WO2021213486A1 - 二氢萘啶类化合物的晶型及其用途 - Google Patents

二氢萘啶类化合物的晶型及其用途 Download PDF

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WO2021213486A1
WO2021213486A1 PCT/CN2021/089149 CN2021089149W WO2021213486A1 WO 2021213486 A1 WO2021213486 A1 WO 2021213486A1 CN 2021089149 W CN2021089149 W CN 2021089149W WO 2021213486 A1 WO2021213486 A1 WO 2021213486A1
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crystal form
present
ray powder
powder diffraction
pharmaceutical composition
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PCT/CN2021/089149
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English (en)
French (fr)
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宗乔
阳传文
陈亮
左应林
王晓军
张英勋
陈小舟
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东莞市东阳光新药研发有限公司
广东东阳光药业有限公司
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Publication of WO2021213486A1 publication Critical patent/WO2021213486A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the invention belongs to the technical field of medicine, and relates to the crystal form of dihydronaphthyridine compounds and their uses, and specifically to 4-(4-cyano-2-methoxyphenyl)-5-cyclobutyloxy-2,
  • the stereoisomer of 8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide and its crystal form and use thereof further relate to a pharmaceutical composition containing the crystal form.
  • MR Mineralocorticoid Receptor
  • aldosterone is a nuclear hormone receptor activated by aldosterone, which regulates the expression of many genes involved in electrolyte homeostasis and cardiovascular diseases.
  • the increase in circulating aldosterone increases blood pressure through its effect on urinary sodium excretion, while potentially affecting the brain, heart, and vascular system.
  • hyperaldosteronism is related to many physiological processes that lead to kidney and cardiovascular diseases. Although hyperaldosteronism is usually caused by aldosterone-producing adenomas, patients with refractory hypertension often have elevated aldosterone levels, commonly referred to as "aldosterone escape", which is due to serum potassium Due to increased content or residual AT1R activity.
  • MR antagonists can be effective antihypertensive agents and can also be effective in the treatment of heart failure and primary aldosterone disease.
  • MR antagonists have also been shown to be effective in preclinical models of kidney disease, and can be combined with standard therapies to reduce proteinuria in patients with kidney disease, such as chronic kidney disease, including diabetic nephropathy.
  • WO 2019223629 A1 discloses a dihydropyrimidine compound, wherein the compound has mineralocorticoid receptor (MR) antagonism and can be used to treat and prevent hyperaldosteronism, diabetic nephropathy, and hypertension , Heart failure (including chronic heart failure, etc.), sequelae of myocardial infarction, liver cirrhosis, renal failure, stroke and other diseases.
  • MR mineralocorticoid receptor
  • the patent application discloses the compound 4-(4-cyano-2-methoxyphenyl)-5-cyclobutyloxy-2,8-dimethyl-1,4-dihydro-1 ,6-Naphthyridine-3-carboxamide (the compound represented by formula (Ia)) and its stereoisomers, but there is no research and report on the compound or its stereo configuration crystal form in the prior art.
  • Drug polymorphism is a common phenomenon in drug development and an important factor affecting drug quality. Different crystal forms of the same drug may have significant differences in appearance, solubility, melting point, dissolution, bioavailability, etc., and also have different effects on drug stability, bioavailability, and efficacy. Therefore, in drug research and development, the issue of drug polymorphism should be fully considered.
  • Prior art WO 2019223629 A1 discloses a compound represented by formula (Ia) and a preparation method thereof, as well as its stereoisomers, that is, the compound represented by formula (I) according to the present invention.
  • the present invention provides a method for preparing the stereoisomer, and at the same time provides the crystal form or amorphous form of the stereoisomer, wherein the crystal form, especially the crystal form I, can significantly improve the stability of the compound. Properties such as pharmacokinetics and pharmacokinetics, which have better drug-making properties.
  • the present invention relates to the compound represented by formula (I) and its crystal form or amorphous form, and the crystal form or amorphous form of the compound or a pharmaceutical composition containing the crystal form or amorphous form for use as a mineralocorticoid
  • the crystal form of the present invention may also be in the form of a solvate, such as a hydrate form.
  • the present invention provides a compound represented by formula (I):
  • the present invention provides a crystal form of the compound represented by formula (I),
  • the crystal form of the compound represented by formula (I) according to the present invention is crystal form I, crystal form II or crystal form III.
  • the crystal form I of the present invention is characterized in that the X-ray powder diffraction pattern of the crystal form I has diffraction peaks at the following 2 ⁇ angles: 6.70° ⁇ 0.2°, 7.29° ⁇ 0.2° , 11.18° ⁇ 0.2°, 19.04° ⁇ 0.2°, 27.27° ⁇ 0.2°.
  • the crystal form I of the present invention is characterized in that the X-ray powder diffraction pattern of the crystal form I has diffraction peaks at the following 2 ⁇ angles: 6.70° ⁇ 0.2°, 7.29° ⁇ 0.2 °, 8.07° ⁇ 0.2°, 11.18° ⁇ 0.2°, 16.16° ⁇ 0.2°, 19.04° ⁇ 0.2°, 21.50° ⁇ 0.2°, 22.03° ⁇ 0.2°, 22.70° ⁇ 0.2°, 27.27° ⁇ 0.2°.
  • the crystal form I of the present invention is characterized in that the X-ray powder diffraction pattern of the crystal form I has diffraction peaks at the following 2 ⁇ angles: 5.69° ⁇ 0.2°, 6.70° ⁇ 0.2 °, 7.29° ⁇ 0.2°, 8.07° ⁇ 0.2°, 11.18° ⁇ 0.2°, 16.16° ⁇ 0.2°, 19.04° ⁇ 0.2°, 21.50° ⁇ 0.2°, 22.03° ⁇ 0.2°, 22.70° ⁇ 0.2°, 27.27° ⁇ 0.2°.
  • the crystal form I of the present invention is characterized in that the X-ray powder diffraction pattern of the crystal form I has diffraction peaks at the following 2 ⁇ angles: 5.69° ⁇ 0.2°, 6.70° ⁇ 0.2 °, 7.29° ⁇ 0.2°, 8.07° ⁇ 0.2°, 11.18° ⁇ 0.2°, 11.67° ⁇ 0.2°, 12.73° ⁇ 0.2°, 13.34° ⁇ 0.2°, 14.48° ⁇ 0.2°, 14.78° ⁇ 0.2°, 15.68° ⁇ 0.2°, 16.16° ⁇ 0.2°, 16.95° ⁇ 0.2°, 17.40° ⁇ 0.2°, 17.93° ⁇ 0.2°, 18.40° ⁇ 0.2°, 19.04° ⁇ 0.2°, 19.24° ⁇ 0.2°, 19.64° ⁇ 0.2°, 19.99° ⁇ 0.2°, 20.19° ⁇ 0.2°, 21.13° ⁇ 0.2°, 21.50° ⁇ 0.2°, 22.03° ⁇ 0.2°, 22.70° ⁇ 0.2°, 23.34° ⁇ 0.2°, 23.73° ⁇ 0.2 °, 24.27° ⁇ 0.2°,
  • the crystal form I of the present invention is characterized in that the X-ray powder diffraction pattern of the crystal form I has diffraction peaks at the following 2 ⁇ angles: 5.69° ⁇ 0.2°, 6.70° ⁇ 0.2 °, 7.29° ⁇ 0.2°, 8.07° ⁇ 0.2°, 11.18° ⁇ 0.2°, 11.67° ⁇ 0.2°, 12.73° ⁇ 0.2°, 13.34° ⁇ 0.2°, 14.48° ⁇ 0.2°, 14.78° ⁇ 0.2°, 15.68° ⁇ 0.2°, 16.16° ⁇ 0.2°, 16.95° ⁇ 0.2°, 17.40° ⁇ 0.2°, 17.93° ⁇ 0.2°, 18.40° ⁇ 0.2°, 19.04° ⁇ 0.2°, 19.24° ⁇ 0.2°, 19.64° ⁇ 0.2°, 19.99° ⁇ 0.2°, 20.19° ⁇ 0.2°, 21.13° ⁇ 0.2°, 21.50° ⁇ 0.2°, 22.03° ⁇ 0.2°, 22.70° ⁇ 0.2°, 23.34° ⁇ 0.2°, 23.73° ⁇ 0.2 °, 24.27° ⁇ 0.2°,
  • the crystal form I of the present invention is characterized in that the crystal form I has an X-ray powder diffraction pattern substantially as shown in FIG. 1.
  • the crystalline form I of the present invention is characterized in that the differential scanning calorimetry of the crystalline form I includes an endothermic peak at 251.88°C ⁇ 3°C.
  • the crystal form I of the present invention is characterized in that the crystal form I has a differential scanning calorimeter substantially as shown in FIG. 2.
  • the crystal form II of the present invention is characterized in that the X-ray powder diffraction pattern of the crystal form II has diffraction peaks at the following 2 ⁇ angles: 11.55°, 12.72°, 18.77°, 21.91° , 23.80°, wherein the diffraction peak has an error tolerance of ⁇ 0.2°.
  • the crystal form II of the present invention is characterized in that the X-ray powder diffraction pattern of the crystal form II has diffraction peaks at the following 2 ⁇ angles: 11.55°, 11.74°, 12.72°, 14.93° , 17.89°, 18.77°, 21.52°, 21.91°, 22.20°, 23.80°, wherein the diffraction peak has an error tolerance of ⁇ 0.2°.
