WO2021083347A1 - 喹唑啉衍生物或其盐、或其药物组合物的用途 - Google Patents

喹唑啉衍生物或其盐、或其药物组合物的用途 Download PDF

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Publication number
WO2021083347A1
WO2021083347A1 PCT/CN2020/125384 CN2020125384W WO2021083347A1 WO 2021083347 A1 WO2021083347 A1 WO 2021083347A1 CN 2020125384 W CN2020125384 W CN 2020125384W WO 2021083347 A1 WO2021083347 A1 WO 2021083347A1
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WIPO (PCT)
Prior art keywords
compound
formula
pharmaceutically acceptable
acceptable salt
pharmaceutical composition
Prior art date
Application number
PCT/CN2020/125384
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English (en)
French (fr)
Inventor
杨朝强
封帆
葛琪
李琳
唐晓闻
王训强
尚磊
何佳丽
晏彩霞
董平
周杰
孙迎迎
许易
陈智林
Original Assignee
正大天晴药业集团股份有限公司
连云港润众制药有限公司
首药控股(北京)有限公司
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Application filed by 正大天晴药业集团股份有限公司, 连云港润众制药有限公司, 首药控股(北京)有限公司 filed Critical 正大天晴药业集团股份有限公司
Priority to CN202080071551.0A priority Critical patent/CN114787151B/zh
Publication of WO2021083347A1 publication Critical patent/WO2021083347A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • This application belongs to the field of medical technology, and relates to the use of quinazoline derivatives or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, and specifically relates to the use of N 6 -(1-acryloylazcyclohexane-4-yl ) -N 4 -(3-chloro-4-fluorophenyl)-7-methoxyquinazoline-4,6-diamine or a pharmaceutically acceptable salt thereof, or use of a pharmaceutical composition thereof.
  • EGFR epithelial growth factor receptor
  • epithelial growth factor receptor is a tyrosine kinase receptor, a member of the HER/ErbB family, which includes EGFR, HER2, HER3 and HER4, and consists of three parts: extracellular The ligand binding region, the transmembrane region composed of a single chain, and the intracellular tyrosine kinase region.
  • EGFR is widely distributed on the surface of mammalian epithelial cells, fibroblasts, glial cells, keratinocytes and other cells.
  • the EGFR signaling pathway plays an important role in physiological processes such as cell growth, proliferation and differentiation. Loss of function of protein tyrosine kinases such as EGFR or abnormal activity of key factors in related signal pathways or abnormal cell positioning can cause tumors, diabetes, immunodeficiency and cardiovascular diseases.
  • the compound of formula (I) disclosed in WO2015043515A is a selective epidermal growth factor receptor inhibitor that can competitively bind to the phosphorylation site of intracellular tyrosine kinase to block its interaction with ATP and inhibit tyrosine Acid phosphorylation and a series of downstream signal transduction, and then inhibit the growth of tumor cells, can be used to treat a variety of malignant tumors such as non-small cell lung cancer and breast cancer.
  • the chemical name of the compound of formula (I) is N 6 -(1-acryloylazcyclohexane-4-yl)-N 4 -(3-chloro-4-fluorophenyl)-7-methoxyquinazole Morino-4,6-diamine.
  • the application provides a method for preventing or treating cancer, comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof to an individual in need
  • the cancer is selected from lung adenocarcinoma, lung squamous cell carcinoma, pharyngeal squamous cell carcinoma or esophageal carcinoma.
  • the application provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicine for preventing or treating cancer, wherein the cancer is selected from lung adenocarcinoma, lung squamous cell carcinoma, and pharyngeal squamous cell carcinoma Or esophageal cancer.
  • the application provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the prevention or treatment of cancer, wherein the cancer is selected from lung adenocarcinoma, lung squamous cell carcinoma, pharyngeal squamous cell carcinoma or esophageal cancer.
  • the present application provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for preventing or treating cancer, wherein the cancer is selected from lung adenocarcinoma, lung squamous cell carcinoma, pharyngeal squamous cell carcinoma, or esophageal cancer.
