica gel (20-120 mm), eluting with ethyl acetate a! 20- 5? 54 / year to yield 0.350 g (6354) of 2-methyl-3- (2-chloropyrid-3-yl) -3H-thienoC3 »2-d3-pyrimidin-4-one in the form of a yellow foam.

* H NMR < 5 8.58-8.56 (m, 1H), 7.83 (d, J = 5.2 Hz, 1H), 7.74-7.71 (m, 1H), 7.50-7.46 (m, 1H), 7.33 (d, J = 5.3 Hz, 1H), 2.24 (S, 3H) i MS m / e = 227.

PRE ARACIÓ 5 2-Me l-3- (2-bromo enyl) -3H-thienoC3.2-d3Pirimidin-4-one To a mixture of pyridine (6 ml), 2-bromoanil ina (1.03 g »6 mmoles) and 3-acetamidothiophene-2-carboalionic acid (0.555 g, 3 mmoles) was added phosphorus trichloride (0.03 ml). 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 separated and the aqueous layer was brought with chloroform. The combined organic phase was washed with water and brine, dried over magnesium sulfate and concentrated until a yellow matte film was obtained. This residue was subjected to flash chromatography on silica gel (30 x 125 mm) eluting with 15-2554 ethyl acetate / well to yield 0.411 g (4754) of 2-methyl-3- (2-bromophenyl) - 3H-thieno 3 »2-d3-pyrimidin-4-one in the form of a yellow foam. a-H NMR α 7.76-7.55 (m »2H). 7.44 (t J = 7.2 Hz »1H)» 7 »39-7» 05 (m »3H>» 2.10 (ß, 3H) Í EM m / e = 322.

PREPARATION 6 O-toluaraida de! 3-aminopyrazole-2-carboxylic acid A mixture of carbohydric 3-aminopyrazine (5.0 g »35.94 mmoles)» methylene chloride (110 ml), 4-dimethylaminopyridine (10.98 g, 89.95 mmoles) »o-toluidine (4.22 ml» 39.53 mmoles) and hydrochloride l- (3-Dimeti lam nopropi 1) -3-eti Icarbodi imide (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 lNI (LiCl) chloride, water and brine, dried over calcium sulfate and concentrated. The residue was subjected to flash chromatography on silica gel (2 »75? 4 inches) with the elution being carried out as follows: he? Ano (300 ml)» nothing »ethyl acetate at 2054 / year (50? mi), o-toluidine recovered not weighed; ethyl acetate at 2054 / year (1000 ml) and ethyl acetate at 3054 / year (2000 ml) »4.79 g (5854) of o-toluamide of 3-amine irazine-2-carbo? ion in the form of a yellow crystalline solid. P.F .. 135-137 ° C; AH NMR or 9.80 (S a, 1H); 8.22 (d, J = 2.5 Hz, 1H> »8» 11 (d »J = 8» 0 HZ »1H), 7.87 (d, J = 2.5 Hz, 1H), 7.33 -7.23 (m, 2H), 7.10 (dt, J = 1, 7.5 Hz »1H), 2» 39 (8, 3H).

PR PAR CIÓ 0-to uaptida of 3-acetamidopyrazine-2-carboxylic acid? l ico A mixture of 3-ami-opyrazine-2-carboalic acid o-toluamide (1.0 g »4.39 mmol) and acetic anhydride (12 ml) was heated to reflux for 2 hours. AND! 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 (7654) of 3-acetamidopyrazine-2-carboalkyl o-toluamide. aH NMR or 11.88 (S a., 1H), 10.0 (S a., 1H> »8.65 (d, J = 2.5 HZ, 1H), 8.28 (d, J = 2.5 Hz» 1H> 8 , 04 (d, J = 8 Hz, 1H) .7.38-7 »24 (m, 2H)» 7 »20-7» ll (m »1H)» 2 »39 (S» 3H) »2» 38 (s »3H) The material was used without further purification.

PREPARATION 8 g-Heti l-3- (2-me i 1-feni 1 > -3H-Pteridin-4-one) To a mixture of 3-acetamidopyrazine-2-carboalic acid o-to olume (1.0 g, 3.70 mmol). triphenyl amines (2.1 g »ll.l mmoles) and 4-dimethylaminopyridine (0.045 g» approximately 1054 mol) in dioxane (45 ml) »diethyl azodicarbohydrate was added dropwise by means of a syringe. (1.75 ml »11.1 mmoles). The reaction was refluxed overnight, cooled to room temperature and concentrated. The residue was partitioned between methylene 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 (2.25 x 4 inches, packed in hexane) »elution being carried out as follows: ethyl acetate 20-8054 / well» precursor; ethyl acetate 8554 / Helene (1000 mL), 0.71 g (7654) of 2-methyl 1-3- (2-methyl-1-phenyl) -3H-pteridin-4-one which was suitable for use without purification additional. A sample was recrystallized from ethyl acetate. P.F .. 186-1B7 ° C; * H NMR at 8.98 (d, J - 2 Hz, 1H), 8.83 (d, J - 2 Hz, 1H), 7.51-7.35 (m, 3H), 7.18 (d, J = 7 Hz, 1H>, 2.30 (s, 3H) , 2.16 (s, 3H).

