FR3025197B1 - NOVEL SALT OF 3 - [(DIMETHYLAMINO) METHYL] -N- {2- [4- (HYDROXYCARBAMOYL) PHENOXY] ETHYL} -1-BENZOFURAN-2-CARBOXAMIDE, ASSOCIATED CRYSTALLINE FORMS, PROCESS FOR PREPARING THEM AND PHARMACEUTICAL COMPOSITIONS THEREOF CONTAIN - Google Patents

Abstract

3 - [(dimethylamino) methyl] -N- {2- [4- (hydroxycarbamoyl) phenoxy] ethyl} -1-benzofuran-2-carboxamide hydrogenosulphate of formula (I): wherein HA represents sulfuric acid, and that its hydrates, and their crystalline forms characterized by their powder X-ray diffraction pattern and their 13C solid state NMR spectrum CP / MAS.

Description

- 1 -

The present invention relates to 3 - [(dimethylamino) methyl] -N- {2- [4- (hydioxycarbamoyl) phenoxy] ethyl} -1-benzofuran-2-carboxamide sulfate, process for its preparation and pharmaceutical compositions who contain it.

More particularly, the subject of the invention relates to 3 - [(dimethylamino) methyl] -1-N- {2 - [4- (hydroxycarbamoyl) phenoxy] ethyl] -1-benzofuran-2-carboxamide hydrogen sulphate. formula (I):

HA (1) in which HA represents sulfuric acid, as well as its hydrates.

The present invention also relates to novel hydrous crystalline forms of 3 - [(dimethylamino) methyl] -N- [2- [4- (hydroxycarbamoyl) phenoxy] ethyl] -1-benzofuran-2-carboxamide hydrogenosulfate of the formula ( I), the process for their preparation and the pharmaceutical compositions containing them.

3 - [(Dimethylamino) methyl] -N- {2- [4- (hydroxycarbamoyl) phenoxy] ethyl} -1-benzofuran-2-carboxamide, also called abexinostat, is a histone deacetylase inhibitor (HDAC) described in US Pat. patent application WO 2004/092115. It inhibits cell growth and induces apoptosis in tumor cells cultured in vitro, and inhibits tumor growth in vivo in xenograft models (Buggy et al., Mol Cancer Ther 2006, 5 (5) , 1309). Given its pharmacological profile, abexinostat is intended for use in the treatment of cancer.

From the industrial point of view, it is essential to be able to synthesize the compound with an excellent purity, and in particular in a perfectly reproducible form, presenting

interesting characteristics of dissolution, filtration, drying, ease of formulation and stability allowing its prolonged storage without particular conditions of temperature, light, humidity or oxygen level.

The patent application WO 2004/092115 describes two different access routes to obtain 3 - [(dimethylamino) methyl] - / V "{2" [4 "(hydroxycarbamoyl) phenoxy] ethyl} -1-benzofuran-2 carboxamide. In both cases, 3-methyl-benzofuran-2-carboxylic acid is used as starting material, but the functionalization of this central nucleus by the dimethylaminomethyl group at the 3-position is carried out at different stages of the synthesis process, the occurrence before or after coupling of the derivative of benzofuran-2-carboxylic acid with methyl 4- (2-aminoethoxy) benzoate. Obtaining 3 - [(dimethylamino) methyl] -7- {2- [4- (hydroxycarbamoyl) phenoxy] ethyl} -1-benzofuran-2-carboxamide hydrochloride is specifically described in WO 2004/092115. However, the use of this salt on an industrial scale is delicate because of its hygroscopic properties.

The present invention also describes a process for obtaining 3 - [(dimethylamino) methyl] -N- {2 - [4- (hydroxycarbamoyl) phenoxy] ethyl} -1-benzofuran-2-carboxamide hydrogen sulphate in two crystalline forms well defined hydrate, perfectly reproducible, and having a very good stability compatible with the industrial constraints of preparation and preservation of pharmaceutical compositions.

