CN117126175A - Co-crystals of thienopyrimidines and uses thereof - Google Patents

Co-crystals of thienopyrimidines and uses thereof Download PDF

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CN117126175A
CN117126175A CN202310582949.6A CN202310582949A CN117126175A CN 117126175 A CN117126175 A CN 117126175A CN 202310582949 A CN202310582949 A CN 202310582949A CN 117126175 A CN117126175 A CN 117126175A
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crystal
cancer
crystal form
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powder diffraction
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陈亮
单岳峰
彭飞
黎健豪
顾峥
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Guangdong HEC Pharmaceutical
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    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
    • C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
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Abstract

The invention relates to a eutectic crystal of thienopyrimidine compounds and application thereof. In particular, the invention relates to co-crystals formed by 2- [1- [ (2R) -2- [ [ (3 ar,6 ar) -3,3a,4,5,6 a-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 pharmaceutical compositions comprising said co-crystals, and further to their use in the manufacture of medicaments for the treatment and prevention of diseases modulated by acetyl coa carboxylase.

Description

Co-crystals of thienopyrimidines and uses thereof
Technical Field
The invention belongs to the technical field of medicines, relates to a co-crystal of a thienopyrimidine compound and application thereof, in particular to a co-crystal formed by 2- [1- [ (2R) -2- [ [ (3 aR,6 aR) -3,3a,4,5,6 a-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 ] pyrimidine-3-yl ] -2-methyl-propionic acid and piperazine and a pharmaceutical composition containing the co-crystal, and further relates to application thereof in preparing a medicament for treating and preventing diseases regulated by acetyl-CoA carboxylase.
Background
Acetyl-CoA carboxylase (ACC) is the rate-limiting enzyme in the first step of fatty acid anabolism, at ATP-powered, mg 2+ In the presence of HCO 3 - Carboxylation of acetyl-coa to malonyl-coa, a carboxyl donor, is a biotin-dependent enzyme.
In humans and other mammals the enzyme belongs to a tissue-specific enzyme, there are two subtypes, ACC1 and ACC2, which differ in tissue distribution and function; ACC1 is usually expressed in all tissues, but most in adipogenic tissues (e.g. liver and adipose tissue), ACC2 is highly expressed in skeletal muscle and heart, and less in liver tissue. ACC1 catalyzes the biosynthesis of long chain fatty acids, which is metabolized by the citric acid cycle (Krebs cycle) if acetyl-coa is not carboxylated to form malonyl-coa; ACC2 catalyzes the production of malonyl-coa at the cytoplasmic surface of mitochondria and regulates the amount of fatty acids for β -oxidation by inhibiting carnitine palmitoyl transferase-1 (carnitine palmityl transferase, CPT-1).
Studies have shown that ACC inhibitors inhibit ACC1, which reduces fatty acid synthesis, and ACC2, which promotes oxidation of fatty acids in the liver, thereby reducing lipid accumulation in the body, are effective in treating diseases associated with obesity, hypertension, diabetes, tumors, dyslipidemia, and hyperlipidemia, and type II diabetes, nonalcoholic fatty liver disease (NAFLD), and nonalcoholic steatohepatitis (NASH) caused by liver insulin resistance and due to lipid accumulation in the liver.
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. NASH is induced for a number of reasons, such as 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), etc. Patients presenting with manifestations of metabolic syndrome (mainly central obesity, hypertension, insulin resistance, high triglycerides and low high density lipoproteins) are reported to be positively correlated with risk of NASH. In patients with diabetes or obesity older than 50 years, 66% liver biopsies suggest that NASH is accompanied by severe fibrosis. In the united states, about 12% of people are deeply affected by the disease, and the proportion increases to 22% in people with diabetes, and more notably about 15 to 25% of NASH patients develop cirrhosis, which is a cause of liver cancer next to viral hepatitis and alcoholic hepatitis. Cirrhosis is the leading cause of death from liver disease, which directly leads to liver decompensation and nearly 4% of deaths per year.
