EP1119552A1

EP1119552A1 - Ureidopiperidine derivatives as selective human nk 3? receptor antagonists

Info

Publication number: EP1119552A1
Application number: EP99970379A
Authority: EP
Inventors: Alain Aulombard; Xavier Edmonds-Alt; Vincenzo Proietto; Didier Van Broeck
Original assignee: Sanofi Synthelabo SA
Current assignee: Sanofi Aventis France
Priority date: 1998-10-09
Filing date: 1999-10-04
Publication date: 2001-08-01
Also published as: NO20011779L; NO20011779D0; CA2346729A1; FR2784377A1; AR029148A1; TW539669B; HUP0201709A2; NZ510779A; TR200101030T2; WO2000021931A1; AU751592B2; AU5988799A; FR2784377B3; PL347910A1; DZ2905A1; YU26001A; SK4642001A3; CN1329594A; KR20010085903A; CO5180555A1

Abstract

The invention concerns compounds of formula (I) in racemic or optically pure form, methods for obtaining them and pharmaceutical compositions containing same. Said compounds are selective NK3 receptor antagonists.

Description

UREIDOPIPERIDINE DERIVATIVES AS SELECTIVE ANTAGONISTS OF HUMAN NK ₃ RECEPTORS

The subject of the present invention is novel compounds which are selective antagonists of human NK3 receptors for the preparation of medicaments useful in the treatment of psychiatric diseases, diseases of psychosomatic origin, hypertension and in general of any central or peripheral in which neurokinin B and the NK3 receptor are involved in interneuronal regulations, a process for obtaining them and pharmaceutical compositions containing them as active ingredient.

By disease of psychosomatic origin is meant diseases having their origin in the central nervous system and pathological consequences at the peripheral level.

In recent years, a lot of research has been done 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 are classified into three types: NK], NK2, NK3. Substance P (SP) is the endogenous ligand of the NKj receptors, neurokinin A (NK) that of the NK2 receptors and neurokinin B (NKg), that of the NK3 receptors.

The NK], NK2, NK3 receptors have been demonstrated in different species. Thus, the NK3 receptors have been identified in the guinea pig, the rat, the monkey (Br. J. Pharmacol., 1990, 99, 767-773; Neurochem. Int., 1991, 18, 149-165); they have also been demonstrated in humans (FEBS Letters, 1992, 299 (1), 90-95).

A CA review. Maggi et al. takes stock of tachykinin receptors and their antagonists and explains pharmacological studies and applications in human therapy (J. Autonomie Pharmacol., 1993, 3, 23-93).

Patent application EP-A-0 673 928 describes a family of human NK3 receptor antagonist compounds of formula: in which R ^, R ^ and R ^ have different values

More specifically, a selective antagonist, (+) - N- [1- [3- [1- benzoyl-3- (3,4-dichlorophenyl) piperid-3-yl] propyl] -4-phenylpiperid-hydrochloride -yl] -N-methyl acetamide has been described (EP-A-0673 928, Peptides and their antagonists in tissue injury,

Montréal, Canada, 1994, July 31 -August 3 Canadian J Physiol Pharmacol, 1994, 72 (suppl 2), 25, Abst III 0 9, Life Sci, 1994, 56 (1), 27-32, British Pharmacol Society, Canterburry , 1995, April 6-8, Eur J Pharmacol, 1995, 278 (1), 17-25, lst Eur Congress Pharmacol, Milan, 1995, June 16-19) The subject of patent application WO 97/10 211 relates to compounds of formula

in which B, R *, R ^ and Ari have different values These compounds are described as having a very strong affinity for human NK3 receptors We have now found non-peptide compounds which have a very strong affinity for human NK3 receptors and a high specificity for said receptors and good bioavailability when administered orally

In addition, the compounds according to the present invention exhibit good pharmacological activity in animals, clearly superior to that of (+) - N- [1- [3- [1- benzoyl-3- (3,4-dichlorophenyl) piperid-3-yl] propyl] -4-phenylpiperid-4-yl] -N-methyl acetamide

These compounds can be used for the preparation of medicaments useful in the treatment of psychiatric diseases or of psychosomatic origin and of all central or peripheral diseases in which the neurokinin B and the NK3 receptor intervene in interneuronal regulations.

By very strong affinity for human NK3 receptors is meant an affinity characterized by an inhibition constant Ki generally less than 5 10 ⁻⁹ M In ligand binding studies, the inhibition constant Ki is defined by the relationship of Cheng-PrusofT (in Receptor Binding in Drug Research, eds. RA O'BRIEN. Marcel Dekker, New York, 1986): ιc ₅₀

Ki =

Kd [L]: concentration of ligand,

Kd: ligand dissociation constant, IC50: concentration which inhibits 50% of ligand binding. By high specificity for human NK3 receptors, it is meant that the inhibition constant (Ki) for human NK3 receptors is generally at least 100 times lower than the inhibition constant (Ki) for NK2 receptors or that for NKi receptors of different species.

The subject of the present invention is compounds of formula:

in which :

- Ri and R2 each represent independently of one another hydrogen or a (Cι-C ₃ ) alkyl;

- or R] and R2 together with the nitrogen atom to which they are linked constitute a heterocyclic radical chosen from: a pyrrolidin-1-yl, a piperidin-1-yl, a morpholin-4-yl

- or R 1 represents a methyl and R 2 represents a methoxy;

- R3 represents hydrogen or a (Cι -C3) alkyl; as well as their salts with mineral or organic acids and their solvates.

The compounds of formula (I) according to the invention include both optically pure isomers and racemates.

Salts of the compounds of formula (I) can be formed. These salts also include those with mineral or organic acids which allow proper separation or crystallization of the compounds of formula (I), such as picric acid or oxalic acid or an optically active acid, for example a mandelic acid or camphosulfonic, than those which form pharmaceutically acceptable salts, such as the hydrochloride, hydrobromide, sulfate, hydrogen sulfate, dihydrogen phosphate, methanesulfonate, methyl sulfate, maleate, fumarate, succinate, naphthalene-2-sulfonate , glyconate, gluconate, citrate, isethionate, benzenesulfonate, paratoluenesulfonate, benzoate. Pharmaceutically acceptable salts are preferred.

According to the present invention, the compounds of formulas (I) are preferred in which Ri and R2 each independently represent hydrogen or a (Ci -

C3) alkyl. More particularly, the compounds in which R 1 and R 2 each independently represent hydrogen or methyl are preferred. The compounds of formula (I) in which R3 is hydrogen are particularly preferred.

According to the present invention, the optically pure compounds of formula (I) are preferred and very particularly the (+) isomers of configuration (R).

Thus according to one of its aspects, the present invention relates in particular to 1-benzoyl-3- (3,4-dichlorophenyl) -3- [3- [4- (N ', N'-dimethylureido) -4-phenylpiperidin-1 - yl] propyl] piperidine, as well as its salts and solvates. The (+) isomer of this compound being particularly preferred.

