WO2021104319A1 - 喹唑啉衍生物或其盐的联用药物组合物及其用途 - Google Patents

喹唑啉衍生物或其盐的联用药物组合物及其用途 Download PDF

Info

Publication number
WO2021104319A1
WO2021104319A1 PCT/CN2020/131537 CN2020131537W WO2021104319A1 WO 2021104319 A1 WO2021104319 A1 WO 2021104319A1 CN 2020131537 W CN2020131537 W CN 2020131537W WO 2021104319 A1 WO2021104319 A1 WO 2021104319A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
formula
pharmaceutical composition
pharmaceutically acceptable
capecitabine
Prior art date
Application number
PCT/CN2020/131537
Other languages
English (en)
French (fr)
Inventor
张硕钰
封帆
黄云虎
唐晓闻
王训强
尚磊
何佳丽
晏彩霞
董平
周杰
孙迎迎
许易
陈智林
Original Assignee
正大天晴药业集团股份有限公司
连云港润众制药有限公司
首药控股(北京)有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 正大天晴药业集团股份有限公司, 连云港润众制药有限公司, 首药控股(北京)有限公司 filed Critical 正大天晴药业集团股份有限公司
Priority to CN202080071610.4A priority Critical patent/CN114761010B/zh
Publication of WO2021104319A1 publication Critical patent/WO2021104319A1/zh

