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 piperazine 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, and relates to a co-crystal of a thienopyrimidine compound and uses thereof, 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 piperazine and a pharmaceutical composition comprising said co-crystal, and further to their use in the manufacture 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+ and HCO3 - as a carboxyl donor, and is a biotin-dependent enzyme.

[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 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 abnormal activity of liver-related enzymes (such as alanine aminotransferase (ALT) or aspartate aminotransferase (AST)), etc. It has been reported that patients with metabolic syndrome manifestations (mainly central obesity, hypertension, insulin resistance, high triglycerides and low high-density lipoprotein) are positively correlated with the risk of NASH. In patients over 50 years of age with diabetes or obesity, 66% of liver biopsies suggest NASH with severe fibrosis. In the United States, about 12% of people are affected by this disease, and the proportion increases to 22% in people with diabetes. More notably, about 15-25% of NASH patients develop cirrhosis, which is the second leading cause of liver cancer after viral hepatitis and alcoholic hepatitis. Cirrhosis is the leading cause of death due to liver disease, which directly leads to liver decompensation and nearly 4% of annual mortality.

[0006] International application WO2021000242 A1 discloses a compound 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 (compound shown in formula (I)), which can treat or alleviate diseases modulated by acetyl-CoA carboxylase, such as nonalcoholic steatohepatitis, etc. The compound has problems such as poor solubility, unsatisfactory absorption in animals and poor stability, which brings many inconveniences to the subsequent formulation development.

[0007]

[0008] A "pharmaceutical co-crystal" is a specific crystal structure formed by a pharmaceutical active ingredient (API) and a pharmaceutically acceptable ligand (CCF) through molecular recognition, without breaking the chemical bonds of the API itself, by intermolecular forces (hydrogen bonds, halogen bonds, π-stacking interactions and van der Waals forces). For a pharmaceutical active ingredient, the form of its crystalline state can affect many physicochemical properties, which have a direct impact on its ability to process and / or manufacture drugs and corresponding final dosage forms, for example, co-crystals can improve the solubility, hygroscopicity, stability and its production and manufacturing (such as compressibility, flowability, filterability) of the drug substance, and also affect the stability, dissolution and bioavailability of the drug. Co-crystals can affect the quality, safety and efficacy of drugs. The formation of pharmaceutical co-crystals can provide a better means to change the physicochemical properties of the pharmaceutical active ingredient, and achieve the desired properties of a specific API by forming a co-crystal of the API and the co-crystallizing agent (ligand). When the active compound forms a co-crystal with a suitable ligand, the crystalline properties are improved, it is easier to crystallize, and the obtained co-crystal has very good stability. SUMMARY

[0009] The present application provides a co-crystal of a compound of formula (I) and piperazine. Specifically, the present application provides a co-crystal of a compound of formula (I) and piperazine Form I, which can significantly improve the stability and pharmacokinetics of the compound, thereby having better drugability.

[0010] Specifically, the present application relates to a co-crystal of a compound of formula (I), and a pharmaceutical composition comprising the same, and also relates to the use thereof in the preparation of a medicament for treating or preventing a disease modulated by acetyl-CoA carboxylase.

[0011] In one aspect, the present application provides a co-crystal of a compound of formula (I) and piperazine,

[0012]

[0013] In some embodiments, the co-crystal of a compound of formula (I) and piperazine according to the present application is co-crystal Form I.

[0014] In some embodiments, the co-crystal according to the present application is characterized in that the X-ray powder diffraction pattern of the co-crystal Form I comprises diffraction peaks at the following 2θ angles: 9.46°±0.2°, 11.33°±0.2°, 15.55°±0.2°, 18.20°±0.2°, 25.66°±0.2°, 26.47°±0.2°.

[0015] In some embodiments, the co-crystal of the present application is characterized in that the X-ray powder diffraction pattern of said co-crystal Form I comprises the following diffraction peaks at the following 2Q angles: 9.46°±0.2°, 10.56°±0.2°, 11.33°±0.2°, 15.55°±0.2°, 16.06°±0.2°, 16.59°±0.2°, 18.20°±0.2°, 19.04°±0.2°, 24.05°±0.2°, 25.66°±0.2°, 26.47°±0.2°.

