WO2017177962A1 - 一种用于治疗胃癌的喹啉衍生物 - Google Patents

一种用于治疗胃癌的喹啉衍生物 Download PDF

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Publication number
WO2017177962A1
WO2017177962A1 PCT/CN2017/080563 CN2017080563W WO2017177962A1 WO 2017177962 A1 WO2017177962 A1 WO 2017177962A1 CN 2017080563 W CN2017080563 W CN 2017080563W WO 2017177962 A1 WO2017177962 A1 WO 2017177962A1
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Prior art keywords
compound
gastric cancer
adenocarcinoma
pharmaceutically acceptable
pharmaceutical composition
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PCT/CN2017/080563
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English (en)
French (fr)
Inventor
陈杰
韩溪
江海
王训强
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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 JP2018554049A priority Critical patent/JP2019513789A/ja
Priority to CN201780022398.0A priority patent/CN109069500B/zh
Priority to CN202211146699.3A priority patent/CN115624550B/zh
Priority to EP17781938.0A priority patent/EP3443962B1/en
Priority to CN202211146855.6A priority patent/CN115487187B/zh
Priority to US16/092,745 priority patent/US10736887B2/en
Publication of WO2017177962A1 publication Critical patent/WO2017177962A1/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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • the present application belongs to the field of medical technology, and the present application relates to the use of a quinoline derivative for the treatment of gastric cancer.
  • Gastric cancer originates from the most epithelial mucosal epithelial cells of the stomach wall and can occur in various parts of the stomach, such as the antrum of the stomach, the small curvature of the stomach and the anterior and posterior walls, the fundus and the sacral region, the corpus of the stomach, and the gastroesophageal junction.
  • Visual observation of gastric cancer by the naked eye or gastroscope has various forms, such as superficial type, mass type, ulcer type, infiltration type, and ulcerated cancer (for chronic gastric ulcer cancer).
  • the World Health Organization classifies gastric cancer into adenocarcinoma by histological classification (including papillary adenocarcinoma, tubular adenocarcinoma, mucinous adenocarcinoma, and signet ring cells).
  • Cancer also known as mucinous carcinoma
  • adenosquamous carcinoma adenosquamous carcinoma, squamous cell carcinoma, carcinoid, undifferentiated carcinoma, and unclassified carcinoma
  • adenocarcinoma including papillary adenocarcinoma, tubular adenocarcinoma, mucinous adenocarcinoma
  • signet ring cell carcinoma also known as mucinous carcinoma
  • undifferentiated carcinoma special type of cancer (including adenosquamous carcinoma, squamous cell carcinoma, carcinoid, unclassified cancer and mixed cancer); adenocarcinoma accounts for about 90%.
  • the application provides a method of treating gastric cancer, the method comprising administering to a patient in need of treatment a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof.
  • the application provides the use of Compound 1, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of gastric cancer.
  • the present application provides a Compound I or a pharmaceutical composition for treating gastric cancer, the pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
  • the present application provides a kit for treating gastric cancer, comprising: (a) at least one unit dose of a pharmaceutical composition of Compound I or a pharmaceutically acceptable salt thereof, and (b) instructions for treating gastric cancer .
  • the application provides a method of treating gastric cancer, the method comprising administering to a patient in need of treatment a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof.
  • the gastric cancer is advanced and/or metastatic gastric cancer; in some more typical embodiments, the gastric cancer is a taxane antineoplastic agent, a camptothecin antineoplastic agent, Doxorubicin antineoplastic agents, platinum complexes and/or fluoropyrimidine derivatives are used to treat advanced and/or metastatic gastric cancer.
  • the gastric cancer is a moderately differentiated or poorly differentiated gastric cancer.
  • a method of treating gastric adenocarcinoma comprising administering to a patient in need of treatment a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof.
  • the gastric adenocarcinoma includes, but is not limited to, papillary adenocarcinoma, tubular adenocarcinoma, mucinous adenocarcinoma, signet ring cell carcinoma, or a mixed adenocarcinoma of the above histological type.
  • the gastric adenocarcinoma is advanced and/or metastatic gastric adenocarcinoma; in some more typical embodiments, the gastric adenocarcinoma is a taxane antineoplastic, camptothecin resistant Advanced and/or metastatic gastric adenocarcinoma for treatment failure with oncology drugs, doxorubicin antineoplastic agents, platinum complexes and/or fluoropyrimidine derivatives. In some typical embodiments, the gastric adenocarcinoma is a moderately differentiated or poorly differentiated gastric adenocarcinoma.
  • a method of treating papillary adenocarcinoma comprising administering to a patient in need of treatment a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof.
  • the papillary adenocarcinoma is advanced and/or metastatic papillary adenocarcinoma; in some more typical embodiments, the papillary adenocarcinoma is a taxane-like anti-tumor Drugs, camptothecin antineoplastic agents, doxorubicin antineoplastic agents, platinum complexes and/or fluoropyrimidine derivatives for the treatment of advanced and/or metastatic papillary adenocarcinoma.
  • the papillary adenocarcinoma is Moderately differentiated or poorly differentiated papillary adenocarcinoma.
  • a method of treating tubular adenocarcinoma comprising administering to a patient in need of treatment a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof.
  • the tubular adenocarcinoma is advanced and/or metastatic tubular adenocarcinoma; in some more typical embodiments, the tubular adenocarcinoma is a taxane antineoplastic agent, hi A late stage and/or metastatic tubular adenocarcinoma that fails treatment with a sulphate antineoplastic, a doxorubicin antineoplastic, a platinum complex, and/or a fluoropyrimidine derivative.
  • the tubular adenocarcinoma is a moderately differentiated or poorly differentiated tubular adenocarcinoma.
  • a method of treating mucinous adenocarcinoma comprising administering to a patient in need of treatment a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof.
  • the mucinous adenocarcinoma is advanced and/or metastatic mucinous adenocarcinoma; in some typical embodiments, the mucinous adenocarcinoma is a taxane antineoplastic agent, camptothecin Advanced anti-tumor drugs, doxorubicin antineoplastic agents, platinum complexes and/or fluoropyrimidine derivatives for the treatment of advanced and/or metastatic mucinous adenocarcinoma. In some typical embodiments, the mucinous adenocarcinoma is a moderately differentiated or poorly differentiated mucinous adenocarcinoma.
  • a method of treating signet ring cell carcinoma comprising administering to a patient in need of treatment a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof.
  • the signet ring cell carcinoma is advanced and/or metastatic signet ring cell carcinoma; in some more typical embodiments, the signet ring cell carcinoma is a taxane antitumor Drugs, camptothecin antineoplastic agents, doxorubicin antineoplastic agents, platinum complexes and/or fluoropyrimidine derivatives for the treatment of advanced and/or metastatic signet ring cell carcinoma.
  • a method of treating a gastroesophageal junction adenocarcinoma comprising administering to a patient in need of treatment a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof.
  • the gastroesophageal junction adenocarcinoma is a late stage and/or metastatic gastroesophageal junction adenocarcinoma; in some more typical embodiments, the gastroesophageal junction adenocarcinoma is Taxane-type antineoplastic agents, camptothecin antineoplastic agents, doxorubicin antineoplastic agents, platinum complexes and/or fluoropyrimidine derivatives have failed to treat advanced and/or metastatic gastroesophageal junctional adenocarcinoma. In some typical embodiments, the gastroesophageal junction cancer is a moderately differentiated or poorly differentiated gastroesophageal junction adenocarcinoma.
  • taxane antineoplastic agents include, but are not limited to, paclitaxel and docetaxel; camptothecin antineoplastic agents include, but are not limited to, irinotecan; doxorubicin antineoplastic agents include But not limited to epirubicin; platinum complexes include, but are not limited to, one or more of cisplatin, carboplatin, nedaplatin, oxaliplatin; in some embodiments, fluoropyrimidine derivatives include but not It is limited to one or more of capecitabine, fluorouracil, difurfuryluracil, deoxyfluorouridine, tegafur, and carmofur.
  • Compound I can be administered in the form of its free base or it can be administered in the form of its salts, hydrates and prodrugs which are converted in vivo to the free base form of Compound I.
  • a pharmaceutically acceptable salt of Compound I is in the scope of the present application.
  • the salt can be produced from different organic and inorganic acids by methods well known in the art.
  • the administration is in the form of Compound I hydrochloride. In some embodiments, the administration is in the form of Compound I monohydrochloride. In some embodiments, the administration is in the form of Compound I dihydrochloride. In some embodiments, the administration is in the form of a crystal of Compound I hydrochloride. In a particular embodiment, it is administered in the form of a crystal of Compound I dihydrochloride.
  • Compound 1, or a pharmaceutically acceptable salt thereof can be administered by a variety of routes including, but not limited to, those selected from the group consisting of oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, Intramuscular, rectal, buccal, intranasal, by inhalation, vaginal, intraocular, topical, subcutaneous, intra-, intra-articular, intraperitoneal, and intrathecal. In some specific embodiments, it is administered orally.
  • the amount of Compound I or a pharmaceutically acceptable salt thereof administered can be determined based on the severity of the disease, the response to the disease, any treatment-related toxicity, the age and health of the patient.
  • the daily dose of Compound 1, or a pharmaceutically acceptable salt thereof is from 2 mg to 20 mg. In some embodiments, the daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, is from 5 mg to 20 mg. In some embodiments, the daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, is from 8 mg to 20 mg. In some embodiments, the daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, is from 10 mg to 16 mg.
  • the daily dose of Compound 1, or a pharmaceutically acceptable salt thereof is from 10 mg to 14 mg. In some specific embodiments, the daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, is 10 mg. In some specific embodiments, the daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, is 12 mg. In some specific embodiments, the daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, is 14 mg. In some specific embodiments, the daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, is 16 mg.
  • Compound I or a pharmaceutically acceptable salt thereof can be administered one or more times a day. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered once daily. In some embodiments, the oral solid formulation is administered once a day.
