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WO2025201325A1 - Forme solide de 4-[3-(cyclopropylméthoxy)-4-(difluorométhoxy)phénéthyl]pyridine-2(1h)-one et son procédé de préparation - Google Patents

Forme solide de 4-[3-(cyclopropylméthoxy)-4-(difluorométhoxy)phénéthyl]pyridine-2(1h)-one et son procédé de préparation

Info

Publication number
WO2025201325A1
WO2025201325A1 PCT/CN2025/084719 CN2025084719W WO2025201325A1 WO 2025201325 A1 WO2025201325 A1 WO 2025201325A1 CN 2025084719 W CN2025084719 W CN 2025084719W WO 2025201325 A1 WO2025201325 A1 WO 2025201325A1
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WO
WIPO (PCT)
Prior art keywords
crystalline form
carbon atoms
solvent
ether
cyclopropylmethoxy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/CN2025/084719
Other languages
English (en)
Chinese (zh)
Inventor
王红军
冯泽旺
沈会杰
赵焰平
候思予
田娜娜
付深振
张慧政
姜春雪
黄建宝
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Beijing Tide Pharmaceutical Co Ltd
Original Assignee
Beijing Tide Pharmaceutical Co Ltd
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Filing date
Publication date
Application filed by Beijing Tide Pharmaceutical Co Ltd filed Critical Beijing Tide Pharmaceutical Co Ltd
Publication of WO2025201325A1 publication Critical patent/WO2025201325A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • 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
    • 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
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/34—One oxygen atom
    • C07D239/36—One oxygen atom as doubly bound oxygen atom or as unsubstituted hydroxy radical

Definitions

  • the present invention relates to a solid form of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one (hereinafter referred to as "Compound A”) and/or its tautomers, a method for preparing the solid form, a pharmaceutical composition containing the solid form, and use of the solid form for preventing and/or treating phosphodiesterase-related diseases.
  • Compound A 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one
  • COPD Chronic obstructive pulmonary disease
  • First-line treatments for COPD primarily include various bronchodilators, including short-acting and long-acting ⁇ 2-agonists, short-acting and long-acting anticholinergics, combinations of ⁇ 2-agonists and anticholinergics, oral methylxanthines and roflumilast, and combinations of glucocorticoids and long-acting ⁇ 2-agonists.
  • bronchodilators including short-acting and long-acting ⁇ 2-agonists, short-acting and long-acting anticholinergics, combinations of ⁇ 2-agonists and anticholinergics, oral methylxanthines and roflumilast, and combinations of glucocorticoids and long-acting ⁇ 2-agonists.
  • existing drug therapies can mitigate the long-term decline in lung function in COPD patients. Therefore, as a chronic inflammatory disease, effective anti-inflammatory treatment for COPD patients should slow down the progression and exacerbation of the disease and reduce mortality and the occurrence of COPD-related complications.
  • Cyclic adenosine monophosphate is a crucial intracellular second messenger, primarily involved in physiological activities such as visual transmission, cell proliferation and differentiation, gene expression, inflammatory responses, apoptosis, and metabolism, through activation of the PKA pathway. Elevated intracellular cAMP levels can regulate various inflammatory mediators, thereby achieving broad-spectrum anti-inflammatory effects.
  • the balance of cAMP in the body is primarily regulated by adenylate cyclase (CA) and phosphodiesterase (PDE).
  • CA catalyzes the synthesis of cAMP from ATP, while PDE promotes the degradation of cAMP to inactive 5' - AMP. Therefore, targeted inhibition of PDE activity can elevate intracellular cAMP levels, achieving broad-spectrum anti-inflammatory effects.
  • PDE4 is the primary cAMP-degrading enzyme.
  • Roflumilast is the first selective PDE4 inhibitor for the treatment of COPD. Initially, it was developed by Nycomed and approved in Europe and Canada in 2010 for the adjuvant treatment of patients with severe chronic obstructive pulmonary disease who are frequently exacerbated. However, due to dose-dependent side effects, such as nausea, vomiting and other gastrointestinal adverse reactions, their severity is sufficient to reduce their compliance. More and more evidence shows that PDE4 inhibitors have greatly limited the widespread clinical use of this type of drug due to adverse reactions such as nausea and vomiting caused by acting on PDE4 in the central nervous system (see CN202210096345.6, which is incorporated herein by reference in its entirety).
  • the present invention provides Compound A (4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one) as shown below, which undergoes tautomerism at a certain temperature.
  • the present invention relates to a solid form of Compound A and/or its tautomers:
  • the present invention provides crystalline forms of Compound A (4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one) (and/or its tautomers), including Form I and Form II, wherein Compound A is an anhydrate.
