WO2023046200A1 - Cdk4/6抑制剂和芳香酶抑制剂的联用药物组合物 - Google Patents

Cdk4/6抑制剂和芳香酶抑制剂的联用药物组合物 Download PDF

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WO2023046200A1
WO2023046200A1 PCT/CN2022/121752 CN2022121752W WO2023046200A1 WO 2023046200 A1 WO2023046200 A1 WO 2023046200A1 CN 2022121752 W CN2022121752 W CN 2022121752W WO 2023046200 A1 WO2023046200 A1 WO 2023046200A1
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pharmaceutical composition
compound
formula
pharmaceutically acceptable
acceptable salt
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PCT/CN2022/121752
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English (en)
French (fr)
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封帆
于鼎
张喜全
王月婷
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正大天晴药业集团股份有限公司
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Priority to CA3232226A priority Critical patent/CA3232226A1/en
Publication of WO2023046200A1 publication Critical patent/WO2023046200A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • 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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings

Definitions

  • the disclosure belongs to the technical field of medicine, and relates to a combination pharmaceutical composition of a CDK4/6 inhibitor and an aromatase inhibitor, and its use for treating breast cancer.
  • Cyclin-dependent kinase (CDK) 4/6 is a key regulator of the cell cycle, which can trigger the cell cycle from the growth phase (G1 phase) to the DNA replication phase (S1 phase).
  • CDK4/6 and cyclin D can phosphorylate retinoblastoma protein (Rb).
  • Rb retinoblastoma protein
  • E2F activates further transcription to push the cell cycle through the restriction point (R point) and progress from G1 phase to S phase .
  • WO2016141881 discloses substituted 2-hydro-pyrazole derivatives as selective CDK4/6 inhibitors, and specifically discloses a compound of formula (I) with the following structure,
  • endocrine therapy is the main treatment for hormone receptor-positive breast cancer
  • about 30% of hormone receptor-positive breast cancers are primary resistant to endocrine therapy, and almost all patients develop secondary drug resistance in subsequent treatments, so how Overcoming resistance to endocrine therapy has become an urgent problem in the field of breast cancer treatment.
  • the present disclosure provides a combined pharmaceutical composition
  • the present disclosure provides a combined pharmaceutical composition for treating or preventing breast cancer, which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof and an aromatase inhibitor.
  • the present disclosure provides a method for treating or preventing breast cancer, comprising administering the above combined pharmaceutical composition to a subject in need.
  • the present disclosure provides the use of the above combined pharmaceutical composition in the preparation of a medicament or a kit for treating or preventing breast cancer.
  • the present disclosure provides a method of administration, comprising administering the above combined pharmaceutical composition to a subject in need.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof and the aromatase inhibitor in the combined pharmaceutical composition are packaged in the same kit, and the kit also contains Contains instructions for using a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with an aromatase inhibitor for the treatment or prevention of breast cancer.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof and the aromatase inhibitor in the combined pharmaceutical composition are packaged separately in respective kits, and the reagents
  • the kit also comprises instructions for using a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with an aromatase inhibitor for the treatment or prevention of breast cancer.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof and the aromatase inhibitor in the combined pharmaceutical composition are each in the form of a pharmaceutical composition, which can be administered simultaneously, sequentially or at intervals .
  • the combined pharmaceutical composition includes a pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutical composition of an aromatase inhibitor.
  • the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof and the pharmaceutical composition of the aromatase inhibitor in the combined pharmaceutical composition are packaged in the same reagent
  • the kit also includes instructions for using the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof and the pharmaceutical composition of an aromatase inhibitor in combination to treat or prevent breast cancer.
  • the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof and the pharmaceutical composition of the aromatase inhibitor in the combined pharmaceutical composition are packaged separately in their respective
  • the kit also includes instructions for using the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof and the pharmaceutical composition of an aromatase inhibitor in combination to treat or prevent breast cancer.
  • the pharmaceutically acceptable salt of the compound of formula (I) is a maleate salt, such as monomaleic acid of the compound of formula (I) Salt.
  • the aromatase inhibitor is selected from letrozole or anastrozole.
  • the combined pharmaceutical composition contains 20-240 mg, 40-180 mg, 60-180 mg, 80-180 mg, 100-180 mg, 120-180 mg or 150 mg of the compound of formula (I) ⁇ 180 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • the combined pharmaceutical composition contains 20 mg, 40 mg, 60 mg, 80 mg, 100 mg, 120 mg, 150 mg, 180 mg or 240 mg of the compound of formula (I) or its A pharmaceutically acceptable salt, or a pharmaceutical composition thereof.
  • the combined pharmaceutical composition contains 60 mg, 120 mg or 180 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof .
  • the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the form of single dose or multiple doses. In some embodiments of the present disclosure, in the combined pharmaceutical composition, the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is in the form of multiple doses.
  • the content of the compound of formula (I) or a pharmaceutically acceptable salt thereof is a daily dose or a daily dose.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof is contained in a once-a-day dose or a once-a-day dose.
  • the content of the compound of formula (I) or a pharmaceutically acceptable salt thereof is once a day or once a day, and each dose is a single A dose or multiple doses, preferably multiple doses.
  • the combined pharmaceutical composition contains a single dose of 50 mg, 60 mg, 120 mg or 180 mg of the compound of formula (I) or its pharmaceutically acceptable Salt pharmaceutical composition.
  • the combined pharmaceutical composition is in the form of a single administration preparation, and the combined pharmaceutical composition contains 50 mg, 60 mg, 120 mg or 180 mg of the compound of formula (I) or its pharmaceutical composition in terms of the compound of formula (I). acceptable salts or pharmaceutical compositions thereof.
  • the combined pharmaceutical composition in the combined pharmaceutical composition, it contains multiple doses of the compound of formula (I) or its pharmaceutically acceptable Salt pharmaceutical composition.
  • the combined pharmaceutical composition is in the form of a single administration preparation, and each dose is multiple doses, and the combined pharmaceutical composition contains 50 mg, 60 mg, 120 mg or 180 mg of the compound of formula (I) ( I) A compound or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
  • the combined pharmaceutical composition in the combined pharmaceutical composition, it contains a single dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof, which is calculated as 50 mg or 60 mg of the compound of formula (I) thing.
  • the combined pharmaceutical composition is in the form of a single administration preparation, and the combined pharmaceutical composition contains 50 mg or 60 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof in terms of the compound of formula (I) or its pharmaceutical composition.
  • the combined pharmaceutical composition in the combined pharmaceutical composition, it contains a single dose of 60 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the combined pharmaceutical composition is in the form of a single administration preparation, and the combined pharmaceutical composition contains 60 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof or pharmaceutical composition.
  • the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is packaged in a kit, and the kit also contains Instructions containing a compound of formula (I) or a pharmaceutically acceptable salt thereof for treating or preventing breast cancer.
  • the aromatase inhibitor in the combined pharmaceutical composition, is letrozole.
  • the combined pharmaceutical composition contains 2.5mg-12.5mg, 2.5mg-10mg, 2.5mg-7.5mg or 2.5mg-5mg of letrozole or the pharmaceutical composition thereof.
  • the combination pharmaceutical composition is in the form of a single administration formulation containing 2.5 mg-12.5 mg, 2.5 mg-10 mg, 2.5 mg-7.5 mg or 2.5 mg-5 mg of letrozole or its pharmaceutical composition.
  • the combination pharmaceutical composition contains 2.5 mg, 5 mg, 7.5 mg or 10 mg of letrozole or a pharmaceutical composition thereof.
  • the combination pharmaceutical composition is in the form of a single administration formulation, and the combination pharmaceutical composition contains 2.5 mg, 5 mg, 7.5 mg or 10 mg of letrozole or a pharmaceutical composition thereof.
  • the combination pharmaceutical composition contains 2.5 mg of letrozole or a pharmaceutical composition thereof.
  • the combination pharmaceutical composition is in the form of a single administration formulation, and the combination pharmaceutical composition contains 2.5 mg of letrozole or a pharmaceutical composition thereof.
  • the pharmaceutical composition of letrozole in the combined pharmaceutical composition, is in the form of single dose or multiple doses.
  • the pharmaceutical composition of letrozole in the combined pharmaceutical composition, is in the form of a single dose.
  • the content of letrozole is a daily dose or a daily dose.
  • the content of the letrozole is a once-a-day dose or a once-a-day dose.
  • the content of letrozole is once a day or once a day, and each dose is a single dose or multiple doses, preferably a single dose.
  • the combined pharmaceutical composition in the combined pharmaceutical composition, it contains a single dose of 2.5 mg letrozole.
  • the pharmaceutical composition containing letrozole in the combined pharmaceutical composition, is packaged in a kit, and the kit also contains letrozole for the treatment or prevention of breast cancer. Cancer illustration.
  • the pharmaceutical composition containing letrozole in the combined pharmaceutical composition, is packaged in a kit, and the kit also contains letrozole for the treatment or prevention of breast cancer.
  • the description of the cancer the description may be the description in the instructions of the commercially available letrozole kit.
  • the combined pharmaceutical composition contains 20-240 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof and 2.5 mg-12.5 mg of the compound of formula (I). Dorozole.
  • the combined pharmaceutical composition contains 120-180 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof and 2.5 mg-5 mg of letroxan azole.
  • the combined pharmaceutical composition contains a daily dose of 20 mg, 40 mg, 60 mg, 80 mg, 100 mg, 120 mg, 150 mg, 180 mg or 240 mg of the compound of formula (I) ) compound or a pharmaceutically acceptable salt thereof; and a daily dose of letrozole comprising 2.5 mg.
  • the combined pharmaceutical composition contains a daily dose of 60 mg, 120 mg, 180 mg or 240 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof ; and letrozole containing a daily dose of 2.5 mg.
  • the combined pharmaceutical composition contains a single dose of 50 mg or 60 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof based on the compound of formula (I); and a pharmaceutical composition containing letrozole in a single dose of 2.5 mg.
  • the combined pharmaceutical composition contains a single dose of 60 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof based on the compound of formula (I); and Pharmaceutical composition of letrozole in a single dose of 2.5 mg.
  • the combined pharmaceutical composition contains a mass ratio of 1:1 to 100:1, preferably 1.5:1 to 96:1, 5:1 to 90:1, 10:1 to 85 :1, 10:1 to 75:1, 20:1 to 75:1, 24:1 to 72:1, or a compound of formula (I) or a pharmaceutically acceptable salt thereof in any ratio within the above range or Its pharmaceutical composition and letrozole or its pharmaceutical composition, wherein, the amount of said formula (I) compound or its pharmaceutically acceptable salt or its pharmaceutical composition is based on the mass of formula (I) compound, said The amount of letrozole or its pharmaceutical composition is based on the mass of letrozole.
  • the combined pharmaceutical composition is a formulation suitable for administration in a single treatment cycle (eg, 28 days), and the formulation contains: 1680mg-5040mg (eg, 3360mg-5040mg, preferably 5040mg) of the formula (I) a compound or its pharmaceutically acceptable salt or its pharmaceutical composition;
  • the accepted amount of the salt or its pharmaceutical composition is based on the mass of the compound of formula (I), and the amount of said letrozole or its pharmaceutical composition is based on the mass of letrozole.
  • the combined pharmaceutical composition is a formulation suitable for administration in a single treatment cycle (eg, 28 days), and the formulation includes a mass ratio of 12:1 to 72:1, such as 24:1 to 72:1, 72:1 or the compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof and letrozole or a pharmaceutical composition thereof of any ratio within the above-mentioned range, wherein, the formula The amount of the compound (I) or its pharmaceutically acceptable salt or its pharmaceutical composition is based on the mass of the compound of formula (I), and the amount of the letrozole or its pharmaceutical composition is based on the mass of letrozole.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof and letrozole may be in the form of a pharmaceutical composition separately or together in a pharmaceutical composition form.
  • the present disclosure also provides a kit, which contains (a) a first pharmaceutical composition containing the compound of formula (I) described in the present disclosure or a pharmaceutically acceptable salt thereof; and (b) a second A pharmaceutical composition containing letrozole.
  • the present disclosure also provides a kit of a pharmaceutical composition for treating or preventing breast cancer, which contains (a) a first pharmaceutical composition containing the compound of formula (I) described in the present disclosure or its pharmaceutical composition acceptable salts above; and (b) a second pharmaceutical composition comprising letrozole.
  • the present disclosure also provides a method for treating or preventing breast cancer, which comprises administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and letrozole to an individual in need, for example, to an individual in need A therapeutically effective amount of the combination pharmaceutical composition described above of the present disclosure is administered to an individual in need thereof.
  • the present disclosure provides a method of administration, the method comprising: administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and letrozole to an individual in need, for example, to an individual in need
  • the present disclosure also provides a combined therapy for treating an individual with breast cancer, the method comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to the individual alone and administering a therapeutically effective amount of letrozole alone.
  • the present disclosure also provides the use of the compound of formula (I) or its pharmaceutically acceptable salt in combination with letrozole in the preparation of a drug for treating or preventing breast cancer, such as the above-mentioned combined pharmaceutical composition of the present disclosure Use in the preparation of medicaments for treating or preventing breast cancer.
  • the combined pharmaceutical composition is the above-mentioned combined pharmaceutical composition of the present disclosure.
  • the present disclosure also provides the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with letrozole for the treatment or prevention of breast cancer. Use for the prevention of breast cancer.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof and letrozole are as defined above Definitions of the compound of formula (I) or a pharmaceutically acceptable salt thereof and letrozole in the combined pharmaceutical composition, such as content, dosage, existing form, packaging form and the like.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof and letrozole are each in the form of a pharmaceutical composition, which can be simultaneously and separately , concurrent, sequential or interval administration.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof and letrozole have the same or different treatment cycles, respectively.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof and letrozole have the same treatment cycle, for example, every 1 Weekly, every 2 weeks, every 3 weeks or every 4 weeks is a treatment cycle.
  • the content of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the combined pharmaceutical composition is a daily dose, which The administration is as follows: the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once a day.
