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WO2025162289A2 - Forme cristalline d'un inhibiteur de pde4b et son utilisation pharmaceutique - Google Patents

Forme cristalline d'un inhibiteur de pde4b et son utilisation pharmaceutique

Info

Publication number
WO2025162289A2
WO2025162289A2 PCT/CN2025/074794 CN2025074794W WO2025162289A2 WO 2025162289 A2 WO2025162289 A2 WO 2025162289A2 CN 2025074794 W CN2025074794 W CN 2025074794W WO 2025162289 A2 WO2025162289 A2 WO 2025162289A2
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WO
WIPO (PCT)
Prior art keywords
crystalline form
positions
formula
following
ray powder
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/CN2025/074794
Other languages
English (en)
Chinese (zh)
Other versions
WO2025162289A3 (fr
Inventor
宫正
陈清平
马金翼
蒋琦
范江
窦赢
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.)
Tibet Haisco Pharmaceutical Co Ltd
Original Assignee
Tibet Haisco Pharmaceutical Co Ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Tibet Haisco Pharmaceutical Co Ltd filed Critical Tibet Haisco Pharmaceutical Co Ltd
Publication of WO2025162289A2 publication Critical patent/WO2025162289A2/fr
Publication of WO2025162289A3 publication Critical patent/WO2025162289A3/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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention relates to a crystal form of a compound and a salt thereof, a preparation method and application thereof, and specifically to a PDE4B inhibitor compound and a crystal form of a salt thereof, a preparation method thereof and application thereof in preparing drugs for treating PDE4B-mediated related diseases, belonging to the field of medicinal chemistry.
  • PDE4 inhibitors produce antidepressant effects in humans and animals by enhancing cAMP signaling in the brain.
  • PDE4 inhibitors also play an important role in the treatment of other central nervous system diseases, including Alzheimer's disease, Parkinson's disease, schizophrenia, stroke, and Huntington's disease.
  • Significant progress has also been made in the research and development of PDE4 inhibitors for the treatment of respiratory diseases such as asthma and chronic obstructive pulmonary disease.
  • the rationale behind the development of these drugs stems from the role of PDE4 in inhibiting the functions of a range of inflammatory cells and resident cells, which is believed to be involved in the pathogenesis of these diseases.
  • cyclic adenosine monophosphate can block the proliferation and chemotaxis of inflammatory cells and inhibit the release of inflammatory and cytotoxic mediators in the lungs.
  • PDE4 is particularly abundant in immune cells, inflammatory cells, and smooth muscle cells.
  • PDE4 inhibitors primarily exert their anti-inflammatory effects by inhibiting PDE4 hydrolysis, increasing cAMP levels in the body, suppressing the release of inflammatory factors, and promoting the production of anti-inflammatory mediators.
  • Roflumilast is clinically used to treat COPD and has significant anti-inflammatory effects, inhibiting the release of inflammatory mediators such as TNF- ⁇ , interleukins, and chemokines by monocytes, macrophages, and T cells.
  • these inhibitors are commonly associated with serious side effects such as nausea and vomiting, which limits their clinical application.
  • isoform B of phosphodiesterase 4 (PDE4B) is involved in inflammatory responses and participates in the release of various inflammatory mediators, while isoform D is closely associated with side effects such as nausea and vomiting. This provides new insights into the identification of PDE4 inhibitors with reduced side effects. Designing PDE4B inhibitors may reduce the impact of these side effects and promote further clinical application.
  • Phosphodiesterase 4 (PDE4A), a phosphodiesterase (PDE4B), is highly selective for c-AMP and has four isoforms: PDE4A, 4B, 4C, and 4D, with at least 25 splice variants.
  • the protein sequences of the catalytic domains of the four PDE4 isoforms are highly homologous, and inhibitors targeting the catalytic domain do not exhibit isoform selectivity, whereas most reported classical PDE4 inhibitors target the catalytic domain.
  • polymorphs or salt forms have different physical properties, which influence pharmaceutical parameters such as storage stability, compressibility, and density (which are important for formulation and product manufacturing), as well as dissolution rate (a key factor in determining bioavailability). Therefore, the discovery of polymorphs or salt forms with excellent activity, high safety, and minimal side effects holds great promise for clinical development.
  • PCT/CN2023/112061 describes a compound of formula (I) which has a good inhibitory effect on PDE4B.
  • the present invention provides a small molecule compound having PDE4B inhibitory activity or a crystalline form of a pharmaceutically acceptable salt thereof.
  • the compound is represented by formula (I) and has high activity, low toxic side effects, excellent pharmacokinetic characteristics and high bioavailability.
  • the crystalline form of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof has advantages including, but not limited to, ease of processing and crystallization, convenient handling, ease of purification, ease of industrialization, good fluidity, ease of micronization, high solubility, good pharmacokinetic properties and good stability, and is suitable for the preparation of pharmaceutical preparations.
  • the present invention provides a crystalline form of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof.