International application WO2021000242A1 discloses the compound 2- [1- [ (2R) -2- [ [ (3 ar,6 ar) -3,3a,4,5,6 a-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 (compound of formula (I)) which can treat or alleviate diseases mediated by acetyl coa carboxylase, such as non-alcoholic steatohepatitis and the like. The compound has the problems of poor solubility, unsatisfactory absorption in animals, poor stability and the like, and the defects bring a plurality of inconveniences to subsequent preparation development.
"pharmaceutical co-crystals" are molecules that are recognized by pharmaceutically active components (APIs) and pharmaceutically acceptable ligands (CCFs) to form specific crystal structures by intermolecular forces (hydrogen bonds, halogen bonds, pi stacking and Van der Waals forces) without destroying the chemical bonds of the APIs themselves. For pharmaceutical active ingredients, the crystalline form thereof can affect a number of physicochemical properties that can have a direct impact on their ability to process and/or prepare the drug and corresponding final dosage form, e.g., co-crystals can improve the solubility, hygroscopicity, stability and manufacturing (e.g., compressibility, flowability, filterability) of the drug substance, as well as affect drug stability, dissolution and bioavailability. The eutectic can affect the quality, safety and efficacy of the drug. The formation of a pharmaceutical co-crystal can provide a better means of altering the physicochemical properties of the pharmaceutically active ingredient, by forming a co-crystal of the API and the co-crystallizing agent (ligand) to achieve the desired properties of a particular API. After the active compound forms a co-crystal with a suitable ligand, the crystallization properties are improved, crystallization is easier and the co-crystal obtained has very good stability.
Disclosure of Invention
The invention provides a eutectic of a compound shown in a formula (I) and piperazine. Specifically, the invention provides a eutectic crystal form I of the compound shown in the formula (I) and piperazine, which can obviously improve the stability, pharmacokinetics and other properties of the compound, thereby having better patentability.
In particular, the invention relates to co-crystals of compounds of formula (I), pharmaceutical compositions comprising said co-crystals, and to their use in the manufacture of a medicament for the treatment or prophylaxis of diseases modulated by acetyl-CoA carboxylase.
In one aspect, the invention provides a co-crystal of a compound shown in formula (I) and piperazine,
in some embodiments, the co-crystal of the compound represented by formula (I) and piperazine described in the present invention is co-crystal form I.
In some embodiments, the invention features an X-ray powder diffraction pattern of the co-crystal form I comprising 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 °.
In some embodiments, the invention features an X-ray powder diffraction pattern of the co-crystal form I comprising diffraction peaks at the following 2θ 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 ° and 26.47 ° ± 0.2 °.
In other embodiments, the co-crystals of the present invention are characterized in that the X-ray powder diffraction pattern of co-crystal form I comprises diffraction peaks at the following 2θ 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 °,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 ° ± 0.43 ° ± 0.24 ° ± 0.45 ° ± 0.24 °, and 4639.45 ° ± 0.43 ° ± 0.52 °, and 3924 ° ± 0.52 °, and 35 ° ± 0.52 °, 35.35 ° ± 0.52.52 °,38 ° ± 0.52.35 ° ± 0.52.52 °, and 38 ° ± 0.52.35 ° ± 0.2 °, 38.52.35 ° ± 0.45 ° ± 0.52.52.52 °, and/37.45 ° ± 0.52.45 ° ± 0.52.52.52 ° ± 0.52.52.52.52 ° ± and/37.45 ° ± 0.45.45 ° ± and/0.52.52.52.52.52 °.
In some embodiments, the invention features a co-crystal form I, wherein the co-crystal form I has an X-ray powder diffraction pattern substantially as shown in figure 1.
In some embodiments, the invention provides a eutectic crystal form I, wherein the differential scanning calorimetry pattern of the eutectic crystal form I comprises an endothermic peak at 165.78 ℃ ± 3 ℃.
In some embodiments, the invention features a eutectic crystal form I, wherein the eutectic crystal form I has a differential scanning calorimeter substantially as shown in fig. 2.
