WO2019223672A1 - Quinoline derivative for treating non-small cell lung cancer - Google Patents

Quinoline derivative for treating non-small cell lung cancer Download PDF

Info

Publication number
WO2019223672A1
WO2019223672A1 PCT/CN2019/087721 CN2019087721W WO2019223672A1 WO 2019223672 A1 WO2019223672 A1 WO 2019223672A1 CN 2019087721 W CN2019087721 W CN 2019087721W WO 2019223672 A1 WO2019223672 A1 WO 2019223672A1
Authority
WO
WIPO (PCT)
Prior art keywords
lung cancer
cell lung
small cell
compound
formula
Prior art date
Application number
PCT/CN2019/087721
Other languages
French (fr)
Chinese (zh)
Inventor
王训强
缪亚东
韩溪
代洁
刘雯雯
Original Assignee
正大天晴药业集团股份有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
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 CN202310227490.8A priority Critical patent/CN116440134A/en
Priority to CN201980033590.9A priority patent/CN112105361A/en
Publication of WO2019223672A1 publication Critical patent/WO2019223672A1/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention relates to the use of a quinoline derivative for treating non-small cell lung cancer, and belongs to the technical field of medicine.
  • Non-small cell lung cancer is the malignant tumor with the highest morbidity and mortality in China. Its main histological types include adenocarcinoma, squamous cell carcinoma (SCC), and large cell carcinoma. . Based on cell morphology, adenocarcinoma is a common histological type of NSCLC. Surgical resection combined with chemotherapy is the main method for its treatment. However, most patients have lost the opportunity for surgery at the advanced stage when diagnosed, and most patients undergoing surgery also need adjuvant chemotherapy. Therefore, chemotherapy is the main method of treatment. Traditional chemotherapeutic drugs have limited clinical applications due to their poor specificity and large toxic and side effects. Choosing the right medicine and targeted individualized treatment is the development direction of tumor treatment.
  • the present invention provides a method for treating non-small cell lung cancer, said method comprising administering to a patient in need of treatment a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, wherein said non-small cell Lung cancer is EGFR-mutated non-small cell lung cancer and / or ALK-positive non-small cell lung cancer.
  • the non-small cell lung cancer is an EGFR-mutated non-small cell lung cancer and / or an ALK-positive non-small cell lung cancer, and the non-small cell lung cancer that has previously failed a targeted drug treatment.
  • the non-small cell lung cancer is EGFR-mutated non-small cell lung cancer and / or ALK-positive non-small cell lung cancer, and the targeted drug treatment for EGFR mutation and / or ALK-positive failure has failed.
  • the non-small cell lung cancer is an EGFR-mutated non-small cell lung cancer and / or an ALK-positive non-small cell lung cancer, and the non-small cell lung cancer still progresses after the targeted drug treatment.
  • the non-small cell lung cancer is EGFR-mutated non-small cell lung cancer and / or ALK-positive non-small-cell lung cancer, and the disease is treated after the targeted drug treatment for EGFR mutation and / or ALK-positive Non-small cell lung cancer still progressing.
  • the non-small cell lung cancer is a non-small cell lung cancer that has progressed or relapsed after receiving at least two types of systemic chemotherapy.
  • the non-small cell lung cancer is locally advanced or metastatic non-small cell lung cancer that has progressed or relapsed after receiving at least two types of systemic chemotherapy.
  • the compound of formula I can be administered in its free base form or in the form of its salts, hydrates and prodrugs, which prodrugs are converted in vivo into the free base form of the compound of formula I.
  • a pharmaceutically acceptable salt of a compound of formula 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 is administered as the hydrochloride salt of a compound of formula I. In some embodiments, the compound is administered as the monohydrochloride salt of a compound of formula I. In some embodiments, the compound is administered as a dihydrochloride salt. In some embodiments, the compound is administered as a crystalline form of the hydrochloride salt of a compound of Formula I. In a particular embodiment, the compound is administered as a crystalline form of the dihydrochloride salt of the compound of formula I.
  • the compound of formula 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 the compound of formula I or a pharmaceutically acceptable salt thereof administered can be determined according to 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 the compound of Formula I or a pharmaceutically acceptable salt thereof is from 2 mg to 20 mg. In some embodiments, the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is 5 mg to 20 mg. In some embodiments, the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is from 8 mg to 20 mg. In some embodiments, the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is 10 mg to 16 mg.
  • the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is 10 mg to 14 mg. In some specific embodiments, the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is 6 mg. In some specific embodiments, the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is 8 mg. In some specific embodiments, the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is 10 mg. In some specific embodiments, the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is 12 mg. In some specific embodiments, the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is 14 mg. In some specific embodiments, the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is 16 mg.
  • the compound of formula I or a pharmaceutically acceptable salt thereof may be administered one or more times daily. In some embodiments, a compound of formula I or a pharmaceutically acceptable salt thereof is administered once a day. In some embodiments, the oral solid formulation is administered once a day.
  • the method of administration can be comprehensively determined according to the activity, toxicity, and tolerance of the patient.
  • the compound of formula I or a pharmaceutically acceptable salt thereof is administered in spaced administration.
  • the interval administration includes an administration period and a withdrawal period, and the compound of formula I or a pharmaceutically acceptable salt thereof can be administered once or multiple times per day during the administration period.
  • the compound of formula 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 dosing 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, and thus for 2 weeks.
  • 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 discontinued for 2 days; then it is administered once a day for 5 days and then discontinued for 2 days, and thus for 5 consecutive days.
  • the two-day interval administration can be repeated several times.
  • the drug is administered orally at a dose of 8 mg once a day for two consecutive weeks and one week off.
  • 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 12 mg once a day for 2 weeks and the drug is stopped for 1 week.
  • the present application also provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating non-small cell lung cancer, wherein the non-small cell lung cancer is a non-small cell with EGFR mutation Cell lung cancer and / or ALK positive non-small cell lung cancer.
  • the non-small cell lung cancer is an EGFR-mutated non-small cell lung cancer and / or an ALK-positive non-small cell lung cancer, and the non-small cell lung cancer that has previously failed a targeted drug treatment.
  • the non-small cell lung cancer is EGFR-mutated non-small cell lung cancer and / or ALK-positive non-small cell lung cancer, and the targeted drug treatment for EGFR mutation and / or ALK-positive failure has Non-small cell lung cancer.
  • the non-small cell lung cancer is an EGFR-mutated non-small cell lung cancer and / or an ALK-positive non-small cell lung cancer, and the non-small cell lung cancer still progresses after the targeted drug treatment.
  • the non-small cell lung cancer is EGFR-mutated non-small cell lung cancer and / or ALK-positive non-small-cell lung cancer, and the disease is treated after the targeted drug treatment for EGFR mutation and / or ALK-positive Non-small cell lung cancer still progressing.
  • the non-small cell lung cancer is a non-small cell lung cancer that has progressed or relapsed after receiving at least two types of systemic chemotherapy.
  • the non-small cell lung cancer is locally advanced or metastatic non-small cell lung cancer that has progressed or relapsed after receiving at least two types of systemic chemotherapy.
  • the compound of formula I may be in its free base form, or in the form of its salt, hydrate and prodrug, which prodrug is converted in vivo to the free base form of the compound of formula I.
  • a pharmaceutically acceptable salt of a compound of formula I is within the scope of the present invention, and salts can be produced from different organic and inorganic acids according to methods known in the art.
  • the compound of Formula I or a pharmaceutically acceptable salt thereof is the hydrochloride form of a compound of Formula I. In some embodiments, it is in the form of a monohydrochloride salt of a compound of Formula I. In some embodiments, it is in the form of a dihydrochloride salt of a compound of Formula I. In some embodiments, it is a crystalline form of the hydrochloride salt of a compound of Formula I. In a particular embodiment, it is a crystalline form of the dihydrochloride salt of a compound of Formula I.
  • the compound of formula 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 a compound of formula 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 the compound of Formula I or a pharmaceutically acceptable salt thereof is from 2 mg to 20 mg.
  • the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is 5 mg to 20 mg.
  • the amount of the compound of Formula I or a pharmaceutically acceptable salt thereof is 8 mg to 20 mg.
  • the amount of the compound of Formula I or a pharmaceutically acceptable salt thereof is 10 mg to 16 mg.
  • the amount of the compound of Formula I or a pharmaceutically acceptable salt thereof is 10 mg to 14 mg. In some specific embodiments, the amount of the compound of Formula I or a pharmaceutically acceptable salt thereof is 10 mg. In some specific embodiments, the amount of the compound of Formula I or a pharmaceutically acceptable salt thereof is 12 mg. In some specific embodiments, the amount of the compound of Formula I or a pharmaceutically acceptable salt thereof is 14 mg. In some specific embodiments, the amount of the compound of formula I or a pharmaceutically acceptable salt thereof is 16 mg.
  • the compound of formula I or a pharmaceutically acceptable salt thereof may be administered one or more times daily. In some embodiments, a compound of formula 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.
  • the compound of formula I or a pharmaceutically acceptable salt thereof is administered in spaced administration.
  • the interval administration includes an administration period and a withdrawal period, and the compound of formula I or a pharmaceutically acceptable salt thereof can be administered once or multiple times per day during the administration period.
  • the compound of formula 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 dosing 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, and thus for 2 weeks.
  • 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 discontinued for 2 days; then it is administered once a day for 5 days and then discontinued for 2 days, and thus for 5 consecutive days.
  • the two-day interval administration can be repeated several times.
  • the compound of formula I or a pharmaceutically acceptable salt thereof is administered orally at a dose of 8 mg once daily for two consecutive weeks and one week off.
  • the compound of formula I or a pharmaceutically acceptable salt thereof is administered orally at a dose of 10 mg once daily for two consecutive weeks and one week off.
  • the compound of Formula I or a pharmaceutically acceptable salt thereof is administered orally at a dose of 12 mg once daily for two consecutive weeks and one week off.
  • the present invention provides a pharmaceutical composition for treating EGFR-mutated non-small cell lung cancer and / or ALK-positive non-small cell lung cancer, comprising a compound of formula I or a pharmaceutically acceptable salt thereof, and at least one A pharmaceutically acceptable carrier.
  • the non-small cell lung cancer is an EGFR-mutated non-small cell lung cancer and / or an ALK-positive non-small cell lung cancer, and the non-small cell lung cancer that has previously failed a targeted drug treatment.
  • the non-small cell lung cancer is EGFR-mutated non-small cell lung cancer and / or ALK-positive non-small cell lung cancer, and the targeted drug treatment for EGFR mutation and / or ALK-positive failure has Non-small cell lung cancer.
  • the non-small cell lung cancer is an EGFR-mutated non-small cell lung cancer and / or an ALK-positive non-small cell lung cancer, and the non-small cell lung cancer still progresses after the targeted drug treatment.
  • the non-small cell lung cancer is EGFR-mutated non-small cell lung cancer and / or ALK-positive non-small-cell lung cancer, and the disease is treated after the targeted drug treatment for EGFR mutation and / or ALK-positive Non-small cell lung cancer still progressing.
  • the non-small cell lung cancer is a non-small cell lung cancer that has progressed or relapsed after receiving at least two types of systemic chemotherapy.
  • the non-small cell lung cancer is locally advanced or metastatic non-small cell lung cancer that has progressed or relapsed after receiving at least two types of systemic chemotherapy.
  • the compound of formula I may be in its free base form, or it may be in the form of a salt, a hydrate and a prodrug, which prodrug is converted in vivo to the free base form of the compound of formula I.
  • a pharmaceutically acceptable salt of a compound of formula I is within the scope of the present invention, and salts can be produced from different organic and inorganic acids according to methods known in the art.
  • the compound of Formula I or a pharmaceutically acceptable salt thereof is the hydrochloride form of a compound of Formula I. In some embodiments, it is in the form of a monohydrochloride salt of a compound of Formula I. In some embodiments, it is in the form of a dihydrochloride salt of a compound of Formula I. In some embodiments, it is a crystalline form of the hydrochloride salt of a compound of Formula I. In a particular embodiment, it is a crystalline form of the dihydrochloride salt of a compound of Formula I.
  • the amount of a compound of formula 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 the compound of Formula I or a pharmaceutically acceptable salt thereof is from 2 mg to 20 mg.
  • the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is 5 mg to 20 mg.
  • the amount of the compound of formula I or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is 8 mg to 20 mg.
  • the amount of the compound of Formula I or a pharmaceutically acceptable salt thereof is 10 mg to 16 mg.
  • the amount of the compound of Formula I or a pharmaceutically acceptable salt thereof is 10 mg to 14 mg. In some specific embodiments, the amount of the compound of Formula I or a pharmaceutically acceptable salt thereof is 10 mg. In some specific embodiments, the amount of the compound of Formula I or a pharmaceutically acceptable salt thereof is 12 mg. In some specific embodiments, the amount of the compound of Formula I or a pharmaceutically acceptable salt thereof is 14 mg. In some specific embodiments, the amount of the compound of Formula I or a pharmaceutically acceptable salt thereof is 16 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 may be an ordinary tablet, a dispersible tablet, an effervescent tablet, a sustained-release tablet, a controlled-release tablet, or an enteric tablet
  • the capsule may 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.
  • a pharmaceutical composition is provided that is formulated in a unit dosage form.
