CN116063288A - Crystal form of succinate, preparation method and application thereof - Google Patents

Abstract

The invention discloses a crystal form of a polysubstituted benzene ring compound succinate, a preparation method and application thereof.

Description

Crystal form of succinate, preparation method and application thereof

Technical Field

The invention relates to a crystal form of a polysubstituted benzene ring compound succinate, a preparation method and application thereof.

Background

A polysubstituted benzene ring compound has a structure as shown in formula I

This compound has been disclosed in patent WO2020020374A1 as an inhibitor of EZH2 (Zeste homolog enhancer 2,Enhancer Of Zeste Homolog 2) and can be used to prevent or treat EZH2 mediated diseases including brain cancer, thyroid cancer, cardiac sarcoma, lung cancer, oral cancer, gastric cancer and various other cancers.

A phenomenon in which a substance exists in two or more different crystal structures is called polymorphism. For drugs, this polymorphism may affect absorption of the drug, and thus affect bioavailability of the drug, thereby exhibiting different clinical effects and toxic and side effects. In view of this, it is of great importance to develop a dominant crystalline form of a salt of a polysubstituted benzene ring compound as shown in formula I with advantageous properties.

In the process of drug development, solubility and hygroscopicity are factors to be considered in drug development, but the solubility and hygroscopicity are usually related to each other to a certain extent, and active raw materials which are easy to dissolve in water can absorb water, so that substances with high solubility are usually easy to absorb moisture. Therefore, the development of compounds with higher solubility and lower hygroscopicity is of great importance for drug development.

Disclosure of Invention

The invention aims to overcome the defects of low solubility and easy moisture absorption of a polysubstituted benzene ring compound shown as a formula I in the prior art in the process of preparing medicines, thereby providing a crystal form of a polysubstituted benzene ring compound salt shown as a formula III, a preparation method and application thereof. The X-ray powder diffraction pattern of crystal form a of the polysubstituted benzene ring compound succinate shown in formula III, expressed in terms of 2θ angle, may also be substantially as shown in fig. 1.

In the invention, all X-ray powder diffraction patterns are measured by using K alpha spectrum lines of a Cu target.

The invention also provides a pharmaceutical composition, which comprises the crystal form A of the polysubstituted benzene ring compound succinate shown in the formula III and a pharmaceutically acceptable carrier.

The crystal form A of the polysubstituted benzene ring compound succinate shown in the formula III or the pharmaceutical composition can be used for treating and/or preventing EZH2 mediated diseases. Preferably, the EZH 2-mediated disease comprises: cancer, pulmonary hypertension, myelofibrosis, human Immunodeficiency Virus (HIV) disease, graft Versus Host Disease (GVHD), weaver syndrome, psoriasis, liver fibrosis. More preferably, the EZH 2-mediated disease is cancer.

Preferably, the cancer comprises a metastatic or malignant tumor.

Preferably, the cancer includes brain cancer, thyroid cancer, cardiac sarcoma, lung cancer, oral cancer, stomach cancer, liver cancer, kidney cancer, pancreatic cancer, esophageal cancer, nasopharyngeal cancer, laryngeal cancer, colorectal cancer, breast cancer, prostate cancer, bladder cancer, ovarian cancer, uterine cancer, bone cancer, melanoma, glioblastoma, lymphoma, blood cancer, adrenal neuroblastoma, skin cancer, astrocytoma, and the like.

In the invention, the crystal form A of the polysubstituted benzene ring compound succinate shown in the formula III can be used in combination with one or more other active ingredients; when used in combination, the active ingredients may be separate compositions for simultaneous administration by the same or different routes of administration in the treatment or at different times, respectively, or they may be administered together in the same pharmaceutical composition.

In the present invention, the administration method of the pharmaceutical composition is not particularly limited, and various dosage forms of preparation administration can be selected according to the age, sex and other conditions and symptoms of the patient; for example, tablets, pills, solutions, suspensions, emulsions, granules or capsules for oral administration; the injection can be administered alone or mixed with injectable delivery solution (such as glucose solution and amino acid solution) for intravenous injection; suppositories are administered into the rectum.

In the present invention, room temperature means 10-35 ℃.

In the present invention, the water activity a of the solvent used _w <0.2。

In the present invention, "control" means "prevention". "preventing" refers to a reduced risk of acquiring or developing a disease or disorder (i.e., resulting in at least one of the clinical symptoms of a disease not occurring in a subject that may be exposed to a disease agent or a disease susceptible prior to onset of the disease).

In the present invention, "treating" refers to ameliorating a disease or disorder (i.e., preventing a disease or reducing its manifestation, the extent or severity of its clinical symptoms); alternatively, at least one physical parameter is improved, which may not be perceived by the subject; or slowing disease progression.

The crystalline forms of the invention may be identified by one or more solid state analysis methods. Such as X-ray powder diffraction, single crystal X-ray diffraction, infrared absorbance spectra, differential scanning calorimeter, thermogravimetric curves, and the like. Those skilled in the art will appreciate that the peak intensity and/or peak condition of X-ray powder diffraction may vary depending on the experimental conditions. Meanwhile, due to different accuracies of the instrument, the measured 2 theta value has an error of about + -0.2 degrees. The relative intensity value of the peak is more dependent on certain properties of the sample to be measured, such as the size of the crystal and the purity, than the position of the peak, so that the measured peak intensity may deviate by about + -20%. Those skilled in the art can obtain sufficient information to identify individual crystalline forms from the X-ray powder diffraction data provided by this patent despite experimental error, instrumental error, orientation priority, and the like. In infrared spectrometry, the shape of the spectrum and the position of the absorption peak are affected to some extent due to different instrument performances of various types, different grinding degrees during preparation of the test sample, different water absorption degrees and the like. In contrast, in DSC measurement, the initial temperature, the maximum temperature and the heat of fusion data of the endothermic peak obtained by actual measurement have a degree of variability depending on the heating rate, the crystal shape and purity and other measurement parameters.

