WO2024008138A1 - Combinaison pharmaceutique d'un dérivé de 1,3,5-triazine - Google Patents

Combinaison pharmaceutique d'un dérivé de 1,3,5-triazine Download PDF

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Publication number
WO2024008138A1
WO2024008138A1 PCT/CN2023/106034 CN2023106034W WO2024008138A1 WO 2024008138 A1 WO2024008138 A1 WO 2024008138A1 CN 2023106034 W CN2023106034 W CN 2023106034W WO 2024008138 A1 WO2024008138 A1 WO 2024008138A1
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WO
WIPO (PCT)
Prior art keywords
compound
formula
pharmaceutically acceptable
tautomer
azacitidine
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PCT/CN2023/106034
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English (en)
Chinese (zh)
Inventor
屠礼凡
严辉
张喜全
王训强
于鼎
刘志
Original Assignee
正大天晴药业集团股份有限公司
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Publication of WO2024008138A1 publication Critical patent/WO2024008138A1/fr

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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
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • This application belongs to the field of medicinal chemistry and relates to pharmaceutical combinations of 1,3,5-triazine derivatives, specifically to pharmaceutical combinations of compounds of formula I, their tautomers or pharmaceutically acceptable salts thereof, and their pharmaceutical uses.
  • Isocitrate dehydrogenase is a family of oxidoreductases that uses NAD + or NADP + as coenzymes to catalyze the oxidative decarboxylation of isocitrate into ⁇ -ketoglutarate ( ⁇ -KG). Restore NAD + or NADP + to NADH or NADPH.
  • the generated ⁇ -KG and NADH/NADPH can participate in a variety of important physiological functions of the body, including demethylation of DNA and histones, oxidative energy supply of the tricarboxylic acid cycle, biosynthesis of fatty acids, and reduction of glutathione. Status etc.
  • IDH2 mutations are related to the occurrence and development of various malignant tumors.
  • somatic gene mutations occur in the gene encoding IDH2
  • Changing the residues in the active site of the enzyme and giving the mutant cells new functions can catalyze the conversion of ⁇ -KG into 2-hydroxyglutarate (2-HG).
  • Inhibiting the IDH2 mutant enzyme thereby inhibits its downstream 2-HG levels, reduces DNA and histone methylation levels, and restores somatic cells to normal growth and proliferation, becoming an effective target for tumor treatment.
  • Azacitidine is a DNA methyltransferase inhibitor drug that non-specifically reduces DNA methylation levels by inhibiting DNA methyltransferase activity.
  • the combined use of IDH2 mutant protein inhibitors and azacitidine may produce synergistic antitumor effects.
  • the present application provides a pharmaceutical combination comprising a compound of formula I, its tautomer or a pharmaceutically acceptable salt thereof and azacitidine,
  • the present application provides a pharmaceutical combination for treating hematological neoplasms in a patient, comprising a compound of formula I, a tautomer thereof or a pharmaceutically acceptable salt thereof and azacitidine.
  • the pharmaceutical combination is used to treat hematological tumors in patients.
  • the compound of formula I, its tautomer or its pharmaceutically acceptable salt and azacitidine are each in the form of a pharmaceutical composition.
  • the compound of formula I, its tautomer or its pharmaceutically acceptable salt and azacitidine are each in the form of a pharmaceutical composition, which can be simultaneously, sequentially or at intervals. Medication.
  • the pharmaceutical combination is packaged in the same pharmaceutical kit, which further includes a compound of formula I, its tautomer or a pharmaceutically acceptable salt thereof, and azacitidine used in combination Instructions for treating blood cancer in patients.
  • the pharmaceutical combination is packaged in the same pharmaceutical kit, which further includes a pharmaceutical composition of a compound of formula I, its tautomer or a pharmaceutically acceptable salt thereof, and azaza. Illustration of the combined use of pharmaceutical compositions of cytidine for the treatment of hematological malignancies in patients.
  • the compound of formula I, its tautomer or its pharmaceutically acceptable salt and azacitidine are separately packaged in respective pharmaceutical kits, and the pharmaceutical kits Also included are instructions for using a compound of Formula I, a tautomer thereof, or a pharmaceutically acceptable salt thereof, in combination with azacitidine to treat hematological malignancies in a patient.
  • the present application provides a kit, which includes the pharmaceutical combination of the present application, and a compound of formula I, its tautomer or a pharmaceutically acceptable salt thereof and azacitidine for the treatment of hematological tumors. illustrate.
  • the present application provides a kit for treating hematological tumors, which includes the pharmaceutical combination of the present application, and a compound of formula I, its tautomer or a pharmaceutically acceptable salt thereof and azacitidine Instructions for combined use in the treatment of hematological malignancies.
  • the present application provides the use of a pharmaceutical combination as described above in the preparation of a medicament for treating hematological tumors in a patient.
  • the present application provides the use of a pharmaceutical combination as described above in the treatment of hematological tumors in a patient.
  • the present application provides a method of treating a hematological tumor in a patient, the method comprising administering to the patient a therapeutically effective amount of a pharmaceutical combination as described above.
  • the present application provides the use of the kit as described above in the preparation of a pharmaceutical/medical product for treating hematological tumors in a patient.
  • the present application provides the use of the kit as described above in the treatment of hematological tumors in a patient.
  • the present application provides a method of treating a hematological tumor in a patient, the method comprising administering to the patient a therapeutically effective amount of the kit as described above.
  • the pharmaceutical combination contains 20-500 mg of the compound of formula I, its tautomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • the pharmaceutical combination contains 25-300 mg, 50-200 mg, 50-100 mg, 75-150 mg or 75-100 mg of the compound of formula I, its tautomers or Its pharmaceutically acceptable salt, or its pharmaceutical composition.