  • the crystal form II of the present invention is characterized in that the X-ray powder diffraction pattern of the crystal form II has diffraction peaks at the following 2 ⁇ angles: 7.25°, 9.82°, 10.64°, 11.17° , 11.55°, 11.74°, 12.72°, 14.35°, 14.93°, 15.31°, 15.67°, 17.89°, 18.77°, 19.11°, 19.71°, 20.98°, 21.33°, 21.52°, 21.91°, 22.20°, 22.97 °, 23.55°, 23.80°, 24.07°, 24.32°, 24.77°, 25.56°, 25.80°, 26.27°, 26.89°, 27.37°, 27.88°, 28.10°, 28.27°, 28.55°, 28.79°, 29.21°, 30.06°, 30.41°, 30.66°, 30.86°, 31.39°, 31.70°, 32.03°,
  • the crystal form II of the present invention is characterized in that the X-ray powder diffraction pattern of the crystal form II has diffraction peaks at the following 2 ⁇ angles: 7.25°, 9.82°, 10.64°, 11.17° , 11.55°, 11.74°, 12.72°, 14.35°, 14.93°, 15.31°, 15.67°, 17.89°, 18.77°, 19.11°, 19.71°, 20.98°, 21.33°, 21.52°, 21.91°, 22.20°, 22.97 °, 23.55°, 23.80°, 24.07°, 24.32°, 24.77°, 25.56°, 25.80°, 26.27°, 26.89°, 27.37°, 27.88°, 28.10°, 28.27°, 28.55°, 28.79°, 29.21°, 30.06°, 30.41°, 30.66°, 30.86°, 31.39°, 31.70°, 32.03°,
  • the crystal form II of the present invention is characterized in that the crystal form II has an X-ray powder diffraction pattern substantially as shown in FIG. 3.
  • the crystalline form II of the present invention is characterized in that the differential scanning calorimetry of the crystalline form II includes endothermic peaks of 125.00°C ⁇ 3°C and 255.60°C ⁇ 3°C.
  • the crystal form II of the present invention is characterized in that the crystal form II has a differential scanning calorimeter substantially as shown in FIG. 4.
  • the crystal form III of the present invention is characterized in that the X-ray powder diffraction pattern of the crystal form III has diffraction peaks at the following 2 ⁇ angles: 8.54°, 14.34°, 20.16°, 20.70° , 21.95°, wherein the diffraction peak has an error tolerance of ⁇ 0.2°.
  • the crystal form III of the present invention is characterized in that the X-ray powder diffraction pattern of the crystal form III has diffraction peaks at the following 2 ⁇ angles: 8.54°, 11.82°, 14.34°, 16.23° , 20.16°, 20.46°, 20.70°, 21.15°, 21.95°, 26.39°, wherein the diffraction peak has an error tolerance of ⁇ 0.2°.
  • the crystal form III of the present invention is characterized in that the X-ray powder diffraction pattern of the crystal form III has diffraction peaks at the following 2 ⁇ angles: 7.88°, 8.54°, 11.82°, 12.71° , 14.34°, 14.83°, 15.79°, 16.23°, 16.94°, 19.32°, 20.16°, 20.46°, 20.70°, 21.15°, 21.32°, 21.74°, 21.95°, 22.38°, 22.80°, 23.64°, 24.42 °, 24.83°, 25.75°, 26.39°, 26.91°, 27.56°, 27.95°, 29.52°, 29.76°, 30.14°, 30.41°, 31.21°, 31.80°, 32.86°, 33.63°, 34.08°, 34.64°, 35.09°, 36.20°, 36.63°, 37.05°, 37.28°, 39.98°,
  • the crystal form III of the present invention is characterized in that the crystal form III has an X-ray powder diffraction pattern substantially as shown in FIG. 5.
  • the crystalline form III of the present invention is characterized in that the differential scanning calorimetry of the crystalline form III includes endothermic peaks of 119.04°C ⁇ 3°C and 255.59°C ⁇ 3°C.
  • the crystal form III of the present invention is characterized in that the crystal form III has a differential scanning calorimeter substantially as shown in FIG. 6.
  • the present invention provides an amorphous form of the compound represented by formula (I),
  • the amorphous shape has an X-ray powder diffraction pattern substantially as shown in FIG. 7.
  • the present invention relates to a pharmaceutical composition, which comprises the compound represented by formula (I) of the present invention or its crystal form I, crystal form II, crystal form III, amorphous or a combination thereof, and a pharmaceutical composition.
  • the pharmaceutical composition of the present invention further comprises one or more other active ingredients selected from ACE inhibitors, renin inhibitors, angiotensin II receptor antagonists Agents, ⁇ -receptor blockers, acetylsalicylic acid, diuretics, calcium antagonists, statins, digitalis derivatives, calcium sensitizers, nitrates and antithrombotic agents.
  • active ingredients selected from ACE inhibitors, renin inhibitors, angiotensin II receptor antagonists Agents, ⁇ -receptor blockers, acetylsalicylic acid, diuretics, calcium antagonists, statins, digitalis derivatives, calcium sensitizers, nitrates and antithrombotic agents.
  • the present invention relates to the use of the compound represented by formula (I) or its crystal form I, crystal form II, crystal form III or amorphous or the pharmaceutical composition in the preparation of medicines, wherein the The drug is used to treat, prevent or alleviate the following diseases in patients: diabetic nephropathy, hyperaldosteronism, hypertension, heart failure, sequelae of myocardial infarction, liver cirrhosis, renal failure or stroke.
  • the present invention relates to the use of the compound represented by formula (I) or its crystal form I, crystal form II, crystal form III or amorphous or the pharmaceutical composition in the preparation of medicines, wherein The drug is used as a mineralocorticoid receptor antagonist.
  • One aspect of the present invention relates to a method for preventing, treating or alleviating a disease in a patient, wherein the disease is diabetic nephropathy, hyperaldosteronism, hypertension, heart failure, sequelae of myocardial infarction, liver cirrhosis, renal failure or stroke;
  • the method includes using the compound represented by formula (I) of the present invention or any crystalline form or the amorphous form or the pharmaceutical composition in a pharmaceutically acceptable effective dose to the patient.
  • the present invention also relates to a method for preparing the compound represented by formula (I) or its crystal form or amorphous form.
  • the solvent used in the preparation method of the compound represented by formula (I) or its crystalline form or amorphous form of the present invention is not particularly limited. Any solvent that can dissolve the starting material to a certain extent and does not affect its properties is included in In the present invention. In addition, many similar modifications, equivalent substitutions, or different ratios of solvents, solvent combinations, and solvent combinations described in the present invention are all deemed to be included in the scope of the present invention.
  • the present invention provides preferable solvents used in each reaction step.
  • the preparation experiment of the compound represented by formula (I) or its crystalline form or amorphous form of the present invention will be described in detail in the example section.
  • the present invention provides an activity test experiment (such as a pharmacokinetic experiment), solubility experiment, stability experiment, moisture absorption experiment, etc. of the crystal form.
  • an activity test experiment such as a pharmacokinetic experiment
  • solubility experiment such as a solubility experiment
  • stability experiment such as a pharmacokinetic experiment
  • moisture absorption experiment etc.
  • the crystal form I of the present invention is not susceptible to deliquescent due to high humidity, which is convenient for long-term storage and placement of drugs.
  • Crystal form or “crystalline form” refers to a solid with a highly regular chemical structure, including, but not limited to, single-component or multi-component crystals, and/or compound polymorphs, solvates, hydrates, Inclusion compounds, co-crystals, salts, salt solvates, and salt hydrates.
  • the crystalline form of the substance can be obtained by many methods known in the art.
  • Such methods include, but are not limited to, melt crystallization, melt cooling, solvent crystallization, crystallization in a defined space, for example, in nanopores or capillaries, crystallization on a surface or template, for example, on polymers, Crystallization, solvent removal, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, reactive crystallization, anti-solvent addition, grinding and solvent drop grinding in the presence of additives such as co-crystal anti-molecules.
  • Solvent refers to a substance (typically a liquid) that can completely or partially dissolve another substance (typically a solid).
  • Solvents used in the practice of the present invention include, but are not limited to, water, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, dichloromethane, dimethyl sulfoxide, 1,4-dioxane, ethanol , Ethyl acetate, butanol, tert-butanol, N,N-dimethylacetamide, N,N-dimethylformamide, formamide, formic acid, heptane, hexane, isopropanol, methanol, Methyl ethyl ketone, mesitylene, nitromethane, polyethylene glycol, propanol, pyridine, tetrahydrofuran, toluene, xylene, their mixtures, etc.
  • Solvate refers to a compound that has a solvent on the surface, in the crystal lattice, or on the surface and in the crystal lattice.
  • the solvent may be water, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, Dichloromethane, dimethyl sulfoxide, 1,4-dioxane, ethanol, ethyl acetate, butanol, tert-butanol, N,N-dimethylacetamide, N,N-dimethylformaldehyde Amide, formamide, formic acid, heptane, hexane, isopropanol, methanol, methyl ethyl ketone, methyl pyrrolidone, mesitylene, nitromethane, polyethylene glycol, propanol, pyridine, tetrahydrofuran, Toluene, xylene and
  • a specific example of a solvate is a hydrate, where the solvent on the surface, in the crystal lattice, or on the surface and in the crystal lattice is water.
  • the hydrate On the surface of the substance, in the crystal lattice, or on the surface and in the crystal lattice, the hydrate may or may not have other solvents other than water.
  • the crystal form can be identified by a variety of technical means, such as X-ray powder diffraction (XRPD), infrared absorption spectroscopy (IR), melting point method, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), nuclear magnetism Resonance method, Raman spectroscopy, X-ray single crystal diffraction, dissolution calorimetry, scanning electron microscope (SEM), quantitative analysis, solubility and dissolution rate, etc.
  • XRPD X-ray powder diffraction
  • IR infrared absorption spectroscopy
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • Raman spectroscopy Raman spectroscopy
  • X-ray single crystal diffraction X-ray single crystal diffraction
  • dissolution calorimetry scanning electron microscope (SEM), quantitative analysis, solubility and dissolution rate, etc.
  • X-ray powder diffraction can detect the change of crystal form, crystallinity, crystal structure state and other information, and it is a common method to identify crystal form.
