HK1038927B - (1-phenacy-3-phenyl-3-piperidylethyl) piperidine derivatives, method for the production thereof and pharmaceutical compositions containing the same - Google Patents

Description

The present invention relates to new piperidine derivatives, a process for their preparation and pharmaceutical formulations containing piperidine as an active ingredient.

In particular, the present invention relates to novel piperidine derivatives for therapeutic use in pathological events involving the tachykinin system such as but not limited to: 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 (S. H. Buck, 1994, The Tachykinin Receptors, Humana Press, Totowa, New Jersey), gastrointestinal disorders (P. Holzer and U. Holzer-Pulse, Phamacol., 1997, 73, 173-217 and 219-263), respiratory disorders (J. Atsina, 1995, 73, 173-263), neurological disorders (J. Mizrahi and A. Nephrology, C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C

In recent years, much research has been conducted on tachykinins and their receptors. Tachykinins are distributed in both the central nervous system and the peripheral nervous system. Tachykinin receptors have been recognized and classified into three types: NK1, NK2, NK3.

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

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

Many patents or patent applications describe compounds active on tachykinin receptors, for example European patent application 0 512 901 concerns compounds with formula: - What? including in particular: Q' represents one oxygen atom or two hydrogen atoms,T' = -C(O) - or -CH2-, andY, Ar', Z', m', n', p' and q have different values.

Err1:Expecting ',' delimiter: line 1 column 143 (char 142)

New compounds have now been found which have very high affinity and selectivity for human substance P NK1 receptors and are antagonists of these receptors.

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

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

Thus, in one aspect, the present invention relates to compounds with the formula: - What? in which: Ar is a phenyl monosubstituted or dissubstituted by a halogen atom; a (C1-C3) alkyl; X is a group - What? ; a group R1 represents a chlorine atom, a bromine atom, a (C1-C3) alkyl or a trifluoromethyl;R2 represents a -CR3R4CONR5R6 group;R3 and R4 represent the same radical chosen from a methyl, an ethyl, an n-propyl or an n-butyl;or R3 and R4 together with the carbon atom to which they are bound constitute a (C3-C6) cycloalkyl;R5 and R6 each independently represent a hydrogen; a (C1-C3) alkyl;or R5 and R6 together with the nitrogen atom to which they are bound constitute a heterocyclic radical chosen from the azet-1-in, pyrrolidin, piperidine, morpho-1-in, morpho-1-in, pyrrolidine, or per-4-hydroyle-1-in; and their salts, if any, with mineral acids or organic compounds, their solvates and/or hydrates.

The compounds of formula (I) of the invention include both optically pure isomers and mixtures thereof in any proportion.

These salts include both those with mineral or organic acids which allow proper separation or crystallization of formula (I) compounds, such as picric acid or oxalic acid or an optically active acid, e.g. a mandelic or camphosulfonic acid, and those which form pharmaceutically acceptable salts, such as hydrochloride, hydrobromide, sulphate, hydrogen sulphate, dihydrogen phosphate, methanesulfonate, methanol sulphate, oxalate, male, leucine, fumarate, naphtal-2-confonate, citrate, benzene, citrate, sulfonate.

Halogen is an atom of chlorine, bromine, fluorine, or iodine.

In this description the alkyl groups are straight or branched.

According to the present invention, the compounds of formula: - What? wherein X and R1 are as defined for a compound of formula (I), and their salts with mineral or organic acids, their solvates and/or their hydrates.

According to the present invention, compounds of formula (I) in which Ar is 3,4-dichlorophenyl or 3,4-dimethylphenyle are preferred.

According to the present invention, compounds of formula (I) are preferred in which the substituents R1 represent one chlorine atom, one methyl, one ethyl or trifluoromethyl.

According to the present invention, compounds of formula (I) in which X represents a group of - What? where R2 is a group -CR3R4CONR5R6.

In particular, compounds in which R3 and R4 each represent a methyl or together with the carbon atom to which they are bound constitute a cyclohexyl are preferred.

According to the present invention, compounds of formula (I) in which X represents a group of - What? In particular, compounds in which R3 and R4 each represent a methyl or, together with the carbon atom to which they are bound, constitute a cyclopropyl or a cyclohexyl are preferred.

According to the present invention, the compounds of formula: in which: R1 represents a chlorine, methyl, ethyl or trifluoromethyl atom; R'3 and R'4 each represent a methyl or together with the carbon atom to which they are bound constitute a cyclohexyl; R'5 and R'6 each represent hydrogen or a methyl; and their salts with mineral or organic acids, their solvates and/or their hydrates.

According to the present invention, the compounds of formula: - What? in which: R1 represents a chlorine, methyl, ethyl or trifluoromethyl atom; R'3 and R'4 each represent a methyl or together with the carbon atom to which they are bound constitute a cyclohexyl or cyclopropyl; R'5 and R'6 each represent hydrogen or methyl; and their salts with mineral or organic acids, their solvates and/or their hydrates.

Err1:Expecting ',' delimiter: line 1 column 120 (char 119)

The following compounds: 3-[2-[4-(1-carbamoyl-1-methyl) piperidine-1-yl]ethyl]-3-(3-(3-dichloroethyl)-1-piperidine, isomer (-) ; the 3-[2-[3-dichloroethyl) -acetyl]piperidine, isomer (-) ; the 3-[2-[3-dichloroethyl) -acetyl-carbamethyl) -carbamethyl-carbamethyl-carbamethyl-carbamethyl-carbamethyl-carbamethyl-carbamethyl-carbamethyl-carbamethyl-carbamethyl-carbamethyl-carbamethyl-carbamethyl-carbamethyl-carbamethyl-carbamethyl-carbamethyl-carbamethyl-carbamethyl-carbamethyl-carbamethyl-carbamethyl-carbamethyl-carbamethyl-carbamethyl-carbamethyl-carbamethyl-carbamethyl-carbamethyl-carbamethyl-carbamethyl-carbamethyl-carbamethyl-carbamethyl-carbamethyl-carbamethyl-carbamethyl-carbamethyl-carbamethyl-carbamethyl-carbamethyl-carbamethyl-carbamethyl-carbamethyl-carbamethyl-carbamethyl-carbamethyl-carbamethyl-carbamethyl-carbamethyl-carbamethyl-carbamethyl-carbamethyl-carbamethyl-carbamethyl-carbamethyl-carbamethyl-carbamethyl-carbamethyl-carbamethyl-carbamethyl-carbamethyl-carbamethyl-carbamethyl-carbamethyl-carbamethyl-carbamethyl-carbamethyl-carbamethyl-carbamethyl-carbamethyl-carbamethyl-carbamethyl-carbamethyl-carbamethyl-carbamethyl-carbamethyl-carbamethyl-carbamethyl-carbamethyl-carbamethyl-carbamethyl-carbamethyl The use of these substances is not restricted to the areas of the European Union where they are most commonly used.

The present invention relates, in another respect, to a process for the preparation of compounds of formula (I), their salts, solvates and/or hydrates, characterized by: (a) a compound of formula: - What? where Ar is as defined for a compound of formula (I) and E is the hydrogen or an O-protective group, with a functional derivative of an acid of formula: - What? where R1 is as defined for a compound of formula (I), to obtain a compound of formula: (a) where E is a protective group, it may be removed by the action of an acid or a base to obtain the alcohol of formula: (a) the alcohol obtained at step 1a or step 2a of formula (IV, E = H) is treated with a compound of formula: - What? The following shall be added: - What? where Y is a methyl, phenyl, tolyl, trifluoromethyl group, to obtain a compound of formula:4a) the compound of formula (VI) is reacted with a compound of formula: - What? where X is as defined for a compound of formula (I) 5a and, if necessary, the resulting compound is transformed into one of its salts with a mineral or organic acid.

Where E represents an O-protector, it is chosen from the classical O-protector groups well known to the art, such as, for example, tetrahydropyran-2-yl, benzoyl or a (C1-C4) alkylcarbonyl.

In step 1a), the acid itself or one of the functional derivatives that react with amines, e.g. an anhydride, a mixed anhydride, acid chloride, or an activated ester, such as the para-nitrophenyl ester, is used as the functional derivative of the acid (III).

When formula (III) acid itself is used, it is used in the presence of a peptide chemistry coupling agent such as 1,3-dicyclohexylcarbodiimide or benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate in the presence of a base such as triethylamine or N,N-diisopropylethylamine in an inert solvent such as dichloromethane or N,N-dimethylformamide at a temperature between 0 °C and room temperature.

When using acid chloride, 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 between -60°C and room temperature.

The resulting compound of formula (IV) may be de-protected at step 2a) by methods known to the art. For example, where E represents a tetrahydropyran-2-yl group, the de-protection 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 pyridinium p-toluene pyrulfonate in a solvent such as methanol or by using an Amberlyst® resin in a solvent such as methanol. The reaction is carried out at a temperature between 0 °C and the ambient temperature of the solvent. When E represents a benzoyl group or a de-protected group such as methanol or benzoyl-1-yl group, the reaction is carried out at a temperature between 0 °C and the solvent, using a medium such as sodium or alkyl hydroxyde oxide, by de-hydrolysis of the solvent, for example, by using a hydroxydehydroxyde oxide, such as methanol.

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, N,N-diisopropylethylamine or N-methylmorpholine in an inert solvent such as dichloromethane, benzene or toluene, at a temperature between -20°C and the reflux temperature of the solvent.

The resulting formula (VI) compound is reacted in step 4a) with a formula (VII) compound. 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 using a base, the base is chosen from organic bases such as triethylamine, N,N-diisopropylethylamine or N-methylmorpholine or from alkaline alkaline carbonates or bicarbonates such as sodium carbonate, sodium carbonate, potassium bicarbonate or sodium compound. In the absence of a base, the reaction is carried out in the presence of an alkaline sodium or sodium compound at a temperature between 100 °C and 100 °C. The reaction is carried out in the presence of an alkaline sodium or potassium compound.

According to one variation of the process: (b) the compound of formula (IV, E = H) obtained is oxidized to a compound of formula: (b) the compound of formula (VIII) is reacted with a compound of formula (VII) as defined above in the presence of an acid, then the intermediate iminium salt is reduced by means of a reducing agent;

Depending on the variant of the process, in step 2 (b) an alcohol of formula (IV, E = H) is oxidized to an aldehyde of formula (VIII). The oxidation reaction is carried out using, for example, oxalyl chloride, dimethyl sulfoxide 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 a formula (VIII) aldehyde in the presence of an acid such as acetic acid in an inert solvent such as methanol or dichloromethane to form an intermediate imine in situ which is reduced chemically using e.g. sodium cyanoborohydride or sodium triacetotoxyborohydride, or catalytically using hydrogen and a catalyst such as palladium on carbon or Raney's nickel®.

