EA043016B1 - PHARMACEUTICAL COMPOUND, METHOD FOR ITS PRODUCTION AND APPLICATION AS A MEDICINE - Google Patents

Description

The invention relates to the crystalline form of the compound (I)

at which the crystalline form exhibits the strongest reflection, expressed in the value of 2Θ, at 25 ± 0.2°, determined using the X-ray powder diffraction method. The invention also relates to a method for obtaining a crystalline form, as well as pharmaceutical compositions containing a crystalline form. In addition, the invention relates to methods of using this crystalline form as a drug and, in particular, as an anesthetic.

Prerequisites for creating an invention:

Compound (I) (7-bromo-3-propoxy-5-(2-chlorophenyl)-1,3-dihydrobenzo[e][1,4]diazepin-2-one) is a compound known in the art. In particular, 7-bromo-3-propoxy-5(2-chlorophenyl)-1,3dihydrobenzo[e][1,4]diazepin-2-one and a method for its synthesis are described in UA patent No. 108246 (see Application 3- alkoxy-1,2-dihydro-3H-1,4-benzodiazepin-2-ones as highly active analgesic agents, Pavlovsky V.I., Semenishina K.A., Andronati S.A., Kabanova T.A., Khalimov A I., Reder A.S.; application No. a 2013 01685; published on 10.04.2015, Bull. No. 7).

The international application (see WO 2018/067102) relates to medicinal chemistry, in particular to the use of 7-bromo-3-propoxy-5-(2-chlorophenyl)-1,2-dihydro-3H-1,4-benzodiazepine-2 -on as a drug that suppresses neuropathic pain without damaging the gastric mucosa (ulcerogenic effect) and has anticonvulsant properties.

The crystalline state of the compound is an important aspect when using the compound for pharmaceutical purposes. Unlike substances in the amorphous state, the physical properties of a compound in the crystalline state may change, which may affect its suitability for pharmaceutical use.

Polymorphism is the ability of a solid to exist in more than one crystalline form, each of which has different orientations and/or conformations of molecules in the crystal lattice. Each of the forms of the crystalline state or polymorph has a unique set of physicochemical properties due to differences in the crystal structure.

In addition, polymorphs may have different mechanical properties, such as fluidity and densification, which affect the processing properties of the joint. The stability and shelf life of the compound may also depend on the polymorph.

Polymorphs can be distinguished from each other using various methods. The polymorphs exhibit differences in vibrational spectroscopic characteristics, which can be determined, for example, using the method of infrared spectroscopy, Raman spectroscopy (Raman spectroscopy) and 13 C-NMR spectroscopy. Given that each crystalline form refracts X-rays differently, X-ray powder diffraction (XRD) can be used to characterize polymorphs. In addition, thermal methods such as differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) can display unique information about a particular polymorph.

Compound (I), which is described in UA Patent No. 108246 and in International Application WO 2018/067102, has been found to have a specific crystal structure, designated Form I in this invention. FIG. 1 shows an X-ray diffraction pattern of a powder of a crystalline compound, which is described in the patent UA No. 108246 Ukraine and in the International application WO 2018/067102. As shown in FIG. 1, the strongest reflection, expressed in terms of 2Θ, is observed at approximately 19°. In FIG. 2 shows a DSC thermogram of a sample of a crystalline compound described in Ukraine patent No. 108246 and in International application WO 2018/067102. Based on FIG. 2, an endothermic transition is observed at a temperature that is about 195°C. Based on this, the melting point of Form I is about 195°C.

The invention is based on the following tasks:

obtaining a crystalline form that has the same or greater analgesic effect compared to the known crystalline forms of the compound (I);

obtaining a crystalline form that has a higher or comparable bioavailability compared to known crystalline forms of the compound (I) or combinations thereof;

obtaining a crystalline form that exhibits less or similar toxicity compared to known crystalline forms of the compound (I) or combinations thereof.

The problem is solved in the first invention in that the proposed crystalline form of the compound (I)

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at which the crystalline form exhibits the strongest reflection, expressed in the value of 2Θ, at 25 ± 0.2°, determined using the X-ray powder diffraction method. Each aspect or embodiment of the present invention defined by this patent may be combined with any other aspect(s) or embodiment(s) unless expressly stated otherwise. In particular, any feature marked as superior or advantageous may be combined with another feature or features marked as superior or advantageous.