  • the peak position of the XRPD spectrum mainly depends on the structure of the crystal form and is relatively insensitive to experimental details, while its relative peak height depends on many factors related to sample preparation and instrument geometry. Therefore, in some embodiments, the crystalline form of the present invention is characterized by an XRPD pattern with certain peak positions, which is substantially as shown in the XRPD pattern provided in the drawings of the present invention.
  • the 2 ⁇ measurement of the XRPD pattern may have experimental errors.
  • the 2 ⁇ measurement of the XRPD pattern may be slightly different between different instruments and different samples, so the 2 ⁇ value cannot be regarded as absolute. According to the condition of the instrument used in this experiment, the diffraction peak has an error tolerance of ⁇ 0.2°.
  • DSC Differential scanning calorimetry
  • ⁇ -Al 2 O 3 inert reference material
  • 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. Therefore, in some embodiments, the crystalline form of the present invention is characterized by a DSC chart with characteristic peak positions, which is substantially as shown in the DSC chart provided in the accompanying drawings of the present invention.
  • the DSC spectrum may have experimental errors.
  • the peak position and peak value of the DSC spectrum may be slightly different between different instruments and different samples. Therefore, the peak position or the value of the peak value of the DSC endothermic peak cannot be regarded as absolute. According to the conditions of the instruments used in this experiment, there is an error tolerance of ⁇ 3°C for the endothermic peak.
  • the 2 ⁇ values in the X-ray powder diffraction pattern are all in degrees (°).
  • substantially as shown in the figure means 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 are shown in the graph.
  • peak refers to a feature that can be identified by those skilled in the art that will not be attributed to background noise.
  • the present invention relates to a new crystal form of the compound represented by formula (I), for example, crystal form I, II or III, which exists in a substantially pure crystal form.
  • substantially pure means that one crystal form is substantially free of another one or more crystal forms, that is, the purity of the crystal form is at least 80%, or at least 85%, or at least 90%, or at least 93%, or At least 95%, or at least 98%, or at least 99%, or at least 99.5%, or at least 99.6%, or at least 99.7%, or at least 99.8%, or at least 99.9%, or the crystal form contains other crystal forms, the The percentage of other crystal forms in the total volume or weight of the crystal form is less than 20%, or less than 10%, or less than 5%, or less than 3%, or less than 1%, or less than 0.5%, Or less than 0.1%, or less than 0.01%.
  • substantially free means that the percentage of one or more other crystal forms in the total volume or weight of the crystal 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%.
  • the “relative intensity” (or “relative peak height”) in the XRPD diagram means that when the intensity of the first strong peak in all diffraction peaks of the X-ray powder diffraction pattern (XRPD) is 100%, the intensity of the other peaks is the same as that of the first peak. The ratio of the intensity of the strong peak.
  • room temperature refers to a temperature ranging from about 10°C to about 40°C. In some embodiments, “room temperature” refers to a temperature from about 20°C to about 30°C; in other embodiments, “room temperature” refers to 20°C, 22.5°C, 25°C, 27.5°C, and so on.
  • the characteristics of the pharmaceutical composition of the present invention include the compound represented by formula (I) or its crystal form or amorphous form and a pharmaceutically acceptable carrier, adjuvant, or excipient.
  • the amount of the compound or its crystalline form or amorphous form in the pharmaceutical composition of the present invention can effectively and detectably treat or alleviate mineralocorticoid-related diseases in patients.
  • the pharmaceutically acceptable composition of the present invention further comprises pharmaceutically acceptable carriers, adjuvants, or excipients, which, like those used in the present invention, include any solvents, diluents, or other Liquid excipients, dispersants or suspending agents, surfactants, isotonic agents, thickeners, emulsifiers, preservatives, solid binders or lubricants, etc., are suitable for specific target dosage forms.
  • pharmaceutically acceptable carriers, adjuvants, or excipients which, like those used in the present invention, include any solvents, diluents, or other Liquid excipients, dispersants or suspending agents, surfactants, isotonic agents, thickeners, emulsifiers, preservatives, solid binders or lubricants, etc.
  • Substances that can be used as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers; aluminum; aluminum stearate; lecithin; serum proteins such as human serum proteins; buffer substances such as phosphate; glycine; sorbic acid; Potassium acid; a mixture of partial glycerides of saturated plant fatty acids; water; salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt; colloidal silicon; magnesium trisilicate; polyethylene Pyrrolidone; polyacrylate; wax; polyethylene-polyoxypropylene-blocking polymer; lanolin; sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as carboxymethyl Sodium base cellulose, ethyl cellulose and cellulose acetate; gum powder; malt; gelatin; talc; excipients such as cocoa butter and
  • the pharmaceutical composition of the present invention can be capsules, tablets, pills, powders, granules and water suspensions or solutions; it can be administered by the following routes: oral administration, injection administration, spray inhalation, topical administration, Rectal administration, nasal administration, buccal administration, vaginal administration or via implantable kits.
  • Oral administration can be administered in the following forms: tablets, pills, capsules, dispersible powders, granules or suspensions, syrups, elixirs, etc.; topical administration can be administered in the following forms: ointment, gel, Medicated tape, etc.
  • the compound represented by the formula (I) of the present invention or its crystal form or amorphous form is preferably prepared into a dosage unit form according to the formulation of the preparation to reduce the uniformity of the dosage and dosage.
  • dosage unit type herein refers to a physically dispersed unit of the drug required for proper treatment by the patient.
  • the total daily usage of the compound of formula (I) of the present invention or its crystalline or amorphous form, or the pharmaceutical composition of the present invention will be determined by the attending doctor according to the judgment of a reliable medical scope.
  • the specific effective dosage level for any particular patient or organism will depend on many factors including the condition being treated and the severity of the condition, the specific compound or its crystalline form or amorphous activity, the specific composition used, and the age of the patient. , Weight, health status, gender and eating habits, time of administration, route of administration and excretion rate of the specific compound or its crystalline or amorphous form, the duration of treatment, the application of the drug in combination or with specific compounds or Its crystal form or amorphous form is used in combination, as well as some other factors well known in the field of pharmacy.
  • the effective dose of the active ingredient used may vary with the compound used or its crystal form or amorphous form, the mode of administration and the severity of the disease to be treated. However, generally, when the compound of the present invention or its crystalline form or amorphous form is administered at a dose of about 0.25-1000 mg/kg of animal body weight per day, satisfactory effects can be obtained, preferably in divided doses of 2-4 times per day. Administer, or administer in a sustained-release form. For most large mammals, the total daily dose is about 1-100 mg/kg, preferably about 2-80 mg/kg of the active compound or its crystalline or amorphous form.
  • a dosage form suitable for oral administration contains about 0.25-500 mg of the active compound or its crystalline or amorphous form intimately mixed with a solid or liquid pharmaceutically acceptable carrier. This dosage regimen can be adjusted to provide the best therapeutic response. In addition, due to different treatment conditions, several divided doses can be given every day, or the dose can be reduced proportionally.
  • the compound of the present invention or its crystalline or amorphous form, and the pharmaceutical composition of the present invention can be used for the prevention and/or treatment of various diseases and disease-related conditions, especially characterized by increased plasma aldosterone concentration or plasma aldehydes.
  • Conditions in which the concentration of sterone changes relative to the concentration of plasma renin, or conditions related to these changes are: spontaneous primary aldosteronism, hyperaldosteronism associated with adrenal hyperplasia, adrenal adenoma and/or adrenal cancer, hyperaldosteronism associated with cirrhosis, Hyperaldosteronism associated with heart failure, and (relative) hyperaldosteronism associated with essential hypertension, etc.
  • the compounds of the present invention or their crystalline or amorphous forms can be used to treat or prevent the following diseases: diabetic nephropathy, hyperaldosteronism, hypertension, heart failure, sequelae of myocardial infarction, liver cirrhosis, renal failure or Stroke.
  • Figure 1 is an X-ray powder diffraction (XRPD) pattern of the crystal form I of the compound represented by formula (I).
  • Figure 2 is a differential scanning calorimetry (DSC) chart of the crystalline form I of the compound represented by formula (I).
  • Figure 3 is an X-ray powder diffraction (XRPD) pattern of the crystal form II of the compound represented by formula (I).
  • FIG. 4 is a differential scanning calorimetry (DSC) chart of the crystal form II of the compound represented by formula (I).
  • Figure 5 is an X-ray powder diffraction (XRPD) pattern of the crystal form III of the compound represented by formula (I).
  • Fig. 6 is a differential scanning calorimetry (DSC) chart of the crystal form III of the compound represented by formula (I).
  • Figure 7 is an amorphous X-ray powder diffraction (XRPD) pattern of the compound represented by formula (I).
  • FIG. 8 is an X-ray powder diffraction (XRPD) pattern of the compound represented by formula (I) prepared according to Example 1.
  • XRPD X-ray powder diffraction
  • the X-ray powder diffraction analysis method used in the present invention is: an Empyrean diffractometer, using Cu-K ⁇ radiation (45KV, 40mA) to obtain an X-ray powder diffraction pattern.
  • the powdered sample is prepared into a thin layer on the single crystal silicon sample holder, placed on the rotating sample stage, and analyzed in 0.0167° steps in the range of 3°-60°.
  • Use Data Collector software to collect data
  • HighScore Plus software to process the data
  • Data Viewer software to read the data.
  • the differential scanning calorimetry (DSC) analysis method used in the present invention is: using a TA Q2000 module with a thermal analysis controller to perform differential scanning calorimetry. Collect data and use TA Instruments Thermal Solutions software for analysis. Approximately 1-5 mg of the sample is accurately weighed into a special aluminum crucible with a lid, and the sample is analyzed from room temperature to about 300°C using a linear heating device of 10°C/min. During use, the DSC cell was purged with dry nitrogen.
