WO2020029918A1 - 用于治疗结外nk/t细胞淋巴瘤的喹啉衍生物 - Google Patents

用于治疗结外nk/t细胞淋巴瘤的喹啉衍生物 Download PDF

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WO2020029918A1
WO2020029918A1 PCT/CN2019/099264 CN2019099264W WO2020029918A1 WO 2020029918 A1 WO2020029918 A1 WO 2020029918A1 CN 2019099264 W CN2019099264 W CN 2019099264W WO 2020029918 A1 WO2020029918 A1 WO 2020029918A1
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acid
compound
extranodal
cell lymphoma
pharmaceutically acceptable
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PCT/CN2019/099264
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English (en)
French (fr)
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陶荣
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正大天晴药业集团股份有限公司
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Priority to CN201980050370.7A priority Critical patent/CN112584834B/zh
Publication of WO2020029918A1 publication Critical patent/WO2020029918A1/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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention belongs to the field of medicine, and specifically relates to the use of quinoline derivatives in the treatment of extranodal NK / T-cell lymphoma.
  • Lymphoma is a hematological malignancy and one of the fastest growing malignancies. Lymphoma is the most rapidly updated tumor with the most classification changes, including Hodgkin's lymphoma (HL) and non-Hodgkin's lymphoma (NHL). Among them, there are more types of non-Hodgkin's lymphoma. In China, the incidence of non-Hodgkin's lymphoma is significantly higher than Hodgkin's lymphoma.
  • Extranodal NK / T-cell lymphoma belongs to non-Hodgkin's lymphoma, which is characterized by vascular centrality caused by malignant cells of NK or cytotoxic T cell phenotype And vascular destructive infiltration, often involving the nasal cavity.
  • NK / TCL is a rare highly aggressive lymphoma that is closely related to EB virus infection. China has the highest incidence in the world.
  • the 5-year survival rate of patients with advanced chemotherapy after traditional chemotherapy is 9%.
  • the latest domestic retrospective research results show that the 5-year survival rate of advanced patients is only about 20%, and the prognosis is extremely poor.
  • L-asparaginase-based chemotherapy has emerged in recent years, with significant improvements in efficacy.
  • Chemotherapy based on L-asparaginase or Pespartase has significantly improved treatment response and survival rates in patients with NK / TCL, and contains high-dose methotrexate, etoposide, dexamethasone, ifosfamide
  • the combined chemotherapy regimen with L-asparaginase enables about 40-60% of patients with advanced or relapsed / refractory patients to achieve a complete response (CR) with a 1-year survival rate of more than 45%.
  • CR complete response
  • the prognosis of relapsed NK / TCL is extremely poor.
  • the median progression-free survival (PFS) is only 4.1 months, and the median overall survival (OS) is 6.4 months even after retreatment.
  • the present invention provides a method of treating extranodal NK / T-cell lymphoma, 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 present invention also provides a method for treating extranodal NK / T-cell lymphoma that has failed treatment with chemotherapy drugs and / or targeted drugs, which method comprises administering a therapeutically effective amount of Compound I or a pharmaceutically acceptable compound thereof to a patient in need of treatment. Accepted salt.
  • the chemotherapeutic drugs include, but are not limited to, asparaginase antitumor drugs, antifolate antitumor drugs, podophyllum anticancer drugs, steroid hormone drugs, and alkylating agents. One or more antitumor drugs.
  • the chemotherapeutic drugs include, but are not limited to, L-asparaginase, peiase, methotrexate, etoposide, dexamethasone, ifosfamide, gemcitabine, oxa One or more of Riboplatin, Cytarabine, Capecitabine, Docetaxel, Bortezomib, Sindizumab, Apatinib, Lenalidomide, Prednisone.
  • the asparaginase-type antitumor drug includes, but is not limited to, one or more of L-asparaginase and peparinase.
  • the chemotherapeutic drug and / or targeted drug failed to treat extranodal NK / T-cell lymphoma is asparagine-resistant extranodal NK / T-cell lymphoma. In some more typical embodiments, the chemotherapeutic drug and / or targeted drug failed to treat extranodal NK / T-cell lymphoma is asparagine-resistant clinical stage IV extranodal NK / T-cell lymphoma.
  • the extranodal NK / T-cell lymphoma is refractory extranodal NK / T-cell lymphoma. In some embodiments, the extranodal NK / T cell lymphoma is a recurrent extranodal NK / T cell lymphoma. In some embodiments, the extranodal NK / T cell lymphoma is a relapsed and / or refractory extranodal NK / T cell lymphoma. In some embodiments, the extranodal NK / T-cell lymphoma is an extranodal NK / T-cell lymphoma that recurs after failure of radiation therapy.
  • 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, intraarticular, 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.
  • a method for treating extranodal NK / T-cell lymphoma by administering targeted drugs to concurrent radiotherapy wherein the method of administering targeted drugs to concurrent radiotherapy is to concurrently administer a therapeutically effective amount of a patient in need of treatment.
  • Compound I or a pharmaceutically acceptable salt thereof as well as radiotherapy.
  • a method for treating extranodal NK / T-cell lymphoma by administering targeted drug sequential radiotherapy is provided, wherein the method of administering targeted drug sequential radiotherapy is effective in first treating patients in need of treatment An amount of Compound I or a pharmaceutically acceptable salt thereof is followed by radiation therapy.
  • Compound I or a pharmaceutically acceptable salt thereof is administered alone as the sole active ingredient to a patient with extranodal NK / T-cell lymphoma. In some embodiments, Compound I or a pharmaceutically acceptable salt thereof is administered to a patient with extranodal NK / T-cell lymphoma at the same time or sequentially with other antitumor drugs.
  • other antitumor drugs include, but are not limited to, antifolate antitumor drugs, podophyllotium anticancer drugs, steroid hormone drugs, alkylating agent antitumor drugs, camptothecin antitumor drugs, One or more of a platinum complex, a fluoropyrimidine derivative, an anthraquinone antitumor antibiotic, a taxane compound, 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 extranodal NK / T-cell lymphoma.
  • the present invention also provides the use of Compound I or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of extranodal NK / T-cell lymphomas for which chemotherapy drugs and / or targeted drug treatments fail.
  • the chemotherapeutic drugs include, but are not limited to, asparaginase antitumor drugs, antifolate antitumor drugs, podophyllum anticancer drugs, steroid hormone drugs, and alkylating agents.