PREPARATION 9 2-Chlorophene 3-aminopyrazine-2-carboxylic acid lamido A mixture of 3-aminopyrazine carboxylic acid (7.0 g, 50.32 mmol), methylene chloride (60 ml), dimethylformamide (4? Mi), 4-dimethyl laminopyridine (15.37 g, 126 mmol), 2-chloroane-1-ene (5.82 ml, 55.35 mmol) and 1- (3-dimethylaminopropyl-1) -3-ethylcarbodiimide hydrochloride (11.58 g, 60.38 mmol) were stirred overnight. room temperature. The solvent was removed and the residue was mixed with ethyl acetate and 1N lithium chloride. The precipitate that formed was filtered and rinsed with 1 N lithium chloride, ethyl acetate and ether and then air dried to yield 6.22 g (5054) of 3-aminopyrazole-2-carbo-2-chlorophenylamide. ico in the form of spongy yellow crystals. P.f .. 177-179 ° C; a-H NMR > 10.47 (s a »1H). 8.52 (dd, J = 1.5, 8.5 HZ, 1H), 8.23 (d, J = 2.5 Hz, 1H), 7.92 (d, J = 5 2.5 Hz, 1H), 7.43 (dd, J = 1.5, 8 Hz, 1H), 7.33 (dt, J = 1.5, 7.5 Hz, 1H), 7.09 (dt, J = 1 , 5 »7.5 Hz, 1H).

PREPARATION 10 2-Chlorophene 3-acetamido irazine-2-carboalonic acid lamido A mixture of 2-c-orophenyl of 3-ami-opyrazine-2- (2-chlorophenylcarboxylic acid) (4.Og, 16.1 mmoles) and acetic anhydride (25 ml) was heated to reflux for 2 hours. The solvent was removed and e! waste was divided between Methylene chloride and saturated aqueous sodium bicarbonate. 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 (2.25? 4 inches), elution being carried out as follows: he? Anus (200 ml) and '2? ethyl acetate at 2554 / well (500 ml). precursor; hexane (200 ml) and ethyl acetate 5054 / year (500 ml), 0.836 g (1854) of 2-chlorophenolamide of 3-acetamidopyrazine-2-carboalionic acid, PF 194-196 ° C;.H NMR? 11.70 (sa, 1H), 10.65 (S a, 1H), 8.66 (d, J = 2.5 HZ, 1H), 8.49 (dd, J »1 , 5 8 Hz, 1H), 8 »31 (d» J s 2.5 HZ, 1H), 7.46 (dd, J = 1.5, 10 Hz, 1H), 7.36 (dt, J = 1.5, 9 Hz, 1H), 7.14 (dt, J = 1.5, 7.5 Hz, 1H), 2.42 (s, 3H). The material was used without further purification.PREPARATION 11 2-Me il-3- (2-chloro-pheny1) -3H-Pte idin-4-one To a mixture of 3-acetamidopyrazine-2-carboxylic acid 2-chlorophenylamide (0.816 g »2.81 mmol), triphenylphosphine (2.21 g, 8.43 mmol) and 4-dimethylaminopyridine (0.034 g» 0.2 B mmsles) in dioxane (35 ml) diethyl azodicarboxylate (1.33 ml »8.43 mmol) was added dropwise via syringe. The reaction was heated to reflux overnight, cooled to room temperature and concentrated. The residue was partitioned between methylene 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? 5 inches, packed in hexane), elution being carried out as follows: ethyl acetate at 2054 / well (250 ml), precursor; ethyl acetate at 4054 / year (1600 ml), no heavy triphenylphosphine; ethyl acetate at 6054 / well (500 ml) and ethyl acetate at 7554 / well (500 ml), nothing; ethyl acetate a! 8054 / year (1000 ml), 0.62 g (8154) of 2-methyl 1-3- (2-c! Gold-phenyl) -3H-pteridin-4-one in the form of a brown foam which was suitable for use without further purification. A sample was crushed with frost. P.F .. 74-80 ° C; aH NMR cS 8.98 (d, J = 2 Hz, 1H), 8 »84 (d, J = 2 Hz» 1H) »7» 70-7.63 (m.1H) »7.53 (m sim »2H)» 7.42-17 »33 (m.1H)» 2 »34 (s.3H).

PREPARATION 12 3-Acetamido iofeno-4-carbvoxilato of methyl A mixture of methyl 3-aminothiophene-4-carboxylic acid hydrochloride (3.1 g, 16 mmol) and triethylamine (6.7 m »48 mmol) in methylene chloride (75 ml) was stirred for 30 minutes and then cooled on humid ice. Acetyl chloride (1.4 ml, 19.2 mmol) was added and the reaction was warmed to room temperature and stirred for 1 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 (9154) of methyl 3-acetamidothiophene-4-carbohydrate in the form of a brown oil which solidified after a repopulation period. The product was suitable for use without purification. a-H NMR or 7.98 (d, 2H) »3.87 (S, 3H), 2.18 (s, 3H).

PREPARATION 13 3-Acetamidothium ene-4-carboxylic acid Methyl 3-acetyl-di-phenophene-4-carboxylate (10.0 g »50.25 mmole) was added to a methane solution! ica to 554 of potassium hydroxide (100 ml). The mixture was heated to reflux 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 (HCl) IN. AND! The precipitate was collected, washed with water and dried in the air to yield 8.66 g (9354) of 3-acetyl-amidothiophene-4-carboxylic acid. P.F. 206 ° C; -H NMR or 8.29 (d, 1H), 7.88 (d, 1H), 2.11 (s, 3H). The product was used without purification.

