MX2008008318A - Aryl-isoxazol-4-yl-imidazo[1, 5-a]pyridine derivatives - Google Patents

Abstract

The present invention is concerned with aryl-isoxazol-4-yl-imidazo[1,5-a]pyridine derivatives of formula (I) wherein:R1is hydrogen, halogen, hydroxy, lower alkyl, benzyloxy or -O-(CH2)-(CO)-5 or 6 membered heteroaryl optionally substituted by aryl and lower alkyl;R2is hydrogen, lower alkyl, or -(CO)-Ra;R3is hydrogen, halogen, cyano, lower alkyl, or -(CO)-Ra;Rais hydroxy, lower alkoxy, NR'R'', wherein R'and R''are each independently hydrogen, cycloalkyl, 5 or 6-membered heterocycloalkyl or lower alkyl optionally substituted by cycloalkyl, cyano, 5 or 6-membered heterocycloalkyl or 5 or 6-membered heteroaryl;as well as pharmaceutically acceptable acid addition salts thereof. It has been found that this class of compounds show high affinity and selectivity for GABA Aα5 receptor binding sites and might be useful as cognitive enhancer or for the treatment of cognitive disorders like Alzheimer's disease.

Description

DERIVATIVES OF ARI -ISOXAZO -4-I -IMIDAZO [1, 5-a] PYRIDINE DESCRIPTION OF THE INVENTION The present invention relates to aryl-isoxazol-4-yl-imidazo [1,5-a] pyridine derivatives of formula I: wherein: R1 is hydrogen, halogen, hydroxy, lower alkyl, benzyloxy or -O- (CH2) - (CO) -sheteroaryl 5- or 6-membered optionally substituted by aryl and lower alkyl; R2 is hydrogen, lower alkyl or - (CO) -Ra; R3 is hydrogen, halogen, cyano, lower alkyl or - (CO) -Ra; Ra is hydroxy, lower alkoxy, NR'R ", wherein R 'and R" are each independently hydrogen, cycloalkyl, 5- or 6-membered heterocycloalkyl or lower alkyl optionally substituted by cycloalkyl, cyano, 5- or 6-membered heterocycloalkyl or 5 or 6 membered heteroaryl; as well as pharmaceutically acceptable acid addition salts thereof.

REF. : 194069 We have found that this class of compounds have a high affinity and selectivity for the binding sites of the GABA A5 receptor and may be useful as cognitive enhancers or for the treatment of cognitive disorders, for example Alzheimer's disease. The receptors of the main inhibitory neurotransmitter, gamma-aminobutyric acid (GABA), are divided into two main groups: (1) GABA A receptors, which are members of the ion channel receptor superfamily controlled by ligands and (2) GABA B receptors, which are members of the family of receptors fixed on protein G. The GABA A receptor complex, which is a heteropentameric protein polymer fixed on membrane, is composed mainly of subunits a, β and β. Currently a total of 21 subunits of GABA A receptors have been cloned and sequenced. Three types of subunits (a, ß and?) Are needed to construct recombinant GABA A receptors, which closely mimic the biochemical, electrophysiological and pharmacological functions of the native GABA A receptors, obtained from brain cells of mammals. There is strong evidence that the benzodiazepine binding site is located between subunits a and y. Among the recombinant GABA A receptors, alß2? 2 mimics many effects of the classical type I subtypes BzR, while the ion channels a2? 2? 2, a3? 2? 2 and a5? 2? 2 are referred to as type II BzR. It has been shown by McNamara and Skelton in Psychobiology 21: 101-108 that the β-CCM reverse agonist of the benzodiazepine receptor improves spatial learning in the Morris water maze. However, ß-CCM and other conventional benzodiazepine receptor inverse agonists are pro-convulsive or convulsive, which prevents their use as knowledge-enhancing agents in humans. In addition, these compounds are not selective for subunits of GABA A receptors, whereas an inverse agonist partially or wholly of a GABA A a5 receptor, which is relatively free of activity at the binding sites of GABA A receptors to and / or a2 and / oc < 3, may be used to make a drug that is useful for improving cognition and has reduced or no proconvulsive activity. It is also possible to use the inverse agonists of GABA A or 