WO2022143969A1 - 一种治疗癌症的药物组合物 - Google Patents

一种治疗癌症的药物组合物 Download PDF

Info

Publication number
WO2022143969A1
WO2022143969A1 PCT/CN2021/143483 CN2021143483W WO2022143969A1 WO 2022143969 A1 WO2022143969 A1 WO 2022143969A1 CN 2021143483 W CN2021143483 W CN 2021143483W WO 2022143969 A1 WO2022143969 A1 WO 2022143969A1
Authority
WO
WIPO (PCT)
Prior art keywords
cancer
pharmaceutically acceptable
acceptable salt
compound
formula
Prior art date
Application number
PCT/CN2021/143483
Other languages
English (en)
French (fr)
Inventor
徐艳君
李嘉逵
Original Assignee
轩竹生物科技股份有限公司
山东轩竹医药科技有限公司
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 轩竹生物科技股份有限公司, 山东轩竹医药科技有限公司 filed Critical 轩竹生物科技股份有限公司
Priority to CN202180085717.9A priority Critical patent/CN116710095A/zh
Priority to US18/270,495 priority patent/US20240075032A1/en
Publication of WO2022143969A1 publication Critical patent/WO2022143969A1/zh

Links

Images

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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis

Definitions

  • the present invention belongs to the technical field of medicine, and specifically relates to a pharmaceutical composition for preventing and/or treating cancer, especially a compound containing the compound of formula (I) or a pharmaceutically acceptable salt thereof and a second therapeutic agent or a pharmaceutically acceptable salt thereof.
  • Breast cancer is the most common malignant tumor in women, and there are about 2 million new breast cancer patients worldwide every year. Breast cancer is a highly heterogeneous tumor at the molecular level, with great differences in histomorphology, immunophenotype, biological behavior and treatment response. Breast cancers are classified into three subtypes based on the expression of three receptors: estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (Her2). Estrogen receptor-positive (ER+) breast cancer is the most common molecular subtype of breast cancer, with an incidence of approximately 65%-70% of the population. In breast cancer, the prognosis is the best, and there are more patients in the early stage.
  • ER estrogen receptor
  • PR progesterone receptor
  • Her2 human epidermal growth factor receptor-2
  • ER+ breast cancer Compared with other molecular subtypes of breast cancer, ER+ breast cancer has a better prognosis, but still has a 5-year recurrence and metastasis rate of about 15-30%.
  • Human epidermal growth factor receptor-2 (HER2) molecule is an independent factor for poor prognosis of breast cancer, and about 20%-30% of Chinese breast cancer patients have HER2 gene amplification/overexpression.
  • HER2 overexpression is typically associated with aggressive, metastatic forms of breast cancer that have high recurrence rates and/or are associated with poor patient outcomes.
  • the general treatment goal for all patients with ER/PR-positive metastatic breast cancer is to prolong survival and improve quality of life. This can be achieved through surgical intervention and medical therapy (where possible).
  • Endocrine (anti-estrogenic) drugs are usually used initially and maintained until resistance develops. Their use avoids the toxicity of chemotherapy-based regimens, but their own drug toxicity and drug resistance still need to be well addressed.
  • Estrogen receptor (ER) drugs are mainly divided into selective estrogen receptor modulator (SERM), selective estrogen receptor downregulator (SERD), aromatization enzyme inhibitors, etc.
  • SERM selective estrogen receptor modulator
  • SESD selective estrogen receptor downregulator
  • the listed SERD drugs are fulvestrant (Astrazeneca, AstraZeneca), and the SERDs under development are AZD-9496 (Astrazeneca, AstraZeneca), RAD1901 (Eisai, Eisai) and ZB-716 (Louisiana University, Louisiana) the University).
  • CDKs cyclin-dependent kinases
  • CDK4/6 play an irreplaceable role.
  • CDK4/6-specific activation is closely related to the proliferation of some tumors, and about 80% of human tumors have abnormalities in the cyclin D-CDK4/6-INK4-Rb pathway.
  • CDK4/6 inhibitors include PD0332991 (Palbociclib, Ibrance) developed by Pfizer, LY2835219 (Abemaciclib, Verzenio) by Eli Lilly and LEE011 (Ribociclib, Kisqali) by Novartis.
  • CDK4/6 inhibitors Like other kinase inhibitors used to treat cancer, the effective use of CDK4/6 inhibitors is also limited by drug resistance, and the present invention provides a tumor treatment composition that can effectively solve the problem of drug resistance and has lower toxicity , resistance is mainly directed against endocrine and CDK inhibitory therapy.
  • the present invention provides a pharmaceutical composition for preventing and/or treating cancer, comprising a compound of the following formula (I) or a pharmaceutically acceptable salt thereof and at least one second therapeutic agent or a pharmaceutically acceptable salt thereof accepted salt,
  • the second therapeutic agent is selected from selective estrogen receptor down-regulating agents, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof and the active ingredient weight of the second therapeutic agent or a pharmaceutically acceptable salt thereof The ratio is 1:1-3000:1.
  • the active ingredient weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the second therapeutic agent or a pharmaceutically acceptable salt thereof is from 1:1 to 2672:1.
  • the active ingredient weight ratio of the compound of formula (I), or a pharmaceutically acceptable salt thereof, to the second therapeutic agent, or a pharmaceutically acceptable salt thereof ranges from 5.2:1 to 2672:1.
  • the active ingredient weight ratio of the compound of formula (I), or a pharmaceutically acceptable salt thereof, to the second therapeutic agent, or a pharmaceutically acceptable salt thereof is from 1:1 to 800:1.
  • the active ingredient weight ratio of the compound of formula (I), or a pharmaceutically acceptable salt thereof, to the second therapeutic agent, or a pharmaceutically acceptable salt thereof is from 1:1 to 500:1.
  • the second therapeutic agent is fulvestrant.
  • the second therapeutic agent is fulvestrant, and the compound of formula (I) or a pharmaceutically acceptable salt thereof and the active ingredient weight of fulvestrant or a pharmaceutically acceptable salt thereof The ratio is 10:1-1200:1.
  • the second therapeutic agent is fulvestrant, and the compound of formula (I) or a pharmaceutically acceptable salt thereof and the active ingredient weight of fulvestrant or a pharmaceutically acceptable salt thereof
  • the ratio is 10:1-800:1.
  • the second therapeutic agent is fulvestrant, and the compound of formula (I) or a pharmaceutically acceptable salt thereof and the active ingredient weight of fulvestrant or a pharmaceutically acceptable salt thereof The ratio is 10:1-600:1.
  • the second therapeutic agent is fulvestrant, and the compound of formula (I) or a pharmaceutically acceptable salt thereof and the active ingredient weight of fulvestrant or a pharmaceutically acceptable salt thereof The ratio is 10:1-400:1.
  • the second therapeutic agent is fulvestrant, and the compound of formula (I) or a pharmaceutically acceptable salt thereof and the active ingredient weight of fulvestrant or a pharmaceutically acceptable salt thereof The ratio is 10:1-200:1.
  • the second therapeutic agent is fulvestrant, and the compound of formula (I) or a pharmaceutically acceptable salt thereof and the active ingredient weight of fulvestrant or a pharmaceutically acceptable salt thereof The ratio is 20:1-150:1.
  • the second therapeutic agent is fulvestrant, and the compound of formula (I) or a pharmaceutically acceptable salt thereof and the active ingredient weight of fulvestrant or a pharmaceutically acceptable salt thereof The ratio is 30:1-150:1.
  • the second therapeutic agent is fulvestrant, and the compound of formula (I) or a pharmaceutically acceptable salt thereof and the active ingredient weight of fulvestrant or a pharmaceutically acceptable salt thereof
  • the ratio is 40:1-150:1.
  • the second therapeutic agent is fulvestrant, and the compound of formula (I) or a pharmaceutically acceptable salt thereof and the active ingredient weight of fulvestrant or a pharmaceutically acceptable salt thereof The ratio is 20:1-120:1.
  • the second therapeutic agent is fulvestrant, and the compound of formula (I) or a pharmaceutically acceptable salt thereof and the active ingredient weight of fulvestrant or a pharmaceutically acceptable salt thereof The ratio is 30:1-120:1.
  • the second therapeutic agent is fulvestrant, and the compound of formula (I) or a pharmaceutically acceptable salt thereof and the active ingredient weight of fulvestrant or a pharmaceutically acceptable salt thereof
  • the ratio is 40:1-120:1.
  • the second therapeutic agent is fulvestrant, and the compound of formula (I) or a pharmaceutically acceptable salt thereof and the active ingredient weight of fulvestrant or a pharmaceutically acceptable salt thereof The ratio is 20:1-100:1.
  • the second therapeutic agent is fulvestrant, and the compound of formula (I) or a pharmaceutically acceptable salt thereof and the active ingredient weight of fulvestrant or a pharmaceutically acceptable salt thereof The ratio is 30:1-100:1.
