WO2021213493A1 - Crystal form of dihydronaphthyridine compound and use thereof - Google Patents

Abstract

The present invention relates to a crystal form of a dihydronaphthyridine compound and use thereof. The present invention also relates to a pharmaceutical composition containing the crystal form, and use of the crystal form or the pharmaceutical composition in preparation of drugs for treatment and prevention of diseases such as hyperaldosteronism, diabetic nephropathy, hypertension, heart failure (comprising chronic heart failure, etc.), sequelae of myocardial infarction, liver cirrhosis, renal failure, and stroke.

Description

Crystal forms of dihydronaphthyridine compounds and their uses Technical field

The invention belongs to the technical field of medicine, and relates to the crystal form of dihydronaphthyridine compounds and their uses, and specifically to 4-(4-cyano-2-methoxyphenyl)-5-cyclobutyloxy-2, The stereoisomer of 8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide and its crystal form and use thereof further relate to a pharmaceutical composition containing the crystal form.

Background technique

Mineralocorticoid Receptor (MR) is a nuclear hormone receptor activated by aldosterone, which regulates the expression of many genes involved in electrolyte homeostasis and cardiovascular diseases. The increase in circulating aldosterone increases blood pressure through its effect on urinary sodium excretion, while potentially affecting the brain, heart, and vascular system. In addition, hyperaldosteronism is related to many physiological processes that lead to kidney and cardiovascular diseases. Although hyperaldosteronism is usually caused by aldosterone-producing adenomas, patients with refractory hypertension often have elevated aldosterone levels, commonly referred to as "aldosterone escape", which is due to serum potassium Due to increased content or residual AT1R activity. Hyperaldosteronism and aldosterone escape typically lead to increased MR activity. It has been proven that MR antagonists can be effective antihypertensive agents and can also be effective in the treatment of heart failure and primary aldosterone disease. In addition, MR antagonists have also been shown to be effective in preclinical models of kidney disease, and can be combined with standard therapies to reduce proteinuria in patients with kidney disease, such as chronic kidney disease, including diabetic nephropathy.

International application WO 2019223629 A1 discloses a dihydropyrimidine compound, wherein the compound has mineralocorticoid receptor (MR) antagonism and can be used to treat and prevent hyperaldosteronism, diabetic nephropathy, and hypertension , Heart failure (including chronic heart failure, etc.), sequelae of myocardial infarction, liver cirrhosis, renal failure, stroke and other diseases. Specifically, the patent application discloses the compound 4-(4-cyano-2-methoxyphenyl)-5-cyclobutyloxy-2,8-dimethyl-1,4-dihydro-1 ,6-naphthyridine-3-carboxamide (a compound represented by formula (Ia)) and its stereoisomers, but the prior art does not disclose information about the compound or its stereo configuration crystal form.

Drug polymorphism is a common phenomenon in drug development and an important factor affecting drug quality. Different crystal forms of the same drug may have significant differences in appearance, solubility, melting point, dissolution, bioavailability, etc., and also have different effects on drug stability, bioavailability, and efficacy. Therefore, in drug research and development, the issue of drug polymorphism should be fully considered.

Summary of the invention

Prior art WO 2019223629 A1 discloses a compound represented by formula (Ia) and a preparation method thereof, as well as its stereoisomers, that is, the compound represented by formula (I) according to the present invention. The present invention provides a method for preparing the stereoisomers, and at the same time provides a crystal form of the stereoisomers, wherein the crystal form, especially the crystal form IV, can significantly improve the stability and medicine of the compound. The generation dynamics and other properties, which have better drug-making properties.

Specifically, the present invention relates to the compound represented by formula (I) and its crystal form, and the use of the compound or its crystal form or a pharmaceutical composition containing the crystal form as a mineralocorticoid antagonist, and/or Use in the preparation of medicines for treating or preventing mineralocorticoid-related diseases. The crystal form of the present invention may also be in the form of a solvate, such as a hydrate form.

In one aspect, the present invention provides a compound represented by formula (I):

On the other hand, the present invention provides a crystal form of the compound represented by formula (I),

In some embodiments, the crystal form of the compound represented by formula (I) according to the present invention is crystal form IV, crystal form V, crystal form VI, crystal form VII or crystal form VIII.

In some embodiments, the crystal form IV of the present invention is characterized in that the X-ray powder diffraction pattern of the crystal form IV has diffraction peaks at the following 2θ angles: 8.41°±0.2°, 9.67°±0.2° , 21.13°±0.2°, 21.67°±0.2°, 21.98°±0.2°.

In other embodiments, the crystal form IV of the present invention is characterized in that the X-ray powder diffraction pattern of the crystal form IV has diffraction peaks at the following 2θ angles: 8.41°±0.2°, 9.67°±0.2 °, 14.60°±0.2°, 15.69°±0.2°, 15.84°±0.2°, 21.13°±0.2°, 21.67°±0.2°, 21.98°±0.2°, 24.47°±0.2°, 25.58°±0.2°.

In other embodiments, the crystal form IV of the present invention is characterized in that the X-ray powder diffraction pattern of the crystal form IV has diffraction peaks at the following 2θ angles: 8.41°±0.2°, 9.67°±0.2 °, 12.63°±0.2°, 14.60°±0.2°, 15.69°±0.2°, 15.84°±0.2°, 19.23°± 0.2°, 19.90°±0.2°, 21.13°±0.2°, 21.67°±0.2°, 21.98°±0.2°, 23.90°±0.2°, 24.47°±0.2°, 25.58°±0.2°, 26.29°±0.2°, 26.85°±0.2°, 27.34°±0.2°.

In other embodiments, the crystal form IV of the present invention is characterized in that the X-ray powder diffraction pattern of the crystal form IV has diffraction peaks at the following 2θ angles: 8.41°±0.2°, 9.67°±0.2 °, 10.50°±0.2°, 11.07°±0.2°, 12.63°±0.2°, 14.60°±0.2°, 15.69°±0.2°, 15.84°±0.2°, 16.36°±0.2°, 17.44°±0.2°, 19.23°±0.2°, 19.90°±0.2°, 21.13°±0.2°, 21.67°±0.2°, 21.98°±0.2°, 23.90°±0.2°, 24.47°±0.2°, 24.92°±0.2°, 25.27° ±0.2°, 25.50°±0.2°, 25.58°±0.2°, 26.29°±0.2°, 26.85°±0.2°, 27.34°±0.2°, 28.40°±0.2°, 29.00°±0.2°, 29.73°±0.2 °, 31.05°±0.2°, 31.60°±0.2°, 32.09°±0.2°, 32.72°±0.2°, 33.09°±0.2°, 33.50°±0.2°, 34.15°±0.2°, 34.49°±0.2°, 35.27°±0.2°, 35.99°±0.2°, 36.54°±0.2°, 37.15°±0.2°, 38.41°±0.2°, 38.92°±0.2°, 39.12°±0.2°, 39.87°±0.2°.

