WO2020057536A1 - 用于治疗脑肿瘤的喹啉衍生物 - Google Patents

用于治疗脑肿瘤的喹啉衍生物 Download PDF

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Publication number
WO2020057536A1
WO2020057536A1 PCT/CN2019/106379 CN2019106379W WO2020057536A1 WO 2020057536 A1 WO2020057536 A1 WO 2020057536A1 CN 2019106379 W CN2019106379 W CN 2019106379W WO 2020057536 A1 WO2020057536 A1 WO 2020057536A1
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Prior art keywords
acid
compound
cancer
brain
pharmaceutically acceptable
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PCT/CN2019/106379
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English (en)
French (fr)
Inventor
王善春
钱文娟
卢琴
徐宏江
于鼎
王训强
彭邦安
刘璐
代洁
Original Assignee
正大天晴药业集团股份有限公司
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Application filed by 正大天晴药业集团股份有限公司 filed Critical 正大天晴药业集团股份有限公司
Priority to CN201980052519.5A priority Critical patent/CN112638385B/zh
Publication of WO2020057536A1 publication Critical patent/WO2020057536A1/zh

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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
    • A61K31/435—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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further 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
    • A61P35/04—Antineoplastic agents specific for metastasis

Definitions

  • the present invention belongs to the field of medicine, and specifically relates to the use of quinoline derivatives in treating brain tumors.
  • the adult brain is a site that is easily metastasized by tumor cells.
  • brain tumors There are two types of brain tumors: primary brain tumors and brain metastatic tumors.
  • Primary brain tumors are the primary lesions of brain tumors that appear in the brain. There are 10 times more brain metastatic tumors than primary brain tumors. It is estimated that 20% to 40% of cancer patients have intracranial metastases.
  • Metastatic brain tumors include brain metastasis (BM) and meningeal metastasis (LM). The most common location of brain parenchymal metastases is the cerebral hemisphere, followed by the cerebellum and brain stem. Meningeal metastases are rarer than parenchymal metastases, but the prognosis is worse.
  • NSCLC non-small cell lung cancer
  • SCLC small cell lung cancer
  • brain metastatic tumors often deteriorates because the drugs cannot effectively penetrate the blood-brain barrier. Once patients have brain metastases, the disease often progresses quickly. Current treatments for brain metastatic tumors are limited. Prompt diagnosis and appropriate treatment are very important for patients with brain metastases, because nerve damage has a great impact on their quality of life, and any delay or wrong treatment will bring serious sequelae to the patient. About 53% of patients with brain metastases have multiple lesions and are suitable for radiotherapy and chemotherapy. Therefore, new chemotherapeutic methods are urgently needed to treat brain metastatic tumors in order to control the progress of multiple lesions in patients.
  • the present invention provides a method for treating a brain tumor, the method comprising administering a therapeutically effective amount of Compound I or a pharmaceutically acceptable salt thereof to a patient in need of treatment.
  • the brain tumor is a primary brain tumor.
  • the brain tumor is a brain metastatic tumor.
  • brain metastatic tumors include, but are not limited to, parenchymal metastases and meningeal metastases.
  • brain metastatic tumors include, but are not limited to, metastatic tumors in patients caused by failure of treatment with chemotherapeutic drugs and / or targeted drugs.
  • the primary cancer of a brain metastatic tumor includes, but is not limited to, lung cancer, melanoma, breast cancer, kidney cancer, gastric cancer, adrenal cancer, cervical chorionic epithelial cancer, nasopharyngeal cancer, thyroid cancer, pelvic cancer And colorectal cancer.
  • the brain metastatic tumor is a lung metastatic brain tumor. In some embodiments, the brain metastatic tumor is a non-small cell lung cancer metastatic brain tumor. In some embodiments, the brain metastatic tumor is a small cell lung cancer metastatic brain tumor.
  • the invention also provides a method for treating a brain metastatic tumor, the method comprising administering a therapeutically effective amount of Compound I or a pharmaceutically acceptable salt thereof to a patient in need of treatment.
  • the invention also provides a method for treating a lung metastatic brain tumor, which method comprises administering a therapeutically effective amount of Compound I or a pharmaceutically acceptable salt thereof to a patient in need of treatment.
  • the chemotherapy drugs include first-line chemotherapy drugs and second-line chemotherapy drugs.
  • first-line chemotherapy drugs including but not limited to one or more of podophyllum, alkylating agents, camptothecin, taxanes, antimetabolites, antibiotics and antitumor drugs; examples can be enumerated Including but not limited to temozolomide, pemetrexed, cisplatin, etoposide, carboplatin, nedaplatin, oxaliplatin, mitoplatin, loplatin, irinotecan, topotecan, paclitaxel, docetaxel , Temozolomide, vinorelbine, gemcitabine, cyclophosphamide, doxorubicin, vincristine, bendamustine, epirubicin, methotrexate, amrubicin.
  • podophyllum including but not limited to one or more of podophyllum, alkylating agents, camptothecin, taxanes, anti
  • Compound I can be administered in its free base form, or in the form of its salts, hydrates and prodrugs, which prodrugs are converted into the free base form of Compound I in vivo.
  • a pharmaceutically acceptable salt of Compound I is within the scope of the present invention, and the salt can be produced from different organic and inorganic acids according to methods known in the art.
  • the compound I is administered as the hydrochloride salt. In some embodiments, administration is in the form of Compound I monohydrochloride. In some embodiments, administration is in the form of Compound I dihydrochloride. In some embodiments, administration is in the form of a crystal of Compound I hydrochloride. In a particular embodiment, administration is in the form of a crystal of Compound I dihydrochloride.
  • Compound I or a pharmaceutically acceptable salt thereof can be administered by a variety of routes including, but not limited to, routes selected from the group consisting of oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, Intramuscular, rectal, buccal, intranasal, inhalation, vaginal, intraocular, topical, subcutaneous, intrafat, intra-articular, intraperitoneal and intrathecal. In some specific embodiments, it is administered orally.
  • the amount of Compound I or a pharmaceutically acceptable salt administered can be determined based on the severity of the disease, the response of the disease, any treatment-related toxicity, the age and health status of the patient.
  • the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 2 mg to 30 mg.
  • the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 6 mg to 20 mg.
  • the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 8 mg to 20 mg.
  • the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 10 mg to 16 mg.
  • the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 10 mg to 14 mg.
  • the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 8 mg. In some specific embodiments, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 10 mg. In some specific embodiments, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 12 mg. In some specific embodiments, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 14 mg.
  • Compound I or a pharmaceutically acceptable salt thereof may be administered one or more times daily. In some embodiments, Compound I or a pharmaceutically acceptable salt thereof is administered once a day. In some embodiments, the oral solid formulation is administered once daily.
  • the method of administration can be comprehensively determined according to the activity, toxicity, and tolerance of the patient.
  • Compound I or a pharmaceutically acceptable salt thereof is administered in a spaced manner.
  • the interval administration includes an administration period and a withdrawal period, and Compound I or a pharmaceutically acceptable salt thereof can be administered once or multiple times per day during the administration period.
  • Compound I or a pharmaceutically acceptable salt thereof is administered daily during the administration period, and then the administration is stopped for a period of time during the withdrawal period, followed by the administration period, and then the withdrawal period, which can be repeated multiple times.
  • the ratio in days between the administration period and the withdrawal period is 2: 0.5 to 5, preferably 2: 0.5 to 3, more preferably 2: 0.5 to 2, and even more preferably 2: 0.5 to 1.
  • the administration is discontinued for 2 weeks for 2 weeks.
  • the drug is administered once a day for 14 days and then discontinued for 14 days; then it is administered once a day for 14 days and then discontinued for 14 days.
  • the drug can be administered repeatedly at intervals of 2 weeks.
  • the administration is discontinued for 2 weeks for 1 week.
  • the drug is administered once a day for 14 days and then discontinued for 7 days; then it is administered once a day for 14 days and then discontinued for 7 days.
  • the drug can be administered repeatedly at intervals of 1 week.
  • the dosing is discontinued for 5 days for 2 days.
  • the drug is administered once a day for 5 days, and then the drug is discontinued for 2 days; then the drug is administered once a day, for 5 days, and then discontinued for 2 days.
  • the two-day interval administration can be repeated several times.
  • the drug is administered orally at a dose of 12 mg once a day for 2 weeks and then stopped for 1 week.
  • the drug is administered orally at a dose of 10 mg once a day for two consecutive weeks and one week off.
  • the drug is administered orally at a dose of 8 mg once a day for 2 weeks and then stopped for 1 week.
  • Compound I or a pharmaceutically acceptable salt thereof is administered alone as the sole active ingredient to a patient with a brain metastatic tumor. In some embodiments, Compound I or a pharmaceutically acceptable salt thereof is administered to a brain metastatic tumor patient simultaneously or sequentially with other antitumor drugs.
  • other antitumor drugs include, but are not limited to, antifolate antitumor drugs, podophyllum anticancer drugs, hormone antitumor drugs, alkylating agent antitumor drugs, camptothecin antitumor drugs, One or more of a fluoropyrimidine derivative, an anthracycline, a taxane, an EGFR inhibitor, a VEGFR inhibitor, mitomycin, and trastuzumab.
  • the present invention provides the use of Compound I or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a brain tumor.
  • the brain tumor is a primary brain tumor.
  • the brain tumor is a brain metastatic tumor.
  • brain metastatic tumors include, but are not limited to, parenchymal metastases and meningeal metastases.
  • brain metastatic tumors include, but are not limited to, metastatic tumors in patients caused by failure of treatment with chemotherapeutic drugs and / or targeted drugs.
  • the primary cancer of a brain metastatic tumor includes, but is not limited to, lung cancer, melanoma, breast cancer, kidney cancer, gastric cancer, adrenal cancer, cervical chorionic epithelial cancer, nasopharyngeal cancer, thyroid cancer, pelvic cancer And colorectal cancer.
  • the brain metastatic tumor is a lung metastatic brain tumor. In some embodiments, the brain metastatic tumor is a non-small cell lung cancer metastatic brain tumor. In some embodiments, the brain metastatic tumor is a small cell lung cancer metastatic brain tumor.
  • the invention also provides the use of Compound I or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating brain metastatic tumors.
  • the present invention also provides the use of Compound I or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a lung metastatic brain tumor.
  • the chemotherapy drugs include first-line chemotherapy drugs and second-line chemotherapy drugs.
