WO2020156446A1 - 一种含cdk4/6抑制剂的组合物与阿那曲唑联合在制备治疗肿瘤疾病的药物中的用途 - Google Patents

一种含cdk4/6抑制剂的组合物与阿那曲唑联合在制备治疗肿瘤疾病的药物中的用途 Download PDF

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WO2020156446A1
WO2020156446A1 PCT/CN2020/073815 CN2020073815W WO2020156446A1 WO 2020156446 A1 WO2020156446 A1 WO 2020156446A1 CN 2020073815 W CN2020073815 W CN 2020073815W WO 2020156446 A1 WO2020156446 A1 WO 2020156446A1
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formula
pharmaceutically acceptable
cancer
acceptable salt
compound represented
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PCT/CN2020/073815
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English (en)
French (fr)
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朱晓宇
李国荣
邹建军
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江苏恒瑞医药股份有限公司
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Priority to KR1020217027639A priority Critical patent/KR20210121188A/ko
Priority to EP20748834.7A priority patent/EP3919058A4/en
Priority to BR112021014820-5A priority patent/BR112021014820A2/pt
Priority to CN202080011642.5A priority patent/CN113395969A/zh
Priority to US17/427,501 priority patent/US20220125792A1/en
Priority to AU2020214930A priority patent/AU2020214930A1/en
Priority to JP2021544382A priority patent/JP2022523088A/ja
Priority to CA3128072A priority patent/CA3128072A1/en
Priority to MX2021009188A priority patent/MX2021009188A/es
Publication of WO2020156446A1 publication Critical patent/WO2020156446A1/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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • A61K31/4196—1,2,4-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • composition containing a CDK4/6 inhibitor in combination with anastrozole in the preparation of a medicine for treating tumors.
  • Breast cancer is one of the most common malignant tumors in women. There are approximately 1.3 million new cases worldwide each year. In China, the incidence of breast cancer accounts for 7%-10% of the incidence of various malignant tumors in the whole body, and about 18% of all female tumors. The number of patients in China has exceeded 500,000, and its incidence is increasing rapidly. It has been ranked first in the incidence spectrum of female tumors, and nearly 50% of patients have recurrence and metastasis after treatment. In recent years, with the deepening of tumor molecular biology research, molecular targeted therapy has become more and more widely used in the treatment of breast cancer and has achieved more significant curative effects. It has become the first after the three traditional modes of surgery, radiotherapy and chemotherapy. This new treatment model is also a hot spot in the field of breast cancer treatment.
  • Cyclin-dependent kinase is a type of serine/threonine kinase that forms a dimer with the corresponding cyclin (Cyclin) to phosphorylate downstream protein molecules, thereby promoting the cell cycle Orderly progress in each phase to achieve cell growth and proliferation.
  • CDK4/6 selective inhibitors are in clinical trials or have been approved for listing in foreign countries, including Pfizer's Palbociclib, Novartis's Ribociclib, and Eli Lilly's Abemaciclib.
  • PCT application WO2014183520 discloses a chemical name 6-acetyl-8-cyclopentyl-5-methyl-2-((5-(piperidin-4-yl)pyridin-2-yl)amino)pyrido [2,3-d]pyrimidin-7(8H)-one, the structural formula is as the CDK4/6 inhibitor shown in formula (I), it has significant CDK4/6 inhibitory activity and high selectivity.
  • PCT application WO2016124067A discloses the isethionate of the compound represented by the above formula (I) and a preparation method thereof.
  • Prior art CN107137408A also studied the combination of the compound represented by formula (I) and its pharmaceutically acceptable salt with an aroma kinase inhibitor.
  • a pharmacokinetic study of letrozole and anastrozole as a single agent showed that:
  • letrozole For postmenopausal women with metastatic breast cancer, letrozole (2.5 mg once a day) is a more effective systemic aromatization and plasma estrogen level inhibitor (PMID) than anastrozole (1 mg daily). : 11821457).
  • PMID systemic aromatization and plasma estrogen level inhibitor
  • Another open randomized trial comparing letrozole and anastrozole in the second-line endocrine therapy of advanced breast cancer came to this conclusion: it supports the previous description of letrozole's higher aromatase inhibitory activity as a second-line hormone In treatment, advanced breast cancer has a stronger response to letrozole than to anastrozole (PMID: 14556923).
  • the present disclosure provides a use of a pharmaceutical composition containing a compound represented by formula (I) or a pharmaceutically acceptable salt thereof in combination with anastrozole in the preparation of a medicament for the treatment of tumor diseases,
  • the tumor disease described in the present disclosure is selected from sarcoma, lymphoma, lung cancer, bronchial cancer, prostate cancer, pancreatic cancer, gastrointestinal cancer, colon cancer, rectal cancer, colorectal adenoma, thyroid cancer, liver cancer, intrahepatic cholangiocarcinoma , Hepatocellular carcinoma, adrenal cancer, gastric cancer, gastric tumor, glioma, glioblastoma, endometrial cancer, melanoma, kidney cancer, renal pelvis cancer, bladder cancer, uterine body cancer, cervical cancer, vaginal cancer , Ovarian cancer, multiple myeloma, esophageal cancer, leukemia, acute myeloid leukemia, chronic myeloid leukemia, lymphocytic leukemia, myelogenous leukemia, brain tumor, brain cancer, oral and pharynx cancer, laryngeal cancer, Small bowel cancer, non-Hodgkin's lymphoma, melanoma,
  • the breast cancer described in the present disclosure is preferably hormone receptor positive (HR+) and/or human epidermal growth factor receptor 2 negative (HER2-) breast cancer; more preferably, it is locally advanced or metastatic breast of the above phenotype cancer.
  • HR+ hormone receptor positive
  • HER2- human epidermal growth factor receptor 2 negative
  • the pharmaceutically acceptable salt of the compound represented by formula (I) is selected from hydrochloride, phosphate, hydrogen phosphate, sulfate, hydrogen sulfate, sulfite, acetate, oxalate, malonate Acid salt, valerate, glutamate, oleate, palmitate, stearate, laurate, borate, p-toluenesulfonate, methanesulfonate, isethionate , Maleate, malate, tartrate, benzoate, pamoate, salicylate, vanillate, mandelate, succinate, gluconate, lactobionate and laurel
  • sulfonates preferably isethionates, the structure of which is shown in formula (II)
  • the amount of the compound represented by formula (I) or its pharmaceutically acceptable salt in the pharmaceutical composition containing the compound represented by formula (I) or its pharmaceutically acceptable salt taken daily is 1-500 mg , Preferably 50-200 mg, more preferably 100-150 mg.
  • the amount of the compound represented by formula (I) or its pharmaceutically acceptable salt in the pharmaceutical composition containing the compound represented by formula (I) or its pharmaceutically acceptable salt taken daily is 50 mg , 75mg, 100mg, 125mg, 150mg, 175mg, preferably 100mg, 125mg or 150mg.
  • the frequency of administration of the pharmaceutical composition containing the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is once a day, twice a day, preferably once a day.
  • the daily dose of anastrozole is selected from 0.1-50 mg, preferably 1-25 mg, most preferably 1-10 mg.
  • the daily dose of anastrozole is selected from 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5.0 mg, preferably 1.0 mg .
  • the frequency of administration of anastrozole is once a day, twice a day, preferably once a day.
  • the amount of the compound represented by formula (I) or its pharmaceutically acceptable salt in the pharmaceutical composition containing the compound represented by formula (I) or its pharmaceutically acceptable salt taken daily is 50 mg, 75 mg , 100mg, 125mg, 150mg, 175mg, the pharmaceutical composition containing the compound represented by formula (I) or its pharmaceutically acceptable salt is administered once a day, twice a day, preferably once a day, anastrozole
  • the daily dose is selected from 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5.0 mg, preferably 1.0 mg.
  • the frequency of administration of anastrozole is once a day, Twice a day, preferably once a day.
  • the amount of the compound represented by formula (I) or its pharmaceutically acceptable salt in the pharmaceutical composition containing the compound represented by formula (I) or its pharmaceutically acceptable salt taken daily is 100 mg, 125 mg, 150 mg, the pharmaceutical composition containing the compound represented by formula (I) or its pharmaceutically acceptable salt is administered once a day, the daily dose of anastrozole is 1.0 mg, and the frequency of administration of anastrozole is once a day.
  • the amount of the compound represented by formula (I) or its pharmaceutically acceptable salt in the pharmaceutical composition containing the compound represented by formula (I) or its pharmaceutically acceptable salt taken daily is 100 mg, containing The composition of the compound represented by formula (I) or its pharmaceutically acceptable salt is administered once a day, the daily dose of anastrozole is 1.0 mg, and the frequency of administration of anastrozole is once a day.
  • the amount of the compound represented by formula (I) or its pharmaceutically acceptable salt in the pharmaceutical composition containing the compound represented by formula (I) or its pharmaceutically acceptable salt taken daily is 125 mg, containing The pharmaceutical composition of the compound represented by formula (I) or its pharmaceutically acceptable salt is administered once a day, the daily dose of anastrozole is 1.0 mg, and the frequency of administration of anastrozole is once a day.
  • the amount of the compound represented by formula (I) or its pharmaceutically acceptable salt in the pharmaceutical composition containing the compound represented by formula (I) or its pharmaceutically acceptable salt taken daily is 150 mg, containing The pharmaceutical composition of the compound represented by formula (I) or its pharmaceutically acceptable salt is administered once a day, the daily dose of anastrozole is 1.0 mg, and the frequency of administration of anastrozole is once a day.
  • the pharmaceutical composition containing the compound represented by formula (I) or a pharmaceutically acceptable salt thereof in the present disclosure may further contain at least one pharmaceutically acceptable excipient selected from diluents, binders, Disintegrant, lubricant.
  • the content of the diluent in the pharmaceutical composition containing the compound represented by formula (I) or its pharmaceutically acceptable salt in the present disclosure may be 1%-99%, preferably 5%-95% (by mass) relative to the total weight of the pharmaceutical composition percentage).
  • the content of the lubricant in the pharmaceutical composition containing the compound represented by formula (I) or its pharmaceutically acceptable salt in the present disclosure may be 0.01%-25%, preferably 0.1%-10% (by mass) relative to the total weight of the pharmaceutical composition percentage).
  • anastrozole can be administered in the form of a pharmaceutical composition.
  • the specific anastrozole is administered in the form of a pharmaceutical composition suitable for intestinal administration or parenteral administration, such as tablets, capsules, and suppositories.
  • a pharmaceutical composition suitable for intestinal administration or parenteral administration such as tablets, capsules, and suppositories.
  • Anastrozole can be in a commercially available form (e.g. ) Application.
  • the pharmaceutical composition containing the compound represented by formula (I) or a pharmaceutically acceptable salt thereof and anastrozole are both administered orally.
  • the pharmaceutical composition containing the compound represented by formula (I) or a pharmaceutically acceptable salt thereof provided in the present disclosure is used in combination with anastrozole in the preparation of a drug for treating tumors, wherein anastrozole increases the formula (I) The AUC of the compound or its pharmaceutically acceptable salt in the patient.
  • the pharmaceutical composition containing the compound represented by formula (I) or a pharmaceutically acceptable salt thereof provided in the present disclosure is used in combination with anastrozole in the preparation of a drug for treating tumors, wherein anastrozole reduces The incidence of adverse reactions.
  • the adverse reaction is preferably hematological toxicity, and the hematological toxicity can be selected from the group consisting of neutrophil decline, leukocyte decline and/or platelet decline; preferably grade 3, 4 neutrophil decline and/or 3, Level 4 white blood cell decreased.
  • the patients with tumor diseases described in the present disclosure are humans.
  • the present disclosure provides a method for anastrozole to increase the AUC of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof in a patient, comprising administering to the patient a therapeutically effective amount of formula (I)
  • the compound or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of anastrozole and the patient is preferably a human.
  • increase the AUC of the compound represented by formula (I) or its pharmaceutically acceptable salt in the patient's body means that the same dose of the compound represented by formula (I) or its pharmaceutically acceptable salt in the patient's body is administered alone.
  • Reducing the incidence of adverse reactions in patients also means that the compound of formula (I) combined with anastrozole is compared with the same dose of the compound of formula (I) alone and/or the compound of formula (I) with the same dose. Or a combination of its pharmaceutically acceptable salt and letrozole.
  • the AUC produced in the patient increases by more than 18%, optionally, the AUC increases by 20%-150%; optionally, the AUC increases by 25%-100%; optionally, the AUC increases by 30%-85%;
  • AUC is increased by 35%-80%; optionally, AUC is increased by 40%-80%; preferably, AUC is increased by 45%-80%; preferably, AUC is increased by 50%-80%; preferably, AUC is increased 55%-80%; preferably, the AUC is increased by 60%-80%; specifically, the AUC of the compound represented by formula (I) or its pharmaceutically acceptable salt is increased by about 18%, 19%, 20%, 21%, 22% , 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%
  • the AUC ratio of the compound represented by formula (I) or its pharmaceutically acceptable salt in the patient is greater than 1:1, optionally, the AUC ratio is selected from 1-10:1; optionally , The AUC ratio is selected from 1 to 5:1; optionally, the AUC ratio is selected from 1 to 4:1; optionally, the AUC ratio is selected from 1 to 3:1; preferably, the AUC ratio is selected from 1 to 2: 1; Preferably, the AUC ratio is selected from 1 to 1.5:1, specifically, the AUC ratio may be 1.01:1, 1.02:1, 1.03:1, 1.04:1, 1.05:1, 1.06:1, 1.07:1, 1.08:1, 1.09:1, 1.10:1, 1.11:1, 1.12:1, 1.13:1, 1.14:1,
  • the compound represented by formula (I) or a pharmaceutically acceptable salt thereof provides 2800 -8000ng*h/mL AUC; alternatively, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof provides an AUC of 2800-7800ng*h/mL in the patient's body; alternatively, represented by formula (I)
  • the compound or its pharmaceutically acceptable salt provides an AUC of 3000-7600ng*h/mL in the patient's body; alternatively, the compound represented by formula (I) or its pharmaceutically acceptable salt provides 3000-7400ng*h/mL in the patient's body AUC; alternatively, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof provides an AUC of 3000-7200 ng*h/mL in the patient's body; alternatively, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof Provide an AUC of
  • the method for increasing the AUC of the compound represented by formula (I) or its pharmaceutically acceptable salt in the patient’s body provided by the present disclosure, optionally simultaneously increasing the AUC of the compound represented by formula (I) or its pharmaceutically acceptable salt in the patient’s body C max .
  • the ratio of C max of the compound represented by formula (I) or its pharmaceutically acceptable salt in the patient is greater than 1:1, optionally, the ratio of C max is selected from 1-10:1; optionally, the ratio of C max Selected from 1 to 5:1; optionally, the C max ratio is selected from 1 to 4:1; optionally, the C max ratio is selected from 1 to 3:1; preferably, the C max ratio is selected from 1 to 2: 1; Preferably, the C max ratio is selected from 1 to 1.5:1.
  • the specific C max ratio can be 1.02:1, 1.04:1, 1.06:1, 1.08:1, 1.10:1, 1.12:1, 1.14:1, 1.16:1, 1.18:1, 1.20:1, 1.22:1 , 1.24:1, 1.26:1, 1.28:1, 1.30:1, 1.32:1, 1.34:1, 1.36:1, 1.38:1, 1.40:1, 1.42:1, 1.44:1, 1.46:1, 1.48 :1, 1.50:1, 1.52:1, 1.54:1, 1.56:1, 1.58:1, 1.60:1, 1.62:1, 1.64:1, 1.66:1, 1.68:1, 1.70:1, 1.72:1 , 1.74:1, 1.76:1, 1.78:1, 1.80:1, 1.82:1, 1.84:1, 1.86:1, 1.88:1, 1.90:1, 1.92:1, 1.94:1, 1.96:1, 1.98 :1, 2.00:1.
  • the method for increasing the AUC of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof in a patient by anastrozole may include administering to the patient 1-500 mg/day of the compound represented by formula (I) or Its pharmaceutically acceptable salt, preferably 50-200 mg/day of the compound represented by formula (I) or its pharmaceutically acceptable salt, more preferably 100-150 mg/day of the compound represented by formula (I) or its pharmaceutically acceptable salt, and Anastrozole at 0.1-50 mg/day, preferably anastrozole at 1-25 mg/day, and most preferably anastrozole at 1-10 mg/day.
  • the amount of the compound represented by formula (I) or its pharmaceutically acceptable salt administered daily is 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, preferably 100 mg, 125 mg or 150 mg.
  • the frequency of administration of the pharmaceutical composition of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is once a day, twice a day, preferably once a day.
  • the daily dose of anastrozole is selected from 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5.0 mg, preferably 1.0 mg.
  • the frequency of administration of anastrozole is once a day, twice a day, preferably once a day.
  • the amount of the compound represented by formula (I) or its pharmaceutically acceptable salt administered daily is 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, and the compound represented by formula (I) or its pharmaceutically acceptable salt
  • the frequency of administration of salt is once a day, twice a day, preferably once a day
  • the daily dose of anastrozole is selected from 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5.0 mg, preferably 1.0 mg
  • the frequency of administration is once a day, twice a day, preferably once a day.
  • the amount of the compound represented by formula (I) or its pharmaceutically acceptable salt administered daily is 100 mg, 125 mg, 150 mg, the frequency of administration is once a day, and the daily dose of anastrozole is 1.0 mg , The frequency of administration is once a day.
