Crystal form XIV of sGC agonist as well as preparation method and application of crystal form XIV

Abstract

The invention belongs to the technical field of medicines, and particularly relates to a crystal form XIV of an sGC agonist as well as a preparation method and application of the crystal form XIV. The crystal form XIV has diffraction peaks at the positions of 8.746 degrees, 8.9487 degrees, 9.5388 degrees, 14.0763 degrees, 16.3184 degrees, 16.5286 degrees, 17.2373 degrees, 18.3355 degrees, 19.1287 degrees, 19.3844 degrees, 20.1885 degrees, 21.4895 degrees, 23.5043 degrees, 23.8672 degrees, 24.9351 degrees, 25.1009 degrees, 25.3026 degrees and 26.7261 degrees in an X-ray powder diffraction pattern represented by a diffraction angle of 2 theta + / -0.2 degrees. Technical guarantee is provided for research and development of subsequent drugs and maintenance of consistency of pharmacokinetic and pharmacokinetic properties of the drugs.

Description

[0001] This application is a divisional application of the following application: application date is January 2, 2025, application number is 202510000935.8, and the invention name is polymorphs of sGC agonists and preparation method and application thereof. TECHNICAL FIELD

[0002] The present application belongs to the technical field of medicine, and specifically relates to a crystal form XIV of sGC agonist and a preparation method and application thereof. BACKGROUND

[0003] Pulmonary arterial hypertension (PAH) is a high-fatal pulmonary vascular occlusive disease, and its clinical manifestations are the progressive increase of pulmonary arterial pressure and pulmonary vascular resistance of patients, the increase of right ventricular afterload, and finally the right heart failure and even death. Although the traditional PAH treatment drugs can improve the survival rate of patients to a certain extent, the traditional treatment drugs can only dilate blood vessels to "treat the symptoms" and cannot "treat the root cause", and have drug resistance and side effects such as easy to cause systemic hypotension, so the research and development of PAH targeted treatment drugs is still urgently needed in the clinic.

[0004] Riociguat is the first soluble guanylate cyclase (sGC) agonist developed by Bayer Pharmaceuticals in Germany, and in 2013, the US FDA approved Riociguat for the treatment of chronic thromboembolic pulmonary hypertension and arterial pulmonary hypertension. Riociguat solves the problem of poor long-term prognosis of traditional drugs, but it can only "treat the symptoms" and has too strong vasodilator effect, which can cause mild systemic hypotension side effects in patients. At present, Riociguat has not been marketed in China. With the increasing number of patients with pulmonary arterial hypertension, more and more attention is paid to finding new drugs for treating pulmonary arterial hypertension that can act as sGC agonists to "treat the symptoms" and inhibit AMPK to "treat the root cause".

[0005] LXH-1211, chemical name: 2-(3-methyl-1-phenyl-6-((2-methyl)benzyloxy)-1H-pyrazolo[3,4-b]pyridin-5-yl)pyrimidine-4,6-diamine, is a sGC agonist drug. Pharmacological data shows that the drug has good anti-pulmonary arterial smooth muscle cell proliferation activity, which is stronger than the positive control drug Riociguat; and the vasodilator effect is weaker than the positive control drug Riociguat. The above results show that LXH-1211 will overcome the systemic hypotension caused by Riociguat in the treatment of PAH, thereby achieving the effect of "treating the symptoms and the root cause", and the drug also shows certain anti-pulmonary fibrosis effect. So far, there is no report on the crystal form of LXH-1211. SUMMARY

[0006] The application aims to provide a crystal form XIV of sGC agonist, and provide technical support for subsequent drug research and industrial production.