1 -benzoyl-3 - (3, 4-dichlorophenyl) -3 - [3 - [4- (N'-methylureido) -4-phenyl piperidin-1-yl] propyl] piperidine and l-benzoyl-3- (3,4-dichlorophenyl) -3- [3- (4-ureido) - 4-phenylpiperidin-1-yl) propyl] piperidine are also preferred, said compounds in the form of (+) isomer being particularly preferred.

The present invention also relates to a process for the preparation of a compound of formula (I), its salts and its solvates. This process is characterized in that: a1) a compound of formula is treated:

in which G represents a methyl, phenyl, tolyl or trifluoromethyl group, with a piperidine derivative of formula:

in which R4 represents a group NR3CONR1 R2 or a group COOH, Rj, R2 and R3 being as defined above for (I); bl) when R4 = COOH the compound thus obtained of formula is transformed:

into a compound of formula (I).

Optionally, the compound thus obtained in step a1) or in step b1) is transformed into one of its salts or solvates.

Step al) of the process according to the invention is carried out in an inert solvent such as N, N-dimethylformamide, acetonitrile, methylene chloride, toluene, isopropanol or a mixture of these solvents and in presence or absence of a base.

When a base is used, it is chosen from organic bases such as triethylamine, N, N-diisopropylethylamine or N-methylmorpholine or from carbonates or bicarbonates of alkali metal such as potassium carbonate, carbonate sodium or sodium bicarbonate. In the absence of a base, the reaction is carried out using an excess of the compound of formula (III) and optionally in the presence of an alkali metal iodide such as potassium iodide or sodium iodide. The reaction is carried out at a temperature between room temperature and 100 ° C.

In step b1), when the compound (III) used in step a1 of the process comprises a carboxy group COOH, the transformation into the ureido group NHCONR1R2 is carried out in a conventional manner by intermediate formation of an isocyanato group -N = C = O on which the appropriate NHR1R2 amine is reacted. Where appropriate, the compound obtained is alkylated with a (Cι -C3) alkyl halide to obtain a compound according to the invention in which R3 = (Cι -C3) alkyl. According to a variant of the process: a2) a compound of formula is treated: in which G is as defined above, and Pr represents a protective group chosen from the trityl, tert-butoxycarbonyl or benzyloxycarbonyl group, with a piperidine derivative of formula:

wherein R4 represents an NR3CONR1R2 group or a COOH group; b2) the protective group Pr is eliminated selectively from the compound thus obtained of formula:

c2) the compound thus obtained of formula is treated

with a benzoyl halide; d2) when the group R4 = COOH, the compound thus obtained of formula is transformed: into a compound of formula (I).

Optionally, the compound thus obtained in step c2) or in step d2) is transformed into one of its salts or solvates.

In step b2) the deprotection can be carried out according to methods known to those skilled in the art, for example in an acid medium.

According to another variant of the process: a3) an alcohol of formula:

b3) the aldehyde thus obtained of formula is treated

with a piperidine derivative of formula

wherein R4 is as defined above; c3) when R4 = COOH the compound thus obtained of formula is transformed into a compound of formula (I).

Optionally, the compound thus obtained in step b3) or in step c3) is transformed into one of its salts or solvates.

According to this last variant of the process, in step a3), the oxidation reaction is carried out using for example oxalyl chloride, dimethylsulfoxide and triethylamine in a solvent such as dichloromethane, at a temperature between -78 ° C and room temperature. In step b3) the compound of formula (III) is reacted in the presence of an acid such as acetic acid, in an alcoholic solvent such as methanol, to form an imine which is chemically reduced in situ, using, for example, sodium cyanoborohydride, or catalytically, using hydrogen and a catalyst such as palladium on carbon or Raney® nickel.

According to a variant of the process: a4) a compound of formula is treated:

in the presence of a base, with an ester of (4-phenylpiperidin-4-ylcarbamic acid, preferably the tert-butyl exter, of formula:

in which R '= (Cι -C6) alkyl; b4) the compound thus obtained of formula is deprotected by the action of an acid; c4) the compound thus obtained of formula:

Cl is treated first with a reactive derivative of carbonic acid, in the presence or absence of a base, then with an amine of formula N 1R2 to obtain the expected compound of formula (I).

Optionally, the compound obtained is transformed into one of its salts or solvates.

In the latter process, it is possible to combine one or more steps. Thus, for example, steps a4) and b4) can be combined in order to directly obtain the compound (XI) from the compound (II). It is also possible to combine all the steps of the process according to the invention, that is to say not to isolate the intermediate compounds of formula (X) and (XI).

In step a4) the base used is chosen from alkali metal hydroxides, such as sodium hydroxide or potassium hydroxide, or from alkali metal carbonates or bicarbonates such as potassium carbonate or bicarbonate potassium. Preferably, potassium carbonate is used.

In step b4), to carry out the deprotection, a strong acid such as hydrochloric acid, trifluoroacetic acid or formic acid is preferably used.

Among the reactive carbonic acid derivatives, 1,1'-carbonyldiimidazole, phosgene or p-nitrophenyl chloroformate are preferred. Particularly preferred is l, l'-carbonyldiimidazole, in which case the reaction is carried out in the absence of base. When phosgene or /? - nitrophenyl chloroformate is used, the reaction is carried out in the presence of an organic base such as N, N-diisopropylethylamine, N-methylmorpholine or preferably triethylamine.

Finally, according to another variant, a 4-phenylpiperidine derivative of the formula is made to act on the compound of formula (II):

(IXbis)

to directly prepare the compound of formula (XI) then proceed according to step c4) to prepare the compound of formula (I).

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

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

By treatment of the free base, dissolved for example in an ether such as diethyl ether or in an alcohol such as propan-2-ol or in acetone or in dichloromethane or in ethyl acetate, with a solution of the acid chosen from one of these solvents, the corresponding salt is obtained which is isolated according to conventional techniques.

Thus, for example, the hydrochloride, hydrobromide, sulphate, hydrogen sulphate, dihydrogenphosphate, methanesulphonate, oxalate, maleate, fumarate, succinate, glyconate, gluconate, citrate, isethionate are prepared. , benzoate, naphthalene-2-sulfonate, benzenesulfonate, paratoluenesulfonate.