  • the thermal weight loss (TGA) analysis method used in the present invention is: using a TA Q500 module with a thermal analysis controller to perform thermal weight loss. Collect data and use TA Instruments Thermal Solutions software for analysis. Approximately 10 mg of the sample is accurately weighed into the platinum sample pan, and the sample is analyzed from room temperature to about 300°C using a linear heating device of 10°C/min. During use, the TGA furnace chamber is purged with dry nitrogen.
  • the hygroscopicity of the present invention is measured by DVS INT-Std dynamic moisture and gas adsorption analyzer from Surface Measurement Systems, UK, humidity test range: 0%-95%, airflow: 200mL/min, temperature: 25°C, test point: per liter Take a test point for 5% humidity.
  • the compound of formula (I) (52 mg) prepared according to the method of Example 1 was added to acetonitrile (1.0 mL), stirred at room temperature until the solid was dissolved, water (2.0 mL) was slowly added dropwise, and solids gradually precipitated. Continue stirring to precipitate After crystallization for 5 hours, suction filtration, the filter cake was washed with water (1.0 mL ⁇ 2), and then vacuum dried at room temperature for 6 hours to obtain a white solid (23 mg, 44.23%).
  • the crystal form I of the present invention has an X-ray powder diffraction pattern substantially as shown in FIG. 1.
  • the scanning speed is 10°C/min, including the endothermic peak of 251.88°C, and there is an error tolerance of ⁇ 3°C.
  • the crystalline form I of the present invention has a differential scanning calorimeter basically as shown in FIG. 2.
  • the scanning speed is 10°C/min, including the endothermic peaks of 125.00°C and 255.60°C, and there is an error tolerance of ⁇ 3°C.
  • the crystalline form II of the present invention has a differential scanning calorimeter basically as shown in FIG. 4.
  • the scanning speed is 10°C/min, including the endothermic peaks of 119.04°C and 255.59°C, and there is an error tolerance of ⁇ 3°C.
  • the crystalline form III of the present invention has a differential scanning calorimeter basically as shown in FIG. 6.
  • the compound represented by formula (I) of the present invention or its crystal form or amorphous form is respectively filled into capsules for oral administration.
  • Illumination test Put an appropriate amount of the test product into a flat weighing bottle, spread it into a thin layer ⁇ 5mm thick, and place it in an open light box (with ultraviolet lamp) at an illuminance of 4500 ⁇ 500lx, Place for 30 days under the condition of ultraviolet light ⁇ 0.7w/m 2 , take samples on the 5th, 10th, and 30th day, observe the color change of the sample, and check the purity of the sample by HPLC.
  • open light box with ultraviolet lamp
  • the crystal form I of the present invention has good stability under various lofting conditions and is suitable for pharmaceutical applications.
  • test product ie, the compound of the present invention or its crystalline form or amorphous form
  • dynamic moisture adsorption meter to test its moisture absorption
  • the crystal form of the present invention is not easily affected by high humidity and deliquescence.

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Abstract

涉及二氢萘啶类化合物的晶型，包含所述晶型的药物组合物，以及所述晶型或所述药物组合物在制备用于治疗和预防醛甾酮过多症、糖尿病肾病、高血压、心力衰竭(包括慢性心力衰竭等)、心肌梗死的后遗症、肝硬化、肾衰竭和中风等疾病的药物中的用途。

Description

二氢萘啶类化合物的晶型及其用途 技术领域
本发明属于医药技术领域，涉及二氢萘啶类化合物的晶型及其用途，具体涉及4-(4-氰基-2-甲氧基苯基)-5-环丁基氧基-2,8-二甲基-1,4-二氢-1,6-萘啶-3-甲酰胺的立体异构体及其晶型和用途，进一步涉及包含所述的晶型的药物组合物。
背景技术
盐皮质激素受体(Mineralocorticoid Receptor，MR)是醛甾酮活化的核激素受体，其调节许多涉及电解质体内平衡和心血管疾病的基因的表达。循环醛甾酮的增加，通过其对尿钠排泄的影响而提高血压，同时潜在地对脑、心脏和血管系统造成影响。另外，醛甾酮过多症与许多导致肾和心血管疾病的疾病生理过程有关。尽管醛甾酮过多症通常由产生醛甾酮的腺瘤所引起，但顽固性高血压的患者的醛甾酮水平常常升高，通常称为“醛甾酮逃逸”，这是由于血清钾含量提高或残留的AT1R活性所致。醛甾酮过多症和醛甾酮逃逸典型地导致MR活性提高，已经证明，MR拮抗剂可作为有效的抗高血压剂，并且还可以有效的治疗心力衰竭和原发性醛甾酮过多症。另外，MR拮抗剂在肾病临床前模型中也被证明是有效的，可以与标准疗法组合用于降低肾病患者的蛋白尿，例如慢性肾病，包括糖尿病性肾病。
国际申请WO 2019223629 A1公开了一种二氢嘧啶类化合物，其中，所述化合物具有盐皮质激素受体(MR)拮抗作用，可以用于治疗和预防醛甾酮过多症、糖尿病肾病、高血压、心力衰竭(包括慢性心力衰竭等)、心肌梗死的后遗症、肝硬化、肾衰竭和中风等疾病等。具体地，该专利申请公开了化合物4-(4-氰基-2-甲氧基苯基)-5-环丁基氧基-2,8-二甲基-1,4-二氢-1,6-萘啶-3-甲酰胺(式(Ia)所示化合物)及其立体异构体，但现有技术中并没有关于该化合物或其立体构型的晶型的研究和报道。
Figure PCTCN2021089149-appb-000001
药物多晶型是药物研发中的常见现象，是影响药物质量的重要因素。同一药物的不同晶型在外观、溶解度、熔点、溶出度、生物有效性等方面可能会有显著不同，也会对药物的稳定性、生物利用度及疗效等方面产生不同的影响。因此，在药物研发中，应全面考虑药物的多晶型问题。
发明内容