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • This application belongs to the field of medical technology, and relates to a combined pharmaceutical composition of a quinazoline derivative or a salt thereof, and its use for the treatment of breast cancer.
  • EGFR epidermal growth factor receptor
  • HER2/ErbB family which includes EGFR, HER2, HER3 and HER4, and consists of three parts: extracellular The ligand binding region, the transmembrane region composed of a single chain, and the intracellular tyrosine kinase region.
  • EGFR is widely distributed on the surface of mammalian epithelial cells, fibroblasts, glial cells, keratinocytes and other cells.
  • the EGFR signaling pathway plays an important role in the physiological processes of cell growth, proliferation and differentiation. Loss of function of protein tyrosine kinases such as EGFR or abnormal activity of key factors in related signal pathways or abnormal cell positioning can cause tumors, diabetes, immunodeficiency and cardiovascular diseases.
  • the compound of formula (I) disclosed in WO2015043515A is a selective epidermal growth factor receptor inhibitor, which can competitively bind to the phosphorylation site of intracellular tyrosine kinase to block its interaction with ATP and inhibit tyrosine Phosphorylation and a series of downstream signal transduction, and then inhibit the growth of tumor cells, can be used to treat a variety of malignant tumors such as non-small cell lung cancer and breast cancer.
  • the application provides a combined pharmaceutical composition, which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof and capecitabine
  • the present application provides a combined pharmaceutical composition for the treatment or prevention of breast cancer, which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof and capecitabine.
  • the present application provides a method for treating or preventing breast cancer, which comprises administering a combined pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and capecitabine to an individual in need.
  • a combined pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and capecitabine in the preparation of a medicament for treating or preventing breast cancer.
  • a combined pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and capecitabine in the treatment or prevention of breast cancer.
  • the present application provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for the treatment or prevention of breast cancer.
  • this application also provides the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof for the treatment or prevention of breast cancer.
  • this application also provides the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment or prevention of breast cancer.
  • this application provides a method for treating or preventing breast cancer, which comprises administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to an individual in need.
  • the application provides a combined pharmaceutical composition, which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof and capecitabine
  • the present application provides a combined pharmaceutical composition for the treatment or prevention of breast cancer, which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof and capecitabine.
  • the combination pharmaceutical composition is packaged in the same kit, and the kit further comprises a combination of a compound of formula (I) or a pharmaceutically acceptable salt thereof and capecitabine for treatment Or instructions to prevent breast cancer.
  • the combination pharmaceutical composition includes a pharmaceutical composition containing capecitabine and a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the combination pharmaceutical composition is packaged in the same kit, and the kit further comprises a pharmaceutical composition containing capecitabine and a compound containing formula (I) or its medicinal product. Instructions for the combined use of salt-based pharmaceutical compositions to treat or prevent breast cancer.
  • the combination pharmaceutical composition contains 150 mg-4600 mg capecitabine.
  • the combination pharmaceutical composition contains 500 mg-4600 mg capecitabine. In some embodiments of the application, the combination pharmaceutical composition contains 1200 mg-4600 mg capecitabine.
  • the combination pharmaceutical composition contains capecitabine of 1200mg-4600mg and 0.5mg-40mg of the compound of formula (I) or its pharmaceutically acceptable compound. salt.
  • the combination pharmaceutical composition contains 1200mg, 1500mg, 1600mg, 1800mg, 2000mg, 2100mg, 2300mg, 2200mg, 2400mg, 2600mg, 2800mg, 2900mg, 3000mg, 3200mg, 3500mg, 3600mg, 4000mg , 4300mg or 4600mg of capecitabine.
  • the combination pharmaceutical composition contains 2300 mg, 2600 mg, 2900 mg, 3200 mg, 3500 mg, 3600 mg, 4000 mg, 4300 mg or 4600 mg of capecitabine.
  • the combination pharmaceutical composition contains 1600mg-3500mg capecitabine.
  • the combination pharmaceutical composition contains 1600 mg, 2000 mg, 2200 mg, 2400 mg, 2600 mg, 2800 mg, 3000 mg, 3200 mg or 3500 mg of capecitabine.
  • the combination pharmaceutical composition contains 1200mg-2200mg capecitabine.
  • the combination pharmaceutical composition contains 1200 mg, 1500 mg, 1600 mg, 1800 mg, 2000 mg, 2100 mg or 2200 mg of capecitabine.
  • the combination pharmaceutical composition contains 1000 mg/m 2 , 1500 mg/m 2 or 2000 mg/m 2 of capecitabine based on the body surface area of the individual.
  • body surface area BSA (m2) 0.00616 ⁇ height (cm)+0.01286 ⁇ weight (kg)-0.1529.
  • capecitabine in the combination pharmaceutical composition, is in a single dose or multiple doses.
  • capecitabine in the combination pharmaceutical composition, is in multiple doses.
  • the content of capecitabine in the combination pharmaceutical composition is a daily dose. In some embodiments of the present application, in the combination pharmaceutical composition, the content of the capecitabine is twice a day. In some embodiments of the application, each dose of the two doses is the same.
  • the content of the capecitabine is two doses per day, and each dose is a multiple dose.
  • the capecitabine in the combination pharmaceutical composition, is a multiple dose, which consists of a single dose of 150 mg and/or 500 mg of capecitabine. In some embodiments of the present application, the combination pharmaceutical composition contains a single dose of 150 mg and/or 500 mg of capecitabine.
  • the pharmaceutical composition containing capecitabine in the combination pharmaceutical composition, is packaged in a kit, and the kit also contains capecitabine for the treatment or prevention of mammary glands. Explanation of cancer.
  • the pharmaceutical composition containing capecitabine in the combination pharmaceutical composition, is packaged in a kit, and the kit also contains capecitabine for the treatment or prevention of mammary glands.
  • the description of the cancer the description may be the description in the description in the commercially available capecitabine tablet kit.
  • the description is capecitabine tablets produced by Zhengda Tianqing Pharmaceutical Group Co., Ltd. (e.g. ) The description in the manual.
  • the combination pharmaceutical composition contains 0.2 mg to 60 mg, or 0.5 mg to 40 mg, or 1.0 mg to 40 mg, or 1.5 mg to 40 mg, or 2 mg based on the compound of formula (I) itself.
  • the compound or its pharmaceutically acceptable salt is 0.2 mg to 60 mg, or 0.5 mg to 40 mg, or 1.0 mg to 40 mg, or 1.5 mg to 40 mg, or 2 mg based on the compound of formula (I) itself.
  • the combined pharmaceutical composition contains 0.5 mg-40 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof based on the compound of formula (I) itself.
  • the combined pharmaceutical composition contains 2 mg-20 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof based on the compound of formula (I) itself.
  • the combination pharmaceutical composition contains 0.2 mg, 0.5 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5mg, 5mg, 5.5mg, 6mg, 6.5mg, 7mg, 7.5mg, 8mg, 8.5mg, 9mg, 9.5mg, 10mg, 10.5mg, 11mg, 11.5mg, 12mg, 12.5mg, 13mg, 13.5mg, 14mg, 14.5 mg, 15 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg or 18 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the combined pharmaceutical composition contains 2 mg, 4 mg, 5 mg, 6 mg, 8 mg, 10 mg, 12 mg or 16 mg of the compound of formula (I) or its pharmaceutically acceptable compound based on the compound of formula (I) itself.
  • Use salt 2 mg, 4 mg, 5 mg, 6 mg, 8 mg, 10 mg, 12 mg or 16 mg of the compound of formula (I) or its pharmaceutically acceptable compound based on the compound of formula (I) itself.
  • the combined pharmaceutical composition contains 2 mg, 5 mg or 10 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof based on the compound of formula (I) itself.
  • the combined pharmaceutical composition contains 4 mg, 6 mg, 8 mg, 10 mg, 12 mg or 16 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof based on the compound of formula (I) itself.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof in the combination drug composition, is in a single dose or multiple doses; in some embodiments of the present application, the combination drug In the composition, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a single dose.
  • the content of the compound of formula (I) or a pharmaceutically acceptable salt thereof is the daily dose.
  • the content of the compound of formula (I) or a pharmaceutically acceptable salt thereof is a once-daily dose.
  • the content of the compound of formula (I) or its pharmaceutically acceptable salt is a once-daily dose, and each dose is a single dose or multiple doses, usually Single dose.
  • the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is packaged in a kit, and the kit further contains formula (I) ) Instructions for the use of the compound or its pharmaceutically acceptable salt in the treatment or prevention of breast cancer.
  • the combination pharmaceutical composition contains capecitabine at a daily dose of 2000 mg/m 2 based on the body surface area of the individual; and 4 mg, 6 mg based on the compound of formula (I) itself. , 8mg, 10mg, 12mg or 16mg daily dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the combination pharmaceutical composition contains a single dose of 150 mg and/or 500 mg of capecitabine; and the compound of formula (I) itself contains a single dose of 2 mg, 4 mg, 5 mg, 6mg, 8mg, 10mg, 12mg or 16mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof and capecitabine may be in the form of a pharmaceutical composition or together as a pharmaceutical composition. Composition form.
  • this application also provides a method for treating or preventing breast cancer, which comprises administering a therapeutically effective amount of the above-mentioned combination pharmaceutical composition of this application to an individual in need.
  • the content of capecitabine in the combination pharmaceutical composition is a daily dose, which is administered in the following manner: capecitabine Tabine is administered once or twice a day; in some embodiments of the application, capecitabine is administered twice a day; in some embodiments of the application, capecitabine is administered 2 times a day In some embodiments of the present application, capecitabine is administered twice a day, and each dosage is the same, and the interval between each administration is 12 hours.
  • the content of capecitabine in the combination pharmaceutical composition is a daily dose, wherein capecitabine is in a single dose or Multi-dose administration. In some embodiments of the application, wherein the capecitabine is administered in multiple doses.
  • the content of capecitabine in the combination pharmaceutical composition is a daily dose, wherein the capecitabine is in a multi-dose manner.
  • the multiple doses consist of a single dose of 150 mg and/or 500 mg of capecitabine.
  • capecitabine in the method of treating or preventing breast cancer, wherein capecitabine is administered by the following manner: each time it is administered to the individual 500 mg/m 2 -1250 mg/m 2 or 500 mg/m Capecitabine of 2 -1000 mg/m 2 (based on the body surface area of the individual) is administered twice a day. In some embodiments of the present application, 500 mg/m 2 , 750 mg/m 2 or 1000 mg/m 2 (based on the body surface area of the individual) of capecitabine is administered to the individual each time, twice a day.
  • the content of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the combined pharmaceutical composition is a daily dose, which is determined by The administration is as follows: the compound of formula (I) or its pharmaceutically acceptable salt is administered once a day.
  • the content of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the combination pharmaceutical composition is a daily dose, wherein the formula (I)
  • the compound or its pharmaceutically acceptable salt is administered in a single dose or multiple doses, usually in a single dose; further, the compound of formula (I) or its pharmaceutically acceptable salt is administered once a day.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in the following manner: a daily dose of 4 mg; alternatively, a daily dose of 6 mg; alternatively, a daily dose of 8 mg; Or the daily dose is 10 mg; or the daily dose is 12 mg; or the daily dose is 16 mg.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in the manner of continuous daily administration.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof and capecitabine are each in the form of a pharmaceutical composition, which can be administered simultaneously, separately, concurrently, sequentially or at intervals.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof and capecitabine have the same or different treatment cycles, respectively.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof and capecitabine have the same treatment cycle, for example, every 1 week, every 2 weeks, every 3 weeks or every 4 weeks. One week is a treatment cycle.
  • 21 days is a treatment cycle
  • capecitabine is continuously administered on days 1-14 of each treatment cycle
  • the formula is administered daily on days 1-21 of each treatment cycle.
  • 21 days is a treatment cycle
  • capecitabine is continuously administered twice a day (for example, once every 12 hours) on days 1-14 of each treatment cycle.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once a day on the 1st to 21st day of each treatment cycle.
  • the capecitabine is administered in an interval administration manner. In some embodiments of the present application, the capecitabine can be continuously administered on days 1-14 of each treatment cycle, with the drug stopped for 7 days.
  • 21 days is a treatment cycle, once a day is administered for 21 consecutive days, and the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in each treatment cycle
  • the total dose is 168 ⁇ 336mg (based on the active ingredient compound of formula (I) itself).
  • the total dose of the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the range formed by 168 mg, 210 mg, 252 mg, 336 mg or any two of the foregoing values.
  • the total dose of the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is preferably 168 mg to 252 mg.
  • the content of capecitabine and the compound of formula (I) or its pharmaceutically acceptable salt in the combination pharmaceutical composition is each Daily dosage, which is administered in the following way: 21 days is a treatment cycle, capecitabine is administered twice a day on days 1-14 of each treatment cycle, and each dosage is the same, and each administration The interval is 12 hours and the drug is stopped for 7 days; the compound of formula (I) or its pharmaceutically acceptable salt is administered once a day on the 1st to 21st day of each treatment cycle.
  • the capecitabine is prepared to be suitable for administering 1150 mg-2300 mg, or 800 mg-1750 mg, or 600-1100 mg of capecitabine to the patient twice a day for 14 consecutive days
  • the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is prepared in a single dose or multiple doses of 4 mg, 6 mg, 8 mg, and 4 mg, 6 mg, 8 mg, and the compound of formula (I) for continuous daily administration to patients.
  • 1150mg, 1300mg, 1450mg, 1600mg, 1750mg, 1800mg, 2000mg, 2150mg or 2300mg of capecitabine are administered to the patient each time; or 800mg, 1000mg, 1100mg, 1200mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg or 1750 mg capecitabine; or each time 600 mg, 750 mg, 800 mg, 900 mg, 1000 mg, 1050 mg or 1100 mg capecitabine is administered to the patient.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof is prepared to be suitable for administering to a patient a single dose of 8 mg, 10 mg, 12 mg and/or 16 mg of the compound of formula (I) or Multiple doses; or, the compound of formula (I) or a pharmaceutically acceptable salt thereof is prepared to be suitable for continuous daily administration of a single dose or multiple doses of 8 mg, 10 mg, and/or 12 mg of the compound of formula (I) itself to the patient.
  • this application also provides the use of a combined pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and capecitabine in the preparation of a medicament for the treatment or prevention of breast cancer.
  • the combination pharmaceutical composition is the combination pharmaceutical composition described above in the application.
  • aspects such as the content of each component and the administration mode of the combined pharmaceutical composition are as described above.
  • the present application also provides the use of a combination pharmaceutical composition for the treatment or prevention of breast cancer.
  • the combination pharmaceutical composition is the above-mentioned combination pharmaceutical composition of the application.
  • the breast cancer is selected from HER 2 positive and/or fluorescent in situ hybridization (FISH) positive breast cancer.
  • FISH fluorescent in situ hybridization
  • the breast cancer is HER2-positive breast cancer.
  • the breast cancer is breast cancer whose HER 2 is 2+ or 3+. In some embodiments of the present application, the breast cancer is breast cancer whose HER 2 is 3+. In some embodiments of the present application, the breast cancer is a breast cancer whose HER 2 is 2+ and FISH positive.
  • the breast cancer is HER2, which is fluorescent in situ hybridization (FISH) positive breast cancer.
  • FISH fluorescent in situ hybridization
  • the breast cancer is advanced breast cancer or metastatic breast cancer.
  • the breast cancer is breast cancer that has previously been treated with a recombinant human HER-2 monoclonal antibody (such as trastuzumab, Herceptin) (such as HER-2 overexpression metastasis).
  • a recombinant human HER-2 monoclonal antibody such as trastuzumab, Herceptin
  • HER-2 overexpression metastasis breast cancer
  • the breast cancer is breast cancer that has previously been treated with trastuzumab drugs.
  • trastuzumab is used for ⁇ 3 months in the treatment phase, or ⁇ 2 cycles in the post-relapse/metastasis phase (eg: 21 days/cycle).
  • trastuzumab is used for ⁇ 3 months in the neoadjuvant/adjuvant treatment phase, or ⁇ 2 cycles (eg, 21 days/cycle) in the post-relapse/metastasis phase.
  • the breast cancer is breast cancer that has previously been treated with taxanes.
  • the treatment time of taxanes is ⁇ 2 cycles (e.g., 21 days/cycle).
  • taxanes are applied in the neoadjuvant/adjuvant treatment phase or in the treatment phase after recurrence/metastasis, and the treatment time is ⁇ 2 cycles (eg: 21 days/cycle), or it contains yew Drug-like treatment programs have disease progression in the treatment.
  • the breast cancer is breast cancer that has previously been treated with trastuzumab and/or taxanes.
  • the taxanes include but are not limited to paclitaxel, docetaxel, paclitaxel liposomes, or albumin-bound paclitaxel.
  • the breast cancer is selected from: invasive cancer, further FISH positive, and/or Her-2(3+), and/or c-erbB-2(2+/3+) ;
  • it also includes ER (+/-), PR (-/+), Ki67 (+, for example 30%-60%), P53 (-/3+).
  • the breast cancer is treated with epirubicin hydrochloride, cyclophosphamide, docetaxel, recombinant human HER-2 monoclonal antibody (such as trastuzumab, Herceptin Tine), breast cancer treated by one or more drugs in the recombinant humanized anti-Her-2 monoclonal antibody-maytansine conjugate for injection alone and/or in combination.
  • epirubicin hydrochloride such as trastuzumab, Herceptin Tine
  • breast cancer treated by one or more drugs in the recombinant humanized anti-Her-2 monoclonal antibody-maytansine conjugate for injection alone and/or in combination.
  • the breast cancer is an invasive cancer and has the following characteristics: ER (5%), PR (-), Her-2 (3+), Ki67 (40%).
  • the breast cancer has the following characteristics: Her-2(3+), ER(+), PR(-), c-erbB-2(2+), Ki67(40%) , P53(3+), FISH positive.
  • the breast cancer is breast cancer that has previously been treated with epirubicin hydrochloride combined with cyclophosphamide.
  • the breast cancer is breast cancer that has previously been treated with docetaxel combined with trastuzumab.
  • the breast cancer is breast cancer that has previously been treated with a recombinant humanized anti-Her-2 monoclonal antibody-maytansine conjugate for injection.
  • the breast cancer has the following characteristics: Her-2(3+), ER(-), PR(-), CerbB-2(3+), Ki67(30%), P53 (-).
  • the breast cancer is selected from breast cancers that have previously received cyclophosphamide, epirubicin hydrochloride combined with docetaxel, or trastuzumab combined with docetaxel. Treatment of breast cancer.
  • the active components in the pharmaceutical combination of the present application may be each independently, or part or all of them may be formulated together with pharmaceutically acceptable carriers and/or excipients.
  • the pharmaceutical combination of the present application may also contain additional therapeutic agents.
  • the additional therapeutic agent may be a therapeutic agent for cancer known in the art, preferably a therapeutic agent for breast cancer.
  • the present application provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for the treatment or prevention of breast cancer.
  • this application also provides the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof for the treatment or prevention of breast cancer.
  • this application also provides the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment or prevention of breast cancer.
  • this application provides a method for treating or preventing breast cancer, which comprises administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to an individual in need.
  • the breast cancer is selected from HER 2 positive and/or fluorescent in situ hybridization (FISH) positive breast cancer.
  • FISH fluorescent in situ hybridization
  • the breast cancer is HER2-positive breast cancer.
  • the breast cancer is breast cancer whose HER 2 is 2+ or 3+. In some embodiments of the present application, the breast cancer is breast cancer whose HER 2 is 3+. In some embodiments of the present application, the breast cancer is a breast cancer whose HER 2 is 2+ and FISH positive.
  • the breast cancer is HER2, which is fluorescent in situ hybridization (FISH) positive breast cancer.
  • FISH fluorescent in situ hybridization
  • the breast cancer is advanced breast cancer or metastatic breast cancer.
  • the breast cancer is a breast cancer that has previously been treated with a recombinant human HER-2 monoclonal antibody (e.g., trastuzumab, Herceptin) (e.g., HER-2 overexpression metastasis) Breast cancer).
  • a recombinant human HER-2 monoclonal antibody e.g., trastuzumab, Herceptin
  • HER-2 overexpression metastasis breast cancer
  • the recombinant human HER-2 monoclonal antibody is used for ⁇ 3 months in the treatment phase, or ⁇ 2 cycles in the post-relapse/metastasis phase (eg: 21 days/cycle).
  • the recombinant human HER-2 monoclonal antibody is used for ⁇ 3 months in the neoadjuvant/adjuvant treatment phase, or ⁇ 2 cycles in the post-relapse/metastasis phase (eg: 21 days/cycle) .
  • the dosage of recombinant human HER-2 monoclonal antibody is 512 mg/cycle or 384 mg/cycle (eg, 21 days/cycle).
  • the breast cancer is breast cancer that has previously been treated with taxanes.
  • the treatment time of taxanes is ⁇ 2 cycles (e.g., 21 days/cycle).
  • taxanes are applied in the neoadjuvant/adjuvant treatment phase or in the treatment phase after recurrence/metastasis, and the treatment time is ⁇ 2 cycles (eg: 21 days/cycle), or they contain taxanes
  • the drug treatment program has disease progression in the treatment.
  • the breast cancer is breast cancer that has previously been treated with trastuzumab and/or taxanes.
  • the taxanes include but are not limited to paclitaxel, docetaxel, paclitaxel liposomes, or albumin-bound paclitaxel.
  • the breast cancer is an invasive cancer and has the following characteristics: ER (-), PR (-), HER-2 (3+), Ki67 (20%), P53.
  • the breast cancer is a recombinant human HER-2 monoclonal antibody (e.g. trastuzumab, Herceptin) or a recombinant human HER-2 monoclonal antibody (e.g., trastuzumab).
  • trastuzumab Herceptin
  • trastuzumab Herceptin
  • docetaxel for breast cancer such as HER2-positive breast cancer
  • the dosage of recombinant human HER-2 monoclonal antibody is 512 mg/cycle or 384 mg/cycle, and the dosage of docetaxel is 127.5 mg/cycle.
  • the breast cancer is breast cancer that has been sequentially treated as follows: recombinant human HER-2 monoclonal antibody (for example, 512 mg/cycle) combined with docetaxel (for example, 127.5 mg/cycle) Treatment (for example, 1 cycle); recombinant human HER-2 monoclonal antibody (for example, 384 mg/cycle) combined with docetaxel (for example, 127.5 mg/cycle) (for example, 8 cycles); recombinant human HER-2 monoclonal antibody (For example, 384mg/cycle).
  • the breast cancer is breast cancer that has undergone radical mastectomy in the past.
  • the breast cancer is invasive breast cancer and has the following characteristics: HER-2 (3+), ER (-), PR (-), cerbB-2 (3+).
  • the breast cancer is breast cancer that has been treated with a urine polypeptide (for example, 300 ml/cycle) in the past; for example, it may be treated for 2 cycles; for example, it may be used as an adjuvant therapy.
  • a urine polypeptide for example, 300 ml/cycle
  • the breast cancer is breast cancer that has previously been treated with epirubicin hydrochloride (for example, 135 mg/cycle) combined with cyclophosphamide (for example, 0.9 g/cycle); for example, it may be treated for 4 cycles ; For example, it can be used as an adjuvant therapy.
  • epirubicin hydrochloride for example, 135 mg/cycle
  • cyclophosphamide for example, 0.9 g/cycle
  • it may be treated for 4 cycles ;
  • it can be used as an adjuvant therapy.
  • the breast cancer is breast cancer that has been treated with thalidomide in the past; for example, it can be 2 capsules/time, 2 times/day, po d1-d5/cycle, treatment for 2 cycles; For example, it can be used as an adjuvant therapy.
  • the breast cancer is breast cancer that has been previously treated with docetaxel (for example, 140 mg/cycle); for example, it may be treated for 4 cycles; for example, it may be used as an adjuvant therapy.
  • docetaxel for example, 140 mg/cycle
  • it may be treated for 4 cycles; for example, it may be used as an adjuvant therapy.
  • the breast cancer is breast cancer that has previously been treated with trastuzumab combined with docetaxel.
