WO2021104319A1

WO2021104319A1 - Combined pharmaceutical composition of quinazoline derivative or salt thereof and use thereof

Info

Publication number: WO2021104319A1
Application number: PCT/CN2020/131537
Authority: WO
Inventors: 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: 2019-11-25
Filing date: 2020-11-25
Publication date: 2021-06-03
Also published as: CN114761010B; CN114761010A

Abstract

The present application relates to a compound of formula (I) for treating or preventing breast cancer (chemical name: N 6-(1-acryloylazacyclohexan-4-yl)-N 4-(3-chloro-4-fluorophenyl)-7-methoxyquinazolin-4,6-diamine) or a pharmaceutically acceptable salt thereof, a combined pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof with capecitabine, and a use of the combined pharmaceutical composition in the treatment and prevention of breast cancer.

Description

Combined pharmaceutical composition of quinazoline derivative or its salt and its use

Cross-references to related applications

This application claims the priority and rights of the Chinese patent application No. 201911162618.7 filed with the State Intellectual Property Office of China on November 25, 2019, and the content disclosed in the application is incorporated herein by reference in its entirety.

Technical field

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.

Background technique

EGFR (epidermal growth factor receptor) is a tyrosine kinase receptor, a member of the HER/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. Wherein the chemical name of the compound of formula (I) is N ⁶ -(1-acryloylazcyclohexane-4-yl)-N ⁴ -(3-chloro-4-fluorophenyl)-7-methoxyquinazole Morino-4,6-diamine.

Summary of the invention

In one aspect, the application provides a combined pharmaceutical composition, which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof and capecitabine

On the other hand, 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.

In yet another aspect, 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.

In another aspect, 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 treating or preventing breast cancer.

In yet another aspect, the use of 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.

In another aspect, the present application provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for the treatment or prevention of breast cancer.

On the other hand, 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.

On the other hand, 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.

On the other hand, 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.

Detailed description of the invention

In some embodiments of the application, 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.

In some embodiments of the present application, 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. In some embodiments of the present application, 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.

In some embodiments of the present application, the combination pharmaceutical composition contains 150 mg-4600 mg capecitabine.

In some embodiments of the application, 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.

In some embodiments of the present application, 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.

In some embodiments of the application, 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.

In some embodiments of the application, 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.

In some embodiments of the present application, the combination pharmaceutical composition contains 1600mg-3500mg capecitabine.

In some embodiments of the present application, 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.

In some embodiments of the application, the combination pharmaceutical composition contains 1200mg-2200mg capecitabine.

In some embodiments of the present application, the combination pharmaceutical composition contains 1200 mg, 1500 mg, 1600 mg, 1800 mg, 2000 mg, 2100 mg or 2200 mg of capecitabine.

In some embodiments of the present application, in combination with the subject pharmaceutical compositions containing, body surface area 1000mg / m ² -2500mg / m ² gemcitabine capecitabine.

In some embodiments of the present application, in combination with the subject pharmaceutical compositions containing, body surface area 1000mg / m ² -2000mg / m ² gemcitabine capecitabine.

In some embodiments of the present application, 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.

The body surface area calculation formula of this application is: body surface area BSA (㎡)=0.00616×height (cm)+0.01286×weight (kg)-0.1529.

In some embodiments of the present application, in the combination pharmaceutical composition, capecitabine is in a single dose or multiple doses.

In some embodiments of the present application, in the combination pharmaceutical composition, capecitabine is in multiple doses.

In some embodiments of the present application, 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.

In some embodiments of the present application, in the combination pharmaceutical composition, the content of the capecitabine is two doses per day, and each dose is a multiple dose.

In some embodiments of the present application, in the combination pharmaceutical composition, the capecitabine 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.

In some embodiments of the present application, in the combination pharmaceutical composition, the pharmaceutical composition containing capecitabine is packaged in a kit, and the kit also contains capecitabine for the treatment or prevention of mammary glands. Explanation of cancer.

In some embodiments of the present application, in the combination pharmaceutical composition, the pharmaceutical composition containing capecitabine 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. In some embodiments of the application, the description is capecitabine tablets produced by Zhengda Tianqing Pharmaceutical Group Co., Ltd. (e.g.

) The description in the manual.

In some embodiments of the present application, 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. To 40 mg, or 4 mg to 40 mg, or 5 mg to 40 mg, or 6 mg to 40 mg, or 7 mg to 40 mg, or 8 mg to 40 mg, or 8 mg to 30 mg, or 8 mg to 25 mg, or 8 mg to 20 mg, or 8 mg to 16 mg ( I) The compound or its pharmaceutically acceptable salt.

In some embodiments of the present application, 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.

In some embodiments of the present application, 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.

In some embodiments of the application, 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.

In some embodiments of the present application, 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.

In some specific embodiments, 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.

In some specific embodiments, 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.

In some embodiments of the present application, in the combination drug composition, the compound of formula (I) or a pharmaceutically acceptable salt thereof 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.

In some embodiments of the present application, in the combination pharmaceutical composition, the content of the compound of formula (I) or a pharmaceutically acceptable salt thereof is the daily dose.