  • the pharmaceutical combination contains 75-150 mg or 75-100 mg of the compound of formula I, its tautomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical combination thereof things.
  • the pharmaceutical combination contains 75 mg, 100 mg or 150 mg of the compound of formula I, its tautomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • the pharmaceutical combination contains 75 mg or 100 mg of the compound of formula I, its tautomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • the pharmaceutical combination contains 100 mg of the compound of formula I, its tautomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • the pharmaceutical composition of the compound of formula I, its tautomer or its pharmaceutically acceptable salt in a single dose or multiple dose form. In some embodiments of the present application, in the pharmaceutical combination, the composition of the compound of formula I, its tautomer or its pharmaceutically acceptable salt is in multiple dosage form.
  • the content of the compound of formula I, its tautomer or its pharmaceutically acceptable salt is a daily dose.
  • the pharmaceutical combination contains a compound of formula I, its tautomer or a pharmaceutically acceptable salt thereof in a once-daily dose.
  • the content of the compound of formula I, its tautomer or its pharmaceutically acceptable salt is one dose per day, and each dose is a single dose or multiple doses. , usually in multiple doses.
  • the pharmaceutical combination contains a single dose of 5 mg, 25 mg and/or 50 mg of a compound of formula I, a tautomer thereof or a pharmaceutically acceptable salt thereof. things.
  • the pharmaceutical combination is in the form of a single administration preparation, and the pharmaceutical combination contains 5 mg, 25 mg and/or 50 mg of a compound of formula I, a tautomer thereof or a pharmaceutically acceptable version thereof calculated as a compound of formula I. salts or pharmaceutical compositions thereof.
  • the pharmaceutical combination contains a pharmaceutical composition in which a single dose of a compound of formula I, its tautomer or a pharmaceutically acceptable salt thereof is 5 mg and/or 50 mg calculated as the compound of formula I.
  • the pharmaceutical combination is in the form of a single administration preparation, and the pharmaceutical combination contains 5 mg and/or 50 mg of a compound of formula I, a tautomer thereof or a pharmaceutically acceptable salt thereof, calculated as a compound of formula I. Its pharmaceutical composition.
  • the pharmaceutical combination contains a pharmaceutical composition in which a single dose of the compound of formula I, its tautomer or a pharmaceutically acceptable salt thereof is 50 mg calculated as the compound of formula I.
  • the pharmaceutical combination is in the form of a single administration preparation, the pharmaceutical combination Containing 50 mg of the compound of formula I, its tautomer or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof calculated as the compound of formula I.
  • the pharmaceutical combination contains 50-150 mg/m 2 , 50-100 mg/m 2 or 75-100 mg/m 2 of azacitidine based on the body surface area of the subject, or its Pharmaceutical compositions.
  • the pharmaceutical combination contains 50 mg/m 2 , 75 mg/m 2 , 100 mg/m 2 or 150 mg/m 2 azacitidine, or a drug thereof, based on the body surface area of the subject. combination.
  • the pharmaceutical combination contains 75 mg/ m or 100 mg/ m of azacitidine, or a pharmaceutical composition thereof, based on the subject's body surface area.
  • the pharmaceutical composition of azacitidine is in single dose or multiple dose form.
  • the pharmaceutical composition of azacitidine is in a multi-dose form.
  • the pharmaceutical composition of azacitidine is a daily dose.
  • the pharmaceutical composition of azacitidine is a once-daily dose.
  • the pharmaceutical combination contains a single dose of 100 mg of azacitidine.
  • the pharmaceutical combination is in the form of a single administration formulation, the pharmaceutical combination containing 100 mg of azacitidine or a pharmaceutical composition thereof.
  • the pharmaceutical combination contains 25-500 mg of the compound of formula I, its tautomer or a pharmaceutically acceptable salt thereof, calculated as the compound of formula I, and the body surface area of the subject Calculate 50-150mg/ m2 of azacitidine.
  • the pharmaceutical combination contains 75-150 mg of the compound of formula I, its tautomer or a pharmaceutically acceptable salt thereof, calculated as the compound of formula I, and the body surface area of the subject Calculate 75-100mg/ m2 of azacitidine.
  • the pharmaceutical combination contains a daily dose of 75 mg, 100 mg or 150 mg of a compound of formula I, a tautomer thereof or a pharmaceutically acceptable salt thereof, calculated as a compound of formula I, and Subjects received a daily dose of azacitidine of 75 mg/ m or 100 mg/ m based on body surface area.
  • the pharmaceutical combination contains a daily dose of 75 mg or 100 mg of a compound of formula I, its tautomer or a pharmaceutically acceptable salt thereof, and the subject A daily dose of azacitidine of 75 mg/ m2 based on the patient's body surface area.
  • the pharmaceutical combination contains a daily dose of 100 mg of the compound of formula I, its tautomer or a pharmaceutically acceptable salt thereof, and the subject's A daily dose of azacitidine of 75 mg/ m2 based on body surface area.
  • every 2-6 weeks is a treatment cycle, for example, every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks or every 6 weeks, and consists of any two days therein.
  • the period within the range is a treatment cycle.
  • every 28 days is a treatment cycle.
  • the pharmaceutical combination contains: a single dose of 5 mg, 25 mg and/or 50 mg of a compound of formula I, its tautomer or a pharmaceutically acceptable salt thereof, calculated as a compound of formula I.
  • the pharmaceutical combination is in the form of a single-administration preparation, and the pharmaceutical combination contains: 5 mg, 25 mg and/or 50 mg of a compound of formula I, a tautomer thereof or a pharmaceutically acceptable compound thereof, calculated as a compound of formula I. a salt or a pharmaceutical composition thereof, and 100 mg of azacitidine or a pharmaceutical composition thereof.