The crystalline form hemipentahydrate of 3 - [(dimethylamino) methyl] W- {2- [4- (hydroxycarbamoyl) phenoxy] ethyl} -1-benzofuran-2-carboxamide hydrogen sulphate obtained by the process of the invention is characterized by an X-ray powder diffraction pattern having the following diffraction lines (Bragg 2 theta angle, expressed in degrees ± 0.2 °): 6.92; 9.01; 11.04; 13.87; 14.24; 14.89; 15.06; 17.34; 18.96; 20.05; 21.49; 24.34; 24.59; 25.19; 25.89. More particularly, the crystalline form hemipentahydrate of 3 "[(dimethylamino) methyl] -N- {2- [4- (hydroxy carbamoyl) phenoxy] ethyl} -1-benzofuran-2-carboxamide hydrogen sulfate is characterized by the lines diffraction pattern: 6.92; 9.01; 11.04; 11.82; 13.87; 14.24; 14.89; 15.06; 17.34; 18.96; 20.05; 20.84; 21.23; 21.49; 22.68; 22.85; 24.34; 24.59; 25.19; 25.89; 28.28.

More specifically, the crystalline form hemipentahydrate of 3 - [(di methylamino) methyl] -A'- {2- [4- (hydroxycarbamoyl) phenoxy] ethyl} -1-benzofuran-2-carboxamide hydrogen sulfate is characterized by the X-ray powder diffraction pattern below, measured using a PANalytical X'Pert Pro MPD diffractometer with X'Celerator detector, and expressed in terms of line position (Bragg 2 theta angle, expressed in degrees ± 0.2 °) and inter-reticular distance d (expressed in Â):

Finally, the crystalline form hemipentahydrate of 3 - [(dimethylamino) methyl] -2- {2- [4- (hydroxycarbamoyl) phenoxy] ethyl} -1-benzofuran-2-carboxamide hydrogen sulphate

has also been characterized by solid-state NMR spectroscopy and the 13C CP / MAS spectrum (Cross Polarization / Magic Angle Spinning) has the following peaks (expressed in ppm ± 0.2 ppm):

The present invention also relates to the crystalline form hemiheptahydrate of 3 - [(dimethylamino) methyl] -N- [2- [4- (hydroxycarbamoyl) phenoxy] ethyl] -1-benzofuran-2-carboxamide hydrogen sulphate obtained by the process of the invention is characterized by a powder X-ray diffraction pattern having the following diffraction lines (Bragg 2 theta angle, expressed in degrees ± 0.2 °): 9.99; 10.67; 13.79; 13.92; 14.25; 14.67; 15.18; 16.21; 18.44; 18.82; 20.42; 21.71; 22.47; 23.30; 24.25. More particularly, the crystalline form hemiheptahydrate of 3 - [(dimethylamino) methyl] - [V- {2- [4- (hydroxycarbamoyl) phenoxy] ethyl] -sulfate

benzofuran-2-carboxamide is characterized by the following diffraction lines: 9.99; 10.67; 12.65; 13.79; 13.92; 14.25; 14.67; 15.18; 16.21; 16.43; 18.44; 18.82; 20.42; 20.76; 21.09; 21.45; 21.71; 22.47; 22.92; 23.30; 23.89; 24.25; 26.02; 26.54.

More specifically, the crystalline form hemiheptahydrate of 3 - [(dimethylamino) methyl] -N- {2- [4- (hydroxycarbamoyl) phenoxy] ethyl} -1-bnzofuran-2-carboxamide hydrogen sulfate is characterized by the powder X-ray diffraction pattern below, measured using a PANalytical X'Pert Pro MPD diffractometer with an X'Celerator detector, and expressed in terms of line position (Bragg 2 theta angle, expressed in degrees ± 0.2 °) and inter-reticular distance d (expressed in Å): The invention also extends to the process for the preparation of 3 - [(dimethylamino) methyl] -7V- {2-hydrogen sulphate - [4- (hydroxycarbamoyl) phenoxy] ethyl] -1-benzofuran-2-carboxamide in two well-defined hydrated crystalline forms, characterized in that 3 - [(dimethylamino) methyl] -A- {2- [4- ( hydiOxycarbamoyi) phenoxy] ethyl} -1-benzofuran-2-carboxamide is crystallized in a polar medium in the presence of sulfuric acid. Preferably, the polar medium consists of one or more solvents chosen from water, ketones, nitrites and esters, it being understood that: - "ketones" means Cs-Ce ketones such that acetone, methyl ethyl ketone, 2-pentanone, 3-pentanone, 3-methyl-2-butanone, 2-hexanone, 3-hexanone, ethyl isopropyl ketone, methyl isopropyl ketone, 2,2-dimethyl-3- butanone; "Nitrile" means acetonitrile, acrylonitrile, propanenitrile or benzonitrile; - "Esters" means esters C3-C8 such as ethyl formate, isopropyl formate, ethyl acetate, propyl acetate, isopropyl acetate, acetate butyl acetate, isobutyl acetate, β-butyl acetate, pentyl acetate, isopentyl acetate, hexyl acetate.