  • the content of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the combined pharmaceutical composition is a daily dose, wherein The compound of formula (I) or its pharmaceutically acceptable salt is administered in single dose or multi-dose mode, usually in multi-dose mode; further, wherein the compound of formula (I) or its pharmaceutically acceptable salt is administered daily Administration 1 time.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in the following manner: the daily dose is 60 mg; The daily dose is 120 mg; alternatively, the daily dose is 180 mg; alternatively, the daily dose is 240 mg.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof in the combined pharmaceutical composition is administered in multiple doses, so Said multi-dose consists of a single dose of 50 mg or 60 mg of the compound of formula (I) or a pharmaceutical composition of a pharmaceutically acceptable salt thereof; preferably, said multi-dose consists of a single dose of 60 mg of the compound of formula (I) or its pharmaceutical composition A pharmaceutical composition of a pharmaceutically acceptable salt.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered as continuous daily administration.
  • the content of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the combined pharmaceutical composition is a dose per cycle, which Administration is carried out by daily administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the content of letrozole in the combined pharmaceutical composition is a daily dose, which is administered in the following manner: letrozole per Dosing once a day.
  • the content of letrozole in the combined pharmaceutical composition is a daily dose, wherein letrozole is administered as a single dose or in multiple doses. Administration is usually administered in a single dose; further, letrozole is administered once a day.
  • the letrozole in the method, combination therapy or use, is administered in a daily dose of 2.5 mg.
  • the letrozole in the combination pharmaceutical composition is administered as a single dose, the single dose is 2.5 mg of letrozole pharmaceutical composition. In some embodiments of the present disclosure, in the method, combination therapy or use, the letrozole is administered as continuous daily administration.
  • the content of letrozole in the combination pharmaceutical composition is a weekly dose, which is administered by: administering letrozole every day azole.
  • 28 days is a treatment cycle, and the compound of formula (I) or its pharmaceutical preparation is administered every day on the 1-28th day of each treatment cycle.
  • acceptable salts and letrozole are included in the method, combined therapy or use.
  • 28 days is a treatment cycle, and the formula (I ) compound or a pharmaceutically acceptable salt thereof and letrozole.
  • 28 days is a treatment cycle, administered once a day, for 28 consecutive days, each treatment cycle is administered with the formula (I )
  • the total dose of the pharmaceutical composition of the compound or a pharmaceutically acceptable salt thereof is 1680-5040 mg.
  • the total dose of the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from 1680 mg, 3360 mg, 5040 mg or the range formed by any two of the above values .
  • the total dose of the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is preferably 5040 mg.
  • 28 days is a treatment cycle, administered once a day, for 28 consecutive days, and the drug containing letrozole is administered in each treatment cycle
  • the total dose of the composition is 70-210 mg.
  • the total dose of the letrozole-containing pharmaceutical composition is selected from 70 mg, 140 mg, 210 mg or the range formed by any two of the above values.
  • the total dose of the letrozole-containing pharmaceutical composition is preferably 70 mg.
  • 28 days is a treatment cycle, administered once a day, for 28 consecutive days, and a total dose of 5040 mg containing A pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing letrozole with a total dose of 70 mg.
  • the treatment cycles described above are repeated as long as the disease remains under control and the dosing regimen is clinically tolerable.
  • the letrozole is prepared as a single dose or multiple doses suitable for continuous daily administration of 2.5 mg-7.5 mg or 2.5 mg-5 mg letrozole to the patient;
  • the pharmaceutical composition of the compound or a pharmaceutically acceptable salt thereof is prepared as single or multiple doses of 60 mg, 120 mg, 180 mg and/or 240 mg of the compound of formula (I) itself, suitable for continuous daily administration to patients.
  • said letrozole is prepared as a single dose suitable for continuous daily administration of 2.5 mg letrozole to a patient; a medicament containing said compound of formula (I) or a pharmaceutically acceptable salt thereof
  • the composition is prepared as multiple doses of 180 mg of the compound of formula (I) itself suitable for successive daily administration to a patient.
  • the aromatase inhibitor in the combined pharmaceutical composition, is anastrozole.
  • the combined pharmaceutical composition contains 1 mg-5 mg, 1 mg-4 mg, 1 mg-3 mg or 1 mg-2 mg of anastrozole or a pharmaceutical composition thereof.
  • the combined pharmaceutical composition is in the form of a single administration formulation, and the combined pharmaceutical composition contains 1 mg-5 mg, 1 mg-4 mg, 1 mg-3 mg or 1 mg-2 mg of anastrozole or the pharmaceutical composition thereof.
  • the combined pharmaceutical composition contains 1 mg, 2 mg, 3 mg or 4 mg of anastrozole or a pharmaceutical composition thereof.
  • the combined pharmaceutical composition is in the form of a single administration formulation, and the combined pharmaceutical composition contains 1 mg, 2 mg, 3 mg or 4 mg of anastrozole or a pharmaceutical composition thereof.
  • the combined pharmaceutical composition contains 1 mg of anastrozole or a pharmaceutical composition thereof.
  • the combination pharmaceutical composition is in the form of a single administration formulation, the combination pharmaceutical composition containing 1 mg of anastrozole or a pharmaceutical composition thereof.
  • the pharmaceutical composition of anastrozole in the combined pharmaceutical composition, is in the form of single dose or multiple doses.
  • the pharmaceutical composition of anastrozole in the combined pharmaceutical composition, is in the form of a single dose.
  • the content of anastrozole is a daily dose or a daily dose.
  • the content of the anastrozole is a once-a-day dose or a once-a-day dose.
  • the content of anastrozole is once a day or once a day, and each dose is a single dose or multiple doses, preferably a single dose.
  • the combined pharmaceutical composition contains a single dose of 1 mg of anastrozole.
  • the pharmaceutical composition of anastrozole contained in it is packaged in a kit, and the kit also contains anastrozole for treating or preventing breast cancer. Cancer illustration.
  • the pharmaceutical composition of anastrozole contained in it is packaged in a kit, and the kit also contains anastrozole for treating or preventing breast cancer.
  • the description of the cancer the description may be the description in the instructions of the commercially available Anastrozole kit.
  • the combined pharmaceutical composition contains 20-240 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof and 1 mg-5 mg of anastrozole .
  • the combined pharmaceutical composition contains 120-180 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof and 1 mg-2 mg of anastrozole .
  • the combined pharmaceutical composition contains a daily dose of 20 mg, 40 mg, 60 mg, 80 mg, 100 mg, 120 mg, 150 mg, 180 mg or 240 mg of the compound of formula (I) ) compound or a pharmaceutically acceptable salt thereof; and a daily dose of 1 mg of anastrozole.
  • the combined pharmaceutical composition contains a daily dose of 60 mg, 120 mg, 180 mg or 240 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof ; and Anastrozole containing a daily dose of 1 mg.
  • the combined pharmaceutical composition contains a single dose of 50 mg or 60 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof based on the compound of formula (I); and a pharmaceutical composition containing a single dose of 1 mg of anastrozole.
  • the combined pharmaceutical composition contains a single dose of 60 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof based on the compound of formula (I); and Pharmaceutical composition of anastrozole in a single dose of 1 mg.
  • the combined pharmaceutical composition contains a mass ratio of 4:1 to 240:1, preferably 10:1 to 180:1, 25:1 to 180:1, 30:1 to 180 : 1, 60: 1 to 180: 1, or the compound of formula (I) or its pharmaceutically acceptable salt or its pharmaceutical composition and Anastrozole or its pharmaceutical composition thereof and any ratio in the above-mentioned range, wherein, The amount of the compound of formula (I) or its pharmaceutically acceptable salt or its pharmaceutical composition is based on the mass of the compound of formula (I), and the amount of the anastrozole or its pharmaceutical composition is based on the mass of anastrozole count.
  • the combined pharmaceutical composition is a formulation suitable for administration in a single treatment cycle (eg, 28 days), and the formulation contains: 1680mg-5040mg (eg, 3360mg-5040mg, preferably 5040mg) of the formula (I) compound or its pharmaceutically acceptable salt or its pharmaceutical composition; and Anastrozole or its pharmaceutical composition of 28mg-140mg (such as 28mg-56mg, preferably 28mg), wherein, said formula (I) compound
  • the amount of the pharmaceutically acceptable salt thereof or its pharmaceutical composition is based on the mass of the compound of formula (I), and the anastrozole or its pharmaceutical composition is based on the mass of Anastrozole.
  • the combined pharmaceutical composition is a preparation suitable for administration in a single treatment cycle (for example, 28 days), and the preparation includes a mass ratio of 12:1 to 180:1, such as 60:1 to 180:1, 180:1 or any ratio within the above range of formula (I) compound or its pharmaceutically acceptable salt or its pharmaceutical composition and Anastrozole or its pharmaceutical composition, wherein, said formula
  • the amount of the compound (I) or its pharmaceutically acceptable salt or its pharmaceutical composition is based on the mass of the compound of formula (I), and the anastrozole or its pharmaceutical composition is based on the mass of Anastrozole.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof and anastrozole can be in the form of a pharmaceutical composition respectively or together in a pharmaceutical composition form.
  • the present disclosure also provides a kit, which contains (a) a first pharmaceutical composition containing the compound of formula (I) described in the present disclosure or a pharmaceutically acceptable salt thereof; and (b) a second A pharmaceutical composition containing anastrozole.
  • the present disclosure also provides a kit of a pharmaceutical composition for treating or preventing breast cancer, which contains (a) a first pharmaceutical composition containing the compound of formula (I) described in the present disclosure or its pharmaceutical composition acceptable salts; and (b) a second pharmaceutical composition comprising anastrozole.
  • the present disclosure also provides a method for treating or preventing breast cancer, which comprises administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and anastrozole to an individual in need, for example, to an individual in need A therapeutically effective amount of the combination pharmaceutical composition described above of the present disclosure is administered to an individual in need thereof.
  • the present disclosure also provides a method of administration, the method comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and anastrozole to an individual in need, for example, to an individual in need
  • a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the individual alone and the treatment is administered separately.
  • An effective amount of anastrozole is administered to the individual alone and the treatment is administered separately.
  • the present disclosure also provides a combined therapy for treating an individual with breast cancer, the method comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to the individual alone and administering a therapeutically effective amount of anastrozole alone.
  • the present disclosure also provides the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with anastrozole in the preparation of a drug for treating or preventing breast cancer, such as the above-mentioned combined pharmaceutical composition of the present disclosure Use in the preparation of medicaments for treating or preventing breast cancer.
  • the combined pharmaceutical composition is the above-mentioned combined pharmaceutical composition of the present disclosure.
  • the present disclosure also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with anastrozole for treating or preventing breast cancer. Use for the prevention of breast cancer.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof and Anastrozole are as defined above Definitions of the compound of formula (I) or a pharmaceutically acceptable salt thereof and anastrozole in the combined pharmaceutical composition, such as content, dosage, existing form, packaging form and the like.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof and anastrozole are each in the form of a pharmaceutical composition, which can be simultaneously or separately , concurrent, sequential or interval administration.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof and anastrozole have the same or different treatment cycles, respectively.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof and anastrozole have the same treatment cycle, for example, every 1 Weekly, every 2 weeks, every 3 weeks or every 4 weeks is a treatment cycle.
  • the content of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the combined pharmaceutical composition is a daily dose, which The administration is as follows: the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once a day.
  • the content of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the combined pharmaceutical composition is a daily dose, wherein The compound of formula (I) or its pharmaceutically acceptable salt is administered in single dose or multi-dose mode, usually in multi-dose mode; further, wherein the compound of formula (I) or its pharmaceutically acceptable salt is administered daily Administration 1 time.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in the following manner: the daily dose is 60 mg; The daily dose is 120 mg; alternatively, the daily dose is 180 mg; alternatively, the daily dose is 240 mg.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof in the combined pharmaceutical composition is administered in multiple doses, so Said multi-dose consists of a single dose of 50 mg or 60 mg of the compound of formula (I) or a pharmaceutical composition of a pharmaceutically acceptable salt thereof; preferably, said multi-dose consists of a single dose of 60 mg of the compound of formula (I) or its pharmaceutical composition A pharmaceutical composition of a pharmaceutically acceptable salt.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered as continuous daily administration.
  • the content of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the combined pharmaceutical composition is a dose per cycle, which Administration is carried out by daily administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the content of anastrozole in the combined pharmaceutical composition is a daily dose, which is administered in the following manner: anastrozole per Dosing once a day.
  • the content of anastrozole in the combined pharmaceutical composition is a daily dose, wherein anastrozole is administered in a single dose or in multiple doses. Administration is usually administered in a single dose; further, anastrozole is administered once a day.
  • the anastrozole in the method, combination therapy or use, is administered in a daily dose of 1 mg.
  • the anastrozole in the combined pharmaceutical composition is administered in a single dose, and the single dose is 1 mg of anastrozole pharmaceutical composition. In some embodiments of the present disclosure, in the method, combination therapy or use, the anastrozole is administered as continuous daily administration.
  • the content of anastrozole in the combination pharmaceutical composition is a per cycle dose, which is administered by: daily administration of anastrozole azole.
  • 28 days is a treatment cycle, and the compound of formula (I) or its pharmaceutical preparation is administered every day on the 1-28th day of each treatment cycle.
  • acceptable salts and anastrozole are included in the method, combined therapy or use.
  • 28 days is a treatment cycle, and the formula (I ) compound or a pharmaceutically acceptable salt thereof and anastrozole.
  • 28 days is a treatment cycle, administered once a day, for 28 consecutive days, each treatment cycle is administered with the formula (I )
  • the total dose of the pharmaceutical composition of the compound or a pharmaceutically acceptable salt thereof is 1680-5040 mg.
  • the total dose of the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from 1680 mg, 3360 mg, 5040 mg or the range formed by any two of the above values.
  • the total dose of the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is preferably 5040 mg.
  • 28 days is a treatment cycle, administered once a day, for 28 consecutive days, and the drug containing anastrozole is administered in each treatment cycle
  • the total dose of the composition is 28-140 mg.
  • the total dose of the pharmaceutical composition containing anastrozole is selected from 28 mg, 56 mg, 84 mg or the range formed by any two of the above values.
  • the total dose of the pharmaceutical composition containing anastrozole is preferably 28 mg.
  • 28 days is a treatment cycle, administered once a day, for 28 consecutive days, and a total dose of 5040 mg containing A pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing anastrozole with a total dose of 28 mg.
  • the treatment cycles described above are repeated as long as the disease remains under control and the dosing regimen is clinically tolerable.
  • the anastrozole is prepared as a single dose or multiple doses suitable for continuous daily administration of 1 mg-3 mg or 1 mg-2 mg anastrozole to the patient; containing the compound of formula (I) or Pharmaceutical compositions of pharmaceutically acceptable salts are prepared as single or multiple doses of 60 mg, 120 mg, 180 mg and/or 240 mg of the compound of formula (I) itself, suitable for continuous daily administration to patients.
