FIELD OF THE INVENTION

The present invention relates to a new crystalline form of Imepitoin and a process for obtaining it.

BACKGROUND

Imepitoin (INN), sold under the brand name Pexion, is an anticonvulsant which is used in veterinary medicine in Europe to treat epilepsy in dogs.

Imepitoin is firstly described in the patent US5,869,481 as belonging to a family of compounds having an antiepileptic activity. The process for obtaining the compound Imepitoin, 1 -(4-chlorophenyl)-4-morpholin-1-yl-1 ,5-dihydro-imidazol-2-one, of Formula (I) is reported in column 4, following the process details of Variant A. Specifically, 1 - arylimidazolin-2.4-dione and 200 mg of 4-toluenesulfonic acid were added to an appropriate secondary amine. After a reaction time from about 8 to about 30 hours, the solution was filtered hot and distilled to approximately to half the volume in a rotary evaporator. The clear solution was cooled in an ice bath and the crystal magma obtained was separated from the amine. The starting substance contained in the crude product was then extracted with hot acetone. The product Imepitoin is hence recrystallized from n-propanol.

New series of imidazolones and pyrrolones were described in “Synthesis, Pharmacology, and Structure- Activity Relationships of Novel Imidazolones and Pyrrolones as Modulators of GABAA Receptors", Christian Grunwald, Chris Rundfeldt, Hans-Joachim Lankau, Thomas Arnold, Norbert Hdfgen, Rita Dost, Ute Egerl and, Hans-Jorg Hofmann, and Klaus Unverferth; J. Med. Chem. 2006, 49, 6, 1855-1866. In this article the prepared compounds were tested regarding their anxiolytic properties due to modulation of the GABAA receptor response. The described derivatives exhibited considerable pharmacological activity, while lacking the typical side effects of benzodiazepine receptor agonists. In particular, 1 -(4- chlorophenyl)-4-morpholin-1 -y 1-1 ,5-dihydro-imidazol-2-one (Imepitoin) was protective in the pentylene tetrazole test in rats with oral ED50 of 27.4 and 12.8 mg/kg and TD50 (rotarod) of >500. In the article Imepitoin was synthetized according to Scheme 1 reported on page 1856:

According to the general procedure reported on page 1861 a mixture of 1 -ar(alk)-yl- hydantoin and the appropriate amine hydrochloride in the corresponding amine was stirred and heated at a bath temperature of 100-140 °C for 2-12 h. After the mixture had been cooled to room temperature, a solid precipitated, which was collected by filtration, washed with water, and purified by recrystallization from alcohol.

Both the prior art processes known for preparing Imepitoin provided for a crystallization step, which was deemed necessary after the preparation of the crude product in order to obtain a product adapted to a pharmaceutical field.

The inventors repeated the processes as reported in the prior art and noticed that the final crystalline form that was obtained was not reproducible after repeating the same recrystallization procedure as it will be evident from the experimental part.

The object of the present invention is hence to provide Imepitoin with a process that allows to obtain always the same crystalline form.

SUMMARY OF THE INVENTION

The inventors realized that the prior art procedures to provide Imepitoin in crystalline form were not reproducible, since the crystalline forms finally obtained showed an X-ray powder diffraction spectrum (XRPD) always different as it will be evident from the experimental part.

Crystal polymorphism is formation of two or more types of crystals by a compound. Generally, it is known that different crystal forms of crystal polymorphs may be different in stability and physical properties. Further, when there are crystal polymorphs, crystal transition may generally occur. Crystal transition is a phenomenon often observed, for example, in small changes in the recrystallization procedure or even during drying, grinding, and storage in chemical industries. Crystals that do not undergo crystal transition to another crystal form are suitable as drug substances for pharmaceutical and veterinary fields. Hence, when a plurality of crystal forms is obtained, it is important to validate the stability of each and finding a reproducible way to product them.

The inventors found out surprisingly a process for preparing a reproducible crystalline form of Imepitoin.