[0007] The crystal form XIV of sGC agonist is a crystal form XIV of compound I, and the structural formula of the compound I is as follows: The crystal form XIV has diffraction peaks at 8.746°, 8.9487°, 9.5388°, 14.0763°, 16.3184°, 16.5286°, 17.2373°, 18.3355°, 19.1287°, 19.3844°, 20.1885°, 21.4895°, 23.5043°, 23.8672°, 24.9351°, 25.1009°, 25.3026°, 26.7261° in the X-ray powder diffraction spectrum expressed by 2θ±0.2° diffraction angle; Preferably, the crystal form XIV has diffraction peaks at 8.746°, 8.9487°, 9.5388°, 14.0763°, 14.9162°, 16.3184°, 16.5286°, 17.2373°, 17.9255°, 18.3355°, 18.6382°, 18.9497°, 19.1287°, 19.3844°, 20.1885°, 21.4895°, 21.7479°, 22.6605°, 22.813°, 23.5043°, 23.8672°, 24.9351°, 25.1009°, 25.3026°, 26.1261°, 26.7261°, 31.4344°, 31.8331°, 33.1575° in the X-ray powder diffraction spectrum expressed by 2θ±0.2° diffraction angle; ​Preferably, the Form XIV has an X-ray powder diffraction pattern, expressed in terms of 2-theta ± 0.2° degrees 2-theta diffraction angles, having diffraction peaks at 8.746°, 8.9487°, 9.5388°, 14.0763°, 14.9162°, 15.0777°, 16.3184°, 16.5286°, 17.2373°, 17.5152°, 17.7266°, 17.9255°, 18.3355°, 18.6382°, 18.9497°, 19.1287°, 19.3844°, 19.8064°, 20.1885°, 21.4895°, 21.7479°, 22.6605°, 22.813°, 23.5043°, 23.8672°, 24.9351°, 25.1009°, 25.3026°, 25.708°, 26.1261°, 26.7261°, 27.0206°, 28.8713°, 29.2053°, 29.7983°, 30.142°, 30.4013°, 31.4344°, 31.8331°, 33.1575°; Preferably, the Form XIV has an X-ray powder diffraction pattern, expressed in terms of 2-theta ± 0.2° degrees 2-theta diffraction angles, having diffraction peaks at 8.746°, 8.9487°, 9.5388°, 14.0763°, 14.9162°, 15.0777°, 16.3184°, 16.5286°, 17.2373°, 17.5152°, 17.7266°, 17.9255°, 18.3355°, 18.6382°, 18.9497°, 19.1287°, 19.3844°, 19.8064°, 20.1885°, 21.4895°, 21.7479°, 22.6605°, 22.813°, 23.5043°, 23.8672°, 24.9351°, 25.1009°, 25.3026°, 25.708°, 26.1261°, 26.7261°, 27.0206°, 28.8713°, 29.2053°, 29.7983°, 30.142°, 30.4013°, 31.4344°, 31.8331°, 32.6225°, 33.1575°, 33.985°, 34.8527°, 35.8313°, 36.2587°, 37.138°, 37.74°, 38.7228°; Preferably, the Form XIV has one or more of the following characteristics: (1) the TGA curve of Form XIV has a weight loss of 18.92 ± 1% at 200.0 ± 3°C; (2) the TGA curve of Form XIV has a decomposition endotherm at 287.3 ± 3°C; (3) The DSC curve of crystalline Form XIV has a desolvation endotherm peak at 144.2±3℃; (4) The DSC curve of crystalline Form XIV has a melting endotherm peak at 222.5±3℃.

[0008] The preparation method of the crystalline Form XIV of the sGC agonist described in the present application is to add compound I into a solvent, 0-50℃ suspension beating stirring for 4-7 days, centrifugation, removing supernatant, vacuum drying, and then obtaining.

[0009] The solvent is one or both of water or an organic solvent, the organic solvent is one or several of alcohol, chloroalkane, ketone, ether, cyclic ether, ester, alkane, benzene, sulfoxide or amide, and the organic solvent is preferably one or several of methanol, ethanol, isopropanol, dimethyl sulfoxide, acetone, butanone, ethyl acetate, isopropyl acetate, methyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, methyl tert-butyl ether, toluene, N-methyl pyrrolidone, n-heptane, cyclohexane, 1,4-dioxane, dichloromethane or N,N-dimethylformamide.

[0010] The application of the crystalline Form XIV of the sGC agonist described in the present application is a pharmaceutical composition comprising the crystalline Form XIV and a pharmaceutically acceptable carrier.

[0011] The application of the crystalline Form XIV of the sGC agonist described in the present application is for preparing a drug for treating a pulmonary disease.

[0012] The pulmonary disease is pulmonary arterial hypertension or pulmonary fibrosis.