  • the amount of the compound represented by formula (I) or its pharmaceutically acceptable salt administered daily is 150 mg, the dosage frequency is once a day, the daily dosage of anastrozole is 1.0 mg, and the dosage frequency is Once a day.
  • the amount of the compound represented by formula (I) or its pharmaceutically acceptable salt administered daily is 175 mg, the dosage frequency is once a day, the daily dosage of anastrozole is 1.0 mg, and the dosage frequency is Once a day.
  • the pharmaceutically acceptable salt of the compound represented by formula (I) is isethionate.
  • the present disclosure provides a method for increasing the AUC of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof in a patient's body with anastrozole, wherein the compound represented by formula (I) or a pharmaceutically acceptable salt thereof can be administered in the form of a pharmaceutical composition
  • the pharmaceutical composition of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof may further contain at least one pharmaceutically acceptable excipient selected from diluents, binders, Disintegrant, lubricant.
  • the content of the diluent in the pharmaceutical composition of the compound represented by formula (I) or its pharmaceutically acceptable salt is 1%-99%, preferably 5%-95% (mass percentage) relative to the total weight of the composition,
  • the content of the lubricant is 0.01%-25%, preferably 0.1%-10% (mass percentage) relative to the total weight of the composition.
  • anastrozole is administered in the form of a pharmaceutical composition suitable for enteral administration or parenteral administration, such as tablets, capsules, suppositories, ampoules, injection solutions or injection suspensions liquid.
  • a pharmaceutical composition suitable for enteral administration or parenteral administration such as tablets, capsules, suppositories, ampoules, injection solutions or injection suspensions liquid.
  • Anastrozole can be in a commercially available form (e.g. ) Application.
  • the present disclosure provides a method for treating tumor diseases, comprising administering to a patient a therapeutically effective amount of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of anastrozole.
  • the method for treating tumor diseases provided in the present disclosure may include administering to a patient a therapeutically effective amount of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of anastrozole, wherein anastrozole increases the formula (I) ) AUC of the compound or its pharmaceutically acceptable salt in the patient.
  • the hematological toxicity may be selected from the group consisting of neutrophil decline, leukocyte decline and/or platelet decline; Preferably, grade 3, 4 neutrophil decline and/or grade 3, 4 leukocyte decline.
  • the present disclosure provides a method for reducing adverse reactions in patients.
  • the adverse reactions are preferably hematological toxicity, and the hematological toxicity may be selected from neutrophil decline, leukocyte decline and/or thrombocytopenia; preferably Grade 3 and 4 neutrophil decline and/or 3 and 4 leukopenia; the method may include administering to the patient a therapeutically effective amount of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of Natrozole, the patient may be a patient with a tumor disease.
  • the tumor disease can be selected from sarcoma, lymphoma, lung cancer, bronchial cancer, prostate cancer, pancreatic cancer, gastrointestinal cancer, colon cancer, rectal cancer, colorectal adenoma, thyroid cancer, liver cancer, intrahepatic cholangiocarcinoma, liver Cell cancer, adrenal gland cancer, gastric cancer, gastric cancer, glioma, glioblastoma, endometrial cancer, melanoma, kidney cancer, renal pelvis cancer, bladder cancer, uterine body cancer, cervical cancer, vaginal cancer, ovarian cancer Cancer, multiple myeloma, esophageal cancer, leukemia, acute myeloid leukemia, chronic myeloid leukemia, lymphocytic leukemia, myelogenous leukemia, brain tumor, brain cancer, oral and pharynx cancer, laryngeal cancer, small intestine cancer , Non-Hodgkin's lymphoma, melanoma, colon chori
  • the breast cancer is preferably hormone receptor positive (HR+) and/or human epidermal growth factor receptor 2 negative (HER2-) breast cancer; more preferably, it is locally advanced or metastatic breast cancer of the above phenotype.
  • HR+ hormone receptor positive
  • HER2- human epidermal growth factor receptor 2 negative
  • the method for treating tumors provided in the present disclosure includes administering to the patient 1-500 mg/day of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, preferably 50-200 mg/day of formula
  • the compound represented by (I) or its pharmaceutically acceptable salt more preferably 100-150 mg/day of the compound represented by formula (I) or its pharmaceutically acceptable salt, and 0.1-50 mg/day of anastrozole, preferably 1-25 mg Anastrozole per day, most preferably anastrozole 1-10 mg per day.
  • the amount of the compound represented by formula (I) or its pharmaceutically acceptable salt administered daily is 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, preferably 100 mg, 125 mg or 150 mg.
  • the frequency of administration of the compound represented by formula (I) or its pharmaceutically acceptable salt is once a day, twice a day, preferably once a day.
  • the daily dose of anastrozole is selected from 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5.0 mg, preferably 1.0 mg.
  • the frequency of administration of anastrozole is once a day, twice a day, preferably once a day.
  • the amount of the compound represented by formula (I) or its pharmaceutically acceptable salt administered daily is 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, and the compound represented by formula (I) or its pharmaceutically acceptable salt
  • the frequency of administration of salt is once a day, twice a day, preferably once a day
  • the daily dose of anastrozole is selected from 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5.0 mg, preferably 1.0 mg
  • the frequency of administration is once a day, twice a day, preferably once a day.
  • the amount of the compound represented by formula (I) or its pharmaceutically acceptable salt administered daily is 100 mg, 125 mg, 150 mg, the frequency of administration is once a day, and the daily dose of anastrozole is 1.0 mg, The frequency of administration is once a day.
  • the amount of the compound represented by formula (I) or its pharmaceutically acceptable salt administered daily is 150 mg, the dosage frequency is once a day, the daily dosage of anastrozole is 1.0 mg, and the dosage frequency is Once a day.
  • the amount of the compound represented by formula (I) or its pharmaceutically acceptable salt administered daily is 175 mg, the dosage frequency is once a day, the daily dosage of anastrozole is 1.0 mg, and the dosage frequency is Once a day.
  • the method for treating tumors provided in the present disclosure can be a 28-day dosing cycle, wherein the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is administered on day 1 to 21, and after the drug is stopped for 7 days, anastrozole is It is administered daily during a 28-day treatment cycle.
  • the present disclosure provides a method for treating local recurrence or metastatic breast cancer in a human patient, comprising orally administering to the patient an effective amount of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, and an effective amount of anastrozole.
  • the patient is a postmenopausal or premenopausal or perimenopausal female patient or a premenopausal female who has undergone ovariectomy,
  • the method for treating locally recurring or metastatic breast cancer in a human patient is a treatment cycle every 28 days, wherein the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is on the first day Continue to take until the 21st day, anastrozole is administered every day during the 28-day treatment cycle.
  • the present disclosure provides a method for treating local recurrence or metastatic breast cancer in a human patient, when the patient takes the compound represented by formula (I) or a pharmaceutically acceptable salt thereof on an empty stomach.
  • the present disclosure provides a method for treating locally recurring or metastatic breast cancer in a human patient, said breast cancer being hormone receptor positive (HR+) and/or human epidermal growth factor receptor 2 negative (HER2 -) Breast cancer.
  • HR+ hormone receptor positive
  • HER2 - human epidermal growth factor receptor 2 negative
  • the daily dose of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is 100-150 mg.
  • the daily dose of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is 100 mg, 125 mg or 150 mg.
  • the daily dose of anastrozole is 0.1-10 mg.
  • the daily dose of anastrozole is 0.5 mg, 1 mg or 1.5 mg.
  • the present disclosure provides a method for treating locally recurring or metastatic breast cancer in a human patient, wherein the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is administered in the morning.
  • the pharmaceutically acceptable salt of the compound represented by formula (I) is isethionate.
  • the present disclosure provides a method of treating breast cancer, administering 150 mg/day of the compound represented by formula (I) or its pharmaceutically acceptable salt and 0.1-50 mg/day of anastrozole to monitor the patient’s adverse reactions ( AE grade), if a grade 3/4 AE occurs, the patient is given a dose of 125 mg/day or 100 mg/day of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof.
  • the method for treating breast cancer provided by the present disclosure administers 150 mg/day of the compound represented by formula (I) or its pharmaceutically acceptable salt and 1 mg/day of anastrozole to monitor the patient’s adverse reactions (AE grade) If the patient has a grade 3/4 AE, the compound or pharmaceutically acceptable salt of the compound represented by formula (I) or its pharmaceutically acceptable salt will be given to the patient at a dose of 125 mg/day or 100 mg/day.
  • adverse reactions AE grade
  • the method for treating breast cancer provided by the present disclosure is to administer 150 mg/day of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, orally once a day, and administer 1 mg/day of anatril to the patient Azole, orally administered once a day, monitor the patient's adverse reactions (AE grade), if the patient has a grade 3/4 AE, give the patient 125mg/day or 100mg/day of the compound represented by formula (I) or its drug Use salt.
  • AE grade adverse reactions
  • anastrozole increases the AUC of the compound represented by formula (I) or its pharmaceutically acceptable salt, after the dose is reduced, compared with the original dose, the drug has a greater chance of maintaining the efficacy of the drug on the patient.
  • the present disclosure provides a use of anastrozole in the preparation of a medicament for increasing the AUC of the compound represented by formula (I) or its pharmaceutically acceptable salt in a patient.
  • the AUC produced in the patient is increased by more than 18%, optionally, the AUC is increased by 20%-150%; optionally, the AUC is increased by 25%-100%; optionally, the AUC is increased by 30%-85%; optionally, AUC is increased by 35%-80%; optionally, AUC is increased by 40%-80%; preferably, AUC is increased by 45%-80%; preferably, AUC is increased by 50%-80%; preferably, AUC Increased by 55%-80%; preferably, AUC increased by 60%-80%; specifically, the AUC of the compound represented by formula (I) or its pharmaceutically acceptable salt increased by about 18%, 19%, 20%, 21%, 22 %, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 3
  • the AUC ratio of the compound represented by formula (I) or its pharmaceutically acceptable salt in the patient is greater than 1:1, optionally, the AUC ratio is selected from 1-10:1; optional Preferably, the AUC ratio is selected from 1 to 5:1; optionally, the AUC ratio is selected from 1 to 4:1; optionally, the AUC ratio is selected from 1 to 3:1; preferably, the AUC ratio is selected from 1 to 2 :1; preferably, the AUC ratio is selected from 1 to 1.5:1, specifically, the AUC ratio may be 1.01:1, 1.02:1, 1.03:1, 1.04:1, 1.05:1, 1.06:1, 1.07:1 , 1.08:1, 1.09:1, 1.10:1, 1.11:1, 1.12:1, 1.13:1,
  • the compound of formula (I) or its pharmaceutically acceptable salt is provided in the patient 2800-8000ng*h/mL; optionally, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof provides an AUC of 2800-7800ng*h/mL in the patient; optionally, the formula (I)
  • the compound or its pharmaceutically acceptable salt provides an AUC of 3000-7600 ng*h/mL in the patient’s body; alternatively, the compound of formula (I) or its pharmaceutically acceptable salt provides 3000-7400 ng*h/mL in the patient’s body
  • the compound represented by formula (I) or its pharmaceutically acceptable salt provides an AUC of 3000-7200 ng*h/mL in the patient’s body; alternatively, the compound represented by formula (I) or its pharmaceutically acceptable The salt provides an AUC of 3000-7000 ng*h/mL in the patient;
  • anastrozole provided in the present disclosure in the preparation of a medicament for increasing the AUC of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof in a patient, optionally anastrozole increases the compound represented by formula (I) or C max of pharmaceutically acceptable salts in patients.
  • the ratio of C max of the compound represented by formula (I) or its pharmaceutically acceptable salt in the patient’s body is greater than 1:1, optionally, the ratio of C max is selected from 1-10:1; optionally, C max The ratio is selected from 1 to 5:1; optionally, the C max ratio is selected from 1 to 4:1; optionally, the C max ratio is selected from 1 to 3:1; preferably, the C max ratio is selected from 1 to 2 :1; Preferably, the C max ratio is selected from 1 to 1.5:1.
  • the specific C max ratio can be 1.02:1, 1.04:1, 1.06:1, 1.08:1, 1.10:1, 1.12:1, 1.14:1, 1.16:1, 1.18:1, 1.20:1, 1.22:1 , 1.24:1, 1.26:1, 1.28:1, 1.30:1, 1.32:1, 1.34:1, 1.36:1, 1.38:1, 1.40:1, 1.42:1, 1.44:1, 1.46:1, 1.48 :1, 1.50:1, 1.52:1, 1.54:1, 1.56:1, 1.58:1, 1.60:1, 1.62:1, 1.64:1, 1.66:1, 1.68:1, 1.70:1, 1.72:1 , 1.74:1, 1.76:1, 1.78:1, 1.80:1, 1.82:1, 1.84:1, 1.86:1, 1.88:1, 1.90:1, 1.92:1, 1.94:1, 1.96:1, 1.98 :1, 2.00:1.
  • the dose of the compound represented by formula (I) or its pharmaceutically acceptable salt is less than or equal to 175 mg, preferably less than or equal to 150 mg.
  • the frequency of administration of the compound represented by formula (I) or its pharmaceutically acceptable salt is once a day or twice a day
  • the daily dose of the compound represented by formula (I) or its pharmaceutically acceptable salt is It is 1-500 mg, preferably 50-200 mg, more preferably 100-150 mg
  • the frequency of administration of anastrozole is once a day or twice a day
  • the daily dose is 0.1-50 mg, preferably 1-25 mg, and most preferably 1- 10mg.
  • the frequency of administration of the compound represented by formula (I) or its pharmaceutically acceptable salt is once a day, the daily dose is 150 mg, the frequency of administration of anastrozole is once a day, and the daily dose is 1mg.
  • the present disclosure provides a method for increasing the AUC of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof after taking the medicine, which comprises a patient taking an effective amount of anastrozole,
  • the patient suffers from breast cancer, and the patient is fasting when the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is administered.
  • the present disclosure provides a method for treating tumor diseases, comprising administering to a patient a therapeutically effective amount of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of at least one aroma kinase inhibitor or female Hormone receptor antagonist,
  • the aroma kinase inhibitor is selected from one of formestane, atamestane, anastrozole, fadrozole, letrozole, voclozole, exemestane and fenrozole Or more, preferably letrozole and/or anastrozole
  • the estrogen receptor antagonist is selected from one or more of tamoxifen and fulvestrant, preferably fulvestrant, wherein the formula ( I)
  • the compound or pharmaceutically acceptable salt thereof is administered on an empty stomach, and the patient is preferably a human.
  • food especially high-fat meals, can increase the exposure level of the compound represented by formula (I) or its pharmaceutically acceptable salt, and avoid it by separating administration and eating for a longer time.
  • the effect of food on the pharmacokinetics of the compound represented by formula (I) or its pharmaceutically acceptable salt is ensured, and the therapeutic safety and effect of the drug are guaranteed.
  • the aroma kinase inhibitor is anastrozole
  • the dose of the compound represented by formula (I) or its pharmaceutically acceptable salt is 1-500 mg, preferably 50-200 mg, more preferably 100-150 mg
  • the frequency of the medicine is once a day, twice a day, preferably once a day.
  • the dosage of anastrozole is selected from 0.1-50 mg, preferably 1-25 mg, most preferably 1-10 mg, once a day, twice a day, preferably once a day.
  • the compound represented by formula (I) or its pharmaceutically acceptable salt is administered on an empty stomach.
  • the aroma kinase inhibitor is anastrozole
  • the dose of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is selected from 50mg, 75mg, 100mg, 125mg, 150mg, 175mg, preferably 100mg, 125mg or 150mg, the frequency of administration is once a day
  • the dose of anastrozole is selected from 0.5mg, 1.0mg, 1.5mg, 2.0mg, 2.5mg, 3.0mg, 3.5mg, 4.0mg, 4.5mg, 5.0mg, preferably 1.0 mg
  • the frequency of administration is once a day
  • the compound represented by formula (I) or its pharmaceutically acceptable salt is administered on an empty stomach.
  • the aroma kinase inhibitor is anastrozole
  • the dose of the compound represented by formula (I) or its pharmaceutically acceptable salt is 100 mg, 125 mg or 150 mg, and the frequency of administration is once a day.
  • the dose of azole is 1.0 mg, and the frequency of administration is once a day, wherein the compound represented by formula (I) or its pharmaceutically acceptable salt is administered on an empty stomach.
  • the aroma kinase inhibitor is anastrozole
  • the dose of the compound represented by formula (I) or its pharmaceutically acceptable salt is 100 mg
  • the frequency of administration is once a day
  • the dose of anastrozole is 1.0 mg
  • the frequency of administration is once a day
  • the compound represented by formula (I) or its pharmaceutically acceptable salt is administered on an empty stomach.
  • the aroma kinase inhibitor is anastrozole
  • the dose of the compound represented by formula (I) or its pharmaceutically acceptable salt is 125 mg
  • the frequency of administration is once a day
  • the dose of anastrozole is 1.0 mg
  • the frequency of administration is once a day
  • the compound represented by formula (I) or its pharmaceutically acceptable salt is administered on an empty stomach.
  • the aroma kinase inhibitor is anastrozole
  • the dose of the compound represented by formula (I) or its pharmaceutically acceptable salt is 150 mg
  • the frequency of administration is once a day
  • the dose of anastrozole is 1.0 mg
  • the frequency of administration is once a day
  • the compound represented by formula (I) or its pharmaceutically acceptable salt is administered on an empty stomach.
