MXPA99004771A - Pyridin-2-yl-methylamine derivatives, method of preparing and application as medicine - Google Patents

Abstract

The invention concerns novel pyridin-2-yl-methylamine derivatives of formula (I) in which:u represents a hydrogen atom or a methyl radical;v represents a hydrogen atom or a chlorine atom or a methyl radical;w represents a hydrogen atom or a fluorine atom or a methyl radical;x represents a hydrogen atom or a fluorine atom;y represents a chlorine atom or a methyl radical;z represents a hydrogen atom or a fluorine atom or a chlorine atom or a methyl radical;A represents a hydrogen atom or a fluorine atom or a chlorine atom;a C 1-C 5 alkyl radical;a fluoroalkyl radical;a cyclopropyl radical;an aromatic heterocyclic group with 5 chains;an alkoxy or alkythio group;an amine group;an amino cyclic group;an alkoxycarbonyl group. These compounds are useful as medicine in particular as antidepressant or analgesic.

Description

DERIVATIVES OF PIRIDIN-2-IL-METHYLAMINE. METHOD OF PREPARATION AND APPLICATION AS A MEDICINE Serotonin (5-hydroxytryptamine, 5-HT) is a neurotransmitter and a neuromodulator of the central nervous system, which exerts its multiple physiological functions by interaction with specific 5-HT receptors. These 5-HT receptors have been grouped into several main classes. Among those major classes, the 5-HT1 class comprises receptors characterized by a high affinity for serotonin. The class 5-HT1, in turn, is divided into a 0 subclass of receptors whose pharmacological characteristics and whose regional distributions in the central nervous system are different. Clinical studies of compounds that have an agonist activity for the 5-HT1A subtype have shown that 5-HT1A agonists were effective in the treatment of anxiety (J. Clin. Psychiatry, 1987, 48 (12 5 suppl.) 3- 6; Clin Psychopharma, 8, 1993, 8, 173-6), of depression (J. Clin. Psychopharmacol, 1990, 10 (3 suppl.), 67-76; (J. Clin. Psychiatry, 1991 , 52, 217-20), of compulsive-obsessive disorders (Am. J. Psychiatry, 1991, 148, 127-9), of panic attacks (J. Clin. Psychopharmacol., 1993, 13, 145-9), of sleep disorders (Psychopharmacol., 1995, 117, 186-92) and alcohol abuse (J. Clin. or Psychopharmacol., 1989, 9, 379-80) Animal studies have shown that agonists 5- HT1A possess analgesic properties (Eur. J. Pharmacol., 1996, 295, 181-8), antiaggressive (Neurosci. Biobehav. Rev., 1994, 18, 325-38) and antiemetics 1995, 52, 571-5) It has also been reported that compounds having a 5-HT 1A agonist activity are capable of being useful in the treatment of disorders in sexual behavior (Behavioural Pharmacol., 1995, 6, 276-82 ), to regulate food intake (Int Clin Clinical Psychopharmacol., 1994, 9, 7-17) and to regulate gastric secretion (J. Pharmacol. Exp. Ther., 1995, 272, 832-7). The antihypertensive action of 5-HT 1A agonists, by means of a central mechanism, is recognized (Trends Pharm, Sci., 1990, 11, 95-6); Fundam. Clin. Pharmacol., 1993, 7, 499-511); Additionally, the agonists of -HT1A have been shown to have neuroprotective properties in models of local and global ischemia in rodents (Brain Research 1993, 630, 10-20; Arch. Int.

Pharmacodyn. Ther., 1995, 329-347-59). In vitro studies also tend to implicate 5HT-1A receptors in the stimulation of lymphocyte proliferation (INPHAR A®, August 26, 1995, 10; Life Sciences, 57, 2197-203). Given the substantial therapeutic potential of the compounds, related to the agonist activity for the 5-HT1A subtype receptors, the discovery of new structures possessing properties of the 5-HT1A agonist is highly desirable. The inventors have discovered that various compounds derived from pyridin-2-yl-methylamine have agonist activity towards the central receptor 5-HT1 A. Therefore, the present invention relates to new compounds corresponding to the general formula (I): wherein: u represents a hydrogen atom or a methyl radical, provided that when u is a methyl radical, then v and w represent a hydrogen atom; v represents a hydrogen atom or a chlorine atom or a methyl radical, provided that when v represents a chlorine atom or a methyl radical, then u and w represent a hydrogen atom; w represents a hydrogen atom or a fluorine atom or a methyl radical, provided that when w represents a fluorine atom or a methyl radical, then u and v represent a hydrogen atom; x represents a hydrogen atom or a fluorine atom; and represents a chlorine atom or a methyl radical; z represents a hydrogen atom or a fluorine atom, or a chlorine atom or a methyl radical; A represents: a hydrogen atom or a fluorine atom or a chlorine atom; - an alkyl radical of 1 to 5 carbon atoms, that is to say, a straight or branched chain saturated aliphatic hydrocarbon radical containing 1 to 5 carbon atoms, such as methyl, ethyl, propyl, butyl, pentyl, isopropyl, 1-methylethyl, 1-methylpropyl, 1-methylbutyl, 2-methylpropyl, -methylbutyl or 3-methylbutyl, 1-ethylpropyl, 2-ethylpropyl; - a fluoroalkyl radical, such as monofluoromethyl (-CH2F) or difluoromethyl (-CHF2), or trifluoromethyl (-CF3), or 1-fluoro-1-ethyl (-CHFCH3) or 1, 1-difluoro-1-ethyl (-CF2CH3 ); - a cyclopropyl or cyclobutyl or cyclopentyl radical; - a 5-membered substituted or unsubstituted aromatic heterocyclic group containing 1, 2, 3 or 4 heteroatoms, selected from nitrogen, oxygen and sulfur; however, no more than one oxygen and / or sulfur atom is present in heterocycle A. Preferably, the aromatic heterocyclics are: furan-2-yl (O.CH: CH.CH: C-) or furan -3-yl (CH: CH.O.CH: C-) or 1 H-pirtol-2-lll (NH-CH: CH.CH: C-) or 1H-pyrrol-3-yl (CH: CH. NH.CH:C-) or 1-methyl-pyrrol-2-yl (N (CH3) .CH: CH.CH: C-) or 1-methyl-pyrrol-3-yl (CH: CH.N (CH3 ) .CH: C-) or thiophen-2-yl (S.CH.CH.CH: C-) or thiophen-3-yl (CH: CH.S.CH: C-) or pyrazol-1-yl (N: CH.CH: CH.N-), or 1 Hp? Razol-3-yl (CH: CH.NH.N: C-) or 1H-pyrazol-4-yl (CH: N.NH.CH : C-) or 1-methyl-p -razol-3-yl (CH: CH.N (CH3) .N: C-) or m? dazol-1-? lo (CH N CH CH N-) or 1H-? m? dazol-2-? lo, (NH CH CH N C-) or 1H-? m? dazol-4-? lo? , (N CH NH CH C-) or oxazole-2-? Lo, (O CH CH N C-) or oxazole-4-? Lo, (N CH O CH C-), or oxazole-5-? Lo, (O CH N CH C-) or? Soxazol-5-? Lo, (ON CH CH C-) or isoxazol-4-? Lo, (CH NO CH C-) or? Soxazol-3-? Lo, (CH CH ON C-) ot? Aol-2-? Lo, (S CH CH N C-) ot? Aol-4-? Lo, (N CH S CH C-) ot? Azol-5-? Lo, (S CH N CH C-) or? Sot? Azole-5-? Lo, (SN CH CH C-) or? Sot? Azole-4-? Lo (CH NS CH C-) or? Sot? Azole-3? lo, (CH CH SN C-) or [1, 2,4] tnazol-3-? lo, (N CH NH N C-) or 1H- [1,2,4] tpazol-3-? lo, ( N CH NH N C-) or [1,2,4] oxad? Azole-3-? Lo, (N CH ON C-) or [1, 2,4] oxad? Azole-5-? Lo, (ON CH N C-) or 5-met? L- [1, 2,4] oxad? Azole-3-? Lo, (NC (CH3) ON C-) or 1 H-tetrazol-5? Lo, (NH NNN C-) - an alkoxyl group (R ??-) or alkylthio (RiS-), in which the radical Ri represents * an alkyl radical of 1 to 5 carbon atoms, as defined above; * a monofluoromethyl or trifluoromethyl radical; * a cyclopropyl or cyclobutyl or cyclopentyl radical, - an amino group of type II:, R2 - (II) R3 wherein R2 and 3, which are identical or different, represent hydrogen or an alkyl radical of 1 to 5 carbon atoms , as defined above, or a cyclopropyl or cyclobutyl radical, or a trifluoromethyl radical; - a saturated cyclic amino group, of type III.

(CH2) n N- where "n" can represent integers 1 or 2; - an alkoxycarbonyl group, preferably a methoxycarbonyl group (CH3OCO-) or an ethoxycarbonyl group (CH3CH2OCO-); as well as the addition salts of the compounds of the general formula (I), with inorganic acids or pharmaceutically acceptable organic acids. All the compounds of this invention were compared with Buspirone, 4-butyl-4-methyl-1 - [4- (4-pyrimid-2-yl-piperazin-1-yl) -but] -1] -piperidino-2 , 6-dione, the only HT1A receptor agonist currently available in the trade, and with 8-OH-DPAT, 7-dipropylamino-5,6,7,8-ttrahydronaphthalen-1 -ol, which is the standard 5-HT 1 A agonist. Like Buspirone and 8-OH-DPAT, the compounds of the invention possess high affinity towards 5-HT 1A receptors. However, the compounds of the invention, in general, show in vitro selectivity, which is higher than that of Buspirone and of 8-OH-DPAT, in relation to the dopaminergic receptors of subtype D2. The electivity of 5-HT1A against D2 is defined in the present application, as the ratio of the affinity constants (Ki) D2 / (Ki) 5-HT1A. Therefore, the compounds of the invention have less undesirable side effects than Buspirone and 8-OH-DPAT, in particular, the neurological and / or endocrine disorders caused by the occupation of subtype D2 receptors (CNS Drugs, 1996, 5 (Suppl 1), 21-35). It has been possible to demonstrate the agonist activity for 5-HT1A of several compounds of the invention, after oral administration in rats. The agonist activity for 5-HT1A of the compounds in question, in vivo, in this case in general it is greater than that of Buspirone and 8-OH-DPAT. The central activity of the compounds of this invention and of the standards in rats, due to their ability to cause retraction of the lower lip of the animal, was evaluated as a sensitive and specific marker for an agonist activity for central 5-HT1A (Pharmacol, Biochem. Behav., 1989, 33, 821-27). Therefore, several compounds of the invention possess high affinity for the 5-HT1A receptors in vitro and show agonist activity on these receptors, in vivo. Because of this, the compounds of the invention are considered capable of being useful in the treatment of the many pathologies that involve serotoninergic dysfunctions, such as anxiety, depression, compulsive-obsessive disorders, panic attacks, aggression, alcohol abuse, sexual disorders, sleep disorders, pain perception, vomiting, regulation of gastric secretion, regulation of food intake, immunological diseases, vascular and cerebrovascular disorders, such as high blood pressure or migraine. The invention also relates to the addition salts and optionally to the hydrates of the addition salts of the compounds of the general formula (1) with pharmaceutically acceptable inorganic acids or organic acids. The object of the invention is also pharmaceutical compositions containing, as an active ingredient, at least one of the derivatives of the general formula (I) or one of its salts or hydrates of its salts, in combination with one or more excipients, adjuvants or pharmaceutically acceptable vehicles. By way of example, inclusion complexes can be mentioned, in particular the inclusion complexes formed by the compounds of the invention with beta-cyclodextrins. The pharmaceutical compositions according to the invention can be compositions that can be administered orally, nasally, sublingually, rectally or parenterally. In general it is advantageous to formulate said pharmaceutical compositions in unit dosage form. Each dose then comprises a predetermined amount of the active ingredient, combined with the suitable vehicle, excipients and / or adjuvants; the quantity is calculated, in order to obtain a certain therapeutic effect. By way of example, a dosage unit form that can be administered orally is formed by tablets, gelatin capsules, granules, powders and oral solutions or suspensions. Formulations that are appropriate for the selected mode of administration are known and are described, for example, in Remington, The Science and Practice of Pharmacy, 19th edition, 1995, Mack Publishing Company and, therefore, can be easily prepared by art experts. It is known that the dose varies from one individual to another, depending on the nature and severity of the condition, the route of administration selected, the weight, age and sex of the patient; consequently, effective doses will have to be determined as a function of these parameters, by a specialist in this field. As a guideline, the effective doses can vary between 0.001 mg / kg and 100 mg / kg / day. The compounds of the general formula (I) can exist in various tautomeric forms. These tautomeric forms, although they are not explicitly reported in the present application, in order to simplify the graphic representation of the schemes, nevertheless they are included in the field of application of the invention. Finally, the invention extends to the process for the preparation of the pyridin-2-yl-methanamine derivatives of the general formula (I).

The chemical process used for the preparation of the compounds of the general formula (I) depends, in particular, on the nature of the substituents A and x. The compounds of the formula (la) in which: - x is a hydrogen atom or a fluorine atom; - A, u, v, w, "and" and z have the same meanings as before; they can be obtained by means of one of the two procedures (a) and (b) described in scheme A.

SCHEME A According to process (a), the compound of the formula (la) is prepared by means of a conventional reductive amination reaction between the aldehyde of the formula (IV) and the primary amine of the formula (V). The expression "a conventional reductive amination reaction" means that the aldehyde (IV) and the amine (V) are reacted in the appropriate solvent, and then the mixture of reactants (IV) and (V) is exposed to the agent reducer, according to a method well known to persons skilled in the art. The reducing agent in question can be a simple or complex boron hydride, such as, for example, sodium borohydride, potassium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride.

According to process (b), the condensation between the azido derivative of the formula (VI) and the aldehyde of the formula (IV), in the presence of tpphenylphosphine or tri-n-butylphosphine in methanol, leads to the imine intermediate of the formula (VII) The imine of the formula (VII) is not purely isolated, but is reduced in situ to the amine of the formula (la) by means of a simple boron hydride or complex, such as, for example, sodium borohydride or borohydride of potassium The term "in situ" means that the imine of the formula (VII) is not subjected to any purification procedure, but the mixture of the reactants (IV), (VI) and (Ph) 3P or (nBu) 3P, in the appropriate solvent, it is used directly in the reduction step. The compounds of the formula (Ib), specific cases of the compounds of the formula (la) in which: - x is a hydrogen atom, - A, u, v, w, "and" yz are as defined above , can be prepared according to the method described in scheme B.

SCHEME B The condensation between p-peridin-4-l-methylamine, which can be obtained commercially, and the aldehyde of the formula (IV) in a solvent, such as benzene, toluene, cyclohexane or dichloromethane, at room temperature or the reflux temperature of the solvent, with removal of the water formed with the aid of a drying agent, or by azeotropic entrainment, leads to the imine of the formula (Vlll). The imine of the pure uninsulated formula (Vlll) is then acylated by means of the appropriate acid chloride, which can be obtained commercially, or which is prepared according to a conventional method from the corresponding carboxylic acid, in order to give the acylated imine of the formula (IX). The acylation reaction in question is carried out in the presence of a base, generally a tertiary amine, in order to trap the hydrochloric acid liberated during the reaction. The acylated imine of the formula (IX), which is not purely isolated, is then converted to the amine of the formula (Ib) by reduction: - a protic solvent or a mixture of solvents, of which at least one of the constituents is a protic solvent, by means of sodium borohydride, potassium borohydride or sodium cyanoborohydride; - or in an aprotic solvent, by means of sodium triacetoxyborohydride. The reaction sequence which is described in Scheme B can be carried out, if desired, according to a "single vessel" technique. The term "a single container" means that the successive steps are carried out in a single container, with no other manipulation than the sequential addition of the reagents, the change of solvent or the addition of a cosolvent The compounds of the formula (le), specific cases of the compounds of the formula (la) in which: - u and v represent a hydrogen atom, - w is a hydrogen atom or a methyl radical, - x is a hydrogen atom or a fluorine atom, -? and z have the same meaning as before, - A is selected from: "a radical pyrrol-1-yl, pyrazole-1-yl, β-midazole-1α or [1, 2,4] triazole-1- lo, an amino group of type (II) or a cyclic amino group of type (III) can be prepared according to the procedure summarized in scheme C SCHEME C The compounds of the formula (le) can be obtained directly from the compounds of the formula (la), in which the group A is a fluorine atom or a chlorine atom, by refinishing with an appropriate reagent of the type ( HA) or (Na + A "). This procedure, when applicable, has the advantage of avoiding a protective step and a deprotection step during the preparation of the aldehyde of the formula (IV) The reagent symbolized by (HA) represents a commercially available primary or secondary amine, such as methylamine, ethylamine, n-propylamine, isopropylamine, isobutylamine, dimethylamine, N-ethylmethylamine, N-methypropylamine, diethylamine, cyclobutylamine, cyclopropylamine, azetidine or pyrrolidine. The reaction between the compound of the formula (la: A = F or Cl) and the reagent (HA), which gives the compound of the formula (le), wherein A is an amino group of type (II) or a cyclic amino group of type (III), is generally carried out in the presence of an excess of the reagent (HA) at a temperature between 25 ° C and 150 ° C. The ionized reagent (Na * A ") symbolizes the sodium salt of the reagent (HA) obtained after removing a proton by means of a strong base, such as, for example, sodium hydride. The reagents advantageously used in the ionized form (Na + A ") for the substitution of the fluorine or chlorine atom present in the compound (la: A = F or Cl) are the sodium salts of pyrrole, pyrazole, midazole or [1, 2,4] triazole The reaction between the compounds of the formula (la: A = F or Cl) and the reactant (Na + A "), which leads to the compound of the formula (le) in which A is a pyrrol-1-yl, pyrazol-1-yl, imidazol-1-yl or [1, 2,4] triazol-1-yl radical, generally carried out at a temperature between 25 ° C and 100 ° C, in a polar aprotic solvent. The compounds of the formula (la), (Ib) and (le) which constitute the series of compounds of the formula (I) are purified according to one or more methods selected from: crystallization techniques, liquid phase chromatography, extraction and filtration. Then, if desired, they can be: • salified by means of a pharmaceutically acceptable acid; • be used in the formation of an inclusion complex. The preparation of the primary amines of the formula (V), as well as the azido derivatives of the formula (VI), is detailed in scheme D.

