Cocrystals of thienopyrimidine compounds and uses thereof

Abstract

The present invention relates to co-crystals of thienopyrimidine compounds and uses thereof. In particular, the present invention relates to co-crystals 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-oxazol-2-yl-2,4-dioxo-thieno[2,3-d]pyrimidin-3-yl]-2-methyl-propanoic acid and benzimidazole and pharmaceutical compositions comprising said co-crystals, further to their use in the manufacture of a medicament for the treatment and prevention of diseases modulated by acetyl-CoA carboxylase.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of medicine, in particular to a co-crystal 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-oxazol-2-yl-2,4-dioxo-thieno[2,3-d]pyrimidin-3-yl]-2-methyl-propionic acid and benzimidazole and pharmaceutical compositions comprising said co-crystal, further to their use in the preparation of a medicament for the treatment and prevention of diseases modulated by acetyl-CoA carboxylase. BACKGROUND

[0002] Acetyl-CoA carboxylase (ACC) is a rate-limiting enzyme in the first step of fatty acid synthesis metabolism, which catalyzes the carboxylation of acetyl-CoA to malonyl-CoA in the presence of ATP, Mg 2+ - HCO3

[0003] In humans and other mammals, the enzyme is a tissue-specific enzyme, and there are two subtypes, ACC1 and ACC2, which differ in tissue distribution and function; ACC1 is usually expressed in all tissues, but is most expressed in lipogenic tissues such as liver and adipose tissue, and ACC2 is highly expressed in skeletal muscle and heart, and is less expressed in liver tissue. ACC1 catalyzes the biosynthesis of long-chain fatty acids, which are metabolized through the Krebs cycle if acetyl-CoA is not carboxylated to form malonyl-CoA; ACC2 catalyzes the production of malonyl-CoA on the cytosolic surface of mitochondria, and regulates the amount of fatty acids for beta-oxidation by inhibiting carnitine palmityl transferase-1 (CPT-1).

[0004] Studies have shown that ACC inhibitors can reduce the synthesis of fatty acids by inhibiting ACC1, and promote the oxidation of fatty acids in the liver by inhibiting ACC2, thereby reducing the accumulation of lipids in the body, and can effectively treat diseases related to obesity, hypertension, diabetes, tumors, dyslipidemia and hyperlipidemia, and type II diabetes, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) caused by the accumulation of lipids in the liver and resulting in insulin resistance in the liver.

[0005] ​Nonalcoholic 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. Many factors can trigger NASH, including age, obesity, body mass index (BMI), insulin sensitivity, dyslipidemia, hypertension, and abnormal activity of liver function-related enzymes such as alanine aminotransferase (ALT) or aspartate aminotransferase (AST). It has been reported that patients exhibiting metabolic syndrome symptoms (primarily central obesity, hypertension, insulin resistance, high triglycerides, and low high-density lipoprotein) have a positive correlation with the risk of developing NASH. In diabetic or obese patients over 50 years of age, 66% of liver biopsies reveal NASH with severe fibrosis. In the United States, approximately 12% of the population is affected by this disease, a proportion that rises to 22% in people with diabetes. More importantly, approximately 15–25% of NASH patients will develop cirrhosis, making it another leading cause of liver cancer after viral hepatitis and alcoholic hepatitis. Cirrhosis is a leading cause of death from liver disease, directly leading to liver decompensation and an annual mortality rate of nearly 4%.

[0006] International application WO2021000242 A1 discloses compound 2-[1-[(2R)-2-[[(3aR,6aR)-3,3a,4,5,6,6a-hexahydro-1H-cyclopentadieno[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 (the compound shown in formula (I)), which can treat or alleviate diseases regulated by acetyl-CoA carboxylase, such as non-alcoholic steatohepatitis. This compound suffers from poor solubility, inadequate absorption in animals, and poor stability, which pose significant challenges to subsequent formulation development.

[0007]

[0008] "Drug cocrystallization" refers to the formation of a specific crystal structure by an active pharmaceutical ingredient (API) and a pharmaceutically acceptable ligand (CCF) through molecular recognition, without disrupting the API's own chemical bonds, via intermolecular forces (hydrogen bonds, halogen bonds, π-stacking interactions, and van der Waals forces). For active pharmaceutical ingredients, the crystalline form can influence numerous physicochemical properties, directly impacting their processing and / or preparation capabilities and the resulting dosage forms. For example, cocrystallization can improve the solubility, hygroscopicity, stability, and manufacturing properties of the active pharmaceutical ingredient (API), as well as its compressibility, flowability, and filterability. It also affects drug stability, dissolution rate, and bioavailability. Cocrystallization can influence drug quality, safety, and efficacy. The formation of drug cocrystallization provides a better means of altering the physicochemical properties of active pharmaceutical ingredients, achieving desired properties for specific APIs through the formation of cocrystallizations of APIs and co-crystallizing agents (ligands). When an active compound forms a cocrystallization with a suitable ligand, crystallization properties are improved, crystallization is easier, and the resulting cocrystallization exhibits excellent stability. Summary of the Invention

[0009] This invention provides a co-crystal of the compound shown in formula (I) and benzimidazole. Specifically, this invention provides a co-crystal form I of the compound shown in formula (I) and benzimidazole, which can significantly improve the stability and pharmacokinetic properties of the compound, thereby exhibiting superior drug-like properties.

