FR2789389A1 - (1-Phenacy-3-phenyl-3-piperidylethyl)piperidine derivatives as substance P antagonists useful for treating e.g. obstructive chronic bronchitis or asthma, ulcerative colitis, pain, migraine, inflammation or vomiting - Google Patents

Abstract

(1-Phenacy-3-phenyl-3-piperidylethyl)piperidine derivatives (I) are new. (1-Phenacy-3-phenyl-3-piperidylethyl)piperidine derivatives (I), their mineral or organic salts, solvates or hydrates are new. X = R2-N or R2-CH; Ar' = phenyl substituted by 1 or 2 halo or 1-3C alkyl; R1 = Cl, Br, 1-3C alkyl or CF3; R2 = -CR3R4C(O)NR5R6; R3, R4 = methyl, ethyl, n-propyl, n-butyl; or CR3R4 = 3-6C cycloalkyl; R5, R6 = H or 1-3C alkyl; and NR5R6 = azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl or perhydroazepin-1-yl. An Independent claim is also included for the preparation of (I).

Description

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 The present invention relates to novel piperidine derivatives, a process for their preparation and pharmaceutical compositions containing them as active principle.

 More particularly, the present invention relates to novel piperidine derivatives for therapeutic use, in the pathological phenomena that involve the tachykinin system, for example without limitation: pain (L.

Urban et al., TINS, 1994, 17, 432-438; L. Seguin et al., Pain, 1995, 61, 325-343; S.

H. Buck, 1994, The Tachykinin Receptors, Humana Press, Totowa, New Jersey), Allergy and Inflammation (SH Buck, 1994, The Tachykinin Receptors, Humana Press, Totowa, New Jersey), Gastro Disorders (Holzer and U. Holzer Petsche, Phamacol Ther, 1997, 73, 173-217 and 219-263), respiratory disorders (J.

Mizrahi et al., Pharmacology, 1982, 25, 39-50; C. Advenier et al., Eur. Respir. J., 1997, 10, 1892-1906; C. Advenier and X. Emonds-Alt, Pulmonary Pharmacol., 1996, 9, 329-333), Urinary Disorders (SH Buck, 1994, The Tachykinin Receptors, Humana Press, Totowa, New Jersey, CA Maggi, Progress in Neurobiology, 1995, 45, 1-98), neurological disorders, neuropsychiatric disorders (CA Maggi et al., J. Autonomy Pharmacol., 1993, 13, 23-93, M. Otsuka and K. Yoshioka, Physiol.

Rev. 1993, 73, 229-308).

 In recent years, many research projects have been carried out on tachykinins and their receptors. Tachykinins are distributed both in the central nervous system and in the peripheral nervous system. Tachykinin receptors have been recognized and are classified into three types: NK1, NK2, NK3. The substance P (SP) is the endogenous ligand of the NK1 receptors, the neurokinin A (NKA) that of the NK2 receptors and the neurokinin B (NKB), that of the NK3 receptors.

 NK1, NK2, NK3 receptors have been demonstrated in different species.

 A review by C. A. Maggi et al (J. Autonomie Pharmacol., 1993, 13, 23-93) and a review by D. Regoli et al. (Pharmacol, Rev., 1994, 46, 551-599) review tachykinin receptors and their antagonists and discuss pharmacological studies and applications in human therapy.

dans laquelle notamment : Many patents or patent applications describe compounds active on tachykinin receptors. Thus the European patent application 0 512 901 relates to the compounds of formula:

in which, in particular:

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 Q 'represents an oxygen atom or two hydrogen atoms, - T' = -C (O) - or -CH2-, and - Y, Ar ', Z', m ', n', p 'and q have different values.

dans laquelle : - p"estl,2ou3; - m" et n" sont indépendamment 0 à 6 ; - W, Ra, Rb, Rc, Rd et Re ont différentes valeurs. The patent application EP-0 714 891 relates to the compounds of formula:

where: - p "isl, 2 or 3; - m" and n "are independently 0 to 6; - W, Ra, Rb, Rc, Rd and Re have different values.

 We have now found new compounds which have a very high affinity and a high selectivity for NK receptors. Substance P and which are antagonists of said receptors.

 In addition, the compounds of the present invention exhibit good bioavailability when administered orally.

 These compounds can be used for the preparation of medicaments that are useful in the treatment of any pathology in which the substance P and the NK1 receptors are involved, in particular in the treatment of pathologies of the respiratory, gastrointestinal, urinary, immune, cardiovascular and central nervous systems. as well as in the treatment of pain, migraine, inflammation, nausea and vomiting, skin diseases.

dans laquelle : Thus, according to one of its aspects, the subject of the present invention is compounds of formula:

in which :

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X represents a group R2-N; an R2-CH group; R 1 represents a chlorine atom, a bromine atom, a (C 1 -C 3) alkyl or a trifluoromethyl; R2 represents a group -CR3R4CONR5R6; R3 and R4 represent the same radical chosen from methyl, ethyl, n-propyl or n-butyl; - or R3 and R4 together with the carbon atom to which they are attached constitute a (C3-C6) cycloalkyl; R5 and R6 each independently represent hydrogen; a (C1-C3) alkyl; or else R 5 and R 6 together with the nitrogen atom to which they are bonded constitute a heterocyclic radical chosen from azetidin-1-yl, pyrrolidin-1-yl, piperidine-1-yl,
1-yl, morpholin-4-yl, thiomorpholin-4-yl or perhydroazepin-1-yl; as well as their possible salts with mineral or organic acids, their solvates and / or their hydrates.

 The compounds of formula (I) according to the invention comprise both the optically pure isomers and their mixtures in any proportions.

 Salts of the compounds of formula (I) can be formed. These salts also include those with inorganic or organic acids which allow a suitable separation or crystallization of the compounds of formula (I), such as picric acid or oxalic acid or an optically active acid, for example a mandelic acid. or camphorsulfonic acid, than those which form pharmaceutically acceptable salts, such as hydrochloride, hydrobromide, sulfate, hydrogen sulfate, dihydrogenphosphate, methanesulfonate, methylsulfate, maleate, fumarate, succinate, naphthalene-2-sulphonate , glyconate, gluconate, citrate, isethionate, benzenesulfonate, paratoluenesulfonate.

 In the present description, the alkyl groups are straight or branched.

 According to the present invention, the compounds of formula (I) in which the substituents R 1 represent a chlorine atom, a methyl, an ethyl or a trifluoromethyl are preferred.

 According to the present invention, the compounds of formula (I) in which X represents a group R2-N in which R2 represents a group -CR3R4CONR5R6 are preferred.

 In particular, the compounds in which R 3 and R 4 each represent a methyl or together with the carbon atom to which they are bonded, are preferred.

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 constitute a cyclohexyl. Particularly, compounds in which R 5 and R 6 are each hydrogen or methyl are also preferred.

 According to the present invention, the compounds of formula (I) in which X is a group R2-CH in which R2 represents a group -CR3R4CONR5R6 are preferred.

 Particularly preferred are compounds wherein R 3 and R 4 are each methyl or together with the carbon atom to which they are attached constitute cyclohexyl. Particularly, compounds in which R 5 and R 6 are each hydrogen or methyl are also preferred.

dans laquelle : - R'1 représente un atome de chlore, un méthyle, un éthyle ou un trifluorométhyle ; - R'3 et R'4 représentent chacun un méthyle ou bien, ensemble avec l'atome de carbone auquel ils sont liés constituent un cyclohexyle ; - R'5 et R'6 représentent chacun l'hydrogène ou un méthyle ; ainsi que leurs sels avec des acides minéraux ou organiques, leurs solvats et/ou leurs hydrates. According to the present invention, the compounds of formula:

in which: R'1 represents a chlorine atom, a methyl, an ethyl or a trifluoromethyl; - R'3 and R'4 each represent a methyl or together with the carbon atom to which they are attached constitute a cyclohexyl; - R'5 and R'6 each represent hydrogen or methyl; as well as their salts with mineral or organic acids, their solvates and / or their hydrates.

dans laquelle : - R'1 représente un atome de chlore, un méthyle, un éthyle ou un trifluorométhyle ; - R'3 et R'4 représentent chacun un méthyle ou bien, ensemble avec l'atome de carbone auquel ils sont liés, constituent un cyclohexyle ; - R'5 et R'6 représentent chacun l'hydrogène ou un méthyle ; According to the present invention, the compounds of formula:

in which: R'1 represents a chlorine atom, a methyl, an ethyl or a trifluoromethyl; - R'3 and R'4 each represent a methyl or together with the carbon atom to which they are attached, constitute a cyclohexyl; - R'5 and R'6 each represent hydrogen or methyl;

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 as well as their salts with mineral or organic acids, their solvates and / or their hydrates.