  • the method of administration can be comprehensively determined based on the activity, toxicity, and tolerance of the patient.
  • Compound 1, or a pharmaceutically acceptable salt thereof is administered in a separate manner.
  • the interval administration includes a administration period and a withdrawal period, and Compound I or a pharmaceutically acceptable salt thereof may be administered one or more times a 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 certain period of time during the withdrawal period, followed by the administration period, and then the withdrawal period, which can be repeated a plurality of times.
  • the ratio of the administration period to the withdrawal period in days is 2:0.5 to 5, preferably 2:0.5 to 3, more preferably 2:0.5 to 2, still more preferably 2:0.5 to 1.
  • the continuous administration is discontinued for 2 weeks for 2 weeks. In some embodiments, administration once a day for 14 days, followed by 14 days of withdrawal; followed by 1 administration per day for 14 days, followed by 14 days of discontinuation, such continuous administration for 2 weeks
  • the two-week interval administration method can be repeated a plurality of times.
  • the continuous administration is discontinued for 2 weeks for 1 week. In some embodiments, administration once a day continues After 14 days of administration, the drug was stopped for 7 days; then administered once a day for 14 days, and then discontinued for 7 days, such that the continuous administration of 2 weeks of withdrawal for 1 week can be repeated several times. .
  • the administration is continued for 5 days for 2 days.
  • the drug is administered once a day for 5 days, then for 2 days; then once a day for 5 days, then for 2 days, such continuous administration for 5 days.
  • the two-day interval administration method can be repeated multiple times.
  • Compound 1, or a pharmaceutically acceptable salt thereof is administered to a gastric cancer patient separately as the sole active ingredient. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered to a gastric cancer patient simultaneously or sequentially with other anti-tumor drugs.
  • other anti-tumor drugs include, but are not limited to, platinum complexes, fluoropyrimidine derivatives, camptothecin and its derivatives, terpenoid anti-tumor antibiotics, taxanes, mitomycin, koji One or several of tocilizumab.
  • the platinum complex includes, but is not limited to, one or more of cisplatin, carboplatin, nedaplatin, oxaliplatin; in some embodiments, the fluoropyrimidine derivative includes, but is not limited to, a card One or more of pecitabine, fluorouracil, difurfuryluracil, deoxyfluorouridine, tegafur, carmofur; in some embodiments, camptothecin and its derivatives include, but are not limited to, camptothecin One or more of a base, hydroxycamptothecin, irinotecan, topotecan; in some embodiments, steroid anti-tumor antibiotics include, but are not limited to, doxorubicin, epirubicin, soft red One or more of the mycins, mitoxantrone; in some embodiments, the taxanes include, but are not limited to, paclitaxel and/or docetaxel.
  • the application provides the use of Compound 1, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of gastric cancer.
  • the gastric cancer is advanced and/or metastatic gastric cancer; in some more typical embodiments, the gastric cancer is a taxane antineoplastic agent, a camptothecin antineoplastic agent, Doxorubicin antineoplastic agents, platinum complexes and/or fluoropyrimidine derivatives are used to treat advanced and/or metastatic gastric cancer.
  • the gastric cancer is a moderately differentiated or poorly differentiated gastric cancer.
  • gastric adenocarcinoma includes, but is not limited to, papillary adenocarcinoma, tubular adenocarcinoma, mucinous adenocarcinoma, signet ring cell carcinoma, or a mixed adenocarcinoma of the above histological type.
  • the gastric adenocarcinoma is advanced and/or metastatic gastric adenocarcinoma; in some more typical embodiments, the gastric adenocarcinoma is a taxane antineoplastic, camptothecin resistant Advanced and/or metastatic gastric adenocarcinoma for treatment failure with oncology drugs, doxorubicin antineoplastic agents, platinum complexes and/or fluoropyrimidine derivatives. In some typical embodiments, the gastric adenocarcinoma is a moderately differentiated or poorly differentiated gastric adenocarcinoma.
  • the papillary adenocarcinoma is advanced and/or metastatic papillary adenocarcinoma; in some more typical embodiments, the papillary adenocarcinoma is a taxane-like anti-tumor Drugs, camptothecin antineoplastic agents, doxorubicin antineoplastic agents, platinum complexes and/or fluoropyrimidine derivatives for the treatment of advanced and/or metastatic papillary adenocarcinoma. In some typical embodiments, the papillary adenocarcinoma is a moderately differentiated or poorly differentiated papillary adenocarcinoma.
  • the tubular adenocarcinoma is advanced and/or metastatic tubular adenocarcinoma; in some more typical embodiments, the tubular adenocarcinoma is a taxane antineoplastic agent, hi A late stage and/or metastatic tubular adenocarcinoma that fails treatment with a sulphate antineoplastic, a doxorubicin antineoplastic, a platinum complex, and/or a fluoropyrimidine derivative. In some typical embodiments, the tubular adenocarcinoma is a moderately differentiated or poorly differentiated tubular adenocarcinoma.
  • the mucinous adenocarcinoma is advanced and/or metastatic mucinous adenocarcinoma; in some more typical embodiments, the mucinous adenocarcinoma is a taxane antineoplastic agent, hi Late and/or metastatic mucinous adenocarcinomas that fail to treat alkaloid antineoplastic agents, doxorubicin antineoplastic agents, platinum complexes, and/or fluoropyrimidine derivatives. In some typical embodiments, the mucinous adenocarcinoma is a moderately differentiated or poorly differentiated mucinous adenocarcinoma.
  • the signet ring cell carcinoma is advanced and/or metastatic signet ring cell carcinoma; in some more typical embodiments, the signet ring cell carcinoma is a taxane antitumor Drugs, camptothecin antineoplastic agents, doxorubicin antineoplastic agents, platinum complexes and/or fluoropyrimidine derivatives for the treatment of advanced and/or metastatic signet ring cell carcinoma.
  • the gastroesophageal junction adenocarcinoma is a late stage and/or metastatic gastroesophageal junction adenocarcinoma; in some more typical embodiments, the gastroesophageal junction adenocarcinoma is Taxane-type antineoplastic agents, camptothecin antineoplastic agents, doxorubicin antineoplastic agents, platinum complexes and/or fluoropyrimidine derivatives have failed to treat advanced and/or metastatic gastroesophageal junctional adenocarcinoma.
  • the gastroesophageal junction cancer is a moderately differentiated or poorly differentiated gastroesophageal junction adenocarcinoma.
  • taxane antineoplastic agents include, but are not limited to, paclitaxel and docetaxel; camptothecin antineoplastic agents include, but are not limited to, irinotecan; doxorubicin antineoplastic agents include But not limited to epirubicin; platinum complexes include, but are not limited to, one or more of cisplatin, carboplatin, nedaplatin, oxaliplatin; in some embodiments, fluoropyrimidine derivatives include but not It is limited to one or more of capecitabine, fluorouracil, difurfuryluracil, deoxyfluorouridine, tegafur, and carmofur.
  • Compound I may be in its free base form, or it may be in the form of its salts, hydrates and prodrugs which are converted in vivo to the free base form of Compound I.
  • a pharmaceutically acceptable salt of Compound I is within the scope of the present application, and salts can be produced from different organic and inorganic acids by methods well known in the art.
  • Compound 1, or a pharmaceutically acceptable salt thereof is the hydrochloride salt form of Compound I.
  • the amount of Compound I or a pharmaceutically acceptable salt thereof can be determined depending on the severity of the disease, the response of the disease, any treatment-related toxicity, the age of the patient, and the state of health.
  • the daily dose of Compound 1, or a pharmaceutically acceptable salt thereof is from 2 mg to 20 mg. In some embodiments, the daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, is from 5 mg to 20 mg. In some embodiments, the amount of Compound 1, or a pharmaceutically acceptable salt thereof, is from 8 mg to 20 mg. In some embodiments, the amount of Compound 1, or a pharmaceutically acceptable salt thereof, is from 10 mg to 16 mg. In some embodiments, the amount of Compound 1, or a pharmaceutically acceptable salt thereof, is from 10 mg to 14 mg.
  • the amount of Compound 1, or a pharmaceutically acceptable salt thereof is 10 mg. In some specific embodiments, the amount of Compound 1, or a pharmaceutically acceptable salt thereof, is 12 mg. In some specific embodiments, the amount of Compound 1, or a pharmaceutically acceptable salt thereof, is 14 mg. In some specific embodiments, the amount of Compound 1, or a pharmaceutically acceptable salt thereof, is 16 mg.
  • the use of Compound 1, or a pharmaceutically acceptable salt thereof, as the sole active ingredient in the manufacture of a medicament for the treatment of gastric cancer is provided.
  • the use of Compound 1, or a pharmaceutically acceptable salt thereof, and other anti-tumor agents together as an active ingredient in the manufacture of a medicament for the treatment of gastric cancer is provided.
  • other anti-tumor drugs include, but are not limited to, platinum complexes, fluoropyrimidine derivatives, camptothecin and its derivatives, terpenoid anti-tumor antibiotics, taxanes, mitomycin, koji One or several of tocilizumab.
  • the platinum complex includes, but is not limited to, one or more of cisplatin, carboplatin, nedaplatin, oxaliplatin; in some embodiments, the fluoropyrimidine derivative includes, but is not limited to, a card One or more of pecitabine, fluorouracil, difurfuryluracil, deoxyfluorouridine, tegafur, carmofur; in some embodiments, camptothecin and its derivatives include, but are not limited to, camptothecin One or more of a base, hydroxycamptothecin, irinotecan, topotecan; in some embodiments, steroid anti-tumor antibiotics include, but are not limited to, doxorubicin, epirubicin, soft red One or more of the mycins, mitoxantrone; in some embodiments, the taxanes include, but are not limited to, paclitaxel and/or docetaxel.