Finally, the compounds of formula (I) according to the invention are obtained.

The resulting compounds of formula (I) are isolated as free base or salt, according to conventional techniques.

When the compounds of formula (I) are obtained in the form of free base, the salicycation is carried out by treatment with the selected 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 dichloromethane, or in ethyl acetate with a solution of the selected acid in one of the above solvents, the corresponding salt is obtained which is isolated by the conventional techniques.

For example, hydrochloride, bromohydrate, sulphate, hydrogen sulphate, dihydrogen phosphate, methanesulfonate, methyl sulphate, oxalate, maleate, succinate, fumarate, naphthalene-2-sulfonate, benzenesulfonate, para-tolueneulfonate and gluconate are prepared.

At the end of the reaction, the compounds of formula (I) may be isolated as one of their salts, e.g. hydrochloride, or oxalate; in this case, if necessary, the free base may be prepared by neutralizing the salt with a mineral or organic base, such as sodium hydroxide or triethylamine or with an alkaline carbonate or bicarbonate, such as sodium or potassium carbonate or bicarbonate.

The compounds of formula (II) shall be prepared by methods known in particular as those described in Applications EP-A-0 512 901, EP-A-0 591 040 or EP-A-0 714 891.

Compounds of formula (III) are commercially available or prepared by known methods.

For example, compounds of formula (III) are prepared according to SCHEME 1 below. - What?

Steps a1 and b1 of SCHEME 1 are performed 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) by methods known to the art.

The ester (XII) thus obtained is reduced to the d1 stage into alcohol of formula (XIII) by methods known to the art.

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

The resulting phenylacetonitrile derivatives of formula (XV) are hydrolysed at step g1 to compounds of formula (III) by the methods described in J. Org. Chem., 1968, 33, 4288 or EP-A-O 714 891.

Brominated derivatives of formula (IX) are known or prepared by known methods such as those described in J. Org. Chem., 1971, 36(1), 193-196, or J. Am. Chem. Soc., 1941, 63, 3280-3282.

Compounds of formula (VII) where X represents a group - What? where R2 represents a group -CR3R4CONR5R6 are prepared according to SCHEME 2 below:

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

The nitrile derivative of formula (XVII) thus obtained is hydrolysed at step b2 according to methods known to man to give an acid derivative of formula (XVIII).

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

Alternatively, the nitrile derivative of formula (XVII) is hydrolysed in step d2 using the known methods to obtain the carboxamide derivative of formula (XX), which is possibly unprotected in step e2 using the conventional methods to obtain the compound (VII) in which R5 = R6 = H.

At step f2, by reaction of the compound of formula (XX) in the presence of a strong base with one halogen of (C1-C3) alkyl, respectively, or successively with two halogen of (C1-C3) alkyl, or with a dihalogen of formula Hal-R5-R6-Hal, according to the classical alkylation methods, a compound of formula (XXI) is prepared in which respectively R5 represents a (C1-C3) alkyl and R6 = H, or R5 and R6 each independently represent a (C1-C3) alkyl, or R5 and R6 together with the nitrogen atom to which they are bound constitute a heterocycle.

The resulting compound (XXI) is de-protected at step g2 using known methods to give the expected compound (VII).

Compounds of formula (VII) where X represents a group - What? where R2 represents a group -CR3R4CONR5R6 are prepared according to SCHEME 3 below.

In step a3 of SCHEME 3, the reaction of compound 2, in the presence of a strong base such as sodium hydride or sodium amidide, with a linear (C1-C4) alkyl halide, respectively, or with a dihalogenide of formula Hal ((CH2) m-Hal in which m = 2 to 5 and Hal represents a halogen atom, in an inert solvent such as N,N-dimethylformamide or dichloromethane and at a temperature between 0 °C and room temperature, according to the classical alkylation methods, gives the compound of formula (XXII) in which each, respectively, R3 and R4 represents a linear (C1-C4-alkylated) compound, or a carbonate with a carbonate (C3-alkylated) group.

The nitrile (XXII) derivative thus obtained is hydrolysed at step b3 according to the methods known to man to give the carboxamide (XXIII) derivative.

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

At step d5, by alkylation of the compound of formula (XXIII) and then reduction of the compound (XXIV) by classical catalytic hydrogenation, a compound of formula (VII) is obtained in which R5 and/or R6 ≠ H.

Compounds of formula (VII) where X is a group can also be obtained. - What? according to SCHEME 4 below. - What?

In step a4 of SCHEME 4, the reaction of compound 3 with an appropriate organolithium or organomagnesia derivative such as methyllithium, ethylmagnesium chloride, propylmagnesium chloride or pentane-1,5-di (magnesium chloride) by the methods described in EP-A-0 625 509 results in the formula alcohol (XXV).

The resulting alcohol (XXV) is oxidised to the b4 stage in acid of formula (XXVI) by the method described in Helvetica Chimica Acta, 1972, 55 (7), 2439.

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

The compound (XXVII) is unprotected at step d4, using known methods, to yield the expected compound (VII).

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

The compounds of formula (VII) are new and are part of the invention.

Thus, according to another aspect of the invention, the subject matter of the invention is a compound of the formula: - What? in which: X is a group - What? a group R2 represents a group -CR3R4CONR5R6; R3 and R4 represent the same radical chosen from a methyl, an ethyl, an n-propyl or an n-butyl; or R3 and R4 together with the carbon atom to which they are bound constitute a (C3-C6) cycloalkyl;R5 and R6 each independently represent a hydrogen; or a (C1-C3) alkyl or R5 and R6 together with the nitrogen atom to which they are bound constitute a heterocyclic radical chosen from the acetidinyl-1-yl, pyrrolidin-1-yl, piperyl-1-yl, morphidin-1-yl, thiomorph-4-azidine--1-yl or perhydroylepine; and its salts with mineral or organic acids.

Err1:Expecting ',' delimiter: line 1 column 184 (char 183)

It is, however, preferable to perform the splitting 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.

Another aspect of the present invention relates to a stereospecific process for the preparation of compounds of formula (I) having the configuration (S), their salts, solvates and/or hydrates, characterized by: 1d) the isomer (S) of a compound of formula: - What? where Ar is as defined for a compound of formula (I), with a functional derivative of the acid of formula: where R1 is as defined for a compound of formula (I), to obtain a compound of formula: (d) the compound of formula (IV*) is oxidized to a compound of formula: (d) the compound of formula (VIII*) is reacted with a compound of formula: - What? where X is as defined for a compound of formula (I), In the presence of an acid, the intermediate iminium salt is reduced by means of a reducing agent; 4d) and, if necessary, the resulting compound is transformed 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 e.g. tritium, or carbon-14. Such labeled compounds are useful in research, metabolism or pharmacokinetics, in biochemical assays as receptor ligands.

The compounds of the invention have been subjected to biochemical tests.

The affinity of the compounds for tachykinin receptors has been evaluated in vitro by several biochemical tests using radio-ligands: 1) Binding of [125I] BH-SP (Substance P marked with iodine-125 using Bolton-Hunter reagent) to the NK1 receptors of human lymphocytic cells (D. G. Payan et al., J. Immunol., 1984, 133, 3260-3265).2) Binding of [125I] His-NKA to human cloned NK2 receptors expressed by CHO cells (Y. Takeda et al., J. Neurochem., 1992, 59, 740-745).3) Binding of [125I] [MeP7] His to the NK3 receptors of the cerebral cortex of, the cerebral cortex of, and the cerebral cortex of gerbil as well as human cloned NK3 receptors expressed by CHO cells (Buebell et al., 1992, Letters 90 and 299, FEBES, 1992-95).

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 of the invention strongly inhibit the binding of substance P to the NK1 receptors of human IM9 lymphocytes. The Ki inhibition constant for human LC receptors is in the range of 10-11M.

Ki inhibition constants for human cloned NK2 receptors are in the range of 10-8M and Ki inhibition constants for human cloned NK3 receptors are greater than 10-7M.

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

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

In the test subject, local application of a specific NK1 receptor agonist, e.g. [Sar9, Met (O2) 11] substance P, to the striatum increases the release of acetylcholine, which is inhibited by oral or intraperitoneal administration of the compounds of the present invention. This test was adapted from the method described by R. Steinberg et al., J. Neurochemistry, 1995, 65, 2543-2548.

These results show that the compounds of formula (I) are active orally, that they cross the blood-brain barrier and that they may block the central nervous system action of NK1 receptors.

Formula (I) compounds were evaluated in the test subject bronchoconstriction test, using the method described by X. Emonds-Alt et al., European Journal of Pharmacology, 1993, 250, 403-413.

The in vivo pharmacological activity of formula (I) compounds has also been evaluated in the hypotension model in dogs, using the method described by X. Emonds-Alt et al., Eur. J. Pharmacol., 1993, 250, 403-413.

These results show that the compounds of formula (I) block the action of NK1 receptors in the peripheral nervous system.

The compounds of the present invention are, inter alia, active substances in pharmaceutical formulations, the toxicity of which is compatible with their use as medicinal products.

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 be preferentially between 0.1 and 4000 mg per day, in particular between 0.5 and 1000 mg depending on the age of the subject to be treated or the type of treatment: prophylactic or curative.

For use as medicinal products, compounds of formula (I) are generally administered in dosage units, preferably in pharmaceutical formulations in which the active substance is mixed with one or more pharmaceutical excipients.

Thus, in another aspect, the present invention relates to pharmaceutical compositions containing, as an active ingredient, a compound of formula (I) or one of its pharmaceutically acceptable salts, solvates and/or hydrates.

In the pharmaceutical formulations of the present invention for oral, sublingual, inhaled, subcutaneous, intramuscular, intravenous, transdermal, local or rectal administration, the active substances may be administered in unit dosage forms, in combination with conventional pharmaceutical media, to animals and humans. The appropriate unit dosage forms include oral forms such as tablets, capsules, powders, granules and oral solutions or suspensions, sublingual and oral dosage forms, aerosols, topical dosage forms, implants, subcutaneous, intramuscular, intravenous, intranasal or intraocular dosage forms and recoupled dosage forms.

When preparing a solid formulation in the form of tablets or capsules, a mixture of pharmaceutical excipients is added to the active substance, whether or not micronized, which may be composed of diluents such as lactose, microcrystalline cellulose, starch, dicalcium phosphate, binders such as polyvinylpyrrolidone, hydroxypropylmethyl cellulose, deliverables such as rectifying polyvinylpyrrolidone, rectifying carboxymethylcellulose, drainage agents such as silica, talc, lubricants such as magnesium stearate, stearic acid, stearate glycerol, sodium trifumarate.