SCHEME D The epoxide of the formula (XI) is obtained from the acylated piperidone of the formula (X) according to a method similar to the method described by Popp (J. Heterocyclic Chem., 1978, 15, 675-76). When the epoxide of the formula (XI) is treated with an excess of the hydrogen fluoride-pyridine complex, it leads to the regioselectivity of the fluorohydrin of the formula (Xll) (Synthesis, 1994, 225-38). The primary alcohol function of the fluorohydrin of the formula (Xll) is then activated in the form of a sulfonic acid ester, to give the compound of the formula (XIII), in which "LG" symbolizes a 4-methylphenylsulfonyloxy, methanesulfonyloxy group or trifluor-O-methanesulfonyloxy. According to the route (c), the reaction of the derivative of the formula (XIII) with potassium phthalimide gives the compound of the formula (XIV) which, by treatment with an excess of hydrazine hydrate, ethylenediamine or ethanolamine, gives The primary amine of the formula (V) results. According to the route (d) the reaction of the derivative of the formula (XIII) with an alkali metal azide, for example, sodium or lithium azide, gives the compound of the formula (VI) which, in turn, can : • be used in a condensation of the Staudinger-aza-Wittig type, as described above, scheme A, procedure (b); • or be converted to the primary amine of the formula (V) by reduction of the azido function by means of a metal salt, such or, for example, stannous chloride in a protic solvent or a mixture of protic solvents route (e) The process for the preparation of the aldehydes of the formula (IV) depends on the nature of the group A and on the nature of the substituents u, vyw IV The aldehyde of the formula (IVa) can be obtained, in which the substituents u, v and w represent a hydrogen atom, • Group A is a fluorine atom can be obtained by the procedure that is described in scheme E SCHEME E The aldehyde of the formula (IVa) is prepared by means of an oxidant division of the enamine of the formula (XV), by a sodium pyridadate, according to an experimental protocol, similar to the deptide by Coe.

(Tetrahedron Lett, 1994, 35, 219-22) In turn, the enamine of the formula (XV), which is usually not isolated pure, can be prepared from 2-fluoro-6- methylpyridine, which is obtained commercially, following a procedure similar to the deptide by Bredereck (Chem Ber., 1968, 101, 4048-56) The method for preparing the aldehyde of the formula (IVb), wherein: • the substituents u, v and w represent a hydrogen atom; • Group A is a chlorine atom, is described in Chem Pharm Bull., 1990, 38, 2446-58. The aldehydes of the formula (IVc), in which: • the substituents u, v and w represent a hydrogen atom, • Group A represents: - an alkoxy group (RiO-) or an alkylthio group (RiS-) in which Ri is as defined anteporously; - an amino group of type (II) (R2R3N-), wherein R2 and R3, which are identical or different, are as defined above; • a cyclic amino group of type (III), preferably an azetidin-1-yl radical, can be prepared according to the procedure described in scheme F SCHEME F First the aldehyde function is protected in the compound of the formula (IVa), in the form of a [1, 3] dioxolan-2-yl group, under operating conditions similar to those used for the formation of 2- [1, 3] d? Oxolan-2-yl-pyridine from d? 2-p? Pdincarbaldehyde (J. Heterocyclic Chem 1987, 24, 623-28). The replacement of the fluorine atom present in the compound of the formula (XVI) by means of the appropriate reagent (HA) or (Na * A ") then allows the introduction of the desired group A. The reagent symbolized by (HA) represents a primary amine or secondary of the mono- or di (alkyl of 1 to 5 carbon atoms) -5 amine type, or a cyclic amine, such as azetidine or pyrrolidine, Sß carries out the reaction between the acetal of the formula (XVI) and the reactant ( HA), which gives the compound of the formula (XVII) in which A is an amino group of the mono- or di (alkyl of 1 to 5 carbon atoms) amino type or an azetidin-1-yl radical or a pirtolidin radical -1-lyl, in the presence of an excess of the reagent (HA), at a temperature 0 of 100 ° C, in a polar solvent The ionized reagent (Na * A ") symbolizes a thiolate or sodium alcoholate, obtained by deprotonation of thiol or corresponding alcohol, by means of a strong base. The reaction between the acetal of the formula (XVII) and the reagent (Na * A ") giving the compound of the formula (XVII) in which A represents a group of the alkoxy type of 1 to 5 carbon atoms or alkylthio of 1 to 5 carbon atoms is carried out at a temperature between 25 ° C and 100 ° C in a polar solvent.The aldehyde function present in the compound of the formula (IVc) is then regenerated by acid hydrolysis of the acetal function of the compound of the formula (XVII), by means of an aqueous solution of acid or formic, at a temperature of between 20 ° C and 60 ° C. The aldehydes of the formula (IVd) can be obtained in which: • the substituents u, v and w represent a hydrogen atom, • group A is a furan-2-yl radical or a furan-3-llo radical, they can be obtained by following the procedure described in the following scheme G.

SCHEME G Patent JP 05255251 describes the preparation of the 6-methylpyridin-2-yl ester of trifluoromethanesulfonic acid, of the formula (XXIV), from 6-methylpyridin-2-ylamine. In the present application, the compound (XXIV) was obtained by reacting an appropriate derivative of trifluoromethanesulfonic acid, with 6-methy1pyridin-2-ol, which is commercially available. The derivative of the formula (XXIV) can then be coupled with the organozinc compounds derived from 2-lithiofuran or 3-lithiofuran, in the presence of an appropriate paired catalyst, in order to give, respectively, 2-furan-2-ii. -6-methiipyridine or 2-furan-3-yl-6-methylpyridine, of the formula (XXV). 2-Lithio-urane and 3-lithiofuran were obtained according to the methods described in J. Heterocyclic Chem., 1975, 195-96). The intermediate N-oxide dß is then prepared by the formula (XXVI) by treating the compound of the formula (XXV) by means of an organic peroxide, such as, for example, 3-chloroperoxybenzoic acid, in a halogenated solvent, such as, for example, dichloromethane or chloroform. The reaction between the N-oxide derivative of the formula (XXVI) and trifiuoroacetic anhydride, according to the method described by atsumoto (Heterocycles, 1986, 24, 2169-72), gives as an intermediate the 6-furan-2-yl ester trifluoroacetic acid-2-pyridin-2-methyl, or the ester 6-furan-3-yl-pyridin-2-yl- methyl of trifluoroacetic acid, which are not isolated pure, but are saponified in situ by means of an aqueous solution of an inorganic base, to give the compound of the formula (XXVII). Sß can advantageously replace the reaction solvent for the experimental protocol of Matsumoto (N, N-dimethylformamide) by an anhydrous ether solvent, such as, for example, 1,4-dioxane or tetrahydrofuran. The oxidation of the alcohol of the formula (XXVII) to the aldehyde of the formula (IVd) can be carried out by means of manganese dioxide, or of an activated derivative of dimethyl sulfoxide, such as, for example, dimethyl sulfoxide activated by the trioxide complex of sulfur-pyridine, or by oxalyl chloride, according to techniques known to those skilled in the art. It is also possible to obtain the derivative of the formula (IVd) in which the group A is a furan-2-yl radical or a furan-3-yl radical, according to the chemical process used for the preparation of the aldehydes of the formula (IVe), in which: • the substituents u and v represent a hydrogen atom or a methyl radical; • the substituyentß w is a hydrogen atom or a fluorine atom or a methyl radical; however, more than one methyl radical is present simultaneously at positions 3, 4 and 5 of the pyridine ring; and when w is a fluorine atom, then u and v are hydrogen atoms; • group A of a furan-2-yl or furan-3-yl or thiophen-2-yl or pyrrole-2-yl or 1-methyl-pyrrole-2-yl radical is selected. The process used to prepare the aldehydes of the formula (IVe) is summarized in scheme H. All the primary alcohols of the formula (LVII), starting compounds used in the process outlined in scheme H, are compounds that are known or which are prepared according to conventional methods: (6-chloropyridin-2-yl) methanol (LVIla) is a compound whose method of preparation is described in the chemical literature (Tetrahedron, 1982, 38 (3277-80); (5-methy1-6-chloropyridin-2-yl) methanol (LVIIb) is obtained by reducing the ethyl ester of 5-methyl-6-chloropyridine-2-carboxylic acid by means of sodium borohydride, in ethanol, prepared, in turn, according to the method described by Hoornaert (Tetrahedron, 1996, 52, 2591-2602); (3-methyl-6-chloropyridin-2-yl) methanol (LVIIc) is obtained by reducing 3-methyl-6-chloropyridine-2-carbaldehyde by means of sodium borohydride in methanol, prepared, in turn, by methylation of 6-chloropyridine-2-carbaldehyde (IVb), according to the method described by Comins (J. Org. Chem., 1990, 55, 69-73); (4-methyl-6-bromopyridin-2-yl) methanol (LVIId) is obtained from 2-bromo-4,6-dimethylpyridine, by the modified Matsumoto method. The preparation of 2-bromo-4,6-dimethylpyridine is carried out from 2- am? no-4,6-d? met? lp? pd? na, according to a procedure similar to the dept. by Adams (J Amer Chem Soc, 1954, 76, 3168-71) SCHEME H The primary alcohol function of the compound of the formula (LVII) is first protected, for example, in the form of a tpmethylsilanyl-ethoxymethyl group, abbreviated "SEM", according to an experimental protocol well known to those skilled in the art. substituent which is in the 6-position is a bromine atom, the compound of the formula (XXVIIIb) can be directly used in the next step. When the substituent which is in the 6-position is a chlorine atom, the compound is converted ( XXVIlla) to intermediate (XXXI), before using it in the next step The compound of formula (XXX), an intermediate in the preparation of the tpflato of formula (XXXI), is obtained by applying a method similar to that described by Sieburth (J Amer Chem Soc, 1991, 113, 8163-64) The coupling of the derivatives of the formula (XXXI) or (XXVIIIb) with the boronic acids or esters or esters derived from the aromatic heterocycles, symbolized by (AM), in pres of a suitable palladium catalyst, according to the conventional methods of Suzuki or Stille, gives the compound of the formula (XXXII) In the case that the boronic acids or the aromatic heterocycles (AM) are not available on trade, they can be prepared by transmethylation of the corresponding heterocycles containing lithium; which, in turn, are obtained according to experimental protocols well known by experts in the field. The division of the trimethylsilanyl-ethoxymethyl group by means of tetrabutylammonium fluoride, according to the method described in Tetrahedron Lett., 1988, 29, 5417-18, gives the primary alcohol of the formula (XXXIII), which is oxidized to the aldehyde of the formula (IVe) under experimental conditions identical to those described above for the oxidation of (XXVII) to the aldehyde (IVd). The aldehydes of the formulas (IVf), (IVg) and (IVh), described below, are all derived from a common precursor, 2- [1, 3] dioxolan-2-ylpyridine-2-carbonitrile, of the formula ( XXXVI), whose method of preparation is summarized in Scheme I.

SCHEME I The N-oxide intermediate of the formula (XXXV), obtained by oxidation of the derivative of the formula (XXXIV), by means of an organic peroxide, treated under conditions similar to those described by Fife (J. Org. Chem., 1983, 48, 1375-77), gives the compound of the formula (XXXVI). The aldehydes of the formulas (IVf) are prepared, in which: • the substituents u, v and w represent a hydrogen atom; • group A represents up radical 1 H-imidazol-2-yl or thiazol-2-yl or oxazol-2-yl, are prepared in accordance with the procedure outlined in scheme J, route f.

SCHOOL J. RUTA f The derivative of the formula (XXXVII) is obtained by adding methanol to the compound of the formula (XXXVI). The condensation of a bifunctional derivative, such as ethylenediamine, 2-aminoethanethiol or 2-aminoethanol, or its hydrochlorides, with the derivative of the formula (XXXVII), gives the compounds of the formula (XXXVIII), in which Q represents a group NH or a sulfur atom or an oxygen atom. The condensation reaction in question is carried out by heating the compound of the formula (XXXVII) and the desired bifunctional reagent, in the absence of solvent or at the reflux temperature of an alcohol solvent. Oxidation of the derivatives of the formula (XXXVIII) by means of manganese dioxide, nickel peroxide or barium permanganate gives the compounds of the formula (XXXIX). The oxidation reaction in question is generally carried out at the reflux temperature of an inert apolar solvent, optionally removing the water formed during the reaction by one of the conventional techniques well known to those skilled in the art. Acid hydrolysis of the acetal of the formula (XXXIX), under conditions similar to those used for the hydrolysis of the acetal of the formula (XVII), gives the aldehyde (IVf).

The aldehydes of the formula (IVg) are obtained, in which the substituents u, v and w represent a hydrogen atom, • Group A represents an oxadiazol-3-yl or methyl-5-oxadiazol-3-yl radical, can be obtained in accordance with the procedure outlined in scheme 1 ESQUEMA J. RUTA a The addition of hydroxylamine hydrochloride to the compound of the formula (XXXVI) gives the compound of the formula (XXXX). Condensation of an appropriate acetic acid derivative, such as acetyl chloride, with the intermediary of the formula (XXXX), gives the derivative of the formula (XXXXI), wherein R is a methyl radical. Similarly, condensation of an appropriate derivative of formic acid, such as an alkyl orthoformate, with the compound of the formula (XXXX), gives the derivative of the formula (XXXXI) wherein R 4 is a hydrogen atom. The aldehyde of the formula (IVg) is then obtained by hydrolysis of the [1, 3] dioxolan-2-yl function of the compound of the formula (XXXXI) under conditions similar to those used for the hydrolysis of the acetal (XVII) to the aldehyde (IVc). Sß can obtain the aldehydes of the formula (IVh), in which: • the substituent u is a hydrogen atom or a methyl radical, • the substituents v and w represent a hydrogen atom, • group A represents a radical 1 H-pyrazol-3-yl or 1-methyl-1-pyrazol-3-yl, can be obtained according to the procedure described in scheme J, route h. SCHOOL J. ROUTE h The addition of methylmagnesium bromide or methylmagnesium chloride to the compound of the formula (XXXVI) gives the derivative of the formula (XXXXII). Then the compound of the formula (XXXXIII) is prepared by condensing the N, N-dimethylformamide dimethylacetal, or an equivalent reagent such as, for example, terbutoxy-bis (dimethylamino) methane or tris (dimethylamino) methane, with the ketone of the formula (XXXXII). The condensation reaction in question is carried out in an anhydrous solvent, such as, for example, tetrahydrofuran or N, N-dimethylformamide. The reaction of the hydrazine hydrate with the intermediate of the formula (XXXXIII), according to methods well known to those skilled in the art, then gives the compound of the formula (XXXXIV). According to the route (i), the acid hydrolysis of the acetal of the formula (XXXXIV), under conditions similar to those previously used, gives the aldehyde of the formula (IVh-1). According to the route (j). The compound of the formula (XXXXIV) is first regioselectively mssted by means of methyl iodide in a basic medium, and then the aldehyde acid function (IVh-2) is hydrolysed under conditions similar to those used for the hydrolysis of! acetal of the formula (XVII) to the aldehyde (IVc). The aldehyde of the formula (IVi), in which: • the substituents u, v and w represent a hydrogen atom, • group A represents an isopropyl radical, is described in patent WO 93/21158, in which it was prepared by methylation of 6-ethylpyridin-2-carbaldehyde. In the present application, the aldehyde of the formula (IVi) was advantageously obtained according to the procedure outlined in scheme K.

SCHEME K The unsaturated derivative of the formula (XXXXV) can be prepared by a conventional Wittig reaction between 1- (6- [1, 3] dioxolan-2-yl-pyridin-2-yl) ethanone, of the formula (XXXXII) and the anion derived from (methyl) triphenylphosphonium bromide, by means of potassium terbutoxide. The reduction of the double ligation of the 2- [1,3] dioxolan-2-yl-6-isopropenylpyridine of the formula (XXXXV), at a low hydrogen pressure, in the presence of a suitable catalyst, for example , palladium on carbon, gives the 2- [1, 3] dioxolan-2-yl-6-isopropylpyridine of the formula (XXXXVI). Hydrolysis of the acetal of the formula (XXXXVI), under conditions similar to the conditions previously used for the hydrolysis of the acetal of the formula (XVII) to the aldehyde (IVe), gives the aldehyde (IVi).

It is possible to prepare the aldehydes of the formula (IVj) in which • the substituents u, v and w represent a hydrogen atom, • group A represents a 1-fluoro-1-ethyl group, ppoorrmeme diiod of the procedure described in scheme L SCHEME L The reduction of the ketone function of the compound of the formula (XXXXII), which is carried out by sodium borohydride in methanol, at room temperature, gives the secondary alcohol of the formula (XXXXVII). The fluorinated acetal of the formula (XXXXVIll) treating the alcohol of the formula (XXXVII) by means of diethylamine tpfluorosulfide, abbreviated DAST, according to a conventional method, known to those skilled in the art Aldehyde (IVj) is obtained by hydrolysis with acid of the acetal function of the compound of the formula (XXXXVIII), under conditions identical to those previously described for the hydrolysis of the acetal (XVII) to the aldehyde (IVe) Sß, can obtain the aldehyde of the formula (IVk) in which the substituents , v and w represent a hydrogen atom, "group A represents an oxazole-5-? lo radical, can be obtained in accordance with the method described in scheme M SCHEME M The method for preparing 6- [1,3] d? Oxolan-2-yl-pyrid? N-2-carbaldehyde of the formula (XXXXIX) in the chemical literature (Monatsh, Chem., 1993, 124, 881-91) The condensation of tosylmethyl isocyanate, abbreviated TOSMIC, with the derivative of formula (XXXXIX), according to an experimental protocol similar to that reported in Tetrahedron Lett., 1972, 2369-72, gives the acetal of the formula (L) The aldehyde (IVk) is then obtained by hydrolysis of the acetal function of the compound of the formula (L) under operating conditions similar to those described above for the hydrolysis of the acetal (XVII) to the aldehyde ( IVe) The aldehyde of the formula (IVI) can be prepared, in which. • the substituents u, v and w represent a hydrogen atom, • group A represents a cyclopropyl radical, using the descpto procedure in scheme N SCHEME N The intermediate of the formula (Ll) is obtained by a d-Wittig reaction, between the aldehyde of the formula (XXXXIX) and d-bromide. (methylene) triphenylphosphonium, in the presence of a base such as, for example, potassium carbonate. It then prepares the cyclopropane derivative of the formula (Lll) by adding the anion derived from tpmethylsulfonyl iodide, to 2- [1, 3] - dioxolan-2-yl-6-ethenyl-pyridine (Ll), according to a method similar to that described in J. Org. Chem. 1973, 38, 3942-44. The deprotonation of the trimethylsulfonium iodide is carried out by means of n-butyllithium in tetrahydrofuran. The aldehyde of the formula (IVI) is then obtained from the derivative of the formula (Lll), under operating conditions similar to the conditions previously used for the hydrolysis of the acetal of the formula (XVII) to the aldehyde (IVc). The aldehydes of the formula (IVm) are obtained, in which: • the substituents u, v and w represent a hydrogen atom, • group A represents a monof luoromethyl group or a difluoromethyl group, can be obtained by the procedure described in scheme O.