  • the aroma kinase inhibitor is letrozole
  • the dose of the compound represented by formula (I) or its pharmaceutically acceptable salt is 1-500 mg, preferably 50-200 mg, more preferably 100-150 mg
  • the frequency of medication is once a day, twice a day, preferably once a day
  • the dose of letrozole is selected from 1-100 mg, preferably 1-10 mg, most preferably 1-5 mg
  • the dosing frequency is once a day, twice a day Twice, preferably once a day, wherein the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is administered on an empty stomach.
  • the aroma kinase inhibitor is letrozole
  • the dose of the compound represented by formula (I) or its pharmaceutically acceptable salt is selected from 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, preferably 100 mg, 125mg or 150mg
  • the frequency of administration is once a day
  • the dose of letrozole is selected from 0.5mg, 1.0mg, 1.5mg, 2.0mg, 2.5mg, 3.0mg, 3.5mg, 4.0mg, 4.5mg, 5.0mg, preferably 2.5 mg
  • the frequency of administration is once a day
  • the compound represented by formula (I) or its pharmaceutically acceptable salt is administered on an empty stomach.
  • the aroma kinase inhibitor is letrozole
  • the dose of the compound represented by formula (I) or its pharmaceutically acceptable salt is 100 mg, 125 mg or 150 mg, and the frequency of administration is once a day.
  • the dose of azole is 2.5 mg, and the frequency of administration is once a day, wherein the compound represented by formula (I) or its pharmaceutically acceptable salt is administered on an empty stomach.
  • the aroma kinase inhibitor is letrozole
  • the dose of the compound represented by formula (I) or its pharmaceutically acceptable salt is 100 mg
  • the administration frequency is once a day
  • the dose of letrozole is 2.5 mg
  • the frequency of administration is once a day
  • the compound represented by formula (I) or its pharmaceutically acceptable salt is administered on an empty stomach.
  • the aroma kinase inhibitor is letrozole
  • the dose of the compound represented by formula (I) or its pharmaceutically acceptable salt is 125 mg
  • the frequency of administration is once a day
  • the dose of letrozole is 2.5 mg
  • the frequency of administration is once a day
  • the compound represented by formula (I) or its pharmaceutically acceptable salt is administered on an empty stomach.
  • the aroma kinase inhibitor is letrozole
  • the dose of the compound represented by formula (I) or its pharmaceutically acceptable salt is 150 mg
  • the administration frequency is once a day
  • the dose of letrozole is 2.5 mg
  • the frequency of administration is once a day
  • the compound represented by formula (I) or its pharmaceutically acceptable salt is administered on an empty stomach.
  • the estrogen receptor antagonist is fulvestrant
  • the dose of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is 1-500 mg, preferably 50-200 mg, more preferably 100- 150 mg
  • the frequency of administration is once a day, twice a day, preferably once a day
  • the dosage of fulvestrant is selected from 1-2000 mg, preferably 10-1000 mg, more preferably 100-1000 mg
  • the dosing frequency is one week
  • the compound represented by formula (I) or its pharmaceutically acceptable salt is administered on an empty stomach.
  • the estrogen receptor antagonist is fulvestrant
  • the dose of the compound represented by formula (I) or its pharmaceutically acceptable salt is selected from 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, Preferably 100mg, 125mg or 150mg, the frequency of administration is once a day
  • the dose of Fulvestrant is selected from 200mg, 300mg, 400mg, 500mg, 600mg, 700mg, 800mg, preferably 500mg
  • the frequency of administration is once a week or once every two weeks
  • the compound represented by formula (I) or its pharmaceutically acceptable salt is administered on an empty stomach.
  • the estrogen receptor antagonist is fulvestrant
  • the dose of the compound represented by formula (I) or its pharmaceutically acceptable salt is selected from 100 mg, 125 mg or 150 mg, and the administration frequency is one day One time
  • the dose of Fulvestrant is 500 mg
  • the frequency of administration is once a week or once every two weeks, wherein the compound represented by formula (I) or its pharmaceutically acceptable salt is administered on an empty stomach.
  • the estrogen receptor antagonist is fulvestrant
  • the dose of the compound represented by formula (I) or its pharmaceutically acceptable salt is 100 mg
  • the frequency of administration is once a day.
  • the dose of the group is 500 mg
  • the frequency of administration is once a week or once every two weeks, wherein the compound represented by formula (I) or its pharmaceutically acceptable salt is administered on an empty stomach.
  • the estrogen receptor antagonist is fulvestrant
  • the dose of the compound represented by formula (I) or its pharmaceutically acceptable salt is 125 mg
  • the frequency of administration is once a day.
  • the dosage of is 500mg
  • the frequency of administration is once a week or once every two weeks, wherein the compound represented by formula (I) or its pharmaceutically acceptable salt is administered on an empty stomach.
  • the estrogen receptor antagonist is fulvestrant
  • the dose of the compound represented by formula (I) or its pharmaceutically acceptable salt is 150 mg
  • the frequency of administration is once a day.
  • the dose of the group is 500 mg
  • the frequency of administration is once a week or once every two weeks, wherein the compound represented by formula (I) or its pharmaceutically acceptable salt is administered on an empty stomach.
  • the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is administered on an empty stomach in the morning.
  • a pharmaceutical composition containing a compound represented by formula (I) or a pharmaceutically acceptable salt thereof in combination with anastrozole is more effective than the compound represented by formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating tumors
  • the combination of salt and letrozole can be expressed as objective response rate (ORR) or progression-free survival (PFS) or duration of response (DoR) or disease control rate (DCR) or overall survival (OS) after medication
  • ORR objective response rate
  • PFS progression-free survival
  • DoR duration of response
  • DCR disease control rate
  • OS overall survival
  • Treatment includes prophylactic and therapeutic treatments (including but not limited to alleviation, cure, symptom relief, symptom reduction) and delay in progression of tumor diseases or disorders.
  • “Pharmaceutical composition” refers to a mixture containing at least one therapeutic agent and at least one pharmaceutically acceptable excipient.
  • the pharmaceutically acceptable excipient includes, but is not limited to, diluents, binders, disintegrants, and lubricants.
  • the diluent includes but is not limited to mannitol, dextrose microcrystalline cellulose, pregelatinized starch, dicalcium phosphate, lactose, sorbitol;
  • the binder may be selected from starch, carboxymethyl One or more of sodium cellulose, polyvinylpyrrolidone, pregelatinized starch, hypromellose and hydroxypropyl cellulose;
  • the disintegrant can be selected from croscarmellose sodium, One or more of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose and crospovidone;
  • the lubricant can be selected from talc, magnesium stearate, zinc stearate, and behenate One or more of acid glycerides.
  • the pharmaceutical composition containing the compound represented by formula (I) or its pharmaceutically acceptable salt and the pharmaceutical composition containing anastrozole in the present disclosure can also be administered in parenteral form, and the pharmaceutical composition may contain a pharmaceutical Acceptable excipients, which are selected from one or more of preservatives, stabilizers, solubilizers, emulsifiers, osmotic pressure regulators, and buffers.
  • a pharmaceutical Acceptable excipients which are selected from one or more of preservatives, stabilizers, solubilizers, emulsifiers, osmotic pressure regulators, and buffers.
  • “Therapeutically effective” preferably refers to an amount of a therapeutic agent that is therapeutically effective or, more broadly, also prophylactically effective in combating tumor progression.
  • the "combination" described in the present disclosure is a mode of administration, which refers to the administration of at least one dose of a pharmaceutical composition containing a compound represented by formula (I) or a pharmaceutically acceptable salt thereof and anatrex within a certain period of time Azoles, two of which show pharmacological effects.
  • the said time period can be within one administration cycle, preferably within 24 hours.
  • the pharmaceutical composition containing the compound represented by formula (I) or a pharmaceutically acceptable salt thereof and anastrozole can be administered simultaneously or sequentially. This period includes treatments in which a pharmaceutical composition containing a compound represented by formula (I) or a pharmaceutically acceptable salt thereof and anastrozole are administered through the same route of administration or different routes of administration.
  • the “ Cmax” mentioned in the present disclosure refers to the peak concentration of a pharmacokinetic drug in the blood. This parameter is an important indicator for evaluating the rate of drug absorption and reflects the exposure characteristics of the drug in the body.
  • the AUC mentioned in the present disclosure refers to the average AUC 0-24 of the patient after a single administration or multiple administrations reach a steady state, preferably the average AUC 0-24 of the patient after multiple administrations reach a steady state (ie AUC ss ).
  • a "high-fat meal” is a high-fat (providing about 50% of the calories in food), high-calorie (about 800-1000 kcal) meals, in which protein provides about 150 kcal and carbohydrates provides about 250 kcal. Fat provides about 500-600 kilocalories.
  • “Fasting” means that the interval between administration and eating is at least 0.5 hours, or at least 1 hour, or at least 2 hours, or at least 3 hours, or at least 4 hours, or at least 5 hours, or at least 6 hours, or at least 7 hours, or At least 8 hours, specifically at least 0.5 hours before a meal, or at least 1 hour before a meal, or at least 1.5 hours before a meal, or at least 2 hours before a meal, or at least 2 hours after a meal, or at least 3 hours after a meal, or a meal At least 4 hours later, preferably at least 0.5 hour before breakfast, or at least 1 hour before breakfast, or at least 1.5 hours before breakfast, or at least 2 hours before breakfast.
  • the criteria for judging the severity of adverse events in this disclosure refer to the NCI-CTC AE 4.03 version of the grading standard for adverse drug events. If there are adverse events that are not listed in the NCI-CTC AE 4.03 version table, the following standards can be referred to:
  • Figure 1 Mean (Mean ⁇ SD) plasma concentration-time curve of compound isethionate of formula (I) (PK concentration analysis population);
  • FIG. Box and whisker diagram of the main PK parameters of the compound isethionate represented by formula (I) (PK parameter analysis population).
  • Example 1 The compound isethionate of formula (I) (drug A) combined with letrozole or anastrozole or fulvestrant treats stage Ib/II of hormone receptor-positive and HER2-negative advanced breast cancer Clinical research
  • Drug A prepared according to the method provided by WO2016124067A, the specifications are 25mg/tablet, 125mg/tablet;
  • Fulvestrant injection (Fu Shide); manufacturer: Vetter Pharma-Fertist GmbH&Co.KG; dosage form: injection; specification: 5ml: 0.25mg.
  • AE adverse events
  • SAE severe adverse events
  • Pharmacokinetic parameters of drug A combined with letrozole or anastrozole or fulvestrant AUC, T max , t 1/2 and C max, etc.;
  • PFS Progression Free Survival
  • DCR Disease Control Rate
  • AE adverse events
  • SAE severe adverse events
  • Cohort 1 Drug A 150mg qd(d1-21) + Letrozole 2.5mg qd or Anastrozole 1mg qd;
  • Cohort 3 Drug A 150mg qd(d1-21) + Fulvestrant 500mg intramuscular injection (first cycle: d1 and d15, followed by cycle d1);
  • Cohort 4 Drug A dose to be determined qd (d1-21) + Fulvestrant 500 mg intramuscular injection (first cycle: d1 and d15, followed by cycle d1).
  • Every 28 days is a treatment cycle: the first 3 weeks of drug A (day 1 to day 21), the next week (day 22 to day 28) rest (no drug); letrozole or anastrozole Take the medicine once a day. Fulvestrant was administered on the 1st and 15th days of the first cycle, followed by the first day of each cycle.
  • the recommended dose of phase II study is selected to carry out further efficacy and safety evaluation in patients with advanced breast cancer:
  • Drug A (RP2D, d1-21) + letrozole 2.5 mg qd or anastrozole 1 mg qd;
  • the screening period does not exceed 28 days.
  • qualified subjects enter the research treatment period (every 28 days is a treatment cycle), and conduct research treatment and visits in accordance with the protocol.
  • tumor imaging evaluation was performed every 2 cycles (8 weeks ⁇ 7 days); thereafter, tumor imaging evaluation was performed every 4 cycles (16 weeks ⁇ 7 days).
  • Subjects should visit the research center at the end of treatment/withdraw from the study, and complete the corresponding safety inspection and imaging evaluation; and visit the research center 30 days after the last treatment to complete the corresponding safety assessment.
  • cohort 1 In the first phase, according to the cohort (dose level) the subject belongs to, they will be taken in the following manner: cohort 1, drug A 150 mg, orally, once a day; cohort 2, drug A 125 mg, orally, once a day; cohort 3, Drug A 150mg, orally, once a day; Cohort 4, drug A dose to be determined, orally, once a day. Every 28 days is a treatment cycle, take drug A continuously from day 1 to day 21 (once a day), and rest from day 22 to day 28 (drug A)
  • the recommended dose of phase II study (RP2D) is used for administration.
  • Drug A (RP2D) is taken orally once a day, every 28 days is a treatment cycle, from day 1 to Continue to take the medicine on the 21st day (once a day), and rest from the 22nd to the 28th day (no medicine).
  • Letrozole 2.5mg or Anastrozole 1mg, orally, once a day, continuous taking, every 28 days as a treatment cycle. It is recommended to take medicine A and letrozole or anastrozole on an empty stomach at 8:00 every morning, and take it with warm water.
  • Subjects should continue to receive research treatment until the disease progresses, toxicity becomes intolerable, the subject actively requests to terminate the research treatment or withdraw from the study, or the researcher determines that the subject needs to withdraw from the study.
  • menopause is defined as:
  • Age ⁇ 60 years; or age ⁇ 60 natural postmenopausal state (defined as the spontaneous cessation of regular menstruation for at least 12 consecutive months without other pathological or physiological reasons).
  • pre-menopausal or perimenopausal female patients can also Enrolled, but must be willing to receive LHRH agonist treatment during the study period, and received LHRH agonist administration at least 14 days before enrollment in the study.
  • the Eastern Cooperative Oncology Group (ECOG) physical fitness score is 0-1.
  • Hb Hemoglobin
  • AST/SGOT Aspartate aminotransferase
  • ALT/SGPT alanine aminotransferase
  • Participants in cohort 1 and cohort 2 must meet all the following enrollment criteria to be eligible to enter this trial.
  • the patient needs to meet one of the following criteria:
  • Cohort 1 17 patients were enrolled with the drug A150mg, of which 13 were combined with letrozole and 4 were combined with anastrozole.
  • Cohort 2 Drug A 125mg was enrolled in 16 cases, of which 15 cases were combined with letrozole and 1 case was combined with anastrozole. Thirty-two subjects (cohort 1: 16 cases in the 150 mg dose group; cohort 2: 16 cases in the 125 mg dose group) underwent at least one efficacy evaluation, and 33 subjects completed at least the first cycle of safety evaluation.
  • Efficacy evaluation results (see Table 1 below): A total of 16 subjects in the 150mg dose group of drug A were evaluated at least once, including 7 cases of PR (44%), 1 case of PD (6%), and 8 cases of SD (50%) . A total of 16 subjects in the 125mg dose group of the drug were evaluated for at least one curative effect, including 5 cases of PR (31%) and 11 cases of SD (69%). In cohorts 1 and 2, there were 5 subjects in combination with anastrozole (4 in cohort 1; 1 in cohort 2), and 4 of them were evaluated at the first efficacy evaluation (2 months) after the first administration. The evaluation is PR (see Table 1 for details).
  • the decline in grade 3 and 4 white blood cells was 38.5% and 20% in the two groups, and the decline in platelets was 23.1% and 5.0%, respectively.
  • the 125mg cohort dropped in grade 3 and 4 neutrophils in the two groups, respectively, 73.3 % And 44.4%, the decline in grade 3 and 4 white blood cells was 26.7% and 22.2% in the two groups, and the decline in platelets was 33.3% and 11.1%, respectively.
  • the trends of the two cohorts were consistent, indicating that compound A combined with anastrozole was compared with combined letrozole It has advantages in hematological toxicity and is safer.
  • Cmax and AUC are geometric mean (CV%).
  • cohort 1 further enrolled 9 patients, of which 1 case was combined with letrozole, 8 cases were combined with anastrozole, and cohort 2 further enrolled 5 patients, of which 2 cases were combined with letrozole and 3 cases
  • the PK data of drug A combined with trazole and drug A combined with anastrozole after multiple administrations in the first dosing cycle are compared with the PK data of single drug. The specific results are shown in Table 4 And Table 5.
  • Example 2 The effect of high-fat diet on the pharmacokinetics of Chinese healthy adult subjects after oral administration of isethionate tablets of the compound represented by formula (I)
  • the compound isethionate tablets represented by formula (I) have specifications of 25 mg/tablet and 125 mg/tablet.
  • 24 healthy adult subjects were enrolled in a randomized, open, single-dose, two-period, two-sequence, and cross-controlled trial design.
  • the 24 healthy subjects were randomly divided into two sequence groups, A and B, each The 12 subjects in the sequence group were administered in the sequence of fasting ⁇ after meal or after meal ⁇ fasting, and the washing period was 14 days.
  • Sequence A group On the first day, 150 mg of isethionate tablets of the compound represented by formula (I) were taken on an empty stomach, and PK plasma samples were collected for 0 to 144 hours. On the 15th day, a single dose of the compound of formula (I) was taken after a meal. The compound isethionate tablets 150mg, and PK plasma samples were collected for 0-144 hours.