Therefore in a first aspect the invention relates to a new crystalline form of Imepitoin of formula 1 -(4-chlorophenyl)-4-morpholin-1 -y 1-1 ,5-dihydro-imidazol-2-one, characterized by a X-ray powder diffraction spectrum (XRPD) with characteristic peaks at diffraction angle (2 ± 0.1 ) values of 6.3°, 14.4°, 14.7°, 15.7°, 17.2°, 18.9°, 19.1 °, 25.5°.

Values of diffraction angles in powder X-ray diffraction may contain errors in the range of 2 ± 0.1 due to, for example, difference in instruments and analyzing methods.

In another aspect the invention relates to a new process for preparing the new crystalline form of Imepitoin that guarantee to obtain always the same crystalline form other than the processes known in the prior art.

The process for preparing the above new crystalline form hence comprises the step of: a) charging 4-chlorophenyl hydantoin and morpholine in the presence of an organic solvent, thus obtaining a first reaction mixture; b) adding to the reaction mixture a catalytic amount of HCI and heating to reflux the obtained slurry, thus obtaining a second reaction mixture; c) diluting the second mixture with an organic solvent and cooling and maintaining it to room temperature thus obtaining the crude product; d) isolating the crude product and making a slurry of it with acetone; e) stirring the slurry at a temperature in the range from room temperature and reflux; filtering, washing and drying the crystalline Imepitoin so obtained; and f) micronizing the dried crystalline imepitoin. As a result of conducting the above process in order to solve the problem described above, the present inventors have succeeded in obtaining a new crystalline form of a compound represented by Formula (I).

In another aspect the invention relates to the above new crystalline form for use in the veterinary field.

In a still another aspect the invention relates to the above crystalline form for use as medicament, i.e. as a drug substance suitable for preparing pharmaceutical drugs.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 shows the results of example 2; and

Figures 2 and 3 shows the results of example 3.

DETAILED DESCRIPTION OF THE INVENTION

The invention relates to a new crystalline form of Imepitoin, 1 -(4-chlorophenyl)-4- morpholin-1 -y 1-1 .5-dihydro-imidazol-2-one, of Formula (I), characterized by an X-ray powder diffraction spectrum (XRPD) with characteristic peaks at diffraction angle (20 ± 0.1 ) values of 6.3°, 14.4°, 14.7°, 15.7°, 17.2°, 18.9°, 19.1 °, 25.5°.

Values of diffraction angles in powder X-ray diffraction may contain errors in the range of 2 ± 0.1 due to, for example, difference in instruments analyzing methods. In another aspect the invention relates to a new process for preparing the new crystalline form of Imepitoin that guarantees to obtain always the same crystalline form other than the processes known in the prior art.

The process for preparing the above new crystalline form hence comprises the step of: a) charging 4-chlorophenylhydantoin and morpholine in the presence of an organic solvent, thus obtaining a first reaction mixture; b) adding to the reaction mixture a catalytic amount of HCI and heating to reflux the obtained slurry, thus obtaining a second reaction mixture; c) diluting the second mixture with an organic solvent and cooling and maintaining it to room temperature thus obtaining the crude product; d) isolating the crude product and making a slurry of it with acetone; e) stirring the slurry at a temperature in the range from room temperature and reflux; filtering, washing and drying the crystalline Imepitoin so obtained; and f) micronizing the dried crystalline imepitoin. In the present invention when room temperature is indicated it is intended a temperature in the range from 20 to 25°C.

As a result of conducting the above process in order to solve the problem described above, the present inventors have succeeded in obtaining a new crystalline form of a compound represented by Formula (I).

Step a) of the process provides for charging 4-chlorophenyl hydantoin and morpholine in the presence of an organic solvent, thus obtaining a first reaction mixture.

Step a) is carried out in the presence of an organic solvent, preferably high boiling solvents, more preferably isobutyl alcohol.

