TW202400151A - Crystal form of thienopyrimidine compound and uses thereof - Google Patents

Abstract

The present invention relates to a crystal form of a thienopyrimidine compound and the use thereof. In particular, the present invention relates to a crystal form of 2-[1-[(2R)-2-[[(3aR,6aR)-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]furan-5-yl]oxy]-2-(2-methoxyphenyl)ethyl]-5-methyl-6-oxazole-2-yl-2,4-dioxo-thieno[2,3-d]pyrimidin-3-yl]-2-methyl-propionic acid and a pharmaceutical composition comprising same, and further to the use thereof in the preparation of a drug for the treatment and prevention of diseases modulated by acetyl-CoA carboxylase.

Description

Crystal forms of thienopyrimidine compounds and their uses

The invention belongs to the field of medical technology and relates to the crystal form of thienopyrimidine compounds and their uses, specifically 2-[1-[( 2R )-2-[[( 3aR,6aR ) -3,3a ,4,5 ,6,6 a -hexahydro-1 H -cyclopenta[ c ]furan-5-yl]oxy]-2-(2-methoxyphenyl)ethyl]-5-methyl- Crystal forms of 6-oxazol-2-yl-2,4-dioxo-thieno[2,3-d]pyrimidin-3-yl]-2-methyl-propionic acid and uses thereof, further involving The pharmaceutical composition of the crystalline form.

Acetyl-CoA carboxylase (ACC) is the rate-limiting enzyme in the first step of fatty acid anabolism. In the presence of ATP energy and Mg ²⁺ , HCO ₃ ^- is used as the carboxyl donor to convert Acetyl-CoA carboxylase into the first step of fatty acid anabolism. The carboxylation of coenzyme A to malonate monocoenzyme A is a biotin-dependent enzyme.

In humans and other mammals, this enzyme is a tissue-specific enzyme. There are two subtypes, ACC1 and ACC2, which are different in tissue distribution and function. ACC1 is usually expressed in all tissues, but is not expressed in lipogenesis. Expressed most in tissues such as liver and adipose tissue, ACC2 is highly expressed in skeletal muscle and heart and less expressed in liver tissue. ACC1 catalyzes the biosynthesis of long-chain fatty acids. If acetyl-CoA is not carboxylated to form malonate monocoenzyme A, it is metabolized through the citric acid cycle (Krebs cycle); ACC2 catalyzes the biosynthesis of long-chain fatty acids on the cytoplasmic surface of mitochondria. Malonate monocoenzyme A is produced and regulates the amount of fatty acids available for β-oxidation by inhibiting carnitine palmityl transferase (CPT-1).

Studies have shown that ACC inhibitors inhibit ACC1 to reduce the synthesis of fatty acids, while inhibiting ACC2 can promote the oxidation of fatty acids in the liver, thereby reducing the accumulation of lipids in the body. They can effectively treat obesity, hypertension, diabetes, tumors, dyslipidemia and hyperlipidemia. Diseases related to dyslipidemia and hepatic insulin resistance due to accumulation of lipids in the liver leading to type II diabetes, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).

Non-alcoholic steatohepatitis (NASH) is a chronic progressive liver disease caused by the accumulation of fat in the liver, which can lead to cirrhosis, liver failure and hepatocellular carcinoma. There are many causes of NASH, such as age, obesity, body mass index (BMI), insulin sensitivity, dyslipidemia, hypertension, and liver function-related enzymes (such as alanine aminotransferase (ALT) or aspartame Abnormal activity of amino acid transaminase (AST), etc. It has been reported that patients with symptoms of metabolic syndrome (mainly central obesity, hypertension, insulin resistance, high triglycerides and low high-density lipoprotein) are positively associated with the risk of NASH. Among diabetic or obese patients older than 50 years, 66% of liver biopsies revealed severe fibrosis in NASH. In the United States, about 12% of people are affected by this disease, and the proportion rises to 22% among people with diabetes. What's more noteworthy is that about 15 to 25% of patients with NASH will develop Cirrhosis is another cause of liver cancer after viral hepatitis and alcoholic hepatitis. Cirrhosis is the leading cause of death from liver disease, directly leading to liver decompensation and an annual mortality rate of nearly 4%.

International application WO2021000242A1 discloses compound 2-[1-[ (2R )-2-[[( 3aR,6aR )-3,3 a ,4,5,6,6 a -hexahydro-1 H- cyclopentadiene [ c ]furan-5-yl]oxy]-2-(2-methoxyphenyl)ethyl]-5-methyl-6-oxazol-2-yl-2,4-dioxo - Thieno[2,3- d ]pyrimidin-3-yl]-2-methyl-propionic acid (i.e., the crystalline form A of the compound represented by formula (I) of the present invention), which can treat or alleviate the symptoms caused by acetyl coenzyme Diseases regulated by A carboxylase, such as non-alcoholic steatohepatitis. This compound has problems such as poor solubility, unsatisfactory absorption in animals, poor hygroscopicity, and poor stability. These defects bring a lot of inconvenience to subsequent formulation development. (I)

The present invention provides the crystal form of the compound represented by formula (I). Among them, the crystal form, especially the crystal form C, can significantly improve the stability, pharmacokinetics and other properties of the compound, thereby having better pharmaceutical properties.

Specifically, the present invention relates to the crystalline form of the compound represented by formula (I), as well as pharmaceutical compositions containing the crystalline form, and also relates to their preparation for the treatment or prevention of diseases modulated by acetyl-CoA carboxylase uses in medicines. The crystalline form described in the present invention may also be in the form of a solvate, such as a hydrate form.

On the one hand, the present invention provides a crystalline form or amorphous form of the compound represented by formula (I), (I).

In some embodiments, the crystal form of the compound represented by formula (I) of the present invention is crystal form B, C or D.

In some embodiments, the crystal form B of the present invention is characterized in that the X-ray powder diffraction pattern of the crystal form B has diffraction peaks at the following 2θ angles: 5.07° ± 0.2°, 10.93° ± 0.2° , 16.61° ± 0.2°, 17.11° ± 0.2°, 19.82° ± 0.2° and 25.76° ± 0.2°.

In some embodiments, the crystal form B of the present invention is characterized in that the X-ray powder diffraction pattern of the crystal form B has diffraction peaks at the following 2θ angles: 5.07° ± 0.2°, 10.93° ± 0.2° , 12.79° ± 0.2°, 15.83° ± 0.2°, 16.61° ± 0.2°, 17.11° ± 0.2°, 18.47° ± 0.2°, 19.59° ± 0.2°, 19.82° ± 0.2°, 25.76° ± 0.2° and 27.48 °±0.2°.

In other embodiments, the crystal form B of the present invention is characterized in that the X-ray powder diffraction pattern of the crystal form B has diffraction peaks at the following 2θ angles: 5.07° ± 0.2°, 9.19° ± 0.2 °, 9.98° ± 0.2°, 10.12° ± 0.2°, 10.67° ± 0.2°, 10.93° ± 0.2°, 11.35° ± 0.2°, 11.61° ± 0.2°, 11.96° ± 0.2°, 12.79° ± 0.2°, 13.77° ± 0.2°, 14.39° ± 0.2°, 14.95° ± 0.2°, 15.14° ± 0.2°, 15.83° ± 0.2°, 16.61° ± 0.2°, 17.11° ± 0.2°, 17.56° ± 0.2°, 18.47° ± 0.2°, 19.09° ± 0.2°, 19.59° ± 0.2°, 19.82° ± 0.2°, 20.19° ± 0.2°, 21.00° ± 0.2°, 22.07° ± 0.2°, 22.36° ± 0.2°, 22.76° ± 0.2 °, 23.21° ± 0.2°, 23.48° ± 0.2°, 23.97° ± 0.2°, 24.84° ± 0.2°, 25.20° ± 0.2°, 25.76° ± 0.2°, 26.43° ± 0.2°, 26.70° ± 0.2°, 26.89° ± 0.2°, 27.48° ± 0.2°, 28.17° ± 0.2°, 28.49° ± 0.2°, 29.14° ± 0.2°, 29.89° ± 0.2°, 30.38° ± 0.2°, 30.94° ± 0.2°, 31.43° ± 0.2°, 31.85° ± 0.2°, 32.27° ± 0.2°, 33.13° ± 0.2°, 33.65° ± 0.2°, 34.36° ± 0.2°, 35.60° ± 0.2°, 36.76° ± 0.2°, 37.62° ± 0.2 °, 38.80° ± 0.2°, 40.04° ± 0.2°, 40.44° ± 0.2°, 40.85° ± 0.2°, 42.73° ± 0.2°, 44.09° ± 0.2°, 45.69° ± 0.2°, 47.23° ± 0.2°, 48.36° ± 0.2°, 51.23° ± 0.2°, 54.44° ± 0.2° and 56.20° ± 0.2°.