  • the present application provides a Compound I or a pharmaceutical composition for treating gastric cancer, the pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
  • the gastric cancer is advanced and/or metastatic gastric cancer; in some more typical embodiments, the gastric cancer is a taxane antineoplastic agent, a camptothecin antineoplastic agent, Doxorubicin antineoplastic agents, platinum complexes and/or fluoropyrimidine derivatives are used to treat advanced and/or metastatic gastric cancer.
  • the gastric cancer is a moderately differentiated or poorly differentiated gastric cancer.
  • a Compound I or a pharmaceutical composition for treating gastric adenocarcinoma the pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable Carrier.
  • the gastric adenocarcinoma includes, but is not limited to, papillary adenocarcinoma, tubular adenocarcinoma, mucinous adenocarcinoma, signet ring cell carcinoma, or a mixture of the above histological types. Syndrome of adenocarcinoma.
  • the gastric adenocarcinoma is advanced and/or metastatic gastric adenocarcinoma; in some more typical embodiments, the gastric adenocarcinoma is a taxane antineoplastic, camptothecin resistant Advanced and/or metastatic gastric adenocarcinoma for treatment failure with oncology drugs, doxorubicin antineoplastic agents, platinum complexes and/or fluoropyrimidine derivatives. In some typical embodiments, the gastric adenocarcinoma is a moderately differentiated or poorly differentiated gastric adenocarcinoma.
  • a Compound I or a pharmaceutical composition for treating papillary adenocarcinoma the pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable Accepted carrier.
  • the papillary adenocarcinoma is advanced and/or metastatic papillary adenocarcinoma; in some more typical embodiments, the papillary adenocarcinoma is a taxane-like anti-tumor Drugs, camptothecin antineoplastic agents, doxorubicin antineoplastic agents, platinum complexes and/or fluoropyrimidine derivatives for the treatment of advanced and/or metastatic papillary adenocarcinoma. In some typical embodiments, the papillary adenocarcinoma is a moderately differentiated or poorly differentiated papillary adenocarcinoma.
  • a Compound I or a pharmaceutical composition for treating tubular adenocarcinoma the pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable a.
  • the tubular adenocarcinoma is advanced and/or metastatic tubular adenocarcinoma; in some more typical embodiments, the tubular adenocarcinoma is a taxane antineoplastic agent, hi A late stage and/or metastatic tubular adenocarcinoma that fails treatment with a sulphate antineoplastic, a doxorubicin antineoplastic, a platinum complex, and/or a fluoropyrimidine derivative.
  • the tubular adenocarcinoma is a moderately differentiated or poorly differentiated tubular adenocarcinoma.
  • a Compound I or a pharmaceutical composition for treating mucinous adenocarcinoma the pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable a.
  • the mucinous adenocarcinoma is advanced and/or metastatic mucinous adenocarcinoma; in some more typical embodiments, the mucinous adenocarcinoma is a taxane antineoplastic agent, hi Late and/or metastatic mucinous adenocarcinomas that fail to treat alkaloid antineoplastic agents, doxorubicin antineoplastic agents, platinum complexes, and/or fluoropyrimidine derivatives. In some typical embodiments, the mucinous adenocarcinoma is a moderately differentiated or poorly differentiated mucinous adenocarcinoma.
  • a Compound I or a pharmaceutical composition for treating signet ring cell carcinoma comprising Compound 1, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable Accepted carrier.
  • the signet ring cell carcinoma is advanced and/or metastatic signet ring cell carcinoma; in some more typical embodiments, the signet ring cell carcinoma is a taxane antitumor Drugs, camptothecin antineoplastic agents, doxorubicin antineoplastic agents, platinum complexes and/or fluoropyrimidine derivatives for the treatment of advanced and/or metastatic signet ring cell carcinoma.
  • a Compound I or a pharmaceutical composition for treating a gastroesophageal junction adenocarcinoma the pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable An acceptable carrier.
  • the gastroesophageal junction adenocarcinoma is a late stage and/or metastatic gastroesophageal junction adenocarcinoma; in some more typical embodiments, the gastroesophageal junction adenocarcinoma is Taxane antineoplastic agents, camptothecin antibiotics Advanced and/or metastatic gastroesophageal junctional adenocarcinoma that fails treatment with oncology drugs, doxorubicin antineoplastic agents, platinum complexes, and/or fluoropyrimidine derivatives. In some typical embodiments, the gastroesophageal junction cancer is a moderately differentiated or poorly differentiated gastroesophageal junction adenocarcinoma.
  • taxane antineoplastic agents include, but are not limited to, paclitaxel and docetaxel; camptothecin antineoplastic agents include, but are not limited to, irinotecan; doxorubicin antineoplastic agents include But not limited to epirubicin; platinum complexes include, but are not limited to, one or more of cisplatin, carboplatin, nedaplatin, oxaliplatin; in some embodiments, fluoropyrimidine derivatives include but not It is limited to one or more of capecitabine, fluorouracil, difurfuryluracil, deoxyfluorouridine, tegafur, and carmofur.
  • Compound I can be in its free base form or in the form of a salt, hydrate and prodrug which is converted in vivo to the free base form of Compound I.
  • a pharmaceutically acceptable salt of Compound I is within the scope of the present application, and salts can be produced from different organic and inorganic acids by methods well known in the art.
  • Compound 1, or a pharmaceutically acceptable salt thereof is the hydrochloride salt form of Compound I.
  • the amount of Compound I or a pharmaceutically acceptable salt thereof to be administered can be determined depending on the severity of the disease, the response of the disease, any treatment-related toxicity, the age of the patient, and the state of health.
  • the daily dose of Compound 1, or a pharmaceutically acceptable salt thereof is from 2 mg to 20 mg. In some embodiments, the daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, is from 5 mg to 20 mg. In some embodiments, the amount of Compound 1, or a pharmaceutically acceptable salt thereof, in the pharmaceutical composition is from 8 mg to 20 mg. In some embodiments, the amount of Compound 1, or a pharmaceutically acceptable salt thereof, is from 10 mg to 16 mg.
  • the amount of Compound 1, or a pharmaceutically acceptable salt thereof is from 10 mg to 14 mg. In some specific embodiments, the amount of Compound 1, or a pharmaceutically acceptable salt thereof, is 10 mg. In some specific embodiments, the amount of Compound 1, or a pharmaceutically acceptable salt thereof, is 12 mg. In some specific embodiments, the amount of Compound 1, or a pharmaceutically acceptable salt thereof, is 14 mg. In some specific embodiments, the amount of Compound 1, or a pharmaceutically acceptable salt thereof, is 16 mg.
  • the pharmaceutical composition is a formulation suitable for oral administration, including tablets, capsules, powders, granules, dropping pills, pastes, powders, and the like, preferably tablets and capsules.
  • the tablet may be a common tablet, a dispersible tablet, an effervescent tablet, a sustained release tablet, a controlled release tablet or an enteric coated tablet
  • the capsule may be a general capsule, a sustained release capsule, a controlled release capsule or an enteric coated capsule.
  • the oral preparations can be prepared by conventional methods using pharmaceutically acceptable carriers well 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, povidone, microcrystalline cellulose, etc.; disintegrants include croscarmellose sodium, crospovidone, surfactants, low substitution Hydroxypropyl cellulose, etc.; lubricants include magnesium stearate, talc, polyethylene glycol, sodium lauryl sulfate, micronized silica gel, talc, and the like. Pharmaceutical excipients also include coloring agents, sweeteners, and the like.
  • the pharmaceutical composition is a solid preparation suitable for oral administration.
  • the composition may for example be in the form of a tablet or capsule.
  • the pharmaceutical composition is a capsule.
  • pharmaceutically acceptable carriers for oral solid preparations include mannitol, microcrystalline cellulose, hydroxypropylcellulose, magnesium stearate.
  • a pharmaceutical composition formulated in a unit dosage form for treating gastric cancer contains from 2 mg to 20 mg of Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition in unit dosage form contains from 5 mg to 20 mg of Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition in unit dosage form contains from 8 mg to 20 mg of Compound 1, or a pharmaceutically acceptable salt thereof, preferably from 10 mg to 16 mg of Compound 1, or a pharmaceutically acceptable salt thereof, More preferably, 10 mg to 14 mg of the compound I or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition in unit dosage form contains 10 mg of Compound 1, or a pharmaceutically acceptable salt thereof. In some specific embodiments, the pharmaceutical composition in unit dosage form contains 12 mg of Compound 1, or a pharmaceutically acceptable salt thereof. In some specific embodiments, the pharmaceutical composition in unit dosage form contains 14 mg of Compound 1, or a pharmaceutically acceptable salt thereof. In some specific embodiments, the pharmaceutical composition in unit dosage form contains 16 mg of Compound 1, or a pharmaceutically acceptable salt thereof.
  • pharmaceutical composition in unit dosage form means tablet or capsule per tablet.
  • the above pharmaceutical composition is administered in a separate manner.
  • the interval administration includes a administration period and a withdrawal period, and the above pharmaceutical composition may be administered one or more times a day during the administration period.
  • the pharmaceutical composition is administered daily during the administration period, and then the administration is stopped for a certain period of time during the withdrawal period, followed by the administration period, and then the withdrawal period, which can be repeated several times.
  • the ratio of the administration period to the withdrawal period in terms of days is 2: 0.5 to 5, preferably 2: 0.5 to 3, more preferably 2: 0.5 to 2, still more preferably 2: 0.5 to 1.
  • the continuous administration is discontinued for 2 weeks for 2 weeks. In some embodiments, administration once a day for 14 days, followed by 14 days of withdrawal; followed by 1 administration per day for 14 days, followed by 14 days of discontinuation, such continuous administration for 2 weeks
  • the two-week interval administration method can be repeated a plurality of times.
  • the continuous administration is discontinued for 2 weeks for 1 week. In some embodiments, administration once a day for 14 days, followed by 7 days of withdrawal; followed by 1 administration per day for 14 days, followed by 7 days of discontinuation, such continuous administration for 2 weeks
  • the interval of administration of the drug for one week can be repeated a plurality of times.