More preferably, step a) is carried out with an amount of an organic solvent, preferably isobutyl alcohol, in the range from 0.5 to 20 volumes and in the presence of morpholine in the range from 0.5 to 20 molar equivalents. More preferably step a) is carried out under nitrogen atmosphere and stirring.

The first reaction mixture deriving from step a) is hence added in step b) with a catalytic amount of HCI and the slurry so obtained is heated to reflux, thus obtaining a second reaction mixture.

Preferably in step b) the catalytic amount of HCI is added as either gas or alcoholic solution and the slurry is heated to reflux for obtaining a second reaction mixture.

In step c) the second mixture is diluted with an organic solvent, cooled and maintained at room temperature, thus obtaining the crude product.

In a preferred embodiment in step c) the second reaction mixture is firstly cooled to 50-60°C and then diluted with more preferably methanol in an amount in the range from 0.5 to 20 volumes. Then the mixture is preferably left in such a state, more preferably for a time from 10 minutes to 5 hours, before being cooled at room temperature and maintained at this temperature over a preferred time period from 1 to 20 hours.

The heating to reflux of step b) and the preferred condition of long reaction times as per step c) permitted advantageously very good yields of the crude product.

In step d) the crude product is firstly isolated.

The product of step c) is advantageously isolated, preferably by filtration, and washed with more preferably methanol. The crude product so obtained is hence preferably a wet crude product. According to step d) the crude product is added with acetone for forming a slurry. Acetone was preferably added in an amount in the range from 2 to 20 volumes based on estimated dried substance.

Without being bound to any theory the inventors deem that the specific solvent acetone allows a better quality of the final crystalline product.

In step e) the slurry so obtained is stirred at a temperature in the range from room temperature and reflux, preferably for a time from 1 to 20 hours.

The suspension so obtained after a preferred cooling at room temperature is hence filtered, washed with preferably acetone, more preferably in an amount from 1 to 2 volumes. The wet product Imepitoin is hence dried under vacuum by heating, preferably, in the range from 40 to 70°C.

In step f) the dried crystalline Imepitoin is hence micronized for example by a ProMill8/FPS device.

Preferably the micronization step f) is carried out in the presence of a pressure in the range from 0.5- 10 ⁵ Pa to 1 .2- 10 ⁶ Pa with a feeding speed in the range from 1 kg/hour to 100 Kg/hour. The final particle size measurement was in the range from 2 pm to 50 pm, more preferably with D90 lower than 10 pm as measured with Malvern, Model Mastersizer 3000.

As it will be evident from the experimental part, the process of the invention allowed to obtain the crystalline form of Imepitoin here disclosed and claimed in a reproducible way with respect to the prior art method of obtaining Imepitoin that produced always different crystalline forms by repeating the same processes as disclosed in the prior art.

In another aspect the invention relates to the above new crystalline form for use in the veterinary field.

In a still another aspect the invention relates to the above crystalline form for use as medicament, i.e. as a drug substance suitable for preparing pharmaceutical drugs.

EXPERIMENTAL PART

Example 1 . Preparation of the new crystalline form of imepitoin

In a 500 ml flask, under nitrogen atmosphere and stirring, 4-chlorophenyl hydantoin (1 eq), isobutyl alcohol (3 volumes) and morpholine (11 eq) were sequentially charged. Keeping the reaction temperature at 20-25°C a solution of 22.0% HCI (gas) in isobutyl alcohol (1 eq of HCI) was slowly added over a period of 1 h (high exotermic reaction). The resulting thick slurry was heated to reflux and held for 48 hours. The reaction mixture was cooled to 70-75°C and methanol (8 vol) was added and the mixture was stirred at this temperature for 30 minutes. The suspension was cooled to 20-25°C held for about 1 hour, filtered and the product was washed with methanol (1.5 vol) to give wet crude Imepitoin (yield about 70%).

A slurry of wet crude product (1 eq) in acetone (10 vol) was heated at 53-55°C and stirred for 1 hour. The suspension was cooled at 20-25°C, held for 1 hour, filtered and washed with acetone (1 vol).