PREPARATION 14 2 - I was given 3,4 ~ 3Cl, 3 oxazi-4-one A mixture of 3-acetamidothiophene-4-carbohydrate (1.5 g, 8.65 mmol), dioxane (40 ml), acetic anhydride (10.2 ml, 86.5 mmol) and sodium acetate (0.75 g, 9.08 mmol) was heated to reflux during one night. The reaction was cooled and concentrated. The residue was partitioned between ethyl acetate and water. The phases were separated and the aqueous layer was brought with ethyl acetate. The combined organic layer was washed with water and brine, dried over sodium sulfate and concentrated to yield 1.39 g (9654) of 2-methyl-1-thienoC3 »4-d3C1.33o or azin-4-one as a solid. of chestnut color. a-H NMR δ 8.34 (d, J = 3.4, 1H), 7.40 D, J = 3.4 1H), 2.38 (s »3H >) The product was suitable for use without purification.

PREPARATION 15 2- ethyl-3-o-tolyl-3H-ienoC3 »4- 3-pyrireidine -one To a suspension of 2-methyl-1-thienoC3.4-d3-pyrimidin-4-one (l.Og, 5.99 mmoleß) and acetic acid (15 ml) was added o-toluidine (1.2 ml. 10.78 mmole). 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 phases were separated and the aqueous layer was brought with ethyl acetate. The combined organic layer was washed with water and brine, dried over sodium sulfate and concentrated to a black oil. The oil was subjected &; Flash chromatography on silica gel (30? 100 mm) eluyends with 2054 ethyl acetate / hexane. The product fractions were combined to yield 0.303 g of 2-methyl-3-o-tol-3H-thienoC3 »4-d3-pyrimidin-4-one in the form of a brown oil that solidified after a period of repo . P.F. 122-123 ° CJ .H NMR a »25 (d, J = 3.2 Hz» 1H) »7» 47 (d.J = 3 »3 Hz» 1H). 7.37-7.32 (m, 3H), 7.12 (d, J = 6.8 Hz »1H)» 2.13 (s, 3H), 2.10 (ß, 3H).

The fractions of each were chromatographed again. The product fractions from this purification were combined and concentrated, and the residues were triturated with 1054 ethyl acetate / hexane to yield 0.447 g of product. In this way, 0.75 g (4954) of product were obtained. Subsequent fractions of the chromatography contained a non-cyclized diamide as a by-product which could be cyclized according to the procedure of preparation 17.

PREPARATION 16 2-Chlorophene 3-acetapHdothiophene-4-carboxylic acid lamide A suspension of 2-methyl-1-thienoC3 »4-d3Cl» 33o? Azin-4-one (1.3 g »7.78 mmol) and acetic acid (15 ml) was added 2-chloroanyl (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 brought with ethyl acetate. The combined organic layer was washed with water and brine, dried over sodium sulfate and concentrated to a black oil. The oil was subjected to flash chromatography in ge! of silica (30? 100 mm) eluting with ethyl acetate at 1054 / well. The first component that eluted from the column, O.363 g of white solid, was identified as 2-chloropheni ida of 3-acetyl idothiophene-4-carbohydrate. a-H NMR? 8.33 (d, J = 9.7 Hz, 1H), 8.28 (d, J = 3.4 Hz, 1H), 8.23 (sa, 1H) »7.78 (d, J = 3.3 Hz »1H), 7.44-7.41 (, 1H), 7, 30-7, 24 (, 1H), 7.14-7.11 (, 1H), 2.19 8s, 3H); MS m / e = 249. The continued elution gave 0.273 g of an unidentified white solid having α-H NMR < 58 »36 (d, J = 8.3 Hz» 1H> »7» 56 (S a »1H), 7.35-7» 33 (m »1H)» 7 »28-7» 22 (m 1H). 7.04-6.99 (m, 1H), 2.22 (s.3H).

PREPARATION 17 2-Methyl-3- (2-chloro-enyl) -3H-enoC3! »4 ~ d3Pirimidin-4-one A mixture of 3-acetamidothiophene-4-carboxylic acid 2-chlorophenimide (0.36 g »1.23 mmoles)» toluene (15 ml) and phosphorus ochloride (0.35 ml »3.7 mmol) were heated to reflux for 8 hours with azeotropic removal of water (Dean-Stark apparatus). The reaction was cooled and partitioned between ethyl acetate and water. The phases were separated and the aqueous layer was brought with ethyl acetate. The combined organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The residue was subjected to flash chromatography on silica gel (20-85 mm) eluting with ethyl acetate a! lOíí / he? an. After a non-heavy precursor, 2-methyl 1-3- (2-chloro-phenyl) -3H-thienoC3 »4-d3-pyrimidin-4-one was isolated in the form of an off-white solid. aH NMR or 8.28-8.26 (m, 1H), 7.56-7.55 (m, 1H), 7.49-7.40 (m, 3H), 7.31 (m, 1H) , 2.10 (S, 3H) i MS m / e = 277.

PREPARATION 18 Aci or 3-aroinopyridine ~ 4-carboxylic acid To a cooled mixture with 3,4-pyridinedicarboxylic acid (5.2 g, 35.11 mmol) in 10% sodium hydroxide (85 ml), bromine (1.84 ml, 35.8 mmol) was added dropwise, the solution The mixture 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 dried in the air to produce 3-amino-4-carbohydric acid (2.74 g, 5754). a.H_RMW (DMSO d ^ 8.20 (S, 1H), 7 »72 (d, J = 5 Hz, 1H), 7.45 (d, J = 5 Hz, 1H). The material was used without purification.