  • first-line chemotherapy drugs including but not limited to one or more of podophyllum, alkylating agents, camptothecin, taxanes, antimetabolites, antibiotics and antitumor drugs; examples can be enumerated Including but not limited to temozolomide, pemetrexed, cisplatin, etoposide, carboplatin, nedaplatin, oxaliplatin, mitoplatin, loplatin, irinotecan, topotecan, paclitaxel, docetaxel , Temozolomide, vinorelbine, gemcitabine, cyclophosphamide, doxorubicin, vincristine, bendamustine, epirubicin, methotrexate, amrubicin.
  • podophyllum including but not limited to one or more of podophyllum, alkylating agents, camptothecin, taxanes, anti
  • Compound I may be in its free base form, or in the form of its salts, hydrates, and prodrugs, which prodrugs are converted into the free base form of Compound I in vivo.
  • the pharmaceutically acceptable salts of Compound I are within the scope of the present invention, and salts can be produced from different organic and inorganic acids according to methods well known in the art.
  • Compound I or a pharmaceutically acceptable salt thereof is the hydrochloride form of Compound I. In some embodiments, it is in the form of Compound I monohydrochloride. In some embodiments, it is in the form of Compound I dihydrochloride. In some embodiments, it is a crystalline form of Compound I hydrochloride. In a particular embodiment, it is a crystalline form of the dihydrochloride salt of Compound I.
  • Compound I or a pharmaceutically acceptable salt thereof can be administered by a variety of routes including, but not limited to, routes selected from the group consisting of oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, Intramuscular, rectal, buccal, intranasal, inhalation, vaginal, intraocular, topical, subcutaneous, intrafat, intra-articular, intraperitoneal and intrathecal. In some specific embodiments, it is administered orally.
  • the amount of Compound I or a pharmaceutically acceptable salt thereof can be determined based on the severity of the disease, the response of the disease, any treatment-related toxicity, the age and health status of the patient.
  • the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 2 mg to 30 mg.
  • the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 6 mg to 20 mg.
  • the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 8 mg to 20 mg.
  • the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 10 mg to 16 mg.
  • the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 10 mg to 14 mg.
  • the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 8 mg. In some specific embodiments, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 10 mg. In some specific embodiments, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 12 mg. In some specific embodiments, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 14 mg.
  • Compound I or a pharmaceutically acceptable salt thereof may be administered one or more times daily. In some embodiments, Compound I or a pharmaceutically acceptable salt thereof is administered once a day. In some embodiments, the oral solid formulation is administered once daily.
  • the method of administration can be comprehensively determined according to the activity, toxicity, and tolerance of the patient.
  • Compound I or a pharmaceutically acceptable salt thereof is administered in a spaced manner.
  • the interval administration includes an administration period and a withdrawal period, and Compound I or a pharmaceutically acceptable salt thereof can be administered once or multiple times per day during the administration period.
  • Compound I or a pharmaceutically acceptable salt thereof is administered daily during the administration period, and then the administration is stopped for a period of time during the withdrawal period, followed by the administration period, and then the withdrawal period, which can be repeated multiple times.
  • the ratio in days between the administration period and the withdrawal period is 2: 0.5 to 5, preferably 2: 0.5 to 3, more preferably 2: 0.5 to 2, and even more preferably 2: 0.5 to 1.
  • the administration is discontinued for 2 weeks for 2 weeks.
  • the drug is administered once a day for 14 days and then discontinued for 14 days; then it is administered once a day for 14 days and then discontinued for 14 days.
  • the drug can be administered repeatedly at intervals of 2 weeks.
  • the administration is discontinued for 2 weeks for 1 week.
  • the drug is administered once a day for 14 days and then discontinued for 7 days; then it is administered once a day for 14 days and then discontinued for 7 days.
  • the drug can be administered repeatedly at intervals of 1 week.
  • the dosing is discontinued for 5 days for 2 days.
  • the drug is administered once a day for 5 days, and then the drug is discontinued for 2 days; then the drug is administered once a day, for 5 days, and then discontinued for 2 days.
  • the two-day interval administration can be repeated several times.
  • the drug is administered orally at a dose of 12 mg once a day for 2 weeks and then stopped for 1 week.
  • the drug is administered orally at a dose of 10 mg once a day for two consecutive weeks and one week off.
  • the drug is administered orally at a dose of 8 mg once a day for 2 weeks and then stopped for 1 week.
  • Compound I or a pharmaceutically acceptable salt thereof is administered alone as the sole active ingredient to a patient with a brain metastatic tumor. In some embodiments, Compound I or a pharmaceutically acceptable salt thereof is administered to a brain metastatic tumor patient simultaneously or sequentially with other antitumor drugs.
  • other antitumor drugs include, but are not limited to, antifolate antitumor drugs, podophyllum anticancer drugs, hormone antitumor drugs, alkylating agent antitumor drugs, camptothecin antitumor drugs, One or more of a fluoropyrimidine derivative, an anthracycline, a taxane, an EGFR inhibitor, a VEGFR inhibitor, mitomycin, and trastuzumab.
  • the present invention provides a pharmaceutical composition for treating a brain tumor, which comprises Compound I or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
  • the brain tumor is a primary brain tumor.
  • the brain tumor is a brain metastatic tumor.
  • brain metastatic tumors include, but are not limited to, parenchymal metastases and meningeal metastases.
  • brain metastatic tumors include, but are not limited to, metastatic tumors in patients caused by failure of treatment with chemotherapeutic drugs and / or targeted drugs.
  • the primary cancer of a brain metastatic tumor includes, but is not limited to, lung cancer, melanoma, breast cancer, kidney cancer, gastric cancer, adrenal cancer, cervical chorionic epithelial cancer, nasopharyngeal cancer, thyroid cancer, pelvic cancer And colorectal cancer.
  • the brain metastatic tumor is a lung metastatic brain tumor. In some embodiments, the brain metastatic tumor is a non-small cell lung cancer metastatic brain tumor. In some embodiments, the brain metastatic tumor is a small cell lung cancer metastatic brain tumor.
  • the present invention also provides a pharmaceutical composition for treating brain metastatic tumors, which comprises Compound I or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
  • the present invention also provides a pharmaceutical composition for treating a lung metastatic brain tumor, which comprises Compound I or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
  • the chemotherapy drugs include first-line chemotherapy drugs and second-line chemotherapy drugs.
  • first-line chemotherapy drugs including but not limited to one or more of podophyllum, alkylating agents, camptothecin, taxanes, antimetabolites, antibiotics and antitumor drugs; examples can be enumerated Including but not limited to temozolomide, pemetrexed, cisplatin, etoposide, carboplatin, nedaplatin, oxaliplatin, mitoplatin, loplatin, irinotecan, topotecan, paclitaxel, docetaxel , Temozolomide, vinorelbine, gemcitabine, cyclophosphamide, doxorubicin, vincristine, bendamustine, epirubicin, methotrexate, amrubicin.
  • podophyllum including but not limited to one or more of podophyllum, alkylating agents, camptothecin, taxanes, anti
  • Compound I can be in its free base form, or in the form of salts, hydrates and prodrugs, which prodrugs are converted into the free base form of Compound I in vivo.
  • the pharmaceutically acceptable salts of Compound I are within the scope of the present invention, and salts can be produced from different organic and inorganic acids according to methods well known in the art.
  • Compound I or a pharmaceutically acceptable salt thereof is the hydrochloride form of Compound I. In some embodiments, it is in the form of Compound I monohydrochloride. In some embodiments, it is in the form of Compound I dihydrochloride. In some embodiments, it is a crystalline form of Compound I hydrochloride. In a particular embodiment, it is a crystalline form of the dihydrochloride salt of Compound I.
  • the pharmaceutical composition may be suitable for oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, intramuscular, rectal, buccal, intranasal, inhalation, Preparations for vaginal, intraocular, topical, subcutaneous, intrafat, intra-articular, intraperitoneal and intrathecal administration.
  • the amount of the pharmaceutical composition administered can be determined based on the severity of the disease, the response of the disease, any treatment-related toxicity, the age and health status of the patient.
  • the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 2 mg to 30 mg. In some embodiments, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 6 mg to 20 mg. In some embodiments, the daily dose of Compound I or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is from 8 mg to 20 mg. In some embodiments, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 10 mg to 16 mg. In some embodiments, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 10 mg to 14 mg.
  • the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 8 mg. In some specific embodiments, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 10 mg. In some specific embodiments, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 12 mg. In some specific embodiments, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 14 mg.
  • the pharmaceutical composition is a formulation suitable for oral administration, including tablets, capsules, powders, granules, dripping pills, pastes, powders, etc., preferably tablets and capsules.
  • the tablet can be an ordinary tablet, a dispersible tablet, an effervescent tablet, a sustained-release tablet, a controlled-release tablet, or an enteric tablet
  • the capsule can be an ordinary capsule, a sustained-release capsule, a controlled-release capsule, or an enteric capsule.
  • the oral preparation can be prepared by conventional methods using pharmaceutically acceptable carriers known in the art.
  • Pharmaceutically acceptable carriers include fillers, absorbents, wetting agents, binders, disintegrants, lubricants, and the like.
  • Fillers include starch, lactose, mannitol, microcrystalline cellulose, etc .; absorbents include calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc .; wetting agents include water, ethanol, etc .; binders include hypromellose, polymer Retinone, microcrystalline cellulose, etc .; disintegrants include croscarmellose sodium, crospovidone, surfactants, low-substituted hydroxypropyl cellulose, etc .; lubricants include magnesium stearate, talc Powder, polyethylene glycol, sodium lauryl sulfate, micronized silica gel, talc, etc. Pharmaceutical excipients also include colorants, sweeteners, and the like.
  • the pharmaceutical composition is a solid formulation suitable for oral administration.
  • the composition may be in the form of a tablet or capsule, for example.
  • the pharmaceutical composition is a capsule.
  • pharmaceutically acceptable carriers for oral solid formulations include mannitol, microcrystalline cellulose, hydroxypropyl cellulose, and magnesium stearate.
  • Compound I or a pharmaceutically acceptable salt thereof may be administered one or more times daily. In some embodiments, Compound I or a pharmaceutically acceptable salt thereof is administered once a day. In some embodiments, the oral solid formulation is administered once daily.
  • the method of administration can be comprehensively determined according to the activity, toxicity, and tolerance of the patient.