  • the present invention provides a method for preparing crystalline forms of Compound A (and/or its tautomers) of the present invention, including Form I and Form II.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising any one or more crystalline forms of Compound A (and/or its tautomers) of the present invention (e.g., Form I and Form II), and one or more pharmaceutically acceptable carriers or excipients.
  • the present invention provides use of a crystalline form (eg, Form I and Form II) of Compound A (and/or its tautomers) of the present invention in the preparation of a medicament for preventing and/or treating phosphodiesterase-related diseases.
  • a crystalline form eg, Form I and Form II
  • Compound A and/or its tautomers
  • the crystalline form of Compound A (and/or its tautomers) of the present invention not only has excellent effects in preventing and/or treating phosphodiesterase-related diseases, but also has other advantages.
  • the crystalline form of Compound A (and/or its tautomers) of the present invention has excellent physical properties (including solubility, dissolution rate, light resistance, low hygroscopicity, high temperature resistance, high humidity resistance, fluidity, etc.), and in properties such as bioavailability, physical and/or chemical stability and ease of preparation, the crystalline form of Compound A (and/or its tautomers) of the present invention has more excellent properties.
  • FIG1 is an X-ray powder diffraction pattern of Form I of anhydrate of Compound A.
  • FIG2 is a differential scanning calorimetry (DSC) spectrum and a thermogravimetric analysis (TGA) spectrum of Form I of anhydrate of Compound A.
  • FIG3 is a scanning electron micrograph of Form I of anhydrate of Compound A.
  • FIG4 is an X-ray powder diffraction pattern of Form II of anhydrate of Compound A.
  • FIG5 is a differential scanning calorimetry (DSC) spectrum and a thermogravimetric analysis (TGA) spectrum of Form II of anhydrate of Compound A.
  • FIG6 is a scanning electron micrograph of Form II of anhydrate of Compound A.
  • FIG7 is a comparison of XRPD patterns of Form I of anhydrate of Compound A before and after the room temperature stability test.
  • FIG8 is a comparison of XRPD patterns of the anhydrate crystalline form I of compound A in the water activity experiment.
  • FIG9 is a comparison of HPLC spectra of Form I of anhydrate of Compound A before and after the solid stability experiment.
  • FIG11 is a comparison of X-ray powder diffraction patterns of Form I and Form II of anhydrate of Compound A before and after the solid stability experiment.
  • FIG12 is a comparison of X-ray powder diffraction patterns of Form I of Compound A anhydrate before and after the high humidity stability test.
  • FIG15 is an XRPD pattern of samples obtained by competitive beating of Form I and Form II of Compound A anhydrate.
  • Figure 16 is the XRPD patterns of the samples obtained by competitive beating of Form I and Form II of Compound A anhydrate at 50°C.
  • FIG24 shows the differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) spectra of compound A obtained by medium-pressure column chromatography.
  • thermogravimetric analysis (TGA) spectrum refers to a curve recorded by a thermogravimetric analyzer.
  • the term "substantially the same" for X-ray diffraction peak positions means that representative peak position and intensity variations are taken into account. For example, one skilled in the art will understand that peak positions (2 ⁇ ) will show some variation, typically up to ⁇ 0.1, ⁇ 0.2, or ⁇ 0.3 degrees, and that the instrument used to measure diffraction will also show some variation. In addition, one skilled in the art will understand that relative peak intensities will show variation between instruments as well as variation due to degree of crystallinity, preferred orientation, prepared sample surface, and other factors known to one skilled in the art. Similarly, as used herein, “substantially the same” for DSC spectra is also intended to encompass variations associated with these analytical techniques known to one skilled in the art. For example, for well-defined peaks, there will typically be variations of up to ⁇ 0.3°C in differential scanning calorimetry spectra, and even greater (e.g., up to ⁇ 1°C) for broad peaks.
  • liquid-state NMR spectra in this application are preferably collected on a Bruker 400M NMR spectrometer, and unless otherwise stated, DMSO- d6 is used as the solvent.
  • the polarizing microscopy data in this application are preferably collected using Polarizing Microscope ECLIPSE LV100POL (Nikon, JPN).
  • the prepared salt or its crystalline form can be recovered by methods including decantation, centrifugation, evaporation, gravity filtration, suction filtration or any other technique for solid recovery under increased or reduced pressure.
  • the recovered solid can be optionally dried.
  • "Drying" in the present invention is carried out under reduced pressure (preferably vacuum) until the content of residual solvent is reduced to within the limits given by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (“ICH”) guidelines.
  • the residual solvent content depends on the type of solvent, but does not exceed about 5000 ppm, or preferably about 4000 ppm, or more preferably about 3000 ppm.
