MXPA06007984A - Derivatives of 1,4-diazabicyclo[3.2.1]octanecarboxamide, preparation method thereof and use of same in therapeutics - Google Patents

Abstract

The invention relates to compounds having general formula (I), wherein X represents N or a group having formula C-R2;P, Q, R and W each represent N or a group having formula C-R3;R1 represents H or an alkyl;R2 represents an alkyl;R3 represents H or a halogen, or an alkyl, alkoxy, nitro, amino, trifluoromethyl, cyano group, or having general formula -NR4R5, -NR4C (=O ) R5, -NR4C (=O ) NR5R6, - NR4C (=O ) OR5, -NR4S (=) 2NR5R6, -OR4, -OC (=O ) R4, -OC (=O ) OR4, -OC (=O ) ONR4R5, -OC (=O ) SR4, -C (=O ) OR4, -C (=O ) R4, -C (=O ) NR4R5, -SR4, -S (=O )R4, -S (=O ) 2R4, -S (=O ) 2NR4R5, or a heterocycle;and R4, R5, and R6 each represent H or an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, or heterocycloalkyl or aryl. The invention also relates to the use of same in therapeutics.

Description

yri DERIVATIVES OF THE 1, 4- DIAZABICICLO [3.2.1] OCTANOCARBOXAMIDA, ITS PREPARATION AND ITS APPLICATION IN THERAPEUTICS The present invention is aimed at compounds, ligands of the nicoinic receptors. They are useful in the irradiation or prevention of events related to dysfunction of nicotinic receptors. The compounds of the invention correspond to the general formula (I): wherein: X represented a niirogen atom or a group of general formula C-R2, P, Q, R and W each represented, independently of each other, a nitrogen atom or a group of general formula C-R3 , Ri represents a hydrogen atom or an alkyl group (C-α-C6), R2 represents an alkyl group (Ci-Ce), R3 represents a hydrogen or halogen atom or an alkyl group (C -? - C6) , alkoxy nitro, amino, trifluoromethyl, cyano, or of the general formula -NR4R5, -NR4C (= O) R5, -NR4C (= O) NR5R6, -NR4C (= O) OR5, NR4S (= O) 2NR5R6, -OR5, - OC (= O) R5, -OC (= O) OR5, -OC (= O) ONR4R5, -OC (= O) SR5, -C (= O) OR5, C (= O) R5, -C (= O) NR4R5, SR5, -S (= O) R5, -S ( = O) 2R5, -S (= O) 2NR4R6, or a phenyl group optionally substituted with one or more groups chosen from the halogen atoms and the alkyl groups (C -? - C6), alkoxy (Ci-Ce), , amino, frifluoromethyl, cyano, or of the general formula -NR4R5, -NR4C (= O) R5, --NR4C (= O) NR5R6, -NR4C (= O) OR5, NR4S (= O) 2NR5R6, -OR5, - OC (= O) R5, -OC (= O) OR5, -OC (= O) ONR4R5, -OC (= O) SR5, -C (= O) ORS, C (= O) NR4R5, SR5, -S (= O) R5, -S (= O) 2R5, -S (= O) 2NR4R6, or R3 represents a group selected from the cycles imidazole, pine, pazine, pidine, pyrazole, pyrazine, triazole, quinoline, isoquinoline, tefrazol , furane, iiophene, isoazole, isoazole, oxazole, isoxazole, pyrrole, hydroalkyne, tetrahydroisoquinoline, indole, benzimidazole, benzofuran, dihydrobenzofuran, quinoline, indazole, phthalazine, triazine, isoindol, oxadiazole, thiadiazole, furazane, benzofurazane, benzoylophene, dihydrobenzoylophene, benzofriazole , benzoyiazole, ben zoisothiazole, benzoxazole, benzoisoxazole, quinazoline, quinoxaline, naphthine, dihydroquinoline, dihydroisoquinoline, furopine, dihydrofuropine; pyrrolopine, íienopiridina, dihidrofienopiridina, imidazopine, pyrazolopine, oxazolopine, isoxazolopiridina, íiazolopiridina, isoíiazolopiridina, pyrrolopidine, furopidine, dihidrofuropirimidina, íienopip'midina, dihidrofienopirimidina, imidazopidine, pyrazolopidine, oxazolopidine, isoxazolopirimidina, íiazolopirimidina, isoíiazolopirimidina, furopirazina, dihidrofuropirazina, pyrrolopyrazine, íienopirazina, dihydroienopyrazine, imidazopyrazine, pyrazolopyrazine, oxazolopirazina, isoxazolopirazina, tiazolopirazina, isofiazolopirazina, furopazine, dihidrofuropiridazina, pyrrolopazine, íienopiridazina, dihidroíienopiridazina, imidazopazine, pirazolopiridazina, oxazolopiridazina, isoxazolopiridazina, íiazolopiridazina