HK1060129B - Novel piperidinecarboxamide derivatives, method for preparing same and pharmaceutical compositions containing same - Google Patents

Description

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

In particular, the present invention relates to novel piperidinecarboxamide derivatives for therapeutic use in pathological events involving the tachykinin system, including 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, Totowa, New Jersey), gastrointestinal disorders (P. Holzer and U. Holzer-Pets, Otsamachi Pharmaceuticals, 1997, 73, 173-217 and 21-23), respiratory disorders (J. Mizzi and al., 1994) and neurological disorders (J. Nephrology, C. Nephrology, Yoshi, J. Nephrology, and C. Nephrology, J. Nephrology, J. Nephrology, J. Nephrology, J. Nephrology, J. Nephrology, J. Nephrology, J. Nephrology, J. Nephrology, J. Nephrology, J. Nephrology, J. Nephrology, J. Nephrology, J. Nephrology, J. Nephrology, J. Nephrology, J. Nephrology, J. Nephrology, J. Nephrology, J. Nephrology, J. Nephrology, J. Nephrology, J. Nephrology, J. Nephrology, J. Nephrology, J. Nephrology, J. Nephrology, J. Nephrology, J. Nephrology, J. Nephrology, J. Nephrology, J. Nephrology, J. Nephrology, J. Nephrology, J. Nephrology, J. Nephrology, J. Nephrology, J. Nephrology, J. Nephrology, Nephrology, J. Nephrology, Nephrology, Ne

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 international application WO 96/23787 concerns compounds with formula: A can represent the bivalent radical -O-CH2-CH2-;Am, m, Ar1 and T have different values.

In particular, 1-[2-[4-benzoyl-2-(3,4-dichlorophenyl) morpholin-2-yl]ethyl]-4-(pipéridine-1-yl)pipéridine-4-carboxamide (compound α) is described in Example 65 of WO 96/23787.

This compound has a high affinity for human NK2 receptors but a lower affinity for human NK3 receptors.

Application for patent EP-A-0 776 893 concerns compounds with formula: including in particular: D-E can represent a bivalent radical -O-CH2-CH2-; L, G, E, A, B, Ra and Rb have different values.

Application WO 00/34274 concerns cyclohexylpipperidine derivatives which are antagonists of both the NK1 receptor of substance P and the NK2 receptor of neurokinin A.

New compounds have now been found that have a very high affinity for both human NK2 neurokinine A receptors and human NK3 neurokinine B 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 disease in which either neurokinine A and/ or NK2 receptors, or neurokinine B and/ or NK3 receptors, or both neurokinine A and neurokinine B and/ or NK2 and NK3 receptors are involved, including in the treatment of diseases 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: in which: R1 represents a hydrogen atom or a methyl radical; B represents a direct bond or a -CH2- group; Z represents a phenyl, a 2,3-dichlorophenyl or a 2,6-dichlorophenyl; and their salts with mineral or organic acids, their solvates and/or their 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, bromide, sulphate, hydrogen sulphate, dihydrogen phosphate, methanesulfonate, methanol sulphate, oxalate, maleate, fumarate, naphtal-2-conic, citrate, citron, acetone, benzene, sulfonate, sulfonate.

Halogen atoms are atoms of chlorine, bromine, fluorine or iodine.

According to the present invention, the compounds of formula (I) are preferred as optically pure isomers.

The following compounds: N,N-dimethyl-1-[2-[4-benzoyl-2-(3,4-dichlorophenyl) morpholine-2-yl]ethyl]-4- ((piperidin-1-yl) piperidin-4-carboxamide, dextrogyre isomer ;N-methyl-1-[2-[4-benzoyl-2-(3,4-dichlorophenyl) morpholine-2-yl]ethyl]-4- (((piperidin-1-yl) piperidin-4-carboxamide, dextrogyre isomer ;N,N-dimethyl-1-[2-[2-[4-[[2,3-dichlorobenzoyl-2-yl) piperidin-2-dichlorophenyl) -carboxamide]-4-[4-dimethyl]pyridin-1- (dichlorophenid) -carboxamide, dextrogyre isophenid;N-dimethyl-2-yl-nitrile (N-dimethyl-1- (dichlorophenid) -nitrile) - (dichlorophenid) - (dichlorophenid) - (dichlorophenid) - (dichlorophenid) - (dichlorophenid) - (dichlorophenid) -2- (dichlorophenid) -2- (dichlorophenid) -2- (dichlorophen) -2- (dichlorophen) -2- (dichlorophen) -2- (dichlorophen) -2- (dichlorophen) -2- (dichlorophen) -2- (dichlorophen) -2- (dichlorophen) -2- (dichlorophen) -2- (dichlorophen) -2- (dichlorophen) -2- (dichlorophen) -2- (dichlorophen) -2- (dichlorophen) -2-) -2- (dichlorophen) -2- (dichlorophen) -2- (dichlorophen) -2- (dichlorophen) -2- (dichlorophen) -2- (dichlorophen) -2-) -2- (dichlorophen) -2- (dichlorophen) -2- (dich

The following compound: N,N-dimethyl-1-[2-[4-benzoyl-2-(3,4-dichlorophenyl) morpholin-2-yl]ethyl]-4-(pipéridin-1-yl)pipéridine-4-carboxamide, dextrogyre isomer; as well as its salts with mineral or organic acids, its solvates and/or hydrates is particularly preferred.

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: We react a compound with the formula: where B and Z are as defined for a compound of formula (I), with a compound of formula : where R1 is as defined for a compound of formula (I), in the presence of an acid, in a solvent, then the intermediate iminium salt is reduced by means of a reducing agent.