  • the second therapeutic agent is fulvestrant, and the compound of formula (I) or a pharmaceutically acceptable salt thereof and the active ingredient weight of fulvestrant or a pharmaceutically acceptable salt thereof The ratio is 40:1-100:1.
  • the second therapeutic agent is fulvestrant, and the compound of formula (I) or a pharmaceutically acceptable salt thereof and the active ingredient weight of fulvestrant or a pharmaceutically acceptable salt thereof
  • the ratio is 1:1-150:1, preferably 10:1-20:1, 20:1-30:1, 30:1-40:1, 40:1-50:1, 50:1-60:1 , 60:1-70:1, 70:1-80:1, 80:1-90:1, 90:1-100:1, 100:1-110:1, 110:1-120:1, 120 :1-130:1, 130:1-140:1, 140:1-150:1.
  • the second therapeutic agent is fulvestrant, and the compound of formula (I) or a pharmaceutically acceptable salt thereof and the active ingredient weight of fulvestrant or a pharmaceutically acceptable salt thereof
  • the ratios are 107.52:1, 94.08:1, 80.64:1, 67.2:1, 62.72:1, 53.76:1, 47.04:1, 40.32:1, 33.6:1, 31.36:1, 26.88:1, 23.52:1, 20.16:1, 16.8:1, 15.68:1, 13.44:1, 11.76:1.
  • the second therapeutic agent is fulvestrant, and the compound of formula (I) or a pharmaceutically acceptable salt thereof and the active ingredient weight of fulvestrant or a pharmaceutically acceptable salt thereof
  • the ratios are 115.2:1, 100.8:1, 86.4:1, 72:1, 67.2:1, 57.6:1, 50.4:1, 43.2:1, 36:1, 33.6:1, 28.8:1, 25.2:1, 21.6:1, 18:1, 16.8:1, 14.4:1, 12.6:1.
  • the active ingredient of a compound of formula (I) or a pharmaceutically acceptable salt thereof is used in a daily dosage of 200-2000 mg.
  • the active ingredient of a compound of formula (I) or a pharmaceutically acceptable salt thereof is used in a daily dosage of 200-1000 mg.
  • the active ingredient of a compound of formula (I) or a pharmaceutically acceptable salt thereof is used in a daily dosage of 400-1000 mg.
  • the active ingredient of a compound of formula (I) or a pharmaceutically acceptable salt thereof is used in a daily dosage of 960 mg, 840 mg, 720 mg, 600 mg, 560 mg, 480 mg or 420 mg.
  • the frequency of administration of the compound of formula (I), or a pharmaceutically acceptable salt thereof is once a day, twice a day, or three times a day.
  • the frequency of administration of the second therapeutic agent or a pharmaceutically acceptable salt thereof is once a month, once every 28 days, once every half month, or once every 14 days.
  • the active ingredient of the second therapeutic agent or a pharmaceutically acceptable salt thereof is used in an amount of 1-1000 mg, such as 10-1000 mg, such as 100-1000 mg, such as 250-1000 mg, per time.
  • the second therapeutic agent is fulvestrant.
  • the second therapeutic agent is fulvestrant
  • the active ingredient of fulvestrant or a pharmaceutically acceptable salt thereof is 250 mg or 500 mg each time.
  • the second therapeutic agent is fulvestrant
  • the active ingredient of fulvestrant or a pharmaceutically acceptable salt thereof is 250 mg or 500 mg each time
  • the dosing frequency is once a month, Once every 28 days, once every half month or once every 14 days.
  • the compound of formula (I) is administered concurrently or sequentially with the second therapeutic agent.
  • the route of administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof is oral.
  • the second therapeutic agent or a pharmaceutically acceptable salt thereof is administered orally or by injection.
  • the present invention also provides a pharmaceutical preparation comprising the aforementioned pharmaceutical composition and one or more pharmaceutically acceptable excipients, and the pharmaceutical preparation can be in any pharmaceutically acceptable dosage form.
  • a pharmaceutically acceptable excipient is one that is nontoxic, compatible with the active ingredient and otherwise biologically suitable for the organism. The choice of a particular excipient will depend on the mode of administration or disease type and state used to treat the particular patient.
  • the pharmaceutical formulations described above may be administered orally, parenterally, rectally, or pulmonary to a patient or subject in need of such treatment.
  • the pharmaceutical composition can be made into oral preparations, for example, can be made into conventional oral solid preparations, such as tablets, capsules, pills, granules, etc.; can also be made into oral liquid preparations, such as Oral solution, oral suspension, syrup, etc.
  • the above-mentioned pharmaceutical preparations can also be prepared into injections, including injection solutions, sterile powders for injection and concentrated solutions for injection.
  • the pharmaceutical composition can be formulated into suppositories and the like.
  • the pharmaceutical composition can be formulated into inhalation formulations, aerosol formulations, powder aerosol formulations or spray formulations, and the like.
  • the present invention also relates to the use of the aforementioned pharmaceutical composition in the preparation of a medicament for preventing and/or treating cancer, the cancer being selected from brain tumor, lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer , ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, rectal cancer, liver cancer, kidney cancer, esophageal adenocarcinoma, esophageal squamous cell carcinoma, prostate cancer, female reproductive tract cancer , lymphoma, neurofibromatosis, thyroid cancer, bone cancer, skin cancer, brain cancer, colon cancer, testicular cancer, gastrointestinal stromal tumor, prostate tumor, mast cell tumor, multiple myeloma, melanoma, glial tumor or sarcoma, preferably breast cancer.
  • the cancer being selected from brain tumor, lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer , ovarian cancer, peritoneal
  • the cancer is selected from HR + , HER2- breast cancer.
  • the cancer is selected from postmenopausal HR + , HER2- breast cancer.
  • the cancer is selected from locally advanced or metastatic breast cancer.
  • the cancer is selected from HR + , HER2- advanced or metastatic breast cancer.
  • the cancer is selected from HR + , HER2- advanced or metastatic breast cancer that has progressed after endocrine therapy alone.
  • the present invention also relates to a combination of a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, and fulvestrant, or a pharmaceutically acceptable salt thereof, in the manufacture of a compound for the prevention and/or treatment of cancer.
  • the cancer is selected from brain tumor, lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer , rectal cancer, liver cancer, kidney cancer, esophageal adenocarcinoma, esophageal squamous cell carcinoma, prostate cancer, female reproductive tract cancer, lymphoma, neurofibromatosis, thyroid cancer, bone cancer, skin cancer, brain cancer, colon cancer, testicular cancer Carcinoma, gastrointestinal stromal tumor, prostate tumor, mast cell tumor, multiple myeloma, melanoma, glioma or sarcoma, preferably breast cancer.
  • the cancer is selected from HR + , HER2- breast cancer.
  • the cancer is selected from postmenopausal HR + , HER2- breast cancer.
  • the cancer is selected from locally advanced or metastatic breast cancer.
  • the cancer is selected from HR + , HER2- advanced or metastatic breast cancer.
  • the cancer is selected from HR + , HER2- advanced or metastatic breast cancer that has progressed after endocrine therapy alone.
  • the present invention also relates to the use of a pharmaceutical preparation containing the aforementioned pharmaceutical composition in the preparation of a medicament for preventing and/or treating cancer.
  • the present invention also provides a kit comprising the aforementioned pharmaceutical composition, and instructions for how to administer the pharmaceutical composition or the compound of formula (I) and the second therapeutic agent contained therein.
  • the present invention also provides a method of treating cancer, the method comprising administering to a patient in need thereof an effective amount of the aforementioned pharmaceutical composition and a pharmaceutical formulation containing the same; the cancer is as described above .
  • a compound of formula (I), or a pharmaceutically acceptable salt thereof is administered in combination with a second therapeutic agent, or a pharmaceutically acceptable salt thereof, according to a particular dosage regimen.
  • the compound of formula (I), or a pharmaceutically acceptable salt thereof is administered orally at a dose of 400-1000 mg per day.
  • the compound of formula (I), or a pharmaceutically acceptable salt thereof is administered orally at a dose of 960 mg, 840 mg, 720 mg, 600 mg, 560 mg, 480 mg, or 420 mg per day.
  • the frequency of administration of the compound of formula (I), or a pharmaceutically acceptable salt thereof is once a day or twice a day.
  • the second therapeutic agent is fulvestrant, and fulvestrant is administered at a dose of 250 mg or 500 mg once a month or every 28 days thereafter on days 1, 15, 29, and thereafter Setran or a pharmaceutically acceptable salt thereof.
  • the HR positive (HR + ) in the present invention refers to the positive expression of ER (estrogen receptor) and/or the positive expression of PR (progesterone receptor), that is, HR + includes ER + , PR + or ER + /PR + .
  • the HER2 - in the present invention means that the expression of human epidermal growth factor receptor 2 (HER2) is negative.