[0010] Specifically, the present invention relates to cocrystals of compounds of formula (I), pharmaceutical compositions comprising said cocrystals, and their use in the preparation of medicaments for treating or preventing diseases regulated by acetyl-CoA carboxylase.

[0011] On the one hand, the present invention provides a co-crystal of the compound of formula (I) and benzimidazole.

[0012]

[0013] In some embodiments, the eutectic of the compound of formula (I) and benzimidazole described in this invention is of eutectic crystal form I.

[0014] In some embodiments, the eutectic of the present invention is characterized in that the X-ray powder diffraction pattern of the eutectic crystal type I has diffraction peaks at the following 2θ angles: 11.17°±0.2°, 16.42°±0.2°, 17.01°±0.2°, 20.38°±0.2°, 25.15°±0.2°, 26.33°±0.2°.

[0015] In some embodiments, the eutectic of the present invention is characterized in that the X-ray powder diffraction pattern of the eutectic crystal type I has diffraction peaks at the following 2θ angles: 4.93°±0.2°, 9.95°±0.2°, 11.17°±0.2°, 13.72°±0.2°, 16.42°±0.2°, 16.73°±0.2°, 17.01°±0.2°, 18.72°±0.2°, 19.96°±0.2°, 20.38°±0.2°, 25.15°±0.2°, 26.33°±0.2°.

[0016] In other embodiments, the eutectic of the present invention is characterized in that the X-ray powder diffraction pattern of the eutectic crystal type I includes diffraction peaks at the following 2θ angles: 4.93°±0.2°, 8.97°±0.2°, 9.95°±0.2°, 10.51°±0.2°, 10.78°±0.2°, 11.04°±0.2°, 11.17°±0.2°, 12.64°±0.2°, 12.92°±0.2°, 13.14°±0.2°, 13.72°±0.2°, 14.75°±0.2°, 15.76°±0.2°, 16.42°±0.2°, 16.73°±0.2°, 17.01°±0.2°, 17.55°±0.2°. °±0.2°, 17.78°±0.2°, 18.26°±0.2°, 18.43°±0.2°, 18.72°±0.2°, 18.95°±0.2°, 19.41°±0.2°, 19.96°±0.2°, 20.38°±0.2°, 20.62°±0.2°, 20.73°±0.2° 2°, 21.21°±0.2°, 21.35°±0.2°, 21.75°±0.2°, 22.13°±0.2°, 22.45°±0.2°, 23.07°±0.2°, 24.03°±0.2°, 24.26°±0.2°, 24.81°±0.2°, 25.15°±0.2°, 25 0.87°±0.2°, 26.33°±0.2°, 26.88°±0.2°, 27.57°±0.2°, 27.88°±0.2°, 28.39°±0.2°, 28.58°±0.2°, 29.19°±0.2°, 29.38°±0.2°, 29.50°±0.2°, 29.79° ±0.2°, 30.16°±0.2°, 30.45°±0.2°, 31.07°±0.2°, 31.37°±0.2°, 31.75°±0.2°, 32.07°±0.2°, 32.77°±0.2°, 33.15°±0.2°, 33.24°±0.2°, 34.23°±0.2° 34.87°±0.2°, 35.29°±0.2°, 35.49°±0.2°, 36.08°±0.2°, 36.44°±0.2°, 37.16°±0.2°, 37.51°±0.2°, 38.07°±0.2°, 38.52°±0.2°, 39.42°±0.2°, 39.5 7°±0.2°, 40.16°±0.2°, 41.36°±0.2°, 41.80°±0.2°, 42.24°±0.2°, 42.78°±0.2°, 43.16°±0.2°, 44.10°±0.2°, 44.85°±0.2°, 45.69°±0.2°, 46.16°±0.2°2°, 46.62°±0.2°, 47.09°±0.2°, 47.94°±0.2°, 49.44°±0.2°, 50.62°±0.2°, 52.16°±0.2°, 52.67°±0.2°, 54.26°±0.2°, 54.68°±0.2°, 56.22°±0.2°.

[0017] In some embodiments, the eutectic form I of the present invention is characterized in that the eutectic form I has substantially the following properties: Figure 1 The X-ray powder diffraction pattern shown.

[0018] In some embodiments, the eutectic form I of the present invention is characterized in that the differential scanning calorimetry spectrum of the eutectic form I contains an endothermic peak at 169.41℃±3℃.

[0019] In some embodiments, the eutectic form I of the present invention is characterized in that the eutectic form I has substantially the following properties: Figure 2 The differential scanning calorimeter shown is a thermal image.