SCHEME O According to route (i), (6- [1, 3] dioxolan-2-yl-pyridin-2-yl) methanol (Lili), a precursor of the aldehyde of the formula (XXXXIX), treated with diethylamine trifluorosulfide (DAST), in a halogenated solvent, gives the fluorinated acetal of the formula (LIV). The derivative of the formula (L1V) is then converted to the aldehyde of the formula (IVm-1), under conditions similar to those previously used for the hydrolysis of the acetal (XVII) to the aldehyde (IVc). According to the route (I), the aldehyde of the formula (XXXXIX), treated with trifluorosulfide d-diethylamine (DAST) gives the difluorinated acetal of the formula (LV). Then the difluorinated acetal of the formula (LV) is converted to aldehyde of the formula (IVm-2) under experimental conditions similar to those described above (route k) The aldehyde of the formula (IVo) is obtained, in which: • the substituents u, v and w represent a hydrogen atom, "the group A represents a methoxycarbomlo group, can be obtained by the descpto method in the P scheme SCHEME P The 6-hydroxylmethylpipdin-2-carboxylic acid methyl ester of the formula (LVI) is prepared from the methyl ester of 2,6-pyridinecarboxylic acid, according to the protocol descpto in Z Naturforsch, 1994, 49b , 1127-36. The oxidation of the alcohol of the formula (LVI), under experimental conditions similar to those described for the oxidation of the alcohol of the formula (XXVII) to the aldehyde (IVd), then gives the aldehyde of the formula (IVo). The methods for preparing the aldehyde of the formula (IVp), wherein: • substituents A, u and w represent a hydrogen atom, • the group v is a chlorine atom and the aldehyde (IVr) in which: • the substituents A, v and w represent a hydrogen atom, • group u is a methyl radical, they are described in Arch. Pharm. (Weinheim Ger.) 1977, 310, 128-36) The aldehyde of the formula (IVq) in which the substituents A, u and v represent a hydrogen atom, • the group w represents a fluorine atom, is a known compound whose preparation is described in Tetrahedron, 1983, 39, 2009-21. The aldehydes of the formula (IVs) are prepared, in which: • the substituents u, v and w represent a hydrogen atom or a methyl radical, however, without more than one methyl radical present at the 3, 4 positions being simultaneously present and 5 of the pyridine ring, • group A is up to amino group of type (II) (R2R3N-) wherein R2 and R3 are as defined above, or a cyclic amino group of type (III), are prepared by procedures described in the Q scheme.

SCHEME Q The primary alcohols of the formula (LVII), whose preparation methods are given in the descriptive part of the H scheme, are reacted with a primary or secondary amine of the mono- or di (alkyl) type of 1 to 5 carbon atoms. carbon) -amina, of preferential methylamma or dimethylamine, or a cyclic amine of type (III), preferably azetidine, to give the compound of the formula (LVIII). Generally this reaction is carried out at a temperature between 70 ° C and 120 ° C in a polar solvent The oxidation of the primary alcohol function of the compound of the formula (LIX) to the aldehyde of the formula (IVs) is then carried out by means of activated manganese dioxide, a the reflux temperature of a halogenated solvent, such as, for example, chloroform. The compounds of the formula (IVa), (IVb), (IVe), (IVd), (IVe), (IVf), (IVg), (IVh), (IVi), (IVj), (IVk), (IVI), (IVm), (IVn), (IVo), (IVp), (IVq), (IVr) Y (IVs) ), constitute the series of compounds of the formula (IV) SCHEME A SCHEME B Vlll Ib SCHEME C "AH or Na + A" " SCHEME D XIII XII Staudipger - aza - Witting SCHEME E SCHEME F XVI "AH or A'Na" * XVII rvc SCHEME G XXIV XXV XXVII Ná SCHEME H xxx • ot SCHEME I XXXV XXXV XXXVI SCHEME J SCHEME K XXXXII XXXXV XXXXVI SAW SCHEME L XXXXII XXXXVIll J SCHEME M TOS MIC rvk SCHEME N fVI XXXXIX IVm-1 IVm-2 SCHEME P LVI IVo SCHEME Q LVII t The following examples illustrate the invention, but do not limit it in any way. , In the examples that follow: (i) the progress of the reactions is monitored by thin layer chromatography (TLC) and, consequently, the reaction times are only indicated as a guide (ii) Several crystalline forms can give points of different fusion; the melting points reported in the present application are those of the products prepared according to the method described, and are not corrected. (iii) The structure of the products obtained according to the invention is confirmed by nuclear magnetic resonance (NMR) spectrum, infrared (IR) spectrum and percentage analysis; and the purity of the final products is checked by TLC. (iv) Record the NMR spectra in the appropriate solvent. Chemical shifts (delta) are expressed in parts per million (ppm) relative to tetramethylsilane. The multiplicity of the signals is indicated by: s = a single band; d = double band; t = triple band; c = quad band; m = multiple bands; b = broad. (v) The various symbols for the units have their usual meanings: mg (milligrams); g (grams); kg (kilograms); ml (milliliters); ° C (degrees Celsius); mmol (millimoles); nmol (nanomoles); cm (centimeter), μm (micras) Abbreviations have the following meanings: p. F. = melting point; p e. = boiling point. (vi) "Ambient temperature" means a temperature between ° C and 25 ° C. In the present application, the pressure values are given in millibars EXAMPLE 1 PREPARATION OF β-FLUOROPIRIDIN-2-CARBALDEHYDE (IVal) g of 2-fluoro-6-methylpyridine (270 mmol) and 70 g of terbutoxibis (dimethylamido) methane (405 mmol) are mixed under nitrogen. Sß warms the mixture at 140 ° C for 24 hours. The mixture is diluted with 50 ml of tetrahydrofuran and the solution obtained is added dropwise to an aqueous solution of 115 g of sodium periodate (538 mmol). The mixture is stirred overnight at room temperature, the formed precipitate is filtered off and then tetrahydrofuran is evaporated off. The residue is extracted with dichloromethane, the organic phase is dried over magnesium sulphate, filtered and then the solvent is evaporated in vacuo. The title product is isolated by distillation in a bulb oven, at 70-80 ° C. 34 g of a yellow oil containing about 20% N, N-dimethylformamide is recovered. 1 H NMR (CDCl 3) delta: 7.16 (dd, 1 H), 7.82 (dd, 1 H), 7 96 (m, 1 H), 9.90 (s, 1 H).

IR (film) a: 1713 cm "1 (C = 0).

EXAMPLE 2 PREPARATION OF 6-DIMETHYLAMINQPIRIDIN-2-CARBALDEHYDE (IVc-1) Stage 1 (6-l, 3-dioxolan-2-yl-pyridin-2-y [] dimethylamine 0.60 g of 2- [1, 3] -dioxolan-2-α- [-6-fluoiOpyridine (3.55 mmol) and 2.50 ml of 33% dimethylamine in etapol (17.7 mmol) are mixed, and then the mixture is heated to the temperature of 100 ° C for 2 hours. After evaporation in vacuo, the residue is taken up in chloroform, the mixture is washed with water, dried over magnesium sulfate, filtered and the chloroform evaporated in vacuo. The title product is obtained in the form of a yellow oil which is used in the next step, without further purification. 1 H NMR (CDCl 3) delta: 3.07 (s, 6H), 4.10 (m, 4H), 5.72 (s, 1 H), 6.46 (d, 1 H), 6.73 (d, 1 H), 7.45 (dd, 1 HOUR).

Stage 2 6-dimethylaminopyridyl-2-carbaldehyde 0.60 g of (6- [1, 3] dioxolap-2-yl-pyridin-2-yl) dimethylamine (3.09 mmol) is mixed in 10 ml of a 80% aqueous formic acid solution, and then the solution is heated at 60 ° C for 20 hours. The solvents are separated by azeotropic entrainment with toluene, the residue is collected in water, the mixture is cooled to 0 ° C and the medium is basified by adding potassium carbonate. The mixture is extracted with ethyl acetate, the organic phase is washed with water and then with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and the solvent is evaporated in vacuo. The title product is obtained in the form of a yellow oil (0.43 g), which is used in the next step without ultepor purification. 1 H NMR (CDCl 3) delta: 3.12 (s, 6 H), 6.68 (d, 1 H), 7.18 (d, 1 H), 7.44 (dt, 1 H), 9.87 (s, 1 H). IR film a: 1697 cm "1 (C = 0).

EXAMPLE 3 PREPARATION OF 6-FURAN-2-IL-PIPERIDIN-2-CARBALDEHYDE? LVd-1) Stage 1 2-furap-2-yl-6-methy1pyridine 40 ml of a 1.6 M solution of n-butyllithium in hexane is introduced dropwise into a solution of 4.36 ml of furan (60 mmol) and 40 ml of tetrahydrofuran, cooled to 0 ° C. The solution is stirred for 3 hours at 0 ° C and then cooled to -40 ° C before introducing 120 ml of a 0.5M solution of zinc dichloride in tetrahydrofuran. The mixture is stirred for two hours at ambient temperature and then the reaction mixture is added to a solution of 9.17 g of 6-methylpyridin-2-yl ester of trifluoromethanesulfonic acid (40 mmol) in 20 ml of tetrahydrofuran containing 2. 30 g of tetracis (triphenylphosphine) palladium (2 mmol). The reaction mixture is kept at reflux for two hours, under nitrogen, and then cooled and extracted with 1 N HCl. The acidic aqueous phase is neutralized with 10N NaOH, and then extracted with ethyl acetate. The organic phase is washed with water, dried over magnesium sulfate, filtered and the solvent is evaporated off. The expected product is isolated by rectification at reduced pressure. Pe5.6xio "2 = 100-105 ° C 5.20 g of a colorless oil is recovered Yield: 81.5% 1 H NMR (CDCI3) delta: 2.56 (s, 3H), 6.48 (dd, 1 H), 6.99 (m, 2H), 7.50 (m, 3H).

Stage 2 1-2-furan-2-yl-6-methylpyridine oxide 4.90 g of meta-chloroperbenzoic acid is added in portions to a solution of 2.20 g of 2-furan-2-yl-6-methyl-pyridine (13.8 mmol) in 50 ml of chloroform cooled to 0 ° C. The mixture is stirred for 12 hours at room temperature and then the precipitate is removed by filtration and the filtrate is washed with a 5% aqueous solution of sodium bicarbonate. After drying over magnesium sulfate, filtering and evaporating, the title product is isolated by chromatography on a silica column (eluent: chloroform / methanol, 99: 1). 1.25 g of white powder is recovered. Yield: 52%. p. F. 79 ° C. 1 H NMR (CDCl 3) delta: 2.58 (s, 3 H), 6.60 (c, 1 H), 7.18 (m, 2 H), 7. 58 (d, 1 H), 7.85 (dd, 1 H); 8.03 (d, 1 H).

Stage 3 (ß-furan-2-yl-pirin-2-y-methyl-ol) 2.75 g of 1-oxide of 2-furan-2-yl-6-methylpyridine (15.7 mmol) is dissolved in 27 ml of tetrahydrofuran. 6.65 ml of trifluoroacetic anhydride (47.1 mmol) is added to the solution cooled to 0 ° C under a nitrogen atmosphere. The mixture is stirred for 12 hours at room temperature and then 25 ml of a 4N aqueous solution of sodium hydroxide is added. Tetrahydrofuran is evaporated offThe residue is taken up in a saturated aqueous solution of sodium chloride and then the mixture is extracted with chloroform. The organic phase is dried over magnesium sulfate, filtered and concentrated in vacuo. The title product is isolated by chromatography on a silica column (eluent: chloroform / ethyl acetate, 90:10). 2.03 g of a yellow oil is recovered.

Yield- 73 8% NMR with 1H (CDCI3) delta: 3.99 (bs, 1 H (exchangeable)), 4 74 (s, 2H), 6.53 (c, 1 H), 7.09 (m, 2H), 7 57 ( m, 2H), 7.71 (t, 1 H) Stage 4 ß-furan-2-yl-p¡r¡d¡n-2-carbaldβhido 8 g of manganese dioxide is added to a solution of 2 g of (6-furan-2-yl-pyridin-2-yl) methanol (11.4 mmol) and 50 ml of chloroform. The reaction mixture is heated at reflux for one hour and 30 minutes, eliminating the continuously formed water. The suspended solid is filtered off over Celite, and then the solvent is evaporated off. The title product is isolated by chromatography on a silica column (eluent: chloroform) 1.45 g of a yellow solid is recovered. 73.4% p. F. 46-48 ° C NMR with 1H (CDCl) delta: 6.55 (c, 1 H), 7.16 (d, 1 H), 7.55 (d, 1 H), 7.82 (m, 3H), 10.07 (s, 1 H) ). IR (KBr) u: 1717 cm "1 (C = 0).

EXAMPLE 4 6-FURAN-3-IL-PYRIDINE-2-CARBALDEHYDE (IVd-2) The title compound is prepared by carrying out procedure 5 as in example 3, but replacing in step 1, 2-lithiofuran by 3-lithofuran, obtained by subjecting 3-bromofuran to halogen / metal. p.f. 59-61 ° C. 1 H NMR (CDCl 3) delta: 6.94 (c, 1 H), 7.54 (t, 1 H), 7.68 (dd, 1 H), 7.83 (m, 2 H), 8.12 (s, 1 H), 10.05 (s) , 1 HOUR). i o¡ IR (KBr) a: 1713 cm "1 (C = 0) EXAMPLE 5 6- (1H-PIRROL-2-IL) PYRIDINE-2-CARBALDEHYDE .IVe-1) Step 1 2-Chloro-6- (2-trimethylsilanyl-ethoxymethoxymethyl) -pyridine 3.20 ml of chlorhexyl-2- (trimethylsilyl) ethyl ether (18.2 mmol) is added dropwise to a solution containing 2.50 g of (6-chloropyridin-2-yl) methanol 20, (17.4 mmol), 3.30 ml of diisopropylethylamine ( 19.1 mmol) and 20 ml of dichloromethane, cooled to 0 ° C, maintained under a nitrogen atmosphere. The mixture is stirred for 3 hours at room temperature and then the dichloromethane is expelled by evaporation. The residue is collected in water, the mixture with diethyl ether, the organic phase is washed with water and then dried over sodium sulfate. After filtration and evaporation of the solvent, the title product is isolated by chromatography on a silica column (eluent: dichloromethane). 3.65 g of a colorless oil is recovered. Performance: 76.6%. NMR with 1H (CDCl 3) delta: 0 (s, 9H), 0.95 (t, 2H), 3.68 (t, 2H), 4.67 (s, 2H), 4.80 (s, 2H), 7.24 (d, 1 H) , 7.35 (d, 1 H), 7.64 (t, 1 H).

Step 2 2-Benzyloxy-6- (2-trimethylsilyanoxy-ethoxy-methoxymethyl) -pyridine 2.10 ml of benzyl alcohol (19.9 mmol) diluted in 3 ml of N, N-dimethylformamide are added dropwise to a suspension of 0.91 g of sodium hydride (22.6 mmol) in 20 ml of N, N-dimethylformamide, cooled to 0 ° C and maintained under a nitrogen atmosphere. The mixture is stirred for one hour and 30 minutes at 0 ° C and then a solution of 3.65 g of 2-chloro-6- (2-trimethylsilanyl-ethoxymethoxymethyl) pyridine (13.3 mmol) in 3 ml of N is added dropwise. N-dimethylformamide. The reaction is carried out at 40 ° C for 12 hours, the reaction mixture is poured into ice water, extracted with diethyl ether and the combined organic phases are washed with water and dried over magnesium sulfate. After filtering and evaporating the solvent, the title product is isolated by chromatography on a silica column (eluent: dichloromethane / hexane 60:40). 3 g of a colorless oil is recovered.

Yield: 65.3% NMR with 1H (CDCI3) delta: (s, 9H), 0.94 (t, 2H), 3.67 (t, 2H), 4.61 (s, 2H), 4.80 (s, 2H), 5.35 (s, 2H), 6.66 (d, 1 H), 6.97 (d, 1 H), 7.34 (m, 3H), 7.42 (m, 2H), 7.54 (t, 1 H).

Step 3 6- (2-Trimethylsilanyl-ethoxymethoxymethyl) -pyridin-2-ol 7 g of Raney nickel is added to a solution of y of 2-benzyloxy-6- (2-tritymethylsilanyl-ethoxymethoxymethyl) pyridine in 75 ml of ethanol saturated with hydrogen. The suspension is stirred vigorously at low pressure of hydrogen, at room temperature, for one hour and 30 minutes. The solid is removed in suspension, by filtration in Celite, and then the ethanol is evaporated. The title product is isolated by chromatography on a silica column (eluent: dichloromethane / methanol, 98: 2). 4 g of a colorless oil is recovered.

Yield: 76.8%. NMR with 1H (CDCl 3) delta: 0 (s, 9H), 0.93 (t, 2H), 3.61 (t, 2H), 4.50 (s, 1H), 4.75 (s, 2H), 6.21 (d, 1H), 6.47 (d, 1H), 7.36 (d, 1H), 7.41 (d, 1H), 12.28 (s, 1 H (exchangeable)).

Step 4: Trifluoromethanesulfonic acid 6- (2-trimethylsilyanyl-? Toximetoxymetho) pyridin-2-yl ester 2.63 ml of trifluoromethanesulfonic anhydride (14.9 mmol) are added dropwise to a solution of 3.80 g of 6- (2-trimethylsilanyl-ethoxymethoxymethyl) pyridin-2-ol (14.8 mmol) and 35 ml of pyridine containing 0.10 g of 4- N, N-dimethylaminopyridine, maintained at 0 ° C under nitrogen atmosphere. The solution is stirred for two hours at 0 ° C and then the mixture is poured into ice water and extracted with diethyl ether. The organic phase is washed with an aqueous solution of potassium bisulfate and then with water, dried over magnesium sulfate, filtered and stripped off. The title product is isolated by chromatography on a silica column (eluent: dichloromethane). 4.30 g of a colorless oil are recovered. Performance: 75%. NMR with 1H (CDCl 3) delta: 0 (s, 9H), 0.93 (t, 2H), 3.66 (t, 2H), 4.68 (s, 2H), 4.80 (s, 2H), 7.05 (d, 1 H) , 7.52 (d, 1 H), 7.87 (t, 1 H).