In some embodiments, the crystalline Form B of the present invention is characterized in that the crystalline Form B has an X-ray powder diffraction pattern substantially as shown in Figure 4.

In some embodiments, the crystalline form B of the present invention is characterized in that the differential scanning calorimeter of the crystalline form B includes endothermic peaks of 84.14°C ± 3°C and 161.75°C ± 3°C.

In some embodiments, the crystalline Form B of the present invention is characterized in that the crystalline Form B has a differential scanning calorimetry diagram substantially as shown in Figure 5.

In some embodiments, the crystalline form B of the present invention is characterized in that when the crystalline form B is heated to about 150°C, the weight loss is about 2.819%, and there is an error tolerance of ±0.1%.

In some embodiments, the crystalline form C of the present invention is characterized in that the X-ray powder diffraction pattern of the crystalline form C has diffraction peaks at the following 2θ angles: 5.61° ± 0.2°, 14.31° ± 0.2° , 17.28° ± 0.2°, 18.68° ± 0.2°, 20.15° ± 0.2° and 23.63° ± 0.2°.

In some embodiments, the crystalline form C of the present invention is characterized in that the X-ray powder diffraction pattern of the crystalline form C has diffraction peaks at the following 2θ angles: 5.61° ± 0.2°, 9.58° ± 0.2° , 10.05° ± 0.2°, 10.27° ± 0.2°, 12.00° ± 0.2°, 14.31° ± 0.2°, 17.28° ± 0.2°, 18.68° ± 0.2°, 19.18° ± 0.2°, 19.33° ± 0.2°, 20.15 ° ± 0.2° and 23.63° ± 0.2°.

In other embodiments, the crystalline form C of the present invention is characterized in that the X-ray powder diffraction pattern of the crystalline form C has diffraction peaks at the following 2θ angles: 5.61° ± 0.2°, 9.58° ± 0.2 °, 10.05° ± 0.2°, 10.27° ± 0.2°, 11.19° ± 0.2°, 12.00° ± 0.2°, 12.63° ± 0.2°, 13.23° ± 0.2°, 14.31° ± 0.2°, 16.13° ± 0.2°, 17.28° ± 0.2°, 17.88° ± 0.2°, 18.68° ± 0.2°, 19.18° ± 0.2°, 19.33° ± 0.2°, 20.15° ± 0.2°, 20.93° ± 0.2°, 21.66° ± 0.2°, 22.73° ± 0.2°, 23.63° ± 0.2°, 25.39° ± 0.2°, 26.60° ± 0.2°, 27.87° ± 0.2°, 28.93° ± 0.2°, 29.62° ± 0.2°, 30.88° ± 0.2°, 32.61° ± 0.2 °, 33.16° ± 0.2°, 33.85° ± 0.2°, 35.65° ± 0.2°, 36.68° ± 0.2°, 38.82° ± 0.2°, 39.72° ± 0.2°, 40.52° ± 0.2°, 42.64° ± 0.2°, 46.90° ± 0.2°, 48.43° ± 0.2° and 50.86° ± 0.2°.

In some embodiments, the crystalline Form C of the present invention is characterized in that the crystalline Form C has an X-ray powder diffraction pattern substantially as shown in Figure 7.

In some embodiments, the crystalline form C of the present invention is characterized in that the differential scanning calorimeter of the crystalline form C includes an endothermic peak of 166.88°C ± 3°C.

In some embodiments, the crystalline Form C of the present invention is characterized in that the crystalline Form C has a differential scanning calorimetry diagram substantially as shown in Figure 8.

In some embodiments, the crystalline form C of the present invention is characterized in that when the crystalline form C is heated to about 150°C, the weight loss is about 0.008%, and there is an error tolerance of ±0.1%.

In some embodiments, the crystalline form D of the present invention is characterized in that the X-ray powder diffraction pattern of the crystalline form D has diffraction peaks at the following 2θ angles: 6.08° ± 0.2°, 8.58° ± 0.2°. , 9.62° ± 0.2°, 13.60° ± 0.2°, 15.52° ± 0.2° and 22.01° ± 0.2°.

In some embodiments, the crystalline form D of the present invention is characterized in that the X-ray powder diffraction pattern of the crystalline form D has diffraction peaks at the following 2θ angles: 6.08° ± 0.2°, 8.58° ± 0.2°. , 9.62° ± 0.2°, 12.17° ± 0.2°, 13.60° ± 0.2°, 15.52° ± 0.2°, 17.26° ± 0.2°, 17.74° ± 0.2°, 18.31° ± 0.2°, 22.01° ± 0.2° and 24.05 °±0.2°.

In other embodiments, the crystalline form D of the present invention is characterized in that the X-ray powder diffraction pattern of the crystalline form D has diffraction peaks at the following 2θ angles: 4.33° ± 0.2°, 6.08° ± 0.2 °, 8.58° ± 0.2°, 9.62° ± 0.2°, 12.17° ± 0.2°, 12.91° ± 0.2°, 13.60° ± 0.2°, 14.06° ± 0.2°, 14.75° ± 0.2°, 15.07° ± 0.2°, 15.52° ± 0.2°, 16.04° ± 0.2°, 17.26° ± 0.2°, 17.74° ± 0.2°, 17.93° ± 0.2°, 18.31° ± 0.2°, 18.51° ± 0.2°, 18.86° ± 0.2°, 19.28° ± 0.2°, 20.45° ± 0.2°, 21.21° ± 0.2°, 21.68° ± 0.2°, 22.01° ± 0.2°, 22.43° ± 0.2°, 23.30° ± 0.2°, 23.66° ± 0.2°, 24.05° ± 0.2 °, 24.46° ± 0.2°, 25.22° ± 0.2°, 25.61° ± 0.2°, 26.29° ± 0.2°, 26.65° ± 0.2°, 27.41° ± 0.2°, 27.76° ± 0.2°, 28.30° ± 0.2°, 28.95° ± 0.2°, 29.63° ± 0.2°, 30.10° ± 0.2°, 31.23° ± 0.2°, 32.19° ± 0.2°, 33.10° ± 0.2°, 34.23° ± 0.2°, 35.08° ± 0.2°, 35.98° ± 0.2°, 37.43° ± 0.2°, 38.28° ± 0.2°, 39.16° ± 0.2°, 39.96° ± 0.2°, 40.43° ± 0.2°, 41.44° ± 0.2°, 42.19° ± 0.2°, 42.71° ± 0.2 °, 43.31° ± 0.2°, 44.87° ± 0.2°, 45.39° ± 0.2°, 46.02° ± 0.2°, 47.76° ± 0.2°, 48.82° ± 0.2°, and 49.37° ± 0.2°.