  • Sequence B group A single dose of 150 mg of isethionate tablets of the compound represented by formula (I) was taken on the 1st day, PK plasma samples were collected for 0 to 144 hours, and a single dose of formula (I) was taken on an empty stomach on the 15th day.
  • the subjects were admitted to the phase I clinical research center at D-1, and the phase I clinical research center provided a standard dinner and fasted overnight for at least 10 hours.
  • D 1 On the morning of the day of administration (D 1), the sequence A group was given 150 mg of isethionate tablets of the compound represented by formula (I) with 240 mL of warm water on an empty stomach in the morning, and blood samples were collected for 0 to 144 hours.
  • the sequence B group a high-fat meal was taken in the morning. After 30 minutes of eating (time from the start of eating), 150 mg of isethionate tablets of the compound of formula (I) were taken with 240 mL of warm water, and blood samples were collected for 0 to 144 hours .
  • Drinking water is forbidden from 1 hour before taking the medicine to 1 hour after taking the medicine (except for the water content of high-fat/high-calorie meals). Drinking water is free at other times. Fasting within 4 hours after taking the medicine, and providing a standard diet for 4 hours and 10 hours after the administration. You can leave the Phase I clinical research center 72 hours after administration.
  • the subjects were admitted to the Phase I clinical research center on D14, and the Phase I clinical research center provided a standard dinner and fasted overnight for at least 10 hours.
  • D15 On the day of administration (D15), in the morning of the B sequence group, 150 mg of isethionate tablets of the compound represented by formula (I) were taken with 240 mL of warm water on an empty stomach, and blood samples were collected for 0-144 hours.
  • a high-fat meal was taken in the morning, 30 minutes after eating (time from the start of eating), 150 mg of isethionate tablets of the compound represented by formula (I) were taken with 240 mL of water, and blood samples were collected for 0-144 hours .
  • Drinking water is forbidden from 1 hour before taking the medicine to 1 hour after taking the medicine (except for the water content of high-fat/high-calorie meals). Drinking water is free at other times. Fasting within 4 hours after taking the medicine, and providing a standard diet for 4 hours and 10 hours after the administration. You can leave the Phase I clinical research center 72 hours after administration.
  • Breakfast requirements are high-fat (providing about 50% of the calories in food), high-calorie (about 800-1000 kcal) breakfast, in which protein provides about 150 kcal, carbohydrate provides about 250 kcal, and fat provides about 500 -600 kilocalories.
  • Statistics include: number of subjects (n), number of BQL (n of BQL), arithmetic mean (Mean), standard deviation (SD), median (Median), minimum (Min), maximum Value (Max), coefficient of variation (%CV), geometric mean (GeoMean), logarithmic standard deviation (SD log) and geometric coefficient of variation (%CV b ).
  • the mean (Mean ⁇ SD) plasma concentration-time curve of the compound isethionate represented by formula (I) is shown in Figure 1; the median plasma concentration-time of the compound isethionate represented by formula (I) The graph is shown in Figure 2.
  • NCA non-compartmental model
  • GeoLSM is the geometrically adjusted mean.
  • the fasting group and the postprandial group had the same plasma concentration-time curve trend, peaking at about 5-6h, but the postprandial group The plasma exposure level was higher than that of the fasting group.
  • the semi-logarithmic drug-time curve shows that after a single oral dose of isethionate tablets of the compound represented by formula (I), the isethionate of the compound represented by formula (I) in plasma shows a linear elimination trend.
  • the geometric coefficient of variation of Cmax, AUC 0-t and AUC 0- ⁇ in the fasting group were 53.20%, 42.44% and 40.58%.
  • the geometric coefficients of variation of Cmax, AUC 0-t and AUC 0- ⁇ of the postprandial group were 38.57%, 28.00% and 27.38%, respectively.
  • the PK parameters showed a decreasing trend of variation after a meal.
  • a high-fat diet has an effect on the exposure level of isethionate of the compound represented by formula (I) in healthy subjects. Eating a high-fat meal can increase the exposure of isethionate of the compound represented by formula (I) Level.
  • the Cmax, AUC 0-t and AUC 0- ⁇ of the compound isethionate of formula (I) after a meal increased by 56.9%, 38.6% and respectively. 37.5%.

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Abstract

本公开涉及一种含CDK4/6抑制剂的组合物与阿那曲唑联合在制备治疗肿瘤疾病的药物中的用途。具体而言，申请涉及的CDK4/6抑制剂为式(I)所示化合物或其可药用盐。

Description

一种含CDK4/6抑制剂的组合物与阿那曲唑联合在制备治疗肿瘤疾病的药物中的用途
本申请要求申请日为2019年1月30日的中国专利申请CN201910089738.2，2019年4月25日的中国专利申请CN201910339438.5，2019年6月14日的中国专利申请CN201910516489.0，2019年7月10日的中国专利申请CN201910620303.6和2019年9月24日的中国专利申请CN201910907616.X的优先权。本申请引用上述中国专利申请的全文。
技术领域
一种含CDK4/6抑制剂的组合物与阿那曲唑联合在制备治疗肿瘤的药物中的用途。
背景技术
乳腺癌是女性最常见的恶性肿瘤之一，全世界每年约有130万新发病例。在我国，乳腺癌发病率占全身各种恶性肿瘤发病率的7％-10％，约占所有女性肿瘤的18％，目前国内患者人数已超过50万，其发病率增长迅速，在一些大城市已经位列女性肿瘤发病谱首位，并且近50％患者出现治疗后复发和转移。近年来，随着肿瘤分子生物学研究的日趋深入，分子靶向治疗在乳腺癌治疗中越来越受到广泛应用并取得了较为显著的疗效，已成为继手术、放疗和化疗三大传统模式之后一种全新的治疗模式，也是当前乳腺癌治疗领域研究的热点。
细胞周期蛋白依赖性激酶(Cyclin-dependent kinase，CDK)是一类丝氨酸/苏氨酸激酶，通过与相应的细胞周期蛋白(Cyclin)形成二聚体，进而磷酸化下游蛋白分子，从而推动细胞周期各时相的有序行进，实现细胞生长和增殖。目前，国外已有多种CDK4/6选择性抑制剂在临床试验阶段或已获批上市，其中包括辉瑞公司的Palbociclib、诺华公司的Ribociclib及礼来公司的Abemaciclib等。
PCT申请WO2014183520公开了一种化学名为6-乙酰基-8-环戊基-5-甲基-2-((5-(哌啶-4-基)吡啶-2-基)氨基)吡啶并[2,3-d]嘧啶-7(8H)-酮，结构式如式(I)所示CDK4/6抑制剂，具有显著的CDK4/6的抑制活性和高度选择性。
Figure PCTCN2020073815-appb-000001
PCT申请WO2016124067A公开了上述式(I)所示化合物的羟乙基磺酸盐及其制备 方法。现有技术CN107137408A也对式(I)所示化合物以及其药学上可接受的盐与芳香激酶抑制剂的联用进行了研究。一项针对于来曲唑和阿那曲唑单药的药动学研究表明：
针对于绝经后转移性乳腺癌女性，来曲唑(2.5mg每日一次)相比于阿那曲唑(每日1mg)是一种更有效的全身芳构化和血浆雌激素水平抑制因子(PMID：11821457)。另一项关于晚期乳腺癌二线内分泌治疗的来曲唑与阿那曲唑对比的开放随机试验得出了如此结论：支持在先的关于来曲唑的芳香酶抑制活性更高的描述，作为二线激素治疗，晚期乳腺癌对来曲唑的反应比对阿那曲唑的反应更强(PMID：14556923)。
European Journal of Cancer 39(2003)2318–2327涉及一项二线内分泌治疗晚期乳腺癌的开放性随机试验，具体为芳香酶抑制剂来曲唑和阿那曲唑的比较，摘要部分公开：在总缓解率(ORR)方面，来曲唑显著地优于阿那曲唑。
发明内容
本公开提供一种含式(I)所示化合物或其可药用盐的药物组合物与阿那曲唑联合在制备治疗肿瘤疾病的药物中的用途，
Figure PCTCN2020073815-appb-000002
本公开中所述的肿瘤疾病选自肉瘤、淋巴瘤、肺癌、支气管癌、前列腺癌、胰腺癌、胃肠癌、结肠癌、直肠癌、结直肠腺瘤、甲状腺癌、肝癌、肝内胆管癌、肝细胞癌、肾上腺癌、胃癌、胃肿瘤、胶质瘤、成胶质细胞瘤、子宫内膜癌、黑素瘤、肾癌、肾盂癌、膀胱癌、子宫体癌、宫颈癌、阴道癌、卵巢癌、多发性骨髓瘤、食管癌、白血病、急性髓细胞性白血病、慢性髓细胞性白血病、淋巴细胞性白血病、骨髓性白血病、脑肿瘤、脑癌、口腔及咽部癌、喉癌、小肠癌、非霍奇金淋巴瘤、黑素瘤、结肠绒毛腺瘤、赘生物、上皮癌、乳腺癌、基底细胞癌、鳞状细胞癌、光化性角化病、肿瘤疾病、颈部或头部肿瘤、原发性血小板增多症、髓样化生性骨髓纤维化和巨球蛋白血症中的一种或多种，优选乳腺癌。
本公开中所述的乳腺癌优选为激素受体阳性(HR+)、和/或人表皮生长因子受体2阴性(HER2-)的乳腺癌；更优选为上述表型的局部晚期或转移性乳腺癌。
本公开中，式(I)所示化合物的可药用盐选自盐酸盐、磷酸盐、磷酸氢盐、硫酸盐、硫酸氢盐、亚硫酸盐、乙酸盐、草酸盐、丙二酸盐、戊酸盐、谷氨酸盐、油酸盐、棕榈酸盐、硬脂酸盐、月桂酸盐、硼酸盐、对甲苯磺酸盐、甲磺酸盐、羟乙基磺酸盐、马来 酸盐、苹果酸盐、酒石酸盐、苯甲酸盐、双羟萘酸盐、水杨酸盐、香草酸盐、扁桃酸盐、琥珀酸盐、葡萄糖酸盐、乳糖酸盐和月桂基磺酸盐中的一种或多种，优选羟乙基磺酸盐，其结构如式(II)所示，
Figure PCTCN2020073815-appb-000003
在本公开的一些实施方案中，每日服用的含式(I)所示化合物或其可药用盐的药物组合物中式(I)所示化合物或其可药用盐的量为1-500mg，优选50-200mg，更优选100-150mg。
在本公开的一些优选的实施方案中，每日服用的含式(I)所示化合物或其可药用盐的药物组合物中式(I)所示化合物或其可药用盐的量为50mg、75mg、100mg、125mg、150mg、175mg，优选100mg、125mg或150mg。
在本公开的优选的实施方案中，含式(I)所示化合物或其可药用盐的药物组合物的给药频率为一日一次、一日两次，优选一日一次。
在本公开的一些实施方案中，阿那曲唑的每日剂量选自0.1-50mg，优选1-25mg，最优选1-10mg。
在本公开优选的实施方案中，阿那曲唑每日剂量选自0.5mg、1.0mg、1.5mg、2.0mg、2.5mg、3.0mg、3.5mg、4.0mg、4.5mg、5.0mg，优选1.0mg。
在本公开的优选的实施方案中，阿那曲唑的给药频率为一日一次、一日两次，优选一日一次。
在本公开优选的实施方案中，每日服用的含式(I)所示化合物或其可药用盐的药物组合物中式(I)所示化合物或其可药用盐的量为50mg、75mg、100mg、125mg、150mg、175mg，含式(I)所示化合物或其可药用盐的药物组合物一日一次给药、一日两次给药，优选一日一次给药，阿那曲唑每日剂量选自0.5mg、1.0mg、1.5mg、2.0mg、2.5mg、3.0mg、3.5mg、4.0mg、4.5mg、5.0mg，优选1.0mg，阿那曲唑的给药频率一日一次、一日两次，优选一日一次。