  • the aforementioned cancer is selected from lung adenocarcinoma. In some embodiments, the aforementioned cancer is selected from lung squamous cell carcinoma. In some embodiments, the aforementioned cancer is selected from pharyngeal squamous cell carcinoma. In some embodiments, the aforementioned cancer is selected from esophageal cancer.
  • the aforementioned lung adenocarcinoma contains mutant EGFR.
  • the above-mentioned mutants include, but are not limited to, EGFR exon 18 point mutation (G719A), EGFR exon 19 deletion mutation (Del19, such as E746-A750), EGFR exon 20 point mutation (S768I), EGFR exon 21 point mutation (L858R).
  • the above-mentioned EGFR mutation type may involve one or more mutation types at the same time, for example, one, two, three or four mutations.
  • the present application provides a method for preventing or treating lung cancer, comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof to an individual in need, wherein the lung cancer contains one or more mutants
  • the mutation type is selected from: EGFR exon 18 point mutation (G719A), EGFR exon 19 deletion mutation (Del19, such as E746-A750), EGFR exon 20 point mutation (S768I), EGFR 21 Point mutation in exon (L858R).
  • the application provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the prevention or treatment of lung cancer, wherein the lung cancer contains one or more mutant types of EGFR.
  • the type is selected from: EGFR exon 18 point mutation (G719A), EGFR exon 19 deletion mutation (Del19, such as E746-A750), EGFR exon 20 point mutation (S768I), EGFR exon 21 point mutation ( L858R).
  • the present application provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the prevention or treatment of lung cancer, wherein the lung cancer comprises one or more mutant types of EGFR, and the mutant types are selected from: EGFR Exon 18 point mutation (G719A), EGFR exon 19 deletion mutation (Del19, such as E746-A750), EGFR exon 20 point mutation (S768I), EGFR exon 21 point mutation (L858R).
  • G719A EGFR Exon 18 point mutation
  • Del19 such as E746-A750
  • S768I EGFR exon 20 point mutation
  • L858R EGFR exon 21 point mutation
  • the present application provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for preventing or treating lung cancer, wherein the lung cancer comprises one or more mutant types of EGFR, and the mutant types are selected from: EGFR Point mutation in exon 18 (G719A), deletion mutation in exon 19 of EGFR (Del19, such as E746-A750), point mutation in exon 20 (S768I) of EGFR, point mutation in exon 21 (L858R) of EGFR.
  • the mutant types are selected from: EGFR Point mutation in exon 18 (G719A), deletion mutation in exon 19 of EGFR (Del19, such as E746-A750), point mutation in exon 20 (S768I) of EGFR, point mutation in exon 21 (L858R) of EGFR.
  • the above-mentioned EGFR mutant is EGFR exon 18 point mutation (G719A). In some embodiments, the aforementioned EGFR mutant is EGFR exon 19 deletion mutation (Del19, for example, E746-A750). In some embodiments, the above-mentioned EGFR mutant is EGFR exon 20 point mutation (S768I). In some embodiments, the above-mentioned EGFR mutant is EGFR exon 21 point mutation (L858R).
  • the above-mentioned mutant type is a combination of EGFR exon 18 point mutation (G719A) and EGFR exon 20 point mutation (S768I).
  • the aforementioned lung cancer is selected from non-small cell lung cancer.
  • the aforementioned lung cancer is selected from lung adenocarcinoma or lung squamous cell carcinoma.
  • the aforementioned individuals with lung cancer are selected from patients who have received previous treatment (eg, previous chemotherapy treatment).
  • the aforementioned individual with lung cancer has received a previous treatment selected from the group consisting of gefitinib, bevacizumab, pemetrexed, platinum drugs (such as carboplatin), and combinations thereof.
  • the aforementioned individual with lung cancer is selected from patients who have previously been treated with gefitinib and/or bevacizumab.
  • the aforementioned individual with lung cancer is selected from patients who have previously received pemetrexed, carboplatin and bevacizumab combination or pemetrexed and bevacizumab combination therapy.
