CN118271330A - Amorphous form of tricyclic compound and use thereof - Google Patents
Amorphous form of tricyclic compound and use thereof Download PDFInfo
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- CN118271330A CN118271330A CN202311840803.3A CN202311840803A CN118271330A CN 118271330 A CN118271330 A CN 118271330A CN 202311840803 A CN202311840803 A CN 202311840803A CN 118271330 A CN118271330 A CN 118271330A
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- amorphous form
- amorphous
- liver
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Abstract
The present invention relates to an amorphous form of a tricyclic compound and its use. In particular, the invention relates to amorphous forms of 2- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy-10, 11-dihydrobenzo [6,7] oxazepin [3,2-b ] pyridine-7-carboxylic acid and pharmaceutical compositions comprising said amorphous forms, and further to their use in the manufacture of a medicament for the prevention, treatment or alleviation of FXR mediated diseases in a patient.
Description
Technical Field
The invention belongs to the technical field of medicines, relates to an amorphous tricyclic compound and application thereof, and in particular relates to an amorphous compound of 2- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy-10, 11-dihydrobenzo [6,7] oxazepin [3,2-b ] pyridine-7-carboxylic acid and a pharmaceutical composition containing the amorphous compound, and further relates to application thereof in preparing medicines for treating FXR-mediated diseases.
Background
The Farnesol X Receptor (FXR) is a member of the nuclear hormone receptor superfamily, expressed primarily in the liver, kidneys and intestines (Seol et al, mol. Endocrinol (1995), 9:72-85; forman et al, cell (1995), 81:687-693). It acts as a heterodimer with retinoic acid X receptor (RXR) and binds to a response element in the target gene promoter to regulate gene transcription. FXR-RXR heterodimers bind with highest affinity to an inverted repeat-1 (IR-1) response element, where the hexamer binding to the consensus receptor (consensus receptor) is separated by a nucleotide. FXR can be activated by bile acids (end products of cholesterol metabolism) (MAKISHIMA et al Science (1999), 284:1362-1365; parks et al Science (1999), 284:1365-1368; wang et al, moI.cell. (1999), 3:543-553), whereas bile acids are used to inhibit catabolism of cholesterol (Urizar et al, (2000) J.biol. Chem. 275:39313-393170).
FXR is a key regulator of cholesterol homeostasis, triglyceride synthesis, and adipogenesis (Crawley, expert Opinion Ther.patents (2010), 20:1047-1057). In addition to being useful as a target for the treatment of dyslipidemia, obesity, vitamin D related diseases, intestinal diseases, drug-induced side effects and hepatitis (Crawley, expertOpinion th et al patent (2010), 20:1047-1057), FXR can also be useful as a therapeutic target for hepatobiliary diseases, chronic hepatitis, nonalcoholic fatty liver (NAFLD), nonalcoholic steatohepatitis (NASH), cholestasis, liver fibrosis, cirrhosis, hepatitis B, metabolic diseases, lipid metabolism diseases, carbohydrate metabolism diseases, cardiovascular metabolism diseases, atherosclerosis, type II diabetes and diabetic complications (Frank G.Schaap et al, journal of MEDICINAL CHEMISTRY (2005), 48:5383-5402).
Patent applications WO 2016127924A1 and CN 105884758A disclose tricyclic compounds useful as modulators of FXR activity, and methods of preparing and using them, in particular example 3, namely compound 2- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy-10, 11-dihydrobenzo [6,7] oxazepin [3,2-b ] pyridine-7-carboxylic acid (compound of formula (I)).
It is well known in the art that drug polymorphism is a common phenomenon in drug development and is an important factor affecting drug quality. Different crystal forms of the same medicine may be obviously different in appearance, solubility, melting point, dissolution rate, bioavailability and the like, and also have different effects on the aspects of stability, bioavailability, curative effect and the like of the medicine. In order to better control the quality of the pharmaceutical, and to meet the requirements of formulation, production, transportation, storage, etc., it is necessary to study the crystal structure of the compound of formula (I) in order to find a crystal structure with good properties.