  • the pharmaceutically acceptable salt is selected from maleate, 2-naphthalenesulfonate, 1,5-naphthalenedisulfonate, fumarate, hydrohalide (preferably hydrobromide and hydrochloride), sulfate, phosphate, L-tartrate, citrate, L-malate, hippurate, D-glucuronate, glycolate, mucate, succinate, lactate, orotate, pamoate, glycinate, alanine, arginine, cinnamate, benzoate, benzenesulfonate, p-toluenesulfonate, acetate, propionate, valerate, triphenylacetate, L-proline, ferulate, 2-hydroxyethanesulfonate, mandelate, nitrate, methanesulfonate, malonate, gentisate, salicylate, oxalate, or glutarate;
  • hydrohalide preferably hydrobromide and hydroch
  • the pharmaceutically acceptable salt is selected from benzenesulfonate, L-malate, phosphate, sulfate, p-toluenesulfonate, hydrochloride, maleate, 2-naphthalenesulfonate, hydrobromide, methanesulfonate, citrate, mandelate, lactobionate, succinate, salicylate, 1,5-naphthalenedisulfonate, fumarate, nicotinate, hippurate, and oxalate;
  • the pharmaceutically acceptable salt is selected from the group consisting of methanesulfonate, hydrochloride, p-toluenesulfonate;
  • the pharmaceutically acceptable salt is selected from hydrochloride
  • the molar ratio of the compound represented by formula (I): the pharmaceutically acceptable salt is 1:0.5 to 1:3.5;
  • the molar ratio of the compound represented by formula (I): the pharmaceutically acceptable salt is 1:1;
  • the pharmaceutically acceptable salt is selected from hydrochloride, and the molar ratio of the compound represented by formula (I): hydrochloric acid is 1:1;
  • the pharmaceutically acceptable salt is selected from p-toluenesulfonate, and the molar ratio of the compound represented by formula (I): p-toluenesulfonic acid is 1:2 or 1:1;
  • the pharmaceutically acceptable salt is selected from methanesulfonate, and the molar ratio of the compound represented by formula (I): methanesulfonic acid is 1:1, 1:2;
  • the present invention provides a hydrochloride crystalline form A of a compound represented by formula (I); in some embodiments, using Cu-K ⁇ radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 9.44° ⁇ 0.2°, 11.21° ⁇ 0.2°, 20.27° ⁇ 0.2°, 21.82° ⁇ 0.2°, and 26.50° ⁇ 0.2°; in some embodiments, using Cu-K ⁇ radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 9.44° ⁇ 0.2°, 11.21° ⁇ 0.2°, 19.84° ⁇ 0.2°, 20.27° ⁇ 0.2°, 21.82° ⁇ 0.2°, 22.65° ⁇ 0.2°, 25 .23° ⁇ 0.2°, 26.50° ⁇ 0.2°; in some embodiments, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 9.44° ⁇ 0.2°, 11.21° ⁇ 0.2°, 19.06° ⁇ 0.2°, 19.
  • DSC differential scanning calorimetry analysis curve
  • TGA thermogravimetric analysis curve
  • isothermal adsorption curve shows that there is a 0.431% weight gain in the 0-80% RH range, and it is slightly hygroscopic
  • differential scanning calorimetry analysis curve, thermogravimetric analysis curve and isothermal adsorption curve are shown in Figures 2-4.
  • the present invention provides a hydrochloride crystalline form B of a compound represented by formula (I); in some embodiments, using Cu-K ⁇ radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 4.46° ⁇ 0.2°, 7.85° ⁇ 0.2°, 15.07° ⁇ 0.2°, 21.85° ⁇ 0.2°, and 22.03° ⁇ 0.2°; in some embodiments, using Cu-K ⁇ radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 4.46° ⁇ 0.2°, 7.85° ⁇ 0.2°, 15.07° ⁇ 0.2°, 19.35° ⁇ 0.2°, 21.85° ⁇ 0.2°, 22.03° ⁇ 0.2°, 23.37° ⁇ 0.2°, 25.06° ⁇ 0.2°; in some embodiments, Cu-K ⁇ radiation is used, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 4.46° ⁇ 0.2°, 7.85° ⁇ 0.2°, 10.
  • DSC differential scanning calorimetry analysis curve
  • TGA thermogravimetric analysis curve
  • the present invention provides a hydrochloride crystalline form C of a compound represented by formula (I); in some embodiments, using Cu-K ⁇ radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 4.96° ⁇ 0.2°, 8.86° ⁇ 0.2°, 20.60° ⁇ 0.2°, 21.88° ⁇ 0.2°, and 24.38° ⁇ 0.2°; in some embodiments, using Cu-K ⁇ radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 4.96° ⁇ 0.2°, 8.86° ⁇ 0.2°, 19.93° ⁇ 0.2°, 20.60° ⁇ 0.2°, 21.22° ⁇ 0.2°, 21.88° ⁇ 0.2°, and 24.38° ⁇ 0 .2°, 25.72° ⁇ 0.2°; in some embodiments, Cu-K ⁇ radiation is used, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 4.96° ⁇ 0.2°, 8.86°
  • DSC differential scanning calorimetry analysis curve
  • TGA thermogravimetric analysis curve
  • the present invention provides a p-toluenesulfonate crystalline form A of a compound represented by formula (I); in some embodiments, using Cu-K ⁇ radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 5.50° ⁇ 0.2°, 6.33° ⁇ 0.2°, 7.77° ⁇ 0.2°, 16.52° ⁇ 0.2°, and 19.63° ⁇ 0.2°; in some embodiments, using Cu-K ⁇ radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 5.50° ⁇ 0.2°, 6.33° ⁇ 0.2°, 7.77° ⁇ 0.2°, 12.69° ⁇ 0.2°, 16.52° ⁇ 0.2°, 19.63° ⁇ 0.2°, 20.58° ⁇ 0.2°, 22.79° ⁇ 0.2°; in some embodiments, Cu-K ⁇ radiation is used, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 5.50° ⁇ 0.2°, 6.33°
  • DSC differential scanning calorimetry analysis curve
  • TGA thermogravimetric analysis curve
  • the present invention provides a p-toluenesulfonate crystalline form B of a compound represented by formula (I); in some embodiments, using Cu-K ⁇ radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 8.00° ⁇ 0.2°, 9.70° ⁇ 0.2°, 18.16° ⁇ 0.2°, 19.50° ⁇ 0.2°, and 23.15° ⁇ 0.2°; in some embodiments, using Cu-K ⁇ radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 7.62° ⁇ 0.2°, 8.00° ⁇ 0.2°, 9.70° ⁇ 0.2°, 18.16° ⁇ 0.2°, 18.39° ⁇ 0.2°, 19.50° ⁇ 0.2°, and 23.15° ⁇ 0.2°.