[0020] In some embodiments, the eutectic crystal form I of the present invention is characterized in that when the eutectic crystal form I is heated to about 150°C, the weight loss is about 0.3434%, with an error tolerance of ±0.1%.

[0021] On the other hand, the present invention relates to a pharmaceutical composition comprising a cocrystal of the compound of formula (I) of the present invention and benzimidazole, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant or combination thereof.

[0022] On one hand, the present invention relates to the use of the cocrystal or the pharmaceutical composition thereof in the preparation of a medicament for the prevention, treatment or relief of a disease regulated by acetyl-CoA carboxylase.

[0023] In some embodiments, the diseases regulated by acetyl-CoA carboxylase described in this invention are metabolic diseases and tumors.

[0024] On the other hand, the present invention relates to the use of the cocrystal or the pharmaceutical composition thereof in the preparation of a medicament for the prevention, treatment or relief of a disease in a patient that is at least partially regulated by acetyl-CoA carboxylase.

[0025] In some embodiments, the metabolic diseases described in this invention include insulin resistance, obesity, dyslipidemia, metabolic syndrome, type II diabetes, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, hepatic steatosis, macrovesicular steatosis, advanced fibrosis, or cirrhosis; the tumors include liver cancer, kidney cancer, lung cancer, breast cancer, melanoma, papillary thyroid tumor, cholangiocarcinoma, colon cancer, ovarian cancer, malignant lymphoma, bladder cancer, prostate cancer, pancreatic cancer, skin cancer, or recurrent solid tumors.

[0026] One aspect of this invention relates to methods for preventing, treating, or alleviating diseases regulated by acetyl-CoA carboxylase, including administering medication to a patient at a pharmaceutically acceptable and effective dose using the cocrystal or pharmaceutical composition described herein.

[0027] On the other hand, the present invention also relates to a method for preparing a co-crystal form of the compound shown in formula (I) and benzimidazole.

[0028] The solvent used in the preparation method of the eutectic described in this invention is not particularly limited; any solvent capable of dissolving the starting material to a certain extent without affecting its properties is included in this invention. Furthermore, many similar modifications, equivalent substitutions, or solvents, solvent combinations, and different proportions of solvent combinations described in this invention are considered to be within the scope of this invention. This invention provides preferred solvents for each reaction step.

[0029] The preparation of the benzimidazole cocrystal described in this invention is described in detail in the Examples section. Furthermore, this invention provides pharmacological testing experiments (such as pharmacokinetic experiments) and stability experiments for the benzimidazole cocrystal. Experiments have demonstrated that the benzimidazole cocrystal described in this invention possesses good stability and pharmacokinetic properties.

[0030] Definitions and general terms

[0031] Unless otherwise stated, all technical and scientific terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. All patents and publications related to this invention are incorporated herein by reference in their entirety. Although any methods and substances similar to or identical to those described herein may be used in the practice or testing of this invention, preferred methods, apparatus, and substances are described herein.

[0032] "Crystal form" or "crystalline shape" refers to a solid having a highly regular chemical structure, including, but not limited to, single-component or multi-component crystals, and / or polymorphs of compounds, solvates, hydrates, inclusion compounds, eutectics, salts, solvates of salts, and hydrates of salts. The crystalline form of a substance can be obtained by many methods known in the art. These methods include, but are not limited to, melt crystallization, melt cooling, solvent crystallization, crystallization in a confined space, such as in nanopores or capillaries, crystallization on a surface or template, such as on a polymer, crystallization in the presence of additives such as co-crystallized antimolecules, desolventization, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, reactive crystallization, antisolvent addition, grinding, and solvent drop grinding, etc.

[0033] "Co-crystal" is a crystalline substance formed by two or more different molecules. A typical co-crystal is a crystalline substance formed by a drug and a ligand in the same crystal lattice.

[0034] "Solvent" refers to a substance (typically a liquid) that can completely or partially dissolve another substance (typically a solid). Solvents used in the implementation of this 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, mixtures thereof, etc.

[0035] An antisolvent is a fluid that promotes the precipitation of a product (or product precursor) from a solvent. Antisolvents can include cold gases, fluids that promote precipitation through chemical reactions, or fluids that reduce the solubility of a product in a solvent; they can be the same liquid as the solvent but at a different temperature, or they can be a different liquid from the solvent.

[0036] A "solvent" is a compound that has a solvent on its surface, in its crystal lattice, or both on its surface and in its crystal lattice. The solvent can 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-dimethylformamide, formamide, formic acid, heptane, hexane, isopropanol, methanol, methyl ethyl ketone, methyl pyrrolidone, mesitylene, nitromethane, polyethylene glycol, propanol, pyridine, tetrahydrofuran, toluene, xylene, and mixtures thereof. A specific example of a solvate is a hydrate, in which water is the solvent on its surface, in its crystal lattice, or both on its surface and in its crystal lattice. A hydrate may or may not have other solvents besides water on its surface, in its crystal lattice, or both on its surface and in its crystal lattice.