PREPARATION 19 2-Meti 1-3-oxa-l, 7-diza-naf a1en-4-one A mixture of 3-aminopyridine-4-carbo? Í acid! ico (3.38 g, 24.5 mmol), acetic anhydride (15 ml) and sulfuric acid (3 drops) was heated to reflux for 4 hours. The reaction was cooled and carefully quenched with solid sodium bicarbonate. The mixture was filtered through Celite R (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 1-3-oα, 7-diaza-naphthalen-4-one (1.95 g »4954) as a material crystalline color extra.

PREPARATION 2Q 2-Me il-3-o-tol i l-3H-pyridoC3,4-d3pyrimidin-4-one 2-meti 1-3-o? A-l.7-diaza-naf was dissolved in en-4-one (1.95 g »12.0 mmol) in acetic acid (30 ml) and o-toluidine (1.92 ml» 18 mmol). The reaction was refluxed for 7 hours, cooled and concentrated. The residue was taken up in ethyl acetate and washed with water, saturated aqueous sodium bicarbonate and brine. The organic layer was dried over magnesium sulfate and concentrated. The residue was subjected to flash chromatography on ge! of silica (2? 4 inches? padded in the blood) with elution performed as follows: ethyl acetate 1054 / well (500 ml) »ethyl acetate 2554 / well (SOO ml); ethyl acetate at 2554 / well (200 ml) and ethyl acetate at 4054 / well (200 ml). 2-methyl-3- o? A-l, 7-diaza-naphthalen-4-one recovered, not weighed; ethyl acetate at 4054 / year (300 ml), non-heavy compound mixture fraction; ethyl acetate at 4054 / well (3000 ml) »2-methyl-3-o-toli l-3H-pyridoC3» 4-d3-pyrimidin-4-one (2.47 g, 8154) as an off-white solid.

H NMR or 9 »15 (S. 1H)» 8 »70 (d» J = 5 Hz »1H)» 8.05 (d »J = 5 HZ, 1H), 7.46-7.35 (m, 3H) , 7.16 (d, J = 7 Hz, 1H), 2.23 (s.3H). 2.13 (s, 3H). This product was suitable for use without further purification.

PREPARATION 21 O-Toluami a of cyanoacetic acid A mixture of o-to! Uidine (5.0 ml »47 mmol)» methylene chloride (15 ml) »cyanoacetic acid (8.0 g» 94 mmol) »1-hydrobenzotriazole (12.7 g, 94 mmol)» 4-dimethylaminopyridine (5 crystals »catalytic amount) and l- (3-dimeti laminopropi 1) -3-eti Icarbodi imide hydrochloride (16.2 g »94 mmol) was stirred at room temperature overnight. The reaction was concentrated and the light yellow residual oil was partitioned between ethyl acetate and water. The phases were separated and the organic layer was washed with saturated sodium bicarbonate and brine, dried over sodium sulfate and concentrated to obtain 5.2 g of an off-white solid. This solid was recrystallized from methylene chloride in two collections to produce cyanoacetic o-toluamide (4.71 g »5754) in the form of white crystals. P.f. 129-130 ° C, "aH NMR or 9.66 (S, 1H), 8» 00-7.07 (m »6H), 3, 2 (s, 2H), 2.20 (s, 3H > .

BO PREPARATION 22 Q-Toluamine of 5-a ino-1-benzyl-, 2 »3-triazole-4-carboxylic acid A mixture of sodium (0.598 g, 26 mmol) and ethanol (50 ml) was stirred until all the sodium had reacted, to form sodium sodium. To this solution was added cyanoacetic acid o-to α-amide (2.32 g, 13 mmol). In a short period of time. The mixture became homogeneous and took on a yellow color, and then a yellow solid precipitated. At this time benzyl azide (1.73 ml, 13 mmol) was added and the reaction was stirred at room temperature for 17 hours. The mixture was concentrated and the yellow solid residue ß 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 that formed was collected and pulled out (5.2 g). The solid was subjected to flash chromatography on silica gel (100 g) eluting with 0.0554 ammonium hydroxide / 154% ethanol / methylene chloride to yield 3.5 g of an impure product in two fractions. This crude product was recrystallized from methane! to 1654 / isopropyl ether to produce 5-amino-1-benzyl-l, 2,3-triazo1-4-carboxylic acid o-toluamide (1.52 g, 38X) as a light orange solid. P.f. 140-144 ° C; -H NMR or 8.54 (s, 1H), 8.0O (d, J = 7.9 Hz, 1H), 7.43-7.22 (m, 7H), 7.07 (t, J = 7 , 5 Hz, 1H), 5.41 (s, 2H), 4.86 (s, 2H), 2.37 (s, 3H). The concentration of the mother liquors produced 0.618 g more of product.

PREPARATION 23 l-Benzyl-5-roethyl-6-o-tolyl-3.6-dihi roC1.2.3 riazoloC4.5- d3Pi imi in ~ 7-one A mixture of sodium (1.14 g, 49.5 mmol) and ethanol (100 ml) was stirred until all the sodium had reacted, to form sodium ethoxide. To this solution was added 5-amino-1-benzyl-1,2,3-triazo-4-carboalkyl o-toluamide (7.6 g »24.7 mmol) and ethyl acetate (50 ml). The reaction was heated to reflux for 48 hours, it was cooled and concentrated until an orange solid was obtained. 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 from the e? Traceion was acidified to pH 6.5 with acetic acid and subjected to traction with chloroform (2? 100 ml). Methanol (20 ml) was added to the chloroform to help maintain the resulting product without precipitating. This organic phase was dried over magnesium sulfate and concentrated to give 6.93 g of white crystals. The products were combined yielding 7.43 g (9054) of 1-benzyl-5-methyl-6-o- o! i -3 »6-dihydro-Cl» 2 »33-triazoloe4» 5-d3-pyrimidin-7-one. P.f. 178-180 ° C; a.H NMR (DMSO dβ) < 59.86 (s »1 H)» 7 »49 7.09 (m, 6H), 5.49 (s, 2H), 2.24 (s, 3H) 2.05 (s a, 3H).

