WO2023174399A1 - Forme cristalline d'un dérivé d'oxopyridine substitué et son procédé de préparation - Google Patents

Forme cristalline d'un dérivé d'oxopyridine substitué et son procédé de préparation Download PDF

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Publication number
WO2023174399A1
WO2023174399A1 PCT/CN2023/082138 CN2023082138W WO2023174399A1 WO 2023174399 A1 WO2023174399 A1 WO 2023174399A1 CN 2023082138 W CN2023082138 W CN 2023082138W WO 2023174399 A1 WO2023174399 A1 WO 2023174399A1
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WIPO (PCT)
Prior art keywords
crystal form
present
crystal
formula
compound
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PCT/CN2023/082138
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English (en)
Chinese (zh)
Inventor
鲁霞
陈智雄
张晓宇
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苏州晶云药物科技股份有限公司
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Publication of WO2023174399A1 publication Critical patent/WO2023174399A1/fr

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    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

  • the present invention relates to the field of chemical medicine, and in particular to the crystal form of substituted oxopyridine derivatives and their preparation method.
  • Factor XIa Factor XIa
  • FXIIa Factor XIa
  • thrombin also activates factor XI to factor XIa, whereby factor IX is converted into factor IXa, by which Of the factor IXa/factor VIIIa complex, factor
  • Patent WO2017005725A1 discloses the compound of formula (I) and its synthesis.
  • the disclosed synthesis method requires the use of Chiralpak AD-H SFC chromatographic column for separation. The method process is cumbersome and produces toxic and harmful waste liquid.
  • Patent WO2019175043A1 discloses three solvates of the compound of formula (I), namely isopropyl acetate solvate, tetrahydrofuran solvate and acetone solvate, which do not meet the safety requirements of pharmaceutical raw materials.
  • Patent WO2022189279A1 discloses two crystal forms of the compound of formula (I), namely modification I and II.
  • modification I needs to be prepared using modification A, an analogue of the compound of formula (I), as a seed crystal.
  • Modification II is obtained by vacuum drying the acetone solvate of the compound of formula (I) under high temperature conditions.
  • the preparation method is complicated. And it is difficult to control, so it is necessary to develop more crystal forms that meet the safety requirements of pharmaceutical raw materials and simple preparation methods.
  • the present invention provides crystalline form A of the compound of formula (I) and its preparation method.
  • a pharmaceutical composition comprising the crystal according to any one of 1 to 3 above and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition having FXIa inhibitory activity which contains the crystal according to any one of 1 to 3 above as an active ingredient.
  • a drug for treating stroke and thromboembolism which contains the crystal according to any one of 1 to 3 above as an active ingredient.
  • the crystal form A of the compound of formula (I) provided by the present invention has better performance in solubility, melting point, stability, dissolution, hygroscopicity, adhesion, fluidity, biological effectiveness, processing performance, purification effect, It has advantages in at least one aspect of preparation production and safety, and provides a new and better choice for the preparation of pharmaceutical preparations containing compounds of formula (I), which is of great significance for drug development.
  • the X-ray powder diffraction of the crystalline form A has a 2 ⁇ value of 14.5° ⁇ 0.2°, 20.3° ⁇ 0.2°, 23.4° ⁇ 0.2° at one, two or three places. There are characteristic peaks.
  • the X-ray powder diffraction of the crystal form A has characteristic peaks at 2 ⁇ values of 14.5° ⁇ 0.2°, 20.3° ⁇ 0.2°, and 23.4° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form A has a 2 ⁇ value of 13.6° ⁇ 0.2°, 19.3° ⁇ 0.2°, or 25.1° ⁇ 0.2° at one, two or three places. There are characteristic peaks.
  • the X-ray powder diffraction of the crystal form A has characteristic peaks at 2 ⁇ values of 13.6° ⁇ 0.2°, 19.3° ⁇ 0.2°, and 25.1° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form A has a 2 ⁇ value of 6.6° ⁇ 0.2°, 12.4° ⁇ 0.2°, 13.6° ⁇ 0.2°, 14.5° ⁇ 0.2°, and 18.3° ⁇ Any 4, or 5, or 6, or 7, or 8, or 9 of 0.2°, 19.3° ⁇ 0.2°, 20.3° ⁇ 0.2°, 23.4° ⁇ 0.2°, 25.1° ⁇ 0.2° There are characteristic peaks everywhere.
  • the X-ray powder diffraction of the crystal form A has a 2 ⁇ value of 6.6° ⁇ 0.2°, 12.4° ⁇ 0.2°, 13.6° ⁇ 0.2°, 14.5° ⁇ 0.2°, and 18.3° ⁇ There are characteristic peaks at 0.2°, 19.3° ⁇ 0.2°, 20.3° ⁇ 0.2°, 23.4° ⁇ 0.2°, and 25.1° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form A is shown in Figure 1.
