TWI751220B - Polymorphism of gnrh receptor antagonist and a preparation method thereof - Google Patents

Abstract

The present invention relates polymorphism of GnRH receptor antagonist and a preparation method thereof. In particular, the present invention relates a type A,B,C,D crystal of 1-(4-(7-(2,6-difluorobenzyl)-3-((dimethylamino)methyl)-5-(6-methoxypyridazin-3-yl)-4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-2-yl)phenyl)-3-methoxyurea(compound of formula (I)) and a preparation method thereof, pharmaceutical use thereof, and type A,B,C,D crystal of formula (I) and pharmaceutical composition in the preparation of a medicament for treating and/ or preventing GnRH receptor antagonist related diseases.

Description

A kind of polymorphic form of GnRH receptor antagonist and preparation method thereof

The present invention relates to 1-(4-(7-(2,6-difluorobenzyl)-3-((dimethylamino)methyl)-5-(6-methoxypyridazin-3-yl) A of -4,6-dicarbonyl-4,5,6,7-tetrahydro- 2H -pyrazolo[3,4- d ]pyrimidin-2-yl)phenyl)-3-methoxyurea , B, C, D crystal form and preparation method, its application in pharmaceutical composition, and this A, B, C, D crystal form, its pharmaceutical composition are related to GnRH receptor antagonist in preparation treatment and/or prevention Use in medicine for disease.

Endometriosis is a common estrogen-dependent gynecological disease that often occurs during the reproductive years of women, and its mechanism of action is unclear. Currently, endometriosis is mainly diagnosed by laparoscopic surgery and treated by surgery or controlled by taking birth control pills, GnRH receptor agonists or progestins to reduce estrogen levels in the body.

Gonadotropin-releasing hormone (GnRH), also known as luteinizing hormone-releasing hormone (LHRH), is a central regulator in the endocrine reproductive system. The secretion and release of gonadotropins such as luteinizing hormone (LH) and follicle-stimulating hormone (FSH) regulate the normal development of the ovary and corpus luteum, and play an important role in the hypothalamic-pituitary-gonadal axis. The GnRH receptor exerts its regulatory role by coupling with G proteins capable of initiating the calcium phosphatidylinositol second messenger system, while LH regulates the production of sex steroids, and FSH regulates spermatogenesis in males and follicular development in females.

LH and FSH are released into the circulation and bind to receptors on specific cells of the ovary or testis to stimulate steroid production. In the presence of sex steroids, diseases such as endometriosis, uterine fibroids, and prostate cancer are exacerbated, and long-acting peptide GnRH receptor agonists and antagonists are required for treatment control.

Peptide compounds have many unsolved problems including oral absorption, dosage form, dose volume, drug stability, sustained action, and metabolic stability. The main reason why small-molecule GnRH receptor antagonist therapy is better than existing peptide-based therapy is that small-molecule GnRH receptor antagonist can be directly administered orally, which is convenient and quick.

The mechanism of indirect tumor inhibition mediated by GnRH receptor agonists is through long-term effects on the hypothalamus-pituitary-gonadal axis, resulting in the reduction of pituitary gonadotropins (FSH, LH), thereby reducing the secretion of sex hormones and indirectly inhibiting the growth of tumor cells . GnRH receptor antagonists directly inhibit the release of pituitary gonadotropins, thereby inhibiting the growth of tumor cells.

At present, a series of small molecule GnRH receptor antagonist patents have been disclosed, including WO2006096785, WO2010026993, WO2011076687, WO2012175514 and so on. Small molecule GnRH receptor antagonists have good application prospects in the pharmaceutical industry as drugs. The applicant provided a novel structure of GnRH receptor antagonists with high efficiency and low toxicity in patent application WO2015062391A1 (published on 2015.05.07), It has excellent effects and effects, and can effectively treat endocrine and reproductive system diseases, its chemical name is 1-(4-(7-(2,6-difluorobenzyl)-3-((dimethylamino)methyl) -5-(6-Methoxypyridazin-3-yl)-4,6-dicarbonyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidine-2 -yl)phenyl)-3-methoxyurea, the structure is as follows

The crystal structure of a medicinal active ingredient often affects the chemical stability of the drug. Different crystallization conditions and storage conditions may lead to changes in the crystal structure of the compound, sometimes accompanied by the generation of other crystal forms. Generally speaking, amorphous pharmaceutical products have no regular crystal structure and often have other defects, such as poor product stability, finer crystallization, difficult filtration, easy agglomeration, and poor fluidity. Therefore, it is necessary to improve various properties of the above products, and we need to conduct in-depth research to find new crystal forms with higher crystal purity and good chemical stability.