  • the pharmaceutical combination contains: a single dose of 5 mg and/or 50 mg of a compound of formula I, a tautomer thereof or a pharmaceutically acceptable salt thereof, calculated as a compound of formula I. drug, and a pharmaceutical composition of azacitidine in a single dose of 100 mg.
  • the pharmaceutical combination is in the form of a single-administration preparation, and the pharmaceutical combination contains: 5 mg and/or 50 mg of a compound of formula I, its tautomer or a pharmaceutically acceptable salt thereof, calculated as a compound of formula I. or a pharmaceutical composition thereof, and 100 mg of azacitidine or a pharmaceutical composition thereof.
  • the pharmaceutical combination contains: a single dose of 50 mg of a compound of formula I, a tautomer thereof or a pharmaceutically acceptable salt thereof, and a single Pharmaceutical composition of azacitidine at a dose of 100 mg.
  • the pharmaceutical combination is in the form of a single-administration preparation, and the pharmaceutical combination contains: 50 mg of a compound of formula I, its tautomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical combination thereof calculated as a compound of formula I. substance, and 100 mg of azacitidine or a pharmaceutical composition thereof.
  • the pharmaceutical combination is a preparation suitable for administration within a single treatment cycle (for example, a treatment cycle of 28 days), and the preparation includes: a total dose of 1400 mg to 4200 mg based on the compound of formula I.
  • the pharmaceutical combination is a preparation suitable for administration within a single treatment cycle (for example, a treatment cycle of 28 days), and the preparation includes: a total dose of 1400 mg to 4200 mg based on the compound of formula I.
  • the pharmaceutical combination is a preparation suitable for administration within a single treatment cycle (for example, a treatment cycle of 28 days), and the preparation includes: a total dose of 2100 mg to 2800 mg based on the compound of formula I.
  • the pharmaceutical combination is a formulation suitable for administration within a single treatment cycle (eg, a treatment cycle of 28 days), and the formulation includes: a total dose of 2100 mg or 2800 mg based on the compound of formula I.
  • the pharmaceutical combination is a formulation suitable for administration within a single treatment cycle (eg, a treatment cycle of 28 days), and the formulation includes: a total dose of 2800 mg of a compound of formula I.
  • the compound of formula I, its tautomer or a pharmaceutically acceptable salt thereof, and azacitidine can be in the form of a pharmaceutical composition respectively or together.
  • Pharmaceutical composition form in the pharmaceutical combination, the compound of formula I, its tautomer or a pharmaceutically acceptable salt thereof, and azacitidine can be in the form of a pharmaceutical composition respectively or together.
  • kits which contains (a) a first pharmaceutical composition containing the compound of formula I described in the present application, its tautomer or a pharmaceutically acceptable salt thereof; and (b) A second pharmaceutical composition containing azacitidine.
  • the present application also provides a kit of pharmaceutical compositions for treating hematological tumors in patients, which contains (a) a first pharmaceutical composition containing the compound of formula I described in the present application, and its tautomorphic The construct or a pharmaceutically acceptable salt thereof; and (b) a second pharmaceutical composition containing azacitidine.
  • the compound of formula I, its tautomer or a pharmaceutically acceptable salt thereof is prepared into a unit preparation containing 5 mg or 25 mg based on the compound of formula I. or a first pharmaceutical composition of 50 mg of a compound of formula I, a tautomer thereof or a pharmaceutically acceptable salt thereof, said azacitidine being prepared as a second unit formulation containing 100 mg of azacitidine Pharmaceutical compositions.
  • the compound of formula I, its tautomer or a pharmaceutically acceptable salt thereof is prepared into a unit preparation containing 5 mg or 50 mg based on the compound of formula I.
  • the compound of formula I, its tautomer or a pharmaceutically acceptable salt thereof is prepared into a unit preparation containing 50 mg of the compound of formula I calculated as the compound of formula I.
  • a first pharmaceutical composition of compound I, a tautomer thereof or a pharmaceutically acceptable salt thereof, the azacitidine is prepared into a second pharmaceutical composition containing 100 mg of azacitidine in a unit preparation.
  • the present application provides a kit, which includes the pharmaceutical combination of the present application, and a compound of formula I, its tautomer or a pharmaceutically acceptable salt thereof and azacitidine for the treatment of hematological tumors. illustrate.
  • the present application provides a kit for treating hematological tumors, which includes the pharmaceutical combination of the present application, and a compound of formula I, its tautomer or a pharmaceutically acceptable salt thereof and azacitidine Instructions for combined use in the treatment of hematological malignancies.
  • the compound of formula I, its tautomer or a pharmaceutically acceptable salt thereof is prepared into a unit preparation containing 5 mg or 25 mg of the compound of formula I. or 50 mg of a compound of formula I, a tautomer thereof or a pharmaceutically acceptable salt thereof, said azacitidine being prepared as a unit dosage form containing 100 mg of azacitidine.
  • the compound of formula I, its tautomer or a pharmaceutically acceptable salt thereof is prepared into a unit preparation containing 5 mg or 50 mg calculated as the compound of formula I.
  • a compound of formula I, a tautomer thereof or a pharmaceutically acceptable salt thereof, the azacitidine is prepared into a unit preparation containing 100 mg of azacitidine.
  • the compound of formula I, its tautomer or a pharmaceutically acceptable salt thereof is prepared into a unit preparation containing 50 mg of the compound of formula I.
  • the azacitidine is prepared into a unit preparation containing 100 mg of azacitidine.
  • the present application also provides a method of treating hematological tumors in a patient, which includes administering to a patient (or individual) in need thereof a therapeutically effective amount of a compound of formula I, a tautomer thereof, or a pharmaceutically acceptable form thereof.
  • Salt and azacitidine for example, a therapeutically effective amount of a pharmaceutical combination described herein is administered to a patient (or individual) in need thereof.