 According to the present invention, the compounds of formula (I), (I '), (I ") in optically pure form are preferred.

- la 3-[2-[4-(I-carbamoyl-1-méthyléthyl)pipéridin-1-yl]éthyl]-3-(3,4- dichlorophényl)-l-[2-(3,5-diméthylphényl)acétyl]pipéridine, isomère (-) ; ainsi que ses sels, ses solvats et/ou ses hydrates est plus particulièrement préféré. The following compound:

3- [2- [4- (I-Carbamoyl-1-methylethyl) piperidin-1-yl] ethyl] -3- (3,4-dichlorophenyl) -1- [2- (3,5-dimethylphenyl)) acetyl] piperidine, isomer (-); as well as its salts, its solvates and / or its hydrates is more particularly preferred.

dans laquelle E représente l'hydrogène ou un groupe O-protecteur, avec un dérivé fonctionnel d'un acide de formule : #R1 HO-CO-CH2# (ni)
R1 dans laquelle RI est tel que défini pour un composé de formule (I), pour obtenir un composé de formule :

According to another of its aspects, the present invention relates to a process for the preparation of the compounds of formula (I), their salts, their solvates and / or their hydrates, characterized in that:
1 a) a compound of formula

wherein E represents hydrogen or an O-protecting group, with a functional derivative of an acid of the formula ## STR1 ##
Wherein R1 is as defined for a compound of formula (I), to obtain a compound of formula:

2a) optionally, when E represents a protecting group, it is removed by the action of an acid or a base, to obtain the alcohol of formula:

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4a) on fait réagir le composé de formule (VI) avec un composé de formule :

dans laquelle X est tel que défini pour un composé de formule (I) ;
5a) et, éventuellement, on transforme le composé ainsi obtenu en l'un de ses sels avec un acide minéral ou organique. 3a) the alcohol obtained in step la) or in step 2a) of formula (IV, E = H) is treated with a compound of formula:
Y-SO 2 -Cl (V) wherein Y represents a methyl, phenyl, tolyl or trifluoromethyl group, to obtain a compound of formula:

4a) the compound of formula (VI) is reacted with a compound of formula:

wherein X is as defined for a compound of formula (I);
5a) and, optionally, the compound thus obtained is converted into one of its salts with an inorganic or organic acid.

 When E represents an O-protecting group, it is selected from conventional O-protecting groups well known to those skilled in the art, such as, for example, tetrahydropyran-2-yl, benzoyl or C1-C4) alkylcarbonyl.

 In step la), as functional derivative of the acid (III), the acid itself is used, or one of the functional derivatives which react with the amines, for example an anhydride, a mixed anhydride, the chloride of acid, or an activated ester, such as paranitrophenyl ester.

 When the acid of formula (III) itself is used, the reaction is carried out in the presence of a coupling agent used in peptide chemistry such as 1,3-dicyclohexylcarbodiimide or benzotriazol-1-yloxytris hexafluorophosphate. (dimethylamino) phosphonium in the presence of a base such as triethylamine or

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 N, N-Diisopropylethylamine in an inert solvent such as dichloromethane or N, N-dimethylformamide at a temperature between 0 C and room temperature.

 When an acid chloride is used, the reaction is carried out in an inert solvent such as dichloromethane or benzene, in the presence of a base such as triethylamine or N-methylmorpholine and at a temperature of between -60.degree. C and the ambient temperature.

 The compound of formula (IV) thus obtained is optionally deprotected in step 2a) according to methods known to those skilled in the art. For example, when E represents a tetrahydropyran-2-yl group, the deprotection is carried out by acid hydrolysis using hydrochloric acid in a solvent such as ether, methanol or a mixture of these solvents, or by using the p-toluenesulfonate pyridinium in a solvent such as methanol or alternatively, using a resin Amberlyst # in a solvent such as methanol. The reaction is carried out at a temperature between room temperature and the reflux temperature of the solvent. When E represents a benzoyl group or a (C 1 -C 4) alkylcarbonyl group, the deprotection is carried out by hydrolysis in an alkaline medium using, for example, an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide or potassium hydroxide. lithium hydroxide, in an inert solvent such as water, methanol, ethanol, dioxane or a mixture of these solvents, at a temperature between 0 C and the reflux temperature of the solvent.

 In step 3a) the reaction of the alcohol of formula (IV, E = H) with a sulphonyl chloride of formula (V) is carried out in the presence of a base such as triethylamine, pyridine, NN diisopropylethylamine or N-methylmorpholine, in an inert solvent such as dichloromethane, benzene or toluene, at a temperature of between -20 ° C. and the reflux temperature of the solvent.

 The compound of formula (VI) thus obtained is reacted in step 4a) with a compound of formula (VII). The reaction is carried out in an inert solvent such as N, N-dimethylformamide, acetonitrile, methylene chloride, toluene or isopropanol and in the presence or absence of a base. When a base is used, it is chosen from organic bases such as triethylamine, N, N-diisopropylethylamine or N-methylmorpholine or from alkali metal carbonates or bicarbonates, such as potassium carbonate or carbonate. sodium or sodium bicarbonate. In the absence of base, the reaction is carried out using an excess of the compound of formula (VII) and in the presence of an alkali metal iodide such as potassium iodide or sodium iodide. The reaction is carried out at a temperature between room temperature and 100 C.

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According to a variant of the method: 1b), the procedure is as in step 1a) and optionally in step 2a);
2b) the compound of formula (IV, E = H) thus obtained is oxidized to prepare a compound of formula:

3b) the compound of formula (VU1) is reacted with a compound of formula (VII) as defined above, in the presence of an acid, and the intermediate imminium salt formed is reduced by means of a reducing agent ;
4b) and optionally converting the compound thus obtained into one of its salts with an inorganic or organic acid.

 According to the variant of the process, in step 2b) an alcohol of formula (IV, E = H) is subjected to oxidation to obtain an aldehyde of formula (VIII). The oxidation reaction is carried out using, for example, oxalyl chloride, dimethylsulfoxide and triethylamine in a solvent such as dichloromethane and at a temperature between -78 ° C. and room temperature.

 Then in step 3b), the compound of formula (VII) is reacted with an aldehyde of formula (VIII) in the presence of an acid such as acetic acid, in an inert solvent such as methanol or dichloromethane to form in-situ an intermediate imine which is chemically reduced using, for example, sodium cyanoborohydride or sodium triacetoxyborohydride, or catalytically using hydrogen and a catalyst such as palladium on carbon or Raney nickel.

 The compounds of formula (I) according to the invention are finally obtained.

 The compounds of formula (I) thus obtained are isolated in free base or salt form, according to conventional techniques.

 When the compounds of formula (I) are obtained in free base form, the salification is carried out by treatment with the chosen acid in an organic solvent.

By treatment of the free base, dissolved for example in an ether such as diethyl ether or in an alcohol such as propan-2-ol or in acetone or in dichloromethane, or in ethyl acetate with a solution of the acid chosen in a

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 of the aforementioned solvents, the corresponding salt is obtained which is isolated according to conventional techniques.

 For example, hydrochloride, hydrobromide, sulfate, hydrogen sulfate, dihydrogenphosphate, methanesulphonate, oxalate, maleate, succinate, fumarate, naphthalene-2-sulphonate, benzenesulphonate, para are prepared for example. toluenesulfonate.

 At the end of the reaction, the compounds of formula (1) can be isolated in the form of one of their salts, for example the hydrochloride, or the oxalate; this case, if necessary, the free base can be prepared by neutralizing said salt with a mineral or organic base, such as sodium hydroxide or triethylamine or with an alkali carbonate or bicarbonate, such as carbonate or bicarbonate sodium or potassium.

 The compounds of formula (II) are prepared by known methods, in particular those described in EP-A-0 512 901 and EP-A-0 591 040.

 The compounds of formula (III) are commercially available or prepared according to known methods.

 Thus, for example, the compounds of formula (III) are prepared according to SCHEME 1 below.