  • the drying can be carried out in a tray dryer, a vacuum oven, an air oven, a cone vacuum dryer, a rotary vacuum dryer, a fluidized bed dryer, a rotary flash dryer, a flash dryer, etc.
  • the drying can be carried out at a temperature of less than about 100°C, less than about 80°C, less than about 60°C, less than about 50°C, less than about 30°C, or any other suitable temperature, at atmospheric pressure or reduced pressure (preferably vacuum) for any desired time (such as about 1, 2, 3, 5, 10, 15, 20, 24 hours or overnight) that can achieve the desired result, as long as the quality of the salt does not deteriorate.
  • the drying can be carried out any desired number of times until the desired product quality is achieved.
  • the dried product can optionally undergo a comminution operation to produce the desired particle size. Grinding or micronization can be performed before or after drying of the product. Techniques that can be used to reduce particle size include, but are not limited to, ball milling, roller milling, and hammer milling, as well as jet milling.
  • anhydrate as used herein preferably means a crystalline form which does not contain water molecules as structural elements.
  • a “good solvent” is a solvent that has a good solubility for the solute.
  • Anti-solvent refers to a solvent that is miscible with the solvent but slightly soluble, slightly soluble, extremely slightly soluble, or almost insoluble or insoluble in the solute in a given solution system.
  • Alkanes having 5-10 carbon atoms refers to straight-chain or branched saturated hydrocarbon groups having 5 to 10 carbon atoms.
  • the alkane is an alkane containing 5-8 carbon atoms.
  • the alkane is selected from n-pentane, n-hexane, n-heptane and n-octane.
  • Olefins having 5-10 carbon atoms refers to straight-chain or branched hydrocarbon groups having 5 to 10 carbon atoms and at least one carbon-carbon double bond.
  • Alkynes having 5-10 carbon atoms refers to straight or branched chain hydrocarbon groups having 5 to 10 carbon atoms, at least one carbon-carbon triple bond, and optionally one or more carbon-carbon double bonds.
  • Halo or "halogen” refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).
  • “Ether having 2 to 10 carbon atoms” refers to a chain or cyclic compound of the formula RO-R' having 2 to 10 carbon atoms, wherein R and R' each represent a C 1-6 alkyl group and one or more (e.g., 1, 2, 3, or 4) carbon atoms in the C 1-6 alkyl group are optionally replaced by oxygen atoms, or R and R' together with the oxygen atom to which they are attached form a 3-8 membered cyclic ether, which optionally contains 1-2 oxygen atoms.
  • the ether is an ether having 3 to 10 carbon atoms.
  • the ether is a 3-6 membered cyclic ether containing 1-2 oxygen atoms, preferably selected from tetrahydrofuran, 2-methyltetrahydrofuran, and dioxane.
  • the ether is a chain ether having 2 to 6 carbon atoms containing 1-2 oxygen atoms, preferably ethyl ether, propyl ether, butyl ether, diisopropyl ether, and methyl tert-butyl ether, more preferably ethyl ether, diisopropyl ether, and methyl tert-butyl ether.
  • the ketone is a chain hydrocarbon ketone having 3 to 6 carbon atoms selected from acetone, butanone, pentanone, and hexanone, preferably selected from acetone and butanone.
  • alcohols having 3 to 8 carbon atoms refers to an alcohol of the formula R-OH having 3 to 8 carbon atoms, wherein R represents a C 1-6 alkyl group.
  • the volume ratio of the good solvent to the anti-solvent is about 1:1 to 1:10, preferably 1:3.
  • the present invention provides Form II of an anhydrate of Compound A (and/or its tautomers):
  • the XRPD pattern of the Form II includes characteristic peaks at approximately 12.5 ⁇ 0.3, 17.3 ⁇ 0.3, 20.6 ⁇ 0.3 and 23.2 ⁇ 0.3 2 ⁇ (°).
  • the XRPD pattern of Form II further includes characteristic peaks at approximately 4.1 ⁇ 0.3, 8.3 ⁇ 0.3, 12.5 ⁇ 0.3, 17.3 ⁇ 0.3, 20.6 ⁇ 0.3, 21.0 ⁇ 0.3, 23.2 ⁇ 0.3, 23.5 ⁇ 0.3 and 26.5 ⁇ 0.3 2 ⁇ (°).
  • the XRPD spectrum of the crystalline form II also includes characteristic peaks at approximately 4.1 ⁇ 0.3, 8.3 ⁇ 0.3, 10.9 ⁇ 0.3, 12.5 ⁇ 0.3, 17.3 ⁇ 0.3, 19.0 ⁇ 0.3, 19.5 ⁇ 0.3, 20.6 ⁇ 0.3, 21.0 ⁇ 0.3, 23.2 ⁇ 0.3, 23.5 ⁇ 0.3, and 26.5 ⁇ 0.3 2 ⁇ (°).