  • Cu-K ⁇ radiation is used, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 7.62° ⁇ 0.2°, 8.00° ⁇ 0.2°, 9.70° ⁇ 0.2°, 11.10° ⁇ 0.2°, 11.91° ⁇ 0.2°, 18.16° ⁇ 0.2°, 18.39° ⁇ 0.2°, 19.01° ⁇ 0.2°, 19.50° ⁇ 0.2°, 20.56° ⁇ 0.2°, 23.15° ⁇ 0.2°, 25.01° ⁇ 0.2°, and 26.38° ⁇ 0.2°; in some embodiments, Cu-K ⁇ radiation is used, and its X-ray powder diffraction pattern is shown in Figure 14.
  • DSC differential scanning calorimetry analysis curve
  • TGA thermogravimetric analysis curve
  • the present invention provides a mesylate salt crystalline form A of a compound represented by formula (I); in some embodiments, using Cu-K ⁇ radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 7.28° ⁇ 0.2°, 17.93° ⁇ 0.2°, 18.51° ⁇ 0.2°, 20.58° ⁇ 0.2°, and 24.06° ⁇ 0.2°; in some embodiments, using Cu-K ⁇ radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 6.23° ⁇ 0.2°, 7.28° ⁇ 0.2°, 17.93° ⁇ 0.2°, 18.51° ⁇ 0.2°, 20.58° ⁇ 0.2°, 20.81° ⁇ 0.2°, 21.55° ⁇ 0.2°, 24.06° ⁇ 0.2°; in some embodiments, Cu-K ⁇ radiation is used, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 6.23° ⁇ 0.2°, 7.28° ⁇ 0.2°,
  • DSC differential scanning calorimetry analysis curve
  • TGA thermogravimetric analysis curve
  • the present invention provides a mesylate salt form B of a compound represented by formula (I); in some embodiments, using Cu-K ⁇ radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 6.11° ⁇ 0.2°, 19.51° ⁇ 0.2°, 19.87° ⁇ 0.2°, 22.53° ⁇ 0.2°, and 23.71° ⁇ 0.2°; in some embodiments, using Cu-K ⁇ radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 6.11° ⁇ 0.2°, 9.71° ⁇ 0.2°, 14.90° ⁇ 0.2°, 19.51° ⁇ 0.2°, 19.87° ⁇ 0.2°, 20.85° ⁇ 0.2°, 22.53° ⁇ 0.2°.
  • Cu-K ⁇ radiation is used, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 6.11° ⁇ 0.2°, 9.71° ⁇ 0.2°, 14.90° ⁇ 0.2°, 18.33° ⁇ 0.2°, 19.51° ⁇ 0.2°, 19.87° ⁇ 0.2°, 20.33° ⁇ 0.2°, 20.85° ⁇ 0.2°, 22.53° ⁇ 0.2°, 23.71° ⁇ 0.2°, 25.06° ⁇ 0.2°, 26.42° ⁇ 0.2°, 29.71° ⁇ 0.2°; in some embodiments, Cu-K ⁇ radiation is used, and its X-ray powder diffraction pattern is shown in Figure 20.
  • DSC differential scanning calorimetry analysis curve
  • TGA thermogravimetric analysis curve
  • the present invention provides a crystalline form A of a compound represented by formula (I); in some embodiments, using Cu-K ⁇ radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 14.96° ⁇ 0.2°, 17.88° ⁇ 0.2°, 20.12° ⁇ 0.2°, 20.54° ⁇ 0.2°, and 27.07° ⁇ 0.2°; in some embodiments, using Cu-K ⁇ radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 10.60° ⁇ 0.2°, 12.79° ⁇ 0.2°, 14.96° ⁇ 0.2°, 17.88° ⁇ 0.2°, 20.12° ⁇ 0.2°, 20.54° ⁇ 0.2°, and 23.3 4° ⁇ 0.2°, 27.07° ⁇ 0.2°; in some embodiments, Cu-K ⁇ radiation is used, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 10.60° ⁇ 0.2°, 11.08° ⁇ 0.2°, 12.79° ⁇
  • DSC differential scanning calorimetry analysis curve
  • TGA thermogravimetric analysis curve
  • the present invention also provides a method for preparing a pharmaceutically acceptable salt of a compound represented by formula (I), wherein the method comprises: a step of forming a salt with the compound represented by formula (I) and an acid; in some embodiments, the solvent used is selected from one or more of C1-6 halogenated alkane solvents, C2-6 ester solvents, C2-6 ether solvents, C1-6 alcohol solvents or water; in some embodiments, the solvent used is selected from one or more of dichloromethane, 1,2-dichloroethane, ethyl acetate, methanol, ethanol, isopropanol, propanol, diethyl ether, tetrahydrofuran and water.