In some embodiments of the present application, in the combination pharmaceutical composition, the content of the compound of formula (I) or a pharmaceutically acceptable salt thereof is a once-daily dose.

In some embodiments of the present application, in the combination pharmaceutical composition, 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.

In some embodiments of the present application, in the combination pharmaceutical composition, the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is packaged in a kit, and the kit further contains formula (I) ) Instructions for the use of the compound or its pharmaceutically acceptable salt in the treatment or prevention of breast cancer.

In some embodiments of the present application, 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.

In some embodiments of the present application, 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.

In some embodiments of the present application of the present application, in the combination pharmaceutical composition, 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.

On the other hand, 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.

In some embodiments of the present application, in the method for treating or preventing breast cancer, 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.

In some embodiments of the present application, in the method for treating or preventing breast cancer, 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.

In some embodiments of the present application, in the method for treating or preventing breast cancer, the content of capecitabine in the combination pharmaceutical composition is a daily dose, wherein the capecitabine is in a multi-dose manner. For administration, the multiple doses consist of a single dose of 150 mg and/or 500 mg of capecitabine.

In some embodiments of the present application, 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.

In some embodiments of the present application, in the method for treating or preventing breast cancer, 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.

In some embodiments of the present application, in the method for treating or preventing breast cancer, 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.

In some embodiments of the present application, 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.

In some embodiments of the present application, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in the manner of continuous daily administration.

In some embodiments of the present application, 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. In some embodiments of the present application, the compound of formula (I) or a pharmaceutically acceptable salt thereof and capecitabine have the same or different treatment cycles, respectively. In some specific embodiments of the present application, 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.

In some embodiments of the present application, 21 days is a treatment cycle, capecitabine is continuously administered on days 1-14 of each treatment cycle, and the formula is administered daily on days 1-21 of each treatment cycle. (I) The compound or its pharmaceutically acceptable salt.

In some specific embodiments of the present application, 21 days is a treatment cycle, and 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.

In some embodiments of the present application, 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.

In some embodiments of the present application, 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). In some embodiments, 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. In some embodiments, 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.

In some embodiments of the present application, in the method for treating or preventing breast cancer, 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.

In the embodiments of the present application, as long as the disease is still under control and the dosing regimen is clinically tolerable, the above treatment cycle is repeated.

In some embodiments of the present application, 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. Single or multiple doses of 10mg, 12mg and/or 16mg.

In some embodiments of the present application, 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.

In some embodiments of the present application, 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.

In another aspect, 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. In some embodiments of the application, the combination pharmaceutical composition is the combination pharmaceutical composition described above in the application. For example, aspects such as the content of each component and the administration mode of the combined pharmaceutical composition are as described above.

In another aspect, 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.

In some embodiments of the present application, the breast cancer is selected from HER 2 positive and/or fluorescent in situ hybridization (FISH) positive breast cancer.

In some embodiments of the present application, the breast cancer is HER2-positive breast cancer.

In some embodiments of the present application, 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.

In some embodiments of the present application, the breast cancer is HER2, which is fluorescent in situ hybridization (FISH) positive breast cancer.

In some embodiments of the application, the breast cancer is advanced breast cancer or metastatic breast cancer.

In some embodiments of the present application, 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). Breast cancer).

In some embodiments of the present application, the breast cancer is breast cancer that has previously been treated with trastuzumab drugs.

In some embodiments of the present application, trastuzumab is used for ≥3 months in the treatment phase, or ≥2 cycles in the post-relapse/metastasis phase (eg: 21 days/cycle).

In some embodiments of the present application, 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.

In some embodiments of the present application, the breast cancer is breast cancer that has previously been treated with taxanes.

In some embodiments of the present application, the treatment time of taxanes is ≥ 2 cycles (e.g., 21 days/cycle).

In some embodiments of the present application, 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.

In some embodiments of the present application, the breast cancer is breast cancer that has previously been treated with trastuzumab and/or taxanes.

In some embodiments of the present application, the taxanes include but are not limited to paclitaxel, docetaxel, paclitaxel liposomes, or albumin-bound paclitaxel.

In some embodiments of the present application, the breast cancer is selected from: invasive cancer, further FISH positive, and/or Her-2(3+), and/or c-erbB-2(2+/3+) ; Optionally, it also includes ER (+/-), PR (-/+), Ki67 (+, for example 30%-60%), P53 (-/3+). In some embodiments of the present application, 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.

In some embodiments of the present application, the breast cancer is an invasive cancer and has the following characteristics: ER (5%), PR (-), Her-2 (3+), Ki67 (40%).

In some embodiments of the present application, the breast cancer has the following characteristics: Her-2(3+), ER(+), PR(-), c-erbB-2(2+), Ki67(40%) , P53(3+), FISH positive.

In some embodiments of the present application, the breast cancer is breast cancer that has previously been treated with epirubicin hydrochloride combined with cyclophosphamide.

In some embodiments of the present application, the breast cancer is breast cancer that has previously been treated with docetaxel combined with trastuzumab.

In some embodiments of the present application, the breast cancer is breast cancer that has previously been treated with a recombinant humanized anti-Her-2 monoclonal antibody-maytansine conjugate for injection.