现有技术WO 2019223629 A1公开了式(Ia)所示化合物及其制备方法，同时给出了其立体异构体，即，本发明所述的式(I)所示化合物。本发明提供了所述立体异构体的制备方法，同时提供了所述立体异构体的晶型或无定形，其中，所述晶型，特别是晶型I，可以明显改善了化合物的稳定性和药代动力学等性质，从而具有更优良的成药性。
具体而言，本发明涉及式(I)所示化合物及其晶型或无定形，以及所述化合物的晶型或无定形或包含所述晶型或无定形的药物组合物用作盐皮质激素拮抗剂的用途，和/或在制备用于治疗或预防与盐皮质激素相关的疾病的药物中的用途。本发明的晶型还可以为溶剂化物形式，例如水合物形式。
一方面，本发明提供了式(I)所示化合物：
Figure PCTCN2021089149-appb-000002
另一方面，本发明提供了一种式(I)所示化合物的晶型，
Figure PCTCN2021089149-appb-000003
在一些实施方案中，本发明所述的式(I)所示化合物的晶型为晶型I、晶型II或晶型III。
在一些实施方案中，本发明所述的晶型I，其特征在于，所述晶型I的X射线粉末衍射图谱在下列2θ角处具有衍射峰：6.70°±0.2°,7.29°±0.2°,11.18°±0.2°,19.04°±0.2°,27.27°±0.2°。
在另一些实施方案中，本发明所述的晶型I，其特征在于，所述晶型I的X射线粉末衍射图谱在下列2θ角处具有衍射峰：6.70°±0.2°,7.29°±0.2°,8.07°±0.2°,11.18°±0.2°,16.16°±0.2°,19.04°±0.2°,21.50°±0.2°,22.03°±0.2°,22.70°±0.2°,27.27°±0.2°。
在另一些实施方案中，本发明所述的晶型I，其特征在于，所述晶型I的X射线粉末衍射图谱在下列2θ角处具有衍射峰：5.69°±0.2°,6.70°±0.2°,7.29°±0.2°,8.07°±0.2°,11.18°±0.2°,16.16°±0.2°,19.04°±0.2°,21.50°±0.2°,22.03°±0.2°,22.70°±0.2°,27.27°±0.2°。
在另一些实施方案中，本发明所述的晶型I，其特征在于，所述晶型I的X射线粉末衍射图谱在下列2θ角处具有衍射峰：5.69°±0.2°,6.70°±0.2°,7.29°±0.2°,8.07°±0.2°,11.18°±0.2°,11.67°±0.2°,12.73°±0.2°,13.34°±0.2°,14.48°±0.2°,14.78°±0.2°,15.68°±0.2°,16.16°±0.2°,16.95°±0.2°,17.40°±0.2°,17.93°±0.2°,18.40°±0.2°,19.04°±0.2°,19.24°±0.2°,19.64°±0.2°,19.99°±0.2°,20.19°±0.2°,21.13°±0.2°,21.50°±0.2°,22.03°±0.2°,22.70°±0.2°,23.34°±0.2°,23.73°±0.2°,24.27°±0.2°,25.11°±0.2°,25.56°±0.2°,25.94°±0.2°,26.47°±0.2°,26.78°±0.2°,27.27°±0.2°,28.36°±0.2°,29.22°±0.2°,29.78°±0.2°,30.69°±0.2°,31.19°±0.2°,31.60°±0.2°,32.58°±0.2°,33.26°±0.2°,33.90°±0.2°。
在另一些实施方案中，本发明所述的晶型I，其特征在于，所述晶型I的X射线粉末衍射图谱在下列2θ角处具有衍射峰：5.69°±0.2°,6.70°±0.2°,7.29°±0.2°,8.07°±0.2°,11.18°±0.2°,11.67°±0.2°,12.73°±0.2°,13.34°±0.2°,14.48°±0.2°,14.78°±0.2°,15.68°±0.2°,16.16°±0.2°,16.95°±0.2°,17.40°±0.2°,17.93°±0.2°,18.40°±0.2°,19.04°±0.2°,19.24°±0.2°,19.64°±0.2°,19.99°±0.2°,20.19°±0.2°,21.13°±0.2°,21.50°±0.2°,22.03°±0.2°,22.70°±0.2°,23.34°±0.2°,23.73°±0.2°,24.27°±0.2°,25.11°±0.2°,25.56°±0.2°,25.94°±0.2°,26.47°±0.2°,26.78°±0.2°,27.27°±0.2°,28.36°±0.2°,29.22°±0.2°,29.78°±0.2°,30.69°±0.2°,31.19°±0.2°,31.60°±0.2°,32.58°±0.2°,33.26°±0.2°,33.90°±0.2°,35.50°±0.2°,37.57°±0.2°,38.11°±0.2°,39.60°±0.2°,41.83°±0.2°,42.91°±0.2°,43.96°±0.2°,47.03°±0.2°。
在一些实施方案中，本发明所述的晶型I，其特征在于，所述晶型I具有基本上如图1所示的X射线粉末衍射图。
在一些实施方案中，本发明所述的晶型I，其特征在于，所述晶型I的差示扫描量热图包含251.88℃±3℃的吸热峰。
在一些实施方案中，本发明所述的晶型I，其特征在于，所述晶型I具有基本上如图2所示的差示扫描量热图。
在一些实施方案中，本发明所述的晶型II，其特征在于，所述晶型II的X射线粉末衍射图谱在下列2θ角处具有衍射峰：11.55°,12.72°,18.77°,21.91°,23.80°，其中所述衍射峰存在±0.2°的误差容限。
在一些实施方案中，本发明所述的晶型II，其特征在于，所述晶型II的X射线粉末衍射图谱在下列2θ角处具有衍射峰：11.55°,11.74°,12.72°,14.93°,17.89°,18.77°,21.52°,21.91°,22.20°,23.80°，其中所述衍射峰存在±0.2°的误差容限。
在一些实施方案中，本发明所述的晶型II，其特征在于，所述晶型II的X射线粉末衍射图谱在下列2θ角处具有衍射峰：7.25°,9.82°,10.64°,11.17°,11.55°,11.74°,12.72°,14.35°,14.93°,15.31°,15.67°,17.89°,18.77°,19.11°,19.71°,20.98°,21.33°,21.52°,21.91°,22.20°,22.97°,23.55°,23.80°,24.07°,24.32°,24.77°,25.56°,25.80°,26.27°,26.89°,27.37°,27.88°,28.10°,28.27°,28.55°,28.79°,29.21°,30.06°,30.41°,30.66°,30.86°,31.39°,31.70°,32.03°,32.50°,33.03°,33.19°,33.88°,34.35°,35.08°,35.51°,35.67°，其中所述衍射峰存 在±0.2°的误差容限。
在一些实施方案中，本发明所述的晶型II，其特征在于，所述晶型II的X射线粉末衍射图谱在下列2θ角处具有衍射峰：7.25°,9.82°,10.64°,11.17°,11.55°,11.74°,12.72°,14.35°,14.93°,15.31°,15.67°,17.89°,18.77°,19.11°,19.71°,20.98°,21.33°,21.52°,21.91°,22.20°,22.97°,23.55°,23.80°,24.07°,24.32°,24.77°,25.56°,25.80°,26.27°,26.89°,27.37°,27.88°,28.10°,28.27°,28.55°,28.79°,29.21°,30.06°,30.41°,30.66°,30.86°,31.39°,31.70°,32.03°,32.50°,33.03°,33.19°,33.88°,34.35°,35.08°,35.51°,35.67°,37.04°,37.19°,38.02°,38.75°,39.57°,40.15°,40.61°,41.01°,41.80°,42.20°,42.95°,43.87°，其中所述衍射峰存在±0.2°的误差容限。
在一些实施方案中，本发明所述的晶型II，其特征在于，所述晶型II具有基本上如图3所示的X射线粉末衍射图。
在一些实施方案中，本发明所述的晶型II，其特征在于，所述晶型II的差示扫描量热图包含125.00℃±3℃和255.60℃±3℃的吸热峰。
在一些实施方案中，本发明所述的晶型II，其特征在于，所述晶型II具有基本上如图4所示的差示扫描量热图。
在一些实施方案中，本发明所述的晶型III，其特征在于，所述晶型III的X射线粉末衍射图谱在下列2θ角处具有衍射峰：8.54°,14.34°,20.16°,20.70°,21.95°，其中所述衍射峰存在±0.2°的误差容限。
在一些实施方案中，本发明所述的晶型III，其特征在于，所述晶型III的X射线粉末衍射图谱在下列2θ角处具有衍射峰：8.54°,11.82°,14.34°,16.23°,20.16°,20.46°,20.70°,21.15°,21.95°,26.39°，其中所述衍射峰存在±0.2°的误差容限。
在一些实施方案中，本发明所述的晶型III，其特征在于，所述晶型III的X射线粉末衍射图谱在下列2θ角处具有衍射峰：7.88°,8.54°,11.82°,12.71°,14.34°,14.83°,15.79°,16.23°,16.94°,19.32°,20.16°,20.46°,20.70°,21.15°,21.32°,21.74°,21.95°,22.38°,22.80°,23.64°,24.42°,24.83°,25.75°,26.39°,26.91°,27.56°,27.95°,29.52°,29.76°,30.14°,30.41°,31.21°,31.80°,32.86°,33.63°,34.08°,34.64°,35.09°,36.20°,36.63°,37.05°,37.28°,39.98°,40.40°,40.89°,41.71°,43.16°,44.36°,44.77°，其中所述衍射峰存在±0.2°的误差容限。
在一些实施方案中，本发明所述的晶型III，其特征在于，所述晶型III具有基本上如图5所示的X射线粉末衍射图。
在一些实施方案中，本发明所述的晶型III，其特征在于，所述晶型III的差示扫描量热图包含119.04℃±3℃和255.59℃±3℃的吸热峰。