PREPARATION 24 l-Methyl-6-o-tol il-3 »6-dihydro-Cl» 2 »33-triazo1oC4» 5 ~ d3Pirimidin-7-one A mixture of 1-benzyl-5-methyl-6-o-tolyl-3,6-dihydro-Cl, 2,33-triazolo-C4,5-d3-pyrimidin-7-one (4.Og, 12.07 mmol), acetic acid (150 ml), ethanol (25 ml) and hydrogenated palladium on carbon (4.0 g) was hydrogenated in a Parr apparatus. After 5 hours, the catalyst was filtered off and replaced with 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 1-6-o-tol i 1-3,6-dihydro-Cl, 2,33-triazo1oC4 »5-d3-pyrimidin-7-one (O.488 g» 1754) in the form of white powder. a-H NMR cS 9.31 (S, 1H), 7.85 (m, 1H), 7.30-6.95 (m, 3H). 1.88 (s, 6H). The product was used without purification.

PREPARATION 25 1-Me i 1 thiazole-2-carboxal and do A solution of 4-methyl thiazole (0.91 mL, 10.0 mmol) in tetrahydrofuran (30 mL) was cooled to -78 ° C and butyl lithium (6.0 mL, 15 mmol, 2.5 solution) was added dropwise over 15 minutes. molar in the child). The light yellow solution was stirred for 1 hour at -78 ° C and turned into a slurry. Dimethylformamide (1.2 ml, 15 mmol) was added to the reaction via syringe for 5 minutes. The reaction was stirred for an additional 2 hours 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 was brought with ether. The combined ether extracts were washed with brine, dried over sodium sulfate and concentrated to yield 4-methyl-l-thiazole-2-carboxaldehyde (0.734 g, 5754) as a brown oil. a-H NMR or 9.88 (S, 1H), 7.29 (S, 1H), 2.50 (s, 3H). The material was used without further purification.

PREPARATION 5 2-Meti 1 thiazole-4-carboxa! A solution of ethyl 2-methylthiazole-4-carboxylate (1.0 g, 5.8 mol) in tetrahydrofuran (35 ml) was cooled to -50 ° C and hydride was added dropwise via syringe for 15 minutes. di isobutylalu inium (12 ml, 11.97 mmole, 1 molar solution in tetrahydrofuran). The solution was stirred for 30 minutes at -50 ° C and then allowed to warm to room temperature for 3 hours. The reaction was cooled on wet ice and carefully quenched with 10 ml of 5054 methanol / tetrahydrofuran. The reaction was treated with sodium tartrate and saturated aqueous potassium to half (Rochelle's salt) and the mixture was filtered. The filter layer was washed thoroughly with ether and water. The whole filtrate was combined and subjected to extraction with ethyl acetate. The combined organic layer was washed with brine, dried over sodium sulfate and concentrated until 4-hydro? Imeti 1-2-methyl-thiazole (0.57 g »7654) was obtained as a brown oil. a-H NMR or 6.97 (s, 1H), 4.54 (s, 2H), 4.43 (s a, 1H), 2.63 (s, 2H). This material was used without purification. additional . A further solution at room temperature of 4- hydro? Imeti 1-2-methylazole (10 g, 7.75 mmol) and dichloromethane (50 ml) was treated with Dess-Martin periodinane (4.12 g »9.69 mmol) of a single time. The mixture was allowed to stir overnight. Additional periodinane (1.2 g) was added and the reaction was allowed to stir for a further 4 hours. The reaction was poured into 50 mL of saturated aqueous sodium thiosulfate and extracted with methylene chloride. The combined organic layer was washed with saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate and concentrated to yield 0.901 g (9254) of 2-methyl-1-thiazole-4-carboaldehyde as an off-white waxy solid. it had: aH NMR at 9.96 (s, 1H), 8.03 (s, 1H), 2.77 (s, 3H). The product was suitable for use without further purification.