The technical problem to be solved by the present invention is to provide a kind of 1-(4-(7-(2,6-difluorobenzyl)-3-((dimethylamino)methyl)-5-(6-methoxyl) Pyridazin-3-yl)-4,6-dicarbonyl-4,5,6,7-tetrahydro- 2H -pyrazolo[3,4- d ]pyrimidin-2-yl)phenyl)-3 -A, B, C, D crystal forms of methoxyurea (represented by formula (I)), the polycrystalline has good crystal stability and chemical stability, and the used crystallization solvent has low toxicity and low residue, and can be better clinical application.

The technical scheme of the present invention is as follows: the present invention provides a crystal form A of the compound represented by the formula (I), characterized in that: using Cu-K α radiation to obtain an X-ray powder diffraction pattern represented by a diffraction angle 2θ, The crystal form A has characteristic peaks at 6.19, 8.45, 9.10, 9.78, 11.22, 17.15, 21.10, 22.63 and 24.21, wherein the error range of each characteristic peak 2θ is ±0.2,

In a preferred embodiment of the present invention, the present invention provides a crystal form A of the compound represented by formula (I), which is characterized in that: using Cu-K α radiation to obtain X-rays represented by the diffraction angle 2 θ angle Powder diffraction pattern, the A crystal form at 4.86, 6.19, 8.45, 9.10, 9.78, 10.41, 11.22, 12.39, 12.99, 13.41, 15.54, 17.15, 17.61, 18.33, 18.77, 19.15, 19.72, 21.10, 22.63, 24.21 and 2 There are characteristic peaks at , where the error range of each characteristic peak 2θ is ±0.2. In a preferred embodiment of the present invention, the present invention provides a method for preparing a crystal form of compound A represented by formula (I), the method comprising: placing the compound represented by formula (I) in water, beating, and filtering Crystallization and washing, and the target A crystal form is obtained after drying.

In a preferred embodiment of the present invention, the present invention provides a B crystal form of the compound represented by formula (I), which is characterized in that: using Cu-K α radiation to obtain X- X-ray powder diffraction pattern, the crystal form B has characteristic peaks at 5.80, 7.97, 11.53, 13.15, 17.06, 21.02, 23.09, 24.38, 26.39, and 28.73, wherein the error range of each characteristic peak 2θ is ±0.2,

In a preferred embodiment of the present invention, the present invention provides a B crystal form of the compound represented by formula (I), characterized in that: using Cu-K α radiation to obtain X-rays represented by the diffraction angle 2 θ Powder diffraction pattern, the B crystal form has characteristic peaks at 5.80, 7.97, 8.85, 9.76, 11.53, 13.15, 17.06, 18.69, 19.45, 21.02, 23.09, 24.38, 24.94, 26.39, 27.35, 28.73, 31.74 and 34.58, among which , the error range of each characteristic peak 2θ is ±0.2. In a preferred embodiment of the present invention, the present invention provides a method for preparing a crystal form of compound B represented by formula (I), the method comprising: dissolving the compound represented by formula (I) in a nitrile solvent, Crystallization, filtration and washing of the crystals, and drying to obtain the target crystal form B, the nitrile solvent is preferably acetonitrile.

