WO2023109939A1 - Forme cristalline d'un dérivé de pyridine et procédé de préparation s'y rapportant - Google Patents

Forme cristalline d'un dérivé de pyridine et procédé de préparation s'y rapportant Download PDF

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Publication number
WO2023109939A1
WO2023109939A1 PCT/CN2022/139499 CN2022139499W WO2023109939A1 WO 2023109939 A1 WO2023109939 A1 WO 2023109939A1 CN 2022139499 W CN2022139499 W CN 2022139499W WO 2023109939 A1 WO2023109939 A1 WO 2023109939A1
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Prior art keywords
crystal form
present
crystal
formula
compound
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PCT/CN2022/139499
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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 WO2023109939A1 publication Critical patent/WO2023109939A1/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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides

Definitions

  • the invention relates to the field of chemistry and medicine, in particular to a crystal form of pyridine derivatives and a preparation method thereof.
  • CF transmembrane conductance regulator is a protein kinase A (PKA)-activated epithelial anion channel involved in salt and fluid transport in multiple organs.
  • PKA protein kinase A
  • Cystic fibrosis is a fatal genetic disease caused by mutations in the gene encoding CFTR, which typically reduce the number of CFTR channels on the cell surface or impair channel function. Studies have shown the potential to improve systemic inflammation, bacterial counts, and symptoms of airway disease by enhancing the CFTR ion channel on the cell surface.
  • Patent WO2011113894A1 discloses the compound of formula (I) and its synthesis.
  • the disclosed synthesis method needs to use supercritical fluid for chiral resolution or continuously use silica gel chromatography and isohexane/dichloromethane recrystallization for purification.
  • the present invention provides crystal form A of the compound of formula (I) and a preparation method thereof.
  • Compound 3-amino-6-methoxyl group-5-trifluoromethyl-pyridine-2-carboxylic acid ((S)-3,3,3-trifluoro-2-hydroxyl-2 -A type crystal of -methyl-propyl)-amide, i.e. crystal form A, is characterized in that, using Cu-K ⁇ radiation, the X-ray powder diffraction of the crystal form A has a 2 ⁇ value of 14.4° ⁇ 0.2°, 17.5 There are characteristic peaks at ° ⁇ 0.2°, 19.4° ⁇ 0.2°,
  • a pharmaceutical composition comprising the crystal according to any one of 1 to 3 above and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition having CFTR-enhancing activity comprising the crystal according to any one of 1 to 3 above as an active ingredient.
  • a therapeutic agent for chronic obstructive pulmonary disease, cystic fibrosis and bronchiectasis comprising 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 solubility, melting point, stability, dissolution rate, hygroscopicity, adhesion, fluidity, bioavailability and processing performance, purification,
  • solubility melting point
  • stability dissolution rate
  • hygroscopicity adhesion
  • fluidity fluidity
  • bioavailability and processing performance purification
  • the X-ray powder diffraction of the crystal form A has one or two or three 2 ⁇ values of 15.9° ⁇ 0.2°, 20.7° ⁇ 0.2°, and 22.6° ⁇ 0.2° have characteristic peaks.
  • the X-ray powder diffraction of the crystal form A has characteristic peaks at 2 ⁇ values of 15.9° ⁇ 0.2°, 20.7° ⁇ 0.2°, and 22.6° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form A has one or two or three 2 ⁇ values of 10.0° ⁇ 0.2°, 21.5° ⁇ 0.2°, and 25.2° ⁇ 0.2° have characteristic peaks.
  • the X-ray powder diffraction of the crystal form A has characteristic peaks at 2 ⁇ values of 10.0° ⁇ 0.2°, 21.5° ⁇ 0.2°, and 25.2° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form A has a 2 ⁇ value of 10.0° ⁇ 0.2°, 14.4° ⁇ 0.2°, 15.9° ⁇ 0.2°, 17.5° ⁇ 0.2°, 19.4° ⁇ 0.2° Any 4, or 5, or 6, or 7, or 8, or 9 of 0.2°, 20.7° ⁇ 0.2°, 21.5° ⁇ 0.2°, 22.6° ⁇ 0.2°, 25.2° ⁇ 0.2° There are characteristic peaks.
  • the X-ray powder diffraction of the crystal form A has a 2 ⁇ value of 10.0° ⁇ 0.2°, 14.4° ⁇ 0.2°, 15.9° ⁇ 0.2°, 17.5° ⁇ 0.2°, 19.4° ⁇ 0.2° There are characteristic peaks at 0.2°, 20.7° ⁇ 0.2°, 21.5° ⁇ 0.2°, 22.6° ⁇ 0.2°, 25.2° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form A is shown in FIG. 1 .
  • the halogenated alkane solvent is dichloromethane, and the alkane solvent is n-heptane.
  • the temperature of the dissolving, dropping and stirring is 10-50°C, for example, 20-30°C.