In some embodiments, the eutectic crystal form I of the present invention is characterized by a weight loss of about 0.4716% when heated to about 150 ℃ with a margin of error of ± 0.1%.
In another aspect, the present invention relates to a pharmaceutical composition comprising the co-crystal of the present invention, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, or combination thereof.
In one aspect, the invention relates to the use of said co-crystal or said pharmaceutical composition for the preparation of a medicament for the prevention, treatment or alleviation of a disease mediated by acetyl-coa carboxylase.
In some embodiments, the diseases modulated by acetyl-coa carboxylase according to the invention are metabolic diseases and tumors.
In another aspect, the invention relates to the use of said co-crystal or said pharmaceutical composition for the preparation of a medicament for preventing, treating or alleviating a disease in a patient that is at least partially mediated by acetyl-coa carboxylase.
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, liver steatosis, macrovesicular steatosis, advanced fibrosis or cirrhosis; the tumor comprises liver cancer, renal cancer, lung cancer, breast cancer, melanoma, papillary thyroid tumor, bile duct cancer, colon cancer, ovarian cancer, malignant lymphoma, bladder cancer, prostate cancer, pancreatic cancer, skin cancer or recurrent solid tumor.
In one aspect, the invention relates to a method of preventing, treating or alleviating a disease mediated by acetyl-coa carboxylase comprising administering to a patient a pharmaceutically acceptable effective dose of the co-crystal described herein or of the pharmaceutical composition described herein.
In another aspect, the invention also relates to a method for preparing a co-crystal of the compound shown in the formula (I).
The solvent used in the method for producing a co-crystal according to the present invention is not particularly limited, and any solvent that can dissolve the starting material to a degree and does not affect the properties thereof is included in the present invention. In addition, many similar modifications, equivalent substitutions, or equivalent solvents, combinations of solvents, and different proportions of solvent combinations described herein are considered to be encompassed by the present invention. The present invention gives the preferred solvents to be used in each reaction step.
Experiments for preparing the co-crystals according to the present invention will be described in detail in the examples section. Meanwhile, the invention provides pharmacological test experiments (such as pharmacokinetic experiments) and stability experiments of the eutectic crystal. Experiments prove that the eutectic crystal has good stability and pharmaceutical property.
Definitions and general terms
Unless defined otherwise, all technical and scientific terms used herein have the same meaning 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, devices, and materials are described herein.
"crystalline form" or "crystalline form" refers to a solid having a highly regular chemical structure, including, but not limited to, single or multicomponent crystals, and/or polymorphs, solvates, hydrates, clathrates, co-crystals, salts, solvates of salts, hydrates of salts of the compounds. The crystalline form of a substance may 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 a nanopore or capillary, crystallization on a surface or template, e.g., on a polymer, crystallization in the presence of additives such as co-crystallizing anti-molecules, desolvation, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, reactive crystallization, anti-solvent addition, milling, solvent drop milling, and the like.
A "co-crystal" is a crystalline substance formed from two or more different molecules, a typical co-crystal being a crystalline substance formed from a drug and a ligand in the same crystal lattice.
"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 invention include, but are not limited to, water, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, methylene chloride, dimethyl sulfoxide, 1, 4-dioxane, ethanol, ethyl acetate, butanol, tertiary butanol, N-dimethylacetamide, 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.
"antisolvent" refers to a fluid that facilitates precipitation of a product (or product precursor) from a solvent. The antisolvent may comprise a cold gas, or a fluid that promotes precipitation by a chemical reaction, or a fluid that reduces the solubility of the product in the solvent; it may be the same liquid as the solvent but at a different temperature, or it may be a different liquid than the solvent.