Step 5 2-rß- (2-trimethylsilanyl-ethoxymethoxymethyl) pyridin-2-l-pyrrol-1-carboxylic acid tertbutyl ester The preparation of 1-terbutoxycarbonylpyrrole-2-yl-boronic acid is carried out according to the method described in Synthesis, 1991, 613-15. 9.68 g of stem carbonate (20.6 mmol), 1 g of tetracis (triphenylphosphine) palladium (0.86 mmol) and 2.45 g of 1-tert-butoxycarbonylpyrrol-2-yl-boronic acid (11.6 mmol) are added to a solution of 4 g of the trifluoromethanesulfonic acid 6- (2-trimethylsilanyl-ethoxymethoxymethyl) pyridin-2-yl ester (10.3 mmol), and 40 ml of degassed benzene, sparged with nitrogen. The mixture is stirred for 23 hours under an argon atmosphere. The insoluble material is separated by filtration in Celite and then the solution is concentrated in vacuo. The title product is isolated by column chromatography on silica (eluent: dichloromethane / ethyl acetate, 99: 1). 3.90 g of a yellow oil is recovered. Yield: 93.6%. NMR with 1H (CDCl 3) delta: 0 (s, 9H), 0.94 (t, 2H), 1.32 (s, 9H), 3.67 (t, 2H), 4.73 (s, 2H), 4.82 (s, 2H), 6.21 (t, 1 H), 6.37 (m, 1 H), 7.27 (d, 1 H), 7.32 (m, 1 H), 7.34 (d, 1 H), 7.68 (t, 1 H).

Step 6 f6- (1 H-pyrrol-2-yl) pyridn-2-p-methanol 3 g of 2- [6- (2-trimethylsilanyl-ethoxymethoxy-methyl) pyridin-2-yl] pyrrole-1-carboxylic acid tertbutyl ester (7.41 mmol) is added to a solution of 3 ml of tetrabutylammonium fluoride 1.1M. in tetrahydrofuran, 45 ml of tetrahydrofuran and 5 ml of hexamethylphosphoramide, containing 10 g of molecular sieve (4 angstrom). The mixture is stirred at 45 ° C under argon for 8 hours. After filtering the insolubie material into Celite, tetrahydrofuran is evaporated off. The title product is chromatographed on a silica column (eluent: dichloromethane / ethyl acetate, 99: 1). 0.50 g of a white solid is recovered. Performance: 38.7%. p. F. 73-75 ° C. 1 H NMR (CDCl 3) delta: 3.61 (bs, 1 H), 4.74 (s, 2 H), 6.30 (dd, 1 H), 6.73 (m, 1 H), 6.92 (m, 1 H), 6.98 (d, 1 H), 7.45 (d, 1 H), 7.62 (t, 1 H), 9.56 (bs, 1 H) ).

Step 7 6- (1 H-pyrrol-2-yl) pyridine-2-carbaldehyde 0.75 g of manganese dioxide (8.61 mmol) is added to a solution of 0.30 g of [6- (1H-pyrrol-2-yl) pyrid? N-2-yl] methanol (1.72 mmol) in 6 ml of dichloromethane. The suspension is stirred vigorously for three hours at room temperature, and the insoluble material is then filtered off in Celite. After evaporating the dichloromethane the residue is purified by chromatography on a silica column (eluent: dichloromethane). It recovers 0.20 g of a white powder. Performance: 69%. p. F. 112-113 ° C. 1 H NMR (CDCl 3) delta: 6.31 (dd, 1 H), 6.77 (m, 1 H), 6.95 (m, H), 7.63-7.81 (m, 3 H), 9.67 (bs, 1 H), 10.03 ( s, 1 H). l? ' IR (KBr) a: 1701 cm "1 (C = 0).

EXAMPLE 6 PREPARATION OF 6-TIQFEN-2-ILPIRIDIN-2-CARBALDEHYDE (IVß-2) The title compound is obtained by carrying out the procedure as in example 5, but replacing in step 5 the 1-terbutoxycarbonyl-pyrrol-2-yl-boronic acid with thiophen-2-ylboronic acid, which can be obtained in trade, in the form of a yellow solid, p. f.48-50 ° C. 20 NMR with 1H (CDCl 3) delta: 7.15 (d, 1H), 7.46 (dd, 1H), 7.69 (dd, 1 H), 7.78-7.88 (m, 3H), 10.16 (s, 1 H). IR (KBr) un: 1714 cm "1 (C = 0).

EXAMPLE 7 PREPARATION OF 6-TIAZOL-2-IL-PIRIDIN-2-CARBALDEHYDE (IVf-1) Stage 1 6-f1,31-dioxolan-2-yl-pyridin-2-carbonitrile 3.34 g of 2- [2,3] dioxolan-2-yl-pyridine-1-oxide (19.98 mmol) are dissolved in 409 ml of dichloromethane and then 2.93 ml of cyanotrimethylsilane (21.97 mmol) and 2.53 ml of chloride are successively added. of diethylcarbamoyl (19.96 mmol). The solution is stirred for 240 hours at room temperature, under a nitrogen atmosphere. The reaction mixture is poured slowly into an ice-cold 10% aqueous solution of potassium carbonate; The mixture is extracted with chloroform and then the organic phase is washed with a 10% aqueous solution of potassium carbonate. Dry the mixture over magnesium sulfate, filter and evaporate the chloroform under reduced pressure. The title compound is isolated by chromatography on a silica column (eluent, chloroform). 2.75 g of a white solid is recovered. Yield: 78.1% p. F. 64 ° C. NMR with 1H (CDCl 3) delta: 4.14 (m, 4H), 5.86 (s, 1 H), 7.71 (dd, 1 H), 7.78 (dd, 1 H), 7.91 (t, 1 H).

Stage 2 6-Ri, 31-dioxolan-2-yl-pyridine-2-carboxymethic acid methyl ester 0.20 g of sodium methoxide (3.7 mmol) is added to a solution of 2 g of 2- [1, 3] dioxolan-2-yl-pyridine-2-carbonitrile (11.35 mmol) in 10 ml of methanol. The reaction mixture is stirred for 24 hours under a nitrogen atmosphere. The methanol is evaporated off and then the residue is taken up in a saturated aqueous solution of sodium chloride and the mixture is extracted with ethyl acetate. The organic phase is dried over sodium sulfate, filtered and the solvent is evaporated off. 2.30 g of a white solid is obtained, which is used directly in the next step without further purification.

Step 3 2- (4,5-dihydrothiazol-2-yl) -6-H, 31d -oxolan-2-yl-pyridine 1 g of methyl- [1, 3] dioxolan-2-yl-pyridine-2-carboxylic acid methyl ester (4.80 mmol) and 0.47 g of 2-aminoethanethiol (2.16 mmol) are mixed. The mixture is heated at 130 ° C for 1 hour 30 minutes. The reaction mixture is taken up in chloroform, washed with water and then dried over magnesium sulfate. After filtering and evaporating the solvent, the title product is isolated by chromatography on a silica column (eluent: chloroform / methanol, 98: 2). 1.10 g of solid is recovered. Yield: 97%. p.f. 50-52 ° C. 1 H NMR (CDCl 3) delta: 3.36 (t, 2 H), 4.15 (m, 4 H), 4.55 (t, 2 H), 5.91 (s, 1 H), 7.60 (dd, 1 H), 7.81 (t, 1 H), 8.03 (dd, 1 H).

Step 4 2-thiazol-2-yl-β-H, 31-dioxolan-2-yl-pyridine g of nickel peroxide hydrate are added in portions of 1 g, for 20 hours, to a solution of 1.33 g of 2- (4,5-dihydrothiazol-2-yl) -6- [1, 3] dioxolan- 2-pyridine (5.62 mmol) in 50 ml of benzene, maintained at reflux, with continuous elimination of the water formed. The insoluble material is separated by filtering in Celite, and then the solvent is evaporated off. The title product is isolated by chromatography on a silica column (eluent: chloroform / ethyl acetate, 85:15). 0.42 g of a white solid is recovered. Performance: 31.5%. p.f. 71 ° C. NMR with 1H (CDCl 3) delta: 4.16 (m, 4H), 5.91 (s, 1 H), 7.42 (d, 1 H), 7.54 (dd, 1 H), 7.81 (d, 1 H), 7.89 (t , 1 H), 8.17 (dd, 1 H).

Step 5 6-thiazol-2-yl-pyridine-2-carbaldehyde A solution of 0.93 g of 2-thiazole-2-ii-6- [1, 3] dioxoian-2-yl-pyridine (3.97 mmol) in 8 ml of acid is heated at 60 ° C for one hour and thirty minutes. Formic and 2 ml of water. Solvents are removed by azeotropic entrainment with toluene. The residue is collected in ice-cooled waterThe mixture is neutralized with a 4N aqueous solution of sodium hydroxide and the mixture is then extracted with ethyl acetate. The organic phase is washed with a saturated solution of sodium chloride and then dried over magnesium sulfate, filtered and the solvent is evaporated off. The title product crystallizes by the addition of isopropyl ether. 0.59 g of a white solid is recovered. Performance: 78%. p. F. 91 ° C. 1 H NMR (CDCl 3) delta: 7.48 (d, 1 H), 7.96 (m, 3 H), 8.38 (m, 1 H), . 09 (s, 1 H). IR (KBr) a: 1705 cm "1 (C = 0).

EXAMPLE 8 PREPARATION OF 2-f 1.31DIQXQLAN-2 -IL-ß- (1h-IMIDAZOL-2-ILLPYRIDIN-2-CARBALDEHYDE (IVf-2) The title compound is obtained, in the form of a yellow solid, by carrying out the procedure as in example 7, but replacing in step 3 the 2-aminoethanethiol with ethylenediamine, and in step 4, replacing the peroxide hydrate of nickel with barium permanganate, mp 148 ° C. 1 H NMR (CDCl 3) delta: 4.77 (s, 1 H (exchangeable)), 7.22 (d, 2H), 7.89 (m, 2H), 8.35 (d, 1 H), 10.03 (s, 1 H). IR (KBr) a: 1704 cm "1 (C = 0) EXAMPLE 9 PREPARATION OF 6- (METHYL-5-OXADIAZOL-3-IL) PYRIDINE-2-CARBALDEHYDQ (ivq-1) Stage 1 6-ri, 31-dioxolan-2-yl-N-hydroxypyridine-2-carboxamide 0.88 g of 2- [1, 3] dioxolan-2-yl-pyridine-2-carbonitrile (4.99 mmol), 1.74 g of hydroxyl amine hydrochloride (25 mmol) and 3.45 g of potassium carbonate (25 mmol) are mixed. ) in 15 ml of ethanol, and then the mixture is heated reaction to reflux, for 4 hours. After evaporating the ethanol, the title product crystallizes upon adding water to the residue. 0.80 g of a colorless powder is recovered. Yield: 76.6% p. F. 148 ° C. NMR with 1H (DMSOd6) delta: 4.06 (m, 4H); 5.77 (s, 1 H), 5.82 (s, 2H (exchangeable)), 7.52 (m, 1 H), 7.85 (m, 2H), 9.98 (s, 1 H (exchangeable)).

Step 2 2-ri, 31-dioxolan-2-yl-6- (methyl-5-oxadiazol-3-yl) pyridine 0.30 g of 6- [1, 3] dioxolan-2-yl-Nh? Drox? -p? Ridin-2-carboxyamide (1.43 mmol) is dissolved in 0.60 ml of pyridine and then 0.15 ml of acetyl chloride is added ( 2.11 mmol). The reaction mixture is heated to a reflux temperature of the solvent for 2 hours and 15 minutes. The mixture is poured into an aqueous, ice-cooled solution of potassium bisulfate, and then extracted with ethyl acetate. The organic phase is washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and the ethyl acetate is evaporated off. The title product is isolated by chromatography on a silica column (eluent: chloroform / ethyl acetate, 80:20). 0.15 g of a white powder is recovered. Yield: 45% p.f. 90-91 ° C 1 H NMR (CDCl 3) delta: 2.67 (s, 3 H), 4.13 (m, 4 H), 5.95 (s, 1 H), 7.68 (dd, 1 H), 7 87 (t, 1 H), 8.07 (t , 1 HOUR).

Step 3 6- (Methyl-5-oxadiazol-3-yl) pyridin-2-carbaldehyde The acid hydrolysis of 0.74 g of 6- [1, 3] dioxolan-2-yl-Nh? Droxipyridine-2-carboxamidine (3.17 mmol) is carried out according to a protocol similar to that used in step 5 of the example 7. 0.42 g of the title compound is obtained, in the form of a white powder. Yield: 70%. p.f. 123 ° C. 1 H NMR (CDCl 3) delta: 2.74 (s, 3 H), 8.04 (t, 1 H), 8.10 (dd, 1 H), 8.34 (dd, 1 H), 10.23 (s, 1 H). IR (KBr) a: 1703 cm "1 (C = 0).

EXAMPLE 10 PREPARATION OF 6- (1 H-PIRAZOL-3-IL) -PIRIDIN-2-CARBALDEHYDE (IVh-lai) Step 1 1 - (6-p, 31-dioxolan-2-yl-pyridin-2-yl) ethanone 0.88 g of 2- [1,3] dioxolan-2-yl-pyridine-2-carbonitrile (4.99 mmol) is dissolved in 10 ml of tetrahydrofuran. 3.50 ml of a 3M solution of methylmagnesium bromide in diethyl ether is introduced dropwise into the solution cooled to -10 ° C. The reaction mixture is stirred for three hours at room temperature under a nitrogen atmosphere. The mixture is poured into a saturated aqueous solution of ammonium chloride, the mixture is extracted with ethyl acetate, the organic phase is washed with a saturated aqueous solution of ammonium chloride and then dried over magnesium sulfate, filtered and Concentrate to vacuum. The title product is isolated by chromatography on a silica column (eluent: chloroform). 0.80 g of a yellow oil is recovered. Yield: 83% 1 H NMR (CDCI3) delta: Error! Indefinite marker. 2.72 (s, 3H), 4.15 (m, 4H), 5.89 (s, 1 H), 7.70 (dd, 1 H), 7.86 (t, 1 H), 8.01 (dd, 1 H). IR (film) a: 1700 cm "1 (C = 0) Step 2 3-dimethylamino-1 - (6-H, 31-dioxolan-2-yl-pyridin-2-yl) propenone 0.80 g of 1- (6- [1, 3] dioxolan-2-yl-pyridin-2-yl) ethanone (4.14 mmol) and 1 ml of N, N-dimethylformamide-dlmethylacetal (7.53 mmol) are mixed. The mixture is refluxed for 12 hours and the excess of N, N-dimethylformamide-dimethylacetal is evaporated under vacuum. The title product is obtained in the form of an orange oil, which is used directly in the next step without further purification.

Step 3 2-p, 3ldioxolan-2-yl-6- (1 H -pyrazol-3-ll) pyridine Collect the crude product obtained in step 2 in 5 ml of ethanol and then add 0.80 ml of hydrazine hydrate (25.68 mmol). The solution is heated to reflux for 5 minutes. The ethanol is evaporated off, the residue is taken up in water and the mixture is extracted with chloroform. The organic phase is washed with water, dried over magnesium sulfate, filtered and evaporated. The title product is isolated by chromatography on a silica column (eluent: chloroform / methanol, 98: 2). 0.65 g of a pale yellow gum is obtained. Performance for stages 2 and 3 combined: 72.3%. 1 H NMR (CDCl 3) delta: 4.15 (m, 4 H), 5.90 (s, 1 H), 6.80 (d, 1 H), 7.48 (dd, 1 H), 7.65 (d, 1 H), 7.76 (m , 2H), 11.23 (bs, 1 H).

Stage 4 6- (1 H-pyrazol-3-yl) pyridyl-2-carbaldehyde The deprotection of the acetal function of 2- [1, 3] dioxolan-2-yl-6- (1 H -pyrazol-3-yl) pyridine is carried out in 0.65 g of product (2.99 mmol) according to a protocol similar to that used in step 5 of example 7. The title compound is isolated by chromatography on a silica column (eluent: chloroform / methanol, 98: 2). 0.31 g of a white foam is obtained.

Yield: 59.9% NMR with 1H (DMSOds) delta: 6.91 (d, 1 H), 7.80 (m, 2H), 8.03 (t, 1 H), 8.20 (d, 1 H), 9.99 (s, 1 H) , 13.17 (bs, 1 H (interchangeable)). IR (film) a: 1710 cm "1 (C = 0) EXAMPLE 11 PREPARATION OF 6- (1-METHYLPIRAZZQL-3-IL) PIRIDIN-2-CARBALDEHYD? Step 1 2-p, 3ldioxolan-2-yl-6- (1-methylpyrazol-3-yl) pyridine 2.50 g of 2- [1, 3] -dioxolan-2-yl-6- (1 H -pyrazole-3?) Pipdin (11.5 mmol) dissolved in 4 ml of N, N-dimet is added dropwise. iformam? da, to a suspension of 0.48 g of sodium hydride (20 mmol) in 4 ml of N, N-dimethylformamide. The reaction mixture is stirred for one hour under a nitrogen atmosphere, and then 0.93 ml of methyl iodide (15 mmol), diluted in 1 ml of N.N-dirnethylformamide, is added dropwise to the reaction mixture. The solution is stirred for 12 hours at room temperature and then the mixture is poured into ice water and the mixture is extracted with ethyl acetate. The organic phase is washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated in vacuo. The title product is isolated by chromatography on a silica column (eluent: chloroform / methanol, 99: 1). 0.83 g of a white solid is obtained. Performance: 31%. p.f. 88 ° C NMR with 1H (CDCl 3) delta: 3.99 (s, 3H), 4.11 (m, 4H), 5.90 (s, 1 H), 6.91 (d, 1 H), 7.36 (d, 1 H), 7.42 (dd, 1 H), 7.72 (t, 1 H), 7.90 (dd, 1 H).

