FR2999179A1 - PROCESS FOR THE SYNTHESIS OF A SALT FOR ADDITION TO A PHARMACEUTICALLY ACCEPTABLE ACID OF 4- {3- [CIS-HEXAHYDROCYCLOPENTA [C] PYRROL-2 (1H) -YL] PROPOXY} BENZAMIDE, AND ASSOCIATED CRYSTALLINE FORMS - Google Patents

Abstract

Process for the industrial synthesis of a pharmaceutically acceptable acid addition salt of 4- {3- [cis-hexahydrocyclopenta [c] pyrrol-2 (1H) -yl] propoxy} benzamide of formula (I): wherein HX represents a pharmaceutically acceptable acid, as well as the associated crystalline forms.

Description

The present invention relates to a process for the industrial synthesis of a pharmaceutically acceptable acid addition salt of 4- {3- [cis-hexahydrocyclopentarcipyrrol-2 (111) -ylpropoxylbenzamide of formula (I):, HX ( 1) in which FIX represents a pharmaceutically acceptable acid.

4- {3- [cis-Hexahydrocyclopentarelpyrrol-2 (1R) -yl} propoxy} benzamide has the particularity of interacting with central histaminergic systems in vivo. These properties give it an activity in the central nervous system and more particularly in the treatment of cognitive deficits associated with cerebral aging and neurodegenerative diseases.

4- {3- [cis-Hexahydrocyclopentalc] pyrrol-2 (1H) -ylpropoxy} benzamide, its preparation in oxalate form and its therapeutic use have been described in patent application WO2005 / 089747. Given the pharmaceutical interest of this compound, it was important to be able to access it with a high-performance synthesis process, easily transferable on an industrial scale, leading to a pharmaceutically acceptable acid addition salt of 4- ( 3- [cis-hexahydrocyclopenta [c] pyrrol-2 (1R) -yl] propoxy} benzamide with good yield and excellent purity Patent application WO2005 / 089747 describes the access to 443- [cishexahydrocyclopenta] oxalate [c] pyrrol-2 (11-1) -ylbropoxylbenzamide in three steps from 4-hydroxybenzonitrile, which undergoes an O-alkylation reaction before being coupled to an octahydrocyclopenta [c] pyrrole ring to form the 4-hydroxybenzonitrile - {3- [cishexahydrocyclopentaMpyrrol-2 (111) -ylipropoxylbenzonitrile This latter compound is finally subjected to basic hydrolysis to give 4- {3-vis-2-hexahydrocyclopenta [c] pyrrol-2 (1H) -yl] propoxybenzamide, which is crystallized as oxalate. three stages is 46.6%. The present invention relates to a novel process of industrial synthesis which results in a pharmaceutically acceptable acid addition salt of 4- {3-cis-hexahydrocyclopenta [c] pyrrol-2 (1H) -ylpropoxy} benzamide with a satisfactory purity on the pharmaceutical plan and an efficient performance at the industrial level. Thanks to this process, it is possible to guarantee a very low level of genotoxic impurities, compatible with the regulatory requirements. More specifically, the present invention relates to a process for the industrial synthesis of the compound of formula (I): 1-1 (= N 0, HX (I) H, characterized in that a compound of formula (II) is subjected to NH 2 R 2 NH 2 in which R 'and R "independently of one another represent a (C 1 -C 6) -alkyl group, or R' and R" together form a - (CH 2) - group - where n = 2-3, or one of the groups R 'or R "represents a hydrogen atom and the other a (C1-C6) alkyl group, or a compound of formula (III): H NI-12 ° 1 o to a reductive amination in the presence of a reducing agent, a stoichiometric amount of a pharmaceutically acceptable acid HX and bicyclic amine of formula (IV): NH to conduct in a single step after isolation, to the addition salt of 4- {3,4c-hexahydrocyclopentarcipyrrol-2 (1H) -yl] propoxy} benzamide with HX acid In another embodiment of the invention, the process for the industrial synthesis of the composed of formula (I): HH is characterized by subjecting: - a compound of formula (II):, HX (I) ## STR1 ## wherein R 'and R "independently of one another represent a (C1-C6) alkyl group, or R 'and R" together form a - (CH2) 1- group where n = 2-3, or one of groups R 'or R "represents a hydrogen atom and the other a (C1-C6) alkyl group, or a compound of formula (III): HN H2 at a reductive amination in the presence of a reducing agent , and a pharmaceutically acceptable acid addition salt HX of the bicyclic amine of formula (IV '): NH, FiX (IV') for conducting in a single step, after isolation, to the addition salt of the 4- {3-Pishexahydrocyclopenta [c] pyrrol-2 (1R) -yl] propoxy} benzamide with HX acid.

Among the pharmaceutically acceptable acids HX, there may be mentioned, without limitation, hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, trifluoroacetic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, tartaric, maleic, nitric, citric, ascorbic, oxalic, methanesulfonic, benzenesulfonic, paratoluenesulfonic, benzoic, adipic, hippuric and camphoric.