or isoíiazolopiridazina, R4, R5 and R6 represenían each, independently of one another, a halogen atom or a straight or branched (C? -C6) alkyl group, linear or branched (C2-C6) alkenyl or straight or branched (C2-C6) alkynyl, or a (C3-C8) cycloalkyl, (C3-C8) cycloalkyl group alkyl (C- | -C3), cycloalkenyl (C4-C8), or phenyl, the groups of general formulas NR R5 and NR5R6 being able to form with the nitrogen atom that supports them, a group selected from the aziridinyl, azetidinyl, pyrrolidinyl groups , piperidinyl, azepinyl, piperazinyl, morpholinyl, fiomorpholinyl, pyrrolinyl, indolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, 3H-indolyl, quinuclidinyl and quinolizinyl. The compounds of the invention can exist in the state of bases or addition salts to acids, hydrates or solvates. Since the diazabicyclooctane rings comprise an asymmetric carbon atom, the compounds of the invention can exist in the pure enantiomers or mixtures of enantiomers. The enantiomers can be separated by methods known to the professional, such as separation by fractional chiralization of diastereomeric salts of chiral acids or separation by chromatography on chiral support. According to the invention, the compounds of general formula (I) can be prepared by a process illustrated by the following scheme 1. The 1,4-diazabicyclo [3.2.1] octane of formula (II) is reacted with a compound of general formula (III) wherein X, P, Q, R, W and Rt are as defined above , in the presence of a coupling agent such as, for example,? /,? / '- carbonyldi-imidazole, in a solvent such as dimethylformamide. The carboxylic acid function present in the compound of general formula (III) can also be converted, in a previous step, into an acid chloride function, to react with 1,4-diazabicyclo [3.2.1] octane in a solvent such as like dichloroethane. Scheme 1 Alternatively, the compounds of general formula (I) can be prepared by a process illustrated in the following scheme 2. The 1,4-diazabicyclo [3.2.1] octane of formula (II) is reacted with a compound of general formula ( IV), in which X, P, Q, R, W and Ri, are as defined above and Z represented a bromine or iodine, in the presence of carbon monoxide and a palladium catalyst such as, for example, bis (triphenylphosphino) -d -Gloropalladium, and a base such as, for example, triethylamine, in a solvent such as, for example, dimethylformamide. Scheme 2 Compounds of general formula (11) are available commercially or are accessible by methods described in the literature, as for example in Can. J. Chem. 1 988, 66, 420-8. The compounds of general formula (IV) are available in commerce or are accessible by methods described in the literature, as for example in J. Het. Chem 1 983, 475. The preparation of 1,4-diazabicyclo [3.2.1] octane is described in J. Med. Chem. 1 977, 20, 1333. The following examples illustrate in detail the preparation of some compounds according to the invention. . The elemental microanalyses and the IR and NMR spectra confirm the structures of the obtained compounds. The numbers of the compounds indicated in parentheses in the titles correspond to those in the table given below. In the names of the compounds, the hyphen "-" is part of the word, and the hyphen "-" serves only for the cut at the end of the line; It should be deleted in the absence of a cut, and should not be replaced by a normal script or by a space. Example 1 (Compound No. 2) 3- (1,4-Diazabicyclo [3.2.1] oct-4-ylcarbonyl) -1 / -indazole 1: 1 hydrochloride. In a 50 ml reactor, 0.165 g (1.02 mmoles) of 1H-indazole-3-carboxylic acid and 1 ml of thionyl chloride are introduced, the mixture is heated at reflux for 1 h 30 min. and concentrated at reduced pressure. Then, 1.2 ml of pyridine and 0.30 g (2.67 mmol) of 1,4-diazabicyclo [3.2.1] octane are added and the mixture is heated under reflux for 1 h 30 min. The solvent is evaporated under reduced pressure, the residue is taken up in 1 ml of chloroform and the residue is purified by chromatography on a silica gel column, eluting with a mixture. 