5 which are not free of activity at the binding sites of the GABA A receptors a and / or a2 and / or a3 but which are functionally selective for the subunits containing a5 . However, inverse agonists that are selective for the GABA A a5 subunits are preferred and are also relatively free of activity for the GABA A, a2 and a3 receptor binding sites. The objects of the present invention are compounds of formula I and their pharmaceutically acceptable salts, the preparation of the aforementioned compounds, the medicaments containing them and their manufacture as well as the use of the aforementioned compounds for the control or prevention of diseases , especially of diseases and disorders of the type mentioned above and for the manufacture of the corresponding medicaments. The most preferred indication according to the present invention is Alzheimer's disease. The following definitions of the general terms used in the present description apply regardless of whether the terms in question appear alone or in combination. As used here, the term "lower alkyl" denotes a straight or branched chain alkyl group, containing from 1-7 carbon atoms, preferably from 1-4, for example, methyl, ethyl, propyl, isopropyl, n-butyl, -butyl, t-butyl and the like. The term "lower alkoxy" denotes a lower alkyl group, defined above, linked through an oxygen atom. Examples of lower alkoxy groups are methoxy and ethoxy. The term "aryl" means an unsaturated carbon ring, for example a phenyl, benzyl or naphthyl group. A preferred aryl group is phenyl. The term "halogen" denotes chlorine, iodine, fluorine or bromine. The term "cycloalkyl" denotes a cyclic alkyl ring, having from 3 to 7 carbon atoms in the ring, for example, cyclopropyl, cyclopentyl or cyclohexyl. The term "heterocycloalkyl" means a 5- or 6-membered ring containing one to three heteroatoms, for example N, 0 or S atoms. Examples of these heterocycloalkyl groups are morpholinyl or tetrahydropyranyl as well as those groups that are specifically illustrated in examples that are described below. The term "heteroaryl" means a 5- or 6-membered aromatic ring, containing one to three heteroatoms, for example N, O or S atoms. Examples of such aromatic heteroaryl groups are pyridinyl, triazolyl, isoxazolyl, furanyl, thiophenyl, imidazolyl, oxazolyl or pyrazinyl. The term "pharmaceutically acceptable acid addition salts" embraces the salts with organic and inorganic acids, for example hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid , tartaric acid, methanesulfonic acid, p-toluenesulfonic acid and the like. Preferred are compounds, which have a binding activity (hKi) of less than 100 nM and are selective for the GABA A a5 subunits and are relatively free of activity at the binding sites of GABA A receptors a, a2 and a3. As mentioned above, the compounds of the invention are those compounds of formula I, in which: R 1 is hydrogen, halogen (preferably Cl and Br), hydroxy, lower alkyl (preferably methyl), benzyloxy or -0- (CH 2 ) - (CO) - 5- or 6-membered heteroaryl (preferably izoxazolyl) optionally substituted by aryl (preferably phenyl) and lower alkyl (preferably methyl); R2 is hydrogen, lower alkyl (preferably methyl or ethyl) or - (C0) -Ra; R3 is hydrogen, halogen (preferably Cl or Br), cyano, lower alkyl (preferably methyl or ethyl) or - (CO) -Ra; Ra is hydroxy, lower alkoxy (preferably methoxy or ethoxy), NR'R ", wherein R 'and R" are each independently hydrogen, cycloalkyl (preferably cyclopropyl), 5- or 6-membered heterocycloalkyl (preferably morpholinyl) or tetrahydropyranyl) or lower alkyl optionally substituted by cycloalkyl (preferably cyclopropyl), cyano, 5- or 6-membered heterocycle (preferably morpholinyl or tetrahydropyranyl) or 5- or 6-membered heteroaryl (preferably pyridinyl or furanyl); as well as the pharmaceutically acceptable acid addition salts thereof. In a certain embodiment of the compounds of formula I of the