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

Abstract

The invention belongs to the technical field of medicines, and particularly relates to a crystal form VIII of an sGC agonist as well as a preparation method and application of the crystal form VIII. The crystal form VIII of the sGC agonist is the crystal form VIII of the compound I. The X-ray powder diffraction pattern of the crystal form VIII, which is represented by a diffraction angle of 2 theta + / -0.2 degrees, has diffraction peaks at the positions of 8.8902 degrees, 9.818 degrees, 15.9516 degrees, 16.5412 degrees, 17.851 degrees, 19.5499 degrees, 20.0096 degrees, 21.4687 degrees, 24.3685 degrees and 25.3691 degrees. The crystal form VIII of the sGC agonist LXH-1211 provided by the invention provides a technical guarantee for subsequent research and development of drugs and maintenance of consistency of pharmacokinetic and pharmacokinetic properties of the drugs, and also can provide a technical support for subsequent industrial production of drugs with specific crystal forms.

Description

[0001] This application is a divisional application of the following application: filed on January 2, 2025, application number 202510000935.8, entitled "Polymorphism of sGC agonist and its preparation method and application". Technical Field

[0002] This invention belongs to the field of pharmaceutical technology, specifically relating to a crystal form VIII of an sGC agonist, its preparation method, and its application. Background Technology

[0003] Pulmonary arterial hypertension (PAH) is a highly fatal pulmonary vascular occlusive disease, clinically characterized by progressively increasing pulmonary artery pressure and pulmonary vascular resistance, increased right ventricular afterload, and ultimately, right ventricular failure and death. While traditional PAH treatments can improve patient survival rates to some extent, they only treat the symptoms by dilating blood vessels and do not address the root cause. Furthermore, these drugs can lead to drug resistance and side effects such as systemic hypotension. Therefore, the development of targeted therapies for PAH remains a pressing clinical need.

[0004] Riociguat, developed by Bayer Pharma in Germany, is the first soluble guanylate cyclase (sGC) agonist. In 2013, the US FDA approved Riociguat for the treatment of chronic thromboembolic pulmonary hypertension (CPH) and arterial pulmonary hypertension (APPH). Riociguat addresses the poor long-term prognosis of traditional drugs, but it only treats the symptoms and its strong vasodilatory effect can cause mild systemic hypotension as a side effect. Currently, Riociguat is not yet available in China. With the increasing number of pulmonary hypertension patients, the search for novel drugs that can both act as sGC agonists to treat the symptoms and inhibit AMPK to address the root cause of pulmonary hypertension is attracting increasing attention.

[0005] LXH-1211, chemically named 2-(3-methyl-1-phenyl-6-((2-methyl)benzyloxy)-1H-pyrazolo[3,4-b]pyridin-5-yl)pyrimidine-4,6-diamine, is an sGC agonist. Pharmacological data show that this drug has good anti-pulmonary artery smooth muscle cell proliferation activity, stronger than the positive control drug Riociguat; however, its vasodilatory effect is weaker than that of Riociguat. These results indicate that LXH-1211, while possessing anti-pulmonary hypertension activity, may overcome the systemic hypotension caused by Riociguat in the treatment of PAH, thus achieving a "combination of symptomatic and root-cause treatment" effect. Simultaneously, this drug also exhibits some anti-pulmonary fibrosis activity. To date, there are no reports on the crystal forms of LXH-1211. Summary of the Invention

[0006] The purpose of this invention is to provide a crystal form VIII of an sGC agonist, providing technical support for subsequent drug development and industrial production; this invention also provides a method for preparing crystal form VIII of the sGC agonist and its application.