[0016] In other embodiments, the co-crystal of the present application is characterized in that the X-ray powder diffraction pattern of said co-crystal Form I comprises the following diffraction peaks at the following 2Q angles: 4.68°±0.2°, 9.46°±0.2°, 10.56°±0.2°, 11.19°±0.2°, 11.33°±0.2°, 11.66°±0.2°, 12.03°±0.2°, 13.17°±0.2°, 13.91°±0.2°, 14.32°±0.2°, 15.07°±0.2°, 15.55°±0.2°, 16.06°±0.2°, 16.59°±0.2°, 16.75°±0.2°, 17.48°±0.2°, 18.20°±0.2°, 18.50°±0.2°, 19.04°±0.2°, 19.96°±0.2°, 20.24°±0.2°, 20.85°±0.2°, 21.11°±0.2°, 21.70°±0.2°, 22.07°±0.2°, 22.53°±0.2°, 23.33°±0.2°, 24.05°±0.2°, 24.36°±0.2°, 24.99°±0.2°, 25.35°±0.2°, 25.66°±0.2°, 25.96°±0.2°, 26.47°±0.2°, 27.30°±0.2°, 27.56°±0.2°, 27.86°±0.2°, 28.08°±0.2°, 28.95°±0.2°, 29.19°±0.2°, 29.63°±0.2°, 29.96°±0.2°, 30.36°±0.2°, 30.90°±0.2°, 31.49°±0.2°, 32.16°±0.2°, 32.74°±0.2°, 33.17°±0.2°, 33.43°±0.2°, 33.71°±0.2°, 35.88°±0.2°, 36.77°±0.2°, 37.51°±0.2°, 38.14°±0.2°, 38.71°±0.2°, 39.02°±0.2°, 40.28°±0.2°, 41.02°±0.2°, 41.39°±0.2°, 42.22°±0.2°, 42.99°±0.2°, 43.86°±0.2°, 45.43°±0.2°, 45.80°±0.2°, 47.28°±0.2°, 49.44°±0.2°, 51.43°±0.2°, 53.17°±0.2°, 54.48°±0.2°, 56.23°±0.2°, 58.44°±0.2°.

[0017] In some embodiments, the co-crystal Form I of the present application is characterized in that said co-crystal Form I has an X-ray powder diffraction pattern substantially as shown in Figure Figure 1 .

[0018] In some embodiments, the co-crystal Form I of the present application is characterized in that the differential scanning calorimetry pattern of the co-crystal Form I comprises an endothermic peak at 165.78 °C ± 3 °C.

[0019] In some embodiments, the co-crystal Form I of the present application is characterized in that the co-crystal Form I has a differential scanning calorimetry pattern substantially as shown in Figure 2

[0020] In some embodiments, the co-crystal Form I of the present application is characterized in that the co-crystal Form I has a weight loss of about 0.4716% when heated to about 150 °C, with an error tolerance of ± 0.1%.

[0021] In another aspect, the present application relates to a pharmaceutical composition comprising the co-crystal of the present application, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, or a combination thereof.

[0022] In one aspect, the present application relates to the use of the co-crystal or the pharmaceutical composition for the preparation of a medicament for preventing, treating or alleviating a disease modulated by acetyl-CoA carboxylase.

[0023] In some embodiments, the disease modulated by acetyl-CoA carboxylase of the present application is a metabolic disease and a tumor.

[0024] In another aspect, the present application relates to the use of the co-crystal or the pharmaceutical composition for the preparation of a medicament for preventing, treating or alleviating a disease modulated at least in part by acetyl-CoA carboxylase in a patient.

[0025] In some embodiments, the metabolic disease of the present application comprises 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; and the tumor comprises 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 tumor.

[0026] In one aspect, the present application relates to a method for preventing, treating or alleviating a disease modulated by acetyl-CoA carboxylase, comprising administering to a patient a pharmaceutically acceptable effective amount of the co-crystal or the pharmaceutical composition of the present application.

[0027] In another aspect, the present application also relates to a method for preparing the co-crystal of the compound of formula (I).

[0028] ​The solvent used in the preparation method of the co-crystal of the present application is not particularly limited, and any solvent that can dissolve the starting material to some extent and does not affect the properties thereof is included in the present application. In addition, many similar modifications, equivalent substitutions, or different proportions of the solvent, the solvent combination, and the solvent combination described in the present application are considered to be included in the scope of the present application. The present application provides the preferred solvent used in each reaction step.