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SCHEME 1

Steps al and b1 of SCHEME 1 are carried out according to the methods described in J. Am. Chem. Soc., 1941, 63, 3280-3282.

 In step c1 an ester of formula (XII) is prepared from an acid of formula (XI) according to the methods known to those skilled in the art.

 The ester (XII) thus obtained is reduced in step d1 to the alcohol of formula (XIII) according to the methods known to those skilled in the art.

 Steps e1 and f1 are carried out according to the methods described in J. Med. Chem., 1973, 16, 684-687.

 The phenylacetonitrile derivatives of formula (XV) thus obtained are hydrolysed in step g1 to compounds of formula (III) according to the methods described in J. Org.

Chem., 1968, 33, 4288 or in EP-A-0 714 891.

 The brominated derivatives of formula (IX) are known or prepared according to known methods such as those described in J. Org. Chem., 1971, 36 (1), 193-196, or in J.

Am. Chem. Soc., 1941, 63, 3280-3282.

/
Compounds of formula (VII) in which X represents an R2-N group

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in which R2 represents a group -CR3R4CONRSR6 are prepared according to SCHEME 2 below:
SCHEME 2

In step a2 of SCHEME 2, compound 1 is reacted with a ketone of formula (XVI), in the presence of 2-hydroxyisobutyronitrile, according to the method described in Eur. J. Med. Chem., 1990, 25, 609-615.

 The nitrile derivative of formula (XVII) thus obtained is hydrolysed in step b2 according to the methods known to those skilled in the art to give an acid derivative of formula (XVIII).

 The acid (XVIII) is reacted in step c2 with an amine of formula (XIX) according to conventional methods of peptide coupling to give the derivative (XXI).

 Alternatively, the nitrile derivative of formula (XVTI) is hydrolysed, in step d2, according to the known methods to obtain the carboxamide derivative of formula (XX), which

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 is optionally deprotected at step e2, according to conventional methods, to obtain the compound (VII) in which R5 = R6 = H.

 In step f2, by reaction of the compound of formula (XX), in the presence of a strong base, respectively, with a (C1-C3) alkyl halide, or successively with two (C1-C3) alkyl halides, or with a dihalide of formula Hal-R5-R6-Hal, according to the conventional alkylation methods, a compound of formula (XXI) is prepared in which R5 represents a (C1-C3) alkyl and R6 = H, or R5 respectively; and R6 are each independently (C1-C3) alkyl, or R5 and R6 together with the nitrogen atom to which they are attached constitute a heterocycle.

 The compound (XXI) thus obtained is deprotected at step g2, according to the known methods, to give the compound (VII) expected.

Compounds of formula (VII) in which X represents a group
R2-CH in which R2 represents a group -CR3R4CONR5R6 are prepared according to SCHEME 3 below.

SCHEME 3

In step a3 of SCHEME 3, the reaction of compound 2, in the presence of a strong base, with a linear (C 1 -C 4) alkyl halide respectively, or with a

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 dihalide of formula Hal (CH 2) m-Hal in which m = 2 to 5 and Hal represents a halogen atom, according to the conventional alkylation methods, makes it possible to obtain the compound of formula (XXII) in which, respectively, R 3 and R4 are each a linear (C1-C4) alkyl or together with the carbon atom to which they are bonded constitute a (C3-C6) cycloalkyl.

 The nitrile derivative (XXII) thus obtained is hydrolysed in step b3 according to the methods known to those skilled in the art to give the carboxamide derivative (XXIII).

Optionally, in step c3, the pyridine ring is hydrogenated, in the presence of a catalyst such as platinum oxide, according to conventional methods, to obtain a compound of formula (VII) in which R5 and R6 = H.

 In step d5, by alkylation reaction, according to the conventional methods previously described, the compound of formula (XXIII), then reduction, by conventional catalytic hydrogenation, of the compound (XXIV) thus obtained, a compound of formula ( VU) in which R5 and / or R6 # H.

 Compounds of formula (VU) in which X represents a group -CH-CR3R4CONR5R6 may also be obtained according to SCHEME 4 below.

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SCHEMA 4

In step a4 of SCHEME 4, the reaction of compound 3 with a suitable organolithium or organomagnesium derivative such as, for example, methyllithium, ethylmagnesium chloride, propylmagnesium chloride or pentane-1,5di (magnesium chloride ), according to the methods described in EP-A-0 625 509, makes it possible to obtain the alcohol of formula (XXV).

 The alcohol (XXV) thus obtained is oxidized in step b4 to the acid of formula (XXVI) according to the method described in Helvetica Chimica Acta, 1972, 55 (7), 2439.

 The acid (XXVI) is reacted in step c4 with an amine of formula (XIX) according to conventional methods of peptide coupling to give the compound (XXVII).

 Compound (XXVII) is deprotected in step d4, according to known methods, to give the expected compound (VII).

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 Compound 3 is prepared by reaction of ethyl isonipecotate with benzyl bromide, in the presence of a base, according to conventional alkylation methods.

dans laquelle : - "*" signifie que l'atome de carbone ainsi marquée à la configuration absolue (S) ou (R) déterminée ; - X et RI sont tels que définis pour un composé de formule (I) ; ainsi que leurs sels éventuels avec des acides minéraux ou organiques, leurs solvats et/ou leurs hydrates. The resolution of the racemic mixtures of the compounds of formula (I) makes it possible to isolate the enantiomers of formula:

in which: - "*" means that the carbon atom thus marked in the absolute configuration (S) or (R) determined; X and RI are as defined for a compound of formula (I); as well as their possible salts with mineral or organic acids, their solvates and / or their hydrates.

 However, it is preferable to perform the resolution of the racemic mixtures from the intermediate compound of formula (II, E = H) useful for the preparation of the compound of formula (I) as described in the patent applications: EP-A- 0512901, EP-A-0612716 and EP-A-0591040.

avec un dérivé fonctionnel de l'acide de formule :

pour obtenir un composé de formule : According to another of its aspects, the present invention relates to a stereospecific process for the preparation of compounds of formula (I) having the configuration (S), their salts, their solvates and / or hydrates, characterized in that: Id) the (-) isomer of a compound of formula:

with a functional derivative of the acid of formula:

to obtain a compound of formula:

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2d) on oxyde le composé de formule (IV*)pour obtenir un composé de formule :

3d) on fait réagir le composé de formule (VIII*) avec un composé de formule :

dans laquelle X est tel que défini pour un composé de formule (I), en présence d'un acide, puis on réduit le sel d'iminium formé intermédiairement au moyen d'un agent réducteur ;
4d) et, éventuellement on transforme le composé ainsi obtenu en l'un de ses sels avec un acide minéral ou organique.

2d) the compound of formula (IV *) is oxidized to obtain a compound of formula:

3d) the compound of formula (VIII *) is reacted with a compound of formula:

wherein X is as defined for a compound of formula (I), in the presence of an acid, and then reducing the iminium salt formed intermediately by means of a reducing agent;
4d) and optionally converting the compound thus obtained into one of its salts with a mineral or organic acid.

 The compounds of formula (I) above also include those in which one or more hydrogen or carbon atoms have been replaced by their radioactive isotope, for example tritium, or carbon-14. Such labeled compounds are useful in research, metabolism or pharmacokinetic work in biochemical assays as receptor ligands.

 The compounds according to the invention have been the subject of biochemical tests.

The affinity of compounds for tachykinin receptors has been evaluated in vitro by several biochemical tests using radioligands:
1) The binding of [1251] BH-SP (Iodine-125-labeled Substance P with Bolton-Hunter reagent) to NK1 receptors of human lymphoblastic cells (DG Payan et al., J. Immunol. 1984, 133, 3260-3265).

 2) [1251] His-NKA binding to cloned human NK2 receptors expressed by CHO cells (Y. Takeda et al., J. Neurochem., 1992, 59, 740-745).

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 3) [125I] His [MePhe7] NKB binding to NK3 receptors of rat cerebral cortex, guinea pig cerebral cortex and gerbil brain cortex as well as to cloned human NK3 receptors expressed by CHO cells (Buell et al. , FEBS Letters, 1992, 299, 90-95).

 The tests were carried out according to X. Emonds-Alt et al. (Eur J Pharmacol., 1993, 250, 403-413, Life Sci., 1995, 56, PL 27-32).