  • the anastrozole is prepared as a single dose suitable for continuous daily administration of 1 mg anastrozole to the patient; the pharmaceutical combination containing the compound of formula (I) or a pharmaceutically acceptable salt thereof
  • the compound is prepared as multiple doses of 180 mg of the compound of formula (I) itself suitable for consecutive daily administration to a patient.
  • the breast cancer is selected from HR positive breast cancer.
  • the breast cancer is selected from HER2 negative breast cancer.
  • the breast cancer is selected from HR-positive, HER2-negative breast cancer.
  • the breast cancer is selected from locally advanced and/or metastatic breast cancer. In some embodiments of the present disclosure, the breast cancer is selected from HER2-negative locally advanced and/or metastatic breast cancer.
  • the breast cancer is selected from HR-positive, HER2-negative locally advanced and/or metastatic breast cancer.
  • the breast cancer is selected from HR-positive, HER2-negative locally advanced and/or metastatic breast cancer that cannot receive radical surgery or radiotherapy.
  • the breast cancer patient is a patient with HR-positive, HER2-negative locally advanced and/or metastatic breast cancer who cannot receive radical surgery or radiotherapy.
  • the breast cancer is selected from postmenopausal or premenopausal/perimenopausal breast cancer.
  • the breast cancer patient is a postmenopausal or premenopausal/perimenopausal breast cancer patient.
  • the breast cancer is selected from postmenopausal or premenopausal/perimenopausal HR-positive, HER2-negative locally advanced and/or metastatic breast cancer.
  • the breast cancer patient is a postmenopausal or premenopausal/perimenopausal HR-positive, HER2-negative locally advanced and/or metastatic breast cancer patient.
  • the breast cancer is selected from breast cancers that have previously undergone bilateral oophorectomy. In some embodiments of the present disclosure, the breast cancer patient is a breast cancer patient who has previously undergone bilateral oophorectomy.
  • the breast cancer is selected from postmenopausal or premenopausal/perimenopausal breast cancer who have previously undergone bilateral oophorectomy.
  • the breast cancer patient is a postmenopausal or premenopausal/perimenopausal breast cancer patient who has previously undergone bilateral oophorectomy.
  • the breast cancer is selected from postmenopausal or premenopausal/perimenopausal HR-positive, HER2-negative locally advanced and/or metastatic breast cancer who have previously undergone bilateral oophorectomy.
  • the breast cancer patient is a postmenopausal or premenopausal/perimenopausal HR-positive, HER2-negative locally advanced and/or metastatic breast cancer patient who has previously undergone bilateral oophorectomy.
  • the breast cancer is selected from postmenopausal or premenopausal/perimenopausal HR-positive, HER2-negative locally advanced and/or metastatic breast cancer that cannot receive radical surgery or radiotherapy.
  • the breast cancer patients are postmenopausal or premenopausal/perimenopausal patients with HR-positive, HER2-negative locally advanced and/or metastatic breast cancer who cannot receive radical surgery or radiotherapy.
  • HR positivity includes estrogen receptor ER positivity and/or progesterone receptor PR positivity, defined as: positively stained tumor cells account for ⁇ 1% of all tumor cells.
  • HER2 negative is defined as: immunohistochemical staining (IHC) detection shows that HER2 is 0/1+; if the detection shows 2+, fluorescent in situ hybridization (FISH) is required to confirm that it is negative or FISH only was negative.
  • IHC immunohistochemical staining
  • FISH fluorescent in situ hybridization
  • the breast cancer is selected from HR-positive, HER2-negative locally advanced and/or metastatic breast cancer that has previously received no more than 1 line of chemotherapy.
  • the breast cancer is selected from HR-positive, HER2-negative breast cancer that recurs or progresses during adjuvant endocrine therapy or within 1 year after completion of adjuvant endocrine therapy, and does not subsequently receive endocrine therapy.
  • the breast cancer is selected from HR-positive, HER2-negative breast cancer that recurs or progresses more than 1 year after the completion of adjuvant endocrine therapy, and then progresses again after receiving advanced endocrine therapy; the advanced endocrine therapy Do not use aromatase inhibitors.
  • the breast cancer is selected from breast cancer with primary metastatic disease progressing after receiving advanced endocrine therapy; aromatase inhibitors cannot be used for the advanced endocrine therapy.
  • the breast cancer is selected from HR-positive, HER2-negative locally advanced and/or metastatic breast cancer that has not previously received any systemic anti-tumor therapy for local recurrence or metastatic disease .
  • completion of adjuvant endocrine therapy refers to discontinuation of the drug after at least 2 years of continuous therapy.
  • the endocrine therapy refers to tamoxifen, toremifene, fulvestrant, goserelin and leuprolide treatment.
  • the endocrine therapy refers to tamoxifen and goserelin therapy.
  • the active components in the pharmaceutical combination of the present disclosure can be formulated independently, or part or all of them together with pharmaceutically acceptable carriers and/or excipients.
  • the pharmaceutical combinations of the present disclosure may also comprise additional therapeutic agents.
  • the additional therapeutic agent may be a therapeutic agent known in the art for cancer, preferably for breast cancer.
  • the period is 28 days.
  • the amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof administered may be determined according to the severity of the disease, the response of the disease, any treatment-related toxicity, the age and health of the patient.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof can be administered by various routes including but not limited to the following routes: oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, Intramuscular, rectal, buccal, intranasal, by inhalation, vaginal, intraocular, topical, subcutaneous, intrafacial, intraarticular, intraperitoneal, and intrathecal.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered orally.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered orally in a continuous daily manner.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof can be administered once or more than once a day. In some embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once a day. Compounds of formula (I) or pharmaceutically acceptable salts thereof may also be administered in single or multiple doses. In one embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once daily in multiple doses.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once a day in the form of multiple doses of oral solid preparations. In one embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once daily in multiple doses.
  • the method of administration can be comprehensively determined according to the activity, toxicity and patient tolerance of the drug.
  • a pharmaceutically acceptable salt of a compound of formula (I) may be a maleate salt of a compound of formula (I) (eg, a monomaleate salt of a compound of formula (I)).
  • doses of the compound of formula (I) or the pharmaceutically acceptable salt thereof involved in the present disclosure are based on the molecular weight of the compound of formula (I), unless otherwise stated.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof used in the present disclosure can be prepared by methods of the prior art, for example, referring to the method of WO2016141881.
  • the single dose of the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof may be 50 mg or 60 mg based on the compound of formula (I).
  • the single dose of the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 60 mg.
  • the method of administration can be comprehensively determined according to the activity, toxicity and patient tolerance of the drug.
  • the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof further contains pharmaceutically acceptable excipients.
  • Pharmaceutically acceptable excipients include fillers, absorbents, wetting agents, binders, disintegrants, lubricants and the like.
  • the pharmaceutical composition includes, but is not limited to, formulations suitable for oral, parenteral, and topical administration.
  • the pharmaceutical composition is a formulation suitable for oral administration.
  • the pharmaceutical composition is a solid preparation suitable for oral administration.
  • the pharmaceutical composition includes, but is not limited to, tablets, capsules.
  • the pharmaceutical composition is a solid pharmaceutical composition.
  • the pharmaceutical composition is a capsule.
  • the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is a solid pharmaceutical composition of the compound of formula (I).
  • the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is a capsule of the compound of formula (I).
  • composition of the disclosed compound of formula (I) or its pharmaceutically acceptable salt can be produced by methods well known in the art, such as conventional mixing, dissolving, granulating, sugar-coated pills, pulverizing, emulsifying method, freeze-drying method, etc.
  • Solid oral compositions can be prepared by conventional methods of mixing, filling or tabletting. It can be obtained, for example, by mixing the active compound with solid excipients, optionally milling the resulting mixture, adding other suitable excipients if desired, and then processing the mixture into granules to obtain tablets or Dragee cores, or capsule filling to obtain capsules.
  • suitable auxiliary materials include but are not limited to: binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, etc.
  • letrozole 1-[bis(4-cyanophenyl)methyl]-1,2,4-triazole, which has the following structural formula:
  • the pharmaceutical composition of letrozole further contains pharmaceutically acceptable excipients.
  • the pharmaceutically acceptable excipients include fillers, absorbents, wetting agents, binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents wait.
  • the pharmaceutical composition is a solid pharmaceutical composition.
  • the pharmaceutical composition is a tablet.
  • the pharmaceutical composition is an oral tablet.
  • the single dose of the letrozole pharmaceutical composition is 2.5 mg.
  • anastrozole is a,a,a',a'-tetramethyl-5-(1H-1,2,4-triazole-1-methyl)-1,3-benzene Diacetonitrile, which has the following structural formula:
  • the pharmaceutical composition of anastrozole further contains pharmaceutically acceptable excipients.
  • the pharmaceutically acceptable excipients include fillers, absorbents, wetting agents, binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents wait.
  • the pharmaceutical composition is a solid pharmaceutical composition.
  • the pharmaceutical composition is a tablet.
  • the pharmaceutical composition is an oral tablet.
  • the single dose of the pharmaceutical composition of Anastrozole is 1 mg.
  • the active ingredients in the combined pharmaceutical composition of the present disclosure can be administered independently, or some or all of them can be administered in various suitable ways, including but not limited to, oral or parenteral (by intravenous, intramuscular, topical or subcutaneous routes). In some embodiments of the present disclosure, the active ingredients in the combined pharmaceutical composition of the present disclosure can be administered independently, or some or all of them can be administered orally together.
  • the active ingredients in the combination pharmaceutical composition of the present disclosure can be each independently, or some or all of them can be suitable dosage forms together, including but not limited to, tablets, buccal tablets, pills, capsules (such as hard capsules, soft capsules, enteric-coated capsules, microcapsules), elixirs, granules, syrups, injections (intramuscular, intravenous, intraperitoneal), granules, emulsions, suspensions, solutions, dispersions and for oral or The dosage form of the sustained-release preparation for parenteral administration.
  • suitable dosage forms together including but not limited to, tablets, buccal tablets, pills, capsules (such as hard capsules, soft capsules, enteric-coated capsules, microcapsules), elixirs, granules, syrups, injections (intramuscular, intravenous, intraperitoneal), granules, emulsions, suspensions, solutions, dispersions and for oral or The dosage form of the sustained-release preparation
  • the treated patients have a longer survival period (such as median survival period, progression-free survival period or overall survival period);
  • the combined pharmaceutical composition of the present disclosure is "clinically beneficial", including but not limited to: the progression-free survival (PFS) of clinical patients is prolonged, the overall survival (OS) is prolonged, the objective response rate (ORR) is improved, the disease The control rate (DCR) is improved, the number and/or degree of adverse reactions are reduced, the distant metastasis rate and the local control rate are decreased, etc.
  • combined pharmaceutical composition refers to two or more active ingredients administered simultaneously or sequentially (administered in the form of each active ingredient itself, or in the form of its respective pharmaceutically acceptable salt or ester, etc. administration in the form of derivatives, prodrugs or compositions).
  • combination pharmaceutical composition and “drug combination” are used interchangeably.
  • patient or “individual/subject” refers to mammals such as primates (humans, macaques, chimpanzees, etc.), rodents (mice, rats, rabbits, etc.), felines, canines, etc. Animals etc., preferably humans.
  • the patient and the individual are patients who have failed or lacked standard therapy.
  • pharmaceutically acceptable refers to a carrier, excipient or adjuvant used in the preparation of a pharmaceutical composition which is generally safe, non-toxic and non-toxic in biological It is neither medically nor otherwise desirable, and is acceptable, including for use in human medicine.
  • terapéuticaally effective amount means an amount of a compound which, when administered to a human to treat a disease, is sufficient to effect treatment of the disease.
  • treating means administering a compound or formulation described herein to ameliorate, alleviate or eliminate a disease or one or more symptoms associated with the disease, and includes: (i) inhibiting the disease or disease state, i.e. arrest or retard its development; (ii) alleviate a disease or disease state, even if the disease or disease state subsides.
  • prevention means administering a compound or formulation described herein to prevent a disease or one or more symptoms associated with the disease, including: preventing a disease or disease state from occurring in a mammal, especially when the when the mammalian mammal is susceptible to the disease state but has not been diagnosed as having the disease state.
  • systemic treatment refers to treatment in which a drug substance is delivered through the bloodstream to reach and affect cells throughout the body.
  • systemic therapy refers to systemic chemotherapy, systemic or localized radiation therapy.
  • first-line treatment refers to treatment with drugs that can be selected first or standard according to the patient's condition.
  • an "adverse event” is any adverse and often unintentional or unwanted sign (including abnormal laboratory findings), symptom or disease associated with the application of a medical treatment.
  • an adverse event can be associated with activation of the immune system or expansion of immune system cells (eg, T cells) in response to therapy.
  • a medical treatment may have one or more associated AEs, and each AE may be of the same or different levels of severity.
  • Reference to a method capable of "modifying an adverse event” refers to a treatment regimen that reduces the incidence and/or severity of one or more AEs associated with the use of a different treatment regimen.
  • pharmaceutically acceptable excipients refers to those excipients that have no obvious stimulating effect on the organism and will not impair the biological activity and performance of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like.
  • administering and “administering” mean the physical introduction of a composition comprising a therapeutic agent to an individual using any of a variety of methods and delivery systems known to those skilled in the art.
  • the administration is oral administration.
  • daily dose refers to the daily dose administered to a patient.
  • daily dose refers to a dose administered to a patient for one day.
  • single dose or "unit preparation” refers to the smallest packaged unit of a medicinal product containing a certain amount of active ingredient, for example, a box of seven capsules, each capsule is a single dose or unit preparation; for example, a box of seven capsules Each tablet is a single dose or unit preparation.
  • multiple dose consists of a number of single doses.
  • “combination” or “combined use” means that two or more active substances may be administered to an individual simultaneously, concurrently, or sequentially in any order, each as a single formulation.
  • composition refers to a mixture of one or more active ingredients of the present application or its pharmaceutical combination and pharmaceutically acceptable excipients.
  • the purpose of a pharmaceutical composition is to facilitate the administration of a compound of the present application, or a pharmaceutical combination thereof, to an individual.
  • day refers to the time within a calendar day beginning at midnight and ending at midnight the next following.