In other embodiments, the crystal form IV of the present invention is characterized in that the X-ray powder diffraction pattern of the crystal form IV has diffraction peaks at the following 2θ angles: 8.41°±0.2°, 9.67°±0.2 °, 10.50°±0.2°, 11.07°±0.2°, 12.63°±0.2°, 14.60°±0.2°, 15.69°±0.2°, 15.84°±0.2°, 16.36°±0.2°, 17.44°±0.2°, 19.23°±0.2°, 19.90°±0.2°, 21.13°±0.2°, 21.67°±0.2°, 21.98°±0.2°, 23.90°±0.2°, 24.47°±0.2°, 24.92°±0.2°, 25.27° ±0.2°, 25.50°±0.2°, 25.58°±0.2°, 26.29°±0.2°, 26.85°±0.2°, 27.34°±0.2°, 28.40°±0.2°, 29.00°±0.2°, 29.73°±0.2 °, 31.05°±0.2°, 31.60°±0.2°, 32.09°±0.2°, 32.72°±0.2°, 33.09°±0.2°, 33.50°±0.2°, 34.15°±0.2°, 34.49°±0.2°, 35.27°±0.2°, 35.99°±0.2°, 36.54°±0.2°, 37.15°±0.2°, 38.41°±0.2°, 38.92°±0.2°, 39.12°±0.2°, 39.87°±0.2°, 41.01° ±0.2°, 41.98°±0.2°, 42.58°±0.2°, 43.03°±0.2°, 44.57°±0.2°, 44.83°±0.2°.

In other embodiments, the crystal form IV of the present invention is characterized in that the X-ray powder diffraction pattern of the crystal form IV has diffraction peaks at the following 2θ angles: 8.41°±0.2°, 9.67°±0.2 °, 10.50°±0.2°, 11.07°±0.2°, 12.63°±0.2°, 14.60°±0.2°, 15.69°±0.2°, 15.84°±0.2°, 16.36°±0.2°, 17.44°±0.2°, 19.23°±0.2°, 19.90°±0.2°, 21.13°±0.2°, 21.67°±0.2°, 21.98°±0.2°, 23.90°±0.2°, 24.47°±0.2°, 24.92°±0.2°, 25.27° ±0.2°, 25.50°±0.2°, 25.58°±0.2°, 26.29°±0.2°, 26.85°±0.2°, 27.34°±0.2°, 28.40°±0.2°, 29.00°±0.2°, 29.73°±0.2 °, 31.05°±0.2°, 31.60°±0.2°, 32.09°±0.2°, 32.72°±0.2°, 33.09°±0.2°, 33.50°±0.2°, 34.15°±0.2°, 34.49°±0.2°, 35.27°±0.2°, 35.99°±0.2°, 36.54°±0.2°, 37.15°±0.2°, 38.41°±0.2°, 38.92°±0.2°, 39.12°±0.2°, 39.87°±0.2°, 41.01° ±0.2°, 41.98°±0.2°, 42.58°±0.2°, 43.03°±0.2°, 44.57°±0.2°, 44.83°±0.2°, 45.89°±0.2°, 48.04°±0.2°, 50.02°±0.2 °, 51.00°±0.2°, 53.46°±0.2°, 54.05°±0.2°.

In some embodiments, the crystal form IV of the present invention is characterized in that the crystal form IV has an X-ray powder diffraction pattern substantially as shown in FIG. 1.

In some embodiments, the crystalline form IV of the present invention is characterized in that the differential scanning calorimetry of the crystalline form IV includes an endothermic peak at 254.25°C±3°C.

In some embodiments, the crystal form IV of the present invention is characterized in that the crystal form IV has a differential scanning calorimeter substantially as shown in FIG. 2.

In some embodiments, the crystal form V of the present invention is characterized in that the X-ray powder diffraction pattern of the crystal form V has diffraction peaks at the following 2θ angles: 11.32°, 18.96°, 21.43°, 21.92° , 22.04°, wherein the diffraction peak has an error tolerance of ±0.2°.

In some embodiments, the crystal form V of the present invention is characterized in that the X-ray powder diffraction pattern of the crystal form V has diffraction peaks at the following 2θ angles: 11.32°, 11.41°, 17.80°, 18.96° , 21.43°, 21.92°, 22.04°, 23.22°, 23.57°, 25.76°, wherein the diffraction peak has an error tolerance of ±0.2°.

In some embodiments, the crystal form V of the present invention is characterized in that the X-ray powder diffraction pattern of the crystal form V has diffraction peaks at the following 2θ angles: 7.37°, 10.16°, 11.32°, 11.41° , 11.51°, 11.79°, 12.49°, 14.27°, 14.68°, 15.20°, 16.04°, 17.80°, 18.96°, 20.23°, 21.43°, 21.92°, 22.04°, 22.84°, 23.22°, 23.57°, 24.18 °, 24.99°, 25.68°, 25.76°, 25.84°, 26.33°, 27.51°, 27.81°, 28.16°, 28.65°, 29.11°, 29.54°, 30.02°, 30.61°, 30.93°, 31.26°, 31.77°, 32.61°, 32.97°, 34.17°, 35.25°, 36.07°, 37.18°, 38.33°, 39.73°, 40.26°, 40.53°, 41.27°, 42.18°, 43.18°, 43.68°, 44.95°, 45.97°, 47.34° , Wherein the diffraction peak has an error tolerance of ±0.2°.

In some embodiments, the crystal form V of the present invention is characterized in that the crystal form V has an X-ray powder diffraction pattern substantially as shown in FIG. 3.

In some embodiments, the crystalline form V of the present invention is characterized in that the differential scanning calorimetry of the crystalline form V includes endothermic peaks of 141.79°C±3°C and 254.04°C±3°C.

In some embodiments, the crystal form V of the present invention is characterized in that the crystal form V has a differential scanning calorimeter substantially as shown in FIG. 4.

In some embodiments, the crystal form VI of the present invention is characterized in that the X-ray powder diffraction pattern of the crystal form VI has diffraction peaks at the following 2θ angles: 12.50°, 18.57°, 21.25°, 21.74° , 23.37°, wherein the diffraction peak has an error tolerance of ±0.2°.

In some embodiments, the crystal form VI of the present invention is characterized in that the X-ray powder diffraction pattern of the crystal form VI has diffraction peaks at the following 2θ angles: 10.98°, 11.33°, 11.54°, 12.50° , 14.74°, 18.57°, 21.25°, 21.74°, 23.37°, 25.12°, wherein the diffraction peak has an error tolerance of ±0.2°.

In some embodiments, the crystal form VI of the present invention is characterized in that the X-ray powder diffraction pattern of the crystal form VI has diffraction peaks at the following 2θ angles: 7.15°, 9.61°, 10.98°, 11.33° , 11.54°, 12.50°, 14.07°, 14.30°, 14.74°, 15.03°, 15.36°, 17.61°, 17.89°, 18.57°, 18.92°, 19.52°, 20.57°, 21.25°, 21.74°, 22.53°, 23.16 °, 23.37°, 23.61°, 24.08°, 24.37°, 25.12°, 25.53°, 25.79°, 26.53°, 26.84°, 27.40°, 27.76°, 28.30°, 28.52°, 28.81°, 28.97°, 29.91°, 30.34°, 30.88°, 31.31°, 32.37°, 33.71°, 34.39°, 34.88°, 35.24°, 36.24°, 36.82°, 37.73°, 39.46°, 40.49°, 41.19°, 41.82°, 42.53°, 43.44° , 44.74°, 45.11°, wherein the diffraction peak has an error tolerance of ±0.2°.

In some embodiments, the crystal form VI of the present invention is characterized in that the crystal form VI has an X-ray powder diffraction pattern substantially as shown in FIG. 5.

In some embodiments, the crystalline form VI of the present invention is characterized in that the differential scanning calorimetry of the crystalline form VI includes endothermic peaks of 99.00°C±3°C and 253.60°C±3°C.