The compound of formula (I) is then transformed into one of its salts with mineral or organic acids.

The reaction is carried out in the presence of an acid such as acetic acid in a solvent such as methanol or dichloromethane at a temperature between room temperature and the reflux temperature of the solvent and forms in situ an intermediate imine which is reduced chemically using, for example, sodium cyanoborohydride or sodium triacethoxyborohydride or catalytically using hydrogen and a catalyst such as palladium on coal or Raney's nickel®.

According to one variation of the process: We react a compound with the formula: wherein B and Z are as defined for a compound of formula (I) and Y is a methyl, phenyl, tolyl or trifluoromethyl group, with a compound of formula: where R1 is as defined for a compound of formula (I).

Alternatively, the compound of formula (I) is transformed into one of its salts with mineral or organic acids.

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-diisopropylamine or N-methylmorpholine or from alkaline metal carbonates or bicarbonates such as potassium carbonate, sodium carbonate or sodium bicarbonate. In the absence of a base, the reaction is carried out using an excess of the compound formula (III) and in the presence of an alkali metal such as sodium or potassium iodide. The reaction is carried out at an ambient temperature of 100 °C.

According to another variant of the process We react a compound with the formula: where R1 is as defined for a compound of formula (I), with a functional derivative of an acid of formula: - What? The following information shall be provided: - What? wherein B and Z are as defined for a compound of formula (I).

The compound of formula (I) is then transformed into one of its salts with mineral or organic acids.

As a functional derivative of the acid (VI), the acid itself is used, or one of the functional derivatives that reacts with amines, for example an anhydride, a mixed anhydride, acid chloride, or an activated ester, such as the paranitrophenyl ester.

When formula (VI) acid is used itself, it is used in the presence of a peptide chemistry coupling agent such as 1,3-dicyclohexyl carbodiamine or benzotriazol-1-yloxytris dimethylamino hexafluorophosphate phosphonium in the presence of a base such as triethylamine or N,N-diisopropyl ethylamine 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 compounds of formula (I) can then be separated from the reaction medium and purified by conventional methods, e.g. by crystallization or chromatography.

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 or acetonitrile with a solution of the selected acid in one of the above solvents, the corresponding salt is obtained which is isolated according to the conventional techniques.

For example, hydrochloride, bromohydrate, sulphate, trifluoroacetate, hydrogen sulphate, dihydrogen phosphate, methanesulfonate, oxalate, maleate, succinate, fumarate, naphthalene-2-sulfonate, benzenesulfonate, para-toluenesulfonate, gluconate, citrate and acetate 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) are prepared by known methods such as those described in WO 96/23787.

For example, a compound of formula (II) is prepared according to SCHEME 1 below in which E represents a hydrogen atom or an O-protective group.

Where E represents a protective group, it is chosen from the classic O-protective groups well known to the artisan, such as, for example, tetrahydropyran-2-yl, benzoyl or a (C1-C4) alkylcarbonyl.

In step a1 of SCHEME 1 a compound of formula (VII) is reacted with a functional derivative of a formula (VI) acid, using the methods described above, to obtain a compound of formula (VIII).

The resulting compound of formula (VIII) may be de-protected at step b1 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-cyl 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, or a solution of methanol.

At step c1 the alcohol of formula (IX) is oxidised to the adehyde of formula (II). 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.

The formula (III) compounds are known and are prepared by known methods. e.g. a formula (III) compound is prepared according to SCHEME 2 below. - What?

Steps a2 and b2 of SCHEME 2 shall be performed according to the operating modes described in Steps A and B of Preparation 2.16 in WO 96/23787.

At step c2, the compound 3 is reacted with a methyl halides, preferably methyl iodide, in the presence of a strong base such as sodium hydride, in a solvent such as tetrahydrofuran and at a temperature between ambient and reflux temperature of the solvent and a mixture of the compound of formula (X) in which R1 = H and the compound of formula (X) in which R1 = CH3 is obtained separated by conventional methods such as chromatography.

The compounds (X) are de-protected at steps d2 or e2 using known methods to yield the expected compounds of formula (III).

For formula (IV) compounds, known methods such as those described in WO 96/23787 are used. For example, a formula (IX) compound is reacted with a formula: - What? The following shall be added: - What? The reaction is carried out in the presence of a base such as triethylamine, pyridine, N,N-diisopropylamine or N-methylmorpholine in a solvent such as dichloromethane or toluene and at a temperature between -20°C and the reflux temperature of the solvent.

The compounds of formula (V) are prepared according to SCHEME 3 below in which E represents the hydrogen or an O-protective group and Pr represents an N-protective group.

Where Pr represents an N-protective group, it is chosen from the classic N-protective groups well known to the artisan, such as the tert-butoxycarbonyl group, benzyloxycarbonyl or trityl.

Compounds of formula (VI) are commercially available or prepared by known methods, e.g. 2- (2,3-dichlorophenyl) acetic acid is prepared according to SCHEME 4 below by following the procedures described in Preparation 1.1.

Compounds of formula (VII) are known and prepared by known methods such as those described in WO 96/23787, WO 01/04105, WO 00/58292 or Tetrahedron: Asymmetry,1988, 9, 3251-3262.