  • Compound I or a pharmaceutically acceptable salt thereof is administered in a spaced manner.
  • the interval administration includes an administration period and a withdrawal period, and Compound I or a pharmaceutically acceptable salt thereof can be administered once or multiple times per day during the administration period.
  • Compound I or a pharmaceutically acceptable salt thereof is administered daily during the administration period, and then the administration is stopped for a period of time during the withdrawal period, followed by the administration period, and then the withdrawal period.
  • the ratio in days between the administration period and the withdrawal period is 2: 0.5 to 5, preferably 2: 0.5 to 3, more preferably 2: 0.5 to 2, and even more preferably 2: 0.5 to 1.
  • the administration is discontinued for 2 weeks for 2 weeks.
  • the drug is administered once a day for 14 days and then discontinued for 14 days; then it is administered once a day for 14 days and then discontinued for 14 days.
  • the drug can be administered repeatedly at intervals of 2 weeks.
  • the administration is discontinued for 2 weeks for 1 week.
  • the drug is administered once a day for 14 days and then discontinued for 7 days; then it is administered once a day for 14 days and then discontinued for 7 days.
  • the drug can be administered repeatedly at intervals of 1 week.
  • the dosing is discontinued for 5 days for 2 days.
  • the drug is administered once a day for 5 days, and then the drug is discontinued for 2 days; then the drug is administered once a day, for 5 days, and then discontinued for 2 days.
  • the two-day interval administration can be repeated several times.
  • the drug is administered orally at a dose of 12 mg once a day for 2 weeks and then stopped for 1 week.
  • the drug is administered orally at a dose of 10 mg once a day for two consecutive weeks and one week off.
  • the drug is administered orally at a dose of 8 mg once a day for 2 weeks and then stopped for 1 week.
  • a pharmaceutical composition formulated to treat brain tumors in a unit dosage form contains 2 mg to 30 mg of Compound I or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition in a unit dosage form contains 6 mg to 20 mg of Compound I or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition in a unit dosage form contains 8 mg to 20 mg of Compound I or a pharmaceutically acceptable salt thereof, preferably 10 mg to 16 mg of Compound I or a pharmaceutically acceptable salt thereof, More preferably, 10 mg to 14 mg of Compound I or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition in the unit dosage form contains 8 mg of Compound I or a pharmaceutically acceptable salt thereof. In some specific embodiments, the pharmaceutical composition in the unit dosage form contains 10 mg of Compound I or a pharmaceutically acceptable salt thereof. In some specific embodiments, the unit dosage form pharmaceutical composition contains 12 mg of Compound I or a pharmaceutically acceptable salt thereof. In some specific embodiments, the unit dosage form pharmaceutical composition contains 14 mg of Compound I or a pharmaceutically acceptable salt thereof.
  • the brain tumor is a primary brain tumor.
  • the brain tumor is a brain metastatic tumor.
  • brain metastatic tumors include, but are not limited to, parenchymal metastases and meningeal metastases.
  • brain metastatic tumors include, but are not limited to, metastatic tumors in patients caused by failure of treatment with chemotherapeutic drugs and / or targeted drugs.
  • the primary cancer of a brain metastatic tumor includes, but is not limited to, lung cancer, melanoma, breast cancer, kidney cancer, gastric cancer, adrenal cancer, cervical chorionic epithelial cancer, nasopharyngeal cancer, thyroid cancer, pelvic cancer And colorectal cancer.
  • the brain metastatic tumor is a lung metastatic brain tumor. In some embodiments, the brain metastatic tumor is a non-small cell lung cancer metastatic brain tumor. In some embodiments, the brain metastatic tumor is a small cell lung cancer metastatic brain tumor.
  • the invention also provides a pharmaceutical composition formulated for brain metastatic tumors in a unit dosage form, comprising Compound I or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
  • the present invention also provides a pharmaceutical composition formulated in a unit dose form of a lung metastatic brain tumor, comprising Compound I or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
  • the chemotherapy drugs include first-line chemotherapy drugs and second-line chemotherapy drugs.
  • first-line chemotherapy drugs including but not limited to one or more of podophyllum, alkylating agents, camptothecin, taxanes, antimetabolites, antibiotics and antitumor drugs; examples can be enumerated Including but not limited to temozolomide, pemetrexed, cisplatin, etoposide, carboplatin, nedaplatin, oxaliplatin, mitoplatin, loplatin, irinotecan, topotecan, paclitaxel, docetaxel , Temozolomide, vinorelbine, gemcitabine, cyclophosphamide, doxorubicin, vincristine, bendamustine, epirubicin, methotrexate, amrubicin.
  • podophyllum including but not limited to one or more of podophyllum, alkylating agents, camptothecin, taxanes, anti
  • the above-mentioned pharmaceutical composition is administered in a spaced manner.
  • the interval administration includes an administration period and a withdrawal period, and the above-mentioned pharmaceutical composition can be administered once or multiple times per day during the administration period.
  • the pharmaceutical composition is administered every day during the administration period, and then the administration period is stopped for a period of time, followed by the administration period, and then the administration period, which can be repeated multiple times.
  • the ratio in days between the administration period and the withdrawal period is 2: 0.5 to 5, preferably 2: 0.5 to 3, more preferably 2: 0.5 to 2, and even more preferably 2: 0.5 to 1.
  • the administration is discontinued for 2 weeks for 2 weeks.
  • the drug is administered once a day for 14 days and then discontinued for 14 days; then it is administered once a day for 14 days and then discontinued for 14 days.
  • the drug can be administered repeatedly at intervals of 2 weeks.
  • the administration is discontinued for 2 weeks for 1 week.
  • the drug is administered once a day for 14 days and then discontinued for 7 days; then it is administered once a day for 14 days and then discontinued for 7 days.
  • the drug can be administered repeatedly at intervals of 1 week.
  • the dosing is discontinued for 5 days for 2 days.
  • the drug is administered once a day for 5 days, and then the drug is discontinued for 2 days; then the drug is administered once a day, for 5 days, and then discontinued for 2 days.
  • the two-day interval administration can be repeated several times.
  • the drug is administered orally at a dose of 12 mg once a day for 2 weeks and then stopped for 1 week.
  • the drug is administered orally at a dose of 10 mg once a day for two consecutive weeks and one week off.
  • the drug is administered orally at a dose of 8 mg once a day for 2 weeks and then stopped for 1 week.
  • Compound I or a pharmaceutically acceptable salt thereof is administered alone as the sole active ingredient to a patient with a brain metastatic tumor. In some embodiments, Compound I or a pharmaceutically acceptable salt thereof is administered to a brain metastatic tumor patient simultaneously or sequentially with other antitumor drugs.
  • other antitumor drugs include, but are not limited to, antifolate antitumor drugs, podophyllum anticancer drugs, hormone antitumor drugs, alkylating agent antitumor drugs, camptothecin antitumor drugs, One or more of a fluoropyrimidine derivative, an anthracycline, a taxane, an EGFR inhibitor, a VEGFR inhibitor, mitomycin, and trastuzumab.
  • the present invention provides a kit comprising (a) a pharmaceutical composition of at least one unit dose of Compound I or a pharmaceutically acceptable salt thereof, and (b) instructions for treating a brain tumor.
  • kits comprising (a) at least one unit dose of a suitable formulation for oral administration of Compound I or a pharmaceutically acceptable salt thereof, and (b) an interval administration for treating brain Instructions for tumors.
  • a kit is provided that comprises (a) at least one unit dose of a tablet or capsule of Compound I or a pharmaceutically acceptable salt thereof and (b) is administered at intervals Instructions for treating brain tumors.
  • the brain tumor is a brain tumor that fails treatment with a chemotherapeutic drug and / or a targeted drug.
  • the brain tumor is a primary brain tumor.
  • the brain tumor is a brain metastatic tumor.
  • brain metastatic tumors include, but are not limited to, parenchymal metastases and meningeal metastases.
  • brain metastatic tumors include, but are not limited to, metastatic tumors in patients caused by failure of treatment with chemotherapeutic drugs and / or targeted drugs.
  • the primary cancer of a brain metastatic tumor includes, but is not limited to, lung cancer, melanoma, breast cancer, kidney cancer, gastric cancer, adrenal cancer, cervical chorionic epithelial cancer, nasopharyngeal cancer, thyroid cancer, pelvic cancer And colorectal cancer.
  • the brain metastatic tumor is a lung metastatic brain tumor. In some embodiments, the brain metastatic tumor is a non-small cell lung cancer metastatic brain tumor. In some embodiments, the brain metastatic tumor is a small cell lung cancer metastatic brain tumor.
  • the invention also provides a kit comprising (a) a pharmaceutical composition of at least one unit dose of Compound I or a pharmaceutically acceptable salt thereof and (b) instructions for treating a brain metastatic tumor.
  • the invention also provides a kit comprising (a) a pharmaceutical composition of at least one unit dose of Compound I or a pharmaceutically acceptable salt thereof and (b) instructions for treating a lung metastatic brain tumor.
  • radiotherapy and chemotherapy can also be received in an alternating, sequential or synchronous manner.
  • unit dose or unit dose refers to a pharmaceutical composition, such as each tablet or capsule, packaged in a single package for convenience.
  • a pharmaceutical composition in a unit dosage form means each tablet or capsule.
  • the crystalline form of the hydrochloride salt of the compound I includes, but is not limited to, A, B and C type crystals disclosed in Chinese patent application CN102344438A, wherein the A and B type crystals are substantially free of crystal water and other solvents. Crystals, C-type crystals are crystals containing two crystal waters. In some embodiments, the crystalline form of the dihydrochloride salt of Compound I is Form A crystal.
  • Patient means a mammal, preferably a human.
  • “Pharmaceutically acceptable” means its use in the preparation of a pharmaceutical composition that is generally safe, non-toxic and neither biologically or otherwise undesirable, and includes that it is acceptable for human pharmaceutical use Accepted.
  • “Pharmaceutically acceptable salts” include, but are not limited to, acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with organic acids such as acetic acid, trifluoroacetic acid, and propionic acid , Hexanoic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvate, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, Mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-chlorobenzenesulfonic acid, p-toluenesulfonic acid,
  • terapéuticaally effective amount is meant an amount of a compound that, when administered to a human for treating a disease, is sufficient to effect treatment of the disease.
