CN110577534B - Salts of benzoylaminopyridine derivatives and their use in medicine - Google Patents
Salts of benzoylaminopyridine derivatives and their use in medicine Download PDFInfo
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- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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- A—HUMAN NECESSITIES
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/235—Saturated compounds containing more than one carboxyl group
- C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
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- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Abstract
The invention relates to a salt of a benzoylaminopyridine derivative and an application thereof in medicines, and further relates to a pharmaceutical composition containing the salt or crystal form or a combination thereof, and an application of the salt or crystal form or the pharmaceutical composition in preparation of medicines for preventing, treating or relieving diseases regulated by ASK1 of patients.
Description
Technical Field
The invention belongs to the field of medicines, relates to salts of benzoylaminopyridine derivatives and application thereof in medicines, and particularly relates to citrate of 5- (4-cyclopropyl-1H-imidazole-1-yl) -N- (6- (6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazole-3-yl) pyridine-2-yl) -2-fluoro-4-methylbenzamide and application thereof in medicines, and further relates to a crystal form of the citrate and a pharmaceutical composition containing the citrate. The salt or the pharmaceutical composition is used for preventing, treating or alleviating a disease in a patient regulated by ASK 1.
Background
Apoptosis signal-regulating kinase 1 (ASK 1) is one of the members of the mitogen-activated protein kinase kinase kinase (MAP 3Ks) family, also known as mitogen-activated protein kinase kinase kinase kinase kinase 5(mitogen-activated protein kinase kinase 5, MAPKK 5, MAP3K5), and comprises 1375 amino acid residues constituting 11 kinase sub-domains and a serine/threonine kinase region located in the middle of the molecule flanking the N-terminal and C-terminal coiled coil regions (Wa. J.biol. chem.1996,271, 31607-31611; Ichijo et al. science.1997,275, 90-94; Tobium et al. Biochem.Biophys. Res. 905, Commun.239, 910). ASK1 can be activated by a variety of stimuli, such as: oxidative stress, active oxygen, endotoxin, tumor necrosis factor-alpha, endoplasmic reticulum stress, intracellular calcium ion concentration, and the like.
ASK1 has been shown to not only regulate cell death, but also play an important role in cellular activities such as cytokine responses, cell differentiation, innate immune responses, and the like. Modulating the activity of ASK1 can treat or prevent a variety of diseases including neurodegenerative diseases, cardiovascular diseases, inflammation, autoimmune diseases, and metabolic disorders. ASK1 modulators have great potential, especially in the treatment of cardiorenal diseases (including kidney disease, diabetic nephropathy and chronic kidney disease), fibrotic diseases (including pulmonary fibrosis and renal fibrosis), respiratory diseases (including chronic obstructive pulmonary obstruction and acute lung injury) and liver diseases.
Data indicate that liver disease has now become one of the leading causes of human death. Liver diseases are generally classified into acute and chronic liver diseases according to the duration of the disease. Liver disease may be caused by infection, injury, medication, poisoning, drinking, poor food intake, abnormal accumulation of normal components in the blood, autoimmunity, genetic defects, or other unknown factors. Common liver diseases include chronic liver disease, metabolic liver disease, hepatic fibrosis, primary sclerosing cholangitis, non-alcoholic fatty liver, non-alcoholic steatohepatitis, hepatic ischemia-reperfusion injury, primary biliary cirrhosis, and the like.
Patent application WO 2018133866 discloses pyridine derivatives useful as ASK1 inhibitors, and a preparation method and use thereof, wherein compound WX001, i.e., compound 5- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -2-fluoro-4-methylbenzamide (compound represented by formula (I)), is specifically disclosed. Patent application WO2019034096 discloses a fused bicyclic compound and application thereof in medicine, wherein example 2 specifically discloses 5- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -2-fluoro-4-methylbenzamide (a compound shown in formula (I)) and a preparation method thereof. However, none of these patent applications disclose the crystal structure of the compound, nor the pharmaceutically acceptable salts thereof and the crystal forms of said salts.
Drug polymorphism is also a common phenomenon in drug development and is an important factor affecting drug quality. Different crystal forms of the same drug may be significantly different in appearance, solubility, melting point, dissolution rate, bioavailability and the like, and also have different influences on the stability, bioavailability, curative effect and the like of the drug. Therefore, the choice of the salt of the drug and the problem of polymorphism should be considered comprehensively in drug development.
Disclosure of Invention
The invention provides a salt of a compound shown in a formula (I) and a pharmaceutical composition thereof, wherein the salt or the pharmaceutical composition has better biological activity (for example, good pharmacokinetic property), and obviously improved properties such as stability and the like, so that the salt or the pharmaceutical composition has better pharmaceutical performance. Salts of the present invention include amorphous, crystalline, partially crystalline, polymorphic, and solvate forms thereof. The invention further provides crystal forms of salts of the compound shown in the formula (I) and compositions thereof, and application of the crystal forms and the compositions in preparation of medicines for treating diseases or symptoms related to ASK1 regulation.
In particular, the invention relates to citrate of a compound shown as a formula (I) and a pharmaceutical composition thereof, and application of the citrate or the pharmaceutical composition in preparing a medicament for preventing, treating or relieving ASK 1-modulated diseases of a patient. The citrate salt of the present invention may also be in the form of a solvate, for example a hydrate.