70/30/3 of acétalo of ethyl, methanol and ammonia. 0.16 g of product are obtained which are dissolved in 10 ml of acetone before adding 0.47 ml of a 5N solution of hydrochloric acid in isopropyl alcohol. The obtained crystals (0.17 g) are collected by filtration and dried under reduced pressure. Melting point: 286-287 ° C. Example 2 (Compound No. 3) 6-Bromo-3- (1,4-diazabicyclo [3.2.1] oct-4-ylcarbonyl) -1H-indazole 1: 1 hydrobromide. 0.25 g (0.9 mmol) of 3-iodo-6-chloro-1 H-indazole, 0.09 g (0.13 mmol) of bis (triphenylphosphino) dichloropalladium are successively introduced into a 10 ml reactor. , 0.25 g (2.24 mmoles) of 1,4-diazabicyclo [3.2.1] oclan and 0.31 ml (2.24 mmoles) of triethylamine in solution in 1 ml of dimethylformamide. The mixture is then purged with carbon monoxide and heated at 70 ° C for 8 h. The reaction medium is poured into 10 ml of a saturated aqueous solution of ammonium chloride and the aqueous phase is extracted with chloroform. The organic phases are dried, they are filtered and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel eluting with a 90/1 0/1 mixture of chloroform, methanol and ammonia. 0.2 g of product are thus obtained, which are dissolved in 1 ml of isopropyl alcohol to then add 0.1 ml of a 5N solution of hydrochloric acid in isopropyl alcohol. The obtained crystals (0.076 g) are collected by filtration and dried under reduced pressure.

Melting point: 285-286 ° C. Example 3 (Compound No. 1) 3- (1,4-Diazabicyclo [3.2.1] oct-4-ylcarbonyl) -6-methyl-1 H-pyrazolo [3,4-b] pyridine hydrobromide: 1 . By analogy with example 2, 0.7 g is reacted (3.3 mmoles) of 3-bromo-6-methyl-1 / -pyrazolo [3,4 - /)] pyridine with 1.1 g (9.9 moles) of 1,4-diazabicyclo [3.2.1] octane in the presence of 0.35 g (0.5 mmol) of bis (triphenylphosphino) dichloro-palladium and 2.3 ml of ethyrylamine in 10 ml of dimethylformamide under the conditions described for Example 1, and 0.21 g of product are obtained, which are dissolved in 20 ml of acetone to then add 0.27 ml of a solution .7N of hydrobromic acid in acetic acid. The dihydrobromide crystals are collected by filtration and dried in vacuo. Melting point: 290-291 ° C. Example 4 (Compound No. 4) Hydrobromide of 3- (1,4-di azabicyclo [3.2.1] oct-4-ylcarbon i) -5-f luoro-1-H-indazole 2: 1. By analogy with example 2, 0.23 g is reacted (0.88 mmole) of 3-iodo-5-fluoro-1 H-indazole with 0.25 g (2.19 mmole) of 1,4-diazabicyclo [3.2.1] octane in the presence of 0.092 g (0.13 mmol) of bis (triphenylphosphino) dichloro palladium and 0.3 ml of erytylamine in 1 ml of dimethylformamide under the conditions described for example 2. 0. 136 g of the product is obtained which is dissolved in 20 ml of acelline , and 0.18 ml of a 5.7N solution of hydrobromic acid in acyl acid is added. The crystals of dihydrobromide by filtration and dried in vacuo. Melting point: 283-284 ° C. The following table illustrates the chemical structures and physical properties of some compounds of the invention. In the column "Q", "Me" designates a mephyl group and "Ms" designates a methanesulfonyl group. In the column "Est.", "(+/-)" designates a racemate, "(+)" and "(-)" designate the dextrorotatory and levorotatory enantiomers, respectively. In the column "Salt", "-" designates a compound in the base state, "H Br" designates a hydrobromide, "HCl" designates a hydrochloride and "ox." designates an oxalalo, or eioodioaío.