[0029] The preparation experiment of the co-crystal of the present application is described in detail in the example part. At the same time, the present application provides pharmacological test experiments (such as pharmacokinetic experiments) and stability experiments of the co-crystal. The experiments prove that the co-crystal of the present application has good stability and pharmacokinetic properties.

[0030] Definitions and general terms

[0031] Unless otherwise defined, all technical and scientific terms used in the present application have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. All patents and publications referred to in this application are incorporated herein by reference in their entirety. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present application, the preferred methods, devices, and materials are described.

[0032] "Crystal form" or "crystalline form" refers to a solid having a highly regular chemical structure, including, but not limited to, single component or multi-component crystals, and / or polymorphs, solvates, hydrates, clathrates, co-crystals, salts, solvates of salts, hydrates of salts of a compound. The crystalline form of a substance can be obtained by many methods known in the art. Such methods include, but are not limited to, melt crystallization, melt cooling, solvent crystallization, crystallization in a defined space, for example, in a nanopore or capillary, crystallization on a surface or template, for example, on a polymer, crystallization in the presence of additives such as co-crystallization counter-molecules, desolvation, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, reaction crystallization, anti-solvent 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] A "solvent" refers to a substance (typically a liquid) that is capable of completely or partially dissolving another substance (typically a solid). Solvents useful in the practice of the present application 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, t-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, and the like.

[0035] A "anti-solvent" refers to a fluid that promotes precipitation of a product (or a precursor to a product) from a solvent. An anti-solvent can include a cold gas, or a fluid that promotes precipitation through a chemical reaction, or a fluid that decreases the solubility of a product in a solvent; it can be the same liquid as the solvent but at a different temperature, or it can be a different liquid from the solvent.

[0036] A "solvate" refers to a compound having a solvent on the surface, in the lattice, or both on the surface and in the lattice, of the compound, which solvent can be water, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, dichloromethane, dimethyl sulfoxide, 1,4-dioxane, ethanol, ethyl acetate, butanol, t-butanol, N,N-dimethylacetamide, N,N-dimethylformamide, formamide, formic acid, heptane, hexane, isopropanol, methanol, methyl ethyl ketone, methylpyrrolidinone, mesitylene, nitromethane, polyethylene glycol, propanol, pyridine, tetrahydrofuran, toluene, xylene, mixtures thereof, and the like. One particular example of a solvate is a hydrate, in which the solvent on the surface, in the lattice, or both on the surface and in the lattice, of the compound is water. A hydrate can or can not have other solvents in addition to water on the surface, in the lattice, or both on the surface and in the lattice, of the compound.

[0037] Crystal forms can be identified by 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, solubility calorimetry, scanning electron microscopy (SEM), quantitative analysis, solubility and dissolution rate, and the like.

[0038] X-ray powder diffraction (XRPD) can detect information of change of crystal form, crystallinity, crystal state, etc. and is a common means for identifying crystal form. The peak position of XRPD pattern mainly depends on the structure of crystal form and is relatively insensitive to experimental details, while the relative peak height depends on many factors related to sample preparation and instrument geometry. Therefore, in some embodiments, the crystal forms of the present application are characterized by XRPD patterns having certain peak positions, which are substantially as shown in the XRPD patterns provided in the figures of the present application. Meanwhile, the measurement of 2Θ of XRPD pattern can have experimental error, and the measurement of 2Θ of XRPD pattern can be slightly different between different instruments and different samples, therefore the numerical value of 2Θ cannot be considered as absolute. There is an error tolerance of ±0.2° for the diffraction peak according to the condition of the instrument used in the present experiment.

[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 heating or cooling. The endothermic peak height of 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 forms of the present application are characterized by DSC patterns having characteristic peak positions, which are substantially as shown in the DSC patterns provided in the figures of the present application. Meanwhile, the DSC pattern can have experimental error, and the peak position and peak value of DSC pattern can be slightly different between different instruments and different samples, therefore the numerical value of the peak position or peak value of the DSC endothermic peak cannot be considered as absolute. There is an error tolerance of ±3° for the endothermic peak according to the condition of the instrument used in the present experiment.