[0007] The sGC agonist described in this invention has crystal form VIII, which is the same as crystal form VIII of compound I. The structural formula of compound I is as follows: ; The X-ray powder diffraction pattern of crystal form VIII, expressed as a diffraction angle of 2θ±0.2°, shows diffraction peaks at 8.8902°, 9.818°, 15.9516°, 16.5412°, 17.851°, 19.5499°, 20.0096°, 21.4687°, 24.3685°, and 25.3691°. Preferably, the X-ray powder diffraction pattern of crystal form VIII, expressed as a diffraction angle of 2θ±0.2°, shows diffraction peaks at 8.8902°, 9.818°, 15.9516°, 16.5412°, 17.851°, 18.2837°, 19.5499°, 20.0096°, 21.4687°, 21.8612°, 22.6366°, 24.3685°, 25.3691°, 25.6532°, 26.8742°, and 28.063°. Preferably, the X-ray powder diffraction pattern of crystal form VIII, expressed as a diffraction angle of 2θ±0.2°, shows diffraction peaks at 8.8902°, 9.818°, 14.8678°, 15.9516°, 16.5412°, 17.851°, 18.2837°, 18.7011°, 19.5499°, 20.0096°, 21.4687°, 21.8612°, 22.6366°, 23.9934°, 24.3685°, 24.8029°, 25.3691°, 25.6532°, 26.8742°, and 28.063°. Preferably, the X-ray powder diffraction pattern of crystal form VIII, expressed as a diffraction angle of 2θ±0.2°, shows diffraction peaks at 8.8902°, 9.818°, 14.4868°, 14.8678°, 15.9516°, 16.5412°, 17.851°, 18.2837°, 18.7011°, 19.5499°, 20.0096°, 21.4687°, 21.8612°, 22.6366°, 23.9934°, 24.3685°, 24.8029°, 25.3691°, 25.6532°, 26.8742°, 28.063°, 32.3583°, and 33.2506°. Preferably, crystal form VIII has one or more of the following characteristics: (1) The TGA curve of crystal form VIII showed a weight loss of 12.97±1% at 150.0±3℃; (2) The TGA curve of crystal form VIII shows a decomposition endothermic peak at 294.7±3℃; (3) The DSC curve of crystal form VIII has an endothermic peak for solvent removal at 121.3±3℃; (4) The DSC curve of crystal form VIII has a melting endothermic peak at 226.0±3℃.

[0008] The method for preparing crystal form VIII of the sGC agonist described in this invention is to add compound I to a solvent, suspend and stir at 0-50°C for 4-7 days, centrifuge, remove the supernatant, and vacuum dry to obtain the product.

[0009] The solvent is one or two of water or organic solvents. The organic solvent is one or more of alcohols, chloroalkanes, ketones, ethers, cyclic ethers, esters, alkanes, benzene, sulfoxides, or amides. The organic solvent is preferably one or more of methanol, ethanol, isopropanol, dimethyl sulfoxide, acetone, butanone, ethyl acetate, isopropyl acetate, methyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, methyl tert-butyl ether, toluene, N-methylpyrrolidone, n-heptane, cyclohexane, 1,4-dioxane, dichloromethane, or N,N-dimethylformamide.

[0010] The application of crystal form VIII of the sGC agonist described in this invention, wherein the pharmaceutical composition includes crystal form VIII and a pharmaceutically acceptable carrier.

[0011] The application of crystal form VIII of the sGC agonist described in this invention is for the preparation of drugs for treating lung diseases.

[0012] Lung diseases include pulmonary hypertension or pulmonary fibrosis.

[0013] The beneficial effects of this invention are as follows: This invention provides crystal form VIII of the sGC agonist LXH-1211, which provides technical support for subsequent drug development and maintaining the consistency of drug pharmacokinetic and pharmacokinetic properties. It can also provide technical support for the subsequent industrial production of drugs with specific crystal forms. Attached Figure Description

[0014] Figure 1 The image shows the XRPD spectrum of crystal form VIII.

[0015] Figure 2 The TGA / DSC spectrum is for crystal form VIII. Detailed Implementation

[0016] The present invention will be further described below with reference to embodiments.

[0017] Definitions and Explanations Unless otherwise stated, all technical and scientific terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. All patents and publications related to this invention are incorporated herein by reference in their entirety. Although any methods and substances similar to or identical to those described herein may be used in the practice or testing of this invention, preferred methods, apparatus, and substances are described herein.

[0018] "Crystal form" or "crystalline shape" refers to a solid having a highly regular chemical structure, including, but not limited to, single-component or multi-component crystals, and / or polymorphs of compounds, solvates, hydrates, inclusion compounds, eutectics, salts, solvates of salts, and hydrates of salts. The crystalline form of a substance can be obtained by many methods known in the art. These methods include, but are not limited to, melt crystallization, melt cooling, solvent crystallization, crystallization in a confined space, such as in nanopores or capillaries, crystallization on a surface or template, such as on a polymer, crystallization in the presence of additives such as co-crystallized antimolecules, desolventization, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, reactive crystallization, antisolvent addition, grinding, and solvent drop grinding, etc.