  • the suspension stirring time is 0.5-4 hours, such as 1 hour.
  • the ester solvent is isopropyl acetate
  • the ether solvent is methyl tert-butyl ether
  • the alkane solvent is n-heptane
  • the dissolution and volatilization temperature is 10-50°C, such as 20-30°C.
  • the mixed solvent is isopropanol/n-heptane, ethyl acetate/n-heptane, ethyl formate/cyclohexane.
  • the volume ratio of the isopropanol/n-heptane is 1:1 ⁇ 4, such as 1:2; the volume ratio of the ethyl acetate/n-heptane is 1:2 ⁇ 4. 6, such as 1:4; the volume ratio of ethyl formate/cyclohexane is 1:2-6, such as 1:4.
  • the dissolution and volatilization temperature is 10-50°C, for example, 20-30°C.
  • said compound of formula (I) as starting material refers to its solid (crystalline or amorphous), semi-solid, waxy or oily form.
  • the compound of formula (I) as starting material is in the form of a solid powder.
  • the "stirring” is accomplished by conventional methods in the art, such as magnetic stirring or mechanical stirring, with a stirring speed of 50-1800 rpm, wherein magnetic stirring is 200-1500 rpm, preferably 300-1000 rpm , The mechanical stirring is preferably 100 to 300 rpm.
  • the above-mentioned crystals of the present invention can be used to prepare a pharmaceutical composition, which contains the above-mentioned crystals of the present invention and a pharmaceutically acceptable carrier.
  • the above-mentioned crystals of the present invention can be used to prepare a pharmaceutical composition with CFTR-enhancing activity, which contains the above-mentioned crystals of the present invention as active ingredients.
  • the above-mentioned crystals of the present invention can be used to prepare preventive or therapeutic drugs for chronic obstructive pulmonary disease, cystic fibrosis and bronchiectasis, which contain the above-mentioned crystals of the present invention as active ingredients.
  • the present invention also provides a pharmaceutical composition comprising the above-mentioned crystal of the present invention and a pharmaceutically acceptable carrier.
  • the present invention also provides a pharmaceutical composition having CFTR enhancing 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 chronic obstructive pulmonary disease, cystic fibrosis, and bronchiectasis, which contains the above-mentioned crystal of the present invention as an active ingredient.
  • crystal or “polymorph” refers to what is characterized by the shown X-ray diffraction pattern.
  • X-ray diffraction patterns often vary with the conditions of the instrument.
  • the relative intensity of the X-ray diffraction pattern may also vary with the experimental conditions, so the order of peak intensities cannot be used as the only or decisive factor.
  • the relative intensity of the diffraction peaks in the X-ray diffraction pattern is related to the preferred orientation of the crystal, and the peak intensities shown here are illustrative rather than for absolute comparison.
  • the experimental error of the peak angle is usually 5% or less, and the error of these angles should also be taken into account, and the error of ⁇ 0.2° is usually allowed.
  • due to the influence of experimental factors such as sample thickness it will cause the overall deviation of the peak angle, and a certain deviation is usually allowed.
  • the X-ray diffraction pattern of a crystal form in the present invention does not have to be completely consistent with the X-ray diffraction pattern in the example referred to here, and the "same X-ray diffraction pattern" mentioned herein does not mean absolutely identical, identical peak positions may differ by ⁇ 0.2° and peak intensities allow for some variability. Any crystal 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 spectrum reflect the same or different crystal forms.
  • the crystalline Form A of the present invention is pure, single, substantially free of any other crystalline forms.
  • substantially free when used to refer to a new crystal form means that this crystal form contains less than 20% (weight) of other crystal forms, especially refers to less than 10% (weight) of other crystal forms, and even less More than 5% (weight) of other crystal forms, more refers to less than 1% (weight) of other crystal forms.
