TW201817733A - 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

 Polymorph 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) -4,6-Dicarbonyl-4,5,6,7-tetrahydro- 2H -pyrazolo[3,4- d ]pyrimidin-2-yl)phenyl)-3-methoxyurea A , B, C, D crystal forms and preparation methods, their use in pharmaceutical compositions, and the A, B, C, D crystal forms, their pharmaceutical compositions in the preparation of treatment and / or prevention associated with GnRH receptor antagonists Use in medicines for diseases.

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

Gonadotropin-releasing hormone (GnRH), also known as luteinizing hormone-releasing hormone (LHRH), is a central regulator of 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 effect by coupling with the G protein capable of initiating the phospholipid inositol calcium second messenger system, while LH regulates the production of sex steroids, which regulate male spermatogenesis and female follicular development.

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 GnRH receptor agonists and antagonists of long-acting peptides need to be administered for therapeutic control.

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

The GnRH receptor agonist-mediated indirect tumor suppressor mechanism inhibits the growth of tumor cells by long-term action on the hypothalamic-pituitary-gonadal axis, resulting in decreased pituitary gonadotropin (FSH, LH), thereby reducing the secretion of sex hormones. . GnRH receptor antagonists directly inhibit the release of pituitary gonadotropins, thereby inhibiting the growth of tumor cells.

A series of small molecule GnRH receptor antagonist patents are currently disclosed including WO2006096785, WO2010026993, WO2011076687, WO2012175514, and the like. Small molecule GnRH receptor antagonists have good application prospects in the pharmaceutical industry. The applicant provides a novel high-efficiency and low-toxic GnRH receptor antagonist in the patent application WO2015062391A1 (publication date 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 the medicinal active ingredient often affects the chemical stability of the drug, and the difference in crystallization conditions and storage conditions may lead to changes in the crystal structure of the compound, sometimes accompanied by the formation of other forms of crystal form. In general, amorphous drug products have no regular crystal structure and often have other defects, such as poor product stability, fine crystallization, difficult filtration, easy agglomeration, and poor fluidity. Therefore, it is necessary to improve the various properties of the above products, and we need to study in depth 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 1-(4-(7-(2,6-difluorobenzyl)-3-((dimethylamino)methyl)-5-(6-methoxy group). Pyridazin-3-yl)-4,6-dicarbonyl-4,5,6,7-tetrahydro- 2H -pyrazolo[3,4- d ]pyrimidin-2-yl)phenyl)-3 a crystal form of A, B, C, and D of methoxyurea (as shown in formula (I)), the polycrystal has good crystal form stability and chemical stability, and the crystallization solvent used is low in toxicity and low in residue, Better applied to the clinic.

The technical scheme of the present invention is as follows: The present invention provides a crystal form A of the compound of the formula (I), characterized in that an X-ray powder diffraction pattern represented by a diffraction angle of 2 θ is obtained by using Cu-K α radiation. The A crystal forms have 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 2 θ is ±0.2.

In a preferred embodiment of the present invention, the present invention provides a crystalline form A of the compound of the formula (I), characterized in that X-rays expressed by a diffraction angle of 2 θ are obtained using Cu-K α radiation. 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 25.11 There are characteristic peaks where the error range of each characteristic peak 2 θ is ±0.2. In a preferred embodiment of the present invention, the present invention provides a method for preparing a crystal form of the compound A represented by the formula (I), which comprises: placing a compound of the formula (I) in water, beating, filtering Crystallized and washed, and after drying, the target A crystal form is obtained.

In a preferred embodiment of the present invention, the present invention provides a crystalline form B of a compound of the formula (I), characterized in that X-ray represented by a diffraction angle of 2 θ is obtained using Cu-K α radiation. a ray powder diffraction pattern having 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 2 θ is ± 0.2,

In a preferred embodiment of the present invention, the present invention provides a crystalline form B of a compound of the formula (I), characterized in that X-rays expressed by a diffraction angle of 2 θ are obtained using Cu-K α radiation. a powder diffraction pattern having 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, wherein The error range of each characteristic peak 2 θ is ±0.2. In a preferred embodiment of the present invention, the present invention provides a process for preparing a crystal form of the compound B represented by the formula (I), which comprises dissolving a compound represented by the formula (I) in a nitrile solvent, Crystallization, filtration and washing, and drying, the target B crystal form is obtained, and the nitrile solvent is preferably acetonitrile.