"solvate" means a compound having a solvent on, in, or on and in the crystal lattice that can be water, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, methylene chloride, dimethyl sulfoxide, 1, 4-dioxane, ethanol, ethyl acetate, butanol, t-butanol, N-dimethylacetamide, N-dimethylformamide, formamide, formic acid, heptane, hexane, isopropanol, methanol, methyl ethyl ketone, methyl pyrrolidone, mesitylene, nitromethane, polyethylene glycol, propanol, pyridine, tetrahydrofuran, toluene, xylene, mixtures thereof, and the like. A specific example of a solvate is a hydrate, wherein the solvent on the surface, in the crystal lattice or both is water. The hydrate may or may not have other solvents than water on the surface of the substance, in the crystal lattice, or both.
The crystalline forms may be identified by a variety of techniques such as X-ray powder diffraction (XRPD), infrared absorption spectroscopy (IR), melting point, differential Scanning Calorimetry (DSC), thermogravimetric analysis (TGA), nuclear magnetic resonance, raman spectroscopy, X-ray single crystal diffraction, dissolution calorimetry, scanning Electron Microscopy (SEM), quantitative analysis, solubility and dissolution rate, and the like.
The X-ray powder diffraction (XRPD) can detect the information of crystal form change, crystallinity, crystal structure state and the like, and is a common means for identifying the crystal form. The peak positions of the XRPD patterns are largely dependent on the structure of the crystalline form, relatively insensitive to experimental details, and their relative peak heights depend on many factors related to sample preparation and instrument geometry. Thus, 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. Meanwhile, the measure of 2θ of the XRPD pattern may have experimental errors, and the measure of 2θ of the XRPD pattern may slightly differ from instrument to instrument and sample to sample, so the value of 2θ cannot be regarded as absolute. Depending on the instrument conditions used in this test, diffraction peaks have a margin of error of + -0.2 deg..
Differential Scanning Calorimeter (DSC) is programmedUnder the condition of continuously heating or cooling, the sample and inert reference substance (commonly used alpha-Al 2 O 3 ) A technique in which the energy difference between them varies with temperature. The endothermic peak height of the DSC curve depends on many factors related to sample preparation and instrument geometry, while peak position is relatively insensitive to experimental details. Thus, in some embodiments, the crystalline forms of the invention are characterized by a DSC profile with characteristic peak positions substantially as shown in the DSC profile provided in the accompanying figures of the invention. Meanwhile, the DSC profile may have experimental errors, and the peak position and peak value of the DSC profile may slightly differ from instrument to instrument and from sample to sample, so that the peak position or the value of the DSC endothermic peak cannot be regarded as absolute. Depending on the instrument conditions used in this test, there is a margin of error of + -3 deg. for the endothermic peak.
Thermogravimetric analysis (TGA) is a technique for measuring the mass of a substance as a function of temperature under program control, and is suitable for examining the loss of a solvent in a crystal or the sublimation and decomposition processes of a sample, and can be used to infer the presence of water of crystallization or a crystallization solvent in the crystal. The quality change exhibited by the TGA profile depends on many factors such as sample preparation and instrumentation; the quality of TGA detection varies slightly from instrument to instrument and from sample to sample. Depending on the instrument conditions used in this test, there was a margin of error of + -0.1% for the mass change.
In the context of the present invention, the 2 theta values in the X-ray powder diffraction pattern are all in degrees (°).
The term "substantially as shown in the figures" 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 figure.
When referring to a spectrogram or/and data appearing in the graph, a "peak" refers to a feature that one skilled in the art can recognize that is not attributable to background noise.
The present invention relates to co-crystals of said 2- [1- [ (2R) -2- [ [ (3 ar,6 ar) -3,3a,4,5,6 a-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, e.g. piperazine co-crystal form I, which are present in a substantially pure crystalline form.
By "substantially pure" is meant that one form is substantially free of the other form or forms, i.e., the purity of the 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 form contains 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 forms.
By "substantially free" is meant that the percentage of one or more other crystalline forms in the total volume or weight of the crystalline forms 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%.
"relative intensity" (or "relative peak height") in an XRPD pattern refers to the ratio of the intensity of the first intensity peak to the intensity of the first intensity peak in all diffraction peaks of the X-ray powder diffraction pattern (XRPD) at 100%.