In some embodiments, the crystalline form D of the present invention is characterized in that the crystalline form D has an X-ray powder diffraction pattern substantially as shown in Figure 10.

In some embodiments, the crystalline form D of the present invention is characterized in that the differential scanning calorimeter of the crystalline form D includes an endothermic peak of 122.02°C ± 3°C.

In some embodiments, the crystalline form D of the present invention is characterized in that the crystalline form D has a differential scanning calorimetry diagram substantially as shown in Figure 11.

In some embodiments, the crystalline form D of the present invention is characterized in that when the crystalline form D is heated to about 150°C, the weight loss is about 7.634%, and there is an error tolerance of ±0.1%.

In some embodiments, the amorphous form of the present invention is characterized in that the amorphous form has an X-ray powder diffraction pattern substantially as shown in Figure 13.

In some embodiments, the amorphous form of the present invention is characterized in that the amorphous form has a differential scanning calorimetry pattern substantially as shown in Figure 14.

In some embodiments, the amorphous form of the present invention is characterized in that when the amorphous form is heated to about 150°C, the weight loss is about 2.423%, and there is an error tolerance of ±0.1%.

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

In some embodiments, the salt of the compound represented by formula (I) of the present invention is a sodium salt or a potassium salt.

In some embodiments, the sodium salt of the compound represented by formula (I) of the present invention is the amorphous form of the sodium salt of the compound represented by formula (I).

In some embodiments, the amorphous form of the sodium salt of the present invention is characterized in that the amorphous form of the sodium salt has an X-ray powder diffraction pattern substantially as shown in Figure 16.

In some embodiments, the potassium salt of the compound represented by formula (I) of the present invention is the amorphous form of the potassium salt of the compound represented by formula (I).

In some embodiments, the amorphous form of the potassium salt of the present invention is characterized in that the amorphous form of the potassium salt has an X-ray powder diffraction pattern substantially as shown in Figure 17.

On the other hand, the present invention relates to a pharmaceutical composition, which contains any crystal form described in the present invention, and a pharmaceutically acceptable carrier, excipient, diluent, auxiliary agent or their combination.

In one aspect, the present invention relates to the use of any of the crystalline forms or the pharmaceutical composition in the preparation of medicaments for preventing, treating or alleviating diseases regulated by acetyl-CoA carboxylase.

In some embodiments, the diseases regulated by the acetyl-CoA carboxylase of the present invention are metabolic diseases and tumors.

On the other hand, the present invention relates to the use of any of the crystalline forms or the pharmaceutical composition in the preparation of a medicament for preventing, treating or alleviating the disease in patients at least partially regulated by acetyl-CoA carboxylase disease.

In some embodiments, the metabolic diseases of the invention include insulin resistance, obesity, dyslipidemia, metabolic syndrome, type II diabetes, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, hepatic steatosis, bullous vesicles steatosis, advanced fibrosis or cirrhosis; the tumors include liver cancer, kidney cancer, lung cancer, breast cancer, melanoma, papillary thyroid tumors, cholangiocarcinoma, colon cancer, ovarian cancer, malignant lymphoma, bladder cancer, prostate cancer cancer, pancreatic cancer, skin cancer, or recurrent solid tumors.

One aspect of the present invention relates to a method for preventing, treating or alleviating diseases modulated by acetyl-CoA carboxylase, comprising administering to a patient a pharmaceutically acceptable effective dose of the crystalline form of the present invention or the pharmaceutical composition. Medication.

On the other hand, the present invention also relates to a method for preparing the crystalline form of the compound represented by formula (I).

The solvent used in the preparation method of the crystalline form of the present invention is not particularly limited. Any solvent that can dissolve the starting materials to a certain extent and does not affect its properties is included in the present invention. In addition, many similar modifications, equivalent substitutions, or equivalent solvents, solvent combinations, and different ratios of solvent combinations described in the present invention are deemed to be within the scope of the present invention. The present invention provides preferred solvents used in each reaction step.

The preparation experiments of the crystalline forms of the present invention will be described in detail in the Examples section. At the same time, the present invention provides pharmacological testing experiments (such as pharmacokinetic experiments) and stability experiments of the crystal form. Experiments have proven that the crystal form of the present invention has good stability and pharmacokinetic properties.

Definitions and general terms

Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated 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 invention, the preferred methods, equipment, and materials are described herein.

"Crystalline 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 polymorphs, solvates, hydrates, Clathrate, eutectic, salt, salt solvate, salt hydrate. Crystalline forms of substances 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 a defined space, e.g., in nanopores or capillaries, crystallization on a surface or template, e.g., on a polymer , crystallization in the presence of additives such as co-crystallized antimolecules, desolvation, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, reactive crystallization, antisolvent addition, grinding and solvent drop grinding, etc.

"Solvent" refers to a substance (typically a liquid) that is capable of completely or partially dissolving another substance (typically a solid). Solvents used for the implementation of the present invention include, but are not limited to, water, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, methylene chloride, dimethyl styrene, 1,4-dioxane, ethanol , Ethyl acetate, butanol, tert-butanol, N,N -dimethylacetamide, N,N -dimethylformamide, formamide, formic acid, heptane, hexane, isopropyl alcohol, Methanol, methyl ethyl ketone, mesitylene, nitromethane, polyethylene glycol, propanol, pyridine, tetrahydrofuran, toluene, xylene, their mixtures, etc.

"Antisolvent" refers to a fluid that promotes the precipitation of a product (or product precursor) from a solvent. The antisolvent can include a cold gas, or a fluid that promotes precipitation through a chemical reaction, or a fluid that reduces the solubility of the product in the solvent; it can be the same liquid as the solvent but at a different temperature, or it can be a different liquid than the solvent.

"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, dimethylstyrene, 1,4-dioxane, ethanol, ethyl acetate, butanol, tert-butanol, N, N-dimethylacetamide, N,N -dimethyl Formamide, formamide, formic acid, heptane, hexane, isopropyl alcohol, methanol, methyl ethyl ketone, methyl pyrrolidone, mesitylene, nitromethane, polyethylene glycol, propanol, pyridine, Tetrahydrofuran, toluene, xylene and their mixtures, etc. A specific example of a solvate is a hydrate, in which the solvent on the surface, in the crystal lattice, or on the surface and in the crystal lattice is water. The hydrate may or may not have a solvent other than water on the surface of the substance, in the crystal lattice, or on the surface and in the crystal lattice.

Crystal forms can be identified through a variety of technical methods, such as X-ray powder diffraction (XRPD), infrared absorption spectroscopy (IR), melting point method, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and nuclear magnetic resonance. , Raman spectroscopy, X-ray single crystal diffraction, solution calorimetry, scanning electron microscopy (SEM), quantitative analysis, solubility and dissolution rate, etc.

X-ray powder diffraction (XRPD) can detect changes in crystal form, crystallinity, crystal structure state and other information, and is a common method for identifying crystal forms. The peak position of the XRPD spectrum 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 and instrument geometry. Accordingly, in some embodiments, the crystalline forms of the invention are characterized by XRPD patterns having certain peak positions substantially as shown in the XRPD patterns provided in the Figures of the invention. At the same time, the measurement of 2θ of the XRPD spectrum may have experimental errors. The measurement of 2θ of the XRPD spectrum may be slightly different between different instruments and different samples, so the value of 2θ cannot be regarded as absolute. According to the conditions of the instrument used in this test, there is an error tolerance of ± 0.2 ^° for the diffraction peak.