本公开优选的实施方案中，每日服用的含式(I)所示化合物或其可药用盐的药物组合物中式(I)所示化合物或其可药用盐的量为100mg、125mg、150mg，含式(I)所示化合物或其可药用盐的药物组合物一日一次给药，阿那曲唑每日剂量为1.0mg，阿那曲唑的给药频率为一日一次。
在本公开的一个实施方案中，每日服用的含式(I)所示化合物或其可药用盐的药物组合物中式(I)所示化合物或其可药用盐的量为100mg，含式(I)所示化合物或其可药用盐的组合物一日一次给药，阿那曲唑每日剂量为1.0mg，阿那曲唑的给药频率为一日一次。
在本公开的一个实施方案中，每日服用的含式(I)所示化合物或其可药用盐的药物组合物中式(I)所示化合物或其可药用盐的量为125mg，含式(I)所示化合物或其可药用盐的药物组合物一日一次给药，阿那曲唑每日剂量为1.0mg，阿那曲唑的给药频率为一日一次。
在本公开的一个实施方案中，每日服用的含式(I)所示化合物或其可药用盐的药物组合物中式(I)所示化合物或其可药用盐的量为150mg，含式(I)所示化合物或其可药用盐的药物组合物一日一次给药，阿那曲唑每日剂量为1.0mg，阿那曲唑的给药频率为一日一次。
本公开中含式(I)所示化合物或其可药用盐的药物组合物可进一步含有至少一种药学上可接受的赋形剂，所述赋形剂选自稀释剂、粘合剂、崩解剂、润滑剂。
本公开中含式(I)所示化合物或其可药用盐的药物组合物中稀释剂的含量可为相对于药物组合物总重的1％-99％，优选5％-95％(质量百分比)。
本公开中含式(I)所示化合物或其可药用盐的药物组合物中润滑剂的含量可为相对于药物组合物总重的0.01％-25％，优选0.1％-10％(质量百分比)。
本公开中阿那曲唑可以药物组合物的形式给药，具体的阿那曲唑以适于通过肠部施用或者胃肠外给药的药物组合物的形式给药，例如片剂、胶囊剂、栓剂、安瓿瓶、注射溶液或者注射混悬液。阿那曲唑能够以例如市售形式(如
Figure PCTCN2020073815-appb-000004
)施用。
本公开的优选的实施例方案中，含式(I)所示化合物或其可药用盐的药物组合物与阿那曲唑均口服给药。
在一些实施方案中，本公开提供的含式(I)所示化合物或其可药用盐的药物组合物与阿那曲唑联合在制备治疗肿瘤的药物中的用途，其中阿那曲唑增加了式(I)所示化合物或其可药用盐在患者体内的AUC。
在一些实施方案中，本公开提供的含式(I)所示化合物或其可药用盐的药物组合物与阿那曲唑联合在制备治疗肿瘤的药物中的用途，其中阿那曲唑降低了患者不良反应的发生率。其中，所述的不良反应优选血液学毒性，所述的血液学毒性可选自中性粒细胞下降、白细胞下降和/或血小板下降；优选3、4级中性粒细胞下降和/或3、4级白细胞下降。
优选的实施方案中，本公开中所述肿瘤疾病的患者为人类。
另一方面，本公开提供一种阿那曲唑增加式(I)所示化合物或其可药用盐在患者体内的AUC的方法，包括向所述患者施用治疗有效量的式(I)所示化合物或其可药用盐和治疗有效量的阿那曲唑，所述患者优选为人类。
本公开中所述“增加式(I)所示化合物或其可药用盐在患者体内的AUC”是指相对于单独施用同等剂量式(I)所示化合物或其可药用盐在患者体内产生的AUC，和/或相对于施用同等剂量式(I)所示化合物或其可药用盐与来曲唑的联用在患者体内产生的AUC。“降低患者不良反应的发生率”也是指式(I)所示化合物联合阿那曲唑相对于单独施用同等剂量式(I)所示化合物和/或相对于施用同等剂量式(I)所示化合物或其可药用盐与来曲唑的联用。
在一些实施方案中，通过向患者施用有效量式(I)所示化合物或其可药用盐和有效量阿那曲唑，相对于单独施用同等剂量式(I)所示化合物或其可药用盐，在患者体内产生的AUC增加大于18％，可选地，AUC增加20％-150％；可选地，AUC增加25％-100％；可选地，AUC增加30％-85％；可选地，AUC增加35％-80％；可选地，AUC增加40％-80％；优选地，AUC增加45％-80％；优选地，AUC增加50％-80％；优选地，AUC增加55％-80％；优选地，AUC增加60％-80％；具体地，式(I)所示化合物或其可药用盐AUC增加约18％、19％、20％、21％、22％、23％、24％、25％、26％、27％、28％、29％、30％、31％、32％、33％、34％、35％、36％、37％、38％、39％、40％、41％、42％、43％、44％、45％、46％、47％、48％、49％、50％、51％、52％、53％、54％、55％、56％、57％、58％、59％、60％、61％、62％、63％、64％、65％、66％、67％、68％、69％、70％、71％、72％、73％、74％、75％、76％、77％、78％、79％、80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％、100％、101％、102％、103％、104％、105％、106％、107％、108％、109％、110％、111％、112％、113％、114％、115％、116％、117％、118％、119％、120％、121％、122％、123％、124％、125％、126％、127％、128％、129％、130％、131％、132％、133％、134％、135％、136％、137％、138％、139％、140％、141％、142％、143％、144％、145％、146％、147％、148％、149％、150％。
在一些实施方案中，通过向患者施用有效量式(I)所示化合物或其可药用盐和有效量阿那曲唑，相比于施用同等剂量式(I)所示化合物或其可药用盐与来曲唑的联用，患者体内式(I)所示化合物或其可药用盐的AUC的比大于1:1，可选地，AUC比选自1～10:1；可选地，AUC比选自1～5:1；可选地，AUC比选自1～4:1；可选地，AUC比选自1～3:1； 优选地，AUC比选自1～2:1；优选地，AUC比选自1～1.5:1，具体地，AUC比可以是1.01:1、1.02:1、1.03:1、1.04:1、1.05:1、1.06:1、1.07:1、1.08:1、1.09:1、1.10:1、1.11:1、1.12:1、1.13:1、1.14:1、1.15:1、1.16:1、1.17:1、1.18:1、1.19:1、1.20:1、1.21:1、1.22:1、1.23:1、1.24:1、1.25:1、1.26:1、1.27:1、1.28:1、1.29:1、1.30:1、1.31:1、1.32:1、1.33:1、1.34:1、1.35:1、1.36:1、1.37:1、1.38:1、1.39:1、1.40:1、1.41:1、1.42:1、1.43:1、1.44:1、1.45:1、1.46:1、1.47:1、1.48:1、1.49:1、1.50:1、1.51:1、1.52:1、1.53:1、1.54:1、1.55:1、1.56:1、1.57:1、1.58:1、1.59:1、1.60:1、1.61:1、1.62:1、1.63:1、1.64:1、1.65:1、1.66:1、1.67:1、1.68:1、1.69:1、1.70:1、1.71:1、1.72:1、1.73:1、1.74:1、1.75:1、1.76:1、1.77:1、1.78:1、1.79:1、1.80:1、1.81:1、1.82:1、1.83:1、1.84:1、1.85:1、1.86:1、1.87:1、1.88:1、1.89:1、1.90:1、1.91:1、1.92:1、1.93:1、1.94:1、1.95:1、1.96:1、1.97:1、1.98:1、1.99:1、2.00:1。
在一些实施方案中，通过向患者施用有效量式(I)所示化合物或其可药用盐和有效量阿那曲唑，式(I)所示化合物或其可药用盐在患者体内提供2800-8000ng*h/mL的AUC；可选地，式(I)所示化合物或其可药用盐在患者体内提供2800-7800ng*h/mL的AUC；可选地，式(I)所示化合物或其可药用盐在患者体内提供3000-7600ng*h/mL的AUC；可选地，式(I)所示化合物或其可药用盐在患者体内提供3000-7400ng*h/mL的AUC；可选地，式(I)所示化合物或其可药用盐在患者体内提供3000-7200ng*h/mL的AUC；可选地，式(I)所示化合物或其可药用盐在患者体内提供3000-7000ng*h/mL的AUC；可选地，式(I)所示化合物或其可药用盐在患者体内提供3000-6800ng*h/mL的AUC；可选地，式(I)所示化合物或其可药用盐在患者体内提供3000-6600ng*h/mL的AUC；可选地，式(I)所示化合物或其可药用盐在患者体内提供3000-6400ng*h/mL的AUC；可选地，式(I)所示化合物或其可药用盐在患者体内提供3000-6200ng*h/mL的AUC；可选地，式(I)所示化合物或其可药用盐在患者体内提供3000-6000ng*h/mL的AUC；可选地，式(I)所示化合物或其可药用盐在患者体内提供3000-5800ng*h/mL的AUC；可选地，式(I)所示化合物或其可药用盐在患者体内提供3000-5600ng*h/mL的AUC；可选地，式(I)所示化合物或其可药用盐在患者体内提供3000-5400ng*h/mL的AUC；可选地，式(I)所示化合物或其可药用盐在患者体内提供3000-5200ng*h/mL的AUC；可选地，式(I)所示化合物或其可药用盐在患者体内提供3000-5000ng*h/mL的AUC；优选地，式(I)所示化合物或其可药用盐在患者体内提供3000-4800ng*h/mL的AUC；优选地，式(I)所示化合物或其可药用盐在患者体内提供3200-4600ng*h/mL的AUC；优选地，式(I)所示化合物或其可药用盐在患者体内提供3400-4400ng*h/mL的AUC； 优选地，式(I)所示化合物或其可药用盐在患者体内提供3600-4200ng*h/mL的AUC。
本公开提供的阿那曲唑增加式(I)所示化合物或其可药用盐在患者体内的AUC的方法，任选同时增加式(I)所示化合物或其可药用盐在患者体内的C max。
在可选实施方案中，通过向患者施用有效量式(I)所示化合物或其可药用盐和有效量阿那曲唑，相对于单独施用同等剂量式(I)所示化合物或其可药用盐，患者体内式(I)所示化合物或其可药用盐的C max的比大于1:1，可选地，C max比选自1～10:1；可选地，C max比选自1～5:1；可选地，C max比选自1～4:1；可选地，C max比选自1～3:1；优选地，C max比选自1～2:1；优选地，C max比选自1～1.5:1。具体的C max比可以是1.02:1、1.04:1、1.06:1、1.08:1、1.10:1、1.12:1、1.14:1、1.16:1、1.18:1、1.20:1、1.22:1、1.24:1、1.26:1、1.28:1、1.30:1、1.32:1、1.34:1、1.36:1、1.38:1、1.40:1、1.42:1、1.44:1、1.46:1、1.48:1、1.50:1、1.52:1、1.54:1、1.56:1、1.58:1、1.60:1、1.62:1、1.64:1、1.66:1、1.68:1、1.70:1、1.72:1、1.74:1、1.76:1、1.78:1、1.80:1、1.82:1、1.84:1、1.86:1、1.88:1、1.90:1、1.92:1、1.94:1、1.96:1、1.98:1、2.00:1。
本公开提供的阿那曲唑增加式(I)所示化合物或其可药用盐在患者体内的AUC的方法，可包括向所述患者施用1-500mg/天的式(I)所示化合物或其可药用盐，优选50-200mg/天的式(I)所示化合物或其可药用盐，更优选100-150mg/天的式(I)所示化合物或其可药用盐，以及0.1-50mg/天的阿那曲唑，优选1-25mg/天的阿那曲唑，最优选1-10mg/天的阿那曲唑。
可选的实施方案中，每日施用的式(I)所示化合物或其可药用盐的量为50mg、75mg、100mg、125mg、150mg、175mg，优选100mg、125mg或150mg。
可选的实施方案中，式(I)所示化合物或其可药用盐的药物组合物的给药频率为一日一次、一日两次，优选一日一次。
可选的实施方案中，阿那曲唑每日剂量选自0.5mg、1.0mg、1.5mg、2.0mg、2.5mg、3.0mg、3.5mg、4.0mg、4.5mg、5.0mg，优选1.0mg。
可选的实施方案中，阿那曲唑的给药频率为一日一次、一日两次，优选一日一次。
可选的实施方案中，每日施用的式(I)所示化合物或其可药用盐的量为50mg、75mg、100mg、125mg、150mg、175mg，式(I)所示化合物或其可药用盐给药频率为一日一次、一日两次，优选一日一次，阿那曲唑每日剂量选自0.5mg、1.0mg、1.5mg、2.0mg、2.5mg、3.0mg、3.5mg、4.0mg、4.5mg、5.0mg，优选1.0mg，给药频率一日一次、一日两次，优选一日一次。
优选的实施方案中，每日施用的式(I)所示化合物或其可药用盐的量为100mg、125 mg、150mg，给药频率为一日一次，阿那曲唑每日剂量为1.0mg，给药频率为一日一次。
优选的实施方案中，每日施用的式(I)所示化合物或其可药用盐的量为150mg，给药频率为一日一次，阿那曲唑每日剂量为1.0mg，给药频率为一日一次。
优选的实施方案中，每日施用的式(I)所示化合物或其可药用盐的量为175mg，给药频率为一日一次，阿那曲唑每日剂量为1.0mg，给药频率为一日一次。
在特别优选的实施方案中，式(I)所示化合物的可药用盐为羟乙基磺酸盐。
本公开提供的阿那曲唑增加式(I)所示化合物或其可药用盐在患者体内的AUC的方法，其中式(I)所示化合物或其可药用盐可以药物组合物形式给药，具体地，式(I)所示化合物或其可药用盐的药物组合物可进一步含有至少一种药学上可接受的赋形剂，所述赋形剂选自稀释剂、粘合剂、崩解剂、润滑剂。
优选地，式(I)所示化合物或其可药用盐的药物组合物中稀释剂的含量为相对于组合物总重的1％-99％，优选5％-95％(质量百分比)，润滑剂的含量为相对于组合物总重的0.01％-25％，优选0.1％-10％(质量百分比)。
在具体的实施方案中，阿那曲唑以适于通过肠部施用或者胃肠外给药的药物组合物的形式给药，例如片剂、胶囊剂、栓剂、安瓿瓶、注射溶液或者注射混悬液。阿那曲唑能够以例如市售形式(如
Figure PCTCN2020073815-appb-000005
)施用。
另一方面，本公开提供一种治疗肿瘤疾病的方法，包括施与患者治疗有效量的式(I)所示化合物或其可药用盐及治疗有效量的阿那曲唑。
本公开提供的治疗肿瘤疾病的方法，可包括施与患者治疗有效量的式(I)所示化合物或其可药用盐及治疗有效量的阿那曲唑，其中阿那曲唑增加了式(I)所示化合物或其可药用盐在患者体内的AUC。在一个可选的实施方案中，其中阿那曲唑减少了式(I)所示化合物的血液学毒性，所述的血液学毒性可选自中性粒细胞下降、白细胞下降和/或血小板下降；优选3、4级中性粒细胞下降和/或3、4级白细胞下降。
另一方面，本公开提供了一种降低患者不良反应的方法，所述不良反应优选血液学毒性，所述的血液学毒性可选自中性粒细胞下降、白细胞下降和/或血小板下降；优选3、4级中性粒细胞下降和/或3、4级白细胞下降；所述方法可包括施与患者治疗有效量的式(I)所示化合物或其可药用盐及治疗有效量的阿那曲唑，所述患者可为肿瘤疾病患者。
所述的肿瘤疾病可选自肉瘤、淋巴瘤、肺癌、支气管癌、前列腺癌、胰腺癌、胃肠癌、结肠癌、直肠癌、结直肠腺瘤、甲状腺癌、肝癌、肝内胆管癌、肝细胞癌、肾上腺癌、胃癌、胃肿瘤、胶质瘤、成胶质细胞瘤、子宫内膜癌、黑素瘤、肾癌、肾盂癌、膀胱癌、子宫体癌、宫颈癌、阴道癌、卵巢癌、多发性骨髓瘤、食管癌、白血病、急性髓 细胞性白血病、慢性髓细胞性白血病、淋巴细胞性白血病、骨髓性白血病、脑肿瘤、脑癌、口腔及咽部癌、喉癌、小肠癌、非霍奇金淋巴瘤、黑素瘤、结肠绒毛腺瘤、赘生物、上皮癌、乳腺癌、基底细胞癌、鳞状细胞癌、光化性角化病、肿瘤疾病、颈部或头部肿瘤、原发性血小板增多症、髓样化生性骨髓纤维化和巨球蛋白血症中的一种或多种，优选乳腺癌。
所述的乳腺癌优选为激素受体阳性(HR+)、和/或人表皮生长因子受体2阴性(HER2-)的乳腺癌；更优选为上述表型的局部晚期或转移性乳腺癌。
在可选实施方案中，本公开提供的治疗肿瘤的方法，包括向所述患者施用1-500mg/天的式(I)所示化合物或其可药用盐，优选50-200mg/天的式(I)所示化合物或其可药用盐，更优选100-150mg/天的式(I)所示化合物或其可药用盐，以及0.1-50mg/天的阿那曲唑，优选1-25mg/天的阿那曲唑，最优选1-10mg/天的阿那曲唑。
可选的实施方案中，每日施用的式(I)所示化合物或其可药用盐的量为50mg、75mg、100mg、125mg、150mg、175mg，优选100mg、125mg或150mg。
可选的实施方案中，式(I)所示化合物或其可药用盐的给药频率为一日一次、一日两次，优选一日一次。
可选的实施方案中，阿那曲唑每日剂量选自0.5mg、1.0mg、1.5mg、2.0mg、2.5mg、3.0mg、3.5mg、4.0mg、4.5mg、5.0mg，优选1.0mg。
可选的实施方案中，阿那曲唑的给药频率为一日一次、一日两次，优选一日一次。