At the end of the reaction, the compounds of formula (I) can be isolated in the form of one of their salts, for example the hydrochloride; in this case, if necessary, the free base can be prepared by neutralizing said salt with an inorganic or organic base, such as sodium hydroxide or triethylamine or with an alkali carbonate or bicarbonate, such as carbonate or sodium or potassium bicarbonate. The compounds of formula (II), (IN) and (VII) are obtained by known methods in particular those which are described in patent application EP-A-0 474

561 and EP-A-0 673 928. The piperidines of formula (III) and (IX) are known or prepared according to known methods such as those described in EP-A-673 928 or WO 96/23787. The resolution of the racemic mixtures of the compounds of formula (I) makes it possible to isolate the enantiomers II is however preferable to carry out the resolution of the racemic mixtures from an intermediate compound useful for the preparation of a compound of formula (I) as described in patent applications EP-A-0 474 561, EP-A-0 512 901, EP-A-0 591 040 and EP-A-0 673 928

It is particularly preferable to use as starting material a compound of formula (II), of formula (IV) or of formula (VII) in optically pure form

Thus according to another of its aspects, the present invention relates to a stereospecific process for the preparation of a compound of formula (I) having the configuration (R), of its salts and of its solvates, characterized in that the a compound of formula is used as starting material

in which G is as defined above, in the form of the (+) isomer, and then one proceeds according to step b1) or alternatively according to steps a4) to c4) described above The present invention also has for subject another stereospecific process for the preparation of a compound of formula (I) having the configuration (R), its salts and its solvates, characterized in that an alcohol of formula is used as starting material

in the form of a (+) isomer, and then we proceed according to steps a3) to c3) described above

The present invention also relates to a compound of formula as well as its salts, in racemic form or in optically pure form, as a key intermediate for the preparation of a compound of formula (I) The compounds of formula (I) above also include those in which one or more hydrogen or carbon atoms have been replaced by their radioactive isotope, for example tritium or carbon- 14 Such labeled compounds are useful in research, metabolism or pharmacokinetics, in biochemical tests as ligand of receptors The affinity of the compounds of formula (I) for tachykinin receptors has been evaluated in vitro by several biochemical tests using radioligands

1) The binding of [ ¹²⁵ I] BH-SP (substance P labeled with iodine 125 using the Bolton-Hunter reagent) to the NK] receptors of the rat cortex, the guinea pig ileum and human lymphoblastic cells (DG Payan et al, J Immunol, 1984, 133, 3260-3265)

2 °) The binding [I ^ -> I] His-NK ^ ^to receptors 2 of the rat duodenum or the guinea pig ileum

3 °) The binding [I- ^ I] His [MePhe ^] NKβ to the NK3 receptors of the rat cerebral cortex, the cerebral cortex of the guinea pig and the cerebral cortex of gerbil as well as to the clone receptors NK3 human 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)

The compounds according to the invention strongly inhibit the binding of [I25ηHi _s r] y [ _e pτ ^j [ _e 7-] NK _{β to} the NK3 receptors of the cerebral cortex of guinea pigs and gerbils as well as to human NK3 clone receptors the constant d inhibition Ki is generally less than 5 10 "^ M For the same compounds it has been found that the inhibition constant (Ki) for the NK3 receptors of the rat cerebral cortex is generally greater than 10" ^ M and that the constant d inhibition (Ki) for the rat duodenum NK2 receptor and the rat cortex NK _] receptors is generally greater than or equal to 10 ^" 'M The compounds according to the present invention have also been evaluated in vivo in animal models.

In gerbils, rotational behavior is induced by intrastriatal administration of a specific NK3 receptor agonist. the senktide; it has been found that a unilateral application of senktide in the gerbil striatum leads to strong contralateral rotations which are inhibited by the compounds according to the invention administered either by the intraperitoneal route or by the oral route. In these tests, the compounds according to the invention are active at doses varying from 0.1 mg to 30 mg per kg. This result shows that the compounds according to the invention cross the blood-brain barrier and that they are capable of blocking, at the level of the central nervous system, the action specific to NK3 receptors. They can thus be used for the treatment of any central NKg-dependent pathology, such as psychiatric diseases, or of any pathology mediated centrally by the NK3 receptor, such as psychosomatic diseases. In the guinea pig, the effect on citric acid-induced bronchial response and cough was studied according to the model described by S. Daoui et al. in Am. J. Resp. Crit. Care Med., 1998, 158, 42-48. In this test, the compound of Example 10 showed an activity 10 times greater than that of osanetant.

The compounds of the present invention are generally administered in dosage units. Said dosage units are preferably formulated in pharmaceutical compositions in which the active principle is mixed with a pharmaceutical excipient.

According to another of its aspects, the present invention relates to pharmaceutical compositions containing, as active principle, a compound of formula (I) or one of its pharmaceutically acceptable salts and solvates.

The compounds of formula (I) and their pharmaceutically acceptable salts can be used in daily doses of 0.01 to 100 mg per kilo of body weight of the mammal to be treated, preferably in daily doses of 0.1 to 50 mg / kg . In humans, the dose may preferably vary from 0.5 to 4000 mg per day, more particularly from 2.5 to 1000 mg depending on the age of the subject to be treated or the type of treatment: prophylactic or curative. 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 doctor according to the age, weight and response of said patient. According to another of its aspects, the present invention relates to the use of the compounds of formula (I), or of one of their pharmaceutically acceptable salts and solvates for the preparation of medicaments intended for treating any pathology where neurokinin B and the Human NK3 receptors are involved. The diseases for the treatment of which the compounds and their pharmaceutically acceptable salts can be used, are for example diseases of the central nervous system such as diseases associated with a dysfunction of the dopaminergic systems such as schizophrenia, Parkinson's disease, diseases associated with dysfunction of the noradrenergic and serotonergic systems such as anxiety, panic attacks, disturbances of alertness, mood disorders, in particular depression, as well as epileptic diseases of any form and in particular the Great Evil , dementia, neurodegenerative diseases, and peripheral diseases in which the participation of the central nervous system and / or the peripheral nervous system takes place via neurokinin B acting as a neurotransmitter or neuromodulator such as somatic disorders linked to stress , pain, migra ine, acute or chronic inflammation, cardiovascular disorders in particular hypertension, heart failure, and rhythm disorders, respiratory disorders (asthma, rhinitis, cough, bronchitis, chronic obstructive bronchitis, allergies, hypersensitivity), disorders of the gastrointestinal system such as esophageal ulcer, colitis, gastritis, stress-related disorders, irritable bowel syndrome (IBS), irritable bowel disease (IBD), acid hypersecretion (acidic secretion), emesis / nausea (consecutive to chemotherapy or postoperative, due to motion sickness or vestibular disorders), food allergies, emesis, vomiting, nausea, motion sickness, diarrhea, urinary system disorders (incontinence , neurological bladder), diseases of the immune system (rheumatoid arthritis), and more generally any neurokinin B dependent pathology.

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

When a solid composition is prepared in the form of tablets, a wetting agent such as sodium lauryl sulphate can be added to the active principle, micronized or not, and the whole is mixed with a pharmaceutical vehicle such as silica, gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like. The tablets can be coated with sucrose, various polymers or other suitable materials or else treated so that they have an activity. prolonged or delayed and that they continuously release a predetermined amount of active ingredient.

A preparation in capsules is obtained by mixing the active principle with a diluent such as a glycol or a glycerol ester and by incorporating the mixture obtained in soft or hard capsules. A preparation in the form of a syrup or elixir may contain the active principle together with a sweetener, preferably calorie-free, methylparaben and propylparaben as an antiseptic, as well as a flavoring agent and an appropriate color.