  • One or more antitumor drugs include, but are not limited to, asparaginase antitumor drugs, antifolate antitumor drugs, podophyllum anticancer drugs, steroid hormone drugs, and alkylating agents.
  • One or more antitumor drugs are examples of antitumor drugs.
  • the chemotherapeutic drugs include, but are not limited to, L-asparaginase, peparinase, methotrexate, etoposide, dexamethasone, ifosfamide, mitoxantrone , Gemcitabine, oxaliplatin, cytarabine, capecitabine, docetaxel, bortezomib, apatinib, lenalidomide, prednisone.
  • the asparaginase-type antitumor drug includes, but is not limited to, one or more of L-asparaginase and peparinase.
  • the chemotherapeutic drug and / or targeted drug failed to treat extranodal NK / T-cell lymphoma is asparagine-resistant extranodal NK / T-cell lymphoma. In some more typical embodiments, the chemotherapeutic drug and / or targeted drug failed to treat extranodal NK / T-cell lymphoma is asparagine-resistant clinical stage IV extranodal NK / T-cell lymphoma.
  • the extranodal NK / T-cell lymphoma is refractory extranodal NK / T-cell lymphoma. In some embodiments, the extranodal NK / T cell lymphoma is a recurrent extranodal NK / T cell lymphoma. In some embodiments, the extranodal NK / T cell lymphoma is a relapsed and / or refractory extranodal NK / T cell lymphoma. In some embodiments, the extranodal NK / T-cell lymphoma is an extranodal NK / T-cell lymphoma that recurs after failure of radiation therapy.
  • 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.
  • administration is in the form of Compound I maleate. 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, administration is in the form of Compound I dimaleate. 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. In a particular embodiment, Compound I dimaleate is administered in the form of a crystal.
  • 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. Oral preparations are more preferably tablets, capsules, powders, granules, drip pills, pastes or powders, and more preferably tablets or capsules.
  • 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 amount of Compound I or a pharmaceutically acceptable salt thereof is from 8 mg to 20 mg.
  • the amount of Compound I or a pharmaceutically acceptable salt thereof is 10 mg to 16 mg.
  • the amount of Compound I or a pharmaceutically acceptable salt thereof is 10 mg to 14 mg.
  • the amount of Compound I or a pharmaceutically acceptable salt thereof is 8 mg. In some specific embodiments, the amount of Compound I or a pharmaceutically acceptable salt thereof is 10 mg. In some specific embodiments, the amount of Compound I or a pharmaceutically acceptable salt thereof is 12 mg. In some specific embodiments, the amount 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. This 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.
  • a method for treating extranodal NK / T-cell lymphoma by administering targeted drugs to concurrent radiotherapy wherein the method of administering targeted drugs to concurrent radiotherapy is to concurrently administer a therapeutically effective amount of a patient in need of treatment.
  • Compound I or a pharmaceutically acceptable salt thereof as well as radiotherapy.
  • a method for treating extranodal NK / T-cell lymphoma by administering targeted drug sequential radiotherapy is provided, wherein the method of administering targeted drug sequential radiotherapy is effective in first treating patients in need of treatment An amount of Compound I or a pharmaceutically acceptable salt thereof is followed by radiation therapy.
  • Compound I or a pharmaceutically acceptable salt thereof is administered alone as the sole active ingredient to a patient with extranodal NK / T-cell lymphoma. In some embodiments, Compound I or a pharmaceutically acceptable salt thereof is administered to a patient with extranodal NK / T-cell lymphoma at the same time or sequentially with other antitumor drugs.
  • other antitumor drugs include, but are not limited to, antifolate antitumor drugs, podophyllotium anticancer drugs, steroid hormone drugs, alkylating agent antitumor drugs, camptothecin antitumor drugs, One or more of a platinum complex, a fluoropyrimidine derivative, an anthraquinone antitumor antibiotic, a taxane compound, an EGFR inhibitor, a VEGFR inhibitor, mitomycin, and trastuzumab.
  • the present invention provides a pharmaceutical composition for treating extranodal NK / T-cell lymphoma, 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 extranodal NK / T-cell lymphoma that fails chemotherapy treatment and / or targeted drug treatment, which comprises Compound I or a pharmaceutically acceptable salt thereof, and at least one pharmaceutical Acceptable carrier.
  • the chemotherapeutic drugs include, but are not limited to, asparaginase antitumor drugs, antifolate antitumor drugs, podophyllum anticancer drugs, steroid hormone drugs, and alkylating agents. One or more antitumor drugs.
  • the chemotherapeutic drugs include, but are not limited to, L-asparaginase, peparinase, methotrexate, etoposide, dexamethasone, ifosfamide, mitoxantrone , Gemcitabine, oxaliplatin, cytarabine, capecitabine, docetaxel, bortezomib, apatinib, lenalidomide, prednisone.
  • the asparaginase-type antitumor drug includes, but is not limited to, one or more of L-asparaginase and peparinase.
  • the chemotherapeutic drug and / or targeted drug failed to treat extranodal NK / T-cell lymphoma is asparagine-resistant extranodal NK / T-cell lymphoma. In some more typical embodiments, the chemotherapeutic drug and / or targeted drug failed to treat extranodal NK / T-cell lymphoma is asparagine-resistant clinical stage IV extranodal NK / T-cell lymphoma.
  • the extranodal NK / T-cell lymphoma is refractory extranodal NK / T-cell lymphoma. In some embodiments, the extranodal NK / T cell lymphoma is a recurrent extranodal NK / T cell lymphoma. In some embodiments, the extranodal NK / T cell lymphoma is a relapsed and / or refractory extranodal NK / T cell lymphoma. In some embodiments, the extranodal NK / T-cell lymphoma is an extranodal NK / T-cell lymphoma that recurs after failure of radiation therapy.
  • 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 amount of Compound I or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is from 8 mg to 20 mg. In some embodiments, the amount of Compound I or a pharmaceutically acceptable salt thereof is 10 mg to 16 mg. In some embodiments, the amount of Compound I or a pharmaceutically acceptable salt thereof is 10 mg to 14 mg.
  • the amount of Compound I or a pharmaceutically acceptable salt thereof is 8 mg. In some specific embodiments, the amount of Compound I or a pharmaceutically acceptable salt thereof is 10 mg. In some specific embodiments, the amount of Compound I or a pharmaceutically acceptable salt thereof is 12 mg. In some specific embodiments, the amount 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, 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.
  • a pharmaceutical composition formulated to treat extranodal NK / T-cell lymphoma 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.