[0013] The beneficial effects of the present application are as follows: The present application provides the crystalline Form XIV of the sGC agonist LXH-1211, which provides a technical guarantee for subsequent drug research and development and keeping the consistency of the pharmacokinetics and pharmacodynamics properties of the drug, and also provides technical support for subsequent industrial production of a drug of a specific crystal form. BRIEF DESCRIPTION OF DRAWINGS

[0014] Figure 1 The XRPD spectrum of the crystalline Form XIV.

[0015] Figure 2 The TGA / DSC spectrum of the crystalline Form XIV. DETAILED DESCRIPTION

[0016] The present application is further described below in combination with examples.

[0017] DEFINITIONS AND EXPLANATIONS Unless otherwise indicated, all technical and scientific terms used herein have the same meaning as those commonly understood by one of ordinary skill in the art to which the application pertains. All patents and publications referred to in this application are incorporated herein by reference in their entirety. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present application, the preferred methods, devices, and materials are described.

[0018] "Crystal form" or "crystalline form" refers to a solid having a highly ordered chemical structure, including, but not limited to, single component or multi-component crystals, and / or polymorphs, solvates, hydrates, clathrates, co-crystals, salts, solvates of salts, hydrates of salts of a compound. Crystalline forms of a substance can be obtained by a number of methods known in the art. Such methods include, but are not limited to, melt crystallization, melt cooling, solvent crystallization, crystallization in confined spaces, e.g., in nanopores or capillaries, crystallization on surfaces or templates, e.g., on polymers, crystallization in the presence of additives such as co-crystallizing counter-molecules, desolvation, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, reactive crystallization, anti-solvent addition, milling, and solvent-drop grinding, etc.

[0019] "Solvate" refers to a molecular complex of a compound of the present application with one or more solvent molecules, either organic or inorganic. Non-limiting examples of solvents that can form solvates include water, methanol, ethanol, isopropanol, dimethyl sulfoxide, acetone, butanone, ethyl acetate, isopropyl acetate, methyl acetate, tetrahydrofuran, 2-methyl tetrahydrofuran, acetonitrile, methyl tert-butyl ether, toluene, N-methylpyrrolidone, n-heptane, cyclohexane, 1,4-dioxane, dichloromethane, N,N-dimethylformamide, and the like.

[0020] X-ray powder diffraction (XRPD) is a common method for identifying crystal forms, which can detect changes in crystal form, crystallinity, crystal state, etc. The peak positions of XRPD patterns are mainly dependent on the structure of the crystal form, and are relatively insensitive to experimental details, while the relative peak heights depend on many factors related to sample preparation and instrument geometry. Thus, in some embodiments, the crystal forms of the present application are characterized by XRPD patterns having certain peak positions, substantially as shown in the XRPD patterns provided in the figures of the present application. Also, the measurement of 2Θ of XRPD patterns can have experimental errors, and the measurement of 2Θ of XRPD patterns can be slightly different between different instruments and different samples, thus the values of 2Θ should not be considered as absolute. According to the condition of the instrument used in the experiments of the present application, there is an error tolerance of ±0.2° for the diffraction peaks.

[0021] Differential scanning calorimetry (DSC) is a technique that measures the energy difference between a sample and an inert reference (commonly a-Al203) as a function of temperature under programmed conditions by either heating or cooling. The height of the melting peak in a DSC curve depends on many factors related to sample preparation and instrument geometry, while the position of the peak is relatively insensitive to experimental details. Thus, in some embodiments, the crystalline forms described herein are characterized by DSC curves having characteristic peak positions, as substantially shown in the DSC curves provided in the figures of the present application. At the same time, DSC curves can have experimental errors, and the peak position and peak value of a DSC endothermic peak can vary slightly between different instruments and different samples, and thus the numerical values of the peak position or peak value of the DSC endothermic peak should not be considered absolute. There is an error tolerance of ± 3 °C for the melting peak, depending on the condition of the instrument used in the experiments according to the present application.

