WO2020239051A1 - Cdk4/6抑制剂与vegfr抑制剂联合在制备治疗肿瘤的药物中的用途 - Google Patents

Cdk4/6抑制剂与vegfr抑制剂联合在制备治疗肿瘤的药物中的用途 Download PDF

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WO2020239051A1
WO2020239051A1 PCT/CN2020/093144 CN2020093144W WO2020239051A1 WO 2020239051 A1 WO2020239051 A1 WO 2020239051A1 CN 2020093144 W CN2020093144 W CN 2020093144W WO 2020239051 A1 WO2020239051 A1 WO 2020239051A1
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cancer
inhibitor
days
tumor
cdk4
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PCT/CN2020/093144
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French (fr)
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张岚
林侃
廖成
张连山
孙飘扬
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江苏恒瑞医药股份有限公司
上海恒瑞医药有限公司
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Priority to CN202080038010.8A priority Critical patent/CN113840608B/zh
Publication of WO2020239051A1 publication Critical patent/WO2020239051A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

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  • the application relates to the use of a combination of a CDK4/6 inhibitor and a VEGFR inhibitor in the preparation of drugs for treating tumor diseases.
  • Breast cancer is one of the most common malignant tumors in women. There are approximately 1.3 million new cases worldwide each year. In my country, the incidence of breast cancer accounts for 7%-10% of the incidence of various malignant tumors throughout the body, and about 18% of all female tumors. At present, the number of patients in China has exceeded 500,000, and its incidence is increasing rapidly in some large cities. It has been ranked first in the spectrum of female tumor incidence, and nearly 50% of patients have recurrence and metastasis after treatment. In recent years, with the deepening of tumor molecular biology research, molecular targeted therapy has become more and more widely used in the treatment of breast cancer and has achieved more significant curative effects. It has become the first after the three traditional modes of surgery, radiotherapy and chemotherapy. This new treatment model is also a hot spot in the field of breast cancer treatment.
  • Cyclin-dependent kinase (Cyclin-dependent kinase, CDK) is a type of serine/threonine kinase that forms a dimer with the corresponding cyclin (Cyclin), and then phosphorylates downstream protein molecules to promote the cell cycle Orderly progress in each phase to achieve cell growth and proliferation.
  • CDK4/6 selective inhibitors are in clinical trials or have been approved for listing in foreign countries, including Pfizer’s Palbociclib, Novartis’s Ribociclib and Eli Lilly’s Abemaciclib.
  • WO2014183520 discloses a chemical named 6-acetyl-8-cyclopentyl-5-methyl-2-((5-(piperidin-4-yl)pyridin-2-yl)amino)pyrido[2 ,3-d]pyrimidin-7(8H)-one, the structural formula is the CDK4/6 inhibitor shown in formula (I), it has significant CDK4/6 inhibitory activity and high selectivity,
  • WO2016124067A discloses the isethionate of the compound represented by the above formula (I) and a preparation method thereof.
  • WO2017193141A discloses that the combination of CDK4/6 inhibitors and EGFR inhibitors can be used to treat triple-negative breast cancer
  • WO2016024-232A discloses that CDK4/6 inhibitors and BTK kinase inhibitors are combined to treat cancer
  • CN103781480A discloses that the combination of a CDK4/6 inhibitor and an FGFR kinase inhibitor can be used to treat cancer; J. Bollard et al.
  • Palbociclib(PD-0332991)a selective CDK4/6 inhibitor, restricts tumor growth in preclinical models of hepatocellular carcinoma discloses that Palbociclib alone or in combination with sorafenib may be a new strategy for the treatment of hepatocellular carcinoma; CN106029097A discloses that the combination of abemaciclib and ramucirumab can be used to treat non-small cell lung cancer; CN108883182A discloses that abemaciclib and lei The combination of moluzumab can be used to treat mantle cell lymphoma.
  • the application provides a use of a combination of a CDK4/6 inhibitor and a VEGFR inhibitor in the preparation of drugs for treating tumor diseases.