In one aspect, the invention provides a salt of a compound of formula (I),
in some embodiments, the salt of the present invention is an organic acid salt of a compound of formula (I).
In some embodiments, the organic acid salts described herein are formate, acetate, propionate, butyrate, benzoate, malonate, succinate, pyruvate, ethanesulfonate, propanesulfonate, citrate, 4-nitrobenzoate, benzenesulfonate, p-toluenesulfonate, L-malate, methanesulfonate, propiolate, 2-butynoate, vinylacetate, L-tartrate, fumarate, lactate, lactobionate, pamoate, salicylate, galactarate, glucoheptonate, mandelate, 1, 2-ethyldisulfonate, naphthalenesulfonate, beta-naphthalenesulfonate, oxalate, maleate, tartrate, trifluoroacetate, triflate, adipate, suberate, sebacate, butyn-1, 4-dioate, hexyne-1, 6-dioate, glycolate, alginate, ascorbate, isoascorbate, aspartate, glutamate, 2-phenoxybenzoate, 2- (4-hydroxybenzoyl) benzoate, acetoacetate, 2-hydroxyethanesulfonate, borate, chlorobenzoate, camphorate, itaconate, levocamphorsulfonate, methylbenzoate, dinitrobenzoate, sulfamate, lactobionate, galacturonate, cyclopentylpropionate, dodecylsulfate, acrylate, cyclopentanepropionate, glycerophosphate, methoxybenzoate, digluconate, gluconate, heptanoate, hexanoate, pivalate, glucuronate, laurate, phthalate, acetate, or salt, or a mixture of a, Lauryl sulfate, 2-acetoxybenzoate, nicotinate, cinnamate, oleate, palmitate, embonate, pectate, phthalate, glutarate, hydroxymaleate, hydroxybenzoate, phenylacetate, 3-hydroxy-2-naphthoate, 3-phenylpropionate, isobutyrate, pivalate, picrate, stearate, 2-dichloroacetate, acylated amino acid salt, alginate, 4-acetamidobenzenesulfonate, decanoate, cholate, octanoate, nonanoate, cyclamate, phthalate, cysteine hydrochloride, sorbate, pamoate, mucate, glycinate hydrochloride, napadisylate, xylenesulfonate, cystine dihydrochloride, undecanoate, polyvinyl sulfonate, sulfosalicylate, phenylbutyrate, 4-hydroxybutyrate, polyvinyl sulfate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, valerate, or any combination thereof.
In some embodiments, the organic acid salt of the present invention is a citrate salt of a compound of formula (I).
In some embodiments, the salt of the invention is form I citrate of the compound of formula (I), wherein form I citrate has an X-ray powder diffraction pattern with diffraction peaks at one or more of the following 2 Θ angles: 9.35 ° ± 0.2 °,10.86 ° ± 0.2 °,19.16 ° ± 0.2 °,24.87 ° ± 0.2 °,27.44 ° ± 0.2 °.
In some embodiments, the salt of the invention is form I citrate of the compound of formula (I), wherein form I citrate has an X-ray powder diffraction pattern with diffraction peaks at one or more of the following 2 Θ angles: 9.35 ° ± 0.2 °,10.86 ° ± 0.2 °,14.66 ° ± 0.2 °,16.61 ° ± 0.2 °,17.35 ° ± 0.2 °,19.16 ° ± 0.2 °,23.63 ° ± 0.2 °,24.87 ° ± 0.2 °,25.56 ° ± 0.2 °,27.44 ° ± 0.2 °.
In some embodiments, the salt of the invention is form I citrate of the compound of formula (I), wherein form I citrate has an X-ray powder diffraction pattern with diffraction peaks at one or more of the following 2 Θ angles: 5.20 ° ± 0.2 °,8.72 ° ± 0.2 °,9.35 ° ± 0.2 °,10.43 ° ± 0.2 °,10.86 ° ± 0.2 °,11.84 ° ± 0.2 °,12.50 ° ± 0.2 °,13.62 ° ± 0.2 °,14.66 ° ± 0.2 °,15.24 ° ± 0.2 °,15.62 ° ± 0.2 °,16.40 ° ± 0.2 °,16.61 ° ± 0.2 °,17.35 ° ± 0.2 °,18.25 ° ± 0.2 °,18.78 ° ± 0.2 °,19.16 ° ± 0.2 °,19.54 ° ± 0.20 ° ± 0.2 °,24 ° ± 0.2 °,21.31 ° ± 0.2 °,21.80 ° ± 0.2 °,22.70 ° ± 0.23.12 ° ± 0.2 ° ± 0.2.2 °, 0.2 ° ± 0.2.3 ° ± 0.2 °, 0.2.2 ° ± 0.2 °, 2.3 ° ± 0.2 °, 2.2.2 °,2 ° ± 0.3 ° ± 0.2 °,2 °, 2.2 °, 2.26 ° ± 0.2.2.2 °,2 °, 2.2 °,2 ° ± 0.2.3 ° ± 0.2.2.2 °,2 °, 2.2 °, 2.2.2 °, 2.2.3 ° ± 0.2 °,2 °, 2.2 °,2 °, 2.2.2 °,2 °, 2.2 °, 2.3 ° ± 0.3 ° ± 0.2.2.2 °,2 °, 2.3 ° ± 0.2.3 ° ± 0.2 °,2 °, 2.2.2 °,2 °, 2.3 ° ± 0.2 °,2 °, 2.2.3 ° ± 0.3 ° ± 0.2.2 °,2 °, 2.2.2.2.2 °,2 °, 2.3 ° ± 0.2 °,2 °, 2.2.2 °,2 °, 2.2 °,2 ° ± 0.3 ° ± 0.2 ° ± 0.3 ° ± 0.2 °,2 °, 2.2.2.2.2 °, 2.2.3 ° ± 0.2 °,2 °, 2.2 °,2 °, 2.3 ° ± 0.2.2.3 ° ± 0.3 ° ± 0.2 °,2 °, 2.2.3 ° ± 0.2 °,2 °, 2.3 ° ± 0.2.3 ° ± 0.2.2.2.3 ° ± 0.3 ° ± 0.2.2 °,2 °, 2.3 ° ± 0.3 ° ± 0.2.3 ° ± 0.2.2.2 °,2 °,3 ° ± 0.2.2.2.2.2 °,3 ° ± 0.2 °,2 °, 2.2.2 °,3 ° ± 0.2 °, 0.3 ° ± 0.2 °,2 °, 0.2.2.3 ° ± 0.3 ° ± 0.2.3 ° ± 0.3 ° ± 0.2.2 °,3 ° ± 0.2 °,3 °,36.13 ° ± 0.2 °,37.42 ° ± 0.2 °,37.74 ° ± 0.2 °,38.28 ° ± 0.2 °,38.81 ° ± 0.2 °,39.26 ° ± 0.2 °,39.56 ° ± 0.2 °,41.60 ° ± 0.2 °,43.47 ° ± 0.2 °,44.05 ° ± 0.2 °,46.32 ° ± 0.2 °,46.90 ° ± 0.2 °,48.01 ° ± 0.2 °,48.33 ° ± 0.2 °,50.03 ° ± 0.2 °,50.74 ° ± 0.2 °,52.02 ° ± 0.2 °,53.64 ° ± 0.2 °,54.86 ° ± 0.2 °.