In the context of the present invention, when used or whether or not the word "about" or "about" is used, means within 10%, suitably within 5%, particularly within 1% of a given value or range. Alternatively, the term "about" or "approximately" means within an acceptable standard error of the average value to one of ordinary skill in the art. Whenever a number is disclosed having a value of N, any number within the values of N+/-1%, N+/-2%, N+/-3%, N+/-5%, N+/-7%, N+/-8% or N+/-10% will be explicitly disclosed, where "+/-" means plus or minus.
"room temperature" in the present invention means a temperature from about 10℃to about 40 ℃. In some embodiments, "room temperature" refers to a temperature from about 20 ℃ to about 30 ℃; in other embodiments, "room temperature" refers to 20 ℃,22.5 ℃,25 ℃,27.5 ℃, and so forth.
Pharmaceutical compositions, formulations, administration and uses of co-crystals of the compounds of the invention
The pharmaceutical compositions of the present invention are characterized by comprising a co-crystal of a compound 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 invention is effective to detectably treat or ameliorate diseases mediated by acetyl-coa carboxylase.
As described herein, the pharmaceutically acceptable compositions of the present invention further comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle, as used herein, including any solvents, diluents, or other liquid excipients, dispersing or suspending agents, surfactants, isotonic agents, thickening agents, emulsifying agents, preservatives, solid binders or lubricants, and the like, suitable for the particular target dosage form. As described in the following documents: 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, in combination with the teachings of the present document, shows that different carriers can be used In the preparation of pharmaceutically acceptable compositions and their well-known methods of preparation. In addition to any conventional carrier vehicle that is incompatible with the co-crystals of the present invention or crystalline forms thereof, such as any adverse biological effects produced or interactions with any other component of the pharmaceutically acceptable composition in a deleterious manner, their use is also contemplated by the present invention.
Materials that can be used as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers; aluminum; aluminum stearate; lecithin; serum proteins, such as human serum proteins; buffer substances such as phosphates; glycine; sorbic acid; potassium sorbate; a partial glyceride mixture of saturated vegetable fatty acids; water; salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts; colloidal silicon; magnesium trisilicate; polyvinylpyrrolidone; polyacrylate; a wax; polyethylene-polyoxypropylene-block 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; a gum powder; malt; gelatin; talc powder; adjuvants such as cocoa butter and suppository waxes; oils such as peanut oil, cotton seed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycol compounds such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic salt; ringer's solution; ethanol; phosphate buffer solution; and other non-toxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate; a colorant; a release agent; coating the clothing material; a sweetener; a flavoring agent; a perfume; preservatives and antioxidants.
The pharmaceutical compositions of the present invention may be in the form of capsules, tablets, pills, powders, granules and aqueous suspensions or solutions; the administration may be by the following route: oral administration, injection, spray inhalation, topical administration, rectal administration, nasal administration, buccal administration, vaginal administration or administration via an implantable drug cassette.
Oral administration may be in the form of: tablets, pills, capsules, dispersible powders, granules or suspensions, syrups, elixirs and the like; administration by topical means may be by the following forms: ointments, gels, medicated plasters, and the like.
The co-crystals or crystalline forms thereof of the present invention are preferably formulated in dosage unit form to reduce the amount and uniformity of dosing. The term "dosage unit form" as used herein refers to physically discrete units of medicament for the patient for the appropriate treatment. However, it will be appreciated that the co-crystal of the compound of formula (I) of the present invention, or a crystalline form thereof, or the daily total use of the pharmaceutical composition of the present invention will be determined by the attending physician according to the sound judgment of the medical scope. The particular effective dosage level for any particular patient or organism will depend upon a number of factors including the condition being treated and the severity of the condition, the particular composition used, the age, weight, health, sex and dietary habits of the patient, the time of administration, the route of administration and rate of excretion of the co-crystal or crystalline form of the particular compound being used, the duration of the treatment, the application of the drug to a combination or combination with a salt or crystalline form of the particular compound, and other factors well known in the pharmaceutical arts.