[0022] The same chemical composition of a solid can form different crystal structures under different thermodynamic conditions, and this phenomenon is called polymorphism or homomorphism. When the temperature and pressure conditions change, the polymorphs will transform into each other, and this phenomenon is called crystal transformation. Due to crystal transformation, the mechanical, electrical, magnetic, and other properties of the crystal will change greatly. When the temperature of the crystal transformation is within the measurable range, the transformation process can be observed on the differential scanning calorimetry (DSC) curve, which is characterized by an exothermic peak reflecting the transformation process, and at the same time, there are two or more endothermic peaks, which are the characteristic endothermic peaks of different crystal forms before and after the transformation. The crystalline forms of the compounds of the present application can undergo crystal transformation under appropriate conditions.

[0023] Thermogravimetric analysis (TGA) is a technique that measures the mass of a substance as a function of temperature under programmed conditions, which is suitable for checking the loss of solvent in the crystal or the process of sublimation or decomposition of the sample, and can be used to infer the presence of crystalline water or crystalline solvent in the crystal. The mass change shown in the TGA curve depends on many factors such as sample preparation and instrument; the mass change detected by TGA is slightly different between different instruments and different samples. According to the condition of the instrument used in the experiments according to the present application, there is an error tolerance of ± 0.3% for the mass change.

[0024] In the context of the present application, the 2Θ (°2Th., °2Theta or Two Theta) values in the X-ray powder diffraction pattern are in degrees (°).

[0025] In the present application, "room temperature" generally refers to 22 °C to 28 °C, unless otherwise specified.

[0026] When referring to a spectrum or / and data appearing in a figure, "peak" refers to a feature that can be recognized by a person skilled in the art and cannot be attributed to background noise.

[0027] In the context of the present application, when using or whether using the words "about" or "approximately" or the like, it is meant to indicate that the given value or range is within 10%, suitably within 5%, and particularly within 1% of the stated value or range. Alternatively, for those skilled in the art, the term "about" or "approximately" means within an acceptable standard deviation of the mean. Whenever a number is disclosed having a plus or minus value, any number within + / - 1%, + / - 2%, + / - 3%, + / - 5%, + / - 7%, + / - 8%, or + / - 10% of the stated value is also expressly disclosed.

[0028] The term "comprising" is an open-ended term that includes the stated elements, but not to the exclusion of other elements.

[0029] The test methods are as follows: I. X-ray powder diffraction (XRPD) XRPD test conditions: detection instrument: Rigaku SmartLab SE; detection conditions: X-ray light tube voltage 40 kV, X-ray light tube current 40 mA, scanning range 3-40° (2θ), step 0.02°, scanning speed 5° / min.

[0030] II. Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) TGA / DSC test conditions: detection instrument: NETZSCH STA 449 F3; detection conditions: nitrogen, 50 mL / min; scanning program: 30-400℃, temperature rise rate: 10℃ / min; detection sample amount: 3 mg (alumina sample pan).

[0031] Example 1 Take 50 mg of compound I, suspend and beat in 1 ml of N-methylpyrrolidone at room temperature for 4 days, centrifuge, remove the supernatant, and vacuum dry at 40℃ for 4 hours. Then take a sample for testing, which is labeled as crystal form XIV. The test results are shown in Figure 1 and Figure 2 . Figure 2 The TGA results in the middle show that the sample loses 18.92% of weight when heated from room temperature to 200℃; the sample starts to decompose near 287.3℃. Figure 2 The DSC results in the middle show that the sample has a desolvation endothermic peak near 144.2℃ and a melting endothermic peak near 222.5℃.

[0032] The XRPD diffraction peak data of crystal form XIV are shown in Table 1.