In some embodiments, the crystal form VI of the present invention is characterized in that the crystal form VI has a differential scanning calorimeter substantially as shown in FIG. 6.

In some embodiments, the crystal form VII of the present invention is characterized in that the X-ray powder diffraction pattern of the crystal form VII has diffraction peaks at the following 2θ angles: 18.72°, 21.53°, 21.90°, 23.86° , 25.81°, wherein the diffraction peak has an error tolerance of ±0.2°.

In some embodiments, the crystal form VII of the present invention is characterized in that the X-ray powder diffraction pattern of the crystal form VII has diffraction peaks at the following 2θ angles: 11.09°, 12.79°, 15.01°, 18.72° , 21.53°, 21.90°, 23.86°, 23.95°, 25.72°, 25.81°, wherein the diffraction peak has an error tolerance of ±0.2°.

In some embodiments, the crystal form VII of the present invention is characterized in that the X-ray powder diffraction pattern of the crystal form VII has diffraction peaks at the following 2θ angles: 7.21°, 9.72°, 11.09°, 11.63° , 11.83°, 12.79°, 14.36°, 15.01°, 15.32°, 15.52°, 15.76°, 17.90°, 18.08°, 18.72°, 19.18°, 19.46°, 19.77°, 21.53°, 21.90°, 22.39°, 22.83 °, 23.49°, 23.86°, 23.95°, 24.36°, 24.66°, 25.26°, 25.72°, 25.81°, 26.36°, 26.65°, 27.20°, 27.45°, 27.97°, 28.52°, 28.83°, 29.26°, 29.88°, 30.23°, 30.61°, 30.88°, 31.21°, 31.76°, 32.32°, 32.98°, 33.20°, 33.73°, 34.00°, 34.33°, 35.00°, 35.29°, 35.73°, 36.18°, 36.47° , 37.17°, 38.10°, 39.44°, 40.12°, 40.61°, 41.12°, 41.72°, 42.11°, 42.82°, 43.80°, 45.09°, 45.47°, wherein the diffraction peak has an error tolerance of ±0.2° .

In some embodiments, the crystal form VII of the present invention is characterized in that the crystal form VII has an X-ray powder diffraction pattern substantially as shown in FIG. 7.

In some embodiments, the crystalline form VII of the present invention is characterized in that the differential scanning calorimetry of the crystalline form VII includes endothermic peaks at 123.29°C±3°C and 254.67°C±3°C.

In some embodiments, the crystal form VII of the present invention is characterized in that the crystal form VII has a differential scanning calorimeter substantially as shown in FIG. 8.

In some embodiments, the crystal form VIII of the present invention is characterized in that the X-ray powder diffraction pattern of the crystal form VIII has diffraction peaks at the following 2θ angles: 14.83°, 18.72°, 21.41°, 21.87° ,23.56°, wherein the diffraction peak has an error tolerance of ±0.2°.

In some embodiments, the crystal form VIII of the present invention is characterized in that the X-ray powder diffraction pattern of the crystal form VIII has diffraction peaks at the following 2θ angles: 11.42°, 12.61°, 14.83°, 17.77° , 18.72°, 21.41°, 21.87°, 23.56°, 23.74°, 25.69°, wherein the diffraction peak has an error tolerance of ±0.2°.

In some embodiments, the crystal form VIII of the present invention is characterized in that the X-ray powder diffraction pattern of the crystal form VIII has diffraction peaks at the following 2θ angles: 7.21°, 9.75°, 11.09°, 11.42° , 11.61°, 12.61°, 14.21°, 14.40°, 14.83°, 15.18°, 15.55°, 17.77°, 18.09°, 18.72°, 19.04°, 19.65°, 20.80°, 21.41°, 21.87°, 22.79°, 23.34 °, 23.56°, 23.74°, 24.24°, 24.61°, 25.34°, 25.69°, 26.03°, 26.72°, 27.17°, 27.64°, 27.97°, 28.48°, 28.69°, 29.13°, 29.92°, 30.16°, 30.58°, 31.21°, 31.79°, 32.74°, 33.69°, 34.01°, 34.71°, 35.49°, 36.71°, 37.07°, 38.07°, 39.47°, 40.51°, 41.05°, 41.54°, 42.07°, 42.86° , 43.76°, 45.01°, 45.50°, wherein the diffraction peak has an error tolerance of ±0.2°.

In some embodiments, the crystal form VIII of the present invention is characterized in that the crystal form VIII has an X-ray powder diffraction pattern substantially as shown in FIG. 9.

In some embodiments, the crystal form VIII of the present invention is characterized in that the differential scanning calorimeter of the crystal form VIII includes endothermic peaks of 134.09°C±3°C and 254.86°C±3°C.

In some embodiments, the crystal form VIII of the present invention is characterized in that the crystal form VIII has a differential scanning calorimeter substantially as shown in FIG. 10.

In another aspect, the present invention relates to a pharmaceutical composition comprising the compound represented by formula (I) of the present invention or its crystal form IV, crystal form V, crystal form VI, crystal form VII, crystal form VIII, or the like And pharmaceutically acceptable carriers, excipients, diluents, adjuvants, or combinations thereof.

In some embodiments, the pharmaceutical composition of the present invention further comprises one or more other active ingredients selected from ACE inhibitors, renin inhibitors, angiotensin II receptor antagonists Agents, β-receptor blockers, acetylsalicylic acid, diuretics, calcium antagonists, statins, digitalis derivatives, calcium sensitizers, nitrates and antithrombotic agents.

In one aspect, the present invention relates to the use of the compound represented by formula (I) or its crystal form IV, crystal form V, crystal form VI, crystal form VII or crystal form VIII or the pharmaceutical composition in the preparation of medicines , Wherein the drug is used to treat, prevent or alleviate the following diseases in patients: diabetic nephropathy, hyperaldosteronism, hypertension, heart failure, sequelae of myocardial infarction, liver cirrhosis, renal failure or stroke.

On the other hand, the present invention relates to the compound represented by formula (I) or its crystal form IV, crystal form V, crystal form VI, crystal form VII or crystal form VIII or the pharmaceutical composition in the preparation of medicines Uses, wherein the drug is used as a mineralocorticoid receptor antagonist.

One aspect of the present invention relates to a method for preventing, treating or alleviating a disease in a patient, wherein the disease is diabetic nephropathy, hyperaldosteronism, hypertension, heart failure, sequelae of myocardial infarction, liver cirrhosis, renal failure or stroke; The method includes administering the compound represented by formula (I) according to the present invention or any crystalline form thereof or the pharmaceutical composition in a pharmaceutically acceptable effective dose to the patient.

On the other hand, the present invention also relates to a method for preparing the compound represented by formula (I) or its crystal form IV, crystal form V, crystal form VI, crystal form VII or crystal form VIII.

The solvent used in the preparation method of the compound represented by formula (I) or its crystal form in the present invention is not particularly limited, and any solvent that can dissolve the starting material to a certain extent and does not affect its properties is included in the present invention . In addition, many similar modifications, equivalent substitutions, or different ratios of solvents, solvent combinations, and solvent combinations described in the present invention are all deemed to be included in the scope of the present invention. The present invention provides preferable solvents used in each reaction step.

The preparation experiment of the compound represented by formula (I) or its crystal form in the present invention will be described in detail in the example section. At the same time, the present invention provides an activity test experiment (such as a pharmacokinetic experiment), solubility experiment, stability experiment, moisture absorption experiment, etc. of the crystal form. Experiments have proved that the crystal form of the present invention, especially the crystal form IV, has better biological activity, better solubility, higher stability, and is suitable for pharmaceutical applications.