  • recurrent cancer is cancer that regenerates at the original site or at a distant site after a response to initial treatment (eg, surgery).
  • a "locally recurrent” cancer is one that, after treatment, arises in the same location as a previously treated cancer.
  • metalstatic cancer refers to cancer that has spread from one part of the body, such as the lungs, to another part of the body.
  • “combination” or “combined use” means that two or more active substances can be administered to a subject together in a mixture, simultaneously as a single formulation, or sequentially in any order as a single formulation.
  • the research drugs were all compounds of formula (I) combined with aromatase inhibitors, and patients with HR-positive, HER2-negative locally advanced and/or metastatic breast cancer were enrolled. 30-60 subjects were enrolled in each cohort, and the preliminary efficacy and safety of the compound of formula (I) combined with aromatase inhibitors were evaluated. Among them, the aromatase inhibitor is selected from letrozole or anastrozole, and 15-30 subjects are enrolled in each cohort of the two drugs.
  • Age 18-75 years old (when signing the informed consent);
  • ECOG PS score 0-1 point; expected survival time is more than 3 months;
  • Completion of adjuvant endocrine therapy in cohort 1 is defined as discontinuation of the drug after at least 2 years of continuous treatment;
  • Subjects enrolled in cohort 2 have not previously received any systemic anti-tumor therapy for local recurrence or metastatic disease;
  • ALT and AST Alanine-based transferase (ALT) and aspartate-based transferase (AST) ⁇ 2.5 ⁇ ULN. If accompanied by liver metastasis, ALT and AST ⁇ 5 ⁇ ULN;
  • Coagulation function tests should meet the following criteria:
  • Prothrombin time (PT), activated partial thromboplastin time (APTT), international normalized ratio (INR) ⁇ 1.5 ⁇ ULN (no anticoagulant therapy);
  • LVEF left ventricular ejection fraction
  • Female subjects of childbearing age should agree to use contraceptive measures (such as intrauterine devices, contraceptives or condoms) during the study period and within 6 months after the end of the study; negative serum pregnancy test within 7 days before study enrollment , and must be a non-lactating subject.
  • contraceptive measures such as intrauterine devices, contraceptives or condoms
  • Capsules of the compound of formula (I) 180 mg (based on the mass of the compound of formula (I)), orally taken on an empty stomach, once a day, and taken continuously for 28 days as a treatment cycle.
  • Aromatase inhibitor letrozole or anastrozole can be selected, and the specific dosage regimen is as follows:
  • Letrozole tablets 2.5 mg (based on the mass of letrozole) orally, once a day, taken continuously, every 28 days as a treatment cycle.
  • Anastrozole tablets 1 mg (based on the mass of anastrozole) orally, once a day, taken continuously, every 28 days as a treatment cycle.
  • Effectiveness evaluation criteria The RECIST 1.1 standard was used to determine the disease status.
  • cohort 2 Of the 43 subjects, 38 were enrolled in cohort 2, and the others were cohort 1 subjects. 35 subjects (cohort 2: 32 cases, cohort 1: 3 cases) can be evaluated for efficacy.
  • the curative effect showed that the ORR was 65.7% (23/35), and the effective rate of cohort 2 subjects was 65.6% (21/32), which was consistent with the ORR of the whole population.
  • the clinical benefit rate CBR of cohort 2 was 90.6% (29/32 ).
  • the effective rate of subjects in cohort 1 was 66.7% (2/3), consistent with the ORR of the general population, and the clinical benefit rate CBR of cohort 1 was 100% (3/3).
  • NA means not evaluated
  • * means the percentage of tumor volume reduction
  • -- means not reached the tumor evaluation point.

Abstract

本公开涉及CDK4/6抑制剂和芳香酶抑制剂的联用药物组合物、及其用于治疗乳腺癌的用途。本公开的联用药物组合物与该组合中的任一药物单独给药相比，在减少肿瘤的生长或甚至消除肿瘤方面产生更好的疗效。

Description

CDK4/6抑制剂和芳香酶抑制剂的联用药物组合物
相关申请的引用
本申请要求于2021年09月27日向中华人民共和国国家知识产权局提交的第202111133804.5号中国专利申请的优先权和权益，在此将其全部内容以援引的方式整体并入本文中。
技术领域
本公开属于医药技术领域，涉及CDK4/6抑制剂和芳香酶抑制剂的联用药物组合物、及其用于治疗乳腺癌的用途。
背景技术
周期蛋白依赖性激酶(CDK)4/6是细胞周期的关键调节因子，能够触发细胞周期从生长期(G1期)进入DNA复制期(S1期)。在细胞增殖过程中，CDK4/6与细胞周期素D(CyclinD)形成的复合物能够磷酸化视网膜母细胞瘤蛋白(Rb)。肿瘤抑制蛋白Rb一旦发生磷酸化，可释放其在未被磷酸化的状态下紧密结合的转录因子E2F，E2F激活进一步转录而推动细胞周期通过限制点(R点)并从G1期进展到S期。因此，抑制CDK4/6使之无法形成CyclinD-CDK4/6复合物，能够阻滞细胞周期自G1期向S期的进程，从而达到抑制肿瘤增殖的目的。WO2016141881公开了作为选择性的CDK4/6抑制剂取代的2-氢-吡唑衍生物，并具体公开了如下结构的式(I)化合物，
Figure PCTCN2022121752-appb-000001
世界癌症报告数据显示2012年全球乳腺癌新发病例约达170万，死亡约50万，分别占女性所有新发癌症的25％，所有癌症死亡的15％，均列居首位。在每年新发乳腺癌病例中，3％-10％的妇女在确诊时即有远处转移。早期患者中，30％-40％可发展为晚期乳腺癌，5年生存率约20％。
晚期乳腺癌(ABC)患者在治疗方案的选择及疗效方面有其特殊性，目前尚缺乏公认的标准治疗方案。晚期乳腺癌的总体中位生存期为2-3年，不同分子亚型的情况有所不同。对于人表皮生长因子受体2(HER2)阳性的ABC患者，抗HER2治疗可改变HER2阳性ABC患者的自然病程，并显著延长生存时间；但对于三阴性ABC患者，其总体预后尚未取得明显改善。激素受体阳性(HR+)乳腺癌约占乳腺癌的65％-75％，内分泌治疗以其与化疗相当的治疗疗效和较小的毒副作用，成为激素受体阳性(HR+)转移性乳腺癌的首选治疗方案。
尽管内分泌治疗是激素受体阳性乳腺癌的主要治疗方案，但约有30％激素受体阳性乳腺癌对内分泌治疗原发耐药，而且几乎全部患者在后续治疗中出现继发耐药，因此如何克服内分泌治疗耐药已经成为乳腺癌治疗领域亟待解决的难题。
发明内容
一方面，本公开提供了一种联用药物组合物，其包含式(I)化合物或其药学上可接受的盐和芳香酶抑制剂：
Figure PCTCN2022121752-appb-000002
另一方面，本公开提供了用于治疗或预防乳腺癌的联用药物组合物，其包含式(I)化合物或其药学上可接受的盐和芳香酶抑制剂。或者，本公开提供一种治疗或预防乳腺癌的方法，包括向有需要的受试者给予上述的联用药物组合物。或者，本公开提供上述的联用药物组合物在制备用于治疗或预防乳腺癌的药物或试剂盒中的用途。或者，本公开提供一种给药方法，包括向有需要的受试者给予上述的联用药物组合物。
在本公开的一些实施方案中，所述联用药物组合物中的所述式(I)化合物或其药学上可接受的盐和芳香酶抑制剂包装于同一试剂盒中，所述试剂盒还包含将式(I)化合物或其药学上可接受的盐和芳香酶抑制 剂联合使用以治疗或预防乳腺癌的说明。
在本公开的一些实施方案中，所述联用药物组合物中的所述式(I)化合物或其药学上可接受的盐和芳香酶抑制剂分开包装于各自的试剂盒中，所述试剂盒还包含将式(I)化合物或其药学上可接受的盐和芳香酶抑制剂联合使用以治疗或预防乳腺癌的说明。
在本公开的一些方案中，所述联用药物组合物中的所述式(I)化合物或其可药用盐和芳香酶抑制剂各自呈药物组合物形式，可同时、顺序或间隔给药。
在本公开的一些实施方案中，所述联用药物组合物包括式(I)化合物或其药学上可接受的盐的药物组合物和芳香酶抑制剂的药物组合物。
在本公开的一些实施方案中，所述联用药物组合物中的所述式(I)化合物或其药学上可接受的盐的药物组合物和芳香酶抑制剂的药物组合物包装于同一试剂盒中，所述试剂盒还包含将式(I)化合物或其药学上可接受的盐的药物组合物和芳香酶抑制剂的药物组合物联合使用以治疗或预防乳腺癌的说明。
在本公开的一些实施方案中，所述联用药物组合物中的所述式(I)化合物或其药学上可接受的盐的药物组合物和芳香酶抑制剂的药物组合物分开包装于各自的试剂盒中，所述试剂盒还包含将式(I)化合物或其药学上可接受的盐的药物组合物和芳香酶抑制剂的药物组合物联合使用以治疗或预防乳腺癌的说明。
在本公开的一些实施方案中，在所述联用药物组合物中，所述式(I)化合物的药学上可接受的盐是马来酸盐，例如式(I)化合物的单马来酸盐。
在本公开的一些实施方案中，所述芳香酶抑制剂选自来曲唑或阿那曲唑。
在本公开的一些实施方案中，所述联用药物组合物含有以式(I)化合物计为20～240mg、40～180mg、60～180mg、80～180mg、100～180mg、120～180mg或150～180mg的式(I)化合物或其药学上可接受的盐，或其药物组合物。