Differential scanning calorimetry (DSC) is a technique that measures the energy difference between a sample and an inert reference substance (commonly used α-Al ₂ O ₃ ) as the temperature changes by continuously heating or cooling under program control. The endothermic peak height of a DSC curve depends on many factors related to sample preparation and instrument geometry, while the peak position is relatively insensitive to experimental details. Accordingly, in some embodiments, the crystalline forms described herein are characterized by a DSC pattern having characteristic peak positions substantially as shown in the DSC patterns provided in the Figures herein. 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 peak value of the DSC endothermic peak cannot be regarded as absolute. According to the conditions of the instrument used in this test, there is an error tolerance of ±3 ^° for the endothermic peak.

Thermogravimetric analysis (TGA) is a technology that measures the quality of substances as they change with temperature under program control. It is suitable for checking the loss of solvent in crystals or the process of sample sublimation and decomposition. It can be inferred that crystals contain crystal water or crystallization solvent. condition. The quality changes displayed by the TGA curve depend on many factors such as sample preparation and instrument; the quality changes detected by TGA are slightly different between different instruments and different samples. According to the condition of the instrument used in this test, there is an error tolerance of ± 0.1% for quality changes.

In the context of this invention, 2θ values in X-ray powder diffraction patterns are expressed in degrees (°).

The term "substantially as shown" 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 its plot.

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

The present invention relates to said 2-[1-[ (2R )-2-[[( 3aR,6aR ) -3,3a , 4,5,6,6a -hexahydro-1H - cyclopenta [ c ]furan-5-yl]oxy]-2-(2-methoxyphenyl)ethyl]-5-methyl-6-oxazol-2-yl-2,4-dioxo- Crystalline forms of thieno[2,3- d ]pyrimidin-3-yl]-2-methyl-propionic acid, for example, Form C, exist in a substantially pure crystalline form.

"Substantially pure" means a crystalline form that is substantially free of one or more other crystalline forms, that is, the purity of the crystalline 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, and the other crystal forms The percentage of the total volume or total weight of the crystalline 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 crystalline forms in the total volume or total weight of the crystalline 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 pattern refers to when the intensity of the first strongest peak among all diffraction peaks in the The ratio of the intensity of strong peaks.

In the context of this invention, the words "about" or "approximately" when or whether they are used, mean within 10%, suitably within 5%, and especially within 1% of a given value or range. . Alternatively, to those of ordinary skill in the art, the term "about" or "approximately" means within an acceptable standard error of the mean. Whenever a number with a value of N is disclosed, any number with N+/-1%, N+/-2%, N+/-3%, N+/-5%, N+/-7%, N+/-8%, or N+ Numbers within /-10% are clearly disclosed, where "+/-" means plus or minus.

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

Pharmaceutical compositions, preparations, administration and uses of crystalline forms of the compounds of the present invention

The characteristics of the pharmaceutical composition of the present invention include the crystal form of the compound represented by formula (I) and a pharmaceutically acceptable carrier, adjuvant, or excipient. The pharmaceutical compositions of the invention contain the crystalline form of the compound in an amount effective to detectably treat or alleviate a disease mediated by acetyl-CoA carboxylase.

As described in the present invention, the pharmaceutically acceptable compositions of the present invention further comprise pharmaceutically acceptable carriers, auxiliaries, 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 the unique target dosage form. As described in the following literature: "In Remington: The Science and Practice of Pharmacy, 21st edition, 2005 , ed. DB Troy, Lippincott Williams& Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and JC Boylan, 1988 -1999 , Marcel Dekker, New York", combined with the contents of this document, it is shown that different carriers can be used in the formulation of pharmaceutically acceptable compositions and their well-known preparation methods. Except to the extent that any conventional carrier medium is incompatible with the crystalline form of the compounds of the invention, such as resulting in any adverse biological effects or interacting in a deleterious manner with any other component of the pharmaceutically acceptable composition. Functions and their uses are also within the scope of the present invention.

Substances that can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers; aluminum; aluminum stearate; lecithin; serum proteins, such as human serum albumin; buffer substances such as phosphate; glycine; sorbic acid Potassium sorbate; partial glyceride mixture of saturated vegetable fatty acids; water; salt or electrolyte, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt; colloidal silicon; magnesium trisilicate; Polyvinylpyrrolidone; polyacrylates; waxes; polyethylene-polyoxypropylene-blocked polymers; lanolin; sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as Sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; gum powder; malt; gelatin; talc; excipients such as cocoa bean butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, Sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide ;Alginic acid; pyrogen-free water; isotonic salts; Ringer's solution; ethanol; phosphate buffered solution; and other nontoxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate; coloring agents; release agents ; Coatings; sweeteners; flavorings; spices; preservatives and antioxidants.

The pharmaceutical composition of the present invention can be capsules, tablets, pills, powders, granules and aqueous suspensions or solutions; it can be administered through the following routes: oral administration, injection administration, spray inhalation, topical administration, Administer rectally, nasally, bucally, vaginally, or via an implantable cartridge.

Oral administration can be administered in the following forms: tablets, pills, capsules, dispersible powders, granules or suspensions, syrups, and elixirs; external administration can be administered in the following forms: ointments, gels , medicated tape, etc.

The crystalline form of the present invention is preferably prepared in dosage unit form according to the formulation to reduce dosage and uniformity of dosage. The term "dosage unit type" as used herein refers to physically discrete units of drug required for appropriate treatment of a patient. However, it should be understood that the crystalline form of the compound of formula (I) of the present invention, or the total daily usage of the pharmaceutical composition of the present invention will be determined by the attending physician based on reliable medical judgment. The specific effective dosage level for any particular patient or organism will depend on many factors including the condition being treated and the severity of the condition, the activity of the specific crystalline form of the compound, the specific composition used, the age, weight, health of the patient. Condition, gender and dietary habits, timing of administration, route of administration and excretion rate of the specific compound used, duration of treatment, use of the drug in combination or with specific active forms of the compound, and others Factors well known in the pharmaceutical field.

The effective dose of the active ingredient employed may vary depending on the crystalline form of the compound employed, the mode of administration and the severity of the disease to be treated. However, generally satisfactory effects can be obtained when the crystalline form of the compound of the present invention is administered at a dose of about 0.25-1000 mg/kg of animal body weight per day, preferably in 2-4 divided doses per day, or Administer in extended-release form. This dosage regimen can be adjusted to provide optimal therapeutic response. In addition, depending on the treatment situation, several divided doses may be administered per day, or the dose may be proportionally reduced.

The crystal form of the compound involved in the present invention and the pharmaceutical composition of the present invention can be used to inhibit the activity of acetyl-CoA carboxylase, thereby regulating the stability and/or activity of acetyl-CoA carboxylase. The crystalline form of the compound or the pharmaceutical composition can be used in methods for treating, pre-treating or delaying the onset or progression of acetyl-CoA carboxylase-related disorders, including but not limited to non-alcoholic diseases steatohepatitis.

Specifically, the crystalline form of the compound involved in the present invention can be used to inhibit the activity of acetyl-CoA carboxylase. Crystalline forms of the compounds may be administered to prevent, pre-treat or treat conditions modulated by acetyl-CoA carboxylase, including, for example, insulin resistance, obesity, dyslipidemia, metabolic syndrome, type II diabetes, non-alcoholic Fatty liver disease, non-alcoholic steatohepatitis, hepatic steatosis, bullous steatosis, advanced fibrosis or cirrhosis; the tumors include liver cancer, kidney cancer, lung cancer, breast cancer, melanoma, papillary thyroid tumors, bile duct carcinoma, colon cancer, ovarian cancer, lymphoid neoplasm, bladder cancer, prostate cancer, pancreatic cancer, skin cancer, or recurrent solid tumors.

General preparation and detection methods

The present invention will be further described below by means of examples, but 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: Empyrean diffractometer, using Cu-Kα radiation (45 KV, 40 mA) to obtain the X-ray powder diffraction pattern. The powdered sample was prepared into a thin layer on a single crystal silicon sample holder, placed on a rotating sample stage, and analyzed with a step size of 0.0168° in the range of 3°-40°. Use Data Collector software to collect data, HighScore Plus software to process data, and Data Viewer software to read data.