In addition, according to the results of hygroscopicity experiments, the crystal form IV of the present invention is not susceptible to being affected by high humidity and deliquescence, which is convenient for long-term storage and placement of the medicine.

Definitions and general terms

Unless otherwise specified, all technical and scientific terms used in the present invention have the same meanings as commonly understood by those of ordinary skill in the art to which the present invention belongs. All patents and publications related to the present invention are incorporated into the present invention in their entirety by reference. Although any methods and materials similar or identical to those described in the present invention can be used in the practice or testing of the present invention, the preferred methods, equipment and materials are described in the present invention.

"Crystal form" or "crystalline form" refers to a solid with a highly regular chemical structure, including, but not limited to, single-component or multi-component crystals, and/or compound polymorphs, solvates, hydrates, Inclusion compounds, co-crystals, salts, salt solvates, and salt hydrates. The crystalline form of the substance can be obtained by many methods known in the art. Such methods include, but are not limited to, melt crystallization, melt cooling, solvent crystallization, crystallization in a defined space, for example, in nanopores or capillaries, crystallization on a surface or template, for example, on polymers, Crystallization, solvent removal, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, reactive crystallization, anti-solvent addition, grinding and solvent drop grinding in the presence of additives such as co-crystal anti-molecules.

"Solvent" refers to a substance (typically a liquid) that can completely or partially dissolve another substance (typically a solid). Solvents used in the practice of the present invention include, but are not limited to, water, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, dichloromethane, dimethyl sulfoxide, 1,4-dioxane, ethanol , Ethyl acetate, butanol, tert-butanol, N,N-dimethylacetamide, N,N-dimethylformamide, formamide, formic acid, heptane, hexane, isopropanol, methanol, Methyl ethyl ketone, mesitylene, nitromethane, polyethylene glycol, propanol, pyridine, tetrahydrofuran, toluene, xylene, their mixtures, etc.

"Solvate" refers to a compound that has a solvent on the surface, in the crystal lattice, or on the surface and in the crystal lattice. The solvent may be water, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, Dichloromethane, dimethyl sulfoxide, 1,4-dioxane, ethanol, ethyl acetate, butanol, tert-butanol, N,N-dimethylacetamide, N,N-dimethylformaldehyde Amide, formamide, formic acid, heptane, hexane, isopropanol, methanol, methyl ethyl ketone, methyl pyrrolidone, mesitylene, nitromethane, polyethylene glycol, propanol, pyridine, tetrahydrofuran, Toluene, xylene and their mixtures and so on. A specific example of a solvate is a hydrate, where the solvent on the surface, in the crystal lattice, or on the surface and in the crystal lattice is water. On the surface of the substance, in the crystal lattice, or on the surface and in the crystal lattice, the hydrate may or may not have other solvents other than water.

The crystal form can be identified by a variety of technical means, such as X-ray powder diffraction (XRPD), infrared absorption spectroscopy (IR), melting point method, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), nuclear magnetism Resonance method, Raman spectroscopy, X-ray single crystal diffraction, dissolution calorimetry, scanning electron microscope (SEM), quantitative analysis, solubility and dissolution rate, etc.

X-ray powder diffraction (XRPD) can detect the change of crystal form, crystallinity, crystal structure state and other information, and it is a common method to identify crystal form. The peak position of the XRPD pattern mainly depends on the structure of the crystal form and is relatively insensitive to experimental details, while its relative peak height depends on many factors related to sample preparation, equipment and geometry. Therefore, in some embodiments, the crystalline form of the present invention is characterized by an XRPD pattern with certain peak positions, which is substantially as shown in the XRPD pattern provided in the drawings of the present invention. At the same time, the 2θ measurement of the XRPD pattern may have experimental errors. The 2θ measurement of the XRPD pattern may be slightly different between different instruments and different samples, so the 2θ value cannot be regarded as absolute. According to the condition of the instrument used in this experiment, the diffraction peak has an error tolerance of ±0.2°.

Differential scanning calorimetry (DSC) is a technique that measures the energy difference between a sample and an inert reference material (commonly used α-Al ₂ O _{3) with temperature changes under program control through continuous heating or cooling.} The endothermic 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 crystalline form of the present invention is characterized by a DSC chart with characteristic peak positions, which is substantially as shown in the DSC chart provided in the accompanying drawings of the present invention. At the same time, the DSC spectrum may have experimental errors. The peak position and peak value of the DSC spectrum may be slightly different between different instruments and different samples. Therefore, the peak position or the value of the peak value of the DSC endothermic peak cannot be regarded as absolute. According to the conditions of the instruments used in this experiment, there is an error tolerance of ±3°C for the endothermic peak.

In the context of the present invention, the 2θ values in the X-ray powder diffraction pattern are all in degrees (°).

The term "substantially as shown in the figure" means at least 50%, or at least 60%, or at least 70%, or at least 80%, or At least 90%, or at least 95%, or at least 99% of the peaks are shown in the graph.

When referring to a spectrum or/and data appearing in the graph, "peak" refers to a feature that can be identified by those skilled in the art that will not be attributed to background noise.

The present invention relates to a new crystal form of the compound represented by formula (I), for example, crystal form IV, V, VI, VII or VIII, which exists in a substantially pure crystalline form.

"Substantially pure" means that one crystal form is substantially free of another one or more crystal forms, that is, the purity of the crystal form is at least 80%, or at least 85%, or at least 90%, or at least 93%, or At least 95%, or at least 98%, or at least 99%, or at least 99.5%, or at least 99.6%, or at least 99.7%, or at least 99.8%, or at least 99.9%, or the crystal form contains other crystal forms, the The percentage of other crystal forms in the total volume or weight of the crystal form is less than 20%, or less than 10%, or less than 5%, or less than 3%, or less than 1%, or less than 0.5%, Or less than 0.1%, or less than 0.01%.

"Substantially free" means that the percentage of one or more other crystal forms in the total volume or weight of the crystal form is less than 20%, or less than 10%, or less than 5%, or less than 4% , Or less than 3%, or less than 2%, or less than 1%, or less than 0.5%, or less than 0.1%, or less than 0.01%.

The "relative intensity" (or "relative peak height") in the XRPD diagram means that when the intensity of the first strong peak in all diffraction peaks of the X-ray powder diffraction pattern (XRPD) is 100%, the intensity of the other peaks is the same as that of the first peak. The ratio of the intensity of the strong peak.

In the context of the present invention, when the words "about" or "about" are used or whether or not they are used, they mean within 10% of a given value or range, suitably within 5%, especially within 1% . Alternatively, to those of ordinary skill in the art, the term "about" or "about" means within an acceptable standard error range of the average. Whenever a number with the value of N is disclosed, any number with N+/-1%, N+/-2%, N+/-3%, N+/-5%, N+/-7%, N+/-8% or N+ Numbers within the value of /-10% will be clearly disclosed, where "+/-" means plus or minus.

In the present invention, "room temperature" refers to a temperature ranging from about 10°C to about 40°C. In some embodiments, "room temperature" refers to a temperature from about 20°C to about 30°C; in other embodiments, "room temperature" refers to 20°C, 22.5°C, 25°C, 27.5°C, and so on.