  • "a pharmaceutical composition in a unit dosage form" means each tablet or capsule.
  • the present invention also provides a pharmaceutical composition for treating extranodal NK / T-cell lymphoma that fails to treat chemotherapeutic drugs and / or targeted drugs, which is formulated in a unit dosage form, and comprises a compound I or a pharmaceutically acceptable salt thereof. , And at least one pharmaceutically acceptable carrier.
  • the chemotherapeutic drugs include, but are not limited to, asparaginase antitumor drugs, antifolate antitumor drugs, podophyllum anticancer drugs, steroid hormone drugs, and alkylating agents.
  • One or more antitumor drugs are not limited to, asparaginase antitumor drugs, antifolate antitumor drugs, podophyllum anticancer drugs, steroid hormone drugs, and alkylating agents.
  • the chemotherapeutic drugs include, but are not limited to, L-asparaginase, peparinase, methotrexate, etoposide, dexamethasone, ifosfamide, mitoxantrone , Gemcitabine, oxaliplatin, cytarabine, capecitabine, docetaxel, bortezomib, apatinib, lenalidomide, prednisone.
  • the asparaginase-type antitumor drug includes, but is not limited to, one or more of L-asparaginase and peparinase.
  • the chemotherapeutic drug and / or targeted drug failed to treat extranodal NK / T-cell lymphoma is asparagine-resistant extranodal NK / T-cell lymphoma. In some more typical embodiments, the chemotherapeutic drug and / or targeted drug failed to treat extranodal NK / T-cell lymphoma is asparagine-resistant clinical stage IV extranodal NK / T-cell lymphoma.
  • 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.
  • a method for treating extranodal NK / T-cell lymphoma by administering targeted drugs to concurrent radiotherapy wherein the method of administering targeted drugs to concurrent radiotherapy is to concurrently administer a therapeutically effective amount of a patient in need of treatment.
  • Compound I or a pharmaceutically acceptable salt thereof as well as radiotherapy.
  • a method for treating extranodal NK / T-cell lymphoma by administering targeted drug sequential radiotherapy is provided, wherein the method of administering targeted drug sequential radiotherapy is effective in first treating patients in need of treatment An amount of Compound I or a pharmaceutically acceptable salt thereof is followed by radiation therapy.
  • Compound I or a pharmaceutically acceptable salt thereof is administered alone as the sole active ingredient to a patient with extranodal NK / T-cell lymphoma. In some embodiments, Compound I, or a pharmaceutically acceptable salt thereof, is administered to an extranodal NK / T-cell lymphoma patient simultaneously or sequentially with other antitumor drugs.
  • other antitumor drugs include, but are not limited to, antifolate antitumor drugs, podophyllotium anticancer drugs, steroid hormone drugs, alkylating agent antitumor drugs, camptothecin antitumor drugs, One or more of a platinum complex, a fluoropyrimidine derivative, an anthraquinone antitumor antibiotic, a taxane compound, 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) for treating extranodal NK / T cells Instructions for lymphoma.
  • 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) administered at intervals for treating the disease Instructions for outer NK / T-cell lymphoma.
  • 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 extranodal NK / T-cell lymphoma.
  • the extranodal NK / T-cell lymphoma is an extranodal NK / T-cell lymphoma that fails to be treated with a chemotherapeutic drug and / or a targeted drug.
  • the “unit dose or unit dose” refers to a pharmaceutical composition packaged in a single package for convenience of administration. For example, each tablet or capsule.
  • the chemotherapeutic drugs include, but are not limited to, asparaginase antitumor drugs, antifolate antitumor drugs, podophyllum anticancer drugs, steroid hormone drugs, and alkylating agents.
  • antitumor drugs include, but are not limited to, asparaginase antitumor drugs, antifolate antitumor drugs, podophyllum anticancer drugs, steroid hormone drugs, and alkylating agents.
  • One or more antitumor drugs include, but are not limited to, asparaginase antitumor drugs, antifolate antitumor drugs, podophyllum anticancer drugs, steroid hormone drugs, and alkylating agents.
  • One or more antitumor drugs include, but are not limited to, asparaginase antitumor drugs, antifolate antitumor drugs, podophyllum anticancer drugs, steroid hormone drugs, and alkylating agents.
  • One or more antitumor drugs include,
  • the chemotherapeutic drugs include, but are not limited to, L-asparaginase, peparinase, methotrexate, etoposide, dexamethasone, ifosfamide, mitoxantrone , Gemcitabine, oxaliplatin, cytarabine, capecitabine, docetaxel, bortezomib, apatinib, lenalidomide, prednisone.
  • the asparaginase-type antitumor drug includes, but is not limited to, one or more of L-asparaginase and peparinase.
  • the chemotherapeutic drug and / or targeted drug failed to treat extranodal NK / T-cell lymphoma is asparagine-resistant extranodal NK / T-cell lymphoma. In some more typical embodiments, the chemotherapeutic drug and / or targeted drug failed to treat extranodal NK / T-cell lymphoma is asparagine-resistant clinical stage IV extranodal NK / T-cell lymphoma.
  • the extranodal NK / T-cell lymphoma is refractory extranodal NK / T-cell lymphoma. In some embodiments, the extranodal NK / T cell lymphoma is a recurrent extranodal NK / T cell lymphoma. In some embodiments, the extranodal NK / T cell lymphoma is a relapsed and / or refractory extranodal NK / T cell lymphoma. In some embodiments, the extranodal NK / T-cell lymphoma is an extranodal NK / T-cell lymphoma that recurs after failure of radiation therapy.
  • 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 pharmaceutical composition in the 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. In some specific embodiments, the pharmaceutical composition in the unit dosage form contains 8 mg of Compound I or a pharmaceutically acceptable salt thereof.
  • 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.
  • a pharmaceutical composition in a unit dosage form means each tablet or capsule.
  • 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 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.
  • a method for treating extranodal NK / T-cell lymphoma by administering simultaneous radiotherapy to a targeted drug wherein the simultaneous radiotherapy is administered to a patient in need of a therapeutically effective amount of the same drug Compound I or a pharmaceutically acceptable salt thereof as well as radiotherapy.
  • a method for treating extranodal NK / T-cell lymphoma by administering targeted drug sequential radiotherapy is provided, wherein the method of administering targeted drug sequential radiotherapy is effective in first treating patients in need of treatment An amount of Compound I or a pharmaceutically acceptable salt thereof is followed by radiation therapy.