[0019] "Solvent" refers to a substance (typically a liquid) that can completely or partially dissolve another substance (typically a solid). Solvents used in embodiments of the present invention include, but are not limited to, water, methanol, ethanol, isopropanol, dimethyl sulfoxide, acetone, butanone, ethyl acetate, isopropyl acetate, methyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, methyl tert-butyl ether, toluene, N-methylpyrrolidone, n-heptane, cyclohexane, 1,4-dioxane, dichloromethane, N,N-dimethylformamide, etc.

[0020] X-ray powder diffraction (XRPD) can detect changes in crystal form, crystallinity, and crystal structure, and is a commonly used method for identifying crystal forms. The peak positions of XRPD spectra mainly depend on the structure of the crystal form and are relatively insensitive to experimental details, while their relative peak heights depend on many factors related to sample preparation and instrument geometry. Therefore, in some embodiments, the crystal form of the present invention is characterized by XRPD patterns with certain peak positions, which are essentially as shown in the XRPD patterns provided in the accompanying drawings. Meanwhile, the measurement of 2θ in the XRPD spectra can have experimental errors; the measurement of 2θ in XRPD spectra may differ slightly between different instruments and different samples, therefore the value of 2θ cannot be considered absolute. Based on the instrument conditions used in the experiments according to the present invention, 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 α-Al₂O₃) as a function of temperature under programmed control by continuously heating or cooling. The melting peak height of the DSC curve depends on many factors related to sample preparation and instrument geometry, while the peak position is relatively insensitive to experimental details. Therefore, in some embodiments, the crystal form described in this invention is characterized by a DSC curve with characteristic peak positions, which are essentially as shown in the DSC curves provided in the accompanying drawings. However, DSC curves can be subject to experimental errors; the peak positions and peak values ​​of DSC curves may vary slightly between different instruments and different samples. Therefore, the peak position or peak value of the DSC endothermic peak cannot be considered absolute. Based on the instrument conditions used in the experiments according to this invention, the melting peak has an error tolerance of ±3°C.

[0022] Solids with the same chemical composition often form isomers, or polymorphs, with different crystal structures under different thermodynamic conditions. This phenomenon is called polymorphism or polyphase polymorphism. When temperature and pressure conditions change, these polymorphs can transform into each other; this phenomenon is called crystal form transformation. Due to crystal form transformation, the mechanical, electrical, and magnetic properties of the crystal undergo significant changes. When the temperature of the crystal form transformation is within a measurable range, this transformation process can be observed on a differential scanning calorimetry (DSC) curve. The DSC curve is characterized by having an exothermic peak reflecting this transformation process, and simultaneously possessing two or more endothermic peaks, which are characteristic endothermic peaks of the different crystal forms before and after the transformation. The crystal form of the compound of this invention can undergo a crystal form transformation under appropriate conditions.

[0023] Thermogravimetric analysis (TGA) is a technique used under programmed control to determine the change in mass of a substance with temperature. It is suitable for examining the loss of solvent in crystals or the sublimation and decomposition of samples, and can infer the presence of water of crystallization or crystallization solvent in the crystal. The mass change shown by the TGA curve depends on many factors, including sample preparation and instrumentation; the mass change detected by TGA varies slightly between different instruments and different samples. Based on the instrumentation used in this invention, there is an error tolerance of ±0.3% for the mass change.

[0024] In the context of this invention, the 2θ (°2Th., °2Theta, or Two Theta) values ​​in X-ray powder diffraction patterns are all in degrees (°).

[0025] Unless otherwise specified, "room temperature" in this invention usually refers to 22°C to 28°C.

[0026] When referring to a spectrum or / and the data appearing in the graph, a "peak" refers to a feature that a person skilled in the art can identify and that is not attributable to background noise.

[0027] In the context of this invention, when the terms "about" or "approximately" are used, whether or not they are used, it means within 10% of a given value or range, appropriately within 5%, and particularly within 1%. Alternatively, for those skilled in the art, the term "about" or "approximately" means within an acceptable standard error of the average. Whenever a number with a value of N is disclosed, any number having a value within N+ / -1%, N+ / -2%, N+ / -3%, N+ / -5%, N+ / -7%, N+ / -8%, or N+ / -10% is explicitly disclosed, where "+ / -" refers to addition or subtraction.

[0028] The term "comprising" is an open-ended expression, meaning it includes the contents specified in this invention, but does not exclude other aspects.

[0029] The testing method is as follows: I. X-ray Powder Diffraction (XRPD) XRPD testing conditions: Instrument: Rigaku SmartLab SE; Testing conditions: X-ray tube voltage 40kV, X-ray tube current 40mA, scanning range 3-40° (2θ), step size 0.02°, scanning speed 5° / min.