  • Treatment means any administration of a therapeutically effective amount of a compound, and includes:
  • “Failure to treat” refers to intolerable toxic or side effects, disease progression during treatment, or relapse after treatment is completed.
  • Extensive phase according to the 1973 US Army Veterans Hospital Lung Cancer Research Group's staging criteria, is defined as: lesions on more than one side of the thoracic cavity and including malignant and effusion or blood metastases.
  • EGFR inhibitor refers to an epidermal growth factor receptor inhibitor.
  • VEGFR inhibitor refers to a vascular endothelial growth factor receptor inhibitor.
  • CR means complete remission, specifically the disappearance of a target lesion of a tumor.
  • PR means partial remission, the sum of the diameters of the target lesions is reduced by at least 30% from the baseline level.
  • PD refers to disease progression, taking the minimum value of the sum of the diameters of all target lesions measured throughout the study as a reference, with a relative increase in diameter of at least 20% (if the baseline measurement is the smallest, the baseline value is used as a reference); and The relative value of the sum of the diameters must be increased by at least 5mm, and the occurrence of one or more new lesions is also considered to be disease progression.
  • SD refers to stable disease, specifically, the extent to which the tumor target lesion decreases does not reach the level of PR, and the degree of increase does not reach the level of PD, somewhere in between.
  • PFS progression-free survival, defined as the time from randomization to objective tumor progression or death.
  • DCR refers to the rate of disease control, including complete remission, partial remission, and stable disease, and the percentage of patients who have maintained disease for more than 4 weeks among evaluable patients.
  • OS overall survival refers to the time from enrollment to death for any reason. In terms of days, lost follow-up subjects usually calculated the last follow-up time as death.
  • FES refers to the full analysis data set. According to the intention to analyze (ITT) principle, the efficacy analysis is performed on all cases where the drug is used at least once.
  • RECIST 1.1 refers to the standard 1.1 for evaluating the efficacy of solid tumors.
  • Example 24 in WO2008112407 1-[[[[4- (4-fluoro-2-methyl-1H-indol-5-yl) oxy-6-methoxyquinolin-7-yl was prepared. [Oxy] methyl] cyclopropylamine, and then referring to the preparation method of "Example of Salt Form" in the specification of WO2008112407, the title compound was prepared. Or it can be prepared by referring to the method disclosed in Chinese patent application CN102344438A.
  • Capsules of dihydrochloride of compound I with other contents can be prepared by referring to the above manner in corresponding proportions and prescriptions.
  • Phase A 0.1% formic acid aqueous solution
  • Phase B 0.1% formic acid in methanol
  • a multicenter, randomized, double-blind, placebo-controlled phase II clinical study was performed in patients with measurable lesions who had previously received standard treatment and relapsed.
  • 120 patients were enrolled and randomized to receive 12 mg / 0 mg of the compound I dihydrochloride capsule once a day.
  • Oral administration was discontinued for 2 weeks for 1 week, that is, 3 weeks (21 days) was a treatment cycle.
  • These patients were aged 18-75 years old, using the dihydrochloride capsules of Compound I and placebo, and had previously used other targeted drugs (such as sunitin, bevacizumab, endo), etc. Patients targeted were excluded.
  • Efficacy evaluation criteria are determined to be disease progression (PD) or clinically considered disease progression, use of other anti-tumor drug treatments (such as chemotherapy, targeted therapy or biologic therapy), accidental pregnancy, death, etc.
  • the test was discontinued (finally).
  • Patients with disease control (CR + PR + SD) who can tolerate adverse reactions continue to take the drug.
  • the investigator believes that the patient is not suitable for continued medication or is evaluated as PD according to the RECIST 1.1 criteria, the medication is terminated.
  • the investigator decides whether to adjust the dose, and the adjustable dose is 8mg / 0mg or 10mg / 0mg.
  • the efficacy of patients with brain metastases was evaluated for data analysis.