invention, R3 is hydrogen, for example the following compound: 3- (5-methyl-3-phenyl-isoxazol-4-yl) -imidazo [1,5-a] pyridine . In a certain embodiment of the compounds of formula I of the invention, R3 is - (CO) -R, where Ra is lower alkoxy or NR'R ", wherein R 'and R" are each independently hydrogen, cycloalkyl, 5- or 6-membered heterocycloalkyl or lower alkyl optionally substituted by cycloalkyl, cyano, 5- or 6-membered heterocycloalkyl or 5- or 6-membered heteroaryl, for example the following compounds: 3- (5-methyl-3-phenyl-isoxazole-4) -yl) -imidazo [1, 5-a] -pyridine-6-carbonitrile and 3- (5-methyl-3-phenyl-isoxazol-4-yl) -imidazo [1,5-a] pyridine-6-carboxylate of methyl. The present compounds of formula I and their pharmaceutically acceptable salts can be prepared by methods known in the art, for example by the process described below, which comprises reacting a compound of formula with thionyl chloride to obtain a compound of formula which can then be reacted with a compound of formula IV to obtain a compound of formula V which can then be reacted with a dehydrating agent, for example phosphorus oxychloride, in a suitable solvent, for example dichloroethane, to obtain a compound of formula I wherein R, R and R are as described above, and if desired, convert a compound of formula I to a pharmaceutically acceptable salt. In the following reaction schemes, the process for obtaining the compounds of formula I is described in greater detail. Reaction scheme 1 The chloride of 5-methyl-3-phenyl-isoxazole-4-carboxylic acid III is treated with the hydrochloride salt of 6-aminomethyl-nicotinonitrile IV (not shown in scheme I) in a mixture of ethyl acetate and water. at 0 ° C, obtaining the intermediate amide Va, which can be heated under reflux with the phosphorus oxychloride in dichloroethane to obtain the compound of formula Ia. Reaction scheme 2 Alternatively, the 5-methyl-3-phenyl-isoxazole-4-carboxylic acid chloride III can be treated with the methyl ester of the 6-aminomethyl-nicotinic acid IV (not shown in scheme 2) in a mixture of ethyl acetate and water at 0 ° C, obtaining the intermediate amide Vb, which can be heated under reflux with phosphorus oxychloride in dichloroethane to obtain the compound of formula Ib. The ester can then be saponified with lithium hydroxide in a mixture of methanol, THF and water, obtaining the acid of formula Ic, which can be activated following standard procedures with l-ethyl-3- (3'-dimethylaminopropyl) carbodiimide, 1-hydroxybenzotriazole , triethylamine and then reacted with an amine (RNH2) to be chosen, to obtain the compounds of the formula Id. As mentioned above, the compounds of formula I and their pharmaceutically usable salts possess valuable pharmacological properties. It has been found that the compounds of the present invention are ligands of GABA A receptors that contain the a5 subunit and therefore, are useful for therapy in which knowledge improvement is required. The compounds are investigated in accordance with the test procedures described below. Membrane preparation and binding assay The affinity of the compounds with the GABA A receptor subtypes is measured by competition for binding, of flumazenil [3 H] (85 Ci / mmol, Roche), with HEK293 cells expressing rat receptors (transfected stably) or human receptors (transfected provisionally) of composition alß3? 2, a2? 3? 2, a3? 3? 2 and a5? 3? 2. The cell pellets are suspended in Krebs-tris buffer (4.8 mM KCl, 1.2 mM CaCl2, 1.2 mM MgCl2, 120 mM NaCl, 15 mM Tris, pH 7.5, binding assay buffer), homogenized in the Polytron during about 20 seconds on ice and centrifuged for 60 min at 4 ° C (50000 rpm; Sorvall, rotor: SM24 = 20,000 rpm). The pellets of the cells are again suspended in Krebs-tris buffer and homogenized in the Polytron for about 15 seconds on ice. The protein is determined (Bradford method, Bio-Rad) and aliquots of 1 ml are prepared and stored at -80 ° C.