In some embodiments of the present application, the breast cancer has the following characteristics: Her-2(3+), ER(-), PR(-), CerbB-2(3+), Ki67(30%), P53 (-).

In some embodiments of the present application, 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. In some embodiments of the present application, the additional therapeutic agent may be a therapeutic agent for cancer known in the art, preferably a therapeutic agent for breast cancer.

In some embodiments of the present application, 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).

In some embodiments of the present application, 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).

In some embodiments of the application, 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) .

In some embodiments of the present application, the dosage of recombinant human HER-2 monoclonal antibody is 512 mg/cycle or 384 mg/cycle (eg, 21 days/cycle).

In some embodiments of the present application, 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.

In some embodiments of the present application, the breast cancer is an invasive cancer and has the following characteristics: ER (-), PR (-), HER-2 (3+), Ki67 (20%), P53.

In some embodiments of the present application, 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). (Lizumab, Herceptin) combined with docetaxel for breast cancer (such as HER2-positive breast cancer).

In some embodiments of the present application, 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.

In some embodiments of the present application, 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).

In some embodiments of the present application, the breast cancer is breast cancer that has undergone radical mastectomy in the past.

In some embodiments of the present application, the breast cancer is invasive breast cancer and has the following characteristics: HER-2 (3+), ER (-), PR (-), cerbB-2 (3+).

In some embodiments of the present application, 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.

In some embodiments of the present application, 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.

In some embodiments of the present application, 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.

In some embodiments of the present application, 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.

In some schemes of the present application, the breast cancer is breast cancer that has previously been treated with trastuzumab combined with docetaxel.

In some embodiments of the present application, 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.

In some embodiments of the application, 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.

In some embodiments of the present application, 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.

In a specific embodiment, 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. In a specific embodiment, 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. In a specific embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered orally.

The compound of formula (I) or a pharmaceutically acceptable salt thereof 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.

In some embodiments of the present application, 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.

In some embodiments of the present application, 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.

Formula (I) compound or its pharmaceutically acceptable salt

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. For example, 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.

In some embodiments of the present application, the pharmaceutically acceptable salt is selected from maleate, malate, fumarate, tartrate, citrate, lactate, phosphate, or acetate.

In some embodiments of the application, the pharmaceutically acceptable salt is maleate.

Regarding the pharmaceutically acceptable salt of the compound of formula (I) described in this application, 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).

In some embodiments of this application, the pharmaceutically acceptable salt of the compound of formula (I) described in this application is a compound of formula (II)

The "compound of formula (I) or its pharmaceutically acceptable salt" mentioned in this application can be replaced with "compound of formula (II)"; for example, the aforementioned "compound of formula (I) or its pharmaceutically acceptable salt and capecitabine" can be Replace with "Capecitabine and compound of formula (II)".

Pharmaceutical composition 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".

In some embodiments of the present application, the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof further contains pharmaceutically acceptable excipients.

In some embodiments of the application, 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.

In some embodiments of the present application, 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.

In some embodiments of the application, 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 .

In some embodiments of the application, the polymethacrylate is

In some embodiments of the present application, the polymethacrylate is selected from

or

In some embodiments of the application, the polymethacrylate is

In some embodiments of the present application, in the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof, 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.

In some embodiments of the present application, in the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof, the weight ratio of polymethacrylate to the compound of formula (II) is 8:1.

In some embodiments of the application, the acid is selected from maleic acid, malic acid, fumaric acid, tartaric acid, citric acid, lactic acid, phosphoric acid, or acetic acid.

In some embodiments of the application, the acid is maleic acid.

In some embodiments of the present application, in the pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof, the 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.

In some embodiments of the present application, 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.

In some embodiments of the present application, the surface stabilizer is hydroxypropyl cellulose (for example, HPC-SL type).

In some embodiments of the present application, in the pharmaceutical composition containing the compound of formula (I) or its pharmaceutically acceptable salt, 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.

In some embodiments of the present application, in the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof, the weight ratio of the surface stabilizer to the compound of formula (II) is 0.16:1.

In some embodiments of the application, the dispersant is selected from sucrose, lactose, or mannitol.

In some embodiments of the application, the dispersant is sucrose.

In some embodiments of the present application, in the pharmaceutical composition containing the compound of formula (I) or its pharmaceutically acceptable salt, 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,

In some embodiments of the present application, in the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof, the weight ratio of the dispersant to the compound of formula (II) is 5:1.

In some embodiments of the present application, 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.

In some embodiments of the application, the carrier is selected from cellulose pellets or sucrose pellet cores.

In some embodiments of the application, the carrier is a sucrose pellet core (e.g., 0.6-0.8 mm).

In some embodiments of the present application, 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%.

In some specific embodiments of the present application, 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).

The pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof contains the following components in the following parts by weight:

In some specific embodiments of the present application, in the pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof, the polymethacrylate, acid, surface stabilizer, dispersant and carrier are respectively as above As defined by the text.

In each of the above pharmaceutical compositions of the present application containing the compound of formula (I) or its pharmaceutically acceptable salt, the particle size range of the compound of formula (I) or its pharmaceutically acceptable salt is D50<10μm, D90<20μm; or D50< 5μm, D90<10μm; or D50<2μm, D90<4μm.