在本公开的一些实施方案中，所述联用药物组合物含有以式(I)化合物计为20mg、40mg、60mg、80mg、100mg、120mg、150mg、180mg或240mg的式(I)化合物或其药学上可接受的盐，或其药物组合物。
在本公开的一些实施方案中，所述联用药物组合物含有以式(I)化合物计为60mg、120mg或180mg的式(I)化合物或其药学上可接受的盐，或其药物组合物。
在本公开的一些实施方案中，所述联用药物组合物中，式(I)化合物或其药学上可接受的盐的药物组合物为单剂量或多剂量形式。在本公开的一些实施方案中，所述联用药物组合物中，式(I)化合物或其药学上可接受的盐的药物组合物为多剂量形式。
在本公开的一些实施方案中，所述联用药物组合物中，式(I)化合物或其药学上可接受的盐的含量为每日剂量或一日剂量。
在本公开的一些实施方案中，所述联用药物组合物中，式(I)化合物或其药学上可接受的盐的含量为每日一次剂量或一日一次剂量。
在本公开的一些实施方案中，所述联用药物组合物中，式(I)化合物或其药学上可接受的盐的含量为每日一次剂量或一日一次剂量，且每次剂量为单剂量或多剂量，优选为多剂量。
在本公开的一些实施方案中，所述联用药物组合物中，其含有单剂量以式(I)化合物计为50mg、60mg、120mg或180mg的式(I)化合物或其药学上可接受的盐的药物组合物。或者，所述联用药物组合物处于单次给予制剂的形式，所述联用药物组合物含有以式(I)化合物计为50mg、60mg、120mg或180mg的式(I)化合物或其药学上可接受的盐或其药物组合物。
在本公开的一些实施方案中，所述联用药物组合物中，其含有多剂量以式(I)化合物计为50mg、60mg、120mg或180mg的式(I)化合物或其药学上可接受的盐的药物组合物。或者，所述联用药物组合物处于单次给予制剂的形式，每次剂量为多剂量，所述联用药物组合物含有以式(I)化合物计为50mg、60mg、120mg或180mg的式(I)化合物或其药学上可接受的盐或其药物组合物。
在本公开的一些实施方案中，所述联用药物组合物中，其含有单剂量以式(I)化合物计为50mg或60mg的式(I)化合物或其药学上可接受的盐的药物组合物。或者，所述联用药物组合物处于单次给予制剂的形式，所述联用药物组合物含有以式(I)化合物计为50mg或60mg的式(I)化合物或其药学上可接受的盐或其药物组合物。
在本公开的一些实施方案中，所述联用药物组合物中，其含有单剂量以式(I)化合物计为60mg的式(I)化合物或其药学上可接受的盐的药物组合物。或者，所述联用药物组合物处于单次给予制剂的形式，所述联用药物组合物含有以式(I)化合物计为60mg的式(I)化合物或其药学上可接受的盐或其药物组 合物。
在本公开的一些实施方案中，所述联用药物组合物中，其含有的式(I)化合物或其药学上可接受的盐的药物组合物包装于一个试剂盒中，所述试剂盒还含有式(I)化合物或其药学上可接受的盐用于治疗或预防乳腺癌的说明。
式(I)化合物或其药学上可接受的盐与来曲唑的联用药物组合物
在本公开的一些实施方案中，所述联用药物组合物中，所述芳香酶抑制剂为来曲唑。
在本公开的一些实施方案中，所述联用药物组合物含有2.5mg-12.5mg、2.5mg-10mg、2.5mg-7.5mg或2.5mg-5mg的来曲唑或其药物组合物。或者，所述联用药物组合物处于单次给予制剂的形式，所述联用药物组合物含有2.5mg-12.5mg、2.5mg-10mg、2.5mg-7.5mg或2.5mg-5mg的来曲唑或其药物组合物。
在本公开的一些实施方案中，所述联用药物组合物含有2.5mg、5mg、7.5mg或10mg的来曲唑或其药物组合物。或者，所述联用药物组合物处于单次给予制剂的形式，所述联用药物组合物含有2.5mg、5mg、7.5mg或10mg的来曲唑或其药物组合物。
在本公开的一些实施方案中，所述联用药物组合物含有2.5mg的来曲唑或其药物组合物。或者，所述联用药物组合物处于单次给予制剂的形式，所述联用药物组合物含有2.5mg的来曲唑或其药物组合物。
在本公开的一些实施方案中，所述联用药物组合物中，来曲唑的药物组合物为单剂量或多剂量形式。
在本公开的一些实施方案中，所述联用药物组合物中，来曲唑的药物组合物为单剂量形式。
在本公开的一些实施方案中，所述联用药物组合物中，来曲唑的含量为每日剂量或一日剂量。
在本公开的一些实施方案中，所述联用药物组合物中，所述来曲唑的含量为每日一次剂量或一日一次剂量。
在本公开的一些实施方案中，所述联用药物组合物中，来曲唑的含量为每日一次剂量或一日一次剂量，以及每次剂量为单剂量或多剂量，优选为单剂量。
在本公开的一些实施方案中，所述联用药物组合物中，其含有单剂量为2.5mg的来曲唑的药物组合物。
在本公开的一些实施方案中，所述联用药物组合物中，其含有的来曲唑的药物组合物包装于一个试剂盒中，所述试剂盒还含有来曲唑用于治疗或预防乳腺癌的说明。
在本公开的一些实施方案中，所述联用药物组合物中，其含有的来曲唑的药物组合物包装于一个试剂盒中，所述试剂盒还含有来曲唑用于治疗或预防乳腺癌的说明，所述说明可以为市售的来曲唑试剂盒中的说明书中的说明。
在本公开的一些实施方案中，所述联用药物组合物含有以式(I)化合物计为20～240mg的式(I)化合物或其药学上可接受的盐和2.5mg-12.5mg的来曲唑。
在本公开的一些实施方案中，所述联用药物组合物含有以式(I)化合物计为120～180mg的式(I)化合物或其药学上可接受的盐和2.5mg-5mg的来曲唑。
在本公开的一些实施方案中，所述联用药物组合物含有以式(I)化合物计为20mg、40mg、60mg、80mg、100mg、120mg、150mg、180mg或240mg的每日剂量的式(I)化合物或其药学上可接受的盐；以及含有2.5mg的每日剂量的来曲唑。
在本公开的一些实施方案中，所述联用药物组合物含有以式(I)化合物计为60mg、120mg、180mg或240mg的每日剂量的式(I)化合物或其药学上可接受的盐；以及含有2.5mg的每日剂量的来曲唑。
在本公开的一些实施方案中，所述联用药物组合物含有以式(I)化合物计的单剂量为50mg或60mg的式(I)化合物或其药学上可接受的盐的药物组合物；以及含有单剂量为2.5mg的来曲唑的药物组合物。
在本公开的一些实施方案中，所述联用药物组合物含有以式(I)化合物计的单剂量为60mg的式(I)化合物或其药学上可接受的盐的药物组合物；以及含有单剂量为2.5mg的来曲唑的药物组合物。
在本公开的一些实施方案中，所述联用药物组合物含有质量比为1:1至100:1、优选1.5:1至96:1、5:1至90:1、10:1至85:1、10:1至75:1、20:1至75:1、24:1至72:1、或者处于上述范围内的任意比值的式(I)化合物或其药学上可接受的盐或其药物组合物和来曲唑或其药物组合物，其中，所述式(I)化合物或其药学上可接受的盐或其药物组合物的量以式(I)化合物的质量计，所述来曲唑或其药物组合物的量以来曲唑的质量计。
在本公开的一些实施方案中，所述联用药物组合物为适用于单个治疗周期(例如28天)给予的制剂，所述制剂含有：1680mg-5040mg(例如3360mg-5040mg、优选5040mg)的式(I)化合物或其药学上可接受的盐或其药物组合物；以及70mg-140mg(例如70mg)的来曲唑或其药物组合物，其中，所述式(I) 化合物或其药学上可接受的盐或其药物组合物的量以式(I)化合物的质量计，所述来曲唑或其药物组合物的量以来曲唑的质量计。
在本公开的一些实施方案中，所述联用药物组合物为适用于单个治疗周期(例如28天)给予的制剂，所述制剂包括质量比为12:1至72:1、例如24:1至72:1、72:1或者处于上述范围内的任意比值的式(I)化合物或其药学上可接受的盐或其药物组合物和来曲唑或其药物组合物，其中，所述式(I)化合物或其药学上可接受的盐或其药物组合物的量以式(I)化合物的质量计，所述来曲唑或其药物组合物的量以来曲唑的质量计。
在本公开的一些实施方案中，所述联用药物组合物中，所述式(I)化合物或其药学上可接受的盐和来曲唑可以分别呈药物组合物形式或者一起呈药物组合物形式。
另一方面，本公开还提供一种试剂盒，其中含有(a)第一药物组合物，含有本公开所述的式(I)化合物或其药学上可接受的盐；和(b)第二药物组合物，其含有来曲唑。
另一方面，本公开还提供一种用于治疗或预防乳腺癌的药物组合物的试剂盒，其中含有(a)第一药物组合物，含有本公开所述的式(I)化合物或其药学上可接受的盐；和(b)第二药物组合物，其含有来曲唑。
另一方面，本公开还提供了治疗或预防乳腺癌的方法，其包括向有需要的个体施用治疗有效量的式(I)化合物或其药学上可接受的盐和来曲唑，例如向有需要的个体施用治疗有效量的本公开的上文所述的联用药物组合物。
另一方面，本公开提供一种给药方法，所述方法包括：向有需要的个体施用治疗有效量的式(I)化合物或其药学上可接受的盐和来曲唑，例如向有需要的个体施用治疗有效量的本公开的上文所述的联用药物组合物，或者向所述个体单独施用治疗有效量的式(I)化合物或其药学上可接受的盐以及单独施用治疗有效量的来曲唑。
另一方面，本公开还提供了一种用于治疗患有乳腺癌个体的联合疗法，所述方法包括给所述个体单独施用治疗有效量的式(I)化合物或其药学上可接受的盐以及单独施用治疗有效量的来曲唑。
另一方面，本公开还提供了式(I)化合物或其药学上可接受的盐联合来曲唑在制备用于治疗或预防乳腺癌的药物中的用途，例如本公开上述联用药物组合物在制备用于治疗或预防乳腺癌的药物中的用途。在本公开的一些实施方案中，所述联用药物组合物为本公开的上文所述的联用药物组合物。
另一方面，本公开还提供了式(I)化合物或其药学上可接受的盐联合来曲唑用于治疗或预防乳腺癌的用途，例如本公开上述联用药物组合物在用于治疗或预防乳腺癌的用途。
在本公开的一些实施方案中，在所述试剂盒、方法、联合疗法或用途中，所述式(I)化合物或其药学上可接受的盐和来曲唑的各定义同上文所述的联用药物组合物中式(I)化合物或其药学上可接受的盐和来曲唑的定义，例如含量、剂量、存在形式、包装形式等等。
在本公开的一些实施方案中，在所述方法、联合疗法或用途中，所述式(I)化合物或其药学上可接受的盐和来曲唑各自呈药物组合物形式，可同时、分开、并行、顺序或间隔给药。
在本公开的一些实施方案中，在所述方法、联合疗法或用途中，所述式(I)化合物或其药学上可接受的盐和来曲唑分别具有相同或者不同的治疗周期。在本公开的一些具体的实施方案中，在所述方法、联合疗法或用途中，所述式(I)化合物或其药学上可接受的盐和来曲唑具有相同的治疗周期，例如每1周、每2周、每3周或每4周为一个治疗周期。
在本公开的一些实施方案中，在所述方法、联合疗法或用途中，所述联用药物组合物中的式(I)化合物或其药学上可接受的盐的含量为每日剂量，其通过如下方式给药：式(I)化合物或其药学上可接受的盐每日给药1次。
在本公开的一些实施方案中，在所述方法、联合疗法或用途中，所述联用药物组合物中的式(I)化合物或其药学上可接受的盐的含量为每日剂量，其中式(I)化合物或其药学上可接受的盐以单剂量或多剂量方式给药，通常以多剂量方式给药；进一步地，其中式(I)化合物或其药学上可接受的盐每日给药1次。
在本公开的一些实施方案中，在所述方法、联合疗法或用途中，所述式(I)化合物或其药学上可接受的盐通过如下方式给药：每日剂量为60mg；或者，每日剂量为120mg；或者，每日剂量为180mg；或者每日剂量为240mg。
在本公开的一些实施方案中，在所述方法、联合疗法或用途中，所述联用药物组合物中的式(I)化合物或其药学上可接受的盐以多剂量方式给药，所述多剂量由单剂量为50mg或60mg的式(I)化合物或其药学上可接受的盐的药物组合物组成；优选的，所述多剂量由单剂量为60mg的式(I)化合物或其药学上可接受的盐的药物组合物组成。在本公开的一些实施方案中，在所述方法、联合疗法或用途中，所述式(I) 化合物或其药学上可接受的盐以连续每日给药的方式给药。
在本公开的一些实施方案中，在所述方法、联合疗法或用途中，所述联用药物组合物中的式(I)化合物或其药学上可接受的盐的含量为每周期剂量，其通过如下方式给药：每天施用式(I)化合物或其药学上可接受的盐。
在本公开的一些实施方案中，在所述方法、联合疗法或用途中，所述联用药物组合物中的来曲唑的含量为每日剂量，其通过如下方式给药：来曲唑每日给药1次。
在本公开的一些实施方案中，在所述方法、联合疗法或用途中，所述联用药物组合物中的来曲唑的含量为每日剂量，其中来曲唑以单剂量或多剂量方式给药，通常以单剂量方式给药；进一步地，其中来曲唑每日给药1次。
在本公开的一些实施方案中，在所述方法、联合疗法或用途中，所述来曲唑通过如下方式给药：每日剂量为2.5mg。
在本公开的一些实施方案中，在所述方法、联合疗法或用途中，所述联用药物组合物中的来曲唑以单剂量方式给药，所述单剂量为2.5mg的来曲唑的药物组合物。在本公开的一些实施方案中，在所述方法、联合疗法或用途中，所述来曲唑以连续每日给药的方式给药。
在本公开的一些实施方案中，在所述方法、联合疗法或用途中，所述联用药物组合物中的来曲唑的含量为每周期剂量，其通过如下方式给药：每天施用来曲唑。
在本公开的一些实施方案中，在所述方法、联合疗法或用途中，28天为一个治疗周期，在每个治疗周期的第1-28天每天施用所述式(I)化合物或其药学上可接受的盐和来曲唑。
在本公开的一些具体的实施方案中，在所述方法、联合疗法或用途中，28天为一个治疗周期，在每个治疗周期的第1-28天每日1次施用所述式(I)化合物或其药学上可接受的盐和来曲唑。
在本公开的一些实施方案中，在所述方法、联合疗法或用途中，28天为一个治疗周期，每天给药1次，连续给药28天，每个治疗周期施用含有所述式(I)化合物或其药学上可接受的盐的药物组合物的总剂量为1680～5040mg。在本公开的部分的实施方案中，所述含有式(I)化合物或其药学上可接受的盐的药物组合物的总剂量选自1680mg、3360mg、5040mg或上述任意两个值所形成的范围。在本公开的部分的实施方案中，所述含有式(I)化合物或其药学上可接受的盐的药物组合物的总剂量优选为5040mg。