  • the breast cancer is breast cancer that has received the following treatments in the past successively: treatment of radical mastectomy; treatment of urinary polypeptides; treatment of epirubicin hydrochloride combined with cyclophosphamide; thalidomide Amine treatment; docetaxel treatment; trastuzumab combined with docetaxel treatment.
  • the period is 21 days.
  • the amount of the compound of formula (I) or its pharmaceutically acceptable salt administered can be determined according to the severity of the disease, the response of the disease, any treatment-related toxicity, the age and health of the patient.
  • the daily dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 0.2 mg to 60 mg, or 0.5 mg to 40 mg, or 1.0 mg to 1.0 mg to 40mg, or 1.5mg to 40mg, or 2mg to 40mg, or 4mg to 40mg, or 5mg to 40mg, or 6mg to 40mg, or 7mg to 40mg, or 8mg to 40mg, or 8mg to 30mg , Or 8mg to 25mg, or 8mg to 20mg, or 8mg to 16mg.
  • the daily dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 0.2 mg, 0.5 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3.0 mg calculated by the compound of formula (I) itself. , 3.5mg, 4.0mg, 4.5mg, 5mg, 5.5mg, 6mg, 6.5mg, 7mg, 7.5mg, 8mg, 8.5mg, 9mg, 9.5mg, 10mg, 10.5mg, 11mg, 11.5mg, 12mg, 12.5mg, 13mg, 13.5mg, 14mg, 14.5mg, 15mg, 15.5mg, 16mg, 16.5mg, 17mg, 17.5mg or 18mg.
  • the daily dose of the compound of formula (I) or its pharmaceutically acceptable salt is calculated as 4 mg of the compound of formula (I) itself; alternatively, the daily dose is 6 mg; alternatively, the daily dose is 8 mg; or The dose is 10 mg; or the daily dose is 12 mg; or the daily dose is 16 mg.
  • the compound of formula (I) or its pharmaceutically acceptable salt can be administered by a variety of routes, including but not limited to the following routes: oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, intramuscular , Rectum, transbuccal, intranasal, inhalation, vagina, intraocular, topical administration, subcutaneous, intra-fat, intra-articular, intraperitoneal and intrathecal.
  • routes including but not limited to the following routes: oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, intramuscular , Rectum, transbuccal, intranasal, inhalation, vagina, intraocular, topical administration, subcutaneous, intra-fat, intra-articular, intraperitoneal and intrathecal.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in the manner of continuous daily administration.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof can be administered one or more times a day. In some embodiments of the present application, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once a day.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof can also be administered in a single dose or multiple doses. In one embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in a single dose once a day.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once a day in the form of a single-dose oral solid preparation. In one embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once a day in multiple doses.
  • the method of administration can be comprehensively determined according to the activity, toxicity and patient tolerance of the drug.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof is prepared to be suitable for continuous daily administration of 4 mg, 6 mg, 8 mg, 10 mg, 12 mg and 12 mg of the compound of formula (I) to the patient every day. / Or a single dose or multiple doses of 16 mg.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof is prepared to be suitable for administering to a patient a single dose of 8 mg, 10 mg, 12 mg and/or 16 mg of the compound of formula (I) or Multiple doses; or, the compound of formula (I) or a pharmaceutically acceptable salt thereof is prepared to be suitable for continuous daily administration of a single dose or multiple doses of 8 mg, 10 mg, and/or 12 mg of the compound of formula (I) itself to the patient.
  • the compound of formula (I) of the present application can be administered in the form of its free base, or in the form of its salt, hydrate and prodrug, which is converted into the free base form of the compound of formula (I) in vivo.
  • a pharmaceutically acceptable salt of the compound of formula (I) is within the scope of the present invention, and the salt can be produced from different organic acids and inorganic acids according to methods well known in the art.
  • the pharmaceutically acceptable salt described in this application is selected from maleate, hydrochloride, hydrobromide, sulfate, phosphate, nitrate, acetate, lactate, malonate, succinic acid Salt, fumarate, malate, mandelate, tartrate, citrate, ascorbate, palmitate, benzoate, phenylacetate, cinnamate, salicylate, methanesulfonate Acid salt, benzene sulfonate or toluene sulfonate.
  • the pharmaceutically acceptable salt is selected from maleate, malate, fumarate, tartrate, citrate, lactate, phosphate, or acetate.
  • the pharmaceutically acceptable salt is maleate.
  • the molar ratio of the compound of formula (I) to the acid radical ion forming the pharmaceutically acceptable salt may be 1:1.
  • the pharmaceutically acceptable salt of the compound of formula (I) described in this application, the compound of formula (I) or the pharmaceutically acceptable salt thereof is selected from the compound of formula (I) or the maleate of the compound of formula (I).
  • the pharmaceutically acceptable salt of the compound of formula (I) described in this application is a compound of formula (II)
  • composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof containing a compound of formula (I) or a pharmaceutically acceptable salt thereof
  • the "compound of formula (I) or a pharmaceutically acceptable salt thereof” mentioned in the present application may be a “pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof", and further, may be “containing a compound of formula (II) ) The pharmaceutical composition of the compound”.
  • the method of administration can be comprehensively determined according to the activity, toxicity and patient tolerance of the drug.
  • the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof further contains pharmaceutically acceptable excipients.
  • the pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, polymethacrylate and a surface stabilizer.
  • the pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, polymethacrylate, acid, surface stable Agent, dispersant and carrier.
  • the pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises a compound of formula (II), polymethacrylate, acid, surface stabilizer, dispersant and carrier .
  • the polymethacrylate is N-(2-methacrylate).
  • the polymethacrylate is selected from or
  • the polymethacrylate is N-(2-methacrylate).
  • the weight ratio of polymethacrylate to the compound of formula (I) or a pharmaceutically acceptable salt thereof is 50 ⁇ 0.5:1, or 45 ⁇ 1:1, or 40 ⁇ 1.5:1, or 35 ⁇ 2:1, or 30 ⁇ 3:1, or 25 ⁇ 4:1, or 20 ⁇ 5:1, or 18 ⁇ 5.5:1, or 16 ⁇ 5.7:1, or 14 ⁇ 5.9:1, or 12 ⁇ 6.1:1, or 10 ⁇ 6.3:1, or 8.5 ⁇ 6.5:1, or 8.5 ⁇ 7:1, or 8.5 ⁇ 7.5:1.
  • the weight ratio of polymethacrylate to the compound of formula (II) is 8:1.
  • the acid is selected from maleic acid, malic acid, fumaric acid, tartaric acid, citric acid, lactic acid, phosphoric acid, or acetic acid.
  • the acid is maleic acid.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof in the pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof, is relative to the total amount of the solid pharmaceutical composition.
  • the mass is 0.1-50% by weight, or 0.1-20% by weight, or 0.1-10% by weight, or 0.1-5% by weight, or 0.1-4% by weight.
  • the surface stabilizer is selected from the group consisting of hydroxypropyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose Methyl-cellulose, hydroxypropylmethyl-cellulose phthalate, or non-crystalline cellulose.
  • the surface stabilizer is hydroxypropyl cellulose (for example, HPC-SL type).
  • the weight ratio of the surface stabilizer to the compound of formula (I) or its pharmaceutically acceptable salt is 0.06- 1:1, or 0.07 ⁇ 0.9:1, or 0.08 ⁇ 0.8:1, or 0.09 ⁇ 0.7:1, or 0.10 ⁇ 0.6:1, or 0.11 ⁇ 0.5:1, or 0.12 ⁇ 0.7:1, or 0.13 ⁇ 0.6 :1. Or 0.14 ⁇ 0.5:1, or 0.15 ⁇ 0.4:1, or 0.15 ⁇ 0.3:1, or 0.15 ⁇ 0.2:1.
  • the weight ratio of the surface stabilizer to the compound of formula (II) is 0.16:1.
  • the dispersant is selected from sucrose, lactose, or mannitol.
  • the dispersant is sucrose.
  • the weight ratio of the dispersant to the compound of formula (I) or its pharmaceutically acceptable salt is 0.5-50 :1, or 0.8 ⁇ 45:1, or 1.1 ⁇ 40:1, or 1.4 ⁇ 35:1, or 1.7 ⁇ 30:1, or 2 ⁇ 25:1, or 2.3 ⁇ 20:1, or 2.8 ⁇ 15: 1. Or 3.1 ⁇ 10:1, or 3.4 ⁇ 9:1, or 3.7 ⁇ 8:1, or 4.0 ⁇ 7:1, or 4.3 ⁇ 6:1, or 4.5 ⁇ 5.5:1,
  • the weight ratio of the dispersant to the compound of formula (II) is 5:1.
  • the carrier is selected from the group consisting of cellulose pellets, mannitol pellets, tartaric acid pellets, lactose/microcrystalline pellets, sucrose pellets, starch pellets, and combinations thereof.
  • the carrier is selected from cellulose pellets or sucrose pellet cores.
  • the carrier is a sucrose pellet core (e.g., 0.6-0.8 mm).
  • the proportion of the carrier in the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from 0.1 to 99% by weight, 0.5 to 99% by weight, 1 to 99% by weight, and 5 to 99% by weight. 99wt%, 10-99wt%, 15-99wt%, 20-99wt%, 25-99wt%, 30-99wt%, 35-99wt%, 40-99wt%, or 45-99wt%.
  • the pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises a compound of formula (II), hydroxypropyl cellulose (for example, HPC-SL type), sucrose , Polymethacrylate (e.g. ), maleic acid, sucrose core (e.g. 0.6-0.8mm).
  • composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof contains the following components in the following parts by weight:
  • the polymethacrylate, acid, surface stabilizer, dispersant and carrier are respectively as above As defined by the text.
  • composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof contains the following components in the following parts by weight:
  • composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof contains the following components in the following parts by weight:
  • composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof contains the following components in the following parts by weight:
  • composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof contains the following components in the following parts by weight:
  • composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof contains the following components in the following parts by weight:
  • the particle size range of the compound of formula (I) or its pharmaceutically acceptable salt is D50 ⁇ 10 ⁇ m, D90 ⁇ 20 ⁇ m; or D50 ⁇ 5 ⁇ m, D90 ⁇ 10 ⁇ m; or D50 ⁇ 2 ⁇ m, D90 ⁇ 4 ⁇ m.
  • the particle size range of the compound of formula (I) or its pharmaceutically acceptable salt is D50 ⁇ 2 ⁇ m and D90 ⁇ 4 ⁇ m.
  • the acid such as maleic acid is added in an appropriate amount, for example, to make the pharmaceutical composition acidic in water.
  • the maleic acid is added in an appropriate amount.
  • the acid in each of the pharmaceutical compositions containing a compound of formula (I) or a pharmaceutically acceptable salt thereof, can be used as a pH adjusting agent.
  • the acid in the preparation process of the solid pharmaceutical composition, is used to adjust the pH range, for example, to make the aqueous solution of the pharmaceutical composition acidic, and more specifically, for example, the pH of the aqueous solution is between 2.0-3.5 (for example, 2.0 ⁇ pH ⁇ 3.0 or 3.0 ⁇ pH ⁇ 3.5).
  • compositions of the present application containing the compound of formula (I) or a pharmaceutically acceptable salt thereof can be formulated into a preparation form suitable for oral administration to humans, for example including but not limited to tablets, pills, capsules, Powder or granule, etc.
  • the pharmaceutical composition of the present application containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered orally.
  • each of the pharmaceutical compositions containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is a solid pharmaceutical composition.
  • the preparation form of the solid pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is a capsule.
  • the capsule is filled with pellet particles, and the pellet particles comprise the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof as described above.
  • the capsule is a hard capsule or a soft capsule.
  • Capsules can be filled according to known methods, for example, by filling the aforementioned pellets containing the compound of formula (I) or a pharmaceutically acceptable salt thereof into those made of gelatin, hydroxypropyl methylcellulose, polyvinyl alcohol, etc. In hard capsules, or in soft gelatin-based capsules.
  • composition of the present application containing the compound of formula (I) or its pharmaceutically acceptable salt can be manufactured by methods well known in the art, such as conventional mixing method, dissolution method, granulation method, sugar-coated pill method, grinding method, Emulsification method, freeze-drying method, etc.
  • the solid oral composition can be prepared by conventional mixing, filling or tableting methods. For example, it can be obtained by the following method: mixing the active compound with solid excipients, optionally grinding the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to obtain tablets Or the core of the dragee.
  • suitable excipients include but are not limited to: binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, and the like.
  • this application provides a method for preparing a solid composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof, including the following processes:
  • capecitabine is 5'-deoxy-5-fluoro-N-[(pentoxy)carbonyl]-cytidine, which has the following structural formula:
  • the pharmaceutical composition containing capecitabine further contains pharmaceutically acceptable excipients.
  • the pharmaceutical composition containing capecitabine may be formulated into a preparation form suitable for oral administration to humans, for example including but not limited to tablets, pills, capsules, powders or Granules and so on.
  • the pharmaceutical composition containing capecitabine is administered orally.
  • the pharmaceutical composition containing capecitabine is a solid pharmaceutical composition.
  • the formulation form of the pharmaceutical composition containing capecitabine is a tablet.
  • the pharmaceutical composition containing capecitabine comprises: capecitabine, anhydrous lactose, microcrystalline cellulose, croscarmellose sodium, hypromellose , Magnesium stearate and film-coated powder (stomach-soluble type).
  • the amount of capecitabine in the pharmaceutical composition containing capecitabine, is 150 mg or 500 mg.
  • the active ingredients in the combined pharmaceutical composition of the present application can be administered independently, or part or all of them can be jointly administered by various suitable routes, including, but not limited to, oral or parenteral (by intravenous, intramuscular) , Local or subcutaneous route).
  • the active ingredients in the combined pharmaceutical composition of the present application may be administered orally independently of each other, or part or all of them may be jointly orally administered.
  • the active ingredients in the combined pharmaceutical composition of the present application may each independently, or part or all of them are jointly suitable dosage forms, including, but not limited to, tablets, troches, pills, capsules (such as hard capsules). , Soft capsules, enteric-coated capsules, microcapsules), elixirs, granules, syrups, injections (intramuscular, intravenous, intraperitoneal), granules, emulsions, suspensions, solutions, dispersions and for oral administration Or a sustained-release formulation for parenteral administration.
  • the treatment regimen of the application for example, the combined pharmaceutical composition of the application, the compound of formula (I) or the pharmaceutically acceptable salt thereof
  • HER 2 is positive (e.g., HER 2 is 3+)
  • the combined drug composition has a better therapeutic effect, a lower dosage, and is well tolerated.
  • patient refers to a mammal, preferably a human.
  • patient and the individual are patients who have failed or lacked standard treatment.
  • pharmaceutically acceptable refers to a carrier, excipient or adjuvant used to prepare a pharmaceutical composition.
  • the carrier, excipient or adjuvant is generally safe, non-toxic and not biologically acceptable. It is undesirable academically or otherwise, and it is acceptable for the use of human medicine.
  • terapéuticaally effective amount means an amount sufficient to achieve treatment of the disease when the compound is administered to a human for the treatment of the disease.
  • treatment means administering the compound or formulation described in this application to ameliorate or eliminate a disease or one or more symptoms related to the disease, and includes:
  • prevention means administering the compounds or formulations described in this application to prevent a disease or one or more symptoms associated with the disease, including: preventing the occurrence of a disease or disease state in a mammal, especially when this When mammals are susceptible to this disease state, but have not been diagnosed as having this disease state.
  • pharmaceutically acceptable excipients refers to those excipients that have no obvious stimulating effect on the organism and do not impair the biological activity and performance of the active compound.
  • Suitable auxiliary materials are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like.
  • administration refers to the physical introduction of a composition containing a therapeutic agent to an individual using any of a variety of methods and delivery systems known to those skilled in the art.
  • the administration is oral administration.
  • daily dose refers to the daily dose administered to a patient.
  • body surface area-based dose refers to the dose administered to the patient calculated based on the patient's body surface area.
  • the term "individual/subject” is a mammal. In some embodiments, the individual is a human.
  • single dose refers to the smallest packaging unit of a medicine containing a certain amount of active ingredients. For example, if a box of medicines has seven capsules, each capsule is a single dose; for example, a box of medicines has seven medicines, and each medicine is Single dose.
  • multi-dose consists of multiple single doses.
  • “combined use” or “combined use” means that two or more active substances can each be administered to an individual simultaneously, concurrently, or each as a single formulation in any order sequentially as a single formulation.
  • pharmaceutical composition refers to a mixture of one or more of the active ingredients of the present application or their pharmaceutical combination and pharmaceutically acceptable excipients.
  • the purpose of the pharmaceutical composition is to facilitate the administration of the compound of the present application or a pharmaceutical combination thereof to an individual.
  • day (day) When referring to a dosing regimen, the terms “day (day)”, “every day (daily)”, etc. refer to the time within a calendar day, starting at midnight and ending at the next midnight.
  • PD Progressive disease, the maximum diameter of the target lesion increases by at least ⁇ 20%, or new lesions appear.
  • PR Partial response, the maximum diameter of the target lesion is reduced by ⁇ 30%, and it is maintained for at least 4 weeks.
  • OS overall survival, the time from the start of randomization to death (for any reason).
  • SD stable disease, the sum of the maximum diameters of the target lesions does not shrink to PR, or the increase does not reach PD.
  • Iv intravenous injection.
  • ER estrogen receptor.
  • FISH Fluorescence in situ hybridization.
  • PR progesterone receptor
  • HER-2 Positive for epidermal growth factor.
  • Ki67 nuclear antigen associated with cell proliferation.
  • P53 P53 gene, human tumor suppressor gene.
  • cerbB-2 a proto-oncogene.
  • ivgtt intravenous drip.
  • IHC Immunohistochemistry. ivgtt: intravenous drip.
  • composition of the specific pharmaceutical capsule preparation is shown in Table 1 below.
  • Examples 2-5 were prepared with reference to the process of Example 1.
  • the specific composition of the pharmaceutical capsule preparation is shown in Table 2 below.
  • Example 3 water 1 : 266.68 mg; water 2 : 200 mg;
  • Example 4 water 1 : 666.7mg; water 2 : 500mg;
  • Example 5 water 1 : 1333.4 mg; water 2 : 1000 mg.
  • step 3 the pH of the suspension is adjusted to be 2.0 ⁇ pH ⁇ 3.0, and water 1 : 25 mg; water 2 : 50 mg.
  • composition of the specific pharmaceutical capsule preparation is shown in Table 3 below.
  • Positive HER2 expression means that standard immunohistochemical staining (IHC) tests show that HER2 is 3+ and/or fluorescent in situ hybridization (FISH) positive;
  • At least one measurable lesion (according to RECIST 1.1 standard);
  • Trastuzumab should be used for ⁇ 3 months in the neoadjuvant/adjuvant treatment phase, or ⁇ 2 cycles in the post-relapse/metastasis phase (e.g. 21 days/cycle). Taxanes can be applied in various treatment stages such as neoadjuvant/adjuvant and recurrence/metastasis, and the treatment time should be ⁇ 2 cycles (e.g. 21 days/cycle);
  • Hb hemoglobin
  • ANC absolute neutrophil count
  • PHT platelets
  • ALT Alanine aminotransferase
  • AST aspartate aminotransferase
  • TBIL serum total bilirubin
  • Tr serum creatinine
  • Cr creatinine clearance ⁇ 60ml/min
  • Blood coagulation function activated partial thromboplastin time (APTT), international normalized ratio (INR), prothrombin time (PT) ⁇ 1.5 ⁇ ULN;
  • LVEF left ventricular ejection fraction
  • the starting dose is 4mg, 6mg, 8mg, 10mg, 12mg or 16mg, once a day, for 21 consecutive days as a treatment cycle, until the study termination criteria.
  • Capecitabine tablets 150mg (commercially available), 500mg (commercially available, produced by Chia Tai Tianqing Pharmaceutical Group Co., Ltd.)
  • the starting dose is 1000mg/m 2 (or 750mg/m 2 or 500mg/m 2 ), 2 times a day, orally within 30 minutes after a meal (1 time in the morning and evening, 12 hours apart, equal to a daily dose of 2000 mg/m 2 (or 1500mg/m 2 or 1000mg/m 2 )), continuous administration on day 1-14, stopping for 7 days, 21 days as a treatment cycle, until the study termination criteria.
  • the main efficacy indicators were evaluated according to the RECIST1.1 standard.
  • left breast 2 points ER(-), PR(-), HER-2(3+), Ki67 (index about 20%), P53; left armpit and left subocclusion: ER(-), PR (-), HER-2 (3+), Ki67 (index approximately 20%), P53.
  • the patient was given (recombinant human HER-2 monoclonal antibody for injection (Herceptin) 512mg/cycle d1 ivgtt + docetaxel 127.5mg/cycle ivgtt d2) regimen of chemotherapy for 1 cycle from 2019.3.4 to 2019.3.5; from 2019.3. 26-2019.8.20 given (recombinant human HER-2 monoclonal antibody for injection (Herceptin) 384mg/cycle d1 ivgtt + docetaxel 127.5mg/cycle ivgtt d2) regimen of chemotherapy for 8 cycles; from 2019.9.11-2020.1.
  • 2020.7.4-2020.8.14 take 10.0 mg capsules of the compound of formula (II) once a day (continuous medication every 21 days is a treatment cycle) for treatment.
  • Enhanced CT showed that the left breast lesion was slightly smaller than before; the liver lesion had little change from before; it was evaluated as PR according to RECIST1.1, and the total target lesion was 41mm.
  • the patient can basically tolerate the adverse reaction and continues to receive treatment.
  • 2015-03-16 The pathology of Heilongjiang Provincial Hospital showed: invasive carcinoma of the right breast, histology grade II.
  • 2015-03-18 pathology showed: the right breast cancer radical mastectomy specimens were cancer-free on each margin and nipple, and cancer metastasis was seen in the axillary lymph nodes 1/12.
  • 2015-03-27 pathology showed: immunohistochemistry: ER(-), PR( -), cerbB-2(3+).
  • 2015-03-31 Hazuma consultation showed: right breast invasive carcinoma was grade II, and 1/12 of the lymph nodes were cancerous. Immunohistochemistry: ER(-), PR(-), cerbB-2(3+).
  • the patient was enrolled in the "Phase IV Clinical Study of Urine Polypeptide Injection” on April 4, 2015, and was given 300ml of Urine Polypeptide Injection on April 24, 2015. IVgtt was treated for 2 cycles.
  • Treatment type adjuvant therapy, curative effect: NA, best curative effect: unknown.
  • the patient was given 4 cycles of chemotherapy (epirubicin hydrochloride 135mg/cycle ivgtt+cyclophosphamide 0.9g/cycle iv) from 2015.4.7 to 2015.6.9.
  • Treatment type adjuvant therapy, efficacy: NA, best efficacy: unknown.
  • thalidomide was given 2 capsules/time, 2 times/day, po d1-d5/cycle, treatment for 2 cycles, treatment type: adjuvant therapy, curative effect: NA, best curative effect: unknown. From 2015.5.18 to 2015.8.11, he was given thalidomide 2 capsules/time, 2 times/day, po d2-d6/cycle, treatment for 5 cycles, treatment type: adjuvant therapy, curative effect: NA, best curative effect: unknown.
  • Enhanced CT showed a nodule (reduced) in the upper lobe of the left lung, which was evaluated as SD according to RECIST1.1.
  • the total target lesion was 18mm, which was 7mm smaller than the baseline.
  • the patient can basically tolerate the adverse reaction and continues to receive treatment.
  • the patient was enrolled in the "Docetaxel combined with Herceptin/recombinant human HER-2 monoclonal antibody test for injection” on November 23, 2018.
  • the patient was given docetaxel 129mg/cycle ivgtt+Herceptin/recombinant human HER-2 monoclonal antibody for injection 616mg/cycle ivgtt on 2018.12.10 for 1 cycle; docetaxel 129mg was given from 2019.1.3-2019.3.5 /Cycle ivgtt+Herceptin/recombinant human HER-2 monoclonal antibody for injection 462mg/cycle ivgtt) 4 cycles of treatment. Best efficacy: unknown.
  • Efficacy PD (2019.3.22, CT target lesions are enlarged).
  • the patient was given Herceptin 440mg/cycle ivgtt for 2 cycles of maintenance treatment from March 25, 2019 to April 16, 2019.
  • Enhanced CT showed that the left breast lesion was smaller than before; the left axillary lymph node lesion was slightly smaller than before; it was evaluated as SD according to RECIST1.1, and the total target lesion was 58.5mm, which was 24.5mm smaller than the baseline.
  • the patient can basically tolerate the adverse reaction and continues to receive treatment.
  • trastuzumab/Herceptin combined with docetaxel was given for 14 cycles (2019.9.5, trastuzumab/Herceptin 472.5mg/cycle ivgtt D1+ Sitaxel 120mg/cycle ivgtt, D2 treatment for 1 cycle, 2019.9.26-2019.10.17, given trastuzumab/Herceptin 354.9mg/cycle ivgtt + docetaxel 120mg/cycle ivgtt for 2 cycles, 2019.11.17 -2020.2.4 give trastuzumab/Herceptin 354mg/cycle ivgtt+docetaxel 119.25mg/cycle ivgtt for 5 cycles; 2020.3.26-2020.4.15 give trastuzumab/Herceptin 354.9mg /Cycle ivgtt treatment for 2 cycles; 2020.5.14-2020.7.14 give trastuzumab/Herceptin 354m
  • the patient (her2 3+) was released from the group and started to receive the treatment of compound capsule of formula (II) combined with capecitabine.
  • the compound of formula (II) capsules combined with capecitabine tablets capsules of compound of formula (II): 10 mg/time, once/day, orally, every 21 days is a treatment cycle + capecitabine).
  • Bin tablets 1000mg/m2, 2 times/day, orally, continuous administration on day 1-14, stop for 7 days, every 21 days is a treatment cycle) for treatment.
  • the patient can basically tolerate the adverse reaction and continues to receive treatment.