[0040] Thermogravimetric analysis (TGA) is a technique that measures the mass of a substance as a function of temperature under programmed control and is suitable for examining the loss of solvent from a crystal or the process of sublimation or decomposition of a sample, which can be used to infer the presence of crystalline water or crystalline solvent in a crystal. The mass change shown by the TGA curve depends on many factors such as sample preparation and instrument; the mass change detected by TGA can be slightly different between different instruments and different samples. There is an error tolerance of ±0.1% for the mass change according to the condition of the instrument used in the present experiment.

[0041] In the context of the present application, the 2Θ values in the X-ray powder diffraction pattern are in degrees (°).

[0042] The term "substantially 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 the X-ray powder diffraction pattern or DSC pattern or Raman spectrum or infrared spectrum are shown in its pattern.

[0043] "Peak" when referring to a spectrum or / and data appearing in a spectrum refers to a feature recognizable by one of skill in the art that is not attributable to background noise.

[0044] The present application 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-propionic acid, for example, the piperazine co-crystal Form I, which exist in a substantially pure crystalline form.

[0045] "Substantially pure" means that one crystalline form is substantially free of another crystalline form or forms, i.e., 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 crystalline form contains other crystalline forms in a percentage of 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% of the total volume or total weight of the crystalline form.

[0046] "Substantially free of" means that one or more other crystalline forms are in a percentage of 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 total weight of the crystalline form.

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

[0048] In the context of the present application, when used or whether or not the words "about" or "approximately" are used, means within 10% of a given value or range, suitably within 5%, particularly within 1%. Alternatively, for those skilled in the art, the terms "about" or "approximately" mean within an acceptable standard deviation of the mean. Whenever a number is disclosed, any number within + / - 1%, + / - 2%, + / - 3%, + / - 5%, + / - 7%, + / - 8%, or + / - 10% of that number is also disclosed, where "+" and "-" refer to plus or minus.

[0049] As used herein, "room temperature" means a temperature from about 10 °C to about 40 °C. In some embodiments, "room temperature" means a temperature from about 20 °C to about 30 °C; in other embodiments, "room temperature" means 20 °C, 22.5 °C, 25 °C, 27.5 °C, and the like.

[0050] Pharmaceutical compositions, formulations, administration and uses of co-crystals of the compounds described herein

[0051] The pharmaceutical compositions of the present application include co-crystals of the compounds of Formula (I) and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of co-crystal of the compound in the pharmaceutical composition of the present application is effective to detectably treat or reduce a disease modulated by acetyl-CoA carboxylase.

[0052] As described herein, the pharmaceutically acceptable compositions of the present application further comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle, which apply to the pharmaceutical compositions of the present application and include any and all solvents, diluents, or other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders or lubricants, and the like, as suited to the particular dosage form desired. General considerations relating to pharmaceutical composition formulation and manufacture can be found, for example, in 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 which are incorporated herein by reference, indicating the variety of conventions carriers that can be employed and their known methods of preparation. The use of any particular carrier with a co-crystal of the present application or a crystalline form thereof is contemplated herein, except to the extent that any conventional carrier is incompatible with the co-crystal or crystalline form thereof, for example, as it produces any adverse biological effect or interacts in a deleterious manner with any other component(s) of the pharmaceutical composition.

[0053] Substances which can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures 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, polyvinyl pyrrolidone, polyacrylate, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, 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, powdered tragacanth, 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 agar, buffering agents such as magnesium hydroxide and aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, phosphate buffer solutions, and other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, coloring agents, releasing agents, coating agents, sweetening agents, flavoring agents, perfuming agents, preservatives and antioxidants.

[0054] The pharmaceutical composition of the present application can be in the form of capsules, tablets, pills, powders, granules and aqueous or non-aqueous solutions, and can be administered by oral administration, injection, spray inhalation, topical administration, rectal administration, nasal administration, buccal administration, vaginal administration or administration through an implantable drug cartridge.

[0055] Oral administration can be administered in the form of tablets, pills, capsules, dispersible powders, granules or suspensions, syrups, elixirs and the like; and external administration can be administered in the form of ointments, gels, medicated plasters and the like.