Moisturizers or surfactants such as sodium lauryl sulphate, polysorbate 80, poloxamer 188 may be added to the formulation.

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

The tablets may be bare or dragged (e.g. by sucrose) or coated with various polymers or other suitable materials.

Tablets may have flash, delayed or prolonged release by making polymer matrices or using specific polymers at the filming level.

The capsules may be soft or hard, filmed or not so as to have flash, prolonged or delayed activity (e.g. by enteriform form).

They may contain not only a solid formulation as previously formulated for tablets but also liquids or semi-solids.

A preparation in the form of a syrup or elixir may contain the active substance together with a sweetener, preferably a non-caloric sweetener, methylparaben and propylparaben as antiseptic, as well as a flavouring agent and an appropriate colouring.

Water-dispersible powders or granules may contain the active substance mixed with dispersing agents, wetting agents or suspension agents, such as polyvinylpyrrolidone, as well as sweeteners or flavour enhancers.

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

For parenteral, intranasal or intraocular administration, aqueous suspensions, isotonic saline solutions or sterile solutions for injection containing dispersing agents and/ or pharmacologically compatible solubilising agents, e. g. propylene glycol, are used.

Thus, to prepare an aqueous solution for intravenous injection, a co-solvent such as alcohol such as ethanol or glycol such as polyethylene glycol or propylene glycol and a hydrophilic surfactant such as polysorbate 80 or poloxamer 188 may be used.

For local administration, you can use creams, ointments, gels, eyeliner, sprays.

For transdermal administration, multi-laminated or tank-like patches in which the active substance may be in an alcoholic solution, sprays, can be used.

For inhalation administration, an aerosol containing, for example, sorbitol trioleate or oleic acid, trichlorofluoromethane, dichlorofluoromethane, dichlorotetrafluoroethane, freon substitute or any other biologically compatible propellant gas, or a system containing the active substance alone or in combination with an excipient, in powder form, may be used.

The active substance may also be presented as a complex with a cyclodextrin, e.g. α, β, γ-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin.

The active substance may also be formulated in the form of microcapsules or microspheres, possibly with one or more media or additives.

Implants are one of the long-release forms useful in the case of chronic treatments, which can be prepared as an oil suspension or as a microsphere suspension in an isotonic medium.

In general, each dosage unit is adjusted according to the dosage and type of administration, e.g. tablets, capsules and similar, sachets, ampoules, syrups and similar, drops, so that such a dosage unit contains 0.1 to 1000 mg of active substance, preferably 0.5 to 250 mg to be administered once to four times a day.

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

Another aspect of the present invention relates to the use of formula (I) compounds, or any of their pharmaceutically acceptable salts, solvates and/or hydrates, in the preparation of drugs for the treatment of any disease involving substance P and human NK1 receptors.

Another aspect of the present invention relates to the use of formula (I) compounds or any of their pharmaceutically acceptable salts, solvates and/or hydrates in the preparation of medicinal products for the treatment of respiratory, gastrointestinal, urinary, immune, cardiovascular and central nervous system disorders, pain, migraine, inflammation, nausea and vomiting, and skin diseases.

For example, but not limited to, compounds of formula (I) are useful: as an analgesic, particularly in the treatment of traumatic pain such as post-operative pain; of neuralgia of the brachial plexus; of chronic pain such as arthritic pain due to osteoarthritis, rheumatoid arthritis or psoriatic arthritis; of neuropathic pain such as post-herpetic neuralgia, trijumbral neuralgia, segmental or intercostal neuralgia, fibromyalgia, causative neuropathy, peripheral neuropathy, diabetic neuropathy, chemotherapy-induced neuropathies, AIDS-related neuropathies, occipital neuralgia, neuralgia, glossopharyngeal neuralgia; of various forms of chronic pain such as migraine or acute amputation,Temporomandibular pain, jaw pain, facial neuralgia, dental pain; cancer pain; pain of visceral origin; gastrointestinal pain; pain due to nerve compression, pain due to intense sports; dysmenorrhea; menstrual pain; pain due to meningitis, arachnoiditis; musculoskeletal pain; lower back pain due to spinal stenosis, prolapse of a disc, sciatica; pain in the angina pectoris; pain due to ankylosing spondylitis; pain due to drop-related pain; pain due to burns;for healing, itchy skin; for thalamic pain; as an anti-inflammatory especially for treating inflammation in asthma, influenza, chronic bronchitis (especially chronic obstructive pulmonary disease), cough, allergies, bronchospasm and rheumatoid arthritis; inflammatory diseases of the gastrointestinal tract such as Crohn' s disease, ulcerative colitis, pancreatitis, gastritis, inflammation of the intestines, disorders caused by non-steroidal anti-inflammatory drugs, inflammatory effects and secretion problems due to bacterial infections such as Clostridium difficile; inflammatory diseases of the breast, such as eczema and inflammatory disorders of the digestive system such as eczema;In the treatment of diseases of the central nervous system, in particular psychosis such as schizophrenia, mania and dementia; cognitive disorders such as Alzheimer's disease, anxiety, AIDS-related dementia; diabetic neuropathies; depression; Parkinson's disease; drug addiction; substance abuse;The main benefits of this approach are that it is used to treat sleep, circadian rhythm, mood, epilepsy; Down syndrome; Huntington's disease; somatic stress-related disorders; neurodegenerative diseases such as Pick's disease, Creutzfeldt-Jacob's disease; panic, phobia and stress-related disorders; changes in the permeability of the blood-brain barrier during inflammatory and autoimmune processes in the central nervous system, for example in AIDS-related infections, such as myorelaxant and antispasmodic drugs; treatment of nausea and vomiting, such as acute and delayed nausea and vomiting; chemotherapy or radiotherapy, such as those used in cancer treatment; and treatment of abdominal cancer.carcinoidosis; by 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, dizziness, Meniere' s syndrome; during postoperative illness; dialysis-induced nausea and vomiting, by prostaglandins; by gastrointestinal obstructions; during reduced gastrointestinal motility; during visceral pain due to myocardial infarction or peritonitis; during migraine; during illness at altitude; during ingestion of opioid analgesics such as morphine; during gastro-oesophageal reflux; when eating or drinking food or drink;In the treatment of diseases of the gastrointestinal tract such as irritable bowel syndrome, gastric and duodenal ulcers, oesophageal ulcers, diarrhoea, hypersecretions, lymphomas, gastritis, gastro-oesophageal reflux, faecal incontinence, Hirschsprung' s disease, food allergies; in the treatment of skin diseases such as psoriasis, pruritus, sunburn, including sunburn; in the treatment of diseases of the gastro- vascular system such as cardiovascular diseases such as hypertension, migraine,edema, thrombosis, angina, vascular spasms, vasodilation-related circulatory diseases, Raynaud' s disease, fibrosis, collagen diseases, atherosclerosis; in the treatment of small cell lung cancers; in brain tumours, adenocarcinomas of the urogenital sphere; in demyelination diseases such as multiple sclerosis or amyotrophic lateral sclerosis; in the treatment of immune system disorders related to the suppression or stimulation of immune function such as rheumatoid arthritis, psoriasis, polymyositis, lupus; in the treatment of reactive cells such as Crohn' s disease; in the treatment of reactive cells such as myeloma; in the treatment of anemia; in the treatment of anemia; in the treatment of anemia; in the treatment of anemia; in the treatment of anemia; in the treatment of anemia; in the treatment of anemia; in the treatment of anemia; in the treatment of anemia; in the treatment of anemia; in the treatment of anemia; in the treatment of anemia; in the treatment of anemia; in the treatment of anemia; in the treatment of anemia; in the treatment of anemia; in the treatment of anemia; in the treatment of anemia; in the treatment of anemia; in the treatment of anemia; in the treatment of anemia; in the treatment of anemia; in the treatment of anemia; in the treatment of anemia; in the treatment of anemia; in the treatment of anemia; in the treatment of anemia; in the treatment of anemia; in the treatment of anemia; in the treatment of anemia; in the treatment of anemia; in the treatment of anemia; in the treatment of anemia; in the treatment of anemia; in the treatment of anemia; in the treatment of anemia; in the treatment of anemia; in the treatment of anemia; in the treatment of anemia; in the treatment of anemia; in the treatment of anemia; in the treatment of anemia; in the treatment of anemia; in the treatment of anemia; in the treatment of anemia; in the treatment of anemia; in the treatment of anemia; in the treatment of anemia; in the treatment of anemia; inocular hypertension, myosis, excessive tearing;in the treatment or prevention of seizures, epilepsy, head trauma, spinal cord trauma, ischemic brain injury due to seizure or vascular occlusion;in the treatment of heart rate and rhythm disorders, particularly those caused by pain or stress;in the treatment of sensitive skin and to prevent or combat skin or mucous membrane irritation, dandruff, erythema or pruritus;in the treatment of neurological skin disorders such as lichen;In the treatment of ulcers and all diseases caused by Helicobacter pylori or gram-negative positive urease bacteria; in the treatment of diseases caused by or symptomatic of angiogenesis; in the treatment of ocular and/or palbebral algae and/or ocular or palpebral dysesthesia; as antiperspirant.

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

The pharmaceutical formulations according to the present invention may also contain other active substances useful for treating the diseases or disorders indicated above, e.g. bronchodilators, antitussives, antihistamines, anti-inflammatories, antiemetics, chemotherapy agents.

In the Preparations and Examples the following abbreviations are used: DMF: dimethylformamideDMSO: dimethylsulfoxydeDCM: dichloromethaneTHF: tetrahydrofuranether: diethyl ether: hydrochloride ether: saturated solution of hydrochloric acid in diethyl ether BOP: benzotriazole-1-yloxytris(dimethylamino) phosphonium hexafluorophosphateF: melting pointTeb: boiling pointTA: ambient temperature H: silica gel 60H marketed by Merck (DARMSTAD)

The proton nuclear magnetic resonance spectra (NMR 1H) are recorded at 200 MHz in DMSO-d6, using the peak of DMSO-d6 as a reference. Chemical displacements δ are indicated in parts per million (ppm). The observed signals are expressed as: s singlet; se: enlarged singlet; t: triple; qd: quadruplet; m: massive.

The Commission has 3- (3,4-Dichlorophenyl) -3- (2,4-hydroxyethyl) piperidine, isomer (-),

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

The Commission has The active substance is a compound with a specific chemical activity, which is a chemical element.