  • the pharmaceutical composition in a unit dosage form contains 2 mg to 20 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition in a unit dosage form contains 5 mg to 20 mg of a compound of formula I or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition in a unit dosage form contains 8 mg to 20 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, preferably 10 mg to 16 mg of a compound of formula I or a pharmaceutically acceptable salt thereof.
  • a salt more preferably 10 mg to 14 mg of a compound of formula I or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition in the unit dosage form contains 8 mg of a compound of formula I or a pharmaceutically acceptable salt thereof. In some specific embodiments, the unit dosage form pharmaceutical composition contains 10 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof. In some specific embodiments, the unit dosage form pharmaceutical composition contains 12 mg of a compound of formula I or a pharmaceutically acceptable salt thereof. In some specific embodiments, the pharmaceutical composition in unit dosage form contains 14 mg of a compound of formula I or a pharmaceutically acceptable salt thereof. In some specific embodiments, the unit dosage form pharmaceutical composition contains 16 mg of a compound of formula I or a pharmaceutically acceptable salt thereof. For example, for a tablet or capsule, "pharmaceutical composition in unit dosage form" means each tablet or capsule.
  • 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 may be administered once or multiple times 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 dosing 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, and thus for 2 weeks.
  • 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 discontinued for 2 days; then it is administered once a day for 5 days and then discontinued for 2 days, and thus for 5 consecutive days.
  • the two-day interval administration can be repeated several times.
  • the present invention also provides a kit comprising (a) a pharmaceutical composition of at least one unit dose of a compound of formula I or a pharmaceutically acceptable salt thereof, and (b) a Instructions for small cell lung cancer and / or ALK positive non-small cell lung cancer.
  • a kit comprising (a) at least one unit dose of an oral formulation suitable for a compound of Formula I or a pharmaceutically acceptable salt thereof, and (b) a mode of intermittent administration Instructions for the treatment of EGFR-mutated non-small cell lung cancer and / or ALK-positive non-small cell lung cancer.
  • kits comprising (a) at least one unit dose of a tablet or capsule of a compound of formula I or a pharmaceutically acceptable salt thereof and (b) Instructions for the treatment of EGFR-mutated non-small cell lung cancer and / or ALK-positive non-small cell lung cancer.
  • the non-small cell lung cancer is an EGFR-mutated non-small cell lung cancer and / or an ALK-positive non-small cell lung cancer, and the non-small cell lung cancer that has previously failed a targeted drug treatment.
  • the non-small cell lung cancer is EGFR-mutated non-small cell lung cancer and / or ALK-positive non-small cell lung cancer, and the targeted drug treatment for EGFR mutation and / or ALK-positive failure has failed.
  • the non-small cell lung cancer is an EGFR-mutated non-small cell lung cancer and / or an ALK-positive non-small cell lung cancer, and the non-small cell lung cancer still progresses after the targeted drug treatment.
  • the non-small cell lung cancer is EGFR-mutated non-small cell lung cancer and / or ALK-positive non-small-cell lung cancer, and the disease is treated after the targeted drug treatment for EGFR mutation and / or ALK-positive Non-small cell lung cancer still progressing.
  • the non-small cell lung cancer is a non-small cell lung cancer that has progressed or relapsed after receiving at least two types of systemic chemotherapy.
  • the non-small cell lung cancer is locally advanced or metastatic non-small cell lung cancer that has progressed or relapsed after receiving at least two types of systemic chemotherapy.
  • the pharmaceutical composition in a unit dosage form contains 2 mg to 20 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition in a unit dosage form contains 5 mg to 20 mg of a compound of formula 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 a compound of formula I or a pharmaceutically acceptable salt thereof, preferably 10 mg to 16 mg of a compound of formula I or a pharmaceutically acceptable salt thereof. A salt, more preferably 10 mg to 14 mg of a compound of formula I or a pharmaceutically acceptable salt thereof. In some specific embodiments, the pharmaceutical composition in the unit dosage form contains 8 mg of a compound of formula I or a pharmaceutically acceptable salt thereof.
  • the unit dosage form pharmaceutical composition contains 10 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof. In some specific embodiments, the unit dosage form pharmaceutical composition contains 12 mg of a compound of formula I or a pharmaceutically acceptable salt thereof. In some specific embodiments, the pharmaceutical composition in unit dosage form contains 14 mg of a compound of formula I or a pharmaceutically acceptable salt thereof. In some specific embodiments, the unit dosage form pharmaceutical composition contains 16 mg of a compound of formula I or a pharmaceutically acceptable salt thereof. For example, for a tablet or capsule, "pharmaceutical composition in unit dosage form" means each tablet or capsule.
  • the tablet may be an ordinary tablet, a dispersible tablet, an effervescent tablet, a sustained-release tablet, a controlled-release tablet, or an enteric tablet
  • the capsule may be an ordinary capsule, a sustained-release capsule, a controlled-release capsule, or an enteric capsule.
  • 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 may be administered once or multiple times 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 dosing 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, and thus for 2 weeks.
  • 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 discontinued for 2 days; then it is administered once a day for 5 days and then discontinued for 2 days, and thus for 5 consecutive days.
  • the two-day interval administration can be repeated several times.
  • the non-small cell lung cancer includes, but is not limited to, lung squamous cell carcinoma and lung adenocarcinoma.
  • the "EGFR mutation” includes, but is not limited to, mutations in exon 19, exon 21, exon 18, and exon 20 (for example, T790M).
  • ALK-positive may also be referred to as ALK (Anaplastic lymphomakinase) fusion gene positive, including but not limited to EML4-ALK fusion mutation.
  • the "targeted drug” includes but is not limited to erlotinib, gefitinib, osimertinib (AZD9291), afatinib, ceritinib, alectinib ), Crizotinib, brigatinib.
  • the "targeted drug for EGFR mutation” includes, but is not limited to, erlotinib, gefitinib, afatinib, and osimertinib.
  • the "targeting drug for ALK positive” includes, but is not limited to, alectinib, crizotinib, ceritinib, and brigatinib.
  • the chemotherapeutic drugs include, but are not limited to, platinum complexes (for example, cisplatin, carboplatin, nedaplatin, oxaliplatin), taxanes (for example, paclitaxel, docetaxel), fluorine Pyrimidine derivatives (e.g. gemcitabine, capecitabine, fluorouracil, bisfurofuracil, deoxyfluorouridine, tegafur, carmofur), pemetrexed, vinorelbine, etoposide, vinblastine.
  • platinum complexes for example, cisplatin, carboplatin, nedaplatin, oxaliplatin
  • taxanes for example, paclitaxel, docetaxel
  • fluorine Pyrimidine derivatives e.g. gemcitabine, capecitabine, fluorouracil, bisfurofuracil, deoxyfluorouridine, tegafur, carmofur
  • pemetrexed
  • the dosages and ranges provided herein are based on the molecular weight of the free base form of the compound of Formula I.
  • the crystal form of the hydrochloride salt of the compound of the formula 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.
  • the crystals of type C are crystals containing two crystal waters.
  • the crystalline form of the dihydrochloride salt of the compound of Formula I is Form A crystal.
  • Patient means a mammal, preferably a human. In some embodiments, the patient is a patient who fails or lacks standard treatment.
  • “Pharmaceutically acceptable” refers to its use in the preparation of pharmaceutical compositions that are generally safe, non-toxic, and neither biologically or otherwise undesirable, and include those that are acceptable for human drug 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, and propionic acid , Hexanoic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvate, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, Mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-chlorobenzenesulfonic acid, p-toluenesulfonic acid, 3-
  • 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:
  • PR refers to partial response, specifically the sum of the diameter of the target lesions of a 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 increased by more than 20% from baseline levels.
  • SD refers to stable disease, specifically the degree to which the tumor target lesion has not decreased to the level of PR, and the degree of increase has not reached the level of PD, somewhere in between.
  • “Failure to treat” refers to intolerable toxic or side effects, disease progression during treatment, or relapse after treatment is completed; among them, intolerance includes, but is not limited to, hematological toxicity up to level IV (platelet reduction level III and above), non-hematological toxicity Reach level III or above.
  • Example 24 in WO2008112407 1-[[[[[[[(4- (4-fluoro-2-methyl-1H-indole-5-yl) oxy-6-methoxyquinolin-7-yl [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 the compound of formula I with other contents can be prepared by referring to the same ratio and prescription as described above.
  • the patients intermittently received the following treatments in chronological order: 4 cycles of pemetrexed + nedaplatin chemotherapy, the best effect SD ; 2 cycles of pemetrexed + carboplatin, curative effect SD; one cycle of docetaxel + nedaplatin, poor efficacy, PD; during the above treatment period, patients also took ectinida for one and a half years, Efficacy SD.
  • the patient started treatment with a capsule of a dihydrochloride salt of a compound of formula I at a dose of 12 mg orally once a day (continuously used for 2 weeks and 1 week as a treatment cycle).
  • the sum of the lengths of the tumor target lesions in the patient is reduced.
  • the sum of the diameters of the two large measurable target lesions was 50 mm (29 mm in the left lower lobe and 21 mm in the left lower lobe).
  • the total diameter of the target lesions was reduced to 41 mm (at the left lower lobe of 24 mm and the left lower lobe at 17 mm) for one cycle (at three weeks) of the dihydrochloride compound of formula I;
  • the sum of the diameters of the target lesions is still 41mm (24mm in the left lower lobe and 17mm in the left lower lobe);
  • the sum of the diameters of the target lesions is reduced to 38mm at four cycles (22mm in the left lower lobe and 16mm in the left lower lobe); at ten cycles 45mm (26mm left lobe, 19mm left lobe); follow-up showed that at 30 cycles, the patient was still receiving the treatment of the dihydrochloride compound of formula I.
  • the tumor continued to respond and the clinical manifestations were good.
  • the sum of the diameters of the three large measurable target lesions was 65 mm (34 mm for the left lung mass, 15 mm for the right supraclavicular lymph node, and 16 mm for the mediastinal lymph node); the patient was taking a disalt of a compound of formula I CT scans were performed regularly after the acid salt capsules, and the sum of the diameter of the target lesions decreased to 57 mm after taking the medicine for six weeks (left lung mass 28 mm, right supraclavicular lymph node 16 mm, mediastinal lymph node 13 mm); subsequent images were reviewed every two cycles The target lesions were always maintained at about 55mm. Non-target lesions did not progress, and no new lesions appeared.
  • a CT scan showed that the sum of the diameters of the measurable target lesions was 239 mm (right lung 71 mm, right adrenal gland 60 mm, right pubic low density mass 26 mm, and left adrenal gland 82 mm). After administration, CT scans were performed regularly. After six cycles of treatment, the sum of the diameter of the target lesions decreased to 190 mm (55 mm in the right lung, 44 mm in the right adrenal gland, 27 mm in the low-density mass of the right pubic bone, and 64 mm in the left adrenal gland). More than 30%.
  • the sum of the diameters of the target lesions decreased to 156 mm (54 mm in the right lung, 39 mm in the right adrenal gland, 20 mm in the low-density mass in the right pubic bone, and 43 mm in the left adrenal gland), and no new lesions appeared.
  • CT showed that the sum of the diameters of the target lesions was 185 mm. After evaluation by the doctor, it was recommended that the medication be continued, and the overall tolerance was good during the treatment.
  • a CT scan revealed that a measurable target lesion was 70 mm in diameter (right lung mass).
  • regular CT scans are performed.
  • the target lesion diameter decreased to 56mm at three weeks, the target lesion diameter was 58mm at six weeks, the target lesion diameter was 62mm at twelve weeks, the target lesion diameter was approximately 58mm at eighteen weeks, and the target lesion was twenty-four weeks. 68mm diameter.
  • no new lesions appeared, and the best effect SD decreased.
  • overall tolerance was good.
  • the patients Before receiving the treatment of the compound dihydrochloride of formula I, from 2014 to 2015, the patients received the following treatments in order: two cycles of gemcitabine combined with nedaplatin chemotherapy, the efficacy SD; one cycle of docetaxel combined with cisplatin chemotherapy, specifically Efficacy is unknown; right lung IMRT radiotherapy (60Gy), curative effect SD; docetaxel combined with cisplatin chemotherapy for two cycles, curative effect is unknown; pemetrexed monotherapy 2 cycles, efficacy PD. Genetic testing showed ALK-positive (ALK-Exon20 EML4 fusion mutation), taking crizotinib for 25 days, and the efficacy was evaluated as PD.
  • ALK-positive ALK-Exon20 EML4 fusion mutation
  • CT showed an irregular mass in the right lower hilar region of 46mm and a left upper lobe metastatic nodule of 28mm.
  • the right lower lobe metastatic nodule was 22mm, with a small amount of pericardial effusion and a small amount of right pleural effusion.
  • CEA results of tumor markers were abnormal, as high as 13.42 ng / mL.
  • a CT scan before administration showed that the sum of the diameters of the three large measurable target lesions was 96 mm (irregular mass in the right lower hilar region 46 mm, upper left metastatic nodules 28 mm, and right lower inferior lobe metastases. 22mm); After the treatment, the sum of the length and diameter of the tumor target lesions of the patient slowly increased, and CEA decreased with the treatment.
  • the sum of the diameters of the target lesions did not change at three weeks after the administration (irregular mass in the right lower hilar region of 47 mm, left upper lobe metastasis nodules of 26 mm, right lower lobe metastasis nodules of 23 mm); the target was at six weeks The sum of lesion diameters increased to 98 mm (47 mm irregular mass in the right lower hilar region, 29 mm in the left upper lobe metastasis nodule, and 22 mm in the right lower lobe metastasis nodule).
  • the tumor marker CEA decreased to 8.76; target at twelve weeks The sum of the diameters of the lesions increased to 104mm, an increase of 8.3% (irregular mass in the right lower hilar region 46mm, upper left lobe metastasis nodule 33mm, right lower lobe metastasis nodule 25mm), the tumor marker CEA was 8.52; ten At eight weeks, the sum of the diameters of the target lesions increased to 106 mm, an increase of 10.4% (irregular mass in the right lower hilar area 45 mm, upper left lobe metastasis nodule 36 mm, right lower lobe metastasis nodule 25 mm) tumor marker CEA was 9.32; the total diameter of the target lesion increased to 126 mm at 24 weeks (53 mm irregular mass in the right lower hilar region, 45 mm in the left upper lobe metastasis nodule, and 28 mm in the right lower lobe metastasis nodule) tumor marker