[0056] The co-crystal of the present application or its crystal form is preferably prepared in a dosage unit form in a formulation to reduce the amount of administration and the uniformity of the dose. The term "dosage unit form" here means a physically discrete unit suitable for the patient to receive the drug for proper treatment. However, it should be understood that the total daily usage of the co-crystal of the compound of formula (I) of the present application or the pharmaceutical composition of the present application will be decided by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular patient or organism will depend upon many factors, including the disorder being treated and the severity of the disorder, the activity of the co-crystal of the specific compound, the specific composition employed, the age, body weight, general health condition, sex and diet of the patient, time of administration, route of administration, rate of excretion of the co-crystal or crystal form of the specific compound being employed, the duration of the treatment, the use of other drugs or salts or crystal forms of the specific compound in combination or in association with the drug, and other factors well known in the medical arts.

[0057] The effective dosage of the active ingredient used can vary with the co-crystal of the compound or the crystalline form thereof used, the mode of administration and the severity of the disease to be treated. However, in general, satisfactory results are obtained when the co-crystal of the compound of the present application or the crystalline form thereof is administered in a dosage of about 0.25-1000 mg / kg of the body weight of the animal per day, preferably in 2-4 divided doses, or in sustained release form. The dosage regimen can be adjusted to provide the optimum therapeutic response. Additionally, several divided doses can be administered daily or the dose can be proportionally reduced as appropriate.

[0058] The co-crystal of the compound or the crystalline form thereof of the present application, the pharmaceutical composition of the present application can be used to inhibit the activity of acetyl-CoA carboxylase, thereby modulating the stability and / or activity of acetyl-CoA carboxylase. The co-crystal of the compound or the pharmaceutical composition can be used in a method for treating, pre-treating or delaying the onset or development of acetyl-CoA carboxylase related disorders, including but not limited to non-alcoholic steatohepatitis.

[0059] In particular, the co-crystal of the compound or the crystalline form thereof of the present application can be used to inhibit the activity of acetyl-CoA carboxylase. The co-crystal of the compound or the crystalline form thereof can be administered to prevent, pre-treat or treat a disorder 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, macrovesicular steatosis, advanced fibrosis or cirrhosis; the tumor including 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 tumor. BRIEF DESCRIPTION OF DRAWINGS

[0060] Figure 1 X-ray powder diffraction (XRPD) pattern of crystalline form I of the co-crystal of the compound of formula (I) with piperazine.

[0061] Figure 2 Differential scanning calorimetry (DSC) pattern of crystalline form I of the co-crystal of the compound of formula (I) with piperazine.

[0062] Figure 3 Thermogravimetric analysis (TGA) pattern of crystalline form I of the co-crystal of the compound of formula (I) with piperazine.

[0063] General preparation and testing methods

[0064] The present application is further illustrated by the following examples without thereby limiting the present application to the examples described.

[0065] The X-ray powder diffraction analysis method used in the present application is: Empyrean diffractometer, using Cu-Ka radiation (45KV, 40mA) to obtain the X-ray powder diffraction spectrum. The powdered sample is prepared into a thin layer on a single crystal silicon sample holder, placed on a rotating sample stage, and analyzed at a step size of 0.0168° in the range of 3°-40°. Data Collector software is used to collect data, HighScore Plus software is used to process data, and Data Viewer software is used to read data.

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

[0067] The thermal gravimetric analysis (TGA) method used in the present application is: using TA Q500 module with thermal analysis controller to perform thermal gravimetric analysis. Data is collected and analyzed using TA Instruments Thermal Solutions software. About 10 mg of sample is accurately weighed into a platinum sample pan, and the sample analysis is performed from room temperature to about 300°C using a linear heating device of 10°C / min. During use, the TGA furnace chamber is purged with dry nitrogen. Specific implementation method

[0068] The specific synthesis method of the compound 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 represented by formula (I) is referred to Example 1) in International Application WO2021000242A1. Example

[0069] Example 1 Crystal Form I of PIPERAZINE COCRYSTAL

[0070] 1. Preparation of crystal form I of piperazine cocrystal

[0071] Method 1: 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 (1.01 g) was suspended in a mixed solvent of acetone (3.0 mL) and ethyl acetate (1.0 mL), piperazine (0.29 g) was added, stirred to dissolve at room temperature, and left overnight. A large amount of solid was precipitated, and the filtrate was suction filtered. The filter cake was washed with isopropyl ether (6.0 mL), suction filtered to near dryness, and dried at room temperature under vacuum overnight to obtain a white solid powder (0.84 g, yield 72.6%).