  • the primary efficacy indicators were progression-free survival (PFS), and the secondary efficacy indicators were overall survival (OS), objective response rate (ORR) (CR + PR), and disease control rate (DCR) (CR + PR + SD). ), Quality of life score, safety.
  • Objective efficacy indicators were evaluated according to the efficacy evaluation criteria for solid tumors (RECIST 1.1).
  • the product limit method was used, and 50% (median) PFS and PFS at different times after the start of treatment were calculated according to the actual situation of the data, and Log-Rank test was used to compare the two groups.
  • the product limit method was used for OS, and 50% (median) OS was calculated according to the actual situation of the data, and Log-Rank test was used to compare the two groups.
  • the statistical data set uses a Full Analysis Data Set (FAS). The research results are summarized in Tables 2 and 3 below.
  • IP regimen 120 mg of irinotecan, d1 of 80 mg, d8; cisplatin 100 mg of d1
  • CT showed stable intrapulmonary and craniocerebral lesions, increased intrahepatic metastases, and the effect was evaluated as PD
  • target lesions 64mm
  • non Target lesion Multiple metastatic tumors in the brain.
  • target lesions 63mm; non-target lesions: non-CR / non-PD.
  • target lesions 65mm; non-target lesions: non-CR / non-PD.
  • target lesions 66mm; non-target lesions: non-CR / non-PD.
  • target lesions 72mm; non-target lesions: non-CR / non-PD.

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Abstract

一种用于治疗脑肿瘤的喹啉衍生物，所述化合物I或其药学上可接受的盐，可用于治疗脑转移性肿瘤，尤其是对于肺转移脑肿瘤患者疗效非常显著。

Description

用于治疗脑肿瘤的喹啉衍生物 技术领域
本发明属于医药领域，具体而言，本发明涉及喹啉衍生物在治疗脑肿瘤中的用途。
背景技术
成年人脑是容易被肿瘤细胞转移的部位。脑肿瘤分为两种，分别为原发性脑肿瘤和脑转移性肿瘤，原发性脑肿瘤即为脑瘤原发病灶就出现在脑部。脑转移性肿瘤比原发性脑肿瘤多10倍，据估计有20％～40％的癌症病人有颅内转移。脑转移性肿瘤包括脑实质转移(brain metastasis,BM)和脑膜转移(leptomeningeal metastasis,LM)。脑实质转移瘤最常见的发生部位为大脑半球，其次为小脑和脑干。脑膜转移较脑实质转移少见，但预后更差。脑转移性肿瘤由于来源不同，程度不一，转移部位各异，所以症状和治疗也有很大的不同。治疗原则要根据具体情况决定，发展慢且局限的转移灶治疗以局部为主，采用手术或放射治疗，辅以全身化疗，广泛的转移则相反。
近年来，随着肺癌发病率上升，诊疗技术不断发展，使患者生存期延长，肺癌脑转移的发生和诊断率也逐年升高。肺癌脑转移发生率明显高于黑色素瘤、乳腺癌、肾癌及结直肠癌。20％-65％的肺癌患者在病程中会发生脑转移，是脑转移性肿瘤中最常见的类型。肺癌脑转移患者预后差，自然平均生存时间仅1-2个月。
美国医疗保险监督、流行病学和最终结果(Surveillance,Epidemiology,and End Results,SEER)数据库的一项长期随访结果显示，在非转移性非小细胞肺癌(non-small cell lung cancer,NSCLC)中，肺腺癌、鳞癌及大细胞癌发生脑转移的风险分别为11％、6％及12％。小细胞肺癌(small cell lung cancer,SCLC)首次就诊时脑转移发生率为10％，诊疗过程中为40％-50％，存活2年以上的患者脑转移达60％-80％，是影响SCLC患者生存及生活质量的重要因素之一。
脑转移性肿瘤的治疗，往往由于药物不能有效透过血脑屏障而效果变差，一旦患者出现脑转移往往病情进展很快。目前针对脑转移性肿瘤的治疗手段有限。迅速诊断和合适的治疗对脑转移的病人十分重要，因为神经损伤对其生活质量影响极大，而任何延迟或错误的治疗将会给病人带来严重的后遗症。约53％的脑转移病人有多个病灶，适合放疗及化疗。因此亟需寻求新的化学治疗方法治疗脑转移性肿瘤，以期控制患者多个病灶的进展情况。
发明内容
第一方面，本发明提供了一种治疗脑肿瘤的方法，所述方法包括给予需要治疗的患者治疗有效量的化合物I或其药学上可接受的盐。
化合物I的化学名为1-[[[4-(4-氟-2-甲基-1H-吲哚-5-基)氧基-6-甲氧基喹啉-7-基]氧基]甲基]环丙胺，其具有如下的结构式：
Figure PCTCN2019106379-appb-000001
在一些实施方案中，所述的脑肿瘤为原发性脑肿瘤。在一些实施方案中，所述的脑肿瘤为脑转移性肿瘤。在一些实施方案中，脑转移性肿瘤包括但不限于脑实质转移和脑膜转移肿瘤。在一些实施方案中，脑转移性肿瘤包括但不限于由化疗药物和/或靶向药物治疗失败引起患者脑转移性肿瘤。在一些实施方案中，脑转移性肿瘤的原发癌包括但不限于肺癌、黑色素瘤、乳腺癌、肾癌、胃癌、肾上腺癌、宫颈绒毛膜上皮癌、鼻咽癌、甲状腺癌、骨盆腔癌及结直肠癌。在一些实施方案中，脑转移性肿瘤为肺转移脑肿瘤。在一些实施方案中，脑转移性肿瘤为非小细胞肺癌转移性脑肿瘤。在一些实施方案中，脑转移性肿瘤为小细胞肺癌转移性脑肿瘤。
本发明还提供了一种治疗脑转移性肿瘤的方法，所述方法包括给予需要治疗的患者治疗有效量的化合物I或其药学上可接受的盐。本发明还提供了一种治疗肺转移脑肿瘤的方法，所述方法包括给予需要治疗的患者治疗有效量的化合物I或其药学上可接受的盐。
在一些典型的实施方案中，所述的化疗药物包括一线化疗药物和二线化疗药物。一些典型的实施方案中，包括但不限于鬼臼类、烷化剂类、喜树碱类、紫杉类、抗代谢类、抗生素类抗肿瘤药物中的一种或多种；可以列举的实例包括但不限于替莫唑胺、培美曲塞、顺铂、依托泊苷、卡铂、奈达铂、奥沙利铂、米铂、洛铂、伊立替康、拓扑替康、紫杉醇、多西他赛、替莫唑胺、长春瑞滨、吉西他滨、环磷酰胺、阿霉素、长春新碱、苯达莫司汀、表阿霉素、甲氨蝶呤、氨柔比星中的一种或多种。本领域技术人员可以理解的是，与所述的化疗同时或者先后，患者也可以接受放疗。
化合物I可以以它的游离碱形式给药，也可以以其盐、水合物和前药的形式给药，该前药在体内转换成化合物I的游离碱形式。例如，化合物I的药学上可接受的盐在本发明的范围内，可按照本领域公知的方法由不同的有机酸和无机酸产生所述盐。
在一些实施方案中，以化合物I盐酸盐的形式给药。在一些实施方案中，以化合物I一盐酸盐的形式给药。在一些实施方案中，以化合物I二盐酸盐的形式给药。在一些实施方案 中，以化合物I盐酸盐的晶体形式给药。在特定的实施方案中，以化合物I二盐酸盐的晶体形式给药。
化合物I或其药学上可接受的盐可通过多种途径给药，该途径包括但不限于选自以下的途径：口服、肠胃外、腹膜内、静脉内、动脉内、透皮、舌下、肌内、直肠、透颊、鼻内、经吸入、阴道、眼内、经局部给药、皮下、脂肪内、关节内、腹膜内和鞘内。在一些特定的实施方案中，通过口服给药。
给予化合物I或其药学上可接受的盐的量可根据疾病的严重程度、疾病的响应、任何治疗相关的毒性、患者的年龄和健康状态来确定。在一些实施方案中，给予化合物I或其药学上可接受的盐的日剂量为2毫克至30毫克。在一些实施方案中，给予化合物I或其药学上可接受的盐的日剂量为6毫克至20毫克。在一些实施方案中，给予化合物I或其药学上可接受的盐的日剂量为8毫克至20毫克。在一些实施方案中，给予化合物I或其药学上可接受的盐的日剂量为10毫克至16毫克。在一些实施方案中，给予化合物I或其药学上可接受的盐的日剂量为10毫克至14毫克。在一些特定的实施方案中，给予化合物I或其药学上可接受的盐的日剂量为8毫克。在一些特定的实施方案中，给予化合物I或其药学上可接受的盐的日剂量为10毫克。在一些特定的实施方案中，给予化合物I或其药学上可接受的盐的日剂量为12毫克。在一些特定的实施方案中，给予化合物I或其药学上可接受的盐的日剂量为14毫克。
化合物I或其药学上可接受的盐可以每日施用一次或多次。在一些实施方案中，每天一次给予化合物I或其药学上可接受的盐。在一些实施方案中，以口服固体制剂每天给药一次。
给药的方法可根据药物的活性、毒性以及患者的耐受性等来综合确定。优选地，以间隔给药的方式给予化合物I或其药学上可接受的盐。所述的间隔给药包括给药期和停药期，在给药期内可以每天一次或多次给予化合物I或其药学上可接受的盐。例如在给药期内每天给予化合物I或其药学上可接受的盐，然后停药期内停止给药一段时间，接着给药期，然后停药期，如此可以反复进行多次。其中，给药期和停药期的以天数计的比值为2:0.5～5，优选2:0.5～3，较优选2:0.5～2，更优选2:0.5～1。
在一些实施方案中，连续给药2周停药2周。在一些实施方案中，每天给药1次，持续给药14天，然后停药14天；接着每天给药1次，持续给药14天，然后停药14天，如此连续给药2周停药2周的间隔给药方式可以反复进行多次。
在一些实施方案中，连续给药2周停药1周。在一些实施方案中，每天给药1次，持续给药14天，然后停药7天；接着每天给药1次，持续给药14天，然后停药7天，如此连续给药2周停药1周的间隔给药方式可以反复进行多次。