Step 2 6- (1-methylpyrazole-3-ii) pyridine-2-carbaldehyde Deprotection of 0.77 g of 2- [1, 3] dioxolan-2-yl-6- (1-methylpyrazol-3-yl) pyridine (3.31 mmol), according to a protocol similar to that used in step 5 of the example 7, gives 0.48 g of the title product (2.51 mmol) after purification by chromatography on a silica column (eluent: ethyl acetate). Yield: 75.8% p.f. 98-100 ° C. 1 H NMR (CDCl 3) delta: 3.98 (s, 3 H), 6.93 (d, 1 H), 7.42 (d, 1 H), 7.84 (m, 2 H), 8.09 (dd, 1 H), 10.12 (s, 1 HOUR). IR (KBr) a: 1710 cm "1 (C = 0) EXAMPLE 12 PREPARATION OF 6-1SOPROPILPIRIDIN-2-CARBALDEHÍDQ (IVi) Stage 1 2-f1, 31-dioxolan-2-yl-6-isopropenylpyridine 1.62 g of potassium terbutoxide (14.4 mmol) is added in portions to a suspension of 5.25 g of (methyl) triphenylphosphonium bromide (14.7 mmol) in 30 ml of tetrahydrofuran, kept under a nitrogen atmosphere. HE The mixture is stirred for 45 minutes and then a solution of 0. 95 g of 1- (6- [1, 3] d -oxolan-2-yl-pyrridin-2-yl) ethanone (4.92 mmol) in 5 ml of tetrahydrofuran. The mixture is stirred for 12 hours at room temperature and then poured into a saturated aqueous solution of ammonium chloride. The mixture is extracted with ethyl acetate, the organic phase is washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is taken up in diethyl ether and the precipitate formed is filtered off. After evaporating the solvent, the title product is isolated by chromatography on a silica column (eluent: hexane / ethyl acetate, 85:15). 0.67 g of a pale yellow oil is obtained. Yield: 71.6% NMR with 1H (CDCI3) delta: 2.22 (s, 3H), 4.16 (m, 4H), 5.31 (m, 1H), 5.87 (s, 1 H), 5.91 (m, 1H), 7.44 (m, m, 2H), 7.70 (t, 1 H).

Stage 2 2-f1, 31dioxol3n-2-l-6-isopropylpyridine A suspension of 0.60 g of 2- [1, 3] dioxolan-2-yl-6-isopropenylpyridine (3.15 mmol) and 0.10 g of 10% palladium on carbon ai in 7 ml of methanol is vigorously stirred under pressure of hydrogen low, for 4 hours, at room temperature. The solid is separated by filtration in Celite and then methanol is evaporated off. The product is isolated from title by chromatography on a silica column (eluent: chloroform / ethyl acetate, 97: 3). 0.40 g of a pale yellow oil is obtained. Yield: 66%. NMR with 1H (CDCl 3) delta: 1.30 (d, 6H), 3.07 (m, 1 H), 4.13 (m, 4H), . 83 (s, 1 H), 7.17 (d, 1 H), 7.36 (d, 1 H), 7.66 (t, 1 H).

Stage 3 6-isopropylpyridin-2-carbaldehyde Deprotection of 0.36 g of 2- [1, 3] dioxolan-2-yl-6-isopropylpyridine (1.87 mmol) according to a protocol similar to that used in step 5 of Example 7, gives 0.31 g of the title product ( 1.81 mmol) after purification by chromatography on a silica column (eluent: chloroform). Yield: 96.8% NMR with 1H (CDCl 3) delta: 1.34 (d, 6H), 3.10 (m, 1 H), 7.37 (m, 1 H), 7.73 (d, 2H), 10.03 (s, 1H). IR (film) a: 1712 cm "1 (C = 0) EXAMPLE 13 PREPARATION OF 6-QXAZQL-5-IL-PIRID1N 2-CARBALDEHÍDQ (IVk) Stage 1 2-ri, 31-dioxolan-2-yl-6-oxazol-5-yl-pyridine g of methanol are mixed with 1 g of 6- [1, 3] dioxolan-2-yl-pyridine-2-carbaldehyde (5.58 mmol), 1.10 g of tosylmethyl isocyanate (5.63 mmol) and 0.80 g of potassium carbonate. (5.79 mmol) in 15 ml of methanol. The suspension is heated at reflux for 2 hours. The methanol is removed, the residue is taken up in a saturated aqueous solution of sodium chloride and the mixture is extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and then concentrated in vacuo. The title product is isolated by chromatography on a silica column (eluent: hexane / ethyl acetate, 50:50). 1.14 g of a yellow oil is obtained. Yield: 93.6 & 1 H NMR (CDCl 3) delta: 4.13 (, 4 H), 5.86 (s, 1 H), 7.48 (d, 1 H), 7.63 (d, 1 H); 7.77 (m, 2H), 7.95 (s, 1 H).

Stage 2 ß-oxazol-5-yl-pyridine-2-carbaldehyde Deprotection of 0.95 g of 2- [1, 3] dioxolan-2-yl-6-oxazol-5-yl-pyridipase (4.35 mmol) according to a protocol similar to that used in step 5 of example 7, gives 0 32 g of the title product, after purification by chromatography on a silica column (eluent: chloroform / ethyl acetate, 80:20). Yield: 42.3% p. F. 151 ° C. NMR with 1H (CDCI3) delta: 7.81 -8.01 (m, 5H), 10.08 (s, 1 H) IR (KBr) un- 1703 cm "1 (C = 0) EXAMPLE 14 PREPARATION OF 6-CICLOPROPYLPYRIDIN-2-CARBALDEHYDE flVI) Stage 1 2-H.31-dioxolan-2-yl-vinylpyridine A mixture of 3.10 g of 6- [1, 3] dioxolan-2-yl-pyridine-2-carbaldehyde (17.3 mmol), 9.26 g of (metii) triphenylphosphonium bromide and 4.80 g of carbonate is maintained at reflux for 5 hours. of potassium (34.8 mmol) in 60 ml of 1,4-dioxane. The solid is filtered off, and then ejected by evaporation the solvent. The residue is taken up in ethyl acetate. The solution is washed with water and then with a saturated aqueous solution of sodium chloride; Dry over magnesium sulfate and filter. After evaporating the solvent the title compound is isolated by chromatography on a silica column (solvent: hexape / ethyl acetate, 80.20). 1.63 g of a yellow oil is obtained. Yield: 53.2% NMR with 1H (CDCI3) delta. 5.47 (dd, 1 H), 5 83 (s, 1 H), 6.18 (dd, 1 H), 6.83 (dd, 1 H), 7 36 (m, 2H), 7 67 (t, 1 H) Stage 2 2-cyclopropyl-6-f1, 31-dioxolan-2-yl-pyridine .60 ml of a 1 6M solution of n-butyllithium in hexane is dropped in a suspension of 2.71 g of tpmethylsulfonium iodide (13.3 mmol) in 25 ml of tetrahydrofuran cooled to -15 ° C. The solution is stirred at -15 ° C for 20 minutes under nitrogen, and then a solution of 1.57 g of 2- [1, 3] dioxolan-2-yl-6-vinylpipdine (8.90 mmol) is added dropwise. 5 ml of tetrahydrofuran. After stirring for one hour at -15 ° C, the suspension is stirred for three hours at room temperature. The tetrahydrofuran is evaporated off, the residue is taken up in water and the mixture is extracted with ethyl acetate. The organic phase is washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and Concentrate to vacuum. The title product is isolated by chromatography on a silica column (eluent: hexane / ethyl acetate: 50:50). 1.24 g of a colorless oil is obtained. Yield: 73% NMR with 1H (CDCl 3) delta: 0.98 (, 4H), 2.06 (m, 1 H), 4.09 (m, 4H), 5.76 (s, 1 H); 7.03 (dd, 1 H), 7.25 (dd, 1 H); 7.55 (t, 1 H).

Stage 3 ß-cyclopropylpyridine-2-carbaldehyde Deprotection of 1.14 g of 2-cyclopropii-6- [1,3] dioxolan-2-yl-pyridine (5.96 mmol), according to a protocol similar to that used in step 5 of example 7, gives 0.75 g of the product of the title, after purification by chromatography on a silica column (eluent: hexane / ethyl acetate, 90:10). Performance: 85%. NMR with 1H (CDC! 3) delta: 1.09 (m, 4H), 2.10 (m, 1 H), 7.33 (m, 1 H), 7.68 (m, 2H), 9.96 (s, 1 H). IR (film) a: 1713 cm'1 (C = 0) EXAMPLE 15 PREPARATION OF 6- (1-FLUOROETHYL) PlRIPIN-2-CARBALDEHYDE (IVi) Step 1 1 - (6-H, 31-dioxolan-2-yl-pyridin-2-yl) ethanol 0 50 g of potassium borohydride (927 mmol) is added in portions to a solution of 0 90 g of 1- (6- [1,3] d? Oxolan-2-yl-p? R? D? N-2 -yl) ethanone (4.66 mmol) in 15 ml of methanol. The mixture is stirred for 12 hours at room temperature and then the methanol is evaporated off and the residue is taken up in chloroform. The organic phase is washed with water and then dried. on sodium sulphate, filtered and concentrated in vacuo. 070 g of a pale yellow oil is obtained, and said oil is used in the next step, without further purification 1 H NMR (CDCl 3) delta-1 47 (d, 3 H), 1 84 (s, 1 H (interchangeable)), 4 11 (m, 4H), 4.88 (m, 1 H), 5.82 (s, 1 H), 7.25 (d, 1 H), 741 (d, 1 H), 7.75 (t, 1 H) Step 2 2-H.3ldioxolan-2-yl-6-. { 1-fluoroetyl) pyridine 0.81 ml of diethylamine trifluorosulfide (6-14 mmol) is added to a solution of 0.60 g of 1- (6- [1,3] -d? Oxolan-2-? L-pyrid? N-2-yl) ethanol in 25 ml of dichloromethane cooled to -78 ° C, and kept under a nitrogen atmosphere. The mixture is stirred for 30 minutes at -78 ° C and then for 2 hours at room temperature. The mixture is slowly poured into a 10% aqueous solution of sodium bicarbonate. The organic phase is dried over magnesium sulfate, filtered and the solvent is evaporated off. The title product is isolated by chromatography on a silica column (eluent: chloroform). 0.42 g of a yellow oil is obtained. Performance for the 2 combined stages: 53.4%. 1 H NMR (CDCl 3) delta: 1.69 (dd, 3 H), 4.11 (m, 4 H), 5.77 (dc, 1 H), 5.83 (s, 1 H), 7.48 (d, 2 H), 7.79 (t, 1 H).

Stage 3 ß-? 1-fluoroethyl) pyridin-2-carbaldehyde Deprotection of 0.40 g of 2- [1, 3] dioxolan-2-yl-6- (1-fluoroethyl-pyridine (2 mmol) according to a protocol similar to that used in step 5 of example 7, gives 0.32 g of the product of the title in the form of a yellow oil used in the next step, without further purification 1 H NMR (CDCl 3) delta: 1.72 (dd, 3 H), 5.75 (dc, 1 H), 7.70 (dd, 1 H); 7.90 (m, 2H), 10.03 (s, 1 H). IR (film) a: 1715 cm "1 (C = 0).

EXAMPLE 16 PREPARATION OF 6- (1-FLUOROMETHYL) -PIRIDLN-2-CARBALDEHYDE (IVm- 11) The title compound is obtained, in the form of a yellow solid, by carrying out the procedure as in example 15 but replacing 1- (6- [1, 3ld? Oxolan-2? Lp? Pd? N-2 -? l) etapol with 1- (6- [1, 3] d? oxolan-2-? lp? r? d? n-2-? l) methanol in step 2 pf 60 ° C NMR with H (CDCb ) delta 5 55 (d, 2H, J = 47 Hz), 7 68 (dd, 1 H), 7 90 (m, 2H), 15 35 (s, 1 H) IR (KBr) u 1721 cm (C = 0) EXAMPLE 17 PREPARATION OF 6-11.1-DIFLUOROMETHYL) -PIRIDIN-2-CARBALDEHYDE (IVm-2) Stage 1 2-p .3ldioxolan-2-yl-6- (1.1 - ifluorotnetillpiridiria 2.21 ml of diethylamine tpfluorosulfide is added dropwise to a solution of 240 g of 6- [1,3] d? Oxolan-2? Lp? Pd? P-2-carbaldehyde (134 mmol) in 20 ml of Chloroform The mixture is stirred at room temperature, under nitrogen, for 12 hours and then the mixture is poured into a 20% solution of sodium bicarbonate, cooled with ice. The organic phase is dried over magnesium sulfate, filtered and concentrated in vacuo. The title product is isolated by chromatography. on a silica column (eluent chloroform) 1 60 g of a yellow oil is obtained Yield 59 3% NMR with 1H (CDCl 3) delta 4 11 (m, 4H), 5 85 (s, 1 H), 6 65 (t , 1 H), 7 63 (m, 2H), 7 88 (t, 1 H) Stage 2 6-11.1 -difluoromßtippiridin-2-carbaldehyde Deprotection of 0 85 g of 2- [1, 3] d? Oxolan-2? L-6- (1, 1-d? Fluoromet? L) p? Nd? Pa (4 20 mmol), in accordance with a protocol similar to that used in step 5 of Example 7, gives 0 70 g of the product in the form of a yellow oil, which is used in the next step without further purification 1 H NMR (CDCl 3) delta 6 69 (t, 1) H), 7 85 (m, 1 H), 8 03 (m, 2H), 10 05 (s, 1 H) IR (film) a 1721 cm "1 (C = 0) EXAMPLE 18 PREPARATION OF THE METHYL ESTER OF 6-FORMILP1RIDIN-2-CARBQXYLIC ACID (IVo) A solution of 3 g of acid methyl ester is heated to reflux. 6-hydroxy-methy1pyridine-2-carboxylic acid (16.5 mmol) in 709 ml of 1,2-d-chloroethane containing 15 g of manganese dioxide (165 mmol), for 4 hours, with continuous removal of the water formed. The solid is filtered through Celite and then the dichloromethane is evaporated off. The title product is isolated by chromatography on a silica column (eluent: dichloromethane / ethyl acetate, 70.30). 2.33 g of a yellow oil is recovered. Yield: 79% NMR with 1H (CDCl 3) delta: 1.36 (t, 3H), 4.41 (m, 2H), 8.13 (dd, 1 H), 8.24 (t, 1 H), 8.32 (dd, 1 H), 10.02 (s, 1 H). IR (film) a: 1 00 cm "1 (C = 0) EXAMPLE 18a PREPARATION OF 5-METHYL-6-METHYLAMINQ-PIRIDIN-2-CARBALDEHYDQ (IVs-1) Stage 1 (6-chloro-5-methylpyridin-2-yl) methanol 0.40 g of sodium borohydride (10.5 mmol) is added in portions to a solution of 1.20 g of 6-chloro-5-methylpyridine-2-carboxylic acid ethyl ester (6.00 mmol) and 10 ml of ethanol, and is maintained at 100 ° C. the room temperature. The mixture is stirred for 4 hours and then the mixture is poured into an aqueous solution of sodium chloride and the mixture is extracted with ethyl acetate.

The organic phase is dried over sodium sulfate, filtered and concentrated in vacuo.

The title product is isolated by chromatography on a silica column (eluent: chloroform). Recover 0.69 g of a colorless oil. Performance: 73%. 1 H NMR (CDCl 3) delta: 2.37 (s, 3 H), 4.70 (s, 2 H), 2.94 (s, broad), 7.17 (d, 1 | H), 7.55 (d, 1 H).

Step 2 (5-methyl-6-methylaminopyridin-2-yl) m? Tanol The mixture is heated at 120 ° C in a pump, for 96 hours, 0.96 g of (6-chloro-5-methylpyridin-2-yl) methanol (6.09 mmol) and 7 ml of methylamine, 33% in ethanol. 2 ml of 33% methylamine in ethanol is added every 24 hours. The reaction mixture is concentrated in vacuo and the title compound is isolated by chromatography on a silica column (eluent: cyclohexane / ethyl acetate, 40:60). 0.34 g of a white solid is recovered. Yield: 37%. p.f. 87 ° C. 1 H NMR (CDCl 3) delta: 2.06 (s, 3 H), 3.05 (d, 3 H), 4.13 (s, 1 H), 4.24 (s, 1 H), 4.59 (d, 2 H), 6.39 (d, 1) H), 7.18 (d, 1 H).

Stage 3 5-methyl-6-methylaminopyridine-2-carbaldehyde A suspension of 0.33 g of (5-methyl-6-methylaminopyridin-2-yl) methanol (2.17 mmol) and 1.6 g of manganese dioxide (18.4 mmol) in 12 ml of chloroform is heated at reflux for 1 hour. The insoluble material is removed by filtration on Celite and then the solvent is evaporated in vacuo. The Title product by chromatography on a silica column (solvent: chloroform). 0.25 g of a yellow solid is recovered. Yield: 77% p.f. 79 ° C. 1 H NMR (CDCl 3) delta: 2.15 (s, 3 H), 3.12 (d, 3 H), 4.36 (s, 1 H), 7. 22 (d, 1 H), 7.35 (d, 1 H); 9.93 (s, 1 H).

EXAMPLE 18b PREPARATION OF 5-METHYL-6-DIMETHYLAMINOPYRIDIN-2-CARBALDEHYDE (IVs-2) The title compound is prepared in the form of a yellow oil following the procedure of example 18a, but replacing in step 2 the 33% methylamine in ethanol, with 33% dimethylamine in ethanol. 1 H NMR (CDCl 3) delta: 2.37 (s, 3 H), 2.93 (s, 6 H), 7.45 (d, 1 H), 7. 50 (d, 1 H), 9.93 (s, 1 H).

EXAMPLE 18c PREPARATION OF 3-METHYL-6-DIMETHYLAMINE-PIRIDIN-2-CARBALDEHYDQ (IV s-3) 2.65 ml of a 1.6M solution of n-butyllithium in hexane is introduced into a 0.53 ml solution of N, N, N'-trimethylethylenediamine (4.24 mmol) and ml of tetrahydrofuran, cooled to -60 ° C. The solution is stirred for 15 minutes at -40 ° C and then cooled to -70 ° C and a solution of 0.50 g of 6-chloropyridin-2-carbaldehyde (3.53 mmol) and 4 ml of tetrahydrofuran is dropped in. . The orange solution is stirred for 30 minutes at -70 ° C and then 1.28 ml of tetramethylethylenediamine (8.48 mmol) is introduced, and then, after 10 minutes, 5.30 ml of a 1.6 M solution of n-butyl- lithium in hexane. The brown solution is stirred for two hours at -78 ° C and 1.50 ml of methyl iodide (25 mmol) is added dropwise. After stirring for one hour at -78 ° C and then for 10 minutes at 20 ° C, the reaction mixture is poured into a saturated aqueous solution of sodium chloride and extracted with ethyl acetate. The organic phase is washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and the solvent is evaporated off. 0.23 g of the title product is recovered after purification by chromatography on a silica column (eluent: hexane / ethyl acetate, 95: 5). Yield: 41.9% 1 H NMR (CDCl 3) delta: 2.64 (s, 1 H), 742 (d, 1 H), 7.61 (d, 1 H), 10.09 (s, 1 H). IR (film) a: 1710 cm "1 (C = 0) EXAMPLE 19 PREPARATION OF (4-AMINOMETHYL-4-FLU? R? PIPERIDIN-1-IL) - (3-CLQR? -4-FLU? RQFENIDMET ANONA (V-1) Stage 1 (4-fluoro-4-hydroxyethylpiperidin-1-yl) - (3-chloro-4-fluorophenyl) rnßtanone 11.9 g of (1-oxa-6-azaspiro [2.5] oct-6-yl) - (3-chloro-4-fluorophenyl) methanone (44.12 mmol) is dissolved in 20 ml of dichloromethane. 13 ml of HF-pyridine complex (441 mmol) is introduced into the solution cooled to ° C and maintained under nitrogen. The solution is stirred for 12 hours at room temperature and then poured into ice-cold water. The medium is basified by adding potassium carbonate and then extracted with chloroform. The organic phase is washed with an aqueous solution 1 of hydrochloric acid, dried over magnesium sulfate, filtered and concentrated in vacuo. The title product is purified by recrystallization from ethanol / ethyl acetate mixture. 6.40 g of a white crystalline powder is obtained. Yield: 50%. p.f. 188-90 ° C Analysis C13H1 CIF2N02: Calculated%: C, 53.90; H, 4.87; Cl, 12.24; N, 4.83 Found: 45.08; 4.86; 12.28; 4.70.