  • the administration is continued for 5 days for 2 days.
  • the drug is administered once a day for 5 days, then discontinued for 2 days; then once a day for 5 days, then discontinued for 2 days, so continuously
  • the interval of administration of the drug for 5 days for 2 days can be repeated a plurality of times.
  • provided pharmaceutical compositions for treating gastric cancer comprise Compound 1, or a pharmaceutically acceptable salt thereof, as the sole active ingredient.
  • provided pharmaceutical compositions for treating gastric cancer comprise Compound 1, or a pharmaceutically acceptable salt thereof, further comprising other anti-tumor drugs.
  • other anti-tumor drugs include, but are not limited to, platinum complexes, fluoropyrimidine derivatives, camptothecin and its derivatives, terpenoid anti-tumor antibiotics, taxanes, mitomycin, koji One or several of tocilizumab.
  • the platinum complex includes, but is not limited to, one or more of cisplatin, carboplatin, nedaplatin, oxaliplatin; in some embodiments, the fluoropyrimidine derivative includes, but is not limited to, a card One or more of pecitabine, fluorouracil, difurfuryluracil, deoxyfluorouridine, tegafur, carmofur; in some embodiments, camptothecin and its derivatives include, but are not limited to, camptothecin One or more of a base, hydroxycamptothecin, irinotecan, topotecan; in some embodiments, steroid anti-tumor antibiotics include, but are not limited to, doxorubicin, epirubicin, soft red One or more of the mycins, mitoxantrone; in some embodiments, the taxanes include, but are not limited to, paclitaxel and/or docetaxel.
  • kits for treating gastric cancer comprising (a) at least one unit dose of a pharmaceutical composition of Compound I or a pharmaceutically acceptable salt thereof and (b) for treating gastric cancer Instructions.
  • a kit is provided comprising (a) at least one unit dose of a formulation suitable for oral administration of Compound 1, or a pharmaceutically acceptable salt thereof, and (b) in a separate administration Instructions for the treatment of gastric cancer.
  • a kit is provided comprising (a) at least one unit dose of a tablet or capsule of Compound 1, or a pharmaceutically acceptable salt thereof, and (b) in a manner of interval administration Instructions for the treatment of gastric cancer.
  • the gastric cancer is advanced and/or metastatic gastric cancer; in some typical embodiments, the gastric cancer is a taxane antineoplastic agent, a camptothecin antineoplastic agent, an adriamycin antitumor
  • the drug, platinum complex, and/or fluoropyrimidine derivative treats advanced and/or metastatic gastric cancer that fails; in some typical embodiments, the gastric cancer is a moderately differentiated or poorly differentiated gastric cancer.
  • the gastric cancer is gastric adenocarcinoma; in some typical embodiments, the gastric adenocarcinoma is a taxane antineoplastic agent, a camptothecin antineoplastic agent, an adriamycin antibiotic Tumor, platinum complex, and/or fluoropyrimidine derivatives fail to treat advanced and/or metastatic gastric adenocarcinoma; in some typical embodiments, the gastric adenocarcinoma is a moderately differentiated or poorly differentiated gastric adenocarcinoma.
  • the gastric adenocarcinoma includes, but is not limited to, papillary adenocarcinoma, tubular adenocarcinoma, mucinous adenocarcinoma, signet ring cell carcinoma, or a mixed adenocarcinoma of the histological type described above.
  • the gastric adenocarcinoma is a treatment failure of a taxane antineoplastic agent, a camptothecin antineoplastic agent, an adriamycin antineoplastic agent, a platinum complex, and/or a fluoropyrimidine derivative.
  • the gastric adenocarcinoma is moderately differentiated Poorly differentiated papillary gland Cancer, tubular adenocarcinoma, mucinous adenocarcinoma or a mixed adenocarcinoma of the above histological type.
  • the gastric cancer is a gastroesophageal junction adenocarcinoma; in some typical embodiments, the gastroesophageal junction adenocarcinoma is a taxane antineoplastic agent, camptothecin antibiotic Advanced and/or metastatic gastroesophageal junctional adenocarcinoma that fails treatment with oncology drugs, doxorubicin antineoplastic agents, platinum complexes, and/or fluoropyrimidine derivatives.
  • the tablet may be a common tablet, a dispersible tablet, an effervescent tablet, a sustained release tablet, a controlled release tablet or an enteric coated tablet
  • the capsule may be a general capsule, a sustained release capsule, a controlled release capsule or an enteric coated capsule.
  • pharmaceutically acceptable carriers include fillers, absorbents, wetting agents, binders, disintegrants, lubricants, and the like.
  • Filling agents 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, poly Retardone, microcrystalline cellulose, etc.; disintegrants include croscarmellose sodium, crospovidone, surfactant, low-substituted hydroxypropyl cellulose, etc.; lubricants include magnesium stearate, talc Powder, polyethylene glycol, sodium lauryl sulfate, micronized silica gel, talcum powder, and the like. Pharmaceutical excipients also include coloring agents, sweeteners, and the like.
  • the pharmaceutical composition in unit dosage form contains from 2 mg to 20 mg of Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition in unit dosage form contains from 5 mg to 20 mg of Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition in unit dosage form contains from 8 mg to 20 mg of Compound 1, or a pharmaceutically acceptable salt thereof, preferably from 10 mg to 16 mg of Compound 1, or a pharmaceutically acceptable salt thereof, More preferably, 10 mg to 14 mg of the compound I or a pharmaceutically acceptable salt thereof. In some specific embodiments, the pharmaceutical composition in unit dosage form contains 10 mg of Compound 1, or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition in unit dosage form contains 12 mg of Compound 1, or a pharmaceutically acceptable salt thereof. In some specific embodiments, the pharmaceutical composition in unit dosage form contains 14 mg of Compound 1, or a pharmaceutically acceptable salt thereof. In some specific embodiments, the pharmaceutical composition in unit dosage form contains 16 mg of Compound 1, or a pharmaceutically acceptable salt thereof.
  • pharmaceutical composition in unit dosage form means tablet or capsule per tablet.
  • the interval administration includes a administration period and a withdrawal period, and the above pharmaceutical composition may be administered one or more times a day during the administration period.
  • the pharmaceutical composition is administered daily during the administration period, and then the administration is stopped for a certain period of time during the withdrawal period, followed by the administration period, and then the withdrawal period, which can be repeated several times.
  • the ratio of the administration period to the withdrawal period in terms of days is 2: 0.5 to 5, preferably 2: 0.5 to 3, more preferably 2: 0.5 to 2, still more preferably 2: 0.5 to 1.
  • the continuous administration is discontinued for 2 weeks for 2 weeks. In some embodiments, administration once a day for 14 days, followed by 14 days of withdrawal; followed by 1 administration per day for 14 days, followed by 14 days of discontinuation, such continuous administration for 2 weeks
  • the two-week interval administration method can be repeated a plurality of times.
  • the continuous administration is discontinued for 2 weeks for 1 week. In some embodiments, administration once a day continues After 14 days of administration, the drug was stopped for 7 days; then administered once a day for 14 days, and then discontinued for 7 days, such that the continuous administration of 2 weeks of withdrawal for 1 week can be repeated several times. .
  • the administration is continued for 5 days for 2 days.
  • the drug is administered once a day for 5 days, then for 2 days; then once a day for 5 days, then for 2 days, such continuous administration for 5 days.
  • the two-day interval administration method can be repeated multiple times.
  • Compound I can be administered in the form of its free base or it can be administered in the form of its salts, hydrates and prodrugs which are converted in vivo to the free base form of Compound I.
  • a pharmaceutically acceptable salt of Compound I is within the scope of the present application, which salt can be produced from different organic and inorganic acids according to methods well known in the art.
  • qd refers to administration once a day unless otherwise stated.
  • the crystalline form of the hydrochloride salt of the compound I includes, but is not limited to, the types A, B, and C crystals disclosed in Chinese Patent Application No. CN102344438A, wherein the A and B type crystals are substantially free of crystal water and other solvents. Crystallization, Form C crystal is a crystal containing two water of crystallization. In some embodiments, the crystalline form of the dihydrochloride salt of Compound I is Form A crystal.
  • Patient means a mammal, preferably a human. In some embodiments, the patient is a patient who fails standard treatment or lacks standard treatment.
  • “Pharmaceutically acceptable” means that it is used in the preparation of a pharmaceutical composition which is generally safe, non-toxic and neither biologically or otherwise undesirable, and which includes its use for human pharmaceutical use. Accepted.
  • “Pharmaceutically acceptable salt” includes, but is 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, propionic acid , caproic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, 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, 3-phenyl
  • “Therapeutically effective amount” means an amount of a compound that is sufficient to effect treatment of a disease when administered to a human.
  • Treatment means any administration of a therapeutically effective amount of a compound and includes:
  • PR refers to partial relief, specifically the sum of the target lesion diameters of the tumor is reduced by more than 30% from the baseline level.
  • PD refers to disease progression, specifically the sum of the target lesion diameters of the tumor is increased by more than 20% from the baseline level.
  • SD refers to the stability of the disease, specifically the extent to which the tumor target lesion has not decreased to the PR level, and the degree of increase has not reached the PD level, which is somewhere in between.
  • Treatment failure refers to intolerance of toxic side effects, progression of disease during treatment, or recurrence after treatment; wherein intolerance means hematological toxicity up to grade IV (platelet decline III and above), non-hematologic toxicity up to III Level or above.
  • Example 2 contains 1-[[[4-(4-fluoro-2-methyl-1H-indol-5-yl)oxy-6-methoxyquinolin-7-yl]oxy]methyl a capsule of cyclopropylamine dihydrochloride (dihydrochloride salt of Compound I)
  • the dihydrochloride salt of the compound I is pulverized and passed through a sieve of 80 mesh; then uniformly mixed with mannitol and hydroxypropylcellulose; Enter the prescribed amount of microcrystalline cellulose, mix evenly, over 0.8mm sieve; finally add the prescribed amount of magnesium stearate to mix evenly, and fill the capsule.