  • the "weight ratio of active ingredients" in the present invention can be the daily dosage ratio of the drug, the weekly dosage ratio, the monthly dosage ratio, or the dosage ratio of each administration cycle. If the administration frequency of the two drugs is different, the same standard is selected for conversion, so as to obtain the weight ratio of active ingredients.
  • the "daily dosage" in the present invention may be the actual daily dosage, or may be the daily dosage obtained by conversion. For example, if the dosing frequency is 360 mg twice a day, the daily dosage is 720 mg; for example, if the dosing frequency is once every 15 days, 300 mg once, the daily dosage is 20 mg.
  • the "second therapeutic agent” in the present invention refers to an agent that has a certain preventive and/or therapeutic effect on tumors, including but not limited to mitotic inhibitors, alkylating agents, selective estrogen receptor modulators, selective estrogen receptors Hormone receptor downregulators, DNA chimeric agents, antitumor antibiotics, growth factor inhibitors, retinoid receptor modulators, topoisomerase inhibitors, hormone drugs, angiogenesis inhibitors, etc.
  • the "effective amount” refers to a dose of a drug capable of preventing, alleviating, delaying, inhibiting or curing a disorder in a subject.
  • the size of the administered dose is related to the mode of drug administration, the pharmacokinetics of the drug, the severity of the disease, and the subject's personality signs (sex, weight, height, age) and the like.
  • the "pharmaceutical composition” described in the present invention includes a composition formed by preparing the compound of formula (I) and the second therapeutic agent and other active ingredients into the same compound preparation, and also includes the compound of formula (I) and the second therapeutic agent and other active ingredients A composition that is separately prepared into a single preparation.
  • the "simultaneous administration" of the compound of formula (I) and the second therapeutic agent according to the present invention includes the compound of formula (I) and the second therapeutic agent being prepared into the same compound preparation and then administered, or the compound of formula (I) and the second therapeutic agent.
  • the reagents are separately prepared into preparations and administered simultaneously.
  • the "separate administration" of the compound of formula (I) and the second therapeutic agent in the present invention means that after the compound of formula (I) and the second therapeutic agent are prepared into preparations, they are administered in sequence according to their respective preparation modes of administration. .
  • the "pharmaceutically acceptable salt” in the present invention refers to a salt formed by an acidic functional group (such as -COOH, -OH, -SO 3 H, etc.) present in a compound and an appropriate inorganic or organic cation (base), including Salts formed with alkali metals or alkaline earth metals, ammonium salts, salts formed with nitrogen-containing organic bases; and salts formed with basic functional groups (such as -NH2, etc.) present in the compounds with appropriate inorganic or organic anions (acids), Included are salts formed with inorganic or organic acids such as carboxylic acids and the like.
  • an acidic functional group such as -COOH, -OH, -SO 3 H, etc.
  • base including Salts formed with alkali metals or alkaline earth metals, ammonium salts, salts formed with nitrogen-containing organic bases; and salts formed with basic functional groups (such as -NH2, etc.) present in the compounds with appropriate inorganic or organic anions (
  • the pharmaceutical composition of the present invention has excellent anti-tumor effects, especially for breast cancer.
  • the pharmaceutical composition of the present invention can effectively solve the problem of drug resistance through endocrine therapy and the drug resistance problem of long-term use of CDK inhibitors.
  • the pharmaceutical composition of the present invention has low or no toxicity and less side effects.
  • Fig. 1 is the cell proliferation inhibition curve of the compound of formula (I) and fulvestrant combined in a fixed ratio, wherein the abscissa is the logarithm of the test concentration (c) of the compound of formula (I), i.e. lg c; the ordinate is the inhibition Rate(%).
  • the compound of formula (I) of the present invention is prepared according to the method of the prior art
  • Fulvestrant purchased or prepared according to prior art methods.
  • the BrdU stock solution with a concentration of 1000 times the stock solution was diluted into a 100 times BrdU labeling solution with the medium corresponding to the cells.
  • the compound of formula (I) was diluted with DMSO to 0.256 mM, and then started from 0.256 mM for two-fold serial dilutions to 9 concentrations; fulvestrant was diluted with DMSO to 1.28 ⁇ M, and then from 1.28 ⁇ M to two-fold serial dilutions 9 each concentration; fulvestrant was diluted with DMSO to 80 nM and 160 nM stock solutions;
  • MCF7 medium MEM+10%FBS+1% double antibody+10 ⁇ g/mL human recombinant insulin
  • the cells were routinely cultured until the cell confluence was 80%-90%, and the cells were collected by trypsinization and centrifuged. Resuspend with the corresponding medium, count and adjust to inoculate a 96-well plate, inoculate 8000 cells/well/100 ⁇ L of MCF7 cells, and place them in a 37°C cell incubator for culture.
  • Solvent control 0.5% DMSO; blank control: medium only, no cells.
  • Flu blank control blank control value
  • Flu solvent control solvent control value
  • the compound of formula (I) of the present invention is prepared according to the method of the prior art
  • Fulvestrant purchased or prepared according to prior art methods.
  • mice were injected subcutaneously with estrogen at 40 ⁇ g/20 ⁇ L (estrogen strength: 4 mg/2 mL) twice a week until the end of the experiment.
  • the tumor grew to a mean volume of 163 mm 3 , the patients were administered into groups.
  • the compound group of formula (I) was orally administered once a day with a dose of 30 mg/kg for 21 consecutive days; the fulvestrant group was administered subcutaneously once a week, 5 mg per animal, for 3 consecutive weeks; formula ( I) The compound and fulvestrant are administered in the same manner as they are administered alone.
  • the relative tumor volume RTV and the relative tumor volume increase ratio (T/C) were calculated.
  • RTV V t /V 0 , wherein V t is the mean tumor volume on day t after group administration, and V 0 is the mean tumor volume on the day of grouping.
  • T/C(%) RTV of treatment group/RTV of control group ⁇ 100%.
  • Tumor growth inhibition rate TGI (%) (1-T/C) ⁇ 100%.
  • SPSS statistical analysis software was used to analyze the tumor volume between groups, and p ⁇ 0.05 was considered to have significant difference.
  • Table 3 The results of tumor growth inhibition in MCF7 human xenograft model by the compound of formula (I) and fulvestrant alone and in combination
  • the compound of formula (I) of the present invention is prepared according to the method of the prior art
  • Fulvestrant purchased or prepared according to prior art methods.
  • ECOG score is 0-1;
  • Blood routine absolute neutrophil count ⁇ 2.0 ⁇ 10 9 /L (or greater than the lower limit of normal laboratory value in the research center), platelet count ⁇ 100 ⁇ 10 9 /L, hemoglobin ⁇ 100g/L;
  • Liver function Serum total bilirubin ⁇ 1.5 times ULN, AST and ALT ⁇ 1.5 times ULN (if there is liver metastasis, AST and ALT ⁇ 3 times ULN);
  • Renal function CrCl ⁇ 60ml/min/1.73m 2 (calculated according to the Cockcroft-Gault formula);
  • the expected life expectancy of the subject is ⁇ 12 weeks
  • the subject is administered a compound of formula (I) and fulvestrant. in,
  • the compound of formula (I) is administered in the following manner: 360 mg orally, twice a day. Every 28 days is a treatment cycle.
  • the administration mode of fulvestrant is: the first day of the first cycle (C1D1), the fifteenth day of the first cycle (C1D15), and the first day of each subsequent cycle (CnD1): 500 mg intramuscularly. Every 28 days is a treatment cycle.
  • the compound of formula (I) of the present invention is prepared according to the method of the prior art
  • Fulvestrant purchased or prepared according to prior art methods.
  • ECOG score is 0-1;
  • the expected life expectancy of the subject is ⁇ 12 weeks
  • the subject is administered a compound of formula (I) and fulvestrant. in,
  • the compound of formula (I) is administered in the following manner: 360 mg orally, twice a day. Every 28 days is a treatment cycle.
  • the administration mode of fulvestrant is: the first day of the first cycle (C1D1), the fifteenth day of the first cycle (C1D15), and the first day of each subsequent cycle (CnD1): 500 mg intramuscularly. Every 28 days is a treatment cycle.
  • the compound of formula (I) of the present invention combined with fulvestrant has excellent therapeutic effect on breast cancer patients with disease progression after previous endocrine therapy, the disease control rate (DCR) reaches 92.3%, and the benefit of combined therapy is obvious.