在本公开的一些实施方案中，在所述方法、联合疗法或用途中，28天为一个治疗周期，每天给药1次，连续给药28天，每个治疗周期施用含有来曲唑的药物组合物的总剂量为70～210mg。在本公开的部分的实施方案中，所述含有来曲唑的药物组合物的总剂量选自70mg、140mg、210mg或上述任意两个值所形成的范围。在本公开的部分的实施方案中，所述含有来曲唑的药物组合物的总剂量优选为70mg。在本公开的一些实施方案中，在所述方法、联合疗法或用途中，28天为一个治疗周期，每天给药1次，连续给药28天，每个治疗周期施用总剂量为5040mg的含有式(I)化合物或其药学上可接受的盐的药物组合物，以及总剂量为70mg的含有来曲唑的药物组合物。
本公开的实施方案中，只要疾病仍处于控制之下和给药方案具有临床耐受性，就重复上述治疗周期。
在本公开的一些实施方案中，所述来曲唑被制备为适合连续每天向患者施用2.5mg-7.5mg或2.5mg-5mg来曲唑的单剂量或多剂量；含有所述式(I)化合物或其药学上可接受的盐的药物组合物被制备为适合连续每天向患者施用的以式(I)化合物本身计的60mg、120mg、180mg和/或240mg的单剂量或多剂量。
在本公开的一些实施方案中，所述来曲唑被制备为适合连续每天向患者施用2.5mg来曲唑的单剂量；含有所述式(I)化合物或其药学上可接受的盐的药物组合物被制备为适合连续每天向患者施用的以式(I)化合物本身计的180mg的多剂量。
式(I)化合物或其药学上可接受的盐与阿那曲唑的联用药物组合物
在本公开的一些实施方案中，所述联用药物组合物中，所述芳香酶抑制剂为阿那曲唑。
在本公开的一些实施方案中，所述联用药物组合物含有1mg-5mg、1mg-4mg、1mg-3mg或1mg-2mg的阿那曲唑或其药物组合物。或者，所述联用药物组合物处于单次给予制剂的形式，所述联用药物组合物含有1mg-5mg、1mg-4mg、1mg-3mg或1mg-2mg的阿那曲唑或其药物组合物。
在本公开的一些实施方案中，所述联用药物组合物含有1mg、2mg、3mg或4mg的阿那曲唑或其药物组合物。或者，所述联用药物组合物处于单次给予制剂的形式，所述联用药物组合物含有1mg、2mg、3mg或4mg的阿那曲唑或其药物组合物。
在本公开的一些实施方案中，所述联用药物组合物含有1mg的阿那曲唑或其药物组合物。或者，所述 联用药物组合物处于单次给予制剂的形式，所述联用药物组合物含有1mg的阿那曲唑或其药物组合物。
在本公开的一些实施方案中，所述联用药物组合物中，阿那曲唑的药物组合物为单剂量或多剂量形式。
在本公开的一些实施方案中，所述联用药物组合物中，阿那曲唑的药物组合物为单剂量形式。
在本公开的一些实施方案中，所述联用药物组合物中，阿那曲唑的含量为每日剂量或一日剂量。
在本公开的一些实施方案中，所述联用药物组合物中，所述阿那曲唑的含量为每日一次剂量或一日一次剂量。
在本公开的一些实施方案中，所述联用药物组合物中，阿那曲唑的含量为每日一次剂量或一日一次剂量，以及每次剂量为单剂量或多剂量，优选为单剂量。
在本公开的一些实施方案中，所述联用药物组合物中，其含有单剂量为1mg的阿那曲唑的药物组合物。
在本公开的一些实施方案中，所述联用药物组合物中，其含有的阿那曲唑的药物组合物包装于一试剂盒中，所述试剂盒还含有阿那曲唑用于治疗或预防乳腺癌的说明。
在本公开的一些实施方案中，所述联用药物组合物中，其含有的阿那曲唑的药物组合物包装于一试剂盒中，所述试剂盒还含有阿那曲唑用于治疗或预防乳腺癌的说明，所述说明可以为市售的阿那曲唑试剂盒中的说明书中的说明。
在本公开的一些实施方案中，所述联用药物组合物含有以式(I)化合物计为20～240mg的式(I)化合物或其药学上可接受的盐和1mg-5mg的阿那曲唑。
在本公开的一些实施方案中，所述联用药物组合物含有以式(I)化合物计为120～180mg的式(I)化合物或其药学上可接受的盐和1mg-2mg的阿那曲唑。
在本公开的一些实施方案中，所述联用药物组合物含有以式(I)化合物计为20mg、40mg、60mg、80mg、100mg、120mg、150mg、180mg或240mg的每日剂量的式(I)化合物或其药学上可接受的盐；以及含有1mg的每日剂量的阿那曲唑。
在本公开的一些实施方案中，所述联用药物组合物含有以式(I)化合物计为60mg、120mg、180mg或240mg的每日剂量的式(I)化合物或其药学上可接受的盐；以及含有1mg的每日剂量的阿那曲唑。
在本公开的一些实施方案中，所述联用药物组合物含有以式(I)化合物计的单剂量为50mg或60mg的式(I)化合物或其药学上可接受的盐的药物组合物；以及含有单剂量为1mg的阿那曲唑的药物组合物。
在本公开的一些实施方案中，所述联用药物组合物含有以式(I)化合物计的单剂量为60mg的式(I)化合物或其药学上可接受的盐的药物组合物；以及含有单剂量为1mg的阿那曲唑的药物组合物。
在本公开的一些实施方案中，所述联用药物组合物含有质量比为4:1至240:1、优选10:1至180:1、25:1至180:1、30:1至180:1、60:1至180:1、或者处于上述范围内的任意比值的式(I)化合物或其药学上可接受的盐或其药物组合物和阿那曲唑或其药物组合物，其中，所述式(I)化合物或其药学上可接受的盐或其药物组合物的量以式(I)化合物的质量计，所述阿那曲唑或其药物组合物的量以阿那曲唑的质量计。
在本公开的一些实施方案中，所述联用药物组合物为适用于单个治疗周期(例如28天)给予的制剂，所述制剂含有：1680mg-5040mg(例如3360mg-5040mg、优选5040mg)的式(I)化合物或其药学上可接受的盐或其药物组合物；以及28mg-140mg(例如28mg-56mg、优选28mg)的阿那曲唑或其药物组合物，其中，所述式(I)化合物或其药学上可接受的盐或其药物组合物的量以式(I)化合物的质量计，所述阿那曲唑或其药物组合物以阿那曲唑的质量计。
在本公开的一些实施方案中，所述联用药物组合物为适用于单个治疗周期(例如28天)给予的制剂，所述制剂包括质量比为12:1至180:1、例如60:1至180:1、180:1或者处于上述范围内的任意比值的式(I)化合物或其药学上可接受的盐或其药物组合物和阿那曲唑或其药物组合物，其中，所述式(I)化合物或其药学上可接受的盐或其药物组合物的量以式(I)化合物的质量计，所述阿那曲唑或其药物组合物以阿那曲唑的质量计。
在本公开的一些实施方案中，所述联用药物组合物中，所述式(I)化合物或其药学上可接受的盐和阿那曲唑可以分别呈药物组合物形式或者一起呈药物组合物形式。
另一方面，本公开还提供一种试剂盒，其中含有(a)第一药物组合物，含有本公开所述的式(I)化合物或其药学上可接受的盐；和(b)第二药物组合物，其中含有阿那曲唑。
另一方面，本公开还提供一种用于治疗或预防乳腺癌的药物组合物的试剂盒，其中含有(a)第一药物组合物，含有本公开所述的式(I)化合物或其药学上可接受的盐；和(b)第二药物组合物，其中含有阿那曲唑。
另一方面，本公开还提供了治疗或预防乳腺癌的方法，其包括向有需要的个体施用治疗有效量的式(I) 化合物或其药学上可接受的盐和阿那曲唑，例如向有需要的个体施用治疗有效量的本公开的上文所述的联用药物组合物。
另一方面，本公开还提供了一种给药方法，所述方法包括向有需要的个体施用治疗有效量的式(I)化合物或其药学上可接受的盐和阿那曲唑，例如向有需要的个体施用治疗有效量的本公开的上文所述的联用药物组合物，或者向所述个体单独施用治疗有效量的式(I)化合物或其药学上可接受的盐以及单独施用治疗有效量的阿那曲唑。
另一方面，本公开还提供了一种用于治疗患有乳腺癌个体的联合疗法，所述方法包括给所述个体单独施用治疗有效量的式(I)化合物或其药学上可接受的盐以及单独施用治疗有效量的阿那曲唑。
另一方面，本公开还提供了式(I)化合物或其药学上可接受的盐联合阿那曲唑在制备用于治疗或预防乳腺癌的药物中的用途，例如本公开上述联用药物组合物在制备用于治疗或预防乳腺癌的药物中的用途。在本公开的一些实施方案中，所述联用药物组合物为本公开的上文所述的联用药物组合物。
另一方面，本公开还提供了式(I)化合物或其药学上可接受的盐联合阿那曲唑用于治疗或预防乳腺癌的用途，例如本公开上述联用药物组合物在用于治疗或预防乳腺癌的用途。
在本公开的一些实施方案中，在所述试剂盒、方法、联合疗法或用途中，所述式(I)化合物或其药学上可接受的盐和阿那曲唑的各定义同上文所述的联用药物组合物中式(I)化合物或其药学上可接受的盐和阿那曲唑的定义，例如含量、剂量、存在形式、包装形式等等。
在本公开的一些实施方案中，在所述方法、联合疗法或用途中，所述式(I)化合物或其药学上可接受的盐和阿那曲唑各自呈药物组合物形式，可同时、分开、并行、顺序或间隔给药。
在本公开的一些实施方案中，在所述方法、联合疗法或用途中，所述式(I)化合物或其药学上可接受的盐和阿那曲唑分别具有相同或者不同的治疗周期。在本公开的一些具体的实施方案中，在所述方法、联合疗法或用途中，所述式(I)化合物或其药学上可接受的盐和阿那曲唑具有相同的治疗周期，例如每1周、每2周、每3周或每4周为一个治疗周期。
在本公开的一些实施方案中，在所述方法、联合疗法或用途中，所述联用药物组合物中的式(I)化合物或其药学上可接受的盐的含量为每日剂量，其通过如下方式给药：式(I)化合物或其药学上可接受的盐每日给药1次。
在本公开的一些实施方案中，在所述方法、联合疗法或用途中，所述联用药物组合物中的式(I)化合物或其药学上可接受的盐的含量为每日剂量，其中式(I)化合物或其药学上可接受的盐以单剂量或多剂量方式给药，通常以多剂量方式给药；进一步地，其中式(I)化合物或其药学上可接受的盐每日给药1次。
在本公开的一些实施方案中，在所述方法、联合疗法或用途中，所述式(I)化合物或其药学上可接受的盐通过如下方式给药：每日剂量为60mg；或者，每日剂量为120mg；或者，每日剂量为180mg；或者每日剂量为240mg。
在本公开的一些实施方案中，在所述方法、联合疗法或用途中，所述联用药物组合物中的式(I)化合物或其药学上可接受的盐以多剂量方式给药，所述多剂量由单剂量为50mg或60mg的式(I)化合物或其药学上可接受的盐的药物组合物组成；优选的，所述多剂量由单剂量为60mg的式(I)化合物或其药学上可接受的盐的药物组合物组成。在本公开的一些实施方案中，在所述方法、联合疗法或用途中，所述式(I)化合物或其药学上可接受的盐以连续每日给药的方式给药。
在本公开的一些实施方案中，在所述方法、联合疗法或用途中，所述联用药物组合物中的式(I)化合物或其药学上可接受的盐的含量为每周期剂量，其通过如下方式给药：每天施用式(I)化合物或其药学上可接受的盐。
在本公开的一些实施方案中，在所述方法、联合疗法或用途中，所述联用药物组合物中的阿那曲唑的含量为每日剂量，其通过如下方式给药：阿那曲唑每日给药1次。
在本公开的一些实施方案中，在所述方法、联合疗法或用途中，所述联用药物组合物中的阿那曲唑的含量为每日剂量，其中阿那曲唑以单剂量或多剂量方式给药，通常以单剂量方式给药；进一步地，其中阿那曲唑每日给药1次。
在本公开的一些实施方案中，在所述方法、联合疗法或用途中，所述阿那曲唑通过如下方式给药：每日剂量为1mg。
在本公开的一些实施方案中，在所述方法、联合疗法或用途中，所述联用药物组合物中的阿那曲唑以单剂量方式给药，所述单剂量为1mg的阿那曲唑的药物组合物。在本公开的一些实施方案中，在所述方法、联合疗法或用途中，所述阿那曲唑以连续每日给药的方式给药。
在本公开的一些实施方案中，在所述方法、联合疗法或用途中，所述联用药物组合物中的阿那曲唑的含量为每周期剂量，其通过如下方式给药：每天施用阿那曲唑。
在本公开的一些实施方案中，在所述方法、联合疗法或用途中，28天为一个治疗周期，在每个治疗周期的第1-28天每天施用所述式(I)化合物或其药学上可接受的盐和阿那曲唑。
在本公开的一些具体的实施方案中，在所述方法、联合疗法或用途中，28天为一个治疗周期，在每个治疗周期的第1-28天每日1次施用所述式(I)化合物或其药学上可接受的盐和阿那曲唑。
在本公开的一些实施方案中，在所述方法、联合疗法或用途中，28天为一个治疗周期，每天给药1次，连续给药28天，每个治疗周期施用含有所述式(I)化合物或其药学上可接受的盐的药物组合物的总剂量为1680～5040mg。在部分的实施方案中，所述含有式(I)化合物或其药学上可接受的盐的药物组合物的总剂量选自1680mg、3360mg、5040mg或上述任意两个值所形成的范围。在部分的实施方案中，所述含有式(I)化合物或其药学上可接受的盐的药物组合物的总剂量优选为5040mg。
在本公开的一些实施方案中，在所述方法、联合疗法或用途中，28天为一个治疗周期，每天给药1次，连续给药28天，每个治疗周期施用含有阿那曲唑的药物组合物的总剂量为28～140mg。在本公开的部分的实施方案中，所述含有阿那曲唑的药物组合物的总剂量选自28mg、56mg、84mg或上述任意两个值所形成的范围。在本公开的部分的实施方案中，所述含有阿那曲唑的药物组合物的总剂量优选为28mg。在本公开的一些实施方案中，在所述方法、联合疗法或用途中，28天为一个治疗周期，每天给药1次，连续给药28天，每个治疗周期施用总剂量为5040mg的含有式(I)化合物或其药学上可接受的盐的药物组合物，以及总剂量为28mg的含有阿那曲唑的药物组合物。
本公开的实施方案中，只要疾病仍处于控制之下和给药方案具有临床耐受性，就重复上述治疗周期。
在本公开的一些实施方案中，所述阿那曲唑被制备为适合连续每天向患者施用1mg-3mg或1mg-2mg阿那曲唑的单剂量或多剂量；含有所述式(I)化合物或其药学上可接受的盐的药物组合物被制备为适合连续每天向患者施用的以式(I)化合物本身计的60mg、120mg、180mg和/或240mg的单剂量或多剂量。
在本公开的一些实施方案中，所述阿那曲唑被制备为适合连续每天向患者施用1mg阿那曲唑的单剂量；含有所述式(I)化合物或其药学上可接受的盐的药物组合物被制备为适合连续每天向患者施用的以式(I)化合物本身计的180mg的多剂量。
在本公开的一些实施方案中，所述乳腺癌选自HR阳性的乳腺癌。
在本公开的一些实施方案中，所述乳腺癌选自HER2阴性的乳腺癌。
在本公开的一些实施方案中，所述乳腺癌选自HR阳性、HER2阴性的乳腺癌。
在本公开的一些实施方案中，所述乳腺癌选自局部晚期和/或转移性乳腺癌。在本公开的一些实施方案中，所述乳腺癌选自HER2阴性的局部晚期和/或转移性乳腺癌。