  • the CDK4/6 inhibitor described in this application can be a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
  • the pharmaceutically acceptable salt of the compound represented by formula (I) is selected from hydrochloride, phosphate, hydrogen phosphate, sulfate, hydrogen sulfate, sulfite, acetate, oxalate, and malonate Acid salt, valerate, glutamate, oleate, palmitate, stearate, laurate, borate, p-toluenesulfonate, methanesulfonate, isethionate , Maleate, malate, tartrate, benzoate, pamoate, salicylate, vanillate, mandelate, succinate, gluconate, lactobionate or laurel Sulfonate, preferably isethionate, the structure of which is shown in formula (II),
  • the VEGFR inhibitor is selected from VEGFR-2 inhibitors, preferably the VEGFR-2 inhibitor is apatinib or a pharmaceutically acceptable salt thereof.
  • the pharmaceutically acceptable salt of apatinib is selected from mesylate, maleate, tartrate, succinate, acetate, difluoroacetate, fumarate, citrate , Citrate, benzene sulfonate, benzoate, naphthalene sulfonate, lactate, malate, hydrochloride, hydrobromide, sulfate, and phosphate, in a preferred embodiment,
  • the pharmaceutically acceptable salt of apatinib is the mesylate salt.
  • the VEGFR inhibitor is apatinib mesylate.
  • the tumor disease described in this application is selected from sarcoma, lymphoma, lung cancer, bronchial cancer, prostate cancer, pancreatic cancer, gastrointestinal cancer, colon cancer, rectal cancer, colorectal adenoma, thyroid cancer, liver cancer, intrahepatic cholangiocarcinoma , Hepatocellular carcinoma, adrenal carcinoma, stomach cancer, stomach tumor, glioma, glioblastoma, endometrial cancer, melanoma, kidney cancer, renal pelvis cancer, bladder cancer, uterine body cancer, cervical cancer, vaginal cancer , Ovarian cancer, multiple myeloma, esophageal cancer, leukemia, acute myeloid leukemia, chronic myeloid leukemia, lymphocytic leukemia, myeloid leukemia, brain tumors, brain cancer, oral and pharynx cancer, laryngeal cancer, Small bowel cancer, non-Hodgkin’s lymphoma, melanoma, colon chori
  • the breast cancer is hormone receptor positive breast cancer.
  • the breast cancer is triple negative breast cancer.
  • the breast cancer is her2 positive breast cancer.
  • the dosage of the CDK4/6 inhibitor is selected from 1-500 mg, preferably 50-200 mg, more preferably 100-150 mg, and the frequency of administration is once a day and twice a day, preferably once a day. Once a day.
  • the dosage of the CDK4/6 inhibitor is 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, preferably 100 mg, 125 mg or 150 mg, and the frequency of administration is once a day or twice a day. Preferably once a day.
  • the dosage of the VEGFR inhibitor is 100-500 mg, and the frequency of administration is once a day, once every two days, once every three days, five days for two days, and seven days for stop. Medicine for seven days.
  • the dose of the VEGFR inhibitor is 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 500 mg, preferably 250 mg or 375 mg, and the frequency of administration is once a day for five days. The drug was stopped for two days and the drug was stopped for seven days.
  • the dose of the CDK4/6 inhibitor is selected from 100 mg, 125 mg or 150 mg, and the frequency of administration is once a day, and the dose of the VEGFR inhibitor is 250 mg or 375 mg, and the frequency of administration is one. Once a day, the drug was discontinued for five days for two days, and the drug was stopped for seven days for seven days.
  • the dosage of the CDK4/6 inhibitor is 100 mg, and the frequency of administration is once a day, and the dosage of the VEGFR inhibitor is 250 mg or 375 mg, and the frequency of administration is once a day. Stop the drug for five days for two days, and stop the drug for seven days for seven days.
  • the dosage of the CDK4/6 inhibitor is 125 mg, and the frequency of administration is once a day, and the dosage of the VEGFR inhibitor is 250 mg or 375 mg, and the frequency of administration is once a day. Stop the drug for five days for two days, and stop the drug for seven days for seven days.
  • the dosage of the CDK4/6 inhibitor is 150 mg, and the frequency of administration is once a day, and the dosage of the VEGFR inhibitor is 250 mg or 375 mg, and the frequency of administration is once a day. Stop the drug for five days for two days, and stop the drug for seven days for seven days.