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

Suppositories are used for rectal administration 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 and injectable solutions are used which contain pharmacologically compatible dispersing agents and / or solubilizing agents, for example propylene glycol or butylene glycol.

Thus, to prepare an aqueous solution for intravenous injection one can use a cosolvent such as for example an alcohol such as ethanol or a glycol such as polyethylene glycol or propylene glycol, and a hydrophilic surfactant such as

Tween® 80. To prepare an oily solution for injection by the intramuscular route, the active principle can be dissolved by a triglyceride or a glycerol ester.

For local administration, creams, ointments, gels can be used. For transdermal administration, it is possible to use patches in multilaminate or reservoir form in which the active principle can be in alcoholic solution.

For administration by inhalation, an aerosol containing, for example, sorbitan trioleate or oleic acid as well as trichlorofluoromethane, dichlorofluoromethane, dichlorotetrafluoroethane or any other biologically compatible propellant is used; one can also use a system containing the active principle, alone or associated with an excipient, in powder form. The active principle can also be presented in the form of a complex with a cyclodextrin, for example, α, β, γ, -cyclodestrine, 2-hydroxypropyl-β-cyclodextrin, methyl-β -cyclodextrin.

The active principle can also be formulated in the form of microcapsules or microspheres, optionally with one or more carriers or additives. Among the sustained-release forms useful in the case of chronic treatments, implants can be used. These can be prepared in the form of an oily suspension or in the form of a suspension of microspheres in an isotonic medium.

In each dosage unit the active principle of formula (I) is present in the quantities adapted to the daily doses envisaged. In general each dosage unit is suitably adjusted according to the dosage and the type of administration intended, for example tablets, capsules and the like, sachets, ampoules, syrups and the like, drops so that such a dosage unit contains 0.5 to 1000 mg of active ingredient, preferably 2.5 to 250 mg to be administered one to four times a day.

The above compositions may also contain other active products useful for the desired therapy such as, for example, bronchodilators, antitussives, antihistamines, anti-inflammatories, corticosteroids, antiemetics, chemotherapy agents. Thanks to their very strong affinity for human NK3 receptors and to their high selectivity, the compounds according to the invention can be used, in radiolabelled form as laboratory reagents.

For example, they make it possible to carry out the characterization, identification and localization of the human NK3 receptor in tissue sections, or of the NK3 receptor in the whole animal by autoradiography. The compounds according to the invention also make it possible to carry out the sorting or screening of the molecules according to their affinity for the human NK3 receptor. We then operate by a reaction of displacement of the radiolabelled ligand, object of the present invention of its human NK3 receptor In the Preparations and in the examples the following abbreviations are used

Ether diethyl ether

Iso diisopropyl ether

DMF dimethylformamide

DMSO dimethyl sulfoxide DCM dichloromethane

THF tetrahydrofuran

AcOEt ethyl acetate

Boc tert-butoxycarbonyle

AcOH acetic acid hydrochloric ether saturated solution of hydrochloric acid in ether

BOP benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate

DBU l, 8-diazabicyclo [5 4 0] undec-7-ene buffer pH2 buffer solution marketed by Merck (DARMSTADT) F melting point

Eb boiling point

RT ambient temperature silica H 60H silica gel marketed by Merck (DARMSTADT)

Rotatory power (αj) is measured at 25 ° C NMR nuclear magnetic resonance recorded at 200 MHz in DMSO- d6 δ chemical shift, s singlet, se singlet widened, sd singlet split

, d doublet, t triplet; qd quadruplet, seven septuplet, mt multiplet, m massive Pd / C palladium on carbon

PTSA acid /? r-sulfonic toluenes

LDA lithium disopropylamide

PREPARATION 1 - 4- (N ', N'-dimethylureido) -4-phenylpiperidine toluenesulfonate A) 4-amino-1-benzyl-4-phenylpiperidine dihydrochloride The starting product is 4-acetylamino-1-benzyl-4-phenylpiperidine prepared according to EP-A-0 474 561

30 g of 4-acetylamino-1-benzyl-4-phenyl piperidine and 58 ml of concentrated HCl in 135 ml of water are heated at reflux for 48 hours. The mixture is evaporated and then the medium is taken up in EtOH 100 and toluene and evaporated. again The foam obtained is dissolved in 50 ml of MeOH and then left to crystallize by adding 250 ml of acetone. 20.5 g of the expected compound are obtained.

B)? -L-Benzyl-4- (N ', N'-dimethylureido) -4-phenylpiperidine toluenesulfonate

6 g of the compound obtained in the preceding step and 7.14 g of triethylamine in 50 ml of 1,2-dichloroethane are mixed at RT. 1.9 g of N, N-dimethylcarbamoyl chloride are added dropwise in 10 ml. dichloroethane and heated to reflux for 8 hours. Add a few drops of triethylamine and maintain the reflux for an additional 3 hours. Concentrate under vacuum, extract the residue with DCM, wash the organic phase with water, a 10% NaOH solution, water, a solution. saturated with NaCl, dried over MgSO 4, evaporated and then the residue is chromatographed on silica, eluting with DCM / MeOH from (99/1, v / v) to (96/4, v / v). 1.8 g of expected compound.

C) / 4- (N ', N'-dimethylureido) -4-phenylpiperidine toluenesulfonate

1.8 g of the compound obtained in the preceding step are dissolved in 150 ml of EtOH 95. 1.1 g of? -Toluenesulfonic acid are added, followed by hydrogenation at 40 ° C. under atmospheric pressure in the presence of 1 g of 10% Pd / C. Filter through Celite®, evaporate, take up 2 times in acetone and evaporate. Dissolve in 25 ml of acetone and then precipitate in 200 ml of ether to obtain 1.86 g of the compound. expected as a white solid, F = 120-122 ° C PREPARATION 2

4-phenyl-4- (N'-methylureido) piperidine benzenesulfonate A) 1-Benzyloxycarbonyl-4-phenylpiperidine-4-carboxylic acid

3.77 g of 4-phenylpiperidine-4-carboxylic acid, -toluenesulfonic acid and 1.6 g of sodium hydroxide are dissolved in 40 ml of water and the mixture is cooled in ice 1.70 g of benzyl chloroformate are added to 10 ml of acetone and left to return to RT overnight The aqueous phase is washed 2 times with ether and then acidified to pH = 2 with concentrated HCl. The white solid which precipitates is drained, washed with water, then dry in vacuo and triturate in an ether-pentane mixture (50/50, v / v) to obtain 3.05 g of the expected compound in the form of a white solid, mp = 142-144 ° C.) 1-Benzyloxycarbonyl-4 -isocyanato-4-phenylpiperidine A mixture is prepared containing 50.89 g of the acid prepared in the preceding step and 71.4 g of thionyl chloride in 400 ml of 1,2-dichloroethane and the mixture is brought to reflux until the end of gas evolution. Evaporated in vacuo then taken up in acetone and evaporated again to remove SO2 gas. The oil obtained is dissolved in 200 ml of acetone, cooled to 5 ° C. in ice and then added at this temperature, drop by drop. , 19.5 g of sodium azide in 60 ml of water After 2 hours at RT, the acetone is evaporated and then extracted with toluene and washed with a 5% solution of NaHCθ3, with water, with saturated NaCl solution Dried over Na2Sθ4, then the toluene is evaporated to 30% of the initial volume and brought to reflux for 1 hour. By dry evaporation, an orange oil is obtained which crystallizes to give 54 g of the expected compound.