The radioligand binding assays are carried out in a volume of 200 μl (96-well plates) containing 100 μl of cell membranes, flumazenil [3 H] at a concentration of 1 nM for subunits a, a2, a3 and 0, 5 nM for a5 subunits and the compound to be tested in a range of 10 - 10 ~ 3 X 10"6 M. Nonspecific binding is defined with diazepam icr5 M and typically represents less than 5% of the total binding. Samples to be tested are incubated until equilibrium for 1 hour at 4 ° C and collected on GF / C uni-filters (Packard) by filtration using a Packard harvester and washing with ice-cold wash buffer (50 mM Tris; , 5) After drying, the radioactivity retained in the filter is detected by liquid phase scintillation counting.The Ki values are calculated using the Excel-Fit program (Microsoft) and are the average of two determinations. attachments are tested in the method described above and found The preferred compounds possess a Ki-value of fumazenyl shift [3H] of the a5 subunits of the GABA A receptor of the rat of 100 nM or less. In a preferred embodiment, the compounds of the invention are selective for the binding of the a5 subunit in relation to the a, a2 and a3 subunits. The compound of example 1, called 3- (5-methyl-3-phenyl-isoxazol-4-yl) -imidazo [1,5-a] pyridine, has a Ki value [nM] ha5 of 77.9 nM. The compounds of formula I and their pharmaceutically usable acid addition salts can be used as medicaments, for example in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, eg in the form of tablets, coated tablets, dragees, hard or soft gelatine capsules, solutions, emulsions or suspensions. However, the administration can also be carried out rectally, for example in the form of suppositories or parenterally, eg in the form of injectable solutions. The compounds of formula I and their pharmaceutically usable acid addition salts can be processed with pharmaceutically inert, organic and inorganic excipients for the production of tablets, coated tablets, dragees and hard gelatine capsules. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts, etc. they can be used as excipients eg for tablets, dragees and hard gelatine capsules. Suitable excipients for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols, etc. Suitable excipients for the manufacture of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose, etc. Suitable excipients for injectable solutions are, for example, water, alcohols, polyols, glycerin, vegetable oils, etc. Convenient excipients for suppositories are, for example, natural or hardened oils, waxes, semi-liquid fats, semi-liquid polyols or liquid polyols, etc. The pharmaceutical preparations may also contain preservatives, solubilizers, stabilizers, humectants, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They may also contain other therapeutically valuable substances. The dosage can vary within wide limits and should obviously conform to the individual requirements of each particular case. In general, in the case of oral administration, a daily dosage of 10 to 1000 mg of a compound of general formula I may be appropriate, although the above-mentioned upper limit may be exceeded, if necessary. The following examples illustrate the present invention without limiting it. All temperatures are indicated in degrees centigrade. Example A Tablets of the following composition are manufactured by a usual method: mg / tablet active substance 5 lactose 45 corn starch 15 microcrystalline cellulose 34 magnesium stearate 1 tablet weight 100 Example B Capsules of the following composition are manufactured: mg / capsule active substance 10 lactose 155 corn starch 30 talcum 5 weight packed in the capsule 200 In a mixer the active substance, lactose and corn starch are first mixed and then passed to a crushing machine. The mixture is returned to the mixer