[0072] Method 2: 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 (1.01 g) was suspended in acetone (3.0 mL), piperazine (0.29 g) was added, and ethyl acetate (3.0 mL) was added. The mixture was stirred to dissolve at room temperature, and left overnight. A large amount of solid was precipitated, and the filtrate was suction filtered. The filter cake was washed with ethyl acetate (5.0 mL), suction filtered to near dryness, and dried at room temperature under vacuum overnight to obtain a white solid (0.71 g, yield 61.6%).

[0073] 2. Identification of the crystal form I of the piperazine co-crystal

[0074] (1) identified by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-Ka radiation, having the following characteristic peaks expressed in degrees 2 theta: 4.68°, 9.46°, 10.56°, 11.19°, 11.33°, 11.66°, 12.03°, 13.17°, 13.91°, 14.32°, 15.07°, 15.55°, 16.06°, 16.59°, 16.75°, 17.48°, 18.20°, 18.50°, 19.04°, 19.96°, 20.24°, 20.85°, 21.11°, 21.70°, 22.07°, 22.53°, 23.33°, 24.05°, 24.36°, 24.99°, 25.35°, 25.66°, 25.96°, 26.47°, 27.30°, 27.56°, 27.86°, 28.08°, 28.95°, 29.19°, 29.63°, 29.96°, 30.36°, 30.90°, 31.49°, 32.16°, 32.74°, 33.17°, 33.43°, 33.71°, 35.88°, 36.77°, 37.51°, 38.14°, 38.71°, 39.02°, 40.28°, 41.02°, 41.39°, 42.22°, 42.99°, 43.86°, 45.43°, 45.80°, 47.28°, 49.44°, 51.43°, 53.17°, 54.48°, 56.23°, 58.44°, with an error tolerance of ±0.2°.

[0075] (2) identified by TA Q2000 differential scanning calorimetry (DSC) analysis: with a scanning speed of 10°C / min, the obtained DSC curve is as shown in Figure 2 , which contains an endothermic peak of 165.78°C, with an error tolerance of ±3°C.

[0076] (3) identified by TA Q500 thermogravimetric (TGA) analysis: with a temperature rising rate of 10°C / min, the obtained TGA curve is as shown in Figure 3 , which contains a weight loss of 0.4716%, with an error tolerance of ±0.1%.

[0077] Pharmacokinetic experiment of the co-crystal of the present application

[0078] The co-crystal of the compound represented by formula (I) of the present application is filled into capsules for oral administration.

[0079] Take 8-12 kg male beagle dogs, 3 for a group, orally administered with capsules containing the test sample, the dose is 5 mg / kg, according to the time point 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24 h blood sampling. According to the sample concentration, the standard curve in the appropriate range is established, using AB SCIEX API4000 type LC-MS / MS, the concentration of the test sample in the plasma sample is determined in MRM mode, and quantitative analysis is carried out. According to the drug concentration-time curve, the WinNonLin 6.3 software non-compartment model method is used to calculate the pharmacokinetic parameters. The experimental results are shown in Table 1.

[0080] Table 1 Pharmacokinetic data of the co-crystal described in the application

[0081]

[0082]

[0083] Conclusion: The piperazine co-crystal described in the application has a higher exposure in beagle dogs, and has good pharmacokinetic properties.

[0084] Example 3 Stability experiment of the co-crystal described in the application

[0085] (1) High temperature experiment : Take an appropriate amount of test product into a flat weighing bottle, spread it into a thin layer ≤3mm thick, and place it at 60℃ and 40℃ respectively for 30 days, take samples at 5th, 10th, 30th day, observe the color change of the sample, detect the purity of the sample by HPLC, and analyze the structure by X-ray powder diffraction.

[0086] (2) High humidity experiment : Take an appropriate amount of test product into a flat weighing bottle, spread it into a thin layer ≤3mm thick, and place it at 60℃ and 40℃ respectively for 30 days, take samples at 5th, 10th, 30th day, observe the color change of the sample, detect the purity of the sample by HPLC, and analyze the structure by X-ray powder diffraction.