The following substances are to be classified in the same heading as the product:

Add 20 g of 3,4-dimethylphenylacetonitrile in 100 ml of anhydrous THF, add 6.6 g of sodium hydride at 60% in oil and in portions to TA and let stand for 2 hours in TA. Then add 29 g of 1-bromo-2-tetrahydropyran-2-yloxyethane in drops and let stand for 2 days in TA. Pour the reaction mixture over ice, extract it in AcOEt, wash the organic phase with water, with a saturated NaCl solution, dry it on Na2SO4 and evaporate under the solvent. Chromatograph the residue on silica gel by eliciting toluene by the gradient of the mixture of (O/O) v/g (O/O) v/g (O/O) v/g (O/O) v/g (O/O) v/g (O) v/g (O) v/g); obtained from the toluene obtained in 17/10 (O/O) v/g (O/O) v/g).

B. 4-Cyano-4- ((3,4-dimethylphenyl)-6- ((tetrahydropyran-2-yloxy) methyl hexanoate

To a mixture of 17 g of the compound obtained in the previous step and 11 ml of methyl acrylate in 30 ml of dioxane, add 0.3 ml of a 40% benzyltrimethylammonium hydroxide (Triton®B) solution in MeOH and leave to agitate for 48 hours at TA. Concentrate the reaction mixture under vacuum, take up the residue with an aqueous solution of 0.5 N HCl, extract it from the ether, wash the organic phase with an aqueous solution of Na2CO3 at 10%, dry on Na2SO4 and evaporate the solvent under vacuum. 23 g of the expected product is obtained.

C) 5- (3,4-Dimethylphenyl) -5-[2- (tetrahydropyran-2-yloxy) ethyl]pipéride-2-one.

To a 23 g solution of the compound obtained in the previous step in 250 ml of EtOH at 95%, add 40 ml of a 20% ammonia solution and then introduce Raney nickel®. Then hydrogenate for 24 hours at 40 °C and at a pressure of 16 bar. Filter the catalyst on Célite® and concentrate the filtrate under vacuum. 22 g of the expected product is obtained.

D) 3- (3,4-dimethylphenyl) -3-[2- (tetrahydropyran-2-yloxy) ethyl]pipéridine.

A suspension of 10 g of aluminium and lithium hydride in 200 ml of THF is added to 22 g of the compound obtained in the previous step and heated at low temperature for 2 hours. After cooling at TA, 10 ml of water and 80 ml of THF are added, then 10 ml of NaOH 4N and 30 ml of water. The mineral salts are filtered on Célite® and concentrated under vacuum. 15 g of the desired product is obtained.

The Commission shall be assisted by the European Parliament.

3,5-dichlorophenyl acetic acid (III) R1 = Cl.

(A) 3,5-dichlorobenzyl chloride.

A solution of 14.5 g of 3.5-dichlorobenzyl alcohol in 150 ml of chloroform is added to TA by dripping a solution of 12.5 g of thionyl chloride in 20 ml of chloroform, then heated to 40-50°C for 8 hours and left to agitate overnight in TA. Concentrate under vacuum to obtain 16 g of the product expected to be used as is.

(b) 3,5-Dichlorophenyllacetonitrile.

To a 16 g solution of the compound obtained in the previous step in 50 ml of EtOH, a 6.5 g solution of potassium cyanide is added in 50 ml of water and heated at low temperature for 4 hours. The solution is concentrated under vacuum, the residue is taken up in water, extracted in ether, the organic phase is washed in water, dried on Na2SO4 and the solvent is evaporated under vacuum. The residue is chromatographed on silica H by eluting by the heptane/toluene mixture (50/50 v/v) and then by toluene. 7 genes of the product are obtained, depending on which one is used.

C) 3,5-dichlorophenyl acetic acid

To a 7 g solution of the compound obtained in the previous step in 50 ml of EtOH, a 8.4 g solution of KOH is added in 10 ml of water, then heated at low temperature for 5 hours. Concentrate under vacuum, take the residue back to water, wash the aqueous phase with ether, acidify the aqueous phase to pH = 1 by adding concentrated HCl and leave overnight under agitation in TA. The crystallized product is exsorted, washed with water and vacuum dried at 60°C. 7 g of the expected product is obtained, F = 112-114.5°C.

Preparation of the work

3,5-diethyl phenylacetic acid. (iii) R1 = and.

(a) 3,5-diethylbromobenzene, which is a chemical compound with a chemical formula of 3,5-diethylbromobenzene.

Cool 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 EtOH to -5°C, add a 6.6 g solution of sodium nitrite in 25 ml of water and stir for 30 minutes at TA. Pour the reaction mixture over 170 ml of H3PO2 at 50% cooled to 0°C, stir for 2 hours at 0°C and 48 hours at TA. Extract the reaction mixture from the ether, wash the organic phase with water, with a solution of NaOH 1N, leave the water, dry on Na2SO4 and evaporate the solvent.

(b) 3,5-diethylbenzonitrile.

After cooling to TA, the reaction mixture is poured over 50 ml of water and stirred to TA until a gum is formed. The mixture is cooled in an ice bath, 150 ml of ethylene diamine is added and stirred to TA for 2 hours. The mixture is extracted from AcOEt, the organic phase is washed with water, dried on Na2SO4 and evaporated empty under the solvent. The residue is chromatographed on silica gel by electrolysis of the mixture Ac/Oethylhexane (95/5 v/v). 12 g of the product is obtained.

C) 3,5-diethylbenzoic acid.

To a 12 g solution of the compound obtained in the previous step in 60 ml of EtOH, a 22 g solution of KOH is added in 15 ml of water and heated at low temperature for 24 hours. The vacuum is concentrated under the reaction mixture, the residue is extracted with water, the aqueous phase is washed with ether, the aqueous phase is acidified at pH = 2 by addition of concentrated HCl, the precipitate is boiled, the precipitate is washed with water and vacuum dried.

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

A mixture of 13 g of the compound obtained in the previous step is heated backwards for 48 hours in 90 ml of MeOH and 10 drops of H2SO4. The reaction mixture is concentrated under vacuum, the residue is taken up with water, neutralized by adding a 10% solution of NaHCO3 extracted from the ether, the organic phase is washed with a 10% solution of NaHCO3 in water, dried on Na2SO4 and evaporated under vacuum in the solvent. 12 g of the expected product is obtained.

E) 3,5-diethylbenzyl alcohol.

A 2.5 g suspension of aluminium and lithium hydride is cooled to 0 °C in 50 ml of THF, a 12 g solution of the previous step is added in 50 ml of THF and left to agitate for 30 minutes. The reaction mixture is hydrolyzed by adding 2.5 ml of water, 2.5 ml of NaOH 4N and 7.5 ml of water. The mineral salts are filtered and the filtrate is vacuum-concentrated.

(F) Methane sulphonate of 3,5-diethylbenzyl.

A solution of 10.9 g of the compound obtained in the previous step and 7.4 g of triethylamine in 100 ml of DCM is added to TA, a solution of 8.4 g of methanesulfonyl chloride in 50 ml of DCM is added to TA and left to agitate for 30 minutes. The reaction mixture is concentrated under vacuum, the residue is taken up with water, extracted with ether, the organic phase is washed with water, dried on Na2SO4 and the solvent is evaporated under vacuum. 16 g of the product is obtained.

(g) 3,5-diethylphenyllacetonitrile.

To a 16 g solution of the compound obtained in the previous step in 100 ml of DMF, a 5.15 g solution of potassium cyanide is added 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 with water, extracted with ether, the organic phase is washed with water, dried on Na2SO4 and evaporated under the solvent. The residue is chromatographed on silica gel H by eluting in DCM. 3 g of the expected product is obtained.

H) 3,5-diethylphenylacetic acid.

To a 3 g solution of the compound obtained in the previous step in 50 ml of EtOH, a 7.8 g solution of KOH is added in 10 ml of water, then heated at low temperature for 5 hours. The solution is concentrated under vacuum, the residue is taken back to the water, the aqueous phase is washed with ether, the aqueous phase is acidified to pH = 1 by addition of concentrated HCl and left overnight under agitation in TA. The crystallized product is then washed with water and vacuum dried.

The following are the main features of the newly introduced NCR:

Preparation of the work The substance is a hydrochloride of 2- (piperidine-4-yl) isobutyramide.

A) 2-methyl-2- ((pyridine-4-yl) propionitrile.

The reaction mixture is cooled at 0°C with an ice bath, 6 g methyl iodide is added by drip and stirred overnight in TA. The reaction mixture is poured on a water/ice mixture, extracted from the ether, the organic phase by a saturated NaCl solution, filtered on SO4, and dried in Mg, evaporating the solvent. The residue is chromatographed on HM silica gel by eluting to DCM by the DCM/OHM mixture (98/Mev/v2); 2.39 g of the resulting oil is obtained in the form of crystal.

B. Hydrochloride of 2-pyridine-4-yl isobutyramide

Heat a mixture of 2.39 g of the compound obtained in the previous step and 10 ml of a concentrated H2SO4 solution at 100 °C for 15 minutes. Cool the reaction mixture in TA, add 50 g of ice, alkaline to pH = 14 by adding a concentrated NaOH solution, filter the mineral salts, extract the filtrate at AcOEt and then at DCM, dry the organic phases attached to MgSO4, filter and evaporate the solvents under vacuum (F = 134 °C, base). Dissolve the resulting product in acetone, acidify to pH = 1 by adding hydrochloride ether and precipitate the essence.

C) Hydrochloride of 2-piperin-4-yl isobutyramide.

A mixture of 2.9 g of the compound obtained in the previous step, 1 g of PtO2 and 50 ml of MeOH is hydrogenated for 3 days at 60 °C, at a pressure of 60 bar. The catalyst is filtered on Cellite®, washed with MeOH and the filtrate is vacuum-concentrated. The residue is taken up in acetonitrile, the precipitate is ejected, the acetonitrile is washed and then etherised. 2.5 g of the expected product is obtained, F > 260 °C.

Preparation of the work The active substance is a hydrochloride of 2- (piperazine-1-yl) isobutyramide.

The following substances are to be classified in the same heading as the active substance:

4.5 ml of acetone, 20 g of dry MgSO4, 10 g of N,N-dimethylacetamide, 10 g of 1-benzylpiperazine and 9.5 ml of 2-hydroxyisobutyronitrile are mixed and heated to 45°C for 48 hours under high stirring. The reaction mixture is poured over ice and stirred for 30 minutes. The mixture is extracted with ether, washed several times in the organic phase with water, dried on Na2SO4 and evaporated under vacuum with the solvent. 13 g of the expected product is obtained.

(B) 2-benzylpiperazine-1-yl isobutyramide dichloride.