In some embodiments of the present application, the particle size range of the compound of formula (I) or its pharmaceutically acceptable salt is D50<2μm and D90<4μm.

In each of the aforementioned pharmaceutical compositions of the present application containing the compound of formula (I) or a pharmaceutically acceptable salt thereof, the acid such as maleic acid is added in an appropriate amount, for example, to make the pharmaceutical composition acidic in water.

In some embodiments of the present application, in each of the above-mentioned pharmaceutical compositions containing a compound of formula (I) or a pharmaceutically acceptable salt thereof, the maleic acid is added in an appropriate amount.

In some embodiments of the present application, in each of the pharmaceutical compositions containing a compound of formula (I) or a pharmaceutically acceptable salt thereof, the acid can be used as a pH adjusting agent. For example, in the preparation process of the solid pharmaceutical composition, the acid 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).

Each of the pharmaceutical 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.

In some embodiments of the present application, the pharmaceutical composition of the present application containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered orally.

In some embodiments of the present application, each of the pharmaceutical compositions containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is a solid pharmaceutical composition.

In some embodiments of the present application, the preparation form of the solid pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is a capsule.

In some embodiments of the present application, 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.

In some embodiments of the application, 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.

The pharmaceutical 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.

On the other hand, 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:

Prepare a suspension containing the compound of formula (I) or its pharmaceutically acceptable salt; add acid and polymethacrylate to the suspension; apply the suspension obtained above on a carrier fluidized bed to obtain Medicated pellets.

Capecitabine

As used in this application, the chemical name of capecitabine is 5'-deoxy-5-fluoro-N-[(pentoxy)carbonyl]-cytidine, which has the following structural formula:

Pharmaceutical composition containing capecitabine

In some embodiments of the application, the pharmaceutical composition containing capecitabine further contains pharmaceutically acceptable excipients.

In some embodiments of the application, 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.

In some embodiments of the application, the pharmaceutical composition containing capecitabine is administered orally.

In some embodiments of the present application, the pharmaceutical composition containing capecitabine is a solid pharmaceutical composition.

In some embodiments of the present application, the formulation form of the pharmaceutical composition containing capecitabine is a tablet.

In some embodiments of the present application, the pharmaceutical composition containing capecitabine comprises: capecitabine, anhydrous lactose, microcrystalline cellulose, croscarmellose sodium, hypromellose , Magnesium stearate and film-coated powder (stomach-soluble type).

In some embodiments of the application, in the pharmaceutical composition containing capecitabine, the amount of capecitabine is 150 mg or 500 mg.

Method of application

The following content does not limit the administration mode of the combined pharmaceutical composition of the present application.

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). In some embodiments of the present application, 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) in the treatment of breast cancer, especially HER 2 is positive (e.g., HER 2 is 3+) Has a good effect on breast cancer. It has outstanding effect data in at least one of ORR, DCR, DoR, PFS or OS; and the patient has good tolerance and low side effects. Compared with a single drug, the combined drug composition has a better therapeutic effect, a lower dosage, and is well tolerated.

Definition and description

The word "comprise" or "comprise" and its English variants such as comprises or comprising should be understood in an open, non-exclusive meaning, that is, "including but not limited to".

The term "patient" refers to a mammal, preferably a human. In some embodiments of the present application, the patient and the individual are patients who have failed or lacked standard treatment.

The term "pharmaceutically acceptable" or "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.

The term "therapeutically 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.

The term "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:

(i) Suppress the disease or disease state, that is, curb its development;

(ii) Alleviate the disease or disease state, even if the disease or disease state subsides.

The term "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.

The term "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.

The terms "administration" and "administration" refer 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. In certain embodiments, the administration is oral administration.

The term "daily dose" refers to the daily dose administered to a patient.

The term "body surface area-based dose" referred to herein 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.

The term "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.

The term "multi-dose" consists of multiple single doses. As used herein, "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.

The term "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.

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.

The following acronyms are used in this application:

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.

PO: Oral. Iv: intravenous injection. ER: estrogen receptor. FISH: Fluorescence in situ hybridization. PR (progesterone receptor): 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.

Example

The purpose of the following specific embodiments is to enable those skilled in the art to understand and implement the application more clearly. They should not be considered as limitations on the scope of this application, but merely exemplary descriptions and typical representatives of this application.

Example 1

1) Add hydroxypropyl cellulose to water ¹ , dissolve it and add the compound of formula (II) under stirring conditions, disperse it uniformly, and sieve;

2) The above-mentioned drug-containing suspension is homogenized under high pressure, so that the particle size of the compound of formula (II) is controlled to: D50<2μm, D90<4μm, and the prescribed amount of sucrose is added;

3) Prepare 0.5mol/L maleic acid water ² solution, take half of the prepared maleic acid water solution to dissolve the prescription amount

After dissolving, add the suspension obtained in step 2), and then adjust the pH of the suspension to 3.0-3.5 with the remaining maleic acid aqueous solution to obtain a suspension;

4) Coating the sucrose blank pellet core with the suspension prepared in step 3) in a fluidized bed to obtain drug-containing pellets;

5) Add the medicine-containing pellets to the hopper mixer and mix well;

6) Fill the capsule.