PREPARATION 27 l-Dimethylamine ometyl iazol-4-carboxal eh do To a suspension of 2-dimethylaminothioacetamide hydrochloride (7.7 g »50 mmol) in ethanol (100 ml)» was added ethyl bromopyruvate (6.3 ml). The mixture was refluxed for 6 hours and then cooled to room temperature ambient. Additional ethyl bromopyruvate (3.2 ml for a total of 75 mmol) was added and the reaction was heated at reflux for a further 2.5 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between water and ethyl acetate and washed at pH 10 with the addition of solid potassium carbonate. The phases were separated and the aqueous layer was extracted with ethyl acetate. The combined organic phase was washed with water and brine, then dried over sodium sulfate and concentrated to yield an amber oil. This oil was purified by flash chromatography on silica gel (120 g). The elution was performed as indicated below; 254 methanol / chloroform, 200 ml, precursor; 1054 methanol / chloroform, 75 ml, nothing; 750 ml, 10.7 g (10054) of ethyl 2-dimethyl-1-omethylthiazole-4-carbohydrate in the form of a light yellow oil. The material was suitable for use without further purification. aH NMR or 8.07 (d, J = 1 »4 Hz, 1H), 4.32 (q, J = Hz, 2H), 3.73 (S, 2H), 2.28 (S, 6H), 1.31 (t, J = 7 Hz, 3H). To a mixture of lithium aluminum hydride (4.5 g, 119 mmol) in ice-cold tetrahydrofuran (100 ml) was added dropwise over "40 min." 2-dimethylaminomethyl-thiazole-4-carbohydrate. ethyl (8.5 g »39.7 mmoles in 40 ml of tetrahydrofuran) maintaining an internal temperature of 5-10 ° C. The mixture was stirred at this temperature range for 90 minutes. The reaction was carefully quenched with saturated aqueous ammonium chloride (30 ml). The resulting gray suspension was stirred for 15 minutes and filtered through celite. The filter layer was washed well with ethyl acetate. The filtrate was washed with brine and dried over sodium sulfate. The concentration of this organic solution gave 4.2 g (6254) of 2-dimeti the inomethyl-4-hydro? Imetyl thiazole in the form of an amber oil. Matter! it was used without further purification. a.H NMR 1.1.2. (s, 1H), 4.71 (s, 2H), 3.73 (s, 2H), 2 »50 (ß a» 1H). 2 »32 (s» 6H). A solution of 2-dime-i-aminomethyl-1-4-hydroxymethyl-thiazole (4.2 g, 27.3 mmol) in methylene chloride (200 ml) was treated with Dess-Martin reagent (14.5 g, 34.1 mmol). The mixture was stirred at room temperature for 24 hours. More Dess-Martin reagent (2.9 g) was added and the mixture was stirred for a further 4 hours. The reaction was quenched by the addition of saturated aqueous sodium thiosulfate (100 ml) and the pH of the resulting mixture was 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. This solid was purified by flash chromatography on silica gel (50-130 mm) eluting first with chloroform (200 ml) and then with methane! to 254 / chloroform collecting 25 ml fractions. Fractions 51-80 were combined and concentrated to give 2.9 g of a yellow milky oil. This oil was triturated with ethereal chloroform at 5054 and a solid was removed by filtration. The filtrate was concentrated yielding 2.6 g (6254) of 2-dimethylaminomethyl l-thia? Ol-4-carboaldehyde as a yellow oil. This product was used without further purification !. a-H NMR δ 9.95 (s, 1H>, 8.14 (s, 1H), 3.81 (S, 2H), 2.36 (S, 6H).

SEPARATION OF THE ATROPISOMEROS The separation of the individual atropisomers from the racemic mixtures of compounds of the formula I or from mixtures containing different amounts of opposite atropisomers of the formula I can be carried out using HPLC, as exemplified below. All the experimental conditions of analytical separation by HPLC described below were carried out with a HPLC Hewlett Packard model 1050. The dimensions of the analytical columns were 4.6 mm? 25 cm and the particle size of the stationary phase was 10 micrometers. All samples were dissolved in methanol.

EJ MP O 13 HPLC conditions for the separation of the atropisomers of example 1, wherein R 3 - is 2-methylphenyl and R 2 is 2-phorophenyl.

Column Chiralcel OD Mobile phase 90/10 hexane / isopropyl alcohol with 0.1% diethylamine Flow rate 1 ml / min UV detection (250 nm) Retention time (first 28,325 min atropisomer) Retention time (second 31,808 min atropisomer) EXAMPLE 14 HPLC conditions for the separation of the atropisomers of example 4 »where R4- is 2-c! Oropyrid-3-yl and R2 is 2-fluorophenyl.

EXAMPLE 15 HPLC conditions for the separation of the atropisomers of example 4 »where R3- is 2-methi Ifeni lo and Rz is 2-chloropheni 1o.

Column Chiralcel OD Mobile phase 80/20 hexane / isopropyl alcohol with 0.1% diethylamine. Flow rate 1 ml / min UV detection (250 nm) Retention time (first 18,434 min atropisomer) Retention time (second 20,585 min atropisomer) EXAMPLE 16 HPLC conditions for the separation of the atropisomers of example 4 »where R4- is 2-chloropheniol and Ra is 2-metho-sieni 1o.

EXAMPLE 17 HPLC conditions for the separation of the atropisomers of Example 4, where R * is 2-methyl Ifeni lo and R * is 2-methi 1-1.3-thiazo! -4-i lo.

Column Chiralpak AD Mobile phase 80/20 hexane / isopropyl alcohol with 0.1% diethylamine Flow rate 1 ml / min UV detection (250 nm) Retention time (first 10,755 min atropisomer) Retention time (second 14,230 min atropisomer) EXAMPLE 18 HPLC conditions for the separation of the atropisomers of Example 4"wherein Ra- is 2-methylfeni 1-3-y lo y * is 2 methy1-, 3-thiazo1-4-y1o.