The second invention proposes a method for obtaining a crystalline form, which is described in this patent, the method includes:

(i) dissolving compound (I) in dimethyl sulfoxide to obtain a solution of compound (I) in dimethyl sulfoxide;

(ii) adding a solution of compound (I) in dimethyl sulfoxide to water to obtain a suspension of compound (I);

(iii) obtaining a precipitate of the crystalline form of the slurry of the compound (I), as described in this patent, when precipitating from the slurry of the compound (I).

Another aspect of the present invention is to provide a pharmaceutical formulation comprising the crystalline form as described in this patent and at least one pharmaceutically acceptable excipient.

Another aspect of the present invention is to provide a crystalline form as described in this patent or a pharmaceutical composition as described in this patent for therapeutic use.

Another aspect of the present invention is the provision of a crystalline form, which is described in this patent, or a pharmaceutical composition, which is described in this patent, for use as a drug.

Another aspect of the present invention is to provide a crystalline form as described in this patent or a pharmaceutical composition as described in this patent for use in the treatment and prevention of neuropathic pain.

Another aspect of the present invention is to provide a crystalline form as described in this patent or a pharmaceutical composition as described in this patent for use in the treatment and prevention of nociceptive pain.

Another aspect of the present invention is to provide a crystalline form as described in this patent or a pharmaceutical composition as described in this patent for use in the treatment and prevention of diabetic neuropathy.

Another aspect of the present invention is to provide a method for treating or preventing neuropathic pain in a patient (human or animal) comprising administering to a patient in need thereof a sufficient amount of the crystalline form described in this patent or the pharmaceutical composition described in this patent.

Another aspect of the present invention is to provide a method for treating or preventing nociceptive pain in a patient (human or animal) comprising administering to a patient in need thereof a sufficient amount of a crystalline form as described in this patent or a pharmaceutical composition as described in this patent. .

Another aspect of the present invention is to provide a method for treating or preventing diabetic neuropathy in a patient (human or animal) comprising administering to a patient in need thereof a sufficient amount of a crystalline form as described in this patent or a pharmaceutical composition as described in this patent. . Other possible uses for the compounds of the invention are given in this patent and in particular in the examples.

The inventors of this invention unexpectedly found that the crystalline form of the present invention has a greater or similar analgesic effect compared to known crystalline forms of the compound (I).

The inventors of this invention unexpectedly found that the crystalline form of the present invention has a higher or similar bioavailability compared to known crystalline forms of the compound (I) or compositions thereof.

The inventors of this invention unexpectedly found that the crystalline form of the present invention has a similar toxicity as compared to known crystalline forms of the compound (I) or compositions thereof.

Without being limited by theory, it is believed that the crystalline form of the present invention tends to exhibit the advantageous effects that have been described above due to its crystalline structure.

Scientific and technical terms used in relation to this invention should have the meanings generally recognized by experts in this field, unless otherwise indicated. The meaning and scope of the terms should be clear, however, in the event of any hidden ambiguity, the definitions given in this patent take precedence over any official or third party definitions.

The claimed invention relates to the crystalline form of the compound (I)

at which the crystalline form exhibits a strong reflection, expressed in the value of 2Θ, at 25 ± 0.2°, determined by X-ray powder diffraction.

All powder diffraction patterns are determined using copper radiation unless otherwise noted.

In general, the crystalline form additionally reflects one or more reflections, expressed in terms of 2Θ, at one or more values with 17.8 ± 0.2°, 19.4 ± 0.2°, 20.9 ± 0.2° and 27.5 ± 0.2° determined using X-ray powder diffraction. The crystalline form additionally reflects two or more reflections, expressed in terms of 2Θ, at two or more values with 17.8 ± 0.2°, 19.4 ± 0.2°, 20.9 ± 0.2° and 27.5 ± 0.2° determined using X-ray powder diffraction. To a greater extent, the crystalline form additionally reflects three or more reflections, expressed in terms of 2Θ, with three or more values with 17.8 ± 0.2°, 19.4 ± 0.2°, 20.9 ± 0.2° and 27.5 ± 0.2° determined using the X-ray powder diffraction method. Most preferably, the crystal form additionally reflects four reflections, expressed in terms of 2Θ, at four or more values with 17.8 ± 0.2°, 19.4 ± 0.2°, 20.9 ± 0.2° and 27 .5 ± 0.2° determined using the X-ray powder diffraction method.