  • the present application also provides a method of treating hematological tumors in a patient, comprising administering to an individual in need thereof a therapeutically effective amount of a compound of formula I, a tautomer thereof or a pharmaceutically acceptable salt thereof, and a Zacitidine, for example, administering to an individual in need thereof a therapeutically effective amount of a pharmaceutical combination described herein above.
  • the present application also provides a combination therapy for treating an individual suffering from a hematological malignancy, the combination therapy comprising separately administering to the individual a therapeutically effective amount of a compound of formula I, a tautomer thereof, or a compound thereof.
  • this application also provides the use of a compound of formula I, its tautomer or a pharmaceutically acceptable salt thereof in combination with azacitidine in the preparation of a medicament for treating hematological tumors in patients, such as this application Use of the above pharmaceutical combination in the preparation of medicaments for treating hematological tumors in patients.
  • the pharmaceutical combination is any of the pharmaceutical combinations described above in the present application.
  • this application also provides the use of the compound of formula I, its tautomer or a pharmaceutically acceptable salt thereof in combination with azacitidine for treating hematological tumors in patients.
  • the above pharmaceutical combination in this application is used for Use to treat hematological malignancies in patients.
  • each of the compound of Formula I, its tautomer or a pharmaceutically acceptable salt thereof, and azacitidine is as defined above.
  • the pharmaceutical combination is defined by the compound of formula I, its tautomer or its pharmaceutically acceptable salt, and azacitidine, such as content, dosage, existence form, packaging form, etc.
  • the compound of Formula I, its tautomer or a pharmaceutically acceptable salt thereof, and azacitidine are each in a pharmaceutical composition Forms may be administered simultaneously, separately, concurrently, sequentially or at intervals.
  • the compound of Formula I, its tautomer or a pharmaceutically acceptable salt thereof, and azacitidine may have the same or different treatment cycle.
  • the compound of formula I, its tautomer or a pharmaceutically acceptable salt thereof, and azacitidine have the same The treatment cycle is, for example, every 1 week, every 2 weeks, every 3 weeks or every 4 weeks. Preferably, every 4 weeks is a treatment cycle.
  • the pharmaceutical combination in the method, combination therapy or use, contains a compound of formula I, a tautomer thereof or a pharmaceutically acceptable salt thereof in a daily dose, It is administered by administering the compound of formula I, its tautomer or its pharmaceutically acceptable salt once daily.
  • the pharmaceutical combination in the method, combination therapy or use, contains a compound of formula I, a tautomer thereof or a pharmaceutically acceptable salt thereof in a daily dose, wherein the compound of formula I, its tautomer or its pharmaceutically acceptable salt is administered in a single dose or in multiple doses, usually in multiple doses; further, wherein the compound of formula I, its tautomer is The body or its pharmaceutically acceptable salt is administered once daily in multiple doses.
  • the compound of Formula I, its tautomer or a pharmaceutically acceptable salt thereof is administered as follows: a daily dose of 50 mg ; Alternatively, the daily dose is 75 mg; Alternatively, the daily dose is 100 mg; Alternatively, the daily dose is 150 mg.
  • the compound of Formula I, its tautomer or a pharmaceutically acceptable salt thereof is administered as follows: a daily dose of 75 mg ; Alternatively, the daily dose is 100 mg.
  • the compound of Formula I, its tautomer or a pharmaceutically acceptable salt thereof is administered as follows: a daily dose of 100 mg .
  • the compound of formula I, its tautomer or a pharmaceutically acceptable salt thereof in the pharmaceutical combination is administered in multiple doses,
  • the multiple doses consist of a single dose of 5 mg and/or 50 mg of a pharmaceutical composition of a compound of formula I, a tautomer thereof or a pharmaceutically acceptable salt thereof.
  • the compound of Formula I, its tautomer or a pharmaceutically acceptable salt thereof is administered as a continuous daily administration.
  • the compound of formula I, its tautomer or a pharmaceutically acceptable salt thereof in the pharmaceutical combination is administered in multiple doses,
  • the multiple dose consists of a single dose of 50 mg of a pharmaceutical composition of a compound of formula I, a tautomer thereof or a pharmaceutically acceptable salt thereof.
  • the compound of Formula I, its tautomer or a pharmaceutically acceptable salt thereof is administered as a continuous daily administration.
  • the pharmaceutical combination in the method, combination therapy or use, contains a compound of formula I, a tautomer thereof or a pharmaceutically acceptable salt thereof in an amount of 0.01% per treatment cycle.
  • the compound of formula I, its tautomer or its pharmaceutically acceptable salt is expressed in a single aliquot or multiple aliquots (for example, 2 aliquots, 4 aliquots, 7 aliquots, 14 aliquots, 28 aliquots, etc. portions or more equal portions) for packaging.
  • the content of azacitidine in the pharmaceutical combination is a daily dose, which is administered in the following manner: azacitidine is administered daily Medicine 1 time.
  • the content of azacitidine in the pharmaceutical combination is a daily dose, wherein azacitidine is administered in a single dose or in multiple doses. , usually administered in multiple doses; further, azacitidine is administered once daily in multiple doses.
  • the azacitidine is administered at a daily dose of 50 mg/m 2 based on the subject's body surface area; or , the daily dose is 75 mg/m 2 ; alternatively, the daily dose is 100 mg/m 2 ; alternatively, the daily dose is 150 mg/m 2 .
  • the azacitidine in the methods, combination therapies or uses, is administered at a daily dose of 75 mg/m 2 based on the subject's body surface area; or , the daily dose is 100mg/m 2 .
  • the azacitidine in the method, combination therapy or use, is administered in a daily dose of 75 mg/m 2 based on the subject's body surface area.
  • the azacitidine in the pharmaceutical combination is administered in multiple doses, the multiple doses consist of a single dose of 100 mg of azacitidine.
  • the pharmaceutical composition consists of.
  • the azacitidine is administered as a continuous daily administration.