 The compounds according to the invention strongly inhibit the binding of substance P to NK1 receptors of IM9 human lymphoblastic cells. The Ki inhibition constant for human lymphoblastic cell receptors is of the order of 10-11M.

 The inhibition constants Ki for the cloned NK2 human receptors are of the order of 10'M and the inhibition constants Ki for the cloned NK3 human receptors are greater than 10-7M.

 The compounds of formula (I) are potent and selective antagonists of human NK1 receptors of the substance P.

 Thus the compounds of formula (I) have also been evaluated in vivo in animal models.

 In gerbils, rotational behavior is induced by intrastriatal administration of an agonist specific for NK1 receptors: the septide; it has been found that a unilateral septide application in the gerbil striatum leads to strong contralateral rotations which are inhibited by the compounds of formula (I) administered either intraperitoneally or orally. This test was adapted from the method described by M. Jung et al., Neuropharmacology, 1994, 33 (2), 167-179.

 These results show that the compounds of formula (I) are orally active, that they pass the blood-brain barrier and that they are capable of blocking, in the central nervous system, the action specific to NK1 receptors.

 The compounds of formula (I) were evaluated in the guinea pig bronchoconstriction test, according to the method described by X. Emonds-Alt et al., European Journal of Pharmacology, 1993, 250, 403-413. The compounds of formula (I) administered intravenously strongly antagonize the bronchoconstriction induced by intravenous administration of septide in guinea pig under these experimental conditions.

 The in vivo pharmacological activity of the compounds of formula (I) was also evaluated in the model of hypotension in dogs, according to the method described by X.

Emonds-Alt et al., Eur. J. Pharmacol., 1993, 250, 403-413. The compounds of formula (I) administered intravenously strongly inhibit hypotension induced by

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 11 intravenous administration of [Sar, Met (O2) 11] substance P in the dog anesthetized under these experimental conditions.

 These results show that the compounds of formula (I) block at the level of the peripheral nervous system, the action specific to NK1 receptors.

 The compounds of the present invention are especially active ingredients of pharmaceutical compositions, the toxicity of which is compatible with their use as medicaments.

 The compounds of formula (I) above may be used at daily doses of 0.01 to 100 mg per kilogram of body weight of the mammal to be treated, preferably at daily doses of 0.1 to 50 mg / kg. In humans, the dose may preferably vary from 0.1 to 4000 mg per day, more particularly from 0.5 to 1000 mg depending on the age of the subject to be treated or the type of treatment: prophylactic or curative.

 For their use as medicaments, the compounds of formula (I) are generally administered in dosage units. Said dosage units are preferably formulated in pharmaceutical compositions in which the active ingredient is mixed with a pharmaceutical excipient.

 Thus, according to another of its aspects, the present invention relates to pharmaceutical compositions containing, as active principle, a compound of formula (I) or a pharmaceutically acceptable salt, solvate and / or hydrate thereof.

 In the pharmaceutical compositions of the present invention for oral, sublingual, inhaled, subcutaneous, intramuscular, intravenous, transdermal, local or rectal administration, the active ingredients can be administered in unit dosage forms, in admixture with conventional pharmaceutical carriers, animals and humans. Suitable unit dosage forms include oral forms such as tablets, capsules, powders, granules and oral solutions or suspensions, sublingual and oral forms of administration, aerosols, dosage forms topical, implants, forms of subcutaneous, intramuscular, intravenous, intranasal or intraocular administration and forms of rectal administration.

 When a solid composition in the form of tablets is prepared, a pharmaceutical carrier which may be composed of diluents, for example lactose, microcrystalline cellulose, starch and formulation adjuvants, is added to the active ingredient, which may or may not be micronized. binders (polyvinylpyrrolidone, hydroxypropylmethylcellulose, etc.), flow agents such as silica,

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 lubricants such as magnesium stearate, stearic acid, glycerol tribehenate, sodium stearyl fumarate.

 Wetting agents or surfactants such as sodium lauryl sulphate may be added to the formulation.

 The tablets can be made by various techniques, direct compression, dry granulation, wet granulation, hot melt.

 The tablets may be bare or sugar-coated (for example with sucrose) or coated with various polymers or other suitable materials.

 The tablets may have flash, delayed or extended release by making polymeric matrices or by using specific polymers in the film coating.

 A capsule preparation is obtained by simply mixing the active ingredient with dry pharmaceutical vehicles (simple mixing or dry granulation, wet, hot melting), liquid or semi-solid.

 The capsules may be soft or hard, film-coated or not, so as to have a flash activity, prolonged or delayed (for example by an enteric form).

 A preparation in syrup or elixir form may contain the active ingredient together with a sweetener, preferably calorie-free, methylparaben and propylparaben as antiseptic, as well as a flavoring agent and a suitable colorant.

 The water dispersible powders or granules may contain the active ingredient in admixture with dispersing agents, wetting agents or suspending agents, such as polyvinylpyrrolidone, as well as with sweeteners or taste correctors .

 For rectal administration, suppositories are used which are prepared with binders melting at the rectal temperature, for example cocoa butter or polyethylene glycols.

 For parenteral, intranasal or intraocular administration, aqueous suspensions, isotonic saline solutions or sterile and injectable solutions containing dispersing agents and / or pharmacologically compatible solubilizing agents, for example propylene glycol or butylene glycol, are used.

 Thus, to prepare an aqueous solution for injectable intravenous use a cosolvent such as an alcohol such as ethanol or a glycol such as polyethylene glycol or propylene glycol, and a hydrophilic surfactant such as the

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 Tween @ 80. To prepare an injectable oily solution intramuscularly, the active ingredient can be solubilized by a triglyceride or a glycerol ester.

 For the local administration it is possible to use creams, ointments, gels, eye drops.

 For transdermal administration, patches may be used in multilaminated or reservoir form in which the active ingredient may be in alcoholic solution.

 For administration by inhalation, an aerosol containing, for example, sorbitan trioleate or oleic acid as well as trichlorofluoromethane, dichlorofluoromethane, dichlorotetrafluoroethane or any other biologically compatible propellant gas is used; it is also possible to use a system containing the active principle alone or in combination with an excipient, in the form of a powder.

 The active ingredient may also be presented as a complex with a cyclodextrin, for example, a, ss. γ-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin.

 The active ingredient may also be formulated in the form of microcapsules or microspheres, optionally with one or more supports or additives.

 Among the sustained-release forms useful in the case of chronic treatments, the implants can be used. These can be prepared as an oily suspension or as a suspension of microspheres in an isotonic medium.

 In each dosage unit the active ingredient of formula (I) is present in the amounts adapted to the daily doses envisaged. In general, each dosage unit is suitably adjusted according to the dosage and the type of administration envisaged, for example tablets, capsules and the like, sachets, ampoules, syrups and the like, drops so that such a dosage unit contains 0.1 to 1000 mg of active ingredient, preferably 0.5 to 250 mg to be administered one to four times daily.

 Although these assays are examples of average situations, there may be special cases where higher or lower dosages are appropriate, such assays also belong to the invention. According to the usual practice, the dosage appropriate to each patient is determined by the physician according to the mode of administration, the age, the weight and the response of said patient.

 The aforesaid compositions may also contain other active products such as, for example, bronchodilators, antitussives, antihistamines, anti-inflammatories, antiemetics, chemotherapy agents.

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 According to another of its aspects, the present invention relates to the use of the compounds of formula (I), or one of their pharmaceutically acceptable salts, solvates and / or hydrates for the preparation of medicaments intended to treat any pathology where the substance P and human NK1 receptors are involved.

 According to another of its aspects, the present invention relates to the use of the compounds of formula (I) or of one of their pharmaceutically acceptable salts, solvates and / or hydrates for the preparation of medicaments intended to treat the pathologies of the respiratory system , gastrointestinal, urinary, immune, cardiovascular and central nervous system as well as pain, migraine, inflammation, nausea and vomiting, skin diseases.