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

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

Specific implementation methods

Compound 2-[1-[ (2R )-2-[[( 3aR,6aR )-3,3 a ,4,5,6,6 a -hexahydro-1 H- cyclopentadienide represented by formula (I) Enzo[ c ]furan-5-yl]oxy]-2-(2-methoxyphenyl)ethyl]-5-methyl-6-oxazol-2-yl-2,4-dioxo The specific synthesis method of thieno[2,3- d ]pyrimidin-3-yl]-2-methyl-propionic acid is obtained by referring to Example 1 (i.e., crystal form A) in international application WO2021000242A1.

Example

Example 1 Mode (I) crystal form of compound A

1. Crystal Form A can be prepared by referring to Example 1 of WO2021000242, and can also be obtained by the following four preparation methods:

Method 1: 2-[1-[ (2R )-2-[[( 3aR,6aR )-3,3 a ,4,5,6,6 a -hexahydro-1 H- cyclopenta[ c ]furan-5-yl]oxy]-2-(2-methoxyphenyl)ethyl]-5-methyl-6-oxazol-2-yl-2,4-dioxo-thiophene [2,3- d ]pyrimidin-3-yl]-2-methyl-propionic acid (50.0 mg) was suspended in acetonitrile (0.5 mL), stirred at room temperature overnight, and added water (0.5 mL). A larger amount of solid precipitated, stirred for 12 hours, filtered with suction, pumped until almost dry, and vacuum dried at room temperature for 4 hours to obtain a white solid (39.1 mg, yield 78.2%).

Method 2: 2-[1-[ (2R )-2-[[( 3aR,6aR )-3,3 a ,4,5,6,6 a -hexahydro-1 H- cyclopenta[ c ]furan-5-yl]oxy]-2-(2-methoxyphenyl)ethyl]-5-methyl-6-oxazol-2-yl-2,4-dioxo-thiophene [2,3- d ]pyrimidin-3-yl]-2-methyl-propionic acid (50.1 mg) was suspended in ethylene glycol ether (0.5 mL), stirred to dissolve at room temperature, and added water (1.0 mL). A solid precipitated, stirred at room temperature for 12 hours, filtered, and vacuum dried at 60 ^° C for 6 hours to obtain a white solid (28.1 mg, yield 56.1%).

Method three: 2-[1-[ (2R )-2-[[( 3aR,6aR )-3,3 a ,4,5,6,6 a -hexahydro-1 H- cyclopenta[ c ]furan-5-yl]oxy]-2-(2-methoxyphenyl)ethyl]-5-methyl-6-oxazol-2-yl-2,4-dioxo-thiophene [2,3- d ]pyrimidin-3-yl]-2-methyl-propionic acid (8.72 g) was suspended in acetic acid (44.0 mL), stirred to dissolve at 50 ^o C, kept incubated for 0.5 hours, and slowly added water (52.0 mL), after adding it, it becomes sticky, add acetic acid (10.0 mL), cool to room temperature naturally, add water (26.0 mL), stir for 2 hours, filter with suction, wash the filter cake with 20 mL of water, and pump until almost dry. After vacuum drying at 60 ^° C for 12 hours, a white solid (7.96 g, yield 91.3%) was obtained.

2. Identification of Form A

(1) Identified by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-Kα radiation, it has the following characteristic peaks expressed in angle 2θ: 4.30°, 6.09°, 8.53°, 9.68°, 12.21°, 12.82°, 13.30 °, 13.53°, 13.78°, 14.15°, 14.80°, 15.11°, 15.32°, 15.53°, 16.10°, 16.41°, 17.28°, 17.52°, 17.69°, 18.03°, 18.16°, 18.38°, 18.86°, 19.35°、20.39°、20.80°、21.29°、21.90°、22.18°、22.75°、23.54°、23.91°、24.63°、25.21°、25.64°、26.03°、26.21°、26.60°、27.14°、27.85° , 28.03°, 28.55°, 29.05°, 29.41°, 29.78°, 30.36°, 30.89°, 31.48°, 32.60°, 33.50°, 34.23°, 34.87°, 35.77°, 37.64°, 38.53°, 39.35°, 40.60 °, 41.45°, 43.64°, 44.68°, 45.85°, 46.56°, 47.14°, 51.14°, 55.02°, with an error tolerance of ± 0.2°.

(2) Analysis and identification by TA Q2000 differential scanning calorimetry (DSC): the scanning speed is 10°C/min, and the obtained DSC curve is shown in Figure 2, which contains endothermic peaks of 95.44°C and 135.65°C, with ± 3 Error tolerance in °C.

(3) Thermal weight loss (TGA) analysis and identification by TA Q500: the heating rate is 10°C/minute, and the resulting TGA curve is shown in Figure 3, which contains a weight loss of 4.157% and has an error tolerance of ± 0.1%.

Example 2 Mode (I) crystal form of compound B

1. Preparation of Form B

2-[1-[ (2R )-2-[[( 3aR,6aR ) -3,3a , 4,5,6,6a -hexahydro- 1H- cyclopenta[ c ]furan -5-yl]oxy]-2-(2-methoxyphenyl)ethyl]-5-methyl-6-oxazol-2-yl-2,4-dioxo-thieno[2 ,3- d ]pyrimidin-3-yl]-2-methyl-propionic acid (10.01 g) was suspended in acetone (50.0 mL), heated to 50 ^o C, stirred to dissolve, kept warm for 0.5 hours, and slowly added water (40.0 mL) , after the addition, keep it at room temperature for 0.5 hours, add seed crystal C (300.2 mg), keep it at room temperature for 0.5 hours, then cool down to room temperature naturally, then add water (20.0 mL), stir at room temperature for 12 hours, filter, and pump until almost dry to obtain white color Solid (9.16 g, yield 91.5%).

2. Identification of Form B

(1) Identified by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-Kα radiation, it has the following characteristic peaks expressed in angle 2θ: 5.07°, 9.19°, 9.98°, 10.12°, 10.67°, 10.93°, 11.35 °, 11.61°, 11.96°, 12.79°, 13.77°, 14.39°, 14.95°, 15.14°, 15.83°, 16.61°, 17.11°, 17.56°, 18.47°, 19.09°, 19.59°, 19.82°, 20.19°, 21.00°、22.07°、22.36°、22.76°、23.21°、23.48°、23.97°、24.84°、25.20°、25.76°、26.43°、26.70°、26.89°、27.48°、28.17°、28.49°、29.14° , 29.89°, 30.38°, 30.94°, 31.43°, 31.85°, 32.27°, 33.13°, 33.65°, 34.36°, 35.60°, 36.76°, 37.62°, 38.80°, 40.04°, 40.44°, 40.85°, 42.73 °, 44.09°, 45.69°, 47.23°, 48.36°, 51.23°, 54.44° and 56.20°, with an error tolerance of ± 0.2°.

(2) Analysis and identification by TA Q2000 differential scanning calorimetry (DSC): the scanning speed is 10°C/min, and the obtained DSC curve is shown in Figure 5, which contains endothermic peaks of 84.14°C and 161.75°C, with ± 3 Error tolerance in °C.

(3) Thermogravimetric (TGA) analysis and identification by TA Q500: the heating rate is 10°C/minute, and the resulting TGA curve is shown in Figure 6, which contains a weight loss of 2.819% and has an error tolerance of ± 0.1%.