可选的实施方案中，每日施用的式(I)所示化合物或其可药用盐的量为50mg、75mg、100mg、125mg、150mg、175mg，式(I)所示化合物或其可药用盐给药频率为一日一次、一日两次，优选一日一次，阿那曲唑每日剂量选自0.5mg、1.0mg、1.5mg、2.0mg、2.5mg、3.0mg、3.5mg、4.0mg、4.5mg、5.0mg，优选1.0mg，给药频率一日一次、一日两次，优选一日一次。
优选的实施式中，每日施用的式(I)所示化合物或其可药用盐的量为100mg、125mg、150mg，给药频率为一日一次，阿那曲唑每日剂量为1.0mg，给药频率为一日一次。
优选的实施方案中，每日施用的式(I)所示化合物或其可药用盐的量为150mg，给药频率为一日一次，阿那曲唑每日剂量为1.0mg，给药频率为一日一次。
优选的实施方案中，每日施用的式(I)所示化合物或其可药用盐的量为175mg，给药频率为一日一次，阿那曲唑每日剂量为1.0mg，给药频率为一日一次。
本公开提供的治疗肿瘤的方法，可以28天为一个给药周期，其中式(I)所示化合物或其可药用盐第1-21天给药，后停药7天，阿那曲唑在28天的治疗周期中每天给药。
本公开提供一种治疗人类患者局部复发或转移性乳腺癌的方法，包括口服给与患者有效量的式(I)所示化合物或其可药用盐，和有效量的阿那曲唑，所述患者为绝经后或绝经前或围绝经期女性患者或者经卵巢切除的绝经前女性，
Figure PCTCN2020073815-appb-000006
可选的实施方案中，本公开提供的治疗人类患者局部复发或转移性乳腺癌的方法，每28天为一个治疗周期，其中式(I)所示化合物或其可药用盐在第1天至第21天连续服用，阿那曲唑在28天的治疗周期中每天给药。
可选的实施方案中，本公开提供的治疗人类患者局部复发或转移性乳腺癌的方法，患者服用式(I)所示化合物或其可药用盐时为空腹。
可选的实施方案中，本公开提供的治疗人类患者局部复发或转移性乳腺癌的方法，所述乳腺癌为激素受体阳性(HR+)、和/或人表皮生长因子受体2阴性(HER2-)的乳腺癌。
可选的实施方案中，本公开提供的治疗人类患者局部复发或转移性乳腺癌的方法，所述式(I)所示化合物或其可药用盐的每日剂量为100-150mg。
可选的实施方案中，本公开提供的治疗人类患者局部复发或转移性乳腺癌的方法，所述式(I)所示化合物或其可药用盐的每日剂量为100mg，125mg或150mg。
可选的实施方案中，本公开提供的治疗人类患者局部复发或转移性乳腺癌的方法，所述阿那曲唑的每日剂量为0.1-10mg。
可选的实施方案中，本公开提供的治疗人类患者局部复发或转移性乳腺癌的方法，所述阿那曲唑的每日剂量为0.5mg，1mg或1.5mg。
可选的实施方案中，本公开提供的治疗人类患者局部复发或转移性乳腺癌的方法，所述式(I)所示化合物或其可药用盐早晨给药。
可选的实施方案中，本公开提供的治疗人类患者局部复发或转移性乳腺癌的方法，所述式(I)所示化合物可药用盐为羟乙基磺酸盐。
另一方面本公开提供一种治疗乳腺癌的方法，给患者施用150mg/天的式(I)所示化合物或其可药用盐及0.1-50mg/天的阿那曲唑，监测患者不良反应(AE等级)，如果出现3/4级AE，则给予患者125mg/天或100mg/天剂量的式(I)所示化合物或其可药用盐。
优选地，本公开提供的治疗乳腺癌的方法，给患者施用150mg/天的式(I)所示化 合物或其可药用盐及1mg/天的阿那曲唑，监测患者不良反应(AE等级)，如果患者出现3/4级AE，则给予患者125mg/天或100mg/天剂量的式(I)所示化合物或其可药用盐。
优选地，本公开提供的治疗乳腺癌的方法，给患者施用150mg/天的式(I)所示化合物或其可药用盐，口服一日一次给药，给患者施用1mg/天的阿那曲唑，口服一日一次给药，监测患者不良反应(AE等级)，如果患者出现3/4级AE，则给予患者125mg/天或100mg/天剂量的式(I)所示化合物或其可药用盐。
由于阿那曲唑增加了式(I)所示化合物或其可药用盐的AUC，降低剂量后，相对于原有给药剂量而言，药物对患者的疗效有较大机会得以保持。
另一方面，本公开提供一种阿那曲唑在制备增加式(I)所示化合物或其可药用盐在患者体内的AUC的药物中的用途。
在可选实施方案中，通过向患者施用有效量式(I)所示化合物或其可药用盐和有效量阿那曲唑，相对于单独施用同等剂量式(I)所示化合物或其可药用盐，在患者体内产生的AUC增加大于18％，可选地，AUC增加20％-150％；可选地，AUC增加25％-100％；可选地，AUC增加30％-85％；可选地，AUC增加35％-80％；可选地，AUC增加40％-80％；优选地，AUC增加45％-80％；优选地，AUC增加50％-80％；优选地，AUC增加55％-80％；优选地，AUC增加60％-80％；具体地，式(I)所示化合物或其可药用盐AUC增加约18％、19％、20％、21％、22％、23％、24％、25％、26％、27％、28％、29％、30％、31％、32％、33％、34％、35％、36％、37％、38％、39％、40％、41％、42％、43％、44％、45％、46％、47％、48％、49％、50％、51％、52％、53％、54％、55％、56％、57％、58％、59％、60％、61％、62％、63％、64％、65％、66％、67％、68％、69％、70％、71％、72％、73％、74％、75％、76％、77％、78％、79％、80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％、100％、101％、102％、103％、104％、105％、106％、107％、108％、109％、110％、111％、112％、113％、114％、115％、116％、117％、118％、119％、120％、121％、122％、123％、124％、125％、126％、127％、128％、129％、130％、131％、132％、133％、134％、135％、136％、137％、138％、139％、140％、141％、142％、143％、144％、145％、146％、147％、148％、149％、150％。
在可选实施方案中，通过向患者施用有效量式(I)所示化合物或其可药用盐和有效量阿那曲唑，相比于施用同等剂量式(I)所示化合物或其可药用盐与来曲唑的联用，患者体内式(I)所示化合物或其可药用盐的AUC的比大于1:1，可选地，AUC比选自1～10:1；可选地，AUC比选自1～5:1；可选地，AUC比选自1～4:1；可选地，AUC比选自1～3:1； 优选地，AUC比选自1～2:1；优选地，AUC比选自1～1.5:1，具体地，AUC比可以是1.01:1、1.02:1、1.03:1、1.04:1、1.05:1、1.06:1、1.07:1、1.08:1、1.09:1、1.10:1、1.11:1、1.12:1、1.13:1、1.14:1、1.15:1、1.16:1、1.17:1、1.18:1、1.19:1、1.20:1、1.21:1、1.22:1、1.23:1、1.24:1、1.25:1、1.26:1、1.27:1、1.28:1、1.29:1、1.30:1、1.31:1、1.32:1、1.33:1、1.34:1、1.35:1、1.36:1、1.37:1、1.38:1、1.39:1、1.40:1、1.41:1、1.42:1、1.43:1、1.44:1、1.45:1、1.46:1、1.47:1、1.48:1、1.49:1、1.50:1、1.51:1、1.52:1、1.53:1、1.54:1、1.55:1、1.56:1、1.57:1、1.58:1、1.59:1、1.60:1、1.61:1、1.62:1、1.63:1、1.64:1、1.65:1、1.66:1、1.67:1、1.68:1、1.69:1、1.70:1、1.71:1、1.72:1、1.73:1、1.74:1、1.75:1、1.76:1、1.77:1、1.78:1、1.79:1、1.80:1、1.81:1、1.82:1、1.83:1、1.84:1、1.85:1、1.86:1、1.87:1、1.88:1、1.89:1、1.90:1、1.91:1、1.92:1、1.93:1、1.94:1、1.95:1、1.96:1、1.97:1、1.98:1、1.99:1、2.00:1。
可选的实施方案中，通过向患者施用有效量式(I)所示化合物或其可药用盐和有效量阿那曲唑，式(I)所示化合物或其可药用盐在患者体内提供2800-8000ng*h/mL的AUC；可选地，式(I)所示化合物或其可药用盐在患者体内提供2800-7800ng*h/mL的AUC；可选地，式(I)所示化合物或其可药用盐在患者体内提供3000-7600ng*h/mL的AUC；可选地，式(I)所示化合物或其可药用盐在患者体内提供3000-7400ng*h/mL的AUC；可选地，式(I)所示化合物或其可药用盐在患者体内提供3000-7200ng*h/mL的AUC；可选地，式(I)所示化合物或其可药用盐在患者体内提供3000-7000ng*h/mL的AUC；可选地，式(I)所示化合物或其可药用盐在患者体内提供3000-6800ng*h/mL的AUC；可选地，式(I)所示化合物或其可药用盐在患者体内提供3000-6600ng*h/mL的AUC；可选地，式(I)所示化合物或其可药用盐在患者体内提供3000-6400ng*h/mL的AUC；可选地，式(I)所示化合物或其可药用盐在患者体内提供3000-6200ng*h/mL的AUC；可选地，式(I)所示化合物或其可药用盐在患者体内提供3000-6000ng*h/mL的AUC；可选地，式(I)所示化合物或其可药用盐在患者体内提供3000-5800ng*h/mL的AUC；可选地，式(I)所示化合物或其可药用盐在患者体内提供3000-5600ng*h/mL的AUC；可选地，式(I)所示化合物或其可药用盐在患者体内提供3000-5400ng*h/mL的AUC；可选地，式(I)所示化合物或其可药用盐在患者体内提供3000-5200ng*h/mL的AUC；可选地，式(I)所示化合物或其可药用盐在患者体内提供3000-5000ng*h/mL的AUC；优选地，式(I)所示化合物或其可药用盐在患者体内提供3000-4800ng*h/mL的AUC；优选地，式(I)所示化合物或其可药用盐在患者体内提供3200-4600ng*h/mL的AUC；优选地，式(I)所示化合物或其可药用盐在患者体内提供3400-4400ng*h/mL的AUC； 优选地，式(I)所示化合物或其可药用盐在患者体内提供3600-4200ng*h/mL的AUC。
本公开提供的阿那曲唑在制备增加式(I)所示化合物或其可药用盐在患者体内的AUC的药物中的用途，任选阿那曲唑增加了式(I)所示化合物或其可药用盐在患者体内的C max。
在可选实施方案中，通过向患者施用有效量式(I)所示化合物或其可药用盐和有效量阿那曲唑，相对于单独施用同等剂量式(I)所示化合物或其可药用盐，患患者体内式(I)所示化合物或其可药用盐的C max的比大于1:1，可选地，C max比选自1～10:1；可选地，C max比选自1～5:1；可选地，C max比选自1～4:1；可选地，C max比选自1～3:1；优选地，C max比选自1～2:1；优选地，C max比选自1～1.5:1。具体的C max比可以是1.02:1、1.04:1、1.06:1、1.08:1、1.10:1、1.12:1、1.14:1、1.16:1、1.18:1、1.20:1、1.22:1、1.24:1、1.26:1、1.28:1、1.30:1、1.32:1、1.34:1、1.36:1、1.38:1、1.40:1、1.42:1、1.44:1、1.46:1、1.48:1、1.50:1、1.52:1、1.54:1、1.56:1、1.58:1、1.60:1、1.62:1、1.64:1、1.66:1、1.68:1、1.70:1、1.72:1、1.74:1、1.76:1、1.78:1、1.80:1、1.82:1、1.84:1、1.86:1、1.88:1、1.90:1、1.92:1、1.94:1、1.96:1、1.98:1、2.00:1。
优选的实施方案中，式(I)所示化合物或其可药用盐的给药的剂量小于等于175mg，优选小于等于150mg。
可选的实施方案中，式(I)所示化合物或其可药用盐的给药频率为一日一次或一日两次，式(I)所示化合物或其可药用盐每日剂量为1-500mg，优选50-200mg，更优选100-150mg；阿那曲唑的给药频率为一日一次或一日两次，每日剂量为0.1-50mg，优选1-25mg，最优选1-10mg。
优选的实施方案中，式(I)所示化合物或其可药用盐的给药频率为一日一次，每日剂量为150mg，阿那曲唑的给药频率为一日一次，每日剂量为1mg。
本公开提供一种增加式(I)所示化合物或其可药用盐服药后AUC的方法，包括患者服用有效量的阿那曲唑，
Figure PCTCN2020073815-appb-000007
所述患者患有乳腺癌，当给与式(I)所示化合物或其可药用盐时患者为空腹。
另一方面，本公开提供一种治疗肿瘤疾病的方法，包括给与患者治疗有效量的式(I)所示化合物或其可药用盐及治疗有效量的至少一种芳香激酶抑制剂或雌激素受体拮抗剂，所述芳香激酶抑制剂选自福美坦、阿他美坦、阿那曲唑、法倔唑、来曲唑、伏氯唑、依 西美坦和芬罗唑中的一种或多种，优选来曲唑和/或阿那曲唑，所述雌激素受体拮抗剂选自他莫昔酚、氟维司群中一种或几种，优选氟维司群，其中式(I)所示化合物或其可药用盐空腹给药，所述患者优选为人类。
本公开提供的治疗肿瘤疾病的方法，由于食物，特别是高脂餐，可增加式(I)所示化合物或其可药用盐的暴露水平，通过将给药与进食间隔较长时间，避免了食物对式(I)所示化合物或其可药用盐的药代动力学影响，保证了药物的治疗安全性与效果。
可选的实施方案中，所述芳香激酶抑制剂为阿那曲唑，式(I)所示化合物或其可药用盐的剂量为1-500mg，优选50-200mg，更优选100-150mg，给药频率为一日一次、一日两次，优选一日一次，阿那曲唑的剂量选自0.1-50mg，优选1-25mg，最优选1-10mg，一日一次、一日两次，优选一日一次，其中式(I)所示化合物或其可药用盐空腹给药。
可选的实施方案中，所述芳香激酶抑制剂为阿那曲唑，式(I)所示化合物或其可药用盐的剂量选自50mg、75mg、100mg、125mg、150mg、175mg，优选100mg、125mg或150mg，给药频率为一日一次，阿那曲唑的剂量选自0.5mg、1.0mg、1.5mg、2.0mg、2.5mg、3.0mg、3.5mg、4.0mg、4.5mg、5.0mg，优选1.0mg，给药频率为一日一次，其中式(I)所示化合物或其可药用盐空腹给药。
可选的实施方案中，所述芳香激酶抑制剂为阿那曲唑，式(I)所示化合物或其可药用盐的剂量为100mg、125mg或150mg，给药频率为一日一次，阿那曲唑的剂量为1.0mg，给药频率为一日一次，其中式(I)所示化合物或其可药用盐空腹给药。
可选的实施方案中，所述芳香激酶抑制剂为阿那曲唑，式(I)所示化合物或其可药用盐的剂量为100mg，给药频率为一日一次，阿那曲唑的剂量为1.0mg，给药频率为一日一次，其中式(I)所示化合物或其可药用盐空腹给药。
可选的实施方案中，所述芳香激酶抑制剂为阿那曲唑，式(I)所示化合物或其可药用盐的剂量为125mg，给药频率为一日一次，阿那曲唑的剂量为1.0mg，给药频率为一日一次，其中式(I)所示化合物或其可药用盐空腹给药。
可选的实施方案中，所述芳香激酶抑制剂为阿那曲唑，式(I)所示化合物或其可药用盐的剂量为150mg，给药频率为一日一次，阿那曲唑的剂量为1.0mg，给药频率为一日一次，其中式(I)所示化合物或其可药用盐空腹给药。
可选的实施方案中，所述芳香激酶抑制剂为来曲唑，式(I)所示化合物或其可药用盐的剂量为1-500mg，优选50-200mg，更优选100-150mg，给药频率为一日一次、一日两次，优选一日一次，来曲唑的剂量选自1-100mg，优选1-10mg，最优选1-5mg，给药频率为一日一次、一日两次，优选一日一次，其中式(I)所示化合物或其可药用盐 空腹给药。
可选的实施方案中，所述芳香激酶抑制剂为来曲唑，式(I)所示化合物或其可药用盐的剂量选自50mg、75mg、100mg、125mg、150mg、175mg，优选100mg、125mg或150mg，给药频率为一日一次，来曲唑的剂量选自0.5mg、1.0mg、1.5mg、2.0mg、2.5mg、3.0mg、3.5mg、4.0mg、4.5mg、5.0mg，优选2.5mg，给药频率为一日一次，其中式(I)所示化合物或其可药用盐空腹给药。
可选的实施方案中，所述芳香激酶抑制剂为来曲唑，式(I)所示化合物或其可药用盐的剂量为100mg、125mg或150mg，给药频率为一日一次，来曲唑的剂量为2.5mg，给药频率为一日一次，其中式(I)所示化合物或其可药用盐空腹给药。
可选的实施方案中，所述芳香激酶抑制剂为来曲唑，式(I)所示化合物或其可药用盐的剂量为100mg，给药频率为一日一次，来曲唑的剂量为2.5mg，给药频率为一日一次，其中式(I)所示化合物或其可药用盐空腹给药。
可选的实施方案中，所述芳香激酶抑制剂为来曲唑，式(I)所示化合物或其可药用盐的剂量为125mg，给药频率为一日一次，来曲唑的剂量为2.5mg，给药频率为一日一次，其中式(I)所示化合物或其可药用盐空腹给药。
可选的实施方案中，所述芳香激酶抑制剂为来曲唑，式(I)所示化合物或其可药用盐的剂量为150mg，给药频率为一日一次，来曲唑的剂量为2.5mg，给药频率为一日一次，其中式(I)所示化合物或其可药用盐空腹给药。