The composition of the specific pharmaceutical capsule preparation is shown in Table 1 below.

Table 1

Water ¹ :26.67mg; Water ² :20mg.

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.

Table 2

Note:

Example 2, Water ¹ : 66.67mg; Water ² : 50mg;

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.

Example 6

Refer to steps 1) to 6) of Example 1, except that in 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.

The composition of the specific pharmaceutical capsule preparation is shown in Table 3 below.

table 3

Experimental example 1 clinical trial

1.1 Selection criteria:

1) 18 to 70 years old; ECOG PS score: 0 to 1 point; expected survival time is more than 3 months;

2) Individuals with advanced metastatic breast cancer with positive HER2 expression confirmed only by pathological examination: Positive HER2 expression means that standard immunohistochemical staining (IHC) tests show that HER2 is 3+ and/or fluorescent in situ hybridization (FISH) positive;

3) At least one measurable lesion (according to RECIST 1.1 standard);

4) Have received treatment with trastuzumab and taxanes in the past:

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);

If the treatment plan containing taxanes has progressed in the treatment, it is not required that the previous usage must meet the above standards.

(Note: In the first and second phases of the dose-climbing study, individuals who have previously been treated with trastuzumab biosimilars are allowed to be included, and the treatment time is consistent with the requirements of trastuzumab)

5) The number of chemotherapy lines received in the recurrence/metastasis stage ≤ 2 lines;

6) A clear disease progression occurred during the most recent treatment period before participating in this trial or after the treatment was completed;

7) The main organs are functioning normally, that is, they meet the following standards:

a) Routine blood examination (under 14 days without blood transfusion and no hematopoietic stimulating factor drugs for correction): hemoglobin (Hb) ≥90g/L; absolute neutrophil count (ANC) ≥1.5×10 ⁹ /L; platelets (PLT)≥100×10 ⁹ /L;

b) Biochemical examination: Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5×ULN (for liver metastasis of tumor, ≤5×ULN); serum total bilirubin (TBIL) ≤1.5×ULN (for patients with Gilbert syndrome) ≤3×ULN); serum creatinine (Cr)≤1.5×ULN, or creatinine clearance ≥60ml/min;

c) Blood coagulation function: activated partial thromboplastin time (APTT), international normalized ratio (INR), prothrombin time (PT)≤1.5×ULN;

d) Doppler ultrasound evaluation: left ventricular ejection fraction (LVEF) ≥50%.

8) Women of childbearing age should agree to use contraceptive measures (such as intrauterine device [IUD], contraceptives or condoms) during the study period and within 6 months after the end of the study; serum or urine within 7 days before study entry The pregnancy test is negative and must be a non-lactating patient; the male should agree to individuals who must use contraceptive measures during the study period and within 6 months after the end of the study period;

9) Individuals voluntarily join the study, sign an informed consent form, and have good compliance.

1.2 Test drug

Formula (II) compound capsules.

Specifications (calculated based on the compound of formula (I) itself): 2mg, 5mg, 10mg; shading, sealed, and stored below 20°C, valid period: 24 months.

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.

1.3 Evaluation criteria

The main efficacy indicators were evaluated according to the RECIST1.1 standard.

1.4 Therapeutic effect

Case 1:

A 50-year-old female, puncture pathology at the Affiliated Tumor Hospital of Harbin Medical University (hereinafter referred to as "Hat") on February 27, 2019: 2019-02-21 "Left breast 2 o'clock" invasive cancer, "Left armpit and "Left lock down" shows poorly differentiated adenocarcinoma. Routine pathological diagnosis on February 27, 2019: "Left breast 2 o'clock" invasive carcinoma, "Left axillary and left subocclusion" showed poorly differentiated adenocarcinoma. Supplementary pathological diagnosis: 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 enrolled on March 4, 2019. "Multi-center evaluation of the efficacy, safety and in vivo metabolic characteristics of recombinant human HER-2 monoclonal antibody (Herceptin) for injection in the treatment of patients with HER-2 overexpression metastatic breast cancer , Randomized, double-blind phase III clinical trial".

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. 16 Administration (recombinant human HER-2 monoclonal antibody for injection (Herceptin) 384mg/cycle d1 ivgtt) targeted therapy for 7 cycles. Treatment type: first-line treatment, curative effect: PD (2020.3.11 CT shows: target lesion enlargement), best curative effect: PR. Released on 2020.3.11.

This patient (her2 3+) began to receive the treatment of the compound capsule of formula (II) after leaving the group:

2020.4.10-2020.7.2, take orally 12.0mg formula (II) compound capsules once a day (continuous medication every 21 days is a treatment cycle) for treatment.

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.

Starting on August 29, 2020, 8.0 mg capsules of the compound of formula (II) were taken orally once a day (every 21 days of continuous medication is a treatment cycle) for treatment.

2020.5.20 The patient received 2 cycles of treatment. Enhanced CT showed that the left breast lesion was smaller than before; the liver lesion was smaller than before; it was evaluated as PR according to RECIST1.1, and the total target lesion was 52mm, which was 38mm smaller than the baseline.