More preferentially, the pharmaceutically acceptable acids HX are chosen from the following group: hydrochloric acid, benzenesulphonic acid, methanesulphonic acid, benzoic acid, fumaric acid, adipic acid, sulfuric acid, para-toluenesulphonic acid, citric acid, hippuric acid, maleic acid, malonic acid, tartaric acid, succinic acid, glutaric acid and oxalic acid. Even more preferably, the pharmaceutically acceptable acids HX are selected from the following group: hydrochloric acid, benzenesulfonic acid, methanesulfonic acid, benzoic acid, fumaric acid, adipic acid and sulfuric acid.

Even more particularly, the process using hydrochloric acid is preferred, thus resulting in 4- {3- {cis-hexahydrocyclopenta [c] pyrrol-2 (11H) -ylpropoxylbenzamide hydrochloride of formula (Ta): HCl (Ta) The preferred compound of formula (II) is 4- (3,3-diethoxypropoxy) benzamide. The reducing agent used is either a hydride or hydrogen gas.

The reductive amination reaction is preferably carried out by hydrogenation in the presence of a metal catalyst, and more preferably still in the presence of palladium. The preferred solvents for the hydrogenation are water, dichloromethane, ethanol and ethyl acetate, alone or as a mixture. More preferably, the solvent used is a water / dichloromethane / ethanol mixture or a water / dichloromethane / ethyl acetate mixture. Alternatively, the compound of formula (I) obtained according to the process of the invention can be subjected to the action of a base to yield free 4- {3-Icishexahydrocyclopentarclpyrrol-2 (1H) -yllpropoxy} benzamide . The process of the invention provides direct access to the addition salts of 4- (cis-hexahydrocyclopenta [cipyrrol-2 (1H) -yl] propoxy} benzamide, and in particular to its hydrochloride, in a single unit. step from the amine of formula (IV) or a salt thereof of formula (IV '), with excellent purity and very good yield. The pharmacological study of the compounds of formula (I) has shown an important activity on the central nervous system which makes it possible to establish its utility in the treatment of cognitive and psycho-behavioral disorders associated with cerebral aging and neurodegenerative diseases, as well as in the treatment mood disorders, attention deficit hyperactivity syndrome, obesity and pain. The neurodegenerative diseases most specifically targeted are Alzheimer's disease, Parkinson's disease, Pick's disease, Korsakoff's disease, Lewy body dementia, frontal and subcortical dementia, frontotemporal dementia, and dementia. vascular. The addition salts with a pharmaceutically acceptable acid of 4-13- {cishexahydrocyclopenta [c] pyrrol-2 (1H) -yl] propoxylbenzamide of formula (I) obtained according to the process described above form an integral part of the invention. The invention relates to the new salts of formula (I) with the exception of addition salts with hydrochloric acid and oxalic acid. Even more particularly, the invention relates to the addition salts with a pharmaceutically acceptable acid of 4- {3-Pis-hexahydrocyclopentarclpyrrol2 (11 /) - ylpropoxy} benzamide of formula (I) chosen from the following group: benzenesulphonic acid, acid methanesulfonic acid, benzoic acid, fumaric acid, citric acid, adipic acid and sulfuric acid, and more preferably benzenesulfonic acid, benzoic acid and adipic acid. The invention also extends to the crystalline forms of the salts according to the invention which are described below. The crystalline forms of 4- {3- [cis-hexahydrocyclopenta [c] pyrrol-2 (1H) -yl] propoxy} benzamide salts can be obtained directly by the process of the invention, or from 4-3 Free [cis-hexahydrocyclopenta [cipyrrol-2 (11H) -yl] propoxy} benzamide synthesized by any method, which is then salified and crystallized under the conditions detailed in the examples below. The crystalline form (I) of 4- {3- [cishexahydrocyclopenta [c] pyrrol-2 (111) -yl] propoxylbenzamide benzenesulphonate (besylate) is characterized by a powder X-ray diffraction pattern showing the diffraction lines. following (Bragg angle 2 theta, expressed in degrees ± 0.2 °): 11.73 °; 12.63 °; 14.84 °; 15.14 °; 15,700; 15.88 °; 16.38 °; 17.890; 18.11 °; 19.50 °; 21.54 °; 22.45 °; 23.21 °. The crystalline form (I) of 4- {3- [cishexahydrocyclopenta [c] pyrrol-2 (1H) -yl] propoxy} benzamide methanesulfonate (mesylate) is characterized by a powder X-ray diffraction pattern showing the following diffraction lines (Bragg angle 2 theta, expressed in degrees ± 0.2 °): 8.12 °; 10.17 °; 13.81 °; 15.51 °; 18.01 °; 18.71 °; 19.15 °; 21.02 °; 21.33 °; 22.49 °. The crystalline form (I) of 4- {3- [cis-hexahydrocyclopenta [c] pyrrol-2 (111) -yl] propoxylbenzamide benzoate is characterized by a powder X-ray diffraction pattern having the following diffraction lines ( Bragg 2 theta, expressed in degrees + 0.2 °): 11.58 °; 12.43 °; 13.68 °; 15.98 °; 16.73 °; 17.83 °; 18.12 °; 18.69 °; 18.91 °; 19.53 °; 20.16 °; 23.12 °. The crystalline form (I) of 4- {3,4cis-hexahydrocyclopenta [c] pyiTol2 (11 /) - yl} propoxy} benzamide hemi-fumarate is characterized by a powder X-ray diffraction pattern having the following diffraction lines ( Bragg 2 theta, expressed in degrees + 0.2 °): 11.76 °; 16.5 °; 19.68 °; 19.98 °; 20.86 °; 21.29 °; 22.75 °; 24.77 °.