The purified wet Imepitoin is dried under vacuum, heating at 60°, for about 16 hours to give the compound as white powder (yield about 95 %)

Dried Imepitoin was then micronized with ProMill8/FPS device.

Conditions:

- pressure in the range from 0.5 10 ⁵ Pa to 1.2-10 ⁶ Pa, preferably T 10 ⁶ Pa with a feeding speed in the range from 1 kg/hour to 100 Kg/hour, preferably 5 Kg/hour. The final particle size measurement was in the range from 2 pm to 50 pm, more preferably with D90 lower than 10 pm.

Example 2. The new crystalline form

The procedure as indicated in example 1 was repeated three times and the samples of the product finally obtained were analyzed through X-Ray Powder Diffraction measurements (XRPD).

XRPD measurements were performed by using a Bruker D5005 diffractometer (Broker BioSpin, Fallanden, Switzerland) using CuKa radiation (A = 1.54056 A), graphite monochromator, and scintillation detector. The patterns were collected in air at room temperature in step scan mode with a step size of 0.02° and counting time of 3 s per step in the angular range 29 of 5-35 ⁰ (voltage = 40 kV, current intensity = 40 mA).

In Figure 1 the XRPD patterns of three samples of the micronized Imepitoin of the new crystalline form of Imepitoin are reported. It is evident that the patterns of all the three samples were almost equal. All peaks are always present, and the relative intensities of the peaks were similar in the patterns of the three samples.

In tables 1 -3 the angular positions and the relative intensities of the main peaks are reported.

Table 1

As it is evident by comparing the values reported in the table 1-3 the relevant peaks were always the same for the three samples, thus confirming that the obtained Imepitoin was made of the same crystalline phase.

Example 3

Preparation of crystalline Imepitoin according to prior art processes

The preparation reported in US5.869.481 until the recrystallization has been repeated. The recrystallization from n-propanol or from other alcohols as suggested in the article were repeated. The solvent ethanol and n-propanol were hence used for precipitating the crystalline form of imepitoin.

Each recrystallization from the crude product from ethanol or n-propanol was repeated three times.

The tests carried out in the laboratory were:

IM ITO 71/22 B:first crystallization by using ethanol

IMITO 71/22 C:second crystallization by using ethanol

IMITO 71/22 D:third crystallization by using ethanol

IMITO 71/22 G first crystallization by using n-propanol

IMITO 71/22 H second crystallization by using n-propanol

IMITO 71/22 I third crystallization by using n-propanol

The final product of crystallized Imepitoin were hence analyzed through X-Ray Powder Diffraction measurements (XRPD).

XRPD measurements were performed by using a Bruker D5005 diffractometer (Broker BioSpin, Fallanden, Switzerland) using CuKa radiation (A = 1.54056 A), graphite monochromator and scintillation detector. The patterns were collected in air at room temperature in step scan mode with a step size of 0.02° and counting time of 3 s per step in the angular range 29 of 5-35 ° (voltage = 40 kV, current intensity = 40 mA).

All the diffraction patterns were reported in the same graph. As it is evident from figure 2 the patterns of all the samples were not superimposable. The relevant peaks were different from one solvent to another one and in case of using the same solvent from the first crystallization to the second or the third ones. This meant that the results were not reproducible by repeating the crystallization by always using the same solvent.

The inventors hence tried to use different solvents such as xilene, chlorobenzene and the patterns finally obtained were never reproducible. The tests were as follow:

IM ITO 69/22 G pulping process by using xylene

IMITO 69/22 H crystallization from xylene

IMITO 69/22 L crystallizationfrom chlorobenzene and drying at high temperature

IMITO 69/22 T crystallization from chlorobenzene The TGA analyses showed that no solvates were formed.

The various crystallization patterns are reported in figure 3. As it is evident from figure 3 the patterns of all the samples were not superimposable. The results were not reproducible by repeating the crystallization.

Therefore it was evident that the process procedure of the invention was the only one that guaranteed the reproducibility of the same crystalline form of Imepitoin.