In some embodiments, the salt of the invention is form I citrate of the compound of formula (I), wherein form I citrate has an X-ray powder diffraction pattern substantially as shown in figure 1.
In some embodiments, the salt of the invention is an amorphous citrate salt of a compound of formula (I), wherein the amorphous citrate salt has an X-ray powder diffraction pattern substantially as shown in figure 2.
In some embodiments, the salt of the invention is form I citrate of the compound of formula (I), wherein the differential scanning calorimetry trace of form I citrate comprises an endothermic peak at 172.02 ℃ ± 3 ℃.
In some embodiments, the salt of the invention is form I citrate of the compound of formula (I), wherein form I citrate has a differential scanning calorimetry trace substantially as shown in figure 3.
In one aspect, the invention also provides a pharmaceutical composition comprising a citrate salt as described herein, or a combination thereof, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, or combination thereof.
In another aspect, the invention also relates to the use of the citrate salt of the compound of formula (I) or the pharmaceutical composition for the manufacture of a medicament for the prevention, treatment or alleviation of a disease or a disorder modulated by ASK1 in a patient; further, the use comprises administering a therapeutically effective amount of the crystalline form of the invention or the pharmaceutical composition to a human or animal.
In some embodiments, the disorder modulated by ASK1 according to the invention is an autoimmune disorder, inflammation, cardiovascular disorder, cardiorenal disorder, fibrotic disorder, respiratory disorder, liver disorder or neurodegenerative disorder.
In other embodiments, the cardiovascular disease of the invention includes diabetes, diabetic nephropathy, or other diabetic complications.
In other embodiments, the fibrotic disease according to the invention comprises pulmonary fibrosis or renal fibrosis.
In other embodiments, the respiratory disease described herein comprises chronic embolic lung obstruction, idiopathic pulmonary fibrosis, or acute lung injury.
In other embodiments, the liver disease according to the present invention comprises chronic liver disease, metabolic liver disease, liver fibrosis, primary sclerosing cholangitis, non-alcoholic fatty liver, non-alcoholic steatohepatitis, hepatic ischemia-reperfusion injury, or primary biliary cirrhosis.
In one aspect, the invention relates to a method of preventing, treating or ameliorating a disorder modulated by ASK1 in a subject, comprising administering to the subject an effective amount of a salt according to the invention or a pharmaceutically acceptable composition thereof.
In another aspect, the invention relates to the use of the citrate salt of the compound of formula (I) or the pharmaceutical composition for preventing, treating or alleviating ASK1 mediated diseases in a patient.
In another aspect, the invention also relates to a preparation method of the citrate of the compound shown in the formula (I) and a crystal form thereof.
The solvent used in the preparation method of the salt and the crystal form thereof according to the present invention is not particularly limited, and any solvent capable of dissolving the starting materials to an extent that does not affect the properties thereof is included in the present invention. Further, many equivalents, substitutions, or equivalents in the art to which this invention pertains, as well as different proportions of solvents, solvent combinations, and solvent combinations described herein, are deemed to be encompassed by the present invention. The invention provides a preferable solvent used in each reaction step.