可选的实施方案中，所述雌激素受体拮抗剂为氟维司群，式(I)所示化合物或其可药用盐的剂量为1-500mg，优选50-200mg，更优选100-150mg，给药频率为一日一次、一日两次，优选一日一次，氟维司群的给药剂量选自1-2000mg，优选10-1000mg，更优选100-1000mg，给药频率为一周一次或两周一次，其中式(I)所示化合物或其可药用盐空腹给药。
可选的实施方案中，所述雌激素受体拮抗剂为氟维司群，式(I)所示化合物或其可药用盐的剂量选自50mg、75mg、100mg、125mg、150mg、175mg，优选100mg、125mg或150mg，给药频率为一日一次，氟维司群的剂量选自200mg、300mg、400mg、500mg、600mg、700mg、800mg，优选500mg，给药频率为一周一次或两周一次，其中式(I)所示化合物或其可药用盐空腹给药。
可选的实施方案中，所述雌激素受体拮抗剂为氟维司群，式(I)所示化合物或其可药用盐的剂量选自100mg、125mg或150mg，给药频率为一日一次，氟维司群的剂量为500mg，给药频率为一周一次或两周一次，其中式(I)所示化合物或其可药用盐空腹 给药。
可选的实施方案中，所述雌激素受体拮抗剂为氟维司群，式(I)所示化合物或其可药用盐的剂量为100mg，给药频率为一日一次，氟维司群的剂量为500mg，给药频率为一周一次或两周一次，其中式(I)所示化合物或其可药用盐空腹给药。
可选的实施方案中，所述雌激素受体拮抗剂为氟维司群，式(I)所示化合物或其可药用盐的剂量125mg，给药频率为一日一次，氟维司群的剂量为500mg，给药频率为一周一次或两周一次，其中式(I)所示化合物或其可药用盐空腹给药。
可选的实施方案中，所述雌激素受体拮抗剂为氟维司群，式(I)所示化合物或其可药用盐的剂量为150mg，给药频率为一日一次，氟维司群的剂量为500mg，给药频率为一周一次或两周一次，其中式(I)所示化合物或其可药用盐空腹给药。特别优选的实施方案中，式(I)所示化合物或其可药用盐早晨空腹给药。
本公开中含式(I)所示化合物或其可药用盐的药物组合物与阿那曲唑联合在制备治疗肿瘤的药物的用途中效果优于式(I)所示化合物或其可药用盐与来曲唑的联合，具体可表现为用药后在客观缓解率(ORR)或无进展生存期(PFS)或缓解持续时间(DoR)或疾病控制率(DCR)或总生存期(OS)方面效果更优，完全缓解(CR)和/或部分缓解(PR)和/或病变稳定(SD)的比例更高，患者不良反应发生率低，这些同样可以用于证明本公开的效果。
术语说明
“治疗”包括肿瘤疾病或病症的预防性和治疗性处理(包括但不限于减轻、治愈、缓解症状、减少症状)以及进展延迟。
“药物组合物”指含至少一种治疗剂和至少一种药学上可接受的辅料的混合物，所述的药学上可接受的辅料包括但不限于稀释剂、粘合剂、崩解剂、润滑剂，所述的稀释剂包括但不限于甘露醇、右旋糖微晶纤维素、预胶化淀粉、磷酸氢钙、乳糖、山梨醇；所述的粘合剂可选自淀粉、羧甲基纤维素钠、聚乙烯吡咯烷酮、预胶化淀粉、羟丙甲纤维素及羟丙基纤维素中的一种或多种；所述的崩解剂可选自交联羧甲基纤维素钠、羧甲基淀粉钠、低取代羟丙基纤维素及交联聚维酮中的一种或多种；所述的润滑剂可选自滑石粉、硬脂酸镁、硬脂酸锌、山嵛酸甘油酯的一种或多种。
本公开中含式(I)所示化合物或其可药用盐的药物组合物与含阿那曲唑的药物组合物也能以胃肠外形式给药，所述的药物组合物可包含药物上可接受的赋形剂，所述赋形剂选自防腐剂、稳定剂、增溶剂、乳化剂、渗透压调节剂、缓冲剂中的一种或多种。
“治疗有效”优选涉及治疗剂的一定量，该量对于抵御肿瘤进展在治疗上或更广义 地还在预防上有效。
本公开中所述的“联合”是一种给药方式，是指在一定时间期限内给予至少一种剂量的含式(I)所示化合物或其可药用盐的药物组合物和阿那曲唑，其中两种药物都显示药理学作用。所述的时间期限可以是一个给药周期内，优选24小时以内。可以同时或依次给予含式(I)所示化合物或其可药用盐的药物组合物和阿那曲唑。这种期限包括这样的治疗，其中通过相同给药途径或不同给药途径给予含式(I)所示化合物或其可药用盐的药物组合物和阿那曲唑。
本公开中所述的“C max”是指药代动力学药物在血中的峰浓度，该参数是评价药物吸收速率的重要指标，反映药物在体内的暴露特性。
“AUC”是指药代动力学血药浓度曲线对时间轴所包围的面积，该参数是评价药物吸收程度的重要指标，反映药物在体内的暴露特性。由于药动学研究中血药浓度只能观察至某时间点t，因此AUC有两种表示方式:AUC( 0-t)和AUC( 0-∞)，前者根据梯形面积法得到，后者计算式:AUC( 0-∞)＝AUC( 0-t)+末端点浓度/末端消除速率。本公开中所述的AUC是指单次给药或多次给药达到稳态后患者的平均AUC 0-24，优选多次给药达到稳态后患者的平均AUC 0-24(即AUC ss)。
“高脂餐”是高脂肪(提供食物中约50％的热量)、高热量(约800-1000千卡)餐食，其中蛋白质约提供150千卡热量，碳水化合物约提供250千卡热量，脂肪约提供500-600千卡热量。
“空腹”是指给药与进食间隔至少0.5小时，或至少1小时，或至少2小时，或至少3小时，或至少4小时，或至少5小时，或至少6小时，或至少7小时，或至少8小时，具体可为餐前至少0.5小时，或餐前至少1小时，或餐前至少1.5小时，或餐前至少2小时，或餐后至少2小时，或餐后至少3小时，或餐后至少4小时，优选的是早餐前至少0.5小时，或早餐前至少1小时，或早餐前至少1.5小时，或早餐前至少2小时。
本公开中不良事件严重程度的判断标准参照NCI-CTC AE 4.03版关于药物不良事件的分级标准。如果出现NCI-CTC AE 4.03版表中未列出的不良事件可参照下列标准：
Figure PCTCN2020073815-appb-000008
Figure PCTCN2020073815-appb-000009
附图说明
图1.式(I)所示化合物羟乙基磺酸盐平均(Mean±SD)血药浓度-时间曲线图(PK浓度分析人群)；
图2.式(I)所示化合物羟乙基磺酸盐中位血药浓度-时间曲线图(PK浓度分析人群)；
图3.式(I)所示化合物羟乙基磺酸盐个体主要PK参数箱须图(PK参数分析人群)。
具体实施方式
以下结合实施例用于进一步描述本公开，但这些实施例并非限制本公开的范围。
实施例1、式(I)所示化合物羟乙基磺酸盐(药物A)联合来曲唑或阿那曲唑或氟维司群治疗激素受体阳性、HER2阴性晚期乳腺癌的Ib/II期临床研究
药物信息
1)药物A，依据WO2016124067A提供的方法制备，规格为25mg/片，125mg/片；
2)来曲唑片，生产厂家：江苏恒瑞医药股份有限公司，规格：2.5mg/片；
3)阿那曲唑片(瑞宁得)；生产厂家：阿斯利康制药有限公司，规格：1mg/片；
4)氟维司群注射液(芙仕得)；生产厂家：Vetter Pharma-Fertigung GmbH&Co.KG；剂型：注射液；规格：5ml：0.25mg。
实验目的
第一阶段的主要研究目的：
评价药物A联合来曲唑或阿那曲唑或氟维司群治疗HR+、HER2-的绝经后或绝经前女性、局部复发或转移性乳腺癌的安全性和耐受性。
第一阶段的次要研究目的：
评价药物A联合来曲唑或阿那曲唑或氟维司群在晚期乳腺癌患者中的药代动力学属性；
初步评价药物A联合来曲唑或阿那曲唑或氟维司群治疗晚期乳腺癌的有效性。
第二阶段的主要研究目的：
评价药物A联合来曲唑或阿那曲唑治疗HR+、HER2-的绝经后或绝经前女性、局部复发或转移性乳腺癌的有效性。
第二阶段的次要研究目的：
评价药物A联合来曲唑或阿那曲唑在晚期乳腺癌患者中的安全性。
研究终点
第一阶段的主要研究终点：
不良事件(AE)及严重不良事件(SAE)的发生率及严重程度和实验室检查异常。
第一阶段的次要研究终点：
药物A联合来曲唑或阿那曲唑或氟维司群的药代动力学参数：AUC、T max、t 1/2和C max等；
客观缓解率(Objective Response Rate,ORR)。
第二阶段的主要研究终点：
客观缓解率(Objective Response Rate,ORR)。
第二阶段的次要研究终点：
无进展生存期(Progression Free Survival,PFS)；
缓解持续时间(Duration of Response,DoR)；
疾病控制率(Disease Control Rate,DCR)；
不良事件(AE)及严重不良事件(SAE)的发生率及严重程度和实验室检查异常。
实验设计
第一阶段
为了有效考察药物A联合来曲唑或阿那曲唑或氟维司群治疗的安全性、药代动力学属性以及有效性，计划进行以下队列(剂量水平)的研究：
队列1：药物A 150mg qd(d1-21)+来曲唑2.5mg qd或阿那曲唑1mg qd；
队列2：药物A 125mg qd(d1-21)+来曲唑2.5mg qd或阿那曲唑1mg qd；
队列3：药物A 150mg qd(d1-21)+氟维司群500mg肌肉注射(第一周期：d1和d15，随后周期d1)；
队列4：药物A剂量待定qd(d1-21)+氟维司群500mg肌肉注射(第一周期：d1和d15，随后周期d1)。
每个队列入选约15例受试者(保证至少有10例受试者可以进行耐受性评价和药代动力学评价)。将联合给药的第一周期(28天)作为耐受性观察期，期间如果出现临床 显著性毒性受试者的比例≤33％(即在10例可进行耐受性评价的受试者中不超过3例出现临床显著性毒性)，则认为该剂量组可耐受。在完成队列1的第1个周期的研究观察后，由研究者和申办方根据安全性和耐受性结果并综合其他相关临床研究的数据，共同协商决定队列2的给药剂量。在完成队列3的第1个周期的研究观察后，由研究者和申办方根据安全性和耐受性结果并综合其他相关临床研究的数据，共同协商决定队列4的给药剂量。
每28天为一个治疗周期：药物A前3周(第1天至第21天)连续服药，后1周(第22天至第28天)休息(不服药)；来曲唑或阿那曲唑为每天服药一次。氟维司群为第一周期第1天和第15天给药，随后每个周期的第1天给药。
第二阶段
根据第一阶段的结果，选择II期研究推荐剂量(RP2D)在晚期乳腺癌患者中开展进一步的疗效和安全性评价：
药物A(RP2D,d1-21)+来曲唑2.5mg qd或阿那曲唑1mg qd；
在本研究中，筛选期不超过28天，完成筛选检查和评估后合格的受试者进入研究治疗期(每28天为一个治疗周期)，按照方案规定进行研究治疗和访视。其中，研究治疗期的前14个治疗周期内，每2个周期(8周±7天)进行一次肿瘤影像学评估；之后每4个周期(16周±7天)进行一次肿瘤影像学评估。受试者在治疗结束/退出研究时应到研究中心进行访视，完成相应的安全性检查和影像学评估；并在末次治疗后30天到研究中心进行访视，完成相应的安全性评估。
给药方法
在第一阶段中，根据受试者所属队列(剂量水平)将按照以下方式服用，队列1，药物A 150mg，口服，每日一次；队列2，药物A125mg，口服，每日一次；队列3，药物A 150mg，口服，每日一次；队列4，药物A剂量待定，口服，每日一次。每28天为一个治疗周期，第1天至第21天连续服用药物A(每日一次)，第22天至第28天休息(药物A)
在第二阶段中，根据第一阶段的结果，采用II期研究推荐剂量(RP2D)进行给药，药物A(RP2D)，口服，每日一次，每28天为一个治疗周期，第1天至第21天连续服药(每日一次)，第22天至第28天休息(不服药)。
所有受试者在第一阶段使用药物A的同时服用来曲唑或阿那曲唑或氟维司群。来曲唑2.5mg或阿那曲唑1mg，口服，每日一次，连续服用，每28天为一个治疗周期。推荐在每天早晨8:00点空腹，同时口服药物A和来曲唑或阿那曲唑，温水送服。
受试者应持续接受研究治疗，直至出现疾病进展、毒性不可耐受、受试者主动要求终止研究治疗或退出研究，或者研究者判定受试者需要退出研究。
入组标准
所有受试者必须符合以下入组标准，才具有进入本试验的资格。
1、病理检测确诊为HR+、HER2-的女性乳腺癌患者，有局灶性复发或转移的证据，不适合以治愈为目的的手术切除或放射治疗，且无进行化疗的临床指征。
2、18岁至75岁的绝经后女性，绝经定义为：
a)既往进行过双侧卵巢切除术，或
b)年龄≥60岁；或年龄<60，自然绝经后状态(定义为连续至少12个月规律月经自发性停止且无其他病理或生理原因)，此外，绝经前或围绝经期女性患者也可以入选，但在研究期间必须愿意接受LHRH激动剂治疗，入组研究至少14天前接受过LHRH激动剂给药。
3、东部肿瘤协作组(ECOG)体力状况评分为0-1。
4、既往抗肿瘤治疗或外科手术所致的所有急性毒性反应缓解至0-1级(根据NCICTCAE 4.03版)或者至入组/排除标准所规定的水平。脱发等研究者认为对患者不产生安全性风险的其他毒性除外。
5、有充足的器官和骨髓功能，定义如下：
a)嗜中性粒细胞计数(ANC)≥1,500/mm 3(1.5×10 9/L)；
b)血小板计数(PLT)≥100,000/mm 3(100×10 9/L)；
c)血红蛋白(Hb)≥9g/dL(90g/L)；
d)血清肌酐≤1.5倍正常值上限(ULN)或肌酐清除率≥60ml/min；
e)总胆红素(BIL)≤1.5倍正常值上限(ULN)；
f)谷草转氨酶(AST/SGOT)或谷丙转氨酶(ALT/SGPT)水平≤2.5倍正常值上限(ULN)，肝转移患者应≤5×ULN。
6、育龄期女性受试者必须在开始研究用药前3天内进行血清妊娠试验，且结果为阴性，并且愿意在研究期间和末次给予研究药物后3个月内采用一种经医学认可的高效避孕措施(如：宫内节育器、避孕药或避孕套)。
7、经本人同意并已签署知情同意书，愿意并有能力遵从计划的访视、研究治疗计划、实验室检查及其他试验程序。
8、有符合RECIST 1.1标准的可测量病灶。
9、预期寿命>12周。
队列1和队列2受试者必须符合以下所有入组标准，才具有进入本试验的资格。
既往未曾接受过任何针对局灶性复发或转移性疾病的系统性抗癌治疗。
队列3和队列4受试者必须符合以下所有入组标准，才具有进入本试验的资格：
1、患者需满足以下其中一条标准：
a)接受辅助内分泌治疗，2年后影像学检查证实复发或进展后，未接受进一步的内分泌治疗；
b)完成辅助内分泌治疗后，1年内影像学检查证实复发或进展；
c)转移性疾病患者接受一线内分泌治疗后，影像学检查证实6个月以后复发或进展。患者未接受转移性疾病一线以后的内分泌治疗或化疗。
2、复发转移性疾病患者允许不超过一线的化学治疗。
实验结果：
目前已纳入33例受试者。队列1：药物A150mg入组17例，其中13例与来曲唑联用，4例与阿那曲唑联用。队列2：药物A 125mg入组16例，其中15例与来曲唑联用，1例与阿那曲唑联用。32例受试者(队列1：150mg剂量组16例；队列2：125mg剂量组16例)进行至少1次疗效评价，33例受试者完成至少第1周期的安全性评价。
疗效评价结果(如下表1)：药物A 150mg剂量组共计16例受试者进行至少1次疗效评价，其中PR7例(44％)，PD 1例(6％)，SD 8例(50％)。药物A125mg剂量组共计16例受试者进行至少1次疗效评价，其中PR 5例(31％)，SD 11例(69％)。队列1和2中，联合阿那曲唑的有5例受试者(队列1中4例；队列2中1例)，其中4例在首次给药后第1次疗效评价(2个月)即评价为PR(详见表1)。
表1.药物A Ib/II期研究疗效
Figure PCTCN2020073815-appb-000010
Figure PCTCN2020073815-appb-000011
总体安全性评价结果，可安全性评价共33例，150mg剂量组17例，125mg组16例。所有受试者均报告了AE，大多数为1-2级。3-4级血液学AE主要包括：白细胞降低(9例，27.3％)和中性粒细胞降低(20例，60.6％)。在队列1、2合计入组57例受试者后，化合物A联合来曲唑和阿那曲唑组的在血液学毒性方面出现较大差异，150mg队列3、4级中性粒细胞下降两组分别为84.6％和60.0％，3、4级白细胞下降两组分别为38.5％和20％，血小板下降分别为23.1％和5.0％；125mg队列3、4级中性粒细胞下降两组分别为73.3％和44.4％，3、4级白细胞下降两组分别为26.7％和22.2％，血小板下降分别为33.3％和11.1％，两队列数据趋势一致，表明化合物A联合阿那曲唑相对于联合来曲唑在血液学毒性方面更有优势，更为安全。
第一给药周期多次给药后对药物A联用来曲唑、药物A联用阿那曲唑的PK数据与单药的PK数据进行比较，具体结果见表2及表3。
表2.
Figure PCTCN2020073815-appb-000012
表3.
Figure PCTCN2020073815-appb-000013
备注：Cmax和AUC均为几何均值(CV％)。
由表2可见，150mg剂量组下，药物A的暴露水平：联用阿那曲唑>联用来曲唑>药物单药。
由表3可见，150mg剂量，阿那曲唑组的AUC是单药研究的1.65倍，阿那曲唑组AUC是来曲唑组的1.41倍。
其中，药物A联用阿那曲唑150mg剂量组，有一例患者4级AE，在第三个给药周期剂量下调至125mg后患者维持PR状态。
后期队列1进一步入组病人9例，其中1例与来曲唑联用，8例与阿那曲唑联用，队列2进一步入组病人5例，其中2例与来曲唑联用，3例与阿那曲唑联用，第一给药周期多次给药后对药物A联用来曲唑、药物A联用阿那曲唑的PK数据与单药的PK数据进行比较，具体结果见表4及表5。
表4.
Figure PCTCN2020073815-appb-000014
Figure PCTCN2020073815-appb-000015
表5.