Abstract

本申请涉及用于治疗或预防乳腺癌的式(I)化合物(化学名称：N6-(1-丙烯酰基氮杂环己烷-4-基)-N4-(3-氯-4-氟苯基)-7-甲氧基喹唑啉-4,6-二胺)或其可药用盐、式(I)化合物或其可药用盐与卡培他滨的联用药物组合物，以及所述联用药物组合物在治疗和预防乳腺癌中的用途。

Description

喹唑啉衍生物或其盐的联用药物组合物及其用途
相关申请的交叉引用
本申请要求于2019年11月25日向中国国家知识产权局提交的第201911162618.7号中国专利申请的优先权和权益，所述申请公开的内容通过援引整体并入本文中。
技术领域
本申请属于医药技术领域，涉及喹唑啉衍生物或其盐的联用药物组合物，及其用于治疗乳腺癌的用途。
背景技术
EGFR(epidermal growth factor receptor，上皮生长因子受体)是一种酪氨酸激酶受体，为HER/ErbB家族成员之一，该家族包括EGFR、HER2、HER3和HER4，由三部分组成：胞外的配体结合区、由单链构成的跨膜区以及胞内的酪氨酸激酶区。EGFR广泛分布于哺乳动物的上皮细胞、成纤维细胞、胶质细胞、角质细胞等细胞的表面。EGFR信号通路对细胞的生长、增殖和分化等生理过程发挥重要的作用。EGFR等蛋白酪氨酸激酶功能缺失或其相关信号通路中关键因子的异常活性或细胞定位异常，均会引起肿瘤、糖尿病、免疫缺陷及心血管疾病的发生。
WO2015043515A公开的式(I)化合物为选择性表皮生长因子受体抑制剂，可通过竞争性结合胞内段酪氨酸激酶的磷酸化位点，阻断其与ATP的相互作用，抑制酪氨酸磷酸化及下游一系列的信号传导，继而抑制肿瘤细胞的生长，可用于治疗非小细胞肺癌和乳腺癌等多种恶性肿瘤。其中式(I)化合物化学名称为N 6-(1-丙烯酰基氮杂环己烷-4-基)-N 4-(3-氯-4-氟苯基)-7-甲氧基喹唑啉-4,6-二胺。
Figure PCTCN2020131537-appb-000001
发明概述
一方面，本申请提供了一种联用药物组合物，其包含式(I)化合物或其可药用盐和卡培他滨
Figure PCTCN2020131537-appb-000002
另一方面，本申请提供用于治疗或预防乳腺癌的联用药物组合物，其包含式(I)化合物或其可药用盐和卡培他滨。
还一方面，本申请提供用于治疗或预防乳腺癌的方法，其包括向有需要的个体施用包含式(I)化合物或其可药用盐和卡培他滨的联用药物组合物。
再一方面，包含式(I)化合物或其可药用盐和卡培他滨的联用药物组合物在制备用于治疗或预防乳腺癌的药物中的用途。
再一方面，包含式(I)化合物或其可药用盐和卡培他滨的联用药物组合物在治疗或预防乳腺癌中的用途。
另一方面，本申请提供用于治疗或预防乳腺癌的式(I)化合物或其可药用盐。
另一方面，本申请还提供式(I)化合物或其可药用盐用于治疗或预防乳腺癌的用途。
另一方面，本申请还提供式(I)化合物或其可药用盐在制备用于治疗或预防乳腺癌的药物中的用途。
另一方面，本申请提供治疗或预防乳腺癌的方法，包括向有需要的个体施用治疗有效量的式(I)化合物或其可药用盐。
发明详述
一方面，本申请提供了一种联用药物组合物，其包含式(I)化合物或其可药用盐和卡培他滨
Figure PCTCN2020131537-appb-000003
另一方面，本申请提供用于治疗或预防乳腺癌的联用药物组合物，其包含式(I)化合物或其可药用盐和卡培他滨。
在本申请的一些实施方案中，所述联用药物组合物包装于同一试剂盒中，所述试剂盒还包含将式(I)化合物或其可药用盐和卡培他滨联合使用以治疗或预防乳腺癌的说明。
在本申请的一些实施方案中，所述联用药物组合物包括含有卡培他滨的药物组合物和含有式(I)化合物或其可药用盐的药物组合物。在本申请的一些实施方案中，所述联用药物组合物包装于同一试剂盒中，所述试剂盒还包含将含有卡培他滨的药物组合物和含有式(I)化合物或其可药用盐的药物组合物联合使用以治疗或预防乳腺癌的说明。
在本申请的一些实施方案中，所述联用药物组合物含有150mg-4600mg的卡培他滨。
在本申请的一些实施方案中，所述联用药物组合物含有500mg-4600mg的卡培他滨。在本申请的一些实施方案中，所述联用药物组合物含有1200mg-4600mg的卡培他滨。
在本申请的一些实施方案中，所述联用药物组合物含有1200mg-4600mg的卡培他滨和以式(I)化合物本身计的0.5mg-40mg的式(I)化合物或其可药用盐。
在本申请的一些实施方案中，所述联用药物组合物含有1200mg、1500mg、1600mg、1800mg、2000mg、2100mg、2300mg、2200mg、2400mg、2600mg、2800mg、2900mg、3000mg、3200mg、3500mg、3600mg、4000mg、4300mg或4600mg的卡培他滨。
在本申请的一些实施方案中，所述联用药物组合物含有2300mg、2600mg、2900mg、3200mg、3500mg、3600mg、4000mg、4300mg或4600mg的卡培他滨。
在本申请的一些实施方案中，所述联用药物组合物含有1600mg-3500mg的卡培他滨。
在本申请的一些实施方案中，所述联用药物组合物含有1600mg、2000mg、2200mg、2400mg、2600mg、2800mg、3000mg、3200mg或3500mg的卡培他滨。
在本申请的一些实施方案中，所述联用药物组合物含有1200mg-2200mg的卡培他滨。
在本申请的一些实施方案中，所述联用药物组合物含有1200mg、1500mg、1600mg、1800mg、2000 mg、2100mg或2200mg的卡培他滨。
在本申请的一些实施方案中，所述联用药物组合物以个体的体表面积计含有1000mg/m 2-2500mg/m 2的卡培他滨。
在本申请的一些实施方案中，所述联用药物组合物以个体的体表面积计含有1000mg/m 2-2000mg/m 2的卡培他滨。
在本申请的一些实施方案中，所述联用药物组合物以个体的体表面积计含有1000mg/m 2、1500mg/m 2或2000mg/m 2的卡培他滨。
本申请的体表面积计算公式为：体表面积BSA(㎡)＝0.00616×身高(cm)+0.01286×体重(kg)-0.1529。
在本申请的一些实施方案中，所述联用药物组合物中，卡培他滨为单剂量或多剂量。
在本申请的一些实施方案中，所述联用药物组合物中，卡培他滨为多剂量。
在本申请的一些实施方案中，所述联用药物组合物中，卡培他滨的含量为每日剂量。在本申请的一些实施方案中，所述联用药物组合物中，所述卡培他滨的含量为每日两次剂量。在本申请的一些实施方案中，所述两次剂量的每次剂量相同。
在本申请的一些实施方案中，所述联用药物组合物中，所述卡培他滨的含量为每日两次剂量，每次剂量分别为多剂量。
在本申请的一些实施方案中，所述联用药物组合物中，所述卡培他滨为多剂量，其由单剂量为150mg和/或500mg的卡培他滨组成。在本申请的一些实施方案中，所述联用药物组合物含有单剂量为150mg和/或500mg的卡培他滨。
在本申请的一些实施方案中，所述联用药物组合物中，含有卡培他滨的药物组合物包装于一试剂盒中，所述试剂盒还含有卡培他滨用于治疗或预防乳腺癌的说明。
在本申请的一些实施方案中，所述联用药物组合物中，含有卡培他滨的药物组合物包装于一试剂盒中，所述试剂盒还含有卡培他滨用于治疗或预防乳腺癌的说明，所述说明可以为市售的卡培他滨片试剂盒中的说明书中的说明。在本申请的一些实施方案中，所述说明为正大天晴药业集团股份有限公司生产的卡培他滨片(例如
Figure PCTCN2020131537-appb-000004
)说明书中的说明。
在本申请的一些实施方案中，所述联用药物组合物以式(I)化合物本身计含有0.2mg至60mg、或0.5mg至40mg、或1.0mg至40mg、或1.5mg至40mg、或2mg至40mg、或4mg至40mg、或5mg至40mg、或6mg至40mg、或7mg至40mg、或8mg至40mg、或8mg至30mg、或8mg至25mg、或8mg至20mg、或8mg至16mg的式(I)化合物或其可药用盐。
在本申请的一些实施方案中，所述联用药物组合物以式(I)化合物本身计含有0.5mg-40mg的式(I)化合物或其可药用盐。
在本申请的一些实施方案中，所述联用药物组合物以式(I)化合物本身计含有2mg-20mg的式(I)化合物或其可药用盐。
在本申请的一些实施方案中，所述联用药物组合物以式(I)化合物本身计含有0.2mg、0.5mg、1mg、1.5mg、2mg、2.5mg、3.0mg、3.5mg、4.0mg、4.5mg、5mg、5.5mg、6mg、6.5mg、7mg、7.5mg、8mg、8.5mg、9mg、9.5mg、10mg、10.5mg、11mg、11.5mg、12mg、12.5mg、13mg、13.5mg、14mg、14.5mg、15mg、15.5mg、16mg、16.5mg、17mg、17.5mg或18mg的式(I)化合物或其可药用盐。
在本申请的一些实施方案中，所述联用药物组合物以式(I)化合物本身计含有2mg、4mg、5mg、6mg、8mg、10mg、12mg或16mg的式(I)化合物或其可药用盐。
在一些特定实施方案中，所述联用药物组合物以式(I)化合物本身计含有2mg、5mg或10mg的式(I)化合物或其可药用盐。
在一些特定实施方案中，所述联用药物组合物以式(I)化合物本身计含有4mg、6mg、8mg、10mg、12mg或16mg的式(I)化合物或其可药用盐。
在本申请的一些实施方案中，所述联用药物组合物中，式(I)化合物或其可药用盐为单剂量或多剂量；在本申请的一些实施方案中，所述联用药物组合物中，式(I)化合物或其可药用盐为单剂量。
在本申请的一些实施方案中，所述联用药物组合物中，式(I)化合物或其可药用盐的含量为每日剂量。
在本申请的一些实施方案中，所述联用药物组合物中，式(I)化合物或其可药用盐的含量为每日一次剂量。
在本申请的一些实施方案中，所述联用药物组合物中，式(I)化合物或其可药用盐的含量为每日一次剂量，以及每次剂量为单剂量或多剂量，通常为单剂量。
在本申请的一些实施方案中，所述联用药物组合物中，含有式(I)化合物或其可药用盐的药物组合物包装于一试剂盒中，所述试剂盒还含有式(I)化合物或其可药用盐用于治疗或预防乳腺癌的说明。
在本申请的一些实施方案中，所述联用药物组合物以个体的体表面积计含有2000mg/m 2的每日剂量的卡培他滨；以及以式(I)化合物本身计含有4mg、6mg、8mg、10mg、12mg或16mg的每日剂量的式(I)化合物或其可药用盐。
在本申请的一些实施方案中，所述联用药物组合物含有单剂量为150mg和/或500mg的卡培他滨；以及以式(I)化合物本身计含有单剂量为2mg、4mg、5mg、6mg、8mg、10mg、12mg或16mg的式(I)化合物或其可药用盐。
在本申请的本申请的一些实施方案中，所述联用药物组合物中，所述式(I)化合物或其可药用盐和卡培他滨可以分别呈药物组合物形式或者一起呈药物组合物形式。
另一方面，本申请还提供治疗或预防乳腺癌的方法，其包括向有需要的个体施用治疗有效量的本申请的上文所述的联用药物组合物。
在本申请的一些实施方案中，在所述治疗或预防乳腺癌的方法中，所述联用药物组合物中的卡培他滨的含量为每日剂量，其通过如下方式给药：卡培他滨每日给药1次或2次；在本申请的一些实施方案中，卡培他滨每日给药2次；在本申请的一些实施方案中，卡培他滨每日给药2次，且每次剂量相同；在本申请的一些实施方案中，卡培他滨每日给药2次，且每次剂量相同，并且每次给药间隔为12小时。
在本申请的一些实施方案中，在所述治疗或预防乳腺癌的方法中，所述联用药物组合物中的卡培他滨的含量为每日剂量，其中卡培他滨以单剂量或多剂量方式给药。在本申请的一些实施方案中，其中卡培他滨以多剂量方式给药。
在本申请的一些实施方案中，在所述治疗或预防乳腺癌的方法中，所述联用药物组合物中的卡培他滨的含量为每日剂量，其中卡培他滨以多剂量方式给药，所述多剂量由单剂量为150mg和/或500mg的卡培他滨组成。
在本申请的一些实施方案中，在所述治疗或预防乳腺癌的方法中，其中卡培他滨通过如下方式给药：每次施用于个体500mg/m 2-1250mg/m 2或500mg/m 2-1000mg/m 2(以个体的体表面积计)的卡培他滨，每日给药2次。在本申请的一些实施方案中，每次施用于个体500mg/m 2、750mg/m 2或1000mg/m 2(以个体的体表面积计)的卡培他滨，每日给药2次。
在本申请的一些实施方案中，在所述治疗或预防乳腺癌的方法中，所述联用药物组合物中的式(I)化合 物或其可药用盐的含量为每日剂量，其通过如下方式给药：式(I)化合物或其可药用盐每日给药1次。
在本申请的一些实施方案中，在所述治疗或预防乳腺癌的方法中，所述联用药物组合物中的式(I)化合物或其可药用盐的含量为每日剂量，其中式(I)化合物或其可药用盐以单剂量或多剂量方式给药，通常以单剂量方式给药；进一步地，其中式(I)化合物或其可药用盐每日给药1次。
在本申请的一些实施方案中，所述式(I)化合物或其可药用盐通过如下方式给药：每日剂量为4mg；或者，每日剂量为6mg；或者，每日剂量为8mg；或者每日剂量为10mg；或者每日剂量为12mg；或者每日剂量为16mg。
在本申请的一些实施方案中，所述式(I)化合物或其可药用盐以连续每日给药的方式给药。
在本申请的一些实施方案中，所述式(I)化合物或其可药用盐和卡培他滨各自呈药物组合物形式，可同时、分开、并行、顺序或间隔给药。在本申请的一些实施方案中，所述式(I)化合物或其可药用盐和卡培他滨分别具有相同或者不同的治疗周期。在本申请的一些具体的实施方案中，所述式(I)化合物或其可药用盐和卡培他滨具有相同的治疗周期，例如每1周、每2周、每3周或每4周为一个治疗周期。
在本申请的一些实施方案中，21天为一个治疗周期，在每个治疗周期的第1-14天连续施用卡培他滨，在每个治疗周期的第1-21天每天施用所述式(I)化合物或其可药用盐。
在本申请的一些具体的实施方案中，21天为一个治疗周期，在每个治疗周期的第1-14天连续每日施用卡培他滨2次(例如每12小时给药一次)，在每个治疗周期的第1-21天每日1次施用所述式(I)化合物或其可药用盐。
在本申请的一些实施方案中，所述卡培他滨以间隔给药的方式给药。在本申请的一些实施方案中，所述卡培他滨可以在每个治疗周期的第1-14天连续给药，停药7天。
在本申请的一些实施方案中，21天为一个治疗周期，每天给药1次，连续给药21天，每个治疗周期施用含有所述式(I)化合物或其药用盐的药物组合物的总剂量为168～336mg(以活性成分式(I)化合物本身计)。在部分的实施方案中，所述含有式(I)化合物或其药用盐的药物组合物的总剂量选自168mg、210mg、252mg、336mg或上述任意两个值所形成的范围。在部分的实施方案中，所述含有式(I)化合物或其药用盐的药物组合物的总剂量优选为168mg～252mg。
在本申请的一些实施方案中，在所述治疗或预防乳腺癌的方法中，所述联用药物组合物中的卡培他滨和式(I)化合物或其药用盐的含量均为每日剂量，其通过如下方式给药：21天为一个治疗周期，在每个治疗周期的第1-14天连续每日2次施用卡培他滨，且每次剂量相同，并且每次给药间隔为12小时，停药7天；在每个治疗周期的第1-21天每日1次施用式(I)化合物或其可药用盐。
本申请的实施方案中，只要疾病仍处于控制之下和给药方案具有临床耐受性，就重复上述治疗周期。