The experiments for the preparation of the salts and their crystalline forms according to the invention are described in detail in the examples section. Meanwhile, the invention provides an activity test experiment (such as a pharmacokinetic experiment), a solubility experiment, a stability experiment, a hygroscopicity experiment and the like of the salt and the crystal form thereof. The experimental results show that the salt and the crystal form of the compound shown in the formula (I) have good biological activity, good solubility and high stability, and are suitable for pharmaceutical application.
Wherein, the description of the hygroscopicity characteristics and the definition of the hygroscopicity increase (the four-part appendix 9103 medicament hygroscopicity test guiding principle of the Chinese pharmacopoeia 2015 year edition, the experimental conditions are 25 ℃ plus or minus 1 ℃ and 80 percent plus or minus 2 percent relative humidity) are shown in the following table:
characterization of hygroscopicity and definition of hygroscopicity increase
The crystal form is not easy to deliquesce under the influence of high humidity, and is convenient for long-term storage and placement of the medicine.
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.
By "citrate salt of a compound of formula (I)" is meant a salt of a compound of formula (I) of the present invention with citric acid, including amorphous, crystalline, solvate, hydrate, and also including polymorphic forms of the salt.
"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 compounds. Crystalline forms of the substance can be obtained by a number of methods known in the art. Such methods include, but are not limited to, melt crystallization, melt cooling, solvent crystallization, crystallization in a defined space, e.g., in a nanopore or capillary, on a surface or template, e.g., on a polymer, in the presence of an additive such as a co-crystallizing counter molecule, desolventization, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, reactive crystallization, anti-solvent addition, milling, and solvent drop milling, among others.
"amorphous" or "amorphous form" refers to a substance formed when particles (molecules, atoms, ions) of the substance are aperiodically arranged in three-dimensional space, and is characterized by a diffuse, non-peaked, X-ray powder diffraction pattern. Amorphous is a particular physical form of solid material, with locally ordered structural features suggesting a myriad of connections to crystalline materials. 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, anti-solvent 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, t-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.
By "anti-solvent" is meant a fluid that facilitates precipitation of the product (or product precursor) from the solvent. The anti-solvent 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" refers to a compound having a solvent on a surface, in a crystal lattice, or on and in a crystal lattice, which may 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 on the surface and in the crystal lattice is water. The hydrates may or may not have other solvents than water on the surface of the substance, in the crystal lattice or both.
Crystalline forms or amorphous forms can be identified by a variety of techniques, such as X-ray powder diffraction (XRPD), infrared absorption spectroscopy (IR), melting point methods, Differential Scanning Calorimetry (DSC), thermogravimetric analysis (TGA), nuclear magnetic resonance methods, raman spectroscopy, X-ray single crystal diffraction, dissolution calorimetry, Scanning Electron Microscopy (SEM), quantitative analysis, solubility and dissolution rate, and the like.
Information such as change, crystallinity, crystal structure state and the like of the crystal form can be detected by X-ray powder diffraction (XRPD), and the method is a common means for identifying the crystal form. The peak positions of the XRPD patterns depend primarily on the structure of the crystalline form, being relatively insensitive to experimental details, while their relative peak heights depend on a number of factors related to sample preparation and instrument geometry. Accordingly, in some embodiments, the crystalline form of the present invention is characterized by an XRPD pattern having certain peak positions, substantially as shown in the XRPD patterns provided in the figures of the present invention. Also, the 2 θ measurement of the XRPD pattern may have experimental error, and the 2 θ measurement of the XRPD pattern may be slightly different from instrument to instrument and from sample to sample, so the 2 θ value cannot be considered absolute. The diffraction peaks have a tolerance of ± 0.2 ° according to the conditions of the instrument used in the test.
Differential Scanning Calorimetry (DSC) is to measure the temperature of a sample and an inert reference substance (usually alpha-Al) by continuously heating or cooling under the control of a program2O3) The energy difference therebetween varies with temperature. The endothermic peak height of the DSC curve depends on many factors related to sample preparation and instrument geometry, while the peak position is relatively insensitive to experimental details. Thus, in some embodiments, the crystalline form of the present invention is characterized by a DSC profile with characteristic peak positions substantially as shown in the DSC profiles provided in the figures of the present invention. Meanwhile, the DSC profile may have experimental errors, and the peak position and peak value of the DSC profile may slightly differ between different instruments and different samples, so the peak position or peak value of the DSC endothermic peak cannot be regarded as absolute. The endothermic peaks have a tolerance of ± 3 ° depending on the condition of the instrument used in the test.
Thermogravimetric analysis (TGA) is a technique for measuring the change in mass of a substance with temperature under program control, and is suitable for examining the loss of a solvent in a crystal or the sublimation and decomposition of a sample, and it can be presumed that the crystal contains crystal water or a crystal solvent. The change in mass shown by the TGA profile depends on many factors such as sample preparation and instrumentation; the mass change of the TGA detection varies slightly from instrument to instrument and from sample to sample. The amorphous form described herein is characterized by a weight loss range of 1.75% to 4.10% as measured by TGA. There is a tolerance of + -0.1% for mass change depending on the condition of the instrument used in the test.
In the context of the present invention, the 2 θ values in the X-ray powder diffraction pattern are all in degrees (°).
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 the figure.