NMR with 1H (CDCl 3) delta: 1.35-2.15 (m, 4H), 1.63 (s, 1 H (exchangeable)), 2.95-3.50 (m, 3H), 3.64 (d, 2H), 4.29-4.70 (m, 1 H), 7.12-7.32 (m, 2H), 7.47 (dd, 1 H). IR (KBr) a: 1512 cm "1 (C = 0); 3328 cm" 1 (O-H).

Stage 2 Ester 1- (3-chloro-4-fluorobenzoyl) -4-fluoropipridin-4-ylmethyl of toluene-4-sulfonic acid 4.87 g of para-toluenesulfonyl chloride is added slowly (25.5 mmol) to a solution of 6.70 g of (4-fluoro-4-hydroxymethylpiperidin-2-yl) - (3-chloro-4-fluorophenyl) -methanone (23.12 mmol) in 40 ml of pyridine., cooled to 0 ° C and maintained under a nitrogen atmosphere. The mixture is stirred for 12 hours at room temperature and then poured into ice-cooled water, extracted with chloroform and then the organic phase is washed with a 1N aqueous solution of hydrochloric acid. The organic phase is dried over magnesium sulfate, filtered and then concentrated in vacuo. The title product is purified by recrystallization from a dichloromethane / diisopropyl ether mixture. 7.73 g of a white crystalline powder is obtained. Yield: 76% p. F. 92 ° C. 1H NMR (CDCI3) delta: 1.35-1.95 (m, 4H), 2.43 (s, 3H), 2.95- 3.90 (m, 2H), 3.60 (dd, 1 H), 3.97 (d, 2H), 4.25- 4.70 (m, 1 H), 7.15 (t, 1 H), 7.25 (m, 2H), 7.34 (d, 1H), 7.44 (dd, 1H), 7.76 (d, 2H).

Step 3 2-ri- (chloro-4-fluorobenzoyl) -4-fluoro-piperidin-4-llmetin-isoindol-1,3-dione.

A mixture of 5.42 g of the toluene-4-sulphonic acid 1- (3-c-oro-4-fluorobenzoyl) -4-fluoropiperidin-4-yl methyl ester is heated at 150 ° C for 5 hours (5 hours). 12.2 mmol) and 2.96 g of potassium phthalimide (16 mmol) in 70 ml of N, N-dimethylformamide. The mixture is poured into ice water and then extracted with chloroform. After evaporating the solvents in vacuo, the title product is isolated by chromatography on a silica column (eluent: chloroform / ethyl acetate, 90:10). 4.02 g of a crystalline, white powder is obtained. Performance: 79%. p. F. 133-34 ° C. Analysis C21H17F2CIN2? 3: Calculated,%: C, 60.22; H, 4.09; Cl, 18.46; N, 6.69; Found: 60.12; 3.97; 8.51; 6.71.

NMR with 'H (CDCl 3) delta: 1 90 (m, 4 H), 3.25 (m, 2 H), 3.65 (m, 1 H), 3.90 (d, 2 H), 4.55 (m, 1 H), 7 12 ( t, 1 H), 7.27 (m, 1 H), 748 (dd, 1 H); 7.75 (m, 2H), 7.88 (m, 2H) IR (KBr) un: 1716 and 1776 cm "1 (C = 0).

Step 4 (4-amomethyl-4-fluoropiperdin-1-yl) -f3-chloro-4-fluorophenyl) methanone 0.10 g of 2- [1- (3-chloro-4-fluorobenzoyl) -4-fluorop? Per? Din-4-yl-methyl] -isoindol-1,3-dione (0.238 mmol) and 0.50 is mixed. ml of ethanolamine (8.28 mmol), and the solution obtained is heated at 55 ° C under nitrogen atmosphere, for 2 hours. The mixture is poured into ice water, then extracted with chloroform. The organic phase is washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and the solvent is evaporated off. 0.06 g of the title product is obtained, in the form of a colorless oil, which is used in the next step without further purification. NMR with 1H (CDCI3) delta: 1 21-1.75 (m, 4H, of which 2 are exchangeable H), 1.90 (m, 2H), 2.79 (d, 2H), 3.22 (m, 2H), 3.62 (m , 1 H), 4.49 (m, 1 H), 7.14 (t, 1 H), 7.25 (m, 1 H), 7.44 (dd, 1 H).

EXAMPLE 20 PREPARATION OF (4-AMINOMETHYL-4-FLUORO-PIPERIDIN-1-IL) - (3,4- DICLOROFENID-MET ANONE (V-2) The title compound is obtained, in the form of a yellow oil, by carrying out the procedure as in example 19, but replacing in step 1 (1-oxa-6-azaspiro [2.5] oct-6-yl) - (3-chloro-4-fluorophen? L) methanone with (1-oxa-6-azaspiro [2.5] oct-6-yl) - (3,4-dichlorophen?) Methanone, in step 2, the ( 4-fluoro-4-hydrox? Met? Lpiperidin-1-? L) - (3-chloro-4-fluorophenyl) methanone with (4-fluoro-4-hydroxymethylpipepd? N-1-yl) - (3, 4-dichlorophen? L) -metanone, in step 3, the 1- (3-chloro-4-fluorobenzoyl) -4-fluoropiperidin-4-yl-methyl ester of toluene-4-sulfonic acid, with ester 1- (3,4-dichlorobenzoyl) -4-fluoropiperidin-4-iimethyl of toluene-4-sulfonic acid, and in step 4, 2- [1- (3-chloro-4-fluorobenzoyl) -4-fluoropiper Din-4-? L-met? L] isoindol-1,3-dione with 2- [1- (3,4-dichlorobenzoyl) -4-fluoropipepdin-4-? Memethyl] isoindol-1,3-d? ona NMR with 1H (CDCI3) delta: 1.24-1.80 (m, 4H, of which 2 are interchangeable H), 1.94 (m, 2H), 2.82 (d, 2H), 3.28 (m, 2H), 3.59 (m, 1 H), 4.52 (m, 1 H), 7.26 (m, 1 H); 7.48 (m, 2H).

EXAMPLE 20a PREPARATION OF (4-AMINOMETHYL-4-FLUOROPIPERIDIN-1 -IL) - (3-CLQR? -4-METHYLPHENIDMETANQNA (V-3) The title compound is obtained, in the form of a yellow oil, by carrying out the procedure as in example 19, but using as starting material (1-oxa-6-azaspiro- [2.5] oct-6-yl) - (3-chloro-4-methylphenyl) methanone. 1 H NMR (CDCl 3) delta: 1.23 (m, 2 H), 1.59 (, 2 H), 1.95 (m, 2 H), 2.40 (s, 2 H), 2.87 (d, 2 H), 3.14 (m, 1 H), 3.37 (m, 1 H), 3.60 (m, 1 H), 4.56 (m, 1 H), 7.21 (dd, 1 H), 7.27 (d, 1 H), 7.39 (d, 1 H).

EXAMPLE 21 PREPARATION OF (4-AZIDOMETHYL-4-FLUOROPIPERIDIN-1-ILH3-CHLORO-4-FLUORO-FENIDMETANONE (VI-1) 0.70 g of the 1- (3-chloro-4-fIuorobenzoyl) -4-fluoroplperidin-4-ylmethyl ester of toluene-4-sulfonic acid (1.57 mmol), 0.308 g of sodium azide (4.70 mmol) and 0.20 g are mixed. of tetrabutylammonium azide (0.70 mmol), in 3.50 ml of dimethyl sulfoxide. The mixture is heated at 110 ° C under nitrogen atmosphere for 20 hours. The reaction mixture is poured into ice water, and then extracted with ethyl acetate. The organic phase is washed with water and then with a saturated aqueous solution of sodium chloride, dried on magnesium sulfate, filtered and concentrated in vacuo. The title product is isolated by chromatography on a neutral alumina column (eluent: hexane / ethyl acetate, 70:30). 0.313 g of a yellow oil is obtained. Performance: 63%. 1 H NMR (CDCl 3) delta: 1.63 (m, 2 H), 1.98 (m, 2 H), 3.25 (m, 2H), 3.36 (d, 2H), 3.66 (m, 1 H), 4.54 (m, 1 H), 7.14-7.50 (m, 3H). IR (film) a: 1635 cm "1 (C = 0); 2102 cm" 1 (N3).

EXAMPLE 22 PREPARATION OF (4-AZLOMETHYL-4-FLUORO-PIPERIDIN-1 -IL) - (3,4-DICHLOROFENID-METANONE (VI-2) The title product is obtained, in the form of a yellow oil, in a manner similar to that of Example 21, but starting with 1- (3,4-dichlorobenzoyl) -4-fluoropiperidin-4-ylmethyl ester of toluene-4 acid. -sulfonic instead of the 1- (3-chloro-4-fluorobenzoyl) -4-fluoropiperidin-4-yl-methyl ester of toluene-4-sulfonic acid. 1 H NMR (CDCl 3) delta: 1.55 (m, 2 H), 1.96 (m, 2 H), 3.20 (m, 2 H), 3.33 (d, 2 H), 3.60 (m, 1 H), 4.54 (m, 1 H) , 7.20 (dd, 1 H), 7.47 (m, 2H). IR (film) a: 1638 cm "1 (C = 0), 2102 cm" 1 (N3).

EXAMPLE 23 PREPARATION OF (3,4-DICHLOROFENILM4-fr (6-FLUOROPIRIDIN-2-ILMETIL) AMIN01METIL1P1PERIDIN-1-IL, METANQNA (I-51) 0 29 g of 6-fluoropyridin-2-carbaldehyde (2 31 mmol) and 0264 g of p? Pepd? N-4-? Lmet? Lam? Na (2 31 mmol) in 20 ml are mixed. of benzene The solution is heated at reflux under nitrogen atmosphere for 2 hours, with continuous elimination of the formed water. The solvent is removed by evaporation and the residue is taken up in 2 ml of tetrahydrofuran. The obtained solution is cooled to 0 ° C. add successively 0 50 ml of tetylamine (350 mmol) and then add 0469 g of 3,4-d-chlorobenzoyl chloride (2 24 mmol) diluted in 1 ml of tetrahydrofurane. The mixture is stirred for two hours. room temperature 10 ml of methanol are added, in portions, by 025 g of potassium borohydride (462 mmol) After 4 hours at room temperature the solvents are removed by evaporation, the residue is taken up in water and extracted with chloroform. The organic phase is washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo. titre by chromatography on a silica column (eluent chloroform / methanol, 95 5) Obtained 0 40 g of a yellow solid Yield 40% p. F. 78 ° C. 1 H NMR (CDCl 3) delta: 1.18 (m, 2 H), 1.77 (m, 3 H), 1.99 (s, 1 H (exchangeable)), 2.52 (d, 2 H), 2.86 (m, 2 H), 3.66 (m , 1 H), 3.82 (s, 2H), 4.67 (m, 1 H), 6.78 (dd, 1 H), 7.22 (m, 2H), 7.46 (m, 2H); 7.72 (c, 1 H).

EXAMPLE 24 PREPARATION OF (4-rr (6-AZETIDIN-1-IL-PIRIDIN-2-IL-METHYL) - AMINOLEMETIC> -PIPERIDIN-1-lL) -3,4-DICHLOROPHENYL) -MET ANONE (1-17) ) 0.121 g of azetidine (3.15 mmol) is added to a solution of 0.70 g of (3,4-dichlorophenyl) - ( { [(6-fluoropyridin-2-y [(methyl) amino] methyl) piperidin- 1-yl) methanone (1.77 mmol) in 10 ml of tetrahydrofuran. The solution is heated at 100 ° C for 32 hours. The solvent is evaporated in vacuo and then the residue is taken up in water, and the mixture is extracted with chloroform. The organic phase is washed with water and then with a saturated solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated in vacuo. The title product is isolated by chromatography on a silica column (eluent: chloroform / methanol, 90:10). 0.401 g of a yellow oil is obtained. Yield: 52.3%. 1 H NMR (CDCl 3) delta: 1.22 (m, 2 H), 1.78 (m, 3 H), 2.13 (s, 1 H (exchangeable)), 2.34 (m, 2 H), 2.51 (d, 2 H), 2.75 (m , 1H), 3.01 (m, 1H), 3.60 (m, 1 H), 3.69 (s, 2H), 3.97 (t, 4H), 4.61 (m, 1 H), 6.10 (d, 1 H), 6.48 (d, 1 H), 7.18 (dd, 1 H), 7.34 (dd, 1 H); 7.42 (m, 2H). 0.34 g of the title product (0.784 mmol) is dissolved in 1 ml of ethanol and then 0.067 g of oxalic acid (0.745 mmol) is added. After the solution, the salt is precipitated by adding ethyl acetate, filtered, washed with ethyl acetate and then dried at 50 ° C under vacuum. 0.290 g of the oxalate of the title compound is obtained in the form of a white crystalline powder. p. F. 220-21 ° C. Analysis C2 H28CI2N4O5: Calculated,%: C, 55.07; H, 5.39; Cl, 13.55; N, 10.70. Found: 54.87 5.41; 13.29; 10.63. 1 H NMR (DOMSODg) delta: 1.19 (m, 2 H), 1.80 (m, 2 H), 2.00 (m, 1 H), 3.35 (m, 2 H), 2.75 (m, 1 H), 2.88 (d, 2 H) ), 3.04 (m, 1 H), 3.49 (m, 1 H), 3.95 (t, 4H); 4.09 (s, 2H), 4.39 (m, 1 H), 6.31 (d, 1 H), 6.68 (d, 1H), 7.35 (dd, 1H), 7.53 (t, 1 H), 7.65 (d, 1) H), 7.70 (d, 1 H). IR (KBr) a: 1632 and 1710 cm "1 (C = 0).

EXAMPLE 25 PREPARATION OF 3-CHLORO-4-FLUOROFENILH4-FLUORO ~ 4-ffl6-FURAN-2-IL-PYRIDIN-2-L-METHYL) AMINQMMETLL} -PIPERIDIN-1-IL) MET ANONA (I-32) 0.687 g of (4-am? Nometyl-4-fluorop? Peridin-1-? L) - (3-chloro-4-fluorophenyl) methanone (2.38 mmol) and 0.371 g of 6-furan-2- are mixed. il-pindin-2-carbaldehyde (2.38 mmol) in 25 ml of toluene. The solution is heated at reflux, under a nitrogen atmosphere, for two hours, continuously removing the water formed. The toluene is evaporated off, the residue is taken up in 25 ml of methanol and then 0.257 g of potassium borohydride (4.51 mmol) is added in portions. The reaction mixture is stirred for 5 hours at room temperature and then the methanol is evaporated off. The residue is taken up in chloroform, the organic phase is washed with water and then with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated in vacuo. The title product is isolated by chromatography on a silica column (eluent: chloroform / methanol: 98: 2). 0.65 g of a yellow oil is obtained. Yield: 61.2%.

NMR with 1H (CDCI3) delta: 1.40-2.20 (m, 5H, of which 1 is exchangeable H), 2.81 (d, 2H), 3.28 (m, 2H), 3.57 (m, 1 H), 3.94 (s) , 2H), 4.48 (m, 1 H), 6.51 (c, 1 H), 7 02 (d, 1 H), 7.19 (m, 4H), 7.55 (m, 3H) 0.620 g of the title product is dissolved (1.39 mmol) in 20 ml of ethanol and then 0.160 g of fumaric acid (1.38 mmol) is added. The solution is concentrated, the salt is precipitated when ethyl acetate is added, it is filtered, washed with ethyl acetate and then dried under vacuum at 50 ° C. 0.520 g of the fumarate of the title compound is obtained, in the form of a white, p-stalk powder, e.g. F. 158 ° C. Analysis C27H26CIF N306: Calculated,%: C, 57.71; H, 4.66; Cl, 6.31; N, 7.48. Found: 57.96; 4.70; 6.31; 7.45. NMR with 1H (DMSOd6) delta: 1.72 (m, 1 H), 1.85 (m, 3H), 2.81 (d, 2H), 2.95-3.55 (m, 3H), 3.91 (s, 2H), 4.25 (m, 1 H), 6.60 (s, 2H), 6.64 (c, 1 H), 7.09 (d, 1 H), 7.34 (d, 1 H); 7.47 (m, 2H), 7 62 (m, 2H), 7.82 (t, 2H). IR (Kbr) a: 1621 and 1701 cm "1 (C = 0). 0 EXAMPLE 26 PREPARATION OF? 3-CHLORINE-4-FLUOROFENIL) - (4-FLUORO-4-Tr (6-DIMETHYLAMIN-PYRIDIN-2-IL-MET1-DAMIN-1-METHYL-PIPERIDIN-1-IL-METHANONE (1-13) The title compound is obtained, in the form of a yellow oil, by carrying out the procedure as in example 25, but replacing di-6-furan-2-yl-pyridine-2-carbaldehyde with 6-dimethylaminopyridin-2. -carbaldehyde, after purification on a silica column (eluent: chloroform / methanol, 97: 3). Yield: 69.5% 1 H NMR (CDCl 3) delta: 1.57 (m, 1 H), 1.73 (m, 1 H), 2.00 (m, 2H), 2.15 (s, 1 H (Interchangeable)), 2.75 (d, 2H), 3.04 (s, 6H), 3.25 (m, 2H), 3.55 (m, 1 H), 3.72 (s, 2H), 4.62 (m, 1 H), 6.34 (d, 1 H), 6.43 (d, 1 H), 7.14 (t, 1 H), 7.27 (m, 1 H), 7.35 (dd, 1 H), 7.46 ( dd, 1 H). Dissolve 0.650 g of the title product (1.53 mmol) in 20 ml of ethanol and then add 0.170 g of fumaric acid (1.46 mmol). The solution is concentrated, the salt is precipitated by adding ethyl acetate, filtered, washed with ethyl acetate and then dried under vacuum at 50 ° C. 0.560 g of the fumarate of the title compound is obtained in the form of a white crystalline powder. p. F. 159 ° C. Analysis C25H29CIF2N 05: Calculated%: C, 55.71; H, 5.42, Cl, 6.58; N, 10.40; Found: 55.87; 5.39; 6.42; 10.38. NMR with H (DMSOd6) delta: 1.65 (m, 1 H), 1.85 (m, 3H), 2.82 (d, 2H), 3.00 (s, 6H), 3.10-3.60 (m, 3H), 3.75 (s, 2H), 4.25 (m, 1 H), 6.50 (d, 1 H), 6.59 (d, 1 H), 6.60 (s, 2H), 7.46 (m, 3H), 7.68 (dd, 1 H). IR (KBr) a: 1637, 1686 and 1700 cm'1 (C = 0).