In a preferred embodiment of the present invention, the present invention provides a C crystal form of the compound represented by formula (I), which is characterized in that: using Cu-K α radiation to obtain X-rays represented by the diffraction angle 2 θ angle Powder diffraction pattern, the C crystal form has characteristic peaks at 5.70, 8.11, 9.15, 10.62, 11.15, 15.02, 16.30, 16.86, 19.28, 21.75, 22.04, 24.17 and 24.95, where the error range of each characteristic peak 2θ is ±0.2,

In a preferred embodiment of the present invention, the present invention provides a C crystal form of the compound represented by formula (I), which is characterized in that: using Cu-K α radiation to obtain X-rays represented by the diffraction angle 2 θ angle Powder diffraction pattern, the crystal form C is at 5.70, 8.11, 8.54, 9.15, 10.62, 11.15, 12.38, 12.67, 15.02, 15.40, 16.30, 16.86, 19.28, 19.92, 21.75, 22.04, 22.94, 24.17, 24.95, 25.34, There are characteristic peaks at and 28.61, where the error range of each characteristic peak 2θ is ±0.2. In a preferred embodiment of the present invention, the present invention provides a method for preparing a crystal form of compound C represented by formula (I), the method comprising: dissolving the compound represented by formula (I) in an ether solvent, Crystallize, filter and wash the crystals, and then obtain the target crystal form C after drying. The ether solvent is preferably 1,4-dioxane.

In a preferred embodiment of the present invention, the present invention provides a D crystal form of the compound represented by formula (I), which is characterized in that: using Cu-K α radiation to obtain X-rays represented by the diffraction angle 2 θ angle Powder diffraction pattern, the D crystal form has characteristic peaks at 7.95, 8.93, 11.52, 13.14, 15.82, 17.10, 20.31, 23.12, 26.30 and 28.86, wherein the error range of each characteristic peak 2θ is ±0.2,

In a preferred embodiment of the present invention, the present invention provides a D crystal form of the compound represented by formula (I), which is characterized in that: using Cu-K α radiation to obtain the characteristic peak represented by the diffraction angle 2θ angle X-ray powder diffraction pattern, the D crystal form at 5.73, 6.64, 7.95, 8.93, 9.73, 10.33, 10.63, 11.52, 12.15, 13.14, 15.82, 17.10, 17.64, 17.99, 18.75, 19.27, 19.53, 20.31, 21.74, There are characteristic peaks at 22.10, 23.12, 24.34, 25.15, 26.30, 26.91 and 28.86, where the error range of each characteristic peak 2θ is ±0.2.

In a preferred embodiment of the present invention, the present invention provides a method for preparing a crystal form of compound D represented by formula (I), the method comprising: dissolving the compound represented by formula (I) in a mixture of ethers and water In the solvent, crystallize, filter the crystallization and wash, and obtain the target crystal form D after drying. The mixed solvent of the ether and water is preferably tetrahydrofuran/water, and the ratio of the ether solvent to water is 0.1:1~1: 0.1, preferably 1:1.

The present invention further relates to the pharmaceutical composition of crystal form A, crystal form B, crystal form C and crystal form D of the compound represented by formula (I), which is characterized by comprising one or more pharmaceutically acceptable carriers, diluents or excipients Form.

The present invention further relates to the pharmaceutical composition of the compound represented by the formula (I) of A crystal form, B crystal form, C crystal form, D crystal form ABCD or A, B, C, D crystal forms in the preparation of treatment and/or prevention and Use of a GnRH receptor antagonist in a medicament for a disease selected from the group consisting of endocrine and reproductive system diseases.

By X-ray powder diffraction pattern (XRPD), differential scanning calorimetry (DSC), etc., the crystal forms A, B, C and D of the compound represented by the formula (I) obtained are subjected to structural determination, crystal form research, etc. .

The method of recrystallization is not particularly limited, and it can be carried out by a general recrystallization operation method. For example, the compound represented by the raw material formula (I) can be heated and dissolved in an organic solvent and then slowly cooled and crystallized. After the crystallization is completed, the desired crystal can be obtained by filtration and drying.

The crystallization methods of the present invention include room temperature crystallization, cooling crystallization and the like.

The starting material used in the method for preparing the crystal form of the present invention can be the compound represented by formula (I) in any form, and the specific form includes but is not limited to: amorphous, any crystal form, and the like.

Detailed description of the invention

In the description of the present application and the scope of the patent application, unless otherwise specified, the scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. However, for a better understanding of the present invention, definitions and explanations of some related terms are provided below. In addition, when the definitions and explanations of terms provided in this application are inconsistent with the meanings commonly understood by those skilled in the art, the definitions and explanations of terms provided in this application shall prevail.