Advantageously, the X-ray powder diffraction pattern of the crystalline form as described in this patent has no 2Θ reflections at 15.1 ± 0.2°.

Preferably, the crystalline form has a melting point of 186 to 191°C. More preferably, the crystalline form has a melting point of 187 to 190°C. Even more preferably, the crystalline form has a melting point of 187.5 to 189.5°C. Most preferably, the crystalline form has a melting point of about 188 to about 189°C.

The melting point is determined using the method of differential scanning calorimetry (DSC), unless expressly stated otherwise.

The invention proposes a method for obtaining a crystalline form, which is described in this patent, the method includes:

(i) dissolving compound (I) in dimethyl sulfoxide to obtain a solution of compound (I) in dimethyl sulfoxide;

(ii) adding a solution of compound (I) in dimethyl sulfoxide to water to obtain a suspension of compound (I);

(iii) obtaining a precipitate of the crystalline form of the suspended compound (I), which is described in this patent, by precipitation from the suspension of the compound (I).

Compound (I) in step (i) may be in any form. For example, compound (I) in step (i) may be amorphous or have a crystalline form such as Form I, which is the crystalline form of compound (I) obtained by the method described in UA Patent No. 108246 and International Application WO 2018/ 067102. Advantageously, compound (I) in step (i) is the crystalline form of the compound obtained by the method described in UA Patent No. 108246 and International Application WO 2018/067102.

Preferably, the solution of compound (I) in dimethyl sulfoxide is a saturated solution of compound (I) in dimethyl sulfoxide.

More preferably, the step of dissolving compound (I) in dimethyl sulfoxide comprises dissolving 0.5 to 1.5 g of compound (I) in dimethyl sulfoxide, with a volume of 5 to 15 ml. More preferably, the step of dissolving compound (I) in dimethyl sulfoxide comprises dissolving 0.75 to 1.25 g of compound (I) in dimethyl sulfoxide, in a volume of 8 to 12 ml. Most preferably, the step of dissolving compound (I) in dimethyl sulfoxide comprises dissolving 0.9 to 1.1 g of compound (I) in dimethyl sulfoxide, in a volume of 9 to 11 ml.

Preferably, the process of adding a solution of compound (I) in dimethyl sulfoxide to water (step (ii)) is carried out at temperatures ranging from 15 to 25°C. It is preferable that the process

- 3 043016 addition of a solution of compound (I) in dimethyl sulfoxide to water (stage (ii)) is carried out at temperatures from 17 to 23°C, or from 18 to 22°C, most preferably from 19 to 21°C.

Preferably, the process of adding a solution of compound (I) in dimethyl sulfoxide to water (step (ii)) is carried out at pressures from 100 to 103 kPa. Preferably, the process of adding a solution of compound (I) in dimethyl sulfoxide to water (step (ii)) is carried out at pressure values from 100.5 to 102.5 kPa, more preferably at values from 101 to 102 kPa. Most preferably, the process of adding a solution of compound (I) in dimethyl sulfoxide to water (step (ii)) is carried out at a pressure value of about 101.325 kPa (atmospheric pressure).

Preferably, the step of adding a solution of compound (I) in dimethyl sulfoxide to water (step (ii)) comprises adding 5-15 ml to 50-150 ml of water. More preferably, the step of adding a solution of compound (I) in dimethyl sulfoxide to water (step (ii)) comprises adding 7.5-12.5 ml of the solution in 75-125 ml of water. Most preferably, the step of adding a solution of compound (I) in dimethyl sulfoxide to water (step (ii)) comprises adding 9-11 ml to 90-110 ml of water.

Preferably, the precipitation process (step (iii)) of the suspended Compound (I) in the suspension of compound (I) takes place at temperatures between 15 and 25°C. Preferably, the precipitation (step (iii)) of the suspended compound (I) in the suspension of compound (I) takes place at a temperature of 17 to 23°C or 18 to 22°C, most preferably 19 to 21°C.

Preferably, the precipitation process (step (iii)) of the suspended compound (I) in the suspension of compound (I) takes place at pressures of 100 to 103 kPa. Preferably, the precipitation process (step (iii)) of the suspended compound (I) in the suspension of compound (I) takes place at pressures from 100.5 to 102.5 kPa, even more preferably at pressures from 101 to 102 kPa. Most preferably, the precipitation process (step (iii)) of the suspended compound (I) in the suspension of compound (I) takes place at a pressure value of about 101.325 kPa (atmospheric pressure).