In a preferred embodiment of the present invention, the present invention provides a crystalline form C of a compound of the formula (I), characterized in that X-rays represented by a diffraction angle of 2 θ are obtained using Cu-K α radiation. a powder diffraction pattern having 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, wherein the error range of each characteristic peak 2 θ Is ±0.2,

In a preferred embodiment of the present invention, the present invention provides a crystalline form C of a compound of the formula (I), characterized in that X-rays represented by a diffraction angle of 2 θ are obtained using Cu-K α radiation. Powder diffraction pattern, the C crystal form 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, 25.87 There are characteristic peaks at 28.61, where the error range of each characteristic peak 2 θ is ±0.2. In a preferred embodiment of the present invention, the present invention provides a process for preparing a crystal form of the compound C represented by the formula (I), which comprises: dissolving a compound represented by the formula (I) in an ether solvent; Crystallization, filtration and washing are carried out, and after drying, the target C crystal form is obtained, and the ether solvent is preferably 1,4-dioxane.

In a preferred embodiment of the present invention, the present invention provides a crystalline form of D of the compound of the formula (I), characterized in that X-rays represented by diffraction angles 2 θ are obtained using Cu-K α radiation. a powder diffraction pattern having 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 each characteristic peak has an error range of ± 0.2.

In a preferred embodiment of the present invention, the present invention provides a crystalline form of D of the compound of the formula (I), characterized in that Cu-Kα radiation is used to obtain a characteristic peak represented by a diffraction angle of 2 θ. 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 2 θ is ±0.2.

In a preferred embodiment of the present invention, the present invention provides a process for the preparation of a crystalline form of the compound D of the formula (I), which comprises dissolving a compound of the formula (I) in a mixture of an ether and water. In the solvent, the crystal is decrystallized, filtered and washed, and after drying, the target D crystal form is obtained. 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 invention further relates to a pharmaceutical composition of Form A, Form B, Form C, Form D of the compound of Formula (I), characterized by comprising one or more pharmaceutically acceptable carriers, diluents or Shape agent.

The present invention further relates to a pharmaceutical composition of Form A, Form B, Form C, Form D of AB, or Form A, B, C, and D of the compound of Formula (I) in the preparation of treatment and/or prevention Use of a GnRH receptor antagonist for a drug associated with a disease selected from the group consisting of endocrine and reproductive system diseases.

Structural determination, crystal form research, etc. of the A, B, C, and D crystal forms of the compound of the formula (I) obtained by X-ray powder diffraction pattern (XRPD), differential scanning calorimetry (DSC), or the like .

The method of recrystallization is not particularly limited and can be carried out by a usual recrystallization operation method. For example, the compound represented by the starting material (I) can be slowly cooled and crystallized by heating in an organic solvent, and after completion of crystallization, it can be dried by filtration to obtain a desired crystal.

The method for crystallization of the present invention includes room temperature crystallization, cooling crystallization, and the like.

The starting material used in the method for preparing a crystal form of the present invention may be any compound of the formula (I), and the specific forms include, but are not limited to, amorphous, arbitrary crystal forms and the like.

 Detailed description of the invention  

In the description and claims of this application, the scientific and technical terms used herein have the meanings commonly understood by those skilled in the art, unless otherwise indicated. 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 the terms provided by the present application are inconsistent with the meanings generally understood by those skilled in the art, the definitions and explanations of the terms provided by the present application shall prevail.

The "beating" as used in the present invention refers to a method in which the solubility of a substance in a solvent is poor, but the solubility of the impurity in a solvent is good, and the purification can be used to remove the color, change the crystal form or remove a small amount of impurities.

The "cyano group" as used in the present invention means a group such as -CN.

The "C _1-6 alkyl group" of the present invention means a linear or branched alkyl group having 1 to 6 carbon atoms, and specific examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl. , n-butyl, isobutyl, t-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 Base, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, 1,2-dimethylpropyl, and the like.

The "nitrile solvent" as used in the present invention means a group derived from one or more hydrogen atoms on one or more "cyano" substituted "C _1-6 alkyl", said "cyano" and "C _1-6 alkyl" is as defined above, and specific examples include, but are not limited to, acetonitrile or propionitrile.

The "ether solvent" as used in the present invention means a chain compound or a cyclic compound having 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 , 4-dioxane.