  • the XRPD pattern of Form II comprises peaks at approximately the following 2 ⁇ (°) positions: 4.1 ⁇ 0.3, 8.3 ⁇ 0.3, 10.9 ⁇ 0.3, 11.5 ⁇ 0.3, 12.0 ⁇ 0.3, 12.5 ⁇ 0.3, 13.4 ⁇ 0.3, 16.1 ⁇ 0.3, 16.7 ⁇ 0.3, 17.3 ⁇ 0.3, 19.0 ⁇ 0.3, 19. 5 ⁇ 0.3, 20.6 ⁇ 0.3, 21.0 ⁇ 0.3, 21.3 ⁇ 0.3, 21.5 ⁇ 0.3, 22.1 ⁇ 0.3, 23.2 ⁇ 0.3, 23.5 ⁇ 0.3, 24.4 ⁇ 0.3, 24.6 ⁇ 0.3, 25.4 ⁇ 0.3, 25.7 ⁇ 0.3, 26.5 ⁇ 0.3, 27.7 ⁇ 0.3, 28.2 ⁇ 0.3 and 29.7 ⁇ 0.3.
  • the XRPD pattern of the Form II includes peaks at diffraction angles (2 ⁇ ) substantially the same as those shown in Figure 4. In a most preferred embodiment, the Form II has an XRPD pattern substantially the same as that shown in Figure 4.
  • the DSC-TGA spectrum of the crystalline Form II includes characteristic peaks substantially the same as those shown in Figure 5. In a most preferred embodiment, the crystalline Form II has a DSC-TGA spectrum substantially the same as that shown in Figure 5.
  • the scanning electron microscope image of the Form II is substantially the same as that shown in FIG6 .
  • the present invention provides a method for preparing Form II, comprising the following steps:
  • Form II 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one (and/or its tautomers) or Form I is suspended in a solvent system to obtain the Form II.
  • the present invention provides a method for preparing Form II, comprising the following steps:
  • step 2) adding an anti-solvent to the solution obtained in step 1), and stirring at room temperature or under heating conditions to obtain the crystal form II.
  • a solvent system is used to convert the anhydrate form I of compound A (and/or its tautomers) into form II under heating conditions (e.g., heating to 30-70°C, preferably 50°C), and the form I is suspended in an anti-solvent system (e.g., for 1-5 days, such as 3 days), and filtered to obtain crystals.
  • the solvent system is a mixture of a good solvent and an anti-solvent system.
  • the good solvent is an ether having 3-10 carbon atoms, preferably a cyclic ether, such as furans (including tetrahydrofurans) and dioxanes, preferably tetrahydrofuran, 2-methyltetrahydrofuran or dioxane, or a simple ketone having 3-10 carbon atoms, preferably a non-cyclic ketone, such as acetone or butanone.
  • a cyclic ether such as furans (including tetrahydrofurans) and dioxanes, preferably tetrahydrofuran, 2-methyltetrahydrofuran or dioxane
  • a simple ketone having 3-10 carbon atoms preferably a non-cyclic ketone, such as acetone or butanone.
  • the anti-solvent is a chain ether with 2-6 carbon atoms containing 1-2 oxygen atoms. More preferably, the anti-solvent is an alkane containing 5-8 carbon atoms, preferably n-heptane.
  • the weight volume ratio (g/mL) of compound A (and/or its tautomers) and good solvent is about 1:(1-50), preferably about 1:(5-30), preferably 1:10 or 1:30; more preferably 1:(5-10); preferably 1:5, 1:6, 1:7, 1:8 or 1:9.
  • the volume ratio of the good solvent to the anti-solvent is about 1:1 to 1:10.
  • the present invention relates to the following technical solutions.
  • the present invention provides Form I of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one (and/or its tautomers), which comprises peaks at approximately 12.6 ⁇ 0.3, 20.3 ⁇ 0.3, 20.9 ⁇ 0.3, 22.0 ⁇ 0.3 and 23.1 ⁇ 0.3 2 ⁇ (°) in an X-ray powder diffraction (XRPD) spectrum obtained using Cu K ⁇ radiation.
  • XRPD X-ray powder diffraction
  • the present invention provides Form I of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one (and/or its tautomers), wherein the XRPD pattern further comprises peaks at approximately 8.4 ⁇ 0.3, 11.3 ⁇ 0.3, 15.3 ⁇ 0.3, 16.9 ⁇ 0.3 and 26.7 ⁇ 0.3 2 ⁇ (°).