  • gastroscopy Male, 60 years old, on November 28, 2013, due to "feeding for two years, aggravated for one month," a gastroscopy showed: gastroesophageal junction cancer. On December 11, 2013, under general anesthesia (partial esophagogastric resection, esophagogastric anastomosis + lymph node dissection), postoperative pathology showed: ulcerative moderate-poor differentiated adenocarcinoma of gastroesophageal junction.
  • CT showed: 1. The anastomosis was slightly thickened, and some nodules in the lungs were enlarged. 2. The metastases in the right lobe of the liver increased and increased, suggesting that the disease progressed. Continue to take oral Teggio capsules 60mg, on July 19th to review CT showed: 1: partial lung nodules increased; the right hepatic lobe metastases slightly increased. Comprehensive evaluation of the progress of the disease.
  • Trongio + oxaliplatin chemotherapy, after 3 cycles of chemotherapy, the effect of PR; after 6 cycles of chemotherapy, chest, abdomen and pelvic CT scan + enhanced tips: 1. Gastric sinus cancer Gastric and para-aortic lymph node metastasis, in situ lesions and partial lymph node metastases appeared to improve. 2. No abnormalities in the pelvic cavity; the effect is PD. Another "paclitaxel + capecitabine” chemotherapy, the effect is PD.
  • liver 41 mm, liver 22 mm refers to two lesions in the liver, one of which has a lesion length of 41 mm and the other lesion has a length of 22 mm.
  • the "injection paclitaxel liposome + 5-fluorouracil” chemotherapy regimen was administered for 1 cycle, and the efficacy was not evaluated.
  • the chemotherapy regimen of “injection paclitaxel liposomes + oxaliplatin + 5-fluorouracil” was administered for 4 cycles, followed by CT examination, suggesting PD.
  • the “Oxaliplatin + Capecitabine” chemotherapy regimen was performed for 2 cycles.
  • chest and abdomen CT showed progression after second-line treatment for gastric cancer.

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Abstract

本申请提供了一种用于治疗胃癌的喹啉衍生物。本申请所提供的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]环丙胺或其药学上可接受的盐、水合物或前药能够有效治疗胃癌，能够稳定或者缓解胃癌患者病情。

Description

一种用于治疗胃癌的喹啉衍生物
相关申请的交叉引用
本申请要求于2016年04月15日向中国国家知识产权局提交的第201610238157.7号中国专利申请的优先权和权益，所述申请公开的内容通过引用整体并入本文中。
技术领域
本申请属于医药技术领域，本申请涉及喹啉衍生物用于治疗胃癌的用途。
背景技术
胃癌起源于胃壁最表层的粘膜上皮细胞，可发生于胃的各个部位，例如胃窦部、胃小弯及前后壁、胃底贲门区、胃体部、胃食管结合部等。肉眼或胃镜观察胃癌有多种形态，如表浅型、肿块型、溃疡型、浸润型、溃疡癌(为慢性胃溃疡癌变)。显微镜放大观察癌细胞有多种类型(组织学分类)，例如世界卫生组织(WHO)按组织学分类将胃癌分为腺癌(包括乳头状腺癌、管状腺癌、粘液腺癌和印戒细胞癌(也称黏液癌))、腺鳞癌、鳞癌、类癌、未分化癌和未分类癌；例如我国将胃癌分为腺癌(包括乳头状腺癌、管状腺癌、粘液腺癌)、印戒细胞癌(也称黏液癌)、未分化癌、特殊类型癌(包括腺鳞癌、鳞状细胞癌、类癌、未分类癌和混合型癌)；其中腺癌占约90％。
胃癌目前常采用手术治疗、放射治疗、靶向治疗、化学治疗和免疫治疗等。近年来中国胃癌新增病例居世界首位，全球接近50％的新发胃癌病例来自中国。胃癌是中国最常见的恶性肿瘤之一，死亡率占中国恶性肿瘤死亡的首位。因此，开发能够有效治疗胃癌的药物是十分必要的。
发明内容
第一方面，本申请提供了治疗胃癌的方法，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的化学名称为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 PCTCN2017080563-appb-000001
第二方面，本申请提供了化合物I或其药学上可接受的盐在制备用于治疗胃癌的药物中的用途。
第三方面，本申请提供了治疗胃癌的化合物I或药物组合物，所述药物组合物包含化合物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。
第四方面，本申请提供了用于治疗胃癌的试剂盒，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)用于治疗胃癌的说明书。
具体实施方式
第一方面，本申请提供了治疗胃癌的方法，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，所述胃癌为晚期和/或转移性胃癌；在一些更为典型的实施方案中，所述胃癌为紫杉烷类抗肿瘤药、喜树碱类抗肿瘤药、阿霉素类抗肿瘤药、铂配合物和/或氟嘧啶衍生物治疗失败的晚期和/或转移性胃癌。在一些典型的实施方案中，所述胃癌为中分化或低分化胃癌。
在本申请的一些实施方案中，提供了一种治疗胃腺癌的方法，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。所述的胃腺癌包括但不限于乳头状腺癌、管状腺癌、粘液腺癌、印戒细胞癌或上述组织学类型的混合性腺癌。在一些典型的实施方案中，所述胃腺癌为晚期和/或转移性胃腺癌；在一些更为典型的实施方案中，所述胃腺癌为紫杉烷类抗肿瘤药、喜树碱类抗肿瘤药、阿霉素类抗肿瘤药、铂配合物和/或氟嘧啶衍生物治疗失败的晚期和/或转移性胃腺癌。在一些典型的实施方案中，所述胃腺癌为中分化或低分化胃腺癌。
在本申请的一些实施方案中，提供了一种治疗乳头状腺癌的方法，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，所述乳头状腺癌为晚期和/或转移性乳头状腺癌；在一些更为典型的实施方案中，所述的乳头状腺癌为紫杉烷类抗肿瘤药、喜树碱类抗肿瘤药、阿霉素类抗肿瘤药、铂配合物和/或氟嘧啶衍生物治疗失败的晚期和/或转移性乳头状腺癌。在一些典型的实施方案中，所述乳头状腺癌为 中分化或低分化乳头状腺癌。
在本申请的一些实施方案中，提供了一种治疗管状腺癌的方法，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，所述管状腺癌为晚期和/或转移性管状腺癌；在一些更为典型的实施方案中，所述的管状腺癌为紫杉烷类抗肿瘤药、喜树碱类抗肿瘤药、阿霉素类抗肿瘤药、铂配合物和/或氟嘧啶衍生物治疗失败的晚期和/或转移性管状腺癌。在一些典型的实施方案中，所述管状腺癌为中分化或低分化管状腺癌。
在本申请的一些实施方案中，提供了一种治疗粘液腺癌的方法，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，所述粘液腺癌为晚期和/或转移性粘液腺癌；在一些典型的实施方案中，所述的粘液腺癌为紫杉烷类抗肿瘤药、喜树碱类抗肿瘤药、阿霉素类抗肿瘤药、铂配合物和/或氟嘧啶衍生物治疗失败的晚期和/或转移性粘液腺癌。在一些典型的实施方案中，所述粘液腺癌为中分化或低分化粘液腺癌。
在本申请的一些实施方案中，提供了一种治疗印戒细胞癌的方法，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，所述印戒细胞癌为晚期和/或转移性印戒细胞癌；在一些更为典型的实施方案中，所述的印戒细胞癌为紫杉烷类抗肿瘤药、喜树碱类抗肿瘤药、阿霉素类抗肿瘤药、铂配合物和/或氟嘧啶衍生物治疗失败的晚期和/或转移性印戒细胞癌。