During any of the steps of preparation of formula (I) compounds or intermediates of formula (II), (III), (IV), (V) or (VI), it may be necessary and/or desirable to protect reactive or sensitive functional groups, such as amine, hydroxyl or carboxy groups, present on any of the molecules concerned. This protection may be achieved by using conventional protective groups, such as those described in Protective Groups in Organic Chemistry, J.F.W. McO, ed. Pressum, 1973, in Protective Groups in Organic Synthesis, T.W. Greene and P.G.M. Wutts, Ed. John Wiley, 1991 or in Georg Wartki, Ed. John P. Thiem, 1994 or in the steps of Vermeeting and Vermix, 1994 or 1994; and the methods of protecting the groups concerned may not be appropriate for the subsequent elimination of the known sound and the sound of the protective groups.

Resolution of racemic mixtures of compounds of formula (I) allows the enantiomers to be isolated.

However, it is preferable to perform the splitting of racemic mixtures from the formula compound (VII, E = H) or from an intermediate compound useful for the preparation of a formula compound (VII), according to the methods described in the previously cited publications for the preparation of a formula compound (VII).

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) The binding of [125I]BH-SP (Substance P labeled 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) The binding of [125I]His-NKA to the human cloned NK2 receptors expressed by CHO cells (Y. Takeda et al., J. Neurochem., 1992, 59, 740-745).3) The binding of [125IHis[MePhe7]BNK to the human cloned 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 of the invention weakly inhibit the binding of substance P to the NK1 receptors of human IM9 lymphocytes. The Ki inhibition constant for human IM9 lymphocytes is greater than or equal to 8.10-9M.

The compounds of the invention strongly inhibit the binding of [125I]His-NKA to human cloned NK2 receptors. The inhibition constant Ki is less than or equal to 5.10-10M. Thus, the compound in Example 1 has a Ki of 4.10-11M.

The compounds of the invention strongly inhibit the binding of [125I]His[MePhe7] NKB to human cloned NK3 receptors: the inhibition constant Ki is less than or equal to 7.10-10M. Thus, the compound in Example 1 has a Ki of 4.10-11M.

The α compound of the previous art inhibits the binding of [125I]His-NKA to cloned NK2 receptors with a Ki equal to 4.10-11M. It inhibits the binding of [125I]His[MePhe7]NKB to human cloned NK3 receptors with a Ki equal to 2.10-9M.

The compounds of the present invention have also been evaluated in vivo in animal models.

In the gerbil, rotational behavior is induced by intrastrial administration of a specific NK2 receptor agonist the [Nle10]NKA(4-10); unilateral application of [Nle10]NKA(4-10) in the gerbil striatum has been shown to lead to strong contralateral rotations which are inhibited by the compounds of the invention administered either intraperiotoneally or orally. This test was performed according to Poncelet et al., Neurosci. Lett., 1993, 149, 40-42. In this test, the compounds of the invention are active at doses ranging from 0.1 mg to 30 mg per kg. For example, the compound in Example 1 has an effective dose (DE 509 mg per kg) of 2.50 mg per kg intrapertoneally and 6.5 mg per kg per kg per oral.

In gerbils, rotational behaviour is induced by intrastral administration of a specific NK3 receptor agonist: senktide; unilateral application of senktide in the gerbil striatum has been shown to lead to strong contralateral rotations which are inhibited by the compounds of the invention administered either intraperiotoneally or orally. This test was performed according to X. Emonds-Alt et al., Life Sci., 1995, 56, PL27-PL32. In this test, the compounds of the invention are active at doses ranging from 0.1 mg to 30 mg per kg. For example, the compound in Example 1 has an DE50 of 2.8 mg per kg intraperiotoneally and an DE50 of 4.3 mg per kg orally.

In rats, the application of an NK2 receptor agonist at the septum level causes an increase in acetylcholine release in the hippocampus (test performed by R. Steinberg et al., Eur. J. Neurosci., 1998, 10, 2337-2345). Similarly in guinea pigs, the topical application of an NK3 receptor agonist at the septum level causes an increase in acetylcholine release in the hippocampus (test performed by N. Marco et al., Neuropeptides, 1998, 32, 481-488). The compounds of the invention block this increase in acetylcholine release either by an NK2 receptor agonist or by an NK3 receptor agonist.

In rats, stress causes an increase in the tissue level of DOPAC (3,4-dihydroxyphenyl acetic acid) in the prefrontal cortex (test performed by B.A. Morrow et al., Eur. J. Pharmacol., 1993, 238, 255-262). This increase is blocked by a specific NK2 receptor antagonist such as saredutant (X. Emonds-Alt et al., Life Sci., 1992, 50, PL101-PL106), and is therefore blocked by activation of NK2 receptors by endogenous neurokinine A. The compound in Example 1 given at 1 mg/kg via the medial intraperitoneal route was found to completely block this increase.

In the test subject, treatment with haloperidol at a dose of 1 mg/kg intraperiotoneally induced an increase in the number of spontaneously active dopaminergic neurons (population response) in the A10 (VTA, ventral tegmental area) region of the brain, as measured in electrophysiology, mediated by activation of NK3 receptors by endogenous neurokinin B (C. Gueudet et al., Synapse, 1999, 33, 71-79).

All of these pharmacological results show that the compounds of the invention, particularly the compound of example 1, are mixed antagonists of the NK2 and NK3 receptors by blocking the pharmacological effects of neurokinine A or neurokinine B, whether they are applied exogenously or induced to be released endogenously.

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, hydroxypropylmethylcellulose, 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 may be used in which the active substance may be in an alcoholic solution, sprays.

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.

In another respect, 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 in which either neurokinine A and/or NK2 receptors, or neurokinine B and/or NK3 receptors, or both neurokinine A and neurokinine B and/or NK2 and NK3 receptors are involved.