Abstract

Provided is a quinoline derivative for treating non-small cell lung cancer. Also provided is a method for treating non-small cell lung cancer, comprising administering to a patient in need of treatment a therapeutically effective amount of a quinazoline compound or a pharmaceutically acceptable salt thereof, wherein the non-small cell lung cancer is EGFR-mutant non-small cell lung cancer and/or ALK-positive non-small cell lung cancer.

Description

用于治疗非小细胞肺癌的喹啉衍生物Quinoline derivatives for treating non-small cell lung cancer 技术领域Technical field
本发明涉及喹啉衍生物用于治疗非小细胞肺癌的用途，属于医药技术领域。The invention relates to the use of a quinoline derivative for treating non-small cell lung cancer, and belongs to the technical field of medicine.
背景技术Background technique
非小细胞肺癌(non-small cell lung cancer,NSCLC)是我国发病率和死亡率最高的恶性肿瘤，其主要组织学分型包括腺癌、鳞状细胞癌(squamous cell carcinoma，SCC)和大细胞癌。基于细胞形态，腺癌是常见的NSCLC组织学分型。手术切除辅以化疗是对其治疗的主要手段。然而多数患者因确诊时已为晚期失去了手术机会，多数接受手术治疗的患者也需辅助化疗，因此，化疗是治疗的最主要方式。传统的化疗药物因特异性差、毒副作用大，临床应用受到了很大限制。选择恰当的药物，有的放矢的进行个体化治疗，是肿瘤治疗的发展方向。Non-small cell lung cancer (NSCLC) is the malignant tumor with the highest morbidity and mortality in China. Its main histological types include adenocarcinoma, squamous cell carcinoma (SCC), and large cell carcinoma. . Based on cell morphology, adenocarcinoma is a common histological type of NSCLC. Surgical resection combined with chemotherapy is the main method for its treatment. However, most patients have lost the opportunity for surgery at the advanced stage when diagnosed, and most patients undergoing surgery also need adjuvant chemotherapy. Therefore, chemotherapy is the main method of treatment. Traditional chemotherapeutic drugs have limited clinical applications due to their poor specificity and large toxic and side effects. Choosing the right medicine and targeted individualized treatment is the development direction of tumor treatment.
NSCLC治疗过程中出现的耐药问题已经极大地限制了其在该疾病治疗中的应用，因此，寻找新的治疗药物或治疗方法，已经成为NSCLC研究领域的迫切任务。The problem of resistance in NSCLC treatment has greatly limited its application in the treatment of this disease. Therefore, finding new therapeutic drugs or treatment methods has become an urgent task in the field of NSCLC research.
发明内容Summary of the Invention
第一方面，本发明提供了一种治疗非小细胞肺癌的方法，所述方法包括给予需要治疗的患者治疗有效量的式I化合物或其药学上可接受的盐，其中所述的非小细胞肺癌为EGFR突变的非小细胞肺癌和/或ALK阳性的非小细胞肺癌。In a first aspect, the present invention provides a method for treating non-small cell lung cancer, said method comprising administering to a patient in need of treatment a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, wherein said non-small cell Lung cancer is EGFR-mutated non-small cell lung cancer and / or ALK-positive non-small cell lung cancer.
式I化合物的化学名为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：The chemical name of the compound of formula I is 1-[[[[4- (4-fluoro-2-methyl-1H-indol-5-yl) oxy-6-methoxyquinolin-7-yl] oxy ] Methyl] cyclopropylamine, which has the following structural formula:
Figure PCTCN2019087721-appb-000001
Figure PCTCN2019087721-appb-000001
在一些实施方案中，所述的非小细胞肺癌为EGFR突变的非小细胞肺癌和/或ALK阳性的非小细胞肺癌，且在先靶向药物治疗失败的非小细胞肺癌。在一些实施方案中，所述的非小细胞肺癌为EGFR突变的非小细胞肺癌和/或ALK阳性的非小细胞肺癌，且在先针对EGFR突变和/或ALK阳性的靶向药物治疗失败的非小细胞肺癌。在一些实施方案中，所述的非小细胞肺癌为EGFR突变的非小细胞肺癌和/或ALK阳性的非小细胞肺癌，且在先靶向药物治疗后疾病仍然进展的非小细胞肺癌。在一些实施方案中，所述的非小细胞肺癌为EGFR突变 的非小细胞肺癌和/或ALK阳性的非小细胞肺癌，且在先针对EGFR突变和/或ALK阳性的靶向药物治疗后疾病仍然进展的非小细胞肺癌。在一些实施方案中，所述的非小细胞肺癌为至少接受过2种***化疗后出现进展或者复发的非小细胞肺癌。在一些实施方案中，所述的非小细胞肺癌为至少接受过2种***化疗后出现进展或者复发的局部晚期或者转移性非小细胞肺癌。In some embodiments, the non-small cell lung cancer is an EGFR-mutated non-small cell lung cancer and / or an ALK-positive non-small cell lung cancer, and the non-small cell lung cancer that has previously failed a targeted drug treatment. In some embodiments, the non-small cell lung cancer is EGFR-mutated non-small cell lung cancer and / or ALK-positive non-small cell lung cancer, and the targeted drug treatment for EGFR mutation and / or ALK-positive failure has failed. Non-small cell lung cancer. In some embodiments, the non-small cell lung cancer is an EGFR-mutated non-small cell lung cancer and / or an ALK-positive non-small cell lung cancer, and the non-small cell lung cancer still progresses after the targeted drug treatment. In some embodiments, the non-small cell lung cancer is EGFR-mutated non-small cell lung cancer and / or ALK-positive non-small-cell lung cancer, and the disease is treated after the targeted drug treatment for EGFR mutation and / or ALK-positive Non-small cell lung cancer still progressing. In some embodiments, the non-small cell lung cancer is a non-small cell lung cancer that has progressed or relapsed after receiving at least two types of systemic chemotherapy. In some embodiments, the non-small cell lung cancer is locally advanced or metastatic non-small cell lung cancer that has progressed or relapsed after receiving at least two types of systemic chemotherapy.
式I化合物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式I化合物的游离碱形式。例如，式I化合物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。The compound of formula I can be administered in its free base form or in the form of its salts, hydrates and prodrugs, which prodrugs are converted in vivo into the free base form of the compound of formula I. For example, a pharmaceutically acceptable salt of a compound of formula 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.
在一些实施方案中，以式I化合物盐酸盐的形式给药。在一些实施方案中，以式I化合物一盐酸盐的形式给药。在一些实施方案中，以式I化合物二盐酸盐的形式给药。在一些实施方案中，以式I化合物盐酸盐的晶体形式给药。在特定的实施方案中，以式I化合物二盐酸盐的晶体形式给药。In some embodiments, the compound is administered as the hydrochloride salt of a compound of formula I. In some embodiments, the compound is administered as the monohydrochloride salt of a compound of formula I. In some embodiments, the compound is administered as a dihydrochloride salt. In some embodiments, the compound is administered as a crystalline form of the hydrochloride salt of a compound of Formula I. In a particular embodiment, the compound is administered as a crystalline form of the dihydrochloride salt of the compound of formula I.
式I化合物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、***、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。The compound of formula 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.
给予式I化合物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，给予式I化合物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，给予式I化合物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，给予式I化合物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，给予式I化合物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，给予式I化合物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，给予式I化合物或其药学上可接受的盐的日剂量为6毫克。在一些特定的实施方案中，给予式I化合物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，给予式I化合物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，给予式I化合物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，给予式I化合物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，给予式I化合物或其药学上可接受的盐的日剂量为16毫克。The amount of the compound of formula I or a pharmaceutically acceptable salt thereof administered can be determined according to the severity of the disease, the response of the disease, any treatment-related toxicity, the age and health status of the patient. In some embodiments, the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is from 2 mg to 20 mg. In some embodiments, the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is 5 mg to 20 mg. In some embodiments, the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is from 8 mg to 20 mg. In some embodiments, the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is 10 mg to 16 mg. In some embodiments, the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is 10 mg to 14 mg. In some specific embodiments, the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is 6 mg. In some specific embodiments, the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is 8 mg. In some specific embodiments, the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is 10 mg. In some specific embodiments, the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is 12 mg. In some specific embodiments, the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is 14 mg. In some specific embodiments, the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is 16 mg.
式I化合物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，每天一次给予式I化合物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。The compound of formula I or a pharmaceutically acceptable salt thereof may be administered one or more times daily. In some embodiments, a compound of formula I or a pharmaceutically acceptable salt thereof is administered once a day. In some embodiments, the oral solid formulation is administered once a day.
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式I化合物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式I化合物或其药学上可接受的盐。例如在给药期内每天给予式I化合物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。The method of administration can be comprehensively determined according to the activity, toxicity, and tolerance of the patient. Preferably, the compound of formula I or a pharmaceutically acceptable salt thereof is administered in spaced administration. The interval administration includes an administration period and a withdrawal period, and the compound of formula I or a pharmaceutically acceptable salt thereof can be administered once or multiple times per day during the administration period. For example, the compound of formula 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. Among them, 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.
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。In some embodiments, the dosing is discontinued for 2 weeks for 2 weeks. In some embodiments, 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.
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。In some embodiments, the administration is discontinued for 2 weeks for 1 week. In some embodiments, 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, and thus for 2 weeks. The drug can be administered repeatedly at intervals of 1 week.
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。In some embodiments, the dosing is discontinued for 5 days for 2 days. In some embodiments, the drug is administered once a day for 5 days and then discontinued for 2 days; then it is administered once a day for 5 days and then discontinued for 2 days, and thus for 5 consecutive days. The two-day interval administration can be repeated several times.
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。In some specific embodiments, the drug is administered orally at a dose of 8 mg once a day for two consecutive weeks and one week off.
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。In some specific embodiments, the drug is administered orally at a dose of 10 mg once a day for two consecutive weeks and one week off.
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。In some specific embodiments, the drug is administered orally at a dose of 12 mg once a day for 2 weeks and the drug is stopped for 1 week.
另一方面，本申请还提供了式I的化合物或其药学上可接受的盐在制备用于治疗非小细胞肺癌的药物中的用途，其中所述的非小细胞肺癌为EGFR突变的非小细胞肺癌和/或ALK阳性的非小细胞肺癌。In another aspect, the present application also provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating non-small cell lung cancer, wherein the non-small cell lung cancer is a non-small cell with EGFR mutation Cell lung cancer and / or ALK positive non-small cell lung cancer.
Figure PCTCN2019087721-appb-000002
Figure PCTCN2019087721-appb-000002
在一些实施方案中，所述的非小细胞肺癌为EGFR突变的非小细胞肺癌和/或ALK阳性的非小细胞肺癌，且在先靶向药物治疗失败的非小细胞肺癌。在一些实施方案中，所述的非小细胞肺癌为EGFR突变的非小细胞肺癌和/或ALK阳性的非小细胞肺癌，且在先针对EGFR突变和/或ALK阳性的靶向药物治疗失败的非小细胞肺癌。在一些实施方案中，所述的非小细胞肺癌为EGFR突变的非小细胞肺癌和/或ALK阳性的非小细胞肺癌，且在先靶向药物治疗后疾病仍然进展的非小细胞肺癌。在一些实施方案中，所述的非小细胞肺癌为EGFR突变的非小细胞肺癌和/或ALK阳性的非小细胞肺癌，且在先针对EGFR突变和/或ALK阳性的靶向药物治疗后疾病仍然进展的非小细胞肺癌。在一些实施方案中，所述的非小细胞肺癌为至少接受过2种***化疗后出现进展或者复发的非小细胞肺癌。在一些实施方案中，所述的非小细胞肺癌为至少接受过2种***化疗后出现进展或者复发的局部晚期或者转移性非小细胞肺癌。In some embodiments, the non-small cell lung cancer is an EGFR-mutated non-small cell lung cancer and / or an ALK-positive non-small cell lung cancer, and the non-small cell lung cancer that has previously failed a targeted drug treatment. In some embodiments, the non-small cell lung cancer is EGFR-mutated non-small cell lung cancer and / or ALK-positive non-small cell lung cancer, and the targeted drug treatment for EGFR mutation and / or ALK-positive failure has Non-small cell lung cancer. In some embodiments, the non-small cell lung cancer is an EGFR-mutated non-small cell lung cancer and / or an ALK-positive non-small cell lung cancer, and the non-small cell lung cancer still progresses after the targeted drug treatment. In some embodiments, the non-small cell lung cancer is EGFR-mutated non-small cell lung cancer and / or ALK-positive non-small-cell lung cancer, and the disease is treated after the targeted drug treatment for EGFR mutation and / or ALK-positive Non-small cell lung cancer still progressing. In some embodiments, the non-small cell lung cancer is a non-small cell lung cancer that has progressed or relapsed after receiving at least two types of systemic chemotherapy. In some embodiments, the non-small cell lung cancer is locally advanced or metastatic non-small cell lung cancer that has progressed or relapsed after receiving at least two types of systemic chemotherapy.
式I化合物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式I化合物的游离碱形式。例如，式I化合物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。The compound of formula I may be in its free base form, or in the form of its salt, hydrate and prodrug, which prodrug is converted in vivo to the free base form of the compound of formula I. For example, a pharmaceutically acceptable salt of a compound of formula I is within the scope of the present invention, and salts can be produced from different organic and inorganic acids according to methods known in the art.
在一些实施方案中，式I化合物或其药学上可接受的盐为式I化合物的盐酸盐形式。在一些实施方案中，为式I化合物一盐酸盐的形式。在一些实施方案中，为式I化合物二盐酸盐的形式。在一些实施方案中，为式I化合物盐酸盐的晶体形式。在特定的实施方案中，为式I化合物二盐酸盐的晶体形式。In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof is the hydrochloride form of a compound of Formula I. In some embodiments, it is in the form of a monohydrochloride salt of a compound of Formula I. In some embodiments, it is in the form of a dihydrochloride salt of a compound of Formula I. In some embodiments, it is a crystalline form of the hydrochloride salt of a compound of Formula I. In a particular embodiment, it is a crystalline form of the dihydrochloride salt of a compound of Formula I.
式I化合物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、***、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。The compound of formula 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.