在本申请的一些实施方案中，提供了一种治疗胃食管结合部腺癌的方法，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，所述胃食管结合部腺癌为晚期和/或转移性胃食管结合部腺癌；在一些更为典型的实施方案中，所述的胃食管结合部腺癌为紫杉烷类抗肿瘤药、喜树碱类抗肿瘤药、阿霉素类抗肿瘤药、铂配合物和/或氟嘧啶衍生物治疗失败的晚期和/或转移性胃食管结合部腺癌。在一些典型的实施方案中，所述胃食管结合部癌为中分化或低分化胃食管结合部腺癌。
在本申请的一些实施方案中，紫杉烷类抗肿瘤药包括但不限于紫杉醇和多西他赛；喜树碱类抗肿瘤药包括但不限于伊立替康；阿霉素类抗肿瘤药包括但不限于表柔比星；铂配合物包括但不限于顺铂、卡铂、奈达铂、奥沙利铂中的一种或几种；在一些实施方案中，氟嘧啶衍生物包括但不限于卡培他滨、氟尿嘧啶、双呋氟尿嘧啶、去氧氟尿苷、替加氟、卡莫氟中的一种或几种。
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申请的范 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5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。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16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胃癌患者的。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胃癌患者。在一些实施方案中，其他抗肿瘤药物包括但不限于铂配合物、氟嘧啶衍生物、喜树碱及其衍生物、蒽醌类抗肿瘤抗生素、紫杉烷类化合物、丝裂霉素、曲妥珠单抗中的一种或几种。在一些实施方案中，铂配合物包括但不限于顺铂、卡铂、奈达铂、奥沙利铂中的一种或几种；在一些实施方案中，氟嘧啶衍生物包括但不限于卡培他滨、氟尿嘧啶、双呋氟尿嘧啶、去氧氟尿苷、替加氟、卡莫氟中的一种或几种；在一些实施方案中，喜树碱及其衍生物包括但不限于喜树碱、羟基喜树碱、伊立替康、拓扑替康中的一种或几种；在一些实施方案中，蒽醌类抗肿瘤抗生素包括但不限于多柔比星、表柔比星、柔红霉素、米托蒽醌中的一种或几种；在一些实施方案中，紫杉烷类化合物包括但不限于紫杉醇和/或多西他赛。
第二方面，本申请提供了化合物I或其药学上可接受的盐在制备用于治疗胃癌的药物中的用途。在一些典型的实施方案中，所述胃癌为晚期和/或转移性胃癌；在一些更为典型的实施方案中，所述胃癌为紫杉烷类抗肿瘤药、喜树碱类抗肿瘤药、阿霉素类抗肿瘤药、铂配合物和/或氟嘧啶衍生物治疗失败的晚期和/或转移性胃癌。在一些典型的实施方案中，所述胃癌为中分化或低分化胃癌。
在本申请的一些实施方案中，提供了化合物I或其药学上可接受的盐在制备用于治疗胃腺癌的药物中的用途。所述的胃腺癌包括但不限于乳头状腺癌、管状腺癌、粘液腺癌、印戒细胞癌或上述组织学类型的混合性腺癌。在一些典型的实施方案中，所述胃腺癌为晚期和/或转移性胃腺癌；在一些更为典型的实施方案中，所述胃腺癌为紫杉烷类抗肿瘤药、喜树碱类抗肿瘤药、阿霉素类抗肿瘤药、铂配合物和/或氟嘧啶衍生物治疗失败的晚期和/或转移性胃腺癌。在一些典型的实施方案中，所述胃腺癌为中分化或低分化胃腺癌。
在本申请的一些实施方案中，提供了化合物I或其药学上可接受的盐在制备用于治疗乳头状腺癌的药物中的用途。在一些典型的实施方案中，所述乳头状腺癌为晚期和/或转移性乳头状腺癌；在一些更为典型的实施方案中，所述的乳头状腺癌为紫杉烷类抗肿瘤药、喜树碱类抗肿瘤药、阿霉素类抗肿瘤药、铂配合物和/或氟嘧啶衍生物治疗失败的晚期和/或转移性乳头状腺癌。在一些典型的实施方案中，所述乳头状腺癌为中分化或低分化乳头状腺癌。
在本申请的一些实施方案中，提供了化合物I或其药学上可接受的盐在制备用于治疗管状腺癌的药物中的用途。在一些典型的实施方案中，所述管状腺癌为晚期和/或转移性管状腺癌；在一些更为典型的实施方案中，所述的管状腺癌为紫杉烷类抗肿瘤药、喜树碱类抗肿瘤药、阿霉素类抗肿瘤药、铂配合物和/或氟嘧啶衍生物治疗失败的晚期和/或转移性管状腺癌。在一些典型的实施方案中，所述管状腺癌为中分化或低分化管状腺癌。
在本申请的一些实施方案中，提供了化合物I或其药学上可接受的盐在制备用于治疗粘液腺癌的药物中的用途。在一些典型的实施方案中，所述粘液腺癌为晚期和/或转移性粘液腺癌；在一些更为典型的实施方案中，所述的粘液腺癌为紫杉烷类抗肿瘤药、喜树碱类抗肿瘤药、阿霉素类抗肿瘤药、铂配合物和/或氟嘧啶衍生物治疗失败的晚期和/或转移性粘液腺癌。在一些典型的实施方案中，所述粘液腺癌为中分化或低分化粘液腺癌。
在本申请的一些实施方案中，提供了化合物I或其药学上可接受的盐在制备用于印戒细胞癌的药物中的用途。在一些典型的实施方案中，所述印戒细胞癌为晚期和/或转移性印戒细胞癌；在一些更为典型的实施方案中，所述的印戒细胞癌为紫杉烷类抗肿瘤药、喜树碱类抗肿瘤药、阿霉素类抗肿瘤药、铂配合物和/或氟嘧啶衍生物治疗失败的晚期和/或转移性印戒细胞癌。
在本申请的一些实施方案中，提供了化合物I或其药学上可接受的盐在制备用于治疗胃食管结合部腺癌的药物中的用途。在一些典型的实施方案中，所述胃食管结合部腺癌为晚期和/或转移性胃食管结合部腺癌；在一些更为典型的实施方案中，所述的胃食管结合部腺癌为紫杉烷类抗肿瘤药、喜树碱类抗肿瘤药、阿霉素类抗肿瘤药、铂配合物和/或氟嘧啶衍生物治疗失败的晚期和/或转移性胃食管结合部腺癌。在一些典型的实施方案中，所述胃食管结合部癌为中分化或低分化胃食管结合部腺癌。
在本申请的一些实施方案中，紫杉烷类抗肿瘤药包括但不限于紫杉醇和多西他赛；喜树碱类抗肿瘤药包括但不限于伊立替康；阿霉素类抗肿瘤药包括但不限于表柔比星；铂配合物包括但不限于顺铂、卡铂、奈达铂、奥沙利铂中的一种或几种；在一些实施方案中，氟嘧啶衍生物包括但不限于卡培他滨、氟尿嘧啶、双呋氟尿嘧啶、去氧氟尿苷、替加氟、卡莫氟中的一种或几种。
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申请的范围内，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5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量为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量为16毫克。
在一些实施方案中，提供了化合物I或其药学上可接受的盐作为唯一活性成份在制备用于治疗胃癌的药物中的用途。在一些实施方案中，提供了化合物I或其药学上可接受的盐和其他抗肿瘤药物共同作为活性成份在制备用于治疗胃癌的药物中的用途。在一些实施方案中，其他抗肿瘤药物包括但不限于铂配合物、氟嘧啶衍生物、喜树碱及其衍生物、蒽醌类抗肿瘤抗生素、紫杉烷类化合物、丝裂霉素、曲妥珠单抗中的一种或几种。在一些实施方案中，铂配合物包括但不限于顺铂、卡铂、奈达铂、奥沙利铂中的一种或几种；在一些实施方案中，氟嘧啶衍生物包括但不限于卡培他滨、氟尿嘧啶、双呋氟尿嘧啶、去氧氟尿苷、替加氟、卡莫氟中的一种或几种；在一些实施方案中，喜树碱及其衍生物包括但不限于喜树碱、羟基喜树碱、伊立替康、拓扑替康中的一种或几种；在一些实施方案中，蒽醌类抗肿瘤抗生素包括但不限于多柔比星、表柔比星、柔红霉素、米托蒽醌中的一种或几种；在一些实施方案中，紫杉烷类化合物包括但不限于紫杉醇和/或多西他赛。
第三方面，本申请提供了治疗胃癌的化合物I或药物组合物，所述药物组合物包含化合物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，所述胃癌为晚期和/或转移性胃癌；在一些更为典型的实施方案中，所述胃癌为紫杉烷类抗肿瘤药、喜树碱类抗肿瘤药、阿霉素类抗肿瘤药、铂配合物和/或氟嘧啶衍生物治疗失败的晚期和/或转移性胃癌。在一些典型的实施方案中，所述胃癌为中分化或低分化胃癌。
在本申请的一些实施方案中，提供了一种治疗胃腺癌的化合物I或药物组合物，所述药物组合物包含化合物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。所述的胃腺癌包括但不限于乳头状腺癌、管状腺癌、粘液腺癌、印戒细胞癌或上述组织学类型的混 合性腺癌。在一些典型的实施方案中，所述胃腺癌为晚期和/或转移性胃腺癌；在一些更为典型的实施方案中，所述胃腺癌为紫杉烷类抗肿瘤药、喜树碱类抗肿瘤药、阿霉素类抗肿瘤药、铂配合物和/或氟嘧啶衍生物治疗失败的晚期和/或转移性胃腺癌。在一些典型的实施方案中，所述胃腺癌为中分化或低分化胃腺癌。
在本申请的一些实施方案中，提供了一种治疗乳头状腺癌的化合物I或药物组合物，所述药物组合物包含化合物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，所述乳头状腺癌为晚期和/或转移性乳头状腺癌；在一些更为典型的实施方案中，所述的乳头状腺癌为紫杉烷类抗肿瘤药、喜树碱类抗肿瘤药、阿霉素类抗肿瘤药、铂配合物和/或氟嘧啶衍生物治疗失败的晚期和/或转移性乳头状腺癌。在一些典型的实施方案中，所述乳头状腺癌为中分化或低分化乳头状腺癌。
在本申请的一些实施方案中，提供了一种治疗管状腺癌的化合物I或药物组合物，所述药物组合物包含化合物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，所述管状腺癌为晚期和/或转移性管状腺癌；在一些更为典型的实施方案中，所述的管状腺癌为紫杉烷类抗肿瘤药、喜树碱类抗肿瘤药、阿霉素类抗肿瘤药、铂配合物和/或氟嘧啶衍生物治疗失败的晚期和/或转移性管状腺癌。在一些典型的实施方案中，所述管状腺癌为中分化或低分化管状腺癌。
在本申请的一些实施方案中，提供了一种治疗粘液腺癌的化合物I或药物组合物，所述药物组合物包含化合物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，所述粘液腺癌为晚期和/或转移性粘液腺癌；在一些更为典型的实施方案中，所述的粘液腺癌为紫杉烷类抗肿瘤药、喜树碱类抗肿瘤药、阿霉素类抗肿瘤药、铂配合物和/或氟嘧啶衍生物治疗失败的晚期和/或转移性粘液腺癌。在一些典型的实施方案中，所述粘液腺癌为中分化或低分化粘液腺癌。
在本申请的一些实施方案中，提供了一种治疗印戒细胞癌的化合物I或药物组合物，所述药物组合物包含化合物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，所述印戒细胞癌为晚期和/或转移性印戒细胞癌；在一些更为典型的实施方案中，所述的印戒细胞癌为紫杉烷类抗肿瘤药、喜树碱类抗肿瘤药、阿霉素类抗肿瘤药、铂配合物和/或氟嘧啶衍生物治疗失败的晚期和/或转移性印戒细胞癌。