  • the above-mentioned individuals with lung cancer are selected from patients who have previously received oral gefitinib 0.25 g qd targeted therapy.
  • the aforementioned individual with lung cancer is selected from patients who have previously received 100 mg of bevacizumab pleural injection.
  • the aforementioned lung adenocarcinoma refers to non-small cell lung adenocarcinoma.
  • the aforementioned lung adenocarcinoma includes, but is not limited to, advanced lung adenocarcinoma.
  • the aforementioned lung adenocarcinoma includes, but is not limited to, lung adenocarcinoma that lacks conventional effective treatment methods or fails or recurs after conventional treatment.
  • the aforementioned lung squamous cell carcinoma refers to non-small cell lung squamous cell carcinoma.
  • the aforementioned lung squamous cell carcinoma includes, but is not limited to, advanced lung squamous cell carcinoma.
  • the aforementioned lung squamous cell carcinoma includes, but is not limited to, lung squamous cell carcinoma that lacks conventional effective treatment methods or fails or recurs after conventional treatment.
  • the amount of the compound of formula (I) or its pharmaceutically acceptable salt administered can be determined based on the severity of the disease, the response of the disease, any treatment-related toxicity, the age and health of the patient.
  • the daily dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 0.2 mg to 60 mg, or 0.5 mg to 40 mg, or 1.0 mg to 40, calculated as the compound of formula (I). Mg, or 1.5 mg to 40 mg, or 2 mg to 40 mg, or 4 mg to 40 mg, or 5 mg to 40 mg, or 6 mg to 40 mg, or 7 mg to 40 mg, Or 8 mg to 40 mg, or 8 mg to 30 mg, or 8 mg to 25 mg, or 8 mg to 20 mg, or 8 mg to 16 mg.
  • the daily dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof is calculated as the compound of formula (I), and is selected from 0.2 mg, 0.5 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg , 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 10.5 mg, 11 Milligrams, 11.5 milligrams, 12 milligrams, 12.5 milligrams, 13 milligrams, 13.5 milligrams, 14 milligrams, 14.5 milligrams, 15 milligrams, 15.5 milligrams, 16 milligrams, 16.5 milligrams, 17 milligrams, 17.5 milligrams or 18 milligrams.
  • the daily dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 8 mg calculated as the compound of formula (I). In a specific embodiment, the daily dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 10 mg calculated as the compound of formula (I). In a specific embodiment, the daily dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 12 mg calculated as the compound of formula (I). In a specific embodiment, the daily dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 16 mg calculated as the compound of formula (I).
  • the compound of formula (I) or its pharmaceutically acceptable salt can be administered by a variety of routes, including but not limited to the following routes: oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, intramuscular , Rectum, transbuccal, intranasal, inhalation, vagina, intraocular, topical administration, subcutaneous, intra-fat, intra-articular, intraperitoneal and intrathecal. In a specific embodiment, it is administered orally.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof can be administered one or more times a day. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once a day.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof can also be administered in a single dose or multiple doses. In one embodiment, it is administered once a day in a single dose.
  • a single oral solid formulation is administered once a day. In one embodiment, multiple doses are administered once a day.
  • the method of administration can be comprehensively determined according to the activity, toxicity, and patient tolerance of the drug.
  • the above-mentioned individual is administered an oral solid pharmaceutical composition at a dose of 8 mg once a day, and a single dose of the solid pharmaceutical composition is 2 mg.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the patient alone as the sole active ingredient.
  • the compound of formula (I) of the present application can be administered in the form of its free base, or in the form of its salt, hydrate and prodrug, which is converted into the free base form of the compound of formula (I) in vivo.
  • a pharmaceutically acceptable salt of the compound of formula (I) is within the scope of the present invention, and the salt can be produced from various organic acids and inorganic acids according to methods well known in the art.