  • the alcoholic solvent is ethanol or n-propanol.
  • the dissolution and volatilization temperature is 10-50°C, such as 20-30°C.
  • the alcoholic solvent is n-propanol; the antisolvent is pure water.
  • the dissolving, dropping, stirring and precipitation temperatures are 10°C to 50°C, such as 20°C to 30°C.
  • the compounds of formula (I) used as starting materials refer to their solid (crystalline or amorphous), semi-solid, waxy or oily form.
  • the compound of formula (I) used as starting material is in solid powder form.
  • the “stirring” is accomplished by conventional methods in the field, such as magnetic stirring or mechanical stirring.
  • the stirring speed is 50 to 1800 rpm.
  • the magnetic stirring is 200 to 1500 rpm, preferably 300 to 1000 rpm.
  • mechanical stirring is preferably 100 to 300 rpm.
  • the above-mentioned crystals of the present invention can be used to prepare pharmaceutical compositions, which contain the above-mentioned crystals of the present invention and pharmaceutically acceptable carriers.
  • the above-mentioned crystal of the present invention can be used to prepare a pharmaceutical composition with FXIa inhibitory activity, which contains the above-mentioned crystal of the present invention as an active ingredient.
  • the above-mentioned crystals of the present invention can be used to prepare preventive or therapeutic drugs for stroke and thromboembolism, which contain the above-mentioned crystals of the present invention as an active ingredient.
  • the present invention also provides a pharmaceutical composition, which contains the above-mentioned crystal of the present invention and a pharmaceutically acceptable carrier.
  • the present invention also provides a pharmaceutical composition with FXIa inhibitory activity, which contains the above-mentioned crystal of the present invention as an active ingredient.
  • the present invention provides a preventive or therapeutic drug for stroke and thromboembolism, which contains the crystal of the present invention as an active ingredient.
  • crystal or “polymorph” means that which is confirmed by the X-ray diffraction pattern characterization shown.
  • X-ray diffraction patterns often change with the conditions of the instrument. It is particularly important to point out that the relative intensity of X-ray diffraction patterns may also change with changes in experimental conditions, so the order of peak intensity cannot be used as the only or decisive factor. In fact, the relative intensity of the diffraction peaks in the X-ray diffraction pattern is related to the preferred orientation of the crystal.
  • the peak intensities shown in this article are illustrative and not used for absolute comparison.
  • the experimental error of the peak angle is usually 5% or less. The error of these angles should also be taken into account, and an error of ⁇ 0.2° is usually allowed.
  • the overall peak angle will shift. Usually A certain offset is allowed. Therefore, those skilled in the art can understand that the X-ray diffraction pattern of a crystalline form in the present invention does not have to be completely consistent with the X-ray diffraction pattern in the example referred to here.
  • the "X-ray diffraction pattern the same" mentioned herein does not mean that absolutely the same, the same peak position can differ by ⁇ 0.2° and the peak intensity allows certain variability.
  • Any crystalline form having the same or similar pattern as the characteristic peaks in these patterns falls within the scope of the present invention.
  • Those skilled in the art can compare the spectrum listed in the present invention with the spectrum of an unknown crystal form to confirm whether the two sets of patterns reflect the same or different crystal forms.
  • Form A of the present invention is pure and unitary, with substantially no admixture of any other crystalline forms.
  • substantially no when used to refer to a new crystal form means that the crystal form contains less than 20% (weight) of other crystal forms, especially less than 10% (weight) of other crystal forms, and even less Less than 5% (weight) of other crystalline forms refers to less than 1% (weight) of other crystalline forms.
  • the numerical values and numerical ranges mentioned in the present invention should not be narrowly understood as the numerical values or numerical ranges themselves. Those skilled in the art should understand that they can be determined according to different specific technical environments without departing from the spirit and scope of the present invention. There will be some fluctuation around the specific numerical value on the basis of principles. In the present invention, such a floating range that can be foreseen by those skilled in the art is often expressed by the term "about”.