[0037] Crystal forms can be identified using a variety of techniques, such as X-ray powder diffraction (XRPD), infrared absorption spectroscopy (IR), melting point method, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), nuclear magnetic resonance, Raman spectroscopy, X-ray single crystal diffraction, calorimetry, scanning electron microscopy (SEM), quantitative analysis, solubility and dissolution rate, etc.

[0038] X-ray powder diffraction (XRPD) can detect changes in crystal form, crystallinity, and crystal structure, and is a commonly used method for identifying crystal forms. The peak positions of XRPD spectra depend primarily on the crystal structure and are relatively insensitive to experimental details, while their relative peak heights depend on many factors related to sample preparation and instrument geometry. Therefore, in some embodiments, the crystal form of the present invention is characterized by XRPD spectra with certain peak positions, which are essentially as shown in the XRPD spectra provided in the accompanying drawings. Furthermore, the measurement of 2θ in the XRPD spectra can be subject to experimental error; the measurement of 2θ in XRPD spectra may vary slightly between different instruments and different samples, therefore the value of 2θ cannot be considered absolute. Based on the instrument used in this experiment, there is an error tolerance of ±0.2° for the diffraction peaks.

[0039] Differential scanning calorimetry (DSC) is a technique that measures the energy difference between a sample and an inert reference (commonly α-Al₂O₃) as a function of temperature under programmed control by continuously heating or cooling. The height of the endothermic peak in a DSC curve depends on many factors related to sample preparation and instrument geometry, while the peak position is relatively insensitive to experimental details. Therefore, in some embodiments, the crystal form described in this invention is characterized by a DSC spectrum with characteristic peak positions, which are essentially as shown in the DSC spectrum provided in the accompanying drawings. However, DSC spectra can be subject to experimental error; the peak positions and peak values ​​may vary slightly between different instruments and different samples. Therefore, the peak positions or peak values ​​of the endothermic peaks in the DSC spectrum should not be considered absolute. Depending on the instrument used in this experiment, there is an error tolerance of ±3° for the endothermic peaks.

[0040] Thermogravimetric analysis (TGA) is a technique used under programmed control to determine the change in mass of a substance with temperature. It is suitable for examining the loss of solvent in crystals or the sublimation and decomposition of samples, and can infer the presence of water of crystallization or crystallization solvent in the crystal. The mass change shown by the TGA curve depends on many factors, including sample preparation and instrumentation; the mass change detected by TGA varies slightly between different instruments and different samples. Based on the instrument used in this experiment, there is an error tolerance of ±0.1% for the mass change.

[0041] In the context of this invention, the 2θ values ​​in X-ray powder diffraction patterns are all in degrees (°).

[0042] The term “basically as shown” means that 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 in an X-ray powder diffraction pattern, DSC pattern, Raman spectrum, or infrared spectrum are shown in its spectrum.

[0043] When referring to a spectrum or / and data appearing in a spectrum, a "peak" refers to a feature that can be identified by a person skilled in the art and is not attributable to background noise.

[0044] The present invention relates to the eutectic forms of 2-[1-[(2R)-2-[[(3aR,6aR)-3,3a,4,5,6,6a-hexahydro-1H-cyclopentadienzo[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, for example, benzimidazole eutectic form I, which exist in a substantially pure crystalline form.

[0045] "Substantially pure" means that a crystal form substantially contains no other crystal forms, i.e., 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 whose percentage in the total volume or total 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%.

[0046] "Substantially free of" means that one or more other crystal forms account for 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% of the total volume or weight of the crystal form.

[0047] In XRPD patterns, "relative intensity" (or "relative peak height") refers to the ratio of the intensity of other peaks to the intensity of the first strongest peak when the intensity of the first strongest peak is 100% in an X-ray powder diffraction pattern (XRPD).

[0048] In the context of this invention, when the terms "about" or "approximately" are used, whether or not they are used, it means within 10% of a given value or range, appropriately within 5%, and particularly within 1%. Alternatively, for those skilled in the art, the term "about" or "approximately" means within an acceptable standard error of the average. Whenever a number with a value of N is disclosed, any number having a value within N+ / -1%, N+ / -2%, N+ / -3%, N+ / -5%, N+ / -7%, N+ / -8%, or N+ / -10% is explicitly disclosed, where "+ / -" refers to addition or subtraction.

[0049] In this invention, "room temperature" refers to a temperature 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, etc.

[0050] Pharmaceutical compositions, formulations, administration and uses of the cocrystals of the compounds described in this invention.

[0051] The pharmaceutical compositions of the present invention are characterized by a cocrystal of the compound of formula (I) with benzimidazole and a pharmaceutically acceptable carrier, excipient, or excipient. The amount of the cocrystal of the compound in the pharmaceutical compositions of the present invention can effectively and detectably treat or alleviate diseases regulated by acetyl-CoA carboxylase.