The composition, preparation, administration and use of the compound represented by formula (I) or its crystal form of the present invention

The characteristics of the pharmaceutical composition of the present invention include the compound represented by formula (I) or its crystal form and a pharmaceutically acceptable carrier, adjuvant, or excipient. The amount of the compound or its crystal form in the pharmaceutical composition of the present invention can effectively and detectably treat or alleviate mineralocorticoid-related diseases in patients.

As described in the present invention, the pharmaceutically acceptable composition of the present invention further comprises pharmaceutically acceptable carriers, adjuvants, or excipients, which, like those used in the present invention, include any solvents, diluents, or other Liquid excipients, dispersants or suspending agents, surfactants, isotonic agents, thickeners, emulsifiers, preservatives, solid binders or lubricants, etc., are suitable for specific target dosage forms. As described in the following documents: In Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. DBTroy, Lippincott, Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick, and 1999-JCB Marcel Dekker, New York, combining the contents of the literature here, shows that different carriers can be applied to the preparation of pharmaceutically acceptable-compositions and their well-known preparation methods. Except for any conventional carrier medium that is incompatible with the compound of the present invention or its crystal form, for example, any adverse biological effects produced or produced in a harmful manner with any other components of the pharmaceutically acceptable composition Interaction, their use is also within the scope of the present invention.

Substances that can be used as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers; aluminum; aluminum stearate; lecithin; serum proteins such as human serum proteins; buffer substances such as phosphate; glycine; sorbic acid; Potassium acid; a mixture of partial glycerides of saturated plant fatty acids; water; salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt; colloidal silicon; magnesium trisilicate; polyethylene Pyrrolidone; polyacrylate; wax; polyethylene-polyoxypropylene-blocking polymer; lanolin; sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as carboxymethyl Sodium base cellulose, ethyl cellulose and cellulose acetate; gum powder; malt; gelatin; talc; excipients such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, Olive oil, corn oil and soybean oil; glycol compounds such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; seaweed Acid; pyrogen-free water; isotonic salt; Ringer's solution; ethanol; phosphate buffer solution; and other non-toxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate; coloring agent; release agent; Coating materials; sweeteners; flavoring agents; spices; preservatives and antioxidants.

The pharmaceutical composition of the present invention can be capsules, tablets, pills, powders, granules and water suspensions or solutions; it can be administered by the following routes: oral administration, injection administration, spray inhalation, topical administration, Rectal administration, nasal administration, buccal administration, vaginal administration or via implantable kits.

Oral administration can be administered in the following forms: tablets, pills, capsules, dispersible powders, granules or suspensions, syrups, elixirs, etc.; topical administration can be administered in the following forms: ointment, gel, Medicated tape, etc.

The compound represented by the formula (I) of the present invention or its crystal form is preferably prepared into a dosage unit form according to the formulation of the preparation to reduce the dosage and uniformity of the dosage. The term "dosage unit type" herein refers to a physically dispersed unit of the drug required for proper treatment by the patient. However, it should be understood that the total daily usage of the compound of formula (I) of the present invention or its crystal form, or the pharmaceutical composition of the present invention will be determined by the attending doctor according to the judgment of a reliable medical scope. The specific effective dosage level for any particular patient or organism will depend on many factors including the disease being treated and the severity of the disease, the activity of the specific compound or its crystalline form, the specific composition used, the patient’s age, weight, Health status, gender and eating habits, time of administration, route of administration and excretion rate of the specific compound or crystal form used, the duration of treatment, the application of the drug in combination or combination with a specific compound or crystal form, and Some other well-known factors in the field of pharmacy.

The effective dose of the active ingredient used may vary with the compound or its crystal form, the mode of administration, and the severity of the disease to be treated. However, generally, when the compound of the present invention or its crystal form is administered at a dose of about 0.25-1000 mg/kg of animal body weight per day, satisfactory effects can be obtained, and it is preferably administered in divided doses of 2-4 times a day, or It is administered in a sustained-release form. For most large mammals, the total daily dose is about 1-100 mg/kg, preferably about 2-80 mg/kg of the active compound or its crystal form. The dosage form suitable for oral administration contains about 0.25-500 mg of the active compound or its crystal form intimately mixed with a solid or liquid pharmaceutically acceptable carrier. This dosage regimen can be adjusted to provide the best therapeutic response. In addition, due to different treatment conditions, several divided doses can be given every day, or the dose can be reduced proportionally.

The compound or its crystal form of the present invention, and the pharmaceutical composition of the present invention can be used for the prevention and/or treatment of various diseases and disease-related conditions, especially characterized by increased plasma aldosterone concentration or plasma aldosterone concentration Conditions that are relative to changes in plasma renin concentration, or conditions related to these changes. Examples that may be mentioned are: spontaneous primary aldosteronism, hyperaldosteronism associated with adrenal hyperplasia, adrenal adenoma and/or adrenal cancer, hyperaldosteronism associated with cirrhosis, Hyperaldosteronism associated with heart failure, and (relative) hyperaldosteronism associated with essential hypertension, etc.

Specifically, the compound or its crystal form involved in the present invention can be used to treat or prevent the following diseases: diabetic nephropathy, hyperaldosteronism, hypertension, heart failure, sequelae of myocardial infarction, liver cirrhosis, renal failure or stroke.

Description of the drawings

Figure 1 is an X-ray powder diffraction (XRPD) pattern of the crystalline form IV of the compound represented by formula (I).

Figure 2 is a differential scanning calorimetry (DSC) chart of the crystalline form IV of the compound represented by formula (I).

Fig. 3 is an X-ray powder diffraction (XRPD) pattern of the crystal form V of the compound represented by formula (I).

Figure 4 is a differential scanning calorimetry (DSC) chart of the crystalline form V of the compound represented by formula (I).

Figure 5 is an X-ray powder diffraction (XRPD) pattern of the crystalline form VI of the compound represented by formula (I).

Figure 6 is a differential scanning calorimetry (DSC) chart of the crystalline form VI of the compound represented by formula (I).

Fig. 7 is an X-ray powder diffraction (XRPD) pattern of the crystal form VII of the compound represented by formula (I).

Figure 8 is a differential scanning calorimetry (DSC) chart of the crystalline form VII of the compound represented by formula (I).

Fig. 9 is an X-ray powder diffraction (XRPD) pattern of the crystal form VIII of the compound represented by formula (I).

Figure 10 is a differential scanning calorimetry (DSC) chart of the crystalline form VIII of the compound represented by formula (I).

FIG. 11 is an X-ray powder diffraction (XRPD) pattern of the compound represented by formula (I) prepared according to Example 1. FIG.

Detailed ways

The following further describes the present invention by way of examples, and therefore the present invention is not limited to the scope of the described examples.

The X-ray powder diffraction analysis method used in the present invention is: an Empyrean diffractometer, using Cu-Kα radiation (45KV, 40mA) to obtain an X-ray powder diffraction pattern. The powdered sample is prepared into a thin layer on the single crystal silicon sample holder, placed on the rotating sample stage, and analyzed in 0.0167° steps in the range of 3°-60°. Use Data Collector software to collect data, HighScore Plus software to process the data, and Data Viewer software to read the data.

The differential scanning calorimetry (DSC) analysis method used in the present invention is: using a TA Q2000 module with a thermal analysis controller to perform differential scanning calorimetry. Collect data and use TA Instruments Thermal Solutions software for analysis. Approximately 1-5 mg of the sample is accurately weighed into a special aluminum crucible with a lid, and the sample is analyzed from room temperature to about 300°C using a linear heating device of 10°C/min. During use, the DSC cell was purged with dry nitrogen.