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 vessels, disorders caused by non-steroidal anti-inflammatory drugs, inflammatory effects and secretions due to bacterial infections such as Clostridium difficile; inflammatory diseases of the breast such as eczema and inflammatory disorders 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 following are the main types of treatment available in the European Union: 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, stress-related disorders; changes in the permeability of the blood-brain barrier during inflammatory and autoimmune processes in the central nervous system, for example during AIDS-related infections; as a myorelaxant and antispasmodic; in the treatment of nausea and vomiting, for example, acute or delayed nausea and vomiting; as chemotherapy agents used in radiotherapy or in the 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 gastrointestinal diseases such as irritable bowel syndrome, gastric and duodenal ulcers, oesophageal ulcers, diarrhoea, hypersecretions, lymphomas, gastritis, gastro-oesophageal reflux, faecal incontinence, Hirschsprung' s disease; • in the treatment of skin diseases such as psoriasis, pruritus, sunburn, including sunburn; • in the treatment of cardiovascular diseases such as hypertension, oedema, vascular aspects of the blood vessels, migraine thrombosis;• in the treatment of angina pectoris, vascular spasms, vasodilation-related circulatory diseases, Raynaud's disease, fibrosis, collagen diseases, atherosclerosis, preeclampsia; in the treatment of small and large cell lung cancers; breast cancers; brain tumours; adjuvant treatment of urogenital adenocarcinomas; in the prevention of metastases; in demyelinating diseases such as multiple sclerosis or amyotrophic lateral sclerosis; in the treatment of diseases of the immune system or related to the suppression of immune cell function such as rheumatoid arthritis;In the treatment of psoriasis, Crohn's disease, diabetes, lupus, rejection reactions after transplantation;in the treatment of urinary disorders, in particular pollakiuria, stress incontinence, emergency incontinence, postpartum incontinence;in the treatment of reticulosis of the histiocysts and lymphatic tissue;as anorexic;in the treatment of emphysema; in the treatment of Reiter's syndrome; in the treatment of haemorrhoids;in the treatment of eye disorders such as glaucoma, hypertension, myosis, excessive tears;in the treatment or prevention of an attack, epilepsy;in the treatment of head trauma, spinal cord injury or stroke;in the treatment of ischemic heart disease, stroke, stroke, and stroke;in the treatment of ischemic heart disease, stroke and stroke;in particular those caused by pain or stress;in the treatment of sensitive skin and to prevent or combat skin or mucosal irritation, dandruff, erythema or pruritus;in the treatment of neurological skin disorders such as lichen, prurigo, pruritic toxidermia, severe pruritus of neurogenic origin;in the treatment of ulcers and any disease 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 oculatory and/or palpebral angiogenesis and/or dyspnea; or anti-oculatory 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.

The following preparations and examples illustrate the invention without limiting it.

In the Preparations and Examples the following abbreviations are used: DMF: dimethylformamideDMSO: dimethylsulfoxydeDCM: dichloromethaneTHF: tetrahydrofuranethyl chloride: saturated solution of hydrochloric acid in BOP: benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphateF: melting pointTA: ambient temperatureTeb: boiling point and Hlice: 60H silica gel 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. The following are the most common types of singlet: s singlet; se: enlarged singlet; t: triple; qd: quadruple; m: massive: mt: multiple.

The MRI spectra confirm the structures of the compounds.

The Commission shall adopt implementing acts laying down the rules for the application of this Regulation. Preparation of compounds of formula (VI). Preparation of the report 1.1 The following shall be indicated in the table:

- What? - What? (VI) B = -CH2-; - What? - What? A) Methyl ester of 2,3-dichlorobenzoic acid. To a solution of 25.08 g 2,3-dichlorobenzoic acid in 125 ml MeOH, add 6 ml concentrated sulfuric acid and reflux heat overnight. Concentrate the reaction mixture under vacuum, take the residue with water, alkaline by addition of a 10% NaHCO3 solution, extract with ether, wash twice the organic phase with water, dry on Na2SO4 and evaporate the solvent under vacuum. (B) 2,3-dichlorobenzyl alcohol, which is a substance of very high purity. Cool a suspension of 10,56 g of aluminium and lithium hydride in 125 ml of THF to 0 °C.Add, drop by drop, a solution of 25.68 g of the compound obtained in the previous step in 100 ml of THF, raise the temperature to TA and leave to agitate for 2 hours at TA. Dilute the reaction mixture by adding 250 ml of THF and hydrolyze by adding 11 ml of water, 11 ml of NaOH 4N and 33 ml of water. Leave overnight at TA, filter the mineral salts and vacuum concentrate the filtrate. Obtain 21.54 g of the expected product after vacuum drying at 30°C. (C) 2,3-dichlorobenzyl methanesulfonate, which is a chemical compound containing a mixture of methanol and chlorobenzyl. We're cooling a 21 solution in the ice bath.54 g of the compound obtained in the previous step and 18.6 ml of triethylamine in 150 ml of DCM, add, drop by drop, a solution of 10.4 ml of methanesulfonyl chloride in 50 ml of DCM at a temperature below 10°C and stir until the temperature reaches TA. Concentrate under vacuum, extract the residue with ether, wash twice with a buffer solution pH = 2, with a saturated NaCl solution, dry on Na2SO4 and evaporate the solvent under vacuum. (d) 2,3-Dichlorophenyllacetonitrile. A solution of 29,25 g of the compound obtained in the previous step in 200 ml of EtOH and 50 ml of water,10,1 g of 97% potassium cyanide is added and then heated at low temperature for 2 hours. The residue is concentrated under vacuum, extracted at AcOEt, the organic phase washed four times with water, with a saturated NaCl solution, dried at Na2SO4 and the solvent is evaporated under vacuum. The residue is then added to 200 ml of pentane and left to crystallize overnight under stirring. The precipitate is squeezed and dried under vacuum. E) 2-2,3-dichlorophenyl acetic acid