在本申请的一些实施方案中，提供了一种治疗胃食管结合部腺癌的化合物I或药物组合物，所述药物组合物包含化合物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，所述胃食管结合部腺癌为晚期和/或转移性胃食管结合部腺癌；在一些更为典型的实施方案中，所述的胃食管结合部腺癌为紫杉烷类抗肿瘤药、喜树碱类抗 肿瘤药、阿霉素类抗肿瘤药、铂配合物和/或氟嘧啶衍生物治疗失败的晚期和/或转移性胃食管结合部腺癌。在一些典型的实施方案中，所述胃食管结合部癌为中分化或低分化胃食管结合部腺癌。
在本申请的一些实施方案中，紫杉烷类抗肿瘤药包括但不限于紫杉醇和多西他赛；喜树碱类抗肿瘤药包括但不限于伊立替康；阿霉素类抗肿瘤药包括但不限于表柔比星；铂配合物包括但不限于顺铂、卡铂、奈达铂、奥沙利铂中的一种或几种；在一些实施方案中，氟嘧啶衍生物包括但不限于卡培他滨、氟尿嘧啶、双呋氟尿嘧啶、去氧氟尿苷、替加氟、卡莫氟中的一种或几种。
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申请的范围内，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5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量为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量为16毫克。
在本申请的一些实施方案中，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。在本申请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。
在一些实施方案中，提供了一种治疗胃癌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5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。在一些特定的实施方案中，该单位剂量形式的药物组合物含有16毫克的化合物I或其药学上可接受的盐。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。
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。
在一些实施方案中，提供的治疗胃癌的药物组合物包含化合物I或其药学上可接受的盐作为唯一的活性成分。在一些实施方案中，提供的治疗胃癌的药物组合物包含化合物I或其药学上可接受的盐，还进一步包含其他抗肿瘤药物。在一些实施方案中，其他抗肿瘤药物包括但不限于铂配合物、氟嘧啶衍生物、喜树碱及其衍生物、蒽醌类抗肿瘤抗生素、紫杉烷类化合物、丝裂霉素、曲妥珠单抗中的一种或几种。在一些实施方案中，铂配合物包括但不限于顺铂、卡铂、奈达铂、奥沙利铂中的一种或几种；在一些实施方案中，氟嘧啶衍生物包括但不限于卡培他滨、氟尿嘧啶、双呋氟尿嘧啶、去氧氟尿苷、替加氟、卡莫氟中的一种或几种；在一些实施方案中，喜树碱及其衍生物包括但不限于喜树碱、羟基喜树碱、伊立替康、拓扑替康中的一种或几种；在一些实施方案中，蒽醌类抗肿瘤抗生素包括但不限于多柔比星、表柔比星、柔红霉素、米托蒽醌中的一种或几种；在一些实施方案中，紫杉烷类化合物包括但不限于紫杉醇和/或多西他赛。
另一方面，本申请还提供了用于治疗胃癌的试剂盒，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)用于治疗胃癌的说明书。在一些实施方案中，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适于口服的制剂和(b)以间隔给药的方式用于治疗胃癌的说明书。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胃癌的说明书。
在一些实施方案中，胃癌为晚期和/或转移性胃癌；在一些典型的实施方案中，所述胃癌为紫杉烷类抗肿瘤药、喜树碱类抗肿瘤药、阿霉素类抗肿瘤药、铂配合物和/或氟嘧啶衍生物治疗失败的晚期和/或转移性胃癌；在一些典型的实施方案中，所述胃癌为中分化或低分化胃癌。
在本申请的一些实施方案中，所述胃癌为胃腺癌；在一些典型的实施方案中，所述胃腺癌为紫杉烷类抗肿瘤药、喜树碱类抗肿瘤药、阿霉素类抗肿瘤药、铂配合物和/或氟嘧啶衍生物治疗失败的晚期和/或转移性胃腺癌；在一些典型的实施方案中，所述胃腺癌为中分化或低分化胃腺癌。
在本申请的一些实施方案中，所述的胃腺癌包括但不限于乳头状腺癌、管状腺癌、粘液腺癌、印戒细胞癌或上述组织学类型的混合性腺癌。在一些典型的实施方案中，所述的胃腺癌为紫杉烷类抗肿瘤药、喜树碱类抗肿瘤药、阿霉素类抗肿瘤药、铂配合物和/或氟嘧啶衍生物治疗失败的晚期和/或转移性乳头状腺癌、管状腺癌、粘液腺癌、印戒细胞癌或上述组织学类型的混合性腺癌；在一些典型的实施方案中，所述的胃腺癌为中分化或低分化的乳头状腺 癌、管状腺癌、粘液腺癌或上述组织学类型的混合性腺癌。
在本申请的一些实施方案中，所述胃癌为胃食管结合部腺癌；在一些典型的实施方案中，所述胃食管结合部腺癌为紫杉烷类抗肿瘤药、喜树碱类抗肿瘤药、阿霉素类抗肿瘤药、铂配合物和/或氟嘧啶衍生物治疗失败的晚期和/或转移性胃食管结合部腺癌。
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，该单位剂量形式的药物组合物含有2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5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。在一些特定的实施方案中，该单位剂量形式的药物组合物含有16毫克的化合物I或其药学上可接受的盐。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。
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。
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申请的范围内，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。
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，除非另有说明，qd指每天给药一次。
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。在一些实施方案中，所述患者为经标准治疗失败或缺乏标准治疗的患者。
“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)。
“PR”是指部分缓解，具体指肿瘤的靶病灶直径之和比基线水平减少30％以上。
“PD”是指疾病进展，具体指肿瘤的靶病灶直径之和比基线水平增加20％以上。
“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。
“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；其中不可耐受是指血液学毒性达IV级(血小板下降III级及以上)、非血液学毒性达到III级或以上。
“晚期”包括“局部晚期”。
具体实施方式
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 PCTCN2017080563-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 PCTCN2017080563-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，可参照上述相同的比例和处方制备得到。
实施例3对胃癌的疗效
1)病史
男，60岁，2013年11月28号因“进食哽咽感两年，加重一月”行胃镜检查示：胃食管结合部癌。于2013年12月11日在全麻下行根治术(食管胃部分切除，食管胃弓下端侧吻合术+淋巴结清扫术)，术后病理示：胃食管结合部溃疡性中-低分化腺癌。
术后于2014年1月15日-5月18日在胸外科行“奈达铂160mg+多西他赛120mg”化疗4周期；期间复查胸部CT提示：“胃食管结合部癌术后”改变，余未见异常。2014年10月29日行胸部CT检查提示：双肺结节影较前增多、增大，考虑转移瘤，肝多发病变，考虑转移瘤。考虑疾病进展。后于2014年10月30日、11月23日、12月18日、2015年1月15日、2月9日、3月10日行6周期化疗，具体用药为“奥沙利铂250mg+替吉奥(即氟嘧啶衍生物口服抗癌剂)胶囊60mg”。2015年6月8日CT提示：1、吻合口处稍增厚，双肺部分结节较前增大；2、肝右叶转移瘤较前增大、增多，提示疾病进展。继续口服替吉奥胶囊60mg，7月19日复查CT示：1：双肺部分结节较前增大；肝右叶部分转移瘤较前略增大。综合评价病情进展。
2015年9月9日开始口服化合物I二盐酸盐胶囊12mg qd治疗，连续用药2周停药1周。
2)CT结果
患者接受化合物I二盐酸盐胶囊(12mg qd)治疗2周期后，增强CT提示肝右叶转移瘤较前增大，腹膜后淋巴结肿大，余大致同前。疗效评价为SD(靶病灶：肝右叶后上段36mm，肝左叶16mm；非靶病灶：双肺多发结节，右肺下叶结节影)
3)耐受性
服药2周期，患者无其他明显不良反应，仍在继续接受治疗。
实施例4对胃癌的疗效
1)病史
47岁男性，因“腹痛及发现左颈部肿物”于2014年7月3日行胃镜检查并行胃窦部肿物活检。病理结果汇报：溃疡型中分化腺癌。行左颈部肿物穿刺活检病理提示：淋巴结转移性癌。
先行“替吉奥+奥沙利铂”化疗，经3个周期的化疗后，疗效为PR；经6个周期的化疗后复查，胸腹及盆腔CT平扫+增强提示：1.胃窦癌并胃周、腹主动脉旁淋巴结转移，原位病变及部分淋巴结转移灶似有好转。2.盆腔未见异常；疗效为PD。又行“紫杉醇+卡培他滨”化疗，疗效为PD。