  • the route of the combination described in this application includes, but is not limited to, oral administration, parenteral administration, and transdermal administration.
  • the parenteral administration includes but is not limited to intravenous injection, subcutaneous injection, and intramuscular injection.
  • This application provides a method for treating tumor diseases, which comprises administering to a patient a therapeutically effective amount of the above-mentioned CDK4/6 inhibitor and VEGFR inhibitor.
  • This application provides a pharmaceutical composition
  • a pharmaceutical composition comprising the above-mentioned CDK4/6 inhibitor, VEGFR inhibitor, and one or more pharmaceutically acceptable excipients, diluents or carriers.
  • the "combination" described in this application is a mode of administration, which means that at least one dose of CDK4/6 inhibitor and VEGFR inhibitor is administered within a certain period of time, and both drugs show pharmacological effects.
  • the time limit may be within one administration cycle, preferably within 4 weeks, within 3 weeks, within 2 weeks, within 1 week, or within 24 hours.
  • the CDK4/6 inhibitor and VEGFR inhibitor can be administered simultaneously or in no particular order. This period includes treatments in which the CDK4/6 inhibitor and the VEGFR inhibitor are administered through the same route of administration or different routes of administration.
  • Figure 2 The relative weight change of the xxT47D xenograft tumor model tumor-bearing mice after administration of the test substance;
  • Example 1 Isethionate (drug A) of the compound represented by formula (I) as a single agent or combined with apatinib mesylate (drug B) subcutaneously in xxT47D human breast cancer cells (ER+, HER2-)
  • drug A a single agent or combined with apatinib mesylate (drug B) subcutaneously in xxT47D human breast cancer cells (ER+, HER2-)
  • ER+, HER2- apatinib mesylate
  • Drug A is prepared by the method disclosed in WO2016124067A;
  • mice Strain: BALB/c nude mice; Week age and weight: 6-8 weeks old, weighing 18-22 grams; Gender: Female; Quantity: 42 (excluding the remaining mice in the group); Supplier: Shanghai West Poole-Bikai Laboratory Animal Co., Ltd.
  • xxT47D tumor cells were isolated from xenograft tumors constructed by parental T47D tumor cells (source: ATCC, HTB-133) to establish a cell line in vitro.
  • xxT47D tumor cells are established by isolating xenograft tumors constructed from parental T47D tumor cells in vitro, and the establishment is completed by performing the same process twice.
  • xxT47D tumor cells were cultured adherently in vitro. The culture conditions were RPMI 1640 medium with 10% fetal bovine serum, 100U/ml penicillin and 100 ⁇ g/ml streptomycin, and cultured at 37°C with 5% CO 2 . Use pancreatin-EDTA for routine digestion and passage twice a week. When the cell saturation is 80%-90%, the cells are collected, counted, and seeded.
  • Estrogen tablets (0.18mg/tablet) were subcutaneously inoculated on the left back of each mouse. Three days later, 0.2mL (10 ⁇ 10e6 cells+Matrigel, volume ratio 1:1) xxT47D cells were subcutaneously inoculated into each mouse On the right back of the mouse, when the average tumor volume reached 173mm 3 , the mice were administered in groups according to the experimental design (Table 1).
  • N Number of mice in each group; Dosing volume: 10 ⁇ l/g based on mouse body weight. If the weight loss exceeds 15%, the dosage regimen should be adjusted accordingly, (Vehicle A+Vehicle B) is the solvent group.
  • the experimental index is to investigate whether the tumor growth is inhibited, delayed or cured.
  • the tumor diameter was measured with vernier calipers twice a week.
  • TGI (%) reflects the tumor growth inhibition rate.
  • TGI(%) [(1-(Average tumor volume at the end of a certain treatment group-average tumor volume at the beginning of the treatment group))/(Average tumor at the end of treatment in the solvent control group Volume-The average tumor volume at the start of treatment in the solvent control group)] ⁇ 100%.
  • Tweight and Cweight represent the tumor weights of the administration group and the vehicle control group respectively.