  • the present invention also provides a pharmaceutical composition, wherein the pharmaceutical composition contains a therapeutically effective amount of a pharmaceutically acceptable salt of any one of the aforementioned compounds represented by formula (I), and a pharmaceutically acceptable carrier or excipient.
  • the present invention belongs to the field of pharmaceutical technology and, more particularly, relates to a small molecule compound with selective PDE4B inhibitory activity, its stereoisomers or pharmaceutically acceptable salts, and its use in the preparation of a medicament for treating related diseases.
  • the PDE4B-mediated disease is cancer, COPD, idiopathic pulmonary fibrosis, or interstitial lung disease.
  • the present invention also provides a method for treating a disease in a mammal or human, comprising administering to a subject a therapeutically effective amount of a compound, a stereoisomer, or a pharmaceutically acceptable salt thereof, as described in any of the foregoing schemes.
  • the disease is preferably cancer or COPD, idiopathic pulmonary fibrosis, or interstitial lung disease.
  • the therapeutically effective amount is 1-1500 mg.
  • the mammal described in the present invention does not include humans.
  • the pharmaceutical composition of the present invention may be in the form of a unit preparation (the amount of the main drug in the unit preparation is also referred to as the "preparation strength").
  • an "effective amount” or “therapeutically effective amount” refers to the administration of a sufficient amount of a compound disclosed herein to alleviate, to some extent, one or more symptoms of the disease or condition being treated. In some embodiments, the result is a reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration in a biological system.
  • an "effective amount” for therapeutic uses is the amount of a compound disclosed herein required to provide a clinically significant reduction in disease symptoms.
  • therapeutically effective amounts include, but are not limited to, 1-1500 mg, 1-1400 mg, 1-1300 mg, 1-1200 mg, 1-1000 mg, 1-900 mg, 1-800 mg, 1-700 mg, 1-600 mg, 1-500 mg, 1-400 mg, 1-300 mg, 1-250 mg, 1-200 mg, 1-150 mg, 1-125 mg, 1-100 mg, 1-80 mg, 1-60 mg, 1-50 mg, 1-40 mg, 1-25 mg, 1-20 mg, 5-1500 mg, 5-1000 mg, 5-900 mg, 5-800 mg, 5-700 mg, 5-600 mg, 5-500 mg, 5-400mg, 5-300mg, 5-250mg, 5-200mg, 5-150mg, 5-125mg, 5-100mg, 5-90mg, 5-70mg, 5-80mg, 5-60mg, 5-50mg, 5-40mg, 5-30mg, 5-25mg, 5-20mg, 10-1 500mg, 10-1000mg, 10-900mg, 10-800mg, 10-700mg, 10-600mg, 10-500mg, 10-
  • the pharmaceutical composition or formulation of the present invention contains the above-mentioned therapeutically effective amount of the compound of the present invention or its stereoisomer, solvate, or pharmaceutically acceptable salt;
  • the present invention relates to a pharmaceutical composition or pharmaceutical preparation, which comprises a therapeutically effective amount of a compound of the present invention or a stereoisomer thereof or a pharmaceutically acceptable salt and a carrier and/or excipient.
  • the pharmaceutical composition can be in the form of a unit preparation (the amount of the main drug in the unit preparation is also referred to as a "preparation specification").
  • the pharmaceutical composition includes but is not limited to 1 mg, 1.25 mg, 2.5 mg, 5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg , 240mg, 250mg, 275mg, 300mg, 325mg, 350mg, 375mg, 400mg, 425mg, 450mg, 475mg, 500mg, 525mg, 550mg, 575mg, 600mg, 625mg, 650mg, 675mg, 700mg, 725mg, 750mg, 775mg, 800mg, 850mg,
  • a method for treating a disease in a mammal comprising administering to a subject a therapeutically effective amount of a compound of the present invention, a stereoisomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and/or excipient, wherein the therapeutically effective amount is preferably 1-1500 mg.
  • the disease is preferably cancer, COPD, idiopathic pulmonary fibrosis or interstitial lung disease.
  • a method for treating a disease in a mammal or a human comprises administering a compound of the present invention, a stereoisomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and/or excipient to a subject at a daily dose of 1-1500 mg/day.
  • the daily dose may be a single dose or divided doses.
  • the daily dose includes but is not limited to 10-1500 mg/day, 20-1500 mg/day, 25-1500 mg/day, 50-1500 mg/day, 75-1500 mg/day, 100-1500 mg/day, 200-1500 mg/day, 10-1000 mg/day, 20-1000 mg/day, 25-1000 mg/day, 50-1000 mg/day, 75-1000 mg/day, 100 -1000 mg/day, 200-1000 mg/day, 25-800 mg/day, 50-800 mg/day, 100-800 mg/day, 200-800 mg/day, 25-400 mg/day, 50-400 mg/day, 100-400 mg/day, 200-400 mg/day, in some embodiments, daily doses include but are not limited to 1 mg/day, 5 mg/day, 10 mg/day, 20 mg/day, 25 mg/day, 50 mg/day, 75 mg/day, 100 mg/day, 125 mg/day, 150 mg/day, 200 mg/day, 400 mg/day, 600 mg/day, 800 mg/day, 1000 mg/day, 10 mg
  • the amount of the compound of the invention or its stereoisomer or pharmaceutically acceptable salt in the present invention is in each case calculated as the free base.
  • Preparation specifications refers to the weight of the main drug contained in each tube, tablet or other unit preparation.