C) 1 -benzyloxycarbonyl-4- (N'-methylureido) -4-phenylpiperidine

25 g of the compound obtained in the preceding step are dissolved in 300 ml of ether and 300 ml of DCM and cooled in ice then the excess methylamine gas is bubbled into the reaction medium After overnight the medium has partially crystallized Evaporated to dryness, taken up hot in AcOEt and then left to crystallize at RT by adding half a volume of ether. 24 g of the expected compound are obtained in the form of white crystals

D) 4-Phenyl-4- (N'-methylureido) piperidine benzenesulfonate.

23 g of the compound of the preceding step are hydrogenated in the presence of 9.9 g of benzenesulfonic acid, in 300 ml of EtOH 95 with 1 g of Pd / C at 5%, at 40 ° C and under atmospheric pressure. The catalyst is filtered through Celite®, evaporated to dryness and the residue is taken up in acetone. 22.4 g of the expected compound are obtained which crystallizes in the form of a white solid, mp = 227 ° C. PREPARATION 3 4-Phenyl-4-ureidopiperidine benzenesulfonate

This compound is prepared by proceeding according to the procedure described in PREPARATION 2 by replacing, in step C), methylamine gas with ammonia gas, mp = 235 ° C.

PREPARATION 4? -Toluenesulfonate 4- (N ', N'-diethylureido) -4-phenylpiperidine

A) 1-tert-butoxycarbonyl-4-phenylpiperidine-4-carboxylic acid

100 g of 4-phenylpiperidine-4-carboxylic acid, toluene sulfonic acid are placed in 800 ml of dioxane, 150 ml of water and 109.7 g of K2CO3 are added. The mixture is heated to 60 ° C. and then added dropwise. drop 60.7 g of (Boc) 2θ in 100 ml of dioxane. The mixture is left stirring for 4 hours at 60 ° C. and then heated under reflux for 1 hour. It is evaporated to dryness, the solid formed is taken up in water, and acidified to pH = 3 by addition of 2N HCl then ether is added. The crystals formed are filtered, washed with water and then with ether. The ethereal filtrate is evaporated to dryness, the residue is taken up in ether and the crystals formed are filtered which are combined with the crystals already obtained to dry them. 71 g of the expected compound are obtained. B) 4-Isocyanato-4-phenyl-1-tert-butoxycarbonylpiperidine.

25 g of the acid obtained in the previous step are placed in 100 ml of acetone and 10.35 g of triethylamine are added. The mixture is cooled in an ice bath and then 8.7 g of methyl chloroformate are added dropwise. in 30 ml of acetone keeping the temperature below 5 ° C. After 30 minutes with stirring in an ice bath, 10.66 g of sodium azide in 30 ml of water are added dropwise, at a temperature below 5 ° C. and stirring is continued for 30 minutes and then pour over 500 ml of ice water. Extracted 4 times with 130 ml of toluene, the organic phase is washed twice with a buffer pH = 2, with a saturated NaCl solution, and dried over MgSθ4 After filtration, the filtrate is heated to 90 ° C in an oil bath for 1 hour Evaporated to dryness and 18.9 g of the expected compound are obtained.

C) 4- (N ', N'-diethylureido) -4-phenyl- 1 - (tert-butoxycarbonyl) piperidine.

6.05 g of the compound of the preceding step are placed in 50 ml of acetone and 1.16 g of diethylamine in 3 ml of acetone are added dropwise. The mixture is evaporated to dryness and then the residue is taken up in 1 'ether. Washed twice with a pH 2 buffer, with a saturated NaCl solution and then dried over MgSθ4 and evaporated to dryness The residue is taken up in acetone and evaporated to dryness to give 7.2 g of the expected compound.

D) 4- (N ', N'-diethylureido) -4-phenylpiperidine.

7.1 g of the compound from the previous step are dissolved in 100 ml of MeOH and 20 ml of concentrated HCl are added. After stirring overnight at RT, the mixture is evaporated to dryness. The residue is taken up in a 10% NaOH solution and then extracted 3 times with DCM. The organic phase is washed 3 times with a 10% NaOH solution and then with a saturated NaCl solution, dried over MgSθ4 and evaporated to dryness. 5.1 g of the expected compound are obtained.

E) 4- (N ', N'-diethylureido) -4-phenylpiperidine 7-Toluenesulfonate. 5.1 g of the compound of the preceding step are placed in 10 ml of acetone and 3.52 g of -toluenesulfonic acid is added dropwise in 3 ml of acetone. The mixture is evaporated to dryness and then the residue is taken up in AcOEt. 5 ml of MeOH are added to the gum formed. Evaporated to dryness then the residue is taken up in Et2θ and left stirring overnight. Evaporated to dryness then dried in the oven to obtain 7.7 g of the expected compound, mp = 95 ° C. Following the procedure described in PREPARATION 4, the intermediate compounds described in TABLE 1 are prepared below.

TABLE 1

PREPARATION 8

N-methyl-N- (4-phenylpiperidin-4-yl) pyrrolidine-1 -carboxamide.

A) Benzyl ester of 4-phenyl-4- (pyrrolidin-1-ylcarbonylamino) piperidine-1-carboxylic acid.

5 g of the compound obtained in PREPARATION 2, step B are placed in 150 ml of ether and 1.05 g of pyrrolidine, diluted in 25 ml of ether, are added. Diluted with 100 ml of DCM and then stirred for 30 minutes at RT. It is evaporated to dryness and then taken up in ether. The product which is crystallized is filtered to obtain 5.23 g of the expected compound in the form of a white solid.

B) 4-Phenyl-4- (pyrrolidin-1-ylcarbonyl- (N-methyl) amino) piperidine-1-carboxylic acid benzyl ester.