When referring to a spectrogram or/and data appearing in a graph, "peak" refers to a feature that one skilled in the art would recognize as not being attributable to background noise.
The invention relates to various salts of 5- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -2-fluoro-4-methylbenzamide (compound shown in formula (I)) and crystal forms thereof, which exist in a basically pure crystal form or an amorphous form.
By "substantially pure" is meant that a crystalline form is substantially free of one or more additional crystalline forms, i.e., 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% pure, or the crystalline form contains additional crystalline forms, the percentage of which in the total volume or weight of the crystalline form is less than 20%, or less than 10%, or less than 5%, or less than 3%, or less than 1%, or less than 0.5%, or less than 0.1%, or less than 0.01%.
By "substantially free" is meant that the percentage of one or more other crystalline forms in the total volume or weight of the crystalline form is less than 20%, or less than 10%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1%, or less than 0.5%, or less than 0.1%, or less than 0.01%.
"relative intensity" (or "relative peak height") in an XRPD pattern refers to the ratio of the intensity of the first strong peak to the intensity of the other peaks when the intensity of the first strong peak is 100% of all the diffraction peaks in an X-ray powder diffraction pattern (XRPD).
In the context of the present invention, the word "about" or "approximately" when used or whether used, means within 10%, suitably within 5%, and especially within 1% of a given value or range. Alternatively, the term "about" or "approximately" means within an acceptable standard error of the mean, for one of ordinary skill in the art. Whenever a number is disclosed with 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% is explicitly disclosed, wherein "+/-" means plus or minus.
"room temperature" in the present invention means a temperature of from about 10 ℃ to about 40 ℃. In some embodiments, "room temperature" refers to a temperature of from about 20 ℃ to about 30 ℃; in other embodiments, "room temperature" refers to 20 ℃, 22.5 ℃,25 ℃, 27.5 ℃, and the like.
Pharmaceutical compositions, formulations, administration and uses of the crystalline forms of the invention
The pharmaceutical composition of the invention is characterized by comprising salts of the compound shown in the formula (I) and crystal forms thereof or any combination thereof and pharmaceutically acceptable carriers, auxiliary agents or excipients. The amount of the salt of the compound and its crystalline forms in the pharmaceutical composition of the present invention is effective to detectably treat or alleviate ASK1 mediated diseases in a patient.
As described herein, the pharmaceutically acceptable compositions of the present invention further comprise a pharmaceutically acceptable carrier, adjuvant, or excipient, as used herein, including any solvent, diluent, or other liquid excipient, dispersant or suspending agent, surfactant, isotonic agent, thickening agent, emulsifier, preservative, solid binder or lubricant, and the like, as appropriate 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. Annu 1999, Marcel Dekker, New York, taken together with The disclosure of this document, indicates that different carriers can be used In The preparation of pharmaceutically acceptable compositions and their well known methods of preparation. Except insofar as any conventional carrier vehicle is incompatible with the salts of the compounds of the invention, e.g., any adverse biological effects that result or interaction in a deleterious manner with any other component of a pharmaceutically acceptable composition, their use is contemplated by the present invention.
Materials that can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers; aluminum; aluminum stearate; lecithin; serum proteins, such as human serum albumin; buffer substances such as 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; polyvinylpyrrolidone; polyacrylate esters; a wax; polyethylene-polyoxypropylene-blocking polymers; lanolin; sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; gum powder; malt; gelatin; talc powder; adjuvants 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; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic salt; ringer's solution; ethanol; phosphoric acid buffer solution; and other non-toxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate; a colorant; a release agent; coating the coating material; a sweetener; a flavoring agent; a fragrance; preservatives and antioxidants.
The salts of the present invention may be incorporated as the active ingredient in a homogeneous mixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous). When preparing compositions for oral dosage form, any conventional pharmaceutical media may be used, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the preparation of oral liquid preparations such as suspensions, elixirs and solutions; or in the preparation of oral solid preparations such as powders, hard capsules, soft capsules and tablets using, for example, starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like.
The pharmaceutical composition of the present invention may be administered orally, by injection, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implantable kit. Can be made into capsule, tablet, pill, powder, granule, and aqueous suspension or solution.
Oral administration may be in the form of: tablets, pills, capsules, dispersible powders, granules or suspensions, syrups, and elixirs, or for topical administration: ointments, gels, medicated plasters, etc., or parenterally in the form of sterile injectable solutions or suspensions.
The pharmaceutical compositions of the present invention may also be administered parenterally or intraperitoneally. Solutions or suspensions of the acid addition salts of the compounds of formula (I) may also be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose, polyvinylpyrrolidone. Dispersions can also be prepared in glycerol, liquids, polyethylene glycols and mixtures thereof in oils. Under normal conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
Pharmaceutical forms suitable for injection include: sterile aqueous solutions or dispersions and sterile powders (for the extemporaneous preparation of sterile injectable solutions or dispersions). In all cases, these forms must be sterile and must be fluid to facilitate the syringe to expel the fluid. Must be stable under the conditions of manufacture and storage and must be resistant to the contaminating effects of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, alcohols (for example, glycerol, propylene glycol and liquid polyethylene glycols), suitable mixtures thereof and vegetable oils.
Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. If desired, the tablets may be coated using standard aqueous or non-aqueous techniques. Such compositions and preparations should contain at least 0.1 percent of active ingredient. Of course, the percentage of active ingredient in these compositions may vary, and may conveniently vary from about 2% to about 60% of the weight of the unit. The active ingredient may be administered intranasally, for example, in the form of droplets or a spray.
The tablets, pills, capsules, etc. may also comprise: binders (such as gum tragacanth, acacia, corn starch or gelatin); excipients (such as dicalcium phosphate); disintegrating agents (such as corn starch, potato starch, alginic acid); lubricants (such as magnesium stearate); and a sweetening agent (such as sucrose, lactose or saccharin). When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.
A wide variety of other materials may be present as coatings or to modify the shape of the dosage unit. For example, tablets may be coated with shellac, sugar or both. A syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl or propylparabens as preservatives, a dye and flavoring (e.g., cherry or orange flavor).
Also included within the scope of the present invention are ophthalmic formulations, ophthalmic ointments, powders, solutions, and the like.
The therapeutically effective dose of the crystalline form, the pharmaceutical composition or the combination thereof of the present invention depends on the species, the weight, the age and the 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 active ingredient required to prevent, treat or inhibit the progression of the disorder or disease.
When the salts of the compounds of the present invention and crystalline forms thereof are used to treat or prevent conditions modulated by ASK1 as described herein, substantially satisfactory results are obtained when the compounds of the present invention or crystalline forms thereof are administered in daily doses of from about 0.1 mg to about 100 mg per kg of animal body weight, preferably in single daily doses, or in divided doses from 2 to 6 times per day, or in continuous release form. For most large mammals, the total daily dosage is from about 1.0 mg to about 1000 mg, preferably from about 1mg to about 50 mg. For a 70 kg adult, the total daily dose is typically from 7 mg to about 350 mg. This dosage regimen can be adjusted to provide the best therapeutic effect.
The salt, the crystal form or the pharmaceutical composition thereof can be effectively used for preventing, treating or relieving the ASK 1-regulated diseases of patients, and particularly can be effectively used for treating diabetes, diabetic nephropathy, other diabetic complications, chronic nephropathy, lung and kidney fibrosis, chronic embolic lung obstruction, idiopathic pulmonary fibrosis, acute lung injury, chronic liver disease, metabolic liver disease, hepatic fibrosis, primary sclerosing cholangitis, non-alcoholic fatty liver, non-alcoholic steatohepatitis, hepatic ischemia-reperfusion injury, primary biliary cirrhosis, other hepatitis and the like.
Drawings
Figure 1 is an X-ray powder diffraction (XRPD) pattern of form I of the citrate salt of the compound of formula (I).
FIG. 2 is an X-ray powder diffraction (XRPD) pattern of the amorphous citrate salt of the compound of formula (I).
Figure 3 is a Differential Scanning Calorimetry (DSC) profile of the citrate form I of the compound of formula (I).
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention.
The X-ray powder diffraction analysis method used by the invention comprises the following steps: an Empyrean diffractometer, using Cu-Ka radiation (45KV,40mA) to obtain an X-ray powder diffraction pattern. The powdered sample was prepared as a thin layer on a single crystal silicon sample holder, placed on a rotating sample stage and analyzed in 0.0167 ° steps over a range of 3 ° -60 °. Data Collector software was used to collect Data, High Score Plus software was used to process Data, and Data Viewer software was used to read Data.
The Differential Scanning Calorimetry (DSC) analysis method used in the invention comprises the following steps: differential scanning calorimetry was performed using a TA Q2000 module with a thermoanalytical 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 the sample analysis was performed from room temperature to about 300 c using a 10 c/min linear heating device. During use, the DSC cell was purged with dry nitrogen.
Detailed description of the invention
A specific synthesis method of the compound 5- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -2-fluoro-4-methylbenzamide shown in the formula (I) refers to example 2 in patent application WO 2019034096.
Example 1 citrate form I
1. Preparation of citrate form I
The compound 5- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -2-fluoro-4-methylbenzamide (51mg, 0.116mmol) was added to acetone (1.0mL), slurried at 60 ℃ for 1 hour, then a solution of citric acid (24.2mg, 0.126mmol) in acetone (1.0mL) was added and reacted for 7 hours; suction filtered and the filter cake was dried under vacuum at room temperature overnight to give a white solid (73.2mg, 99.6%).
2. Identification of citrate form I
(1) Identified by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-ka radiation, having the following characteristic peaks expressed in degrees 2 θ: 5.20 °,8.72 °,9.35 °,10.43 °,10.86 °,11.84 °,12.50 °,13.62 °,14.66 °,15.24 °,15.62 °,16.40 °,16.61 °,17.35 °,18.25 °,18.78 °,19.16 °,19.54 °,20.11 °,20.98 °,21.31 °,21.80 °,22.70 °,23.12 °,23.63 °,24.03 °,24.87 °,25.14 °,25.56 °,25.97 °,26.33 °,26.64 °,27.07 °,27.44 °,28.36 °,28.60 °,29.32 °,30.00 °,30.88 °,32.63 °,33.05 °,33.93 °,34.76 °,37.42 °,37.74 °,38.28 °,38.81 °,39.26 °,39.56 °,41.60 °, 43.47. 43.47 °, 3646.90 °, 33.7.35.13 °,37.42 °, 3550.74 °, 3550 ° and 3650.35 ± 25.33.33.33.33.68 ° of the error tolerance of ± 0.35 ° 3650.33.33.33.33.33 °,3 ° of 3650.