and the talc is added and mixed thoroughly. The mixture is packaged with a machine in hard gelatin capsules. Example C Suppositories of the following composition are manufactured: mg / sup. active substance 15 suppository mass 1285 total 1300 In a glass or steel container, the mass of the suppository is melted, mixed thoroughly and cooled to 45 ° C. The finely powdered active substance is then added and stirred until its total dispersion is achieved. The mixture is poured onto a suppository mold of the appropriate size, allowed to cool, then the suppositories are removed from the molds and individually packaged in wax paper or metal foil. The following examples 1-5 are provided to illustrate the invention. They should not be considered as limiting the scope of the invention, since they are merely representative of it. Example 1 5- (5-Methyl-3-phenyl-isoxazol-4-yl) -imidazo [1,5-a] pyridine a) (pyridin-2-ylmethyl) -amide of 5-methyl-3-phenyl- Isoxazole-4-carboxylic acid It is refluxed for 3 h. a mixture of (4.06 g, 20 mmol, commercial product) of 5-methyl-3-phenyl-isoxazole-4-carboxylic acid and (5 ml) of thionyl chloride. Evaporation of all the volatile components gives (4.4 g, 93%) of the 5-methyl-3-phenyl-isoxazole-4-carboxylic acid chloride as a yellow oil, which is used without further purification in the next reaction. To a mixture of an aqueous solution of (0.182 g, 1.68 mmol) of 2-picolylamine in (2 ml) of water and (4 ml) of ethyl acetate, is added in one portion (362 mg, 4.2 mmol) of sodium bicarbonate. It is then added dropwise with vigorous stirring (0.31 g, 1.4 mmol) of 5-methyl-3-phenyl-isoxazole-4-carboxylic acid chloride in (2 mL) of ethyl acetate by cooling with an ice bath to maintain the temperature at 0 ° C. After the addition is complete, the reaction mixture is stirred at room temperature for 18 h. The resulting solution is then diluted with ethyl acetate. The organic phase is separated and the aqueous phase is extracted with ethyl acetate. The extracts were combined, washed with brine, dried over sodium sulfate and concentrated, yielding (0.38 g, 93%) of the title compound as a white solid. MS: m / e = 294.1 [M + H] +. b) 3- (5-methyl-3-ferdl-isoxazol-4-yl) -i dazo [1, 5-a] pyridine To a solution of (0.293 g, 1 mmol) of (pyridin-2-ylmethyl) - 5-Methyl-3-phenyl-isoxazole-4-carboxylic acid amide in (5 ml) of dichloroethane is added with a syringe (0.47 ml, 5 mmol) of phosphorus oxychloride and the resulting mixture is heated under reflux for one hour. night. After cooling to room temperature, the mixture is diluted with dichloromethane. Then, (15 ml) of a saturated solution of cold sodium bicarbonate are added slowly and the mixture is stirred vigorously for 15 min. The organic phase is separated and the aqueous extracted with dichloromethane. The extracts are combined, washed with water, dried with sodium sulphate and evaporated. Purification by preparative HPLC through reverse phase [0.1% aqueous ammonia (25%)] affords (0.13 g, 47%) of the title compound as an orange solid. MS: m / e = 276.1 [M + H] +. Example 2 3- (5-Methyl-3-phenyl-isoxazol-4-yl) -imidazo [1,5-a] pyridine-6-carbonitrile a) (5-cyano-pyridin-2-ylmethyl) -amide of the acid 5-methyl-3-phenyl-isoxazole-4-carboxylic acid. As described in the example, (0.266 g, 1.2 mmol) of 5-methyl-3-phenyl-isoxazole-4-carboxylic acid chloride are converted, using ( 0.17 g, 1 mmol) of the 6-aminomethyl-nicotinonitrile hydrochloride salt in place of 2-picolylamine, to obtain (296 mg, 93%) of the title compound as a white solid. MS: m / e = 319.0 [M + H] +. a) 3- (5-methyl-3-phenyl-isoxazol-4-yl) -imidazo [1, 5-a] pyridine-6-carbonitrile In the manner described in Example Ib, (5-methyl-3-phenyl-5-methyl-3-phenyl) -simple (0.12 g, 0.377 mmol) of (5-cyano-pyridin-2-ylmethyl) -amide is converted