  • room temperature in the present invention usually refers to 22°C to 28°C.
  • PSD particle size distribution
  • PLM Polarized Light Microscope
  • the X-ray powder diffraction patterns described in the present invention were collected on Empyrean type and X'Pert 3 type X-ray powder diffractometers of Panalytical Company.
  • the method parameters of X-ray powder diffraction according to the present invention are as follows:
  • differential scanning calorimetry analysis diagrams described in the present invention were collected on TA Company's Q200 and Discovery DSC 2500 differential scanning calorimeters.
  • the method parameters of differential scanning calorimetry analysis according to the present invention are as follows:
  • thermogravimetric analysis diagram described in the present invention was collected on the Discovery TGA 5500 and Q5000 thermogravimetric analyzers of TA Company.
  • the method parameters of thermogravimetric analysis according to the present invention are as follows:
  • the hydrogen nuclear magnetic resonance spectrum data ( 1 H NMR) described in the present invention is collected from a Bruker Avance II DMX 400M HZ nuclear magnetic resonance spectrometer. Weigh 1-5 mg of sample, dissolve it in 0.5 mL of deuterated dimethyl sulfoxide, and prepare a solution of 2-10 mg/mL for testing.
  • the dynamic moisture adsorption diagram of the present invention is collected on the Intrinsic type and Intrinsic Plus type dynamic moisture adsorption instruments of SMS Company.
  • the method parameters of the dynamic moisture adsorption test according to the present invention are as follows:
  • Relative humidity gradient 10% (0%RH-90%RH-0%RH), 5% (90%RH-95%RH and 95%RH-90%RH)
  • the particle size distribution results described in the present invention were collected on Microtrac's S3500 laser particle size analyzer.
  • Microtrac S3500 is equipped with SDC (Sample Delivery Controller) sampling system.
  • SDC Sample Delivery Controller
  • This test adopts the wet method, and the test dispersion medium is Isopar G (containing 0.2% lecithin).
  • the method parameters of the laser particle size analyzer are as follows: *: 60% of flow rate is 60% of 65mL/s
  • the polarized light microscope photos described in the present invention were collected at room temperature through a Zeiss microscope Axio Scope.A1.
  • the microscope is equipped with an Axiocam 305 color camera and 5 ⁇ , 10 ⁇ , 20 ⁇ and 50 ⁇ objective lenses.
  • the starting material of formula (I) used in the following examples can be prepared according to the existing technology, for example, according to the method described in patent WO2017005725A1, but the starting crystal form is not a limiting condition for preparing the crystal form of the present invention.
  • Example 1 Preparation of crystal form A (room temperature evaporation method)
  • the crystal form A of the present invention is prepared into a suspension using SGF (simulated artificial gastric juice), FaSSIF (artificial intestinal fluid in a fasting state), FeSSIF (artificial intestinal fluid in a satiated state) and pure water respectively. After equilibrating for 24 hours and 24 hours, filter and obtain a saturated solution. The content of the sample in the saturated solution was determined by high performance liquid chromatography (HPLC). The test results are shown in Table 4, and the solubility curves are shown in Figures 7 to 10. The test results show that the crystal form A of the present invention has good solubility in SGF, FaSSIF, FeSSIF and pure water, and meets the pharmaceutical needs.
  • SGF simulated artificial gastric juice
  • FaSSIF artificial intestinal fluid in a fasting state
  • FeSSIF artificial intestinal fluid in a satiated state
  • pure water pure water
  • Example 5 Compressibility of crystalline forms
  • Example 7 Comparative study on hygroscopicity
  • Hygroscopic weight gain by absorbing moisture is less than 15% but not less than 2%
  • weight gain due to moisture attraction is less than 2% but not less than 0.2%
  • weight gain due to moisture absorption is less than 0.2%
  • the test results show that the crystal form A of the present invention has a unimodal distribution with an average particle size of 13.14 microns and a uniform particle size distribution; the Form II has a bimodal distribution with an average particle size of 67.84 microns. It shows that the crystal form A of the present invention has a more uniform particle size distribution than the form II.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)