Column Chiralcel OD Mobile phase 90/10 hexane / isopropyl alcohol with 0.1% diethylamine Flow rate 1 ml / min UV detection (250 nm) Retention time (first 38.038 min atropisomer) Retention time (second 45.032 min atropisomer)

Claims (14)

1. NOVELTY OF THE INVENTION CLAIMS An atropisomer of the formula where V, X, Y and Z are, all of them, carbons or one of them is nitrogen and the others are carbons; each of Ra-, Ra, Ra, R ** and Rβ is independently selected from hydrogen, halogen, alkyl (Cx-Cß), trifluoromethyl, cyano, alco-i (Cx-Cß), alkylthio (Cx-Cß) ) and C (= 0) -0-a! quilo (Cx-Cß) »with the proviso that: (a) Rx can not be equal to Rß when each of V» X »Y and Z is a carbon; (b) at least one of R * - and Rβ must be other than hydrogen; and (c) when V »X» Y or 2 is nitrogen, then Rβ, R- *, R3 or Rβ »respectively, is absent» e! ring A 'is a fused heteroaromatic ring »where said heteroaromatic ring is a 5- or 6-membered heteroaromatic ring» where 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, taken together with the carbon atoms common to the two rings of the bicyclic system, has the formula wherein said "A", "B", "D" and "E" ring positions can be independently selected from carbon or nitrogen; where said ring positions "F, t," G "and" J "can be selected" independently "between carbon» nitrogen »or oxygen or sulfur, with the proviso that: (a) if more than two" F "» " 6"or" J "is a heteroatom, then said 5-membered heteroaromatic ring is selected from the group consisting of (1, 2,3) -triazole, (1, 2.3) -thiadiazole» (1, 2 »5) - thiazole and (1, 2,5) -o? adiazole, and (b) if two of "F", "G" or "J" are heteroatoms "only one of said heteroatoms may be oxygen or sulfur; Optionally condensed heteroaromatic rings can be independently substi tuted at any of the carbon or nitrogen atoms capable of forming an additional bond, with a substituent selected from hydrogen, alkyl (C x -C b), halogen, trifluoromethyl, amino- (CH-j) ) "-» alkylamino (C -Cß) - (CHa) "-, dialkyl amino (C -Cß) - (CH *>" ~, alco? I (C -Cß), hydro? Ialqui!? (Cx) -Cß), alkyl (Cx-Cß) -0- (Cx-Cß) ~ O-alqu i 1O (CX-Cß), -CN, alkyl (C -Cβ) -CO-0-alkylo (C -Cm) -, alkyl (C -Cβ) -0-CO-O-a1qui 10 ( Cx-Cß), a1 qui 10 (Cx-Cß) -C0-0-hydro? I, -N02, Ra-B- C (= 0) -, Ra- «s-0-C (= 0) -, C (= 0) -, dial qui 1? C -Cβ) -NC (= 0) -, cycloalkyl 1o (C3-C ^) and Ra-B-NH-C (= 0) - »and phenyl optionally substituted with halo »alkyl lo (C -), -CN or CF3. Rß s phenyl of the formula Ph3- or a five- or six-membered heterocycle »where said 6-membered heterocyclic has the formula wherein "N" is nitrogen; where said ring positions "K", "L" and "M" can be selected "independently" between carbon or nitrogen »with the proviso that only one of" K ". "L" and "M" can be nitrogen; where said five-membered heterocycle has the formula wherein said ring positions "P", "Q" and "T" can be selected, independently "from carbon, nitrogen, or? or sulfur; with the proviso that only one of "P", "Q" or "T" can be oxygen or sulfur and at least one of "P", "Q" and "T" must be a heteroatom; where said pH3- is a group of the formula wherein each R? - is »independently» hydrogen or alkyl (C -C?); each of R., R * - ° and Ria- are independently selected from "hydrogen" alkyl (Cx-Cß) optionally substituted by one to three halogen atoms »halo» CF3 »alco? i (C -Cß) optionally substituted with one to three halogen atoms »alky! thiol (Cx-Cß>, RAß0- (CHZ) 0-, alkyl (C -Cß) -NH- (CHß) -, dialkyl (C? -Cβ) -NH- (CHa) ~, Cycloalkyl (C3-C7> -NH- (CHa?)? ¡, -, HseN- (C = 0) - (CHJβ) P > -, alky! (Cx-Cβ) -HN- (C = 0) - (CHJß) | a- »dialquí!? (Cx-Cß) -N- (C = 0) - (CHa) P, -» Cycloalkyl (C3-C) -NH- (C = 0) - (CHJ8) P > - »R -» - «0- (C = 0) - (C _.)" -, alkyl? (Cx-Cß) - (0 = C) -0-alkyl? (Cx-Cß), alky 10 ( C -Cβ) -O- (0 = C) -0-alky1 (Cx-Cß), alkyl (C -Cß) - (0 = C) -0-, alky1 (Cx-Cß) - ( 0 = C) -NH- (CHa) P >; ~, H (0 = C) -NH- (CHse) P > -, alkyl! (Cx-Cß) - (0 = C) -NCalkyl (C -Cß) 3 (CHÍB) (!, -, H (0 = C) -N-Calq? i!? (C -) Cß) 3 (CH ^) ,, -, hydro? I, HC (= 0) -CHIB) ß-, alkyl? (Cx-Cß) -C (= 0) - »alkyl (Cx-Cß) - hydrogel (Cx-Cß), alkyl (Cx-Cß) -0-alkyl (Cx-Cß) and cyano; each of R7, R tx and R3 are independently selected from hydrogen, alkyl or (C -Cβ) optionally substituted with one to three halogen atoms, halo, CF3 »alco? i (C -Cβ) optionally substituted with one to three halogen atoms »alky! thiol (Cx-Cß>, R-ßO-CHCH ^ p- »alkyl? (C -C <B) -NH- (CH5S) | a--, dial qui l? (C? -Cβ) -N -ÍCHjg), -, cycloalkyl (C3-C ^) - NH- (CHaí) p > -, HaN- (C = 0> - (CHg.