Table The compounds of the invention have been the target of pharmacological tests that have demonstrated their interest as active substances of medicines. Thus, it has been studied in relation to its affinity for nicotinic receptors containing the a4ß2 subunit according to the methods described by Anderson and Arneric in Eur. J. Pharmacol. 1 994, 253, 261 and by Hall et al. in Brain Res. 1 993, 600, 127. Male Sprague Dawley rats were decapitated from 150 to 200 g and the entire brain was rapidly excreted, homogenized in 1.5 volumes of a 0.32 M sucrose solution at 4 ° C, and then centrifuged at 1000 G for 10 min. The precipitate is removed and the supernatant is centrifuged at 20,000 G for 20 min at 4 ° C. The precipitate is recovered and homogenized by a Polytron ™ triuretor in 15 volumes of bidistilled water at 4 ° C, and then cenfrifuga at 8,000 G for 20 min. The precipitate is removed and the supernatant and buffy coat concentrate are centrifuged at 40,000 G for 20 min, the precipitate is recovered, resuspended in 15 ml of bidistilled water and centrifuged once more at 40,000. G before storage at -80 ° C. On the day of the experiment, the tissue is slowly thawed and suspended in 3 volumes of tampon. 150 μl of this membrane suspension is incubated at 4 ° C for 120 min in the presence of 1 00 μl of 1 nM [3 H] -cylisin in a final volume of 500 μl of buffer, in the presence or absence of a leaving compound. to rehearse. The reaction is filtered by filtration over Whatman GF / B ™ filters previously treated with polyethylenimine, the filters are washed with twice 5 ml of buffer at 4 ° C, and the radioactivity retained in the filter is measured by liquid scintigraphy. The non-specific binding is determined in the presence of (-) - nicotine at 1 μM; the non-specific binding represents 75 to 85% of the total binding recovered in the filter. For each concentration of fuzzy compound, the percentage of inhibition of the specific binding of [3 H] -citisin, and then calculate the Cl50, compound concentration that inhibits 50% of the specific binding. The Cl50 of the most related compounds of the invention are between 1 and 10 μM. The compounds of the invention have also been studied in relation to their affinity for the nicoinic receptors that comprise the α-subunit, according to the methods described by Mark and Collins in J. Pharmacol. Exp. Ther. 1 982, 22, 564 and by Marks eí coll. in Mol. Pharmacol. 1 986, 30, 427. OFA male rats were decapitated from 150 to 200 g, the entire brain is rapidly extracted, homogenized by a Polytron ™ crusher in 15 volumes of a 0.32M sucrose solution at 4 ° C, and then Cenírifuga to 1 .000 G during the 1 0 min. The precipitate is removed and the supernatant is centrifuged at 8,000 G for 20 min at 4 ° C. The precipitate is recovered and homogenized by a Polyíron ™ tri-sorbent in 15 volumes of bidesilylated water at 4 ° C, and then centrifuged at 8,000 G for 20 min. The precipitate is eliminated and the supernatant and the buffy coat leucoplaquetary concentrate are centrifuged at 40,000 G for 20 min. The precipitate is recovered, resuspended with 15 volumes of bidistilled water at 4 ° C and centrifuged once more at 40,000 G for 20 min before being stored at -80 ° C. The day of the experiment is slowly thawed and suspended in 5 volumes of tampon. Pre-incubate 150 μl of this membrane suspension at 37 ° C for 30 min, in the dark, in the presence or absence of the compound to be tested. The membranes are then incubated for 60 min at 37 ° C, in the dark, in the presence of 50 μl of 1 nM [3 H] -a-bungarotoxin in a final volume of 250 μl of 20 mM HEPES buffer, 0.05% polymylylenimine. The reaction is delayed by filtration on Whatman GF / C ™ filters previously frosted for 3 h with 0.05% polyphenyleneimine). The filters are washed with twice 5 ml of buffer at 4 ° C and the radioactivity retained in each filter is measured by liquid scintigraphy. The non-specific binding is determined in the presence of final 1 μM a-bungarotoxin; the non-specific binding represents approximately 60% of the total union recovered in the filter. For each concentration of compound studied, the inhibition percentage of the specific binding of [3 H] -a-bungaroioxin is determined, and then the Cl 50, compound concentration that inhibits 50% of the specific binding, is calculated. The Cl50 of the compounds of the invention more related are between 0.010 and 0.1 .mu.M. The CI5o of some specific compounds are indicated in the following table.