[0052] As described in this invention, pharmaceutically acceptable compositions of this invention further comprise pharmaceutically acceptable carriers, excipients, or excipients, such as those used in this invention, including any solvent, diluent, or other liquid excipient, dispersant or suspending agent, surfactant, isotonic agent, thickener, emulsifier, preservative, solid binder, or lubricant, etc., suitable for a particular target dosage form. As described in the following literature: In Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. D.B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J.C. Boylan, 1988-1999, Marcel Dekker, New York, the contents of this literature demonstrate that different carriers can be used in the formulation of pharmaceutically acceptable compositions and their known methods of preparation. Except for any conventional carrier media that are incompatible with the salts or crystal forms of the compounds of the present invention, such as those that produce any adverse biological effects or interactions with any other component of a pharmaceutically acceptable composition in a harmful manner, their use is also within the scope of this invention.

[0053] 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; buffering substances such as phosphates; glycine; sorbic acid; potassium sorbate; mixtures of partial glycerides of saturated vegetable fatty acids; water; salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts; colloidal silica; magnesium trisilicate; polyvinylpyrrolidone; polyacrylates; waxes; polyethylene-polyoxypropylene-blocking polymers; lanolin; sugars, such as lactose, glucose, and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as carboxymethyl cellulose. Sodium cellulose, ethyl cellulose, and cellulose acetate; gum powder; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; 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 buffer solutions; and other non-toxic and suitable lubricants such as sodium lauryl sulfate and magnesium stearate; colorants; release agents; coatings; sweeteners; flavorings; fragrances; preservatives and antioxidants.

[0054] The pharmaceutical compositions of the present invention may be capsules, tablets, pills, powders, granules, and aqueous suspensions or solutions; and may be administered via the following routes: oral administration, injection administration, inhalation spray, topical administration, rectal administration, nasal administration, sublingual administration, vaginal administration, or via implantable cassette.

[0055] Oral administration can be in the following forms: tablets, pills, capsules, dispersible powders, granules or suspensions, syrups, and elixirs, etc.; topical administration can be in the following forms: ointments, gels, medicated plasters, etc.

[0056] The cocrystal of the compound of formula (I) of this invention with benzimidazole, or its crystal form thereof, is preferably prepared in a dosage unit form according to a formulation to reduce the uniformity of dosage and administration. The term "dosage unit form" here refers to the physical dispersion unit of the drug required for the patient to receive appropriate treatment. However, it should be understood that the cocrystal of the compound of formula (I) of this invention, or the total daily dosage of the pharmaceutical composition of this 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 its severity, the activity of the salt of the specific compound or its crystal form thereof, the specific composition used, the patient's age, weight, health status, sex and dietary habits, the time of administration, the route of administration and the excretion rate of the salt or crystal form of the specific compound used, the duration of treatment, whether the drug is used in combination therapy or in combination with a salt or crystal form of a potent compound, and other factors known in the pharmaceutical field.

[0057] The effective dose of the active ingredient used can vary depending on the cocrystal of the compound used, the administration method, and the severity of the disease being treated. However, generally, satisfactory results are obtained when the cocrystal of the compound of the present invention is administered daily at a dose of about 0.25-1000 mg / kg animal body weight, preferably in 2-4 separate doses daily, or in a sustained-release form. This dosage regimen can be adjusted to provide the best therapeutic response. Furthermore, depending on the treatment condition, several separate doses may be administered daily, or the dose may be reduced proportionally.

[0058] The cocrystal of the compound of formula (I) and benzimidazole or its crystal form, or 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 cocrystal of the compound or its crystal form, or the pharmaceutical composition thereof, can be used in methods for treating, pre-treating, or delaying the onset or development of acetyl-CoA carboxylase-related conditions, including but not limited to non-alcoholic steatohepatitis.

[0059] Specifically, the cocrystals or crystal forms of the compounds involved in this invention can be used to inhibit the activity of acetyl-CoA carboxylase. The cocrystals or crystal forms of said compounds can be applied to prevent, pre-treat, or treat conditions regulated 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, macrovesicular steatosis, advanced fibrosis, or cirrhosis; said 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, pancreatic cancer, skin cancer, or recurrent solid tumors. Attached Figure Description

[0060] Figure 1 The image shows the X-ray powder diffraction (XRPD) pattern of crystal form I of the compound shown in formula (I) co-crystal with benzimidazole.

[0061] Figure 2 The differential scanning calorimetry (DSC) curve is shown for crystal form I of the compound shown in formula (I) co-crystal with benzimidazole.

[0062] Figure 3 The thermogravimetric analysis (TGA) diagram shows the crystal form I of the co-crystal of the compound shown in formula (I) and benzimidazole.

[0063] General preparation and detection methods

[0064] The present invention will be further illustrated by way of embodiments below, but the invention is not limited to the scope of the embodiments described herein.

[0065] The X-ray powder diffraction analysis method used in this invention is as follows: An Empyrean diffractometer was used, employing Cu-Kα radiation (45 kV, 40 mA) to obtain X-ray powder diffraction patterns. The powdered sample was prepared into a thin layer on a single-crystal silicon sample holder, placed on a rotating sample stage, and analyzed in 0.0168° steps within a range of 3°–40°. Data was collected using Data Collector software, processed using HighScore Plus software, and read using Data Viewer software.