Preferably, the slurry obtained in step (ii) is agitated for at least 10 minutes, more preferably at least 15 minutes, even more preferably at least 20 minutes and most preferably about 30 minutes before the precipitation step (iii) of the suspended compound (I).

Preferably, the suspended compound (I) in the suspension of compound (I) is precipitated (step (iii)) within 30 minutes to 10 hours, more preferably 1 to 7 hours, even more preferably 1 to 5 hours, most preferably 2 to 4 hours

Preferably, the further process includes filtering the crystalline form of the compound (I) after its precipitation in step (iii). Preferably, the further process includes vacuum filtration of the crystalline form of Compound (I) after its precipitation in step (iii). Preferably, the further process comprises washing with water the crystalline form of the compound (I) obtained in step (iii). Alternatively, it is advantageous that the crystalline form of the compound (I) obtained in step (iii) is filtered and then washed with water.

Preferably, the further process includes drying the crystalline form of the compound (I) obtained in step (iii). Alternatively, it is preferable that the crystalline form of the compound (I) obtained in step (iii) is filtered followed by drying. Alternatively, it is more preferable that the crystalline form of the compound (I) obtained in step (iii) is filtered, then washed with water, followed by drying. Preferably, the drying process of the crystalline form of the compound (I) takes place at a temperature of 100 to 140°C, more preferably at a temperature of 110 to 130°C, most preferably at a temperature of 115 to 125°C.

This invention provides a pharmaceutical composition comprising the crystalline form described in this patent and at least one pharmaceutically acceptable excipient.

Appropriate pharmaceutically acceptable excipients may be known to the person skilled in the art, e.g., fats, water, saline, alcohol (e.g. ethanol), glycerol, polyols, aqueous glucose solution, swelling agent, disintegrating agent, binder, lubricant or lubricant. , a wetting agent, a stabilizer, an emulsifier, a dispersant, a preservative, a sweetener, a coloring agent, a taste corrector or flavoring agent, a concentrating agent, a solvent, a buffering agent, a solvent or solubilizing agent, a compound that extends shelf life, a salt for modifying osmotic pressure, a film-forming agent, or antioxidant; sugars such as, but not limited to, lactose or glucose; starch of corn, wheat or rice; fatty acids such as stearic acid; inorganic salts such as magnesium aluminum silicate or anhydrous calcium phosphate; synthetic polymers such as polyvinylpyrrolidone or polyalkylene glycol; alcohols such as stearyl alcohol or benzyl alcohol synthetic cellulose derivatives such as methylcellulose, carboxymethylcellulose, ethylcellulose or hydroxypropylmethylcellulose; and other additives commonly used such as gelatin, talc, vegetable oil and gum arabic.

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Preferably, the pharmaceutical composition includes one or more other pharmaceutically active ingredients.

This invention provides the crystalline form described in this patent, or the pharmaceutical composition described in this patent, for therapeutic use.

This invention provides a crystalline form as described in this patent or a pharmaceutical composition as described in this patent for use as a medicine.

This invention provides the crystalline form described in this patent, or the pharmaceutical composition described in this patent, for use in the treatment and prevention of neuropathic pain. Preferably the neuropathic pain is central neuropathic pain. Alternatively, preferably, the neuropathic pain is peripheral neuropathic pain.

This invention provides the crystalline form described in this patent or the pharmaceutical composition described in this patent for use in the treatment and prevention of nociceptive pain.

This invention provides the crystalline form described in this patent or the pharmaceutical composition described in this patent for use in the treatment and prevention of diabetic neuropathy.

Also proposed is the use of the crystalline form described in this patent, or the pharmaceutical composition described in this patent, for the manufacture of a drug for the treatment of neuropathic pain. Preferably, the neuropathic pain is central neuropathic pain. Alternatively, preferably, the neuropathic pain is peripheral neuropathic pain.

Also proposed is the use of the crystalline form described in this patent, or the pharmaceutical composition described in this patent, for the manufacture of a drug for the treatment of diabetic neuropathy.

Also proposed is the use of the crystalline form described in this patent, or the pharmaceutical composition described in this patent, for the manufacture of a drug for the treatment and prevention of nociceptive pain.