  • the pharmaceutically acceptable salt described in this application is selected from maleate, hydrochloride, hydrobromide, sulfate, phosphate, nitrate, acetate, lactate, malonate, succinic acid Salt, fumarate, malate, mandelate, tartrate, citrate, ascorbate, palmitate, benzoate, phenylacetate, cinnamate, salicylate, methanesulfonate Acid salt, benzene sulfonate or toluene sulfonate.
  • the pharmaceutically acceptable salt is selected from maleate, malate, fumarate, tartrate, citrate, lactate, phosphate, or acetate.
  • the pharmaceutically acceptable salt is selected from maleate.
  • the molar ratio of the compound of formula (I) to the acid radical ion forming the pharmaceutically acceptable salt may be selected from 1:1.
  • the pharmaceutically acceptable salt of the compound of formula (I) described in this application, the compound of formula (I) or the pharmaceutically acceptable salt thereof is selected from the compound of formula (I) or the maleate of the compound of formula (I).
  • the "compound of formula (I) or a pharmaceutically acceptable salt thereof” mentioned in this application may be a "pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof", and further, may be “comprising a compound of formula (II) )
  • the pharmaceutical composition of the compound may be “administering a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof to an individual in need"
  • administering a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof to an individual in need
  • the aforementioned pharmaceutical composition further contains pharmaceutically acceptable excipients.
  • the above-mentioned pharmaceutical composition calculated as the compound of formula (I), a single dose of the composition is 0.2 mg to 60 mg, or 0.5 mg to 40 mg, or 1.0 mg to 40 mg, or 1.5 Mg to 40 mg, or 2 mg to 40 mg, or 4 mg to 40 mg, or 5 mg to 40 mg, or 6 mg to 40 mg, or 7 mg to 40 mg, or 8 mg to 40 mg, or 8 mg to 30 mg, or 8 mg to 25 mg, or 8 mg to 20 mg, or 8 mg to 16 mg.
  • the application provides a pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the prevention or treatment of lung adenocarcinoma, lung squamous cell carcinoma, pharyngeal squamous cell carcinoma and esophageal cancer.
  • the single dose of the composition is 0.2 mg, 0.5 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 Mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 10.5 mg, 11 mg, 11.5 mg, 12 mg, 12.5 mg, 13 mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg or 18 mg.
  • the single dose of the pharmaceutical composition is 8 mg, 10 mg, 12 mg, or 16 mg based on the compound of formula (I); in some specific embodiments, the single dose is 8 mg; in some specific embodiments, the single dose is 8 mg; In an embodiment, a single dose is 10 mg; in some specific embodiments, a single dose is 12 mg; in some specific embodiments, a single dose is 16 mg.
  • Each pharmaceutical composition of the present application may be a solid pharmaceutical composition, and the solid pharmaceutical composition may be formed into a variety of preparation forms suitable for oral administration to patients (such as humans), for example, including tablets, pills, Capsules, powders or granules, etc.
  • the above-mentioned pharmaceutical composition can be administered one or more times a day. In some embodiments, the above-mentioned pharmaceutical composition is administered once a day. The above-mentioned pharmaceutical composition can also be administered in a single dose or multiple doses.
  • it is administered once a day.
  • it is administered once a day in a single dose. In one embodiment, multiple doses are administered once a day.
  • the method of administration can be comprehensively determined according to the activity, toxicity, and patient tolerance of the drug.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the patient alone as the sole active ingredient.
  • the above-mentioned pharmaceutical composition comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof and polymethacrylate.
  • the above-mentioned pharmaceutical composition comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, polymethacrylate and an acid.
  • the above-mentioned pharmaceutical composition comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, polymethacrylate and a surface stabilizer.
  • the above-mentioned pharmaceutical composition comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, polymethacrylate, acid, surface stabilizer, dispersant and carrier.
  • the above-mentioned pharmaceutical composition comprises a compound of formula (II), polymethacrylate, acid, surface stabilizer, dispersant and carrier.
  • the above-mentioned polymethacrylate is N-(2-aminoethacrylate
  • the above-mentioned polymethacrylate is selected from And its combination.
