Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
  • C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
  • C07D211/64—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4 having an aryl radical as the second substituent in position 4
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/04—Centrally acting analgesics, e.g. opioids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D211/56—Nitrogen atoms
  • C07D211/58—Nitrogen atoms attached in position 4
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
  • Y02P20/00—Technologies relating to chemical industry
  • Y02P20/50—Improvements relating to the production of bulk chemicals
  • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

• 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.
• disease of psychosomatic origin diseases having their origin in the central nervous system and pathological consequences at the peripheral level.
• 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 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.
• NK3 receptors have been demonstrated in different species.
• 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).
• 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
• 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.
• NK3 receptors 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): ⁇ c 50
• Kd ligand dissociation constant
• IC50 concentration which inhibits 50% of ligand binding.
• - Ri and R2 each represent independently of one another hydrogen or a (C ⁇ -C 3 ) alkyl
• 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
• R 1 represents a methyl and R 2 represents a methoxy
• R3 represents hydrogen or a (C ⁇ -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.
• Ri and R2 each independently represent hydrogen or a (Ci -
• optically pure compounds of formula (I) are preferred and very particularly the (+) isomers of configuration (R).
• 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.
• 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:
• G represents a methyl, phenyl, tolyl or trifluoromethyl group, with a piperidine derivative of formula:
• 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.
• 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.
• a base 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.
• organic bases such as triethylamine, N, N-diisopropylethylamine or N-methylmorpholine
• carbonates or bicarbonates of alkali metal such as potassium carbonate, carbonate sodium or sodium bicarbonate.
• 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.
• 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:
• R4 represents an NR3CONR1R2 group or a COOH group
• the protective group Pr is eliminated selectively from the compound thus obtained of formula:
• step c2) or in step d2) is transformed into one of its salts or solvates.
• step b2) the deprotection can be carried out according to methods known to those skilled in the art, for example in an acid medium.
• step b3) or in step c3) is transformed into one of its salts or solvates.
• 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.
• 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.
• the compound obtained is transformed into one of its salts or solvates.
• 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).
• 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.
• alkali metal hydroxides such as sodium hydroxide or potassium hydroxide
• alkali metal carbonates or bicarbonates such as potassium carbonate or bicarbonate potassium.
• potassium carbonate is used.
• step b4) to carry out the deprotection, a strong acid such as hydrochloric acid, trifluoroacetic acid or formic acid is preferably used.
• 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.
• 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.
• hydrochloride, hydrobromide, sulphate, hydrogen sulphate, dihydrogenphosphate, methanesulphonate, oxalate, maleate, fumarate, succinate, glyconate, gluconate, citrate, isethionate are prepared.
• benzoate, naphthalene-2-sulfonate, benzenesulfonate, paratoluenesulfonate are prepared.
• 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.
• an inorganic or organic base such as sodium hydroxide or triethylamine
• an alkali carbonate or bicarbonate such as carbonate or sodium or potassium bicarbonate.
• 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
• 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
• 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
• 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
• 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
• the compounds according to the invention strongly inhibit the binding of [I25 ⁇ Hi s r] y [ e p ⁇ j [ e 7-] NK ⁇ 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
• the inhibition constant (Ki) for the NK3 receptors of the rat cerebral cortex is generally greater than 10" ⁇ M
• 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.
• NKg-dependent pathology such as psychiatric diseases
• NK3 receptor such as psychosomatic diseases.
• 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.
• 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.
• 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 .
• 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.
• the appropriate dosage for each patient is determined by the doctor according to the age, weight and response of said patient.
• 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
• 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.
• 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.
• 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.
• aqueous suspensions, isotonic saline solutions or sterile and injectable solutions which contain pharmacologically compatible dispersing agents and / or solubilizing agents, for example propylene glycol or butylene glycol.
• 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.
• creams, ointments, gels can be used.
• transdermal administration it is possible to use patches in multilaminate or reservoir form in which the active principle can be in alcoholic solution.
• 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, ⁇ , ⁇ , ⁇ , -cyclodestrine, 2-hydroxypropyl- ⁇ -cyclodextrin, methyl- ⁇ -cyclodextrin.
• the active principle can also be formulated in the form of microcapsules or microspheres, optionally with one or more carriers or additives.
• 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.
• each dosage unit the active principle of formula (I) is present in the quantities adapted to the daily doses envisaged.
• 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.
• 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.
• Rotatory power ( ⁇ j) is measured at 25 ° C NMR nuclear magnetic resonance recorded at 200 MHz in DMSO- d6 ⁇ chemical shift, s singlet, se singlet widened, sd singlet split
• PREPARATION 1 4- (N ', N'-dimethylureido) -4-phenylpiperidine toluenesulfonate
• the starting product is 4-acetylamino-1-benzyl-4-phenylpiperidine prepared according to EP-A-0 474 561
• 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 NaHC ⁇ 3, with water, with saturated NaCl solution Dried over Na2S ⁇ 4, 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.
• step B 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.
• step A the compounds according to the invention, of configuration (S) described in TABLE 4 are prepared.
• 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.
• 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
• 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%

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