The effective dose of the active ingredient used may vary with the co-crystal of the compound used or its crystalline form, the mode of administration and the severity of the condition to be treated. However, generally satisfactory results are obtained when the co-crystals of the compounds of the invention or crystalline forms thereof are administered daily at a dose of about 0.25-1000mg/kg animal body weight, preferably at 2-4 divided doses daily, or in a slow release form. This dosage regimen can be adjusted to provide the optimal therapeutic response. In addition, separate doses may be administered several times per day, or the doses may be proportionally reduced, depending on the condition being treated.
The co-crystals of the compounds of the present invention or crystalline forms thereof, the pharmaceutical compositions of the present invention may be used to inhibit the activity of acetyl-coa carboxylase, thereby modulating the stability and/or activity of acetyl-coa carboxylase. The co-crystals of the compounds or the pharmaceutical compositions may be used in methods of treating, pre-treating or delaying the onset or progression of acetyl-CoA carboxylase related disorders including, but not limited to, nonalcoholic steatohepatitis.
In particular, the co-crystals of the compounds of the present invention or crystalline forms thereof may be used to inhibit the activity of acetyl-coa carboxylase. The co-crystals of the compounds or crystalline forms thereof 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, liver steatosis, macrovesicular steatosis, advanced fibrosis or cirrhosis; the tumor comprises liver cancer, renal cancer, lung cancer, breast cancer, melanoma, papillary thyroid tumor, bile duct cancer, colon cancer, ovarian cancer, malignant lymphoma, bladder cancer, prostate cancer, pancreatic cancer, skin cancer or recurrent solid tumor.
Drawings
Fig. 1 is an X-ray powder diffraction (XRPD) pattern of crystalline form I of a co-crystal of a compound of formula (I) with piperazine.
FIG. 2 is a Differential Scanning Calorimeter (DSC) of crystalline form I of a co-crystal of a compound of formula (I) with piperazine.
Fig. 3 is a graph of thermogravimetric analysis (TGA) of crystalline form I of the co-crystal of the compound of formula (I) with piperazine.
General preparation and detection methods
The invention is further illustrated by way of examples which are not intended to limit the scope of the invention.
The X-ray powder diffraction analysis method used in the invention comprises the following steps: an Empyrean diffractometer was used to obtain X-ray powder diffraction patterns using Cu-K alpha radiation (45 KV,40 mA). The powdered sample was prepared as a thin layer on a monocrystalline silicon sample holder, placed on a rotating sample stage and analyzed in 0.0168 ° steps in the range of 3 ° -40 °. Data was collected using Data Collector software, highScore Plus software processed the Data, and Data Viewer software read the Data.
The Differential Scanning Calorimeter (DSC) analysis method used in the invention comprises the following steps: differential scanning calorimeter was performed using a TA Q2000 module with a thermal analysis controller. Data were collected and analyzed using TA Instruments Thermal Solutions software. About 1-5mg of the sample was accurately weighed into a specially made aluminum crucible with a lid, and sample analysis was performed from room temperature to about 300 ℃ using a linear heating device of 10 ℃/min. During use, the DSC cell was purged with dry nitrogen.
The thermal weight loss (TGA) analysis method used in the invention comprises the following steps: thermal weightlessness was performed using a TA Q500 module with a thermal analysis controller. Data were collected and analyzed using TA Instruments Thermal Solutions software. About 10mg of the sample was accurately weighed into a platinum sample pan and sample analysis was performed from room temperature to about 300 ℃ using a linear heating device at 10 ℃/min. During use, the TGA furnace chamber was purged with dry nitrogen.
Detailed description of the preferred embodiments
Specific synthetic methods for the compound 2- [1- [ (2R) -2- [ [ (3 ar,6 ar) -3,3a,4,5,6 a-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 of formula (I) refer to example 1 in international application WO2021000242 A1.