The crystalline form (I) of 4- {3,4cis-hexahydrocyclopentarclpyrrol-2 (1/1) -ylpropoxy} benzamide citrate is characterized by a powder X-ray diffraction pattern having the following diffraction lines (Bragg 2 theta angle, expressed in degrees + 0.2 °): 14.03 °; 17.84 °; 18.50 °; 18.93 °; 19.23 °; 20.93 °; 22.07 °; 24.30 °.

The crystalline form (I) of 4- {3- [cis-hexahydrocyclopenta [c] pyrrol-2 (111) -yl] propoxylbenzamide adipate is characterized by a powder X-ray diffraction pattern having the following diffraction lines ( Bragg angle 2 theta, expressed in degrees + 0.2 °): 6.56 °; 13.25 °; 13.75 °; 17.60 °; 18.39 °; 23.58 °; 26.34 °; 28.27 °. The crystalline form (I) of 4- {3- [cis-hexahydrocyclopenta [c] pyrrol-2 (1H) -yl} propoxylbenzamide sulfate is characterized by a powder X-ray diffraction pattern showing the following diffraction lines (Bragg angle 2 theta, expressed in degrees ± 0.2 °): 7.37 °; 8.66 °; 13.57 °; 15.71 °; 16 °; 16.84 °; 17.1 °; 17.37 °; 17.56 °; 20.29 °; 20.72 '; 25.3 °; 26.45 °. The crystalline form (I) of 4- {3-cis-hexahydrocyclopenta [c] pyrrol2 (11β) -propanolbenzamide hemisulfate according to claim 8 characterized by a powder X-ray diffraction pattern having the following diffraction lines (Bragg angle 2 theta, expressed in degrees ± 0.2 °): 7.98 °; 9.12 °; 12.33 °; 14.54 °; 15.24 °; 16.33 °; 16.45 °; 16.93 °; 17.05 °; 17.18 °; 17.81 °; 18.83 °; 19.26 °; 22.44 °; 22.58 °; 22.96 °; 24.68 °; 25.00 '; 25.91 °; 27.67 °. The use of the crystalline forms presented above is well suited to the preparation of pharmaceutical formulations having a constant and reproducible composition, which is particularly advantageous when these formulations are intended for oral administration. In addition, these crystalline forms of various addition salts of 4- (3- [cis-hexahydrocyclopenta [c] pyrrol-2 (111) -ylpropoxylbenzamide with a phantomaceutically acceptable acid have remarkable instant solubility properties. The above-mentioned crystalline crystals are sufficiently stable to allow their prolonged storage without particular conditions of temperature, light, humidity or oxygen levels.Furthermore, these crystalline forms of various addition salts with a pharmaceutically acceptable acid of 4- {3,4cisr-hexahydrocyclopentakipyrrol2 (1H) -yllpropoxy} benzamide have been found to be very stable over periods of up to 6 months under the following conditions: - at 40 ° C with 75% moisture content in open bottle at 50 ° C. with an ambient moisture content in an open bottle The invention also extends to pharmaceutical compositions containing, as active principle, a compound of form Ule (I) described above, with one or more inert, non-toxic and suitable excipients. Among the pharmaceutical compositions according to the invention, mention may be made more particularly of those which are suitable for oral, parenteral (intravenous or subcutaneous), nasal administration, single or coated tablets, granules, sublingual tablets, capsules, tablets, suppositories, creams, ointments, skin gels, injectables, oral suspensions and chewables. The useful dosage is adaptable according to the nature and severity of the condition, the route of administration and the age and weight of the patient. This dosage ranges from 0.01 mg to 100 mg daily in one or more doses. Preferably, the compound of formula (1) is administered at daily doses (expressed in base equivalent) of 2 mg, 5 mg and 20 mg. The examples below illustrate the invention. Preparation 1: cis-Octahydrocyclopenta [c] pyrrole Step A: Tetrahydrocyclopenta [elpyrrole-J, 3 (211,3aH) -dione In an autoclave, load 1 kg of diethyl 1,2-cyclopentanedicarboxylate and 1.02 kg of ammonia at 27%. The reaction mixture is heated in an autoclave for a minimum of 4 hours at a temperature of 130 ° C. After cooling and decompression at 60 ° C, the solvent is evaporated. The residue is then pyrolyzed at 280 ° C for 1 hour. The imide is purified by vacuum distillation (4-12 mbar) at a temperature of 200 ° C. After isolation, the title product is obtained with a yield of 96%. Melting point: 89 ° C Stage B cis-Oetahydroeyelopenta [c] pyrrole 1 kg of imide of Stage A, 250 g of copper chromite and 2 L of dioxane are charged to a reactor. The reaction mixture is stirred until complete absorption of hydrogen at a temperature of 265 ° C and a hydrogen pressure of 205 bar. After cooling the reactor, the catalyst is filtered. The hydrogenation juices are charged by decanter, then 0.37 L of water is added. The p1-1 is adjusted to a pH of less than 3 by addition of 96% sulfuric acid. The lower aqueous phase is withdrawn. After the addition of 2.5 L of water, the residual dioxane is removed by azeotropic distillation with a refractive index tracking. The pH is then adjusted to 113 by adding 30% sodium hydroxide solution. The title product is purified by azeotropic distillation with water to obtain a 30% by weight solution with a yield of 83%.