2020.6.30 The patient received 4 cycles of treatment. Enhanced CT showed that the left breast lesions had little change compared with the previous ones; the liver lesions were slightly smaller than the previous ones; it was evaluated as PR according to RECIST1.1, and the total target lesions were 46mm.

The patient received 6 cycles of treatment on August 12, 2020. 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.

On October 10, 2020, the patient received 8 cycles of treatment. Enhanced CT showed that the left breast lesion was smaller than before; the liver lesion was slightly smaller than before; it was evaluated as PR according to RECIST1.1, and the total target lesion was 20mm.

The patient can basically tolerate the adverse reaction and continues to receive treatment.

Case 2:

A 49-year-old female, the patient found a right breast mass on January 20, 2015, and underwent “radical mastectomy for right breast cancer” in Hazong on March 12, 2015.

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.

From 2015.4.7-2015.4.27 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.

From 2015.6.30 to 2015.9.1, given docetaxel 140mg/cycle ivgtt for 4 cycles, treatment type: adjuvant therapy, curative effect: NA, best curative effect: unknown. 2018.11.22 CT showed: left upper lobe nodules, it is recommended to review. 2018.12.21 PET-CT showed: abnormal uptake of the parapleural nodules in the posterior oblique fissure of the left upper lobe, which is considered to be malignant (may be metastases); abnormal uptake of lymph node shadows in the mediastinum and left hilum, which is considered to be lymph node metastasis. 2018.12.27 CT showed: the left upper lobe nodule, slightly smaller than before, considering the possibility of metastasis.

Enrolled on the day of 2019.1.2 "Efficacy and safety of recombinant anti-HER2 humanized monoclonal antibody for injection combined with docetaxel control trastuzumab combined with docetaxel in the treatment of patients with recurrent and metastatic breast cancer with HER2 overexpression Non-inferiority clinical trial: a multi-center, randomized, double-blind, parallel-controlled phase III study". The patient was given GB211/trastuzumab 480 mg ivgtt + docetaxel 117 mg ivgtt for 1 cycle from 2019.1.2, treatment type: first-line treatment. 2019.1.23-2019.6.18 GB211/trastuzumab 360mg/cycle, ivgtt+docetaxel 117mg/cycle, ivgtt treatment for 8 cycles, treatment type: first-line treatment. 2019.7.10-2019.12.03 given GB211/trastuzumab 360mg/cycle ivgtt, 8 cycles, treatment type: first-line treatment, efficacy: 2019.12.30 CT report: lung target lesions are enlarged, and the total is rated as PD. Best efficacy: SD.

After the patient (her2 3+) was released from the group, the treatment of the compound capsule of formula (II) was started.

From June 18, 2020 to July 29, 2020, 12 mg capsules of the compound of formula (II) were taken orally once a day (21 days is a cycle) for 2 cycles of treatment.

From July 30, 2020 to September 9, 2020, 10 mg capsules of the compound of formula (II) were taken orally once a day (21 days is a cycle) for 2 cycles of treatment.

Starting from September 10, 2020, 8 mg of formula (II) compound capsules were taken orally once a day (21 days is a cycle) for treatment.

On July 28, 2020, the patient received 2 cycles of treatment. 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.

On September 8, 2020, enhanced CT revealed a nodule in the upper lobe of the left lung, which was smaller than before. It was evaluated as PR according to RECIST1.1. The total target lesion was 14mm, which was 11mm smaller than the baseline.

On October 21, 2020, enhanced CT revealed a nodule in the upper lobe of the left lung, which was smaller than before. It was evaluated as PR according to RECIST1.1. The total target lesion was 12mm, which was 13mm smaller than the baseline.

Case 3:

A 63-year-old woman, a patient with a left breast mass in Qiqihar No. 1 Hospital on August 11, 2016, took a biopsy and showed: invasive cancer, IHC showed: ER (5%); PR(-); Her-2(3+) ); Ki67 (40%).

On August 3, 2016, the EC regimen (150 mg ivgtt of epirubicin hydrochloride + 0.9 g ivgtt of cyclophosphamide) chemotherapy was performed in Qiqihar First Hospital for 1 cycle. The patient stopped the treatment due to poor tolerance.

On November 16, 2018, the breast ultrasound performed in Hazhuang showed that there were multiple lymphadenopathy in the left armpit.

2018.11.19 Yuha's swollen bone scan showed: bone metastasis.

2018.11.23 at the Hazong Pathological Consultation showed: (left breast) invasive carcinoma of grade 2-3, biopsy tissue.

2018.11.27 in Hazong ICH shows: ER(+); PR(-); c-erbB-2(2+); Ki67 (+ about 40%), P53(3+); 2018.12.5 at Hazong Pathology showed: FISH was positive.

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.