  • the above-mentioned polymethacrylate is selected from
  • the weight ratio of the polymethacrylate to the compound of formula (I) or its pharmaceutically acceptable salt in the above-mentioned pharmaceutical composition is 50-0.5:1, or 45-1:1, or 40-1.5:1 , Or 35 ⁇ 2:1, or 30 ⁇ 3:1, or 25 ⁇ 4:1, or 20 ⁇ 5:1, or 18 ⁇ 5.5:1, or 16 ⁇ 5.7:1, or 14 ⁇ 5.9:1 Or 12 ⁇ 6.1:1, or 10 ⁇ 6.3:1, or 8.5 ⁇ 6.5:1, or 8.5 ⁇ 7:1, or 8.5 ⁇ 7.5:1.
  • the weight ratio of polymethacrylate to the compound of formula (II) in the above pharmaceutical composition is 8:1.
  • the aforementioned acid is selected from maleic acid, malic acid, fumaric acid, tartaric acid, citric acid, lactic acid, phosphoric acid, acetic acid, and combinations thereof.
  • the aforementioned acid is maleic acid.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof in the above-mentioned pharmaceutical composition is 0.1-50% by weight, or 0.1-20% by weight, or 0.1-10% by weight relative to the total mass of the solid pharmaceutical composition. %, or 0.1 to 5 wt%, or 0.1 to 4 wt%.
  • the above-mentioned surface stabilizer is selected from the group consisting of hydroxypropyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl-cellulose Cellulose, hydroxypropyl methyl-cellulose phthalate, non-crystalline cellulose and combinations thereof.
  • the above-mentioned surface stabilizer is selected from hydroxypropyl cellulose (for example, HPC-SL type).
  • the weight ratio of the surface stabilizer to the compound of formula (I) or its pharmaceutically acceptable salt in the above-mentioned pharmaceutical composition is 0.06 to 1:1, or 0.07 to 0.9:1, or 0.08 to 0.8:1, Or 0.09 ⁇ 0.7:1, or 0.10 ⁇ 0.6:1, or 0.11 ⁇ 0.5:1, or 0.12 ⁇ 0.7:1, or 0.13 ⁇ 0.6:1, or 0.14 ⁇ 0.5:1, or 0.15 ⁇ 0.4:1, or 0.15 ⁇ 0.3:1, or 0.15 ⁇ 0.2:1.
  • the weight ratio of the surface stabilizer to the compound of formula (II) in the above-mentioned pharmaceutical composition is 0.16:1.
  • the aforementioned dispersant is selected from sucrose, lactose, or mannitol.
  • the above-mentioned dispersant is selected from sucrose.
  • the weight ratio of the dispersant to the compound of formula (I) or a pharmaceutically acceptable salt thereof in the above-mentioned pharmaceutical composition is 0.5-50:1, or 0.8-45:1, or 1.1-40:1, or 1.4 ⁇ 35:1, or 1.7 ⁇ 30:1, or 2 ⁇ 25:1, or 2.3 ⁇ 20:1, or 2.8 ⁇ 15:1, or 3.1 ⁇ 10:1, or 3.4 ⁇ 9:1, or 3.7 ⁇ 8:1, or 4.0 ⁇ 7:1, or 4.3 ⁇ 6:1, or 4.5 ⁇ 5.5:1,
  • the weight ratio of the dispersant to the compound of formula (II) in the above pharmaceutical composition is 5:1.
  • the aforementioned carrier is selected from the group consisting of cellulose pellets, mannitol pellets, tartaric acid pellets, lactose/microcrystalline pellets, sucrose pellets, starch pellets, and combinations thereof.
  • the above-mentioned carrier is selected from cellulose pellets or sucrose pellet cores.
  • the aforementioned carrier is selected from sucrose pellet cores (e.g., 0.6-0.8 mm).