  • the present invention relates to a kit, which may include a composition in single-dose or multi-dose form, wherein the kit comprises a pharmaceutically acceptable salt or co-crystal of the compound of the present invention, and the amount of the pharmaceutically acceptable salt or co-crystal of the compound of the present invention is the same as that in the above-mentioned pharmaceutical composition.
  • the crystal form of the compound represented by formula (I) of the present invention has excellent physical properties, including but not limited to solubility, dissolution rate, light resistance, low hygroscopicity, high temperature resistance, and high humidity resistance.
  • the crystal form of the present invention can significantly reduce the filtration time during the preparation process, shorten the production cycle, and save costs.
  • the crystal form of the present invention also has good light stability, thermal stability, and moisture stability, which can ensure the reliability of the crystal form during storage and transportation, thereby ensuring the safety of the preparation, and the crystal form does not need to be specially packaged to prevent the influence of light, temperature, and humidity, thereby reducing costs.
  • the crystal form will not be degraded due to the influence of light, high temperature, and high humidity, thereby improving the safety of the preparation and the effectiveness after long-term storage. Patients taking the crystal form will not worry about the preparation producing photosensitivity reactions due to exposure to sunlight.
  • the crystalline form of the compound represented by formula (I) of the present invention undergoes minimal or minimal degradation when stored or transported at ambient temperature, has good thermal stability, can be maintained stably for a long time, and is suitable for standard formulation production processes.
  • the crystal form of the compound represented by formula (I) described in the present invention is suitable and convenient for large-scale preparation.
  • the preparation prepared using the aforementioned crystal form can reduce irritation and improve absorption, thereby solving the problem of metabolic rate, significantly reducing toxicity, improving safety, and effectively ensuring the quality and efficacy of the preparation.
  • the expressions such as “preferably, ..., its X-ray powder diffraction pattern further has a characteristic diffraction peak at the following 2 ⁇ position” or “more preferably, ..., its X-ray powder diffraction pattern further has a characteristic diffraction peak at the following 2 ⁇ position” described in the present invention mean that on the basis of having a characteristic diffraction peak at the aforementioned 2 ⁇ position, there is further a characteristic diffraction peak at the aforementioned “following 2 ⁇ position”.
  • the crystalline structure of the present invention can be analyzed using various analytical techniques known to those skilled in the art, including but not limited to, X-ray powder diffraction (XRD), ion chromatography (IC), differential scanning calorimetry (DSC) and/or thermogravimetric analysis (TGA), also known as thermogravimetry (TG).
  • XRD X-ray powder diffraction
  • IC ion chromatography
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • TG thermogravimetric analysis
  • crystal form of the present invention is not limited to the characteristic spectra that are exactly the same as the characteristic spectra described in the drawings disclosed in the present invention, such as XRD, DSC, and TGA. Any crystal form having characteristic spectra that are substantially the same or essentially the same as those described in the drawings falls within the scope of the present invention.
  • the melting peak height of a 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 compound of the present invention is characterized by a DSC pattern having characteristic peak positions, having substantially the same properties as the DSC pattern provided in the accompanying drawings of the present invention, with an error tolerance of ⁇ 3°C.
  • the terms “about” and “approximately” are used herein to refer to the numerical value of the variable and all numerical values of the variable within the experimental error (e.g., within a 95% confidence interval for the mean) or within ⁇ 10% of the specified numerical value, or a wider range.
  • amorphous refers to any solid material that is not three-dimensionally ordered.
  • amorphous solids can be characterized by known techniques, including XRPD crystallography, differential scanning calorimetry (DSC), solid-state nuclear magnetic resonance (ssNMR) spectroscopy, or a combination of these techniques. As described below, an amorphous solid produces an XRPD pattern lacking distinct characteristic diffraction peaks.
  • crystalline form or “crystal” refers to any solid material that exhibits a three-dimensional ordering, as opposed to an amorphous solid material, which produces a characteristic XRPD pattern with well-defined peaks.
  • seed crystals refer to the crystal nuclei formed by adding insoluble additives in the crystallization method, which accelerate or promote the growth of enantiomer crystals with the same crystal form or stereo configuration.
  • composition refers to a mixture of one or more compounds described herein or their physiologically/pharmaceutically acceptable salts and other components, wherein the other components include physiologically/pharmaceutically acceptable carriers and excipients.
  • carrier refers to a carrier or diluent that does not cause significant irritation to the organism and does not eliminate the biological activity and properties of the administered compound.
  • excipient refers to an inert substance added to a pharmaceutical composition to further facilitate administration of the compound.
  • excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars and different types of starch, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders, disintegrants, and the like.
  • the “1C50” mentioned in the present invention refers to the half-maximal inhibitory concentration, which refers to the concentration at which half of the maximum inhibitory effect is achieved.
  • ether solvent refers to a chain compound or a cyclic compound containing an ether bond -O- and having 1 to 10 carbon atoms. Specific examples include but are not limited to: tetrahydrofuran, diethyl ether, propylene glycol methyl ether, methyl tert-butyl ether, isopropyl ether or 1,4-dioxane.
  • the "alcohol solvent” described in the present invention refers to a group derived from one or more "hydroxyl groups” replacing one or more hydrogen atoms on a "C 1-6 alkyl group".
  • the "hydroxyl group” and “C 1-6 alkyl group” are as defined above. Specific examples include, but are not limited to, methanol, ethanol, isopropanol, n-propanol, isopentanol, or trifluoroethanol.