  • Table 3 shows the changes of tumor volume in each group after treatment with xxT47D tumor-bearing mice.
  • the cp value is calculated based on the tumor volume.
  • c.p value is calculated based on tumor weight.
  • the average tumor volume of tumor-bearing mice in the solvent control group reached 1283 mm 3
  • the average tumor volume of the test substance 25 mg/kg drug A and 50 mg/kg drug B group were 724 mm 3 and 704 mm 3 , respectively, compared with the solvent control Compared with the group, it has significant anti-tumor effect (p value is 0.019 and 0.015, respectively).
  • the average tumor volume of the 25mg/kg drug A combined with 50mg/kg drug B treatment group was 354mm 3 , which was significantly different compared with the solvent group (p ⁇ 0.001). Compared with the respective single-agent groups, the combined group showed more Strong anti-tumor activity, and the difference is significant, the p value of drug A and drug B combined group compared with single drug are 0.022 and 0.003, respectively.
  • the tumor weight results (Table 5) are basically consistent with the tumor volume results.
  • drug A and drug B single drugs showed significant anti-tumor activity on the xxT47D human breast cancer xenograft tumor model at the dose of the test protocol. Compared with a single drug, the combined application of drug A and drug B can further enhance the anti-tumor effect.

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Abstract

CDK4/6抑制剂与VEGFR抑制剂联合在制备治疗肿瘤疾病的药物中的用途。具体而言， CDK4/6抑制剂为式(I)所示化合物或其可药用盐，VEGFR抑制剂为阿帕替尼或其可药用盐。

Description

CDK4/6抑制剂与VEGFR抑制剂联合在制备治疗肿瘤的药物中的用途
本申请要求申请日为2019年5月30日的中国专利申请CN201910460310.4的优先权。本申请引用上述中国专利申请的全文。
技术领域
本申请涉及一种CDK4/6抑制剂与VEGFR抑制剂联合在制备治疗肿瘤疾病的药物中的用途。
背景技术