" beating " of the present invention refers to the method that utilizes material to have poor solubility in solvent, but the characteristic that impurity has good solubility in solvent is purified, and beating and purification can decolorize, change crystal form or remove a small amount of impurities.

The "cyano group" in the present invention refers to groups such as -CN.

The "C _1-6 alkyl group" in the present invention refers to a straight-chain or branched-chain alkyl group containing 1-6 carbon atoms, and specific examples include but are not limited to: methyl, ethyl, n-propyl, isopropyl , n-butyl, isobutyl, second-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl , 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl group, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, 1,2-dimethylpropyl, etc.

The "nitrile solvent" in the present invention refers to a _{group derived from one or more "cyano groups" substituted for one or more hydrogen atoms on "C 1-6} alkyl", the "cyano group" and "C _1-6 alkyl" is as defined above, and specific examples include, but are not limited to: acetonitrile or propionitrile.

The "ether solvent" in the present invention refers to a chain compound or a cyclic compound containing an ether bond -O- and having 1 to 10 carbon atoms, and specific examples include but are not limited to: propylene glycol methyl ether, tetrahydrofuran or 1 , 4-dioxane.

The "mixed solvent" in the present invention refers to a solvent formed by mixing one or more different types of organic solvents according to a certain ratio, or a solvent formed by mixing an organic solvent and water according to a certain ratio, and the ratio is the volume ratio, the volume The ratio is selected from 0.1:1~1:0.1, preferably 1:1; the mixed solvent is preferably a mixed solvent of alcohols and ethers, a mixed solvent of alcohols and water, or a mixed solvent of ketones and water .

The "X-ray powder diffraction pattern or XRPD" in the present invention refers to according to the Bragg formula 2d sin θ=n λ (where λ is the wavelength of X-ray, λ=1.54056Å, and the diffraction order n is any positive Integer, generally take the first-order diffraction peak, n=1), when the X-ray is incident on a crystal or part of the crystal sample with a d lattice plane spacing at a grazing angle θ (the complementary angle of the incident angle, also known as the Bragg angle). On the atomic plane, the Bragg equation can be satisfied, and this set of X-ray powder diffraction patterns was measured.

The "differential scanning calorimetry or DSC" in the present invention refers to measuring the temperature difference and heat flow difference between the sample and the reference during the heating or constant temperature process of the sample to characterize all physical changes and chemical changes related to thermal effects. change to obtain the phase transition information of the sample.

The "2 θ or 2 θ angle" mentioned in the present invention refers to the diffraction angle, θ is the Bragg angle, the unit is ° or degree, and the error range of 2 θ is ±0.1~±0.5, preferably ±0.1~±0.3, More preferably, it is ±0.2.

The "interplanar spacing or interplanar spacing (d value)" mentioned in the present invention refers to the selection of three non-parallel unit vectors a, b, c connecting two adjacent lattice points in the spatial lattice, and they connect the points The array is divided into juxtaposed parallelepiped units called interplanar spacing. The space lattice is divided according to the determined parallelepiped unit connection, and a set of straight line grids is obtained, which is called space lattice or lattice. Lattice and lattice use geometric points and lines to reflect the periodicity of the crystal structure. Different crystal planes have different interplanar spacing (that is, the distance between two adjacent parallel crystal planes); the unit is Å or Angstrom.

The present invention also relates to a pharmaceutical composition comprising crystal forms A, B, C and D of the compound represented by formula (I), and optionally one or more pharmaceutically acceptable carriers and/or diluents. The pharmaceutical composition can be made into any pharmaceutically acceptable dosage form. For example, the A, B, C, D crystal forms or pharmaceutical preparations of the present invention can be formulated into tablets, capsules, pills, granules, solutions, suspensions, syrups, injections (including injection solutions, sterile injections for injection) powder and concentrated solutions for injection), suppositories, inhalants or sprays.