Landscapes

  • Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Oncology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

本发明属于医药技术领域，具体涉及一种预防和/或治疗癌症的药物组合物。特别是包含式(I)所示的CDK4/6抑制剂化合物或其药学上可接受的盐与第二治疗试剂或其药学上可接受的盐的固定比例或固定剂量组合的药物组合物，上述药物组合物在制备预防和/或治疗癌症的药物中的应用以及含有所述药物组合物的药盒。

Description

一种治疗癌症的药物组合物 技术领域
本发明属于医药技术领域，具体涉及一种预防和/或治疗癌症的药物组合物，特别是含有式(I)化合物或其药学上可接受的盐与第二治疗试剂或其药学上可接受的盐的固定比例或固定剂量组合的药物组合物，以及所述药物组合物治疗癌症的用途。
背景技术
乳腺癌是女性最常见的恶性肿瘤，全世界每年约有200万的新增乳腺癌患者。乳腺癌是一类在分子水平上高度异质性的肿瘤，其在组织形态、免疫表型、生物学行为及治疗反应上存在着极大的差异。基于三种受体：***受体(ER)、孕酮受体(PR)和人表皮生长因子受体-2(Her2)的表达，将乳腺癌分为三种亚型。***受体阳性(ER+)乳腺癌是乳腺癌最常见的分子亚型，人群发病率约为65％-70％。在乳腺癌中预后最好，早期患者较多。与其他分子亚型乳腺癌相比，ER+乳腺癌的预后较好，但仍有约为15-30％的5年复发转移率。人表皮生长因子受体-2(HER2)分子是乳腺癌预后较差的独立因子，中国乳腺癌患者中约20％-30％存在HER2基因的扩增/过表达。HER2过表达是典型地与乳腺癌的侵袭性、转移性形式相关联，这些乳腺癌的侵袭性、转移性形式具有高复发率和/或与患者不良预后相关联。
所有ER/PR阳性转移性乳腺癌患者的一般治疗目标是延长生存期并改善生活质量。这可以通过外科手术介入和药物治疗(可能的话)来实现。通常最初使用内分泌(抗***的)药物，并保持直至出现耐药性。它们的使用避免了基于化疗方案的毒性，但其药物本身的毒性以及耐药性仍需要很好的解决。
***受体(Estrogen receptor,ER)药物主要分为选择性***受体调节剂(selective estrogen receptor modulator,SERM)、选择性***受体下调剂(selective estrogen receptor degrader,SERD)、芳香化酶抑制剂等。上市的SERD药物有氟维司群(Astrazeneca，阿斯利康)，在研的SERD有AZD-9496(Astrazeneca，阿斯利康)，RAD1901(Eisai，卫材)和ZB-716(Louisiana University，路易斯安娜大学)。
几乎所有癌基因、抑癌基因的功能效应，最终都会汇聚到细胞周期上来，调节或阻断细胞周期是***的途径之一。目前，已发现的与细胞周期调控有关的分子很多，其中细胞周期蛋白依赖性激酶(Cyclin-Dependent-Kinases,CDKs)是细胞周期调控网络的核心分子。在参与细胞周期的CDK亚型中，CDK4/6发挥着不可替代的作用。CDK4/6特异性的激活与 一些肿瘤的增殖密切相关，大约80％的人类肿瘤中有cyclin D-CDK4/6-INK4-Rb通路的异常。目前已上市的CDK4/6抑制剂有辉瑞公司开发的PD0332991(Palbociclib,Ibrance)、礼来公司的LY2835219(Abemaciclib,Verzenio)和诺华公司的LEE011(Ribociclib,Kisqali)。
与用于治疗癌症的其他激酶抑制剂一样，CDK4/6抑制剂的有效使用同样受到耐药性的限制，本发明提供了一种可有效解决耐药性问题且毒性较低的肿瘤治疗组合物，耐药性主要针对内分泌和CDK抑制疗法。
发明内容
在一方面，本发明提供了一种预防和/或治疗癌症的药物组合物，其包含以下式(I)化合物或其药学上可接受的盐与至少一种第二治疗试剂或其药学上可接受的盐，
Figure PCTCN2021143483-appb-000001
所述的第二治疗试剂选自选择性***受体下调剂，其中，式(I)化合物或其药学上可接受的盐与第二治疗试剂或其药学上可接受的盐的有效成分重量比为1:1-3000:1。
在某些实施方案中，式(I)化合物或其药学上可接受的盐与第二治疗试剂或其药学上可接受的盐的有效成分重量比为1:1-2672:1。
在某些实施方案中，式(I)化合物或其药学上可接受的盐与第二治疗试剂或其药学上可接受的盐的有效成分重量比为5.2:1-2672:1。
在某些实施方案中，式(I)化合物或其药学上可接受的盐与第二治疗试剂或其药学上可接受的盐的有效成分重量比为1:1-800:1。
在某些实施方案中，式(I)化合物或其药学上可接受的盐与第二治疗试剂或其药学上可接受的盐的有效成分重量比为1:1-500:1。
在上述某些实施方案中，所述第二治疗试剂为氟维司群。
在某些实施方案中，所述第二治疗试剂为氟维司群，且式(I)化合物或其药学上可接受的盐与氟维司群或其药学上可接受的盐的有效成分重量比为10:1-1200:1。
在某些实施方案中，所述第二治疗试剂为氟维司群，且式(I)化合物或其药学上可接受的盐与氟维司群或其药学上可接受的盐的有效成分重量比为10:1-800:1。
在某些实施方案中，所述第二治疗试剂为氟维司群，且式(I)化合物或其药学上可接受的盐与氟维司群或其药学上可接受的盐的有效成分重量比为10:1-600:1。
在某些实施方案中，所述第二治疗试剂为氟维司群，且式(I)化合物或其药学上可接受的盐与氟维司群或其药学上可接受的盐的有效成分重量比为10:1-400:1。
在某些实施方案中，所述第二治疗试剂为氟维司群，且式(I)化合物或其药学上可接受的盐与氟维司群或其药学上可接受的盐的有效成分重量比为10:1-200:1。
在某些实施方案中，所述第二治疗试剂为氟维司群，且式(I)化合物或其药学上可接受的盐与氟维司群或其药学上可接受的盐的有效成分重量比为20:1-150:1。
在某些实施方案中，所述第二治疗试剂为氟维司群，且式(I)化合物或其药学上可接受的盐与氟维司群或其药学上可接受的盐的有效成分重量比为30:1-150:1。
在某些实施方案中，所述第二治疗试剂为氟维司群，且式(I)化合物或其药学上可接受的盐与氟维司群或其药学上可接受的盐的有效成分重量比为40:1-150:1。
在某些实施方案中，所述第二治疗试剂为氟维司群，且式(I)化合物或其药学上可接受的盐与氟维司群或其药学上可接受的盐的有效成分重量比为20:1-120:1。
在某些实施方案中，所述第二治疗试剂为氟维司群，且式(I)化合物或其药学上可接受的盐与氟维司群或其药学上可接受的盐的有效成分重量比为30:1-120:1。
在某些实施方案中，所述第二治疗试剂为氟维司群，且式(I)化合物或其药学上可接受的盐与氟维司群或其药学上可接受的盐的有效成分重量比为40:1-120:1。