A mixture of 13 g of the compound obtained in the previous step and 130 ml of a 90% solution of H2SO4 is heated rapidly at 110 °C for 30 minutes. After cooling at TA, the reaction mixture is poured over ice, alkalinized at pH = 10 by addition of a concentrated NH4OH solution and the crystallized product is ejected. The product is dissolved in DCM, the organic phase is dried on MgSO4 and evaporated under vacuum in the solvent. The product is taken back into the hydrochloric ether and the precipitate ejected.

C) 2-piperazine-1-yl isobutyramide dichloride.

Hydrogenation overnight at atmospheric pressure and at TP of a mixture of 1.3 g of the compound obtained in the previous step and 0.18 g of Palladium on 10% charcoal in 30 ml of EtOH 95 is carried out.

Preparation of the work The substance is a hydrochloride of 1- (piperazine-1-yl) cyclohexane carboxamide.

A) 1-4-Benzylpiperazine-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 mixed and heated to 45°C for 48 hours under high stirring. The reaction mixture is poured over ice and stirred for 30 minutes. The mixture is extracted with ether, washed several times in the organic phase with water, dried on Na2SO4 and evaporated under vacuum with solvent. 15 g of the expected product is obtained.

(B) 1-benzylpiperazine-1-yl) cyclohexanecarboxamide dichloride.

This compound is prepared in the manner described in step B of preparation 3.2 from 15 g of the compound obtained in the previous step and 50 ml of a 90% solution of H2SO4 to obtain 5,5 g of the expected product.

(C) 1-piperazine-1-yl cyclohexane carboxamide dichlorohydrate.

This compound is prepared in the manner described in step C of preparation 3.2 from 2.3 g of the compound obtained in the previous step, 0.3 g of palladium on 10% charcoal in 30 ml of EtOH 95, resulting in 1.6 g of the expected product.

Preparation of the work The chemical composition of the product is determined by the chemical composition of the product.

The 'A' class is defined as the 'sub-class' of the 'sub-class' as defined in the 'A' category.

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 is added in oil in portions. 1.3 ml of methyl iodide is then added by drip and left to agitate at TA for 4 hours. The reaction mixture is poured into water, extracted with ether, the organic phase is dried on MgSO4 and the solvents are evaporated under vacuum. 1.8 g of the expected product is obtained.

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

To a solution of 1.8 g of the compound obtained in the previous step in 30 ml of MeOH, add 2 g of ammonium formate, 0.5 g of palladium on 5% charcoal and leave to agitate at TA for 4 hours. Filter the catalyst on Célite® and concentrate the filtrate in a vacuum. Take the residue back into AcOEt, exhale the precipitate formed, wash it with AcOEt and dry.

The Commission has not yet adopted a decision. Hydrochloride of 1- (piperidine-4-yl) cyclohexane carboxamide

A) 1-Pyridine-4-yl cyclohexanecarbonitrile

Cool a mixture of 3 g pyridine-4-ylacetonitrile hydrochloride in 50 ml DMF to 0 °C, add 2.6 g sodium hydride at 60% in small portions in the oil and let stand for 1 hour 30 minutes in a TA. Cool the reaction mixture in an ice bath, drop 2.7 ml of 1,5-dibromopentane and let stand for 48 hours in a TA. Pour the reaction mixture on a saturated solution of NH4Cl, extract it with ether, wash the organic phase 1a with water, dry on MgSO4 and evaporate empty under the solvent. Chromatograph the residue on silica gel by ejecting it into the DCM using the mixture DCM/OHM (98/Mev/v2); the expected product is obtained at 2.5 °C, or 79 °C.

(B) Hydrochloride of 1- (pyridine-4-yl) cyclohexane carboxamide.

Heat a mixture of 2.5 g of the compound obtained in the previous step and 15 ml of a concentrated H2SO4 solution at 100 °C for 15 minutes. Cool the reaction mixture at TA, pour it over ice, alkaline to pH = 14 by adding a concentrated NaOH solution, exhale the precipitate formed, wash with water and dry. Dissolve the product obtained in acetone, acidify at pH = 1 by adding hydrochloride ether, stir for 30 minutes at TA and exhale the precipitate formed.

C) Hydrochloride of 1-piperin-4-yl cyclohexane carboxamide.

A mixture of 2.9 g of the compound obtained in the previous step, 0.5 g of PtO2 and 50 ml of MeOH is hydrogenated for 3 days at 60 °C at a pressure of 80 bar. The catalyst is filtered on Cellite® and the filtrate is concentrated under vacuum. The residue is taken back into acetonitrile, left to agitate for 1 hour at TA, and the precipitate is exsorted. 2.7 g of the expected product is obtained, F = 235 °C.

The Commission has The chemical composition of the product is determined by the following equation:

A) Ethyl ester of 1-benzylpipperidine-4-carboxylic acid.

To a mixture of 25 g ethyl isonipecotate and 25 g K2CO3 in 125 ml DMF, 30 g benzyl bromide is added by drip drops, maintaining the temperature of the reaction mixture between 25 and 30 °C, and then stirred for 1 hour at TA. The reaction mixture is poured over 1 litre of ice water, extracted twice with ether, washed the organic phase with water, dried on MgSO4 and evaporated under vacuum. The resulting oil is distilled at reduced pressure.

B. 2-benzylpipperidine-4-yl) propan-2-ol.

The reaction mixture is cooled in TA, then poured over 400 ml of a saturated solution of NH4Cl in water previously cooled in an ice bath. The mixture is extracted three times in the ether, the organic phases are dried under 25°C and the medium maintained at a temperature of 25°C to 30°C. To empty the mixture, the remaining solution is dissolved in 100 ml of benzene, then refrozen for 48 hours. The reaction mixture is cooled at TA, then poured over 400 ml of a saturated solution of NH4Cl in water previously cooled in an ice bath. The mixture is extracted three times in the ether, the organic phases are dried under 66°C and the soil is concentrated.

C) 2-benzylpipperidine-4-yl)-2-methylpropionic acid, which is a chemical compound with the formula

A mixture of 5.98 g of 95% sulphuric acid and 4.42 g of 30% SO3 steaming sulphuric acid is cooled at 3°C, a 2 g solution of the compound obtained in the previous step is added, drop by drop and kept below 10°C, in 1.55 g of 100% formic acid, stirred for 2 hours at 3-5°C, then raised to TA and left overnight at TA. The reaction mixture is poured over ice, brought to pH 6.5 by adding a concentrated solution of NaOH by adding a concentrated solution of NH4OH, extracted three times in DCM, dried the organic joints on the ground and dried the remaining MgSO4 in the vacuum. The resulting product is obtained at 1.52°C.

(D) N,N-dimethyl-2- (Bn-pyridine-4-yl) isobutyramide hydrochloride.

A mixture of 1.2 g of the compound obtained in the previous step, 0.8 ml of triethylamine, 2.8 ml of a 2 M solution of dimethylamine in THF and 2.5 g of BOP in 20 ml of DCM is left to agitate for 1 hour at TA. The reaction mixture is concentrated in a vacuum, the residue is taken up in ether, the organic phase is washed with water, a NaOH 1N solution, a saturated NaCl solution, dried on MgSO4 and concentrated under vacuum in the solvent. The residue is chromatographed on silica gel H by eluting in DCM, then the DCM/OH mixture gradient is dissolved from (99/1 v/v) to (95/5 v/v). The product is obtained in acetic acid; the pH of the solution is 1 °C; the resulting hydrochloric acid is added to the solution and the precipitate obtained from the solution is 0.8 °C.

E) N,N-dimethyl-2- (piperidine-4-yl) isobutyramide hydrochloride.

A mixture of 0.8 g of the compound obtained in the previous step and 0.2 g of palladium on 10% charcoal in 20 ml of MeOH is hydrogenated overnight at atmospheric pressure and TA. The catalyst is filtered on Cellite® and the filtrate is concentrated under vacuum. The residue is dissolved in acetonitrile, ether is added, the precipitate is ejected and dried.

The Commission has The substance is a hydrochloride of 1- (piperidine-4-yl) cyclopropane carboxamide.

A) 1-Pyridine-4-yl) cyclopropanecarbonitrile.

To a mixture of 2.5 g of sodium amidre in 80 ml of DCM, add 3.5 g of pyridine-4-ylacetonitrile and then 2.6 ml of 1,2-dibromoethane and leave to agitate at TA overnight. Pour the reaction mixture into water, extract at AcOEt, wash the organic phase with water, dry at Na2SO4 and evaporate the solvents under vacuum. Chromatograph the residue on silica gel by eluting at DCM and then by the DCM/MeOH mixture from (99/1; v/v) to (95/5; v/v).

(B) Hydrochloride of 1-pyridine-4-yl) cyclopropane carboxamide.

A mixture of 2.5 g of the compound obtained in the previous step and 20 ml of a 96% solution of H2SO4 is rapidly heated to 100 °C and left to agitate for 1 hour at 100 °C. After cooling at TA, the reaction mixture is poured over ice, neutralized at pH = 7 by adding a 20% solution of NH4OH, the precipitate formed is exsorted, washed with water and dried. The precipitate is dissolved in the DCM, acidified to pH = 1 by adding hydrochloride ether and the precipitate formed is exsorted. 1,8 g of the expected product is obtained.

C) Hydrochloride of 1- (piperidine-4-yl) cyclopropane carboxamide.

A mixture of 1.8 g of the compound obtained in the previous step and 0.6 g of PtO2 in 50 ml of MeOH is hydrogenated for 15 hours at 80 °C and 100 bar. The catalyst is filtered on Célite®, the filtrate is concentrated under vacuum to a volume of 5 ml, and acetonitrile is added until crystallization.

The Commission has The substance is a hydrochloride of 2-methyl-1- ((morpholine-4-yl)-2- ((pipéridine-4-yl) propane-1-one.

A) 2-benzylpipperidine-4-yl)-2-methyl-1-morpholine-4-yl) propane-1-one hydrochloride, whether or not chemically defined

Heat a mixture of 1 g of the compound obtained in step C of Preparation 3.6 and 1.2 ml of thionyl chloride in 20 ml of 1,2-dichloroethane at 80 °C for 3 hours. Concentrate the reaction mixture under vacuum, dissolve the resulting acid chloride in 20 ml of DCM, add this solution to a mixture of 0.7 g of morpholine, 1.6 ml of trielamine in 20 ml of DCM previously cooled to 0 °C and agitate at TA for 24 hours. Concentrate under the reaction mixture, extract the residue in ether, wash the organic phase in a solution of NaOH 1N in water, dry on SO4 and evaporate the Mg. Dissolve the product in gthylated acid, and obtain the desired pH of the product, which is obtained by adding the product to the etheric acid.