在本申请的一些实施方案中，所述卡培他滨被制备为适合连续14天、每天2次、每次向患者施用1150mg-2300mg、或800mg-1750mg、或者600-1100mg的卡培他滨的单剂量或多剂量，含有所述式(I)化合物或其可药用盐的药物组合物被制备为适合连续每天向患者施用的以式(I)化合物本身计的4mg、6mg、8mg、10mg、12mg和/或16mg的单剂量或多剂量。
在本申请的一些实施方案中，每次向患者施用1150mg、1300mg、1450mg、1600mg、1750mg、1800mg、2000mg、2150mg或2300mg卡培他滨；或者每次向患者施用800mg、1000mg、1100mg、1200mg、1300mg、1400mg、1500mg、1600mg或1750mg卡培他滨；或者每次向患者施用600mg、750mg、800mg、900mg、1000mg、1050mg或1100mg卡培他滨。
在本申请的一些实施方案中，所述式(I)化合物或其可药用盐被制备为适合连续每天向患者施用8mg、 10mg、12mg和/或16mg的式(I)化合物的单剂量或多剂量；或者，所述式(I)化合物或其可药用盐被制备为适合连续每天向患者施用以式(I)化合物本身计的8mg、10mg和/或12mg的单剂量或多剂量。
再一方面，本申请还提供包含式(I)化合物或其可药用盐和卡培他滨的联用药物组合物在制备用于治疗或预防乳腺癌的药物的用途。在本申请的一些实施方案中，所述联用药物组合物为本申请的上文所述的联用药物组合物。例如，所述联用药物组合物的诸如各组分的含量和给药方式等方面均为上文所述。
还一方面，本申请还提供联用药物组合物用于治疗或预防乳腺癌的用途，所述联用药物组合物为本申请的上述联用药物组合物。
在本申请的一些实施方案中，所述乳腺癌选自HER 2为阳性和/或荧光原位杂交技术(FISH)阳性乳腺癌。
在本申请的一些实施方案中，所述乳腺癌为HER 2阳性的乳腺癌。
在本申请的一些实施方案中，所述乳腺癌为HER 2为2+或3+的乳腺癌。在本申请的一些实施方案中，所述乳腺癌为HER 2为3+的乳腺癌。在本申请的一些实施方案中，所述乳腺癌为HER 2为2+并且FISH阳性的乳腺癌。
在本申请的一些实施方案中，所述乳腺癌为HER2为荧光原位杂交技术(FISH)阳性乳腺癌。
在本申请的一些实施方案中，所述乳腺癌为晚期乳腺癌或转移性乳腺癌。
在本申请的一些实施方案中，所述乳腺癌为既往曾接受过重组人HER-2单克隆抗体(例如曲妥珠单抗、赫赛汀)治疗的乳腺癌(例如HER-2过度表达转移性乳腺癌)。
在本申请的一些实施方案中，所述乳腺癌为既往曾接受过曲妥珠单抗药物治疗的乳腺癌。
在本申请的一些实施方案中，曲妥珠单抗在治疗阶段使用≥3个月，或在复发/转移后阶段使用≥2个周期(如：21天/周期)。
在本申请的一些实施方案中，曲妥珠单抗在新辅助/辅助治疗阶段使用≥3个月，或在复发/转移后阶段使用≥2个周期(如：21天/周期)。
在本申请的一些实施方案中，所述乳腺癌为既往曾接受过紫杉类药物治疗的乳腺癌。
在本申请的一些实施方案中，紫杉类药物治疗时间≥2个周期(如：21天/周期)。
在本申请的一些实施方案中，紫杉类药物在新辅助/辅助治疗阶段或在复发/转移后的治疗阶段应用，治疗时间≥2个周期(如：21天/周期)，或者含有紫杉类药物的治疗方案在治疗中存在疾病进展。
在本申请的一些实施方案中，所述乳腺癌为既往曾接受过曲妥珠单抗和/或紫杉类药物治疗的乳腺癌。
在本申请的一些实施方案中，所述紫杉类药物包括但不限于紫杉醇、多西紫杉醇、紫杉醇脂质体或者白蛋白结合型紫杉醇。
在本申请的一些实施方案中，所述乳腺癌选自：浸润性癌，进一步FISH阳性、和/或Her-2(3+)、和/或c-erbB-2(2+/3+)；任选地，还包括ER(+/-)、PR(-/+)、Ki67(+,例如30％-60％)、P53(-/3+)。在本申请的一些实施方案中，所述乳腺癌为既往接受过盐酸表柔比星、环磷酰胺、多西他赛、重组人HER-2单克隆抗体(例如曲妥珠单抗、赫赛汀)、注射用重组人源化抗Her-2单克隆抗体-美登素偶联物中的一种或多种药物的单独和/或组合治疗的乳腺癌。
在本申请的一些实施方案中，所述乳腺癌为浸润性癌，且具有如下特征：ER(5％)，PR(-)，Her-2(3+)，Ki67(40％)。
在本申请的一些实施方案中，所述乳腺癌具有如下特征：Her-2(3+)，ER(+)，PR(-)，c-erbB-2(2+)，Ki67(40％)，P53(3+)，FISH阳性。
在本申请的一些实施方案中，所述乳腺癌为既往接受过盐酸表柔比星联合环磷酰胺治疗的乳腺癌。
在本申请的一些实施方案中，所述乳腺癌为既往接受过多西他赛联合曲妥珠单抗治疗的乳腺癌。
在本申请的一些实施方案中，所述乳腺癌为既往接受过注射用重组人源化抗Her-2单克隆抗体-美登素偶联物治疗的乳腺癌。
在本申请的一些实施方案中，所述乳腺癌具有如下特征：Her-2(3+)，ER(-)，PR(-)，CerbB-2(3+)，Ki67(30％)，P53(-)。
在本申请的一些实施方案中，所述乳腺癌选自既往接受过环磷酰胺、盐酸表柔比星联合多西他赛的治疗的乳腺癌、或者曲妥珠单抗联合多西他赛的治疗的乳腺癌。
本申请的药物组合中的活性组分可以各自独立地，或者其中的部分或全部地共同与药学上可接受的载体和/或赋形剂配制。本申请的药物组合还可以包含另外的治疗剂。本申请的一些实施方案，所述另外的治疗剂可以是本领域已知的用于癌症的治疗剂，优选用于乳腺癌的治疗剂。
另一方面，本申请提供用于治疗或预防乳腺癌的式(I)化合物或其可药用盐。
另一方面，本申请还提供式(I)化合物或其可药用盐用于治疗或预防乳腺癌的用途。
另一方面，本申请还提供式(I)化合物或其可药用盐在制备用于治疗或预防乳腺癌的药物中的用途。
另一方面，本申请提供治疗或预防乳腺癌的方法，包括向有需要的个体施用治疗有效量的式(I)化合物或其可药用盐。
在本申请的一些实施方案中，所述乳腺癌选自HER 2为阳性和/或荧光原位杂交技术(FISH)阳性乳腺癌。
在本申请的一些实施方案中，所述乳腺癌为HER 2阳性的乳腺癌。
在本申请的一些实施方案中，所述乳腺癌为HER 2为2+或3+的乳腺癌。在本申请的一些实施方案中，所述乳腺癌为HER 2为3+的乳腺癌。在本申请的一些实施方案中，所述乳腺癌为HER 2为2+并且FISH阳性的乳腺癌。
在本申请的一些实施方案中，所述乳腺癌为HER2为荧光原位杂交技术(FISH)阳性乳腺癌。
在本申请的一些实施方案中，所述乳腺癌为晚期乳腺癌或转移性乳腺癌。
在本申请的一些实施方案中，所述乳腺癌为既往曾接受过重组人HER-2单克隆抗体(例如曲妥珠单抗、赫赛汀)治疗的乳腺癌(例如HER-2过度表达转移性乳腺癌)。
在本申请的一些实施方案中，重组人HER-2单克隆抗体在治疗阶段使用≥3个月，或在复发/转移后阶段使用≥2个周期(如：21天/周期)。
在本申请的一些实施方案中，重组人HER-2单克隆抗体在新辅助/辅助治疗阶段使用≥3个月，或在复发/转移后阶段使用≥2个周期(如：21天/周期)。
在本申请的一些实施方案中，重组人HER-2单克隆抗体用量为512mg/周期或384mg/周期(如：21天/周期)。
在本申请的一些实施方案中，所述乳腺癌为既往曾接受过紫杉类药物治疗的乳腺癌。
在本申请的一些实施方案中，紫杉类药物治疗时间≥2个周期(如：21天/周期)。
在本申请的一些实施方案中，紫杉类药物在新辅助/辅助治疗阶段或在复发/转移后的治疗阶段应用，治疗时间≥2周期(如：21天/周期)，或者含有紫杉类药物的治疗方案在治疗中存在疾病进展。
在本申请的一些实施方案中，所述乳腺癌为既往曾接受过曲妥珠单抗和/或紫杉类药物治疗的乳腺癌。
在本申请的一些实施方案中，所述紫杉类药物包括但不限于紫杉醇、多西紫杉醇、紫杉醇脂质体或者白蛋白结合型紫杉醇。
在本申请的一些实施方案中，所述乳腺癌为浸润性癌，且具有如下特征：ER(-)，PR(-)，HER-2(3+)，Ki67(20％)，P53。
在本申请的一些实施方案中，所述乳腺癌为既往接受过重组人HER-2单克隆抗体(例如曲妥珠单抗、赫赛汀)或者重组人HER-2单克隆抗体(例如曲妥珠单抗、赫赛汀)联合多西他赛治疗的乳腺癌(例如HER 2阳性的乳腺癌)。
在本申请的一些实施方案中，重组人HER-2单克隆抗体用量为512mg/周期或者384mg/周期，以及多西他赛用量为127.5mg/周期。
在本申请的一些实施方案中，所述乳腺癌为既往依次接受过如下治疗的乳腺癌：重组人HER-2单克隆抗体(例如512mg/周期)联合多西他赛(例如127.5mg/周期)的治疗(例如1周期)；重组人HER-2单克隆抗体(例如384mg/周期)联合多西他赛(例如127.5mg/周期)的治疗(例如8周期)；重组人HER-2单克隆抗体(例如384mg/周期)。
在本申请的一些实施方案中，所述乳腺癌为既往接受过乳腺癌根治术的乳腺癌。
在本申请的一些实施方案中，所述乳腺癌为浸润性乳腺癌，且具有如下特征：HER-2(3+)，ER(-)，PR(-)，cerbB-2(3+)。
在本申请的一些实施方案中，所述乳腺癌为既往接受过尿多肽(例如300ml/周期)治疗的乳腺癌；例如可以是治疗2周期；例如可以是作为辅助治疗。
在本申请的一些实施方案中，所述乳腺癌为既往接受过盐酸表柔比星(例如135mg/周期)联合环磷酰胺(例如0.9g/周期)治疗的乳腺癌；例如可以是治疗4周期；例如可以是作为辅助治疗。
在本申请的一些实施方案中，所述乳腺癌为既往接受过沙利度胺治疗的乳腺癌；例如可以是2粒/次，2次/日，po d1-d5/周期，治疗2周期；例如可以是作为辅助治疗。
在本申请的一些实施方案中，所述乳腺癌为既往接受过多西他赛(例如140mg/周期)治疗的乳腺癌；例如可以是治疗4周期；例如可以是作为辅助治疗。
在本申请的一些方案中，所述乳腺癌为既往接受过曲妥珠单抗联合多西他赛治疗的乳腺癌。
在本申请的一些实施方案中，所述乳腺癌为既往依次接受过如下治疗的乳腺癌：乳癌根治术的治疗；尿多肽的治疗；盐酸表柔比星联合环磷酰胺的治疗；沙利度胺的治疗；多西他赛的治疗；曲妥珠单抗联合多西他赛的治疗。
在本申请的一些实施方案中，所述周期为21天。
施用式(I)化合物或其可药用盐的量可根据疾病的严重程度、疾病的响应、任何治疗相关的毒性、患者的年龄和健康状态来确定。
在本申请的一些实施方案中，施用式(I)化合物或其可药用盐的日剂量以式(I)化合物本身计算为0.2mg至60mg、或为0.5mg至40mg、或为1.0mg至40mg、或为1.5mg至40mg、或为2mg至40mg、或为4mg至40mg、或为5mg至40mg、或为6mg至40mg、或为7mg至40mg、或为8mg至40mg、或为8mg至30mg、 或为8mg至25mg、或为8mg至20mg、或为8mg至16mg。
在一个具体的实施方案中，施用式(I)化合物或其可药用盐的日剂量以式(I)化合物本身计算为0.2mg、0.5mg、1mg、1.5mg、2mg、2.5mg、3.0mg、3.5mg、4.0mg、4.5mg、5mg、5.5mg、6mg、6.5mg、7mg、7.5mg、8mg、8.5mg、9mg、9.5mg、10mg、10.5mg、11mg、11.5mg、12mg、12.5mg、13mg、13.5mg、14mg、14.5mg、15mg、15.5mg、16mg、16.5mg、17mg、17.5mg或18mg。在一个具体的实施方案中，施用式(I)化合物或其可药用盐的日剂量以式(I)化合物本身计算为4mg；或者，日剂量为6mg；或者，日剂量为8mg；或者日剂量为10mg；或者日剂量为12mg；或者日剂量为16mg。
式(I)化合物或其可药用盐可通过多种途径给药，该途径包括但不限于以下途径：口服、肠胃外、腹膜内、静脉内、动脉内、透皮、舌下、肌内、直肠、透颊、鼻内、经吸入、***、眼内、经局部给药、皮下、脂肪内、关节内、腹膜内和鞘内。在一个具体的实施方案中，式(I)化合物或其可药用盐通过口服给药。
在本申请的一些实施方案中，所述式(I)化合物或其可药用盐以连续每日给药的方式给药。
式(I)化合物或其可药用盐可以每日施用1次或多次。在本申请的一些实施方案中，每天1次施用式(I)化合物或其可药用盐。式(I)化合物或其可药用盐也可以单剂量或多剂量形式给药。在一个实施方案中，以单剂量每天1次施用式(I)化合物或其可药用盐。
在本申请的一些实施方案中，式(I)化合物或其可药用盐以单剂量的口服固体制剂形式每天给药1次。在一个实施方案中，式(I)化合物或其可药用盐以多剂量每天给药1次。
给药的方法可根据药物的活性、毒性以及患者的耐受性等来综合确定。
在本申请的一些实施方案中，所述式(I)化合物或其可药用盐被制备为适合连续每天向患者施用以式(I)化合物本身计的4mg、6mg、8mg、10mg、12mg和/或16mg的单剂量或多剂量。
在本申请的一些实施方案中，所述式(I)化合物或其可药用盐被制备为适合连续每天向患者施用8mg、10mg、12mg和/或16mg的式(I)化合物的单剂量或多剂量；或者，所述式(I)化合物或其可药用盐被制备为适合连续每天向患者施用以式(I)化合物本身计的8mg、10mg和/或12mg的单剂量或多剂量。
式(I)化合物或其可药用盐
本申请的式(I)化合物可以以其游离碱形式给药，也可以以其盐、水合物和前药的形式给药，该前药在体内转换成式(I)化合物的游离碱形式。例如，式(I)化合物的可药用盐在本发明的范围内，可按照本领域公知的方法由不同的有机酸和无机酸产生所述盐。
本申请所述的可药用盐选自马来酸盐、盐酸盐、氢溴酸盐、硫酸盐、磷酸盐、硝酸盐、乙酸盐、乳酸盐、丙二酸盐、丁二酸盐、富马酸盐、苹果酸盐、扁桃酸盐、酒石酸盐、柠檬酸盐、抗坏血酸盐、棕榈酸盐、苯甲酸盐、苯乙酸盐、肉桂酸盐、水杨酸盐、甲磺酸盐、苯磺酸盐或甲基苯磺酸盐。
在本申请的一些实施方案中，所述的可药用盐选自马来酸盐、苹果酸盐、富马酸盐、酒石酸盐、柠檬酸盐、乳酸盐、磷酸盐或乙酸盐。
在本申请的一些实施方案中，所述的可药用盐为马来酸盐。
关于本申请所述的式(I)化合物的可药用盐，式(I)化合物与形成可药用盐的酸根离子的摩尔比可为1:1。
本申请所述的式(I)化合物的可药用盐，所述式(I)化合物或其可药用盐选自式(I)化合物或式(I)化合物的马来酸盐。
在本申请的一些实施方案中，本申请所述的式(I)化合物的可药用盐为式(II)化合物
Figure PCTCN2020131537-appb-000005
本申请所述的“式(I)化合物或其可药用盐”可以替换为“式(II)化合物”；例如上述“式(I)化合物或其可药用盐和卡培他滨”可以替换为“卡培他滨和式(II)化合物”。
含有式(I)化合物或其可药用盐的药物组合物
本申请所述的“式(I)化合物或其可药用盐”，可以是“含有式(I)化合物或其可药用盐的药物组合物”，进一步的，可以是“含有式(II)化合物的药物组合物”。
给药的方法可根据药物的活性、毒性以及患者的耐受性等来综合确定。
在本申请的一些实施方案中，所述含有式(I)化合物或其可药用盐的药物组合物还含有药学上可接受的辅料。
在本申请的一些实施方案中，所述含有式(I)化合物或其可药用盐的药物组合物包含式(I)化合物或其可药用盐、聚甲基丙烯酸酯及表面稳定剂。
在本申请的一些实施方案中，所述含有式(I)化合物或其可药用盐的药物组合物包含式(I)化合物或其可药用盐、聚甲基丙烯酸酯、酸、表面稳定剂、分散剂及载体。
在本申请的一些实施方案中，所述含有式(I)化合物或其可药用盐的药物组合物包含式(II)化合物、聚甲基丙烯酸酯、酸、表面稳定剂、分散剂及载体。
在本申请的一些实施方案中，所述聚甲基丙烯酸酯为
Figure PCTCN2020131537-appb-000006
在本申请的一些实施方案中，所述聚甲基丙烯酸酯选自
Figure PCTCN2020131537-appb-000007
Figure PCTCN2020131537-appb-000008