在某些实施方案中，所述第二治疗试剂为氟维司群，且式(I)化合物或其药学上可接受的盐与氟维司群或其药学上可接受的盐的有效成分重量比为20:1-100:1。
在某些实施方案中，所述第二治疗试剂为氟维司群，且式(I)化合物或其药学上可接受的盐与氟维司群或其药学上可接受的盐的有效成分重量比为30:1-100:1。
在某些实施方案中，所述第二治疗试剂为氟维司群，且式(I)化合物或其药学上可接受的盐与氟维司群或其药学上可接受的盐的有效成分重量比为40:1-100:1。
在某些实施方案中，所述第二治疗试剂为氟维司群，且式(I)化合物或其药学上可接受的盐与氟维司群或其药学上可接受的盐的有效成分重量比为1:1-150:1，优选10:1-20:1、20:1-30:1、30:1-40:1、40:1-50:1、50:1-60:1、60:1-70:1、70:1-80:1、80:1-90:1、90:1-100:1、100:1-110:1、110:1-120:1、120:1-130:1、130:1-140:1、140:1-150:1。
在某些实施方案中，所述第二治疗试剂为氟维司群，且式(I)化合物或其药学上可接受的盐与氟维司群或其药学上可接受的盐的有效成分重量比为107.52:1、94.08:1、80.64:1、67.2:1、62.72:1、53.76:1、47.04:1、40.32:1、33.6:1、31.36:1、26.88:1、23.52:1、20.16:1、16.8:1、15.68:1、13.44:1、11.76:1。
在某些实施方案中，所述第二治疗试剂为氟维司群，且式(I)化合物或其药学上可接受的盐与氟维司群或其药学上可接受的盐的有效成分重量比为115.2:1、100.8:1、86.4:1、72:1、67.2:1、57.6:1、50.4:1、43.2:1、36:1、33.6:1、28.8:1、25.2:1、21.6:1、18:1、16.8:1、14.4:1、12.6:1。
在某些实施方案中，式(I)化合物或其药学上可接受的盐的有效成分每日用量为200-2000mg。
在某些实施方案中，式(I)化合物或其药学上可接受的盐的有效成分每日用量为200-1000mg。
在某些实施方案中，式(I)化合物或其药学上可接受的盐的有效成分每日用量为400-1000mg。
在某些实施方案中，式(I)化合物或其药学上可接受的盐的有效成分每日用量为960mg、840mg、720mg、600mg、560mg、480mg或420mg。
在某些实施方案中，式(I)化合物或其药学上可接受的盐的给药频率为一日一次、一日两次或一日三次。
在某些实施方案中，所述第二治疗试剂或其药学上可接受的盐的给药频率为一月一次、28天一次、半月一次或每14天一次。
在某些实施方案中，所述第二治疗试剂或其药学上可接受的盐的有效成分每次用量为1-1000mg，例如10-1000mg，例如100-1000mg，例如250-1000mg。
在上述某些实施方案中，所述第二治疗试剂为氟维司群。
在某些实施方案中，所述第二治疗试剂为氟维司群，氟维司群或其药学上可接受的盐的有效成分每次用量为250mg或500mg。
在某些实施方案中，所述第二治疗试剂为氟维司群，氟维司群或其药学上可接受的盐的有效成分每次用量为250mg或500mg，给药频率为一月一次、28天一次、半月一次或每14天一次。
在某些实施方案中，所述的式(I)化合物与第二治疗试剂同时或先后分别给药。
在某些实施方案中，所述的式(I)化合物或其药学上可接受的盐给药途径为口服。
在某些实施方案中，所述第二治疗试剂或其药学上可接受的盐的给药方式为口服给药或注射给药。
在另一个方面，本发明还提供一种药物制剂，含有前述药物组合物，以及一种或多种药学上可接受的赋形剂，该药物制剂可为药学上可接受的任一剂型。药学上可接受的赋形剂是 无毒性、与活性成分相容且其他方面生物学性质上适用于生物体的物质。特定赋形剂的选择将取决于用于治疗特定患者的给药方式或疾病类型和状态。
在某些实施方案中，上述药物制剂可以以口服、肠胃外、直肠或经肺给药等方式施用于需要这种治疗的患者或受试者。用于口服给药时，所述药物组合物可制成口服制剂，例如可以制成常规的口服固体制剂，如片剂、胶囊剂、丸剂、颗粒剂等；也可制成口服液体制剂，如口服溶液剂、口服混悬剂、糖浆剂等。用于肠胃外给药时，上述药物制剂也可制成注射剂，包括注射液、注射用无菌粉末与注射用浓溶液。用于直肠给药时，所述药物组合物可制成栓剂等。用于经肺给药时，所述药物组合物可制成吸入制剂、气雾剂、粉雾剂或喷雾剂等。
在另一方面，本发明还涉及前述药物组合物在制备用于预防和/或治疗癌症的药物中的应用，所述的癌症选自脑瘤、肺癌、鳞状上皮细胞癌、膀胱癌、胃癌、卵巢癌、腹膜癌、胰腺癌、乳腺癌、头颈癌、子***、子宫内膜癌、直肠癌、肝癌、肾癌、食管腺癌、食管鳞状细胞癌、***癌、雌性生殖道癌、淋巴瘤、神经纤维瘤、甲状腺癌、骨癌、皮肤癌、脑癌、结肠癌、睾丸癌、胃肠道间质瘤、***肿瘤、肥大细胞肿瘤、多发性骨髓瘤、黑色素瘤、胶质瘤或肉瘤，优选乳腺癌。
在某些实施方案中，所述的癌症选自HR +、HER2 -乳腺癌。
在某些实施方案中，所述的癌症选自绝经后HR +、HER2 -乳腺癌。
在某些实施方案中，所述的癌症选自局部晚期或转移性乳腺癌。
在某些实施方案中，所述的癌症选自HR +、HER2 -晚期或转移性乳腺癌。
在某些实施方案中，所述的癌症选自经单独内分泌治疗后进展的HR +、HER2 -晚期或转移性乳腺癌。
在另一方面，本发明还涉及治疗有效量的式(I)化合物或其药学上可接受的盐和氟维司群或其药学上可接受的盐的组合在制备预防和/或治疗癌症的药物中的应用，所述的癌症选自脑瘤、肺癌、鳞状上皮细胞癌、膀胱癌、胃癌、卵巢癌、腹膜癌、胰腺癌、乳腺癌、头颈癌、子***、子宫内膜癌、直肠癌、肝癌、肾癌、食管腺癌、食管鳞状细胞癌、***癌、雌性生殖道癌、淋巴瘤、神经纤维瘤、甲状腺癌、骨癌、皮肤癌、脑癌、结肠癌、睾丸癌、胃肠道间质瘤、***肿瘤、肥大细胞肿瘤、多发性骨髓瘤、黑色素瘤、胶质瘤或肉瘤，优选乳腺癌。
在某些实施方案中，所述的癌症选自HR +、HER2 -乳腺癌。
在某些实施方案中，所述的癌症选自绝经后HR +、HER2 -乳腺癌。
在某些实施方案中，所述的癌症选自局部晚期或转移性乳腺癌。
在某些实施方案中，所述的癌症选自HR +、HER2 -晚期或转移性乳腺癌。
在某些实施方案中，所述的癌症选自经单独内分泌治疗后进展的HR +、HER2 -晚期或转移性乳腺癌。
进一步的，本发明还涉及含有前述药物组合物的药物制剂在制备用于预防和/或治疗癌症的药物中的应用。
在另一方面，本发明还提供了一种药盒，其包含前述药物组合物，和用于说明药物组合物或其包含的式(I)化合物和第二治疗试剂如何用药的说明书。
在另一方面，本发明还提供了一种治疗癌症的方法，该方法包括向有需要的患者施用有效量的前述药物组合物、含有该药物组合物的药物制剂；所述癌症如前文所述。