The previous results show that the compounds of the invention are selective ligands for the a7 subunits of the nicotinic receptor. The results of the different trials suggest the use of the compounds in the treatment or the prevention of the isnas linked to a dysfunction of the nicotinic receptors, mainly at the level of the central nervous system. These transitions include cognitive alterations, more specifically mnesic, but also attention, linked to Alzheimer's disease, pathological aging (Age Assoc / afecí Memory Impairment, AAMI), Parkinsonian syndrome, trisomy 21 (Down syndrome), to the alcoholic syndrome of Korsakoff, to vascular dementias (multi-infarct dementia, MDI). Compounds of the invention may also be useful in the treatment of motor disorders observed in Parkinson's disease or in other neurological diseases such as Huntington's disease, Tourette's syndrome, tardive dyskinesia and hyperkinesia. The compounds of the invention can also constitute a curative or symptomatic treatment of cerebral vascular accidents and hypoxic cerebral episodes. They can also be used in psychiatric pathologies: schizophrenia, depression, anxiety, panic attacks, compulsive and obsessive behaviors. They can also prevent the symptoms due to the abstinence of tobacco, alcohol and the different substances that induce a dependency, such as cocaine, LSD, cannabis or benzodiazepines. On the other hand, the compounds of the invention can also be used for the treatment of ischemia of the lower limbs, arterioid obliquia of the lower limbs (PAD: arterial disease), cardiac ischemia (angor stable), myocardial infarction, heart failure. , deficit of cutaneous scarring of diabetic patients or varicose ulcers due to venous insufficiency. For each of the abovementioned pathologies, the irradiation can be done with the nicotinic agent alone and / or in association with the reference drugs indicated in the pathology. Therefore, the present invention also has pharmaceutical compositions containing an effective dose of at least one compound according to the invention, in the pharmaceutically acceptable base or salt or solvate condition, and optionally in admixture with suitable excipients. . Said excipients are chosen according to the pharmaceutical form and the desired administration mode. The pharmaceutical compositions according to the invention can therefore be divided into oral, sublingual, subcutaneous, intramuscular, intravenous, topical, intratracheal, intranasal, transdermal, recial or infraocular administration. The unit administration forms can be, for example, tablets, capsules, granules, powders, solutions or oral or injectable suspensions, transdermal patches ("patch") or suppositories. For topical administration, ointments, lotions and eye drops may be considered. Said unit forms are dosed to allow a daily administration of 0.01 to 20 mg of active principle per kg of body weight, according to the galenic form. To prepare tablets, a pharmaceutical carrier, which may be composed of diluents, such as lactose, microcrystalline cellulose or starch, and formulation adjuvants such as binders, (polyvinylpyrrolidone, hydroxypropylmethylcellulose, etc.) is added to the active ingredient, micronized or not, micronized or not. ), flow agents such as silica, lubricants such as magnesium stearate, stearic acid, glycerol tribehenate or sodium stearyl fumarate. Wetting agents or surfactants such as sodium lauryl sulfate can also be added. Embodiment techniques can be direct compression, dry granulation, wet granulation or hot melt. The tablets may be uncovered, coated as