In addition, the pharmaceutical composition of the present invention can also be administered to a patient or subject in need of such treatment in any suitable mode of administration, such as oral, parenteral, rectal, pulmonary or topical administration. When used for oral administration, the pharmaceutical composition can be made into oral preparations, such as oral solid preparations, such as tablets, capsules, pills, granules, etc.; or, oral liquid preparations, such as oral solutions, oral suspensions agents, syrups, etc. When formulated for oral administration, the pharmaceutical formulation may also contain suitable fillers, binders, disintegrants, lubricants and the like. When used for parenteral administration, the pharmaceutical preparation can be prepared into injections, including injection solutions, sterile powders for injection and concentrated solutions for injection. When made into an injection, the pharmaceutical composition can be produced by conventional methods in the existing pharmaceutical field. When preparing an injection, the pharmaceutical preparation may not add additives, or may add appropriate additives according to the properties of the drug. When used for rectal administration, the pharmaceutical preparation can be formulated into suppositories and the like. When used for pulmonary administration, the pharmaceutical preparation can be made into inhalants or sprays. In certain preferred embodiments, the A, B, C, D crystalline forms of the present invention are present in a pharmaceutical composition or medicament in a therapeutically and/or prophylactically effective amount. In certain preferred embodiments, the A, B, C, D crystalline forms of the present invention are present in a pharmaceutical composition or medicament in the form of a unit dose.

The crystal forms A, B, C and D of the compound of formula (I) of the present invention can be used for the preparation of the use in the treatment and/or prevention of diseases related to GnRH receptor antagonists. Therefore, the present application also relates to the use of the crystal forms A, B, C, D of the compound of formula (I) of the present invention for the preparation of a medicament for the treatment and/or prevention of GnRH receptor antagonists in a subject related diseases. In addition, the present application also relates to a method for inhibiting a disease associated with a GnRH receptor antagonist, comprising administering to a subject in need thereof a therapeutically and/or prophylactically effective amount of A, B, C, D crystal forms, or the pharmaceutical composition of the present invention.

In certain preferred embodiments, the disease is a disease associated with a GnRH receptor antagonist selected from endocrine reproductive system diseases.

Compared with the prior art, the technical solution of the present invention has the following advantages:

(1) The crystal forms A, B, C, and D of the compound represented by the formula (I) of the present invention do not contain or only contain a relatively low content of residual solvent, and meet the limit requirements for residual solvents in pharmaceutical products stipulated by the National Pharmacopoeia. Therefore, this The crystals of the invention can be preferably used as pharmaceutical active ingredients.

(2) Research shows that the purity of crystal forms A, B, C and D of the compound represented by formula (I) prepared by the present invention is relatively high, and none of the crystal forms is detected by XRPD under the conditions of illumination, high temperature and high humidity. Change, good crystal stability; HPLC purity change is small, chemical stability is high; the A, B, C, D crystal forms of the compound represented by the formula (I) obtained by the technical scheme of the present invention can meet the medicinal requirements of production, transportation and storage , the production process is stable, repeatable and controllable, and can be adapted to industrial production.

Figure 1 is an amorphous XRPD pattern of the compound represented by formula (I).

Figure 2 is the DSC spectrum of the amorphous compound represented by formula (I).

Figure 3 is the XRPD pattern of the crystal form of compound A represented by formula (I).

Figure 4 is the DSC spectrum of the crystal form of Compound A represented by formula (I).

Figure 5 is the XRPD pattern of the crystalline form of compound B represented by formula (I).

Figure 6 is the DSC spectrum of the crystal form of compound B represented by formula (I).

Figure 7 is the XRPD pattern of the crystalline form of compound C represented by formula (I).

Figure 8 is the DSC spectrum of the crystal form of compound C represented by formula (I).

Figure 9 is the XRPD pattern of the crystalline form of compound D represented by formula (I).

Figure 10 is the DSC spectrum of the crystalline form of compound D represented by formula (I).

The present invention will be explained in more detail below with reference to the embodiments. The embodiments of the present invention are only used to illustrate the technical solutions of the present invention, but do not limit the essence and scope of the present invention.