 For example and without limitation, the compounds of formula (I) are useful: as an analgesic, in particular in the treatment of traumatic pain such as postoperative pain; neuralgia of the brachial plexus; chronic pain such as arthritis pain due to osteoarthritis, rheumatoid arthritis or psoriatic arthritis; neuropathic pain such as post-herpetic neuralgia, trigeminal neuralgia, segmental or intercostal neuralgia, fibromyalgia, causalgia, peripheral neuropathy, diabetic neuropathy, chemotherapy-induced neuropathies, AIDS-related neuropathies, occipital neuralgia, geniculate neuralgia, glossopharyngeal neuralgia; pains of the illusion of the amputees; various forms of headache such as chronic or acute migraine, temporomandibular pain, maxillary sinus pain, facial neuralgia, odontalgia; cancer pain; pain of visceral origin; gastrointestinal pain; pain due to nerve compression, pain due to the intensive practice of a sport; dysmenorrhea; menstrual pain; pain due to meningitis, arachnoiditis; musculoskeletal pain; lower back pain due to spinal stenosis, prolapsed disc, sciatica; pain of the angina; pain due to ankylosing spondylitis; pain related to gout; pain associated with burns, scarring, pruritic dermatitis; thalamic pain; as an anti-inflammatory agent in particular for treating inflammations in asthma, influenza, chronic bronchitis, coughs, allergies, bronchospasm and rheumatoid arthritis; inflammatory diseases of the gastrointestinal system for example Crohn's disease, ulcerative colitis, pancreatitis, gastritis, inflammation of the intestines, disorders caused by nonsteroidal anti-inflammatory drugs, inflammatory and secretory effects due to bacterial infections, for example due to Clostridium difficile; inflammatory diseases of the skin, by

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 example herpes and eczema; inflammatory diseases of the bladder such as cystitis and incontinence; ophthalmic inflammations such as conjunctivitis, vitreoretinopathy; dental inflammations such as gingivitis and periodontitis; in the treatment of allergic diseases, in particular of the skin, such as urticaria, contact dermatitis, atopic dermatitis and respiratory diseases such as rhinitis; in the treatment of diseases of the central nervous system, in particular psychoses such as schizophrenia, mania and dementia; cognitive disorders such as Alzheimer's disease, anxiety, AIDS-related dementia; diabetic neuropathies; depression; Parkinson's disease; drug dependence; substance abuse; disorders of alertness, sleep, circadian rhythm, mood, epilepsy; Down syndrome; Huntington's chorea somatic stress-related disorders of neurodegenerative diseases such as Pick's disease, Creutzfeldt-Jacob disease; disorders related to panic, phobia, stress; - as a muscle relaxant and antispasmodic; in the treatment of acute or delayed and anticipated nausea and vomiting, for example nausea and vomiting induced by drugs such as agents used in chemotherapy for cancer; by radiation therapies during irradiation of the thorax or the abdomen in the treatment of cancer, carcinoidosis; ingestion of poison; by toxins due to metabolic or infectious disorders such as gastritis, or produced during bacterial or viral gastrointestinal infection; during pregnancy during vestibular disorders such as motion sickness, vertigo, Meniere's syndrome; post-operative diseases; nausea and vomiting induced by dialysis, by prostaglandins; by gastrointestinal obstructions; during reduced gastrointestinal motility; visceral pain with myocardial infarction or peritonitis; during migraine; during altitude sickness; by ingestion of opioid analgesics such as morphine; during gastroesophageal reflux; during acid indigestion or overconsumption of food or drink, during acidity or gastric acid, regurgitation, heartburn, for example episodic, nocturnal or induced by a meal and dyspepsia; - in the treatment of diseases of the gastrointestinal system such as irritable bowel syndrome, gastric and duodenal ulcers, oesophageal ulcers, diarrhea, hypersecretions, lymphomas, gastritis, gastroesophageal reflux, incontinence fecal, Hirschsprung's disease;

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 - in the treatment of skin diseases such as psoriasis, pruritus, burns, especially sunburn; - in the treatment of diseases of the cardiovascular system such as hypertension, vascular aspects of migraine, oedemas, thrombosis, angina pectoris, vascular spasms, circulatory diseases due to vasodilatation, Raynaud's disease , fibroses, collagen diseases, atheosclerosis; - in the treatment of small cell lung cancers; brain tumors; - demyelination diseases such as multiple sclerosis or amyotrophic lateral sclerosis; in the treatment of diseases of the immune system related to the suppression or stimulation of the functions of immune cells, for example rheumatoid arthritis, psoriasis, Crohn's disease, diabetes, lupus, rejection reactions after transplantation; in the treatment of urination disorders, in particular pollakiuria; in the treatment of histiocytic reticulosis, as in the lymphatic tissues; - as anorectic; - in the treatment of emphysema; Reiter's syndrome; hemorrhoids; - in the treatment of ocular disorders such as glaucoma, ocular hypertension, miosis, excess tears; - in the treatment or prevention of stroke, epilepsy, head trauma, spinal cord trauma, ischemic brain injury due to stroke or vascular occlusion; - in the treatment of disorders of heart rate and rhythm, especially those caused by pain or stress; - in the treatment of sensitive skin and to prevent or fight irritation of the skin or mucous membranes, dandruff, erythema or pruritus; in the treatment of neurological disorders of the skin such as lichens, prurigos, pruriginous toxidermias, severe pruritus of neurogenic origin; - in the treatment of ulcers and all diseases caused by Helicobacter Pylori or a gram-negative positive urease bacterium; in the treatment of diseases caused by angiogenesis or whose angiogenesis is a symtom;

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 in the treatment of eye and / or palpebral pain and / or ocular or palpebral dysaesthesia; - as antiperspirant.

 The present invention also includes a method for treating said conditions at the doses indicated above.

In Preparations and Examples the following abbreviations are used:
DMF: dimethylformamide
DMSO: dimethylsulfoxide
DCM: dichloromethane
THF: tetrahydrofuran hydrochloric ether: saturated solution of hydrochloric acid in ether
BOP: benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate
F: melting point
TA: room temperature silica H: 60H silica gel marketed by Merck (DARMSTAD)
Proton nuclear magnetic resonance spectra (1 H NMR) are recorded at 200 MHz in DMSO-d6, using tetramethylsilane (TMS) as a reference. Chemical shifts are reported in parts per million (ppm). s: singlet; it is: widened singlet; t: triplet; qd: quadruplet.

PREPARATION 1
3- (3,4-Dichlorophenyl) -3- (2-hydroxyethyl) piperidine, isomer (-), compound of formula (II *, E = H).

 The preparation of this compound is described in patent application EP-A-0 591 040.

PREPARATION 2.1
3,5-dichlorophenylacetic acid.

 (m): R1 = Cl.

A) 3,5-dichlorobenzyl chloride.

 To a solution of 14.5 g of 3,5-dichlorobenzyl alcohol in 150 ml of chloroform is added dropwise at RT a solution of 12.5 g of thionyl chloride in 20 ml of chloroform, and then heated to 40.degree. -50 C for 8 hours and left overnight stirring at RT. It is concentrated under vacuum and 16 g of the expected product are obtained, which product is used as it is.

B) 3,5-Dichlorophenylacetonitrile.

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 To a solution of 16 g of the compound obtained in the previous step in 50 ml of EtOH is added a solution of 6.5 g of potassium cyanide in 50 ml of water and refluxed for 4 hours. It is concentrated under vacuum, the residue is taken up in water and extracted with ether, the organic phase is washed with water and dried over Na 2 SO 4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica H eluting with a heptane / toluene mixture (50/50, v / v) and then with toluene. 7 g of the expected product are obtained which is used as such.

C) 3,5-dichlorophenylacetic acid.

 To a solution of 7 g of the compound obtained in the previous step in 50 ml of EtOH is added a solution of 8.4 g of KOH in 10 ml of water and then refluxed for 5 hours. It is concentrated under vacuum, the residue is taken up in water, the aqueous phase is washed with ether, the aqueous phase is acidified to pH 1 by addition of concentrated HCl and the mixture is stirred overnight at RT. The crystallized product formed is filtered off with suction, washed with water and dried under vacuum at 60 ° C. 7 g of the expected product are obtained, mp 112-114.5 ° C.

PREPARATION 2.2
3,5-diethylphenylacetic acid.

 (Ill): RI = and.

A) 3,5-Diethylbromobenzene.

 A mixture of 20 g of 4-bromo-2,6-diethylaniline, 160 ml of acetic acid, 100 ml of concentrated HCl solution, 30 ml of water and 100 ml of water is cooled to -5 ° C. EtOH, dropwise added a solution of 6.6 g of sodium nitrite in 25 ml of water and leave stirring for 30 minutes at RT. The reaction mixture is poured into 170 ml of 50% H3PO2 cooled to 0 ° C., left stirring for 2 hours at 0 ° C. and then 48 hours at RT. The reaction mixture is extracted with ether, the organic phase washed with water, with 1 N NaOH solution, with water, dried over Na 2 SO 4 and the solvent evaporated under vacuum.