在一些实施方案中，本发明所述的晶型III，其特征在于，所述晶型III具有基本上如图6所示的差示扫描量热图。
一方面，本发明提供了一种式(I)所示化合物的无定形，
Figure PCTCN2021089149-appb-000004
其中，所述无定形具有基本上如图7所示的X射线粉末衍射图。
另一方面，本发明涉及一种药物组合物，其包含本发明所述的式(I)所示化合物或其晶型I、晶型II、晶型III、无定形或它们的组合，和药学上可接受的载体、赋形剂、稀释剂、辅剂或它们的组合。
在一些实施方案中，本发明所述的药物组合物，其进一步包含一种或多种其他活性成分，所述其他活性成分选自ACE抑制剂、肾素抑制剂、血管紧张素II受体拮抗剂、β-受体阻断剂、乙酰水杨酸、利尿剂、钙拮抗剂、他汀类、洋地黄衍生物、钙敏化剂、硝酸盐和抗血栓形成剂。
一方面，本发明涉及所述的式(I)所示化合物或其晶型I、晶型II、晶型III或无定形或所述的药物组合物在制备药物中的用途，其中，所述药物用于治疗、预防或减轻患者如下疾病：糖尿病肾病、醛甾酮过多症、高血压、心力衰竭、心肌梗死的后遗症、肝硬化、肾衰竭或中风。
另一方面，本发明涉及所述的式(I)所示化合物或其晶型I、晶型II、晶型III或无定形或所述的药物组合物在制备药物中的用途，其中，所述药物用作盐皮质激素受体拮抗剂。
本发明一方面涉及预防、治疗或减轻患者疾病的方法，其中，所述疾病为糖尿病肾病、醛甾酮过多症、高血压、心力衰竭、心肌梗死的后遗症、肝硬化、肾衰竭或中风；所述方法包括使用本发明所述的式(I)所示化合物或其任一晶型或所述无定形或所述的药物组合物药学上可接受的有效剂量对患者进行给药。
另一方面，本发明还涉及式(I)所示化合物或其晶型或无定形的制备方法。
本发明所述的式(I)所示化合物或其晶型或无定形的制备方法中所使用的溶剂没有特别限制，任何在程度上能溶解起始原料并且不影响其性质的溶剂均包含在本发明中。另外，本领域的许多类似改动，等同替换，或等同于本发明所描述的溶剂，溶剂组合，及溶剂组合的不同比例，均视为本发明的包含范围。本发明给出了各反应步骤所使用的较佳的溶剂。
本发明所述的式(I)所示化合物或其晶型或无定形的制备实验将在实施例部分进行了详细描述。同时，本发明提供了所述晶型的活性测试实验(如药代动力学实验)、溶解度实验、稳定性实验和引湿性实验等。经实验证明，本发明所述的晶型特别是晶型I具有较好的生物活性，较好的溶解性，较高的稳定性，适合制药用途。
此外，根据引湿性实验结果，本发明所述的晶型I不易受高湿度影响而潮解，方便药物的长期贮存放置。
定义和一般术语
除非另有说明，本发明使用的所有技术和科学术语与本发明所属领域的普通技术人员所通常理解的具有相同含义。本发明涉及的所有专利和公开出版物通过引用方式整体并入本发明。尽管在本发明的实践或者测试中可以使用与本发明所述相似或者相同的任何方法和物质，但是本发明中描述的是优选的方法、设备和物质。
“晶型”或“结晶形式”是指具有高度规则化学结构的固体，包括，但不限于，单组分或者多组分晶体，和/或化合物的多晶型物、溶剂化物、水合物、包合物、共晶、盐、盐的溶剂化物、盐的水合物。物质的结晶形式可通过本领域已知的许多方法得到。这种方法包括，但不限于，熔体结晶、熔体冷却、溶剂结晶、在限定的空间中结晶，例如，在纳米孔或者毛细管中，在表面或者模板上结晶，例如，在聚合物上，在添加剂如共结晶反分子的存在下结晶、去溶剂、脱水、快速蒸发、快速冷却、缓慢冷却、蒸气扩散、升华、反应结晶、反溶剂添加、研磨和溶剂滴研磨等。
“溶剂”是指一种物质(典型地是一种液体)，该物质能够完全地或部分地溶解另一种物质(典型地是一种固体)。用于本发明实施的溶剂包括但并不限于，水、乙酸、丙酮、乙腈、苯、氯仿、四氯化碳、二氯甲烷、二甲基亚砜、1,4-二氧六环、乙醇、乙酸乙酯、丁醇、叔丁醇、N,N-二甲基乙酰胺、N,N-二甲基甲酰胺、甲酰胺、蚁酸、庚烷、己烷、异丙醇、甲醇、甲基乙基酮、均三甲苯、硝基甲烷、聚乙二醇、丙醇、吡啶、四氢呋喃、甲苯、二甲苯、它们的混合物等等。
“溶剂化物”是指在表面上、在晶格中或者在表面上和在晶格中具有溶剂的化合物，所述溶剂可以是水、乙酸、丙酮、乙腈、苯、氯仿、四氯化碳、二氯甲烷、二甲基亚砜、1,4-二氧六环、乙醇、乙酸乙酯、丁醇、叔丁醇、N,N-二甲基乙酰胺、N,N-二甲基甲酰胺、甲酰胺、蚁酸、庚烷、己烷、异丙醇、甲醇、甲基乙基酮、甲基吡咯烷酮、均三甲苯、硝基甲烷、聚乙二醇、丙醇、吡啶、四氢呋喃、甲苯、二甲苯以及它们的混合物等等。溶剂化物的一个具体例子是水合物，其中在表面上、在晶格中或者在表面上和在晶格中的溶剂是水。在物质的表面上、在晶格中或者在表面上和在晶格中，水合物可以具有或者不具有除了水以外的其它溶剂。
晶型可以通过多种技术手段进行鉴别，例如X射线粉末衍射(XRPD)、红外吸收光谱法(IR)、熔点法、差示扫描量热法(DSC)、热重分析法(TGA)、核磁共振法、拉曼光谱、X射线单晶衍射、溶解量热法、扫描电子显微镜(SEM)、定量分析、溶解度和溶解速度等等。
X射线粉末衍射(XRPD)可检测晶型的变化、结晶度、晶构状态等信息，是鉴别晶型的常用手段。XRPD图谱的峰位置主要取决于晶型的结构，对实验细节相对不敏感，而其相对峰高取决于与样品制备和仪器几何形状有关的许多因素。因此，在一些实施方案中，本发明的晶型的特征在于具有某些峰位置的XRPD图，其基本上如本发明附图中提供的XRPD图所示。同时，XRPD图谱的2θ的量度可以有实验误差，不同仪器以及不同样品之间，XRPD图谱的2θ的量度可能会略有差别，因此所述2θ的数值不能视为 绝对的。根据本试验所用仪器状况，衍射峰存在±0.2°的误差容限。
差示扫描量热(DSC)是在程序控制下，通过不断加热或降温，测量样品与惰性参比物(常用α-Al 2O 3)之间的能量差随温度变化的一种技术。DSC曲线的吸热峰高取决于与样品制备和仪器几何形状有关的许多因素，而峰位置对实验细节相对不敏感。因此，在一些实施方案中，本发明所述晶型的特征在于具有特征峰位置的DSC图，其基本上如本发明附图中提供的DSC图所示。同时，DSC图谱可以有实验误差，不同仪器以及不同样品之间，DSC图谱的峰位置和峰值可能会略有差别，因此所述DSC吸热峰的峰位置或峰值的数值不能视为绝对的。根据本试验所用仪器状况，吸热峰存在±3℃的误差容限。
在本发明的上下文中，X-射线粉末衍射图中的2θ值均以度(°)为单位。
术语“基本上如图所示”是指X-射线粉末衍射图或DSC图或拉曼光谱图或红外光谱图中至少50％，或至少60％，或至少70％，或至少80％，或至少90％，或至少95％，或至少99％的峰显示在其图中。
当提及谱图或/和出现在图中的数据时，“峰”指本领域技术人员能够识别的不会归属于背景噪音的一个特征。
本发明涉及式(I)所示化合物的新晶型，例如，晶型I、II或III，它们以基本上纯净的结晶形态存在。
“基本上纯净的”是指一种晶型基本上不含另外一种或多种晶型，即晶型的纯度至少80％，或至少85％，或至少90％，或至少93％，或至少95％，或至少98％，或至少99％，或至少99.5％，或至少99.6％，或至少99.7％，或至少99.8％，或至少99.9％，或晶型中含有其它晶型，所述其它晶型在晶型的总体积或总重量中的百分比少于20％，或少于10％，或少于5％，或少于3％，或少于1％，或少于0.5％，或少于0.1％，或少于0.01％。
“基本上不含”是指一种或多种其它晶型在晶型的总体积或总重量中的百分比少于20％，或少于10％，或少于5％，或少于4％，或少于3％，或少于2％，或少于1％，或少于0.5％，或少于0.1％，或少于0.01％。
XRPD图中的“相对强度”(或“相对峰高”)是指X-射线粉末衍射图(XRPD)的所有衍射峰中第一强峰的强度为100％时，其它峰的强度与第一强峰的强度的比值。
在本发明的上下文中，当使用或者无论是否使用“大约”或“约”等字眼时，表示在给定的值或范围的10％以内，适当地在5％以内，特别是在1％以内。或者，对于本领域普通技术人员而言，术语“大约”或“约”表示在平均值的可接受的标准误差范围内。每当公开一个具有N值的数字时，任何具有N+/-1％，N+/-2％，N+/-3％，N+/-5％，N+/-7％，N+/-8％或N+/-10％值以内的数字会被明确地公开，其中“+/-”是指加或减。
本发明中“室温”指的是温度由大约10℃到大约40℃。在一些实施例中，“室温”指的是温度由大约20℃到大约30℃；在另外一些实施例中，“室温”指的是20℃，22.5℃，25℃，27.5℃等等。
本发明所述式(I)所示化合物或其晶型或无定形的组合物，制剂，给药和用途
本发明的药物组合物的特点包括式(I)所示化合物或其晶型或无定形和药学上可接受的载体，辅剂，或赋形剂。本发明的药物组合物中化合物或其晶型或无定形的量能有效地可探测地治疗或减轻患者盐皮质 激素相关的疾病。
像本发明所描述的，本发明药学上可接受的组合物进一步包含药学上可接受的载体，辅剂，或赋形剂，这些像本发明所应用的，包括任何溶剂，稀释剂，或其他液体赋形剂，分散剂或悬浮剂，表面活性剂，等渗剂，增稠剂，乳化剂，防腐剂，固体粘合剂或润滑剂，等等，适合于特有的目标剂型。如以下文献所描述的：In Remington:The Science and Practice of Pharmacy,21st edition,2005,ed.D.B.Troy,Lippincott Williams& Wilkins,Philadelphia,and Encyclopedia of Pharmaceutical Technology,eds.J.Swarbrick and J.C.Boylan,1988-1999,Marcel Dekker,New York,综合此处文献的内容，表明不同的载体可应用于药学上可接-受的组合物的制剂和它们公知的制备方法。除了任何常规的载体媒介与本发明的化合物或其晶型或无定形不相容的范围，例如所产生的任何不良的生物效应或与药学上可接受的组合物的任何其他组分以有害的方式产生的相互作用，它们的用途也是本发明所考虑的范围。