In an ice bath, 2.5 g of the compound obtained in the previous step are dissolved in 10 ml of anhydrous THF, 4.9 ml of 1.5M LDA is added in cyclohexane and the mixture is allowed to return to RT. 0.8 ml of methyl iodide in 1 ml of THF is added dropwise and the mixture is left stirring overnight at RT. Evaporated, extracted with ether, the organic phase is washed with water, with 2N HCl, with water and then with a 5% NaHCO 3 solution, with water and with a saturated NaCl solution, then dries the organic phase on MgS04, filter and evaporate to dryness The oil obtained is chromatographed on silica eluting with DCM and then DCM / CH3CN (98/2, v / v) 1.3 g of the expected compound C) N-methyl-N- (4- phenylpiperidin-4-yl) pyrrolidine- 1 -carboxamide

1.2 g of the compound obtained in the preceding step are dissolved in 25 ml of EtOH and 25 ml of dimethoxyethane, then 0.5 g of 5% Pd / C is added and hydrogenation is carried out at 40 ° C under atmospheric pressure , for 4 hours Filtered on Celite® and then the filtrate is evaporated to dryness to obtain 0.75 g of the expected compound EXAMPLE 1

I, HCl -NR ₃ CONR] R ₂ = -NHCON (CH ₃ ) ₂ In 5 ml of DMF, 3 g of l-benzoyl-3- (3,4-dιchlorophenyl) -3- (3-methanesulfonyloxypropyl) are dissolved piperidine, prepared according to WO 97/10 21 1 2.2 g of K2CO3 are added, followed by 1.897 g of 4- (N ', N'-dimethylureido) -4-phenylpiperidine, compound of PREPARATION 1 released from its salt The reaction medium is heated with stirring for 2 hours at 80 ° C, in a flask surmounted by a CaCl2 guard. It is evaporated to dryness, extracted with DCM and then the organic phase is washed 3 times with saturated NaCl solution. It is dried over MgSθ4 then evaporated and the residue is chromatographed on silica H, eluting with DCM then DCM / methanol (100/2 to 95/5, v / v) The residue is taken up in hydrochloric ether and the precipitate formed is drained. 1.318 g of the compound are obtained expected, F = 165 ° C with decomposition. N NMR (ppm) 1.0 to 2.7. m 12H, 2.7 to 4.5m 16H, 6.25 s 1H,

7.0 to 7.9 m 13H. 10.1 s 1H

By proceeding as in EXAMPLE 1, the compounds according to the invention described in TABLE 2 are prepared by the action of 4-phenyl-4-ureιdoρφéridine in the form of -toluenesulfonate, as obtained in the PREPARATIONS above, on 1- benzoyl-3 - (3, 4-dichlorophenyl) -3 - (3-methanesulfonyloxypropyl) pιperidine, racemic or in the form of (+) isomer, depending on whether one wants to obtain a compound (I) in racemic form or as an (+) isomer

TABLE 2

NMR of EXAMPLE 2 δ (ppm) 0.8 to 2.7 m 18H, 2.7 to 4.4m 14H,

5.8 to 6.2 2s 1H, 7.0 to 7.8m 1H, 10.1 s 1H

NMR of EXAMPLE 3 δ (ppm) 1.5 to 2.8 m 16H, 2.8 to 4.5m 14H,

6.1 s 1H, 7.0 to 7.8 m 1H, 10.1 s 1H

NMR of EXAMPLE 4 δ (ppm) 1.1 to 2.7 m 18H, 2.5 to 4.5m 14H,

6.2 to 6.6 m 1H, 7.0 to 7.8 3s 13H, 10.15 s 1H

NMR of EXAMPLE 5 δ (ppm) 1.1 to 2.8 m 18H, 2.8 to 4.5m 14H,

6.5 s 1H, 7.1 to 7.9 m 1H, 10.0 s 1H

NMR of EXAMPLE 6 δ (ppm) 1.1 to 2.75 m 12H, 2.75 to 4.5m 18H,

6.65 s 1H, 7.05 to 7.8 m 1H, 10.1 s 1H

NMR of EXAMPLE 7 δ (ppm) 1.1 to 4.5 m 33H, 7.0 to 7.8 m 13H,

10.0 to 10.9 2s 1h EXAMPLE 8

I, HCl -NR3CON 1R2 = NHCONH ₂ , (+) isomer A) 1-Benzoyl-3- (3,4-dichlorophenyl) -3- (2-formylethyl) piperidine, (+) isomer

5.24 g of oxalyl chloride in 75 ml of DCM are cooled to -60 ° C. under nitrogen, 8.05 g of DMSO in 10 ml of DCM are added dropwise at -60 ° C. and the mixture is left for 10 minutes. with stirring 13.5 g of 1- benzoyl-3- (3,4-dichlorophenyl) -3- (3-hydroxypropyl) piperidine, (+) isomer, prepared according to EP-, are added dropwise at -60 ° C. A-673 928, in 30 ml of DCM and 10 ml of DMSO After 20 minutes of stirring, 20.8 g of triethylamine are added at -50 ° C. and the mixture is left to return to RT for 1 hour and a half. DCM then the organic phase is washed with 2N HCl, water, a 5% NaHCO 3 solution, a saturated NaCl solution, dried over Na 2 SO 4 and evaporated under vacuum The expected product crystallizes from the pentane / ether mixture, F = 102 -104 ° C α _D = + 36.8 ° (c = 0.5, MeOH) B) Acid 1- [3- [l-benzoyl-3- (3,4-dichlorophenylpiperidin-3-yl] propyl] - 4- phenylpiperidine-4-carboxylic, (+) isomer

2.05 g of 4-phenylpiperidine-4-carboxylic acid and 3.9 g of the compound obtained in the preceding step are mixed in 50 ml of MeOH, at RT, 0.63 g of

NaBH3CN and 5 ml of water then, drop by drop, 0.6 g of AcOH After 2 hours, a white solid crystallizes. The crystals formed are filtered off, washed with methanol and then with ether to obtain 3.8 g of the expected compound, F = 244 ° C α _D = + 28.4 ° (c = 0.5, DCM / MeOH 50/50 , v / v) C) 1-Benzoyl-3- (3,4-dichlorophenyl) -3- [3- (4-isocyanato-4-phenylpiperid-1-yl) propyljpiperidine, isomer (+) One brings to reflux a mixture containing 5.79 g of the compound obtained in the previous step, 4.76 g of thionyl chloride in 100 ml of dichloroethane After 2 hours, there is no more gas evolution, the reaction medium is evaporated and then taken up in acetone and evaporated in vacuo The residue is dissolved in 100 ml of acetone, cooled in ice and then 1.3 g of sodium azide in 15 ml of water are quickly added. After 1 hour at RT, evaporated acetone then taken up in a toluene / DCM mixture The organic phase is washed with 2N NaOH, with saturated NaCl solution, dried over Na2SO4 and the DCM is evaporated at 45 ° C. The mixture is then brought to toluene reflux for 30 minutes. The product obtained is used as is in the next step

D) Gaseous ammonia is bubbled into 100 ml of toluene solution obtained in the previous step, cooled in an ice bath. After a few minutes, allowed to return to RT, then after 2 hours, the solvent is evaporated, taken up in water, then with AcOEt The precipitate which forms between the 2 phases is filtered, then the organic phase is decanted and the organic phase is washed with water, using a 10% K2CO3 solution, with water, with a saturated NaCl solution. Dried over Na2SO4 and evaporated. The gum formed is chromatographed on silica H, eluting with (98/2, v / v) a DCM / MeOH ( 95/5, v / v)