  • the content of azacitidine in the pharmaceutical combination is a dose per treatment cycle (for example, a treatment cycle of 28 days), which is determined by Administration is as follows: azacitidine is administered daily for the first 5-10 days of each cycle (eg, days 1-7) and withheld for the remaining days (eg, days 8-28). Wherein, azacitidine is packaged in single aliquots or multiple aliquots (eg, 2 aliquots, 4 aliquots, 7 aliquots, 14 aliquots, 28 aliquots or more).
  • the content of azacitidine in the pharmaceutical combination is a dose per treatment cycle (for example, a treatment cycle of 28 days), which is determined by Dosing is as follows: azacitidine is administered daily on days 1-7 of each cycle, with azacitidine discontinued on days 8-28. Wherein, azacitidine is packaged in single aliquots or multiple aliquots (eg, 2 aliquots, 4 aliquots, 7 aliquots, 14 aliquots, 28 aliquots or more).
  • 28 days is a treatment cycle, and on days 1-28 of each treatment cycle, a compound containing the compound of formula I, its tautomer is administered continuously.
  • the total dosage of the pharmaceutical composition is 1400 mg to 4200 mg (based on the compound of formula I).
  • the total dosage of the pharmaceutical composition containing the compound of formula I, its tautomer or a pharmaceutically acceptable salt thereof is selected from 2100 mg or 2800 mg (based on the compound of formula I).
  • the total dosage of the pharmaceutical composition containing the compound of formula I, its tautomer or its pharmaceutically acceptable salt is preferably 2800 mg (based on the compound of formula I).
  • a treatment cycle is 28 days, and the total dose containing azacitidine is continuously administered on days 1-7 of each treatment cycle, which is 350 mg/m 2 ⁇ 700mg/m 2 .
  • the total dose containing azacitidine is selected from 525 mg/m 2 or 700 mg/m 2 .
  • the total dose containing azacitidine is preferably 525 mg/m 2 .
  • 28 days is a treatment cycle; a pharmaceutical combination containing the compound of formula I, its tautomer or a pharmaceutically acceptable salt thereof
  • the drug is administered once a day for 28 consecutive days, and the total dose of the pharmaceutical composition containing the compound of formula I, its tautomer or its pharmaceutically acceptable salt is administered in each treatment cycle is 2800 mg (based on Calculated as a compound of formula I); and azacitidine is administered once a day on days 1 to 7 of each treatment cycle, and the total dose containing azacitidine administered in each treatment cycle is 525 mg/m 2 .
  • the compound of formula I described in this application can be obtained by referring to the preparation methods in WO2017016513 or WO2018133856,
  • the compound of formula I of the present application can be administered in the form of its free base, or in the form of its pharmaceutically acceptable salts, hydrates and prodrugs, which are converted into compounds of formula I in the body.
  • pharmaceutically acceptable salts of compounds of formula I are within the scope of the present application and can be produced from various organic and inorganic acids according to methods well known in the art.
  • the molar ratio of the compound of formula I to the acid ion forming the pharmaceutically acceptable salt may be 1:1.
  • a pharmaceutically acceptable salt of a compound of Formula I may be a mesylate salt of a compound of Formula I, such as a monomethanesulfonate salt (monomesylate) of a compound of Formula I.
  • the dosage of the compound of formula I, its tautomer or the pharmaceutically acceptable salt thereof referred to in this application, unless otherwise stated, is based on the molecular weight of the compound of formula I (calculated as C 19 H 17 F 6 N 7 O ).
  • the monomethanesulfonate salt of the compound of formula I described in the present application can be obtained by referring to the preparation method in WO2018133856.
  • the compound of formula I, its tautomer or a pharmaceutically acceptable salt thereof is a compound containing a therapeutically effective amount of a compound of formula I, its tautomer or a pharmaceutically acceptable salt thereof.
  • Pharmaceutical compositions of salts are provided.
  • the pharmaceutical composition contains a single dose of 5 mg, 25 mg or 50 mg of a compound of formula I, a tautomer thereof or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition of the compound of formula I, its tautomer or a pharmaceutically acceptable salt thereof is prepared into a unit preparation containing 5 mg, 25 mg or 50 mg of the compound of formula I, which is calculated as the compound of formula I. tautomers or pharmaceutically acceptable salts thereof.
  • the pharmaceutical composition contains a single dose of 5 mg or 50 mg of a compound of formula I, a tautomer thereof, or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition of the compound of formula I, its tautomer or a pharmaceutically acceptable salt thereof is prepared into a unit preparation containing 5 mg or 50 mg of the compound of formula I, its tautomer calculated as the compound of formula I. isomer or a pharmaceutically acceptable salt thereof.
  • the method of administration can be comprehensively determined based on the activity, toxicity and patient tolerance of the drug.
  • the pharmaceutical composition is in a formulation suitable for administration by various routes, including, but not limited to, suitable for oral or parenteral (by intravenous, intramuscular, topical or subcutaneous route) administration preparations.
  • the pharmaceutical composition is in a suitable dosage form, including, but not limited to, tablets, lozenges, pills, capsules (such as hard capsules, soft capsules, enteric capsules, microcapsules), Dosage forms of elixirs, granules, syrups, injections (intramuscular, intravenous, intraperitoneal), emulsions, suspensions, solutions, dispersions and sustained-release preparations for oral or parenteral administration.
  • a suitable dosage form including, but not limited to, tablets, lozenges, pills, capsules (such as hard capsules, soft capsules, enteric capsules, microcapsules), Dosage forms of elixirs, granules, syrups, injections (intramuscular, intravenous, intraperitoneal), emulsions, suspensions, solutions, dispersions and sustained-release preparations for oral or parenteral administration.