Example 3 Mode (I) crystal form of compound C

Preparation of Form C

Method 1: 2-[1-[ (2R )-2-[[( 3aR,6aR )-3,3 a ,4,5,6,6 a -hexahydro-1 H- cyclopenta[ c ]furan-5-yl]oxy]-2-(2-methoxyphenyl)ethyl]-5-methyl-6-oxazol-2-yl-2,4-dioxo-thiophene Suspended [2,3- d ]pyrimidin-3-yl]-2-methyl-propionic acid (500.2 mg) in acetone (2.5 mL), heated to 50 ^o C, stirred to dissolve, kept warm for 0.5 hours, and slowly added water ( 2.0 mL), keep it warm for 0.5 hours after adding, add seed crystal C (15.2 mg), keep it warm and stir for 0.5 hours, let it naturally cool down to room temperature, add water (1.0 mL), stir for 12 hours, filter with suction, use 5.0 mL for the filter cake Wash with water, pump until almost dry, and vacuum dry at 60 ^° C for 12 hours to obtain a white solid (460.5 mg, yield 92.1%).

Method 2: 2-[1-[ (2R )-2-[[( 3aR,6aR )-3,3 a ,4,5,6,6 a -hexahydro-1 H- cyclopenta[ c ]furan-5-yl]oxy]-2-(2-methoxyphenyl)ethyl]-5-methyl-6-oxazol-2-yl-2,4-dioxo-thiophene [2,3- d ]pyrimidin-3-yl]-2-methyl-propionic acid (500.0 mg) was suspended in acetic acid (2.5 mL), heated to 50 ^o C, stirred to dissolve, kept warm and stirred for 0.5 hours, and slowly added Water (2.5 mL), incubate for 1 hour, add seed crystal C (15 mg), incubate and stir for 2 hours, cool to room temperature (10 ^o C/h), filter, and vacuum dry at 60 ^o C for 8 hours to obtain a white solid (423.2 mg, yield 84.6%).

Method three: 2-[1-[ (2R )-2-[[( 3aR,6aR )-3,3 a ,4,5,6,6 a -hexahydro-1 H- cyclopenta[ c ]furan-5-yl]oxy]-2-(2-methoxyphenyl)ethyl]-5-methyl-6-oxazol-2-yl-2,4-dioxo-thiophene Suspended [2,3- d ]pyrimidin-3-yl]-2-methyl-propionic acid (500.0 mg) in acetone (2.5 mL), heated to 50 ^o C, slowly added water (2.0 mL), and added After incubation for 0.5 hours, add seed crystal C (10.0 mg), keep stirring for 0.5 hours, cool to room temperature naturally, add water (1.0 mL), stir for 5 hours, filter, and vacuum dry at 60 ^o C overnight to obtain a white solid (451.0 mg, yield 90.2%).

Method 4: 2-[1-[ (2R )-2-[[( 3aR,6aR )-3,3 a ,4,5,6,6 a -hexahydro-1 H- cyclopenta[ c ]furan-5-yl]oxy]-2-(2-methoxyphenyl)ethyl]-5-methyl-6-oxazol-2-yl-2,4-dioxo-thiophene The amorphous form of [2,3- d ]pyrimidin-3-yl]-2-methyl-propionic acid (1.01 g) was suspended in a mixed solvent of acetic acid (2.0 mL) and water (10.0 mL), and pulped at room temperature for 12 hour, filtered, and vacuum dried at 60 ^° C for 12 hours to obtain a white solid (0.89 g, yield 88.1%).

2. Identification of Form C

(1) Identified by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-Kα radiation, it has the following characteristic peaks expressed in angle 2θ: 5.61°, 9.58°, 10.05°, 10.27°, 11.19°, 12.00°, 12.63 °, 13.23°, 14.31°, 16.13°, 17.28°, 17.88°, 18.68° ± 0.2°, 19.18°, 19.33°, 20.15°, 20.93°, 21.66°, 22.73°, 23.63°, 25.39°, 26.60°, 27.87°、28.93°、29.62°、30.88°、32.61°、33.16°、33.85°、35.65°、36.68°、38.82°、39.72°、40.52°、42.64°、46.90°、48.43° and 50.86°, there is ± 0.2° error tolerance.

(2) Analysis and identification by TA Q2000 differential scanning calorimetry (DSC): the scanning speed is 10°C/min, and the obtained DSC curve is shown in Figure 8, which contains an endothermic peak of 166.88°C, with an error of ± 3°C. tolerance.

(3) Thermogravimetric (TGA) analysis and identification by TA Q500: the heating rate is 10°C/minute, and the resulting TGA curve is shown in Figure 9, which contains a weight loss of 0.008% and has an error tolerance of ± 0.1%.

Example 4 Mode (I) crystal form of compound D

1. Preparation of Form D

2-[1-[ (2R )-2-[[( 3aR,6aR ) -3,3a , 4,5,6,6a -hexahydro- 1H- cyclopenta[ c ]furan -5-yl]oxy]-2-(2-methoxyphenyl)ethyl]-5-methyl-6-oxazol-2-yl-2,4-dioxo-thieno[2 ,3- d ]pyrimidin-3-yl]-2-methyl-propionic acid (101.2 mg) was suspended in isopropyl alcohol (1.0 mL), heated to 50 ^o C, stirred to dissolve, incubated for 0.5 hours, and allowed to cool to room temperature. , add seed crystal C (50.0 mg), stir for 12 hours, filter until nearly dry, and vacuum dry at room temperature for 2 hours to obtain a white solid (83.1 mg, yield 82.1%).

2. Identification of Form D

(1) Identified by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-Kα radiation, it has the following characteristic peaks expressed in angle 2θ: 4.33°, 6.08°, 8.58°, 9.62°, 12.17°, 12.91°, 13.60 °, 14.06°, 14.75°, 15.07°, 15.52°, 16.04°, 17.26°, 17.74°, 17.93°, 18.31°, 18.51°, 18.86°, 19.28°, 20.45°, 21.21°, 21.68°, 22.01°, 22.43°、23.30°、23.66°、24.05°、24.46°、25.22°、25.61°、26.29°、26.65°、27.41°、27.76°、28.30°、28.95°、29.63°、30.10°、31.23°、32.19° , 33.10°, 34.23°, 35.08°, 35.98°, 37.43°, 38.28°, 39.16°, 39.96°, 40.43°, 41.44°, 42.19°, 42.71°, 43.31°, 44.87°, 45.39°, 46.02°, 47.76 °, 48.82° and 49.37°, there is an error tolerance of ± 0.2°.

(2) Analysis and identification by TA Q2000 differential scanning calorimetry (DSC): the scanning speed is 10°C/minute, and the obtained DSC curve is shown in Figure 11, which contains an endothermic peak of 122.02°C, with an error of ± 3°C. tolerance.

(3) Thermogravimetric (TGA) analysis and identification by TA Q500: the heating rate is 10°C/minute, and the resulting TGA curve is shown in Figure 12, which contains a weight loss of 7.634% and has an error tolerance of ± 0.1%.

Example 5 Mode (I) amorphous form of compound

Amorphous preparation

Method 1: 2-[1-[ (2R )-2-[[( 3aR,6aR )-3,3 a ,4,5,6,6 a -hexahydro-1 H- cyclopenta[ c ]furan-5-yl]oxy]-2-(2-methoxyphenyl)ethyl]-5-methyl-6-oxazol-2-yl-2,4-dioxo-thiophene [2,3- d ]pyrimidin-3-yl]-2-methyl-propionic acid (50.2 mg) was suspended in N,N -dimethylacetamide (0.25 mL), stirred at room temperature, and then Slowly add water (0.25 mL) to precipitate a small amount of solid. Add additional water (0.3 mL), stir at room temperature for 2 hours, filter with suction, and dry the filter cake under vacuum at 60 ^° C for 6 hours to obtain a white solid (25.2 mg, yield 50.2%). ).