> -, a1uil? (C -Cß) -HN- (C = 0) - (CHa?) L =, -, di al qui 1 O (C -Cß,) - N- (C = 0) - (CHjg) ,, -, alky1 (Cx-Cß) - (0 = C) -0-alkyl? (Cx-Cß), a1qui 10 (Cx) -C.sub.10 -O-alky! (C x -C.sub.S), a.kylO (C.sub. -C.sub.be) - (0 = C) -0-, alkyl (C.sub.C.sub.β) - (0 = C) -NH- (CHs) ) r > - H (0 = C) -NH- (CHβ) | ß-, alkyl (Cx-Cß) - (0 = C) -NCa! quil? (C? -Cβ) 3 ( CHse) (S-, H (0 = C) -N-Calqui 1? (C? -Cβ) 3 (CHa) p-, hydro? I, HC (= 0) - (CHar) |!, - »here l (Cx-Cβ) -C (= 0> -, alkyl (C -Cβ) -0-C (= 0) -, Ra-β- (CHas) |:, - 0-C (= 0) -, to ino- (CHa) (S-, hydro? i-alky (Cx-cß), alkylo (Cx-cß) -? - alkylo (Cx-Cß), -CHO and cyano, each R ** * is independently hydrogen or halogen »each R * - * is independently hydrogen» to (C? -Cß) »to the alkyl (Cx-Cß) - (C = 0) -» alkyl (Cx-Cß) -0- (C = 0) - »alkyl 1 or (C -Cß> -NH- (C = 0) -o dia! Quilo (Cx-Cß) -N- (C = 0) -; each Rß is hydrogen »cyano» (Cx-Cß) alkyl, halogen, trifluoromethyl, -CHO or alco? i (Cx-C ^); n is an integer from zero to 3, p is an integer from zero to 3, and where the dashed line represents an optional double link; with the proviso that when R? - is hydrogen, one of R * -3 and RA- * is different from hydrogen; and the pharmaceutically acceptable salts of such atropisomer.
2. 2. A compound according to claim 1, in e! that the ring A 'is thieno »R * is 2» 4 or 5-thiazolyl substituted with a methyl group, R is methyl, Z is carbon or nitrogen and each of V, X and Y is carbon.
3. 3. A compound according to claim 1, in e! that ring A 'is thieno, R * is 2, 4 or 5-thiazole ilo substituted with a methyl group, Ra- is chloro, Z is nitrogen, and each of V, X and Y is carbon.
4. 4. A compound according to claim 1 wherein ring A 'is thieno R is phenyl, 2-chlorophene, 2-fluorophenyl, 2-bromophenyl, or 2-hydro? Ifem. each of Rß, R3. R- * and RB »if present, is hydrogen, and Ra- is methyl or chloro.
5. 5. A compound according to claim 1, wherein e! ring A * is thieno, R * is 2-pyridyl, each of V, X, Y and Z is carbon, each of R3. R3, R- »and Rβ is hydrogen and - is chloro.
6. 6. A compound according to claim 1, wherein ring A »is thien, R * is 2-fluorophenyl, Z is nitrogen, each of V, X and Y is carbon, each of R3, * * and Rβ is hydrogen, and R * - is chlorine.
7. 7. A compound according to any of the re vind drops 2, 3 or 5, in which the ring At is taken and taken together with e! Pyrimidinone ring forms a 3H-thienoC3,2-d3pyrimidin-4-one.
8. 8. A compound according to claim 1, wherein the bond represented by a thick line and dashed line is a carbon-carbon double bond.
9. 9. A compound according to claim 4, wherein Z is nitrogen.
10. A compound according to claim 4, wherein Z is a carbon and wherein ring A 'is thien and taken together with the pyrimidinone ring forms a 3H-thienoE3, 2-d3pir midi -4- ona
11. 11. A pharmaceutical composition for e! treatment of stroke, cerebral ischemia, spinal cord trauma »cephalic trauma» Alzheimer's disease »Huntington's disease, amyotrophic lateral sclerosis, AIDS-induced dementia, muscle spasms, migraine, urinary incontinence, psychosis, convulsioneß, hiccups perinatal, cardiac arrest, neuron injury! hypoglycemic »opioid and abstinence syndrome» ocular lesions »retinopathy» idiopathic and drug-induced Parkinson's disease »anxiety» emesis »cerebral edema» chronic or acute pain »late dysphenia or brain deficits after cardiac bypass surgery and grafts» in a mammal »comprising a pharmacologically effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier.
12. 12. A pharmaceutical composition for treatment of a disorder or condition, whose treatment or prevention can be carried out or facilitated by reducing or inhibiting the neurotransmission of glutamate in a mammal, comprising a pharmacologically effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier.
13. 13. The use of a pharmacologically effective amount of a co-formula according to claim 1, for preparing a composition for treating stroke, cerebral ischemia, spinal cord trauma »cephalic trauma» Alzheimer's disease »Huntington's disease» Amyotrophic lateral sclerosis »AIDS-induced dementia, muscle spasms» migraine »urinary incontinence» psychosis »convulsions» perinatal hiccups »cardiac arrest, neuron injury! hypoglycemic »opioid tolerance and withdrawal syndrome» eye injuries »retinopathy» idiopathic and drug-induced Parkinson's disease »anxiety» emesis »cerebral edema» chronic or acute pain »late dyschezia or cerebraleß deficits after cardiac bypass surgery and grafts »In a mammal.
14. 14. The use of an amount of a compound according to claim 1 for preparing a composition for treating a disorder or condition, the treatment or prevention of which can be carried out or facilitated by reducing or inhibiting the neurotransmission of glutamate in a mammal.