This invention relates to a method for the treatment or prevention of neuropathic pain in a patient (human or animal), which includes administering to a patient in need thereof, the desired amount of the crystalline form described in this patent, or the pharmaceutical composition described in this patent. Preferably the neuropathic pain is central neuropathic pain. Alternatively, preferably the neuropathic pain is peripheral neuropathic pain.

This invention relates to a method for the treatment or prevention of nociceptive pain in a patient (human or animal), which includes administering to a patient in need of it, the desired amount of the crystalline form described in this patent, or the pharmaceutical composition described in this patent.

The present invention relates to a method for treating or preventing diabetic pain neuropathy in a patient (human or animal) comprising administering to a patient in need thereof an appropriate amount of the crystalline form described in this patent or the pharmaceutical composition described in this patent.

The terms containing, including and has characterize the combination of elements and mean the possible presence of additional elements, in addition to those listed.

The above detailed description has been provided by way of explanation and illustration, and is not intended to limit the scope of the claims provided. A significant number of variations in the present advantageous embodiments of the present invention, which have been illustrated in this patent, will be obvious to a person of ordinary skill in this field, and will remain within the scope of the claims and their equivalents.

These and other aspects of the present invention will be described below with reference to the accompanying drawings, in which:

in fig. 1 shows an X-ray powder diffraction pattern of the crystalline compound described in UA Patent No. 108246 and WO 2018/067102 (Form I/Comparative Example 1);

in fig. 2 is a DSC thermogram of a crystalline compound described in UA Patent No. 108246 and WO 2018/067102 (Form I/Comparative Example 1);

in fig. 3 is an X-ray powder diffraction pattern of the crystalline form of Comparative Example 1 (Form II);

in fig. 4 is a DSC thermogram of the crystalline form of Invention Example 1 (Form II).

experimental part

Powder X-ray diffraction studies were carried out using a Siemens D500 5 043016 diffractometer (copper radiation, graphite monochromator on the secondary beam, geometry

Bragg-Brentano).

X-ray single crystal studies were carried out using an Xcalibur3 diffractometer (molybdenum radiation, graphite monochromator, Sapphire3 CCD detector, ω-scan, 2Θmax=50°) at room temperature (about 20°C) and atmospheric pressure (about 101.325 kPa).

Thermographic studies were carried out using a DSC Q2000 Thermo Scientific differential scanning calorimeter, heating rate 5°C/min, heating range 20-210°C.

Crystal size information was obtained using a Mastersizer 3000 Malvent diffractometer; the substance was introduced into a dispersant containing a 1% aqueous solution of sodium lauryl sulfate, kept under ultrasound for 5 min, laser quenching 8-13%.

Micronization (mechanical grinding) was carried out on a laboratory mill Tube Mill control (IKA, Germany) by a method known in the art.

Examples of specific implementation of the inventions

The following examples are given to illustrate the present invention and do not limit it.

Comparison example 1.

Compound (I) was prepared as described in UA Patent No. 108246 and International Application WO 2018/067102.

A sample of this compound (I) was analyzed using copper X-ray powder diffraction on a Siemens D500 diffractometer (copper beam, secondary beam graphite monochromator, Bragg-Brentano geometry). The X-ray powder diffraction image of this Compound (I) is shown in FIG. 1. In particular, the strongest reflection, expressed in terms of 2Θ, is observed at 19°. Compound (I), which is prepared as described in UA Patent No. 108246 and International Application WO 2018/067102, has a specific crystal structure, designated in this patent as Form I.

A sample of the same compound (Form I) was analyzed using differential scanning calorimetry (DSC). The DSC thermogram is shown in Fig. 2. As shown in FIG. 2, an endothermic transition is observed at about 195°C. Based on this Form I has a melting point of about 195°C.

Single crystal x-ray studies were also carried out on Form I of compound I. The results are shown in table. 1 below. Crystals of Form I were obtained by prolonged isothermal (20°C) evaporation (about 1 month) of a sample of compound (I) in Form I (comparison example 1), previously dissolved in ethanol, in a sample vial closed with a dry ground glass stopper.