Method 2: 2-[1-[ (2R )-2-[[( 3aR,6aR )-3,3 a ,4,5,6,6 a -hexahydro-1 H- cyclopenta[ c ]furan-5-yl]oxy]-2-(2-methoxyphenyl)ethyl]-5-methyl-6-oxazol-2-yl-2,4-dioxo-thiophene [2,3- d ]pyrimidin-3-yl]-2-methyl-propionic acid (501.1 mg) was suspended in acetone (10.0 mL), stirred to dissolve at room temperature, the solvent was evaporated under reduced pressure, and dried under vacuum at room temperature. After 4 hours, a white solid (492.6 mg, yield 98.3%) was obtained.

2. Amorphous identification

(1) Identification through Empyrean X-ray powder diffraction (XRPD) analysis: The amorphous X-ray powder diffraction pattern is shown in Figure 13, and there is an error tolerance of ± 0.2°.

(2) Analysis and identification by TA Q2000 differential scanning calorimetry (DSC): the scanning speed is 10°C/min, and the obtained DSC curve is shown in Figure 14.

(3) Thermogravimetric (TGA) analysis and identification by TA Q500: the heating rate is 10°C/minute, and the resulting TGA curve is shown in Figure 15, which contains a weight loss of 2.423% and has an error tolerance of ± 0.1%.

Example 6 Mode (I) Amorphous form of sodium salt of compound

1. Preparation of amorphous sodium salt

2-[1-[ (2R )-2-[[( 3aR,6aR ) -3,3a , 4,5,6,6a -hexahydro- 1H- cyclopenta[ c ]furan -5-yl]oxy]-2-(2-methoxyphenyl)ethyl]-5-methyl-6-oxazol-2-yl-2,4-dioxo-thieno[2 ,3- d ]pyrimidin-3-yl]-2-methyl-propionic acid (50.3 mg, 0.08 mmol) was added to a 25mL single-neck bottle, and then a solution of sodium hydroxide (4.1 mg) in water (0.5 mL) was added, and the chamber Stir warmly until it becomes clear, add acetonitrile (2.0 mL), stir for 2 hours, evaporate the solvent under reduced pressure, add a mixed solvent of ethyl acetate (1.0 mL) and n-heptane (1.0 mL) to make a slurry, and filter the chamber with suction. Dry under warm vacuum for 2 hours to obtain light yellow solid powder (43.1 mg, yield 83.1%).

2. Identification of amorphous sodium salt

Identified by Empyrean X-ray powder diffraction (XRPD) analysis: The amorphous X-ray powder diffraction pattern of the sodium salt is shown in Figure 16, with an error tolerance of ± 0.2°.

Example 7 Mode (I) Amorphous form of the potassium salt of the compound

Preparation of amorphous potassium salts

2-[1-[ (2R )-2-[[( 3aR,6aR ) -3,3a , 4,5,6,6a -hexahydro- 1H- cyclopenta[ c ]furan -5-yl]oxy]-2-(2-methoxyphenyl)ethyl]-5-methyl-6-oxazol-2-yl-2,4-dioxo-thieno[2 ,3- d ]pyrimidin-3-yl]-2-methyl-propionic acid (101.4 mg, 0.17 mmol) and potassium hydroxide (9.5 mg) were added to a 25 mL single-mouth bottle, and suspended in water (1.0 mL). After stirring at room temperature, the solid was completely dissolved, with a small amount of insoluble solid. Add acetonitrile (1.0 mL), stir at room temperature for 6 hours, and evaporate the solvent under reduced pressure to obtain a light yellow solid powder (87.9 mg, yield 81.5%).

Amorphous identification of potassium salts

Identified by Empyrean X-ray powder diffraction (XRPD) analysis: The amorphous X-ray powder diffraction pattern of the potassium salt is shown in Figure 17, with an error tolerance of ± 0.2°.

Example 8 The pharmacokinetics of the crystalline form of the present invention Kinetic experiments

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

Divide 6-8 kg male beagle dogs into 2 groups, 3 in each group, orally administer capsules containing the test sample at a dose of 5 mg/kg, according to time points: 0.25, 0.5, 1.0, 2.0, 4.0, 6.0 , 8.0 and 24 h blood collection. Establish a standard curve with an appropriate range based on the sample concentration, use AB SCIEX API4000 LC-MS/MS in MRM mode to measure the concentration of the test sample in the plasma sample, and perform quantitative analysis. According to the drug concentration-time curve, the WinNonLin 6.3 software non-compartmental model method was used to calculate 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 Dosage(mg/kg) AUC _last (h*ng/ml) C _max (ng/ml) T _max (h) Form A 5 191 159 0.667 Form C 5 183 288 0.333

Experimental conclusion: It can be seen from Table 1 that compared with crystal form A, crystal form C of the present invention has a better maximum blood concentration (C _max ), so crystal form C has better pharmacokinetic properties.

Example 9 Stability experiment of the crystal form of the present invention

(1) High temperature experiment : Put an appropriate amount of a batch of test samples into a flat weighing bottle, spread it into a thin layer ≤ 3 mm thick, and place it at 60 ^o C and 40 ^o C for 30 days respectively. Take samples on 5, 10 and 30 days, observe the color changes of the samples, detect the purity of the samples by HPLC, and analyze the structure by X-ray powder diffraction.

(2) High humidity test : Put an appropriate amount of a batch of test samples into a flat weighing bottle, spread it into a thin layer ≤ 3 mm thick, and place it at 25 ^o C, RH 90% ± 5% and 25 ^o C, RH. Leave it for 30 days under two conditions of 75% ± 5%, take samples on the 5th, 10th, and 30th days to observe the color changes of the samples, detect the purity of the samples by HPLC, and analyze the structure by X-ray powder diffraction.

(3) Illumination experiment : Put an appropriate amount of a batch of test samples into a flat weighing bottle, spread it into a thin layer ≤ 3 mm thick, place it in a light box with an open mouth (with UV), and place it at an illumination of 4500 ± 500lx, UV Place the samples under the condition of light ≥0.7w/ ^m2 for 30 days, take samples on the 5th, 10th, and 30th days, observe the color changes of the samples, detect the purity of the samples by HPLC, and analyze the structure by X-ray powder diffraction.

(4) Long-term stability test : The test sample is packaged in a single-layer PE inner package, an aluminum foil bag outer package, a built-in KD-20 oxygen scavenger, vacuumed and filled with nitrogen, and then heat-sealed and packaged at a low temperature of 5℃ ± 3℃ for a long-term test. Conditions, observe the color change of the sample, and detect the purity of the sample by HPLC.

It can be seen from the experimental results that the crystal form C of the present invention is stable under high temperature and high humidity conditions, especially the appearance and purity of the crystal form C of the present invention do not change significantly.

Under the long-term stability test conditions, the appearance, purity and water content of the crystal form C of the present invention have no significant changes.

In summary, the stability of the crystalline form C of the present invention is relatively good and suitable for pharmaceutical use.

Example 10 Hygroscopicity experiment of the crystal form of the present invention

Take an appropriate amount of the test sample and use a dynamic moisture adsorption instrument to test its hygroscopicity.