To a 17.17 g solution of the compound obtained in the previous step in 188 ml of EtOH, a 24.23 g solution of KOH is added in 74 ml of water, then heated overnight at reflux. The solution is concentrated under vacuum, the residue is taken back in 100 ml of water, the aqueous phase is washed three times with ether, the aqueous phase is acidified at pH = 1 by adding a concentrated solution of HCl and allowed to crystallize by agitation by cooling in the ice bath. The precipitate formed is exsorted, the lava is washed with water and the vacuum is dried at 40°C. The result is 17.17 g of the expected product.

2. Preparations of compounds of formula (II). Preparation of the report 2.1 2-[4-Benzoyl-2-(3,4-dichlorophenyl) morpholin-2-yl]acetaldehyde, isomer only

- What? - What? (II) B = direct connection; - What? - What? A) Benzoate of 2-[2-(3,4-dichlorophenyl) morpholin-2-yl) ethyl, isomer of levogyre. This compound is prepared in accordance with the procedure described in Preparation 1.1 in WO 00/58292. B) [2-(3,4-dichlorophenyl)-2-(2-hydroxyethyl) morpholin-4-yl](phenyl) methane, single isomer A solution of 4 g of the compound obtained in the previous step and 1.5 ml of triethylamine in 100 ml of DCM is cooled to 0 °C, a solution of 1.41 g of benzoyl chloride in 10 ml of DCM is added drop by drop and stirred for 30 minutes. The reaction mixture is concentrated under vacuum, the residue is extracted from the ether, the organic phase is washed with water, a buffer pH = 2, water, a saturated NaCl solution, dried on Na2SO4 and evaporated under vacuum. The oil residue obtained in 70 ml of 9OH, 2.5 ml of a saturated NaOH solution is taken under vacuum and stirred for 1 hour. The residue is washed three times, the saturated NaOH is removed from the organic solution and the resulting NaCl2 is extracted by dried NaCl2 and so on. C) 2-[4-Benzoyl-2-(3,4-dichlorophenyl) morpholin-2-yl]acetaldehyde, isomer only

A solution of 1.85 g of the compound obtained in the previous step and 2.25 ml of DMSO in 25 ml of DCM is cooled to -60°C under nitrogen atmosphere, 1.38 ml of oxalyl chloride is added by drip and stirred for 2 hours at -60°C. Then 4.42 ml of triethylamine is added and stirred while the temperature is allowed to rise to TA. The reaction mixture is diluted by adding DCM, the organic phase is washed with water, by a 10% solution of Na2CO3, twice with water, by a saturated solution of NaCl, dried on Na2SO4 and the solvent is evaporated under vacuum. 1.7 g of the expected product is obtained.

Preparation of the report 2-[2,3-dichlorobenzoyl)-2- (3,4-dichlorophenyl) morpholin-2-yl]acetaldehyde, isomer only

- What? - What? (II) B = direct connection; - What? - What? A) (2,3-Dichlorophenyl) [2-(3,4-Dichlorophenyl)-2-(2-hydroxyethyl) morpholin-4-yl]methane, isomer only To a solution of 2.5 g of the compound obtained in step A) of Preparation 2.1, 1,2 g of 2,3-dichlorobenzoic acid and 0,75 g of triethylamine in 50 ml of DCM, add 3,3 g of BOP and leave to agitate for 30 minutes at TA. Concentrate under vacuum, extract the residue at AcOEt, wash the organic phase with water, with a buffer solution pH = 2, with water, dry on Na2SO4 and evaporate the solvent under vacuum. Take the residue in 30 ml of MeOH, add 3 ml of a 30% NaOH solution,The solution is then concentrated under vacuum, the residue is extracted with ether, the organic phase is washed with water, the solvent is dried on Na2SO4 and the solvent is evaporated under vacuum. The residue is chromatographed on silica H gel by elevating the DCM/MeOH mixture gradient from (100/0.1 v/v) to (100/1 v/v) to obtain 1.55 g of the expected product. B) 2-[4-(2,3-Dichlorobenzoyl)-2-(3,4-Dichlorophenyl) morpholin-2-yl]acetaldehyde, isomer only Cool to -60°C a solution of 1.5 g of the compound obtained in the previous step and 1.5 g of DMSO in 20 ml of DCM, add 1.25 g of oxalyl chloride by drip and leave to agitate for 1 hour at -60°C.The reaction mixture is extracted from the DCM, the organic phase is washed with a solution of 1N HCl, water, dried on Na2SO4 and the solvent is evaporated under vacuum.