  • Compound I or a pharmaceutically acceptable salt thereof is administered alone as the sole active ingredient to a patient with extranodal NK / T-cell lymphoma. In some embodiments, Compound I or a pharmaceutically acceptable salt thereof is administered to a patient with extranodal NK / T-cell lymphoma at the same time or sequentially with other antitumor drugs.
  • other antitumor drugs include, but are not limited to, antifolate antitumor drugs, podophyllotium anticancer drugs, steroid hormone drugs, alkylating agent antitumor drugs, camptothecin antitumor drugs, One or more of a platinum complex, a fluoropyrimidine derivative, an anthraquinone antitumor antibiotic, a taxane compound, an EGFR inhibitor, a VEGFR inhibitor, mitomycin, and trastuzumab.
  • 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.
  • any reference to anlotinib refers to compound I.
  • 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 , Caproic 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, 3-phen
  • 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:
  • CR means complete remission, specifically the disappearance of the target lesion of the tumor, and the short diameter of all pathological lymph nodes must be reduced to ⁇ 10mm.
  • PR refers to partial remission, specifically the sum of the diameter of the target lesions of the tumor is reduced by more than 30% from the baseline level.
  • PD refers to disease progression, specifically the sum of the diameters of the target lesions of a tumor is increased by more than 20% from the baseline level.
  • 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.
  • “Failure to treat” refers to intolerable toxic and side effects, disease progression during treatment, or relapse after treatment; among them, intolerance includes, but is not limited to, hematological toxicity up to level IV (thrombocytopenia level III and above), non-hematological toxicity Reach level III or above.
  • EGFR inhibitor refers to an epidermal growth factor receptor inhibitor.
  • VEGFR inhibitor refers to a vascular endothelial growth factor receptor inhibitor.
  • P-GemOx refers to the combined use of gemcitabine, oxaliplatin, and pepsin.
  • MTX nail methotrexate
  • VP16 means etoposide.
  • EA protocol refers to the combined use of cytarabine and etoposide.
  • the "DX” protocol refers to a combination of capecitabine and docetaxel.
  • the "MEDA” protocol refers to a combination of mitoxantrone, cytarabine, etoposide, and dexamethasone.
  • the "GIFOX” protocol refers to a combination of gemcitabine, ifosfamide and oxaliplatin.
  • the "BD” protocol refers to a combination of bortezomib and dexamethasone.
  • Qd means administration once a day.
  • FIG. 1 CT image of patient case 1 anlotinib after 3 cycles of treatment
  • FIG. 1 CT image of patient case 2 before anlotinib treatment
  • FIG. 4 CT image of patient case 2 anlotinib after 6 cycles of treatment
  • 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 same ratio and prescription as described above.
  • Drug resistance refers to disease progression during treatment or no response after at least 2 cycles of combined chemotherapy.
  • the clinical stage is stage IV, and there is at least one objectively evaluable lesion.
  • Liver function ALT, AST, TBIL ⁇ 3 times the upper limit of normal value
  • Coagulation routine plasma fibrinogen ⁇ 1.0g / L;
  • Cardiac function LVEF ⁇ 50%, ECG did not suggest any acute infarction, arrhythmia, or atrioventricular block above degree 1.
  • the recommended dose is 12 mg orally once a day, taken orally before breakfast, and taken continuously for two weeks and discontinued for one week, that is, a course of treatment every 3 weeks.
  • Dose adjustment Depending on the severity of the adverse reaction, researchers can adjust the dose. If the occurrence of Grade 3 adverse events does not return to Grade 2 before the planned medication, the drug dose can be reduced.
  • the first level of down-dose is 10 mg once a day, taken orally before breakfast and taken continuously for two weeks and discontinued for one week.
  • the second-level down-dose is 10 mg once daily, taken orally before breakfast, and taken continuously for two weeks and discontinued for one week.
  • drugs such as IL-11, serum erythropoietin (EPO), and thrombopoietin (TPO) can be given to support the treatment; the current chemotherapy showed a hematological toxicity of 3 degrees or more without reduction Patients can receive these drugs for prophylactic use.
  • Fibrinogen infusion can be given when plasma fibrinogen is less than 1.0 g / L, and albumin infusion can be given when less than 30 g / L.
  • Anlotinib is administered orally for 12 weeks and 24 weeks. There are 2 disease state assessments, and the allowable time window is +/- 5 days.
  • the efficacy standards refer to the Lugano2014 lymphoma efficacy standards. Objective efficacy scores were complete response (CR), partial response (PR), stability (SD), disease recurrence (after CR), or disease progression (PR, after SD).
  • PET / CT is the basic method of evaluation. Unconditional users require the use of enhanced CT or enhanced MRI. Biopsy should be performed as much as possible for newly emerging lesions or suspicious ones.
  • Adverse events were graded according to the International Oncology Chemotherapy Drug Adverse Reaction Evaluation System-General Adverse Reaction Terminology Standard Version 4.0 (NCI-CTC AE Ver 4.0). Adverse events not listed in the NCI toxicity classification criteria can be judged according to the following levels:
  • NK / T-cell lymphoma Patient, male, 29 years old. The left facial mass showed a nasal malignancy; biopsy showed CD3 (+), CD2 (+), CD20 (-), Pax-5 (-), Bc1-2 (partial +), Ki67 (+ , About 50%), CD56 (+), TIA +, Gran B +, EBER +, and the immunohistochemical results are more supportive for nasal NK / T-cell lymphoma.
  • the diagnosis of NK / T-cell lymphoma leukemia was made by bone puncture. P-GemOx + DEX regimen chemotherapy (1.6 g of gemcitabine, 150 mg of oxaliplatin, 150 mg of oxaliplatin, 3750 U of d2, dexamethasone 10 mg of dl-5) was given twice in September 2018.
  • Figure 1 is an image of anlotinib hydrochloride before treatment. On May 8, 2019, a single dose of anlotinib hydrochloride was given. 12 mg was taken orally daily, and the medication was stopped for two weeks and one week. After taking the medicine, the testicular and ear masses quickly shrink, and the nasal cavity resumes ventilation. After three weeks of anlotinib treatment, CT examination showed that the nasal tumor disappeared (Figure 2). Currently, the treatment is continued and the patient is still alive.
  • GIFOX + Bortezomib was used for radical chemotherapy twice, and the left maxillary sinus mass disappeared after chemotherapy.
  • BD + Gemcitabine was given once for radical chemotherapy.
  • a soft tissue mass appeared in the lower margin of the right orbit.