B) 2-methyl-1- (morpholine-4-yl) -2- (pipéridine-4-yl) propane-1-one hydrochloride, whether or not chemically defined

A mixture of 0.7 g of the compound obtained in the previous step, 0.7 g of ammonium formate and 0.2 g of palladium on 10% charcoal in 10 ml of MeOH is left to agitate for 4 hours in TA. The catalyst is filtered on Célite® and the filtrate is concentrated in a vacuum. The residue is dissolved in acetonitrile, ether is added, the precipitate is ejected and dried. 0.46 g of the expected product is obtained, F = 225°C.

The following paragraphs are added: It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C4.]

A) 3-(3,4-Dichlorophenyl)-3-(2-hydroxyethyl)-1-[2-(3,5-dimethylphenyle) acetyl] piperidine, which is a single isomer.

To a mixture of 2.0 g of 3.5-dimethylphenylacetic acid in 100 ml of DCM, add 2.3 ml of triethylamine to TA, then 3 g of the compound obtained from Preparation 1 and 5.3 g of BOP, and let it agitate at TA for 1 hour. Concentrate the reaction mixture in a vacuum, extract the residue to the ether, wash the organic phase with water, by a solution of HCl 2N, with water, by a 10% NaOH solution in water, dry on NaSO24, then filter under gel and empty the filtrate. Chromatise the silica residue H by ejecting it into DCM, by the mixture DCM/Me (98/v2/OH).

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

Cool at -70°C, under nitrogen atmosphere, a 0.25 ml solution of oxalyl chloride in 3 ml of DCM, add a 0.35 ml solution of DMSO in 3 ml of DCM, then a 0.5 g solution of the previously obtained compound in 5 ml of DCM and stir for 15 minutes at -50°C. Then add 0.9 ml of trielamine and stir until the temperature reaches TA. Wash the reaction mixture with water, with a solution of HCl 1N, with a 10% solution of NaHCO3, dry the organic phase on Na2SO4, and leave the wire under the filter.

C) Hydrochloride of 3- [2- [4- (1-carbamoyl-1-methylethyl) piperidine-1-yl]ethyl]-3- ((3,4-dichlorophenyl)-1-[2-(3,5-dimethylphenyl) acetyl]pipperidine, monohydrate, isomer (-), isomers of which:

After 5 minutes, add 0.08 g of sodium cyanoborohydride and let it agitate overnight in TA. Then pour the reaction mixture on a 10% NaHCO3 solution in water, extract it with ether, wash the organic phase with water, add it on Na2SO4, dry the filter and concentrate the wire under vacuum. Chromatise the residue on HM emulsified silica gel in DC, after trituration of the mixture in DC:M/OH (Mev/OH) and hydrolysis of the product in DC:V/OH (Mev/OH) to pH = 0.5 g/M. The resulting product is obtained by concentrating the ether and concentrating it in DC. - What? ${\alpha }_D^{20}$ The temperature of the water is -27° (c = 1 ; MeOH). RMN 1H: δ (ppm) : 0.7 to 1.2: se: 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 .

The following paragraphs shall apply: The chemical composition of the product is determined by the following equation:

Add 0.55 g of sodium triacethoxyborohydride and stir overnight in TA. Add a 10% Na2CO3 solution in water to the reaction mixture and stir for 15 minutes in TA. Extract the reaction mixture from the DCM, wash the organic phase with a 10% Na2CO3 solution in water, dry on NaSO24, and concentrate under the filter. Wash the remaining chromium in a chlorine gradient; wash the remaining chromium in a gel and leave the product in the vacuum. Wash the resulting v/ v (OH) v/ v (OH) v/ v (OH) v/ v. Wash the product from the DCM, and then pre-filter the product to DCM. - What? ${\alpha }_D^{20}$ The temperature of the water is -37° (c = 1 ; MeOH). RMN 1H: δ (ppm) : 0.6 to 2.3 m: 18H; 2.3 to 4.7 m: 16H; 6.4 to 8.0 m: 8H .

The Commission has It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5 and boiling in the range of approximately -15oC to -15oC.

Add to TA 0.6 g of the compound obtained in step B of Example 1, 0.3 g of the compound obtained in Preparation 3.4, 0.1 ml of acetic acid and 0.12 g of sodium cyanoborohydride and let agitate at TA for 20 ml of MeOH. Add to the reaction mixture a 10% solution of Na2CO3 in water and agitate for 15 minutes. Extract the mixture from AcOEt, wash the organic phase with a 10% solution of Na2CO3 in water, add to the water with a saturated solution of NaCl, dry on Na2SO4 and chromatise underground. - What? ${\alpha }_D^{20}$ - 28 ° 4 (c = 1; MeOH). RMN 1H: δ (ppm) : 0.7 to 2.3 m: 18H; 2.35 to 4.7 m: 22H; 6.5 to 7.8 m: 6H; 10.3 s: 1H .

The Commission shall adopt implementing acts. It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C4.]

A) 3- (3, 4-dichlorophenyl) -3- (2-hydroxyethyl) -1- [2- (3,5-dichlorophenyl) acetyl] piperidine, isomer only

In 150 ml of DCM, add 4.75 g of the compound obtained in Preparation 1, 3.55 g of the compound obtained in Preparation 2.1, 3.6 ml of triethylamine and 8.4 g of BOP to TA and leave to agitate for 2 hours in TA. Concentrate the reaction mixture in a vacuum, extract the residue in AcOEt, wash the organic phase with a solution of HCl 1N, water, NaOH 1N solution, water, a saturated solution of NaCl, dry on Na2SO4 and evaporate the solvent under vacuum.

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

This compound is prepared in the manner described in Step B of Example 1 from 0,25 ml of oxalyl chloride in 6 ml of DCM, 0,38 ml of DMSO in 3 ml of DCM, 1 g of the compound obtained in the previous step in 6 ml of DCM and then 1,5 ml of triethylamine, yielding 1,0 g of the product expected to be used as is.

C) Hydrochloride of 3- [2- [4- (1-carbamoyl-1-methylethyl) piperidine-1-yl]ethyl]-3- ((3,4-dichlorophenyl) -1- [2- (3,5-dichlorophenyl) acetyl] piperidine, sesquihydrate, isomer (-)

Prepare this compound in the manner described in step C of Example 1 from 0.25 g of the compound obtained from Preparation 3.1 (free base) in 3 ml of MeOH, 0.08 ml of acetic acid, 0.5 g of the compound obtained in the previous step in 5 ml of MeOH and then 0.08 g of sodium cyanoborohydride, to obtain 0.52 g of the expected product. - What? ${\alpha }_D^{20}$ - = 0.6 ° (c = 1; MeOH)

The Commission shall adopt implementing acts. It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5 and boiling in the range of approximately -15oC to -15oC.

A) 3- (3, 4-Dichlorophenyl) -3- (2-hydroxyethyl) -1- [2- [3, 5-bis ((trifluoromethyl) phenyl] acetyl]pipéridine, single isomer

In 50 ml of DCM, add to TA 1.2 g of the compound obtained from Preparation 1, 1.2 g of 3,5-bis ((trifluoromethyl) phenylacetic acid, 1.7 ml of triethylamine and then 2.16 g of BOP and leave to agitate for 15 minutes. Concentrate the reaction mixture under vacuum, take up the residue with a solution of HCl 1N, extract with ether, wash the organic phase with a solution of HCl 1N, with water, with a solution of NaOH 1N, with water, dry on Na2SO4 and evaporate the solvent under vacuum.

B) 3-(3,4-Dichlorophenyl)-3-(formylmethyl)-1-[[2-[3,5-bis(trifluoromethyl)phenyl]acetyl]pipéridine, single isomer, which is not a chemical compound.

Cool 20 ml of DCM to -78°C, add 1.5 g of the previously obtained compound, 0.45 ml of DMSO and 0.3 ml of oxalyl chloride to the nitrogen atmosphere and stir for 30 minutes at -78°C.

Add 2 ml of triethylamine and stir until the temperature reaches TA. Add to the reaction mixture a solution of 1N HCl, extracted from the DCM, wash the organic phase with a solution of 1N HCl, water, 10% Na2CO3 solution in water, dry on Na2SO4 and evaporate the solvent under vacuum.

C) Hydrochloride of 3- [2- [4- (1-carbamoyl-1-methylethyl) piperidine-1-yl]ethyl]-3- ((3,4-dichlorophenyl)-1-[2-[3,5-bis ((trifluoromethyl) phenyle]acetyl] piperidine, monohydrate, isomer (+)

The product of Preparation 3.1 in the form of a free base is dissolved in 3 ml of MeOH, 0.08 ml of acetic acid is added, then a solution of 0.5 g of the compound obtained in the previous step is added in 5 ml of MeOH and then stirred in TA for 5 minutes. Then 0.08 g of sodium cyanoborohydride is added and left overnight to be stirred in TA. The mixture is then dissolved in 10 per cent solution of NaCO3 in water, extracted in the organic solution, washed in the water phase, dried and dried; the remaining chloride is obtained by evaporation of the product in the pH of 0.54 g of the liquid and obtained in the vacuum (DCM/H10). - What? ${\alpha }_D^{20}$ The temperature of the water is +28,2° (c = 1 ; MeOH). RMN 1H: δ (ppm) : 0.6 to 2.2: m: 16H; 2.3 to 4.2: m: 12H; 6.6 to 8.0: m: 8H; 10.3: s: 1H.

The Commission has It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5 and boiling in the range of approximately -15oC to -15oC.

A mixture of 0.35 g of the compound obtained from Preparation 3.6 and 0.4 g of K2CO3 is carried backwards for 3 hours in 10 ml of acetonitrile. An insoluble solution is filtered and concentrated under vacuum in the filtrate. The product of Preparation 3.6 in the form of a free base is dissolved in 3 ml of MeOH, 0.1 ml of acetic acid is added, then a solution of 0.6 g of the compound obtained in step B of Example 1 is added in 5 ml of MeOH and then left to agitate for 5 minutes in TA.The reaction mixture is poured into a 10% solution of NaHCO3 in water, extracted with ether, washed with water, dried on MgSO4 and evaporated in a vacuum. The residue is chromatographed on silica gel H by eluting in DCM and then by the gradient of the DCM/MeOH mixture from (99/1; v/v) to (90/10; v/v). The resulting product is dissolved in DCM, acidified to pH = 1 by addition of hydrochloric ether and concentrated under the solvents. 0.68 g of the expected product is obtained after trituration in ether, vacuum extraction and drying, F = 202°C. ${\alpha }_D^{20}$ The value of the product is calculated as follows: RMN 1H: δ (ppm) : 0.6 to 2.5 m: 23H; 2.5 to 4.6 m: 18H; 6.4 to 7.8 m: 6H; 10.1 s: 1H .