The residue is chromatographed on silica gel eluting with cyclohexane. 18 g of the expected product are obtained.

B) 3,5-Diethylbenzonitrile.

 A mixture of 24.7 g of the compound obtained in the preceding step and 12 g of cuprous cyanide in 70 ml of DMF is refluxed for 15 hours. After cooling to RT, the reaction mixture is poured into 50 ml of water and stirred at RT until a gum is formed. The mixture is cooled in an ice bath, 150 ml of ethylenediamine are added and the mixture is stirred for 2 hours at RT. The mixture is extracted with AcOEt, the organic phase is washed with water and dried over Na 2 SO 4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica gel, eluting with a cyclohexane / AcOEt mixture (95/5, v / v). 12 g of the expected product are obtained.

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C) 3,5-diethylbenzoic acid.

 To a solution of 12 g of the compound obtained in the previous step in 60 ml of EtOH is added a solution of 22 g of KOH in 15 ml of water and heated at reflux for 24 hours. The reaction mixture is concentrated under vacuum, the residue is extracted with water, the aqueous phase is washed with ether, the aqueous phase is acidified to pH = 2 by addition of concentrated HCl, the precipitate formed is filtered off, washed with water and dry it under vacuum. 13 g of the expected product are obtained.

D) Methyl ester of 3,5-diethylbenzoic acid.

 A mixture of 13 g of the compound obtained in the preceding step in 90 ml of MeOH and 10 drops of H 2 SO 4 is refluxed for 48 hours. The reaction mixture is concentrated under vacuum, the residue is taken up in water, neutralized by addition of a 10% solution of NaHCO 3, extracted with ether, the organic phase is washed with a 10% solution of NaHCO 3, at 100.degree. water, dried over Na 2 SO 4 and the solvent evaporated under vacuum. 12 g of the expected product are obtained.

E) 3,5-diethylbenzyl alcohol.

 A suspension of 2.5 g of lithium aluminum hydride in 50 ml of THF is cooled to 0 ° C., a solution of 12 g of the compound obtained in the preceding step in 50 ml of THF and added dropwise. leave 30 minutes stirring. The reaction mixture was hydrolyzed by addition of 2.5 ml of water, 2.5 ml of 4N NaOH and 7.5 ml of water.

The inorganic salts are filtered and the filtrate is concentrated under vacuum. 10.9 g of the expected product is obtained which is used as it is.

F) 3,5-diethylbenzyl methanesulfonate.

 To a solution of 10.9 g of the compound obtained in the preceding step and 7.4 g of triethylamine in 100 ml of DCM is added dropwise, at RT, a solution of 8.4 g of methanesulfonyl chloride in 50 ml of DCM and leave stirring for 30 minutes. The reaction mixture is concentrated under vacuum, the residue is taken up in water and extracted with ether, the organic phase is washed with water and dried over Na 2 SO 4 and the solvent is evaporated off under vacuum. 16 g of the expected product are obtained which is used as such.

G) 3,5-Diethylphenylacetonitrile.

 To a solution of 16 g of the compound obtained in the previous step in 100 ml of DMF is added a solution of 5.15 g of potassium cyanide in 20 ml of water and heated at 80 ° C. for 1 hour. The reaction mixture is concentrated under vacuum, the residue is taken up in water and extracted with ether, the organic phase is washed with water and dried over Na 2 SO 4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica gel H, eluting with DCM. 3 g of the expected product are obtained.

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H) 3,5-diethylphenylacetic acid.

 To a solution of 3 g of the compound obtained in the previous step in 50 ml of EtOH is added a solution of 7.8 g of KOH in 10 ml of water, and then refluxed for 5 hours. It is concentrated under vacuum, the residue is taken up in water, the aqueous phase is washed with ether, the aqueous phase is acidified to pH 1 by addition of concentrated HCl and the mixture is stirred overnight at RT. The crystallized product formed is filtered off with suction, washed with water and dried under vacuum. 2.5 g of the expected product are obtained.

 1 H NMR: (ppm): 1.1: t: 6H; 2.4: qd: 4H; 3.4: s: 2H; 6.8: m: 3H; 12.2: se: 1H.

PREPARATION 3.1
2- (Piperidin-4-yl) isobutyramide hydrochloride.

 (VII), HCl: X = -CH-C (CH3) 2-CONH2.

A) 2-Methyl-2- (pyridin-4-yl) propionitrile.

 A mixture of 3 g of pyridin-4-ylacetonitrile hydrochloride in 50 ml of DMF is cooled to 0 ° C., 2.6 g of 60% sodium hydride in oil are added in small portions, and the mixture is left under stirring for 2 hours. stirring at TA. The reaction mixture is cooled in an ice bath, 6 g of methyl iodide are added dropwise and the mixture is stirred overnight at RT. The reaction mixture is poured into a water / ice mixture, extracted with ether, the organic phase is washed with saturated NaCl solution, dried over MgSO 4, filtered and the solvent evaporated under vacuum. The residue is chromatographed on silica gel H, eluting with DCM and then with a DCM / MeOH mixture (98/2, v / v). 2.39 g of the expected product are obtained in the form of an oil which crystallizes.

B) 2- (Pyridin-4-yl) isobutyramide hydrochloride.

 A mixture of 2.39 g of the compound obtained in the preceding step and 10 ml of concentrated H 2 SO 4 solution is heated at 100 ° C. for 15 minutes. The reaction mixture is cooled to RT, 50 g of ice are added, the mixture is basified to pH 14 by addition of a concentrated NaOH solution, the inorganic salts are filtered off, the filtrate is extracted with AcOEt then with DCM and the combined organic phases are dried over MgSO4, filter and evaporate the solvents under vacuum (mp = 134 ° C, base). The product obtained is dissolved in acetone, acidified to pH = 1 by addition of hydrochloric ether and the precipitate formed is filtered off. 2.9 g of the expected product are obtained.

C) 2- (Piperidin-4-yl) isobutyramide hydrochloride.

 A mixture of 2.9 g of the compound obtained in the preceding step, 1 g of PtO 2 and 50 ml of MeOH is hydrogenated for 3 days at 60 ° C. under a pressure of 60 bar. The catalyst is filtered through Celite #, washed with MeOH and the filtrate concentrated under vacuum. We

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 The residue is taken up in acetonitrile, the precipitate formed is filtered off and washed with acetonitrile and then with ether. 2.5 g of the expected product are obtained, mp 260.degree.

PREPARATION 3.2
2- (piperazin-1-yl) isobutyramide dihydrochloride.

 (VII), 2HCl: X = -N-C (CH3) 2-CONH2.

A) 2- (4-Benzylpiperazin-1-yl) -2-methylpropionitrile.

 4.5 ml of acetone, 20 g of dry MgSO 4, 10 g of N, N-dimethylacetamide, 10 g of 1-benzylpiperazine and 9.5 ml of 2-hydroxyisobutyronitrile are heated and heated at 45 ° C. for 48 hours with vigorous stirring. The reaction mixture is poured onto ice and left stirring for 30 minutes. The mixture is extracted with ether, the organic phase is washed several times with water and dried over Na 2 SO 4 and the solvent is evaporated off under vacuum. 13 g of the expected product are obtained.

B) 2- (4-Benzylpiperazin-1-yl) isobutyramide dihydrochloride.

 A mixture of 13 g of the compound obtained in the preceding step and 130 ml of a solution of 90% H 2 SO 4 is heated rapidly to 110 ° C. for 30 minutes. After cooling to RT, the reaction mixture is poured onto ice, basified to pH = 10 by addition of a concentrated solution of NH 4 OH and the crystalline product formed is filtered off.

The product is dissolved in DCM, the organic phase is dried over MgSO 4 and the solvent is evaporated off under vacuum. The product is taken up in hydrochloric ether and the precipitate formed is filtered off. 9.5 g of the expected product are obtained.

C) 2- (piperazin-1-yl) isobutyramide dihydrochloride.