  • oral lenalidomide and prednisone were given from August 20, 2017.
  • the soft tissue mass in the lower margin of the right orbit did not shrink significantly.

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Abstract

提供一种用于治疗结外NK/T细胞淋巴瘤的喹啉衍生物。所提供的化合物I或其药学上可接受的盐，可用于治疗门冬酰胺耐药的结外NK/T细胞淋巴瘤患者，尤其对于门冬酰胺耐药的、复发或难治性结外NK/T细胞淋巴瘤患者，疗效评估结果表明其症状得到缓解，其生存期得到延长。

Description

用于治疗结外NK/T细胞淋巴瘤的喹啉衍生物 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结外NK/T细胞淋巴瘤中的用途。
背景技术
淋巴瘤是血液系统恶性肿瘤，是发病率增长最快的恶性肿瘤之一。淋巴瘤是分类变化最快更新最多的肿瘤，包括霍奇金淋巴瘤(HL)与非霍奇金淋巴瘤(NHL)，其中非霍奇金淋巴瘤的种类更为繁多。在我国，非霍奇金淋巴瘤的发病率明显高于霍奇金淋巴瘤。
结外NK/T细胞淋巴瘤(extranodal NK/T-cell lymphoma，NK/TCL)属于非霍奇金淋巴瘤，其特征为由NK或细胞毒性T细胞表型的恶性细胞所致的血管中心性和血管破坏性浸润，常累及鼻腔。NK/TCL是与EB病毒感染密切相关的一种罕见的高侵袭性淋巴瘤。我国发病率占世界首位。晚期患者接受传统化疗治疗5年生存率为9％。国内最新的回顾性研究结果显示晚期患者的5年生存率仅20％左右，预后极差。近年来出现的以左旋门冬酰胺酶为基础化疗方案，效显著提高。基于左旋门冬酰胺酶或培门冬酶的化疗对NK/TCL患者是治疗反应率和生存率均有明显改善，含有大剂量甲氨喋呤、依托泊苷、地塞米松、异环磷酰胺和左旋门冬酰胺酶的联合化疗方案使得约40-60％的晚期或者复发/难治患者获得完全缓解(CR)，1年生存率达到45％以上。但是现有治疗方式下，复发的NK/TCL预后极差，复发患者即使接受再次治疗中位无进展生存期(PFS)仅4.1个月，中位总生存期(OS)为6.4个月。疾病复发后一旦对门冬酰胺酶耐药，再次进展(耐药)后的中位生存时间仅2.3个月。对门冬酰胺酶耐药的患者目前无已知有效治疗方法，对门冬酰胺酶耐药的患者目前无已知有效治疗方法，因此亟需寻求新的治疗。
发明内容
第一方面，本发明提供了一种治疗结外NK/T细胞淋巴瘤的方法，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 PCTCN2019099264-appb-000001
本发明还提供了一种治疗化疗药物和/或靶向药物治疗失败的结外NK/T细胞淋巴瘤的方法，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但不限于门冬酰胺酶类抗肿瘤药物、抗叶酸类抗肿瘤药物、鬼臼类抗癌药物、甾体激素类药物、烷化剂类抗肿瘤药物的一种或多种。在一些典型的实施方案中，所述的化疗药物包括但不限于左旋门冬酰胺酶、培门冬酶、甲氨喋呤、依托泊苷、地塞米松、异环磷酰胺、吉西他滨、奥沙利铂、阿糖胞苷、卡培他滨、多西紫杉醇、硼替佐米、信迪利单抗、阿帕替尼、来那度胺、强的松的一种或多种。在一些典型的实施方案中，所述的门冬酰胺酶类抗肿瘤药物包括但不限于左旋门冬酰胺酶、培门冬酶的一种或多种。在一些更为典型的实施方案中，所述化疗药物和/或靶向药物治疗失败的结外NK/T细胞淋巴瘤为门冬酰胺耐药的结外NK/T细胞淋巴瘤。在一些更为典型的实施方案中，所述化疗药物和/或靶向药物治疗失败的结外NK/T细胞淋巴瘤为门冬酰胺耐药的临床IV期结外NK/T细胞淋巴瘤。
在一些实施案例中，所述的结外NK/T细胞淋巴瘤为难治性结外NK/T细胞淋巴瘤。在一些实施案例中，所述的结外NK/T细胞淋巴瘤为复发性结外NK/T细胞淋巴瘤。在一些实施案例中，所述的结外NK/T细胞淋巴瘤为复发和/或难治的结外NK/T细胞淋巴瘤。在一些实施案例中，所述的结外NK/T细胞淋巴瘤为放射治疗失败后复发的结外NK/T细胞淋巴瘤。
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，提供一种通过给予靶向药物同步放疗的方式治疗结外NK/T细胞淋巴瘤的方法，其中给予靶向药物同步放疗的方式为同时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以及进行放射治疗。在一些实施方案中，提供一种通过给予靶向药物序贯放疗的方式治疗结外NK/T细胞淋巴瘤的方法，其中给予靶向药物序贯放疗的方式为先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，继而进行放射治疗。
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结外NK/T细胞淋巴瘤患者。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结外NK/T细胞淋巴瘤患者。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、甾体激素类药物、烷化剂类抗肿瘤药物、喜树碱类抗肿瘤药、铂配合物、氟嘧啶衍生物、蒽醌类抗肿瘤抗生素、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结外NK/T细胞淋巴瘤的药物中的用途。
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化疗药物和/或靶向药物治疗失败的结外NK/T细胞淋巴瘤的药物中的用途。在一些典型的实施方案中，所述的化疗药物包括但不限于门冬酰胺酶类抗肿瘤药物、抗叶酸类抗肿瘤药物、鬼臼类抗癌药物、甾体激素类药物、烷化剂类抗肿瘤药物的一种或多种。在一些典型的实施方案中，所述的化疗药物包括但不限于左旋门冬酰胺酶、培门冬酶、甲氨喋呤、依托泊苷、地塞米松、异环磷酰胺、米托蒽醌、吉西他滨、奥沙利铂、阿糖胞苷、卡培他滨、多西紫杉醇、硼替佐米、阿帕替尼、来那度胺、强的松的一种或多种。在一些典型的实施方案中，所述的门冬酰胺酶类抗肿瘤药物包括但不限于左旋门冬酰胺酶、培门冬酶的一种或多种。在一些更为典型的实施方案中，所述化疗药物和/或靶向药物治疗失败的结外NK/T细胞淋巴瘤为门冬酰胺耐药的结外NK/T细胞淋巴瘤。在一些更为典型的实施方案中，所述化疗药物和/或靶向药物治疗失败的结外NK/T细胞淋巴瘤为门冬酰胺耐药的临床IV期结外NK/T细胞淋巴瘤。
在一些实施案例中，所述的结外NK/T细胞淋巴瘤为难治性结外NK/T细胞淋巴瘤。在一些实施案例中，所述的结外NK/T细胞淋巴瘤为复发性结外NK/T细胞淋巴瘤。在一些实 施案例中，所述的结外NK/T细胞淋巴瘤为复发和/或难治的结外NK/T细胞淋巴瘤。在一些实施案例中，所述的结外NK/T细胞淋巴瘤为放射治疗失败后复发的结外NK/T细胞淋巴瘤。