或
Figure PCTCN2020131537-appb-000009
在本申请的一些实施方案中，所述聚甲基丙烯酸酯为
Figure PCTCN2020131537-appb-000010
在本申请的一些实施方案中，所述含有式(I)化合物或其可药用盐的药物组合物中，聚甲基丙烯酸酯与式(I)化合物或其可药用盐的重量比为50～0.5：1、或者45～1：1、或者40～1.5：1、或者35～2：1、或者30～3：1、或者25～4：1、或者20～5：1、或者18～5.5：1、或者16～5.7：1、或者14～5.9：1、或者12～6.1：1、或者10～6.3：1、或者8.5～6.5：1、或者8.5～7：1、或者8.5～7.5：1。
在本申请的一些实施方案中，所述含有式(I)化合物或其可药用盐的药物组合物中，聚甲基丙烯酸酯与式(II)化合物的重量比为8：1。
在本申请的一些实施方案中，所述酸选自马来酸、苹果酸、富马酸、酒石酸、柠檬酸、乳酸、磷酸或乙酸。
在本申请的一些实施方案中，所述酸为马来酸。
在本申请的一些实施方案中，所述含有式(I)化合物或其可药用盐的药物组合物中，式(I)化合物或其可药用盐相对于所述固体药物组合物的总质量为0.1～50wt％，或者为0.1～20wt％，或者为0.1～10wt％，或者为0.1～5wt％，或者为0.1～4wt％。
在本申请的一些实施方案中，所述表面稳定剂选自羟丙基纤维素、羧甲基纤维素钙、羧甲基纤维素钠、 甲基纤维素、羟乙基纤维素、羟丙基甲基-纤维素、羟丙基甲基-纤维素邻苯二甲酸酯、或非结晶纤维素。
在本申请的一些实施方案中，所述表面稳定剂为羟丙基纤维素(例如HPC-SL型)。
在本申请的一些实施方案中，所述含有式(I)化合物或其可药用盐的药物组合物中，表面稳定剂与式(Ⅰ)化合物或其可药用盐的重量比为0.06～1:1、或者0.07～0.9：1、或者0.08～0.8：1、或者0.09～0.7：1、或者0.10～0.6：1、或者0.11～0.5：1、或者0.12～0.7：1、或者0.13～0.6：1、或者0.14～0.5：1、或者0.15～0.4：1、或者0.15～0.3：1、或者0.15～0.2：1。
在本申请的一些实施方案中，所述含有式(I)化合物或其可药用盐的药物组合物中，表面稳定剂与式(II)化合物的重量比为0.16：1。
在本申请的一些实施方案中，所述分散剂选自蔗糖、乳糖、或甘露醇。
在本申请的一些实施方案中，所述分散剂为蔗糖。
在本申请的一些实施方案中，所述含有式(I)化合物或其可药用盐的药物组合物中，分散剂与式(Ⅰ)化合物或其可药用盐的重量比为0.5～50：1、或者0.8～45：1、或者1.1～40：1、或者1.4～35：1、或者1.7～30：1、或者2～25：1、或者2.3～20：1、或者2.8～15：1、或者3.1～10：1、或者3.4～9：1、或者3.7～8：1、或者4.0～7：1、或者4.3～6：1、或者4.5～5.5：1，
在本申请的一些实施方案中，所述含有式(I)化合物或其可药用盐的药物组合物中，分散剂与式(II)化合物的重量比为5：1。
在本申请的一些实施方案中，所述载体选自纤维素球、甘露醇丸芯、酒石酸丸芯、乳糖/微晶丸芯、蔗糖丸芯、淀粉丸芯及其组合。
在本申请的一些实施方案中，所述载体选自纤维素球或者蔗糖丸芯。
在本申请的一些实施方案中，所述载体为蔗糖丸芯(例如0.6-0.8mm)。
在本申请的一些实施方案中，所述载体占含有式(I)化合物或其可药用盐的药物组合物的比例选自0.1～99wt％、0.5～99wt％、1～99wt％、5～99wt％、10～99wt％、15～99wt％、20～99wt％、25～99wt％、30～99wt％、35～99wt％、40～99wt％、或45～99wt％。
在本申请的一些具体的实施方案中，所述含有式(I)化合物或其可药用盐的药物组合物包含式(II)化合物、羟丙基纤维素(例如HPC-SL型)、蔗糖、聚甲基丙烯酸酯(例如
Figure PCTCN2020131537-appb-000011
)、马来酸、蔗糖丸芯(例如0.6-0.8mm)。
所述含有式(I)化合物或其可药用盐的药物组合物以如下重量份包含如下组分：
Figure PCTCN2020131537-appb-000012
在本申请的一些具体实施方案中，所述含有式(I)化合物或其可药用盐的药物组合物中，所述聚甲基丙烯酸酯、酸、表面稳定剂、分散剂及载体分别如上文所定义。
所述含有式(I)化合物或其可药用盐的药物组合物以如下重量份包含如下组分：
Figure PCTCN2020131537-appb-000013
Figure PCTCN2020131537-appb-000014
所述含有式(I)化合物或其可药用盐的药物组合物以如下重量份包含如下组分：
Figure PCTCN2020131537-appb-000015
所述含有式(I)化合物或其可药用盐的药物组合物以如下重量份包含如下组分：
Figure PCTCN2020131537-appb-000016
所述含有式(I)化合物或其可药用盐的药物组合物以如下重量份包含如下组分：
Figure PCTCN2020131537-appb-000017
所述含有式(I)化合物或其可药用盐的药物组合物以如下重量份包含如下组分：
Figure PCTCN2020131537-appb-000018
本申请的上述各个含有式(I)化合物或其可药用盐的药物组合物中，式(Ⅰ)化合物或其可药用盐的粒径范围为D50<10μm，D90<20μm；或者D50<5μm，D90<10μm；或者D50<2μm，D90<4μm。
在本申请的一些实施方案中，式(Ⅰ)化合物或其可药用盐的粒径范围为D50<2μm，D90<4μm。
本申请的上述各个含有式(I)化合物或其可药用盐的药物组合物中，所述的酸如马来酸以适量添加，例如使得药物组合物在水中呈酸性。
在本申请的一些实施方案中，上述各个含有式(I)化合物或其可药用盐的药物组合物中，所述的马来酸以适量添加。
在本申请的一些实施方案中，所述各个含有式(I)化合物或其可药用盐的药物组合物中，所述酸可作为pH调节剂。例如在固体药物组合物的制备过程中，所述酸用于调节pH的范围，例如使得药物组合物的水溶液处于酸性，更具体地，例如水溶液的pH值为2.0-3.5之间(例如2.0≤pH<3.0或3.0≤pH≤3.5)。
本申请的所述各个含有式(I)化合物或其可药用盐的药物组合物可以被配制为适合于向人口服给药的制剂形式，例如包括但不限于片剂、丸剂、胶囊剂、粉剂或颗粒剂等。
在本申请的一些实施方案中，本申请的含有式(I)化合物或其可药用盐的药物组合物通过口服给药。
在本申请的一些实施方案中，所述各个含有式(I)化合物或其可药用盐的药物组合物为固体药物组合物。
在本申请的一些实施方案中，本申请的含有式(I)化合物或其可药用盐的固体药物组合物的制剂形式为胶囊。
在本申请的一些实施方案中，所述胶囊由微丸颗粒填充，所述微丸颗粒包含如前所述的式(I)化合物或其可药用盐的药物组合物。
在本申请的一些实施方案中，所述胶囊为硬胶囊或软胶囊。
胶囊可根据已知的方法填充，例如通过将前述的含有式(Ⅰ)化合物或其可药用盐的微丸颗粒装入由明胶、羟丙基甲基纤维素、聚乙烯醇等制得的硬胶囊中，或装入基于明胶的软胶囊中。
本申请的含有式(I)化合物或其可药用盐的药物组合物可以采用本领域众所周知的方法制造，如常规的混合法、溶解法、制粒法、制糖衣药丸法、磨细法、乳化法、冷冻干燥法等。
可以通过常规的混合、填充或压片方法来制备固体口服组合物。例如，可通过下述方法获得：将所述的活性化合物与固体辅料混合，任选地碾磨所得的混合物，如果需要则加入其它合适的辅料，然后将该混合物加工成颗粒，得到了片剂或糖衣剂的核心。适合的辅料包括但不限于：粘合剂、稀释剂、崩解剂、润滑剂、助流剂、甜味剂或矫味剂等。
另一方面，本申请提供了含有式(I)化合物或其可药用盐的固体组合物的制备方法，包括以下过程：
配制含有式(I)化合物或其可药用盐的混悬液；在混悬液中加入酸和聚甲基丙烯酸酯；将上述得到的混悬液在载体上进行流化床上药，得到含药微丸。
卡培他滨
如本申请所用，所述卡培他滨的化学名为5’-脱氧-5-氟-N-[(戊氧基)羰基]-胞(嘧啶核)苷，其具有如下的结构式：
Figure PCTCN2020131537-appb-000019
含有卡培他滨的药物组合物
在本申请的一些实施方案中，所述含有卡培他滨的药物组合物还含有药学上可接受的辅料。
在本申请的一些实施方案中，所述含有卡培他滨的药物组合物可以被配制为适合于向人口服给药的制剂形式，例如包括但不限于片剂、丸剂、胶囊剂、粉剂或颗粒剂等。
在本申请的一些实施方案中，所述含有卡培他滨的药物组合物通过口服给药。
在本申请的一些实施方案中，所述含有卡培他滨的药物组合物为固体药物组合物。
在本申请的一些实施方案中，所述含有卡培他滨的药物组合物的制剂形式为片剂。
在本申请的一些实施方案中，所述含有卡培他滨的药物组合物包含：卡培他滨、无水乳糖、微晶纤维素、交联羧甲基纤维素钠、羟丙甲纤维素、硬脂酸镁及薄膜包衣粉(胃溶型)。
在本申请的一些实施方案中，所述含有卡培他滨的药物组合物中，卡培他滨的量为150mg或500mg。
施用方式
下述内容并非限制本申请的联用药物组合物的施用方式。
本申请的联用药物组合物中的活性成分可以各自独立地，或者其中的部分或全部共同地以适合的各种途径施用，包括，但不限于，口服或肠胃外(通过静脉内、肌内、局部或皮下途径)。在本申请的一些实施方案中，本申请的联用药物组合物中的活性成分可以各自独立地，或者其中的部分或全部共同地口服施用。
本申请的联用药物组合物中的活性成分可以各自独立地，或者其中的部分或全部共同地是适合的剂型，包括，但不限于，片剂、含片、丸剂、胶囊剂(例如硬胶囊、软胶囊、肠溶胶囊、微囊剂)、酏剂、颗粒剂、糖浆剂、注射剂(肌肉内、静脉内、腹腔内)、颗粒剂、乳剂、悬浮液、溶液、分散剂和用于口服或非口服给药的缓释制剂的剂型。
本申请的治疗方案(例如本申请的联用药物组合物、本申请的式(I)化合物或其可药用盐)在治疗乳腺癌、特别是HER 2为阳性(如HER 2为3+)的乳腺癌方面具有较好的疗效。至少在ORR、DCR、DoR、PFS或OS中的至少一个方面具有突出的效果数据；而且患者耐受性好，副作用小。联用药物组合物相较于单药具有更好的治疗效果、更低的给药剂量，且耐受性良好。
定义和说明
词语“包括(comprise)”或“包含(comprise)”及其英文变体例如comprises或comprising应理解为开放的、非排他性的意义，即“包括但不限于”。
术语"患者"是指哺乳动物，优选人。在本申请的一些实施方案中，所述患者和所述个体为经标准治疗失败或缺乏标准治疗的患者。
术语"药学上可接受的"或“可药用的”是指用于制备药物组合物的载体、赋形剂或辅料，该载体、赋形剂或辅料通常是安全、无毒的并且不在生物学上或其它方面不合乎需要，而且包括其对于人类药物的使用是可接受的。
术语"治疗有效量"意指化合物被施用于人用于治疗疾病时，足以实现对该疾病的治疗的量。
术语“治疗”意为将本申请所述化合物或制剂进行给药以改善或消除疾病或与所述疾病相关的一个或多个症状，且包括：
(i)抑制疾病或疾病状态，即遏制其发展；
(ii)缓解疾病或疾病状态，即使该疾病或疾病状态消退。
术语“预防”意为将本申请所述化合物或制剂进行给药以预防疾病或与所述疾病相关的一个或多个症状，包括：预防疾病或疾病状态在哺乳动物中出现，特别是当这类哺乳动物易患有该疾病状态，但尚未被诊断为已患有该疾病状态时。
术语“药学上可接受的辅料”是指对有机体无明显刺激作用，而且不会损害活性化合物的生物活性及性能的那些辅料。合适的辅料是本领域技术人员熟知的，例如碳水化合物、蜡、水溶性和/或水可膨胀的聚合物、亲水性或疏水性材料、明胶、油、溶剂、水等。
术语“施用”和“给药”表示使用本领域技术人员已知的多种方法和递送***中的任一种向个体物理引入包含治疗剂的组合物。在某些实施方案中，施用为口服施用。
术语“每日剂量”是指每日施用于患者的剂量。
本文提及的术语“基于体表面积的剂量”是指基于患者的体表面积计算出的施用于患者的剂量。
术语“个体/受试者”是哺乳动物。在部分实施方案中，所述个体是人。
术语“单剂量”是指含有一定量活性成分的药品的最小包装单元，例如一盒药有七粒胶囊，则每个胶囊为单剂量；例如一盒药有七片药品，则每片药为单剂量。
术语“多剂量”由多个单剂量组成。如本文所用，“联用”或“联合使用”意指两种或更多种活性物质可以各自作为单一制剂同时地、并行地或各自作为单一制剂以任何顺序依次地施用于个体。
术语“药物组合物”是指一种或多种本申请的活性成分或其药物组合与药学上可接受的辅料组成的混合物。药物组合物的目的是有利于对个体施用本申请的化合物或其药物组合。
涉及给药方案时，术语“天(日)”、“每天(每日)”等指一个日历日内的时间，开始于午夜且终止于下一个午夜。
本申请采用下列缩略词：
PD：疾病进展(progressive disease)，靶病灶最大径之和至少增加≥20％，或出现新病灶。
PR：部分缓解(partial response)，靶病灶最大径之和减少≥30％，至少维持4周。
OS：总生存(overall survival)，从随机化开始至(因任何原因)死亡的时间。
SD：疾病稳定(stable disease)，靶病灶最大径之和缩小未达PR，或增大未达PD。
PO：口服。Iv：静脉注射。ER：***受体。FISH：荧光原位杂交。PR(progesterone receptor)：孕激素受体。HER-2：表皮生长因子阳性。Ki67:细胞增殖相关核抗原。P53：P53基因，人体抑癌基因。cerbB-2：一种原癌基因。ivgtt:静脉滴注。IHC:免疫组织化学。ivgtt：静脉滴注。
实施例
下面的具体实施例的目的是使本领域的技术人员能更清楚地理解和实施本申请。它们不应该被认为是对本申请范围的限制，而只是本申请的示例性说明和典型代表。
实施例1
1)将羟丙基纤维素加入水 1中，溶清后在搅拌的条件下加入式(II)化合物，分散均匀，过筛；
2)将上述含药混悬液高压均质化，使式(II)化合物粒径控制为：D50<2μm，D90<4μm，加入处方量的蔗糖；
3)配制0.5mol/L马来酸水 2溶液，取一半配制好的马来酸水溶液溶解处方量的
Figure PCTCN2020131537-appb-000020
溶清后加入步骤2)所得混悬液，然后用剩余的马来酸水溶液调节混悬液的pH值为3.0-3.5，得混悬液；
4)在流化床中用步骤3)制备的混悬液在蔗糖空白丸芯上进行包衣，得到含药微丸；
5)将含药微丸加入料斗混合机中混匀；
6)充填胶囊。
具体药物胶囊制剂的组成如下表1所示。
表1
Figure PCTCN2020131537-appb-000021
水 1:26.67mg；水 2:20mg。
实施例2-5参照实施例1的过程，进行制备，具体药物胶囊制剂的组成如下表2所示。
表2
Figure PCTCN2020131537-appb-000022
注：
实施例2，水 1：66.67mg；水 2：50mg；
实施例3，水 1：266.68mg；水 2：200mg；
实施例4，水 1：666.7mg；水 2：500mg；
实施例5，水 1：1333.4mg；水 2：1000mg。
实施例6
参照实施例1的步骤1)-步骤6)，除了步骤3)中调节混悬液的pH值为2.0≤pH<3.0，以及水 1：25mg；水 2：50mg。
具体药物胶囊制剂的组成如下表3所示。
表3
Figure PCTCN2020131537-appb-000023
Figure PCTCN2020131537-appb-000024
实验例1临床试验
1.1入选标准：