The "mixed solvent" as used in the present invention refers to a solvent obtained by mixing one or more different kinds of organic solvents in a certain ratio, or a solvent obtained by mixing an organic solvent and water in a certain ratio, the ratio being a volume ratio and a volume. The ratio is selected from 0.1:1 to 1:0.1, preferably 1:1; the mixed solvent is preferably a mixed solvent of an alcohol and an ether, a mixed solvent of an alcohol solvent and water, or a mixed solvent of a ketone solvent and water. .

The "X-ray powder diffraction pattern or XRPD" according to the present invention means that according to the Bragg formula 2d sin θ = n λ (where λ is the wavelength of the X-ray, λ = 1.540456 Å, and the number n of diffraction is any positive Integer, generally taking the first-order diffraction peak, n=1), when the X-ray is incident on the crystal or part of the crystal sample with a d-matrix plane spacing at the sweep angle θ (the angle of incidence angle, also known as the Bragg angle) On the atomic plane, the Bragg equation can be satisfied, and the X-ray powder diffraction pattern is measured.

The "differential scanning calorimetry or DSC" as used in the present invention refers to measuring the temperature difference and heat flow difference between a sample and a reference during temperature rise or constant temperature of the sample to characterize all physical changes and chemistry related to thermal effects. Change, get the phase change information of the sample.

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

The "plane spacing or interplanar spacing (d value)" according to the present invention means that the spatial lattice selects three non-parallel unit vectors a, b, c connecting adjacent two lattice points, which will point The parallelepiped unit, which is divided into juxtapositions, is called the interplanar spacing. The spatial lattice is divided according to the determined parallelepiped unit lines, and a set of linear grids is obtained, which is called a space lattice or a lattice. The lattice and the lattice reflect the periodicity of the crystal structure by geometric points and lines, respectively, and the interplanar spacing (ie, the distance between two adjacent parallel planes) is different; the unit is Å Or ang.

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

Furthermore, the pharmaceutical composition of the present invention can also be administered to a patient or subject in need of such treatment by any suitable mode of administration, such as oral, parenteral, rectal, pulmonary or topical administration. When used for oral administration, the pharmaceutical composition can be formulated into an oral preparation, for example, an oral solid preparation such as a tablet, a capsule, a pill, a granule, or the like; or an oral liquid preparation such as an oral solution or an oral suspension. Agent, syrup, and the like. When formulated into an oral preparation, the pharmaceutical preparation may further contain a suitable filler, binder, disintegrant, lubricant, and the like. When used for parenteral administration, the pharmaceutical preparation can be prepared as an injection, including an injection, a sterile powder for injection, and a concentrated solution for injection. When formulated as an injection, the pharmaceutical composition can be produced by a conventional method in the existing pharmaceutical field. When the injection is formulated, an additional agent may be added to the pharmaceutical preparation, and a suitable additional agent may be added depending on the nature of the drug. When used for rectal administration, the pharmaceutical preparation can be formulated into a suppository or the like. For pulmonary administration, the pharmaceutical preparation can be formulated as an inhalant or a spray. In certain preferred embodiments, the crystalline forms A, B, C, D of the invention are present in a pharmaceutical composition or medicament in a therapeutically and/or prophylactically effective amount. In certain preferred embodiments, the crystalline forms A, B, C, and D of the present invention are present in a pharmaceutical composition or drug in unit dosage form.

The crystalline forms A, B, C, and D of the compounds of formula (I) of the invention are useful in the manufacture of a medicament for the treatment and/or prevention of a disorder associated with a GnRH receptor antagonist. Accordingly, the present application also relates to the use of the crystalline forms A, B, C, and D of the compounds of formula (I) of the present invention for the preparation of a medicament for the treatment and/or prevention of a GnRH receptor antagonist in a subject Related diseases. Further, the present application relates to a method of inhibiting a disease associated with a GnRH receptor antagonist, which comprises administering to a subject in need thereof a therapeutically and/or prophylactically effective amount of A of the compound of the formula (I) of the present invention, Form B, C, D, or a pharmaceutical composition of the invention.

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

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

(1) The crystal forms of A, B, C, and D of the compound of the formula (I) of the present invention do not contain or contain only a relatively low amount of residual solvent, and meet the limit requirements of the residual solvent of the pharmaceutical product specified in the National Pharmacopoeia. The crystal of the invention can be preferably used as a pharmaceutically active ingredient.

(2) Studies have shown that the compounds of formula (I) prepared by the present invention have higher purity of crystal forms A, B, C and D, and no crystal form is detected by XRPD under illumination, high temperature and high humidity. The change, the crystal form stability is good; the HPLC purity change is small, and the chemical stability is high; the A, B, C, and D crystal forms of the compound represented by the formula (I) obtained by the technical scheme of the present invention can meet the pharmaceutical requirements for 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 of formula (I).