在某些实施方案中，式(I)化合物或其药学上可接受的盐与第二治疗试剂或其药学上可接受的盐根据特定的剂量方案联合给药。
在某些实施方案中，式(I)化合物或其药学上可接受的盐以每天400-1000mg的剂量口服给药。
在某些实施方案中，式(I)化合物或其药学上可接受的盐以每天960mg、840mg、720mg、600mg、560mg、480mg或420mg的剂量口服给药。
在某些实施方案中，式(I)化合物或其药学上可接受的盐的给药频率为一天一次或一天两次。
在某些实施方案中，所述第二治疗试剂为氟维司群，在第1天、第15天、第29天，且此后每月一次或每28天一次以250mg或500mg剂量施用氟维司群或其药学上可接受的盐。
在本发明中，除非另有说明，否则本文中使用的科学和技术名词具有本领域技术人员通常理解的含义，然而为了更好地理解本发明，下面提供了部分术语的定义。当本发明所提供的术语的定义和解释与本领域技术人员所通常理解的含义不符的时候，以本发明所提供的术语的定义和解释为准。
本发明所述的HR阳性(HR +)是指ER(***受体)表达阳性和/或PR(孕激素受体)表达阳性，即HR +包括ER +、PR +或ER +/PR +。
本发明所述的HER2 -是指人表皮生长因子受体2(HER2)表达呈阴性。
本发明所述的“有效成分重量比”可以是药物每日用量比，可以是每周用量比，可以是每月用量比，也可以是每一给药周期的用量比。若两种药物的给药频率不同，则选择相同标准进行换算，从而获得有效成分重量比。
本发明所述的“每日用量”可以是实际每日的用量，也可以是通过换算获得的每日用量。 例如给药频率为一天两次，一次360mg，则每日用量为720mg；例如给药频率为每15天一次，一次300mg，则每日用量为20mg。
本发明所述的“第二治疗试剂”是指对肿瘤具有一定预防和/或治疗作用的药剂，包括但不限于有丝***抑制剂、烷化剂、选择性***受体调节剂、选择性***受体下调剂、DNA嵌合剂、抗肿瘤抗生素、生长因子抑制剂、类维生素A受体调控剂、拓扑异构酶抑制剂、激素类药物、血管再生抑制剂等。所述的“有效量”是指能够预防、减轻、延缓、抑制或治愈受试者病症的药物剂量。给药剂量的大小与药物给药方式、药剂的药代动力学、疾病的严重程度、受试者的个性体征(性别、体重、身高、年龄)等相关。
本发明所述的“药物组合物”包括式(I)化合物与第二治疗试剂等有效成分制备成同一复方制剂而形成的组合物，也包括式(I)化合物与第二治疗试剂等有效成分分别制成单一制剂而形成的组合物。
本发明所述的式(I)化合物与第二治疗试剂“同时给药”包括式(I)化合物与第二治疗试剂制备成同一复方制剂后给药，或者式(I)化合物与第二治疗试剂分别制备成制剂后同时给药。
本发明所述的式(I)化合物与第二治疗试剂“分别给药”是指式(I)化合物与第二治疗试剂分别制备成制剂后，按照其各自的制剂给药方式先后分别给药。
本发明所述的“药学上可接受的盐”是指化合物中存在的酸性官能团(例如-COOH、-OH、-SO 3H等)与适当的无机或者有机阳离子(碱)形成的盐，包括与碱金属或碱土金属形成的盐、铵盐、与含氮有机碱形成的盐；以及化合物中存在的碱性官能团(例如-NH2等)与适当的无机或者有机阴离子(酸)形成的盐，包括与无机酸或有机酸(例如羧酸等)形成的盐。
发明的有益效果
1、本发明药物组合物具有优异的抗肿瘤作用，尤其是乳腺癌疗效显著。
2、本发明药物组合物可有效解决经内分泌治疗耐药的问题以及CDK抑制剂长期用药的耐药性问题。
3、本发明药物组合物毒性低或无毒，副作用较小。
附图说明
图1是式(I)化合物和氟维司群固定比例联用的细胞增殖抑制曲线，其中，横坐标为式(I)化合物测试浓度(c)的对数，即lg c；纵坐标为抑制率(％)。
具体实施方案
实验方案
以下提供本发明部分化合物的示例性实验方案，以显示本发明化合物有利活性和有益技术效果。但是应当理解，下述实验方案仅仅是对本发明内容的示例，而不是对本发明范围的限制。
实验例1本发明式(I)化合物和氟维司群单独给药及联合用药的体外细胞学抑制活性供试品：
本发明式(I)化合物，按照现有技术的方法制备；
氟维司群：购买或者按照现有技术方法制备。
下述实验的缩写所代表的含义如下：
Figure PCTCN2021143483-appb-000002
实验方法：采用BrdU方法(BrdU细胞增殖试验试剂盒，PerkinElmer公司)进行细胞增殖检测
1.试剂和化合物配制
1.1 1倍洗液配制：
将母液浓度为25倍的洗液用超纯水稀释成1倍洗液。
1.2 1倍检测抗体溶液配制：
将母液浓度为200倍的BrdU-Eu检测抗体用检测抗体稀释液稀释成1倍检测抗体溶液。
1.3 100倍BrdU标记溶液：
将母液浓度为1000倍的BrdU储备液用细胞对应的培养基稀释成100倍BrdU标记溶液。
1.4配制测试化合物：
式(I)化合物用DMSO稀释母液到0.256mM，再从0.256mM开始两倍连续梯度稀释9个浓度；氟维司群用DMSO稀释母液到1.28μM，再从1.28μM开始两倍连续梯度稀释9个浓度；氟维司群用DMSO稀释母液到80nM和160nM；
单用化合物：式(I)化合物或氟维司群梯度稀释液分别与DMSO 1:1混匀；
固定比例联用化合物：式(I)化合物和氟维司群梯度稀释液1:1混匀；
固定浓度联用化合物：式(I)化合物和氟维司群的80nM、160nM分别1:1混匀。
1.5培养基配制：
MCF7培养基：MEM+10％FBS+1％双抗+10μg/mL人重组胰岛素
2.试验步骤
2.1细胞常规培养至细胞融合度为80％-90％，胰酶消化收集细胞并离心。用相应的培养基重悬，计数并调整接种96孔板，MCF7细胞接种8000个/孔/100μL，置于37℃细胞培养箱中培养，细胞贴壁后换成无血清培养基。
2.2每孔补99μL的含20％FBS的生长培养基，然后加1μL稀释好的200×待测物到孔中，待测物终浓度见下表，37℃培养箱培养48小时；
溶剂对照：0.5％DMSO；空白对照：只加培养基，没有细胞。
Figure PCTCN2021143483-appb-000003
2.3每孔加入2μL 100倍BrdU标记溶液，细胞培养箱中孵育过夜后室温平衡0.5小时,用真空泵吸去培养基；
2.4每孔加入100μL固定液，室温孵育30分钟，弃去溶液；
2.5每孔加入100μL 1倍BrdU-Eu检测抗体溶液，室温孵育1小时，弃去溶液，用1倍洗液250μL/孔洗5次；
2.6每孔加入200μL时间分辨免疫荧光诱导液，室温孵育15分钟，酶标仪检测荧光值(Flu值)。
3.数据处理
1)细胞抑制率(％)＝1-(Flu 测试物-Flu 空白对照)/(Flu 溶剂对照-Flu 空白对照)×100％，
Flu 空白对照：空白对照值，Flu 溶剂对照：溶剂对照值；
2)数据使用GraphPad Prism 6软件作图，得到曲线及IC 50值。