[0066] The differential scanning calorimetry (DSC) analysis method used in this invention is as follows: Differential scanning calorimetry is performed using a TA Q2000 module with a thermal analysis controller. Data is collected and analyzed using TA Instruments Thermal Solutions software. Approximately 1-5 mg of sample is accurately weighed into a specially designed aluminum crucible with a lid, and sample analysis is performed using a linear heating device at 10°C / min, from room temperature to approximately 300°C. During use, the DSC chamber is purged with dry nitrogen.

[0067] The thermogravimetric analysis (TGA) method used in this invention is as follows: TGA is performed using a TA Q500 module equipped with a thermal analysis controller. Data is collected and analyzed using TA Instruments Thermal Solutions software. Approximately 10 mg of sample is accurately weighed into a platinum sample pan, and sample analysis is performed using a linear heating device at 10 °C / min, from room temperature to approximately 300 °C. During use, the TGA furnace chamber is purged with dry nitrogen. Specific implementation methods

[0068] The specific synthetic method of the compound 2-[1-[(2R)-2-[[(3aR,6aR)-3,3a,4,5,6,6a-hexahydro-1H-cyclopentadieno[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 shown in Formula (I) is described in Example 1 of International Application WO2021000242A1. Example

[0069] Example 1: Crystal form I of benzimidazole eutectic

[0070] 1. Preparation of benzimidazole eutectic crystal form I

[0071] Method 1: 1.01 g of 2-[1-[(2R)-2-[[(3aR,6aR)-3,3a,4,5,6,6a-hexahydro-1H-cyclopentadieno[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 was suspended in acetone (5.0 mL). 0.20 g of benzimidazole was added, and the mixture was stirred and dissolved at room temperature overnight. A large amount of solid precipitated. The solid was filtered, and the filter cake was washed with acetone (0.5 mL) and dried to near dryness under vacuum at room temperature for 4 hours to obtain a white solid (0.51 g, yield 41.8%).

[0072] Method 2: 2-[1-[(2R)-2-[[(3aR,6aR)-3,3a,4,5,6,6a-hexahydro-1H-cyclopentadieno[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 (1.00 g) and benzimidazole (397.1 mg) were added to a flask, suspended in acetone (5.0 mL), stirred and dissolved at room temperature, and left overnight. The mixture was then filtered, and the filter cake was washed with acetone (1.5 mL), dried to near dryness, and then dried under vacuum at room temperature for 6 hours to obtain a white solid (0.86 g, yield 71.9%).

[0073] 2. Identification of Crystal Form I of Benzimidazole Cocrystal

[0074] (1) Identification by Empyrean X-ray powder diffraction (XRPD): Using Cu-Kα radiation, the following characteristic peaks, expressed in terms of angle 2θ, were observed: 4.93°, 8.97°, 9.95°, 10.51°, 10.78°, 11.04°, 11.17°, 12.64°, 12.92°, 13.14°, 13.72°, 14.75°, 15.76°, 16.42°, 16.73°, 17.01°, 17.55°, 17.78°, 18... .26°, 18.43°, 18.72°, 18.95°, 19.41°, 19.96°, 20.38°, 20.62°, 20.73°, 21.21°, 21.35°, 21.75°, 22.13°, 22.45°, 23.07°, 24.03°, 24.26°, 24.81°, 25.15°, 25.87°, 26.33°, 26.88°, 27.57°, 27.88°, 28. 39°, 28.58°, 29.19°, 29.38°, 29.50°, 29.79°, 30.16°, 30.45°, 31.07°, 31.37°, 31.75°, 32.07°, 32.77°, 33.15°, 33.24°, 34.23°, 34.87°, 35.29°, 35.49°, 36.08°, 36.44°, 37.16°, 37.51°, 38.07°, 38.5 The following angles are given: 2°, 39.42°, 39.57°, 40.16°, 41.36°, 41.80°, 42.24°, 42.78°, 43.16°, 44.10°, 44.85°, 45.69°, 46.16°, 46.62°, 47.09°, 47.94°, 49.44°, 50.62°, 52.16°, 52.67°, 54.26°, 54.68°, and 56.22°. An error tolerance of ±0.2° exists.

[0075] (2) Identification by TA Q2000 differential scanning calorimetry (DSC): The scanning speed was 10℃ / min, and the obtained DSC curves are as follows: Figure 2 As shown, there is an endothermic peak at 169.41℃, and there is an error tolerance of ±3℃.

[0076] (3) Thermogravimetric analysis (TGA) was performed using a TA Q500: the heating rate was 10℃ / min, and the resulting TGA curve is shown below. Figure 3 As shown, it contains 0.3434% weight loss and has an error tolerance of ±0.1%.

[0077] Example 2: Pharmacokinetic Experiment of the Cocrystal of the Present Invention

[0078] The eutectic of the compound of formula (I) of the present invention is filled into capsules for oral administration.

