阅读说明：本技术 阿帕替尼和c-Met抑制剂联合在制备***的药物中的用途 (Application of apatinib and c-Met inhibitor combination in preparation of drugs for treating tumors ) 是由 蒋家骅 曹国庆 杨昌永 张蕾 张连山 孙飘扬 于 2018-09-21 设计创作，主要内容包括：阿帕替尼和c-Met抑制剂联合在制备治疗肿瘤的药物中的用途。阿帕替尼与化合物(1)或其可药用盐联合在制备治疗肿瘤的药物中的用途。<Image he="201" wi="504" file="DDA0002291066280000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The use of a combination of apatinib and a c-Met inhibitor for the preparation of a medicament for the treatment of a tumour. The application of the apatinib and the compound (1) or the pharmaceutically acceptable salt thereof in preparing the medicament for treating the tumor.)

The application of the apatinib or the pharmaceutical salt thereof in combination with the c-Met inhibitor in preparing the medicine for treating the tumor.

The use according to claim 1, characterized in that the c-Met inhibitor is selected from Compound (1) or a pharmaceutically acceptable salt thereof,

the use according to any one of claims 1-2, wherein the tumor is selected from the group consisting of a malignant tumor, a benign tumor; the malignant tumor is selected from malignant epithelial tumor, sarcoma, myeloma, leukemia, lymphoma, melanoma, head and neck tumor, brain tumor, mixed tumor, and children malignant tumor; preferably, the malignant epithelial tumors are selected from lung cancer, breast cancer, liver cancer, pancreatic cancer, colorectal cancer, stomach cancer, esophageal cancer, small intestine cancer, cardiac cancer, endometrial cancer, ovarian cancer, fallopian tube cancer, vulva cancer, testicular cancer, prostate cancer, penile cancer, kidney cancer, bladder cancer, anal cancer, gall bladder cancer, bile duct cancer, teratoma, heart tumor; preferably, the head and neck tumor is selected from nasopharyngeal carcinoma, laryngeal carcinoma, thyroid carcinoma, tongue carcinoma, oral cancer; preferably the sarcoma is selected from the group consisting of Askin's tumor, chondrosarcoma, ewing's sarcoma, malignant angioendothelioma, malignant schwannoma, osteosarcoma, soft tissue sarcoma; preferably, the myeloma is selected from isolated myeloma, multiple myeloma, diffuse myeloma, leukemia myeloma, and extramedullary myeloma; preferably the leukemia is selected from acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, hairy cell leukemia, T cell lymphocytic leukemia, large granular lymphocytic leukemia, adult T cell leukemia; preferably the lymphoma is selected from non-hodgkin's lymphoma, hodgkin's lymphoma; preferably, the brain tumor is selected from the group consisting of neuroepithelial tissue tumors, cranial and spinal nerve tumors, meningeal tissue tumors; preferably, the childhood malignancy is selected from the group consisting of nephroblastoma, neuroblastoma, retinoblastoma, childhood germ cell tumor.

Use according to claim 3, characterized in that the lung cancer is selected from non-small cell lung cancer, preferably non-small cell lung cancer.

The use according to claim 3, wherein the breast cancer is selected from Hormone Receptor (HR) positive breast cancer, human epidermal growth factor receptor-2 (HER2) positive breast cancer, triple negative breast cancer.

Use according to claim 3, wherein the renal cancer is selected from clear renal cell carcinoma, papillary renal cell carcinoma, chromophobe renal cell carcinoma, collecting duct carcinoma.

Use according to claim 3, characterized in that the neuroepithelial tumors are selected from preferably astrocytomas, anaplastic astrocytomas, glioblastomas.

The use according to claim 3, wherein the liver cancer is selected from primary liver cancer selected from hepatocellular carcinoma, cholangiocellular carcinoma, mixed liver cancer; the colorectal cancer is selected from colon cancer and rectal cancer.

Use according to any one of claims 1 to 8, characterized in that the tumour is selected from VEFGR-overexpressing and/or c-Met-overexpressing tumours, VEFGR-overexpressing and/or c-Met-moderately expressing tumours.