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，以化合物I马来酸盐的形式给药。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，以化合物I二马来酸盐的形式给药。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。在特定的实施方案中，以化合物I二马来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。口服的制剂较优选为片剂、胶囊剂、粉剂、颗粒剂、滴丸、糊剂或散剂，更优选为片剂或胶囊剂。
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。
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，提供一种通过给予靶向药物同步放疗的方式治疗结外NK/T细胞淋巴瘤的方法，其中给予靶向药物同步放疗的方式为同时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以及进行放射治疗。在一些实施方案中，提供一种通过给予靶向药物序贯放疗的方式治疗结外NK/T细胞淋巴瘤的方法，其中给予靶向药物序贯放疗的方式为先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，继而进行放射治疗。
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结外NK/T细胞淋巴瘤患者。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结外NK/T细胞淋巴瘤患者。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、甾体激素类药物、烷化剂类抗肿瘤药物、喜树碱类抗肿瘤药、铂配合物、氟嘧啶衍生物、蒽醌类抗肿瘤抗生素、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结外NK/T细胞淋巴瘤的药物组合物，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化疗药物和/或靶向药物治疗失败的结外NK/T细胞淋巴瘤的药物组合物，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但不限于门冬酰胺酶类抗肿瘤药物、抗叶酸类抗肿瘤药物、鬼臼类抗癌药物、甾体激素类药物、烷化剂类抗肿瘤药物的一种或多种。在一些典型的实施方案中，所述的化疗药物包括但不限于左旋门冬酰胺酶、培门冬酶、甲氨喋呤、依托泊苷、地塞米松、异环磷酰胺、米托蒽醌、吉西他滨、奥沙利铂、阿糖胞苷、卡培他滨、多西紫杉醇、硼替佐米、阿帕替尼、来那度胺、强的松的一种或多种。在一些典型的实施方案中，所述的门冬酰胺酶类抗肿瘤药物包括但不限于左旋门冬酰胺酶、培门冬酶的一种或多种。在一些更为典型的实施方案中，所述化疗药物和/或靶向药物治疗失败的结外NK/T细胞淋巴瘤为门冬酰胺耐药的结外NK/T细胞淋巴瘤。在一些更为典型的实施方案中，所述化疗药物和/或靶向药物治疗失败的结外NK/T细胞淋巴瘤为门冬酰胺耐药的临床IV期结外NK/T细胞淋巴瘤。
在一些实施案例中，所述的结外NK/T细胞淋巴瘤为难治性结外NK/T细胞淋巴瘤。在一些实施案例中，所述的结外NK/T细胞淋巴瘤为复发性结外NK/T细胞淋巴瘤。在一些实施案例中，所述的结外NK/T细胞淋巴瘤为复发和/或难治的结外NK/T细胞淋巴瘤。在一些实施案例中，所述的结外NK/T细胞淋巴瘤为放射治疗失败后复发的结外NK/T细胞淋巴瘤。
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，提供了一种治疗结外NK/T细胞淋巴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。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。
本发明还提供了一种治疗化疗药物和/或靶向药物治疗失败的结外NK/T细胞淋巴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但不限于门冬酰胺酶类抗肿瘤药物、抗叶酸类抗肿瘤药物、鬼臼类抗癌药物、甾体激素类药物、烷化剂类抗肿瘤药物的一种或多种。在一些典型的实施方案中，所述的化疗药物包括但不限于左旋门冬酰胺酶、培门冬酶、甲氨喋呤、依托泊苷、地塞米松、异环磷酰胺、米托蒽醌、吉西他滨、奥沙利铂、阿糖胞苷、卡培他滨、多西紫杉醇、硼替佐米、阿帕替尼、来那度胺、强的松的一种或多种。在一些典型的实施方案中，所述的门冬酰胺酶类抗肿瘤药物包括但不限于左旋门冬酰胺酶、 培门冬酶的一种或多种。在一些更为典型的实施方案中，所述化疗药物和/或靶向药物治疗失败的结外NK/T细胞淋巴瘤为门冬酰胺耐药的结外NK/T细胞淋巴瘤。在一些更为典型的实施方案中，所述化疗药物和/或靶向药物治疗失败的结外NK/T细胞淋巴瘤为门冬酰胺耐药的临床IV期结外NK/T细胞淋巴瘤。
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，提供一种通过给予靶向药物同步放疗的方式治疗结外NK/T细胞淋巴瘤的方法，其中给予靶向药物同步放疗的方式为同时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以及进行放射治疗。在一些实施方案中，提供一种通过给予靶向药物序贯放疗的方式治疗结外NK/T细胞淋巴瘤的方法，其中给予靶向药物序贯放疗的方式为先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，继而进行放射治疗。
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结外NK/T细胞淋巴瘤患者。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结外NK/T细胞淋巴瘤患者。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、甾体激素类药物、烷化剂类抗肿瘤药物、喜树碱类抗肿瘤药、铂配合物、氟嘧啶衍生物、蒽醌类抗肿瘤抗生素、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)用于治疗结外NK/T细胞淋巴瘤的说明书。
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结外NK/T细胞淋巴瘤的说明书。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结外NK/T细胞淋巴瘤的说明书。在一些更为典型的实施方案中，所述结外NK/T细胞淋巴瘤为化疗药物和/或靶向药物治疗失败的结外NK/T细胞淋巴瘤。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。