在一些实施方案中，连续给药5天停药2天。在一些实施方案中，每天给药1次，持续 给药5天，然后停药2天；接着每天给药1次，持续给药5天，然后停药2天，如此连续给药5天停药2天的间隔给药方式可以反复进行多次。
在某些特定的实施方案中，以每日一次12mg的剂量口服给药，连续用药2周，停1周的给药方式给药。
在某些特定的实施方案中，以每日一次10mg的剂量口服给药，连续用药2周，停1周的给药方式给药。
在某些特定的实施方案中，以每日一次8mg的剂量口服给药，连续用药2周，停1周的给药方式给药。
在一些实施方案中，化合物I或其药学上可接受的盐是作为唯一的活性成分单独给予脑转移性肿瘤患者。在一些实施方案中，化合物I或其药学上可接受的盐与其他抗肿瘤药物同时或依照次序给予脑转移性肿瘤患者。在一些实施方案中，其他抗肿瘤药物包括但不限于抗叶酸类抗肿瘤药物、鬼臼类抗癌药物、激素类抗肿瘤药物、烷化剂类抗肿瘤药物、喜树碱类抗肿瘤药、氟嘧啶衍生物、蒽环类药物、紫杉烷类化合物、EGFR抑制剂、VEGFR抑制剂、丝裂霉素、曲妥珠单抗中的一种或几种。
第二方面，本发明提供了化合物I或其药学上可接受的盐在制备用于治疗脑肿瘤的药物中的用途。
在一些实施方案中，所述的脑肿瘤为原发性脑肿瘤。在一些实施方案中，所述的脑肿瘤为脑转移性肿瘤。在一些实施方案中，脑转移性肿瘤包括但不限于脑实质转移和脑膜转移肿瘤。在一些实施方案中，脑转移性肿瘤包括但不限于由化疗药物和/或靶向药物治疗失败引起患者脑转移性肿瘤。在一些实施方案中，脑转移性肿瘤的原发癌包括但不限于肺癌、黑色素瘤、乳腺癌、肾癌、胃癌、肾上腺癌、宫颈绒毛膜上皮癌、鼻咽癌、甲状腺癌、骨盆腔癌及结直肠癌。在一些实施方案中，脑转移性肿瘤为肺转移脑肿瘤。在一些实施方案中，脑转移性肿瘤为非小细胞肺癌转移性脑肿瘤。在一些实施方案中，脑转移性肿瘤为小细胞肺癌转移性脑肿瘤。
本发明还提供了化合物I或其药学上可接受的盐在制备用于治疗脑转移性肿瘤的药物中的用途。本发明还提供了化合物I或其药学上可接受的盐在制备用于治疗肺转移脑肿瘤的药物中的用途。
在一些典型的实施方案中，所述的化疗药物包括一线化疗药物和二线化疗药物。一些典型的实施方案中，包括但不限于鬼臼类、烷化剂类、喜树碱类、紫杉类、抗代谢类、抗生素类抗肿瘤药物中的一种或多种；可以列举的实例包括但不限于替莫唑胺、培美曲塞、顺铂、依托泊苷、卡铂、奈达铂、奥沙利铂、米铂、洛铂、伊立替康、拓扑替康、紫杉醇、多西他 赛、替莫唑胺、长春瑞滨、吉西他滨、环磷酰胺、阿霉素、长春新碱、苯达莫司汀、表阿霉素、甲氨蝶呤、氨柔比星中的一种或多种。本领域技术人员可以理解的是，与所述的化疗同时或者先后，患者也可以接受放疗。
化合物I可以是它的游离碱形式，也可以是其盐、水合物和前药的形式，该前药在体内转换成化合物I的游离碱形式。例如，化合物I药学上可接受的盐在本发明的范围内，可按照本领域公知的方法由不同的有机酸和无机酸产生盐。
在一些实施方案中，化合物I或其药学上可接受的盐为化合物I的盐酸盐形式。在一些实施方案中，为化合物I一盐酸盐的形式。在一些实施方案中，为化合物I二盐酸盐的形式。在一些实施方案中，为化合物I盐酸盐的晶体形式。在特定的实施方案中，为化合物I二盐酸盐的晶体形式。
化合物I或其药学上可接受的盐可通过多种途径给药，该途径包括但不限于选自以下的途径：口服、肠胃外、腹膜内、静脉内、动脉内、透皮、舌下、肌内、直肠、透颊、鼻内、经吸入、阴道、眼内、经局部给药、皮下、脂肪内、关节内、腹膜内和鞘内。在一些特定的实施方案中，通过口服给药。
化合物I或其药学上可接受的盐的量可根据疾病的严重程度、疾病的响应、任何治疗相关的毒性、患者的年龄和健康状态来确定。在一些实施方案中，给予化合物I或其药学上可接受的盐的日剂量为2毫克至30毫克。在一些实施方案中，给予化合物I或其药学上可接受的盐的日剂量为6毫克至20毫克。在一些实施方案中，化合物I或其药学上可接受的盐的日剂量为8毫克至20毫克。在一些实施方案中，化合物I或其药学上可接受的盐的日剂量为10毫克至16毫克。在一些实施方案中，化合物I或其药学上可接受的盐的日剂量为10毫克至14毫克。在一些特定的实施方案中，化合物I或其药学上可接受的盐的日剂量为8毫克。在一些特定的实施方案中，化合物I或其药学上可接受的盐的日剂量为10毫克。在一些特定的实施方案中，化合物I或其药学上可接受的盐的日剂量为12毫克。在一些特定的实施方案中，化合物I或其药学上可接受的盐的日剂量为14毫克。
化合物I或其药学上可接受的盐可以每日施用一次或多次。在一些实施方案中，每天一次给予化合物I或其药学上可接受的盐。在一些实施方案中，以口服固体制剂每天给药一次。
给药的方法可根据药物的活性、毒性以及患者的耐受性等来综合确定。优选地，以间隔给药的方式给予化合物I或其药学上可接受的盐。所述的间隔给药包括给药期和停药期，在给药期内可以每天一次或多次给予化合物I或其药学上可接受的盐。例如在给药期内每天给予化合物I或其药学上可接受的盐，然后停药期内停止给药一段时间，接着给药期，然后停药期，如此可以反复进行多次。其中，给药期和停药期的以天数计的比值为2:0.5～5，优选 2:0.5～3，较优选2:0.5～2，更优选2:0.5～1。
在一些实施方案中，连续给药2周停药2周。在一些实施方案中，每天给药1次，持续给药14天，然后停药14天；接着每天给药1次，持续给药14天，然后停药14天，如此连续给药2周停药2周的间隔给药方式可以反复进行多次。
在一些实施方案中，连续给药2周停药1周。在一些实施方案中，每天给药1次，持续给药14天，然后停药7天；接着每天给药1次，持续给药14天，然后停药7天，如此连续给药2周停药1周的间隔给药方式可以反复进行多次。
在一些实施方案中，连续给药5天停药2天。在一些实施方案中，每天给药1次，持续给药5天，然后停药2天；接着每天给药1次，持续给药5天，然后停药2天，如此连续给药5天停药2天的间隔给药方式可以反复进行多次。
在某些特定的实施方案中，以每日一次12mg的剂量口服给药，连续用药2周，停1周的给药方式给药。
在某些特定的实施方案中，以每日一次10mg的剂量口服给药，连续用药2周，停1周的给药方式给药。
在某些特定的实施方案中，以每日一次8mg的剂量口服给药，连续用药2周，停1周的给药方式给药。
在一些实施方案中，化合物I或其药学上可接受的盐是作为唯一的活性成分单独给予脑转移性肿瘤患者。在一些实施方案中，化合物I或其药学上可接受的盐与其他抗肿瘤药物同时或依照次序给予脑转移性肿瘤患者。在一些实施方案中，其他抗肿瘤药物包括但不限于抗叶酸类抗肿瘤药物、鬼臼类抗癌药物、激素类抗肿瘤药物、烷化剂类抗肿瘤药物、喜树碱类抗肿瘤药、氟嘧啶衍生物、蒽环类药物、紫杉烷类化合物、EGFR抑制剂、VEGFR抑制剂、丝裂霉素、曲妥珠单抗中的一种或几种。
第三方面，本发明提供了一种治疗脑肿瘤的药物组合物，其包含化合物I或其药学上可接受的盐，以及至少一种药学上可接受的载体。
在一些实施方案中，所述的脑肿瘤为原发性脑肿瘤。在一些实施方案中，所述的脑肿瘤为脑转移性肿瘤。在一些实施方案中，脑转移性肿瘤包括但不限于脑实质转移和脑膜转移肿瘤。在一些实施方案中，脑转移性肿瘤包括但不限于由化疗药物和/或靶向药物治疗失败引起患者脑转移性肿瘤。在一些实施方案中，脑转移性肿瘤的原发癌包括但不限于肺癌、黑色素瘤、乳腺癌、肾癌、胃癌、肾上腺癌、宫颈绒毛膜上皮癌、鼻咽癌、甲状腺癌、骨盆腔癌及结直肠癌。在一些实施方案中，脑转移性肿瘤为肺转移脑肿瘤。在一些实施方案中，脑转移性肿瘤为非小细胞肺癌转移性脑肿瘤。在一些实施方案中，脑转移性肿瘤为小细胞肺癌转移 性脑肿瘤。
本发明还提供了一种治疗脑转移性肿瘤的药物组合物，其包含化合物I或其药学上可接受的盐，以及至少一种药学上可接受的载体。本发明还提供了一种治疗肺转移脑肿瘤的药物组合物，其包含化合物I或其药学上可接受的盐，以及至少一种药学上可接受的载体。
在一些典型的实施方案中，所述的化疗药物包括一线化疗药物和二线化疗药物。一些典型的实施方案中，包括但不限于鬼臼类、烷化剂类、喜树碱类、紫杉类、抗代谢类、抗生素类抗肿瘤药物中的一种或多种；可以列举的实例包括但不限于替莫唑胺、培美曲塞、顺铂、依托泊苷、卡铂、奈达铂、奥沙利铂、米铂、洛铂、伊立替康、拓扑替康、紫杉醇、多西他赛、替莫唑胺、长春瑞滨、吉西他滨、环磷酰胺、阿霉素、长春新碱、苯达莫司汀、表阿霉素、甲氨蝶呤、氨柔比星中的一种或多种。本领域技术人员可以理解的是，与所述的化疗同时或者先后，患者也可以接受放疗。
化合物I可以是它的游离碱形式，也可以是盐、水合物和前药的形式，该前药在体内转换成化合物I的游离碱形式。例如，化合物I药学上可接受的盐在本发明的范围内，可按照本领域公知的方法由不同的有机酸和无机酸产生盐。
在一些实施方案中，化合物I或其药学上可接受的盐为化合物I的盐酸盐形式。在一些实施方案中，为化合物I一盐酸盐的形式。在一些实施方案中，为化合物I二盐酸盐的形式。在一些实施方案中，为化合物I盐酸盐的晶体形式。在特定的实施方案中，为化合物I二盐酸盐的晶体形式。
在一些实施方案中，所述的药物组合物可以是适于口服、肠胃外、腹膜内、静脉内、动脉内、透皮、舌下、肌内、直肠、透颊、鼻内、经吸入、阴道、眼内、经局部给药、皮下、脂肪内、关节内、腹膜内和鞘内给药的制剂。
在一些实施方案中，所述的药物组合物的给药量可根据疾病的严重程度、疾病的响应、任何治疗相关的毒性、患者的年龄和健康状态来确定。在一些实施方案中，给予化合物I或其药学上可接受的盐的日剂量为2毫克至30毫克。在一些实施方案中，给予化合物I或其药学上可接受的盐的日剂量为6毫克至20毫克。在一些实施方案中，该药物组合物中化合物I或其药学上可接受的盐的日剂量为8毫克至20毫克。在一些实施方案中，化合物I或其药学上可接受的盐的日剂量为10毫克至16毫克。在一些实施方案中，化合物I或其药学上可接受的盐的日剂量为10毫克至14毫克。在一些特定的实施方案中，化合物I或其药学上可接受的盐的日剂量为8毫克。在一些特定的实施方案中，化合物I或其药学上可接受的盐的日剂量为10毫克。在一些特定的实施方案中，化合物I或其药学上可接受的盐的日剂量为12 毫克。在一些特定的实施方案中，化合物I或其药学上可接受的盐的日剂量为14毫克。
在本发明的一些实施方案中，所述的药物组合物是适于口服的制剂，包括片剂、胶囊剂、粉剂、颗粒剂、滴丸、糊剂、散剂等，优选片剂和胶囊剂。其中片剂可以是普通片剂、分散片、泡腾片、缓释片、控释片或肠溶片，胶囊剂可以是普通胶囊、缓释胶囊、控释胶囊或肠溶胶囊。所述的口服制剂可使用本领域公知的药学上可接受的载体通过常规方法制得。药学上可接受的载体包括填充剂、吸收剂、润湿剂、粘合剂、崩解剂、润滑剂等。填充剂包括淀粉、乳糖、甘露醇、微晶纤维素等；吸收剂包括硫酸钙、磷酸氢钙、碳酸钙等；润湿剂包括水、乙醇等；粘合剂包括羟丙甲纤维素、聚维酮、微晶纤维素等；崩解剂包括交联羧甲基纤维素钠、交联聚维酮、表面活性剂、低取代羟丙基纤维素等；润滑剂包括硬脂酸镁、滑石粉、聚乙二醇、十二烷基硫酸钠、微粉硅胶、滑石粉等。药用辅料还包括着色剂、甜味剂等。