Disclosure of Invention
The present invention provides an amorphous form of a compound of formula (I). Specifically, the amorphous form of the compound shown in the formula (I) provided by the invention can obviously improve the stability, pharmacokinetics and other properties of the compound, so that the compound has better patentability.
In particular, the invention relates to the amorphous form of the compound represented by formula (I), and pharmaceutical compositions comprising said amorphous form, and to their use in the preparation of a medicament for preventing, treating or alleviating FXR mediated diseases in a patient.
In one aspect, the present invention provides an amorphous form of a compound of formula (I);
in some embodiments, the amorphous form of the compounds of formula (I) of the present invention have an X-ray powder diffraction pattern substantially as shown in figure 1.
In some embodiments, the amorphous differential scanning calorimetry pattern of the compound of formula (I) of the present invention comprises an exothermic peak at 126.07 ℃ ± 3 ℃ and an endothermic peak at 198.90 ℃ ± 3 ℃.
In some embodiments, the amorphous forms of the compounds of formula (I) of the present invention have a differential scanning calorimetry pattern substantially as shown in figure 2.
In some embodiments, the amorphous form of the compound of formula (I) of the present invention loses weight 0.6735% in the range of 70 ℃ to 160 ℃ with a margin of error of + -0.1% for the weight loss ratio.
In some embodiments, the amorphous forms of the compounds of formula (I) of the present invention have a thermogravimetric analysis profile substantially as shown in figure 3.
In one aspect, the present invention relates to a pharmaceutical composition comprising an amorphous form according to the present invention, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, or combination thereof.
In a further aspect, the invention also relates to the use of the amorphous form of the compound of formula (I) or of the pharmaceutical composition for the preparation of a medicament for the prevention, treatment or alleviation of FXR mediated diseases in a patient; further, the use comprises administering to a human or animal a therapeutically effective dose of the amorphous or the pharmaceutical composition of the invention.
In some embodiments, the FXR mediated disease described herein is cardiovascular and cerebrovascular disease, a disease associated with dyslipidemia, metabolic syndrome, hyperproliferative disease, fibrosis, inflammatory disease, or a disease associated with liver and gall.
In other embodiments, the cardiovascular and cerebrovascular diseases described herein are atherosclerosis, acute myocardial infarction, venous occlusive diseases, portal hypertension, pulmonary hypertension, heart failure, peripheral arterial occlusive diseases, sexual dysfunction, stroke, or thrombosis.
In other embodiments, the metabolic syndrome of the invention is insulin resistance, hyperglycemia, hyperinsulinemia, elevated levels of fatty acids or glycerol in the blood, hyperlipidemia, obesity, hypertriglyceridemia, hypercholesterolemia, syndrome X, diabetic complications, atherosclerosis, hypertension, acute anemia, neutropenia, dyslipidemia, type II diabetes, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, dyslipidemia, or a combination of diabetes and abnormally high body mass index.
In other embodiments, the hyperproliferative diseases described herein are hepatocellular carcinoma, colon adenoma, polyposis, colon adenocarcinoma, breast cancer, membranous adenocarcinoma, butcher's esophageal cancer, and other forms of gastrointestinal or liver neoplastic diseases.
In other embodiments, the fibrosis, inflammatory disease, or disease associated with liver and gall is non-alcoholic fatty liver, non-alcoholic steatohepatitis, cholestasis, liver fibrosis, primary biliary cirrhosis, primary sclerosing cholangitis, progressive familial cholestasis, cystic fibrosis, drug-induced biliary damage, gallstones, cirrhosis, hepatitis b, sebaceous gland disorders, alcohol-induced cirrhosis, biliary obstruction, cholelithiasis, colitis, neonatal Huang Zheng, scleroderma, or intestinal bacterial overgrowth.
In one aspect, the invention relates to a method for preventing, treating or alleviating FXR mediated diseases in a patient comprising administering to the patient an effective dose of an amorphous or pharmaceutically acceptable pharmaceutical composition according to the invention.
In another aspect, the present invention also relates to a process for the amorphous preparation of a compound of formula (I).
The solvent used in the amorphous production method of the present invention is not particularly limited, and any solvent which dissolves the starting materials to a certain extent 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.