在一些典型的实施方案中，所述的化疗药物包括但不限于门冬酰胺酶类抗肿瘤药物、抗叶酸类抗肿瘤药物、鬼臼类抗癌药物、甾体激素类药物、烷化剂类抗肿瘤药物的一种或多种。在一些典型的实施方案中，所述的化疗药物包括但不限于左旋门冬酰胺酶、培门冬酶、甲氨喋呤、依托泊苷、地塞米松、异环磷酰胺、米托蒽醌、吉西他滨、奥沙利铂、阿糖胞苷、卡培他滨、多西紫杉醇、硼替佐米、阿帕替尼、来那度胺、强的松的一种或多种。在一些典型的实施方案中，所述的门冬酰胺酶类抗肿瘤药物包括但不限于左旋门冬酰胺酶、培门冬酶的一种或多种。在一些更为典型的实施方案中，所述化疗药物和/或靶向药物治疗失败的结外NK/T细胞淋巴瘤为门冬酰胺耐药的结外NK/T细胞淋巴瘤。在一些更为典型的实施方案中，所述化疗药物和/或靶向药物治疗失败的结外NK/T细胞淋巴瘤为门冬酰胺耐药的临床IV期结外NK/T细胞淋巴瘤。
在一些实施案例中，所述的结外NK/T细胞淋巴瘤为难治性结外NK/T细胞淋巴瘤。在一些实施案例中，所述的结外NK/T细胞淋巴瘤为复发性结外NK/T细胞淋巴瘤。在一些实施案例中，所述的结外NK/T细胞淋巴瘤为复发和/或难治的结外NK/T细胞淋巴瘤。在一些实施案例中，所述的结外NK/T细胞淋巴瘤为放射治疗失败后复发的结外NK/T细胞淋巴瘤。
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，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。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。
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。
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，提供一种通过给予靶向药物同步放疗的方式治疗结外NK/T细胞淋巴瘤的方法，其中给予靶向药物同步放疗的方式为同时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以及进行放射治疗。在一些实施方案中，提供一种通过给予靶向药物序贯放疗的方式治疗结外NK/T细胞淋巴瘤的方法，其中给予靶向药物序贯放疗的方式为先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，继而进行放射治疗。
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结外NK/T细胞淋巴瘤患者。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结外NK/T细胞淋巴瘤患者。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、甾体激素类药物、烷化剂类抗肿瘤药物、喜树碱类抗肿瘤药、铂配合物、氟嘧啶衍生物、蒽醌类抗肿瘤抗生素、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。
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。
本申请中，凡是涉及安罗替尼，均是指化合物I。
“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)。
“CR”是指完全缓解，具体指肿瘤的靶病灶消失，全部病理淋巴结短直径必须减少至＜10mm。
“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；其中不可耐受包括但不限于血液学毒性达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”。
“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。
“P-GemOx”方案是指吉西他滨、奥沙利铂和培门冬酶的联用。
“DEX”是指地塞米松。
“MTX”是指甲氨蝶呤。
“VP16”是指依托泊苷。
“EA”方案是指阿糖胞苷和依托泊苷的联用。
“DX”方案是指卡培他滨和多西紫杉醇的联用。
“MEDA”方案是指米托蒽醌、阿糖胞苷、依托泊苷和地塞米松的联用。
“GIFOX”方案是指吉西他滨、异环磷酰胺和奥沙利铂的联用。
“BD”方案是指硼替佐米和地塞米松的联用。
“qd”是指给药一日一次。
附图说明
图1患者案例1安罗替尼治疗前CT图像(左)和PET图像(右)；
图2患者案例1安罗替尼治疗3周期后CT图像；
图3患者案例2安罗替尼治疗前CT图像；
图4患者案例2安罗替尼治疗6周期后CT图像；
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 PCTCN2019099264-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
原辅料名称用量(1000粒)
Figure PCTCN2019099264-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 临床试验方案
符合要求的患者的标准
(1)经活检病理组织学和免疫化及EBER检测符合WHO2008对NK/T细胞淋巴瘤诊断标准的患者。
(2)经包含门冬酰胺的联合化疗治疗后耐药。耐药是指接受治疗过程中出现疾病进展，或者至少经过2周期的联合化疗未产生应答。
(3)临床分期为IV期，且至少有一个客观可评价的病灶。
(4)年龄18-70岁。
(5)一般状况ECOG评分0-3分。
(6)入组前1周内的实验室检查符合以下条件：
血常规：Hb>80g/L,PLT>0g/L,PLT>50×10 9/L
肝功能：ALT，AST，TBIL≤3倍正常值上限；
肾功能：Cr正常；
凝血常规：血浆纤维蛋白原≥1.0g/L；
心功能：LVEF≥50％，心电图未提示任何急性梗，心律失常或I度以上房室传导阻滞。
治疗方案
上述符合要求的患者接受安罗替尼单药口服，推荐剂量为每日1次12mg口服，早餐前口服，连续服药两周停药一周，即每3周为一个疗程。
剂量调整：根据不良反应的严重程度，研究者可以调整剂量。发生三级以上不良事件在计划用药前若未恢复到二级，可以将药物剂量下调。第一级下调剂量为10mg，每日1次，早餐前口服，连续服药两周停药一周。第二级下调剂量为10mg，每日1次，早餐前口服，连续服药两周停药一周。
伴随用药
(1)如果出现粒细胞缺乏，可以给予粒细胞集落刺激因子300ug皮下注射，每天一次，
(2)出现2度以上造血抑制时，可给予IL-11、血清红细胞生成素(EPO)、血小板生成素(TPO)等药物支持治疗；当前一次化疗出现3度以上血液学毒性而未予减量的患者，可接受这些药物预防使用。当血浆纤维蛋白原<1.0g/L可给予纤维蛋白原输注，当低于30g/L可给予白蛋白输注。
疗效评估
(1)安罗替尼口服12周，24周，共有2次疾病状态评估，允许的时间窗为+/-5天。疗效标准参照Lugano2014淋巴瘤疗效标准。客观疗效评分为完全缓解(CR)，部分缓解(PR)，稳定(SD)，疾病复发(CR后)或疾病进展(PR，SD后)。