3)CompuSyn软件拟合联用指数CI，CI＜1证明两个药物联用有协同作用。
实验结果：
表1式(I)化合物和氟维司群单独给药及联合用药的体外细胞学活性
Figure PCTCN2021143483-appb-000004
表2式(I)化合物和氟维司群在MCF7体外细胞学上的联用
Figure PCTCN2021143483-appb-000005
实验结论：
由表1和表2中数据可知，本发明式(I)化合物对于体外细胞具有很高的抑制活性，和氟维司群联用具有协同作用。
实验例2本发明式(I)化合物和氟维司群单独给药及联合用药对不同癌种异种移植模型的 体内药效评价试验
供试品：
本发明式(I)化合物，按照现有技术的方法制备；
氟维司群：购买或者按照现有技术方法制备。
下述中实验的缩写所代表的含义如下：
Figure PCTCN2021143483-appb-000006
实验方法：
1.肿瘤接种及分组
动物接种前一天开始皮下注射***，每周两次，每次40μg/20μL(***规格：4mg/2mL)，直到实验结束。将无血清培养基重悬的MCF7细胞以1.5×10 7+基质胶/0.2mL(细胞:基质胶＝1:1)接种于Balb/c雌性裸鼠的右侧肋部皮下。肿瘤长至体积均值为163mm 3时分组给药。式(I)化合物组每天口服给药一次给药剂量30mg/kg，连续给药21天；氟维司群组每周皮下注射给药一次，每只动物5mg，连续给药3周；式(I)化合物和氟维司群联用时采用和单用相同的给药方式。
2.肿瘤的测量及实验指标
每周使用游标卡尺对肿瘤体积进行2次测量，测量肿瘤的长径和短径，其体积计算公式为：体积＝0.5×长径×短径 2。根据测量结果计算相对肿瘤体积RTV和相对肿瘤体积增比值(T/C)。RTV＝V t/V 0，其中V t为分组给药后第t天的肿瘤体积均值，V 0为分组当天的肿瘤体积均值。T/C(％)＝治疗组RTV/对照组RTV×100％。肿瘤生长抑制率TGI(％)＝(1-T/C)×100％。
3.统计学分析
采用SPSS统计学分析软件对肿瘤体积进行组间统计学分析，p<0.05认为有显著性差异。
实验结果：
表3式(I)化合物和氟维司群单独给药及联合用药在MCF7人源异种移植模型上肿瘤生长抑制结果
Figure PCTCN2021143483-appb-000007
注: a.均数±标准误； b.与对照组比较。
实验结论：
由表3数据可知式(I)化合物和氟维司群联用对MCF7人源乳腺癌细胞生长有显著的抑制作用(肿瘤抑制率TGI为83.3％)，显著优于氟维司群单用。
实验例3本发明式(I)化合物和氟维司群联合用药用于治疗乳腺癌患者的临床试验
供试品：
本发明式(I)化合物，按照现有技术的方法制备；
氟维司群：购买或者按照现有技术方法制备。
试验入组标准：
1.年龄18～70岁(包括18岁及70岁)；
2.实验室结果证实激素受体阳性(HR+)，HER2阴性(HER2-)的局部晚期或转移性乳腺癌患者，不适合以治愈为目的的手术切除或放射治疗，且无化疗临床指征，接受过≤1线内分泌治疗且允许接受过1个化疗方案。
3.必须具有至少一处符合RECIST v1.1定义的可测量的病灶；
4.ECOG评分为0～1；
5.既往抗癌治疗或外科手术的所有急性毒性反应缓解至基线或≤1级(NCI-CTCAE v4.03版，脱发或研究者认为对受试者无安全风险的其它毒性除外)；
6.入组时受试者器官功能良好，且实验室检查数据符合下列标准：
·血常规：中性粒细胞绝对计数≥2.0×10 9/L(或大于研究中心实验室正常值下限)，血小板计数≥100×10 9/L，血红蛋白≥100g/L；
·肝功能：血清总胆红素≤1.5倍ULN，AST和ALT≤1.5倍ULN(如存在肝转移，AST和ALT≤3倍ULN)；
·肾功能：CrCl≥60ml/min/1.73m 2(按照Cockcroft-Gault公式计算)；
7.经研究者判定，预期受试者寿命≥12周；
8.有生育能力的男性或女性受试者必须同意在研究期间和末次研究用药3个月内使用有效的避孕方法，例如双重屏障式避孕方法、避孕套、口服或注射避孕药物、宫内节育器等；
9.研究开始前，受试者必须提供书面的知情同意。
目标病灶的评价标准
Figure PCTCN2021143483-appb-000008
Figure PCTCN2021143483-appb-000009
给药方案：
给予受试者式(I)化合物和氟维司群。其中，
式(I)化合物的给药方式为：360mg，口服，每日两次。每28天为1个治疗周期。
氟维司群的给药方式为：第一周期第一天(C1D1)、第一周期第十五天(C1D15)、以后每个周期第一天(CnD1)：500mg肌肉注射。每28天为1个治疗周期。
试验结果：
表4式(I)化合物和氟维司群联合用药对受试者的肿瘤抑制效果
Figure PCTCN2021143483-appb-000010
试验结论：
由表4数据可以看出，在经历第一阶段2-3个周期的联用治疗后，受试者的病灶就已经明显缩小，部分敏感的患者病灶缩小甚至可以达到50％，五例受试者中有两例达到了PR、另外两例达到了SD，联用治疗的获益明显。
实验例4本发明式(I)化合物和氟维司群联合用药用于既往内分泌治疗后疾病进展的乳腺 癌患者的临床试验
供试品：
本发明式(I)化合物，按照现有技术的方法制备；
氟维司群：购买或者按照现有技术方法制备。
试验入组标准：
1.年龄18～70岁(包括18岁及70岁)；
2.实验室结果证实激素受体阳性(HR+)，HER2阴性(HER2-)的局部晚期、复发或转移阶段接受1线内分泌治疗后疾病进展，且允许患者接受不超过1个化疗方案治疗；
3.必须具有至少一处符合RECIST v1.1定义的可测量的病灶；
4.ECOG评分为0～1；
5.既往抗癌治疗或外科手术的所有急性毒性反应缓解至基线或≤1级(NCI-CTCAE v4.03版，脱发或研究者认为对受试者无安全风险的其它毒性除外)；
6.入组时受试者器官功能良好，且实验室检查数据符合标准：
7.经研究者判定，预期受试者寿命≥12周；
8.有生育能力的男性或女性受试者必须同意在研究期间和末次研究用药3个月内使用有效的避孕方法，例如双重屏障式避孕方法、避孕套、口服或注射避孕药物、宫内节育器等；
9.研究开始前，受试者必须提供书面的知情同意。
给药方案：
给予受试者式(I)化合物和氟维司群。其中，
式(I)化合物的给药方式为：360mg，口服，每日两次。每28天为1个治疗周期。
氟维司群的给药方式为：第一周期第一天(C1D1)、第一周期第十五天(C1D15)、以后每个周期第一天(CnD1)：500mg肌肉注射。每28天为1个治疗周期。
试验结果：
表5式(I)化合物联合氟维司群的治疗响应
Figure PCTCN2021143483-appb-000011
注：DCR＝疾病控制率。
本发明式(I)化合物联合氟维司群对既往经内分泌治疗后疾病进展的乳腺癌患者具有优异的治疗效果，疾病控制率(DCR)达92.3％，联合治疗的获益明显。