The preparation of the amorphous form according to the invention will be described in detail in the examples section. Meanwhile, the invention provides the amorphous activity test experiment, such as a pharmacokinetics experiment, a stability experiment, a hygroscopicity experiment and the like. As shown by experimental results, compared with the prior art, the amorphous compound shown in the formula (I) has better biological activity and high stability, and is suitable for pharmaceutical use. Further research shows that the amorphous compound has better stability and other advantages compared with the crystal form of the compound shown as the formula (I) such as the crystal form II. In particular, the amorphous form of the present invention has more excellent drug substitution properties and higher stability, for example, the amorphous form has higher exposure and higher blood concentration.
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.
"Amorphous" or "amorphous form" refers to a substance that forms when particles (molecules, atoms, ions) of the substance are non-periodically arranged in three dimensions, characterized by a diffuse, non-spiking X-ray powder diffraction pattern. Amorphous is a special physical form of solid material whose locally ordered structural features suggest a myriad of interactions with crystalline material. Amorphous forms of a substance can be obtained by a number of methods known in the art. Such methods include, but are not limited to, quenching, antisolvent flocculation, ball milling, spray drying, freeze drying, wet granulation, and solid dispersion techniques, among others.
"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 amorphous form of the invention is characterized by an XRPD pattern having certain peak locations, substantially as shown in the XRPD pattern provided in the accompanying drawings 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 a technique that measures the energy difference between a sample and an inert reference (commonly used α -Al 2O3) as a function of temperature by continuously heating or cooling under program control. 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 amorphous 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.
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 the figures.
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 the amorphous form of 2- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy-10, 11-dihydrobenzo [6,7] oxazepin [3,2-b ] pyridine-7-carboxylic acid 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. Or for one of ordinary skill in the art, the term "about" or "approximately" means within an acceptable standard error of the average value. 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.
Amorphous pharmaceutical compositions, formulations, administration and uses of the compounds of the invention
The pharmaceutical compositions of the present invention are characterized by comprising an amorphous form of a compound of formula (I) or any combination thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amorphous amount of the compound in the pharmaceutical composition of the invention is effective to detectably treat or ameliorate FXR mediated diseases in a patient.
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. ：：In Remington:The Science and Practiceof 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,, as described in the following documents, taken together with the content of the documents herein, demonstrate that various carriers can be used in the preparation of pharmaceutically acceptable compositions and their known methods of preparation. In addition to any conventional carrier vehicle that is incompatible with the compounds of the present invention or their amorphous forms, 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.
The amorphous form according to the present invention may be homogeneously incorporated in a mixture as an active ingredient together with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may be in a wide variety of forms depending on the form of preparation required for administration, for example, orally or parenterally (including intravenously). When preparing compositions for oral dosage forms, any conventional pharmaceutical medium may be used, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the preparation of oral liquid medicaments such as suspensions, elixirs and solutions; or in the preparation of oral solid preparations such as powders, hard capsules, soft capsules and tablets, such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like, wherein solid oral preparations are more preferable than liquid preparations.
Because tablets and capsules are easy to take, they represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. If desired, the tablets may be coated with standard aqueous or non-aqueous techniques. Such compositions and formulations should contain at least 0.1 percent of the active ingredient. Of course, the percentage of active ingredient in these compositions may vary, and this percentage may conveniently vary from about 2% to about 60% per weight. The active ingredient may be administered intranasally, for example, in the form of droplets or a spray.
The tablets, pills, capsules, and the like may also comprise: binders (such as gum tragacanth, acacia, corn starch or gelatin); excipients (such as dicalcium phosphate); disintegrants (e.g., corn starch, potato starch, alginic acid); lubricants (such as magnesium stearate); and sweeteners (such as sucrose, lactose or saccharin). When the dosage unit form is a capsule, it may contain a liquid carrier (such as a fatty oil) in addition to materials of the type described above.
A wide variety of other materials may be present as coatings or to alter the shape of the dosage unit. For example, the tablets may be coated with shellac, sugar or both. In addition to the active ingredient, a syrup or elixir may contain sucrose as a sweetening agent, methyl or propylparaben as a preservative, a dye and a flavoring (e.g., cherry or orange flavored).