Figure PCTCN2020073815-appb-000016
由表4可见，150mg剂量组下，药物A的暴露水平：联用阿那曲唑>联用来曲唑>药物单药。
由表5可见，150mg剂量，阿那曲唑组的AUC是单药研究的1.38倍，阿那曲唑组AUC是来曲唑组的1.16倍。
实施例2、高脂饮食对中国健康成年受试者口服式(I)所示化合物羟乙基磺酸盐片剂后药代动力学影响
1)试验药物
式(I)所示化合物羟乙基磺酸盐片剂，规格为25mg/片，125mg/片。
2)给药方案
本研究入组24名健康成年受试者，采用随机、开放、单剂量、两周期、两序列、交叉对照试验设计，24例健康受试者随机分为A、B两个序列组，每个序列组12例受试者，按空腹→餐后或餐后→空腹两种序列给药，清洗期为14天。
A序列组：第1日空腹单次服用式(I)所示化合物羟乙基磺酸盐片150mg，采集0～144小时的PK血浆样品，第15日餐后单次服用式(I)所示化合物羟乙基磺酸盐片150mg，采集0～144小时的PK血浆样品。
B序列组：第1日餐后单次服用式(I)所示化合物羟乙基磺酸盐片150mg，采集0～144小时的PK血浆样品，第15日空腹单次服用式(I)所示化合物羟乙基磺酸盐片150mg，采集0～144小时的PK血浆样品。
第一周期：
受试者在D-1入住I期临床研究中心，由I期临床研究中心统一提供标准晚餐，禁食过夜至少10小时。给药当天(D 1)早晨，A序列组于早晨，空腹用240mL温水送服式(I)所示化合物羟乙基磺酸盐片150mg后，采集0～144小时血样。B序列组则于早晨进食高脂餐，进食30分钟时(自开始进食起计时)，用240mL温水送服式(I)所示化合物羟乙基磺酸盐片150mg，采集0～144小时血样。服药前1小时至服药后1小时内禁止饮水(高脂肪/高热量餐所含水分除外)，其他时间可自由饮水。服药后4小时内禁食，给药后4小时及给药后10小时左右分别提供标准饮食。给药后72小时可以离开I期临床研究中心。
第二周期：
经过14天洗脱期后，受试者在D14入住I期临床研究中心，由I期临床研究中心统一提供标准晚餐，禁食过夜至少10小时。给药当天(D15)，B序列组于早晨，空腹用240mL温水送服式(I)所示化合物羟乙基磺酸盐片150mg后，采集0～144小时血样。A序列组则于早晨进食高脂餐，进食30分钟时(自开始进食起计时)，用240mL水送服式(I)所示化合物羟乙基磺酸盐片150mg，采集0～144小时血样。服药前1小时至服药后1小时内禁止饮水(高脂肪/高热量餐所含水分除外)，其他时间可自由饮水。服药后4小时内禁食，给药后4小时及给药后10小时左右分别提供标准饮食。给药后72小时可以离开I期临床研究中心。
早餐要求为高脂肪(提供食物中约50％的热量)、高热量(约800-1000千卡)早餐，其中蛋白质约提供150千卡热量，碳水化合物约提供250千卡热量，脂肪约提供500-600千卡热量。
3)实验结果
1、血药浓度分析
基于PK浓度分析人群，按照方案规定采样时间，分给药状态(空腹和餐后)，对受试者的血药浓度进行描述性统计。统计量包括：受试者例数(n)、BQL的个数(n of BQL)、 算数平均数(Mean)、标准差(SD)、中位数(Median)、最小值(Min)、最大值(Max)、变异系数(％CV)、几何均值(GeoMean)、对数标准差(SD log)和几何变异系数(％CV b)。
基于PK浓度分析人群，按照方案规定采样时间，绘制不同给药状态(空腹和餐后)受试者平均/中位血药浓度-时间曲线(线性和半对数)。
基于PK浓度分析人群，按照实际采样时间，分给药状态(空腹和餐后)绘制个体血药浓度-时间曲线图(线性和半对数)。
式(I)所示化合物羟乙基磺酸盐平均(Mean±SD)血药浓度-时间曲线图见图1；式(I)所示化合物羟乙基磺酸盐中位血药浓度-时间曲线图见图2。
2、PK参数结果
基于PK参数分析人群，根据实际采样时间使用WinNonlin 7.0版本的非房室模型(NCA)计算PK参数，采用SAS 9.4版本软件对PK参数进行列表和描述性统计。
不同给药状态下受试者个体主要PK参数(C max、AUC 0-t和AUC 0-∞)箱须图见图3。
不同给药状态下受试者的PK参数描述性统计分析结果见表6。
表6.PK参数汇总表(PK参数分析人群)
Figure PCTCN2020073815-appb-000017
Figure PCTCN2020073815-appb-000018
由图可知，餐后组与空腹组的C max及AUC分布区间部分重叠，但餐后组普遍高于空腹组，呈现较为明显的分布差异，说明进食高脂餐有使式(I)所示化合物羟乙基磺酸盐的暴露水平增加的趋势。
由表可知，受试者空腹及餐后口服150mg式(I)所示化合物羟乙基磺酸盐片后，T max中位值分别为6.00h和5.00h，说明进食高脂餐对式(I)所示化合物羟乙基磺酸盐的吸收速度影响较小。受试者空腹及餐后口服150mg式(I)所示化合物羟乙基磺酸盐片后，C max的平均值分别为58.2ng/mL和88.2ng/mL，AUC 0-t的平均值分别为1708h*ng/mL和2279h*ng/mL，AUC 0-∞的平均值分别为1841h*ng/mL和2448h*ng/mL，餐后组C max及AUC均高于空腹组，说明进食高脂餐有使式(I)所示化合物羟乙基磺酸盐的吸收程度增加的趋势。另外，空腹组式(I)所示化合物羟乙基磺酸盐的平均t 1/2为43.0h，餐后组式(I)所示化合物羟乙基磺酸盐的平均t 1/2为42.2h，说明进食高脂餐对式(I)所示化合物羟乙基磺酸盐的消除无明显影响。
3、高脂饮食影响
基于PK参数分析人群，采用SAS 9.4版本软件，用混合效应模型(Mixed-effectsmodel)对自然对数转换后的不同给药状态的受试者PK参数(C max、AUC 0-t和AUC 0-∞)进行分析，结果见表7。
表7食物对式(I)所示化合物羟乙基磺酸盐PK的影响(PK参数分析人群)
Figure PCTCN2020073815-appb-000019
注：GeoLSM为几何调整均值。
由上表可知，受试者单次口服150mg式(I)所示化合物羟乙基磺酸盐片后，餐后 组与空腹组C max、AUC 0-t和AUC 0-∞的几何均值比值分别为156.85％、138.57％和137.50％，进食高脂餐后式(I)所示化合物羟乙基磺酸盐的暴露水平相比空腹增加了37.5％～56.9％；餐后组与空腹组C max、AUC 0-t和AUC 0-∞的几何均值比值的90％CI分别为138.42％～177.72％、126.01％～152.39％、125.54％～150.59％，均不在80.00％～125.00％范围内，且均高于125.00％。以上结果说明高脂饮食对式(I)所示化合物羟乙基磺酸盐的暴露水平有影响，进食高脂餐能够增加式(I)所示化合物羟乙基磺酸盐的暴露水平。
4)实验讨论与结论
受试者单次口服150mg式(I)所示化合物羟乙基磺酸盐片后，空腹组与餐后组血药浓度时间曲线趋势一致，约在5～6h达峰，但餐后组的血浆暴露水平高于空腹组。半对数药时曲线显示单剂量口服式(I)所示化合物羟乙基磺酸盐片后，血浆中的式(I)所示化合物羟乙基磺酸盐呈现线性消除的趋势。
另外，受试者单次口服150mg式(I)所示化合物羟乙基磺酸盐片后，空腹组的Cmax、AUC 0-t及AUC 0-∞几何变异系数分别为53.20％、42.44％和40.58％，餐后组的Cmax、AUC 0-t及AUC 0-∞几何变异系数分别为38.57％、28.00％和27.38％，餐后与空腹相比，PK参数呈现变异减小的趋势。
高脂饮食对式(I)所示化合物羟乙基磺酸盐在健康受试者体内的暴露水平有影响，进食高脂餐能够增加式(I)所示化合物羟乙基磺酸盐的暴露水平。150mg给药剂量下，与空腹服药相比，餐后服药式(I)所示化合物羟乙基磺酸盐的Cmax、AUC 0-t和AUC 0- ∞分别升高了56.9％、38.6％和37.5％。
虽然以上描述了本发明的具体实施方式，但是本领域的技术人员应当理解，这些仅是举例说明，在不背离本发明的原理和实质的前提下，可以对这些实施方式做出多种变更或修改。因此，本发明的保护范围由所附权利要求书限定。

Claims (44)

  1. 一种含式(I)所示化合物或其可药用盐的药物组合物与阿那曲唑联合在制备治疗肿瘤疾病的药物中的用途，
    Figure PCTCN2020073815-appb-100001
  2. 根据权利要求1所述的用途，其中，所述肿瘤疾病选自肉瘤、淋巴瘤、肺癌、支气管癌、前列腺癌、胰腺癌、胃肠癌、结肠癌、直肠癌、结直肠腺瘤、甲状腺癌、肝癌、肝内胆管癌、肝细胞癌、肾上腺癌、胃癌、胃肿瘤、胶质瘤、成胶质细胞瘤、子宫内膜癌、黑素瘤、肾癌、肾盂癌、膀胱癌、子宫体癌、宫颈癌、阴道癌、卵巢癌、多发性骨髓瘤、食管癌、白血病、急性髓细胞性白血病、慢性髓细胞性白血病、淋巴细胞性白血病、骨髓性白血病、脑肿瘤、脑癌、口腔及咽部癌、喉癌、小肠癌、非霍奇金淋巴瘤、黑素瘤、结肠绒毛腺瘤、赘生物、上皮癌、乳腺癌、基底细胞癌、鳞状细胞癌、光化性角化病、肿瘤疾病、颈部或头部肿瘤、原发性血小板增多症、髓样化生性骨髓纤维化和巨球蛋白血症中的一种或多种，优选乳腺癌。
  3. 根据权利要求2所述的用途，其中，所述乳腺癌为激素受体阳性(HR+)的乳腺癌。
  4. 根据权利要求2所述的用途，其中，所述乳腺癌为人表皮生长因子受体2阴性(HER2-)的乳腺癌。
  5. 根据权利要求3或4所述的用途，其中，所述的乳腺癌为局部晚期或转移性乳腺癌。
  6. 根据权利要求1所述的用途，其中，式(I)所示化合物的可药用盐为羟乙基磺酸盐。
  7. 根据权利要求1-6任一项所述的用途，其中，含式(I)所示化合物或其可药用盐的药物组合物给药频率为一日一次或一日两次，式(I)所示化合物或其可药用盐每日剂量为1-500mg，优选50-200mg，更优选100-150mg。
  8. 根据权利要求7所述的用途，其中，含式(I)所示化合物或其可药用盐的药物组合物给药频率为一日一次，每日剂量为100mg、125mg或150mg。
  9. 根据权利要求1-8任一项所述的用途，其中，阿那曲唑的给药频率为一日一次或一日两次，每日剂量为0.1-50mg，优选1-25mg，最优选1-10mg。
  10. 根据权利要求9所述的用途，其中，阿那曲唑的给药频率为一日一次，每日剂量为1mg。
  11. 根据权利要求7-10任一项所述的用途，其中，含式(I)所示化合物或其可药用盐的药物组合物给药频率为一日一次，每日剂量为125mg或150mg；阿那曲唑的给药频率为一日一次，每日剂量为1mg。
  12. 根据权利要求7-11任一项所述的用途，其中，含式(I)所示化合物或其可药用盐的药物组合物和阿那曲唑均口服给药。
  13. 根据权利要求1-12任一项所述的用途，其中，含式(I)所示化合物或其可药用盐的药物组合物进一步含有至少一种药学上可接受的赋形剂，所述赋形剂选自稀释剂、粘合剂、崩解剂、润滑剂。
  14. 根据权利要求13所述的用途，其中，所述稀释剂的含量为相对于药物组合物总重的1％-99％，优选5％-95％。
  15. 根据权利要求13所述的用途，其中，所述润滑剂的含量为相对于药物组合物总重的0.01％-25％，优选0.1％-10％。
  16. 根据权利要求1-15任一项所述的用途，其中阿那曲唑增加了式(I)所示化合物或其可药用盐在患者体内的AUC。
  17. 根据权利要求1-15任一项所述的用途，其中阿那曲唑降低了患者不良反应的发生率。
  18. 一种阿那曲唑在制备增加式(I)所示化合物或其可药用盐在患者体内的AUC的药物中的用途，
    Figure PCTCN2020073815-appb-100002
  19. 根据权利要求18所述的用途，其中，相比于单独施用同等剂量式(I)所示化合物或其可药用盐，在患者体内产生的式(I)所示化合物或其可药用盐的AUC增加大于18％，优选AUC增加20％-150％，更优选AUC增加25％-100％。
  20. 根据权利要求18所述的用途，其中，相比于施用同等剂量式(I)所示化合物或其可药用盐与来曲唑的联用，患者体内式(I)所示化合物或其可药用盐的AUC的比大于1:1，优选AUC比选自1～10:1，优选AUC比选自1～5:1。
  21. 根据权利要求18所述的用途，其中，通过向患者施用有效量式(I)所示化合物 或其可药用盐和有效量阿那曲唑，式(I)所示化合物或其可药用盐在患者体内提供2800-8000ng*h/mL的AUC，优选地，式(I)所示化合物或其可药用盐在患者体内提供3000-4800ng*h/mL的AUC，优选地，式(I)所示化合物或其可药用盐在患者体内提供3200-4600ng*h/mL的AUC。
  22. 根据权利要求19-21任一项所述的用途，其中，式(I)所示化合物或其可药用盐的给药的剂量小于等于175mg，优选小于等于150mg。
  23. 根据权利要求18所述的用途，其中，式(I)所示化合物或其可药用盐的给药频率为一日一次或一日两次，式(I)所示化合物或其可药用盐每日剂量为1-500mg，优选50-200mg，更优选100-150mg；阿那曲唑的给药频率为一日一次或一日两次，每日剂量为0.1-50mg，优选1-25mg，最优选1-10mg。
  24. 根据权利要求18所述的用途，其中，式(I)所示化合物或其可药用盐的药物组合物给药频率为一日一次，每日剂量为150mg，阿那曲唑的给药频率为一日一次，每日剂量为1mg。
  25. 一种治疗肿瘤疾病的方法，其中，其包括给与患者治疗有效量的式(I)所示化合物或其可药用盐及治疗有效量的至少一种芳香激酶抑制剂或雌激素受体拮抗剂，
    Figure PCTCN2020073815-appb-100003
    所述芳香激酶抑制剂选自福美坦、阿他美坦、阿那曲唑、法倔唑、来曲唑、伏氯唑、依西美坦和芬罗唑中的一种或多种，优选来曲唑和/或阿那曲唑，所述雌激素受体拮抗剂选自他莫昔酚、氟维司群中一种或几种，优选氟维司群，其中式(I)所示化合物或其可药用盐空腹给药。
  26. 根据权利要求25所述的方法，其中，所述芳香激酶抑制剂为阿那曲唑，式(I)所示化合物或其可药用盐的剂量为1-500mg，优选50-200mg，更优选100-150mg，给药频率为一日一次、一日两次，优选一日一次，阿那曲唑的剂量选自0.1-50mg，优选1-25mg，最优选1-10mg，一日一次、一日两次，优选一日一次。
  27. 根据权利要求25所述的方法，其中，所述芳香激酶抑制剂为来曲唑，式(I)所示化合物或其可药用盐的剂量为1-500mg，优选50-200mg，更优选100-150mg，给药频率为一日一次、一日两次，优选一日一次，来曲唑的剂量选自1-100mg，优选1-10mg，最优选1-5mg，给药频率为一日一次、一日两次，优选一日一次。
  28. 根据权利要求25所述的方法，其中，所述雌激素受体拮抗剂为氟维司群，式(I)所示化合物或其可药用盐的剂量为1-500mg，优选50-200mg，更优选100-150mg，给药频率为一日一次、一日两次，优选一日一次，氟维司群的给药剂量选自1-2000mg，优选10-1000mg，更优选100-1000mg，给药频率为一周一次或两周一次。
  29. 根据权利要求25所述的方法，其中，所述肿瘤疾病选自肉瘤、淋巴瘤、肺癌、支气管癌、前列腺癌、胰腺癌、胃肠癌、结肠癌、直肠癌、结直肠腺瘤、甲状腺癌、肝癌、肝内胆管癌、肝细胞癌、肾上腺癌、胃癌、胃肿瘤、胶质瘤、成胶质细胞瘤、子宫内膜癌、黑素瘤、肾癌、肾盂癌、膀胱癌、子宫体癌、宫颈癌、阴道癌、卵巢癌、多发性骨髓瘤、食管癌、白血病、急性髓细胞性白血病、慢性髓细胞性白血病、淋巴细胞性白血病、骨髓性白血病、脑肿瘤、脑癌、口腔及咽部癌、喉癌、小肠癌、非霍奇金淋巴瘤、黑素瘤、结肠绒毛腺瘤、赘生物、上皮癌、乳腺癌、基底细胞癌、鳞状细胞癌、光化性角化病、肿瘤疾病、颈部或头部肿瘤、原发性血小板增多症、髓样化生性骨髓纤维化和巨球蛋白血症中的一种或多种，优选乳腺癌。
  30. 根据权利要求25-29任一项所述的方法，其中，式(I)所示化合物的可药用盐为羟乙基磺酸盐。
  31. 根据权利要求1-17任一项所述的用途，其中，患有所述肿瘤疾病的患者为人类。
  32. 根据权利要求18-24任一项所述的用途，其中，所述患者为人类。
  33. 根据权利要求25-30任一项所述的方法，其中，所述患者为人类。
  34. 一种治疗人类患者局部复发或转移性乳腺癌的方法，其中，其包括口服给与患者有效量的式(I)所示化合物或其可药用盐，和有效量的阿那曲唑，
    Figure PCTCN2020073815-appb-100004
    所述患者为绝经后或绝经前或围绝经期女性患者或者经卵巢切除的绝经前女性。
  35. 根据权利要求34所述的方法，其中，每28天为一个治疗周期，其中式(I)所示化合物或其可药用盐在第1天至第21天连续服用，阿那曲唑在28天的治疗周期中每天给药。
  36. 根据权利要求34所述的方法，其中，患者服用式(I)所示化合物或其可药用盐时为空腹。
  37. 根据权利要求34-36任一项所述的方法，其中，所述乳腺癌为激素受体阳性 (HR+)、和/或人表皮生长因子受体2阴性(HER2-)的乳腺癌。
  38. 根据权利要求37所述的方法，其中，所述式(I)所示化合物或其可药用盐的每日剂量为100-150mg。
  39. 根据权利要求38所述的方法，其中，所述式(I)所示化合物或其可药用盐的每日剂量为100mg，125mg或150mg。
  40. 根据权利要求37所述的方法，其中，所述阿那曲唑的每日剂量为0.1-10mg。
  41. 根据权利要求40所述的方法，其中，所述阿那曲唑的每日剂量为0.5mg，1mg或1.5mg。
  42. 根据权利要求34-41任一项所述的方法，其中，所述式(I)所示化合物或其可药用盐早晨给药。
  43. 根据权利要求34-42任一项所述的方法，其中，所述式(I)所示化合物可药用盐为羟乙基磺酸盐。
  44. 一种增加式(I)所示化合物或其可药用盐服药后AUC的方法，其中，其包括给予患者有效量的式(I)所示化合物或其可药用盐和阿那曲唑，
    Figure PCTCN2020073815-appb-100005
    所述患者患有乳腺癌，当给与式(I)所示化合物或其可药用盐时患者为空腹。
PCT/CN2020/073815 2019-01-30 2020-01-22 一种含cdk4/6抑制剂的组合物与阿那曲唑联合在制备治疗肿瘤疾病的药物中的用途 WO2020156446A1 (zh)

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