Preparation 2: 4- (3,3-Diethoxypropoxy) benzamide 500 mg of 4-hydroxybenzamide, 1.51 g of potassium carbonate, 10 ml of DMF and 730 mg of 3-chloro-1,1 are added to a flask -diéthoxypropane. The reaction medium is stirred at 100 ° C. for 18 h, then 5 ml of water are added thereto. The aqueous phase is extracted with ethyl acetate and the organic phases are then combined and washed with water. and concentrated under reduced pressure. The product is obtained in the form of a powder with a yield of 89% and a chemical purity of 95%. Melting point: 108 ° C. EXAMPLE 1 4- {3-Fris-hexahydro-yelopenta [c] pyrrol-2 (11 H) -propyl-benzamide hydrochloride In an autoclave, 8 g of 4- (3,3-diethoxypropoxy) are successively charged. ) benzamide, 1.6 g of 5% Pd / C (50% wet), 13.5 g of 30% cis-octahydrocyclopenta [c] pyrrole aqueous solution, 17 mL of demineralized water, 50 mL of dichloromethane 50 ml of ethanol and 3 ml of a concentrated solution of 12N hydrochloric acid. The reaction medium is brought to 40 ° C. and then stirred for 26 hours under a hydrogen pressure of 30 bar. After cooling the reaction medium, 190 ml of isopropanol are added. The solution obtained is stirred for 5 minutes and then filtered on Celite®. The filtrate is concentrated under reduced pressure and the crude obtained is recrystallized from an isopropanol / water mixture to yield the expected product in the form of a white solid with a yield of 65% and a chemical purity of 99%.

The crystalline form of the compound thus obtained is characterized by the X-ray powder diffraction pattern below, measured using a PANalytical X'Pert Pro MPD diffractometer with an X'Celerator detector, and expressed in terms of position of line (Bragg angle 2 theta, expressed in degrees ± 0.2 °) and inter-reticular distance d (expressed in A): Ray n ° Angle 2-theta Inter-(degrees) reticular distance (Â) 1 16, 97 5,219 2 17,84 4,967 3 18,90 4,690 4 20,32 4,366 5 23,87 3,724 6 27,10 3,288 7 27,86 3,200 8 30,34 2,943 Example 2: Other salts of 4-131eis-hexahydroeyelopenta ielpyrrol- 2 (1H) -propylmenzamide The procedure described in Example 1 was repeated for various pharmaceutically acceptable acids. The amount of 4- {3,4cis-hexahydrocyclopenta [c] pyrrol-2 (1H) -yl] propoxylbenzamide obtained in the reaction medium (corresponding to a conversion of the reactants to the final product) was determined by HPLC (N100) after the step filtration, prior to the concentration of the filtrate under reduced pressure and the isolation of the salt.

The conversion levels obtained for the pharmaceutically acceptable acids according to the invention are greater than 30%. More particularly, the conversion ratios corresponding to benzenesulphonic acid, methanesulphonic acid, benzoic acid, fumaric acid, adipic acid and sulfuric acid are collated in the following table: Table 1: Conversion into the reaction medium salt Conversion rate (in%) hydrochloride 93 besylate 90 mesylate 82 benzoate 65 hemi-fumarate 77 adipate 79 sulfate 58 hemi-sulfate 72 Certain crystalline forms of the salts described above have been characterized by a powder X-ray diffraction pattern. The data was recorded on a PANalytical X'Pert Pro MPD diffractometer with an XCelerator detector under the following conditions: Voltage 45 I (V, current 40 mA, theta / theta mount, anode: copper, - wavelength K alpha-1: 1.54060 Wavelength K alpha-2: 1.54443 A, K ratio K alpha-2 / K alpha-1: 0.5 - Metering mode: continuous from 30 to 550 (Bragg angle 2 theta) with an ineration of 0.0170, Measuring time per step: 35.53 to 142.12 s.