  • the present invention provides a crystalline Form I of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one (and/or its tautomers), wherein the XRPD pattern comprises peaks at approximately the following 2 ⁇ (°) positions: 4.0 ⁇ 0.3, 8.4 ⁇ 0.3, 11.3 ⁇ 0.3, 11.9 ⁇ 0.3, 12.6 ⁇ 0.3, 14.0 ⁇ 0.3, 15.3 ⁇ 0.3, 16.9 ⁇ 0.3, 18.3 ⁇ 0.3, 18.9 ⁇ 0.3, 19.9 ⁇ 0.3, .3, 20.3 ⁇ 0.3, 20.9 ⁇ 0.3, 21.2 ⁇ 0.3, 22.0 ⁇ 0.3, 22.5 ⁇ 0.3, 23.1 ⁇ 0.3, 24.1 ⁇ 0.3, 24.7 ⁇ 0.3, 25.2 ⁇ 0.3, 25.8 ⁇ 0.3, 26.2 ⁇ 0.3, 26.7 ⁇ 0.3, 27.9 ⁇ 0.3, 29.1 ⁇ 0.3, 29.5 ⁇ 0.3, 29.8 ⁇ 0.3, 30.4 ⁇ 0.3, 31.3 ⁇ 0.3, 31.6 ⁇ 0.3, 38.2 ⁇ 0.3 and 4
  • the present invention provides Form I of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one (and/or its tautomers), wherein the XRPD pattern comprises peaks at approximately:
  • the present invention provides Form I of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one (and/or its tautomers) having an XRPD pattern substantially the same as shown in FIG1 .
  • the present invention provides Form I of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one (and/or its tautomers), which has endothermic peaks at 96 ⁇ 3°C and 129 ⁇ 3°C in the differential scanning calorimetry (DSC) spectrum.
  • DSC differential scanning calorimetry
  • the present invention provides Form I of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one (and/or its tautomers), which has a thermogravimetric analysis (TGA) spectrum, wherein the TGA spectrum shows that the crystalline form does not lose significant weight before being heated to the melting point.
  • TGA thermogravimetric analysis
  • the present invention provides Form I of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one (and/or its tautomers), which has a DSC-TGA spectrum substantially the same as shown in Figure 2.
  • the present invention provides a method for preparing Form I of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one (and/or its tautomers), comprising:
  • Method 1 includes the following steps:
  • step 1) of method 1 or method 2 is carried out at room temperature or under heating conditions, and the heating is heating to 30-70°C, preferably heating to 50°C.
  • the stirring in step 2) of method 1 is carried out at room temperature or under cooling conditions, and the cooling is cooling to 0-10°C, preferably cooling to 5°C.
  • the present invention provides a method for preparing Form I of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one (and/or its tautomers), wherein the good solvent is selected from an ether solvent having 3 to 10 carbon atoms and a ketone solvent having 3 to 10 carbon atoms.
  • the present invention provides a method for preparing Form I of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one (and/or its tautomers), wherein the ether solvent is a 3-6 membered cyclic ether containing 1-2 oxygen atoms, preferably selected from tetrahydrofuran, 2-methyltetrahydrofuran and dioxane; wherein the ketone solvent is a chain hydrocarbon ketone of 3-6 carbon atoms, preferably selected from acetone and butanone.
  • the present invention provides a method for preparing Form I of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one (and/or its tautomers), wherein the anti-solvents in Method 1 and Method 2 are each an alkane having 5-10 carbon atoms, a halogenated alkane having 5-10 carbon atoms, an olefin having 5-10 carbon atoms, an alkyne having 5-10 carbon atoms, an aromatic hydrocarbon having 6-10 carbon atoms, an ether having 2-6 carbon atoms, an ester having 4-10 carbon atoms, an alcohol having 3-8 carbon atoms, and water; preferably, the anti-solvents are each an alkane containing 5-8 carbon atoms.
  • the present invention provides a method for preparing Form I of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one (and/or its tautomers), wherein the antisolvent is selected from n-hexane, n-heptane, ethyl acetate, isopropanol, toluene, diethyl ether, diisopropyl ether, methyl tert-butyl ether and water.
  • the present invention provides a method for preparing Form I of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one (and/or its tautomers), wherein the weight volume ratio (g/mL) of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one (and/or its tautomers) to the good solvent is about 1:(1-50), preferably 1:(5-30), preferably 1:10 or 1:30; more preferably 1:(5-10); preferably 1:5, 1:6, 1:7, 1:8 or 1:9.
  • the present invention provides a method for preparing Form I of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one (and/or its tautomers), wherein the volume ratio of the good solvent to the antisolvent is about 1:1 to 1:10, preferably 1:3.