患者2015年9月17日开始口服化合物I二盐酸盐胶囊12mg qd治疗，连续用药2周停药1周。服药前临床诊断：1.胃窦癌；2.全身多发转移癌(多发淋巴结、肺)。临床分期：Ⅳ期，TNM分期：cT4N2M1
2)CT结果
Figure PCTCN2017080563-appb-000004
3)耐受性
服药4周期，患者不良反应基本可耐受，面部皮肤色素沉着较之前减轻，精神状态也较之前好，仍在继续接受化合物I二盐酸盐胶囊治疗。
实施例5对胃癌的疗效
1)病史
45岁女性，2014年12月发现左乳肿物，穿刺病理示：左乳慢性乳腺炎改变，2015年5 月15日左锁骨上淋巴结肿块，病理示：少数纤维炎性细胞，2015年6月12日胃镜见为浸润性肿瘤，病理示：印戒细胞癌，2015年6月18日左乳空心针病理提示见到浸润性癌，提示胃癌转移至乳腺。2015年6月25日行3周期“希罗达(即卡培他滨)1500mg+奥沙利铂209.3mg”化疗，3周期后，疗效为PD。
随后开始口服化合物I二盐酸盐胶囊12mg qd治疗，连续用药2周停药1周。
2)CT结果
服药2周期后CT复查，评价为SD。
3)耐受性
服药2周期，患者偶发略微心悸不适，不良反应基本可耐受，仍在继续接受化合物I二盐酸盐治疗。
实施例6对胃癌的疗效
1)病史
61岁男性，2015年6月，因“消瘦、乏力3个月，胃镜检查，示胃腺癌”；，行胃癌根治术。术后病理示：胃：息肉型中分化管状腺癌。2015年7月，术后复查CT提示转移至肝脏。2015年7月至8月，行XELOX方案(奥沙利铂+卡培他滨)化疗2周期，复查CT示肝部病灶较前增大。2015年9月，更换为“紫杉醇+替吉奥”方案化疗5周期。然后复查，判效PD。
2015年12月，患者开始口服化合物I二盐酸盐胶囊12mg qd治疗，连续用药2周停药1周。服药前临床诊断：1.胃癌肝转移；临床分期：T3N3aM0；TNM分期：T3N3aM0。
2)CT检查结果
Figure PCTCN2017080563-appb-000005
Figure PCTCN2017080563-appb-000006
注：上表CT靶病灶选取肝脏两处病灶，例如“肝脏41mm，肝脏22mm”指肝脏的两处病灶中，其中一处病灶长度为41mm，另一处病灶长度为22mm。
实施例7对胃癌的疗效
1)病史
52岁男性，2014年3月无明显诱因下出现进食后哽咽感，胃镜诊断：胃癌；病理示：胃体、胃窦腺癌。2015年1月，在全麻下行根治性全胃切除+食管空肠Roux-en-Y吻合术。术后病理示：全胃切除标本：(胃体、窦小弯侧)腺癌，Ⅱ-Ⅲ级，部分为粘液腺癌，溃疡型肿块，肿瘤大小6*4.5*1.5cm，肿瘤浸润胃壁全层达浆膜外脂肪结缔组织。上下切缘未见癌残留。胃小弯、胃大弯淋巴结可见癌转移。Lauren分型：混合型。
2014年6月至7月，行“注射用紫杉醇脂质体+5-氟尿嘧啶”化疗方案1个周期，未评估疗效。于2014年7月至10月，行“注射用紫杉醇脂质体+奥沙利铂+5-氟尿嘧啶”化疗方案4个周期，后复查CT，提示PD。2015年3月至4月，行“奥沙利铂+卡培他滨”化疗方案2周期，2015年9月，胸腹部CT示胃癌术后二线治疗后出现进展。
患者2015年9月12日开始口服化合物I二盐酸盐胶囊12mg qd治疗，连续用药2周停药1周。服药前临床诊断：胃癌。临床分期：Ⅳ期，TNM分期：T4aN1M1。
2)CT结果
Figure PCTCN2017080563-appb-000007

Claims (34)

  1. 治疗胃癌的方法，所述方法包括给予需要治疗的患者治疗有效量的具有如下结构式的化合物I或其药学上可接受的盐、水合物或前药，
    Figure PCTCN2017080563-appb-100001
  2. 如权利要求1所述的方法，其中所述胃癌为晚期和/或转移性胃癌。
  3. 如权利要求1或2所述的方法，其中所述胃癌为紫杉烷类抗肿瘤药、喜树碱类抗肿瘤药、阿霉素类抗肿瘤药、铂配合物和/或氟嘧啶衍生物治疗失败的胃癌。
  4. 如权利要求1-3中任一项所述的方法，其中所述胃癌为中分化或低分化胃癌。
  5. 如权利要求1-4中任一项所述的方法，其中所述胃癌为胃腺癌或胃食管结合部腺癌。
  6. 如权利要求5所述的方法，其中所述胃腺癌为乳头状腺癌、管状腺癌、粘液腺癌、印戒细胞癌或上述组织学类型的混合性腺癌。
  7. 如根据权利要求1-6中任一项所述的方法，其中所述化合物I的药学上可接受的盐为化合物I的盐酸盐，优选化合物I的二盐酸盐。
  8. 如权利要求1-7中任一项所述的方法，其中以间隔给药的方式给予所述化合物I或其药学上可接受的盐，优选给药期和停药期以天数计的比值为2:0.5～5，优选2:0.5～3，较优选2:0.5～2，更优选2:0.5～1。
  9. 如权利要求1-8中任一项所述的方法，其中将所述化合物I或其药学上可接受的盐连续给药2周停药2周，或者连续给药2周停药1周，或者连续给药5天停药2天。
  10. 如权利要求1-9中任一项所述的方法，其中，给予所述化合物I或其药学上可接受的盐的日剂量为2毫克至20毫克，优选为5毫克至20毫克，更优选为8毫克至20毫克，进一步优选为10毫克至16毫克，最优选为10毫克、12毫克、14毫克或16毫克。
  11. 如权利要求1-10中任一项所述的方法，其中所述化合物I或其药学上可接受的盐以每日一次12mg的剂量口服给药，连续用药2周，停1周的给药方式给药。
  12. 如权利要求1-11中任一项所述的方法，其中所述化合物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胃癌患者；所述其他抗肿瘤药物为铂配合物、氟嘧啶衍生物、 喜树碱及其衍生物、蒽醌类抗肿瘤抗生素、紫杉烷类化合物、丝裂霉素、曲妥珠单抗中的一种或几种。
  13. 具有如下结构式的化合物I或其药学上可接受的盐、水合物或前药在制备用于治疗胃癌的药物中的用途，
    Figure PCTCN2017080563-appb-100002
  14. 如权利要求13所述的用途，其中所述胃癌为晚期和/或转移性胃癌。
  15. 如权利要求13或14所述的用途，其中所述胃癌为紫杉烷类抗肿瘤药、喜树碱类抗肿瘤药、阿霉素类抗肿瘤药、铂配合物和/或氟嘧啶衍生物治疗失败的胃癌。
  16. 如权利要求13-15中任一项所述的用途，其中所述胃癌为中分化或低分化胃癌。
  17. 如权利要求13-16中任一项所述的用途，其中所述胃癌为胃腺癌或胃食管结合部腺癌。
  18. 如权利要求17所述的用途，其中所述胃腺癌为乳头状腺癌、管状腺癌、粘液腺癌、印戒细胞癌或上述组织学类型的混合性腺癌。
  19. 如根据权利要求13-18中任一项所述的用途，其中所述化合物I的药学上可接受的盐为化合物I的盐酸盐，优选化合物I的二盐酸盐。
  20. 如权利要求13-19中任一项所述的用途，所述治疗胃癌的药物进一步包括其他抗肿瘤药物，所述其他抗肿瘤药物为铂配合物、氟嘧啶衍生物、喜树碱及其衍生物、蒽醌类抗肿瘤抗生素、紫杉烷类化合物、丝裂霉素、曲妥珠单抗中的一种或几种。
  21. 治疗胃癌的具有如下结构式的化合物I或药物组合物，其中所述药物组合物包含化合物I或其药学上可接受的盐、水合物或前药，以及至少一种药学上可接受的载体，
    Figure PCTCN2017080563-appb-100003
  22. 如权利要求21所述的化合物I或药物组合物，其中所述胃癌为晚期和/或转移性胃癌。
  23. 如权利要求21或22所述的化合物I或药物组合物，其中所述胃癌为紫杉烷类抗肿瘤药、喜树碱类抗肿瘤药、阿霉素类抗肿瘤药、铂配合物和/或氟嘧啶衍生物治疗失败的胃癌。
  24. 如权利要求21-23中任一项所述的化合物I或药物组合物，其中所述胃癌为中分化或低分化中分化或低分化胃癌。
  25. 如权利要求21-24中任一项所述的化合物I或药物组合物，其中所述胃癌为胃腺癌或胃食管结合部腺癌。
  26. 如权利要求25所述的化合物I或药物组合物，其中所述胃腺癌为乳头状腺癌、管状腺癌、粘液腺癌、印戒细胞癌或上述组织学类型的混合性腺癌。
  27. 如根据权利要求21-26中任一项所述的化合物I或药物组合物，其中所述化合物I的药学上可接受的盐为化合物I的盐酸盐，优选化合物I的二盐酸盐。
  28. 如权利要求21-27中任一项所述的化合物I或药物组合物，其中单位剂量形式的药物组合物含有2毫克至20毫克的化合物I或其药学上可接受的盐，优选为5毫克至20毫克，更优选为8毫克至20毫克，进一步优选为10毫克至16毫克，最优选为10毫克、12毫克、14毫克或16毫克。
  29. 如权利要求21-28中任一项所述的化合物I或药物组合物，其中以间隔给药的方式给予所述化合物I或药物组合物，给药期和停药期以天数计的比值为2:0.5～5，优选2:0.5～3，较优选2:0.5～2，更优选2:0.5～1。
  30. 如权利要求21-29中任一项所述的化合物I或药物组合物，其中将所述化合物I或药物组合物连续给药2周停药2周，或者连续给药2周停药1周，或者连续给药5天停药2天。
  31. 如权利要求21-30中任一项所述的化合物I或药物组合物，其中所述化合物I或药物组合物以每日一次12mg的剂量口服给药，连续用药2周，停1周的给药方式给药。
  32. 如权利要求21-31中任一项所述的化合物I或药物组合物，其中所述化合物I或药物组合物是适于口服的制剂，优选片剂和胶囊剂。
  33. 如权利要求21-32中任一项所述的化合物I或药物组合物，其中所述药物组合物还进一步包含其他抗肿瘤药物，所述其他抗肿瘤药物为铂配合物、氟嘧啶衍生物、喜树碱及其衍生物、蒽醌类抗肿瘤抗生素、紫杉烷类化合物、丝裂霉素、曲妥珠单抗中的一种或几种。
  34. 用于治疗胃癌的试剂盒，其包含(a)至少一个单位剂量的具有如下结构式的化合物I或其药学上可接受的盐、水合物或前药的药物组合物和(b)用于治疗胃癌的说明书；优选一种试剂盒，其包含(a)至少一个单位剂量的具有如下结构式的化合物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胃癌的说明书；进一步优选一 种试剂盒，其包含(a)至少一个单位剂量的具有如下结构式的化合物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胃癌的说明书；
    Figure PCTCN2017080563-appb-100004
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