2019.6.13 was enrolled in the "Clinical study to evaluate the effectiveness and safety of BAT8001 for injection in the treatment of HER2-positive advanced breast cancer-a domestic multi-center, randomized, open, positive-controlled, superiority phase III clinical study". 2019.6.14-2020.1.10 Recombinant humanized anti-Her-2 monoclonal antibody-maytansine conjugate for injection was administered (2019.6.14, cycle 1 280.8mg ivgtt; 2019.7.4, cycle 2 289.8mg ivgtt; 2019.7 .25 Cycle 3 280.8mg ivgtt; April 14th, 2019 Cycle 4 286.2mg ivgtt; 2019 9.4 Cycle 5 282.6mg ivgtt; September 24, Cycle 6 280.8mg ivgtt; 2019.10.17 Cycle 7 284.4mg ivgtt; 2019.11.7 8th cycle 288mg ivgtt;; 2019.11.28 9th cycle 288mg ivgtt; 2019.12.19 10th cycle 291.6mg ivgtt; 2020.1.10 11th cycle 284.4mg ivgtt) 11 cycles of treatment, curative effect: PD (2020.3.24CT, 2020.3. 27MR shows that the target lesion is enlarged), the best effect: unknown.

After the patient (her2 3+) was released from the group, the treatment of compound capsule of formula (II) combined with capecitabine was started.

Beginning on July 15, 2020, give formula (II) compound capsules combined with capecitabine tablets (formula (II) compound capsules: 8 mg/time, 1 time/day, orally, every 21 days is a treatment cycle + capecitata) Bin tablets: 1000mg/㎡, 2 times/day, orally, continuous administration on day 1-14, stop for 7 days, every 21 days is a treatment cycle) for treatment.

2020.8.25 The patient received 2 cycles of treatment. 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.

On October 12, 2020, the patient received 4 cycles of 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 52.8mm.

Case 4:

A 52-year-old female patient underwent "modified radical mastectomy for right breast cancer" at the Central Hospital of Bei'an Agricultural Administration Bureau on April 15th, 2015 due to right breast cancer. The postoperative pathology showed that the right breast was infiltrated at ten o'clock and one o'clock. Ductal carcinoma, superficial fascia of the nipple is negative, cancer metastasis can be seen in the axillary lymph nodes 2/35; 2015-04-21 pathological consultation in this hospital: (right breast) invasive ductal carcinoma 2-3 grade. 2015-04-24 Immunohistochemistry: ER(-), PR(-), CerbB-2(3+), Ki67(+) accounts for about 30%, P53(-); 2015-06-02 to 2015-06 -25 TAC regimen (cyclophosphamide 800mgD1/cycle + epirubicin 80mgD1/cycle + docetaxel 120mgD1/cycle) was performed in this hospital for 2 cycles of postoperative adjuvant chemotherapy. The curative effect and the best curative effect could not be evaluated. 2019-08-29 Chest CT examination due to right supraclavicular mass: multiple lymph nodes enlargement; right supraclavicular isodensity, possibly metastases; metastases in the sternum and the first rib on the right; metastases in both lungs.

2019-08-29 Added "Zhengda Tianqing to compare the efficacy of injection trastuzumab combined with docetaxel and Herceptin combined with docetaxel in the first-line treatment of patients with HER2-positive metastatic breast cancer, and evaluate the safety and safety of patients A double-blind, randomized, multi-center, phase III clinical study of immunogenicity".

From 2019-09-05 to 2020-07-14, 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 354mg/cycle ivgtt for 4 cycles.) Treatment type: first-line treatment; curative effect: PD (2020.8.5 CT shows non-target The number of lesions increased, MR showed brain metastasis, disease progression, best effect: PR.) Tolerable.

The patient (her2 3+) was released from the group and started to receive the treatment of compound capsule of formula (II) combined with capecitabine.

Starting from March 2020, 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/㎡, 2 times/day, orally, continuous administration on day 1-14, stop for 7 days, every 21 days is a treatment cycle) for treatment.

2020.10.12 The patient received 2 cycles of treatment. Enhanced CT showed that the left and right lung lesions were smaller than before; the left succulent lymph node lesions were smaller than before; the PR was evaluated according to RECIST1.1, and the total target lesions were 42mm, which was 21mm smaller than the baseline. .