  • ester solvent refers to a combination of a lower organic acid containing 1 to 4 carbon atoms and a lower alcohol containing 1 to 6 carbon atoms. Specific examples include but are not limited to ethyl acetate, isopropyl acetate or butyl acetate.
  • keton solvent refers to a compound in which a carbonyl group (-C(O)-) is connected to two hydrocarbon groups.
  • ketones can be divided into aliphatic ketones, alicyclic ketones, aromatic ketones, saturated ketones and unsaturated ketones. Specific examples include but are not limited to: acetone, acetophenone, and 4-methyl-2-pentanone.
  • nitrile solvent refers to a group derived from one or more "cyano” groups replacing one or more hydrogen atoms on a “C 1-6 alkyl” group.
  • the "cyano” and “C 1-6 alkyl” are as defined above. Specific examples include, but are not limited to, acetonitrile or propionitrile.
  • halogenated hydrocarbon solvent refers to a group derived from one or more "halogen atoms” replacing one or more hydrogen atoms on a "C 1-6 alkyl group".
  • the "halogen atom” and “C 1-6 alkyl group” are as defined above. Specific examples include, but are not limited to, dichloromethane, 1,2-dichloroethane, chloroform or carbon tetrachloride.
  • crystal of the present invention can be used interchangeably.
  • room temperature generally refers to 4-30°C, preferably 20 ⁇ 5°C.
  • the drying temperature of the present invention is generally 20-100° C., preferably 25-70° C., and can be dried under normal pressure or reduced pressure (vacuum drying). Preferably, the drying is carried out under reduced pressure.
  • an "X-ray powder diffraction pattern (XRPD pattern)” refers to an experimentally observed diffraction pattern or a parameter, data, or value derived therefrom.
  • An XRPD pattern is typically characterized by peak positions (on the abscissa) and/or peak intensities (on the ordinate).
  • 2 ⁇ or 2 ⁇ angle refers to the diffraction angle, where ⁇ is the Bragg angle, which is a peak position expressed in degrees (°) based on an X-ray diffraction experiment, and is typically the horizontal coordinate unit in a diffraction pattern. If the incident beam is diffracted when the incident beam forms an angle ⁇ with a certain lattice plane, the experimental setup requires recording the reflected beam at an angle of 2 ⁇ .
  • the specific 2 ⁇ value of a specific crystal form mentioned herein is intended to represent the 2 ⁇ value (expressed in degrees) measured using the X-ray diffraction experimental conditions described herein, and the error range of the 2 ⁇ is ⁇ 0.3, which may be ⁇ 0.3, ⁇ 0.2, or ⁇ 0.1.
  • substantially the same means that variations in representative peak positions and intensities are taken into account.
  • peak positions (2 ⁇ ) can exhibit some variation, typically as much as 0.1 to 0.2 degrees, and that the instrument used to measure diffraction can also introduce some variation.
  • relative peak intensities can vary due to instrumental differences, as well as the degree of crystallinity, preferred orientation, the surface of the sample being prepared, and other factors known to one skilled in the art, and should be considered merely qualitative measurements.
  • the “differential scanning calorimetry or DSC” mentioned in the present invention refers to measuring the temperature difference and heat flow difference between a sample and a reference object during the process of heating or maintaining the sample at a constant temperature, so as to characterize all physical and chemical changes related to thermal effects and obtain phase change information of the sample.
  • Deliquescent Absorbs sufficient water to form a liquid
  • Hygroscopic weight gain due to moisture absorption is less than 15% but not less than 2%;
  • weight gain due to moisture absorption is less than 2% but not less than 0.2%;
  • weight gain due to moisture is less than 0.2%.
  • the crystal form disclosed in the present invention can be prepared by the following common methods for preparing crystal forms:
  • the volatilization experiment is to evaporate the clear sample solution at different temperatures until the solvent is dry.
  • the slurry experiment is to stir the supersaturated solution of the sample (with insoluble solids present) at a certain temperature in different solvent systems.
  • the antisolvent test is to dissolve the sample in a good solvent, add an antisolvent, stir the precipitated solid for a short time and then filter it immediately.
  • the cooling crystallization experiment is to dissolve a certain amount of sample into the corresponding solvent at high temperature, and then stir and crystallize directly at room temperature or low temperature.
  • the polymer template experiment is to add different types of polymer materials to the sample clear solution and leave it open at room temperature to evaporate until the solvent is dry.
  • the thermal method experiment is to treat the sample according to certain thermal method crystallization conditions and cool it to room temperature.
  • the water vapor diffusion experiment is to place the sample in a certain humidity environment at room temperature.
  • FIG1 is an X-ray powder diffraction pattern of the hydrochloride crystal form A of the compound represented by formula (I).
  • FIG2 is a differential scanning calorimetry analysis spectrum of the hydrochloride salt form A of the compound represented by formula (I).
  • FIG3 is a thermogravimetric analysis curve of the hydrochloride crystal form A of the compound represented by formula (I).
  • FIG4 is an isothermal adsorption curve of the hydrochloride crystal form A of the compound represented by formula (I).
  • FIG5 is an X-ray powder diffraction pattern of the hydrochloride crystal form B of the compound represented by formula (I).
  • FIG6 is a differential scanning calorimetry analysis spectrum of the hydrochloride salt form B of the compound represented by formula (I).
  • FIG7 is a thermogravimetric analysis curve of the hydrochloride crystal form B of the compound represented by formula (I).