The Commission has It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C4.]

A) 3-(3,4-Dichlorophenyl)-3-(2-hydroxyethyl)-1-[2-(3,5-diethylphenyle) acetyl] piperidine, which is a single isomer.

To a mixture of 1.64 g of the compound obtained from Preparation 1 in 30 ml of DCM, add 1.15 g of 3.5-diethylphenylacetic acid to TA, then 3 ml of triethylamine and 3.2 g of BOP and leave to agitate for 2 hours at TA. Concentrate the reaction mixture in a vacuum, take up the residue by a solution of 1N HCl, extract to ether, wash the organic phase by a solution of 1N HCl, water, by a solution of NaOH 1N, water, by a saturated solution of NaCl, dry on Na2SO4 and evaporate under the solvent. Chromatograph the residue on silica gel by emulsifying the gradient of the mixture of DCM (OH/Mev) / 1/5 (Mev) / 1/5 (Mev) V; at whatever the desired temperature the product is obtained.

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

A 0.5 g solution of the compound obtained in the previous step is cooled at -78°C in a nitrogen atmosphere in 10 ml of DCM, 0.23 ml of DMSO is added, then 0.16 ml of oxalyl chloride is added and left to simmer for 30 minutes at -78°C. Then 0.95 ml of triethylamine is added and simmered while the temperature is allowed to rise to TA. A 1 N HCl solution is added to the reaction mixture, extracted from DCM, the organic phase is washed with a 1 N HCl solution, with water, with a 10% Na2CO3 solution, dried on Na2SO4 and evaporated underground.

C) Hydrochloride of 3- [2- [4- (1-carbamoyl-1-methyl) piperidine-1-yl]ethyl]-3- ((3,4-dichlorophenyle)-1-[2-(3,5-diethylphenyle) acetyl]pipperidine, which is the hemihydrate, isomer (-).

After 5 minutes, add 0.08 g of sodium cyanoborohydride and let it agitate overnight in TA. Then pour the reaction mixture on a 10% NaHCO3 solution in water, extract it in ether, wash the organic phase with water, add it in MgSO4 and vacuum dry the solvent. Chromatise the remaining HM-elite silica gel in soil with chlorine after evaporation in the DCM/OH gradient (Me/OH) of 0.7 g (9/M/M) and obtain the resulting product in DCM/OH. - What? ${\alpha }_D^{20}$ The value of the product is calculated as the sum of the values of the products in the product . RMN 1H . δ (ppm) : 0.5 to 2.2 m: 23H; 2.2 to 4.6 m: 16H; 6.4 to 7.8 m: 8H; 9.85 s: 1H .

The methods described in the preceding examples are used to prepare the compounds of the invention, as shown in Table I below. - What? TABLEAU I TABLEAU I

Exemples	X		Sel, hydrate RMN
8 (a)		Me	HCl RMN -23,3°
9 (b)		Me
10 (c)		Cl
11 (d)		Cl
12 (e)		Cl
13 (f)		Cl
14 (g)
15 (h)
16 (i)		Me
17 (j)
18 (k)		Cl	HCl RMN + 37,2°
19 (l)		Et
20 (m)	Me	HCl RMN isomère unique

This compound is prepared in the manner described in step C of Example 1 from the compound obtained in step B of Example 1 and the compound obtained in Preparation 3.5 as a free base.

This compound is prepared in the manner described in Example 3 from the compound obtained in Step B of Example 1 and the compound obtained in Preparation 3.3 as a free base.

This compound is prepared in the manner described in step C of Example 4 from the compound obtained in step B of Example 4 and the compound obtained in Preparation 3.5 as a free base.

This compound is prepared in the manner described in Example 3 from the compound obtained in Step B of Example 4 and the compound obtained in Preparation 3.2 as a free base.

This compound is prepared in the manner described in Example 3 from the compound obtained in Step B of Example 4 and the compound obtained in Preparation 3.4.

This compound is prepared in the manner described in Example 3 from the compound obtained in Step B of Example 4 and the compound obtained in Preparation 3.3 as a free base.

This compound is prepared in the manner described in Step C of Example 5 from the compound obtained in Step B of Example 5 and the compound obtained in Preparation 3.5.

This compound is prepared in the manner described in Example 3 from the compound obtained in Step B of Example 5 and the compound obtained in Preparation 3.3 as a free base.

This compound is prepared in the manner described in Example 2 from the compound obtained in Step B of Example 1 and the compound obtained in Preparation 3.7 as a free base.

This compound is prepared in the manner described in Step C of Example 5 from the compound obtained in Step B of Example 5 and the compound obtained in Preparation 3.7.

This compound is prepared in the manner described in step C of Example 4 from the compound obtained in step B of Example 4 and the compound obtained in Preparation 3.7 as a free base.

This compound is prepared in the manner described in step C of Example 7 from the compound obtained in step B of Example 7 and the compound obtained in Preparation 3.2 as a free base.

This compound is prepared in the manner described in step C of Example 1 from the compound obtained in step B of Example 1 and the compound obtained in Preparation 3.8 as a free base.

Example 8: NMR 1H: δ (ppm) : 0.7 to 2.2 m: 27H; 2.3 to 4.6 m: 14H; 6.4 to 7.7 m: 8H; 10.1 s: 1H .

Example 9: NMR 1H: δ (ppm) : 0.6 to 2.35: m: 22H; 2.4 to 4.6: m: 14H; 6.4 to 8.2: m: 8H.

Example 10: NMR 1H: δ (ppm) : 0.7 to 2.25: m: 21H; 2.3 to 4.4: m: 12H; 6.7 to 7.8: m: 8H; 10.1: s: 1H.

Example 11: NMR 1H: δ (ppm) : 0.6 to 2.2 m: 12H; 2.3 to 4.4 m: 16H; 6.8 to 8.0 m: 8H.

Example 12: NMR 1H: δ (ppm) : 0.8 to 2.3 m: 12H; 2.35 to 4.4 m: 22H; 7.0 to 7.9 m: 6H; 10.6 s: 1H .

Example 13: NMR 1H: δ (ppm) : 0.9 to 2.3 m: 16H; 2.35 to 4.5 m: 16H; 7.0 to 7.9 m: 8H .

Example 14: NMR 1H: δ (ppm) : 0.9 to 2.3 m: 21H; 2.4 to 4.3 m: 12H; 6.8 to 8.1 m: 8H; 10.0 s: 1H .

Example 15: NMR 1H: δ (ppm): 1.0 to 2.4 m: 16H; 2.5 to 4.5 m: 16H; 6.9 to 8.1 m: 8H; 11.0 se: 1H .

Example 16: NMR 1H: δ (ppm) : 0.4 to 2.3 m: 20H; 2.4 to 4.6 m: 13H; 6.5 to 7.7 m: 8H; 9.6 s: 1H .

Example 17: NMR 1H: δ (ppm) : 0.4 to 2.2 m: 14H; 2.3 to 4.4 m: 13H; 6.5 to 7.8 m: 8H; 9.9 s: 1H .

Example 18: NMR 1H: δ (ppm) : 0.4 to 2.2 m: 14H; 2.3 to 4.4 m: 13H; 6.6 to 7.8 m: 8H; 9.9 s: 1H .

Example 19: NMR 1H: δ (ppm) : 0.6 to 2.6 m: 22H; 2.6 to 4.8 m: 16H; 6.5 to 8.0 m: 10H .

Example 20: NMR 1H: δ (ppm) : 0.7 to 2.25: m: 22H; 2.3 to 4.6: m: 21H; 6.4 to 7.7: m: 6H; 10.4: s: 1H .

The Commission shall adopt the implementing acts referred to in Article 21 (2). The active substance is a hydrochloride of 3-[2-[4-[1-carbamoyl-1-methyl) piperidin-1-yl]ethyl]-3-(3,4-dimethylphenyle)-1-[2-(3,5-dichlorophenyl) acetyl]pipéridine.

The substance is classified as a substance of very high concern in the Union for the purposes of the definition of the product concerned.

A mixture of 3 g of the compound obtained from Preparation 1.2, 1.3 g of the compound obtained from Preparation 2.1, 3.2 ml of triethylamine and 4.8 g of BOP in 100 ml of DCM is left to agitate for 2 hours in TA. The reaction mixture is concentrated under vacuum, the residue is taken up by a solution of HCl 1N, extracted at AcOEt, the organic phase is washed with water, by a solution of NaOH 1N, by a saturated solution of NaCl, dried on Na2SO4 and evaporated under the solvent. 4.5 g of the expected product is obtained.

The substance is classified in the additive category 'Chemical products'.

A mixture of 4.5 g of the compound obtained in the previous step and 2 ml of a solution of concentrated HCl in 10 ml of MeOH are left to agitate for 2 hours in TA. The reaction mixture is concentrated under vacuum, the residue is taken up in MeOH and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel by elevating in DCM and then by the gradient of the DCM/MeOH mixture from (99/1 v/v) to (95/5 v/v). 3 g of the expected product is obtained.

C) 1-[2-(3,5-Dichlorophenyl) acetyl]-3- ((formylmethyl)-3-(3,4-dimethylphenyle) piperidine.

Then add 0.75 ml of triethylamine and stir for 30 minutes, raising the temperature to TA. Add to the reaction mixture a solution of HCl 1N, extracted from the DCM, wash the organic phase with water, with a 10% solution of Na2CO3, vacuum on Na2SO4 and evaporate, leaving the soil to dry.

D) Hydrochloride of 3- [2-[4-[1-carbamoyl-1-methylethyl]pipéridine-1-yl]ethyl]-3-[3,4-dimethylphenylethyl)-1-[2-[3,5-dichlorophenyl]acetyl]pipéridine.

A mixture of 0.5 g of the compound obtained in the previous step, 0.35 g of the compound obtained in Preparation 3.1 (free base), 0.1 ml of acetic acid and 0.15 g of sodium cyanoborohydride in 30 ml of MeOH is agitated overnight in TA. A 10% solution of Na2CO3 is added to the reaction mixture, agitated for 15 minutes, extracted in AcOEt, washed off the organic phase with water, by a saturated NaCl solution, dried on Na2SO4 and evaporated under the solvent. The residue is chromographed on silica gel by eluting to the DCM and then the gradient of the mixture DCM/MeOH (99/1 v/v) to (95/5 v/v) is obtained. Once the product is dissolved in the DCM, the pH obtained is obtained by adding 1 g of chloride and the resulting product is obtained by pre-pressuring to the DCM. RMN 1H: δ (ppm) : 0.8 to 2.3 m: 22H; 2.3 to 4.0 m: 13H; 6.5 to 7.6 m: 8H; 9.5 s: 1H .