式I化合物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，给予式I化合物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，给予式I化合物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，式I化合物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，式I化合物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，式I化合物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，式I化合物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，式I化合物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，式I化合物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，式I 化合物或其药学上可接受的盐的量为16毫克。The amount of a compound of formula 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. In some embodiments, the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is from 2 mg to 20 mg. In some embodiments, the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is 5 mg to 20 mg. In some embodiments, the amount of the compound of Formula I or a pharmaceutically acceptable salt thereof is 8 mg to 20 mg. In some embodiments, the amount of the compound of Formula I or a pharmaceutically acceptable salt thereof is 10 mg to 16 mg. In some embodiments, the amount of the compound of Formula I or a pharmaceutically acceptable salt thereof is 10 mg to 14 mg. In some specific embodiments, the amount of the compound of Formula I or a pharmaceutically acceptable salt thereof is 10 mg. In some specific embodiments, the amount of the compound of Formula I or a pharmaceutically acceptable salt thereof is 12 mg. In some specific embodiments, the amount of the compound of Formula I or a pharmaceutically acceptable salt thereof is 14 mg. In some specific embodiments, the amount of the compound of formula I or a pharmaceutically acceptable salt thereof is 16 mg.
式I化合物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，每天一次给予式I化合物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。The compound of formula I or a pharmaceutically acceptable salt thereof may be administered one or more times daily. In some embodiments, a compound of formula I or a pharmaceutically acceptable salt thereof is administered once a day. In some embodiments, the oral solid formulation is administered once daily.
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式I化合物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式I化合物或其药学上可接受的盐。例如在给药期内每天给予式I化合物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。The method of administration can be comprehensively determined according to the activity, toxicity, and tolerance of the patient. Preferably, the compound of formula I or a pharmaceutically acceptable salt thereof is administered in spaced administration. The interval administration includes an administration period and a withdrawal period, and the compound of formula I or a pharmaceutically acceptable salt thereof can be administered once or multiple times per day during the administration period. For example, the compound of formula 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. Among them, 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.
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。In some embodiments, the dosing is discontinued for 2 weeks for 2 weeks. In some embodiments, 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.
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。In some embodiments, the administration is discontinued for 2 weeks for 1 week. In some embodiments, 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, and thus for 2 weeks. The drug can be administered repeatedly at intervals of 1 week.
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。In some embodiments, the dosing is discontinued for 5 days for 2 days. In some embodiments, the drug is administered once a day for 5 days and then discontinued for 2 days; then it is administered once a day for 5 days and then discontinued for 2 days, and thus for 5 consecutive days. The two-day interval administration can be repeated several times.
在某些特定的实施方案中，式I的化合物或其药学上可接受的盐以每日一次8mg的剂量口服给药，连续用药2周，停1周的给药方式给药。In certain specific embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof is administered orally at a dose of 8 mg once daily for two consecutive weeks and one week off.
在某些特定的实施方案中，式I的化合物或其药学上可接受的盐以每日一次10mg的剂量口服给药，连续用药2周，停1周的给药方式给药。In certain specific embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof is administered orally at a dose of 10 mg once daily for two consecutive weeks and one week off.
在某些特定的实施方案中，式I的化合物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。In certain specific embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered orally at a dose of 12 mg once daily for two consecutive weeks and one week off.
第三方面，本发明提供了一种治疗EGFR突变的非小细胞肺癌和/或ALK阳性的非小细胞肺癌的药物组合物，其包含式I化合物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。In a third aspect, the present invention provides a pharmaceutical composition for treating EGFR-mutated non-small cell lung cancer and / or ALK-positive non-small cell lung cancer, comprising a compound of formula I or a pharmaceutically acceptable salt thereof, and at least one A pharmaceutically acceptable carrier.
在一些实施方案中，所述的非小细胞肺癌为EGFR突变的非小细胞肺癌和/或ALK阳性的非小细胞肺癌，且在先靶向药物治疗失败的非小细胞肺癌。在一些实施方案中，所述的非小细胞肺癌为EGFR突变的非小细胞肺癌和/或ALK阳性的非小细胞肺癌，且在先针对EGFR 突变和/或ALK阳性的靶向药物治疗失败的非小细胞肺癌。在一些实施方案中，所述的非小细胞肺癌为EGFR突变的非小细胞肺癌和/或ALK阳性的非小细胞肺癌，且在先靶向药物治疗后疾病仍然进展的非小细胞肺癌。在一些实施方案中，所述的非小细胞肺癌为EGFR突变的非小细胞肺癌和/或ALK阳性的非小细胞肺癌，且在先针对EGFR突变和/或ALK阳性的靶向药物治疗后疾病仍然进展的非小细胞肺癌。在一些实施方案中，所述的非小细胞肺癌为至少接受过2种***化疗后出现进展或者复发的非小细胞肺癌。在一些实施方案中，所述的非小细胞肺癌为至少接受过2种***化疗后出现进展或者复发的局部晚期或者转移性非小细胞肺癌。In some embodiments, the non-small cell lung cancer is an EGFR-mutated non-small cell lung cancer and / or an ALK-positive non-small cell lung cancer, and the non-small cell lung cancer that has previously failed a targeted drug treatment. In some embodiments, the non-small cell lung cancer is EGFR-mutated non-small cell lung cancer and / or ALK-positive non-small cell lung cancer, and the targeted drug treatment for EGFR mutation and / or ALK-positive failure has Non-small cell lung cancer. In some embodiments, the non-small cell lung cancer is an EGFR-mutated non-small cell lung cancer and / or an ALK-positive non-small cell lung cancer, and the non-small cell lung cancer still progresses after the targeted drug treatment. In some embodiments, the non-small cell lung cancer is EGFR-mutated non-small cell lung cancer and / or ALK-positive non-small-cell lung cancer, and the disease is treated after the targeted drug treatment for EGFR mutation and / or ALK-positive Non-small cell lung cancer still progressing. In some embodiments, the non-small cell lung cancer is a non-small cell lung cancer that has progressed or relapsed after receiving at least two types of systemic chemotherapy. In some embodiments, the non-small cell lung cancer is locally advanced or metastatic non-small cell lung cancer that has progressed or relapsed after receiving at least two types of systemic chemotherapy.
式I化合物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式I化合物的游离碱形式。例如，式I化合物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。The compound of formula I may be in its free base form, or it may be in the form of a salt, a hydrate and a prodrug, which prodrug is converted in vivo to the free base form of the compound of formula I. For example, a pharmaceutically acceptable salt of a compound of formula I is within the scope of the present invention, and salts can be produced from different organic and inorganic acids according to methods known in the art.
在一些实施方案中，式I化合物或其药学上可接受的盐为式I化合物的盐酸盐形式。在一些实施方案中，为式I化合物一盐酸盐的形式。在一些实施方案中，为式I化合物二盐酸盐的形式。在一些实施方案中，为式I化合物盐酸盐的晶体形式。在特定的实施方案中，为式I化合物二盐酸盐的晶体形式。In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof is the hydrochloride form of a compound of Formula I. In some embodiments, it is in the form of a monohydrochloride salt of a compound of Formula I. In some embodiments, it is in the form of a dihydrochloride salt of a compound of Formula I. In some embodiments, it is a crystalline form of the hydrochloride salt of a compound of Formula I. In a particular embodiment, it is a crystalline form of the dihydrochloride salt of a compound of Formula I.
式I化合物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，给予式I化合物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，给予式I化合物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，该药物组合物中式I化合物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，式I化合物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，式I化合物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，式I化合物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，式I化合物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，式I化合物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，式I化合物或其药学上可接受的盐的量为16毫克。The amount of a compound of formula 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. In some embodiments, the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is from 2 mg to 20 mg. In some embodiments, the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is 5 mg to 20 mg. In some embodiments, the amount of the compound of formula I or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is 8 mg to 20 mg. In some embodiments, the amount of the compound of Formula I or a pharmaceutically acceptable salt thereof is 10 mg to 16 mg. In some embodiments, the amount of the compound of Formula I or a pharmaceutically acceptable salt thereof is 10 mg to 14 mg. In some specific embodiments, the amount of the compound of Formula I or a pharmaceutically acceptable salt thereof is 10 mg. In some specific embodiments, the amount of the compound of Formula I or a pharmaceutically acceptable salt thereof is 12 mg. In some specific embodiments, the amount of the compound of Formula I or a pharmaceutically acceptable salt thereof is 14 mg. In some specific embodiments, the amount of the compound of Formula I or a pharmaceutically acceptable salt thereof is 16 mg.
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。In some embodiments of the present invention, 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 may be an ordinary tablet, a dispersible tablet, an effervescent tablet, a sustained-release tablet, a controlled-release tablet, or an enteric tablet, and the capsule may 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.
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。In some embodiments, 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. In some specific embodiments, the pharmaceutical composition is a capsule. In some specific embodiments of the invention, pharmaceutically acceptable carriers for oral solid formulations include mannitol, microcrystalline cellulose, hydroxypropyl cellulose, and magnesium stearate.
在一些实施方案中，提供了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毫克的式I化合物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毫克的式I化合物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毫克的式I化合物或其药学上可接受的盐，优选10毫克至16毫克的式I化合物或其药学上可接受的盐，较优选10毫克至14毫克的式I化合物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毫克的式I化合物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毫克的式I化合物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毫克的式I化合物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毫克的式I化合物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毫克的式I化合物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。In some embodiments, a pharmaceutical composition is provided that is formulated in a unit dosage form. In some embodiments, the pharmaceutical composition in a unit dosage form contains 2 mg to 20 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition in a unit dosage form contains 5 mg to 20 mg of a compound of formula 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 a compound of formula I or a pharmaceutically acceptable salt thereof, preferably 10 mg to 16 mg of a compound of formula I or a pharmaceutically acceptable salt thereof. A salt, more preferably 10 mg to 14 mg of a compound of formula I or a pharmaceutically acceptable salt thereof. In some specific embodiments, the pharmaceutical composition in the unit dosage form contains 8 mg of a compound of formula I or a pharmaceutically acceptable salt thereof. In some specific embodiments, the unit dosage form pharmaceutical composition contains 10 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof. In some specific embodiments, the unit dosage form pharmaceutical composition contains 12 mg of a compound of formula I or a pharmaceutically acceptable salt thereof. In some specific embodiments, the pharmaceutical composition in unit dosage form contains 14 mg of a compound of formula I or a pharmaceutically acceptable salt thereof. In some specific embodiments, the unit dosage form pharmaceutical composition contains 16 mg of a compound of formula I or a pharmaceutically acceptable salt thereof. For example, for a tablet or capsule, "pharmaceutical composition in unit dosage form" means each tablet or capsule.
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。Preferably, 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 may be administered once or multiple times during the administration period. For example, 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.
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。In some embodiments, the dosing is discontinued for 2 weeks for 2 weeks. In some embodiments, 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.
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。In some embodiments, the administration is discontinued for 2 weeks for 1 week. In some embodiments, 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, and thus for 2 weeks. The drug can be administered repeatedly at intervals of 1 week.
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。In some embodiments, the dosing is discontinued for 5 days for 2 days. In some embodiments, the drug is administered once a day for 5 days and then discontinued for 2 days; then it is administered once a day for 5 days and then discontinued for 2 days, and thus for 5 consecutive days. The two-day interval administration can be repeated several times.