The X-ray powder diffraction patterns thus obtained are expressed in terms of line position (Bragg 2 theta angle, expressed in degrees ± 0.2 °), inter-reticular distance d (expressed in A) and relative intensity. (expressed as a percentage of the most intense line). Significant lines were collected in the tables presented in the examples below. EXAMPLE 3 4- (3-cis -hexahydroeyelopentalcipyrrol-2 (111) -ylpropoxylbenzamide hydrochloride In an autoclave, 132 mg of cisoctahydrocyclopentarcipyrrole hydrochloride, 1 ml of demineralised water, 200 mg of 4- ( 3,3-diethoxypropoxy) benzamide, 20 mg of Pd / C (50% wetted) and 5 ml of dichloromethane The reaction medium is brought to 40 ° C. and then stirred for 17h30 under a hydrogen pressure of 30 bar. 5 mL of methanol are added to the reaction medium.Analysis of the reaction medium by HPLC (N100) reveals the presence of 50% of the expected product: EXAMPLE 4 Crystalline form I of benzenesulfate (besylate) 4- {3-Fris-hexahydrocyclopenta [e] pyrrol-2 (11 H) -yl] pronoxylbenzamide 3.02 g of 4- (3,4-cis -hexahydrocyclopenta [c] pyrrol-2 (1H) -yl] propoxy} benzamide and 1.49 g. 1 g of benzenesulphonic acid are introduced into a flask containing 240 ml of refluxing dichloromethane. x for 1 hour with magnetic stirring and then allowed to cool to room temperature. The suspension is then stirred at room temperature overnight. The solid is isolated by filtration and then dried under vacuum (10 mbar) at 40 ° C for 12 hours. Line No. Angle 2-theta Inter-distance Intensity (degrees) reticular (A) relative (%) 1 11.73 7.537 49.3 2 12.63 7.002 11.0 3 14.84 5.963 16.7 4 15.14 5.848 13 5 15.70 5.641 12.1 6 15.88 5.576 8.5 7 16.38 5.406 17.4 17.89 4.953 34.2 9 18.11 4.894 28 19.50 4.547 13.2 11 21.54 4.123 43 12 22.45 3.957 16.3 13 23.21 3.829 100 - 15 - Example 5: Crystalline form I of 4- {3-cis-hexahydrocyclopenta [c] pyrrol methanesulfonate (mesylate) -2- (1H) -yllpropoxy} benzamide 2.97 g of 4- {3,4-cis-hexahydrocyclopenta [c] pyrrol-2 (1H) -yl] propoxy} benzamide and 275 ml of acetone are refluxed in a flask. 768 ml of methanesulfonic acid are introduced. The reaction mixture is refluxed for 1 hour with magnetic stirring and then allowed to cool to room temperature. The suspension is then stirred at room temperature overnight. The solid is isolated by filtration and then dried under vacuum (10 mbar) at 40 ° C for 12 hours. Line 2-theta angle Inter-distance Intensity (degrees) reticular (Â) relative (%) 1 8.12 10.876 32.4 2 10.17 8.691 16.3 3 13.81 6.406 18.7 4 15.51 5.707 12.8 5 18.01 4.922 12.7 6 18.71 4.738 47.4 7 19.15 4.631 13.1 8 21.02 4.224 15.6 9 21.33 4.162 23.5 22.49 3.951 100 Example 6: Crystalline Form I of 4-13- [eis-hexahydrocyclopentalc] pyrrol-2 (11 /) - ylpropoxybenzamide benzoate 3.08 g of 4- {34cis hexahydrocycopentapipyrroth-2 (1M-yl) propoxylbenzamide are introduced into a flask containing 300 ml of ethyl acetate, the suspension is bristled at reflux and then 1.43 g of benzoic acid are added. refluxing for 1 hour under magnetic stirring, then allowed to cool to room temperature, the suspension is then stirred at room temperature overnight, the solid is isolated by filtration, and is then dried under vacuum (10 mbar) at 40.degree. 12 o'clock Line No. Angle 2-theta Inter-Intensity Distance (degrees) reticular (Δ) relative (%) 1 11.58 7.636 21.7 2 12.43 7.117 20.9 3 13.68 6.467 20.1 4 15.98 5.543 25.3 5 16.73 5.296 26.3 6 17.83 4.970 29.9 7 18.12 4.892 68.7 8 18.69 4.744 17.7 9 18.91 4.689 13.9 19.53 4.542 47.9 11 20.16 4.400 100 12 23.12 3.845 92.3 Example 7: Crystalline form I of 4- {3- [cis-hexahydrocyclopenta [c] pyrrol-2 (11) -ylpropoxylbenzamide hemi-fumarate 4.05 g of 4- 3- [cis-hexahydrocyclopenta [c] pyrrolo-2 (11H) -ylpropoxy} benzamide and 727 mg of fumaric acid are introduced into a flask containing 50 mL of anhydrous ethanol under reflux. The suspension is refluxed for 5 