在本公开的一些实施方案中，所述乳腺癌选自HR阳性、HER2阴性的局部晚期和/或转移性乳腺癌。
在本公开的一些实施方案中，所述乳腺癌选自不能接受根治性手术或放疗的HR阳性、HER2阴性的局部晚期和/或转移性乳腺癌。在本公开的一些实施方案中，乳腺癌患者为不能接受根治性手术或放疗的HR阳性、HER2阴性的局部晚期和/或转移性乳腺癌患者。
本公开的一些实施方案中，所述乳腺癌选自绝经后或绝经前/围绝经期的乳腺癌。在本公开的一些实施方案中，所述乳腺癌患者为绝经后或绝经前/围绝经期的乳腺癌患者。
本公开的一些实施方案中，所述乳腺癌选自绝经后或绝经前/围绝经期的HR阳性、HER2阴性的局部晚期和/或转移性乳腺癌。本公开的一些实施方案中，所述乳腺癌患者为绝经后或绝经前/围绝经期的HR阳性、HER2阴性的局部晚期和/或转移性乳腺癌患者。
本公开的一些实施方案中，所述乳腺癌选自既往进行过双侧卵巢切除术的乳腺癌。本公开的一些实施方案中，所述乳腺癌患者为既往进行过双侧卵巢切除术的乳腺癌患者。
本公开的一些实施方案中，所述乳腺癌选自既往进行过双侧卵巢切除术的绝经后或绝经前/围绝经期的乳腺癌。本公开的一些实施方案中，所述乳腺癌患者为既往进行过双侧卵巢切除术的绝经后或绝经前/围绝经期的乳腺癌患者。
本公开的一些实施方案中，所述乳腺癌选自既往进行过双侧卵巢切除术的绝经后或绝经前/围绝经期的HR阳性、HER2阴性的局部晚期和/或转移性乳腺癌。本公开的一些实施方案中，所述乳腺癌患者为既往进行过双侧卵巢切除术的绝经后或绝经前/围绝经期的HR阳性、HER2阴性的局部晚期和/或转移性乳腺癌患者。
本公开的一些实施方案中，所述乳腺癌选自绝经后或绝经前/围绝经期的不能接受根治性手术或放疗的HR阳性、HER2阴性的局部晚期和/或转移性乳腺癌。本公开的一些实施方案中，所述乳腺癌患者为绝经后或绝经前/围绝经期的不能接受根治性手术或放疗的HR阳性、HER2阴性的局部晚期和/或转移性乳腺癌患者。
在本公开的一些实施方案中，HR阳性包括***受体ER阳性和/或孕激素受体PR阳性，定义为：阳性染色的肿瘤细胞占所有肿瘤细胞的比例≥1％。
在本公开的一些实施方案中，HER2阴性定义为：免疫组化染色(IHC)检测显示HER2为0/1+；若检测显示为2+，需进行荧光原位杂交(FISH)确认是阴性或仅进行FISH检测为阴性。
在本公开的一些实施方案中，所述乳腺癌选自既往接受不超过1线的化疗的HR阳性、HER2阴性的局部晚期和/或转移性乳腺癌。
在本公开的一些实施方案中，所述乳腺癌选自辅助内分泌治疗期间或辅助内分泌治疗完成后1年内复发或进展，且后续未接受内分泌治疗的HR阳性、HER2阴性的乳腺癌。
在本公开的一些实施方案中，所述乳腺癌选自辅助内分泌治疗完成后超过1年复发或进展，后续接受晚期内分泌治疗后再次进展的HR阳性、HER2阴性的乳腺癌；所述晚期内分泌治疗不能使用芳香酶抑制剂。
在本公开的一些实施方案中，所述乳腺癌选自原发转移性疾病接受晚期内分泌治疗后疾病进展的乳腺癌；所述晚期内分泌治疗不能使用芳香酶抑制剂。
本公开的一些实施方案中，所述乳腺癌选自既往未接受过任何针对局部病灶复发或转移性疾病的全身***性抗肿瘤治疗的HR阳性、HER2阴性的局部晚期和/或转移性乳腺癌。
本公开的一些实施方案中，辅助内分泌治疗完成是指持续治疗至少2年后停药。
本公开的一些实施方案中，所述内分泌治疗是指他莫昔芬、托瑞米芬、氟维司群、戈舍瑞林和亮丙瑞林治疗。
本公开的一些实施方案中，所述内分泌治疗是指他莫昔芬和戈舍瑞林治疗。本公开的药物组合中的活性组分可以各自独立地、或者其中的部分或全部地共同与药学上可接受的载体和/或赋形剂配制。本公开的药物组合还可以包含另外的治疗剂。本公开的一些实施方案，所述另外的治疗剂可以是本领域已知的用于癌症的治疗剂，优选用于乳腺癌的治疗剂。
在本公开的一些实施方案中，所述周期为28天。
施用式(I)化合物或其药学上可接受的盐的量可根据疾病的严重程度、疾病的响应、任何治疗相关的毒性、患者的年龄和健康状态来确定。
式(I)化合物或其药学上可接受的盐可通过多种途径给药，该途径包括但不限于以下途径：口服、肠胃外、腹膜内、静脉内、动脉内、透皮、舌下、肌内、直肠、透颊、鼻内、经吸入、***、眼内、经局部给药、皮下、脂肪内、关节内、腹膜内和鞘内。在一个具体的实施方案中，式(I)化合物或其药学上可接受的盐通过口服给药。
在本公开的一些实施方案中，所述式(I)化合物或其药学上可接受的盐以连续每日口服给药的方式给药。
式(I)化合物或其药学上可接受的盐可以每日施用1次或多次。在本公开的一些实施方案中，每天1次施用式(I)化合物或其药学上可接受的盐。式(I)化合物或其药学上可接受的盐也可以单剂量或多剂量形式给药。在一个实施方案中，以多剂量每天1次施用式(I)化合物或其药学上可接受的盐。
在本公开的一些实施方案中，式(I)化合物或其药学上可接受的盐以多剂量的口服固体制剂形式每天给药1次。在一个实施方案中，式(I)化合物或其药学上可接受的盐以多剂量每天给药1次。
给药的方法可根据药物的活性、毒性以及患者的耐受性等来综合确定。
式(I)化合物或其药学上可接受的盐
如本公开所用，式(I)化合物的药学上可接受的盐可以是式(I)化合物的马来酸盐(例如式(I)化合物的单马来酸盐)。
本公开中涉及的式(I)化合物或其药学上可接受的盐的剂量，除非另有说明，均基于式(I)化合物的分子量。
本公开所用的式(I)化合物或其药学上可接受的盐可以通过现有技术的方法制备，例如参照WO2016141881的方法进行制备。
式(I)化合物或其药学上可接受的盐的药物组合物
在本公开的一些实施方案中，所述式(I)化合物或其药学上可接受的盐的药物组合物的单剂量以式(I)化合物计可为50mg或60mg。
在本公开的一些实施方案中，所述式(I)化合物或其药学上可接受的盐的药物组合物的单剂量为60mg。
给药的方法可根据药物的活性、毒性以及患者的耐受性等来综合确定。
在本公开的一些实施方案中，所述含有式(I)化合物或其药学上可接受的盐的药物组合物还含有药学上可接受的辅料。药学上可接受的辅料包括填充剂、吸收剂、润湿剂、粘合剂、崩解剂、润滑剂等。在本公开的一些实施方案中，所述药物组合物包括但不限于适合口服、肠道外、局部给药的制剂。在一些实施方案中，所述药物组合物为适合口服的制剂。在一些实施方案中，所述药物组合物为适合口服的固体制剂。在一些实施方案中，所述药物组合物包括但不限于片剂、胶囊。
在本公开的一些实施方案中，所述药物组合物为固体药物组合。
在本公开的一些实施方案中，所述药物组合物为胶囊。
在本公开的一些实施方案中，所述式(I)化合物或其药学上可接受的盐的药物组合物为式(I)化合物的固体药物组合物。
在本公开的一些实施方案中，所述式(I)化合物或其药学上可接受的盐的药物组合物为式(I)化合物的胶囊。
本公开的式(I)化合物或其可药用盐的药物组合物可以采用本领域众所周知的方法制造，如常规的混合法、溶解法、制粒法、制糖衣药丸法、磨细法、乳化法、冷冻干燥法等。
可以通过常规的混合、填充或压片方法来制备固体口服组合物。例如，可通过下述方法获得：将所述的活性化合物与固体辅料混合，任选地碾磨所得的混合物，如果需要则加入其它合适的辅料，然后将该混合物加工成颗粒，得到片剂或糖衣剂的核心，或者进行胶囊填充得到胶囊剂。适合的辅料包括但不限于：粘合剂、稀释剂、崩解剂、润滑剂、助流剂、甜味剂或矫味剂等。
来曲唑
如本公开所用，来曲唑化学名为1-[双(4-氰基苯基)甲基]-1,2,4-三氮唑，其具有如下的结构式：
Figure PCTCN2022121752-appb-000003
来曲唑的药物组合物
在本公开的一些实施方案中，所述来曲唑的药物组合物还含有药学上可接受的辅料。在一些实施方案中，所述药学上可接受的辅料包括填充剂、吸收剂、润湿剂、粘合剂、稀释剂、崩解剂、润滑剂、助流剂、甜味剂或矫味剂等。
在本公开的一些实施方案中，所述药物组合物为固体药物组合物。
在本公开的一些实施方案中，所述药物组合物为片剂。
在本公开的一些实施方案中，所述药物组合物为口服片剂。
在本公开的一些实施方案中，所述来曲唑药物组合物的单剂量2.5mg。
阿那曲唑
如本公开所用，阿那曲唑化学名为a,a,a',a'-四甲基-5-(1H-1,2,4-***-1-甲基)-1,3-苯二乙腈，其具有如下的结构式：
Figure PCTCN2022121752-appb-000004
阿那曲唑的药物组合物
在本公开的一些实施方案中，所述阿那曲唑的药物组合物还含有药学上可接受的辅料。在一些实施方案中，所述药学上可接受的辅料包括填充剂、吸收剂、润湿剂、粘合剂、稀释剂、崩解剂、润滑剂、助流剂、甜味剂或矫味剂等。
在本公开的一些实施方案中，所述药物组合物为固体药物组合物。
在本公开的一些实施方案中，所述药物组合物为片剂。
在本公开的一些实施方案中，所述药物组合物为口服片剂。
在本公开的一些实施方案中，所述阿那曲唑药物组合物的单剂量1mg。
施用方式
下述内容并非限制本公开的联用药物组合物的施用方式。
本公开的联用药物组合物中的活性成分可以各自独立地，或者其中的部分或全部共同地以适合的各种途径施用，包括但不限于，口服或肠胃外(通过静脉内、肌内、局部或皮下途径)。在本公开的一些实施方案中，本公开的联用药物组合物中的活性成分可以各自独立地，或者其中的部分或全部共同地口服施用。
本公开的联用药物组合物中的活性成分可以各自独立地，或者其中的部分或全部共同地是适合的剂型，包括但不限于，片剂、含片、丸剂、胶囊剂(例如硬胶囊、软胶囊、肠溶胶囊、微囊剂)、酏剂、颗粒剂、糖浆剂、注射剂(肌肉内、静脉内、腹腔内)、颗粒剂、乳剂、悬浮液、溶液、分散剂和用于口服或非口服给药的缓释制剂的剂型。
本文上述的各实施方案及其中包含的各特征之间可以任何组合或置换，由此得到的实施方案也落在本申请的保护范围内。
技术效果
通常，使用上述的本公开的联用药物组合物将有助于：
(1)与单独给予该组合中的任一药物相比，在减少肿瘤的生长或甚至消除肿瘤方面产生更好的疗效；
(2)与该组合中的任一药物单独给药相比，提供更少量的给药；
(3)提供在患者中具有良好耐受的治疗，与单一给予的任一药物相比，其不良反应和/或并发症更少；
(4)提供在所治疗患者之中的更好的疾病控制率；
(5)提供在所治疗的患者中具有更长的生存期(例如中位生存期、无进展生存期或总生存期)；
(6)提供相比于标准的化疗而言，所治疗患者具有更长的生存期(例如中位生存期、无进展生存期或总生存期)；
(7)提供更长时间的疾病缓解持续时间(DOR)；和/或
(8)与单独给予该组合中的任一药物相比，具有良好的***或增殖性疾病的活性，表现出更优异的抗肿瘤协同效果。
本公开的联用药物组合物“临床有收益”，包括但不限于：临床患者无进展生存期(PFS)得到延长、总生存期(OS)得到延长、客观缓解率(ORR)得到提高、疾病控制率(DCR)得到提高、不良反应数量减少和/或程度降低、远处转移率以及局部控制率下降等。
定义和说明
如文本所用，术语“联用药物组合物”是指同时或先后施用的两种以上的活性成分(以各自的活性成分本身的形式施用，或者以其各自的药学上可接受的盐或酯等衍生物、前药或组合物的形式施用)的组合。在本文中，术语“联用药物组合物”和“药物组合”可互换使用。
词语“包括(comprise)”或“包含(comprise)”及其英文变体例如comprises或comprising以及其等同物应理解为开放的、非排他性的意义，即“包括但不限于”，意味着除所列出的要素、组分和步骤外，还可涵盖其它未指明的要素、组分和步骤。
术语“患者”或“个体/受试者”是指哺乳动物，例如灵长类动物(人、猕猴、黑猩猩等)、啮齿动物(小鼠、大鼠、兔等)、猫科动物、犬科动物等，优选人。在本申请的一些实施方案中，所述患者和所述个体为经标准治疗失败或缺乏标准治疗的患者。
术语“药学上可接受的”或“可药用的”是指用于制备药物组合物的载体、赋形剂或辅料，该载体、赋形剂或辅料通常是安全、无毒的并且不在生物学上或其它方面不合乎需要，而且包括其对于人类药物的使用是可接受的。
术语“治疗有效量”意指化合物被施用于人来治疗疾病时，足以实现对该疾病的治疗的量。
术语“治疗”意为将本申请所述化合物或制剂进行给药以改善、减轻或消除疾病或与所述疾病相关的一个或多个症状，且包括：(i)抑制疾病或疾病状态，即遏制或迟滞其发展；(ii)缓解疾病或疾病状态，即使该疾病或疾病状态消退。
术语“预防”意为将本申请所述化合物或制剂进行给药以预防疾病或与所述疾病相关的一个或多个症状，包括：预防疾病或疾病状态在哺乳动物中出现，特别是当这类哺乳动物易患有该疾病状态，但尚未被诊断为已患有该疾病状态时。
术语“全身治疗”是指药物物质通过血流传送，到达并影响全身细胞的治疗。
术语“***性治疗”是指***性化疗、全身或局部放射性治疗。
术语“一线治疗”是指根据患者病情可以首先选择或者标准选择的药物进行治疗。本文中使用的“不良事件”(AE)是与医学治疗的应用有关的任何不利的和通常非故意的或不希望的迹象(包括异常的实验室发现)、征状或疾病。例如，不利事件可以与响应于治疗的免疫***的激活或免疫***细胞(例如，T细胞)的扩增相关。医学治疗可以具有一种或多种相关的AE，并且每种AE可以具有相同或不同的严重性水平。对能够“改变不利事件”的方法的提及是指降低与不同治疗方案的应用相关的一种或多种AE的发生率和/或严重性的治疗方案。
备选方案(例如，“或”)的应用应当被理解为是指备选方案中的任一个、两个或它们的任意组合。本文中使用的不定冠词“一个”或“一种”应当理解为表示任何列举或枚举的组分中的“一个或多个/一种或多种”。
术语“药学上可接受的辅料”是指对有机体无明显刺激作用，而且不会损害活性化合物的生物活性及性能的那些辅料。合适的辅料是本领域技术人员熟知的，例如碳水化合物、蜡、水溶性和/或水可膨胀的聚合物、亲水性或疏水性材料、明胶、油、溶剂、水等。
术语“施用”和“给药”表示使用本领域技术人员已知的多种方法和递送***中的任一种向个体物理引入包含治疗剂的组合物。在某些实施方案中，施用为口服施用。
术语“每日剂量”是指每日施用于患者的剂量。
术语“一日剂量”是指一日施用于患者的剂量。
术语“单剂量”或“单位制剂”是指含有一定量活性成分的药品的最小包装单元，例如一盒药有七粒胶囊，则每个胶囊为单剂量或单位制剂；例如一盒药有七片药品，则每片药为单剂量或单位制剂。