 A mixture of 1.3 g of the compound obtained in the preceding step and 0.18 g of 10% palladium on charcoal in 30 ml of 95 EtOH is hydrogenated overnight at RT and at atmospheric pressure. the catalyst on Celite # and concentrated under vacuum the filtrate. 0.6 g of the expected product is obtained.

PREPARATION 3.3
1- (Piperazin-1-yl) cyclohexanecarboxamide dihydrochloride.

A) 1- (4-Benzylpiperazin-1-yl) cyclohexanecarbonitrile.

 5.7 g of cyclohexanone, 20 g of dry MgSO4, 10 g of N, N-dimethylacetamide, 10 g of 1-benzylpiperazine and 9.5 ml of 2-hydroxyisobutyronitrile are heated and heated at 45 ° C. for 48 hours with vigorous stirring. Pour the mixture

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 reaction on ice and left stirring for 30 minutes. The mixture is extracted with ether, the organic phase is washed several times with water and dried over Na 2 SO 4 and the solvent is evaporated off under vacuum. 15 g of the expected product are obtained.

B) 1- (4-Benzylpiperazin-1-yl) cyclohexanecarboxamide dihydrochloride.

 This compound is prepared according to the procedure described in step B of Preparation 3.2 from 15 g of the compound obtained in the preceding step and 50 ml of a solution of 90% H 2 SO 4. 5.5 g of the expected product are obtained.

C) 1- (piperazin-1-yl) cyclohexanecarboxamide dihydrochloride.

 This compound is prepared according to the procedure described in step C of Preparation 3. 2 from 2.3 g of the compound obtained in the previous step, 0.3 g of 10% palladium on carbon in 30 ml. EtOH 95. 1.6 g of the expected product are obtained.

PREPARATION 3.4
N, N-dimethyl-2- (piperazin-1-yl) isobutyramide diformate.

A) N,N-diméthyl-2-(4-benzylpipérazin-1-yl)isoburyramide. (VU), 2HCO2H: X = -NC (CH3) 2-CON (Me) 2 '

A) N, N-dimethyl-2- (4-benzylpiperazin-1-yl) isoburyramide.

 To a mixture of 2.6 g of the compound obtained in step B of Preparation 3. 2 (free base) in 50 ml of anhydrous THF, 1.44 g of 60% sodium hydride are added in portions. oil. 1.3 ml of methyl iodide are then added dropwise and the mixture is stirred for 4 hours at RT. The reaction mixture is poured into water and extracted with ether, the organic phase is dried over MgSO 4 and the solvents are evaporated off under vacuum. 1.8 g of the expected product are obtained.

B) N, N-dimethyl-2- (piperazin-1-yl) isobutyramide diformate.

 To a solution of 1.8 g of the compound obtained in the preceding step in 30 ml of MeOH is added 2 g of ammonium formate, 0.5 g of 5% palladium-on-charcoal and left stirring for 4 hours. YOUR. The catalyst is filtered through Celite # and the filtrate is concentrated under vacuum. The residue is taken up in AcOEt, the precipitate formed is filtered off, washed with AcOEt and dried. 1.2 g of the expected product are obtained.

PREPARATION 3.5
1- (Piperidin-4-yl) cyclohexanecarboxamide hydrochloride.

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A) 1- (Pyridin-4-yl) cyclohexanecarbonitrile.

 A mixture of 3 g of pyridin-4-ylacetonitrile hydrochloride in 50 ml of DMF is cooled to 0 ° C., 2.6 g of 60% sodium hydride in the oil are added in small portions and the mixture is left for 1 hour 30 minutes. with stirring at RT. The reaction mixture is cooled in an ice bath, 2.7 ml of 1,5-dibromopentane are added dropwise and the mixture is stirred for 48 hours at RT. The reaction mixture is poured into a saturated solution of NH 4 Cl, extracted with ether, the organic phase is washed three times with water and dried over MgSO 4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica gel H, eluting with DCM and then with a DCM / MeOH mixture (98/2, v / v). 2.5 g of the expected product are obtained, mp = 79 ° C.

B) 1- (Pyridin-4-yl) cyclohexanecarboxamide hydrochloride.

 A mixture of 2.5 g of the compound obtained in the preceding step and 15 ml of concentrated H 2 SO 4 solution is heated at 100 ° C. for 15 minutes. The reaction mixture is cooled to RT, poured over ice, basified to pH 14 by addition of a concentrated NaOH solution, the precipitate formed is filtered off, washed with water and dried. The product obtained is dissolved in acetone, acidified to pH = 1 by addition of hydrochloric ether, stirred for 30 minutes at RT and the precipitate formed is filtered off with suction. 3 g of the expected product are obtained, mp = 224 ° C. (dec.).

C) 1- (Piperidin-4-yl) cyclohexanecarboxamide hydrochloride.

 A mixture of 2.9 g of the compound obtained in the preceding step, 0.5 g of PtO 2 and 50 ml of MeOH is hydrogenated for 3 days at 60 ° C. under a pressure of 80 bar.

The catalyst is filtered through Celite #, and the filtrate is concentrated under vacuum. The residue is taken up in acetonitrile, stirred for 1 hour at RT, and the precipitate formed is filtered off. 2.7 g of the expected product are obtained, mp = 235 ° C.

Chlorhydrate de 3-[2-[4-(1-carbamoyl-1-méthyléthyl)pipéridin-1-yl]éthyl]-3-(3,4dichlorophényl)-l-[2-(3,5-diméthylphényl)acétyl]pipéridine, monohydrate, isomère (-). EXAMPLE 1

3- [2- [4- (1-Carbamoyl-1-methylethyl) piperidin-1-yl] ethyl] -3- (3,4-dichlorophenyl) -1- [2- (3,5-dimethylphenyl) acetyl] hydrochloride] piperidine, monohydrate, (-) isomer.

A) 3- (3,4-Dichlorophenyl) -3- (2-hydroxyethyl) -1- [2- (3,5-dimethylphenyl) acetyl] piperidine, single isomer.

 To a mixture of 2.0 g of 3,5-dimethylphenylacetic acid in 100 ml of DCM, 2.3 ml of triethylamine are added to RT, followed by 3 g of the compound obtained in Preparation 1 and 5.3 g of BOP. and left stirring for 1 hour at RT. The reaction mixture is concentrated under vacuum, the residue is extracted with ether, the organic phase is washed with water, with 2N HCl solution, with water, with a 10% solution of NaOH in water. dried over Na2SO4, filtered and concentrated under vacuum the filtrate. The residue is chromatographed on a gel of

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B) 3-(3,4-Dichlorophényl)-3-(formylméthyl)-1-[2-(3,5-diméthylphényl)acétyl] pipéridine, isomère unique. H silica eluting with DCM and then with DCM / MeOH (98/2; v / v). 3.9 g of the expected product are obtained which is used as it is in the next step.

B) 3- (3,4-Dichlorophenyl) -3- (formylmethyl) -1- [2- (3,5-dimethylphenyl) acetyl] piperidine, single isomer.

 A solution of 0.25 ml of oxalyl chloride in 3 ml of DCM is cooled to -70 ° C. under a nitrogen atmosphere, a solution of 0.35 ml of DMSO in 3 ml of DCM is added dropwise, then a solution of 0.5 g of the compound obtained in the previous step in 5 ml of DCM and left stirring for 15 minutes at -50 C. 0.9 ml of triethylamine are then added and the mixture is stirred while allowing the temperature to rise at TA.

The reaction mixture is washed with water, with a solution of 1N HCl, with a 10% solution of NaHCO 3, the organic phase is dried over Na 2 SO 4, filtered and the filtrate is concentrated under vacuum. 0.5 g of the expected product is obtained which is used as such in the next step.

C) 3- [2- [4- (1-Carbamoyl-1-methylethyl) piperidin-1-yl] ethyl] -3- (3,4-dichlorophenyl) -1- [2- (3,5-dimethylphenyl) hydrochloride) acetyl] piperidine, monohydrate, (-) isomer.