hours under magnetic stirring and then allowed to cool to room temperature. The suspension is then stirred at room temperature overnight. The solid is isolated by filtration and then dried under vacuum (10 mbar) at 40 ° C for 12 hours. Line No. Angle 2-theta Inter-distance Intensity (degrees) reticular (Â) relative ((%) 1 11.76 7.519 9.6 2 16.5 5.369 100 3 19.68 4.507 10.2 4 19.98 4.441 12.5 20.86 4.255 21.5 6 21.29 4.169 10.6 7 22.75 3.905 21.2 8 24.77 3.591 42.3 EXAMPLE 8 Crystalline Form I of 4- {3-cis -hexahydrocyclopenta [c] pyrrol-2 (1M-ylpropoxy) benzanid citrate 2.5 g of 4- {3-cis-hexahydrocyclopentarpyrrol-2 (1H) -ylipropoxylbenzamide are introduced into a flask containing 65 mL of 2-ethoxy-ethanol The suspension is refluxed and 2.01 g of citric acid are then added The solution is refluxed for 1 hour with stirring The suspension is then stirred at room temperature overnight, the solid is isolated by filtration, and is then dried under vacuum at 40 ° C. for 12 hours. Interval Intensity (Degrees) Reticular (Â) Relative (%) 1 14.03 6.313 32.7 2 17.84 4.973 9.85 3 18.50 4.795 34.7 4 18.93 4.688 32 5 19.23 4.615 13.1 6 20.93 4.245 100 7 22.07 4.028 9 8 24.30 3.662 10.9 - 18 - Example 9: Crystalline form I of 4- {3-icis-hexahydrocyclopenta adipate [C] pyrrol-2 (11-1) -ylpropoxy) benzamide 3.0 g of 4- {3-cis-hexahydrocyclopenta [c] pyrrol-2 (11 H) -yl} propoxylbenzamide are introduced into a flask containing 100 ml. of dichloromethane and refluxed until solubilization. 1.52 mg of adipic acid are then added. The reflux is maintained for 1 hour with magnetic stirring and then allowed to cool to room temperature. The suspension is then stirred at room temperature overnight. The solid is isolated by filtration and then dried under vacuum (10 mbar) at 40 ° C for 12 hours. Line No. Angle 2-theta Inter-distance Intensity (degrees) reticular (Â) relative (%) 1 6.56 13.484 12.5 2 13.25 6.680 13.7 3 13.75 6.441 9.3 4 17.60 5.040 100.0 5 18.39 4.825 16.4 6 23.58 3.774 44.7 7 26.34 3.383 14.5 EXAMPLE 10 Crystalline Form 1 of 4- (31-cis -hexahydrocyclopentyl) pyrrol-2 (111) -ylpropoxylbenzamide Sulfate 2.995 g of 4- (3- [cis-hexahydro-yelopenta [c] pyrrol-2 (11 /) - The suspension is refluxed and 830 ml of concentrated sulfuric acid diluted in 10 ml of water are added and the suspension is refluxed for 1 hour under reflux. The suspension is then stirred at room temperature overnight, the solid is isolated by filtration and then dried under vacuum at 40 ° C. for 12 hours. 2-theta angle Inter-distance Intensity (degrees) reticular ( ) Relative (%) 1 7.37 11.990 100 2 8.66 10.203 49.3 3 13.57 6.521 26.5 4 15.71 5.637 50 16 5.536 18.3 6 16.84 5.260 19.5 7 17.1 5.182 49.7 8 17.37 5.102 23.3 9 17.56 5.048 15.4 20.29 4.372 54.4 11 20.72 4.283 47.6 12 25.3 3.517 67.1 13 26.45 3.366 39.6 EXAMPLE 11 Crystalline Form 1 of 4- {3-Icishexahydro-yelopenta [c] pyrrol-2 (1H) -ylpropoxy} benzamide hemi-sulfate 3.5 g of 4,434 cis-hexahydrocyclopenta [ C. pyrrol-2 (1R) -yl] propoxylbenzamide are introduced into a flask containing 50 ml of acetone. The suspension is refluxed and 5,330 μl of concentrated sulfuric acid diluted in 10 μl of water is added. The suspension is refluxed for 1 hour with magnetic stirring and then allowed to cool to room temperature. The suspension is then stirred at room temperature overnight. The solid is isolated by filtration and then dried under vacuum at 40 ° C for 12 hours. - 20 - Line No. Angle 2-theta Inter-distance Intensity (degrees) reticular (A) relative (%) 1 7.98 11.068 76.2 2 9.12 9.683 29.7 3 12.33 7.174 28.9 4 14.54 6.087 23.6 15.24 5.810 20.2 6 16.33 5.423 18.6 7 16.45 5.384 38.1 8 16.93 5.232 12.9 9 17.05 5.197 50.7 17.18 5.157 26.8 11 17.81 4.976 20.1 12 18.83 4.709 17.1 13 19.26 4.605 46.3 14 22.44 3.958 34.9 22.58 3.935 46.9 16 22.96 3.871 17 17 24.68 3.605 100 18 25.00 3.559 58.3 19 25.91 3.436 18.8 27.67 3.221 30.2