Example 1

A sample of compound (I), prepared as described in UA patent No. 108246 and International application WO 2018/067102, is dissolved in dimethyl sulfoxide. In particular, 1 g of a sample of compound (I) is dissolved in 10 ml of dimethyl sulfoxide at a room temperature of about 20°C. The resulting solution is slowly added to water at room temperature (10 ml per 100 ml of water), while stirring vigorously, the resulting suspension is stirred for another 30 minutes. Then the stirring is completed and the suspension is left to settle for 3 hours. The resulting precipitate is filtered off with a vacuum filter using filter paper, washed three times with purified water (100 ml each time) and dried in a drying and heating chamber (FD universal drying and heating chamber -115 from Binder Gmbh, Germany) at 120°C.

The resulting crystalline sample was analyzed by powder X-ray diffraction using copper radiation on a Siemens D500 diffractometer (copper radiation, graphite monochromator on the secondary beam, Bragg-Brentano geometry). The powder X-ray diffraction pattern of the resulting sample is shown in FIG. 3. In particular, the strongest reflection, expressed in terms of 2Θ, is observed at 25 ± 0.2°. The crystalline form is designated Form II.

A Form II sample was analyzed using differential scanning calorimetry (DSC). The DSC thermogram is shown in Fig. 4. As shown in FIG. 4, an endothermic transition occurs at about 188°C. Based on this Form II has a melting point of about 188°C.

Single crystal X-ray studies were also carried out on Form II of compound (I). To obtain a sample for single-crystal X-ray examination, crystals of form II were obtained by long-term isothermal (20°C) evaporation (about 1 month) of a sample of compound (I) in form II (Example of the invention 1), previously dissolved in isobutyl alcohol in a sampling vial, closed with a dry glass ground stopper. As shown below in Table. 1, Form II crystallizes in the monoclinic space group Cc with lattice parameters a=10.9301 (9) A, b=19.7560 (14) A, c=8.5894 (8) Α, β=108.165 (11) and a cell volume of 1762.3 (3) A3.

Comparison of the main crystallographic data of two polymorphic forms of compound (I) is given in Table 6 043016. 1.)

Comparison of Invention Example 1 and Comparison Example 1

Basic crystallographic data and structure refinements of Form I and Form II of Compound (I) (single crystal data).

Table 1

Sample form I \ Form II Empirical formula C ₁₈ H ₁₆ BrClN ₂ O ₂ M _g , a.u.m 407.69 T,K 293(2) λ (ΜοΚα), A 0.71073 Syngony, space group Monoclinic, R 2 Us Monoclinic, C s Lattice parameters (А, °) a=11.7032(15), b=21.5185(17), c=14.509(2), β= 92.867(12) a=10.9301(9), b=19.7560(14), c=8.5894(8), β=108.165(11) Cell volume V, A ³ 3649.3(7) 1762.3(3) Z 8 4 Density d ^ g / cm ³ 1.484 1.537 Coeff, attenuation μ(ΜοΚα), mm' ¹ 2.411 2.497 Fooo 1648 824 Crystal dimensions, mm 0.40x0.12x0.01 0.15x0.12x0.05 Angle interval, ° 2.97<Θ<26.00 3.66<Θ<26.00 Index limits -13<h<14,-26<k<26, -17<1<17 -13<h<13,-24<k<24,10<1<9 Reflections measured/independent 26808/6741 ( _Rint =0.202) 6317/2698 ( _Rint =0.0971) Completeness of coverage, % 93.9 97.4 Transmission _Tmax / _Tmin 0.598/0.128 0.885/0.706 refinement method Full-matrix least squares by F w Data/parameters in OLS 6741/434 2698/222 5 0.980 0.964 Flack parameter - 0.02(2) R-factor for observed neg. (/>2σ/) R^O.0796, wR ² =0.1357 R^O.0590, wR ² =0.1096 R-factor for all neg. Κχ=0.2195, ^wR2 =0.1837 R^O. 1137, wR ² =0. 1391 Ap _ma ax/Ap _m in, EL/A ³ 0.806/-0.364 0.381/-0.386

Example 2 Determination of the median lethal dose (LD50) of polymorphic forms of compound (I)

The preliminary ratio of a substance to a certain toxicity class is determined by an indicator that quantitatively characterizes the acute toxicity of the compound - the dose of a substance that causes a lethal effect in 50% of the animals in the experimental group (LD50). Determining this indicator in one of the types of experimental animals makes it possible to extrapolate it to other species and justify the dose limits for the first phase of clinical trials.