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

Figure 3 is an XRPD pattern of the crystalline form of Compound A shown in Formula (I).

Figure 4 is a DSC chart of the crystalline form of Compound A of formula (I).

Figure 5 is an XRPD pattern of the crystalline form of Compound B of formula (I).

Figure 6 is a DSC chart of the crystalline form of Compound B of formula (I).

Figure 7 is an XRPD pattern of the crystalline form of Compound C of formula (I).

Figure 8 is a DSC chart of the crystalline form of Compound C of formula (I).

Figure 9 is an XRPD pattern of the crystalline form of Compound D of formula (I).

Figure 10 is a DSC chart of the crystalline form of Compound D of formula (I).

The invention is explained in more detail below with reference to the embodiments, which are intended to illustrate the technical scope of the invention and not to limit the scope and scope of the invention.

Test conditions for 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 ° C / min

Temperature range: 40-300 ° C

2. X-ray Powder Diffraction (XRPD)

Instrument model: Bruker D8 Focus X-ray powder diffractometer

Ray: Monochrome Cu-K alpha ray (λ = 1.5406)

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

Voltage: 40kV, current: 40mA

Example 1. Preparation of a compound of the formula (I) according to the method of Example 11 of the patent WO2015062391A1 (publication date 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 (0.5 mL, 2.90 mmol) and triphosgene (46 mg, 0.15 mmol) were reacted at room temperature for 45 minutes, methoxyamine hydrochloride (92 mg, 1.12 mmol) was added, and the reaction was carried out at 40 ° C for 12 hours. , stop the reaction. The mixture was extracted with EtOAc (EtOAc) (EtOAc) The filtrate was concentrated under reduced pressure, and the residue was purified eluting with EtOAc EtOAc Purification 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 Base urea (39 mg, white solid). The X-ray diffraction spectrum of the solid sample is shown in Fig. 1 and shows the characteristic peak of the amorphous form. The DSC spectrum is shown in Fig. 2, and no melting absorption peak is observed below 300 °C. The product was thus 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 Methyl) (prepared as in Example 1) was added to a reaction flask, purified water (10 mL) was added, and the mixture was stirred at room temperature for 5 hours, suction filtered, and dried to give 369 mg. The XRPD pattern of the crystal sample is shown in Fig. 3. The DSC spectrum is shown in Fig. 4. There is a melting endothermic peak near 217 °C. This crystal form is defined as the A crystal form, and the characteristic peak positions are as follows:

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 Methyl) (prepared as in Example 1) was added to a reaction flask, acetonitrile (9 mL) was added, and the mixture was heated to reflux. The solid was completely dissolved, and then the mixture was evaporated, and then evaporated to afford crystals. The XRPD pattern of the crystal sample is shown in Fig. 5. The DSC spectrum is shown in Fig. 6. There is a melting endothermic peak near 212 °C. This crystal form is defined as the B crystal form, and the characteristic peak positions are as follows:

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 Methyl) (prepared as in Example 1) was added to a reaction flask, 1,4-dioxane (15 mL) was added, and the mixture was heated to reflux. The solid was completely dissolved. The XRPD pattern of the crystal sample is shown in Fig. 7. The DSC spectrum is shown in Fig. 8. There is a melting endothermic peak near 157 °C. This crystal form is defined as C crystal form, and the characteristic peak positions are as follows:

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 Ment) (prepared as in Example 1) was added to the reaction flask, tetrahydrofuran / water (15 mL, V: V = 1:1), heated to reflux, the solid was completely dissolved, heating was stopped, cooling and crystallization, suction filtration, drying A solid of 205 mg was obtained. The XRPD pattern of the crystal sample is shown in Fig. 9. The DSC spectrum is shown in Fig. 10. There is a melting endothermic peak near 177 ° C and 204 ° C. This crystal form is defined as D crystal form, and the 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 opened. The sample was placed evenly, and the stability of the sample under illumination (4500 Lux), heating (40 ° C, 60 ° C), high humidity (RH 75%, RH 90%) was investigated. The sampling time was 5 days and 10 days, and the purity was determined by HPLC. The results are shown in Table 5.

test results:  

Test Conclusions

The results of the stability study in Table 5 show that the HPLC purity data of the A, B, C, and D crystal forms of the compound of formula (I) are less than amorphous when exposed to light, high humidity, and high temperature. No change in the crystal form detected by XRPD, indicating that the stability of the A, B, C, and D crystal forms of the present invention is significantly better than that of the amorphous sample.