 To a solution of 0.24 g of the compound obtained in Preparation 3.1 (free base) in 3 ml of MeOH is added at RT and under a nitrogen atmosphere, 0.08 ml of acetic acid and then a solution of 0, 5 g of the compound obtained in the previous step in 5 ml of MeOH. After 5 minutes, 0.08 g of sodium cyanoborohydride and stir overnight at RT. The reaction mixture is poured onto a 10% solution of NaHCO 3 in water, extracted with ether, the organic phase washed with water, dried over Na 2 SO 4, filtered and the filtrate concentrated under vacuum. The residue is chromatographed on silica gel H, eluting with DCM and then with the gradient of the DCM / MeOH mixture from (99/1: v / v) to (90/10; v / v). The product obtained is dissolved in DCM, acidified to pH = 1 by addition of hydrochloric ether and concentrated in vacuo. 0.5 g of the expected product is obtained after trituration in ether, drying and drying under vacuum. a = -27.7 (c = 1, MeOH).

 1H NMR: δ (ppm): 0.7 to 1.2: sec: 6H; 1.2 to 2.4: m: 16H; 2.5 to 4.8: m: 12H; 6.5 to 8.0: m: 8H; 10.2: se: 1H.

Claims (11)

wherein: - X represents an R2-N group; R2-CH-R1 represents chlorine, bromine, (C1-C3) alkyl or trifluoromethyl; R2 represents a group -CR3R4CONR5R6; R3 and R4 represent the same radical chosen from methyl, ethyl, n-propyl or n-butyl; - or R3 and R4 together with the carbon atom to which they are attached constitute a (C3-C6) cycloalkyl; R5 and R6 each independently represent hydrogen; a (C1-C3) alkyl; or else R5 and R6 together with the nitrogen atom to which they are bonded constitute a heterocyclic radical chosen from azetidin-1-yl, pyrrolidin-1-yl and piperidin.Claims 1. Compound of formula: 1-yl, morpholin-4-yl, thiomorpholin-4-yl or perhydroazepin-1-yl; and its salts with mineral or organic acids, its solvates and / or its hydrates. 2. Compound according to claim 1 wherein the substituents RI represent a chlorine atom, a methyl, an ethyl or a trifluoromethyl. The compound of claim 1 wherein X is R2-N # in which R2 is -CR3R4CONR5R6. The compound of claim 3 wherein R 3 and R 4 are each methyl or together with the carbon atom to which they are attached constitute cyclohexyl. The compound of claim 3 wherein R5 and R6 are each hydrogen or methyl. <Desc / Clms Page number 33> The compound of claim 1 wherein X is R2-CH wherein R2 is -CR3R4CONR5R6. The compound of claim 6 wherein R 3 and R 4 are each methyl or together with the carbon atom to which they are attached constitute cyclohexyl. The compound of claim 6 wherein R5 and R6 are each hydrogen or methyl.  wherein: - R1 represents a chlorine atom, a methyl, an ethyl or a trifluoromethyl; - R'3 and R'4 each represent a methyl or together with the carbon atom to which they are attached constitute a cyclohexyl; - R'5 and R'6 each represent hydrogen or methyl; and its salts with mineral or organic acids, its solvates and / or its hydrates.

9. Compound according to claim 1 of formula:  wherein: - R1 represents a chlorine atom, a methyl, an ethyl or a trifluoromethyl; - R'3 and R'4 each represent a methyl or together with the carbon atom to which they are attached, constitute a cyclohexyl; - R'5 and R'6 each represent hydrogen or methyl; and its salts with mineral or organic acids, its solvates and / or its hydrates.

10. Compound according to claim 1 of formula: <Desc / Clms Page number 34>  12. 3- [2- [4- (1-Carbamoyl-1-methylethyl) piperidin-1-yl] ethyl] -3- (3,4-dichlorophenyl) -1- [2- (3,5-dimethylphenyl)) acetyl] piperidine, isomer (-), its salts, solvates and / or hydrates.

 11. A compound according to any one of claims 1 to 10 of formula (I), (I '), (I ") in optically pure form.  2a) optionally, when E represents a protecting group, it is removed by the action of an acid or a base, to obtain the alcohol of formula:

 wherein R1 is as defined for a compound of formula (I) in claim 1, to obtain a compound of formula:

 in which E represents hydrogen or an O-protecting group, with a functional derivative of an acid of formula:

13. Process for the preparation of the compounds of formula (I) according to claim 1, their salts, their solvates and / or their hydrates, characterized in that a) a compound of formula: <Desc / Clms Page number 35> 5a) and, optionally, the compound thus obtained is converted into one of its salts with an inorganic or organic acid.  wherein X is as defined for a compound of formula (I) in claim 1;

 4a) the compound of formula (VI) is reacted with a compound of formula:

Y-SO 2 -Cl (V) wherein Y represents a methyl, phenyl, tolyl or trifluoromethyl group, to obtain a compound of formula:  3a) the alcohol obtained in step la) or in step 2a) of formula (IV, E = H) is treated with a compound of formula:

1b) the compound of formula 14. Process for the preparation of the compounds of formula (I) according to claim 1, their salts, their solvates and / or their hydrates, characterized in that: <Desc / Clms Page number 36>

 3b) the compound of formula (VIII) is reacted with a compound of formula:

 2b) the compound of formula (IV, E = H) thus obtained is oxidized to prepare a compound of formula:

 optionally, when E represents a protecting group, it is removed by the action of an acid or a base, to obtain the alcohol of formula:

 wherein R1 is as defined for a compound of formula (I) in claim 1, to obtain a compound of formula:

 in which E represents hydrogen or an O-protecting group, with a functional derivative of an acid of formula: <Desc / Clms Page number 37> 4b) and optionally converting the compound thus obtained into one of its salts with an inorganic or organic acid.  wherein X is as defined for a compound of formula (I) in claim 1, in the presence of an acid, and then reducing the imminium salt formed intermediately by means of a reducing agent;  3d) the compound of formula (VIII *) is reacted with a compound of formula:

 2d) the compound of formula (IV *) is oxidized to obtain a compound of formula:

 to obtain a compound of formula:

 with a functional derivative of the acid of formula:

15. Stereospecific process for the preparation of the compounds of formula (I) according to claim 1, having the configuration (S), their salts, their solvates and / or hydrates, characterized in that: Id) the isomer is treated (-) of a compound of formula: <Desc / Clms Page number 38> 4d) and optionally converting the compound thus obtained into one of its salts with a mineral or organic acid.  wherein X is as defined for a compound of formula (I) in claim 1, in the presence of an acid, and then the intermediate-formed iminium salt is reduced by means of a reducing agent;

 wherein X is as defined for a compound of formula (I) in claim 1, and optionally converting the compound thus obtained into a salt thereof with a mineral or organic acid.

 in which: Y represents a methyl, phenyl, tolyl or trifluoromethyl group; R1 represents a chlorine atom, a bromine atom, a (C1-C3) alkyl or a trifluoromethyl; with a compound of formula:

16. Process for the preparation of the compounds of formula (I) according to claim 1, their salts, their solvates and / or hydrates, characterized in that: a compound of formula: 17. Process for the preparation of the compounds of formula (I) according to claim 1, their salts, their solvates and / or their hydrates, characterized in that: the compound of formula: <Desc / Clms Page number 39>  wherein X is as defined for a compound of formula (I) in claim 1, in the presence of an acid, and then reducing the imminium salt intermediate formed by means of a reducing agent, and optionally converts the compound thus obtained into one of its salts with a mineral or organic acid.

 wherein R1 is as defined for a compound of formula (I) in claim 1, with a compound of formula:

 wherein X is as defined for a compound of formula (I) in claim 1, in the presence of an acid, and then reducing the imminium salt intermediate formed by means of a reducing agent, and optionally converts the compound thus obtained into one of its salts with a mineral or organic acid.

 wherein R1 is as defined for a compound of formula (I) in claim 1, with a compound of formula:

18. Stereospecific process for the preparation of the compounds of formula (I) according to claim 1, having the configuration (S), their salts, their solvates and / or their hydrates, characterized in that: the compound of formula : <Desc / Clms Page number 40> 19. A pharmaceutical composition comprising as active ingredient a compound according to any one of claims 1 to 12 or a salt thereof, solvates and / or pharmaceutically acceptable hydrates. 20. Use of the compounds of formula (I) according to claim 1 or one of their pharmaceutically acceptable salts, solvates and / or hydrates for the preparation of medicaments intended to treat any pathology in which Substance P and human NK1 receptors are involved. . 21. Use according to claim 20, for the preparation of medicaments for treating diseases of the respiratory system, gastrointestinal, urinary, immune, cardiovascular, central nervous system and pain, migraine, inflammation, nausea and vomiting, skin diseases.