The product obtained is dissolved in acetone, a saturated solution of HCl gas in AcOEt is added and the precipitate formed is filtered off. 1.2 g of the expected compound are obtained in the form of a white solid, F = 192-194 °. C α _D = + 22.8 ° (c - 0.5, MeOH) NMR δ (ppm) 1.0 to 2.6 m 12H, 2.65 to 4.4 m 10H, 5.5 s 2H,

6.8 s 1H, 7.0 to 7.8 m 1H, 9.85 s 1H EXAMPLE 9

I, HCl -NR ₃ CONR] R ₂ = -NHCON (CH ₃ ) OCH ₃ , isomer (+)

This compound is prepared according to the process described in EXAMPLE 8, by reacting in step D, methoxymethylamine hydrochloride on the compound obtained in the previous step, F = 165 ° C α _D = + 22 ° (c = 0.5, MeOH)

N NMR (ppm) 1.0 to 2.7 m 12H, 2.7 to 4.4 m 16H, 7.0 to 7.8 m 13H,

10.35 s 1H EXAMPLE 10

I, HCl -NR3CONR1R2 = -NHCON (CH ₃ ) ₂ , isomer (+)

In 5.4 ml of methanol, 5.4 g of 4- (N ', N'-dimethylureido) -4-phenylpiperidine /? - toluenesulfonate obtained in PREPARATION 1 and 5 g of 1- benzoyl-3- (3) are dissolved. , 4-dichlorophenyl) -3- (2-formylethyl) piperidine, (+) isomer, obtained in EXAMPLE 8, step A 0.7 ml of acetic acid is added and after 5 minutes, 0.8 g is added of NaB ^ CN in 10 ml of methanol and left stirring overnight at RT then the reaction medium is poured into 150 ml of 10% Na2CO3 solution. Extraction with AcOEt, washing the organic phase with water and then dried over MgSθ4 and evaporated The residue is chromatographed on silica H, eluting with DCM then DCM / MeOH (100/1 to 100/7, v / v) The product obtained is taken up in hydrochloric ether and the crystals formed are drained 6.38 g of the expected compound are obtained α _D = + 22.9 ° (c = 1, MeOH)

N NMR (ppm) 1.1 to 2.7 m 12H, 2.7 to 4.4 m 16H, 6.25 s 1H, 7.0 to 7.8 m 13H, 10.4 s 1H Following the procedure of EXAMPLE 10, the compounds according to the invention of configuration (R) described in TABLE 3 are prepared.

TABLE 3

EXAMPLE 11 NMR ppm (ppm) 1.0 to 2.6 m 15H, 2.65 to 4.4 m 10H, 6.0 s 1H, 6.85 s 1H, 7.0 to 7.8 m 13H, 10.15 s 1H NMR of EXAMPLE 12 δ (ppm) 1.0 to 2.7 m 12H, 2.5 to 4.4 m 18H, 6.8 s 1H, 6.9 to 7.75 m 13H, 10 , 4 s 1H EXAMPLE 13 I, HCl -NR ₃ CONRιR ₂ = NHCON (CH ₃ ) ₂ , (-) A isomer l-Benzoyl-3- (3,4-dichlorophenyl) -3- (2-formylethyl) piperidine , isomer (-)

This compound is obtained from l-benzoyl-3- (3,4-dichlorophenyl) -3- (3-hydroxypropyl) piperidine, (-) isomer, by proceeding as in EXAMPLE 8, step A OCD = -35 , 8 ° (c = 0.5, MeOH)

B)

The expected compound is obtained by proceeding as in EXAMPLE 10 α _D = -21.6 ° (c = 0.5, MeOH)

NMR of EXAMPLE 13 δ (ppm) 1.1 to 2.8 m 12H, 2.8 to 4.6m 16H,

6.3 s 1H, 7.1 to 7.9 m 1H, 10.1 s 1H

From the compound obtained in EXAMPLE 13, step A, the compounds according to the invention, of configuration (S) described in TABLE 4 are prepared.

TABLE 4

NMR of EXAMPLE 14 δ (ppm) 1.05 to 2.6 m 12H, 2.6 to 4.4 m 10H,

5.5 s 2H, 6.8 s 1H, 7.0 to 7.8 m 1H. 9.9 s 1H

NMR of EXAMPLE 15 δ (ppm) 1.0 to 2.6 m 15H, 2.75 to 4.4 m 10H,

5.9 s 1H, 6.7 s 1H, 7.0 to 7.8 m 1H, 9.75 s 1H EXAMPLE 16

(I) NR3CONR1R2 = NHCON (CH ₃ ) _2J isomer (+) A)

(X) R ₃ = H, R '= fBu

A mixture containing 300 ml of (+) 1-benzoyl-3- (3,4-dichlorophenyl) - 3- (3-benzenesulfonyloxypropyl) piperidine, prepared according to WO 97/10211, 110 ml of methyl isobutyl ketone and 28.8 is prepared. g of tert-butyhque ester of (4-phenylpipéπdιn-4- yl) carbamic acid then 17.28 g of potassium carbonate and 17 ml of water are added and the mixture is heated at 70 ° C. for 5 hours. cool to 50 ° C. and then 270 ml of water are added and the mixture is allowed to return to RT. The organic phase is decanted, then dried over magnesium sulfate and concentrated. 69.82 g of the expected compound are obtained in the form of a colored oil. yellow HPLC purity 90%

NMR 1.2 ppm s 9H, 1.8-2.4 ppm - m 12H, 2.8-3.6 ppm m 10H,

7-7.6 ppm m 13H B)

(XI) R ₃ = H

61 g of the compound of the preceding step are mixed in solution in 200 ml of toluene and 120 ml of methylisobutyl ketone and then 39 ml of acid are added in 30 minutes hydrochloric The mixture is left to return to RT and then stirred for 1 hour and a half. The aqueous phase is extracted with 200 ml of AcOEt and then 49 ml of NaOH ION is added thereto. It is extracted twice with 200 ml of toluene and then the toluene phase is washed times with 100 ml of water and 20 ml of concentrated HCl are added to it in 100 ml of water The aqueous phase is decanted and 22 ml of NaOH ION is added thereto. Extraction is carried out with 200 ml of dichloromethane, dried over magnesium sulfate. , filter and concentrate 49.4 g of the expected compound are obtained HPLC purity 96%

NMR 0.8-1.6 ppm m ^• 12H, 2-3.6 ppm m 10H, 7-7.6 ppm m 13H

C) A mixture containing 27.5 g of carbonyldiimidazole in 275 ml of is prepared.