Ophthalmic preparations, ophthalmic ointments, powders, solutions, and the like are also included within the scope of the present invention.
The amorphous forms of the present invention may also be administered parenterally. Solutions or suspensions of these active materials can be prepared by appropriate mixing in water with a surfactant such as hydroxypropylcellulose. Dispersants may also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof, and in oils. Under conventional conditions of storage and use, these formulations contain a preservative to prevent the growth of microorganisms.
Pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the pharmaceutical form must be sterile and must be fluid in a form that is easy to inject. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier may be a solvent or dispersion medium containing, for example: water, ethanol, polyols (such as glycerol, propylene glycol and liquid polyethylene glycols), suitable mixtures thereof and vegetable oils.
Any suitable method of administration may be used to provide an effective dose of the amorphous forms of the invention to mammals, particularly humans. For example, oral, rectal, topical, parenteral, ocular, pulmonary, nasal, etc. methods of administration may be used. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, emulsions, ointments, aerosols, and the like. The amorphous form of the present invention is preferably administered orally.
The therapeutically effective dose of the amorphous, pharmaceutical composition or combination thereof of the present invention depends on the species, weight, age and individual condition of the individual, the disorder or disease to be treated or the severity thereof. A physician, clinician or veterinarian of ordinary skill can readily determine the effective amount of each of the active ingredients required to prevent, treat or inhibit the progression of the disorder or disease.
When the compound of the present invention or an amorphous form thereof is used for the treatment or prevention of the FXR mediated disorder described in the present invention, a substantially satisfactory effect is obtained when the compound of the present invention or an amorphous form thereof is administered in a daily dose of about 0.1 mg to about 100 mg per kg of animal body weight, preferably in a single daily dose, or in divided doses of 2 to 6 times per day, or in a continuous release form. For most large mammals, the total daily dose is from about 1.0 mg to about 1000 mg, preferably from about 1mg to about 50 mg. For an adult of 70 kg, the total daily dose is generally from 7 mg to about 350 mg. This dosage regimen can be adjusted to provide the best therapeutic effect.
The amorphous form or the pharmaceutical composition thereof according to the present invention can be effectively used for preventing, treating or alleviating FXR-mediated diseases in patients, and in particular, can be effectively used for treating nonalcoholic fatty liver (NAFLD), nonalcoholic steatohepatitis (NASH), obesity, hypertriglyceridemia, atherosclerosis, chronic intrahepatic cholestasis, primary Biliary Cirrhosis (PBC), primary Sclerosing Cholangitis (PSC), progressive familial cholestasis (PFIC), drug-induced bile duct injury, gallstones, liver cirrhosis, hepatitis b, sebaceous gland disease, alcohol-induced cirrhosis, cystic fibrosis, biliary tract obstruction, cholelithiasis, liver fibrosis, dyslipidemia, atherosclerosis, diabetes II, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, peripheral tissue arterial occlusive disease (PAOD), colitis, neonatal Huang Zheng, core yellow disease, venous occlusive disease, portal hypertension, metabolic syndrome, acute infarction, acute myocardial infarction, thrombosis, hypercholesterolemia, gastrointestinal tract thrombosis, excessive bacterial dysfunction, and neoplastic diseases of the liver, etc.
Drawings
FIG. 1 is an amorphous X-ray powder diffraction (XRPD) pattern of a compound of formula (I).
FIG. 2 is a Differential Scanning Calorimeter (DSC) of an amorphous form of a compound of formula (I).
FIG. 3 is a graph of an amorphous Thermogravimetric (TGA) analysis of a compound of formula (I).
Fig. 4 is an X-ray powder diffraction (XRPD) pattern of crystalline form I of the compound of formula (I).
FIG. 5 is an X-ray powder diffraction (XRPD) pattern of form II of the compound of formula (I)
Detailed Description
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, 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.
Examples
Unless otherwise indicated, compound 2- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy-10, 11-dihydrobenzo [6,7] oxazepin [3,2-b ] pyridine-7-carboxylic acid, i.e. a compound of formula (I), in the following examples was prepared by reference to the synthetic methods of example 3 in patent applications WO 201611927924 A1 and CN 105884758a, identified by Empyrean X-ray powder diffraction (XRPD) analysis, as form I, having an X-ray powder diffraction (XRPD) pattern substantially as shown in figure 4, as described in example 2 of the present invention.