isoxazole-4-carboxylic acid, to obtain (60 mg, 44%) of the title compound as a slightly yellow solid. MS: m / e = 301.3 [M + H] +. Example 3 3- (5-Methyl-3-phenyl-isoxazol-4-yl) -imidazo [1,5-a] pyridine-6-methyl carboxylate a) 6-. { [(5-methyl-3-phenyl-isoxazole-4-carbonyl) -amino] -methyl} Methyl nicotinate As described in the example, (5 g, 2.26 mmol) of 5-methyl-3-phenyl-isoxazole-4-carboxylic acid chloride are converted, using (313 mg, 1.88 mmol) of 6-aminomethyl Methyl nicotinate (J. Med. Chem. 45, 5005-5022, 2002) in place of 2-picolylamine, to obtain (0.56 g, 85%) of the title compound as a white solid. MS: m / e = 352.0 [M + H] +. b) methyl 3- (5-methyl-3-phenyl-isoxazol-4-yl) -imidazo [1,5-a] pyridine-6-carboxylate In the manner described in Example Ib, they are converted (0.56 g, 1.6 mmoles) of 6-. { [(5-methyl-3-phenyl-isoxazole-4-carbonyl) -amino] -methyl} Methyl nicotinate, in (0.266 g, 50%) of the title compound, which is obtained as a yellow solid. MS: m / e = 334.3 [M + H] +.

Example 4 3- (5-Methyl-3-phenyl-isoxazol-4-yl) -imidazo [1,5-a] pyridine-6-carboxylic acid cyclopropylmethyl amide a) 3- (5-methyl-3-) acid phenyl-isoxazol-4-yl) -imidazo [1,5-a] pyridine-6-carboxylic acid To a suspension of (0.25 g, 0.75 mmol) of 3- (5-methyl-3-phenyl-isoxazol-4-yl) ) - methyl imidazo [1,5-a] pyridine-6-carboxylate in (6 ml) of water and (3 ml) of methanol are added in one portion (0.21 g, 5 mmol) of lithium hydroxide monohydrate. The reaction mixture is stirred at room temperature for 4.5 h. After evaporation (removal of methanol), the remaining mixture is extracted with diethyl ether. The aqueous phase is then acidified to pH ~ 5 with aqueous HC1 (2N). The slightly yellow precipitate is collected by filtration and washed with water, obtaining (0.2 g, 83%) of the title compound as a slightly yellow solid. MS: m / e = 320.1 [M + H] +. b) 3- (5-Methyl-3-phenyl-isoxazol-4-yl) -imidazo [1,5-a] pyridine-6-carboxylic acid cyclopropylmethyl-amide is stirred at room temperature overnight containing a solution containing (58 mg, 0.18 mmol) of 3- (5-methyl-3-phenyl-isoxazol-4-yl) -imidazo [1,5-a] pyridine-6-carboxylic acid, (52 mg, 0.27 mmol) of -ethyl-3- (3'-dimethylaminopropyl) carbodiimide, (24 mg, 0.18 mmol) of 1-hydroxybenzotriazole, (60 μl, 0.45 mmol) of triethylamine and (20 mg, 0.27 mmol) of cyclopropyl-methylamine in (1 ml) ) of DMF. Purification by preparative HPLC through reverse phase [0.1% aqueous ammonia (25%)] affords (34 mg, 50%) of the title compound as a light yellow solid. MS: m / e = 373.3 [M + H] +. Example 3 (3- (5-methyl-3-phenyl-isoxazol-4-yl) -imidazo [1,5-a] pyridine-6-carboxylic acid tetrahydro-pyran-4-yl) -amide As described in Example 4b is converted (58 mg, 0.18 mmol) of 3- (5-methyl-3-phenyl-isoxazol-4-yl) -imidazo [1,5-a] pyridine-6-carboxylic acid, using (28 mg , 0.27 mmol) of tetrahydropyran-4-ylamine in place of cyclopropyl methylamine, in (40 mg, 55%) of the title compound, which is obtained as a slightly yellow solid. MS: m / e (ESI) = 403.3 [M + H] +. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (13)

1. CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. Derivatives of aryl-isoxazol-4-yl-imidazo [1,5-a] pyridine of formula I: characterized in that: R1 is hydrogen, halogen, hydroxy, lower alkyl, benzyloxy or -O- (CH2) - (CO) -sheteroaryl 5- or 6-membered optionally substituted by aryl and lower alkyl; R2 is hydrogen, lower alkyl or - (CO) -Ra; R3 is hydrogen, halogen, cyano, lower alkyl or - (CO) -Ra; Ra is hydroxy, lower alkoxy, NR'R ", wherein R 'and R" are each independently hydrogen, cycloalkyl, 5- or 6-membered heterocycloalkyl or lower alkyl optionally substituted by cycloalkyl, cyano, 5- or 6-membered heterocycloalkyl or heteroaryl of 5 or 6 members; as well as pharmaceutically acceptable acid addition salts thereof.