DCM, cooled to -5 ° C and then added in 45 minutes, without exceeding 0 ° C, a solution of 44.48 g of the compound of the previous step in 100 ml of DCM After 2 hours with stirring, the following are introduced: -5 ° C, in 20 minutes, 14.57 g of dimethylamine gas. Allow to return to room temperature then add 350 ml of water. Decant the organic phase and wash 3 times with 100 ml of water. magnesium sulfate, filter and concentrate. 53.6 g of the expected compound are obtained in the form of an oil of yellow color HPLC purity 96.2%

EXAMPLE 17

0.93 g of fumaric acid is dissolved in hot in 35 ml of ethanol and this solution is added to 5 g of the compound of Example 16 in 15 ml of ethanol After 15 minutes, the salt precipitates and left stirring for 12 hours at RT The salt formed is filtered and then washed with 10 ml of ethanol It is filtered again and dried under vacuum We obtain 4.87 g of the expected compound HPLC purity 99%

EXAMPLE 18 A solution of 5 g of compound of Example 16 in 10 ml of acetone is mixed with a solution of 0.9 g of succinic acid in 40 ml of acetone. After 12 hours with stirring at RT, it is filtered. the salt formed to obtain 4.87 g of the expected compound Purity

HPLC ^• 98.2%

EXAMPLE 19 A solution of 8.02 g of the compound of Example 16 is mixed in 25 ml of acetone and a solution of 1.57 g of benzoic acid in 15 ml of acetone After 3 hours with stirring at RT, the salt formed is filtered and then dried under vacuum at 50 ° C to obtain 7.48 g of the expected compound HPLC purity 99%

EXAMPLE 20 A solution of 14.8 g of the compound of Example 16 in 30 ml of dichloromethane is prepared and acidified to pH = 1 by addition of a solution of hydrochloric ether. After 30 minutes with stirring at RT, the mixture is concentrated and taken up in 50 ml of isopropyl ether. The salt formed is filtered and then dried under vacuum at 50 ° C to obtain 13.94 g of the expected compound. HPLC purity: 94.5%.

EXAMPLE 21

Compound of Example 16 25 mg

Pregelatinized starch 78 mg

Lactose monohydrate Q.S. Magnesium stearate 1, 7 mg for a capsule 3 filled with 220 mg

EXAMPLE 22

Compound of Example 16 100 mg

Lactose monohydrate Q.S. Magnesium stearate 1, 7 mg

Purified water Q.S. for a capsule no.3 filled to 170 mg

Claims

A compound of formula

in which

- R] and R2 each independently represent hydrogen or a

(Cι-C ₃ ) alkyl,

- or R] and R2 together with the nitrogen atom to which they are linked constitute a heterocyclic radical chosen from a pyrrolidin-1-yl, a piperidin-1-yl, a morpholin-4-yl

- or R] represents a methyl and R2 represents a methoxy,

- R3 represents hydrogen or a (Cj-C3) alkyl, as well as its salts with mineral or organic acids and its solvates

A compound according to claim 1 of formula (I) in which R] and R2 each independently represent hydrogen or methyl

A compound according to any one of claims 1 to 3 of formula (I) in which R3 represents hydrogen

A compound according to any one of claims 2 or 3 in the form of an (+) isomer of configuration (R)

1-Benzoyl-3- (3,4-dichlorophenyl) -3- [3- [4- (N ', N'-dimethylureido) -4- phenylpiperidin-1-] propyl] piperidine, and its salts and solvates

1-Benzoyl-3- (3,4-dichlorophenyl) -3- [3- [4- (N ', N'-dimethylureido) -4- phenylpiperidin-1-] propyl] piperidine, as isomer ( +), and its solvates

A process for the preparation of a compound of formula (I), according to claim 1, of its salts and of its solvates, characterized in that a) a compound of formula is treated in which G represents a methyl, phenyl, tolyl or trifluoromethyl group, with a piperidine derivative of formula:

wherein R4 represents a group NR3CONR1R2 or a group COOH, R \, R2 and R3 being as defined in claim 1; bl) when R4 = COOH the compound thus obtained of formula is transformed:

into a compound of formula (I); cl) optionally converting the compound thus obtained in step a1) or in step b1) into one of its salts or solvates.

A process for the preparation of a compound of formula (I), according to claim 1, of its salts and of its solvates, characterized in that a2) a compound of formula is treated:

in which G is as defined in claim 9, and Pr represents a protective group chosen from the trityl, tert-butoxycarbonyl or benzyloxycarbonyl group, with a piperidine derivative of formula: in which R4 represents a group NR3CONR1R2 or a group COOH, b2) the protective group Pr is eliminated selectively from the compound thus obtained of formula:

c2) the compound thus obtained of formula is treated:

with a benzoyl halide; d2) when the group R4 = COOH the compound thus obtained of formula is transformed:

into a compound of formula (I); e2) optionally the compound thus obtained in step c2) or in step d2) is converted into one of its salts or solvates. A process for the preparation of a compound of formula (I), according to claim 1, of its salts and of its solvates, characterized in that: a3) an alcohol of formula: b3) the aldehyde thus obtained of formula is treated

with a piperidine derivative of formula

wherein R4 is as defined in claim 9; c3) when R4 = COOH the compound thus obtained of formula is transformed

into a compound of formula (I); d3) optionally the compound thus obtained in step b3) or in step c3) is converted into one of its salts or solvates. A process for the preparation of a compound of formula (I) according to claim 1, of its salts and of its solvates, characterized in that: a4) a compound of formula is treated: in the presence of a base, with the tert-butyl ester of (4-phenylpiperidin-4-ylcarbamic acid of formula:

wherein R '= (C] -C6) alkyl; b4) the compound thus obtained of formula

is deprotected by the action of an acid; c4) the compound thus obtained of formula

Cl is treated first with a reactive carbonic acid derivative, in the presence or absence of a base, then with an amine of formula NR R2 to obtain the expected compound of formula (I).

1 1. A process according to claim 7 or 10 for the preparation of a compound of formula (I) having the configuration (R), its salts and its solvates, characterized in that one uses as starting material a compound of formula:

Cl in which G is as defined in claim 7, in the form of the (+) isomer. 12. A process according to claim 9 for the preparation of a compound of formula (I) having the configuration (R), of its salts and of its solvates, characterized in that a starting alcohol is used. formula :

as (+) isomer. 13. A compound of formula:

in racemic form or in optically pure form, as well as its salts. 14. Pharmaceutical composition containing as active ingredient a compound according to any one of claims 1 to 8 or one of its pharmaceutically acceptable salts and solvates. 15 Use of a compound of formula (I) or one of its pharmaceutically acceptable salts and solvates for the preparation of medicaments intended for treat any pathology where neurokinin B and human NK3 receptors are involved. Use according to claim 15 for the preparation of medicaments intended to treat respiratory disorders. Use according to claim 15 for the preparation of medicaments intended to treat diseases of the central nervous system. Use according to claim 15 for the preparation of medicaments intended to treat pain. Use according to claim 15 for the preparation of medicaments intended to treat disorders of the gastrointestinal system.