Claims (27)

REVENDICATIONS1. Process for the industrial synthesis of the compound of formula (I): H, HX (I) H, characterized in that: - a compound of formula (II): RO in which R 'and R "represent, independently, one of the other a group (C1-C6) - alkyl, or else R 'and R "together form a group - (CH2), - where n = 2-3, or one of the groups R' or R "represents a hydrogen atom and the other a (C 1 -C 6) -alkyl group, or a compound of formula (III): ## STR1 ## at a reductive amination in the presence of a reducing agent, a stoichiometric amount of a pharmaceutically acceptable acid HX and bicyclic amine of formula (IV): NH (IV) to conduct in a single step, after isolation, to the 4- (4) addition salt 3-cishexahydrocyclopentarpyrrol-2 (1H) -yllpropoxylbenzamide with HX acid. 2. Process for the industrial synthesis of the compound of formula (I): HH, characterized in that: - a compound of formula (II): RO N112 in which R 'and R "independently represent one of the other a (C 1 -C 6) alkyl group, or R 'and R "together form a - (CH 2) - group - where n = 2-3, or one of the groups R' or R" represents a hydrogen atom and the other a (C 1 -C 6) -alkyl group, or a compound of formula (III): HN H 2, HX (1) - reductive amination in the presence of a reducing agent , and a pharmaceutically acceptable acid addition salt HX of the bicyclic amine of formula (IV '): N, HX (IV) for conducting in a single step, after isolation, the addition salt of 4 - {3- [cis-hexahydrocyclopenta [c] pyrrol-2 (1H) -yl] propoxy} benzamide with HX acid. 3. Industrial process according to claim 1 or 2 wherein the reductive amination is carried out by hydrogenation. 4. The industrial process of claim 1 wherein the compound of formula (H) is 4- (3,3-diethoxypropoxy) benzamide. 5. Industrial process according to one of claims 1 to 4 wherein the pharmaceutically acceptable acid HX is selected from the following group: hydrochloric acid, benzenesulfonic acid, methanesulfonic acid, benzoic acid, fumaric acid, adipic acid, sulfuric acid, acid para-toluenesulfonic acid, citric acid, hippuric acid, maleic acid, malonic acid, tartaric acid, succinic acid, glutaric acid, oxalic acid, hydrobromic acid, phosphoric acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, nitric acid, acid ascorbic acid and camphoric acid. 6. Industrial process according to one of claims 1 to 5 wherein the pharmaceutically acceptable acid HX is selected from the following group: hydrochloric acid, benzenesulfonic acid, methanesulfonic acid, benzoic acid, fumaric acid, adipic acid, sulfuric acid, acid para-toluenesulfonic acid, citric acid, hippuric acid, maleic acid, malonic acid, tartaric acid, succinic acid, glutaric acid and oxalic acid. 7. Industrial process according to one of claims 1 to 6 wherein the pharmaceutically acceptable acid HX is selected from the following group: hydrochloric acid, benzenesulfonic acid, methanesulfonic acid, benzoic acid, fumaric acid, adipic acid and sulfuric acid. 8. Industrial process according to one of claims I to 7 wherein the pharmaceutically acceptable acid HX is hydrochloric acid. 9. Industrial process for obtaining free 4- {3-cis-hexahydrocyclopentarcipyrrol-2 (1R) -yl-propoxy} benzamide, characterized in that the process according to one of claims 1 to 8 is carried out to give the compound of formula (I), which is subjected to the action of a base to yield free 3- [cis-hexahydrocyclopenta [c] pyrrol-2 (1H) -yl] propoxy} benzamide. 10. Compound of formula (I) obtained according to one of claims 1 to 4: H 1-1 HX (I) provided that rIX is neither hydrochloric acid nor oxalic acid. 11. Compound of formula (I) according to claim 10 wherein the pharmaceutically acceptable acid is selected from the following group: benzenesulfonic acid, methanesulfonic acid, benzoic acid, fumaric acid, adipic acid, sulfuric acid, para-toluenesulfonic acid, acid citric, hippuric acid, maleic acid, malonic acid, tartaric acid, succinic acid and glutaric acid. A compound of formula (I) according to claim 10 wherein the pharmaceutically acceptable acid is selected from the group of benzenesulfonic acid, methanesulfonic acid, benzoic acid, fumaric acid, adipic acid and sulfuric acid. A compound of formula (1) according to claim 10 wherein the pharmaceutically acceptable acid is selected from the group consisting of benzenesulfonic acid, benzoic acid and adipic acid. 14. Crystalline form (I) of 4- {3- [cis-hexahydrocyclopentaMpyrrol-2 (111) -ylpropoxy} benzamide benzenesulfonate (besylate) characterized by a powder X-ray diffraction pattern showing the following diffraction lines (Bragg angle 2 theta, expressed in degrees + 0.2 °): 11.73 °; 12.63 °; 14.84 °; 15.14 °; 15.70 °; 15.88 °; 16.38 °; 17.89 °; 18.11 °; 19.50 °; 21.54 °; 22.45 °; 23.21 °. 