另一方面，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式I化合物或其药学上可接受的盐的药物组合物和(b)用于治疗EGFR突变的非小细胞肺癌和/或ALK阳性的非小细胞肺癌的说明书。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式I化合物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EGFR突变的非小细胞肺癌和/或ALK阳性的非小细胞肺癌的说明书。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式I化合物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EGFR突变的非小细胞肺癌和/或ALK阳性的非小细胞肺癌的说明书。In another aspect, the present invention also provides a kit comprising (a) a pharmaceutical composition of at least one unit dose of a compound of formula I or a pharmaceutically acceptable salt thereof, and (b) a Instructions for small cell lung cancer and / or ALK positive non-small cell lung cancer. In some embodiments, there is provided a kit comprising (a) at least one unit dose of an oral formulation suitable for a compound of Formula I or a pharmaceutically acceptable salt thereof, and (b) a mode of intermittent administration Instructions for the treatment of EGFR-mutated non-small cell lung cancer and / or ALK-positive non-small cell lung cancer. In some specific embodiments, a kit is provided comprising (a) at least one unit dose of a tablet or capsule of a compound of formula I or a pharmaceutically acceptable salt thereof and (b) Instructions for the treatment of EGFR-mutated non-small cell lung cancer and / or ALK-positive non-small cell lung cancer.
在一些实施方案中，所述的非小细胞肺癌为EGFR突变的非小细胞肺癌和/或ALK阳性的非小细胞肺癌，且在先靶向药物治疗失败的非小细胞肺癌。在一些实施方案中，所述的非小细胞肺癌为EGFR突变的非小细胞肺癌和/或ALK阳性的非小细胞肺癌，且在先针对EGFR突变和/或ALK阳性的靶向药物治疗失败的非小细胞肺癌。在一些实施方案中，所述的非小细胞肺癌为EGFR突变的非小细胞肺癌和/或ALK阳性的非小细胞肺癌，且在先靶向药物治疗后疾病仍然进展的非小细胞肺癌。在一些实施方案中，所述的非小细胞肺癌为EGFR突变的非小细胞肺癌和/或ALK阳性的非小细胞肺癌，且在先针对EGFR突变和/或ALK阳性的靶向药物治疗后疾病仍然进展的非小细胞肺癌。在一些实施方案中，所述的非小细胞肺癌为至少接受过2种***化疗后出现进展或者复发的非小细胞肺癌。在一些实施方案中，所述的非小细胞肺癌为至少接受过2种***化疗后出现进展或者复发的局部晚期或者转移性非小细胞肺癌。In some embodiments, the non-small cell lung cancer is an EGFR-mutated non-small cell lung cancer and / or an ALK-positive non-small cell lung cancer, and the non-small cell lung cancer that has previously failed a targeted drug treatment. In some embodiments, the non-small cell lung cancer is EGFR-mutated non-small cell lung cancer and / or ALK-positive non-small cell lung cancer, and the targeted drug treatment for EGFR mutation and / or ALK-positive failure has failed. Non-small cell lung cancer. In some embodiments, the non-small cell lung cancer is an EGFR-mutated non-small cell lung cancer and / or an ALK-positive non-small cell lung cancer, and the non-small cell lung cancer still progresses after the targeted drug treatment. In some embodiments, the non-small cell lung cancer is EGFR-mutated non-small cell lung cancer and / or ALK-positive non-small-cell lung cancer, and the disease is treated after the targeted drug treatment for EGFR mutation and / or ALK-positive Non-small cell lung cancer still progressing. In some embodiments, the non-small cell lung cancer is a non-small cell lung cancer that has progressed or relapsed after receiving at least two types of systemic chemotherapy. In some embodiments, the non-small cell lung cancer is locally advanced or metastatic non-small cell lung cancer that has progressed or relapsed after receiving at least two types of systemic chemotherapy.
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毫克的式I化合物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毫克的式I化合物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毫克的式I化合物或其药学上可接受的盐，优选10毫克至16毫克的式I化合物或其药学上可接受的盐，较优选10毫克至14毫克的式I化合物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毫克的式I化合物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毫克的式I化合物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毫克的式I化合物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毫克的式I化合物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毫克的式I化合物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。In some embodiments, the pharmaceutical composition in a unit dosage form contains 2 mg to 20 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition in a unit dosage form contains 5 mg to 20 mg of a compound of formula 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 a compound of formula I or a pharmaceutically acceptable salt thereof, preferably 10 mg to 16 mg of a compound of formula I or a pharmaceutically acceptable salt thereof. A salt, more preferably 10 mg to 14 mg of a compound of formula I or a pharmaceutically acceptable salt thereof. In some specific embodiments, the pharmaceutical composition in the unit dosage form contains 8 mg of a compound of formula I or a pharmaceutically acceptable salt thereof. In some specific embodiments, the unit dosage form pharmaceutical composition contains 10 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof. In some specific embodiments, the unit dosage form pharmaceutical composition contains 12 mg of a compound of formula I or a pharmaceutically acceptable salt thereof. In some specific embodiments, the pharmaceutical composition in unit dosage form contains 14 mg of a compound of formula I or a pharmaceutically acceptable salt thereof. In some specific embodiments, the unit dosage form pharmaceutical composition contains 16 mg of a compound of formula I or a pharmaceutically acceptable salt thereof. For example, for a tablet or capsule, "pharmaceutical composition in unit dosage form" means each tablet or capsule.
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。The tablet may be an ordinary tablet, a dispersible tablet, an effervescent tablet, a sustained-release tablet, a controlled-release tablet, or an enteric tablet, and the capsule may 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.
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。The interval administration includes an administration period and a withdrawal period, and the above-mentioned pharmaceutical composition may be administered once or multiple times during the administration period. For example, 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.
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。In some embodiments, the dosing is discontinued for 2 weeks for 2 weeks. In some embodiments, 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.
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。In some embodiments, the administration is discontinued for 2 weeks for 1 week. In some embodiments, 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, and thus for 2 weeks. The drug can be administered repeatedly at intervals of 1 week.
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。In some embodiments, the dosing is discontinued for 5 days for 2 days. In some embodiments, the drug is administered once a day for 5 days and then discontinued for 2 days; then it is administered once a day for 5 days and then discontinued for 2 days, and thus for 5 consecutive days. The two-day interval administration can be repeated several times.
本申请中，所述的非小细胞肺癌包括但不限于肺鳞癌和肺腺癌。In the present application, the non-small cell lung cancer includes, but is not limited to, lung squamous cell carcinoma and lung adenocarcinoma.
本申请中，所述的“EGFR突变”包括但不限于19位外显子突变、21外显子、18外显子、20外显子(例如T790M)的突变。In the present application, the "EGFR mutation" includes, but is not limited to, mutations in exon 19, exon 21, exon 18, and exon 20 (for example, T790M).
本申请中，所述的“ALK阳性”也可称为ALK(Anaplastic lymphoma kinase，间变性淋巴瘤激酶)融合基因阳性，包括但不限于EML4-ALK融合突变。In the present application, the "ALK-positive" may also be referred to as ALK (Anaplastic lymphomakinase) fusion gene positive, including but not limited to EML4-ALK fusion mutation.
本申请中，所述的“靶向药物”包括但不限于厄洛替尼、吉非替尼、osimertinib(AZD9291)、阿法替尼、色瑞替尼(ceritinib)、艾克替尼(alectinib)、克唑替尼、brigatinib。In the present application, the "targeted drug" includes but is not limited to erlotinib, gefitinib, osimertinib (AZD9291), afatinib, ceritinib, alectinib ), Crizotinib, brigatinib.
所述的“针对EGFR突变的靶向药物”包括但不限于厄洛替尼、吉非替尼、阿法替尼、 osimertinib。The "targeted drug for EGFR mutation" includes, but is not limited to, erlotinib, gefitinib, afatinib, and osimertinib.
所述的“针对ALK阳性的靶向药物”包括但不限于艾克替尼(alectinib)、克唑替尼、色瑞替尼(ceritinib)、brigatinib。The "targeting drug for ALK positive" includes, but is not limited to, alectinib, crizotinib, ceritinib, and brigatinib.
本申请中，所述的化疗药物包括但不限于铂配合物(例如顺铂、卡铂、奈达铂、奥沙利铂)、紫杉烷类化合物(例如紫杉醇、多西他赛)、氟嘧啶衍生物(例如吉西他滨、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)、培美曲塞、长春瑞滨、依托泊苷、长春花碱。In this application, the chemotherapeutic drugs include, but are not limited to, platinum complexes (for example, cisplatin, carboplatin, nedaplatin, oxaliplatin), taxanes (for example, paclitaxel, docetaxel), fluorine Pyrimidine derivatives (e.g. gemcitabine, capecitabine, fluorouracil, bisfurofuracil, deoxyfluorouridine, tegafur, carmofur), pemetrexed, vinorelbine, etoposide, vinblastine.
本文中，除非另有说明，这里提供的剂量和范围都是基于式I化合物游离碱形式的分子量。Herein, unless stated otherwise, the dosages and ranges provided herein are based on the molecular weight of the free base form of the compound of Formula I.
本文中，所述的式I化合物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，所述的式I化合物的二盐酸盐的晶体形式为A型结晶。Herein, the crystal form of the hydrochloride salt of the compound of the formula 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. The crystals of type C are crystals containing two crystal waters. In some embodiments, the crystalline form of the dihydrochloride salt of the compound of Formula I is Form A crystal.
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。Unless otherwise stated, for the purposes of this application, the following terms used in this specification and claims shall have the following meanings.
“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。"Patient" means a mammal, preferably a human. In some embodiments, the patient is a patient who fails or lacks standard treatment.
“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。"Pharmaceutically acceptable" refers to its use in the preparation of pharmaceutical compositions that are generally safe, non-toxic, and neither biologically or otherwise undesirable, and include those that are acceptable for human drug use. Accepted.
“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。"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, and propionic acid , Hexanoic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvate, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, Mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-chlorobenzenesulfonic acid, p-toluenesulfonic acid, 3-phenylpropionic acid, tris Acid addition salts of methylacetic acid, tert-butylacetic acid, dodecylsulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and the like.
“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。By "therapeutically 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.
“治疗”意指治疗上有效量的化合物的任何施用，并且包括："Treatment" means any administration of a therapeutically effective amount of a compound, and includes:
(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(1) inhibiting the disease in a human who is experiencing or showing the pathology or symptomology of the disease (i.e., retarding further development of the pathology and / or symptomology), or
(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)。(2) Ameliorating the disease in a human who is experiencing or showing the pathology or symptomology of the disease (ie, reversing the pathology and / or symptomology).
“PR”是指部分缓解(partial response)，具体指肿瘤的靶病灶直径之和比基线水平减少30％以上。"PR" refers to partial response, specifically the sum of the diameter of the target lesions of a tumor is reduced by more than 30% from the baseline level.
“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。"PD" refers to disease progression, specifically the sum of the diameters of the target lesions of a tumor increased by more than 20% from baseline levels.
“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。"SD" refers to stable disease, specifically the degree to which the tumor target lesion has not decreased to the level of PR, and the degree of increase has not reached the level of PD, somewhere in between.
“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。"Failure to treat" refers to intolerable toxic or side effects, disease progression during treatment, or relapse after treatment is completed; among them, intolerance includes, but is not limited to, hematological toxicity up to level IV (platelet reduction level III and above), non-hematological toxicity Reach level III or above.
具体实施方式Detailed ways
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(式I化合物的二盐酸盐)Example 1 1-[[[[4- (4-Fluoro-2-methyl-1H-indol-5-yl) oxy-6-methoxyquinolin-7-yl] oxy] methyl] Cyclopropylamine dihydrochloride (dihydrochloride of a compound of formula I)
Figure PCTCN2019087721-appb-000003
Figure PCTCN2019087721-appb-000003
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。According to the method of Example 24 in WO2008112407, 1-[[[[[(4- (4-fluoro-2-methyl-1H-indole-5-yl) oxy-6-methoxyquinolin-7-yl [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.
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(式I化合物的二盐酸盐)的胶囊Example 2 containing 1-[[[[4- (4-fluoro-2-methyl-1H-indole-5-yl) oxy-6-methoxyquinolin-7-yl] oxy] methyl ] Capsules of Cyclopropylamine Dihydrochloride (Dihydrochloride of Compound of Formula I)
Figure PCTCN2019087721-appb-000004
Figure PCTCN2019087721-appb-000004
将式I化合物的二盐酸盐粉碎，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。Crush the dihydrochloride of the compound of formula I and pass through an 80 mesh sieve; then mix with mannitol and hypromellose uniformly; then add the prescribed amount of microcrystalline cellulose and mix evenly through a 0.8mm sieve; finally add the prescription The amounts of magnesium stearate were mixed well and the capsules were filled.
对于式I化合物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。Capsules of dihydrochloride of the compound of formula I with other contents can be prepared by referring to the same ratio and prescription as described above.
实施例3 对非小细胞肺癌的疗效Example 3 Curative Effect on Non-small Cell Lung Cancer
女，70岁，活检病理诊断腺癌，结合影像学检查结果，临床诊断：左肺腺癌，左侧胸膜转移，基因检测显示ALK阴性，EGFR阳性(外显子19突变、T790M突变)。Female, 70 years old, biopsy pathological diagnosis of adenocarcinoma, combined with imaging findings, clinical diagnosis: left lung adenocarcinoma, left pleural metastasis, genetic testing showed ALK negative, EGFR positive (exon 19 mutation, T790M mutation).
在服用式I化合物的二盐酸盐的胶囊之前，2012-2015年间，按照时间先后顺序，患者间断性地依次接受了以下治疗：4周期培美曲塞+奈达铂化疗，最佳疗效SD；2周期培美曲塞+卡铂，疗效SD；一周期的多西他赛+奈达铂，疗效不佳，为PD；在上述治疗期间，患者同时服用埃克替尼达一年半，疗效SD。Before taking the dihydrochloride capsules of the compound of formula I, in 2012-2015, the patients intermittently received the following treatments in chronological order: 4 cycles of pemetrexed + nedaplatin chemotherapy, the best effect SD ; 2 cycles of pemetrexed + carboplatin, curative effect SD; one cycle of docetaxel + nedaplatin, poor efficacy, PD; during the above treatment period, patients also took ectinida for one and a half years, Efficacy SD.
2015年4月，患者开始每日一次口服12mg(连续用2周停1周为一个治疗周期)剂量的式I化合物的二盐酸盐的胶囊进行治疗。In April 2015, the patient started treatment with a capsule of a dihydrochloride salt of a compound of formula I at a dose of 12 mg orally once a day (continuously used for 2 weeks and 1 week as a treatment cycle).