[0079] Male beagle dogs weighing 8-12 kg were divided into groups of three and orally administered capsules containing the test sample at a dose of 5 mg / kg. Blood samples were collected at time points of 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, and 24 h. A standard curve was established based on the sample concentration. The concentration of the test sample in plasma samples was determined using an AB SCIEX API4000 LC-MS / MS in MRM mode, and quantitative analysis was performed. Pharmacokinetic parameters were calculated using the non-compartmental model method in WinNonLin 6.3 software based on the drug concentration-time curve. The experimental results are shown in Table 1.

[0080] Table 1. Pharmacokinetic data of the cocrystal described in this invention.

[0081]

[0082] Conclusion: The benzimidazole cocrystal described in this invention exhibits high exposure levels in beagle dogs and good pharmacokinetic properties.

[0083] Example 3: Stability experiment of the eutectic described in this invention

[0084] (1) High temperature experiment Take an appropriate amount of a batch of test samples and place them in a flat weighing bottle. Spread them into a thin layer ≤3mm thick. Place them at 60℃ and 40℃ for 30 days respectively. Take samples on the 5th, 10th and 30th days, observe the color change of the samples, detect the purity of the samples by HPLC, and analyze the structure by X-ray powder diffraction.

[0085] (2) High humidity experimentTake an appropriate amount of a batch of test samples and place them in a flat weighing bottle. Spread them into a thin layer ≤3mm thick. Place them under two conditions: 25℃, RH 90%±5% and 25℃, RH 75%±5% for 30 days. Take samples on the 5th, 10th and 30th days, observe the color change of the samples, detect the purity of the samples by HPLC, and analyze the structure by X-ray powder diffraction.

[0086] (3) Light experiment Take an appropriate amount of the test sample and place it in a flat weighing bottle, spreading it into a thin layer ≤3mm thick. Place the bottle open in a light box (with UV light) at an illuminance of 4500±500lx and UV light ≥0.7w / m². 2 The samples were placed under the specified conditions for 30 days, and samples were taken on the 5th, 10th and 30th days to observe the color change of the samples. The purity of the samples was detected by HPLC and the structure was analyzed by X-ray powder diffraction.

[0087] (4) Long term stability experiment The experiment investigated the color changes of samples under long-term low-temperature (5℃±3℃) conditions, with the samples packaged in single-layer PE inner packaging, aluminum foil outer packaging, KD-20 deoxidizer inside, vacuum-sealed with nitrogen, and then subjected to a long-term test. The purity of the samples was determined by HPLC.

[0088] The experimental results show that the benzimidazole eutectic described in this invention is stable under high temperature and high humidity conditions; under long-term stability test conditions, the appearance, purity and water content of the benzimidazole eutectic described in this invention do not change significantly.

[0089] In summary, the benzimidazole cocrystal described in this invention has good stability and is suitable for pharmaceutical applications.

[0090] The above description is merely a basic explanation of the concept of this invention, and any equivalent modifications made based on the technical solution of this invention shall fall within the protection scope of this invention.

[0091] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., indicate that a specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of the present invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples. Moreover, without contradiction, those skilled in the art can combine and integrate the different embodiments or examples described in this specification, as well as the features of different embodiments or examples.

[0092] Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Those skilled in the art can make changes, modifications, substitutions and variations to the above embodiments within the scope of the present invention.

Claims

1. A co-crystal of a compound of formula (I) and benzimidazole, wherein, the co-crystal is co-crystal Form I, the X-ray powder diffraction pattern of the co-crystal Form I comprises the following diffraction peaks at 2θ angles: 4.93°±0.2°, 9.95°±0.2°, 11.17°±0.2°, 13.72°±0.2°, 16.42°±0.2°, 16.73°±0.2°, 17.01°±0.2°, 18.72°±0.2°, 19.96°±0.2°, 20.38°±0.2°, 25.15°±0.2°, 26.33°±0.2°.