In order to estimate the mean lethal dose of the various polymorphic forms of compound (I), they were administered (as a stabilized suspension in physiological sodium chloride solution) in increasing doses orally (one of the modes of administration expected in clinical use, for example) to experimental animals (mice), and the lethal effect was determined in the experimental groups within 14 days after administration. Animal mortality/survival rates by the end of the observation period were used to calculate the mean dose.

The LD50 values for Form I and Form II samples were determined to be 1121 ± 190 mg/kg for Form I and 1475 ± 402 mg/kg for Form II.

The obtained values of LD ₅₀ do not have statistically significant differences from each other, on the basis of which it can be concluded that in the doses used, the two polymorphs of compound (I) have comparable toxicity. Based on the LD ₅₀ values for oral administration of the two polymorphs, Compound (I) can be assigned to toxicity class IV (compound with low toxicity) regardless of the polymorph.

Example 3 Analgesic Effect of Crystal Forms of Compound (I) in a Thermal Nociception Model (Tail Flick Test)

Antinociceptive (analgesic) activity was assessed in rats in a tail flick test using a tail-focused light beam. The reaction delay time was determined by the flick of the tail from the light source and was expressed in seconds. Animals were randomized with respect to the initial value of the latent period with parameters from 4 to 12 seconds. The size of the antinociceptive effect was determined by the increase in the duration of the latent period (pain sensitivity threshold, PSP). The output parameters of the PCB and their changes 2 hours after the administration of the test compound were compared. Calculation of ED ₅₀ (mean effective dose) in terms of analgesic activity in this model for rats was carried out using the least squares method.

The tail flick test was performed with three prepared test samples of compound (I):

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The first test sample was prepared using the sample of Comparative Example 1 (Form I). Namely, the sample of Comparative Example 1 was dispersed in saline and stabilized with Tween 80. The crystal structure (Form I) remained unchanged.

A second test sample was prepared using a sample of Comparative Example 1 (Form I), which was mechanically ground by micronization to obtain a test sample of Form I and has a smaller average particle size. Next, the micronized sample was dispersed in saline and stabilized with Tween 80. The crystal structure (Form I) remained unchanged.

A third test sample was prepared using the sample of Invention Example 1 (Compound (I) in crystalline Form II). Namely, a sample of Invention Example 1 was dispersed in saline and stabilized with Tween 80. The crystal structure (Form II) remained unchanged. The third sample had a similar average particle size when compared side by side with the second sample.

The results are shown in table. 2.

table 2

As shown in Table. 2, the value of the average effective dose for Form II (0.17 mg/kg) is significantly lower than for Form I (1.82 mg/kg). The mean effective dose value for Form II (0.17 mg/kg) is also significantly lower than the _ED50 for micronized Form I (1.06 mg/kg), despite the fact that the average particle sizes are largely the same (average particle size with volume fraction 90% < ~ 50 µm).

Thus, these results indicate that there is no significant difference in the particle sizes of Form I and Form II, which may indicate that, with respect to nociceptive pain, Form II (Invention Example 1) surprisingly shows higher bioavailability compared to Form I (Comparative Example 1 ).

Example 4 Analgesic Effect of Crystal Forms of Compound (I) in an Acetic Acid Pain Model (Cramps) in Mice

In order to induce sharp visceral or somatic deep pain (nociceptive), the method of acetic acid writhing in mice was used. Mice were injected with 0.75% acetic acid solution intraperitoneally (at a dose of 0.1 ml per 10 g of body weight) 2 hours after administration of the test compound. The number of seizures was counted from the 1st to the 20th minute (inclusive) after the administration of acetic acid.

Calculation of ED ₅₀ (mean effective dose) analgesic effect in this model for mice was carried out using the least squares method.

Two samples of compound (I) were prepared by the dispersion method:

The first sample was a Form I sample.

A sample was prepared by adding a hot (65°C) saturated solution of Comparative Example 1 (Form I) in ethanol to water, at room temperature (about 20°C) and atmospheric pressure (about 101.325 kPa). The resulting Form I has a particle size (D(50)) of about 29 microns.

The second sample was a sample of Invention Example 1, that is, compound (I) in crystalline Form II. This sample was prepared by dispersing Invention Example 1 in saline stabilized with Tween 80. The crystalline form remained unchanged. The resulting Form II has a particle size (D(50)) of about 24.3 microns.

The results are shown in table. 3.