Examples
EXAMPLE 1 piperazine Co-crystals form I
1. Preparation of piperazine co-crystals of form I
The method comprises the following steps: 2- [1- [ (2R) -2- [ [ (3 aR,6 aR) -3,3a,4,5,6 a-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 at room temperature and dissolved overnight to precipitate more solid, suction filtered, the filter cake was washed with isopropyl ether (6.0 mL), suction was performed to near dryness, and vacuum dried at room temperature overnight to give a white solid powder (0.84 g, yield 72.6%).
The second method is as follows: 2- [1- [ (2R) -2- [ [ (3 aR,6 aR) -3,3a,4,5,6 a-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, ethyl acetate (3.0 mL) was supplemented, and the mixture was stirred at room temperature and dissolved overnight to precipitate a relatively large amount of solid, and the filter cake (5.0 mL) was washed with ethyl acetate, dried under vacuum at room temperature overnight to give a white solid (0.71 g, yield 61.6%).
2. Identification of form I of piperazine co-crystals
(1) Identified by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-ka radiation, there are the following characteristic peaks expressed in degrees 2θ: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 °, there is an error margin of ±0.2 °.
(2) Identification by TA Q2000 Differential Scanning Calorimeter (DSC) analysis: the scan rate was 10 ℃/min and the resulting DSC curve, shown in figure 2, contains an endothermic peak at 165.78 ℃ with a margin of error of ± 3 ℃.
(3) Identification by TA Q500 for Thermogravimetric (TGA) analysis: the ramp rate was 10 ℃/min and the resulting TGA profile, shown in figure 3, contained 0.4716% weight loss with a margin of error of + -0.1%.
EXAMPLE 2 pharmacokinetic experiments of the Co-crystals of the present invention
The eutectic filling capsule of the compound shown in the formula (I) is used for oral administration.
Taking 8-12kg male beagle dogs, 3 beagle dogs as a group, orally administering capsules filled with test samples at a dose of 5mg/kg, and taking blood at 0.25,0.5,1.0,2.0,4.0,6.0,8.0 and 24 hours. A standard curve of a suitable range is established according to the sample concentration, the concentration of the test sample in the plasma sample is determined in MRM mode using the AB SCIEX API4000 type LC-MS/MS, and quantitative analysis is performed. According to the drug concentration-time curve, the pharmacokinetic parameters were calculated using the WinNonLin 6.3 software non-compartmental model method. The experimental results are shown in table 1.
TABLE 1 pharmacokinetic data for the co-crystals of the present invention
Conclusion: the piperazine eutectic has higher exposure in beagle dogs and better pharmacokinetic property.
EXAMPLE 3 stability test of the Co-crystals of the present invention
(1)High temperature experiments: a batch of samples are taken and put into a flat weighing bottle, spread into thin layers with the thickness less than or equal to 3mm, respectively placed at the temperature of 60 ℃ and the temperature of 40 ℃ for 30 days, sampled at the 5 th, 10 th and 30 th days, observed for color change of the samples, detected for purity of the samples by HPLC and analyzed for structure by X-ray powder diffraction.
(2)High humidity experiment: putting a batch of samples into a flat weighing bottle, spreading into thin layers with the thickness less than or equal to 3mm, respectively placing for 30 days under the conditions of 25 ℃ 90% +/-5% RH and 25 ℃ 75% +/-5% RH, sampling on the 5 th, 10 th and 30 th days, observing the color change of the samples, detecting the purity of the samples by HPLC, and analyzing the structure by X-ray powder diffraction.
(3)Illumination experiment: placing a batch of test sample into flat weighing bottle, spreading into thin layer with thickness less than or equal to 3mm, placing into illumination box (with ultraviolet), and placing the sample into illumination box with illuminance of 4500+ -500 lx and ultraviolet light of more than or equal to 0.7w/m 2 The sample was left to stand for 30 days under the condition, sampled on days 5, 10 and 30, the color change of the sample was observed, the purity of the sample was checked by HPLC, and the structure was analyzed by X-ray powder diffraction.
(4)Long-term stability test: and (3) inspecting the sample, namely packaging the sample in a single-layer PE, packaging an aluminum foil bag, internally arranging a KD-20 deoxidizer, vacuumizing, filling nitrogen, and then thermally sealing the sample for a long time under the test condition of 5+/-3 ℃ at a low temperature, observing the color change of the sample, and detecting the purity of the sample by HPLC.