Claims

A combined pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and capecitabine
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
A method for treating or preventing breast cancer, which comprises administering a therapeutically effective amount of a combined pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and capecitabine to an individual in need
The combination pharmaceutical composition according to claim 1 or 2 or the method according to claim 3, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (I) or a compound of formula (I) Optionally, the maleate salt of the compound of formula (I) is a compound of formula (II)
The combination pharmaceutical composition and method according to any one of claims 1 to 4, wherein the combination pharmaceutical composition contains 150 mg-4600 mg capecitabine; alternatively, it contains 500 mg-4600 mg capecitabine ; Or, capecitabine containing 1200mg-4600mg; or, containing 1200mg, 1500mg, 1600mg, 1800mg, 2000mg, 2100mg, 2300mg, 2200mg, 2400mg, 2600mg, 2800mg, 2900mg, 3000mg, 3200mg, 3500mg, 3600mg, 4000mg, 4300mg or 4600mg of capecitabine; or, containing 2300mg, 2600mg, 2900mg, 3200mg, 3500mg, 3600mg, 4000mg, 4300mg or 4600mg of capecitabine; or, containing 1600mg-3500mg of capecitabine; or, containing 1600mg, 2000mg, 2200mg, 2400mg, 2600mg, 2800mg, 3000mg, 3200mg or 3500mg of capecitabine; or, containing 1200mg-2200mg of capecitabine; or, containing 1200mg, 1500mg, 1600mg, 1800mg, 2000mg, 2100mg or 2200mg of capecitabine; or, based on the body surface area of the individual, containing 1000mg/m 2 -2500mg/m 2 of capecitabine; or, based on the individual's body surface area, containing 1000mg/m 2 -2000mg/m 2 of capecitabine; or, based on the body surface area of an individual, it contains 1000 mg/m 2 , 1500 mg/m 2 or 2000 mg/m 2 of capecitabine.
The combination pharmaceutical composition and method according to any one of claims 1-5, wherein the capecitabine is in a single dose or multiple doses; or, the capecitabine is in multiple doses, optionally, the multiple The dose consists of a single dose of 150 mg and/or 500 mg of capecitabine.
The combination pharmaceutical composition and method according to any one of claims 1-6, wherein based on the compound of formula (I) itself, the combination pharmaceutical composition contains 0.2 mg to 60 mg, or 0.5 mg to 40mg, or 1.0mg 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 8 mg to 25 mg, or 8 mg to 20 mg, or 8 mg to 16 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof; or, based on the compound of formula (I) itself, the combination pharmaceutical composition contains 0.5 mg 40 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof; or, 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 Salt; or, based on the compound of formula (I) itself, the combination pharmaceutical composition contains 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, 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; or, based on the compound of formula (I) itself, 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 a pharmaceutically acceptable salt thereof; or, 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; or, based on the compound of formula (I) itself, the combination pharmaceutical composition contains 2 mg, 5 mg or 10 mg The compound of formula (I) or a pharmaceutically acceptable salt thereof.
The combination pharmaceutical composition and method according to any one of claims 1-7, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is in a single dose or multiple doses; or, the formula (I) The compound or its pharmaceutically acceptable salt is a single dose.
The method and method for the combination pharmaceutical composition according to any one of claims 1-8, the combination pharmaceutical composition containing capecitabine at a daily dose of 2000 mg/m 2 based on the body surface area of the individual , And the compound of formula (I) or a pharmaceutically acceptable salt thereof in a daily dose of 4 mg, 6 mg, 8 mg, 10 mg, 12 mg, or 16 mg based on the compound of formula (I) itself; or the combination drug combination The compound contains a single dose of 150mg and/or 500mg of capecitabine, and a single dose of the compound of formula (I) itself is 2mg, 4mg, 5mg, 6mg, 8mg, 10mg, 12mg or 16mg of the formula (I) The compound or its pharmaceutically acceptable salt.
The combination pharmaceutical composition and method according to any one of claims 1-9, wherein capecitabine and the compound of formula (I) or a pharmaceutically acceptable salt thereof may be in the form of a pharmaceutical composition or together The pharmaceutical composition is in the form of simultaneous, concurrent, sequential or interval administration, and optionally, the administration is carried out in the manner of continuous daily administration.
The combined pharmaceutical composition and method according to any one of claims 1-10, wherein capecitabine and the compound of formula (I) or a pharmaceutically acceptable salt thereof respectively have the same or different treatment cycles; optionally , Every 1 week, every 2 weeks, every 3 weeks or every 4 weeks is a treatment cycle; optionally, 21 days is a treatment cycle, and capecitabine is continuously administered on days 1-14 of each cycle. The compound of formula (I) or a pharmaceutically acceptable salt thereof is administered daily on the 1st to 21st day of each cycle; optionally, capecitabine is administered at intervals; optionally, capecitabine It can be administered continuously from day 1-14, and the drug can be stopped for 7 days.
A compound of formula (I) or a pharmaceutically acceptable salt thereof for the treatment or prevention of HER 2 positive and/or FISH positive breast cancer
A method for treating or preventing HER 2 positive and/or FISH positive 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 combination pharmaceutical composition and method according to any one of claims 1-11, the compound according to claim 12 or the method according to claim 13, wherein the breast cancer is selected from HER 2 positive breast Cancer; or, the breast cancer is selected from HER2 which is FISH-positive breast cancer; or, the breast cancer is a breast cancer whose HER2 is 2+ or 3+; or, the breast cancer is HER2 is 2+ and FISH-positive breast cancer.
The combination pharmaceutical composition and method according to any one of claims 1-11 or 14, the compound according to claim 12 or 14, or the method according to claim 13 or 14, wherein the breast cancer is selected Since advanced breast cancer; or the breast cancer is breast cancer that has received trastuzumab drug treatment in the past; or the breast cancer is breast cancer that has received taxane drug treatment in the past; or the breast cancer It is breast cancer that has previously been treated with trastuzumab and/or taxanes; or the breast cancer has been previously treated with urinary peptides, epirubicin hydrochloride, cyclophosphamide, thalidomide, and Single and/or combination therapy of one or more drugs in sitoxet, recombinant human HER-2 monoclonal antibody, and recombinant humanized anti-Her-2 monoclonal antibody-maytansine conjugate for injection Cancer or breast cancer that has been treated for radical mastectomy.