15. Crystalline form (I) of 4- {3-Vis-1-hexahydrocyclopenta-pyrroth-2 (1H) -ylpropoxy} benzamide methanesulfonate (mesylate) characterized by a powder X-ray diffraction pattern having the following diffraction lines ( Bragg 2 theta, expressed in degrees + 0.2 °): 8.12 °; 10.17 °; 13.81 °; 15.51 °; 18.01 °; 18.71 °; 19.15 °; 21.02 °; 21.33 °; 22.49 °. 16, Crystalline form (I) of 4- {3-Pis-hexahydrocyclopentarcipyl-tolyl-2 (11-yl) -propyl] benzylamide benzoate characterized by a powder X-ray diffraction pattern having the following diffraction lines (Bragg 2 theta angle, expressed in degrees + 0.2 °): 11.58 °; 12.43 °; 13.68 °; 15.98 °; 16.73 °; 17.83 °; 18.12 °; 18.69 °; 18.91 °; 19.53 °; 20.16 °; 23.12 °. 17. Crystalline form (I) of 4- {34cis-hexahydrocyclopenta [c] pyrrol-2 (111) -yl] propoxylbenzamide hemi-fumarate characterized by a powder X-ray diffraction pattern having the following diffraction lines ( Bragg angle 2 theta, expressed in degrees + 0.2 °): 11.76 °; 16.5 °; 19.68 °; 19.98 °; 20.86 °; 21.29 °; 22.75 °; 24.77 °. 18. Crystalline form (I) of 4- {3,4cis-hexahydrocyclopenta [c] pyrrol-2 (1H) -yl] propoxy} benzamide citrate characterized by an X-ray powder diffraction pattern showing the following diffraction lines (Bragg angle 2 theta, expressed in degrees + 0.2 °): 14.03 °; 17.84 °; 18.50 °; 18.93 °; 19.23 °; 20.93 °; 22.07 °; 24.30 °. 19. Crystalline form (I) of 4- {3- [cis-hexahydrocyclopentarelpyrrol2 (11 /) - ylpropoxylbenzamide adipate characterized by a powder X-ray diffraction pattern exhibiting the following diffraction lines (Bragg 2 theta angle, expressed in degrees + 0.2 °): 6.56 °; 13.25 °; 13.75 °; 17.60 °; 18.39 °; 23.58 °; 26.34 °; 28.27 °. 20. Crystalline form (I) of 4- {3- [cis-hexahydrocyclopenta [c] pyrrol-2 (1R) -ylpropoxylbenzamide sulfate characterized by an X-ray powder diffraction pattern showing the following diffraction lines (Bragg angle 2 theta, expressed in degrees + 0.2 °): 7.37 °; 8.66 °; 13.57 °; 15.71 °; 16 °; 16.84 °; 17.1 °; 17.37 °; 17.56 °; 20.29 °; 20.72 °; 25.3 °; 26.45 °. 21. Crystalline form (I) of 4- {3- [cis-hexahydrocyclopenta [c] pyrrol-2 (11H) -yl] propoxy} benzamide hemi-sulfate characterized by a powder X-ray diffraction pattern showing following diffraction lines (Bragg 2 theta angle, expressed in degrees + 0.2 °): 7.98 °; 9.12 °; 12.33 °; 14.54 °; 15.24 °; 16.33 °; 16.45 °; 16.93 °; 17.05 °; 17.18 °; 17.81 °; 18.83 °; 19.26 °; 22.44 °; 22.58 °; 22.96 °; 24.68 °; 25.00 '; 25.91 °; 27.67 °. 22. Pharmaceutical composition containing as active ingredient a compound of formula (I) according to one of claims 10 to 21, in combination with one or more inert, non-toxic and pharmaceutically acceptable vehicles. 23. Pharmaceutical composition according to claim 22 for its use in the treatment of cognitive and psycho-behavioral disorders associated with cerebral aging and neurodegenerative diseases, as well as for the treatment of mood disorders, hyperactivity syndrome with attentional deficits, obesity and pain. 24. Pharmaceutical composition according to claim 23 for its use in the treatment of cognitive and psycho-behavioral disorders associated with Alzheimer's disease, Parkinson's disease, Pick's disease, Korsakoff's disease, dementia with Lewy, frontal and subcortical dementia, frontotemporal dementia, and vascular dementia. 25. Use of a compound of formula (I) according to one of claims 10 to 21, for the manufacture of a medicament useful for the treatment of disorders of the histaminergic system. 26. Use of a compound of formula (I) according to one of claims 10 to 21, for the manufacture of a medicament for the treatment of cognitive and psycho-behavioral disorders associated with cerebral aging and neurodegenerative diseases, as well as treatment of mood disorders, hyperactivity syndrome with attention deficit, obesity and pain. 27. Use of a compound of formula (I) according to one of claims 10 to 21, for the manufacture of a medicament for the treatment of cognitive and psycho-behavioral disorders associated with Alzheimer's disease, Parkinson's disease, Pick's disease, Korsakoff's disease, Lewy body dementia, frontal and subcortical dementia, frontotemporal dementia, and vascular dementia.