  • the pharmaceutical composition includes, but is not limited to, formulations suitable for oral, parenteral, and topical administration; in some aspects, the pharmaceutical composition is a formulation suitable for oral administration; in some aspects, The pharmaceutical composition is a solid preparation suitable for oral administration; in some embodiments, the pharmaceutical composition includes but is not limited to tablets and capsules.
  • the pharmaceutical composition is a solid pharmaceutical composition.
  • the pharmaceutical composition of the compound of formula I, its tautomer or its pharmaceutically acceptable salt is a pharmaceutical composition containing the compound of formula I, its tautomer or its pharmaceutically acceptable salt.
  • Solid pharmaceutical compositions of salts are described in detail below.
  • the pharmaceutical composition of the compound of formula I, its tautomer or its pharmaceutically acceptable salt is a pharmaceutical composition containing the compound of formula I, its tautomer or its pharmaceutically acceptable salt. salt tablets.
  • composition of the compound of formula I, its tautomer or its pharmaceutically acceptable salt of the present application may also contain pharmaceutically acceptable carriers and/or excipients and/or auxiliary materials.
  • composition of the compound of formula I, its tautomer or its pharmaceutically acceptable salt of the present application can be manufactured by methods well known in the art, such as conventional mixing methods, dissolving methods, granulation methods, and sugar-coated pill making. method, grinding method, emulsification method, freeze-drying method, etc.
  • Solid oral compositions may be prepared by conventional mixing, filling or tableting methods. For example, it can be obtained by the following method: mixing the active compound with solid excipients, optionally grinding the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to obtain tablets or cores in capsules or dragees.
  • suitable excipients include, but are not limited to: binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, etc.
  • azacitidine As used in this application, the chemical name of azacitidine is 5-azacytidine, which has the structure shown in the following compound of Formula II:
  • the pharmaceutical composition of azacitidine also contains pharmaceutically acceptable carriers and/or excipients and/or auxiliary materials.
  • the pharmaceutically acceptable excipients include fillers, absorbents, wetting agents, binders, disintegrants, lubricants, water for injection, etc.
  • the pharmaceutical composition is in a formulation suitable for administration by various routes, including, but not limited to, formulations suitable for oral or parenteral (by intravenous, intramuscular, topical or subcutaneous routes) .
  • the pharmaceutical combination is suitable for oral administration Administer by injection, such as intravenously or subcutaneously.
  • the pharmaceutical composition is in a suitable dosage form, including, but not limited to, tablets, lozenges, pills, capsules (such as hard capsules, soft capsules, enteric capsules, microcapsules), Dosage forms of elixirs, granules, syrups, injections (intramuscular, intravenous, intraperitoneal), emulsions, suspensions, solutions, dispersions and sustained-release preparations for oral or parenteral administration.
  • a suitable dosage form including, but not limited to, tablets, lozenges, pills, capsules (such as hard capsules, soft capsules, enteric capsules, microcapsules), Dosage forms of elixirs, granules, syrups, injections (intramuscular, intravenous, intraperitoneal), emulsions, suspensions, solutions, dispersions and sustained-release preparations for oral or parenteral administration.
  • the azacitidine is an injection preparation.
  • This application uses any commercially available form to administer azacitidine, including but not limited to azacitidine for injection produced by Chia Tai Tianqing Pharmaceutical Group Co., Ltd. (trade name ).
  • the azacitidine pharmaceutical composition is a single dose of 100 mg of azacitidine for injection.
  • the myeloid tumors include chronic myeloproliferative diseases, myelodysplastic/myeloproliferative diseases, myelodysplastic syndromes (MDS) and acute myeloid leukemia (Acute Myeloid Leukemia, AML).
  • the hematological tumor is selected from the group consisting of myelodysplastic syndrome and acute myeloid leukemia.
  • the hematological tumor is selected from acute myeloid leukemia.
  • the hematological tumor patient is an advanced hematological tumor patient.
  • the hematological tumor patient is an advanced malignant hematological tumor patient.
  • the hematological tumor is a hematological tumor with IDH2 gene mutation.
  • the IDH2 gene mutations include, but are not limited to, one or more mutations in R140Q, R140G, R140L, R140W, R172K, R172S, R172M, R172G or R172W.
  • the hematological tumor is a refractory and/or relapsed advanced hematological tumor.
  • the hematological tumor is refractory and/or relapsed myelodysplastic syndrome.
  • the hematological tumor is refractory and/or relapsed acute myeloid leukemia.
  • the relapse refers to the reappearance of >5% blast cells in the bone marrow after complete remission, or the reappearance of bone marrow blasts in the peripheral blood; or the occurrence of extramedullary lesions.
  • the hematological tumor patient is a myelodysplastic syndrome patient who is initially treated or an acute myeloid leukemia patient who is initially treated.
  • the hematological tumor patients are myelodysplastic syndrome patients who are unable to receive initial treatment of standard treatment due to age, physical status, or the presence of risk factors, or patients with myelodysplastic syndromes who are unable to receive standard treatment due to age, physical status, or the presence of risk factors.
  • Treatment-na ⁇ ve patients with acute myeloid leukemia who are unable to receive standard therapy.
  • the patients with myelodysplastic syndrome are very high risk (>6 points), or high risk (>4.5 points- ⁇ 6 points) according to the Revised International Prognostic Scoring System (IPSS-R), or Patients with myelodysplastic syndrome at intermediate risk (>3 points- ⁇ 4.5 points).
  • IVS-R Revised International Prognostic Scoring System
  • the hematological tumor patient is a hematological tumor patient who has received previous treatment.
  • the patients with hematological tumors have disease progression during previous drug treatment or have not reached complete remission (CR) within 3-5 cycles of treatment or have complete remission (CRi) with incomplete recovery of hematology.