(2)评估基本手段首选PET/CT，无条件使用者要求使用增强CT或增强MRI，对于新出现的病灶或者可疑尽可能行活检。
(3)治疗产生应答的患者完成治疗后每3个月评估疾病状态，直至疾病进展。
不良事件判断标准
详细记录试验期间出现的不良事件及经过，程度，出现时间，处理措施及转归，并填写在CRF中。不良事件按照国际肿瘤化疗药物不良反应评价系统——通用不良反应术语标准4.0版(NCI-CTC AE Ver4.0)进行分级记载。如NCI毒性分级标准未列出的不良事件，可根据下列等级判断：
1度(轻)，有不舒服的感觉，但影响正常日活动。
2度(中)，不舒服的程达到工作减少或影响正常日活动。
3度(重)，不能工作或进行正常的日活动。
4度(致命)，致残或死。
临床实验显示，安罗替尼可以有效治疗结外NK/T细胞淋巴瘤，尤其对于门冬酰胺耐药的、复发或难治性结外NK/T细胞淋巴瘤患者，疗效评估结果表明其症状得到缓解。
实施例4 患者案例
患者，男性，29岁。左面部包块，病检示鼻腔恶性肿瘤；活检免疫组化示CD3(+)，CD2(+)，CD20(-)，Pax-5(-)，Bc1-2(部分+)，Ki67(+，约50％)，CD56(+)，TIA+，Gran B+，EBER+，免疫组化结果较支持为鼻型NK/T细胞淋巴瘤。后经骨穿诊断为NK/T细胞淋巴瘤白血病期。2018年9月起予P-GemOx+DEX方案化疗(吉西他滨1.6g dl，奥沙利铂150mg dl，培门冬酶3750U d2，地塞米松10mg dl-5)2次，同时予以止吐、水化、碱化、保护脏器功能支持治疗，化疗后颈部肿块较前明显缩小，治疗有效。2018年11月13日行第三次化疗，予EA方案(阿糖胞苷200mg dl-4，依托泊苷200mg d1-4)。2019年1月起行鼻腔恶性肿瘤局部放疗28次。2019年3月28日PETCT显示有新生病变，考虑淋巴瘤复发。
2019年4月2日，以信迪利单抗+阿帕替尼治疗(信迪利单抗200mg d1，阿帕替尼250mg qd)，2019年4月17日起以MTX+VP16+DX(MTX 5g d1，VP16 125mg d2-4，DX 20mg d1-4)化疗，发现新生肿块。
图1为盐酸安罗替尼治疗前的影像；2019年5月8日给予单药盐酸安罗替尼治疗，12毫 克每天口服，服2周停一周。服药后睾丸和耳前后肿块迅速缩小，鼻腔恢复通气。安罗替尼治疗三周后CT检查见鼻腔肿瘤消失(图2)，目前持续治疗，患者仍存活。
实施例5 患者案例
患者，女性，51岁。2009年7月于初诊NK/T细胞淋巴瘤，病理检查CD56+，CD3+，CD43+，CD45+，TIA+，Gran B+，Peforin+，LMP1-，CD20-，CD79a-，Ki-67+(约60％)，EBER+。累及右侧鼻腔和鼻咽部。化疗四次后行放疗获得CR。至2016年11月疾病复发，PET/CT评估左侧上颌窦复发，随后予MEDA方案根治化疗4次，2017年5月行PET-CT检查示疾病进展。
2017年5月6日、2017年6月6日开始GIFOX+硼替唑咪方案根治化疗2次，化疗后左侧上颌窦肿块消失，2017年7月30日给予BD+吉西他滨方案根治化疗1次。2017年8月中旬出右眼眶下缘出现软组织肿块，考虑疾病再次进展，2017年8月20日起给予来那度胺与强的松口服治疗，右眼眶下缘软组织肿块无明显缩小。2017年9月8日以信迪利单抗治疗，治疗疾病进展，左上臂出现巨大肿块。
2019年3月14日以盐酸安罗替尼治疗，单药12mg口服，每天1次，连续服2周停药1周。2019年5月8日评估SD(图3、图4分别为盐酸安罗替尼前和治疗6周后左上臂肿块CT图)，目前持续用药14周期，疾病稳定。

Claims (10)

  1. 化合物I或其药学上可接受的盐在制备用于治疗结外NK/T细胞淋巴瘤的药物中的用途，
    Figure PCTCN2019099264-appb-100001
  2. 根据权利要求1所述的用途，其特征在于，所述的结外NK/T细胞淋巴瘤为化疗药物和/或靶向药物治疗失败的结外NK/T细胞淋巴瘤，化疗药物包括但不限于门冬酰胺酶类抗肿瘤药物、抗叶酸类抗肿瘤药物、鬼臼类抗癌药物、甾体激素类药物、烷化剂类抗肿瘤药物的一种或多种，优选为左旋门冬酰胺酶、培门冬酶、甲氨喋呤、依托泊苷、地塞米松、异环磷酰胺、米托蒽醌、吉西他滨、奥沙利铂、阿糖胞苷、卡培他滨、多西紫杉醇、硼替佐米、阿帕替尼、来那度胺、强的松的一种或多种。
  3. 根据权利要求1-2任意一项所述的用途，其特征在于，所述的结外NK/T细胞淋巴瘤为门冬酰胺耐药的结外NK/T细胞淋巴瘤，优选为门冬酰胺耐药的临床IV期结外NK/T细胞淋巴瘤。
  4. 根据权利要求1-3任意一项所述的用途，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。
  5. 根据权利要求1-4任意一项所述的用途，其特征在于，所述药物为适于口服、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、腹膜内或鞘内任一给药方式的制剂；优选适于口服的制剂；较优选为片剂、胶囊剂、粉剂、颗粒剂、滴丸、糊剂或散剂，更优选为片剂或胶囊剂。
  6. 根据权利要求1-5中任意一项所述的用途，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2毫克至30毫克，优选为6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，再优选为10毫克至14毫克，最优选为8毫克、 10毫克、12毫克或14毫克。
  7. 根据权利要求1-6任意一项所述的用途，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；所述间隔给药方式可以反复进行多次。
  8. 根据权利要求1-7任意一项所述的用途，其特征在于，所述化合物I或其药学上可接受的盐与其他抗肿瘤药物同时或依照次序给予结外NK/T细胞淋巴瘤患者，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、甾体激素类药物、烷化剂类抗肿瘤药物、喜树碱类抗肿瘤药、铂配合物、氟嘧啶衍生物、蒽醌类抗肿瘤抗生素、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。
  9. 一种治疗结外NK/T细胞淋巴瘤的药物组合物，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，
    Figure PCTCN2019099264-appb-100002
  10. 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)用于治疗结外NK/T细胞淋巴瘤的说明书，
    Figure PCTCN2019099264-appb-100003
PCT/CN2019/099264 2018-08-06 2019-08-05 用于治疗结外nk/t细胞淋巴瘤的喹啉衍生物 WO2020029918A1 (zh)

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