在一些实施方案中，该药物组合物是适于口服的固体制剂。该组合物例如可以是片剂或胶囊的形式。在一些特定的实施方案中，该药物组合物是胶囊。在本发明的一些特定实施方案中，口服固体制剂的药学上可接受的载体包括甘露醇、微晶纤维素、羟丙纤维素、硬脂酸镁。
化合物I或其药学上可接受的盐可以每日施用一次或多次。在一些实施方案中，每天一次给予化合物I或其药学上可接受的盐。在一些实施方案中，以口服固体制剂每天给药一次。
给药的方法可根据药物的活性、毒性以及患者的耐受性等来综合确定。优选地，以间隔给药的方式给予化合物I或其药学上可接受的盐。所述的间隔给药包括给药期和停药期，在给药期内可以每天一次或多次给予化合物I或其药学上可接受的盐。例如在给药期内每天给予化合物I或其药学上可接受的盐，然后停药期内停止给药一段时间，接着给药期，然后停药期，如此可以反复进行多次。其中，给药期和停药期的以天数计的比值为2:0.5～5，优选2:0.5～3，较优选2:0.5～2，更优选2:0.5～1。
在一些实施方案中，连续给药2周停药2周。在一些实施方案中，每天给药1次，持续给药14天，然后停药14天；接着每天给药1次，持续给药14天，然后停药14天，如此连续给药2周停药2周的间隔给药方式可以反复进行多次。
在一些实施方案中，连续给药2周停药1周。在一些实施方案中，每天给药1次，持续给药14天，然后停药7天；接着每天给药1次，持续给药14天，然后停药7天，如此连续给药2周停药1周的间隔给药方式可以反复进行多次。
在一些实施方案中，连续给药5天停药2天。在一些实施方案中，每天给药1次，持续给药5天，然后停药2天；接着每天给药1次，持续给药5天，然后停药2天，如此连续给药5天停药2天的间隔给药方式可以反复进行多次。
在某些特定的实施方案中，以每日一次12mg的剂量口服给药，连续用药2周，停1周的给药方式给药。
在某些特定的实施方案中，以每日一次10mg的剂量口服给药，连续用药2周，停1周的给药方式给药。
在某些特定的实施方案中，以每日一次8mg的剂量口服给药，连续用药2周，停1周的给药方式给药。
在一些实施方案中，提供了一种治疗脑肿瘤的配制成单位剂量形式的药物组合物。在一些实施方案中，该单位剂量形式的药物组合物含有2毫克至30毫克的化合物I或其药学上可接受的盐。在一些实施方案中，该单位剂量形式的药物组合物含有6毫克至20毫克的化合物I或其药学上可接受的盐。在一些实施方案中，该单位剂量形式的药物组合物含有8毫克至20毫克的化合物I或其药学上可接受的盐，优选10毫克至16毫克的化合物I或其药学上可接受的盐，较优选10毫克至14毫克的化合物I或其药学上可接受的盐。在一些特定的实施方案中，该单位剂量形式的药物组合物含有8毫克的化合物I或其药学上可接受的盐。在一些特定的实施方案中，该单位剂量形式的药物组合物含有10毫克的化合物I或其药学上可接受的盐。在一些特定的实施方案中，该单位剂量形式的药物组合物含有12毫克的化合物I或其药学上可接受的盐。在一些特定的实施方案中，该单位剂量形式的药物组合物含有14毫克的化合物I或其药学上可接受的盐。
在一些实施方案中，所述的脑肿瘤为原发性脑肿瘤。在一些实施方案中，所述的脑肿瘤为脑转移性肿瘤。在一些实施方案中，脑转移性肿瘤包括但不限于脑实质转移和脑膜转移肿瘤。在一些实施方案中，脑转移性肿瘤包括但不限于由化疗药物和/或靶向药物治疗失败引起患者脑转移性肿瘤。在一些实施方案中，脑转移性肿瘤的原发癌包括但不限于肺癌、黑色素瘤、乳腺癌、肾癌、胃癌、肾上腺癌、宫颈绒毛膜上皮癌、鼻咽癌、甲状腺癌、骨盆腔癌及结直肠癌。在一些实施方案中，脑转移性肿瘤为肺转移脑肿瘤。在一些实施方案中，脑转移性肿瘤为非小细胞肺癌转移性脑肿瘤。在一些实施方案中，脑转移性肿瘤为小细胞肺癌转移性脑肿瘤。
本发明还提供了一种脑转移性肿瘤的配制成单位剂量形式的药物组合物，其包含化合物I或其药学上可接受的盐，以及至少一种药学上可接受的载体。本发明还提供了一种肺转移脑肿瘤的配制成单位剂量形式的药物组合物，其包含化合物I或其药学上可接受的盐，以及至少一种药学上可接受的载体。
在一些典型的实施方案中，所述的化疗药物包括一线化疗药物和二线化疗药物。一些典型的实施方案中，包括但不限于鬼臼类、烷化剂类、喜树碱类、紫杉类、抗代谢类、抗生素 类抗肿瘤药物中的一种或多种；可以列举的实例包括但不限于替莫唑胺、培美曲塞、顺铂、依托泊苷、卡铂、奈达铂、奥沙利铂、米铂、洛铂、伊立替康、拓扑替康、紫杉醇、多西他赛、替莫唑胺、长春瑞滨、吉西他滨、环磷酰胺、阿霉素、长春新碱、苯达莫司汀、表阿霉素、甲氨蝶呤、氨柔比星中的一种或多种。本领域技术人员可以理解的是，与所述的化疗同时或者先后，患者也可以接受放疗。
优选地，以间隔给药的方式给予上述药物组合物。所述的间隔给药包括给药期和停药期，在给药期内可以每天一次或多次给予上述药物组合物。例如在给药期内每天给予药物组合物，然后停药期内停止给药一段时间，接着给药期，然后停药期，如此可以反复进行多次。其中给药期和停药期的以天数计的比值为2:0.5～5，优选2:0.5～3，较优选2:0.5～2，更优选2:0.5～1。
在一些实施方案中，连续给药2周停药2周。在一些实施方案中，每天给药1次，持续给药14天，然后停药14天；接着每天给药1次，持续给药14天，然后停药14天，如此连续给药2周停药2周的间隔给药方式可以反复进行多次。
在一些实施方案中，连续给药2周停药1周。在一些实施方案中，每天给药1次，持续给药14天，然后停药7天；接着每天给药1次，持续给药14天，然后停药7天，如此连续给药2周停药1周的间隔给药方式可以反复进行多次。
在一些实施方案中，连续给药5天停药2天。在一些实施方案中，每天给药1次，持续给药5天，然后停药2天；接着每天给药1次，持续给药5天，然后停药2天，如此连续给药5天停药2天的间隔给药方式可以反复进行多次。
在某些特定的实施方案中，以每日一次12mg的剂量口服给药，连续用药2周，停1周的给药方式给药。
在某些特定的实施方案中，以每日一次10mg的剂量口服给药，连续用药2周，停1周的给药方式给药。
在某些特定的实施方案中，以每日一次8mg的剂量口服给药，连续用药2周，停1周的给药方式给药。
在一些实施方案中，化合物I或其药学上可接受的盐是作为唯一的活性成分单独给予脑转移性肿瘤患者。在一些实施方案中，化合物I或其药学上可接受的盐与其他抗肿瘤药物同时或依照次序给予脑转移性肿瘤患者。在一些实施方案中，其他抗肿瘤药物包括但不限于抗叶酸类抗肿瘤药物、鬼臼类抗癌药物、激素类抗肿瘤药物、烷化剂类抗肿瘤药物、喜树碱类抗肿瘤药、氟嘧啶衍生物、蒽环类药物、紫杉烷类化合物、EGFR抑制剂、VEGFR抑制剂、丝裂霉素、曲妥珠单抗中的一种或几种。
第四方面，本发明提供了一种试剂盒，其包含(a)至少一个单位剂量的化合物I或其药学上可接受的盐的药物组合物和(b)用于治疗脑肿瘤的说明书。
本发明还提供了一种试剂盒，其包含(a)至少一个单位剂量的化合物I或其药学上可接受的盐的适于口服的制剂和(b)以间隔给药的方式用于治疗脑肿瘤的说明书。在一些特定的实施方案中，提供了一种试剂盒，其包含(a)至少一个单位剂量的化合物I或其药学上可接受的盐的片剂或胶囊和(b)以间隔给药的方式用于治疗脑肿瘤的说明书。在一些更为典型的实施方案中，所述脑肿瘤为化疗药物和/或靶向药物治疗失败的脑肿瘤。
在一些实施方案中，所述的脑肿瘤为原发性脑肿瘤。在一些实施方案中，所述的脑肿瘤为脑转移性肿瘤。在一些实施方案中，脑转移性肿瘤包括但不限于脑实质转移和脑膜转移肿瘤。在一些实施方案中，脑转移性肿瘤包括但不限于由化疗药物和/或靶向药物治疗失败引起患者脑转移性肿瘤。在一些实施方案中，脑转移性肿瘤的原发癌包括但不限于肺癌、黑色素瘤、乳腺癌、肾癌、胃癌、肾上腺癌、宫颈绒毛膜上皮癌、鼻咽癌、甲状腺癌、骨盆腔癌及结直肠癌。在一些实施方案中，脑转移性肿瘤为肺转移脑肿瘤。在一些实施方案中，脑转移性肿瘤为非小细胞肺癌转移性脑肿瘤。在一些实施方案中，脑转移性肿瘤为小细胞肺癌转移性脑肿瘤。
本发明还提供了一种试剂盒，其包含(a)至少一个单位剂量的化合物I或其药学上可接受的盐的药物组合物和(b)用于治疗脑转移性肿瘤的说明书。本发明还提供了一种试剂盒，其包含(a)至少一个单位剂量的化合物I或其药学上可接受的盐的药物组合物和(b)用于治疗肺转移脑肿瘤的说明书。
本文中，本领域技术人员可以理解的是，在给予需要治疗的患者治疗有效量的化合物I或其药学上可接受的盐期间，也可按照交替、序贯或者同步的方式接受放疗和化疗。
本文中，所述的“单位剂量(unit dosage或unit dose)”是指为了服用的方便，包装在单个包装中的药物组合物，例如每片片剂或者胶囊。例如，对于片剂或胶囊而言，“单位剂量形式的药物组合物”意味着每片片剂或每颗胶囊。
本文中，除非另有说明，这里提供的剂量和范围都是基于化合物I游离碱形式的分子量。
本文中，所述的化合物I的盐酸盐的晶体形式包括但不限于中国专利申请CN102344438A公开的A、B和C型结晶，其中A和B型结晶为基本上不含结晶水和其他溶剂的结晶，C型结晶为含两个结晶水的结晶。在一些实施方案中，所述的化合物I的二盐酸盐的晶体形式为A型结晶。
除非另有说明，为本申请的目的，本说明书和权利要求书中所用的下列术语应具有下述含义。
“患者”是指哺乳动物，优选人。
“药学上可接受的”是指其用于制备药物组合物，该药物组合物通常是安全、无毒的并且既不在生物学上或其它方面不合乎需要，并且包括其对于人类药物使用是可接受的。
“药学上可接受的盐”包括，但不限于与无机酸如盐酸、氢溴酸、硫酸、硝酸、磷酸等等形成的酸加成盐；或者与有机酸如乙酸、三氟乙酸、丙酸、己酸、庚酸、环戊烷丙酸、乙醇酸、丙酮酸、乳酸、丙二酸、琥珀酸、苹果酸、马来酸、富马酸、酒石酸、柠檬酸、苯甲酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、1,2-乙二磺酸、2-羟基乙磺酸、苯磺酸、对氯苯磺酸、对甲苯磺酸、3-苯基丙酸、三甲基乙酸、叔丁基乙酸、十二烷基硫酸、葡糖酸、谷氨酸、羟基萘甲酸、水杨酸、硬脂酸等形成的酸加成盐。
“治疗有效量”意指化合物被给予人用于治疗疾病时，足以实现对该疾病的治疗的量。
“治疗”意指治疗上有效量的化合物的任何施用，并且包括：
(1)抑制正经历或显示出所述疾病的病理学或症状学的人体中的该疾病(即，阻滞所述病理学和/或症状学的进一步发展)，或