EXAMPLE 1 amorphous form of the Compound of formula (I)
1. Amorphous preparation
The method comprises the following steps: compound 2- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy-10, 11-dihydrobenzo [6,7] oxazepin [3,2-b ] pyridine-7-carboxylic acid (3.0 g) was added to dichloromethane (40.0 mL), dissolved with stirring at room temperature, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was dried under vacuum at 60℃to give a white solid (3.0 g, yield 100.00%).
The second method is as follows: compound 2- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy-10, 11-dihydrobenzo [6,7] oxazepin [3,2-b ] pyridine-7-carboxylic acid (200.1 mg) was added to acetone (6.0 mL), stirred under reflux, the solid was completely dissolved, and incubated for 1 hour.
2. Amorphous characterization
(1) Identified by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-ka radiation, the X-ray powder diffraction pattern thereof is substantially as shown in figure 1.
(2) Identification by TA Q2000 Differential Scanning Calorimeter (DSC) analysis: the scanning rate was 10 c/min and the DSC profile obtained, as shown in figure 2, contained an exothermic peak at 126.07 c and an endothermic peak at 198.90 c, with a margin of error of ± 3 c.
(3) Identification by TA Q500 for Thermogravimetric (TGA) analysis: the temperature rise rate was 10 ℃/min and the TGA profile obtained was shown in fig. 3 with a weight loss range of 0.6735% and a margin of error of + -0.1%.
EXAMPLE 2 Crystal form I of Compound of formula (I)
1. Preparation of form I
Reference is made to the synthetic method of example 3 in patent applications WO 201611927924 A1 and CN 105884758 a.
2. Identification of form I
Identified by Empyrean X-ray powder diffraction (XRPD) analysis: cu-kα radiation was used. The X-ray powder diffraction pattern of the crystalline form I of the compound of formula (I) prepared in this example is shown in fig. 4.
EXAMPLE 3 form II of the Compound of formula (I)
1. Preparation of form II
Compound 2- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy-10, 11-dihydrobenzo [6,7] oxazepin [3,2-b ] pyridine-7-carboxylic acid (900.0 mg) was added to methyl acetate (22.0 mL), heated to reflux to complete dissolution of the solid, then cooled to room temperature, n-heptane (22.0 mL) was added, with solid precipitation.
2. Identification of form II
Identified by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-ka radiation, there is a margin of error of + -0.2 ° with the following characteristic peaks ：5.65°,9.63°,11.36°,11.84°,12.11°,12.71°,13.45°,14.69°,14.96°,16.42°,16.97°,17.18°,17.77°,18.26°,18.89°,19.30°,20.11°,20.77°,21.08°,21.31°,21.90°,22.81°,23.56°,24.31°,24.52°,25.29°,26.36°,26.67°,27.03°,27.69°,27.97°,28.33°,28.67°,29.11°,29.91°,30.29°,30.62°,31.54°,31.81°,32.35°,33.15°,33.79°,34.29°,35.10°,35.75°,36.64°,37.99°,38.82°,39.67°,40.78°,43.11°,43.90°,44.95°,45.90°,48.79°,51.65°,52.76° and 53.79 ° expressed in terms of angle 2θ.
EXAMPLE 4 amorphous pharmacokinetic experiments according to the invention
The experimental method comprises the following steps:
The amorphous or crystalline form of the compound of formula (I) according to the invention is filled into capsules for oral administration.
Taking 6 male Beagle dogs (8-12 kg), 3 in each group, orally administering capsules containing test samples at a dose of 9mg/kg, and collecting blood at time points 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 amorphous pharmacokinetic experimental data of the invention
| Sample for sample | Dosage (mg/kg) | AUClast(h*ng/ml) | Cmax(ng/ml) | Tmax(h) |
| Amorphous form | 9 | 3110 | 895 | 1.83 |
| Crystal form I | 9 | 404 | 93.6 | 2.0 |
Conclusion of experiment:
As can be seen from Table 1, the amorphous form of the invention has higher exposure and higher blood concentration in beagle than the prior art, and has better pharmacokinetic property.