  • the ratio of the aforementioned carrier to the pharmaceutical composition ranges from 0.1 to 99% by weight, 0.5 to 99% by weight, 1 to 99% by weight, 5 to 99% by weight, 10 to 99% by weight, 15 to 99% by weight, and 20 to 99% by weight. %, 25-99wt%, 30-99wt%, 35-99wt%, 40-99wt%, or 45-99wt%.
  • the above-mentioned pharmaceutical composition comprises a compound of formula (II), hydroxypropyl cellulose (such as HPC-SL type), sucrose, polymethacrylate (such as ), maleic acid, sucrose core (e.g. 0.6-0.8mm).
  • the above-mentioned pharmaceutical composition comprises the following weight components:
  • the above-mentioned solid pharmaceutical composition wherein the polymethacrylate, acid, surface stabilizer, dispersant and carrier are as defined above, respectively.
  • the above-mentioned pharmaceutical composition comprises the following weight components:
  • the above-mentioned pharmaceutical composition comprises the following weight components:
  • the above-mentioned pharmaceutical composition comprises the following weight components:
  • the above-mentioned pharmaceutical composition comprises the following weight components:
  • the above-mentioned pharmaceutical composition comprises the following weight components:
  • the particle size range of the compound of formula (I) or its pharmaceutically acceptable salt is D50 ⁇ 10 ⁇ m, D90 ⁇ 20 ⁇ m; or D50 ⁇ 5 ⁇ m, D90 ⁇ 10 ⁇ m; or D50 ⁇ 2 ⁇ m, D90 ⁇ 4 ⁇ m .
  • the particle size range of the compound of formula (I) or its pharmaceutically acceptable salt is D50 ⁇ 2 ⁇ m and D90 ⁇ 4 ⁇ m.
  • the acid is added in an appropriate amount, for example, to make the pharmaceutical composition acidic in water.
  • the maleic acid is added in an appropriate amount.
  • the acid can be used as a pH adjusting agent, for example, in the preparation process of a solid pharmaceutical composition, for adjusting the pH range, for example, being acidic in an aqueous solution.
  • the pH value of the aqueous solution is between 3.0-3.5 or 2.0-3.0.
  • compositions of the present application can be formed into a variety of preparation forms suitable for oral administration to patients (for example, humans), including, for example, tablets, pills, capsules, powders or granules.
  • the pharmaceutical composition of the present application is administered orally.
  • each of the aforementioned pharmaceutical compositions is a solid pharmaceutical composition.
  • the preparation form of the solid pharmaceutical composition of the present application is a capsule.
  • the above-mentioned capsules are filled with pellets, which contain the solid pharmaceutical composition as described above.
  • the aforementioned capsules are hard capsules or soft capsules.
  • Capsules can be prepared by filling pellets of the aforementioned compound of formula (I) or pharmaceutically acceptable salts thereof into hard capsules made of gelatin, hydroxypropyl methylcellulose, polyvinyl alcohol, etc., according to a known method. , Or packed in gelatin-based soft capsules.
  • the pharmaceutical composition of the present application can be manufactured by methods well known in the art, such as conventional mixing method, dissolution method, granulation method, sugar-coated pill method, grinding method, emulsification method, freeze-drying method, etc.
  • the solid oral composition can be prepared by conventional mixing, filling or tabletting methods. For example, it can be obtained by the following method: mixing the active compound with solid excipients, optionally grinding the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to obtain tablets Or the core of the dragee.
  • suitable excipients include, but are not limited to: binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, and the like.
  • this application provides a method for preparing a solid composition, including the following processes:
  • the treatment plan of the present application has good curative effect in the treatment of lung adenocarcinoma, lung squamous cell carcinoma, pharyngeal squamous cell carcinoma or esophageal carcinoma.
  • at least one of ORR, DCR, DoR, PFS or OS has outstanding effect data; and the patient has good tolerance and low side effects.
  • the solid pharmaceutical composition comprising the compound of formula (I) and its pharmaceutically acceptable salt provided in this application has a low maximum single impurity content and a small total impurity content.
  • the content of active ingredients and various impurities will not change significantly, and it has good stability. At the same time, it has high bioavailability and high dissolution rate, which is suitable for industrial production, storage, and clinical use.