[0033] Table 1 XRPD diffraction peak data of crystal form XIV

Claims

1. A crystalline Form XIV of an sGC agonist characterized by The crystalline Form XIV of sGC agonist is a crystalline Form XIV of Compound I, which has the structural formula of: ； The X-ray powder diffraction pattern of crystalline Form XIV, expressed in terms of 2Q ± 0.2° diffraction angles, has diffraction peaks at 8.746°, 8.9487°, 9.5388°, 14.0763°, 16.3184°, 16.5286°, 17.2373°, 18.3355°, 19.1287°, 19.3844°, 20.1885°, 21.4895°, 23.5043°, 23.8672°, 24.9351°, 25.1009°, 25.3026°, 26.7261°; Preferably, the X-ray powder diffraction pattern of crystalline Form XIV, expressed in terms of 2Q ± 0.2° diffraction angles, has diffraction peaks at 8.746°, 8.9487°, 9.5388°, 14.0763°, 14.9162°, 16.3184°, 16.5286°, 17.2373°, 17.9255°, 18.3355°, 18.6382°, 18.9497°, 19.1287°, 19.3844°, 20.1885°, 21.4895°, 21.7479°, 22.6605°, 22.813°, 23.5043°, 23.8672°, 24.9351°, 25.1009°, 25.3026°, 26.1261°, 26.7261°, 31.4344°, 31.8331°, 33.1575°; Preferably, the X-ray powder diffraction pattern of crystalline Form XIV, expressed in terms of 2Q ± 0.2° diffraction angles, has diffraction peaks at 8.746°, 8.9487°, 9.5388°, 14.0763°, 14.9162°, 15.0777°, 16.3184°, 16.5286°, 17.2373°, 17.5152°, 17.7266°, 17.9255°, 18.3355°, 18.6382°, 18.9497°, 19.1287°, 19.3844°, 19.8064°, 20.1885°, 21.4895°, 21.7479°, 22.6605°, 22.813°, 23.5043°, 23.8672°, 24.9351°, 25.1009°, 25.3026°, 25.708°, 26.1261°, 26.7261°, 27.0206°, 28.8713°, 29.2053°, 29.7983°, 30.142°, 30.4013°, 31.4344°, 31.8331°, 33.1575°; Preferably, the crystalline Form XIV has an X-ray powder diffraction pattern, in terms of 2Q±0.2° diffraction angles, having diffraction peaks at 8.746°, 8.9487°, 9.5388°, 14.0763°, 14.9162°, 15.0777°, 16.3184°, 16.5286°, 17.2373°, 17.5152°, 17.7266°, 17.9255°, 18.3355°, 18.6382°, 18.9497°, 19.1287°, 19.3844°, 19.8064°, 20.1885°, 21.4895°, 21.7479°, 22.6605°, 22.813°, 23.5043°, 23.8672°, 24.9351°, 25.1009°, 25.3026°, 25.708°, 26.1261°, 26.7261°, 27.0206°, 28.8713°, 29.2053°, 29.7983°, 30.142°, 30.4013°, 31.4344°, 31.8331°, 32.6225°, 33.1575°, 33.985°, 34.8527°, 35.8313°, 36.2587°, 37.138°, 37.74°, 38.7228°; Preferably, the crystalline Form XIV has one or more of the following characteristics: (1) the TGA curve of the crystalline Form XIV has a weight loss of 18.92±1% at 200.0±3°C; (2) the TGA curve of the crystalline Form XIV has a decomposition endothermic peak at 287.3±3°C; (3) the DSC curve of the crystalline Form XIV has a desolvation endothermic peak at 144.2±3°C; (4) the DSC curve of the crystalline Form XIV has a melting endothermic peak at 222.5±3°C.

2. A process for preparing the crystalline Form XIV of the sGC agonist of claim 1, characterized in that Compound I is added into a solvent, and stirred for 4-7 days at 0-50°C, centrifuged, the supernatant is removed, and dried under vacuum to obtain the product.

3. A process for preparing the crystalline Form XIV of sGC agonist according to claim 2, characterized in that The solvent is one or both of water or an organic solvent, and the organic solvent is one or more of an alcohol, a chlorinated alkane, a ketone, an ether, a cyclic ether, an ester, an alkane, benzene, a sulfoxide or an amide.

4. Use of crystalline Form XIV of the sGC agonist of claim 1, characterized in that The pharmaceutical composition comprises the crystalline Form XIV and a pharmaceutically acceptable carrier.

5. Use of crystalline Form XIV of the sGC agonist of claim 1, characterized in that The pharmaceutical composition is used for preparing a medicament for treating a pulmonary disease.

6. Use of the crystalline Form XIV of sGC agonists according to claim 5, characterized in that The pulmonary disease is pulmonary hypertension or pulmonary fibrosis. The pulmonary disease is pulmonary hypertension or pulmonary fibrosis.

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