2. 2. The aryl-isoxazol-4-yl-imidazo [1,2-a] pyridine derivatives of formula I according to claim 1, characterized in that R3 is hydrogen.
3. 3. The aryl-isoxazol-4-yl-imidazo [1,2-a] pyridine derivatives of formula I according to claim 2, characterized in that they are: 3- (5-methyl-3-phenyl-isoxazol-4-, yl) -imidazo [1,5-a] pyridine.
4. 4. The aryl-isoxazol-4-yl-imidazo [1,2-a] pyridine derivatives of formula I according to claim 1, characterized in that R3 is - (CO) -Ra, in which Ra is lower alkoxy or NR'R ", wherein R 'and R" are each independently hydrogen, cycloalkyl, 5- or 6-membered heterocycloalkyl or alkyl lower optionally substituted by cycloalkyl, cyano, 5- or 6-membered heterocycloalkyl 0 heteroaryl of 5 or 6 members.
5. 5. The aryl-isoxazol-4-yl-imidazo [1,2-a] pyridine derivatives of formula I according to claim 4, characterized in that they are: 3- (5-methyl-3-phenyl-isoxazole-4) - il) -imidazo [1,5-a] pyridine-6-carbonitrile and 3- (5-methyl-3-phenyl-isoxazol-4-yl) -imidazo [1,5-a] pyridine-6-carboxylate of methyl.
6. 6. A process for obtaining compounds of formula 1 according to claim 1, characterized in that it comprises reacting a compound of formula II with thionyl chloride to obtain a compound of formula III which is then reacted with a compound of formula IV to obtain a compound of formula V which is then reacted with a dehydrating reagent, in a suitable solvent, to obtain a compound of formula I in which R1, R2 and R3 have the meanings defined above, and, if desired, convert a compound of formula I to a pharmaceutically acceptable salt.
7. 7. The process according to claim 6, characterized in that the dehydrating reagent is phosphorus oxychloride and the solvent is dichloroethane.
8. A compound of formula I according to any one of claims 1 to 5, characterized in that it is prepared by a process according to any of claims 6 or 7 or by an equivalent method.
9. 9. A medicament characterized in that it contains one or more compounds of formula I according to any one of claims 1 to 5 and pharmaceutically acceptable excipients.
10. 10. A medicament according to claim 9, characterized in that it is for the treatment of diseases related to the GABA A5 subunit, selected from cognitive improver or cognitive disorders.
11. 11. A medicine according to claim 10, characterized in that it is for the treatment of Alzheimer's disease.
12. 12. The use of a compound of formula I according to any of claims 1 to 5, for the manufacture of a medicament intended for cognitive enhancer or for the treatment of cognitive disorders.
13. 13. The use of a compound of formula I according to any of claims 1 to 5 for the manufacture of a medicament for the treatment of Alzheimer's disease.