乳腺癌是女性最常见的恶性肿瘤之一，全世界每年约有130万新发病例。在我国，乳腺癌发病率占全身各种恶性肿瘤发病率的7％-10％，约占所有女性肿瘤的18％，目前国内患者人数已超过50万，其发病率增长迅速，在一些大城市已经位列女性肿瘤发病谱首位，并且近50％患者出现治疗后复发和转移。近年来，随着肿瘤分子生物学研究的日趋深入，分子靶向治疗在乳腺癌治疗中越来越受到广泛应用并取得了较为显著的疗效，已成为继手术、放疗和化疗三大传统模式之后一种全新的治疗模式，也是当前乳腺癌治疗领域研究的热点。
细胞周期蛋白依赖性激酶(Cyclin-dependent kinase，CDK)是一类丝氨酸/苏氨酸激酶，通过与相应的细胞周期蛋白(Cyclin)形成二聚体，进而磷酸化下游蛋白分子，从而推动细胞周期各时相的有序行进，实现细胞生长和增殖。目前，国外已有多种CDK4/6选择性抑制剂在临床试验阶段或已获批上市，其中包括辉瑞公司的Palbociclib、诺华公司的Ribociclib及礼来公司的Abemaciclib等。
WO2014183520公开了一种化学名为6-乙酰基-8-环戊基-5-甲基-2-((5-(哌啶-4-基)吡啶-2-基)氨基)吡啶并[2,3-d]嘧啶-7(8H)-酮，结构式如式(I) 所示CDK4/6抑制剂，具有显著的CDK4/6的抑制活性和高度选择性，
Figure PCTCN2020093144-appb-000001
WO2016124067A公开了上述式(I)所示化合物的羟乙基磺酸盐及其制备方法。
关于CDK4/6抑制剂与其他药物的联用已经有较多研究，WO2017193141A公开CDK4/6抑制剂与EGFR抑制剂联用可用于治疗三阴性乳腺癌；WO2016024-232A公开了CDK4/6抑制剂与BTK激酶抑制剂联用治疗癌症的方法；Lori S.Hart等人在“Preclinical Therapeutic Synergy of MEK1/2 and CDK4/6 Inhibition in Neuroblastoma”中发现CDK4/6抑制剂和MEK抑制剂临床前用于成神经细胞瘤具有协同作用；CN103781480A公开CDK4/6抑制剂与FGFR激酶抑制剂的组合可用于治疗癌症；J.Bollard等“Palbociclib(PD-0332991)a selective CDK4/6 inhibitor,restricts tumour growth in preclinical models of hepatocellular carcinoma”公开Palbociclib单药或者联用索拉菲尼可能成为治疗肝细胞癌的新策略；CN106029097A公开了abemaciclib和雷莫芦单抗联用可用于治疗非小细胞肺癌；CN108883182A公开abemaciclib和雷莫芦单抗联用可用于治疗套细胞淋巴瘤。
目前关于CDK4/6抑制剂与小分子的VEGFR抑制剂联合用于治疗癌症的用途鲜有研究。
发明内容
本申请提供一种CDK4/6抑制剂与VEGFR抑制剂联合在制备治疗肿瘤疾病的药物中的用途。
本申请中所述的CDK4/6抑制剂可选式(I)所示化合物或其可药用盐，
Figure PCTCN2020093144-appb-000002
本申请中，式(I)所示化合物的可药用盐选自盐酸盐、磷酸盐、磷酸氢盐、硫酸盐、硫酸氢盐、亚硫酸盐、乙酸盐、草酸盐、丙二酸盐、戊酸盐、谷氨酸盐、油酸盐、棕榈酸盐、硬脂酸盐、月桂酸盐、硼酸盐、对甲苯磺酸盐、甲磺酸盐、羟乙基磺酸盐、马来酸盐、苹果酸盐、酒石酸盐、苯甲酸盐、双羟萘酸盐、水杨酸盐、香草酸盐、扁桃酸盐、琥珀酸盐、葡萄糖酸盐、乳糖酸盐或月桂基磺酸盐，优选羟乙基磺酸盐，其结构如式(II)所示，
Figure PCTCN2020093144-appb-000003
可选的实施方案中，所述的VEGFR抑制剂选自VEGFR-2抑制剂，优选VEGFR-2抑制剂为阿帕替尼或其可药用盐。
一些实施方案中，阿帕替尼可药用盐选自甲磺酸盐、马来酸盐、酒石酸盐、琥珀酸盐、醋酸盐、二氟醋酸盐、富马酸盐、柠檬酸盐、枸橼酸盐、苯磺酸盐、苯甲酸盐、萘磺酸盐、乳酸盐、苹果酸盐、盐酸盐、氢溴酸盐、硫酸盐、以及磷酸盐，在优选方案中，阿帕替尼的可药用盐为甲磺酸盐。