(2) Identification by TA Q2000 Differential Scanning Calorimetry (DSC) analysis: the scan rate was 10 ℃/min, contained an endotherm peak at 172.02 ℃, with a margin of error of ± 3 ℃.
Example 2 citrate amorphous form
1. Preparation of amorphous citrate salt
The compound 5- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -2-fluoro-4-methylbenzamide (51.8mg, 0.117mmol) was added to dichloromethane (1.0mL) at room temperature and dissolved with stirring, followed by addition of citric acid (28.5mg, 0.148mmol) in acetone (1.0mL) for about 7 hours; suction filtration and drying of the filter cake under vacuum at room temperature overnight gave amorphous citrate (56.8mg, 76.5%).
2. Identification of citrate amorphous form
Identified by Empyrean X-ray powder diffraction (XRPD) analysis: the results of the experiment using Cu-ka radiation are shown in fig. 2.
EXAMPLE 3 pharmacokinetic experiments on the salts of the invention
8-12kg of male Beagle dogs were divided into 2 groups of 3 dogs, and capsules containing test samples were orally administered at a dose of 5mg/kg by collecting blood at time points of 0.25,0.5,1.0,2.0,4.0,6.0,9.0 and 24 hours. A standard curve of the appropriate range is established based on the sample concentration, and the concentration of the test sample in the plasma sample is determined in MRM mode using LC-MS/MS model AB SCIEX API4000 and subjected to quantitative analysis. Pharmacokinetic parameters were calculated according to the drug concentration-time curve using the WinNonLin 6.3 software non-compartmental model method. See table 1 for details.
TABLE 1 PK parameters for citrate form I
And (4) experimental conclusion:
as can be seen from Table 1, the citrate salts of the present invention all have superior pharmacokinetic properties. In particular, the citrate crystal form I has higher exposure and blood concentration.
Example 4 stability test of salts according to the invention
(1)High temperature experiment: putting a proper amount of a sample to be tested into a flat weighing bottle, spreading the sample into a thin layer with the thickness of less than or equal to 5mm, standing the thin layer at the temperature of 60 ℃ for 10 days, sampling the sample at the 5 th and 10 th days, observing the color change of the sample, and detecting the purity of the sample by HPLC.
(2)High humidity experiment: taking a proper amount of a batch of test samples, putting the test samples into a flat weighing bottle, spreading the test samples into a thin layer with the thickness of less than or equal to 5mm, standing the test samples for 10 days at the temperature of 25 ℃ and the RH of 90 +/-5 percent, sampling the test samples for 5 and 10 days, observing the color change of the samples, and detecting the purity of the samples by HPLC.
And (4) experimental conclusion:
under the conditions of high temperature (60 ℃) and high humidity (25 ℃, RH 90% +/-5%), the salt has no obvious change in appearance and purity, has good stability effect, and is suitable for pharmaceutical application.
EXAMPLE 5 hygroscopicity test of the salts according to the invention
Taking a proper amount of a sample, and testing the hygroscopicity of the sample by using a dynamic moisture adsorption instrument. The experimental results prove that the salt is not easy to deliquesce under the influence of high humidity.
The above description is only a basic description of the present invention, and any equivalent changes made according to the technical solution of the present invention should fall within the protection scope of the present invention.
In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., mean 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 invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer 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, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.
Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.
Claims (10)
1. A salt of a compound of formula (I),
wherein the salt is citrate crystal form I, characterized in that the X-ray powder diffraction pattern of the citrate crystal form I has diffraction peaks at the following 2 theta angles: 9.35 ° ± 0.2 °,10.86 ° ± 0.2 °,19.16 ° ± 0.2 °,24.87 ° ± 0.2 °,27.44 ° ± 0.2 °.
2. The salt of claim 1, wherein the salt is form I citrate, wherein the form I citrate has an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 9.35 ° ± 0.2 °,10.86 ° ± 0.2 °,14.66 ° ± 0.2 °,16.61 ° ± 0.2 °,17.35 ° ± 0.2 °,19.16 ° ± 0.2 °,23.63 ° ± 0.2 °,24.87 ° ± 0.2 °,25.56 ° ± 0.2 °,27.44 ° ± 0.2 °.