Among the preferred solvents, acetone and methyl ethyl ketone will be used for ketones, and ethyl acetate for esters. Water is a particularly preferred solvent.

Alternatively, the polar medium is a binary mixture of which one of the constituents is water. More preferably still, the polar medium is a hydro-alcoholic mixture. Advantageously, the polar medium is a binary mixture chosen from: acetone / water, ethanol / water, isopropanol / water and methyl ethyl ketone / water.

In the crystallization process according to the invention, it is possible to use 3 - [(dimethylamino) methyl] -N- {2- [4- (hydoxycarbamoyl) phenoxy] ethyl} -1-benzofuran-2-carboxamide (free base) obtained by any method. The invention also extends to another process for the preparation of 3 - [(dimethylamino) methyl] -N- {2 - [4 "(hydroxycarbamoyl) phenoxy] ethyl} -1-benzofuran-2-carboxamide hydrogen sulphate in two well-defined hydrated crystalline forms, wherein the crystallization of 3 - [(1-dimethylamino) methyl] -N- {2- [4- (hydroxycarbamoyl) phenoxy] ethyl} -1-benzofuran-2-carboxamide (base free) is initiated by seeding a very small amount of the hydrated crystalline form of 3 - [(dimethylamino) ethyl] -N- {2- [4- (hydroxycarbamoyl) phenoxy] ethyl} -1-benzofuran hydrogen sulfate -2-carboxamide according to the invention, this reaction being carried out in a polar medium and in the presence of sulfuric acid. In this second crystallization process according to the invention, it is also possible to use 3 "[(dimethylamino) methyl] - {2- [4" (hydroxycarbamoyl) phenoxy] ethyl} -1-benzofuran-2-carboxamide ( free base) obtained by any process. Obtaining the crystalline hydrated forms of 3 - [(dimethylamino) methyl] -N- {2- [4- (hydroxycarbamoyl) phenoxy] ethyl} -1-benzofuran-2-carboxamide hydrogen sulphate according to the invention advantage of being easily manipulated and allow the preparation of pharmaceutical formulations having a constant and reproducible composition, while having good characteristics of dissolution and stability, which is particularly advantageous when the formulations are intended for oral administration. More specifically, the use of the hydrous crystalline forms of 3 - [(dimethylamino) methyl] -N- [2- (4 "(hydroxycarbamoyl) phenoxy] ethyl] -1-benzofuran-2-carboxamide hydrogen sulphate according to US Pat. invention is particularly interesting on the industrial level.

The hydrated crystalline forms of 3 - [(dimethylamino) methyl] - [N - [2- (4 "(hydroxycarbamoyl) phenoxy] ethyl] -1-benzofuran-2-carboxamide hydrogen sulphate according to the invention are intended for the treatment cancer, and more particularly to the treatment of a carcinoma, a tumor, a neoplasm, a lymphoma, a melanoma, a glioma, a sarcoma or a blastoma. The invention also extends to pharmaceutical compositions containing as active principle 3 - [(dimethylamino) methyl] -7- {2- [4- (hydroxycarbamoyl) phenoxy] ethyl} -1-benzofuran-2-carboxamide hydrogen sulphate according to formula (I) and, more particularly, the hydrated crystalline forms of 3 - [(dimethylamino) methyl] -N- {2- [4- (hydroxycarbamoyl) phenoxy] ethyl} -1-benzofuran-3-bisulfate; 2-carboxamide according to the invention, 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) administration, nasal administration, single or coated tablets, granules, sublingual tablets, capsules. , tablets, suppositories, creams, ointments, dermal gels, injectables, oral suspensions and chewables.

Pharmaceutical compositions administered orally are preferred.

The appropriate dosage varies according to the sex, age and weight of the patient, the route of administration, the nature of the cancer and any associated treatments, and the useful dosage ranges from 20 mg to 480 mg of 3 - [( dimethylamino) methyl] - [V- {2- [4- (hydroxy carbamoyl) phenoxy] ethyl} -1-benzofuran-2-carboxamide expressed as the free base per day.