  • CR complete remission
  • CRi complete remission
  • the hematological tumor patient has disease progression during treatment with the compound of formula I or does not achieve complete remission (CR) within 3-5 cycles of treatment or complete remission (CRi) with incomplete hematological recovery. of hematological cancer patients.
  • the hematological tumor patient is a hematological tumor patient who has received one or more prior treatments.
  • the hematologic malignancy patient is a hematologic malignancy patient who has received one, two, three, four, or five prior therapies.
  • the prior treatment includes supportive treatment, drug treatment or hematopoietic stem cell transplantation treatment.
  • the supportive treatment includes component transfusion therapy, erythropoietin (EPO) therapy, granulocyte colony-stimulating factor (G-CSF) therapy, granulocyte-macrocytic Granulocyte-macrophage colony-stimulating factor (GM-CSF) treatment or iron-removing therapy.
  • EPO erythropoietin
  • G-CSF granulocyte colony-stimulating factor
  • GM-CSF granulocyte-macrocytic Granulocyte-macrophage colony-stimulating factor
  • iron-removing therapy iron-removing therapy.
  • the drugs used for iron removal treatment include deferoxamine, deferasirox, etc.
  • the drugs used in the drug treatment include but are not limited to cytarabine, daunorubicin, daunorubicin, homoharringtonine, aclarithromycin, and mitoxantron Quinone, Fludarabine, Cladribine, Decitabine, Venetoclax, Etoposide, Azacitidine, Ivosidenib, Enasidenib, Grazig Glasdegib, thalidomide, lenalidomide, Gemtuzumab ozogamicin, danazol, stanozolol, testosterone undecanoate, Gilteritinib, Sorafenib, or a combination of one or more of the above drugs.
  • the azacitidine described in this application is azacitidine for injection, and the administration method is subcutaneous injection.
  • the dosage of subcutaneous injection of azacitidine described in this application is calculated based on the patient's body surface area.
  • the dosage of subcutaneous injection of azacitidine described in this application can be adjusted in subsequent treatment cycles. For example, if no beneficial effects are seen after 2 treatment cycles, and no toxicity other than nausea and vomiting occurs, the dosage can be increased. , for example, the daily dose of the first treatment cycle is increased from 75 mg/m 2 to the daily dose of 100 mg/m 2 , and the dosing method of the subsequent treatment cycle is the same as that of the first treatment cycle.
  • the components of the pharmaceutical combination of the present application may be administered independently, or part or all thereof may be administered together by any suitable route, including, but not limited to, oral or parenteral (via intravenous, intramuscular, topical or subcutaneous routes). ). In some embodiments, the components of the pharmaceutical combination of the present application may be administered independently, or part or all of them may be administered orally or by injection, such as intravenously or subcutaneously.
  • the components in the pharmaceutical combination of the present application may be suitable dosage forms independently, or part or all of them together, including but not limited to tablets, lozenges, pills, capsules (such as hard capsules, soft capsules, enteric capsules, etc.) capsules, microcapsules), elixirs, granules, syrups, injections (intramuscular, intravenous, intraperitoneal), emulsions, suspensions, solutions, dispersions and sustained-release formulations for oral or parenteral administration
  • suitable dosage forms independently, or part or all of them together, including but not limited to tablets, lozenges, pills, capsules (such as hard capsules, soft capsules, enteric capsules, etc.) capsules, microcapsules), elixirs, granules, syrups, injections (intramuscular, intravenous, intraperitoneal), emulsions, suspensions, solutions, dispersions and sustained-release formulations for oral or parenteral administration
  • the dosage form of the preparation including but
  • the drug combination of the present application has good safety and anti-tumor activity, and patients have good tolerance when receiving treatment with the drug combination of the present application.
  • the drug combination of the present application has higher complete remission (CR) rate and complete remission with incomplete hematological recovery (CRi) rate, good ECOG score, better disease control rate (DCR) and Objective response rate (ORR), longer duration of disease response (DOR), longer survival (such as median survival, progression-free survival, or overall survival).
  • the drug combination of the present application also has synergistic anti-tumor activity. Specifically, the drug combination of the present application has a higher complete remission (CR) rate than the compound of formula I or azacitidine alone, with incomplete recovery of hematology. Complete response (CRi) rate or objective response rate (ORR).
  • CRi complete remission
  • ORR objective response rate
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue without multiple toxicity, irritation, allergic reactions, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salts includes salts of alkali ions and free acids or salts of acid ions and free bases.
  • the content of a compound of formula I, its tautomer, or a pharmaceutically acceptable salt thereof is calculated as the free base form, e.g., in administration amounts, dosages, pharmaceutical compositions.
  • a compound in a pharmaceutical combination of the present application may form an acid addition salt if it has, for example, at least one basic center. If desired, the corresponding acid addition salts with additionally present basic centers can also be formed. Compounds having at least one acidic group (eg COOH) can also form salts with bases. If the compound contains, for example, both carboxyl and amino groups, corresponding internal salts can also be formed.
  • patient refers to mammals such as humans, dogs, cattle, horses, pigs, sheep, goats, cats, mice, rabbits, rats and transgenic non-human animals, and all The above terms are used interchangeably in this article.
  • patient, subject or individual is a human.
  • composition refers to one or more compounds of the present application, isomers (e.g., tautomers) or salts thereof together with pharmaceutically acceptable carriers and/or excipients and/or excipients composed mixture.
  • the purpose of pharmaceutical compositions is to facilitate administration to a patient of a compound of the present application, an isomer thereof (eg, a tautomer), or a salt thereof.
  • treatment generally refers to obtaining a desired pharmacological and/or physiological effect, including partial or complete stabilization or cure of a disease and/or effects resulting from a disease.
  • treatment encompasses any treatment of a patient's disease that: (a) inhibits the symptoms of the disease, i.e., prevents their progression; or (b) alleviates the symptoms of the disease, i.e., causes regression of the disease or symptoms.