式I化合物的二盐酸盐治疗后，患者的肿瘤靶病灶长径之和有所降低。服药前的CT扫描中，2个大的可测量的靶病灶直径之和为50mm(左肺下叶29mm，左肺下叶21mm)。服药后，定期进行CT扫描，给予式I化合物的二盐酸盐一周期(三个星期时)靶病灶直径之和降至41mm(左肺下叶24mm，左肺下叶17mm)；二周期时靶病灶直径之和仍为41mm(左肺下叶24mm，左肺下叶17mm)；四周期时靶病灶直径之和降至38mm(左肺下叶22mm，左肺下叶16mm)；十周期时45mm(左肺下叶26mm，左肺下叶19mm)；随访显示，三十周期时，患者仍在接受式I化合物二盐酸盐的治疗，治疗期间，肿瘤继续应答且临床表现良好。After treatment with the dihydrochloride salt of the compound of formula I, the sum of the lengths of the tumor target lesions in the patient is reduced. In the CT scan before taking the medicine, the sum of the diameters of the two large measurable target lesions was 50 mm (29 mm in the left lower lobe and 21 mm in the left lower lobe). After taking the drug, regular CT scans were performed, and the total diameter of the target lesions was reduced to 41 mm (at the left lower lobe of 24 mm and the left lower lobe at 17 mm) for one cycle (at three weeks) of the dihydrochloride compound of formula I; The sum of the diameters of the target lesions is still 41mm (24mm in the left lower lobe and 17mm in the left lower lobe); the sum of the diameters of the target lesions is reduced to 38mm at four cycles (22mm in the left lower lobe and 16mm in the left lower lobe); at ten cycles 45mm (26mm left lobe, 19mm left lobe); follow-up showed that at 30 cycles, the patient was still receiving the treatment of the dihydrochloride compound of formula I. During the treatment, the tumor continued to respond and the clinical manifestations were good.
服药期间，12mg时患者的耐受性较差，主要的不良事件是高脂血症、TSH升高、手足皮肤反应、特别是腹泻和腹痛频繁。后来剂量降至10mg，再降至8mg，在治疗期间，大部分不良事件可以耐受，患者状态也恢复正常，体重也有所增加。During administration, patients were less tolerated at 12 mg. The main adverse events were hyperlipidemia, elevated TSH, hand-foot skin reactions, especially frequent diarrhea and abdominal pain. Later the dose was reduced to 10 mg and then to 8 mg. During the treatment, most adverse events were tolerated, the patient's condition returned to normal, and his weight increased.
实施例4Example 4
男，66岁，无吸烟史，接受右下肺切除术，术后病理，提示右肺***状腺癌，基因检测提示EGFR19、20外显子突变。Male, 66 years old, had no history of smoking and underwent right lower lung resection. Postoperative pathology revealed a right lung papillary adenocarcinoma. Genetic testing revealed mutations in exons 19 and 20.
在2012年5月至2015年7月期间，间断性地依次接受了以下治疗：培美曲塞与顺铂化疗4周期，疗效不佳；多西他赛治疗15周期，疗效不佳；吉西他滨+奈达铂治疗8周期，疗 效不佳；恩度+长春瑞滨+顺铂治疗1周期，疗效不佳；在治疗期间，患者使用厄罗替尼片3个月，疗效不佳。From May 2012 to July 2015, I intermittently received the following treatments in sequence: pemetrexed and cisplatin chemotherapy for 4 cycles with poor results; 15 cycles of docetaxel for poor efficacy; gemcitabine + Nidaplatin was not effective for 8 cycles of treatment; Endo + Changbin Ruibin + cisplatin was not effective for 1 cycle. During the treatment period, patients received erlotinib tablets for 3 months and the results were not good.
2015年7月开始每日一次口服12mg(连续用2周停1周为一个治疗周期)剂量的式I化合物的二盐酸盐的胶囊进行治疗。Beginning in July 2015, treatment was started with capsules of the dihydrochloride salt of a compound of formula I at a dose of 12 mg orally once a day (continuously used for 2 weeks and 1 week as a treatment cycle).
在给药前一天的CT扫描中，3个大的可测量的靶病灶直径之和为65mm(左肺肿块34mm，右锁骨上***15mm，纵膈***16mm)；患者服用式I化合物的二盐酸盐的胶囊后，定期进行CT扫描，服药六个星期后靶病灶直径之和降至57mm(左肺肿块28mm，右锁骨上***16mm，纵膈***13mm)；随后每两个周期复查一次影像学，靶病灶始终维持在55mm左右，非靶病灶均未进展，也未出现新发病灶。随访显示，三十周期时，患者仍在接受式I化合物二盐酸盐的治疗。治疗期间，患者的总体耐受良好，血常规变化不显著，其他指标未见明显变化，红细胞计数水平始终维持在正常状态，未见与药物相关的心脏毒性。On the CT scan one day before the administration, the sum of the diameters of the three large measurable target lesions was 65 mm (34 mm for the left lung mass, 15 mm for the right supraclavicular lymph node, and 16 mm for the mediastinal lymph node); the patient was taking a disalt of a compound of formula I CT scans were performed regularly after the acid salt capsules, and the sum of the diameter of the target lesions decreased to 57 mm after taking the medicine for six weeks (left lung mass 28 mm, right supraclavicular lymph node 16 mm, mediastinal lymph node 13 mm); subsequent images were reviewed every two cycles The target lesions were always maintained at about 55mm. Non-target lesions did not progress, and no new lesions appeared. Follow-up showed that at thirty cycles, the patient was still receiving treatment with a compound of formula I dihydrochloride. During the treatment, the patient's overall tolerance was good, blood routine changes were not significant, other indicators were not significantly changed, the red blood cell count level was always maintained in a normal state, and no drug-related cardiotoxicity was seen.
实施例5Example 5
男，70岁，吸烟史20年，无手术史。2015年4月穿刺，病理诊断提示：肺癌(分化差)，腺样分化，临床诊断：原发性右肺腺癌，骨转移，肾上腺转移。基因检测提示EGFR 21外显子低丰度突变。Male, 70 years old, smoking history for 20 years, no history of surgery. A puncture in April 2015 revealed pathological diagnosis: lung cancer (poor differentiation), adenoid differentiation, clinical diagnosis: primary right lung adenocarcinoma, bone metastases, and adrenal metastases. Genetic testing revealed low abundance mutations in exon 21.
2015年4月至2015年5月接受了2周期培美曲塞与卡铂化疗，最佳疗效PD。随后更改化疗方案，于2015年6月接受替吉奥化疗1周期，疗效仍不佳。期间使用厄罗替尼片，疗效不佳。2015年4月至2015年5月接受吉非替尼治疗，最佳疗效PD。She received 2 cycles of pemetrexed and carboplatin chemotherapy from April 2015 to May 2015, with the best efficacy PD. Subsequently, the chemotherapy regimen was changed. In June 2015, he received Tiglio chemotherapy for 1 cycle, and the effect was still poor. Erlotinib tablets were used during this period, and the effect was not good. She received gefitinib treatment from April 2015 to May 2015, with the best effect of PD.
2015年8月开始每日一次口服12mg(连续用2周停1周为一个治疗周期)剂量的式I化合物的二盐酸盐的胶囊进行治疗。Beginning in August 2015, treatment was started with capsules of a dihydrochloride compound of formula I at a dose of 12 mg orally once a day (continuously used for 2 weeks and 1 week as a treatment cycle).
在给予式I化合物二盐酸盐的胶囊的前一天，CT扫描显示，可测量的靶病灶直径之和为239mm(右肺71mm，右肾上腺60mm，右耻骨低密度肿块26mm，左肾上腺82mm)。给药后，定期进行CT扫描，治疗六个周期后，靶病灶直径之和降至190mm(右肺55mm，右肾上腺44mm，右耻骨低密度肿块27mm，左肾上腺64mm)，疗效评价为PR，降低超过30％。18个周期时靶病灶直径之和降至156mm(右肺54mm，右肾上腺39mm，右耻骨低密度肿块20mm，左肾上腺43mm)，也未出现新发病灶。服药26周期后，CT显示，靶病灶直径之和为185mm，医生评估后，建议仍可继续服药，治疗期间，总体耐受性良好。The day before the administration of the capsule of the compound of formula I dihydrochloride, a CT scan showed that the sum of the diameters of the measurable target lesions was 239 mm (right lung 71 mm, right adrenal gland 60 mm, right pubic low density mass 26 mm, and left adrenal gland 82 mm). After administration, CT scans were performed regularly. After six cycles of treatment, the sum of the diameter of the target lesions decreased to 190 mm (55 mm in the right lung, 44 mm in the right adrenal gland, 27 mm in the low-density mass of the right pubic bone, and 64 mm in the left adrenal gland). More than 30%. At 18 cycles, the sum of the diameters of the target lesions decreased to 156 mm (54 mm in the right lung, 39 mm in the right adrenal gland, 20 mm in the low-density mass in the right pubic bone, and 43 mm in the left adrenal gland), and no new lesions appeared. After 26 cycles of medication, CT showed that the sum of the diameters of the target lesions was 185 mm. After evaluation by the doctor, it was recommended that the medication be continued, and the overall tolerance was good during the treatment.
实施例6Example 6
女，46岁，既往健康状况良好，无吸烟史。结合影像学检查结果，临床诊断：右肺腺癌，脑转移，伴***转移。2014年3月-7月，接受6周期的培美曲赛和卡铂化疗，疗效评价SD。基因检测结果：EGFR(-)，ALK(+)。2014年8月至2015年1月口服克唑替尼，2014年12月胸部CT显示，肿瘤有增大趋势，疗效为SD。随后进行化疗，化疗期间继续口服克唑替尼。2015年1月至2015年4月接受4周期的紫杉醇和奥沙利铂的化疗，疗效评价SD。Female, 46 years old, with good health and no history of smoking. Combined with imaging findings, clinical diagnosis: right lung adenocarcinoma, brain metastases, and lymph node metastases. From March to July 2014, she received 6 cycles of pemetrexed and carboplatin chemotherapy, and the efficacy evaluation was SD. Genetic test results: EGFR (-), ALK (+). Crizotinib was taken orally from August 2014 to January 2015, and a CT scan of the chest in December 2014 showed that the tumor had an increasing tendency and the curative effect was SD. Chemotherapy was subsequently performed, and crizotinib continued to be taken orally during chemotherapy. She received four cycles of chemotherapy with paclitaxel and oxaliplatin from January 2015 to April 2015. The efficacy evaluation was SD.
2015年4月-7月，口服克唑替尼，2015年7月复查，CT结果显示，右肺上叶肿物较前增大；头颅MRI显示，与2015年4月的相比，左额叶结节较前明显增大，周围水肿，考虑转移瘤，考虑病情进展，随后进行脑肿瘤γ刀治疗。2015年8月接受2周期的培美曲赛和卡铂的治疗，疗效评价PR。2015年9月至2015年10月接受2周期的培美曲赛和卡铂的治疗，疗效评价SD，2015年10月CT显示，右上肺肿物较前增大。From April to July 2015, oral crizotinib was re-examined in July 2015. CT results showed that the tumor in the right upper lobe was larger than before; a skull MRI showed that the left forehead was larger than that in April 2015. Leaf nodules were significantly larger than before, with surrounding edema, metastasis was considered, disease progression was considered, and brain tumor gamma knife treatment was subsequently performed. He received two cycles of pemetrexed and carboplatin in August 2015, and the effect was evaluated by PR. He received two cycles of pemetrexed and carboplatin treatment from September 2015 to October 2015. The curative effect evaluation SD, in October 2015, CT showed that the upper right lung mass increased.
2015年12月11日开始每日一次口服12mg(连续用2周停1周为一个治疗周期)剂量的式I化合物二盐酸盐的胶囊。Capsules of a compound of formula I dihydrochloride at a dose of 12 mg orally once a day (continuously used for 2 weeks and 1 week as a treatment cycle) began once a day on December 11, 2015.
在给予式I化合物之前，CT扫描显示，1个可测量的靶病灶直径为70mm(右肺肿物)。服药后，定期进行CT扫描。三个星期时靶病灶直径降至56mm，六个星期时靶病灶直径58mm，十二个星期时靶病灶直径为62mm，十八个星期时靶病灶直径约58mm，二十四个星期时靶病灶直径68mm。在此期间，未出现新发病灶，最佳疗效SD缩小。治疗期间，总体耐受良好。Prior to the administration of the compound of formula I, a CT scan revealed that a measurable target lesion was 70 mm in diameter (right lung mass). After taking the medicine, regular CT scans are performed. The target lesion diameter decreased to 56mm at three weeks, the target lesion diameter was 58mm at six weeks, the target lesion diameter was 62mm at twelve weeks, the target lesion diameter was approximately 58mm at eighteen weeks, and the target lesion was twenty-four weeks. 68mm diameter. During this period, no new lesions appeared, and the best effect SD decreased. During treatment, overall tolerance was good.
实施例7Example 7
男，52岁，吸烟史20余年(30支/天)，活检病理显示：鳞状细胞癌。结合影像学检查结果，临床诊断：右肺鳞状细胞癌，纵膈、右肺门***转移。Male, 52 years old, smoking history for more than 20 years (30 sticks / day), biopsy pathology showed: squamous cell carcinoma. Combined with the imaging results, the clinical diagnosis was: squamous cell carcinoma of the right lung, mediastinal and right hilar lymph node metastasis.
在接受式I化合物二盐酸盐治疗之前，2014年-2015年间，患者依次接受的治疗如下：两周期的吉西他滨联合奈达铂化疗，疗效SD；多西他赛联合顺铂化疗一个周期，具体疗效不详；右肺IMRT放疗(60Gy)，疗效SD；多西他赛联合顺铂化疗两个周期，疗效不详；培美曲赛单药化疗2周期，疗效PD。基因检测显示：ALK阳性(ALK-Exon20 EML4融合突变)，服用克唑替尼25天，疗效评估为PD，CT显示：右下肺门区不规则肿块46mm，左肺上叶转移结节28mm，右肺下叶转移结节22mm，心包少量积液，右侧胸膜少量积液。肿瘤标志物CEA检查结果异常，高达13.42ng/mL。Before receiving the treatment of the compound dihydrochloride of formula I, from 2014 to 2015, the patients received the following treatments in order: two cycles of gemcitabine combined with nedaplatin chemotherapy, the efficacy SD; one cycle of docetaxel combined with cisplatin chemotherapy, specifically Efficacy is unknown; right lung IMRT radiotherapy (60Gy), curative effect SD; docetaxel combined with cisplatin chemotherapy for two cycles, curative effect is unknown; pemetrexed monotherapy 2 cycles, efficacy PD. Genetic testing showed ALK-positive (ALK-Exon20 EML4 fusion mutation), taking crizotinib for 25 days, and the efficacy was evaluated as PD. CT showed an irregular mass in the right lower hilar region of 46mm and a left upper lobe metastatic nodule of 28mm. The right lower lobe metastatic nodule was 22mm, with a small amount of pericardial effusion and a small amount of right pleural effusion. CEA results of tumor markers were abnormal, as high as 13.42 ng / mL.
随后，患者开始每日一次口服12mg(连续用2周停1周为一个治疗周期)剂量的式I化合物二盐酸盐的胶囊。Subsequently, the patient began to take capsules of a compound of formula I dihydrochloride at a dose of 12 mg orally once a day (2 consecutive weeks off for 1 week as a treatment cycle).
在给药前的CT扫描显示，3个大的可测量的靶病灶直径之和为96mm(右下肺门区不规 则肿块46mm，左肺上叶转移结节28mm，右肺下叶转移结节22mm)；用药后，患者的肿瘤靶病灶长径之和缓慢增大，同时CEA随治疗而下降。给药后三个星期时靶病灶直径之和未发生变化(右下肺门区不规则肿块47mm，左肺上叶转移结节26mm，右肺下叶转移结节23mm)；六个星期时靶病灶直径之和增至98mm(右下肺门区不规则肿块47mm，左肺上叶转移结节29mm，右肺下叶转移结节22mm)肿瘤标志物CEA降至8.76；十二个星期时靶病灶直径之和增至104mm，增大8.3％(右下肺门区不规则肿块46mm，左肺上叶转移结节33mm，右肺下叶转移结节25mm)，肿瘤标志物CEA为8.52；十八个星期时靶病灶直径之和增至106mm，增大10.4％(右下肺门区不规则肿块45mm，左肺上叶转移结节36mm，右肺下叶转移结节25mm)肿瘤标志物CEA为9.32；二十四个星期时靶病灶直径之和增至126mm(右下肺门区不规则肿块53mm，左肺上叶转移结节45mm，右肺下叶转移结节28mm)肿瘤标志物CEA为10.13。治疗期间，非靶病灶均未进展，也未出现新发病灶。患者总体耐受良好。治疗期间，血常规变化不显著，未见与药物相关的心脏毒性等。A CT scan before administration showed that the sum of the diameters of the three large measurable target lesions was 96 mm (irregular mass in the right lower hilar region 46 mm, upper left metastatic nodules 28 mm, and right lower inferior lobe metastases. 22mm); After the treatment, the sum of the length and diameter of the tumor target lesions of the patient slowly increased, and CEA decreased with the treatment. The sum of the diameters of the target lesions did not change at three weeks after the administration (irregular mass in the right lower hilar region of 47 mm, left upper lobe metastasis nodules of 26 mm, right lower lobe metastasis nodules of 23 mm); the target was at six weeks The sum of lesion diameters increased to 98 mm (47 mm irregular mass in the right lower hilar region, 29 mm in the left upper lobe metastasis nodule, and 22 mm in the right lower lobe metastasis nodule). The tumor marker CEA decreased to 8.76; target at twelve weeks The sum of the diameters of the lesions increased to 104mm, an increase of 8.3% (irregular mass in the right lower hilar region 46mm, upper left lobe metastasis nodule 33mm, right lower lobe metastasis nodule 25mm), the tumor marker CEA was 8.52; ten At eight weeks, the sum of the diameters of the target lesions increased to 106 mm, an increase of 10.4% (irregular mass in the right lower hilar area 45 mm, upper left lobe metastasis nodule 36 mm, right lower lobe metastasis nodule 25 mm) tumor marker CEA Was 9.32; the total diameter of the target lesion increased to 126 mm at 24 weeks (53 mm irregular mass in the right lower hilar region, 45 mm in the left upper lobe metastasis nodule, and 28 mm in the right lower lobe metastasis nodule) tumor marker CEA Is 10.13. During treatment, non-target lesions did not progress, and no new lesions appeared. The patient was generally well tolerated. During treatment, blood routine changes were not significant, and no drug-related cardiotoxicity was seen.