Preparation of the report 2.3 2-[2-(3,4-Dichlorophenyl)-4-[2-(2,6-Dichlorophenyl) acetyl]morpholin-2-yl]acetaldehyde, isomer only

- What? - What? (II) B = -CH2-; - What? - What? A) Benzoate of 2-[2-(3,4-dichlorophenyl) -4-[2-(2,6-dichlorophenyl) acetyl]morpholin-2-yl]ethyl, a single isomer. A 4 g solution of the compound obtained in step A of Preparation 2.1 is cooled to 0°C in 43 ml of DCM, 2,16 g of 2-(2,6-dichlorophenyl) acetic acid is added, then a 3 ml solution of triethylamine in 50 ml of DCM and 4,7 g of BOP is added and then stirred, the temperature is raised to TA.The solution is then dried on Na2SO4 and evaporated in a vacuum, giving 6 g of the expected product. B) 2-(2,6-Dichlorophenyl)-1-[2-(3,4-Dichlorophenyl)-2-(2-hydroxyethyl)morpholin-4-yl]-1-ethanol, isomer only A mixture of 6 g of the compound obtained in the previous step is heated by reflux in 100 ml of MeOH, 3.5 ml of a 30% NaOH solution is added and left to reflux for 1 hour under agitation. The residue is concentrated in a vacuum, taken back into water, extracted in AcOEt, the organic phase washed twice in water by a saturated NaCl solution, dried on Na2SO4 and the solvent evaporated in a vacuum. The residue is chromatographed on silica gel H by eluting in the DCM and then by the gradient of the DCM/MeOH mixture from (100/1; v/v) to (100/3; v/v).We get 2.42 grams of the expected product. C) 2-[2-(3,4-Dichlorophenyl)-4-[2-(2,6-Dichlorophenyl) acetyl]morpholin-2-yl]acetaldehyde, isomer only Cool to -60°C a mixture of 0,6 ml of oxalyl chloride in 11 ml of DCM, add a solution of 1,2 ml of DMSO in 5 ml of DCM, then, drop by drop, a solution of 2,42 g of the compound obtained in the previous step and 1,6 ml of DMSO in 11 ml of DCM and stir for 30 minutes at -50°C. Then add 4,6 ml of triethylamine and stir until the temperature reaches TA. Extract the reaction mixture from the DCM, wash the organic phase with a solution of HCl 2N,The solvent is then dried on Na2SO4 and evaporated under vacuum to obtain 2.24 g of the expected product.

Preparation of the product 2-[2-(3,4-Dichlorophenyl)-4-[2-(2,3-Dichlorophenyl) acetyl]morpholin-2-yl] acetaldehyde, isomer only

A) Benzoate of 2-[2-(3,4-dichlorophenyl) -4-[2-(2,3-dichlorophenyl) acetyl]morpholin-2-yl]ethyl, a single isomer. This compound is prepared in the manner described in step A of preparation 2.3 from 4.9 g of the compound obtained in step A of preparation 2.1 in 52 ml of DCM, 2.67 g of the compound obtained in preparation 1.1, a solution of 3.62 ml of triethylamine in 36 ml of DCM and 5.76 g of BOP, resulting in 7.11 g of the expected product. B) 2-[2,3-Dichlorophenyl)-1-[2-(3,4-Dichlorophenyl)-2-(2-hydroxyethyl)morpholin-4-yl]-1-ethanol, isomer only To a solution of 7.11 g of the compound obtained in the previous step in 100 ml of MeOH, add 5 ml of a 30% NaOH solution and leave to agitate for 1 hour at TA.The residue is concentrated under vacuum, the residue is extracted at AcOEt, the organic phase is washed twice with water, with a saturated NaCl solution, the solvent is dried at Na2SO4 and evaporated under vacuum. C) 2-[2-(3,4-Dichlorophenyl)-4-[2-(2,3-Dichlorophenyl) acetyl]morpholin-2-yl] acetaldehyde, isomer only This compound is prepared in the manner described in step C of Preparation 2.3 from 0,5 ml oxalyl chloride in 10 ml DCM, from a solution of 1,02 ml DMSO in 5 ml DCM,A solution of 2.21 g of the compound obtained in the previous step and 1.43 ml of DMSO in 10 ml of DCM and 4.2 ml of triethylamine yields 2.1 g of the expected product.

Preparations of compounds of formula (III). Preparation of the programme 3.1

The term 'technology' includes the use of techniques to measure the performance of a device. - What? (III) R1 = -CH3 - What? - What? A) 1-Benzyl-4-cyano-4- ((piperidine-1-yl) piperidine. To a solution of 18.6 g of 1-benzylpipperidine-4-one and 12.16 g of pipperidine hydrochloride in 25 ml of MeOH and 25 ml of water, add, drop by drop and at TA, a solution of 5.3 g of sodium cyanide in 20 ml of water and leave to agitate for 48 hours at TA. B) 1-Benzyl-4- ((piperidine-1-yl)piperidine-4-carboxamide. It is not intended to be used in the manufacture of other products. Add 28,3 g of the compound obtained in the previous step to 80 ml of 95% sulphuric acid and heat at 100 °C for 10 minutes.After cooling to TA, the reaction mixture is poured on ice, brought to pH = 7 by adding a 25% solution of NH4OH, extracted from the DCM, washed the organic phase with water, by a saturated solution of NaCl, dried on Na2SO4 and evaporated the solvent in a vacuum. The residue is taken up again in acetone, left to agitate for 2 hours at TA and the precipitate formed is exorcised. The following substances are to be classified in the same category as the active substance: To a suspension of 3,6 g of sodium hydride at 60% in oil in 120 ml of THF, add, drop by drop and at TA,a solution of 9,87 g of the compound obtained in the previous step in 120 ml of THF and heated to 60 °C for 2 hours. After cooling at TA, add a solution of 8,52 g of methyl iodide in 60 ml of DMF, drop by drop, and stir at TA for 4 hours. Pour the reaction mixture over ice, extract with ether, wash the organic phase with water, dry on Na2SO4 and evaporate the solvent under vacuum. Chromatise the residue on silica gel H by separating by the mixture DCM/OH/NH4OH/1 (100/0,1 v/v/v) and: The least polar compound: you get 6 g of N,N-dimethyl-1-benzyl-4- ((piperidine-1-yl) piperidine-4-carboxamide; the most polar compound: 2.6 g of N-methyl-1-benzyl-4- ((piperidine-1-yl) piperidine-4-carboxamide is obtained. A mixture of 5.9 g of the least polar compound obtained in the previous step, 3.4 g of ammonium formate and 1.5 g of palladium on 10% charcoal in 60 ml of MeOH is left to agitate for 3 hours in TA. The catalyst is filtered on Célite® and the filtrate is vacuum concentrated. 1.9 g of the expected product is obtained after vacuum drying at 60 °C.