EXAMPLE 27 PREPARATION OF (3,4-DICHLOROPHENYL) - (4-FLUORO-4-IR (6- DIMETHYLAMINOPYRIDIN-2-IL-METHYL) AMINOLEMETIC> PIPERIDIN-1-ID-METANONE 0-14) The title compound is obtained, in the form of a yellow oil, by carrying out the procedure as in example 25, but replacing 6-furan-2-yl-pyridine-2-carbaldehyde with 6-dimethylamino-pyridin-2. -carbaidehyde and (4-aminomethyl-4-fluoropiperidin-1-yl) - (3-chloro-4-fluoro-phenyl) methanone with (4-aminomet M-fluoropiperidin-1-yl) - (3,4- dichlorophenyl) methanone, after purification on a silica column (eluent: ethyl acetate). Yield: 57.8% 1 H NMR (CDCb) delta: 1.40-1.85 (m, 2H), 2.02 (s, 1 H (exchangeable)), 2.04 (m, 2H), 2.76 (d, 2H), 3.05 (s, 6H), 3.10-3.65 (m, 3H), 3.73 (s, 2H), 4.48 (m, 1 H), 6.35 (d, 1 H), 6.44 (d, 1 H), 7.20 (dd, 1 H) , 7.36 (dd, 1 H), 7.47 (m, 2H). 0.450 g of the title product (1.02 mmol) is dissolved in 10 ml of ethanol and then 0.115 g of fumaric acid (0.99 mmol) is added. The solution is concentrated and crystallization is started by adding ethyl acetate. The precipitate is filtered, washed with ethyl acetate and then dried under vacuum at 50 ° C. 0.470 g of the fumarate of the title compound is obtained in the form of a white crystalline powder. p. F. 174 ° C. Analysis C25H2ßCI2FN? 5: Calculated%: C, 54.06, H, 5.26, Cl, 12.77; N, 10.09; Found: 53.82; 5.34; 12.61; 9.83. NMR with H (DMSOd6) delta: 1.71 (m, 1 H), 1.83 (m, 1 H), 2.79 (d, 2H), 2.99 (s, 6H), 3.05-3.50 (m, 3H), 3.72 (s) , 2H), 4.23 (m, 1 H), 6.48 (d, 1 H), 6.56 (d, 1 H), 6.58 (s, 2H), 7.37 (dd, H), 7.44 (dd, 1 H), 7.69 (m, 2H). IR (KBr) a: 1636 and 1702 cm "1 (C = 0).

EXAMPLE 28 PREPARATION OF (3-CHLORO-4-FLUOROPHENYL) - (4-FLUORO-4-rr (5-METHYL-β-METHYLAMIN-PYRIDIN-2-ILMETIL) AMIN-METHYL-PIPERIDIN-1-IDMET ANONE (I-55) The title compound is obtained in the form of a yellow oil. Nevating the procedure as in example 25, but replacing the 6-furan-2-yl-pyridine-2-carbaldehyde with 5-methyl-6-methylaminopyridine-2-carbaldehyde, after purification on a silica column (eluent: dichloromethane / methanol, 95: 5). Yield: 55.6%. NMR with H (CDCl 3) delta: 1.60 (m, 2H), 1.98 (m, 6H), 2.72 (d, 2H), 2. 95 (s, 3H), 3.11 (m, 1 H), 3.32 (m, 1 H), 3.51 (m, 1 H), 3.68 (s, 2H), 4.08 (s, 1 H), 4.44 (m, 1 H), 6.38 (d, 1 H), 7.10 (m, 2 H), 7.21 (m, 1 H), 7.42 (dd, 1 H). Salification of the title product with fumaric acid in ethanol gives 0.345 g of the fumarate of the title compound, in the form of a white crystalline powder. p. F. 163-64 ° C. Analysis: C25H29CIF2N4O5: Calculated%: C, 55.71; H, 5.42; Cl, 6.58; N, 10.39; Found: 55.64; 5.42; 6.46; 10.36. NMR with 1H (DMSOds) delta: 1.72 (m, 2H), 1.78 (m, 3H), 2.00 (s, 3H), 2.80 (d, 2H), 2.83 (s, 3H), 3.06 (m, 1 H) , 3.25 (m, 1 H), 3.51 (m, 1 H), 3.69 (s, 2H), 4.26 (m, 1 H), 5.91 (d, 1 H), 6.44 (d, 1 H), 6.59 ( s, 2H), 7.15 (d, 1 H), 7.46 (m, 2H), 7.64 (dd, 1 H). IE (KBr) a: 1638 and 1690 cm "1 EXAMPLE 29 PREPARATION OF (3-CHLORO-4-FLUOROFENYL) - (4-FLUORO-4-Tr (5-METHYL-6-DIMETHYLAMIN-PIRIDIN-2-IL-METHYL) AMINO-SMETHY-PIPERIDIN-1- IL) METHANONE (l -61) The title compound is isolated by carrying out the procedure as in example 25, but replacing furan-2-yl-pyridine-2-carbaldehyde with 5-methyl-6-dimethylaminopyridine-2-carbaldehyde and the reaction solvent (toluene) with benzene; by chromatography on a silica column (eluent: ethyl acetate / methanol, 98: 2). Performance: 66.7% 1 H NMR (CDCl 3) delta: 1.68 (m, 2 H), 2.04 (m, 2 H), 2.26 (s, 3 H), 2.80 (d, 2 H), 2.85 (s, 6 H), 3.17 (m, 1 H) , 3.39 (m, 1 H), 3.60 (m, 1 H), 3.79 (s, 2H), 4.52 (m, 1 H), 6.69 (d, 1 H), 7.17 (t, 1 H), 7.28 ( m, 2H), 7.48 (d, H). Salification of the title product with oxalic acid in ethanol gives 0.46 g of oxalate of the title compound in the form of a white crystalline powder. p.f. 205 ° C Analysis C24H29CIF2N? 5: Calculated%: C, 54.70; H, 5.55; Cl, 6.73; N, 10.63; Found: 54.62; 5.55; 6.76; 10.48. NMR with 1H (DMSOd6) delta: 1.75 (dt, 1 H), 1.85 (m, 2H), 1.98 (m, 1 H), 2.24 (s, 3H); 2.82 (s, 6H), 3.07 (, 1 H), 3.18 (d, 2H), 3.26 (m, 1 H), 3.44 (m, 1H), 4.08 (s, 2H), 4.30 (m, 1 H) , 6.89 (d, 1 H), 7.45 (m, 3H), 7.67 (dd, 1 H). IR (Kbr) a: 1636 and 1704 cm "1. The compounds of the general formula (I), which are obtained from the intermediates or intermediates analogous to those of examples 1 to 22, according to procedures similar to those of examples 23 to 29, and containing the desired substituents, are listed in the following table 1. Derivatives of the formula (I): TABLE 1 PHARMACOLOGICAL STUDY OF THE COMPOUNDS OF THE INVENTION 1. Measurement of the affinity of the compounds of the invention for 5-HT 1 receptors A. PROTOCOL The ip-vitro affinity of the compounds of the invention for 5-HT 1A receptors was determined by measuring the displacement of (3H) 8-OH-DPAT (TRK 850; 160-240 Ci / mmol). The study of binding to the 5-HT1A receptor was carried out as described by Sleight and Peroutka (Naunyn-Schmiedeberg's Arch. Pharmaco. 1991, 343, 106-16). For this experiment, rat brain cortices were used. After defrosting the brain in 50 mmol Tris-HCl buffer, pH = 7.40 at 25 ° C, the cerebral cortex was removed and homogenized in 20 volumes of regulator, maintained at 4 ° C. The homogenate was centrifuged at 39,000 g for 10 minutes. The centrifugation pellet was suspended in the same volume of regulator and recentrifuged. After suspending again under the same conditions, the homogenate was incubated during minutes at 37 ° C and then centrifuged again. The final pellet was suspended 50 mmol of the reaction regulator Tris-HCl, pH = 7.40 at 25 ° C, containing 10 mmol of pargyline, 4 mmol of CaCl2 and 0.10% of ascorbic acid. The final tissue concentration in the incubation medium is 10 mg / tube. The reaction tubes contain 0.10 ml of (3H) 8-0H-DPAT (0.20 mmol final), 0.10 ml of product to be tested, 6-7 concentrations, and 0.80 ml of tissue Nonspecific binding is defined using 10 mmol of 5-HT. The reaction tubes are incubated at 23 ° C for 30 minutes and then their contents are rapidly filtered in vacuo into Whatman GF / B filters, rinsed twice. tubes with 5 ml of 50 mmol of regulator Tps-HCl, pH = 74 at 25 ° C The radioactivity collected in the filter is analyzed by flashing in liquid, adding 4 ml of flash fluid (Emulsifier Safe, Packard) All experiments are performed in triplicate 2 - Measurement of the affinity of the compounds of the invention for the D2 PROTOCOL receptors The in vitro affinity of the compounds of the invention for the D2 dopaminergic receptors was determined, measuring the displacement of (3H) YM-09151-2 (NET-1004 70-87 Ci / mmol) The D2 receptor binding study is carried out as described by Niznik (Naunyn-Schmiedeberg, Arch Pharmacol Methods, 1985, 329, 333-38). For these experiments, fluted is used. of rat After thawing the brain in 50 mmoi of regulator Tris-HCl, pH = 740 at 25 ° C, the striatum is collected and homogenized in 40 volumes of regulator, kept at 4 ° C. The homogenate is centrifuged at 20,000 g for 10 minutes, the suspension is suspended. centrifugation pellet in the same volume of regulator and centrifuged again. The final pellet is suspended in 50 mmol of cold Tps-HCl reaction regulator, pH = 740, at 25 ° C, containing 120 mmol of NaCl and 5 mmol of KCl The final tissue concentration in the incubation medium is 2 mg / tube The reaction tubes contain 020 ml of pHJYM-O? ldl ^ (O 05 mmol final), 020 ml of the product to be tested, 6-7 concentration, and 1 60 ml of tissue Nonspecific binding is defined using 1 mmol of (-t -) - butaclamol The reaction tubes are incubated at 23 ° C for 60 minutes and then their contents are filtered in vacuo in Whatman GF / B filters, the tubes are rinsed twice with 5 ml of regulator tps-HCl, 50 mmolar, pH = 740 at 25 ° C The radioactivity collected in the filter is analyzed by flash in liquid, adding 4 ml of flash fluid (Emulsifier Safe, Packard). All the experiments are carried out in triplicate. RESULTS The inhibition constants (Ki) of the products of the invention are estimated from displacement experiments, using the non-linear regression program RADLIG version 4 of EBDA (acronym for its English designation Equilibpum Binding Data Analysis = analysis of binding data in equ? l? br? o ) (B? Osolf, Cambridge, UK, McPherson, 1985), the dissociation constants of the radioactive gandos used in the calculations are 0 31 mmol for (3H) 8-OH-DPAT and 0036 mmol for (3H) YM-09151-2 The pKi values (-logKi) are given in the form of the mean ± SEM of at least 3 experiments Table 2 gives, by way of example, the values pKi (D2) as well as the selectivity for 5-HT1A D2, for various compounds of the invention, in comparison with Buspirone and with 8-OH-DPAT, chosen as reference products TABLE 2 The compounds of the general formula (I), therefore, are potent ligands for the 5-HT1A receptors, and are found to be very selective towards the D2 receptors. 3.- Evaluation of the 5-HT1A receptor agonist activity. HT1A of the compounds of the invention in vivo PROTOCOL Male Sprague Dawley rats (ICO OFAD [IOPS], Iffa Credo, France) are used, weighing 160-180 g on arrival and 180-200 g at the beginning of the tests. quarantine the animals for 4 to 8 days, with free access to the normal food of the laboratory, before their use in the experiments. The animals are housed individually in plastic cages on a support (28 cm x 21 cm x 18 cm) with a floor having a wire mesh coverage (RC Iffa Credo), 24 hours before testing. Water filtered at 0.22 μm, ad libitum, is made available through an automatic dispenser. The quarantine area and the experimental laboratory have air conditioning (temperature: 22 ± 1 ° C, relative humidity: 55 ± 5%) and with lighting from 07:00 to 19:00. All rats are treated in accordance with the ethics for laboratory animals (Guide for the care and use of laboratory animals, United States Department of Agriculture, Public Health Service, publication of the National Institute of Health No. 85-23, revised in 1985) and the protocol (No 15) is carried out in accordance with the recommendations of the Local Ethics Committee, on each animal research The methods used are essentially identical to the previously described ones (Drug Dev Res, 1992, 26, 21 -48, Eur J Pharmacol 1995, 281, 219-28). The behavior of the animal is observed for a period of 10 minutes each, centered in t60 minutes, after oral administration Four animals are observed individually during the 10 minute period (from t55 to t65), the four rats are observed in turns every 15 seconds, observation duration 10 seconds per animal during each One of these observation periods is the presence (1) or absence (0) of retraction of the lower lip (LLR, acronym for its designation in English Lower Lip Retraction) It is considered that there is retraction of the lower lip if the animal exhibits uninterrupted signs for at least 3 seconds. This cycle is repeated 10 times during a period of 10 minutes, thus, the frequency of a behavior can range from 0 to 10 during each pepod of observation Each day two animals of each group receive the same dose of the same product The products are dissolved in distilled water or suspended in an aqueous solution of Tweep 80 (2 drops / 10 ml of distilled water) The products are administered in a volume of 10 ml kg and the doses are expressed in basal weight The order of administration of the products and the doses is left to chance RESULTS Table 2 gives, by way of example, the active doses (ED50) for some derivatives of the invention, in comparison with Buspirope and with 8-OH-DPAT. Therefore, the results of the tests show that some compounds of the formula (I) possess an agonist activity on 5-HT1A receptors, after oral administration in rats, which is much greater than that of the reference products

Claims (4)