Claims (7)

  1. 式I的化合物或其药学上可接受的盐在制备用于治疗非小细胞肺癌的药物中的用途，其中所述的非小细胞肺癌为EGFR突变的非小细胞肺癌和/或ALK阳性的非小细胞肺癌，Use of a compound of formula I or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating non-small cell lung cancer, wherein the non-small cell lung cancer is an EGFR-mutated non-small cell lung cancer and / or an ALK-positive non-small cell lung cancer Small Cell Lung Cancer,
    Figure PCTCN2019087721-appb-100001
    Figure PCTCN2019087721-appb-100001
  2. 权利要求1所述的用途，其中所述的非小细胞肺癌为EGFR突变的非小细胞肺癌和/或ALK阳性的非小细胞肺癌，且在先靶向药物治疗失败的非小细胞肺癌。The use according to claim 1, wherein the non-small cell lung cancer is an EGFR-mutated non-small cell lung cancer and / or an ALK-positive non-small cell lung cancer, and the non-small cell lung cancer that has previously failed a targeted drug treatment.
  3. 权利要求1所述的用途，其中所述的EGFR突变包括19位外显子突变、21外显子、18外显子、20外显子(例如T790M)的突变。The use of claim 1, wherein the EGFR mutation comprises mutations in exon 19, exon 21, exon 18, and exon 20 (eg, T790M).
  4. 权利要求1所述的用途，其中式I的化合物或其药学上可接受的盐以间隔给药的方式给药，所述的间隔给药包括给药期和停药期，其中，给药期和停药期的以天数计的比值为2:0.5～5。The use according to claim 1, wherein the compound of formula I or a pharmaceutically acceptable salt thereof is administered at intervals, and the interval administration includes an administration period and a withdrawal period, wherein the administration period The ratio in days to the withdrawal period is 2: 0.5 to 5.
  5. 权利要求1所述的用途，其中式I的化合物或其药学上可接受的盐以下述的给药方案进行给药：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。The use according to claim 1, wherein the compound of formula I or a pharmaceutically acceptable salt thereof is administered in the following dosing schedule: continuous administration for 2 weeks and withdrawal for 2 weeks, continuous administration for 2 weeks and withdrawal for 1 week , Or discontinuation for 2 days after 5 consecutive days of administration.
  6. 权利要求1所述的用途，其中式I的化合物或其药学上可接受的盐给药的日剂量为2毫克-20毫克，优选8毫克、10毫克和12毫克。The use according to claim 1, wherein the compound of formula I or a pharmaceutically acceptable salt thereof is administered at a daily dose of 2 mg to 20 mg, preferably 8 mg, 10 mg and 12 mg.
  7. 权利要求1所述的用途，其中式I的化合物或其药学上可接受的盐为式I化合物的二盐酸盐。The use of claim 1, wherein the compound of formula I or a pharmaceutically acceptable salt thereof is a dihydrochloride salt of a compound of formula I.
PCT/CN2019/087721 2018-05-22 2019-05-21 Quinoline derivative for treating non-small cell lung cancer WO2019223672A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
CN202310227490.8A CN116440134A (en) 2018-05-22 2019-05-21 Quinoline derivatives for the treatment of non-small cell lung cancer
CN201980033590.9A CN112105361A (en) 2018-05-22 2019-05-21 Quinoline derivatives for the treatment of non-small cell lung cancer