Preparation of the report Formiate of N-methyl-4- ((pipéridine-1-yl)pipéridine-4-carboxamide

- What? - What? (III), HCOOH: R1 is equal to H. - What? - What?

A mixture of 4 g of the most polar compound obtained at step C of Preparation 3.1 2,43 g of ammonium formate and 1 g of palladium on 10% charcoal in 50 ml of MeOH is left to agitate for 30 minutes in TA. The catalyst is filtered on Célite® and the filtrate is concentrated under vacuum.

The following paragraphs are added: It is a dichlorohydrate of N,N-dimethyl-1-[2-[4-benzoyl-2-(3,4-dichlorophenyl) morpholin-2-yl]ethyl]-4-(pipéridine-1-yl)pipéridine-4-carboxamide, which is a dextrogyre isomer.

- What? - What? (I), 2HCl: R1 = -CH3; B = direct bonding; - What? - What? - What?

To a 0.8 g solution of the compound obtained from Preparation 2.1 in 15 ml of DCM, add 0.6 g of the compound obtained from Preparation 3.1 and then 0.9 g of sodium triacetatoxyborohydride and 8 drops of acetic acid and let agitate overnight at TA. Alkalize the reaction mixture by adding a 10% solution of Na2CO3, extract from DCM, wash the organic phase with water three times, with a saturated solution of NaCl, dry on Na2SO4 and evaporate the solvent under vacuum. Chromatograph the silicon H residue by taking the gradient of the DCM/OHMe mixture from (100/0.5 v/v) to (100/2 v/v); after isolating the product in chlorine and ether, obtain 0.45 g of the etheric product. α $\frac{\text{20}}{\text{D}}$ The temperature of the water is + 14.4° (c = 0.25; MeOH). The following are the values of the measurements:

The following paragraphs shall apply: The chemical is a hydrochloride of N-methyl-1-[2-[4-benzoyl-2-(3,4-dichlorophenyl) morpholin-2-yl]ethyl]-4-(pipéridin-1-yl)pipéridine-4-carboxamide, which is a dextrogyre isomer.

The compound is prepared as described in Example 1 from 0.58 g of the compound obtained in Preparation 2.1, 15 ml of DCM, 0.345 g of the compound obtained in Preparation 3.2, 0.65 g of sodium triacetatoxyborohydride and 8 drops of acetic acid, to obtain 0.6 g of the expected product after crystallization in the pentane/iso ether mixture. α $\frac{\text{20}}{\text{D}}$ The temperature of the water is + 13,6° (c = 0,25; MeOH).

The Commission has It is a dihydrochloride of N,N-dimethyl-1-[2-[4-(2,3-dichlorobenzoyl)-2-(3,4-dichlorophenyl) morpholin-2-yl]ethyl]-4-(pipéridin-1-yl)pipéridin-4-carboxamide, which is a levogyre isomer.

This compound is prepared as described in Example 1 from 0.75 g of the compound obtained in Preparation 2.2, 20 ml of DCM, 0.43 g of the compound obtained in Preparation 3.1, 0.7 g of sodium triacetatoxyborohydride and 8 drops of acetic acid, to obtain 0.8 g of the product expected after crystallization in the DCM/ether mixture. α $\frac{\text{20}}{\text{D}}$ - = 5,4° (c = 0,5 ; MeOH).

The Commission shall adopt implementing acts. It is a dichlorohydrate of N,N-dimethyl-1-[2-[4-(2,6-dichlorophenyl) acetyl]-2-(3,4-dichlorophenyl) morpholin-2-yl]ethyl]-4-(pipéridin-1-yl)pipéridine-4-carboxamide, which is a dextrogyre isomer.

This compound is prepared as described in Example 1 from 0.45 g of the compound obtained in Preparation 2.3, 50 ml of DCM, 0.28 g of the compound obtained in Preparation 3.1, 0.424 g of sodium triacetatoxyborohydride and 3 drops of acetic acid, to obtain 0.419 g of the product expected after crystallization in ether. α $\frac{\text{20}}{\text{D}}$ The temperature of the water is + 7.6° (c = 0.25; MeOH).

The following is the list of active substances which are to be classified in the additive:

This compound is prepared as described in Example 1 from 0.5 g of the compound obtained in Preparation 2.4, 7 ml of DCM, 0.312 g of the compound obtained in Preparation 3.1, 0.47 g of sodium triacetatoxyborohydride and 3 drops of acetic acid, to obtain 0.446 g of the product expected after crystallization in ether. α $\frac{\text{20}}{\text{D}}$ The temperature of the water is +8.8° (c = 0.25; MeOH).

The Commission has It is a dihydrate of N-methyl-1-[2-[4-[2-(2,3-dichlorophenyl) acetyl]-2-(3,4-dichlorophenyl) morpholin-2-yl]ethyl]-4-(pipéridin-1-yl)pipéridine-4-carboxamide, isomer of dextrogyre, dihydrate.