The examples below illustrate the invention, but do not limit it in any way. EXAMPLE 1 Process for Obtaining the Crystalline Form hemipentahydrate of 3 - [(dimethylamino) methyl] -7- {2- [4- (hydroxy carbamoyl) phenoxy] ethyl} -1-benzofuran-2-carboxamide hydrogen sulphate

In a 50 mL flask, one equivalent of 3 - [(dimethylamino) methyl] -N- {2- [4- (hydroxycarbamoyl) phenoxy] ethyl} -1-benzofuran-2-carboxamide (free base) (1512 8 mg, 3.807 mmol) and then one half-equivalent of sulfuric acid (5.302 mL of a 0.359 mol.L -1 aqueous solution, 1.903 mmol). The mixture is subjected to magnetic stirring until a clear solution is obtained. The water is then evaporated under air flow. The white powder is then resuspended with 25 mL of w-heptane and the reaction mixture is stirred with sustained magnetic stirring at 60 ° C for 1 hour. The reaction mixture is then cooled with sustained magnetic stirring to 10 ° C at a rate of between 1 and 1.5 ° C / min and then maintained for about 1 day at 10 ° C. After filtration on sintered glass of porosity 3, the solid is dried in a desiccator under vacuum (100 mbar) to give the title compound in 96% yield. The solid was characterized by the powder X-ray diffraction pattern and the NMR spectrum detailed in the following Examples 3 and 5. EXAMPLE 2 Process for Obtaining the Crystalline Form Hemiheptahydrate of 3 - [(Dimethylamino) Methyl] -V- {2- [4- (hydroxycarbamoyl) phenoxy] ethyl] -1-benzofu Hydosulphate r e-2-carboxamide e

One vial containing 100 mg of 3 - [(dimethylamino) methyl] -N- [2- (4- (hydroxycarbamoyl) phenoxy] ethyl] -1-benzofuran-2-carboxamide hydrogen sulfate, hemipentahydrate placed 3 days in a bell containing a saturated saline solution of KNO3 (90% RH) at room temperature leads to the formation of the title compound in quantitative yield. The resulting solid was characterized by the powder X-ray diffraction pattern detailed in Example 3 below. EXAMPLE 3: X-ray powder diffraction patterns of the hydrated crystalline forms of 3 - [(dimethylamino) methyl] -7V- {2 - [4- (hydroxycarbamoyl) phenoxy] ethyl} -L-benzofuran-2-carboxamide hydrogen sulphate Data recording was performed on a PANalytical X'Pert Pro MPD diffractometer with X'Celerator detector under the following conditions: - Voltage 45 kV, current 40 mA; - Theta / theta editing; - Anode: copper; - Wavelength K alpha-1: 1.54060 Å; - Wavelength K alpha-2: 1.54443 Å; - K alpha-2 / K alpha-1 ratio: 0.5; - Measuring mode: continuous from 3 ° to 55 ° (Bragg 2 theta angle) with an incrementation of 0.017 °;

Acquisition time: 15 min.

Crystalline form of 3H-dihydrobutyl-naphthalenyl) -methyl] -fluoroyl) -2- [4- (hydroxy) phenylmethyl) phenyl] hexylfuran] -benzylamide

The powder X-ray diffraction pattern of the crystalline form hemipentahydrate of 3 - [(dimethylamino) methyl] -N- [2- [4- (hydroxycarbamoyl) phenoxy] ethyl] -1-benzofuran-2-carboxamide hydrogen sulphate obtained according to the method of Example 1 is expressed in terms of line position (Bragg 2 theta angle, expressed in degrees ± 0.2 °) and inter-reticular distance d (expressed in Â). Significant lines have been collected in the following table:

Calcium form of hydrogen: 3-sulfoxide: 3-dimethylphenylmethyl) phenyl-1-benzylfyron-2-hexamido-1-methylhydroxy