可作为药学上可接受载体的物质包括，但并不限于，离子交换剂；铝；硬脂酸铝；卵磷脂；血清蛋白，如人血清蛋白；缓冲物质如磷酸盐；甘氨酸；山梨酸；山梨酸钾；饱和植物脂肪酸的部分甘油酯混合物；水；盐或电解质，如硫酸鱼精蛋白，磷酸氢二钠，磷酸氢钾，氯化钠，锌盐；胶体硅；三硅酸镁；聚乙烯吡咯烷酮；聚丙烯酸脂；蜡；聚乙烯-聚氧丙烯-阻断聚合体；羊毛脂；糖，如乳糖，葡萄糖和蔗糖；淀粉如玉米淀粉和土豆淀粉；纤维素和它的衍生物如羧甲基纤维素钠，乙基纤维素和乙酸纤维素；树胶粉；麦芽；明胶；滑石粉；辅料如可可豆脂和栓剂蜡状物；油如花生油，棉子油，红花油，麻油，橄榄油，玉米油和豆油；二醇类化合物，如丙二醇和聚乙二醇；酯类如乙基油酸酯和乙基月桂酸酯；琼脂；缓冲剂如氢氧化镁和氢氧化铝；海藻酸；无热原的水；等渗盐；林格(氏)溶液；乙醇；磷酸缓冲溶液；和其他无毒的合适的润滑剂如月桂硫酸钠和硬脂酸镁；着色剂；释放剂；包衣衣料；甜味剂；调味剂；香料；防腐剂和抗氧化剂。
本发明的药物组合物可以是胶囊，片剂，丸剂，粉剂，粒剂和水制悬浮液或溶液；可以通过如下途径给药：口服给药，注射给药，喷雾吸入法，局部给药，经直肠给药，经鼻给药，含服给药，阴道给药或通过植入性药盒给药。
口服给药可以用如下形式给药：片剂、丸剂、胶囊、可分散的粉末、颗粒或悬浮液、糖浆、酏剂等；外用方式给药可以通过如下形式给药：软膏剂、凝胶、含药胶布等。
本发明所述的式(I)所示化合物或其晶型或无定形优选地按制剂配方制备成剂量单位型以减轻给药量和剂量的均匀性。术语“剂量单位型”在此处是指患者得到适当治疗所需药物的物理分散单位。然而，应了解本发明式(I)化合物或其晶型或无定形、或本发明的药物组合物每日总的用法将通过主治医生根据可靠的医学范围判断来确定。具体的有效剂量水平对于任何一个特殊的患者或有机体将取决于许多因素包括被治疗的病症和病症的严重性，具体化合物或其晶型或无定形的活性，所用的具体组合物，患者的年龄、体重、健康状况、性别和饮食习惯，给药时间，给药途径和所用具体化合物或其晶型或无定形的排泄速率， 治疗的持续时间，药物应用于联合用药或与有特效的化合物或其晶型或无定形联用，以及其他一些药学领域公知的因素。
所用的活性成分的有效剂量可随所用的化合物或其晶型或无定形、给药的模式和待治疗的疾病的严重程度而变化。然而，通常当本发明的化合物或其晶型或无定形每天以约0.25-1000mg/kg动物体重的剂量给予时，能得到令人满意的效果，较佳地每天以2-4次分开的剂量给予，或以缓释形式给药。对大部分大型哺乳动物而言，每天的总剂量约为1-100mg/kg，较佳地约为2-80mg/kg的活性化合物或其晶型或无定形。适用于内服的剂量形式，包含与固态或液态药学上可接受的载体密切混合的约0.25-500mg的活性化合物或其晶型或无定形。可调节此剂量方案以提供最佳治疗应答。另外，由于治疗状况的不同，可每天给予若干次分开的剂量，或将剂量按比例减少。
本发明涉及的化合物或其晶型或无定形、本发明的药物组合物可用于适于预防和/或治疗各种病症和疾病的相关状况，特别是特征在于血浆醛甾酮浓度上升或者血浆醛甾酮浓度相对于血浆肾素浓度变化的病症、或与这些变化相关的病症。可被提及的实例是：自发原发性醛甾酮增多症，与肾上腺增生相关的醛甾酮过多症，肾上腺腺瘤和/或肾上腺癌，肝硬化相关的醛甾酮过多症，与心力衰竭相关的醛甾酮过多症，和与原发性高血压相关的(相对的)醛甾酮过多症等。
具体地，本发明涉及的化合物或其晶型或无定形可用于治疗或预防如下疾病：糖尿病肾病、醛甾酮过多症、高血压、心力衰竭、心肌梗死的后遗症、肝硬化、肾衰竭或中风。
附图说明
图1为式(I)所示化合物的晶型I的X射线粉末衍射(XRPD)图。
图2为式(I)所示化合物的晶型I的差示扫描量热(DSC)图。
图3为式(I)所示化合物的晶型II的X射线粉末衍射(XRPD)图。
图4为式(I)所示化合物的晶型II的差示扫描量热(DSC)图。
图5为式(I)所示化合物的晶型III的X射线粉末衍射(XRPD)图。
图6为式(I)所示化合物的晶型III的差示扫描量热(DSC)图。
图7为式(I)所示化合物的无定形的X射线粉末衍射(XRPD)图。
图8为按照实施例1制备得到的式(I)所示化合物的X射线粉末衍射(XRPD)图。
具体实施方式
下面通过实施例的方式进一步说明本发明，并不因此将本发明限制在所述的实施例范围之中。
本发明所用X射线粉末衍射分析方法为：Empyrean衍射仪，使用Cu-Kα辐射(45KV,40mA)获得X射线粉末衍射图。在单晶硅样品架上将粉末状样品制备成薄层，放在旋转样品台上，在3°-60°的范围内以0.0167°步长进行分析。使用Data Collector软件收集数据，HighScore Plus软件处理数据，Data Viewer软件读取数据。
本发明所用差示扫描量热(DSC)分析方法为：使用带有热分析控制器的TA Q2000模件进行差示扫描量热。收集数据并使用TA Instruments Thermal Solutions软件进行分析。将约1-5mg样品准确地称重到带有盖子的特制铝坩埚中，使用10℃/分钟的线形加热装置，从室温至大约300℃进行样品分析。在使用期间，将DSC小室用干燥氮气吹扫。
本发明所用热失重(TGA)分析方法为：使用带有热分析控制器的TA Q500模件进行热失重。收集数据并使用TA Instruments Thermal Solutions软件进行分析。将约10mg样品准确地称重到铂金样品盘中，使用10℃/分钟的线形加热装置，从室温至大约300℃进行样品分析。在使用期间，将TGA炉室用干燥氮气吹扫。
本发明引湿性采用英国Surface Measurement Systems公司DVS INT-Std型动态水分与气体吸附分析仪测定，湿度测试范围：0％-95％，气流：200mL/min，温度：25℃，测试点：每升5％湿度取一个测试点。
具体实施方法
式(Ia)所示化合物，即4-(4-氰基-2-甲氧基苯基)-5-环丁基氧基-2,8-二甲基-1,4-二氢-1,6-萘啶-3-甲酰胺的具体合成方法参照国际申请WO 2019223629 A1中的实施例7。
实施例
实施例1 (S)-4-(4-氰基-2-甲氧基苯基)-5-环丁基氧基-2,8-二甲基-1,4-二氢-1,6-萘啶-3-甲酰胺(式(I)所示化合物)
Figure PCTCN2021089149-appb-000005
称取4-(4-氰基-2-甲氧苯基)-5-环丁氧基-2,8-二甲基-1,4-二氢-1,6-萘啶-3-甲酰胺(4.0g)，加入甲醇、乙腈和甲酸(共57mL)，使样品溶解，采用超临界流体色谱法(仪器：Waters SFC；色谱柱：大赛璐AD-H柱子10mm x 250mm 5um；条件：等梯度，30％MeOH+70％CO 2；流速：8mL/min；柱温：35℃；背压：100bar；每次进样10μL)进行手性拆分，得到白色固体(1.76g，44.0％)，HPLC纯度：99.53％，ee值：99.93％。
通过Empyrean X射线粉末衍射(XRPD)分析鉴定：使用Cu-Kα辐射，所得白色固体产物具有如图8所示的X射线粉末衍射图。
MS(ESI,pos.ion)m/z:405.2(M+1).
1H NMR(400MHz,CDCl 3)δ(ppm)7.63(s,1H),7.29(d,J＝7.9Hz,1H),7.15(dd,J＝7.9,1.2Hz,1H),7.08(s,1H),6.51(s,1H),5.78(s,1H),5.44(s,1H),5.24–4.86(m,2H),3.99(s,3H),2.50(s,3H),2.45–2.34(m,1H),2.24–2.16(m,1H),2.14(s,3H),2.01–1.89(m,1H),1.72–1.52(m,3H).
实施例2 本发明所述晶型I
1.晶型I的制备
将按照实施例1方法制备得到的式(I)所示化合物(52mg)加入到乙腈(1.0mL)中，室温搅拌至固体溶解，缓慢滴加水(2.0mL)，逐渐有固体析出，继续搅拌析晶5小时，抽滤，滤饼用水(1.0mL×2)洗涤，然后室温真空干燥6小时，得白色固体(23mg,44.23％)。
2.晶型I的鉴定
(1)通过Empyrean X射线粉末衍射(XRPD)分析鉴定：使用Cu-Kα辐射，具有下列以角度2θ表示的衍射峰：5.69°,6.70°,7.29°,8.07°,11.18°,11.67°,12.73°,13.34°,14.48°,14.78°,15.68°,16.16°,16.95°,17.40°,17.93°,18.40°,19.04°,19.24°,19.64°,19.99°,20.19°,21.13°,21.50°,22.03°,22.70°,23.34°,23.73°,24.27°,25.11°,25.56°,25.94°,26.47°,26.78°,27.27°,28.36°,29.22°,29.78°,30.69°,31.19°,31.60°,32.58°,33.26°,33.90°,35.50°,37.57°,38.11°,39.60°,41.83°,42.91°,43.96°和47.03°,存在±0.2°的误差容限。
具体地，本发明所述晶型I具有基本上如图1所示的X射线粉末衍射图。
(2)通过TA Q2000差示扫描量热(DSC)分析鉴定：扫描速度为10℃/分钟，包含251.88℃的吸热峰，存在±3℃的误差容限。具体地，本发明所述晶型I具有基本上如图2所示的差示扫描量热图。
实施例3 本发明所述晶型II
1.晶型II的制备
将按照实施例1方法制备得到的式(I)所示化合物(50mg)加入到丙酮(1.0mL)中，室温搅拌至固体溶解，随后又迅速析出固体，搅拌过夜，抽滤，滤饼用丙酮(0.5mL×2)洗涤，然后室温真空干燥5小时，得白色固体(28mg,56.00％)。
2.晶型II的鉴定
(1)通过Empyrean X射线粉末衍射(XRPD)分析鉴定：使用Cu-Kα辐射，具有下列以角度2θ表示的衍射峰：7.25°,9.82°,10.64°,11.17°,11.55°,11.74°,12.72°,14.35°,14.93°,15.31°,15.67°,17.89°,18.77°,19.11°,19.71°,20.98°,21.33°,21.52°,21.91°,22.20°,22.97°,23.55°,23.80°,24.07°,24.32°,24.77°,25.56°,25.80°,26.27°,26.89°,27.37°,27.88°,28.10°,28.27°,28.55°,28.79°,29.21°,30.06°,30.41°,30.66°,30.86°,31.39°,31.70°,32.03°,32.50°,33.03°,33.19°,33.88°,34.35°,35.08°,35.51°,35.67°,37.04°,37.19°,38.02°,38.75°,39.57°,40.15°,40.61°,41.01°,41.80°,42.20°,42.95°,43.87°,45.10°,45.71°,46.98°,47.41°,48.11°和49.25°,存在±0.2°的误差容限。具体地，本发明所述晶型II具有基本上如图3所示的X射线粉末衍射图。