The thermal weight loss (TGA) analysis method used in the present invention is: using a TA Q500 module with a thermal analysis controller to perform thermal weight loss. Collect data and use TA Instruments Thermal Solutions software for analysis. Approximately 10 mg of the sample is accurately weighed into the platinum sample pan, and the sample is analyzed from room temperature to about 300°C using a linear heating device of 10°C/min. During use, the TGA furnace chamber is purged with dry nitrogen.

The hygroscopicity of the present invention is measured by DVS INT-Std dynamic moisture and gas adsorption analyzer from Surface Measurement Systems, UK, humidity test range: 0%-95%, airflow: 200mL/min, temperature: 25°C, test point: per liter Take a test point for 5% humidity.

Specific implementation method

The compound represented by formula (Ia), namely 4-(4-cyano-2-methoxyphenyl)-5-cyclobutyloxy-2,8-dimethyl-1,4-dihydro-1 For the specific synthesis method of 6-naphthyridine-3-carboxamide, refer to Example 7 in International Application WO 2019223629 A1.

Example

Example 1 (S)-4-(4-cyano-2-methoxyphenyl)-5-cyclobutyloxy-2,8-dimethyl-1,4-dihydro-1,6 -Naphthyridine-3-carboxamide (compound represented by formula (I))

Weigh 4-(4-cyano-2-methoxyphenyl)-5-cyclobutoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-methyl Amide (4.0g), add methanol, acetonitrile and formic acid (total 57mL) to dissolve the sample, use supercritical fluid chromatography (instrument: Waters SFC; Column: Daicel AD-H column 10mm x 250mm 5um; condition: etc. Gradient, 30% MeOH+70% CO ₂ ; flow rate: 8mL/min; column temperature: 35°C; back pressure: 100bar; each injection 10μL) for chiral resolution to obtain a white solid (1.76g, 44.0%) , HPLC purity: 99.53%, ee value: 99.93%.

It was identified by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-Kα radiation, the obtained white solid product has an X-ray powder diffraction pattern substantially as shown in FIG. 11.

MS(ESI,pos.ion)m/z:405.2(M+1).

¹ H NMR (400MHz, CDCl ₃ ) δ (ppm) 7.63 (s, 1H), 7.29 (d, J = 7.9 Hz, 1H), 7.15 (dd, J = 7.9, 1.2 Hz, 1H), 7.08 (s, 1H), 6.51 (s, 1H), 5.78 (s, 1H), 5.44 (s, 1H), 5.24 - 4.86 (m, 2H), 3.99 (s, 3H), 2.50 (s, 3H), 2.45 - 2.34 (m,1H), 2.24-2.16(m,1H), 2.14(s,3H), 2.01-1.89(m,1H), 1.72-1.52(m,3H).

Example 2 The crystal form IV of the present invention

1. Preparation of Form IV

method one:

The compound (51 mg) of formula (I) prepared according to the method of Example 1 was added to methyl tert-butyl ether (2.0 mL), slurried overnight at room temperature, filtered with suction, and the filter cake was washed with methyl tert-butyl ether ( 0.5 mL×2) washed, and then vacuum dried at room temperature for 5 hours to obtain a white solid (32 mg, 62.75%).

Method Two:

Add the compound (52 mg) of formula (I) prepared according to the method of Example 1 into water (2.0 mL), heat to 70°C for 6 hours, turn off the heating, cool to room temperature naturally, filter with suction, and filter the cake with water (1.0 mL×2) washed, and then vacuum dried at room temperature for 5 hours to obtain a white solid (24 mg, 46.15%).

Method three:

The compound (51 mg) of formula (I) prepared according to the method of Example 1 was added to methanol (1.0 mL), stirred at room temperature until the solid was dissolved, water (2.0 mL) was slowly added dropwise, and the solution became turbid. Continue stirring overnight. The solid precipitated out, filtered with suction, the filter cake was washed with water (1.0 mL×2), and then vacuum dried at room temperature for 6 hours to obtain a white solid (33 mg, 64.71%).

Method four:

The compound (51 mg) of formula (I) prepared according to the method of Example 1 was added to dimethyl sulfoxide (0.5 mL), stirred at room temperature until the solid was dissolved, water (1.0 mL) was slowly added dropwise, and a solid gradually precipitated , Continue to stir and crystallize for 5 hours, filter with suction, wash the filter cake with water (1.0 mL×2), and then vacuum dry at room temperature for 6 hours to obtain a white solid (32 mg, 62.75%).

Method Five:

The compound (50 mg) of formula (I) prepared according to the method of Example 1 was added to ethyl formate (1.0 mL), stirred at room temperature until the solid was dissolved, and methyl tert-butyl ether (5.0 mL) was slowly added dropwise. The solution was clarified. After stirring for 1 day, a solid precipitated out. The filter cake was washed with methyl tert-butyl ether (0.5 mL×2) and then vacuum dried at room temperature for 4 hours to obtain a white solid (10 mg, 20.00%).

Method Six:

The compound (52 mg) of formula (I) prepared according to the method of Example 1 was added to dichloromethane (1.0 mL), stirred at room temperature until the solid was dissolved, and methyl tert-butyl ether (5.0 mL) was slowly added dropwise. The solution was clear. After stirring for 1 day, a solid precipitated out. The filter cake was washed with methyl tert-butyl ether (0.5 mL×2) and then vacuum dried at room temperature for 4 hours to obtain a white solid (14 mg, 26.92%).

2. Identification of Form IV

(1) Identification by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-Kα radiation, with the following diffraction peaks expressed in angle 2θ: 8.41°, 9.67°, 10.50°, 11.07°, 12.63°, 14.60°, 15.69 °, 15.84°, 16.36°, 17.44°, 19.23°, 19.90°, 21.13°, 21.67°, 21.98°, 23.90°, 24.47°, 24.92°, 25.27°, 25.50°, 25.58°, 26.29°, 26.85°, 27.34°, 28.40°, 29.00°, 29.73°, 31.05°, 31.60°, 32.09°, 32.72°, 33.09°, 33.50°, 34.15°, 34.49°, 35.27°, 35.99°, 36.54°, 37.15°, 38.41° , 38.92°, 39.12°, 39.87°, 41.01°, 41.98°, 42.58°, 43.03°, 44.57°, 44.83°, 45.89°, 48.04°, 50.02°, 51.00°, 53.46° and 54.05° in presence of ±0.2° Error tolerance.

Specifically, the crystal form IV of the present invention has an X-ray powder diffraction pattern substantially as shown in FIG. 1.

(2) Through TA Q2000 Differential Scanning Calorimetry (DSC) analysis and identification: the scanning speed is 10°C/min, including the endothermic peak at 254.25°C, and there is an error tolerance of ±3°C. Specifically, the crystalline form IV of the present invention has a differential scanning calorimeter basically as shown in FIG. 2.

Example 3 The crystal form V of the present invention

1. Preparation of Form V

The compound (49 mg) of formula (I) prepared according to the method of Example 1 was added to tetrahydrofuran (1.0 mL), stirred at room temperature until the solid was dissolved, and then the solid precipitated out quickly, heated to 66°C for 2 hours, and turned off the heating , Cooled to room temperature naturally, filtered with suction, the filter cake was washed with tetrahydrofuran (0.5 mL×2), and then vacuum dried at room temperature for 6 hours to obtain a white solid (31 mg, 63.27%).