The powder X-ray diffraction pattern of the crystalline form hemiheptahydrate of 3 - [(dimethylamino) methyl] -N- [2- [4- (hydroxycarbamoyl) phenoxy] ethyl] -1-benzofuran-2-carboxamide hydrogen sulfate according to the method of Example 2 is expressed in terms of line position (Bragg 2 theta angle, expressed in degrees ± 0.2 °) and inter-reticular distance d (expressed in Å), the significant lines were EXAMPLE 4: Determination of the lattice parameters of the crystalline form hemipentahydrate of 3 - [(dimethylamino) methyl] -7- {2- [4- (hydroxycarbamoyl) phenoxy] ethyl} -1-benzofuran-2-hydrogen sulphate carboxamide

The crystalline structure was determined on the powder obtained in Example 1 above using a PANalytical X'Pert Pro MPD diffractometer with an X'Celerator detector. The following parameters were established: EXAMPLE 5: Solid NMR Spectrum of the Crystalline Form hemipentahydrate of 3 - [(dimethylamino) methyl] -7- {2- [4- (hydroxy carbamoyl) phenoxy] ethyl] -l, hydrogen sulphate benzofuran-2-carboxamide

The 13C NMR spectra were recorded at ambient temperature using a Bruker SB Avance III HD 400 spectrometer with a CP / MAS SB VTN type 4 mm probe under the following conditions:

Frequency: 100.65 MHz; - Spectral width: 40 kHz; - Speed of rotation of the sample at the magic angle: 10 kHz; Pulse sequence: CP (Cross Polarization) with SPINAL64 decoupling; Repetition time: 10 s; - Acquisition time: 46 ms;

Contact time: 4 ms; - Number of scans: 4096.

An apodization function ("10 Hz line broadening") is applied before Fourier transform. The spectra thus obtained were referenced with respect to a sample of adamantane as external standard (the peak of higher frequency has a chemical shift of 38.5 ppm). The peaks observed are expressed in ppm ± 0.2 ppm. Δδppm: Δδ is the difference in chemical displacement between the indexed peak and the peak of the lowest chemical shift referenced.

The crystalline form hemipentahydrate of 3- [(dimethylamino) methyl] -N- {2- [4- (hydroxycarbamoyl) phenoxy] ethyl} -1-benzofuran-2-carboxamide hydrogen sulfate obtained by the method of Example 1 has the following peaks: EXAMPLE 6: Hygroscopy The hygroscopicity of the crystalline form hemipentahydrate of 3 - [(dimethylamino) methyl] -N- {2- [4- (hydroxycarbamoyl) phenoxy] ethyl hydrogen sulfate Benzofuran-2-carboxamide according to the invention was evaluated by gravimetry of water vapor absorption (DVS - Dynamic Vapor Sorption) using a DVS Intrinsic device. A sample of 5 to 10 mg of the drug substance, accurately weighed, was placed in a DVS sample boat operating at 25 ° C under controlled humidity. Mass variation was recorded from a 50% RH equilibrium plateau (relative humidity), followed by three subsequent phases of increase (from 50 to 90%), decrease (from 90 to 0%) and increasing (from 0 to 50%) linear relative humidity at a rate of 10% per hour. The relative humidity was kept constant when it reached either 0, 50, or 90% RH, until the mass change was less than 0.002% per minute, with a time limit of 15 hours.

The crystalline form hemipentahydrate of 3 - [(dimethylamino) methyl] -N- [2- [4- (hydroxycarbamoyl) phenoxy] ethyl] -1-benzofuran-2 "carboxamide hydrogen sulfide obtained by the method of Example 1 is stable between 15% RH and 70% RH, above 70% RH, hydrogen sulfate, hemipentahydrate is converted to hydrogen sulfate, hemiheptahydrate which is stable between 90% RH and 20% RH, below 20% RH and up to 0% RH, the hydrogen sulfate, hemiheptahydrate completely dehydrates and then convert back to hydrogen sulfate, hemipentahydrate from 15% RH.