2. The co-crystal of claim 1, wherein, The X-ray powder diffraction pattern of the eutectic form I includes the following diffraction peaks at the 2θ angle: 4.93°±0.2°, 8.97°±0.2°, 9.95°±0.2°, 10.51°±0.2°, 10.78°±0.2°, 11.04°±0.2°, 11.17°±0.2°, 12.64°±0.2°, 12.92°±0.2°, 13.14°±0.2°, 13.72°±0.2°, 14.75°±0.2°, 15.76°±0.2°, 16.42°±0.2°, 16.73°±0.2°, 17.01°±0.2°, 17.55°±0.2°, 17.78°±0.2°, 18.26° ±0.2°, 18.43°±0.2°, 18.72°±0.2°, 18.95°±0.2°, 19.41°±0.2°, 19.96°±0.2°, 20.38°±0.2°, 20.62°±0.2°, 20.73°±0.2°, 21.21°±0.2°, 21.35°±0.2 °, 21.75°±0.2°, 22.13°±0.2°, 22.45°±0.2°, 23.07°±0.2°, 24.03°±0.2°, 24.26°±0.2°, 24.81°±0.2°, 25.15°±0.2°, 25.87°±0.2°, 26.33°±0.2°, 26. 88°±0.2°, 27.57°±0.2°, 27.88°±0.2°, 28.39°±0.2°, 28.58°±0.2°, 29.19°±0.2°, 29.38°±0.2°, 29.50°±0.2°, 29.79°±0.2°, 30.16°±0.2°, 30.45°± 0.2°, 31.07°±0.2°, 31.37°±0.2°, 31.75°±0.2°, 32.07°±0.2°, 32.77°±0.2°, 33.15°±0.2°, 33.24°±0.2°, 34.23°±0.2°, 34.87°±0.2°, 35.29°±0.2° 35.49°±0.2°, 36.08°±0.2°, 36.44°±0.2°, 37.16°±0.2°, 37.51°±0.2°, 38.07°±0.2°, 38.52°±0.2°, 39.42°±0.2°, 39.57°±0.2°, 40.16°±0.2°, 41.3 6°±0.2°, 41.80°±0.2°, 42.24°±0.2°, 42.78°±0.2°, 43.16°±0.2°, 44.10°±0.2°, 44.85°±0.2°, 45.69°±0.2°, 46.16°±0.2°, 46.62°±0.2°, 47.09°±0.2°2°,47.94°±0.2°,49.44°±0.2°,50.62°±0.2°,52.16°±0.2°,52.67°±0.2°,54.26°±0.2°,54.68°±0.2°,56.22°±0.2°。.

3. The co-crystal of claim 1 or 2, characterized in that, the co-crystal Form I has an X-ray powder diffraction pattern substantially as shown in Figure 1.

4. The co-crystal of claim 1 or 2, wherein, the co-crystal Form I has a differential scanning calorimetry pattern comprising an endothermic peak at 169.41℃±3℃.

5. The co-crystal of claim 1 or 2, wherein, the co-crystal Form I has a differential scanning calorimetry pattern substantially as shown in Figure 2.

6. A pharmaceutical composition comprising the co-crystal of any one of claims 1-5, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, or a combination thereof.

7. Use of the co-crystal of any one of claims 1-5 or the pharmaceutical composition of claim 6 in the manufacture of a medicament for preventing, treating or alleviating a disease modulated by acetyl-CoA carboxylase.

8. Use according to claim 7, wherein, the disease modulated by acetyl-CoA carboxylase is a metabolic disease and a tumor; the metabolic disease is selected from insulin resistance, obesity, dyslipidemia, metabolic syndrome, type II diabetes, non-alcoholic fatty liver disease, hepatic steatosis, macrovesicular steatosis, advanced fibrosis or cirrhosis; the tumor is selected from liver cancer, kidney cancer, lung cancer, breast cancer, papillary thyroid tumor, cholangiocarcinoma, colon cancer, ovarian cancer, malignant lymphoma, bladder cancer, prostate cancer, pancreatic cancer, skin cancer or recurrent solid tumor.

9. Use according to claim 8, wherein, the non-alcoholic fatty liver disease is selected from non-alcoholic fatty liver; the skin cancer is selected from melanoma. the co-crystal is co-crystal Form I, the X-ray powder diffraction pattern of the co-crystal Form I comprises the following diffraction peaks at 2θ angles: 4.93°±0.2°, 9.95°±0.2°, 11.17°±0.2°, 13.72°±0.2°, 16.42°±0.2°, 16.73°±0.2°, 17.01°±0.2°, 18.72°±0.2°, 19.96°±0.2°, 20.38°±0.2°, 25.15°±0.2°, 26.33°±0.2°. the co-crystal Form I has an X-ray powder diffraction pattern substantially as shown in Figure 1. the co-crystal Form I has a differential scanning calorimetry pattern comprising an endothermic peak at 169.41℃±3℃. the co-crystal Form I has a differential scanning calorimetry pattern substantially as shown in Figure 2.

6. A pharmaceutical composition comprising the co-crystal of any one of claims 1-5, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, or a combination thereof.

7. Use of the co-crystal of any one of claims 1-5 or the pharmaceutical composition of claim 6 in the manufacture of a medicament for preventing, treating or alleviating a disease modulated by acetyl-CoA carboxylase. the disease modulated by acetyl-CoA carboxylase is a metabolic disease and a tumor; the metabolic disease is selected from insulin resistance, obesity, dyslipidemia, metabolic syndrome, type II diabetes, non-alcoholic fatty liver disease, hepatic steatosis, macrovesicular steatosis, advanced fibrosis or cirrhosis; the tumor is selected from liver cancer, kidney cancer, lung cancer, breast cancer, papillary thyroid tumor, cholangiocarcinoma, colon cancer, ovarian cancer, malignant lymphoma, bladder cancer, prostate cancer, pancreatic cancer, skin cancer or recurrent solid tumor. the non-alcoholic fatty liver disease is selected from non-alcoholic fatty liver; the skin cancer is selected from melanoma.

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