[0030] II. Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) TGA / DSC test conditions: Instrument: Netzsch STA 449 F3; Test conditions: Nitrogen, 50 mL / min; Scan program: 30-400℃, heating rate: 10℃ / min; Sample volume: 3 mg (alumina sample pan).

[0031] Example 1 Take 50 mg of compound I, suspend it in 1 ml of tetrahydrofuran, stir at room temperature for 4 days, centrifuge, remove the supernatant, dry under vacuum at 40°C for 4 hours, and then take a sample for testing, labeled as crystal form VIII. The test results are shown below. Figure 1 and Figure 2 . Figure 2 The TGA results showed that the sample lost 12.97% of its weight when heated from room temperature to 150°C; and the sample began to decompose around 294.7°C. Figure 2 The DSC results showed that the sample had an endothermic peak for solvent removal near 121.3℃ and an endothermic peak for melting near 226.0℃.

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

[0033] Table 1. XRPD diffraction peak data for crystal form VIII

Claims

1. A crystal form VIII of an sGC agonist, characterized in that... The sGC agonist has the same crystal form VIII as compound I, and the structural formula of compound I is as follows: ； The X-ray powder diffraction pattern of crystal form VIII, expressed as a diffraction angle of 2θ±0.2°, shows diffraction peaks at 8.8902°, 9.818°, 15.9516°, 16.5412°, 17.851°, 19.5499°, 20.0096°, 21.4687°, 24.3685°, and 25.3691°. Preferably, the X-ray powder diffraction pattern of crystal form VIII, expressed as a diffraction angle of 2θ±0.2°, shows diffraction peaks at 8.8902°, 9.818°, 15.9516°, 16.5412°, 17.851°, 18.2837°, 19.5499°, 20.0096°, 21.4687°, 21.8612°, 22.6366°, 24.3685°, 25.3691°, 25.6532°, 26.8742°, and 28.063°. Preferably, the X-ray powder diffraction pattern of crystal form VIII, expressed as a diffraction angle of 2θ±0.2°, shows diffraction peaks at 8.8902°, 9.818°, 14.8678°, 15.9516°, 16.5412°, 17.851°, 18.2837°, 18.7011°, 19.5499°, 20.0096°, 21.4687°, 21.8612°, 22.6366°, 23.9934°, 24.3685°, 24.8029°, 25.3691°, 25.6532°, 26.8742°, and 28.063°. Preferably, the X-ray powder diffraction pattern of crystal form VIII, expressed as a diffraction angle of 2θ±0.2°, shows diffraction peaks at 8.8902°, 9.818°, 14.4868°, 14.8678°, 15.9516°, 16.5412°, 17.851°, 18.2837°, 18.7011°, 19.5499°, 20.0096°, 21.4687°, 21.8612°, 22.6366°, 23.9934°, 24.3685°, 24.8029°, 25.3691°, 25.6532°, 26.8742°, 28.063°, 32.3583°, and 33.2506°. Preferably, crystal form VIII has one or more of the following characteristics: (1) The TGA curve of crystal form VIII showed a weight loss of 12.97±1% at 150.0±3℃; (2) The TGA curve of crystal form VIII shows a decomposition endothermic peak at 294.7±3℃; (3) The DSC curve of crystal form VIII has an endothermic peak for solvent removal at 121.3±3℃; (4) The DSC curve of crystal form VIII has a melting endothermic peak at 226.0±3℃.

2. A method for preparing crystal form VIII of the sGC agonist according to claim 1, characterized in that... Add compound I to a solvent, suspend and stir at 0-50℃ for 4-7 days, centrifuge, remove the supernatant, and vacuum dry to obtain the product.

3. The method for preparing crystal form VIII of the sGC agonist according to claim 2, characterized in that... The solvent is one or two of water or organic solvents, and the organic solvent is one or more of alcohols, chlorinated alkanes, ketones, ethers, cyclic ethers, esters, alkanes, benzene, sulfoxides or amides.

4. The application of crystal form VIII of the sGC agonist according to claim 1, characterized in that... The pharmaceutical composition includes crystal form VIII and a pharmaceutically acceptable carrier.

5. The application of crystal form VIII of the sGC agonist according to claim 1, characterized in that... Used to prepare drugs for treating lung diseases.

6. The application of crystal form VIII of the sGC agonist according to claim 5, characterized in that... Lung diseases include pulmonary hypertension or pulmonary fibrosis.

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