dragees, for example with sucrose, or coated with different polymers or other appropriate materials. They can be designed to allow a rapid, delayed or prolonged release of the active ingredient thanks to polymeric mallets or specific polymers used in the coating. To prepare capsules, the active principle is mixed with dry pharmaceutical vehicles (simple mixture, dry granulation or wet, or hot melt), liquid or semi-solid. The capsules can be hard or soft, coated, so that they have a rapid, prolonged or remanent activity (for example for an enteric form). A composition in the form of syrup or elixir or for administration in the form of drops may contain the active principle conjunctly with a sweetener, preferably caloric, meiilparaben or propylparaben as anisopic, a flavoring agent and a dye. Water dispersible powders or granules may contain the active ingredient mixed with dispersing agents or wetting agents, or disperse agents such as polyvinylpyrrolidone, as well as sweeteners and correcfores agents of the worm. For the private administration, suppositories prepared with agglomerates that melt at a certain temperature are used, for example cocoa butter or polyethylene glycols. For parenteral administration, aqueous suspensions, isotonic saline solutions or sterile injectable solutions are used which contain pharmaceutically compatible dispersing agents and / or humectants, for example propylene glycol or butylene glycol. The active principle can also be formulated in the form of microcapsules, optionally with one or more supports or additives, or with a polymeric mafriz or with a cyclodexphrine. (fransdermic patches, prolonged-release forms). The topical compositions according to the invention comprise a medium compatible with the skin. They can be mainly present in the form of aqueous, alcoholic or hydroalcoholic solutions, gels, water-in-oil or water-in-water emulsions which have the appearance of a cream or a gel, microemulsions, aerosols, or also in the form of vesicular dispersions. containing ionic and / or nonionic lipids. These galenic forms are prepared according to the usual methods of the fields considered. Finally, the pharmaceutical compositions according to the invention may contain, in addition to a compound of general formula (I), other active ingredients which may be useful in the processing of the diseases and diseases indicated above.

Claims (4)

1. REIVI NDICATIONS 1. Compound, in the pure enaniomer or mixture of enaniomers, which corresponds to the general formula (I) wherein: X represents a nitrogen atom or a group of general formula C- R2, P, Q, R and W each represents, independently of the one of the other, a nitrogen atom or a group of general formula C-R3 , Ri represents a hydrogen atom or an alkyl group (d-C6), R2 represents an alkyl group (Ci-Ce), R3 represents a hydrogen or halogen atom or an alkyl group (C -? - C6), alkoxy (C ^ Ce), nifro, amino, frifluoromethyl, cyano, or of the general formula -NR4R5, -NR4C (= O) R5, -NR4C (= O) NR5R6, -NR4C (= O) OR5, NR4S (= O ) 2NR5R6, -OR6 l -OC (= O) R5, -OC (= O) OR5, -OC (= O) ONR4R5, -OC (= O) SR5, -C (= O) OR5, C (= O) ) R5, -C (= O) NR4R5, SR5, -S (= O) R5, -S (= O) 2R5, -S (= O) 2N R4R6, or an optionally phenyl group susfiuid with one or more groups chosen the halogen atoms and the alkyl groups (C -? - C6), (C -? - C6) alkoxy, nitro, amino, trifluoromethyl, cyano, or of the general formula -NR4R5, -NR C (= O) R5, -NR4C (= O) NR5R6, -NR4C (= O) OR5, NR4S (= O) 2NR5R6, -OR5, -OC (= O) R5, -OC (= O ) OR5, -OC (= O) ONR4R5, -OC (= O) SR5, -C (= O) OR5,