  • the numerical values and numerical ranges mentioned in the present invention should not be narrowly interpreted as numerical values or numerical ranges themselves, and those skilled in the art should understand that they can vary according to the specific technical environment without departing from the spirit and scope of the present invention. There are fluctuations around specific numerical values on the basis of principles, and in the present invention, such fluctuation ranges that are foreseeable by those skilled in the art are often expressed by the term "about”.
  • Root temperature in the present invention usually refers to 22°C to 28°C unless otherwise specified.
  • 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 (Panalytical) Company.
  • the method parameter of X-ray powder diffraction of the present invention is as follows:
  • the differential scanning calorimetry chart of the present invention is collected on the Q200 type and Discovery DSC 2500 type differential scanning calorimeter of TA company.
  • the method parameter of differential scanning calorimetry analysis of the present invention is as follows:
  • thermogravimetric analysis figure of the present invention is collected on the Discovery TGA 5500 type of TA company and Q5000 type thermogravimetric analyzer.
  • the method parameter of thermogravimetric analysis of the present invention is as follows:
  • the proton 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 1-5mg sample, dissolve it with 0.5mL deuterated dimethyl sulfoxide, and prepare a 2-10mg/mL solution for testing.
  • the dynamic moisture adsorption figure of the present invention is collected on the Intrinsic type and Intrinsic Plus type dynamic moisture adsorption instrument of SMS company.
  • the method parameters of the dynamic moisture adsorption test of 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 are collected on the S3500 laser particle size analyzer of Microtrac Company.
  • Microtrac S3500 is equipped with SDC (Sample Delivery Controller) sampling system.
  • SDC Sample Delivery Controller
  • This test adopts wet method, and the test dispersion medium is Isopar G (containing 0.2% lecithin).
  • the method parameter of described laser particle size analyzer is as follows:
  • the inherent dissolution rate data described in the present invention is collected on the Agilent 708DS type dissolution apparatus of Agilent Company.
  • the inherent dissolution test conditions described are as follows:
  • the polarizing microscope photos described in the present invention were collected at room temperature by Zeiss microscope Axio Scope.A1, and the microscope was equipped with 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 prior art, for example, according to the method described in patent WO2011113894A1, but the starting crystal form is not a limiting condition for preparing the crystal form of the present invention.
  • Embodiment 1 Preparation of crystal form A (anti-solvent addition-suspension stirring method)
  • the sample is at about 10.0° ⁇ 0.2°, about 14.4° ⁇ 0.2°, about 15.9° ⁇ 0.2°, about 17.5° ⁇ 0.2°, about 19.4° ⁇ 0.2°, about 20.2° ⁇ 0.2°, about 20.7° ⁇ 0.2 °, about 21.5° ⁇ 0.2°, about 22.6° ⁇ 0.2°, about 25.2° ⁇ 0.2°, and about 25.8° ⁇ 0.2° have characteristic peaks.
  • Its XRPD, TGA, DSC, and 1 H NMR are shown in Figures 1 to 4, respectively.
  • Embodiment 2 ⁇ 3 Preparation of crystal form A (gas-liquid diffusion method)
  • Embodiment 4 ⁇ 6 the preparation of crystal form A (room temperature volatilization method)
  • the crystal form A of the present invention was formulated into suspensions with SGF (simulated artificial gastric juice), FaSSIF (artificial intestinal juice in a fasting state), FeSSIF (artificial intestinal juice in a fed state) and pure water respectively, and the suspension was prepared in 1 hour, 2 hours, and 4 hours. After equilibrating for 24 hours and 24 hours, filter to obtain a saturated solution. The content of the samples in the saturated solution was determined by high performance liquid chromatography (HPLC). The test results are shown in Table 6, and the solubility curves are shown in Figures 5-8 respectively. The results show that the crystal form A of the present invention has good solubility in SGF, FaSSIF, FeSSIF and pure water.
  • Embodiment 9 Intrinsic dissolution rate of crystal form
  • the crystal form A of the present invention has a faster dissolution rate.
  • Embodiment 10 Stability comparative study
  • Embodiment 11 Contrastive research on moisture absorption
  • Moisture-absorbing the weight gain of moisture-absorbing is less than 15% but not less than 2%
  • Embodiment 12 crystal habit comparative study
  • Embodiment 13 comparative study of particle size distribution