可选的实施方案中，所述VEGFR抑制剂为甲磺酸阿帕替尼。
本申请中所述的肿瘤疾病选自肉瘤、淋巴瘤、肺癌、支气管癌、前列腺癌、胰腺癌、胃肠癌、结肠癌、直肠癌、结直肠腺瘤、甲状腺癌、肝癌、肝内胆管癌、肝细胞癌、肾上腺癌、胃癌、胃肿瘤、胶质瘤、成胶质细胞瘤、子宫内膜癌、黑素瘤、肾癌、肾盂癌、膀胱癌、子宫体癌、宫颈癌、阴道癌、卵巢癌、多发性骨髓瘤、食管癌、白血病、急性髓细胞性白血病、慢性髓细胞性白血病、淋巴细胞性白血病、骨髓性白血病、脑肿瘤、脑癌、口腔及咽 部癌、喉癌、小肠癌、非霍奇金淋巴瘤、黑素瘤、结肠绒毛腺瘤、赘生物、上皮癌、乳腺癌、基底细胞癌、鳞状细胞癌、光化性角化病、肿瘤疾病、颈部或头部肿瘤、原发性血小板增多症、髓样化生性骨髓纤维化和巨球蛋白血症，优选乳腺癌、肝细胞癌、结肠癌。
可选的实施方案中，所述乳腺癌为激素受体阳性的乳腺癌。
可选的实施方案中，所述乳腺癌为三阴性乳腺癌。
可选的实施方案中，所述乳腺癌为her2阳性乳腺癌。
可选的实施方案中，所述CDK4/6抑制剂的给药剂量选自1-500mg，优选50-200mg，更优选100-150mg，给药频次为一日一次、一日两次，优选一日一次。
可选的实施方案中，所述CDK4/6抑制剂的给药剂量50mg、75mg、100mg、125mg、150mg、175mg，优选100mg、125mg或150mg，给药频次为一日一次、一日两次，优选一日一次。
可选的实施方案中，所述VEGFR抑制剂的给药剂量为100-500mg，给药频次为一日一次、两日一次、三日一次、给药五天停药两天、给药七天停药七天。
可选的实施方案中，所述VEGFR抑制剂的剂量为200mg、225mg、250mg、275mg、300mg、325mg、350mg、375mg、500mg，优选250mg或375mg，给药频次为一日一次、给药五天停药两天、给药七天停药七天。
可选的实施方案中，所述CDK4/6抑制剂的给药剂量选自100mg、125mg或150mg，给药频次为一日一次，所述VEGFR抑制剂的剂量250mg或375mg，给药频次为一日一次、给药五天停药两天、给药七天停药七天。
可选的实施方案中，所述CDK4/6抑制剂的给药剂量为100mg，给药频次为一日一次，所述VEGFR抑制剂的剂量250mg或375mg，给药频次为一日一次、给药五天停药两天、给药七天停药七天。
可选的实施方案中，所述CDK4/6抑制剂的给药剂量为125mg，给药频 次为一日一次，所述VEGFR抑制剂的剂量250mg或375mg，给药频次为一日一次、给药五天停药两天、给药七天停药七天。
可选的实施方案中，所述CDK4/6抑制剂的给药剂量为150mg，给药频次为一日一次，所述VEGFR抑制剂的剂量250mg或375mg，给药频次为一日一次、给药五天停药两天、给药七天停药七天。
本申请所述的联用的途径包括但不限于经口给药、胃肠外给药、经皮给药，所述胃肠外给药包括但不限于静脉注射、皮下注射、肌肉注射。
本申请提供一种治疗肿瘤疾病的方法，包括给与患者治疗有效量的上述CDK4/6抑制剂和VEGFR抑制剂。
本申请提供一种药物组合物，包括上述CDK4/6抑制剂、VEGFR抑制剂以及一种或多种可药用的赋形剂、稀释剂或载体。
本申请中所述的“联合”是一种给药方式，是指在一定时间期限内给予至少一种剂量的CDK4/6抑制剂和VEGFR抑制剂，其中两种药物都显示药理学作用。所述的时间期限可以是一个给药周期内，优选4周内，3周内，2周内，1周内，或24小时以内。可以同时或不分先后顺序给予CDK4/6抑制剂和VEGFR抑制剂。这种期限包括这样的治疗，其中通过相同给药途径或不同给药途径给予CDK4/6抑制剂、VEGFR抑制剂。
附图说明
图1.xxT47D异种移植瘤模型荷瘤鼠在给予受试物后的体重变化；
图2.xxT47D异种移植瘤模型荷瘤鼠在给予受试物后的相对体重变化；
图3.各组肿瘤的生长曲线。
具体实施方式
以下结合实施例用于进一步描述本申请，但这些实施例并非限制本申请的范围。