NOVELTY OF THE INVENTION CLAIMS

1 - . 1 - Derivatives of p? Pdm-2-? L-met? Lam? Na of the formula (I) wherein u represents a hydrogen atom or up to methyl radical, provided that, when u is a methyl radical, then v and w represent a hydrogen atom, v represents a hydrogen atom or a chlorine atom or a methyl radical, provided that, when v represents a chlorine atom or a methyl radical, then u and w represent a hydrogen atom, w represents a hydrogen atom or a fluorine atom or a methyl radical, provided that, when w represents up fluorine atom or a methyl radical, then u and v represent a hydrogen atom, x represents a hydrogen atom or a fluorine atom, and represents up to chlorine atom or up to methyl radical, z represents a hydrogen atom or a fluorine atom , or a chlorine atom or methyl up radical, A represents a hydrogen atom or a fluorine atom or a chlorine atom, an alkyl radical of 1 to 5 carbon atoms, that is, a saturated aliphatic hydrocarbon radical, d straight or branched chain, containing 1 to 5 carbon atoms, such as methyl, ethyl, propium, butyl, peptyl, isopropyl, 1- methylethyl, 1-methylpropyl 1-methylbutyl, 2-methylpropyl 2-methylbutyl or 3-methylbutyl, 1-methylpropyl 2-methyl ? lpropyl, a fluoroalkyl radical, such as monofluoromethyl (-CH2F) or difluoromethyl (-CHF), or trifluoromethyl (-CF3), or 1-fluoro-1-ethyl (-CHFCH3) or 1, 1-d? fluoro- 1-ethyl (-CF2CH3), a cyclopropyl or cyclobutyl or cyclopentyl radical, a 5-membered substituted or unsubstituted aromatic heterocyclic group, containing 1, 2, 3 or 4 heteroatoms, selected from nitrogen, oxygen and sulfur, however , with no more than one oxygen and / or sulfur atom being present in the heterocycle A. Preferably, the aromatic heteroacids are furan-2-? lo (O CH CH CH C-) or furap-3-? lo (CH CH O CH C-) or 1 Hp? Rrol-2-? Lo (NH-CH CH CH C-) or 1 Hp? Rrol-3-? Lo (CH CH NH CH C-) or 1-met? Lp? R-2- (N (CH3) CH CH CH C-) or 1-met? lp? rrol-3-? lo (CH CH N (CH3) CH C-) ot? ofep-2-? lo ( S CH CH CH C-) ot? Ofen-3-? Lo (CH CH S CH C-) op? Razol-1-? Lo (N CH CH CH N-), or 1 Hp? Razol-3-? Lo (CH C H NH N C-) or 1 Hp? Razoi-4-? Io (CH N NH CH C-) or 1-met? Lp? Razol-3-? Lo (CH CH N (CH3) N C-) or? m? dazol-1-? io (CH N CH CH N-) or 1 H-? m? dazol-2-? lo, (NH CH CH N C-) or 1 H-? m? dazol-4-? it, (N CH NH CH C-) or oxazol-2-? lo, (O CH CH N C-) or oxazol-4-? lo, (N CH O CH C-), or oxazole-5-? lo , (O CH N CH C-) or? Soxazol-5-? Lo, (ON CH CH C-) or? Soxazol-4-1I0, (CH NO CH C-) or? Soxazol-3-? Lo, ( CH CH ON C-) ot? Aol-2-? Lo, (S CH CH N C-) ot? Aol-4-? Lo, (N CH S CH C-) ot? Azol-5-? Lo, ( S CH N CH C-) or? Sot? Azole-5-? Lo, (SN CH CH C-) or? Sot? Azole-4-? Lo (CH NS CH C-) or? Sot? Azole-3- ? lo, (CH CH SN C-) or [1, 2,4] tpazol-3? lo, (N CH NH N C-) or 1 H- [1, 2,4] tpazol-3? , (N CH NH N C-) or [1, 2,4] oxad? Azole-3-? Lo, (N CH ON C-) or [1, 2,4] oxad? Azole-5-? Lo, (ON CH N C-) or 5-met? L- [1, 2,4] oxad? Azol-3-? Lo, (NC (CH3) ON C-) or 1 H-tetrazol- 5-? Lo, (NHNNN C-) an alkoxy group (R1O-) or alkylthio (R1S-) in which the radical R1 represents an alkyl radical of 1 to 5 carbon atoms, as defined above, a monofluoromethyl radical or trifluoromethyl a cyclopropyl or cyclobutyl or cyclopentyl radical, an amino group of type II , R2 - < (ll) R3 wherein R2 and R3, which are identical or different, represent hydrogen or an alkyl radical of 1 to 5 carbon atoms as defined above, or a cyclopropyl or cyclobutyl radical, or a trifluoromethyl radical, a group saturated cyclic ammo, type lll (CH2) n M_ (III) jan! that "n" can represent integers 1 or 2, an alkoxycarbonyl group, preferably a methoxycarbonyl group (CH3OCO-) or an ethoxycarbonyl group (CH3CH20C0-), as well as the addition salts of the compounds of the general formula (I) , with inorganic acids or pharmaceutically acceptable organic acids 2. Compounds of the general formula (I), according to claim 1, characterized in that they are selected from (3,4-d? chlorophen? í) - (4-. { [(6-p? Razol-1-? Lp? R? D? N-2-? Lmet? L) am? No] met? L.] P? Pepd? N-1-? L) methanone, (3-chloro-4-fluorophen?) - (4- { [(6-p? Azol-1-? Lp? Pd? N-2-? Lmet? L) am? no] met? l} p? pepd? p-1-? l) methanone (4-chloro-3-met? lfen? l) - (4- { [(6-p? razol-1-? l-p? pd? n -2-? Lmet? L) am? No] met? L.}. P? Pepd? N-1-? L) methanone, (3-chlorophen? I) - (4 - ([(6-p? Razol - 1 -! Lp? Pd? N-2-? Lmet? L) am? No] met? L.] P? Pepd? N-1 -? L) methanone, (4 - ([(6-p? razol-1 -il-pipdin- 2-? lmet? l) am? no] met? l.} p? pepd? n-1 -? l) -m-tol? lme-tanopa (34-d? chlorofen) l) - (4-fluoro-4-5. {[[(6-p? razol-1 -? lp? pd? n-2-? lmet? l) am? no] rnet? l. p. ? pepd? n-1 -? l) methanone, (3,4-d? chlorophen? l) - (4- { [(6-? m? dazol-1 -? lp? pd? n-2- ? lmet? l) am? no] -met? l.}. p? pepd? n-1-? l) methanone, (3,4-d? chlorophen? l) - (4- { [(6 - [1, 2,4] tpazol-1-? Lp? R? D? N-2-? Lmet? L) am? No] met? L.} P? Pepd? N-1-? L) methanone , (3,4-d? Chlorophen? L) - (4- { [(6-p? Rrol-1-? L-p? R? D? P-2-? Lmet? L) am? No ] met? i.}. p? pepd? n-1-? l) methanone, (3,4-d? chlorophen? l) - (4 - ([(6-or met? lam? nop? pd? n -2-? Lmet? L) am? No] -met? L.}. P? Pepd? N-1 -? L) methanone, (3,4-d? Chlorophen? L) - (4-fluoro-4) - [[(6-met? Lam? Nop? Pd? N-2-? Lmet? L) am? Po] met? L.] P? Pepd? N-1-yl) methanone, (3,4- d? chlorophen? l) - (4- { [(6-d? met? lam? nop? pd? n-2-? lmet? l) am? no] met? l} p? pepd? n-1-? l) methanone, (3-chloro-4-fluorofen? l) - (4- { [(6-d? met? lam? nop? r? d? n-2 -? lmet? l) am? no] - met? l.}. -4-fluorop? per? d? p-1 -? l) methanone, (3,4-d? chlorophen? l) - (4- {[[6-5 d? Met? Lam? Nop? Pd? N-2-? Lmet? L) am? No] met? L.}. -4-fluoro-p? Per? D? P- 1-?) Methanone, (3,4-d? Chlorofep? L) - [4- ( { [6-et? L-met? Lam? No) p? R? D? N-2-? lmet? l] am? no} methanol) -4-fluorop? per? d? n- 1-? l) methanopa, (3,4-d? chlorophen? l) - [4- ( { [6- (met? Iprop? lam ? no) -p? r? d? n-2-? lmet? l] am? no.}. met? l) p? pepd? n-1 -? l) methanone, (4- { [( 6-azet? D? N-1 -? Lp? Pd? N-2-? Lmet? L) am? No] met? L.} P? Pepd? N-1-? L) - (3,4 -d? chlorofep? l) methanone, (4 - ([(6-azet? d? n-1-? l-0 p? pd? p-2-? lmet? l) am? no] met?!} -4-fluorop? Per? D? N-1-? L) - (3,4-d? Chlorophen? L) methanone (4- { [(6-c? Clopent? Lp? Pd? N -2-? Lmet? L) am? Po] met? L.}. P? Pepd? N-1-? L) - (3,4-d? Chlorofep? L) methanone, (4- { [ (6-chlorop? Pd? N-2-? Lmet? L) am? No] met? L.) P? Per? D? N-1-? L) - (3,4-d? Chlorophen? ) methanone, (3,4-d? chlorophen? l) - [4- ( { [6 - (1 Hp? razol-3-? l) -p? pd? n-2- tlmet? l) am? no] met? l} p? pepd? n-1-ylmetanone, (34-d? chlorophen? l) - [4- [fluoro-4- ( { [6- (1 H- p? razol-3-? l) p? r? d? n-2-? lmet? l) am? no] met? l} p? pepd? n-1-? l] -methanone, (3,4-d? chlorophen? l) - [4-fluoro-4- ( { [6- (1-methylpyrazole -3-? l) p? pd? n-2-? lmet? l] am? no) met? l} p? pepd? n-1-? l] metapona, (3,4-d? chlorophen? l) - [4- ( { [6- (1 H-? m? dazol-2-? l) p ? pd? p-2-? l-met? l] am? no.}. met? l) p? pepd? p-1 -? l] methanone, (3,4-d? chlorofep? l) - ( 4- { [(6-t? Azol-2-1 -? Lp? Pd? N-2-? Lp? Pd? N-2-? Lmet? L) am? No] met? L.}. p? pepd? n-1 -? l) methanone, (3,4-d? chlorophene-p? l) - (4-fluoro-4- { [(6-thiazole-2-?! p? r ? d? n-2-? lmet? l) am? no] - met? l.} p? pepd? n-1-? l) methanone, (3,4-d? chlorophen? l) - [4 - ( { [6- (1 Hp? Rrol-2-? L) p? R? D? N-2-? Lmet? L] am? No.}. Met? L) p? Pepd? N- 1 -yl] metapopa (3,4-d? Chlorofep? L) - (4- { [(6-t? Ofen-2-? Lp? R? D? N-2-? Lmet? L) am ? no] met? l.) p? pend? n-1-? l) methanopa, (3,4-d? chlorophene-phen?) - (4-fluoro-4- { [(6- t? ofen-2-? lp? pd? n-2-? lmet? l) am? no] - met? l.? p? per? d? n-1 -? l.} metapona, (3 , 4-d? Chlorophen? L) - (4 - [[(6-furan-2-? Ip? R? D? N-2-? Lmet? L) am? No] met? L.}. Piper? d? n-1-l) meta-none, (3,4-d? chlorophen? l) - (4-fluoro-4- [(6-furan-2-lp? pd? p-2-ilmet ? l) am? no] met? l.) p? pepd? n-1-? l) metapona, (3-chloro-4-fluorofen? l) - (4-fluoro-4- { [( 6-furan-2-? Lp? R? D? N-2-? Lmethyl) -am? No] met? L.}. P? Pepd? N-1-? L] goal nona, (34-d? chlorophen? l) - (4-. { [(6-oxazol-5-? L-p? Pd? P-2-? Lmet? L) am? No] met? L} p? pepd? n-1-? i) methanone, (3,4-d? chlorophen? l) - (4-fluoro-4 - ([(5-oxazol-5-? lp? pd? n-2- ? lmet? l) am? no] met? l.) p? pepd? n-1-? l) methanone, (3,4-d? chlorophen? l) - (4-fluoro-4- [(6) -furan-3-? lp? r? d? n-2-? imet? l) -amino] met? l.}. p? pepd? n-1-? l] methanonal (3,4-d? chlorophen (l) - [4- ( { [6- (5-met? l- [1, 2,4] oxad? azole-3? l) p? pd? n-2-? lmet? l] am? no.}. -met? l) p? pepd? n-1-? l) methanone, (3,4-d? chlorophen? l) - (4- { [(6-met? lp? r? d? n-2-? lmet? l) - am? po] met? l.? p? per? d? p-1 -? l) methanone, (34-d? chlorophen? l) - ( 4- {[[6-? Soprop? Lp? Pd? P-2-? Lmet? L) am? No] - met? L.}. P? Per? D? N-1 -? L) methanone , (3,4-d? Chlorophen? L) - (4-. {[[(6- c? Cloprop? Lp? Pd? N-2-? Lmet? L) am? No] met? L.}. -4-fluorop? Per? D? N-1-? L) methanone, (3,4- d? chlorophen? l) - (4-fluoro-4 - ([(6-fluorome-t? lp? r? d? p-2-? lmet? l) am? no] met? l. p. per? d? n-1-? l) methanone, (3,4-d? chlorophen? l) - (4- { [(6-d? fluoromet? lp? pd? p-2-? lmet? l) - am? no] met? l.). p? pepd? n-1-? l) methanone, (3,4-d? chlorophen? l) - (4 - ([(6-d? fluorometho lp? pd? n- 2-? lmet? l) am? no] met? l.}. -4-fluorop? -per? d? n-1-ylmetanone, (3,4-d? Chlorophen? L) - [4-fluoro-4- ( { [6- (1-fluoroet? L) p? R? D¡n-2-? Lmet? L] am ? no.} met? l) pipet? n-1-?!) -methanone, 6- ( { [1- (3,4-d? chlorobenzo? l) p? pepd methyl ester ? p-4-? lmet? l] am? no.}. met? l) p? pd? n-2-carboxylate, ethyl ester of 6- ( { [1- (3, 4-d-chlorobenzoyl) p? Per? D? N-4-? Lmet? L] am? No.}. Met? L) p? Pd? N-2-carboxylate, (3, 4-d? Chlorophen? L) - (4 - ([(6-methox? P? Pd? N-2-? Lmet? L) am? No] met? L.) P? Pepd? N-1- (l) methanone, (3,4-d? chlorophen? l) - (4-fluoro-4-. {[[(6-methox? p? pd? n-2-? lmet? l) am? no] met? l.) p? per? d? n-1-? l) methanopa, (3,4-d? chlorophen? l) - (4-fluoro-4- { [(6-? soprop? lox? pipd? n-2-? lmet? l) am? no] met? l. piper? d? p-1-? l) methanone, (4- { [(6-aclopent? lox? p? pd? n-2-? lmet? l) am? no] -met? l.}. p? pepd? n-1-? l) - (3,4-d? chlorophen? l) methanone, ( 3,4-d? -chlorophen? L) - (4 - ([(6-met? Lsulfan? Lp? Pd? N-2-? Lmet? L) am? No] -met? L.}. P? pepd? n-1-? l) methanone, (3,4-d? chlorophen? i) - (4- { [(6-fluorop? pd? n-2-? memethyl) amino] met? l) p? pepd? p-1-? l) methanone, (3,4-d? chlorophen? l) - (4-fluoro-4- { [(6-fluorop? p d? n-2-? lmet? l) -am? no] met? l} p? per? d? n-1-? l) metapona, (3,4-d? chlorophen? l) - (4-fluoro- {[[3-fluorop? rid? n-2-? lmet? l) am? no] met? l.) p? per? d? n-1-? l) methanopa, (4- { [(4-chlorop? pd? n-2-? lmet? l) am? no] met? l.). -p? pepd? n-1-? l) - (3,4-d? chlorophen? l) methanone, (3-chloro-4-fluorofen? l) - (4 -fluoro-4- { [(5-met? l-6-furan-2-? lp? r? d? n-2-? lmet? l) am? no] met? l.}. p? per? d? n-1 -? l) methanone, (3-chloro-4-fluorophen? l) - [4-fluoro-4- ( { [5-methyl-6- (1 Hp? razol -3-? L) -2-il-p? R? Din-2-? Lmethyl] am? No.} Methyl) p? Per? D? N-1-? L) methanone, (3-) chloro-4-fluorophen? l) - (4-fluoro-4-. {[[(5-met? l-6-met? lam? nop? p-din-2-? lmet? l) amino] met? l.) p? per? d? n-1-? l) methanone, (4 - ([(6-azet? d? n-1-? lp? pd? p-2- lmetil) am? no] met? l} -4-fluorop? Pepd? N -1 -? L) - (3-chloro-4-fluorophen? L) methanone (3-cioro-4-fluorofe-n? L) - (4-fluoro-4-. { [(6-oxazoi-5-? Lp? Pd? N-2-? Lmet? L) am? No] -methyl.} P? Pepd? N-1-? L) methanone, (3- chloro-4-fluorophen?) - (4-fluoro-4. {[[(6-et? lam? nop? r? d? n-2-? lmet? l) am? no] met? l} p? pep-d? n-1-? i) methanone (3-chloro-4-fluorophen?) - (4-fluoro-4-. {[[(6-met? lam? nop? r? d? n-2-? lmet? l) am? no] met? l.}. p? pepd? n-1-? l) meta-pona, (3-chloro-4-met? lfen? l) - (4-fluoro-4-. {[[(6-d? Met? L-am? Nop? Pd? N-2-? Lmet? L) am? No] met? L.}. P? Pepd? N -1 -? L) methanone, (3-chloro-4-fluorophen? L) - (4-fluoro-4-. {[[(5-met? L-6-d? Met? Lam? -nop? R ? d? n-2-? lmet? l) am? no] met? l.}. p? pepd? n-1-? l) methanone, (3-chloro-4-fluorofen? l) - (4- fluoro-4- ( { [6- (1 Hp? razol-3-? l) p? pd? n-2-? lmet? l] am? no.}. methyl) p? pepd? n-1 -ylmetanone, (3,4-d? chlorophen? l) - (4-fluoro-4-. {[[(3-met? l-6-d? met? lam? nop? r? d? p-2 -? lmet? l) am? no] met? l.}. p? pepd? n-1-? l) methanone, (3-chloro-4-fluorofep? l) - (4-fluoro-4-. { [(6-p? Razol-1-? Lp? Pd? N-2-? Lmet? L) am? No] met? L.] P? Pepd? N-1-? L) methanone, (3 , 4-d? Chlorophen? L) - (4-fluoro-4-. { [(5-met? Lp? Pd? N-2-? Lmet? L) am? Po] met? L} p? per? d? n-1-? l) methanone, (3-chloro-4-fluorophen? l) - (4-fluoro-4-. {[[(5-met? lp? pd? n-2 -? lmet? l) am? no] met? l) p? pepd? n-1-? l) methanone, (3-chloro-4-fluorofen? l) - (4-fluoro-4- { [ (6-d? Ethylam? Pop? Pd? N-2-? Lmet? L) am? No] met? L.]. Piper? N? 1-? L) methanone, (3-chloro- 4-fluoromet? L) - (4-fluoro-4- [(5-met? L-6-chlorop? R? D? N-2-? Lm? T? L) am? No] met? L.] P ? pepd? n-1-? l) methanone (3-chloro-4-fluorophen? l) - (4-fluoro-4. {[[(4-met? l-6-d? met? lam? nop ? r? d? n-2-? lmet? l) am? -no] met? l.) p? per? d? n-1-? l) methanone, (3-chloro-4-fluorophen? ) - (4-fluoro-4-. {[[(5-met? L-6-p? Razol-1 -? Lp? R? D? N-2-tlmet? L) am? No] - met? l) p? pepd? n-1-? l) methanone, (3-chlorophen? l) (4-fluoro-4. {[[(6-d? met? laminop? pd? n-

2-ilmet? l) am? no] met? l.}. p? pepd? n-1-? l) methanone

3 - . 3 - Process for preparing the compounds of the general formula (la), according to claims 1 and 2, characterized in that the aldehyde of the general formula (IV) is reacted with an amine of the general formula (V) in a reducing medium rv wherein A, u, v, w, x, "and" and z are as defined above. 4. Process for preparing the compounds of the general formula (Ia), according to claims 1 and 2, characterized in that an aldehyde of the general formula (IV) reacts with a derivative of the azido type of the general formula (VI), in the presence of an apl- or alkylphosphine, in a reducing medium. PR where A, u, v, w, x "y" and z are as defined above. 5. Process for preparing the compound (Ib), specific case of the compounds of the formula (la), wherein x is a hydrogen atom, according to claims 1 and 2, characterized in that an aldehyde is reacted formula (IV), successively, with piperidin-

4-yl-methylamine, with an acid chloride and then with a reducing agent, according to the "single-vessel" technique: where A, u, v, w, x "and" yz are as defined above 6 - Process for preparing the compound (le), specific case of the compounds of the formula (Ia), in accordance with claims 1 and 2, characterized in that a reactant of the type (HA) or (A "Na *) is reacted with a compound of the formula (A = F or Cl) "AH or A" Na + " where u, v, w, x, "y" and z are as defined above, A is selected from an ammo group of type II or a saturated cyclic ammo group of type III, or a radical 1-? Lo, p? Razol-1-? Lo,? M? Dazol-1-? Lo or [1, 2,4] tpazol-1-? Lo 7 - New synthetic intermediates of the formula (V), used for the preparation of the compounds of the general formula (I) where "y" and z are as previously defined. 8.- New synthetic intermediates of the formula (VI), used for the preparation of the compounds of the general formula (I): where "y" and z are as defined above. 9. The use of one of the derivatives of the compound of the formula (I) as defined in claim 1, or of one of its salts or hydrates of its salts, in combination with one or more pharmaceutically acceptable excipients or vehicles, for the manufacture of a medicament for treating pathologies in which serotonergic dysfunctions are involved, in an individual. 10. The use according to claim 9, characterized in that the dysfunctions are selected from the group consisting of: depression, anxiety, compulsive-obsessive disorders, panic attacks, perception of pain, aggression, alcohol abuse, sleep disorders , vascular and cerebrovascular disorders, such as high blood pressure or migraine; vomiting, sexual disorders, regulation of gastric secretion, regulation of food intake, and immunological diseases. 11. Pharmaceutical composition, characterized in that it contains, as an active ingredient, at least one compound according to any of claims 1 and 2, or one of its addition salts with a pharmaceutically acceptable acid, in combination with one or more excipients or pharmaceutically acceptable vehicles.