[0087] (3) Light experiment : Take an appropriate amount of test product into a flat weighing bottle, spread it into a thin layer ≤3mm thick, and place it at 60℃ and 40℃ respectively for 30 days, take samples at 5th, 10th, 30th day, observe the color change of the sample, detect the purity of the sample by HPLC, and analyze the structure by X-ray powder diffraction. 2

[0088] (4) Long term stability experiment ​: The sample was packaged in a single layer PE, packaged in an aluminum foil bag, with KD-20 deoxidizer inside, and after vacuumizing and filling with nitrogen, the mouth was heat sealed and packaged under the condition of low temperature 5℃±3℃ long-term test condition, the color change of the sample was observed, and the purity of the sample was detected by HPLC.

[0089] From the experimental results, it can be seen that the piperazine co-crystal described in the application is stable under high temperature and high humidity conditions; under the long-term stability test condition, the appearance, purity and water content of the piperazine co-crystal described in the application have no obvious change.

[0090] In summary, the piperazine co-crystal described in the application has good stability and is suitable for pharmaceutical use.

[0091] The above-mentioned content is only a basic description of the concept of the application, and any equivalent transformation of the technical scheme according to the application shall belong to the protection scope of the application.

[0092] In the description of the present specification, the description of the terms "one embodiment", "some embodiments", "example", "specific example" or "some examples" means that the specific features, structures, materials or characteristics described in connection with the embodiment or example are included in at least one embodiment or example of the application. In the present specification, the illustrative description of the above terms does not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described can be combined in any appropriate manner in any one or more embodiments or examples. Furthermore, the different embodiments or examples described in the present specification and the features of the different embodiments or examples can be combined and combined by those skilled in the art without contradiction.

[0093] Although the embodiments of the application have been shown and described above, it should be understood that the above-mentioned embodiments are exemplary and should not be construed as limiting the application, and those skilled in the art can make changes, modifications, replacements and variations to the above-mentioned embodiments within the scope of the application.

Claims

1. A co-crystal of a compound of formula (I) and piperazine, 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 2-theta angles: 9.46°±0.2°, 10.56°±0.2°, 11.33°±0.2°, 15.55°±0.2°, 16.06°±0.2°, 16.59°±0.2°, 18.20°±0.2°, 19.04°±0.2°, 24.05°±0.2°, 25.66°±0.2°, 26.47°±0.2°.

2. The co-crystal of claim 1, wherein, The X-ray powder diffraction pattern of the co-crystal Form I comprises the following diffraction peaks at 2-theta angles: 4.68°±0.2°, 9.46°±0.2°, 10.56°±0.2°, 11.19°±0.2°, 11.33°±0.2°, 11.66°±0.2°, 12.03°±0.2°, 13.17°±0.2°, 13.91°±0.2°, 14.32°±0.2°, 15.07°±0.2°, 15.55°±0.2°, 16.06°±0.2°, 16.59°±0.2°, 16.75°±0.2°, 17.48°±0.2°, 18.20°±0.2°, 18.50°±0.2°, 19.04°±0.2°, 19.96°±0.2°, 20.24°±0.2°, 20.85°±0.2°, 21.11°±0.2°, 21.70°±0.2°, 22.07°±0.2°, 22.53°±0.2°, 23.33°±0.2°, 24.05°±0.2°, 24.36°±0.2°, 24.99°±0.2°, 25.35°±0.2°, 25.66°±0.2°, 25.96°±0.2°, 26.47°±0.2°, 27.30°±0.2°, 27.56°±0.2°, 27.86°±0.2°, 28.08°±0.2°, 28.95°±0.2°, 29.19°±0.2°, 29.63°±0.2°, 29.96°±0.2°, 30.36°±0.2°, 30.90°±0.2°, 31.49°±0.2°, 32.16°±0.2°, 32.74°±0.2°, 33.17°±0.2°, 33.43°±0.2°, 33.71°±0.2°, 35.88°±0.2°, 36.77°±0.2°, 37.51°±0.2°, 38.14°±0.2°, 38.71°±0.2°, 39.02°±0.2°, 40.28°±0.2°, 41.02°±0.2°, 41.39°±0.2°, 42.22°±0.2°, 42.99°±0.2°, 43.86°±0.2°, 45.43°±0.2°, 45.80°±0.2°, 47.28°±0.2°, 49.44°±0.2°, 51.43°±0.2°, 53.17°±0.2°, 54.48°±0.2°, 56.23°±0.2°, 58.44°±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 165.78°C ± 3°C.

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.

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