  • the present invention provides Form II of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one (and/or its tautomers), which comprises peaks at approximately 12.5 ⁇ 0.3, 17.3 ⁇ 0.3, 20.6 ⁇ 0.3 and 23.2 ⁇ 0.3 2 ⁇ (°) in an X-ray powder diffraction (XRPD) spectrum obtained using Cu K ⁇ radiation.
  • XRPD X-ray powder diffraction
  • the present invention provides Form II of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one (and/or its tautomers), wherein the XRPD pattern further comprises peaks at approximately 4.1 ⁇ 0.3, 8.3 ⁇ 0.3, 21.0 ⁇ 0.3, 23.5 ⁇ 0.3 and 26.5 ⁇ 0.3 2 ⁇ (°).
  • the present invention provides Form II of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one (and/or its tautomers), wherein the XRPD pattern further comprises peaks at approximately 10.9 ⁇ 0.3, 19.0 ⁇ 0.3 and 19.5 ⁇ 0.3 2 ⁇ (°).
  • the present invention provides Form II of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one (and/or its tautomers), wherein the XRPD pattern comprises peaks at approximately:
  • the present invention provides Form II of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one (and/or its tautomers), which includes endothermic peaks at approximately 108 ⁇ 3°C and 128 ⁇ 3°C and an exothermic peak at approximately 270 ⁇ 3°C in a differential scanning calorimetry (DSC) spectrum.
  • DSC differential scanning calorimetry
  • the present invention provides Form II of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one (and/or its tautomers), which has a thermogravimetric analysis (TGA) spectrum, wherein the TGA spectrum shows that the crystalline form has no obvious weight loss before being heated to the melting point.
  • TGA thermogravimetric analysis
  • Method I It includes the following steps:
  • Method II which comprises the following steps:
  • step 2) adding an anti-solvent to the solution obtained in step 1), and stirring at room temperature or under heating conditions to obtain the crystal form II.
  • the present invention provides a method for preparing Form II of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one (and/or its tautomers), wherein the heating in step 2) of method I or method II is heating to 30-70°C, preferably 50°C.
  • the present invention provides a method for preparing Form II of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one (and/or its tautomers), wherein the solvent system is a two-solvent system composed of a mixture of a good solvent and an anti-solvent system.
  • the present invention provides a method for preparing Form II of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one (and/or its tautomers), wherein the good solvent is selected from an ether solvent having 3 to 10 carbon atoms and a ketone solvent having 3 to 10 carbon atoms.
  • the present invention provides a method for preparing Form II of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one (and/or its tautomers), wherein the ether solvent is a 3-6 membered cyclic ether containing 1-2 oxygen atoms, preferably selected from tetrahydrofuran, 2-methyltetrahydrofuran and dioxane; wherein the ketone solvent is a chain hydrocarbon ketone of 3-6 carbon atoms, preferably selected from acetone and butanone.
  • the present invention provides a method for preparing Form II of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one (and/or its tautomers), wherein the anti-solvent is an alkane having 5-10 carbon atoms, a halogenated alkane having 5-10 carbon atoms, an olefin having 5-10 carbon atoms, an alkyne having 5-10 carbon atoms, an aromatic hydrocarbon having 6-10 carbon atoms, an ether having 2-6 carbon atoms, an ester having 4-10 carbon atoms, an alcohol having 3-8 carbon atoms, and water; preferably, the anti-solvent is an alkane containing 5-8 carbon atoms.
  • the present invention provides a method for preparing Form II of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one (and/or its tautomers), wherein the antisolvent is selected from n-hexane, n-heptane, ethyl acetate, isopropanol, toluene, diethyl ether, diisopropyl ether, methyl tert-butyl ether and water.
  • the present invention provides a method for preparing Form II of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one (and/or its tautomers), wherein the weight volume ratio (g/mL) of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one (and/or its tautomers) to the good solvent is about 1:(1-50), preferably about 1:(5-30), preferably 1:10 or 1:30; more preferably 1:(5-10); preferably 1:5, 1:6, 1:7, 1:8 or 1:9.
  • the present invention provides a method for preparing Form II of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one (and/or its tautomers), wherein the volume ratio of the good solvent to the antisolvent is about 1:1 to 1:10.
  • the present invention provides a composition comprising Form I and/or Form II and a pharmaceutically acceptable carrier or excipient.
  • the present invention provides a composition comprising a crystalline form of a compound of the formula 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2-(1H)-one or a tautomer thereof:
  • the present invention provides a composition comprising the above-mentioned crystalline form, wherein the crystalline form comprises peaks at approximately 12.6 ⁇ 0.3, 20.3 ⁇ 0.3, 20.9 ⁇ 0.3, 22.0 ⁇ 0.3 and 23.1 ⁇ 0.3 2 ⁇ (°) in an X-ray powder diffraction (XRPD) pattern obtained using Cu Ka radiation.