Claims (18)

A crystal form of a compound of the formula (I) characterized in that an X-ray powder diffraction pattern represented by a diffraction angle of 2 θ is obtained using Cu-K α radiation, and the A crystal form is 6.19, 8.45, 9.10. , 9.78, 11.22, 17.15, 21.10, 22.63 and 24.21 have characteristic peaks, wherein the error range of each characteristic peak 2 θ is ±0.2,  The crystal form of A according to claim 1, wherein the crystal form A is 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. There are characteristic peaks at 19.15, 19.72, 21.10, 22.63, 24.21 and 25.11, wherein the error range of each characteristic peak 2 θ is ±0.2.    A method for preparing a crystalline form A according to claim 1 or 2, which comprises: placing a compound of the formula (I) in water, beating, filtering and washing, and drying to obtain a target A crystal. type.   A crystalline form B of a compound of the formula (I), characterized in that an X-ray powder diffraction pattern represented by a diffraction angle of 2 θ is obtained using Cu-K α radiation, the B crystal form being 5.80, 7.97, 11.53 There are characteristic peaks at 13.15, 17.06, 21.02, 23.09, 24.38, 26.39 and 28.73, where the error range of each characteristic peak 2 θ is ±0.2.  For example, the patent application is the B crystal form described in item 4, wherein the B crystal form is 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. There are characteristic peaks at 28.73, 31.74 and 34.58, where the error range of each characteristic peak 2 θ is ±0.2.    A method for preparing a B crystal form as described in claim 4 or 5, which comprises dissolving a compound of the formula (I) in a nitrile solvent, crystallization, filtering and washing, and drying, and obtaining Target B crystal form.    The method of claim 6, wherein the nitrile is acetonitrile.   A crystalline form C of a compound of the formula (I), characterized in that an X-ray powder diffraction pattern represented by a diffraction angle of 2 θ is obtained using Cu-K α radiation, the C crystal form being 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 have characteristic peaks, wherein each characteristic peak 2 θ has an error range of ±0.2.  The crystal form of C according to claim 8 wherein the C crystal form is 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. There are characteristic peaks at 22.04, 22.94, 24.17, 24.95, 25.34, 25.87 and 28.61, wherein the error range of each characteristic peak 2 θ is ±0.2.    A method for preparing a C crystal form as described in claim 8 or claim 9, which comprises: dissolving a compound of the formula (I) in an ether solvent, crystallization, filtering and washing, and drying, and obtaining Target C crystal form.    The method of claim 10, wherein the ether solvent is 1,4-dioxane.   A crystal form of a compound of the formula (I) characterized in that an X-ray powder diffraction pattern represented by a diffraction angle of 2 θ is obtained using Cu-K α radiation, the D crystal form being 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 2 θ is ±0.2.  The crystal form of D as described in claim 12, wherein the D crystal form is 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. There are characteristic peaks at 19.27, 19.53, 20.31, 21.74, 22.10, 23.12, 24.34, 25.15, 26.30, 26.91 and 28.86, where the error range of each characteristic peak 2 θ is ±0.2.    A method for preparing a crystalline form of D according to claim 12 or claim 13, which comprises: dissolving a compound of the formula (I) in a mixed solvent of an ether and water, crystallization, filtering and washing, and washing, After drying, the target D crystal form is obtained, and the ratio of the ether solvent to water is from 0.1:1 to 1:0.1.    The method of claim 14, wherein the mixed solvent of the ether and water is tetrahydrofuran/water.    The method of claim 14, wherein the ratio of the ether solvent to water is 1:1.    Containing the A crystal form described in claim 1 or 2, the B crystal form described in claim 4 or 5, the C crystal form described in claim 8 or 9 of the patent application, and the patent application scope A pharmaceutical composition of Form D according to item 12 or 13 which is characterized by comprising one or more pharmaceutically acceptable carriers, diluents or excipients.    A crystal form containing the crystal form described in claim 1 or 2, the B crystal form described in claim 4 or 5, and the C crystal form described in claim 8 or 9, claiming the patent range The use of the D crystal form according to Item 12 or 13 or the pharmaceutical composition according to claim 17 for the preparation of a medicament for treating and/or preventing a disease associated with a GnRH receptor antagonist, the disease selected From endocrine reproductive system diseases.