Test conditions of the instruments used in the experiment:

1. Differential Scanning Calorimeter (DSC)

Instrument model: Mettler Toledo DSC 1 STAR ^e System

Purge gas: nitrogen

Heating rate: 10.0℃/min

Temperature range: 40-300℃

2. X-ray Powder Diffraction (XRPD)

Instrument model: Bruker D8 Focus X-ray powder diffractometer

Ray: Monochromatic Cu-K α ray (λ=1.5406)

Scanning mode: θ/2 θ, scanning range: 2-40°

Voltage: 40kV, Current: 40mA

Example 1. The compound of formula (I) was prepared according to the method of Example 11 of Patent WO2015062391A1 (published on 2015.05.07)

2-(4-Aminophenyl)-7-(2,6-difluorobenzyl)-3-((dimethylamino)methyl)-5-(6-methoxypyridazine-3 - yl) -2 H - pyrazolo [3,4- d] pyrimidine -4,6 (5 H, 7 H) - dione (100mg, 0.18mmol) was dissolved in dichloromethane (5mL) was added N , N -diisopropylethylamine (0.5mL, 2.90mmol) and triphosgene (46mg, 0.15mmol) were reacted at room temperature for 45 minutes, methoxyamine hydrochloride (92mg, 1.12mmol) was added, and the reaction was performed at 40°C for 12 hours , stop the reaction. Saturated sodium bicarbonate solution (5 mL) was added, extracted with dichloromethane (25 mL×1), the organic phase was washed successively with water (10 mL×1) and saturated sodium chloride solution (10 mL×1), dried over anhydrous sodium sulfate, and filtered. , the filtrate was concentrated under reduced pressure, and the residue was purified by thin layer chromatography with a developing solvent (dichloromethane and methanol system) to obtain a crude product in a combined batch of 54 mg of crude product, which was purified by thin layer chromatography with a developing solvent (dichloromethane and methanol system) ) was purified twice to give 1-(4-(7-(2,6-difluorobenzyl)-3-((dimethylamino)methyl)-5-(6-methoxypyridazine-3) -yl)-4,6-dioxo-4,5,6,7-tetrahydro- 2H -pyrazolo[3,4- d ]pyrimidin-2-yl)phenyl)-3-methoxy baseurea (39 mg, white solid). The X-ray diffraction spectrum of the solid sample is shown in Figure 1, which shows the characteristic absorption peak of no crystal form, and the DSC spectrum is shown in Figure 2, and no melting absorption peak is found below 300°C. Accordingly, the product was determined to be an amorphous solid.

Example 2

1-(4-(7-(2,6-difluorobenzyl)-3-((dimethylamino)methyl)-5-(6-methoxypyridazin-3-yl)-4 ,6-dicarbonyl-4,5,6,7-tetrahydro- 2H -pyrazolo[3,4- d ]pyrimidin-2-yl)phenyl)-3-methoxyurea (500 mg, 0.82 mmol) (prepared according to Example 1) was added to the reaction flask, purified water (10 mL) was added, slurried at room temperature for 5 hours, suction filtered, and dried to obtain 369 mg of solid. The XRPD spectrum of the crystalline sample is shown in Figure 3, and its DSC spectrum is shown in Figure 4. There is a melting endothermic peak near 217°C, and this crystal form is defined as crystal form A, and its characteristic peak positions are shown in the following table:

Example 3

1-(4-(7-(2,6-difluorobenzyl)-3-((dimethylamino)methyl)-5-(6-methoxypyridazin-3-yl)-4 ,6-dicarbonyl-4,5,6,7-tetrahydro- 2H -pyrazolo[3,4- d ]pyrimidin-2-yl)phenyl)-3-methoxyurea (300 mg, 0.49 mmol) (prepared according to Example 1) was added to the reaction flask, acetonitrile (9 mL) was added, heated to reflux, the solid was completely dissolved, stopped heating, cooled for crystallization, suction filtered, and dried to obtain 243 mg of solid. The XRPD spectrum of the crystalline sample is shown in Figure 5, and its DSC spectrum is shown in Figure 6. There is a melting endothermic peak near 212 ° C, and this crystal form is defined as crystal form B, and its characteristic peak positions are shown in the following table:

Example 4

1-(4-(7-(2,6-difluorobenzyl)-3-((dimethylamino)methyl)-5-(6-methoxypyridazin-3-yl)-4 ,6-dicarbonyl-4,5,6,7-tetrahydro- 2H -pyrazolo[3,4- d ]pyrimidin-2-yl)phenyl)-3-methoxyurea (300 mg, 0.49 mmol) (prepared according to Example 1) was added to the reaction flask, 1,4-dioxane (15 mL) was added, heated to reflux, the solid was completely dissolved, stopped heating, cooled for crystallization, suction filtered, and dried to obtain 205 mg of solid. The XRPD spectrum of the crystalline sample is shown in Figure 7, and its DSC spectrum is shown in Figure 8. There is a melting endothermic peak near 157 ° C, and this crystal form is defined as crystal form C, and its characteristic peak positions are shown in the following table:

Example 5

1-(4-(7-(2,6-difluorobenzyl)-3-((dimethylamino)methyl)-5-(6-methoxypyridazin-3-yl)-4 ,6-dicarbonyl-4,5,6,7-tetrahydro- 2H -pyrazolo[3,4- d ]pyrimidin-2-yl)phenyl)-3-methoxyurea (300 mg, 0.49 mmol) (prepared according to Example 1) was added to the reaction flask, tetrahydrofuran/water (15mL, V:V=1:1) was added, heated to reflux, all solids were dissolved, stopped heating, cooled for crystallization, suction filtered, and dried A solid 205mg was obtained. The XRPD spectrum of the crystalline sample is shown in Figure 9, and its DSC spectrum is shown in Figure 10. There are melting endothermic peaks near 177 ° C and 204 ° C, and this crystal form is defined as D crystal form, and its characteristic peak positions are shown in the following table. :

Example 6

The amorphous sample obtained in Example 1, the A crystal form sample obtained in Example 2, the B crystal form sample obtained in Example 3, the C crystal form sample obtained in Example 4, and the D crystal form sample obtained in Example 5 were exposed. The samples were placed on a flat surface, and the stability of the samples under the conditions of light (4500Lux), heating (40°C, 60°C) and high humidity (RH75%, RH90%) was investigated. The sampling time was 5 days and 10 days, and the purity was detected by HPLC The results are shown in Table 5.

test results:

Test Conclusions

The stability investigation results in Table 5 show that under the conditions of exposure to light, high humidity, and high temperature exposure, the HPLC purity data of the A, B, C, D crystal forms of the compound represented by the formula (I) are all less than amorphous. , the crystal forms were not transformed by XRPD detection, indicating that the stability of crystal forms A, B, C and D of the present invention is significantly better than that of amorphous samples.

Since the graphs in this case are all experimental data, they are not representative graphs of this case. Therefore, there is no designated representative map in this case.

Claims (6)

A crystal form D of the compound represented by formula (I), characterized in that, using Cu-K α radiation to obtain an X-ray powder diffraction pattern represented by a diffraction angle of 2 θ, the crystal form D is at 7.95, 8.93, 11.52 , there are characteristic peaks at 13.14, 15.82, 17.10, 20.31, 23.12, 26.30 and 28.86, where the error range of each characteristic peak 2θ is ±0.2,

The crystal form D according to item 1 of the claimed scope, wherein the crystal form D is at 5.73, 6.64, 7.95, 8.93, 9.73, 10.33, 10.63, 11.52, 12.15, 13.14, 15.82, 17.10, 17.64, 17.99, 18.75 , 19.27, 19.53, 20.31, 21.74, 22.10, 23.12, 24.34, 25.15, 26.30, 26.91 and 28.86 have characteristic peaks, where the error range of each characteristic peak 2θ is ±0.2. A method for preparing crystal form D as described in item 1 or 2 of the scope of the application, the method comprising: dissolving the compound represented by formula (I) in a mixed solvent of ethers and water, crystallization, filtering the crystallization and washing, After drying, the target crystal form D is obtained, and the ratio of the ether solvent to water is 0.1:1~1:0.1. The method according to claim 3, wherein the mixed solvent of the ethers and water is tetrahydrofuran/water. The method according to item 4 of the claimed scope, wherein the ratio of the ether solvent to water is 1:1. A pharmaceutical composition containing the D crystal form described in item 1 or 2 of the claimed scope is characterized by comprising one or more pharmaceutically acceptable carriers or excipients.

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