Therefore, the crystalline form hemipentahydrate of 3 - [(dimethylamino) methyl] -N- {2- [4- (hydroxycarbamoyl) phenyl] ethyl} -1-benzofuran-2-carboxamide hydrogen sulfate obtained by the process of Example 1 has properties that allow it to be easily handled - especially, in the preparation of pharmaceutical formulations - over wide ranges of relative humidity values. EXAMPLE 7 Pharmaceutical Composition

Preparation formula for 1000 tablets dosed with 100 mg of 3 - [(dimethylamino) methyl] -N- {2- [4- (hydroxycarbamoyl) phenoxy] ethyl} -1-benzofuran-2-carboxamide (expressed as a base equivalent):

3 - [(Dimethylamino) methyl] -AL {2- [4- (hydroxycarbamoyl) phenoxy] ethyl} -1-benzofuran-2-carboxamide hydrogen sulfate, hemipentahydrate ............... ........................ 153,9g

Lactose monohydrate ................................................ .............................................. 228,7g

2.5 g magnesium stearate

Corn starch 75 g

Maltodextrin 50 g

Anhydrous colloidal silica 1 g

Carboxymethyl Sodium Cellulose 15 g

Claims (6)

1. Crystalline form hemipentahydrate of 3 - [(dimethylamino) methyl] -V- {2- [4- (hydroxycarbamoyl) phenoxy] ethyl} -1-benzofuran-2-carboxamide hydrogen sulphate of formula (I): , 0.5 HA (I) wherein HA represents sulfuric acid, characterized in that it has a powder X-ray diffraction pattern having the following diffraction lines (Bragg 2 theta angle, expressed in degrees ± 0, 2 °): 6.92; 9.01, 11.04, 13.87, 14.24, 14.89, 15.06; 17.34; 18.96; 20.05; 21.49; 24.34; 24.59; 25.19; 25.89. 2. Crystalline form hemipentahydrate of 3 - [(dimethylamino) methyl] -N- {2- [4- (hydroxycarbamoyl) phenoxy] ethyl} -1-benzofuran-2-carboxamide hydrogen sulphate according to claim 1, characterized in that it has an X-ray powder diffraction pattern with the following diffraction lines (Bragg 2 theta angle, expressed in degrees ± 0.2 °): 6.92, 9.01; 11.04; 11.82; 13.87; 14.24; 14.89; 15.06; 17.34; 18.96; 20.05; 20.84; 21.23; 21.49; 22.68; 22.85; 24.34; 24.59; 25.19; 25.89; 28.28. 3. crystalline form hemipentahydrate of 3 - [(dimethylamino) methyl] -N- {2- [4- (hydroxycarbamoyl) phenoxy] ethyl} -1-benzofuran-2-carboxamide hydrogen sulphate according to claim 1 or 2, characterized in it has the following X-ray powder diffraction pattern, expressed in terms of line position (Bragg 2 theta angle, expressed in degrees ± 0.2 °) and inter-reticular distance d (expressed in Â): 4. Crystalline form hemipentahydrate of 3 - [(dimethylamino) methyl] -7- {2- [4- (hydroxycarbanoyl) phenoxy] ethyl} -1-benzofuran-2-carboxamide hydrogen sulfate according to one of claims 1 to 3, characterized in that it has a 13C CP / MAS solid state NMR spectrum having the following peaks (expressed in ppm ± 0.2 ppm): 5. Crystalline form hemiheptahydrate of 3 - [(dimethylamino) hydrogen sulfate methyl] -A- {2- [4- (hydroxycarbanoyl) phenoxy] ethyl} -1-benzofuran-2-carboxamide of formula (T): wherein HA represents sulfuric acid, characterized in that it has a diagram X-ray diffraction pattern having the following diffraction lines (Bragg 2 theta angle, expressed in degrees ± 0.2 °): 9.99; 10.67; 13.79; 13.92; 14.25; 14.67; 15.18; 16.21; 18.44, 18.82,20,42,21,71; 22.47; 23.30; 24.25. 6. Crystalline form hemiheptahydrate of 3 - [(dimethylamino) methyl] - # - {2- [4- (hydroxycarbamoyl) phenoxy] ethyl} -1-benzofuran-2-carboxamide hydrogen sulfate according to claim 5, characterized in that it has a powder X-ray diffraction pattern with the following diffraction lines (Bragg 2 theta angle, expressed in degrees ± 0.2 °): 9.99; 10.67; 12.65; 13.79; 13.92; 14.25; 14.67; 15.18; 16.21; 16.43; 18.44; 18.82; 20, 42, 20, 76; 21.09; 21.45; 21.71, 22.47; 22.92; 23.30; 23.89,24.25; 26.02; 26,54, 7. Crystalline form of 3 - [(dimethylamino) methyl] -7- {2- [4- (hydroxycarbamoyl) phenoxy] ethyl} -1-benzofuran-2-carboxamide, hydrogen sulphate according to claim 5 or 6 characterized in that it has the following X-ray powder diffraction pattern, expressed in terms of line position (Bragg 2 theta angle, expressed in degrees ± 0.2 °) and inter-reticular distance d (expressed in)): 8. Pharmaceutical composition containing as active ingredient a hydrated crystalline form of 3 - [(dimethylamino) nlthyl] -N- [2- (4- (hydroxy carbamoyl) phenoxy] ethyl] -1-benzofuran hydrogen sulphate -2-carboxamide according to one of claims 1 to 7 in combination with one or more pharmaceutically acceptable excipients. 