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201810494121.4 2018-05-22
CN201810494121 2018-05-22

Publications (1)

Publication Number Publication Date
WO2019223672A1 true WO2019223672A1 (en) 2019-11-28

Family

ID=68616136

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2019/087721 WO2019223672A1 (en) 2018-05-22 2019-05-21 Quinoline derivative for treating non-small cell lung cancer

Country Status (2)

Country Link
CN (2) CN112105361A (en)
WO (1) WO2019223672A1 (en)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101809012A (en) * 2007-03-14 2010-08-18 南京爱德程医药科技有限公司 Spiro substituted compounds as angiogenesis inhibitors
CN107001326A (en) * 2014-12-09 2017-08-01 正大天晴药业集团股份有限公司 The quinoline of anti-non-small cell lung cancer
CN106999484A (en) * 2014-12-09 2017-08-01 正大天晴药业集团股份有限公司 Treat the quinoline of non-small cell lung cancer

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101809012A (en) * 2007-03-14 2010-08-18 南京爱德程医药科技有限公司 Spiro substituted compounds as angiogenesis inhibitors
CN107001326A (en) * 2014-12-09 2017-08-01 正大天晴药业集团股份有限公司 The quinoline of anti-non-small cell lung cancer
CN106999484A (en) * 2014-12-09 2017-08-01 正大天晴药业集团股份有限公司 Treat the quinoline of non-small cell lung cancer

Also Published As

Publication number Publication date
CN112105361A (en) 2020-12-18
CN116440134A (en) 2023-07-18

Similar Documents

Publication Publication Date Title
US10888559B2 (en) Quinoline derivatives for non-small cell lung cancer
US10736887B2 (en) Quinoline derivative for treating gastric cancer
CN111012785A (en) Quinoline derivatives for the treatment of thyroid cancer
WO2018214925A1 (en) Quinoline derivative for treatment of colorectal cancer
CN114652723A (en) Quinoline derivatives for treating non-small cell lung cancer
AU2020259565A1 (en) Quinoline compound or pharmaceutically acceptable salt thereof for treating Ewing's sarcoma
CN115025090A (en) Application of quinoline derivative in treatment of esophageal cancer, and treatment method, pharmaceutical composition and kit thereof
CN112638385B (en) Quinoline derivatives for the treatment of brain tumors
WO2020029918A1 (en) Quinoline derivative for treating extranodal nk/t cell lymphoma
WO2019223672A1 (en) Quinoline derivative for treating non-small cell lung cancer
WO2021140478A1 (en) Combination therapy for treating cancer
CN106999485B (en) Anti-squamous cell lung carcinoma quinoline derivatives
CN112533600B (en) Quinoline derivatives for the treatment of small cell lung cancer

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 19806914

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 19806914

Country of ref document: EP

Kind code of ref document: A1