实施例1、式(I)所示化合物羟乙基磺酸盐(药物A)单药或者联用甲磺酸阿帕替尼(药物B)在xxT47D人乳腺癌细胞(ER+，HER2-)皮下异种移植肿瘤BALB/c裸小鼠模型上的体内药效学研究
1、实验材料
药物A采用WO2016124067A公开的方法制备；
小鼠：品系：BALB/c裸小鼠；周龄及体重：6－8周龄，体重18-22克；性别：雌性；数量：42只(不包括分组剩余鼠)；供应商：上海西普尔-必凯实验动物有限公司。
细胞来源：xxT47D肿瘤细胞通过亲代T47D肿瘤细胞(来源：ATCC,HTB-133)构建的异种移植瘤体外分离建立细胞系。
2、实验方法和步骤
1)xxT47D乳腺癌模型的建立
xxT47D肿瘤细胞通过亲代T47D肿瘤细胞构建的异种移植瘤体外分离建立细胞系，同样的过程进行2次而建立完成。xxT47D肿瘤细胞体外贴壁培养，培养条件为RPMI 1640培养基中加10％胎牛血清，100U/ml青霉素和链霉素100μg/ml，在37℃ 5％CO 2培养。一周两次用胰酶-EDTA进行常规消化处理传代。当细胞饱和度为80％-90％时，收取细胞，计数，接种。
2)肿瘤细胞接种
将雌激素片(0.18mg/片)皮下接种于每只小鼠的左后背，三天后，将0.2mL(10×10e6 cells+Matrigel，体积比为1:1)xxT47D细胞皮下接种于每只小鼠的右后背，肿瘤平均体积达到173mm 3时按照实验设计(表1)开始分组给药。
表1.实验动物分组及给药方案
Figure PCTCN2020093144-appb-000004
Figure PCTCN2020093144-appb-000005
注：N:每组小鼠数目；给药容积：根据小鼠体重10μl/g。如果体重下降超过15％，给药方案应做出相应调整，(Vehicle A+Vehicle B)为溶剂组。
3)受试药物配置
表2.受试药物配置
Figure PCTCN2020093144-appb-000006
Figure PCTCN2020093144-appb-000007
4)实验指标是考察肿瘤生长是否被抑制、延缓或治愈。每周两次用游标卡尺测量肿瘤直径。肿瘤体积的计算公式为：V＝0.5a×b 2，a和b分别表示肿瘤的长径和短径。
化合物的抑瘤疗效用TGI(％)或相对肿瘤增殖率T/C(％)评价。TGI(％)，反映肿瘤生长抑制率。TGI(％)的计算：TGI(％)＝【(1-(某处理组给药结束时平均瘤体积－该处理组开始给药时平均瘤体积))/(溶剂对照组治疗结束时平均瘤体积－溶剂对照组开始治疗时平均瘤体积)】×100％。
在实验结束后将检测肿瘤重量，并计算T/C weight百分比，Tweight和Cweight分别表示给药组和溶媒对照组的瘤重。
统计分析，包括每个组的每个时间点的肿瘤体积的平均值和标准误(SEM)。治疗组在试验结束时给药后第21天表现出最好的治疗效果，因此基于此数据进行统计学分析评估组间差异。两组间比较用T-test进行分析，三组或多组间比较用one-way ANOVA进行分析，如果F值有显著性差异，应用Games-Howell法进行检验。如果F值无显著性差异，应用Dunnet(2-sided)法进行分析。用SPSS 17.0进行所有数据分析。p<0.05认为有显著性差异。
3、实验结果
1)体重变化
受试物治疗对xxT47D荷瘤鼠的体重影响如图1和图2所示。
2)肿瘤体积变化
给予xxT47D荷瘤鼠受试物治疗后各组肿瘤体积变化如表3所示。
表3.各组不同时间点的瘤体积
Figure PCTCN2020093144-appb-000008
注：a.平均值±SEM；b.给药后天数
3)肿瘤生长曲线
各组肿瘤的生长曲线如图3所示。
4)抗肿瘤药效评价指标
表4.药物A和药物B对xxT47D异种移植瘤模型的抑瘤药效评价(基于给药后第21天肿瘤体积计算得出)
Figure PCTCN2020093144-appb-000009
注：a.平均值±SEM.b.肿瘤生长抑制由T/C和TGI(TGI(％)＝[1-(T 21-T 0)/(V 21-V 0)]×100)计算。c.p值根据肿瘤体积计算。
表5.药物A和药物B组肿瘤重量分析