9. Pharmaceutical composition according to claim 8 for its use in the treatment of cancer. The pharmaceutical composition of claim 9 wherein the cancer is a carcinoma, a tumor, a neoplasm, a lymphoma, a melanoma, a glioma, a sarcoma or a blastoma. 11. Process for the preparation of a hydrated crystalline form of 3 - [(dimethylamino) methyl] -N- {2- [4- (hydroxycarbamoyl) phenoxy] ethyl} -1-benzofuran-2-carboxamide hydrogen sulphate according to US Pat. one of claims 1 to 7, wherein the 3 - [(dimethylamino) methyl] -7- {2- [4- (hydroxycarbamoyl) phenoxy] ethyl} -1-benzofuran-2-carboxamide is crystallized in the presence of the sulfuric acid in a polar medium. 12. Process for the preparation of a hydrated crystalline form of 3 - [(dimethylamino) methyl] -7- {2- [4- (hydroxycarbamoyl) phenoxy] ethyl} -1-benzofuran-2-carboxamide hydrogen sulphate according to claim 11 wherein the polar medium is one or more solvents selected from water, ketones, nitriles and esters. 13. Process for the preparation of a hydrated crystalline form of 3 - [(dimethylamino) methyl] -N- [2- [4- (hydroxycarbamoyl) phenoxy] ethyl] -1-benzofuran-2-carboxamide hydrogen sulphate according to claim 11, wherein the polar medium is a binary mixture of which one of the constituents is water. The I.N.P.I. appendix to each patent a "RESEARCH REPORT" citing the elements of the state of the art that may be taken into account to assess the patentability of the invention, within the meaning of Articles L. 611-11 (novelty) and L. 611-14 (inventive step) of the intellectual property code. This report deals with the claims of the patent which define the object of the invention and delimit the scope of protection. After delivery, ΓΙ.Ν.Ρ.Ι. may, at the request of any interested person, make a "DOCUMENTARY ADVICE" on the basis of the documents cited in this search report and any other document that the applicant wishes to be taken into consideration. CONDITIONS FOR ESTABLISHING THIS RESEARCH REPORT [x] The applicant submitted comments in response to the preliminary search report. □ The applicant maintained the claims. [x] The applicant amended the claims. □ The applicant amended the description to remove items that were no longer consistent with the new claims. □ Third parties submitted comments after publication of the preliminary search report. □ A complementary preliminary research report has been prepared. DOCUMENTS CITED IN THIS RESEARCH REPORT The distribution of documents between headings 1, 2 and 3 takes into account, where appropriate, the claims filed last and / or the observations submitted. [x] The documents listed in section 1 below may be taken into consideration in assessing the patentability of the invention. □ The documents listed in Section 2 below illustrate the general background technology. □ The documents listed in section 3 below were cited during the procedure, but their relevance depends on the validity of the claimed priorities. □ No documents were cited during the procedure. 1/2 National Registration No: FR1458224 Publication No .: FR3025197 ΪΓ SELECTED TELECENT ELEMENTS CONSIDERED IN ORDER TO CONSIDER THE PATENTABILITY OF INVENTION ________ IWO 2004/092115 A2 (AXYS PHARM INC [US]; VERNER ERIC J [US]; SENDZIK MARTIN [US]; | BASKARAN) October 28, 2004 (2004-10-28) IWO 2014/135776 A1 (SERVIER LAB [EN]; PHARMACYCLICS INC [US]) September 12, 2014 (2014- | 09-12) 2.ELEMENTSOF THEATERATECHNICALCALLINGTHROUGHTS BACKGROUND I GENERAL TECHNOLOGY | __________________________ VALIDITY OF PRIORITIES__________________________ Ineant