术语“多剂量”由多个单剂量组成。如本文所用，“联用”或“联合使用”意指两种或更多种活性物质可以各自作为单一制剂同时地、并行地或各自作为单一制剂以任何顺序依次地施用于个体。
术语“药物组合物”是指一种或多种本申请的活性成分或其药物组合与药学上可接受的辅料组成的混合物。药物组合物的目的是有利于对个体施用本申请的化合物或其药物组合。
涉及给药方案时，术语“天(日)”、“每天(每日)”等指一个日历日内的时间，开始于午夜且终止于下一个午夜。
术语“复发性”癌症是在对初始治疗(例如手术)产生应答后，在初始部位或远处部位再生的癌症。“局部复发性”癌症是在治疗后，在与先前治疗的癌症相同的位置出现的癌症。
术语“不能切除的”癌症是无法通过手术去除的。
术语“转移性”癌症是指从身体的一部分(例如肺部)扩散到身体的另一部分的癌症。
如本文所用，“联用”或“联合使用”意指两种或更多种活性物质可以在混合物中一起、作为单一制剂同时地或作为单一制剂以任何顺序依次地施用于受试者。
在本文中，除非上下文另有明确规定，否则单数术语涵盖复数指代物，反之亦然。类似地，除非上下文另有明确指示，词语“或”意在包括“和”，反之亦然。
除非另有说明，在本文中，代表成分的量或理化性质或者反应条件等的参数值应当被理解为在所有情况下均由术语“约”修饰。当用术语“约”描述本申请时，术语“约”表示存在的误差值，例如表示在某一特定值的±5％、例如±1％或±0.1％的范围内变化。
为了描述和公开的目的，以引用的方式将所有的专利、专利申请和其它已确定的出版物在此明确地并入本文。这些出版物仅因为它们的公开早于本申请的申请日而提供。所有关于这些文件的日期的声明或这些文件的内容的表述是基于申请者可得的信息，并且不构成任何关于这些文件的日期或这些文件的内容的正确性的承认。而且，在任何国家，在本文中对这些出版物的任何引用并不构成关于该出版物成为本领域的公知常识的一部分的认可。
实施例
下面的具体实施例的目的是使本领域的技术人员能更清楚地理解和实施本公开。它们不应该被认为是对本公开范围的限制，而只是本公开的示例性说明和典型代表。
实验例1 临床试验
本研究共分为2个队列，分为队列1和队列2，研究药物均为式(I)化合物联合芳香酶抑制剂，入组HR阳性、HER2阴性的局部晚期和/或转移性乳腺癌受试者，每个队列各入组30-60例，评估式(I)化合物联合芳香酶抑制剂的初步疗效和安全性。其中，芳香酶抑制剂选自来曲唑或阿那曲唑，两个药物每个队列各入组15-30例受试者。
1.1入选标准：
1)受试者自愿加入本研究，签署知情同意书，依从性好；
2)年龄：18-75周岁(签署知情同意书时)；ECOG PS评分：0～1分；预计生存期超过3个月；
3)绝经后或绝经前/围绝经期女性患者；
4)病理检测确诊为HR阳性、HER2为阴性的乳腺癌患者；
5)队列1入组的受试者辅助内分泌治疗期间或辅助内分泌治疗完成后复发或进展；
6)队列1中完成辅助内分泌治疗定义为持续治疗至少2年后停药；
7)队列2入组的受试者既往未接受过任何针对局部病灶复发或转移性疾病的全身***性抗肿瘤治疗；
8)根据RECIST 1.1标准，证实至少有一个可测量病灶；
9)主要器官功能良好，符合下列标准：
血常规检查标准(筛选前7天内未输血、未使用造血刺激因子类药物纠正)：
a)血红蛋白(HB)≥100g/L；
b)中性粒细胞绝对值(NEUT)≥1.5×10 9/L；
c)血小板计数(PLT)≥90×10 9/L。
生化检查需符合以下标准：
a)总胆红素(TBIL)≤2.5倍正常值上限(ULN)；
b)丙氨酸基转移酶(ALT)和天门冬氨酸基转移酶(AST)≤2.5×ULN。若伴肝转移，则ALT和AST≤5×ULN；
c)血清肌酐(CR)≤1.5×ULN，或肌酐清除率(CCR)≥60ml/min。
凝血功能检查需符合以下标准：
凝血酶原时间(PT)、活化部分凝血活酶时间(APTT)、国际标准化比值(INR)≤1.5×ULN(未接受过抗凝治疗)；
心脏彩超评估：左室射血分数(LVEF)≥50％；
10)育龄女性受试者应同意在研究期间和研究结束后6个月内必须采用避孕措施(如宫内节育器、避孕药或避孕套)；在研究入组前的7天内血清妊娠试验阴性，且必须为非哺乳期受试者。
1.2试验药
式(I)化合物的胶囊：规格：60mg，由正大天晴药业集团股份有限公司提供。
来曲唑片：规格：2.5mg，购买自海正药业的
Figure PCTCN2022121752-appb-000005
阿那曲唑片：规格：1mg，购买自海正药业的
Figure PCTCN2022121752-appb-000006
1.3给药方案
(1)式(I)化合物：
式(I)化合物的胶囊：180mg(以式(I)化合物的质量计)，空腹口服，每日一次，连续服用28天为一个治疗周期。
(2)芳香酶抑制剂：可选择来曲唑或阿那曲唑，具体给药方案如下：
来曲唑片：2.5mg(以来曲唑的质量计)口服，每日1次，连续服用，每28天为一个治疗周期。与式(I)化合物的胶囊一起给药。
阿那曲唑片：1mg(以阿那曲唑的质量计)口服，每日1次，连续服用，每28天为一个治疗周期。与式(I)化合物的胶囊一起给药。
1.4评价标准
有效性评价标准：采用RECIST 1.1标准判定疾病状态。
安全性评价标准：采用NCI－CTC AE 5.0标准判断不良事件严重程度。
1.5试验结果
1.5.1安全性
对43例受试者安全性进行统计分析，主要不良事件是胃肠道反应，且多数TRAEs为1-2级，经对症处理后可控，3级TRAEs总体发生率仅27.9％，且未观察到4～5级TRAEs和治疗相关死亡事件。
1.5.2有效性
43例受试者中队列2入组38例，其他为队列1受试者。35例受试者(队列2：32例、队列1：3例)可进行疗效评价。疗效显示ORR为65.7％(23/35)，其中队列2受试者的有效率为65.6％(21/32)，与总人群ORR一致，队列2临床获益率CBR为90.6％(29/32)。队列1受试者的有效率为66.7％(2/3)，与总人群ORR一致，队列1临床获益率CBR为100％(3/3)。
结论：本公开的联用药物组合物可表现出较好的临床收益。
以下为代表性的受试者的情况概述：
Figure PCTCN2022121752-appb-000007
注：“NA”表示未评估；“*”代表肿瘤体积缩小百分比；“--”代表未到肿评点。
本领域技术人员将认识到，本申请的范围并不限于上文描述的各种具体实施方式和实施例，而是能够在不脱离本申请的精神和构思的情况下，进行各种修改、替换、或重新组合，这都落入了本申请的保护范围内。

Claims (15)

  1. 联用药物组合物，其包含式(I)化合物或其药学上可接受的盐和芳香酶抑制剂：
    Figure PCTCN2022121752-appb-100001
  2. 如权利要求1所述的联用药物组合物，其中所述式(I)化合物或其药学上可接受的盐和芳香酶抑制剂包装于同一试剂盒中，所述试剂盒还包含将式(I)化合物或其药学上可接受的盐和芳香酶抑制剂联合使用以治疗或预防乳腺癌的说明。
  3. 如权利要求1所述的联用药物组合物，其包括式(I)化合物或其药学上可接受的盐的药物组合物和芳香酶抑制剂的药物组合物。
  4. 如权利要求1-3中任一项所述的联用药物组合物，所述芳香酶抑制剂选自来曲唑或阿那曲唑。
  5. 如权利要求1-4中任一项所述的联用药物组合物，其含有以式(I)化合物计为20～240mg、40～180mg、60～180mg、80～180mg、100～180mg、120～180mg或150～180mg的式(I)化合物或其药学上可接受的盐或其药物组合物；或者，其含有以式(I)化合物计为20mg、40mg、60mg、80mg、100mg、120mg、150mg和/或240mg的式(I)化合物或其药学上可接受的盐或其药物组合物。
  6. 如权利要求4或5所述的联用药物组合物，其中式(I)化合物的药物组合物为单剂量或多剂量，优选式(I)化合物的药物组合物为多剂量；和/或
    所述来曲唑的药物组合物或阿那曲唑的药物组合物为单剂量。
  7. 如权利要求4所述的联用药物组合物，其含有2.5mg-12.5mg、2.5mg-10mg、2.5mg-7.5mg或2.5mg-5mg的来曲唑或其药物组合物；或者，其含有2.5mg、5mg、7.5mg或10mg的来曲唑或其药物组合物；或者其含有1mg-5mg、1mg-4mg、1mg-3mg或1mg-2mg的阿那曲唑，或其药物组合物；或者，含有1mg、2mg、3mg或4mg的阿那曲唑或其药物组合物。
  8. 如权利要求7所述的联用药物组合物，其中，所述联用药物组合物含有质量比为1:1至100:1、优选1.5:1至96:1、5:1至90:1、10:1至85:1、10:1至75:1、20:1至75:1、24:1至72:1的式(I)化合物或其药学上可接受的盐或其药物组合物和来曲唑或其药物组合物，其中，所述式(I)化合物或其药学上可接受的盐或其药物组合物的量以式(I)化合物的质量计，所述来曲唑或其药物组合物的量以来曲唑的质量计；或者所述联用药物组合物含有质量比为4:1至240:1、优选10:1至180:1、25:1至180:1、30:1至180:1、60:1至180:1的式(I)化合物或其药学上可接受的盐或其药物组合物和阿那曲唑或其药物组合物，其中，所述式(I)化合物或其药学上可接受的盐或其药物组合物的量以式(I)化合物的质量计，所述阿那曲唑或其药物组合物的量以阿那曲唑的质量计。
  9. 如权利要求7所述的联用药物组合物，其中，所述联用药物组合物为适用于单个治疗周期(例如28天)给予的制剂，所述制剂含有：1680mg-5040mg、例如3360mg-5040mg、优选5040mg的式(I)化合物或其药学上可接受的盐或其药物组合物；以及70mg-140mg、例如70mg的来曲唑或其药物组合物，其中，所述式(I)化合物或其药学上可接受的盐或其药物组合物的量以式(I)化合物的质量计，所述来曲唑或其药物组合物的量以来曲唑的质量计；或者
    所述联用药物组合物为适用于单个治疗周期(例如28天)给予的制剂，所述制剂含有：1680mg-5040mg、例如3360mg-5040mg、优选5040mg的式(I)化合物或其药学上可接受的盐或其药物组合物；以及28mg-140mg、例如28mg-56mg、优选28mg的阿那曲唑或其药物组合物，其中，所述式(I)化合物或其药学上可接受的盐或其药物组合物的量以式(I)化合物的质量计，所述阿那曲唑或其药物组合物以阿那曲唑的质量计。
  10. 治疗或预防乳腺癌的方法，其包括向有需要的个体施用治疗有效量的权利要求1-9中任一项所述的联用药物组合物。
  11. 权利要求1-9中任一项所述的联用药物组合物在制备用于治疗或预防乳腺癌的药物的用途。
  12. 用于治疗或预防乳腺癌的权利要求1-9中任一项所述的联用药物组合物。
  13. 给药方法，其包括向有需要的个体施用治疗有效量的权利要求1-9中任一项所述的联用药物组合物。
  14. 根据权利要求10所述的方法、权利要求11所述的用途、或权利要求12所述的用于所述用途的联用药物组合物，所述乳腺癌选自：
    HR阳性、HER2阴性的乳腺癌；
    HR阳性、HER2阴性的局部晚期和/或转移性乳腺癌；
    不能接受根治性手术或放疗的HR阳性、HER2阴性的局部晚期和/或转移性乳腺癌；或者
    绝经后或绝经前/围绝经期的HR阳性、HER2阴性的局部晚期和/或转移性乳腺癌。
  15. 根据权利要求10所述的方法、权利要求11所述的用途、或权利要求12所述的用于所述用途的联用药物组合物，28天为一个治疗周期，每天给药1次，连续给药28天，每个治疗周期施用含有所述式(I)化合物或其药学上可接受的盐的药物组合物的总剂量为1680～5040mg；每个治疗周期施用含有阿那曲唑的药物组合物的总剂量为28～140mg；或者
    28天为一个治疗周期，每天给药1次，连续给药28天，每个治疗周期施用含有所述式(I)化合物或其药学上可接受的盐的药物组合物的总剂量为1680～5040mg；每个治疗周期施用含有来曲唑的药物组合物的总剂量为70～210mg，
    其中，所述含有所述式(I)化合物或其药学上可接受的盐的药物组合物的量以式(I)化合物的质量计，所述含有阿那曲唑的药物组合物或含有来曲唑的药物组合物分别以阿那曲唑或来曲唑的质量计。
PCT/CN2022/121752 2021-09-27 2022-09-27 Cdk4/6抑制剂和芳香酶抑制剂的联用药物组合物 WO2023046200A1 (zh)

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Citations (3)

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US20160184311A1 (en) * 2013-08-14 2016-06-30 Novartis Ag Combination Therapy for the Treatment of Cancer
WO2016141881A1 (zh) 2015-03-11 2016-09-15 南京明德新药研发股份有限公司 作为抗癌药物的取代的2-氢-吡唑衍生物
CN107137408A (zh) * 2016-03-01 2017-09-08 江苏恒瑞医药股份有限公司 一种cdk4/6抑制剂与芳香化酶抑制剂联合在制备治疗乳腺癌的药物中的用途

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160184311A1 (en) * 2013-08-14 2016-06-30 Novartis Ag Combination Therapy for the Treatment of Cancer
WO2016141881A1 (zh) 2015-03-11 2016-09-15 南京明德新药研发股份有限公司 作为抗癌药物的取代的2-氢-吡唑衍生物
CN107137408A (zh) * 2016-03-01 2017-09-08 江苏恒瑞医药股份有限公司 一种cdk4/6抑制剂与芳香化酶抑制剂联合在制备治疗乳腺癌的药物中的用途

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