This compound is prepared as described in Example 1 from 0.6 g of the compound obtained in Preparation 2.4, 60 ml of DCM, 0.3 g of the compound obtained in Preparation 3.2, 0.56 g of sodium triacetatoxyborohydride and 3 drops of acetic acid, to obtain 0.556 g of the product expected after crystallization in ether. α $\frac{\text{20}}{\text{D}}$ The temperature of the water is + 8° (c = 0,25; MeOH).

Claims (13)

1. Compound of formula: in which:

   - R₁ represents a hydrogen atom or a methyl radical;

   - B represents a direct bond or a -CH₂- group;

   - Z represents a phenyl, a 2,3-dichlorophenyl or a 2,6-dichlorophenyl;

   and its salts with inorganic or organic acids, its solvates and/or its hydrates.
2. Compound of formula (I) according to Claim 1, in the form of optically pure isomers.
3. Compound according to Claim 1 or 2, chosen from:

   - N,N-dimethyl-1-[2-[4-benzoyl-2-(3,4-dichlorophenyl)morpholin-2-yl]ethyl]-4-(piperidin-1-yl)piperidine-4-carboxamide, dextrorotatory isomer;

   - N-methyl-1-[2-[4-benzoyl-2-(3,4-dichlorophenyl)-morpholin-2-yl]ethyl]-4-(piperidin-1-yl)piperidine-4-carboxamide, dextrorotatory isomer;

   - N,N-dimethyl-1-[2-[4-(2,3-dichlorobenzoyl)-2-(3,4-dichlorophenyl)morpholin-2-yl]ethyl]-4-(piperidin-1-yl)piperidine-4-carboxamide, laevorotatory isomer;

   - N,N-dimethyl-1-[2-[4-(2,6-dichlorophenyl)acetyl]-2-(3,4-dichlorophenyl)-morpholin-2-yl]ethyl]-4-(piperidin-1-yl)piperidine-4-carboxamide, dextrorotatory isomer;

   - N,N-dimethyl-1-[2-[4-[2-(2,3-dichlorophenyl)-acetyl]-2-(3,4-dichlorophenyl)morpholin-2-yl]-ethyl]-4-(piperidin-1-yl)piperidine-4-carboxamide, dextrorotatory isomer;

   - N-methyl-1-[2-[4-[2-(2,3-dichlorophenyl)acetyl]-2-(3,4-dichlorophenyl)morpholin-2-yl]ethyl]-4-(piperidin-1-yl)piperidine-4-carboxamide, dextrorotatory isomer;

   and its salts with inorganic or organic acids, its solvates and/or its hydrates.
4. Compound according to any one of Claims 1 to 3, which is:

   - N,N-dimethyl-1-[2-[4-benzoyl-2-(3,4-dichlorophenyl)morpholin-2-yl]ethyl]-4-(piperidin-1-yl)-piperidine-4-carboxamide, dextrorotatory isomer;

   and its salts with inorganic or organic acids, its solvates and/or its hydrates.
5. Method for preparing the compounds of formula (I) according to Claim 1, their salts, their solvates and/or their hydrates, characterized in that:

   a compound of formula: in which B and Z are as defined for a compound of formula (I) according to Claim 1, is reacted with a compound of formula: in which R₁ is as defined for a compound of formula (I) according to Claim 1, in the presence of an acid, in a solvent, and then the intermediate iminium salt formed is reduced by means of a reducing agent.
6. Method for preparing the compounds of formula (I) according to Claim 1, their salts, their solvates and/or their hydrates, characterized in that:

   a compound of formula:

   in which B and Z are as defined for a compound of formula (I) in Claim 1 and Y represents a methyl, phenyl, tolyl or trifluoromethyl group, is reacted with a compound of formula: in which R₁ is as defined for a compound of formula (I) in Claim 1.
7. Method for preparing the compounds of formula (I) according to Claim 1, their salts, their solvates and/or their hydrates, characterized in that:

   a compound of formula:

   in which R₁ is as defined for a compound of formula (I) according to Claim 1, is reacted with a functional derivative of an acid of formula:         HOOC-B-Z     (VI) in which B and Z are as defined for a compound of formula (I) according to Claim 1.
8. Pharmaceutical composition comprising, as active ingredient, a compound according to any one of Claims 1 to 4 or one of its pharmaceutically acceptable salts, solvates and/or hydrates.
9. Pharmaceutical composition according to Claim 8, containing from 0.1 to 1000 mg of active ingredient in dosage unit form in which the active ingredient is mixed with at least one pharmaceutical excipient.
10. Use of a compound according to any one of Claims 1 to 4 or one of its pharmaceutically acceptable salts, solvates and/or hydrates for the preparation of medicaments intended for treating any pathology where either neurokinin A and/or NK₂ receptors, or neurokinin B and/or NK₃ receptors, or both neurokinin A and neurokinin B and/or NK₂ and NK₃ receptors are involved.
11. Use according to Claim 10, for the preparation of medicaments intended for treating pathologies of the respiratory, gastrointestinal, urinary, immune and cardiovascular system and of the central nervous system as well as pain, migraine, inflammation, nausea and vomiting, and skin diseases.
12. Use according to Claim 11, for preparing medicaments intended for treating chronic obstructive bronchitis, asthma, urinary incontinence, irritable bowel syndrome, Crohn's disease, ulcerative colitis, depression, anxiety, epilepsy, schizophrenia.
13. Medicament characterized in that it comprises a compound according to any one of Claims 1 to 4 or one of its pharmaceutically acceptable salts, solvates and/or hydrates.