2. Identification of Form V

(1) Identification by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-Kα radiation, with the following diffraction peaks expressed in angle 2θ: 7.37°, 10.16°, 11.32°, 11.41°, 11.51°, 11.79°, 12.49 °, 14.27°, 14.68°, 15.20°, 16.04°, 17.80°, 18.96°, 20.23°, 21.43°, 21.92°, 22.04°, 22.84°, 23.22°, 23.57°, 24.18°, 24.99°, 25.68°, 25.76°, 25.84°, 26.33°, 27.51°, 27.81°, 28.16°, 28.65°, 29.11°, 29.54°, 30.02°, 30.61°, 30.93°, 31.26°, 31.77°, 32.61°, 32.97°, 34.17° , 35.25°, 36.07°, 37.18°, 38.33°, 39.73°, 40.26°, 40.53°, 41.27°, 42.18°, 43.18°, 43.68°, 44.95°, 45.97° and 47.34°, there is an error tolerance of ±0.2° limit. Specifically, the crystal form V of the present invention has an X-ray powder diffraction pattern substantially as shown in FIG. 3.

(2) Through TA Q2000 Differential Scanning Calorimetry (DSC) analysis and identification: the scanning speed is 10°C/min, including the endothermic peaks of 141.79°C and 254.04°C, and there is an error tolerance of ±3°C. Specifically, the crystal form V of the present invention has a differential scanning calorimeter basically as shown in FIG. 4.

Example 4 The crystal form VI of the present invention

1. Preparation of Form VI

The compound (51 mg) of formula (I) prepared according to the method of Example 1 was added to ethyl acetate (1.0 mL), heated to 77° C., the solid was dissolved, the heating was turned off, and it was cooled to room temperature naturally. A solid was precipitated. After suction filtration, the filter cake was washed with ethyl acetate (0.5 mL×2), and then dried under vacuum at room temperature overnight to obtain a white solid (28 mg, 54.90%).

2. Identification of Form VI

(1) Identification by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-Kα radiation, with the following diffraction peaks expressed in angle 2θ: 7.15°, 9.61°, 10.98°, 11.33°, 11.54°, 12.50°, 14.07 °, 14.30°, 14.74°, 15.03°, 15.36°, 17.61°, 17.89°, 18.57°, 18.92°, 19.52°, 20.57°, 21.25°, 21.74°, 22.53°, 23.16°, 23.37°, 23.61°, 24.08°, 24.37°, 25.12°, 25.53°, 25.79°, 26.53°, 26.84°, 27.40°, 27.76°, 28.30°, 28.52°, 28.81°, 28.97°, 29.91°, 30.34°, 30.88°, 31.31° , 32.37°, 33.71°, 34.39°, 34.88°, 35.24°, 36.24°, 36.82°, 37.73°, 39.46°, 40.49°, 41.19°, 41.82°, 42.53°, 43.44°, 44.74° and 45.11°, exist Error tolerance of ±0.2°. Specifically, the crystal form VI of the present invention has an X-ray powder diffraction pattern substantially as shown in FIG. 5.

(2) Through TA Q2000 Differential Scanning Calorimetry (DSC) analysis and identification: the scanning speed is 10°C/min, including the endothermic peaks of 99.00°C and 253.60°C, and there is an error tolerance of ±3°C. Specifically, the crystal form VI of the present invention has a differential scanning calorimeter basically as shown in FIG. 6.

Example 5 The crystal form VII of the present invention

1. Preparation of Form VII

The compound (52 mg) of formula (I) prepared according to the method of Example 1 was added to methyl acetate (1.0 mL), stirred at room temperature until the solid was dissolved, and then the solid precipitated out quickly. Continue stirring to crystallize overnight, and filter with suction The filter cake was washed with methyl acetate (0.5 mL×2), and then vacuum dried at room temperature for 5 hours to obtain a white solid (37 mg, 71.15%).

2. Identification of Form VII

(1) Identification by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-Kα radiation, with the following diffraction peaks expressed in angle 2θ: 7.21°, 9.72°, 11.09°, 11.63°, 11.83°, 12.79°, 14.36 °, 15.01°, 15.32°, 15.52°, 15.76°, 17.90°, 18.08°, 18.72°, 19.18°, 19.46°, 19.77°, 21.53°, 21.90°, 22.39°, 22.83°, 23.49°, 23.86°, 23.95°, 24.36°, 24.66°, 25.26°, 25.72°, 25.81°, 26.36°, 26.65°, 27.20°, 27.45°, 27.97°, 28.52°, 28.83°, 29.26°, 29.88°, 30.23°, 30.61° , 30.88°, 31.21°, 31.76°, 32.32°, 32.98°, 33.20°, 33.73°, 34.00°, 34.33°, 35.00°, 35.29°, 35.73°, 36.18°, 36.47°, 37.17°, 38.10°, 39.44 °, 40.12°, 40.61°, 41.12°, 41.72°, 42.11°, 42.82°, 43.80°, 45.09° and 45.47°, there is an error tolerance of ±0.2°. Specifically, the crystal form VII of the present invention has an X-ray powder diffraction pattern substantially as shown in FIG. 7.

(2) Through TA Q2000 Differential Scanning Calorimetry (DSC) analysis and identification: the scanning speed is 10°C/min, including the endothermic peaks of 123.29°C and 254.67°C, and there is an error tolerance of ±3°C. Specifically, the crystalline form VII of the present invention has a differential scanning calorimetry diagram substantially as shown in FIG. 8.

Example 6 Crystal Form VIII of the present invention

1. Preparation of Form VIII

The compound (51 mg) of formula (I) prepared according to the method of Example 1 was added to butanone (1.0 mL), stirred at room temperature until the solid was dissolved, and then the solid precipitated out quickly, continued stirring and crystallization overnight, and filtered with suction. The filter cake was washed with methyl ethyl ketone (0.5 mL×2), and then vacuum dried at room temperature for 5 hours to obtain a white solid (39 mg, 76.47%).

2. Identification of Form VIII

(1) Identification by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-Kα radiation, with the following diffraction peaks expressed in angle 2θ: 7.21°, 9.75°, 11.09°, 11.42°, 11.61°, 12.61°, 14.21. °, 14.40°, 14.83°, 15.18°, 15.55°, 17.77°, 18.09°, 18.72°, 19.04°, 19.65°, 20.80°, 21.41°, 21.87°, 22.79°, 23.34°, 23.56°, 23.74°, 24.24°, 24.61°, 25.34°, 25.69°, 26.03°, 26.72°, 27.17°, 27.64°, 27.97°, 28.48°, 28.69°, 29.13°, 29.92°, 30.16°, 30.58°, 31.21°, 31.79° , 32.74°, 33.69°, 34.01°, 34.71°, 35.49°, 36.71°, 37.07°, 38.07°, 39.47°, 40.51°, 41.05°, 41.54°, 42.07°, 42.86°, 43.76°, 45.01° and 45.50 °, there is an error tolerance of ±0.2°. Specifically, the crystal form VIII of the present invention has an X-ray powder diffraction pattern substantially as shown in FIG. 9.

(2) Through TA Q2000 Differential Scanning Calorimetry (DSC) analysis and identification: the scanning speed is 10°C/min, including the endothermic peaks of 134.09°C and 254.86°C, and there is an error tolerance of ±3°C. Specifically, the crystalline form VIII of the present invention has a differential scanning calorimetry diagram substantially as shown in FIG. 10.