  • an effective amount means an amount of a compound of the present disclosure that (i) treats a particular disease, condition, or disorder, or (ii) reduces, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder.
  • the amount of a compound of the present application that constitutes a "therapeutically effective amount” will vary depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by one skilled in the art. based on its own knowledge and the contents of this disclosure.
  • single dose refers to the smallest packaging unit containing a certain amount of medicine, for example, each tablet of medicine is a single dose; a box of medicine has seven capsules, each capsule is a single dose; or each bottle of injection is a single dose.
  • relapse refers to the reappearance of ⁇ 5% blasts in the bone marrow after complete remission, or the reappearance of bone marrow blasts in the peripheral blood; or the occurrence of extramedullary lesions.
  • AML relapsed acute myeloid leukemia
  • refractory includes newly treated cases that are ineffective after 2 courses of standard treatment; those who relapse within 12 months after undergoing consolidation and intensive treatment after complete remission; those who relapse after 12 months but are ineffective after conventional chemotherapy; 2 times Or those with multiple relapses; those with persistent extramedullary leukemia.
  • complete response refers to bone marrow blasts ⁇ 5%, no Auer bodies, and no extramedullary lesions; neutrophil count >1.0 ⁇ 10 9 /L, platelet count >100 ⁇ 10 9 /L; and independent Red blood cell transfusion.
  • the term “combination” refers to a fixed combination in the form of a dosage unit, or a non-fixed combination (or kit) for joint administration, wherein the compound of formula I and the other active ingredient of the combination may be administered simultaneously, separately or at a certain time Administer separately at intervals.
  • the term "fixed combination” means that the active ingredients, such as a compound of formula I, and another active ingredient of the combination are administered simultaneously to a patient in a single entity or dose.
  • non-fixed combination or “kit of kit” means that the active ingredients, such as a compound of formula I, and another active ingredient in the combination are each administered to a patient simultaneously or sequentially (without specific time limits) as separate entities.
  • combination use/administration and the like are intended to encompass the administration of selected therapeutic agents (ie, active ingredients) to a single patient, and are intended to include treatment regimens in which the therapeutic agents are not necessarily administered by the same route of administration or simultaneously.
  • the monomethane sulfonate of the compound of formula I is mixed with microcrystalline cellulose, mannitol, hydroxypropyl methylcellulose, croscarmellose sodium and sodium lauryl sulfate through sieving, and then granulated by dry method. After granulation, magnesium stearate is added and mixed evenly, and a tablet press is used for dry tableting to form tablets.
  • This study enrolls treatment-naive AML/MDS subjects who are not suitable for standard treatment regimens, or who have disease progression while receiving compound of formula I mesylate tablets alone or who have not completed treatment within 3-5 cycles.
  • the study drugs are all tablets of Compound I-methanesulfonate combined with azacitidine for injection.
  • the purpose of this study is to evaluate the tablets of Compound I-methanesulfonate combined with injection. Safety and effectiveness of azacitidine.
  • Tablets of the mesylate compound of formula I are 5 mg/tablet or 50 mg/tablet.
  • Azacitidine for injection specification: 100mg/bottle.
  • Tablets of compound of formula I - mesylate daily dose is 75 mg or 100 mg, taken orally on an empty stomach, once a day, continuously for 28
  • a day is a treatment cycle.
  • Azacitidine for injection 28 days is a treatment cycle, and 75 mg/m 2 azacitidine is injected subcutaneously every day on days 1 to 7 of each cycle.
  • MDS Myelodysplastic syndrome
  • AML acute myeloid leukemia
  • PLT Platelets
  • ALT, AST, ALP ⁇ 2.5 ⁇ upper limit of normal (ULN), unless it is believed to be caused by leukemia;
  • Serum total bilirubin ⁇ 1.5 ⁇ ULN for subjects with Gilbert syndrome, BIL ⁇ 3 ⁇ ULN;
  • Renal function serum Cr ⁇ 1.5 ⁇ ULN or creatinine clearance ⁇ 50 mL/min;
  • Safety evaluation standard NCI-CTC AE 5.0 standard is used to judge the severity of adverse events.
  • Effectiveness evaluation standards The International Working Group (IWG) standards are used to evaluate the efficacy. The improvement or deterioration of the general condition is expressed by the change in ECOG score before and after treatment.
  • Table 2 shows the test results of representative cases.
  • C1D28 means a treatment cycle of 28 days, and one treatment cycle
  • C2D28 means a treatment cycle of 28 days, and two treatment cycles of continuous administration
  • SD means the disease is stable
  • CR Indicates complete remission
  • CRi indicates complete remission with incomplete hematological recovery
  • / indicates that no efficacy evaluation has been carried out
  • -- indicates that data are not yet available.

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Abstract

L'invention concerne une combinaison pharmaceutique d'un dérivé de 1,3,5-triazine. Spécifiquement, la présente invention concerne une combinaison pharmaceutique d'un composé de formule I, d'un tautomère de celui-ci ou d'un sel pharmaceutiquement acceptable de celui-ci, et d'azacitidine, et son utilisation pharmaceutique.
PCT/CN2023/106034 2022-07-07 2023-07-06 Combinaison pharmaceutique d'un dérivé de 1,3,5-triazine WO2024008138A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017016513A1 (fr) * 2015-07-30 2017-02-02 正大天晴药业集团股份有限公司 Dérivé 1,3,5-triazine et sa méthode d'utilisation
CN109715143A (zh) * 2016-09-07 2019-05-03 细胞基因公司 片剂组合物

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017016513A1 (fr) * 2015-07-30 2017-02-02 正大天晴药业集团股份有限公司 Dérivé 1,3,5-triazine et sa méthode d'utilisation
CN109715143A (zh) * 2016-09-07 2019-05-03 细胞基因公司 片剂组合物

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