The above preferred conditions can be arbitrarily combined on the basis of not deviating from the common knowledge in the art, and thus, each preferred embodiment of the present invention can be obtained.

The reagents and materials used in the present invention are commercially available.

Drawings

FIG. 1 is an X-ray powder diffraction pattern of form A of a polysubstituted benzene ring compound succinate as shown in formula III.

Detailed Description

The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.

The instruments used in the following examples are shown in table 2:

TABLE 2

Powder X-ray diffraction analysis (XRPD):

XRPD patterns were collected on an Empyrean and pamalytical X' Pert3 ray powder diffraction analyzer, scan parameters as in table 3:

TABLE 3 Table 3

Thermogravimetric analysis (TGA) and Differential Scanning Calorimeter (DSC):

TGA and DSC profiles were collected on Discovery 5500 thermogravimetric analyzer and Discovery 2500 differential scanning calorimeter, respectively, parameters as in table 4:

TABLE 4 Table 4

Parameters (parameters)	TGA	DSC
			Method	Linear temperature rise	Linear temperature rise
Sample tray	Aluminum tray open	Aluminum plate and gland
			Temperature range	Room temperature-350 DEG C	25℃-300℃
Scan rate (. Degree. C./min)	10	50
			Protective gas	Nitrogen gas	Nitrogen gas

Dynamic moisture adsorption (DVS)

Dynamic moisture sorption (DVS) curves were collected on DVS intricic of SMS (Surface Measurement Systems). LiCl, mg (NO) ₃ ) ₂ And deliquescence point correction of KCl. DVS test parameters are listed in table 5:

TABLE 5

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Liquid nuclear magnetism of hydrogen spectrum ¹ H Solution NMR)

Collecting hydrogen spectrum liquid nuclear magnetic spectrum on Bruker 400M nuclear magnetic resonance apparatus, DMSO-d ₆ As a solvent.

Ultra Performance Liquid Chromatography (UPLC)

The purity and solubility of the samples in the test were measured by waters ultra high performance liquid chromatography under the conditions shown in table 6:

TABLE 6

Example 1: preparation of crystal form A of polysubstituted benzene ring compound succinate shown in formula III

395.8mg of the crystal form A of the polysubstituted benzene ring compound shown in formula I obtained in example 1 is weighed into a 20-mL glass vial; 88.0mg of succinic acid is added; adding 7.0-mL of ethyl acetate to form a suspension, and magnetically stirring at room temperature for about 3 days; the resulting solid was isolated by suction filtration and dried overnight at room temperature under vacuum to give 418.9mg of solid. The sample obtained by the X-ray powder diffraction pattern measurement is a crystal form A of the polysubstituted benzene ring compound succinate shown in a formula III, the X-ray powder diffraction pattern is shown in a figure 1, ¹ the H NMR data were: ¹ H NMR(400MHz,DMSO-d6):δ11.51(s,1H),8.10(t,J＝5.2Hz,1H), 6.65(d,J＝2.4Hz,1H),6.44(d,J＝2.4Hz,1H),5.89(s,1H),4.89–4.84(m,1H),4.27(d,J＝ 5.2Hz,2H),3.85(d,J＝10.4Hz,2H),3.33(t,J＝10.8Hz,2H),3.01(dd,J＝6.8,13.6Hz,2H),2.93– 2.89(m,1H),2.85–2.76(m,1H),2.42(s,4H)2.42–2.35(m,4H),2.22(s,3H),2.13(d,J＝4.0,6H), 1.63–1.46(m,10H),0.81(t,J＝7.2Hz,3H)ppm。

Claims (5)

1. a crystal form a of a succinate salt of a multi-substituted benzene ring compound shown in formula III, wherein the X-ray powder diffraction pattern expressed in terms of 2Θ angle is substantially as shown in figure 1;

2. a pharmaceutical composition comprising the crystalline form a of the succinate salt of a multi-substituted benzene ring compound of formula III according to claim 1, and a pharmaceutically acceptable carrier.

3. Use of a crystalline form a of a polysubstituted benzene ring compound succinate as shown in formula III according to any one of claims 1 or a pharmaceutical composition according to claim 2 for the preparation of a medicament for the prevention or treatment of EZH2 mediated diseases.

4. The use of claim 3, wherein the EZH2 mediated disease comprises cancer.

5. The use of claim 4, wherein the cancer comprises brain cancer, thyroid cancer, cardiac sarcoma, lung cancer, oral cancer, stomach cancer, liver cancer, kidney cancer, pancreatic cancer, esophageal cancer, nasopharyngeal cancer, laryngeal cancer, colorectal cancer, breast cancer, prostate cancer, bladder cancer, ovarian cancer, uterine cancer, bone cancer, melanoma, glioblastoma, lymphoma, blood cancer, adrenal neuroblastoma, skin cancer, astrocytoma.

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