Figure PCTCN2020093144-appb-000010
注：a.平均值±SEM。b.肿瘤生长抑制由T/C重量＝TW治疗/TW对照计算。c.p值根据瘤重计算。
4、实验讨论
开始给药后21天，溶剂对照组荷瘤鼠的平均瘤体积达到1283mm 3，受试物25mg/kg药物A，50mg/kg药物B组平均瘤体积分别为724mm 3和704mm 3，与溶剂对照组相比具有显著的抑瘤作用(p值分别为0.019和0.015)。
25mg/kg药物A联合50mg/kg药物B治疗组的平均瘤体积为354mm 3，与溶剂组相比均差异显著(p＜0.001)，与各自的单药组相比，联合组均显示出更强的抗肿瘤活性，并且差异显著，药物A与药物B联用组与单药相比p值分别为0.022和0.003。肿瘤重量结果(表5)与肿瘤体积结果基本一致。
综上所述，药物A和药物B单药在试验方案剂量下在xxT47D人乳腺癌异种移植瘤模型上显示出了显著的抗肿瘤活性。与单药相比，药物A与药物B联合应用可进一步增强抗肿瘤效果。
虽然以上描述了本发明的具体实施方式，但是本领域的技术人员应当理解，这些仅是举例说明，在不背离本发明的原理和实质的前提下，可以对这些实施方式做出多种变更或修改。因此，本发明的保护范围由所附权利要求书限定。

Claims (12)

  1. 一种CDK4/6抑制剂与VEGFR抑制剂联合在制备治疗肿瘤疾病的药物中的用途。
  2. 根据权利要求1所述的用途，所述CDK4/6抑制剂为式(I)所示化合物或其可药用盐，
    Figure PCTCN2020093144-appb-100001
  3. 根据权利要求2所述的用途，式(I)所示化合物的可药用盐为羟乙基磺酸盐。
  4. 根据权利要求1所述的用途，所述VEGFR抑制剂选自VEGFR-2抑制剂，优选VEGFR-2抑制剂为阿帕替尼或其可药用盐。
  5. 根据权利要求4所述的用途，所述VEGFR抑制剂为甲磺酸阿帕替尼。
  6. 根据权利要求1-5任一项所述的用途，所述肿瘤疾病选自肉瘤、淋巴瘤、肺癌、支气管癌、前列腺癌、胰腺癌、胃肠癌、结肠癌、直肠癌、结直肠腺瘤、甲状腺癌、肝癌、肝内胆管癌、肝细胞癌、肾上腺癌、胃癌、胃肿瘤、胶质瘤、成胶质细胞瘤、子宫内膜癌、黑素瘤、肾癌、肾盂癌、膀胱癌、子宫体癌、宫颈癌、阴道癌、卵巢癌、多发性骨髓瘤、食管癌、白血病、急性髓细胞性白血病、慢性髓细胞性白血病、淋巴细胞性白血病、骨髓性白血病、脑肿瘤、脑癌、口腔及咽部癌、喉癌、小肠癌、非霍奇金淋巴瘤、黑素瘤、结肠绒毛腺瘤、赘生物、上皮癌、乳腺癌、基底细胞癌、鳞状细胞癌、光化性角化病、肿瘤疾病、颈部或头部肿瘤、原发性血小板增多症、髓样化生性骨髓纤维化和巨球蛋白血症，优选乳腺癌、肝细胞癌、结肠癌。
  7. 根据权利要求6所述的用途，所述乳腺癌为激素受体阳性的乳腺癌。
  8. 根据权利要求6所述的用途，所述CDK4/6抑制剂的给药剂量选自 1-500mg，优选50-200mg，更优选100-150mg，给药频次为一日一次、一日两次，优选一日一次。
  9. 根据权利要求8所述的用途，所述CDK4/6抑制剂的给药剂量为50mg、75mg、100mg、125mg、150mg、175mg，优选100mg、125mg或150mg，给药频次为一日一次、一日两次，优选一日一次。
  10. 根据权利要求8-9任一项所述的用途，所述VEGFR抑制剂的给药剂量为100-500mg，给药频次为一日一次、两日一次、三日一次、给药五天停药两天、给药七天停药七天。
  11. 根据权利要求10所述的用途，所述VEGFR抑制剂的剂量为200mg、225mg、250mg、275mg、300mg、325mg、350mg、375mg、500mg，优选250mg或375mg，给药频次为一日一次、给药五天停药两天、给药七天停药七天。
  12. 一种药物组合物，其包含权利要求1-11任一项所述的CDK4/6抑制剂、VEGFR抑制剂以及一种或多种可药用的赋形剂、稀释剂或载体。
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