Claims (10)

  1. 一种预防和/或治疗癌症的药物组合物，所述药物组合物含有治疗有效量的式(I)化合物或其药学上可接受的盐和至少一种第二治疗试剂或其药学上可接受的盐，
    Figure PCTCN2021143483-appb-100001
    所述的第二治疗试剂选自选择性***受体下调剂，其中，式(I)化合物或其药学上可接受的盐与第二治疗试剂或其药学上可接受的盐的有效成分重量比为1:1-3000:1。
  2. 如权利要求1所述的药物组合物，式(I)化合物或其药学上可接受的盐与第二治疗试剂或其药学上可接受的盐的有效成分重量比为1:1-2672:1，优选1:1-800:1，优选1:1-500:1。
  3. 如权利要求1所述的药物组合物，其中，所述的第二治疗试剂为氟维司群，且式(I)化合物或其药学上可接受的盐与氟维司群或其药学上可接受的盐的有效成分重量比为20:1-150:1，优选30:1-150:1，更优选40:1-150:1，更优选40:1-50:1、80:1-90:1。
  4. 如权利要求1所述的药物组合物，其中，所述的第二治疗试剂为氟维司群，且式(I)化合物或其药学上可接受的盐与氟维司群或其药学上可接受的盐的有效成分重量比为107.52:1、94.08:1、80.64:1、67.2:1、62.72:1、53.76:1、47.04:1、40.32:1、33.6:1、31.36:1、26.88:1、23.52:1、21.6:1、20.16:1、18:1、16.8:1、15.68:1、14.4:1、13.44:1、12.6:1、11.76:1、115.2:1、100.8:1、86.4:1、72:1、67.2:1、57.6:1、50.4:1、43.2:1、36:1、33.6:1、28.8:1、25.2:1。
  5. 如权利要求1-4任一项所述的药物组合物，其中所述式(I)化合物或其药学上可接受的盐的有效成分每日用量为200-2000mg，例如200-1000mg，例如400-1000mg；其中所述第二治疗试剂或其药学上可接受的盐的有效成分每次用量为1-1000mg，例如10-1000mg，例如100-1000mg。
  6. 如权利要求1-5任一项所述的药物组合物在制备预防和/或治疗癌症的药物中的应用，其中所述的癌症选自脑瘤、肺癌、鳞状上皮细胞癌、膀胱癌、胃癌、卵巢癌、腹膜癌、胰腺癌、乳腺癌、头颈癌、子***、子宫内膜癌、直肠癌、肝癌、肾癌、食管腺癌、食管鳞状细胞癌、***癌、雌性生殖道癌、淋巴瘤、神经纤维瘤、甲状腺癌、骨癌、皮肤癌、脑癌、结肠癌、睾丸癌、胃肠道间质瘤、***肿瘤、肥大细胞肿瘤、多发性骨髓瘤、黑色素瘤、胶质瘤或肉瘤，优选乳腺癌。
  7. 治疗有效量的权利要求1的式(I)化合物或其药学上可接受的盐和氟维司群或其药学上可接受的盐的组合在制备预防和/或治疗癌症的药物中的应用，其中所述的癌症选自脑瘤、肺癌、鳞状上皮细胞癌、膀胱癌、胃癌、卵巢癌、腹膜癌、胰腺癌、乳腺癌、头颈癌、子***、子宫内膜癌、直肠癌、肝癌、肾癌、食管腺癌、食管鳞状细胞癌、***癌、雌性生殖道癌、淋巴瘤、神经纤维瘤、甲状腺癌、骨癌、皮肤癌、脑癌、结肠癌、睾丸癌、胃肠道间质瘤、***肿瘤、肥大细胞肿瘤、多发性骨髓瘤、黑色素瘤、胶质瘤或肉瘤，优选乳腺癌。
  8. 如权利要求6或7所述的应用，其中，所述的癌症选自HR +、HER2 -乳腺癌。
  9. 如权利要求6-8任一项所述的应用，其中，所述的癌症选自局部晚期或转移性乳腺癌。
  10. 一种药盒，包含权利要求1-5任一项所述的药物组合物，和用于说明药物组合物、或其包含的式(I)化合物和第二治疗试剂如何用药的说明书。
PCT/CN2021/143483 2020-12-31 2021-12-31 一种治疗癌症的药物组合物 WO2022143969A1 (zh)

Priority Applications (2)

Application Number Priority Date Filing Date Title
CN202180085717.9A CN116710095A (zh) 2020-12-31 2021-12-31 一种治疗癌症的药物组合物
US18/270,495 US20240075032A1 (en) 2020-12-31 2021-12-31 A Pharmaceutical Composition for Treating Cancer

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202011632660.3 2020-12-31
CN202011632660 2020-12-31

Publications (1)

Publication Number Publication Date
WO2022143969A1 true WO2022143969A1 (zh) 2022-07-07

Family

ID=82259079

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2021/143483 WO2022143969A1 (zh) 2020-12-31 2021-12-31 一种治疗癌症的药物组合物

Country Status (3)

Country Link
US (1) US20240075032A1 (zh)
CN (1) CN116710095A (zh)
WO (1) WO2022143969A1 (zh)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116407540A (zh) * 2023-02-17 2023-07-11 杭州邦顺制药有限公司 药物在预防和治疗her2表达阳性实体瘤中的应用

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015101293A1 (zh) * 2013-12-31 2015-07-09 山东轩竹医药科技有限公司 激酶抑制剂及其用途
WO2019144759A1 (zh) * 2018-01-29 2019-08-01 海南轩竹医药科技有限公司 靶向cdk4/6激酶抑制剂的晶型
CN110092775A (zh) * 2018-01-29 2019-08-06 海南轩竹医药科技有限公司 靶向cdk4/6激酶抑制剂的晶型
WO2020224609A1 (zh) * 2019-05-08 2020-11-12 山东轩竹医药科技有限公司 激酶抑制剂的用途
CN112010839A (zh) * 2019-05-31 2020-12-01 轩竹生物科技有限公司 靶向丝/苏氨酸激酶抑制剂的晶型

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015101293A1 (zh) * 2013-12-31 2015-07-09 山东轩竹医药科技有限公司 激酶抑制剂及其用途
WO2019144759A1 (zh) * 2018-01-29 2019-08-01 海南轩竹医药科技有限公司 靶向cdk4/6激酶抑制剂的晶型
CN110092775A (zh) * 2018-01-29 2019-08-06 海南轩竹医药科技有限公司 靶向cdk4/6激酶抑制剂的晶型
WO2020224609A1 (zh) * 2019-05-08 2020-11-12 山东轩竹医药科技有限公司 激酶抑制剂的用途
CN112010839A (zh) * 2019-05-31 2020-12-01 轩竹生物科技有限公司 靶向丝/苏氨酸激酶抑制剂的晶型

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116407540A (zh) * 2023-02-17 2023-07-11 杭州邦顺制药有限公司 药物在预防和治疗her2表达阳性实体瘤中的应用

Also Published As

Publication number Publication date
CN116710095A (zh) 2023-09-05
US20240075032A1 (en) 2024-03-07

Similar Documents

Publication Publication Date Title
RU2447891C2 (ru) Комбинации терапевтических средств, предназначенные для лечения рака
RU2695228C2 (ru) Прерывистое введение ингибитора mdm2
CN109310754A (zh) 使用包含抗erbb3抗体的联合疗法治疗er+、her2-、hrg+乳腺癌的方法
Xia et al. Vorinostat upregulates MICA via the PI3K/Akt pathway to enhance the ability of natural killer cells to kill tumor cells
Guo et al. Emodin alleviates gemcitabine resistance in pancreatic cancer by inhibiting MDR1/P‑glycoprotein and MRPs expression
WO2022143969A1 (zh) 一种治疗癌症的药物组合物
TW202133857A (zh) 用於乳癌治療之組合療法
TW202146016A (zh) 投予抗癌劑之方法
US20220241294A1 (en) Bisfluoroalkyl-1,4-benzodiazepinone compounds for treating notch-activated breast cancer
AU2020248270B2 (en) Chiauranib for treatment of small cell lung cancer
Yao et al. Cinnamic acid inhibits cell viability, invasion, and glycolysis in primary endometrial stromal cells by suppressing NF-κB-induced transcription of PKM2
CN114748480B (zh) 一种预防和/或治疗癌症的药物组合物
US9387211B2 (en) Methods for treatment of Cushing&#39;S disease and hypercortisolism using gefitinib
WO2021023291A1 (zh) 原黄素在肺癌治疗中的应用
US7812034B2 (en) Method of using protease inhibitors for the treatment of liposarcomas
WO2021104341A1 (zh) 一种取代丁烯酰胺的应用
WO2020073642A1 (zh) 靛玉红类化合物和硼替佐米在制备治疗多发性骨髓瘤的药物中的用途
BR112020008325A2 (pt) terapias de combinação com o inibidor de ezh2
CN113453671A (zh) 用于治疗癌症的Raf抑制剂和CDK4/6抑制剂的组合疗法
WO2023109741A1 (zh) 一种治疗癌症的药物组合物
WO2023143611A1 (zh) 一种治疗癌症的方法
LU505196B1 (en) Carvedilol in the Preparation of Drugs to Reverse Leukaemia Resistance
RU2784869C1 (ru) Чиаураниб для лечения мелкоклеточного рака легкого
CN113876759B (zh) 化合物ngsc12在药物制备中的应用
CN118119610A (zh) 一种治疗癌症的药物组合物

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: 21914698

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 202180085717.9

Country of ref document: CN

WWE Wipo information: entry into national phase

Ref document number: 18270495

Country of ref document: US

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 21914698

Country of ref document: EP

Kind code of ref document: A1