The use according to any one of claims 1 to 9, wherein the tumor is selected from the group consisting of a mid-late stage tumor, a relapsed refractory tumor, a tumor that has failed treatment with a first-line chemotherapeutic drug and/or has relapsed, a tumor that has failed treatment with radiotherapy and/or has relapsed, a tumor that has failed treatment with a targeted drug and/or has relapsed; the chemotherapeutic drug is selected from one or more of alkylating agent, platinum complexing agent, metabolism antagonist, plant alkaloid, hormone anticancer agent, proteasome inhibitor, aromatase inhibitor and immunomodulator; the targeted drug is selected from the group consisting of an EGFR inhibitor, ALK inhibitor, PARP inhibitor, CDK inhibitor, MEK inhibitor, VEGF antibody, VEGFR inhibitor, BTK inhibitor, mTOR inhibitor.

The use according to any one of claims 1 to 10, wherein the weight ratio of apatinib, or a pharmaceutically acceptable salt thereof, to compound (1), or a pharmaceutically acceptable salt thereof, is selected from 0.01 to 100:1, preferably from 1:12, 1:10, 1:9, 1:8, 2:15, 1:7, 1:6, 1:5, 5:24, 2:9, 1:4, 4:15, 5:18, 2:7, 3:10, 5:16, 1:3, 5:14, 3:8, 2:5, 5:12, 3:7, 4:9, 1:2, 8:15, 5:9, 4:7, 7:12, 3:5, 5:8, 2:3, 7:10, 5:7, 3:4, 7:9, 4:5, 5:6, 6:7, 7: 8:9, 9:10, 14:15, 1: 16, 1:5, 4: 5:7, 4:9, 4:5, 5:6, 6: 7: 8:9, 14: 10, 14:15, 1: 15, 5: 5, 3:2, 8:5, 2:1, 5:2, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, more preferably 1:1, 1:6, 1:5, 1:4, 1:3, 2:5, 5:12, 1:2, 3:5, 5:8, 2:3, 3:4, 4:5, 5:6, 6:5, 5:4, 4:3, 3:2, 8:5, 2:1, 5:2, 3:1, 4:1, 5: 1.

The use according to any of claims 1 to 11, wherein the apatinib or pharmaceutically acceptable salt thereof is administered in an amount selected from the group consisting of 100-1000mg, preferably 200mg, 250mg, 300mg, 350mg, 375mg, 400mg, 450mg, 500mg, 550mg, 600mg, 700mg, 750mg, 800mg, 850mg, 900mg, 1000mg, more preferably from 250mg, 300mg, 350mg, 400mg, 450mg, 500mg, 600mg, 700mg, 750 mg.

Use according to any one of claims 1 to 12, wherein the dose of compound (1) or a pharmaceutically acceptable salt thereof is selected from 10 to 1200mg, preferably from 20mg, 50mg, 55mg, 60mg, 75mg, 100mg, 110mg, 200mg, 220mg, 250mg, 260mg, 300mg, 350mg, 400mg, 450mg, 500mg, 550mg, 600mg, 700mg, 750mg, 800mg, 900mg, 1000mg, more preferably 100mg, 110mg, 200mg, 220mg, 250mg, 260mg, 300mg, 350mg, 400mg, 450mg, 500 mg.

Use according to any one of claims 1 to 13, wherein the apatinib or a pharmaceutically acceptable salt thereof is selected from the group consisting of the mesylate salt, the hydrochloride salt, preferably from the mesylate salt.

Use according to any one of claims 1 to 14, characterized in that the compound (1) or a pharmaceutically acceptable salt thereof is selected from the group consisting of hydrochloride, mesylate, maleate, malate, besylate, preferably mesylate.

A pharmaceutical composition comprising apatinib, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 15, and compound (1), or a pharmaceutically acceptable salt thereof, in association with one or more pharmaceutically acceptable excipients, diluents, or carriers.