Table 3

Crystal form of Compound (I) Form I Form II ED50 (average effective dose), mg/kg 1.87 0.89

As shown in Table. 3, the value of the average effective dose for Form II (0.89 mg/kg) is significantly lower than for Form I (1.87 mg/kg). According to this pain model (particularly the treatment of nociceptive pain), Form II surprisingly exhibits more than twice the activity of Form I. higher bioavailability compared to Form I (comparative example 1).

Compound (I) is known to exhibit analgesic properties as demonstrated above and, for example, in WO 2018/067102. The results of Examples 3 and 4 indicate that Compound (I) Form II will exhibit a similar improved bioavailability for neuropathic (central and peripheral) pain and diabetic neuropathy.

These essential features make it possible to obtain such a technical result - to develop a simple method for obtaining a crystalline form of compound (I) and a pharmaceutical composition for use in the treatment and prevention of neuropathic pain, the prevention of nociceptive pain.

Claims (19)

1. Crystalline form of compound (I) (I) at which the crystalline form exhibits the strongest reflection, expressed as a 2Θ value, at 25 ± 0.2°, determined by X-ray powder diffraction. 2. A crystalline form according to claim 1, for which one or more reflections, expressed in terms of 2Θ, at one or more values of 17.8 ± 0.2°, 19.4 ± 0.2°, 20.9 ± 0 .2° and 27.5 ± 0.2° determined using the X-ray powder diffraction method. 3. A crystalline form according to claim 1 or 2, characterized in that its X-ray powder diffraction pattern has no reflection, expressed in terms of 2Θ, at 15.1 ± 0.2°. 4. The crystalline form defined in claims 1 to 3 has a melting point of 186 to 191°C. 5. The crystalline form defined in claims 1 to 4 has a melting point of 187 to 190°C. 6. The method for preparing the crystalline form defined in claims 1 to 5 includes: (i) dissolving compound (I) in dimethyl sulfoxide to obtain a solution of compound (I) in dimethyl sulfoxide; (ii) adding a solution of compound (I) in dimethyl sulfoxide to water to obtain a suspension of compound (I); (iii) obtaining a precipitate of the crystalline form of the suspended compound (I) specified in claim 1 by precipitation from the suspension of the compound (I). 7. The method according to claim 6, characterized in that the solution of compound (I) in dimethyl sulfoxide is a saturated solution of compound (I) in dimethyl sulfoxide. 8. The method defined in claim 6 or 7, characterized in that the process of adding a solution of compound (I) in dimethyl sulfoxide to water takes place at a temperature of from 15 to 25°C. 9. The method defined in claims 6 to 8, characterized in that the process of sedimentation of the suspended compound (I) in the suspension of the compound (I) occurs at a temperature of 15 to 25°C. 10. A pharmaceutical composition comprising a crystalline form as defined in claims 1 to 5 and at least one pharmaceutically acceptable excipient. 11. Pharmaceutical composition as defined in claim 10, characterized in that it additionally contains one or more pharmaceutically active ingredients. 12. The use of a crystalline form as defined in claims 1 to 5 or a pharmaceutical composition as defined in claims 10 or 11 in therapy. 13. Use of a crystalline form as defined in claims 1 to 5 or a pharmaceutical composition as defined in claims 10 or 11 as a drug. 14. The use of a crystalline form as defined in claims 1 to 5 or a pharmaceutical composition as defined in claims 10 or 11 in the treatment and prevention of neuropathic pain. 15. The use of a crystalline form as defined in claims 1 to 5 or a pharmaceutical composition as defined in claims 10 or 11 in the treatment and prevention of nociceptive pain. 16. The use of a crystalline form as defined in claims 1 to 5 or a pharmaceutical composition as defined in claims 10 or 11 in the treatment and prevention of diabetic neuropathy. 17. A method of treating or preventing neuropathic pain in a human or animal patient, comprising administering to a patient in need thereof the required amount of the crystalline form defined in claims 1 to 5 or a pharmaceutical composition that corresponds to claims 10 or 11 . 18. A method of treating or preventing nociceptive pain in a human or animal patient, comprising administering to a patient in need thereof an effective amount of the crystalline form defined in claims 1 to 5 or a pharmaceutical composition that corresponds to claim 10 - 9 043016 or 11. 19. A method of treating or preventing diabetic neuropathy in a human or animal patient, comprising administering to a patient in need thereof the required amount of the crystalline form defined in claims 1 to 5, or a pharmaceutical composition that corresponds to claim 10 or 11.