The Commission has The chemical composition of the active substance is determined by the following equation:

This compound is prepared in the manner described in step D of Example 21 from the compound obtained in step C of Example 21 and the compound obtained in the Preparation 3.2 (free base) RMN 1H: δ (ppm) : 1.4: 1s: 6H; 2.2: 2s: 6H; 1.3 to 4.0: m: 26H; 7.0 to 8.0: m: 6H .

Claims (27)

1. Compound of formula: in which:

   - X represents a group a group

   - Ar represents a phenyl monosubstituted or disubstituted with a halogen atom; a (C₁-C₃)alkyl;

   - R₁ represents a chlorine atom, a bromine atom, a (C₁-C₃) alkyl or a trifluoromethyl;

   - R₂ represents a group -CR₃R₄CONR₅R₆;

   - R₃ and R₄ represent the same radical chosen from a methyl, an ethyl, an n-propyl or an n-butyl;

   - or alternatively R₃ and R₄, together with the carbon atom to which they are attached, constitute a (C₃-C₆)cycloalkyl;

   - R₅ and R₆ each independently represent a hydrogen; a (C₁-C₃)alkyl;

   - or alternatively R₅ and R₆, together with the nitrogen atom to which they are attached, constitute a heterocyclic radical chosen from 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl, 4-morpholinyl, 4-thiomorpholinyl or perhydro-1-azepinyl;

   and the salts thereof with inorganic or organic acids, and the solvates and/or hydrates thereof.
2. Compound according to Claim 1, in which Ar represents a 3,4-dichlorophenyl or a 3,4-dimethylphenyl.
3. Compound according to Claim 1, in which the substituents R₁ represent a chlorine atom, a methyl, an ethyl or a trifluoromethyl.
4. Compound according to Claim 1, in which X represents a group in which R₂ represents a group -CR₃R₄CONR₅R₆.
5. Compound according to Claim 4, in which R₃ and R₄ each represent a methyl or, together with the carbon atom to which they are attached, constitute a cyclohexyl.
6. Compound according to Claim 1, in which X represents a group in which R₂ represents a group -CR₃R₄CONR₅R₆.
7. Compound according to Claim 6, in which R₃ and R₄ each represent a methyl or, together with the carbon atom to which they are attached, constitute a cyclohexyl or a cyclopropyl.
8. Compound according to Claim 4 or Claim 6, in which R₅ and R₆ each represent hydrogen or a methyl.
9. Compound according to Claim 1, of formula: in which:

   - R'₁ represents a chlorine atom, a methyl, an ethyl or a trifluoromethyl;

   - R' ₃ and R' ₄each represent a methyl or alternatively, together with the carbon atom to which they are attached, constitute a cyclohexyl;

   - R'₅ and R'₆ each represent hydrogen or a methyl; and the salts thereof with inorganic or organic acids, and the solvates and/or hydrates thereof.
10. Compound according to Claim 1, 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 alternatively, together with the carbon atom to which they are attached, constitute a cyclohexyl or cyclopropyl;

    - R'₅ and R'₆ each represent hydrogen or a methyl; and the salts thereof with inorganic or organic acids, and the solvates and/or hydrates thereof.
11. Compound according to any one of Claims 1 to 10, of formula (I), (I') or (I" ), in optically pure form.
12. 3- [2- [4- (1-Carbamoyl-1-methylethyl)-1-piperidyl] ethyl] -3- (3, 4-dichlorophenyl) -1- [2-(3, 5-dimethylphenyl) acetyl] piperidine, (-) isomer, the salts thereof and the solvates and/or hydrates thereof.
13. 3-[2-[4-(1-N,N-dimethylcarbamoyl-1-methylethyl)-1-piperidyl]ethyl]-3-(3,4-dichlorophenyl)-1- [2-(3,5-dimethylphenyl)acetyl]piperidine, (-) isomer, the salts thereof and the solvates and/or hydrates thereof.
14. 3-[2-[4-(1-Carbamoyl-1-methylethyl)-1-piperidyl] ethyl] -3- (3, 4-dichlorophenyl) -1- [2-(3,5-diethylphenyl)acetyl]piperidine, (-) isomer, the salts thereof and the solvates and/or hydrates thereof.
15. 3- [2- [4- (1-Carbamoyl-1-methylethyl) - 1-piperidyl] ethyl] -3- (3, 4-dichlorophenyl) -1- [2-[3, 5-bis(trifluoromethyl)phenyl] acetyl] piperidine, (+) isomer, the salts thereof and the solvates and/or hydrates thereof.
16. Process for preparing the compounds of formula (I) according to Claim 1, the salts thereof and the solvates and/or hydrates thereof, characterized in that:

    1a) a compound of formula: in which Ar is as defined for a compound of formula (I) in Claim 1 and E represents hydrogen or an O-protecting group, is treated with a functional derivative of an acid of formula: in which R₁ is as defined for a compound of formula (I) in Claim 1, to give 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 give the alcohol of formula:

    3a) the alcohol obtained in step 1a) or in step 2a) of formula (IV, E = H) is treated with a compound of formula:         Y-SO₂-Cl     (V) in which Y represents a methyl, phenyl, tolyl or trifluoromethyl group, to give a compound of formula:

    4a) the compound of formula (VI) is reacted with a compound of formula: in which X is as defined for a compound of formula (I) in Claim 1;

    5a) and, optionally, the compound thus obtained is converted into one of the salts thereof with an inorganic or organic acid.
17. Process for preparing the compounds of formula (I) according to Claim 1, the salts thereof and the solvates and/or hydrates thereof, characterized in that:

    1b) the compound of formula: in which Ar is as defined for a compound of formula (I) in Claim 1 and E represents hydrogen or an O-protecting group, is treated with a functional derivative of an acid of formula: in which R₁ is as defined for a compound of formula (I) in Claim 1, to give a compound of formula: optionally, when E represents a protecting group, it is removed by the action of an acid or a base, to give the alcohol of formula:

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

    3b) the compound of formula (VIII) is reacted with a compound of formula: in which X is as defined for a compound of formula (I) in Claim 1, in the presence of an acid, followed by reduction of the intermediate iminium salt formed by means of a reducing agent;

    4b) and, optionally, the compound thus obtained is converted into one of the salts thereof with an inorganic or organic acid.
18. Stereospecific process for preparing the compounds of formula (I) according to Claim 1 having the (S) configuration, the salts thereof and the solvates and/or hydrates thereof, characterized in that:

    1d) the (S) isomer of a compound of formula: in which Ar is as defined for a compound of formula (I) in Claim 1, is treated with a functional derivative of the acid of formula: in which R₁ is as defined for a compound of formula (I) in Claim 1, to give a compound of formula:

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

    3d) the compound of formula (VIII*) is reacted with a compound of formula: in which X is as defined for a compound of formula (I) in Claim 1, in the presence of an acid, followed by reduction of the intermediate iminium salt formed by means of a reducing agent;

    4d) and, optionally, the compound thus obtained is converted into one of the salts thereof with an inorganic or organic acid.
19. Process for preparing the compounds of formula (I) according to Claim 1, the salts thereof and the solvates and/or hydrates thereof, characterized in that:

    a compound of formula:

    in which:

    - Ar represents a phenyl monosubstituted or disubstituted with a halogen atom; a (C₁-C₃)alkyl;

    - Y represents a methyl, phenyl, tolyl or trifluoromethyl group;

    - R₁ represents a chlorine atom, a bromine atom, a (C₁-C₃)alkyl or a trifluoromethyl;

    is reacted with a compound of formula: in which X is as defined for a compound of formula (I) in Claim 1, and, optionally, the compound thus obtained is converted into one of the salts thereof with an inorganic or organic acid.
20. Process for preparing the compounds of formula (I) according to Claim 1, the salts thereof and the solvates and/or hydrates thereof, characterized in that:

    the compound of formula:

    in which Ar and R₁ are as defined for a compound of formula (I) in Claim 1, is reacted with a compound of formula: in which X is as defined for a compound of formula (I) in Claim 1, in the presence of an acid, followed by reduction of the intermediate iminium salt formed by means of a reducing agent, and, optionally, the compound thus obtained is converted into one of the salts thereof with an inorganic or organic acid.
21. Stereospecific process for preparing the compounds of formula (I) according to Claim 1, having the (S) configuration, the salts thereof and the solvates and/or hydrates thereof, characterized in that:

    the compound of formula:

    in which Ar and R₁ are as defined for a compound of formula (I) in Claim 1, is reacted with a compound of formula: in which X is as defined for a compound of formula (I) in Claim 1, in the presence of an acid, followed by reduction of the intermediate iminium salt formed by means of a reducing agent, and, optionally, the compound thus obtained is converted into one of the salts thereof with an inorganic or organic acid.
22. Compound of formula: in which:

    - X represents a group of a group

    - R₂ represents a group -CR₃R₄CONR₅R₆;

    - R₃ and R₄ represent the same radical chosen from a methyl, an ethyl, an n-propyl or an 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 a hydrogen; a (C₁-C₃) alkyl ;

    - or alternatively R₅ and R₆, together with the nitrogen atom to which they are attached, constitute a heterocyclic radical chosen from 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl, 4-morpholinyl, 4-thiomorpholinyl or perhydro-1-azepinyl;

    and the salts thereof with inorganic or organic acids.
23. Pharmaceutical composition comprising, as active principle, a compound according to any one of Claims 1 to 15, or one of the pharmaceutically acceptable salts, solvates and/or hydrates thereof.
24. Pharmaceutical composition according to Claim 23, containing from 0.1 to 1000 mg of active principle, in unit dosage form, in which the active principle is mixed with at least one pharmaceutical excipient.
25. Use of a compound according to any one of Claims 1 to 15 or of one of the pharmaceutically acceptable salts, solvates and/or hydrates thereof, for the preparation of medicinal products intended for treating any pathology in which substance P and the human NK₁ receptors are involved.
26. Use according to Claim 25, for the preparation of medicinal products intended for treating pathologies of the respiratory, gastrointestinal, urinary, immune or cardiovascular system or the central nervous system, as well as for pain, migraine, inflammations, nausea and vomiting, and skin diseases.
27. Use according to Claim 26, for the preparation of medicinal products intended for treating obstructive chronic bronchitis, asthma, urinary incontinence, irritable bowel syndrome, Crohn=s disease, ulcerative colitis, depression and anxiety.