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

Abstract

L'invention concerne une forme cristalline A d'un composé tel que représenté dans la formule (I), son procédé de préparation et son utilisation. La forme cristalline A du composé tel que représenté dans la formule (I) a un avantage dans au moins l'une parmi la solubilité, le point de fusion, la stabilité, le taux de dissolution, l'hygroscopicité, l'adhésivité, la fluidité, l'efficacité biologique, l'aptitude au traitement, l'effet de purification, la production de préparation et la sécurité. Un nouveau choix et un meilleur choix sont fournis pour la préparation de la formulation pharmaceutique contenant le composé tel que représenté dans la formule (I), et le procédé a une très grande importance pour le développement de médicaments.
PCT/CN2022/139499 2021-12-17 2022-12-16 Forme cristalline d'un dérivé de pyridine et procédé de préparation s'y rapportant WO2023109939A1 (fr)

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CN202111556283.4 2021-12-17

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102892758A (zh) * 2010-03-19 2013-01-23 诺瓦提斯公司 用于治疗cf的吡啶和吡嗪衍生物
CN110072851A (zh) * 2016-12-19 2019-07-30 诺华股份有限公司 新的吡啶甲酸衍生物及其作为中间体的用途
WO2021009695A1 (fr) * 2019-07-15 2021-01-21 Novartis Ag Formulations de (s)-3-amino-6-méthoxy-n-(3,3,3-trifluoro-2-hydroxy-2-méthylpropyl)-5-(trifluorométhyl)picolinamide

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102892758A (zh) * 2010-03-19 2013-01-23 诺瓦提斯公司 用于治疗cf的吡啶和吡嗪衍生物
CN110072851A (zh) * 2016-12-19 2019-07-30 诺华股份有限公司 新的吡啶甲酸衍生物及其作为中间体的用途
WO2021009695A1 (fr) * 2019-07-15 2021-01-21 Novartis Ag Formulations de (s)-3-amino-6-méthoxy-n-(3,3,3-trifluoro-2-hydroxy-2-méthylpropyl)-5-(trifluorométhyl)picolinamide

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
GRAND DARREN LE, GOSLING MARTIN, BAETTIG URS, BAHRA PARMJIT, BALA KAMLESH, BROCKLEHURST CARA, BUDD EMMA, BUTLER REBECCA, CHEUNG AT: "Discovery of Icenticaftor (QBW251), a Cystic Fibrosis Transmembrane Conductance Regulator Potentiator with Clinical Efficacy in Cystic Fibrosis and Chronic Obstructive Pulmonary Disease", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 64, no. 11, 10 June 2021 (2021-06-10), US , pages 7241 - 7260, XP093071850, ISSN: 0022-2623, DOI: 10.1021/acs.jmedchem.1c00343 *

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