  • FIG8 is an X-ray powder diffraction pattern of Form C of the hydrochloride salt of the compound represented by formula (I).
  • FIG9 is a differential scanning calorimetry analysis spectrum of the hydrochloride salt form C of the compound represented by formula (I).
  • FIG10 is a thermogravimetric analysis curve of Form C of the hydrochloride salt of the compound represented by formula (I).
  • FIG11 is an X-ray powder diffraction pattern of Form A of the p-toluenesulfonate salt of the compound represented by formula (I).
  • FIG12 is a differential scanning calorimetry analysis spectrum of the p-toluenesulfonate crystalline form A of the compound represented by formula (I).
  • FIG13 is a thermogravimetric analysis curve of the p-toluenesulfonate crystalline form A of the compound represented by formula (I).
  • FIG14 is an X-ray powder diffraction pattern of Form B of the p-toluenesulfonate salt of the compound represented by formula (I).
  • FIG15 is a differential scanning calorimetry analysis spectrum of the p-toluenesulfonate crystalline form B of the compound represented by formula (I).
  • FIG16 is a thermogravimetric analysis curve of the p-toluenesulfonate crystalline form B of the compound represented by formula (I).
  • FIG17 is an X-ray powder diffraction pattern of Form A of the mesylate salt of the compound represented by formula (I).
  • FIG18 is a differential scanning calorimetry analysis spectrum of the mesylate salt form A of the compound represented by formula (I).
  • FIG19 is a thermogravimetric analysis curve of Form A of the mesylate salt of the compound represented by formula (I).
  • FIG20 is an X-ray powder diffraction pattern of Form B of the mesylate salt of the compound represented by formula (I).
  • FIG21 is a differential scanning calorimetry analysis spectrum of the mesylate salt form B of the compound represented by formula (I).
  • FIG22 is a thermogravimetric analysis curve of Form B of the mesylate salt of the compound represented by formula (I).
  • FIG23 is an X-ray powder diffraction pattern of Form A of the compound represented by formula (I).
  • FIG24 is a differential scanning calorimetry analysis spectrum of Form A of the compound represented by formula (I).
  • FIG25 is a thermogravimetric analysis curve of Form A of the compound represented by formula (I).
  • FIG26 is a graph showing the anti-TNF- ⁇ secretion activity test results of the compound represented by formula (I) in the LPS-induced mouse lung inflammation model.
  • FIG27 is a microscope image of Form A of the hydrochloride salt of the compound of formula (I).
  • FIG28 is a microscope image of Form A of the compound of formula (I).
  • the structures of the compounds were determined by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS). NMR shifts ( ⁇ ) are given in units of 10 ⁇ 6 (ppm). NMR measurements were performed using Bruker Avance 111 400 and Bruker Avance 300 NMR spectrometers. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), with tetramethylsilane (TMS) as the internal standard.
  • DMSO-d6 deuterated dimethyl sulfoxide
  • CDCl3 deuterated chloroform
  • CD3OD deuterated methanol
  • TMS tetramethylsilane
  • MS determination was performed using (Ag1lent 6120B(ES1) and Ag1lent 6120B(APC1)).
  • HPLC determination was performed using an Agilent 1260DAD high pressure liquid chromatograph (Ecl1pse Plus C18, 150 ⁇ 4.6mm).
  • the known starting materials of the present invention can be synthesized by methods known in the art, or can be purchased from companies such as Titan Technology, Anage Chemical, Shanghai Demer, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, and Bailingwei Technology.
  • Step 2 Dissolve compound B (1.6 g, 3.63 mmol) in dichloromethane (5 mL), add trichloroacetyl isocyanate (820 mg, 4.36 mmol) under ice-cooling, and stir under ice-cooling for one hour. The reaction mixture is concentrated to obtain compound C (2.28 g, 100%).
  • Step 3 Dissolve compound C (2.28 g, 3.63 mmol) in methanol (20 mL). Add potassium carbonate (1.51 g, 10.89 mmol) and water (20 mL) under ice-cooling, and stir at room temperature for 2.5 hours. The reaction mixture is diluted with water and extracted with dichloromethane. The combined organic phases are dried, filtered, and concentrated. Chiral separation by SFC affords compound (I) (1.3 g, 74%).
  • thermogravimetric analysis (TGA) curve showed a weight loss of approximately 2.84% before 186.67°C and a weight loss of approximately 5.08% between 186.67°C and 219.16°C. Its differential scanning calorimetry and thermogravimetric analysis curves are shown in Figures 6-7 .
  • thermogravimetric analysis (TGA) curve showed a weight loss of approximately 4.15% before 138.62°C and a weight loss of approximately 4.00% between 138.62°C and 190.78°C. Its differential scanning calorimetry and thermogravimetric analysis curves are shown in Figures 9-10 .
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • Form A hydrochloride of the compound of formula (I) Two 40 mg portions of Form A hydrochloride of the compound of formula (I) were taken, 1 mL of ethanol was added, and the temperature was raised to 50°C and 70°C, respectively. Samples were taken at regular intervals and submitted to HPLC for stability testing. Specific data are shown in the table below. The test results show that the hydrochloride salt has good thermal stability.
  • each hydrochloride crystal form A, hydrochloride crystal form B, and hydrochloride crystal form C sample was taken, mixed evenly, and sampled for XRPD characterization; the mixed sample was divided into 3 equal parts, and 0.5 mL of solvent (acetone, methanol, and acetonitrile) was added to each to form a suspension. The suspension was stirred at room temperature for 3 days, and samples were taken for XRPD characterization. The results are shown in Table 16. It can be seen that the three crystal forms of the hydrochloride were mixed and eventually converted into crystal form A in different solvents.