Abstract

La présente invention concerne une forme cristalline d'un dérivé d'oxopyridine substitué et son procédé de préparation. L'invention concerne une forme cristalline A d'un composé représenté par la formule (I), ainsi que son procédé de préparation et son utilisation. La forme cristalline A du composé de formule (I) selon la présente invention présente au moins l'un des avantages suivants : solubilité, point de fusion, stabilité, degré de dissolution, hygroscopicité, adhésivité, fluidité, biodisponibilité, aptitude au traitement, effet de purification, production en préparation, sécurité, etc ; un nouveau meilleur choix est offert pour préparer une préparation pharmaceutique contenant le composé de formule (I), avec une grande importance pour le développement de médicament.
PCT/CN2023/082138 2022-03-18 2023-03-17 Forme cristalline d'un dérivé d'oxopyridine substitué et son procédé de préparation WO2023174399A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202210268557 2022-03-18
CN202210268557.8 2022-03-18

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WO2023174399A1 true WO2023174399A1 (fr) 2023-09-21

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108026072A (zh) * 2015-07-09 2018-05-11 拜耳制药股份公司 取代的氧代吡啶衍生物
CN111770917A (zh) * 2018-03-15 2020-10-13 拜耳股份公司 两种4-{[(2s)-2-{4-[5-氯-2-(1h-1,2,3-三唑-1-基)苯基]-5-甲氧基-2-氧代吡啶-1(2h)-基}丁酰基]氨基}-2-氟苯甲酰胺衍生物的制备方法
CN113166099A (zh) * 2018-12-17 2021-07-23 拜耳公司 用于治疗和/或预防血栓形成性或血栓栓塞性疾病和/或血栓形成性或血栓栓塞性并发症的取代的氧代吡啶衍生物
WO2021242970A1 (fr) * 2020-05-29 2021-12-02 Boulder Bioscience Llc Procédés pour une thrombectomie endovasculaire améliorée à l'aide de 3,3'-diindolylméthane
WO2022189278A1 (fr) * 2021-03-09 2022-09-15 Bayer Aktiengesellschaft Formes posologiques pharmaceutiques comprenant du (4s)-24-chloro-4-éthyl-73-fluoro-35-méthoxy-32,5-dioxo-14-(trifluorométhyl)-32h-6-aza-3(4,1)-pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)-dibenzénaheptaphane-74-carboxamide
WO2022189280A1 (fr) * 2021-03-09 2022-09-15 Bayer Aktiengesellschaft Solvates de (4s)-24-chloro-4-éthyl-73-fluoro-35-méthoxy-32,5-dioxo-14-(trifluoro-méthyl)-32 h-6- aza-3(4,1)-pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)-dibenzenaheptaphane-74-carboxamide
WO2022189279A1 (fr) * 2021-03-09 2022-09-15 Bayer Aktiengesellschaft Formes cristallines de (4s)-24-chloro-4-éthyl-73-fluoro-35-méthoxy-32, 5-dioxo-14-(trifluorométhyl)-32h-6-aza-3(4,1)-pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)-5 dibenzenaheptaphane-74-carboxamide

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108026072A (zh) * 2015-07-09 2018-05-11 拜耳制药股份公司 取代的氧代吡啶衍生物
CN111770917A (zh) * 2018-03-15 2020-10-13 拜耳股份公司 两种4-{[(2s)-2-{4-[5-氯-2-(1h-1,2,3-三唑-1-基)苯基]-5-甲氧基-2-氧代吡啶-1(2h)-基}丁酰基]氨基}-2-氟苯甲酰胺衍生物的制备方法
CN113166099A (zh) * 2018-12-17 2021-07-23 拜耳公司 用于治疗和/或预防血栓形成性或血栓栓塞性疾病和/或血栓形成性或血栓栓塞性并发症的取代的氧代吡啶衍生物
WO2021242970A1 (fr) * 2020-05-29 2021-12-02 Boulder Bioscience Llc Procédés pour une thrombectomie endovasculaire améliorée à l'aide de 3,3'-diindolylméthane
WO2022189278A1 (fr) * 2021-03-09 2022-09-15 Bayer Aktiengesellschaft Formes posologiques pharmaceutiques comprenant du (4s)-24-chloro-4-éthyl-73-fluoro-35-méthoxy-32,5-dioxo-14-(trifluorométhyl)-32h-6-aza-3(4,1)-pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)-dibenzénaheptaphane-74-carboxamide
WO2022189280A1 (fr) * 2021-03-09 2022-09-15 Bayer Aktiengesellschaft Solvates de (4s)-24-chloro-4-éthyl-73-fluoro-35-méthoxy-32,5-dioxo-14-(trifluoro-méthyl)-32 h-6- aza-3(4,1)-pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)-dibenzenaheptaphane-74-carboxamide
WO2022189279A1 (fr) * 2021-03-09 2022-09-15 Bayer Aktiengesellschaft Formes cristallines de (4s)-24-chloro-4-éthyl-73-fluoro-35-méthoxy-32, 5-dioxo-14-(trifluorométhyl)-32h-6-aza-3(4,1)-pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)-5 dibenzenaheptaphane-74-carboxamide

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