Example 5 stability experiment
(1) High temperature experiment: and (3) placing a proper amount of sample in a flat weighing bottle, spreading the sample into a thin layer with the thickness of less than or equal to 5mm, standing for 30 days at the temperature of 60+/-2 ℃, sampling at the 0 th, 5 th, 10 th and 30 th days, detecting according to stability key investigation projects, observing the color change of the sample, and detecting the purity of the sample by HPLC.
(2) High humidity experiment: and (3) placing a proper amount of sample in a flat weighing bottle, spreading the sample into a thin layer with the thickness of less than or equal to 5mm, standing for 30 days under the conditions of 25 ℃ and RH 90+/-5%, sampling on days 0, 5, 10 and 30, detecting according to stability key investigation projects, observing the color change of the sample, and detecting the purity of the sample by HPLC.
(3) Illumination test: the visible light illuminance is 4500 lx+/-500 lx, the ultraviolet light energy is not lower than 0.7W.h/m 2, the sample is taken at 0, 5, 10, 15 and 30 days and detected according to stability key investigation projects, the color change of the sample is observed, and the purity of the sample is detected by HPLC.
Experimental results show that the amorphous form provided by the invention has good stability under various lofting conditions, 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. An amorphous form of a compound of formula (I), wherein the amorphous form has an X-ray powder diffraction pattern substantially as shown in figure 1;
2. The amorphous form of claim 1, wherein the amorphous differential scanning calorimetry trace comprises an exothermic peak at 126.07 ℃ ± 3 ℃ and an endothermic peak at 198.90 ℃ ± 3 ℃.
3. An amorphous form according to claim 1 or 2, characterized in that the amorphous form has substantially a differential scanning calorimeter as shown in fig. 2.
4. A pharmaceutical composition comprising the amorphous form of any one of claims 1-3, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, or combination thereof.
5. Use of the amorphous form of any one of claims 1-3 or the pharmaceutical composition of claim 4 for the manufacture of a medicament for preventing, treating or alleviating FXR mediated disease in a patient.
6. The use according to claim 5, wherein the FXR mediated disease is cardiovascular and cerebrovascular disease, dyslipidemia related disease, metabolic syndrome, hyperproliferative disease, fibrosis, inflammatory disease or liver and gall related disease.
7. The use according to claim 6, wherein the cardiovascular and cerebrovascular disease is atherosclerosis, acute myocardial infarction, venous occlusive disease, portal hypertension, pulmonary hypertension, heart failure, peripheral arterial occlusive disease, sexual dysfunction, stroke or thrombosis.
8. The use according to claim 6, wherein the metabolic syndrome is insulin resistance, hyperglycemia, hyperinsulinemia, elevated levels of fatty acids or glycerol in the blood, hyperlipidemia, obesity, hypertriglyceridemia, hypercholesterolemia, syndrome X, diabetic complications, atherosclerosis, hypertension, acute anemia, neutropenia, dyslipidemia, type II diabetes, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, dyslipidemia, or a combination of diabetes and abnormally high body mass index.
9. The use according to claim 6, wherein the hyperproliferative diseases are hepatocellular carcinoma, colon adenoma, polyposis, colon adenocarcinoma, breast cancer, membranous adenocarcinoma, butcher's esophageal cancer and other forms of gastrointestinal or liver neoplastic diseases.
10. The use according to claim 6, wherein the fibrosis, inflammatory disease or disease associated with liver and gallbladder is non-alcoholic fatty liver, non-alcoholic steatohepatitis, cholestasis, liver fibrosis, primary biliary cirrhosis, primary sclerosing cholangitis, progressive familial cholestasis, cystic fibrosis, drug-induced biliary damage, gallstones, cirrhosis, hepatitis b, sebaceous gland disorders, alcohol-induced cirrhosis, biliary obstruction, cholelithiasis, colitis, neonatal Huang Zheng, scleroderma or overgrowth of intestinal bacteria.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2022117216313 | 2022-12-30 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN118271330A true CN118271330A (en) | 2024-07-02 |
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