  • the sample of the hydrochloride crystal form A of the compound of formula (I) is an irregular sample with uneven size, difficult to prepare, and poor fluidity.
  • the sample of the crystal form A of the compound of formula (I) is a block agglomerated sample with uniform size, simple to prepare, and good fluidity.
  • the effects of compounds on PDE4B2 activity were determined using a Fluorescence Polarization Assay Kit (BPS Bioscience, Catalog #60343). According to the kit instructions, a final concentration of 0.1 ⁇ M FAM-Cyclic-3',5'-AMP and 1 ng/well of PDE4B2 were added to each well (negative control wells were treated with PDE buffer). A serial dilution of compound was added (positive control wells were treated with PDE buffer containing 10% DMSO). The mixture was mixed thoroughly and incubated at room temperature for 1 hour. The binding agent was diluted 1:100 with binding agent diluent (cAMP).
  • cAMP binding agent diluent
  • FP is typically expressed as mP values.
  • %Inhibition [1-(mP (sample) -mP (negative control) )/(mP (positive control) -mP (negative control) )] x 100%
  • the IC 50 value of the compounds of the present invention against PDE4B2 is ⁇ 300 nM, preferably some compounds are ⁇ 100 nM, more preferably some compounds are ⁇ 50 nM, and further preferably some compounds are ⁇ 10 nM.
  • the compounds of the present invention exhibit IC50 values for PDE4B2 of less than 300 nM.
  • Preferred compounds exhibit IC50 values of less than 100 nM, more preferably less than 50 nM, and even more preferably less than 10 nM.
  • the IC50 values of some specific compounds are shown in Table 19 below, where A ⁇ 10 nM, 10 nM ⁇ B ⁇ 50 nM, and 50 nM ⁇ C ⁇ 100 nM.
  • %Inhibition [1-(mP (sample) -mP (negative control) )/(mP (positive control) -mP (negative control) )] x 100%
  • IC50 values of some specific compounds of the present invention are shown in Table 20 below, wherein A ⁇ 10 nM, 10 nM ⁇ B ⁇ 50 nM, and 50 nM ⁇ C ⁇ 100 nM.
  • TNF- ⁇ tumor necrosis factor- ⁇
  • hPBMCs Normal human peripheral blood (citrate-anticoagulated) was collected and prepared using Ficoll-Paque PLUS (Cytiva, Cat#17144002, density 1.077 g/mL).
  • the hPBMCs were adjusted to a concentration of 0.25 x 106 cells/mL using RPMI1640 medium and seeded into 96-well plates at a density of 50,000 cells per well. The cells were then pre-incubated with various drug concentrations for 1 hour (final DMSO concentration of 0.1%; positive and negative control wells were treated with an equal volume of RPMI1640 containing 0.1% DMSO).
  • IC50 values were calculated using GraphPad Prism software. The IC50 values for some specific compounds of the present invention are shown in Table 21, where A ⁇ 10 nM, 10 nM ⁇ B ⁇ 50 nM, and 50 nM ⁇ C ⁇ 100 nM.
  • Re IC 50 relative IC 50 .
  • Intravenous administration solvent 10% DMA + 10% Solutol + 80% Saline; Oral administration solvent: 0.5% MC
  • the compound of formula (I) of the present invention exhibits excellent pharmacokinetic properties in the mouse PK test.
  • Intratracheal administration of lipopolysaccharides can induce an increase in the concentration of TNF- ⁇ in lung tissue in mice.
  • a certain number of mice BABL/c, male, weighing 18-22g
  • mice were randomly divided into groups, with 8 mice in each group, and orally administered with a certain dose of the compound of formula (I) (the compound of formula (I) was suspended with 0.5% MC and prepared into a certain concentration, and administered orally in a volume of 10ml/kg body weight).
  • a 0.8mg/mL dose of LPS was administered intratracheally using a lung quantitative nebulizer needle at a dose of 2.5uL/g based on the animal's body weight.
  • mice were anesthetized with 20% urethane intraperitoneally (10mL/kg) and killed by cervical dislocation.
  • the lung tissue was then taken, and the lower half of the left lobe was thoroughly homogenized.
  • the TNF- ⁇ content in the supernatant of the homogenate was detected using the Mouse TNF ⁇ ELISA Kit (RD, SMTA00B).

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Abstract

La présente invention concerne un composé inhibiteur de PDE4B tel que représenté dans la formule (I) ou une forme cristalline d'un sel pharmaceutiquement acceptable de celui-ci, son procédé de préparation, une composition pharmaceutique de celui-ci et une utilisation pharmaceutique associée.
PCT/CN2025/074794 2024-02-04 2025-01-24 Forme cristalline d'un inhibiteur de pde4b et son utilisation pharmaceutique Pending WO2025162289A2 (fr)

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WO2010097332A1 (fr) * 2009-02-27 2010-09-02 Boehringer Ingelheim International Gmbh Combinaisons de médicaments contenant des inhibiteurs de pde4 et des ains
JP2013523792A (ja) * 2010-04-08 2013-06-17 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Ｐｄｅ４阻害剤及びｅｐ４受容体アンタゴニストを含有する医薬の組み合わせ
TW202402289A (zh) * 2022-06-02 2024-01-16 大陸商西藏海思科製藥有限公司 Pde4b抑制劑及其用途
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