2. C (= O) NR4R5, SR5, -S (= O) R5, -S (= O) 2R5, -S (= O) 2NR4R6, or R3 represented a group selected from the cycles imidazole, pyridine, pyridazine, pyrimidine , Pyrazole, Pyrazine, Iriazole, Quinolein, Isoquinoline, Indolerazol, Furan, Iiophene, Furozol, Isozazol, Oxazole, Isoxazole, Pyrrole, Hydroquinoline, Hydroquinoline, Indole, Indole, Benzofuran, Dihydrobenzofuran, Quinoline, Indazole, Phthalazine, Iriazine, Isoindole, Oxadiazole , íiadiazol, furazan, benzofurazan, benzofiofeno, dihidrobenzoíiofeno, benzoíriazol, benzofiazol, benzoisoíiazol, benzoxazole, benzisoxazole, quinazoline, quinoxaline, naffiridina, dihydroquinoline, dihydroisoquinoline, furopyridine, dihidrofuropiridina, pyrrolopyridine, íienopiridina, dihidroíienopiridina, imidazopyridine, pyrazolopyridine, oxazolopyridine, isoxazolopiridina, isoxazolopiridina , liazolopyridine, isoiazolopyridine, pyrrolopyrimidine, furopyrimidine, dihydrofuropyrimidine, thienopyrimidine, dihydrothienopyrimidine, imi dazopirimidina, pyrazolopyrimidine, oxazolopyrimidine, isoxazolopirimidina, fiazolopirimidina, isofiazolopirimidina, furopirazina, dihidrofuropirazina, pyrrolopyrazine, thienopyrazine, dihidrotienopirazina, imidazopyrazine, pirazolopirazina, oxazolopirazina, isoxazolopirazina, íiazolopirazina, isoíiazolopirazina, furopyridazine, dihidrofuropiridazina, pyrrolopyridazine, fienopiridazina, dihidroíienopiridazina, imidazopyridazine, pirazolopiridazina, oxazolopiridazina, isoxazolopyridazine, thiazolopyridazine or isothiazolopyridazine, R4, R5 and R6 each represent, independently of one of the other, a halogen atom or a linear (C-? - C6) alkyl group or branched, straight or branched (C2-C6) alkenyl or straight or branched (C2-C6) alkynyl, or a (C3-C8) cycloalkyl, (C3-C8) cycloalkyl-alkyl (d-Cs), cycloalkenyl (C4-) group C8) or phenyl, the groups of general formulas NR4R5 and NR5R6 being able to form with the nihologen atom that supports them, a group selected from the groups aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, azepinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyrrolinyl, indolinyl, pyrazolinyl, pyrazolidinyl ,. imidazolinyl, 3H-indolyl, quinuclidinyl and quinolizinyl, in the base state, solvafb or acid addition salt. 2. Medicament, characterized in that it consists of a compound according to claim 1.
3. 3. Pharmaceutical composition, characterized in that it confers a compound according to claim 1, associated with an excipient.
4. 4. Use of a compound according to claim 1 for the preparation of a medicament intended for the treatment of disorders due to cognitive and attention disorders or of mo- nore transients, or of neurological or psychiatric disorders or for the prevention of symptoms due to the absiinence of the susancias that induce a dependence or desíinado to the treatment of cardiac, vascular, arial and venous paíologías. RESU MEN Compounds corresponding to the general formula (I) in which X represents N or a group of the formula C-R2, P, Q, R, and W each represent N or a group of the formula C-R3, Ri represents H or alkyl, R2 represents an alkyl, R3 represents an H or a halogen or an alkyl, alkoxy, nitro, amino, trifluoromethyl, cyano group, or of the general formula -NR4R5, -N R4C (= O) R5, - NR4C (= O) NR5R6, -NR4C (= O) OR5, NR4S (= O) 2NR5R6, -OR4, -OC (= O) R4, -OC (= O) OR4, -OC (= O) ONR4R5, - OC (= O) SR4, -C (= O) OR4, C (= O) R4, -C (= O) NR4R5, SR4, -S (= O) R4, -S (= O) 2R4, -S (= O) 2NR4R5, or a heterocycle, R4, R and R6 each represent an H or an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl or heterocycloalkyl or aryl. Application in therapy.