(2)通过TA Q2000差示扫描量热(DSC)分析鉴定：扫描速度为10℃/分钟，包含125.00℃和255.60℃ 的吸热峰，存在±3℃的误差容限。具体地，本发明所述晶型II具有基本上如图4所示的差示扫描量热图。
实施例4 本发明所述晶型III
1.晶型III的制备
方法一：
将按照实施例1方法制备得到的式(I)所示化合物(52mg)加入到乙酸乙酯(2.0mL)中，加热至77℃，固体溶解后关闭加热，让反应自然冷至室温，缓慢滴加正庚烷(1.0mL)，逐渐有固体析出，继续搅拌析晶2小时；抽滤，滤饼用正庚烷(1.0mL×2)洗涤，然后室温真空干燥5小时，得白色固体(35mg,67.31％)。
方法二：
将按照实施例1方法制备得到的式(I)所示化合物(49mg)加入到乙醇(1.0mL)中，室温搅拌至固体溶解，缓慢滴加正庚烷(2.0mL)，逐渐有固体析出，继续搅拌析晶5小时，抽滤，滤饼用正庚烷(1.0mL×2)洗涤，然后室温真空干燥过夜，得白色固体(19mg,38.78％)。
方法三：
将按照实施例1方法制备得到的式(I)所示化合物(50mg)加入到甲酸乙酯(1.0mL)中，室温搅拌固体溶解，缓慢滴加正庚烷(1.0mL)，逐渐有固体析出，继续搅拌析晶5小时，抽滤，滤饼用正庚烷(1.0mL×2)洗涤，然后室温真空干燥过夜，得白色固体(28mg,56.00％)。
2.晶型III的鉴定
(1)通过Empyrean X射线粉末衍射(XRPD)分析鉴定：使用Cu-Kα辐射，具有下列以角度2θ表示的衍射峰：7.88°,8.54°,11.82°,12.71°,14.34°,14.83°,15.79°,16.23°,16.94°,19.32°,20.16°,20.46°,20.70°,21.15°,21.32°,21.74°,21.95°,22.38°,22.80°,23.64°,24.42°,24.83°,25.75°,26.39°,26.91°,27.56°,27.95°,29.52°,29.76°,30.14°,30.41°,31.21°,31.80°,32.86°,33.63°,34.08°,34.64°,35.09°,36.20°,36.63°,37.05°,37.28°,39.98°,40.40°,40.89°,41.71°,43.16°,44.36°和44.77°,存在±0.2°的误差容限。具体地，本发明所述晶型III具有基本上如图5所示的X射线粉末衍射图。
(2)通过TA Q2000差示扫描量热(DSC)分析鉴定：扫描速度为10℃/分钟，包含119.04℃和255.59℃的吸热峰，存在±3℃的误差容限。具体地，本发明所述晶型III具有基本上如图6所示的差示扫描量热图。
实施例5 本发明所述无定形
1.无定形制备
将按照实施例1方法制备得到的式(I)所示化合物(50mg)加入到乙醇(4.0mL)中，室温搅拌至固体溶解，过滤膜得澄清液，将溶液旋转蒸发去除溶剂，收集得淡黄色固体(37mg,74.00％)。
2.无定形的鉴定
通过Empyrean X射线粉末衍射(XRPD)分析鉴定：使用Cu-Kα辐射，所述淡黄色固体具有如图7 所示的X射线粉末衍射图，为无定形。
实施例6 药代动力学实验
本发明所述的式(I)所示化合物或其晶型或无定形分别灌装胶囊，用于口服给药。
取8-12kg雄性Beagle犬分为2组，每组3只，口服给予装有供试样品的胶囊，剂量为5mg/kg，按时间点0.25,0.5,1.0,2.0,4.0,6.0,8.0和24h采血。根据样品浓度建立合适范围的标准曲线，使用AB SCIEX API4000型LC-MS/MS，在MRM模式下测定血浆样品中供试样品的浓度，并进行定量分析。根据药物浓度-时间曲线，采用WinNonLin 6.3软件非房室模型法计算药动学参数。实验结果如表1所示。
表1 本发明所述晶型的药代动力学实验数据
供试样品 T max(h) C max(ng/ml) AUC last(h*ng/ml)
实施例2 3.17 2030 6110
实验结论：
由表1可知，本发明所述晶型I在比格犬体内的暴露量较大，具有较好的药代动力学性质。
实施例7 稳定性实验
(1) 高温实验：取供试样品适量放入扁形称量瓶中，摊成≤5mm厚的薄层，40℃±2℃和/或60℃±2℃温度下放置30天，于第5、10、30天取样按稳定性重点考察项目进行检测，观察样品颜色变化，HPLC检测样品纯度。
(2) 高湿实验：取一批供试品适量放入扁形称量瓶中，摊成≤5mm厚的薄层，25℃、RH 90％±5％条件下放置30天，于第5、10、30天取样按稳定性重点考察项目进行检测，观察样品颜色变化，HPLC检测样品纯度。
(3) 光照试验：取一批供试品适量放入扁形称量瓶中，摊成≤5mm厚的薄层，敞口置于光照箱内(带紫外灯)，在照度为4500±500lx、紫外光≥0.7w/m 2的条件下放置30天，于第5、10和30天取样，观察样品颜色变化，HPLC检测样品纯度。
(4) 加速实验：取一批供试品适量用单层PE包装加铝箔包装，在40±2℃/75％±5％RH条件下放置6个月，于第1、2、3和6月取样，观察样品颜色变化，HPLC检测样品纯度，TGA测试水分。
实验结论：
在高温(60℃)、高湿(25℃,RH 90％±5％)、光照条件下，本发明所述晶型I的外观和纯度均无明显变化；在加速实验条件下，本发明所述晶型I的外观、纯度和水含量均无明显变化。
综上可知，本发明所述晶型I在各放样条件下的稳定性较好，适合制药用途。
实施例8 引湿性实验
取供试品(即，本发明所述化合物或其晶型或无定形)适量，采用动态水分吸附仪测试其引湿性。
结论：本发明所述晶型不易受高湿度影响而潮解。
以上所述内容仅为本发明构思下的基本说明，而依据本发明的技术方案所作的任何等效变换，均应属于本发明的保护范围。
在本说明书的描述中，参考术语“一个实施例”、“一些实施例”、“示例”、“具体示例”、或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中，对上述术语的示意性表述不必须针对的是相同的实施例或示例。
尽管上面已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本发明的限制，本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。

Claims (10)

  1. 式(I)所示化合物的晶型I，其特征在于，所述晶型I的X射线粉末衍射图谱在下列2θ角处具有衍射峰：6.70°±0.2°,7.29°±0.2°,11.18°±0.2°,19.04°±0.2°,27.27°±0.2°；
    Figure PCTCN2021089149-appb-100001
  2. 根据权利要求1所述的晶型I，其特征在于，所述晶型I的X射线粉末衍射图谱在下列2θ角处具有衍射峰：6.70°±0.2°,7.29°±0.2°,8.07°±0.2°,11.18°±0.2°,16.16°±0.2°,19.04°±0.2°,21.50°±0.2°,22.03°±0.2°,22.70°±0.2°,27.27°±0.2°。
  3. 根据权利要求1或2所述的晶型I，其特征在于，所述晶型I的X射线粉末衍射图谱在下列2θ角处具有衍射峰：5.69°±0.2°,6.70°±0.2°,7.29°±0.2°,8.07°±0.2°,11.18°±0.2°,11.67°±0.2°,12.73°±0.2°,13.34°±0.2°,14.48°±0.2°,14.78°±0.2°,15.68°±0.2°,16.16°±0.2°,16.95°±0.2°,17.40°±0.2°,17.93°±0.2°,18.40°±0.2°,19.04°±0.2°,19.24°±0.2°,19.64°±0.2°,19.99°±0.2°,20.19°±0.2°,21.13°±0.2°,21.50°±0.2°,22.03°±0.2°,22.70°±0.2°,23.34°±0.2°,23.73°±0.2°,24.27°±0.2°,25.11°±0.2°,25.56°±0.2°,25.94°±0.2°,26.47°±0.2°,26.78°±0.2°,27.27°±0.2°,28.36°±0.2°,29.22°±0.2°,29.78°±0.2°,30.69°±0.2°,31.19°±0.2°,31.60°±0.2°,32.58°±0.2°,33.26°±0.2°,33.90°±0.2°。
  4. 根据权利要求1-3任意一项所述的晶型I，其特征在于，所述晶型I具有基本上如图1所示的X射线粉末衍射图。
  5. 根据权利要求1-4任意一项所述的晶型I，其特征在于，所述晶型I的差示扫描量热图包含251.88℃±3℃的吸热峰。
  6. 根据权利要求1-5任意一项所述的晶型I，其特征在于，所述晶型I具有基本上如图2所示的差示扫描量热图。
  7. 一种药物组合物，其包含权利要求1-6任意一项所述的晶型I，和药学上可接受的载体、赋形剂、稀释剂、辅剂或它们的组合。
  8. 根据权利要求7所述的药物组合物，其进一步包含一种或多种其他活性成分，所述其他活性成分选自ACE抑制剂、肾素抑制剂、血管紧张素II受体拮抗剂、β-受体阻断剂、乙酰水杨酸、利尿剂、钙拮抗剂、他汀类、洋地黄衍生物、钙敏化剂、硝酸盐和抗血栓形成剂。
  9. 权利要求1-6任意一项所述的晶型I或权利要求7-8所述的药物组合物在制备药物中的用途，其中，所述药物用于治疗、预防或减轻患者如下疾病：糖尿病肾病、醛甾酮过多症、高血压、心力衰竭、心肌梗 死的后遗症、肝硬化、肾衰竭或中风。
  10. 权利要求1-6任意一项所述的晶型I或权利要求7-8任意一项所述的药物组合物在制备药物中的用途，其中，所述药物用作盐皮质激素受体拮抗剂。
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