(2)改善正经历或显示出所述疾病的病理学或症状学的人体中的该疾病(即逆转所述病理学和/或症状学)。
“治疗失败”是指毒副作用不可耐受、治疗过程中疾病进展或治疗结束后复发。
“局限期”，根据1973年美国退伍军人医院肺癌研究组VALG的分期标准，定义为：病变于一侧胸腔，且能被纳入个放射治疗野内。
“广泛期”，根据1973年美国退伍军人医院肺癌研究组VALG的分期标准，定义为：病变超过一侧胸腔，且包括恶性和心积液或血行转移。
“EGFR抑制剂”是指表皮生长因子受体抑制剂。
“VEGFR抑制剂”是指血管内皮生长因子受体抑制剂。
“CR”是指完全缓解，具体指肿瘤的靶病灶消失。
“PR”是指部分缓解，靶病灶直径之和比基线水平减少至少30％。
“PD”是指疾病进展，以整个研究过程中所有测得的靶病灶直径之和的最小值为参照，直径和相对增加至少20％(如果基线测量值最小就以基线值为参照)；且必须满足直径和的相对值增加至少5mm，若出现一个或多个新病灶也视为疾病进展。
“SD”是指疾病稳定，具体指肿瘤靶病灶减小的程度没达到PR水平，增加的程度也没达到PD水平，介于两者之间。
“PFS”是指无进展生存期，定义为从随机分组直至肿瘤客观进展或死亡的时间。
“DCR”是指疾病控制率，包括完全缓解、部分缓解和疾病稳定并维持4周以上病例 数在可评价疗效患者中的百分比。
“OS”总生存期，是指入组开始至因任何原因引起死亡的时间。以天数计，失访的受试者，通常将最后一次随访时间计算为死亡。
“FAS”是指全分析数据集，按照意向性分析(ITT)原则，对至少使用一次药物的全部病例进行疗效分析。
“RECIST1.1”是指实体瘤疗效评价标准1.1。
具体实施方式
下面结合具体实施例，进一步阐述本申请。应理解，这些实施例仅用于说明本申请而不用于限制本申请的保护范围。
实施例1 1-[[[4-(4-氟-2-甲基-1H-吲哚-5-基)氧基-6-甲氧基喹啉-7-基]氧基]甲基]环丙胺二盐酸盐(化合物I的二盐酸盐)
Figure PCTCN2019106379-appb-000002
参照WO2008112407中实施例24的方法制备得到1-[[[4-(4-氟-2-甲基-1H-吲哚-5-基)氧基-6-甲氧基喹啉-7-基]氧基]甲基]环丙胺，然后参照WO2008112407的说明书中“盐形式的实施例”的制备方法，制备得到标题化合物。或者参照中国专利申请CN102344438A中公开的方法制备得到。
实施例2 含有1-[[[4-(4-氟-2-甲基-1H-吲哚-5-基)氧基-6-甲氧基喹啉-7-基]氧基]甲基]环丙胺二盐酸盐(化合物I的二盐酸盐)的胶囊
Figure PCTCN2019106379-appb-000003
将化合物I的二盐酸盐粉碎，过80目筛；然后与甘露醇、羟丙纤维素混合均匀；接着加入处方量的微晶纤维素，混合均匀，过0.8mm筛网；最后加入处方量的硬脂酸镁混合均匀， 并填充胶囊。
对于化合物I的二盐酸盐为其它含量的胶囊，可参照上述方式以相应的比例和处方制备得到。
实施例3 肺癌脑转移透过性研究生物样本分析
取100μL肺癌脑转移患者脑脊液，加50μL内标([D5]-氘代式I化合物，结构如下所示)(10ng/mL)混匀，加入400μL甲醇，涡旋3min，4℃离心4000rpm*10min，取上清液150μL于新板中，加入100μL的流动相A，涡旋3min，LC-MS/MS系统进样分析。
Figure PCTCN2019106379-appb-000004
检测方法——LC-MS/MS法
液相条件：
A相：0.1％的甲酸水溶液
B相：0.1％的甲酸甲醇溶液
流速：0.3mL/min
柱温：40℃
色谱柱：Waters BEH C18 1.7μ50*2.1mm
Figure PCTCN2019106379-appb-000005
质谱条件：
离子化方式：(+)ESI
扫描模式：(MRM)母离子，碎片离子和碰撞能量(CE)：
化合物 母离子(m/z) 碎片离子(m/z) CE(eV)
式I化合物 408.0 339.1 30
[D5]-氘代式I化合物(IS) 413.4 344.2 30
测定结果：
表1肺癌脑转移患者脑脊液中药物浓度
序列号 测定浓度(ng/mL)
1 0.358
2 0.353
3 0.350
4 0.365
5 0.327
6 0.350
7 0.352
8 0.353
由上表1说明式I化合物能一定比例透过血脑屏障，在脑脊液中存在一定的浓度。
实施例4
在患有具有可测量病灶的、既往接受过标准治疗和复发的小细胞肺癌实施了一项多中心、随机双盲、与安慰剂对照的II期临床研究。在该研究中，120位患者入组，并随机接受每天一次，每次1粒口服12mg/0mg的化合物I的二盐酸盐胶囊的治疗。连续口服2周停药1周，即3周(21天)为1个治疗周期。这些患者的年龄在18-75岁之间，采用化合物I的二盐酸盐胶囊与安慰剂对照，既往使用过其他靶向药物(比如舒尼替、贝伐单抗、恩度)等、免疫靶向药物的患者排除在外。出现疗效评价标准确定为疾病进展(PD)或者临床上认为疾病进展、使用其它影响疗效判断的抗肿瘤药物治疗(如化疗、靶向治疗或生物制剂治疗)、意外妊娠、死亡等情况时，受试者中(终)止用药。疾病控制(CR+PR+SD)且不良反应可以耐受的患者，持续用药。当研究者认为患者不适合继续用药或按RECIST 1.1标准评价为PD，则用药结束。用药过程中，根据患者出现的物相关性毒性反应度和可能的疗效受益情况，由研究者决定是否进剂量调整，可调整的剂量为8mg/0mg或10mg/0mg。
在该研究中，对其中已发生脑转移的患者(共30例)的疗效评价，进行数据分析。主要疗效评价的指标为无进展生存期(PFS)，次要疗效指标为总生存期(OS)、客观缓解率(ORR)(CR+PR)、疾病控制率(DCR)(CR+PR+SD)、生活质量评分、安全性。客观疗效指标按实体瘤的疗效评价标准(RECIST 1.1)进行评价。
所有统计分析采用SAS 9.2统计分析软件编程计算。所有的统计学检验均采用双侧检验， P值≤0.05被认为所检验的差别有统计意义，可信区间采用95％的可信度。
对于主要疗效指标PFS，采用乘积限法，并根据资料的实际情况分别计算50％(中位)PFS及治疗开始后不同时间的PFS，并采用Log-Rank检验对两组进行比较。对OS采用乘积限法，并根据资料的实际情况分别计算50％(中位)的OS，并采用Log-Rank检验对两组进行比较。统计数据集采用全分析数据集(FAS)。研究结果总结如下表2、3中。
表2患者的无进展生存期(PFS，月)的分析
Figure PCTCN2019106379-appb-000006
表3患者的总生存期(OS，月)的分析
Figure PCTCN2019106379-appb-000007
实施例5
49岁女性，2013年10月，术后病理诊断为左肺下叶小细胞肺癌。2016年12月24日MRI显示双侧大脑半球、小脑半球及脑干多发转移瘤，肝多发异常信号结节，考虑转移瘤，提示病情进展。患者入院接受脂质体紫杉醇+卡铂+替莫唑胺化疗1周期，12月28日出院。2017年1月1月17日开始TC方案(紫杉醇+卡铂)化疗1周期，2017年2月10日，疗效评价PD。2017年2月16日进行IP方案(伊立替康120mg d1,80mg d8；顺铂100mg d1)化疗1周期。4月24日，CT提示肺内及颅脑病灶稳定，肝内转移瘤较前增大，疗效评估为PD；靶病灶(64mm)：肝左内叶结节和肝右后叶结节；非靶病灶：脑内多发转移瘤。
2017年5月12日，开始每日一次口服化合物I二盐酸的胶囊12mg治疗，连服2周停1周，每3周为一个给药周期，直至疾病进展或不能耐受。患者服药期间整体耐受性良好，可继续用药。
CT结果如下：
第1周期给药后：靶病灶：63mm；非靶病灶：非CR/非PD。
第2周期给药后：靶病灶：65mm；非靶病灶：非CR/非PD。
第4周期给药后：靶病灶：66mm；非靶病灶：非CR/非PD。
第6周期给药后：靶病灶：72mm；非靶病灶：非CR/非PD。

Claims (10)

  1. 化合物I或其药学上可接受的盐在制备用于治疗脑肿瘤的药物中的用途，
    Figure PCTCN2019106379-appb-100001
  2. 根据权利要求1所述的用途，其特征在于，所述脑肿瘤为脑转移性肿瘤。
  3. 根据权利要求2所述的用途，其特征在于，所述脑转移性肿瘤的原发癌为肺癌、黑色素瘤、乳腺癌、肾癌、胃癌、肾上腺癌、宫颈绒毛膜上皮癌、鼻咽癌、甲状腺癌、骨盆腔癌及结直肠癌。
  4. 根据权利要求1-3任一项所述的用途，其特征在于，所述脑肿瘤为肺转移脑肿瘤。
  5. 根据权利要求1-4任一项所述的用途，其特征在于，所述脑肿瘤为非小细胞肺癌转移性脑肿瘤和小细胞肺癌转移性脑肿瘤。
  6. 根据权利要求1-5任一项所述的用途，其特征在于，所述脑肿瘤为化疗药物和/或靶向药物治疗失败引起患者脑转移性肿瘤。
  7. 根据权利要求6所述的用途，其特征在于，所述化疗为替莫唑胺、培美曲塞、顺铂、依托泊苷、卡铂、奈达铂、奥沙利铂、米铂、洛铂、伊立替康、拓扑替康、紫杉醇、多西他赛、替莫唑胺、长春瑞滨、吉西他滨、环磷酰胺、阿霉素、长春新碱、苯达莫司汀、表阿霉素、甲氨蝶呤、氨柔比星中的一种或多种。
  8. 根据权利要求1-7任一项所述的用途，其特征在于，其药学上可接受的盐为化合物I与任意如下酸所形成的盐：盐酸、氢溴酸、硫酸、硝酸、磷酸、乙酸、三氟乙酸、丙酸、己酸、庚酸、环戊烷丙酸、乙醇酸、丙酮酸、乳酸、丙二酸、琥珀酸、苹果酸、马来酸、富马酸、酒石酸、柠檬酸、苯甲酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、1,2-乙二磺酸、2-羟基乙磺酸、苯磺酸、对氯苯磺酸、对甲苯磺酸、3-苯基丙酸、三甲基乙酸、叔丁基乙酸、十二烷基硫酸、葡糖酸、谷氨酸、羟基萘甲酸、水杨酸、硬脂酸；优选为盐酸盐或马来酸盐的形式，更优选为二盐酸盐。
  9. 根据权利要求1-8任一项所述的用途，其特征在于，给予所述化合物I或其药学上可接受的盐的日剂量为3毫克至30毫克，优选为5毫克至20毫克，更优选为8毫克至16毫克，进一步优选为8毫克至14毫克，最优选为8毫克、10毫克或12毫克。
  10. 根据权利要求1-9任一项所述的用途，其特征在于，所述化合物I或其药学上可接受的盐以给药期和停药期间隔的给药方式；优选的给药期和停药期以天数计的比值为2:0.5～5，更优选2:0.5～3，较优选2:0.5～2，进一步优选2:0.5～1；作为更进一步优选的间隔给药方式，为如下方式中的一种：连续给药2周停药2周、连续给药2周停药1周或连续给药5天停药2天。
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