1)18～70岁；ECOG PS评分：0～1分；预计生存期超过3个月；
2)仅病理学检查证实的HER2表达阳性的晚期转移性乳腺癌个体：HER2表达阳性指标准免疫组化染色(IHC)检测显示HER2为3+和/或荧光原位杂交技术(FISH)阳性；
3)至少有一个可测量病灶(根据RECIST 1.1标准)；
4)既往曾接受过曲妥珠单抗和紫杉类药物治疗：
曲妥珠单抗在新辅助/辅助治疗阶段使用应≥3个月，或在复发/转移后阶段使用应≥2个周期(如：21天/周期)。紫杉类药物可在新辅助/辅助以及复发/转移后等各治疗阶段应用，治疗时间应≥2个周期(如：21天/周期)；
如含紫杉类药物的治疗方案在治疗中存在疾病进展，则不要求既往使用量必须达到以上标准。
(注：在第一和第二阶段剂量爬坡研究中，允许纳入既往曾接受过曲妥珠单抗生物类似物治疗的个体，其治疗时间与曲妥珠单抗要求一致)
5)复发/转移阶段曾接受过的化疗线数≤2线；
6)在参加本试验之前最近的一个治疗阶段中或治疗完成后，出现明确的疾病进展；
7)主要器官功能正常，即符合下列标准：
a)血常规检查(14天内未输血、未使用造血刺激因子类药物纠正状态下)：血红蛋白(Hb)≥90g/L；绝对中性粒细胞计数(ANC)≥1.5×10 9/L；血小板(PLT)≥100×10 9/L；
b)生化检查：谷丙转氨酶(ALT)及谷草转氨酶(AST)≤2.5×ULN(肿瘤肝脏转移者，≤5×ULN)；血清总胆红素(TBIL)≤1.5×ULN(Gilbert综合症患者≤3×ULN)；血清肌酐(Cr)≤1.5×ULN，或肌酐清除率≥60ml/min；
c)凝血功能：活化部分凝血活酶时间(APTT)、国际标准化比值(INR)、凝血酶原时间(PT)≤1.5×ULN；
d)多普勒超声评估：左室射血分数(LVEF)≥50％。
8)育龄期女性应同意在研究期间和研究结束后6个月内必须采用避孕措施(如宫内节育器[IUD]，避孕药或避孕套)；在研究入组前的7天内血清或尿妊娠试验阴性，且必须为非哺乳期患者；男性应同意在研究期间和研究期结束后6个月内必须采用避孕措施的个体；
9)个体自愿加入本研究，签署知情同意书，依从性好。
1.2试验药
式(II)化合物胶囊。
规格(以式(I)化合物本身计算)：2mg、5mg、10mg；遮光、密封、在20℃以下保存，有效期：24个月。
起始剂量为4mg、6mg、8mg、10mg、12mg或16mg，每日1次，连续服用21天为1个治疗周期，直至研究终止标准。
卡培他滨片：规格150mg(市售)、500mg(市售，由正大天晴药业集团股份有限公司生产)
起始剂量为1000mg/m 2(或750mg/m 2或500mg/m 2)，每日2次，餐后30分钟内口服(早晚各1次，间隔12小时，等于每日剂量为2000mg/m 2(或1500mg/m 2或1000mg/m 2))，第1-14天连续给药，停药7天，21天为1个治疗周期，直至研究终止标准。
1.3评价标准
主要疗效指标按RECIST1.1标准评价疗效。
1.4治疗效果
病例1：
一名50岁女性，2019年2月27日于哈尔滨医科大学附属肿瘤医院(以下简称“哈肿”)穿刺病理：2019-02-21《左乳2点》浸性癌，《左腋下及左锁下》可见低分化腺癌。2019年2月27日常规病理诊断：《左乳2点》浸润性癌，《左腋下及左锁下》可见低分化腺癌。补充病理诊断：左乳2点：ER(-)，PR(-)，HER-2(3+)，Ki67(指数约20％)，P53；左腋下及左锁下：ER(-)，PR(-)，HER-2(3+)，Ki67(指数约20％)，P53。
该患者于2019年3月4日入组“注射用重组人HER-2单克隆抗体(赫赛汀)治疗HER-2过度表达转移性乳腺癌患者的疗效、安全性及体内代谢特征的多中心、随机、双盲III期临床试验”。
患者自2019.3.4-2019.3.5给予(注射用重组人HER-2单克隆抗体(赫赛汀)512mg/周期d1 ivgtt+多西他赛127.5mg/周期ivgtt d2)方案化疗1周期；自2019.3.26-2019.8.20给予(注射用重组人HER-2单克隆抗体(赫赛汀)384mg/周期d1 ivgtt+多西他赛127.5mg/周期ivgtt d2)方案化疗8周期；自2019.9.11-2020.1.16给予(注射用重组人HER-2单克隆抗体(赫赛汀)384mg/周期d1 ivgtt)靶向治疗7周期。治疗类型：一线治疗，疗效：PD(2020.3.11CT显示:靶病灶增大)，最佳疗效：PR。于2020.3.11出组。
该患者(her2 3+)出组后开始接受式(II)化合物胶囊的治疗：
2020.4.10-2020.7.2，每日一次口服12.0mg式(II)化合物胶囊(连续用药每21天为一个治疗周期)进行治疗。
2020.7.4-2020.8.14，每日一次口服10.0mg式(II)化合物胶囊(连续用药每21天为一个治疗周期)进行治疗。
2020.8.29开始每日一次口服8.0mg式(II)化合物胶囊(连续用药每21天为一个治疗周期)进行治疗。
2020.5.20患者接受治疗2周期，增强CT提示左乳病灶较前缩小；肝部病灶，较前缩小；按RECIST1.1评价为PR，靶病灶总和为52mm，较基线缩小38mm。
2020.6.30患者接受治疗4周期，增强CT提示左乳病灶较前变化不大；肝部病灶，较前略缩小；按RECIST1.1评价为PR，靶病灶总和为46mm。
2020.8.12患者接受治疗6周期，增强CT提示左乳病灶较前略缩小；肝部病灶，较前变化不大；按RECIST1.1评价为PR，靶病灶总和为41mm。
2020.10.10患者接受治疗8周期，增强CT提示左乳病灶较前缩小；肝部病灶，较前略缩小；按RECIST1.1评价为PR，靶病灶总和为20mm。
患者基本可耐受不良反应，仍在继续接受治疗。
病例2：
一名49岁女性，患者于2015.1.20发现右乳肿物，2015-3-12于哈肿行“右乳癌根治术”。
2015-03-16黑龙江省医院病理示：右侧乳腺浸润性癌，组织学Ⅱ级。2015-03-18病理示：右乳腺癌根治标本各切缘及***无癌，腋下***见癌转移1/12。2015-03-27病理示：免疫组化：ER(-)，PR(-)，cerbB-2(3+)。2015-03-31哈肿会诊示：右乳浸润性癌Ⅱ级，***见有癌1/12。免疫组化：ER(-)，PR(-)，cerbB-2(3+)。
患者于2015.4.2入组“尿多肽注射液IV期临床研究”，2015.4.2-2015.4.24给予尿多肽注射液300ml ivgtt治疗2周期，治疗类型：辅助治疗，疗效：NA，最佳疗效：未知。
患者自2015.4.7-2015.6.9给予(盐酸表柔比星135mg/周期ivgtt+环磷酰胺0.9g/周期iv)方案化疗4周期，治疗类型：辅助治疗，疗效：NA，最佳疗效：未知。
自2015.4.7-2015.4.27给予沙利度胺2粒/次，2次/日，po d1-d5/周期，治疗2周期，治疗类型：辅助治疗，疗效：NA，最佳疗效：未知。自2015.5.18-2015.8.11给予沙利度胺2粒/次，2次/日，po d2-d6/周期，治疗5周期，治疗类型：辅助治疗，疗效：NA，最佳疗效：未知。
自2015.6.30-2015.9.1给予多西他赛140mg/周期ivgtt治疗4周期，治疗类型：辅助治疗，疗效：NA，最佳疗效：未知。2018.11.22CT示：左肺上叶结节，建议复查。2018.12.21PET-CT示：左肺上叶尖后段斜裂胸膜旁异常摄取结节，考虑为恶性(可能为转移瘤)；纵隔内及左肺门异常摄取***影，考虑为***转移。2018.12.27CT示：左肺上叶结节，较前略缩小，考虑转移瘤的可能性。
2019.1.2日入组“注射用重组抗HER2人源化单克隆抗体联合多西他赛对照曲妥珠单抗联合多西他赛治疗HER2过表达的复发转移性乳腺癌患者有效性、安全性的非劣效临床试验：一项多中心、随机、双盲、平行对照的III期研究”。患者自2019.1.2给予GB211/曲妥珠单抗480mg ivgtt+多西他赛117mg ivgtt治疗1周期，治疗类型：一线治疗。2019.1.23-2019.6.18给予GB211/曲妥珠单抗360mg/周期，ivgtt+多西他赛117mg/周期，ivgtt治疗8周期，治疗类型：一线治疗。2019.7.10-2019.12.03给予GB211/曲妥珠单抗360mg/周期ivgtt，8周期，治疗类型：一线治疗，疗效：2019.12.30CT报告：肺部靶病灶增大，总评为PD。最佳疗效：SD。
该患者(her2 3+)出组后开始式(II)化合物胶囊的治疗。
2020年6月18日-2020年7月29日，每日一次口服12mg式(II)化合物胶囊(21天为1个周期)，进行治疗2周期。
2020年7月30日-2020年9月9日，每日一次口服10mg式(II)化合物胶囊(21天为1个周期)，进行治疗2周期。
2020年9月10日开始，每日一次口服8mg式(II)化合物胶囊(21天为1个周期)，进行治疗。
2020年7月28日患者接受治疗2周期，增强CT提示左肺上叶结节(减小)，按RECIST1.1评价为SD，靶病灶总和为18mm，较基线缩小7mm。
2020年9月8日，增强CT提示左肺上叶结节，较前缩小，按RECIST1.1评价为PR，靶病灶总和为14mm，较基线缩小11mm。
2020年10月21日，增强CT提示左肺上叶结节，较前缩小，按RECIST1.1评价为PR，靶病灶总和为12mm，较基线缩小13mm。
患者基本可耐受不良反应，仍在继续接受治疗。
病例3：
一名63岁女性，患者于2016.8.11因左乳肿物于齐齐哈尔第一医院穿刺取活检示：浸润性癌，IHC示：ER(5％)；PR(-)；Her-2(3+)；Ki67(40％)。
2016.8.13于齐齐哈尔第一医院行EC方案(盐酸表柔比星150mg ivgtt+环磷酰胺0.9g ivgtt)化疗1周期，患者因耐受性差，停止治疗。
2018.11.16于哈肿行乳腺超声示：左腋下多发***肿大。
2018.11.19于哈肿骨扫描示：骨转移。
2018.11.23于哈肿病理会诊示：(左乳)浸润性癌2-3级，穿刺活检组织。
2018.11.27于哈肿ICH示：ER(+)；PR(-)；c-erbB-2(2+)；Ki67(+约占40％)，P53(3+)；2018.12.5于哈肿病理示：FISH阳性。
患者于2018.11.23入组“多西他赛联合赫赛汀/注射用重组人HER-2单克隆抗体试验”。患者于2018.12.10给予多西他赛129mg/周期ivgtt+赫赛汀/注射用重组人HER-2单克隆抗体616mg/周期ivgtt 1周期治疗；于2019.1.3-2019.3.5给予多西他赛129mg/周期ivgtt+赫赛汀/注射用重组人HER-2单克隆抗体462mg/周期ivgtt)4周期治疗。最佳疗效：未知。疗效：PD(2019.3.22，CT靶病灶增大)。患者于2019.3.25-2019.4.16给予赫赛汀440mg/周期ivgtt 2周期维持治疗。
2019.6.13入组“评价注射用BAT8001治疗HER2阳性的晚期乳腺癌有效性和安全性的临床研究-一项国内多中心、随机、开放、阳性对照的、优效性的III期临床研究”。2019.6.14-2020.1.10给予注射用重组人源化抗Her-2单克隆抗体-美登素偶联物(2019.6.14第1周期280.8mg ivgtt；2019.7.4第2周期289.8mg ivgtt；2019.7.25第3周期280.8mg ivgtt；2019.8.14第4周期286.2mg ivgtt；2019 9.4第5周期282.6mg ivgtt；2019.9 24第6周期280.8mg ivgtt；2019.10.17第7周期284.4mg ivgtt；2019.11.7第8周期288mg ivgtt；；2019.11.28第9周期288mg ivgtt；2019.12.19第10周期291.6mg ivgtt；2020.1.10第11周期284.4mg ivgtt)11周期治疗，疗效:PD(2020.3.24CT、2020.3.27MR示靶病灶增大)，最佳疗效:未知。
该患者(her2 3+)出组后开始式(II)化合物胶囊联合卡培他滨的治疗。
2020.7.15开始，给予式(II)化合物胶囊联合卡培他滨片(式(II)化合物胶囊：8mg/次，1次/日，口服，连续用药每21天为一个治疗周期+卡培他滨片：1000mg/㎡，2次/日，口服，第1-14天连续给药，停药7天，每21天为一个治疗周期)进行治疗。
2020.8.25患者接受治疗2周期，增强CT提示左乳病灶较前缩小；左腋下***病灶，较前略缩小；按RECIST1.1评价为SD，靶病灶总和为58.5mm，较基线缩小24.5mm。
2020.10.12患者接受治疗4周期，增强CT提示左乳病灶较前略缩小；肝部病灶，较前变化不大；按RECIST1.1评价为PR，靶病灶总和为52.8mm。
患者基本可耐受不良反应，仍在继续接受治疗。
病例4：
一名52岁女性患者，患者因右乳癌于2015-04-15在北安市农管局中心医院行“右乳癌改良根治术”，术后病理示:<右乳>十点及一点处浸润性导管癌，***浅筋膜阴性，腋下***可见癌转移2/35；2015-04-21病理于该院会诊:(右乳)浸润性导管癌2-3级。2015-04-24免疫组化:ER(-),PR(-),CerbB-2(3+)，Ki67(+)约占30％，P53(-)；2015-06-02至2015-06-25于该院行TAC方案(环磷酰胺800mgD1/周期+表柔比星80mgD1/周期+多西他赛120mgD1/周期)术后辅助化疗2周期，疗效及最佳疗效无法评价。2019-08-29因右锁上肿物行胸部CT检查:多发***增大；右侧锁骨上等密度影，可能为转移瘤；胸骨及右侧第一肋骨转移瘤；双肺转移瘤。
2019-08-29加入“正大天晴比较注射用曲妥珠单抗联合多西他赛与赫赛汀联合多西他赛一线治疗HER2阳性转移性乳腺癌患者的疗效并评价患者的安全性与免疫原性的双盲、随机化、多中心、III期临床研究”。
2019-09-05至2020-07-14行曲妥珠单抗/赫赛汀联合多西他赛治疗14周期(2019.9.5给予曲妥珠单抗/赫赛汀472.5mg/周期ivgtt D1+多西他赛120mg/周期ivgtt,D2治疗1周期，2019.9.26-2019.10.17给予曲妥珠单抗/赫赛汀354.9mg/周期ivgtt+多西他赛120mg/周期ivgtt治疗2周期，2019.11.17-2020.2.4给予曲妥 珠单抗/赫赛汀354mg/周期ivgtt+多西他赛119.25mg/周期ivgtt治疗5周期；2020.3.26-2020.4.15给予曲妥珠单抗/赫赛汀354.9mg/周期ivgtt治疗2周期；2020.5.14-2020.7.14给予曲妥珠单抗/赫赛汀354mg/周期ivgtt治疗4周期。)治疗类型：一线治疗；疗效：PD(2020.8.5 CT示非靶病灶增多增大，MR示脑转移，疾病进展，最佳疗效：PR。)可耐受。
该患者(her2 3+)出组开始接受式(II)化合物胶囊联合卡培他滨的治疗。
2020.9.3开始，给予式(II)化合物胶囊联合卡培他滨片(式(II)化合物胶囊：10mg/次，1次/日，口服，连续用药每21天为一个治疗周期+卡培他滨片：1000mg/㎡，2次/日，口服，第1-14天连续给药，停药7天，每21天为一个治疗周期)进行治疗。
2020.10.12患者接受治疗2周期，增强CT提示左肺、右肺病灶较前缩小；左锁上***病灶，较前缩小；按RECIST1.1评价为PR，靶病灶总和为42mm，较基线缩小21mm。
患者基本可耐受不良反应，仍在继续接受治疗。