Example 7 Pharmacokinetic experiment

The compound represented by formula (I) of the present invention or its crystal form is respectively filled into capsules for oral administration.

Take 8-12kg male Beagle dogs and divide them into 2 groups, 3 in each group, and orally give capsules with test samples at a dose of 5mg/kg, according to time points 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and Blood is collected 24h. Establish a standard curve with an appropriate range based on the sample concentration, use AB SCIEX API4000 LC-MS/MS to determine the concentration of the test sample in the plasma sample in the MRM mode, and perform quantitative analysis. According to the drug concentration-time curve, the WinNonLin 6.3 software non-compartmental model method was used to calculate the pharmacokinetic parameters. The experimental results are shown in Table 1.

Table 1 Pharmacokinetic experimental data of the crystal form of the present invention

Test sample	T max (h)	C max (ng/ml)	AUC last (h*ng/ml)
Example 2	1.17	271	610

Experimental results:

It can be seen from Table 1 that the crystal form IV of the present invention has a relatively large exposure in beagle dogs and has good pharmacokinetic properties.

Example 8 Stability experiment of the crystal form of the present invention

(1) High temperature experiment : Take an appropriate amount of the sample to be tested and put it into a flat weighing bottle, spread it into a thin layer ≤5mm thick, and place it at 40℃±2℃ and/or 60℃±2℃ for 30 days. , 10, 30 days sampling according to the stability key inspection items for testing, observe the color change of the sample, HPLC test the purity of the sample.

(2) High-humidity experiment : Put an appropriate amount of the test sample into a flat weighing bottle, spread it into a thin layer ≤5mm thick, and place it for 30 days under the conditions of 25℃ and RH 90%±5%. 10. Sampling for 30 days is carried out according to the key stability inspection items, the color changes of the samples are observed, and the purity of the samples is checked by HPLC.

(3) Illumination test : Put an appropriate amount of the test product into a flat weighing bottle, spread it into a thin layer ≤5mm thick, and place it in an open light box (with ultraviolet lamp) at an illuminance of 4500±500lx, Place for 30 days under the condition of ultraviolet light ≥ 0.7w/m ² , take samples on the 5th, 10th, and 30th day, observe the color change of the sample, and check the purity of the sample by HPLC.

(4) Accelerated experiment : Take an appropriate amount of a batch of test products and pack them in single-layer PE packaging and aluminum foil, and place them at 40±2℃/75%±5%RH for 6 months. Take a sample every month to observe the color change of the sample, the purity of the sample is tested by HPLC, and the moisture is tested by TGA.

Experimental results:

Under high temperature (60°C), high humidity (25°C, RH 90%±5%), and light conditions, the appearance and purity of the crystal form IV of the present invention have no significant changes; under accelerated experimental conditions, the present invention There was no significant change in the appearance, purity and water content of the crystal form IV.

In summary, the crystal form IV of the present invention has good stability under various lofting conditions and is suitable for pharmaceutical applications.

Example 9 Moisture absorption experiment of the crystal form of the present invention

Take an appropriate amount of the test product (ie, the compound of the present invention or its crystal form), and use a dynamic moisture adsorption meter to test its moisture absorption.

In conclusion, the crystal form of the present invention is not susceptible to deliquescence due to the influence of high humidity.

The above-mentioned content is only a basic description under the concept of the present invention, and any equivalent changes made according to the technical solution of the present invention should belong to the protection scope of the present invention.

In the description of this specification, descriptions with reference to the terms "one embodiment", "some embodiments", "examples", "specific examples", or "some examples" etc. mean specific features described in conjunction with the embodiment or example , Structures, materials or features are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example.

Although the embodiments of the present invention have been shown and described above, it can be understood that the above-mentioned embodiments are exemplary and should not be construed as limiting the present invention. Those of ordinary skill in the art can comment on the above-mentioned embodiments within the scope of the present invention. The embodiment undergoes changes, modifications, substitutions, and modifications.

Claims (10)

1. The crystal form IV of the compound represented by formula (I) is characterized in that the X-ray powder diffraction pattern of the crystal form IV has diffraction peaks at the following 2θ angles: 8.41°±0.2°, 9.67°±0.2°, 21.13° ±0.2°, 21.67°±0.2°, 21.98°±0.2°;

   
2. The crystal form IV of claim 1, wherein the X-ray powder diffraction pattern of the crystal form IV has diffraction peaks at the following 2θ angles: 8.41°±0.2°, 9.67°±0.2°, 14.60°± 0.2°, 15.69°±0.2°, 15.84°±0.2°, 21.13°±0.2°, 21.67°±0.2°, 21.98°±0.2°, 24.47°±0.2, 25.58°±0.2°.
3. The crystal form IV of claim 1 or 2, wherein the X-ray powder diffraction pattern of the crystal form IV has diffraction peaks at the following 2θ angles: 8.41°±0.2°, 9.67°±0.2°, 10.50 °±0.2°, 11.07°±0.2°, 12.63°±0.2°, 14.60°±0.2°, 15.69°±0.2°, 15.84°±0.2°, 16.36°±0.2°, 17.44°±0.2°, 19.23°± 0.2°, 19.90°±0.2°, 21.13°±0.2°, 21.67°±0.2°, 21.98°±0.2°, 23.90°±0.2°, 24.47°±0.2°, 24.92°±0.2°, 25.27°±0.2° , 25.50°±0.2°, 25.58°±0.2°, 26.29°±0.2°, 26.85°±0.2°, 27.34°±0.2°, 28.40°±0.2°, 29.00°±0.2°, 29.73°±0.2°, 31.05 °±0.2°, 31.60°±0.2°, 32.09°±0.2°, 32.72°±0.2°, 33.09°±0.2°, 33.50°±0.2°, 34.15°±0.2°, 34.49°±0.2°, 35.27°± 0.2°, 35.99°±0.2°, 36.54°±0.2°, 37.15°±0.2°, 38.41°±0.2°, 38.92°±0.2°, 39.12°±0.2°, 39.87°±0.2°.
4. The crystal form IV according to any one of claims 1 to 3, wherein the crystal form IV has an X-ray powder diffraction pattern substantially as shown in FIG. 1.
5. The crystal form IV according to any one of claims 1 to 4, wherein the differential scanning calorimeter of the crystal form IV comprises an endothermic peak at 254.25°C±3°C.
6. The crystal form IV according to any one of claims 1 to 5, wherein the crystal form IV has a differential scanning calorimetry diagram substantially as shown in FIG. 2.
7. A pharmaceutical composition comprising the crystal form IV of any one of claims 1-6, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant or a combination thereof.
8. The pharmaceutical composition according to claim 7, which further comprises one or more other active ingredients selected from the group consisting of ACE inhibitors, renin inhibitors, angiotensin II receptor antagonists, β- Receptor blockers, acetylsalicylic acid, diuretics, calcium antagonists, statins, digitalis derivatives, calcium sensitizers, nitrates and antithrombotic agents.
9. The use of the crystal form IV of any one of claims 1-6 or the pharmaceutical composition of claims 7-8 in the preparation of a medicine, wherein the medicine is used to treat, prevent or alleviate the following diseases in patients: diabetes Kidney disease, hyperaldosteronism, hypertension, heart failure, sequelae of myocardial infarction, liver cirrhosis, renal failure, or stroke.
10. Use of the crystal form IV of any one of claims 1-6 or the pharmaceutical composition of any one of claims 7-8 in the preparation of a medicine, wherein the medicine is used as a mineralocorticoid receptor antagonist .

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