  • XRPD X-ray powder diffraction
  • the XRPD pattern of the crystalline form further comprises peaks at approximately 4.0 ⁇ 0.3, 22.5 ⁇ 0.3, 24.1 ⁇ 0.3, 25.2 ⁇ 0.3 and 26.2 ⁇ 0.3 2 ⁇ (°).
  • the XRPD pattern of the crystalline form further comprises peaks at approximately 8.4 ⁇ 0.3, 11.3 ⁇ 0.3, 15.3 ⁇ 0.3, 16.9 ⁇ 0.3 and 26.7 ⁇ 0.3 2 ⁇ (°).
  • the present invention provides a composition comprising the above-mentioned crystalline form, wherein the XRPD pattern of the crystalline form comprises peaks at about the following 2 ⁇ (°) positions: 4.0 ⁇ 0.3, 8.4 ⁇ 0.3, 11.3 ⁇ 0.3, 11.9 ⁇ 0.3, 12.6 ⁇ 0.3, 14.0 ⁇ 0.3, 15.3 ⁇ 0.3, 16.9 ⁇ 0.3, 18.3 ⁇ 0.3, 18.9 ⁇ 0.3, 19.9 ⁇ 0.3, 20.3 ⁇ 0.3, 20.9 ⁇ 0.3, 0.3, 21.2 ⁇ 0.3, 22.0 ⁇ 0.3, 22.5 ⁇ 0.3, 23.1 ⁇ 0.3, 24.1 ⁇ 0.3, 24.7 ⁇ 0.3, 25.2 ⁇ 0.3, 25.8 ⁇ 0.3, 26.2 ⁇ 0.3, 26.7 ⁇ 0.3, 27.9 ⁇ 0.3, 29.1 ⁇ 0.3, 29.5 ⁇ 0.3, 29.8 ⁇ 0.3, 30.4 ⁇ 0.3, 31.3 ⁇ 0.3, 31.6 ⁇ 0.3, 38.2 ⁇ 0.3 and 40.3 ⁇ 0.3.
  • the present invention provides a composition comprising the above-described crystalline form, wherein the XRPD pattern of the crystalline form comprises a peak at about:
  • the present invention provides a composition comprising the above-described crystalline form, wherein the crystalline form has an XRPD pattern substantially the same as that shown in FIG. 1 .
  • the crystalline form comprises endothermic peaks at 96 ⁇ 3°C and 129 ⁇ 3°C in a differential scanning calorimetry (DSC) spectrum.
  • the crystalline form has a thermogravimetric analysis (TGA) spectrum, and the TGA spectrum shows that the crystalline form does not lose significant weight before being heated to the melting point.
  • the crystalline form has a DSC-TGA spectrum substantially the same as that shown in Figure 2.
  • the present invention provides a composition comprising a crystalline form, wherein the crystalline form comprises peaks at approximately 12.5 ⁇ 0.3, 17.3 ⁇ 0.3, 20.6 ⁇ 0.3, and 23.2 ⁇ 0.3 2 ⁇ (°) in an X-ray powder diffraction (XRPD) pattern obtained using Cu Ka radiation.
  • XRPD X-ray powder diffraction
  • the XRPD pattern of the crystalline form further comprises peaks at approximately 4.1 ⁇ 0.3, 8.3 ⁇ 0.3, 21.0 ⁇ 0.3, 23.5 ⁇ 0.3, and 26.5 ⁇ 0.3 2 ⁇ (°).
  • the XRPD pattern of the crystalline form further comprises peaks at approximately 10.9 ⁇ 0.3, 19.0 ⁇ 0.3, and 19.5 ⁇ 0.3 2 ⁇ (°).
  • the present invention provides a composition comprising a crystalline form, wherein the XRPD pattern of the crystalline form comprises peaks at about the following 2 ⁇ (°) positions: 4.1 ⁇ 0.3, 8.3 ⁇ 0.3, 10.9 ⁇ 0.3, 11.5 ⁇ 0.3, 12.0 ⁇ 0.3, 12.5 ⁇ 0.3, 13.4 ⁇ 0.3, 16.1 ⁇ 0.3, 16.7 ⁇ 0.3, 17.3 ⁇ 0.3, 1 9.0 ⁇ 0.3, 19.5 ⁇ 0.3, 20.6 ⁇ 0.3, 21.0 ⁇ 0.3, 21.3 ⁇ 0.3, 21.5 ⁇ 0.3, 22.1 ⁇ 0.3, 23.2 ⁇ 0.3, 23.5 ⁇ 0.3, 24.4 ⁇ 0.3, 24.6 ⁇ 0.3, 25.4 ⁇ 0.3, 25.7 ⁇ 0.3, 26.5 ⁇ 0.3, 27.7 ⁇ 0.3, 28.2 ⁇ 0.3 and 29.7 ⁇ 0.3.