3. The crystalline form of claim 1 or 2, wherein the salt is form I citrate, characterized in that the form I citrate has an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 5.20 ° ± 0.2 °,8.72 ° ± 0.2 °,9.35 ° ± 0.2 °,10.43 ° ± 0.2 °,10.86 ° ± 0.2 °,11.84 ° ± 0.2 °,12.50 ° ± 0.2 °,13.62 ° ± 0.2 °,14.66 ° ± 0.2 °,15.24 ° ± 0.2 °,15.62 ° ± 0.2 °,16.40 ° ± 0.2 °,16.61 ° ± 0.2 °,17.35 ° ± 0.2 °,18.25 ° ± 0.2 °,18.78 ° ± 0.2 °,19.16 ° ± 0.2 °,19.54 ° ± 0.20 ° ± 0.2 °,24 ° ± 0.2 °,21.31 ° ± 0.2 °,21.80 ° ± 0.2 °,22.70 ° ± 0.23.12 ° ± 0.2 ° ± 0.2.2 °, 0.2 ° ± 0.2.3 ° ± 0.2 °, 0.2.2 ° ± 0.2 °, 2.3 ° ± 0.2 °, 2.2.2 °,2 ° ± 0.3 ° ± 0.2 °,2 °, 2.2 °, 2.26 ° ± 0.2.2.2 °,2 °, 2.2 °,2 ° ± 0.2.3 ° ± 0.2.2.2 °,2 °, 2.2 °, 2.2.2 °, 2.2.3 ° ± 0.2 °,2 °, 2.2 °,2 °, 2.2.2 °,2 °, 2.2 °, 2.3 ° ± 0.3 ° ± 0.2.2.2 °,2 °, 2.3 ° ± 0.2.3 °,36.13 ° ± 0.2 °,37.42 ° ± 0.2 °,37.74 ° ± 0.2 °,38.28 ° ± 0.2 °,38.81 ° ± 0.2 °,39.26 ° ± 0.2 °,39.56 ° ± 0.2 °,41.60 ° ± 0.2 °,43.47 ° ± 0.2 °,44.05 ° ± 0.2 °,46.32 ° ± 0.2 °,46.90 ° ± 0.2 °,48.01 ° ± 0.2 °,48.33 ° ± 0.2 °,50.03 ° ± 0.2 °,50.74 ° ± 0.2 °,52.02 ° ± 0.2 °,53.64 ° ± 0.2 °,54.86 ° ± 0.2 °.
4. The crystalline form of claim 1, wherein the salt is form I citrate, characterized in that the form I citrate has an X-ray powder diffraction pattern substantially as shown in figure 1.
5. A salt of a compound of formula (I),
wherein the salt is citrate form I, characterized in that the differential scanning calorimetry trace of citrate form I comprises an endothermic peak at 172.02 ℃ ± 3 ℃.
6. The salt of claim 5, wherein the salt is citrate form I, wherein the citrate form I has a differential scanning calorimetry pattern substantially as shown in figure 3.
7. A pharmaceutical composition comprising a salt of any one of claims 1-6, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, or combination thereof.
8. Use of a salt according to any one of claims 1 to 6 or a pharmaceutical composition according to claim 7 in the manufacture of a medicament for the prevention, treatment or alleviation of a disease or a disorder modulated by ASK1 in a patient.
9. The use according to claim 8, wherein the disorder modulated by ASK1 is an autoimmune disorder, inflammation, cardiovascular disorder, cardiorenal disorder, fibrotic disorder, respiratory disorder, hepatic disorder or neurodegenerative disorder.
10. The use according to claim 9, wherein the cardiovascular disease is diabetes, diabetic nephropathy or other diabetic complications;
the fibrotic disease is pulmonary fibrosis or renal fibrosis;
the respiratory disease is chronic embolic lung obstruction, idiopathic pulmonary fibrosis or acute lung injury;
the liver disease is chronic liver disease, metabolic liver disease, hepatic fibrosis, primary sclerosing cholangitis, non-alcoholic fatty liver, non-alcoholic steatohepatitis, hepatic ischemia-reperfusion injury or primary biliary cirrhosis.
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| CN110577541B (en) * | 2019-07-16 | 2021-07-23 | 广州安岩仁医药科技有限公司 | Salts of benzoylaminopyridine derivatives and their use in medicine |
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| CN110577537B (en) * | 2019-07-16 | 2021-07-23 | 广州安岩仁医药科技有限公司 | Salts of benzoylaminopyridine derivatives and their use in medicine |
| CN110577538B (en) * | 2019-07-16 | 2021-07-23 | 广州安岩仁医药科技有限公司 | Salts of benzoylaminopyridine derivatives and their use in medicine |
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| CN110577536A (en) * | 2019-07-16 | 2019-12-17 | 广州安岩仁医药科技有限公司 | Salts of benzoylaminopyridine derivatives and their use in medicine |
| CN110577533A (en) * | 2019-07-16 | 2019-12-17 | 广州安岩仁医药科技有限公司 | Salts of benzoylaminopyridine derivatives and their use in medicine |
| CN110577535A (en) * | 2019-07-16 | 2019-12-17 | 广州安岩仁医药科技有限公司 | Salts of benzoylaminopyridine derivatives and their use in medicine |
| CN110577537A (en) * | 2019-07-16 | 2019-12-17 | 广州安岩仁医药科技有限公司 | Salts of benzoylaminopyridine derivatives and their use in medicine |
| CN110577541A (en) * | 2019-07-16 | 2019-12-17 | 广州安岩仁医药科技有限公司 | Salts of benzoylaminopyridine derivatives and their use in medicine |
| CN110577539A (en) * | 2019-07-16 | 2019-12-17 | 广州安岩仁医药科技有限公司 | Salts of benzoylaminopyridine derivatives and their use in medicine |
| CN110577538A (en) * | 2019-07-16 | 2019-12-17 | 广州安岩仁医药科技有限公司 | Salts of benzoylaminopyridine derivatives and their use in medicine |
| CN110577540A (en) * | 2019-07-16 | 2019-12-17 | 广州安岩仁医药科技有限公司 | Salts of benzoylaminopyridine derivatives and their use in medicine |
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