Claims (15)

  1. 联用药物组合物，其包含式(I)化合物或其可药用盐和卡培他滨
    Figure PCTCN2020131537-appb-100001
  2. 用于治疗或预防乳腺癌的联用药物组合物，其包含式(I)化合物或其可药用盐和卡培他滨
    Figure PCTCN2020131537-appb-100002
  3. 用于治疗或预防乳腺癌的方法，其包括向有需要的个体施用治疗有效量的包含式(I)化合物或其可药用盐和卡培他滨的联用药物组合物
    Figure PCTCN2020131537-appb-100003
  4. 如权利要求1或2所述的联用药物组合物或如权利要求3所述的方法，其中所述式(I)化合物或其可药用盐为式(I)化合物或式(I)化合物的马来酸盐；任选地，所述式(I)化合物的马来酸盐为式(II)化合物
    Figure PCTCN2020131537-appb-100004
  5. 如权利要求1-4中任一项所述的联用药物组合物和方法，其中所述联用药物组合物含有150mg-4600mg的卡培他滨；或者，含有500mg-4600mg的卡培他滨；或者，含有1200mg-4600mg的卡培他滨；或者，含有1200mg、1500mg、1600mg、1800mg、2000mg、2100mg、2300mg、2200mg、2400mg、2600mg、2800mg、2900mg、3000mg、3200mg、3500mg、3600mg、4000mg、4300mg或4600mg的卡培他滨；或者，含有2300mg、2600mg、2900mg、3200mg、3500mg、3600mg、4000mg、4300mg或4600mg的卡培他滨；或者，含有1600mg-3500mg的卡培他滨；或者，含有1600mg、2000mg、2200mg、2400mg、2600mg、2800mg、3000mg、3200mg或3500mg的卡培他滨；或者，含有1200mg-2200mg的卡培他滨；或者，含有1200mg、1500mg、1600mg、1800mg、2000mg、2100mg或2200mg的卡培他滨；或者， 以个体的体表面积计，含有1000mg/m 2-2500mg/m 2的卡培他滨；或者，以个体的体表面积计，含有1000mg/m 2-2000mg/m 2的卡培他滨；或者，以个体的体表面积计，含有1000mg/m 2、1500mg/m 2或2000mg/m 2的卡培他滨。
  6. 如权利要求1-5中任一项所述的联用药物组合物和方法，其中卡培他滨为单剂量或多剂量；或者，卡培他滨为多剂量，任选地，所述多剂量由单剂量为150mg和/或500mg的卡培他滨组成。
  7. 如权利要求1-6中任一项所述的联用药物组合物和方法，其中以所述式(I)化合物本身计，所述联用药物组合物含有0.2mg至60mg、或0.5mg至40mg、或1.0mg至40mg、或1.5mg至40mg、或2mg至40mg、或4mg至40mg、或5mg至40mg、或6mg至40mg、或7mg至40mg、或8mg至40mg、或8mg至30mg、或8mg至25mg、或8mg至20mg、或8mg至16mg的所述式(I)化合物或其可药用盐；或者，以式(I)化合物本身计，所述联用药物组合物含有0.5mg-40mg的所述式(I)化合物或其可药用盐；或者，以式(I)化合物本身计，所述联用药物组合物含有2mg-20mg的所述式(I)化合物或其可药用盐；或者，以式(I)化合物本身计，所述联用药物组合物含有0.2mg、0.5mg、1mg、1.5mg、2mg、2.5mg、3.0mg、3.5mg、4.0mg、4.5mg、5mg、5.5mg、6mg、6.5mg、7mg、7.5mg、8mg、8.5mg、9mg、9.5mg、10mg、10.5mg、11mg、11.5mg、12mg、12.5mg、13mg、13.5mg、14mg、14.5mg、15mg、15.5mg、16mg、16.5mg、17mg、17.5mg或18mg的所述式(I)化合物或其可药用盐；或者，以式(I)化合物本身计，所述联用药物组合物含有2mg、4mg、5mg、6mg、8mg、10mg、12mg或16mg的所述式(I)化合物或其可药用盐；或者，以式(I)化合物本身计，所述联用药物组合物含有4mg、6mg、8mg、10mg、12mg或16mg的所述式(I)化合物或其可药用盐；或者，以式(I)化合物本身计，所述联用药物组合物含有2mg、5mg或10mg的所述式(I)化合物或其可药用盐。
  8. 如权利要求1-7中任一项所述的联用药物组合物和方法，其中所述式(I)化合物或其可药用盐为单剂量或多剂量；或者，所述式(I)化合物或其可药用盐为单剂量。
  9. 如权利要求1-8中任一项所述的联用药物组合物途和方法，所述联用药物组合物含有以个体的体表面积计的2000mg/m 2的每日剂量的卡培他滨，以及以所述式(I)化合物本身计的4mg、6mg、8mg、10mg、12mg或16mg的每日剂量的所述式(I)化合物或其可药用盐；或者所述联用药物组合物含有单剂量为150mg和/或500mg的卡培他滨，以及以所述式(I)化合物本身计的单剂量为2mg、4mg、5mg、6mg、8mg、10mg、12mg或16mg的所述式(I)化合物或其可药用盐。
  10. 如权利要求1-9中任一项所述的联用药物组合物和方法，其中卡培他滨和所述式(I)化合物或其可药用盐可以分别呈药物组合物形式或一起呈药物组合物形式以进行同时、并行、顺序或间隔给药，任选地，所述给药以连续每日给药的方式进行。
  11. 如权利要求1-10中任一项所述联用药物组合物和方法，卡培他滨和所述式(I)化合物或其可药用盐分别具有相同或不同的治疗周期；任选地，每1周、每2周、每3周或每4周为一个治疗周期；任选地，21天为一个治疗周期，在每个周期的第1-14天连续施用卡培他滨，在每个周期的第1-21天每天施用所述式(I)化合物或其可药用盐；任选地，卡培他滨以间隔给药的方式给药；任选地，卡培他滨可以第1-14天连续给药，并停药7天。
  12. 用于治疗或预防HER 2为阳性和/或FISH阳性乳腺癌的式(I)化合物或其可药用盐
    Figure PCTCN2020131537-appb-100005
  13. 用于治疗或预防HER 2为阳性和/或FISH阳性乳腺癌的方法，其包括向有需要的个体施用治疗有效量的式(I)化合物或其可药用盐
    Figure PCTCN2020131537-appb-100006
  14. 如权利要求1-11中任一项所述的联用药物组合物和方法、如权利要求12所述的化合物或权利要求13所述的方法，其中所述乳腺癌选自HER 2为阳性乳腺癌；或者，所述乳腺癌选自HER 2为FISH阳性乳腺癌；或者，所述乳腺癌为HER 2为2+或3+的乳腺癌；或者，所述乳腺癌为HER 2为2+并且FISH阳性的乳腺癌。
  15. 如权利要求1-11或14中任一项所述的联用药物组合物和方法、如权利要求12或14所述的化合物或权利要求13或14所述的方法，其中所述乳腺癌选自晚期乳腺癌；或者所述乳腺癌为既往曾接受过曲妥珠单抗药物治疗的乳腺癌；或者所述乳腺癌为既往曾接受过紫杉类药物治疗的乳腺癌；或者所述乳腺癌为既往曾接受过曲妥珠单抗和/或紫杉类药物治疗的乳腺癌；或者所述乳腺癌为既往接受过尿多肽、盐酸表柔比星、环磷酰胺、沙度利胺、多西他赛、重组人HER-2单克隆抗体、注射用重组人源化抗Her-2单克隆抗体-美登素偶联物中的一种或多种药物的单独和/或组合治疗的乳腺癌或接受过为乳癌根治术的治疗的乳腺癌。
PCT/CN2020/131537 2019-11-25 2020-11-25 喹唑啉衍生物或其盐的联用药物组合物及其用途 WO2021104319A1 (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202080071610.4A CN114761010B (zh) 2019-11-25 2020-11-25 喹唑啉衍生物或其盐的联用药物组合物及其用途

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201911162618 2019-11-25
CN201911162618.7 2019-11-25

Publications (1)

Publication Number Publication Date
WO2021104319A1 true WO2021104319A1 (zh) 2021-06-03

Family

ID=76129928

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2020/131537 WO2021104319A1 (zh) 2019-11-25 2020-11-25 喹唑啉衍生物或其盐的联用药物组合物及其用途

Country Status (2)

Country Link
CN (1) CN114761010B (zh)
WO (1) WO2021104319A1 (zh)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105147713A (zh) * 2008-08-04 2015-12-16 惠氏有限责任公司 4-苯胺基-3-氰基喹啉和卡培他滨的抗肿瘤组合
CN107406430B (zh) * 2015-03-20 2019-04-26 正大天晴药业集团股份有限公司 喹唑啉衍生物的盐及其制备方法

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2793286T3 (es) * 2014-12-09 2020-11-13 Chai Tai Tianqing Pharmaceutical Group Co Ltd Derivado de quinolina contra carcinoma de pulmón no microcítico
WO2019096194A1 (zh) * 2017-11-16 2019-05-23 江苏恒瑞医药股份有限公司 Pd-1抗体和vegfr抑制剂联合治疗小细胞肺癌的用途
CN107970241B (zh) * 2018-01-22 2020-05-22 正大天晴药业集团股份有限公司 一种新型酪氨酸激酶抑制剂安罗替尼在制备抑制骨肉瘤的药物中的应用

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105147713A (zh) * 2008-08-04 2015-12-16 惠氏有限责任公司 4-苯胺基-3-氰基喹啉和卡培他滨的抗肿瘤组合
CN107406430B (zh) * 2015-03-20 2019-04-26 正大天晴药业集团股份有限公司 喹唑啉衍生物的盐及其制备方法

Also Published As

Publication number Publication date
CN114761010B (zh) 2024-04-16
CN114761010A (zh) 2022-07-15

Similar Documents

Publication Publication Date Title
TWI607754B (zh) 醫藥組合
US10736887B2 (en) Quinoline derivative for treating gastric cancer
WO2015185014A1 (zh) 喹啉衍生物用于治疗软组织肉瘤的方法和用途以及用于治疗软组织肉瘤的药物组合物
WO2015185011A1 (zh) 喹啉衍生物用于治疗甲状腺癌的方法和用途以及用于治疗甲状腺癌的药物组合物
CA3080644A1 (en) Use of parp inhibitor in treating chemotherapy-resistant ovarian cancer or breast cancer
US20230119759A1 (en) Pharmaceutical combination comprising pyridino[1,2-a]pyrimidinone compound
WO2019057141A1 (zh) 阿帕替尼和c-Met抑制剂联合在制备***的药物中的用途
WO2020029918A1 (zh) 用于治疗结外nk/t细胞淋巴瘤的喹啉衍生物
WO2021104319A1 (zh) 喹唑啉衍生物或其盐的联用药物组合物及其用途
WO2020238932A1 (zh) Parp抑制剂联合vegfr抑制剂用于治疗卵巢癌或乳腺癌的用途
WO2019174508A1 (zh) 治疗鼻咽癌的喹啉衍生物
CN114787151B (zh) 喹唑啉衍生物或其盐、或其药物组合物的用途
RU2777519C2 (ru) Применение ингибитора parp в лечении резистентного к химиотерапии рака яичников или рака молочной железы
WO2023038030A1 (ja) 固形腫瘍治療用医薬組成物
WO2020156446A1 (zh) 一种含cdk4/6抑制剂的组合物与阿那曲唑联合在制备***疾病的药物中的用途
CN111065395B (zh) 用于治疗神经内分泌肿瘤的喹啉衍生物
WO2021185234A1 (zh) 作为c-Met激酶抑制剂的化合物的联用药物组合物及其用途
WO2020057539A1 (zh) 用于治疗小细胞肺癌的喹啉衍生物
TW202302084A (zh) 以安森司坦和帕博西尼治療乳癌
TW202342051A (zh) 用於治療高風險轉移性激素敏感性***癌之組合
WO2022184146A1 (zh) Cdk4/6抑制剂的联用药物组合物及其用途
US20240139208A1 (en) Combined pharmaceutical composition containing cdk4/6 inhibitor and use thereof
CN111110681A (zh) 喹啉衍生物联合卡培他滨在治疗肝癌的用途

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 20894756

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 20894756

Country of ref document: EP

Kind code of ref document: A1