  • the present invention provides a composition comprising a crystalline form, wherein the crystalline form has an XRPD pattern substantially the same as shown in FIG. 4 .
  • the present invention provides the use of Form I or Form II or a composition comprising the same in the preparation of a medicament for preventing and/or treating a phosphodiesterase-related disease.
  • the phosphodiesterase-related disease is chronic obstructive pulmonary disease (COPD) and/or asthma.
  • COPD chronic obstructive pulmonary disease
  • Test conditions The anode target material is copper, the light tube is set to (40KV 40mA), the 2 ⁇ scanning angle of the sample is from 3° to 40°, and the scanning step is 0.02°.
  • Test conditions automatic weighing in a heating furnace, heating rate of 10°C/min, dry nitrogen as purge gas.
  • reaction solution was cooled to room temperature, quenched with saturated aqueous sodium bicarbonate (10 mL) and extracted three times with ethyl acetate (3 ⁇ 20 mL). The organic phases were combined, washed twice with saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate.
  • A-3 was obtained as a white solid by medium-pressure column chromatography in a 52.4% yield.
  • the Form I prepared in Example 2 was placed in an open container at 92.5% RH/25°C for 7 days for stability investigation.
  • the XRPD spectrum was measured using a Bruker D8 advance X-ray powder diffractometer (see Figure 12). The results showed that the Form I sample showed no change in crystal form at 92.5% RH/25°C within 7 days, indicating excellent stability.
  • the crystalline form of the present invention has good fluidity and is easy to crush, thereby facilitating the preparation of pharmaceutical compositions.

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Abstract

La présente invention concerne une forme cristalline de 4-[3-(cyclopropylméthoxy)-4-(difluorométhoxy)phénéthyl]pyridine-2(1H)-one, son procédé de préparation, une composition contenant la forme cristalline et son utilisation dans le traitement de maladies associées aux phosphodiestérases.
PCT/CN2025/084719 2024-03-26 2025-03-25 Forme solide de 4-[3-(cyclopropylméthoxy)-4-(difluorométhoxy)phénéthyl]pyridine-2(1h)-one et son procédé de préparation Pending WO2025201325A1 (fr)

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CN102311382A (zh) * 2010-06-29 2012-01-11 大道隆达（北京）医药科技发展有限公司 罗氟司特的新晶态及其制备方法
CN103012256A (zh) * 2012-12-11 2013-04-03 四川科伦药物研究有限公司 罗氟司特的合成方法
CN103382177A (zh) * 2012-05-02 2013-11-06 中国药科大学 罗氟司特n-氧化物的多晶型物、制备方法和药物组合物
CN111777550A (zh) * 2020-06-01 2020-10-16 山东希尔康泰药业有限公司 罗氟司特结晶性粉末原料药生产制备方法
CN115466169A (zh) * 2021-06-10 2022-12-13 中国医学科学院药物研究所 取代邻苯二酚醚类化合物及其制备方法和应用
CN116535350A (zh) * 2022-01-26 2023-08-04 中国医学科学院药物研究所 3,4-烷氧取代苯乙基内酰胺类化合物及其制备方法和应用
CN117820209A (zh) * 2022-09-27 2024-04-05 中国医学科学院药物研究所 一种4-[3-（环丙基甲氧基）-4-（二氟甲氧基）苯乙基]吡啶-2-醇的制备方法

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102311382A (zh) * 2010-06-29 2012-01-11 大道隆达（北京）医药科技发展有限公司 罗氟司特的新晶态及其制备方法
CN103382177A (zh) * 2012-05-02 2013-11-06 中国药科大学 罗氟司特n-氧化物的多晶型物、制备方法和药物组合物
CN103012256A (zh) * 2012-12-11 2013-04-03 四川科伦药物研究有限公司 罗氟司特的合成方法
CN111777550A (zh) * 2020-06-01 2020-10-16 山东希尔康泰药业有限公司 罗氟司特结晶性粉末原料药生产制备方法
CN115466169A (zh) * 2021-06-10 2022-12-13 中国医学科学院药物研究所 取代邻苯二酚醚类化合物及其制备方法和应用
CN116535350A (zh) * 2022-01-26 2023-08-04 中国医学科学院药物研究所 3,4-烷氧取代苯乙基内酰胺类化合物及其制备方法和应用
CN117820209A (zh) * 2022-09-27 2024-04-05 中国医学科学院药物研究所 一种4-[3-（环丙基甲氧基）-4-（二氟甲氧基）苯乙基]吡啶-2-醇的制备方法

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