Among them, the DVS diagrams of the hygroscopicity experiments of crystal form A and crystal form C of the present invention are basically as shown in Figures 18 and 19, and the specific experimental results are shown in Table 2. According to the description of hygroscopic characteristics and the definition standards of hygroscopic weight gain (Chinese Pharmacopoeia 2015 Edition General Chapter 9103 Guiding Principles for Drug Hygroscopic Tests, see Table 3 for details). [Table 2] Hygroscopicity test of the crystal form of the present invention Test sample Weight gain/% at 20% relative humidity Weight gain/% at 60% relative humidity Weight gain/% at 80% relative humidity Weight gain/% at 95% relative humidity Form A 4.086 4.433 4.688 4.896 Form C 0.234 0.562 0.772 1.035 [Table 3] Description of hygroscopic characteristics and definition of hygroscopic weight gain (25°C ± 1°C, 80% ± 2% relative humidity) hygroscopic properties Dampness and weight gain deliquescence Absorbs enough water to form a liquid Very hygroscopic Not less than 15% Hygroscopic Less than 15% but not less than 2% Slightly hygroscopic Less than 2% but not less than 0.2% No or almost no hygroscopicity Less than 0.2%

It can be seen from the experimental results that the crystalline form A has hygroscopicity at 20% humidity, while the crystalline form C of the present invention has slight hygroscopicity, indicating that the crystalline form C is not easily affected by high humidity and deliquesces.

The above content is only a basic description of the concept of the present invention, and any equivalent transformation made based on the technical solution of the present invention shall fall within the protection scope of the present invention.

In the description of this specification, reference to the terms "one embodiment," "some embodiments," "examples," "specific examples," or "some examples" means that specific features are described in connection with the embodiment or example. , structures, materials or features are included in at least one embodiment or example of the invention. In this specification, the schematic expressions of the above terms are not necessarily directed to the same embodiment or example. Furthermore, the specific features, structures, materials or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, those skilled in the art may combine and combine different embodiments or examples and features of different embodiments or examples described in this specification unless they are inconsistent with each other.

Although the embodiments of the present invention have been shown and described above, it can be understood that the above-mentioned embodiments are illustrative and should not be construed as limitations of the present invention. Those of ordinary skill in the art can make modifications to the above-mentioned embodiments within the scope of the present invention. The embodiments are subject to changes, modifications, substitutions and variations.

[Fig. 1] is an X-ray powder diffraction (XRPD) pattern of crystal form A of the compound represented by formula (I). [Fig. 2] is a differential scanning calorimetry (DSC) chart of crystal form A of the compound represented by formula (I). [Fig. 3] is a thermogravimetric (TGA) analysis diagram of crystal form A of the compound represented by formula (I). [Fig. 4] is an X-ray powder diffraction (XRPD) pattern of crystal form B of the compound represented by formula (I). [Fig. 5] is a differential scanning calorimetry (DSC) chart of crystal form B of the compound represented by formula (I). [Fig. 6] is a thermogravimetric (TGA) analysis chart of crystal form B of the compound represented by formula (I). [Fig. 7] is an X-ray powder diffraction (XRPD) pattern of crystal form C of the compound represented by formula (I). [Fig. 8] is a differential scanning calorimetry (DSC) chart of crystal form C of the compound represented by formula (I). [Fig. 9] is a thermogravimetric (TGA) analysis chart of crystal form C of the compound represented by formula (I). [Fig. 10] is an X-ray powder diffraction (XRPD) pattern of crystal form D of the compound represented by formula (I). [Fig. 11] is a differential scanning calorimetry (DSC) chart of crystal form D of the compound represented by formula (I). [Fig. 12] is a thermogravimetric (TGA) analysis diagram of crystal form D of the compound represented by formula (I). [Fig. 13] is an amorphous X-ray powder diffraction (XRPD) pattern of the compound represented by formula (I). [Fig. 14] is a differential scanning calorimetry (DSC) chart of the amorphous form of the compound represented by formula (I). [Fig. 15] is a thermogravimetric (TGA) analysis chart of the amorphous form of the compound represented by formula (I). [Fig. 16] Fig. 16 is an amorphous X-ray powder diffraction (XRPD) pattern of the sodium salt of the compound represented by formula (I). [Fig. 17] Fig. 17 is an amorphous X-ray powder diffraction (XRPD) pattern of the potassium salt of the compound represented by formula (I). [Fig. 18] is a dynamic moisture adsorption (DVS) diagram of crystal form A of the compound represented by formula (I). [Fig. 19] is a dynamic moisture adsorption (DVS) diagram of crystal form C of the compound represented by formula (I).

Claims (10)

A crystal form C of a compound represented by formula (I), wherein the X-ray powder diffraction pattern of the crystal form C has diffraction peaks at the following 2θ angles: 5.61° ± 0.2°, 14.31° ± 0.2°, 17.28 ° ± 0.2°, 18.68° ± 0.2°, 20.15° ± 0.2° and 23.63° ± 0.2°, (I). The crystal form C according to claim 1, wherein the X-ray powder diffraction pattern of the crystal form C has diffraction peaks at the following 2θ angles: 5.61° ± 0.2°, 9.58° ± 0.2°, 10.05° ± 0.2° , 10.27° ± 0.2°, 12.00° ± 0.2°, 14.31° ± 0.2°, 17.28° ± 0.2°, 18.68° ± 0.2°, 19.18° ± 0.2°, 19.33° ± 0.2°, 20.15° ± 0.2° and 23.63 °±0.2°. The crystal form C as described in claim 1 or 2, wherein the X-ray powder diffraction pattern of the crystal form C has diffraction peaks at the following 2θ angles: 5.61° ± 0.2°, 9.58° ± 0.2°, 10.05° ± 0.2°, 10.27° ± 0.2°, 11.19° ± 0.2°, 12.00° ± 0.2°, 12.63° ± 0.2°, 13.23° ± 0.2°, 14.31° ± 0.2°, 16.13° ± 0.2°, 17.28° ± 0.2° , 17.88° ± 0.2°, 18.68° ± 0.2°, 19.18° ± 0.2°, 19.33° ± 0.2°, 20.15° ± 0.2°, 20.93° ± 0.2°, 21.66° ± 0.2°, 22.73° ± 0.2°, 23.63 ° ± 0.2°, 25.39° ± 0.2°, 26.60° ± 0.2°, 27.87° ± 0.2°, 28.93° ± 0.2°, 29.62° ± 0.2°, 30.88° ± 0.2°, 32.61° ± 0.2°, 33.16° ± 0.2°, 33.85° ± 0.2°, 35.65° ± 0.2°, 36.68° ± 0.2°, 38.82° ± 0.2°, 39.72° ± 0.2°, 40.52° ± 0.2°, 42.64° ± 0.2°, 46.90° ± 0.2° , 48.43° ± 0.2° and 50.86° ± 0.2°. The crystalline form C according to any one of claims 1 to 3, wherein the crystalline form C has an X-ray powder diffraction pattern substantially as shown in Figure 7. The crystalline form C according to any one of claims 1 to 4, wherein the differential scanning calorimeter of the crystalline form C contains an endothermic peak of 166.88°C ± 3°C. The crystalline form C according to any one of claims 1 to 5, wherein the crystalline form C has a differential scanning calorimetry diagram substantially as shown in FIG. 8 . A pharmaceutical composition comprising the crystal form C as described in any one of claims 1 to 6, and a pharmaceutically acceptable carrier, excipient, diluent, auxiliary agent or a combination thereof. The use of a crystal form C as described in any one of claims 1 to 6 or a pharmaceutical composition as described in claim 7 in the preparation of medicines for preventing, treating or alleviating the symptoms caused by acetyl-coenzyme A Carboxylase-regulated diseases. The use as described in claim 8, wherein the diseases regulated by the acetyl-CoA carboxylase are metabolic diseases and tumors. The use as described in claim 9, wherein the metabolic diseases include insulin resistance, obesity, dyslipidemia, metabolic syndrome, type II diabetes, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, and hepatic steatosis. , bullous steatosis, advanced fibrosis or cirrhosis; the tumors include liver cancer, kidney cancer, lung cancer, breast cancer, melanoma, papillary thyroid tumors, cholangiocarcinoma, colon cancer, ovarian cancer, malignant lymphoma, bladder cancer cancer, prostate cancer, pancreatic cancer, skin cancer, or recurrent solid tumors.