The experimental result shows that the piperazine eutectic is stable under the conditions of high temperature and high humidity; under the long-term stability test condition, the appearance, purity and water content of the piperazine eutectic are not obviously changed.
In conclusion, the piperazine eutectic crystal has good stability and is suitable for pharmaceutical use.
The above description is merely a basic description of the inventive concept, and any equivalent transformation according to the technical solution of the present invention shall fall within the protection scope of the present invention.
In the description of the present specification, a description referring to terms "one embodiment," "some embodiments," "examples," "specific examples," or "some examples," etc., means that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the present invention. In this specification, schematic representations of the above terms are not necessarily directed to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, the different embodiments or examples described in this specification and the features of the different embodiments or examples may be combined and combined by those skilled in the art without contradiction.
While embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and not to be construed as limiting the invention, and that variations, modifications, alternatives and variations may be made to the above embodiments by one of ordinary skill in the art within the scope of the invention.

Claims (10)

1. A eutectic of a compound shown in a formula (I) and piperazine, wherein the eutectic is a eutectic crystal form I,
2. the co-crystal of claim 1, wherein the X-ray powder diffraction pattern of 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 °.
3. The co-crystal of claim 1 or 2, wherein the X-ray powder diffraction pattern of co-crystal form I comprises diffraction peaks at the following 2Θ 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 ° and 26.47 ° ± 0.2 °.
4. A co-crystal according to any one of claims 1-3, characterized in that the X-ray powder diffraction pattern of co-crystal form I comprises diffraction peaks at the following 2Θ 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 °,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 ° ± 0.43 ° ± 0.24 ° ± 0.45 ° ± 0.24 °, and 4639.45 ° ± 0.43 ° ± 0.52 °, and 3924 ° ± 0.52 °, and 35 ° ± 0.52 °, 35.35 ° ± 0.52.52 °,38 ° ± 0.52.35 ° ± 0.52.52 °, and 38 ° ± 0.52.35 ° ± 0.2 °, 38.52.35 ° ± 0.45 ° ± 0.52.52.52 °, and/37.45 ° ± 0.52.45 ° ± 0.52.52.52 ° ± 0.52.52.52.52 ° ± and/37.45 ° ± 0.45.45 ° ± and/0.52.52.52.52.52 °.
5. The co-crystal of any one of claims 1-4, wherein the co-crystal form I has an X-ray powder diffraction pattern substantially as shown in figure 1.
6. The co-crystal of any one of claims 1-5, wherein the differential scanning calorimetry pattern of the co-crystal form I comprises an endothermic peak at 165.78 ℃ ± 3 ℃.
7. The co-crystal of any one of claims 1-6, wherein the co-crystal form I has a differential scanning calorimeter pattern substantially as shown in fig. 2.
8. A pharmaceutical composition comprising the co-crystal of any one of claims 1-7, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, or combination thereof.
9. Use of the co-crystal of any one of claims 1-7 or the pharmaceutical composition of claim 8 in the manufacture of a medicament for preventing, treating or alleviating a disease modulated by acetyl-coa carboxylase.
10. The use according to claim 9, wherein the diseases modulated by acetyl-coa carboxylase are metabolic diseases and tumors;
the metabolic disease includes insulin resistance, obesity, dyslipidemia, metabolic syndrome, type II diabetes, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, liver steatosis, bullous steatosis, advanced fibrosis or cirrhosis; the tumor comprises liver cancer, renal cancer, lung cancer, breast cancer, melanoma, papillary thyroid tumor, bile duct cancer, colon cancer, ovarian cancer, malignant lymphoma, bladder cancer, prostate cancer, pancreatic cancer, skin cancer or recurrent solid tumor.
CN202310582949.6A 2022-05-26 2023-05-23 Co-crystals of thienopyrimidines and uses thereof Pending CN117126175A (en)

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