  • patient refers to a mammal, preferably a human. In some embodiments, the patient is a patient who has failed 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 It is acceptable for human drug use.
  • pharmaceutically acceptable and “pharmaceutically acceptable” are used interchangeably herein.
  • terapéuticaally effective amount means an amount sufficient to achieve treatment of the disease when the compound is administered to a human for the treatment of the disease.
  • treatment means administering the compound or formulation described in this application to ameliorate or eliminate a disease or one or more symptoms related to the disease, and includes:
  • prevention means administering the compound or formulation described in this application to prevent a disease or one or more symptoms related to the disease, including: preventing the occurrence of a disease or disease state in a mammal, especially when this When mammals are susceptible to this disease state, but have not been diagnosed as having this disease state.
  • pharmaceutically acceptable excipients refers to those excipients that have no obvious stimulating effect on the organism and will not damage the biological activity and performance of the active compound.
  • Suitable auxiliary materials are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like.
  • single dose refers to the smallest packaging unit that contains a certain amount of medicine. For example, if a box of medicine has seven capsules, each capsule is a single dose; or each bottle of injection is a single dose.
  • PD Progressive disease, the maximum diameter of the target lesion increases by at least ⁇ 20%, or new lesions appear.
  • PR Partial response, the total maximum diameter of the target lesion is reduced by ⁇ 30%, and it is maintained for at least 4 weeks.
  • OS overall survival, the time from randomization to death (for any reason).
  • SD stable disease, the sum of the maximum diameters of the target lesions does not shrink to PR, or the increase does not reach PD.
  • step 3 Prepare 0.5mol/L maleic acid water 2 solution, take half of the prepared maleic acid water solution to dissolve the prescription amount After dissolving, add the suspension obtained in step 2), and then adjust the pH of the suspension to be between 3.0-3.5 with the remaining maleic acid aqueous solution to obtain a suspension;
  • composition of the specific pharmaceutical capsule preparation is shown in Table 1 below.
  • Examples 2-5 were prepared with reference to the process of Example 1.
  • the composition of the specific pharmaceutical capsule preparation is shown in Table 2 below.
  • Example 3 water 1 : 266.68 mg; water 2 : 200 mg;
  • Example 4 water 1 : 666.7mg; water 2 : 500mg;
  • Example 5 water 1 : 1333.4 mg; water 2 : 1000 mg.
  • step 3 the pH of the suspension is adjusted to be 2.0 ⁇ pH ⁇ 3.0, and water 1 : 25 mg; water 2 : 50 mg.
  • composition of the specific pharmaceutical capsule preparation is shown in Table 3 below.
  • SRB method Sulforhodamine B protein staining method
  • FaDu cells Human pharyngeal squamous cell carcinoma (FaDu cells) (purchased from the Cell Bank of Shanghai Institute of Biological Sciences, Chinese Academy of Sciences) were cultured in RPMI 1640 medium containing 10% FBS.
  • Sample preparation method Prepare to 10mM with dimethyl sulfoxide (DMSO) and store at -80°C.
  • DMSO dimethyl sulfoxide
  • Inhibition rate (OD value control hole-OD value dosing hole)/OD value control hole ⁇ 100%
  • the inhibition rate at each concentration to calculate the median inhibitory concentration IC 50.
  • BALB/cA-nude nude mice 6-7 weeks old, female, purchased from Shanghai Slack Laboratory Animal Co., Ltd. Production license number: SCXK (Shanghai) 2012-0002; animal certificate number 2007000570156. Feeding environment: SPF level. Nude mice were subcutaneously inoculated with FaDu cells of human pharyngeal squamous cell carcinoma. After the tumor grew to 80-150 mm 3 , the animals were randomly divided into groups (D0). See Table 4 for dosing dosage and dosing schedule. The tumor volume was measured twice a week, the mouse was weighed, and the data was recorded.
  • BALB/cA-nude nude mice 6-7 weeks old, female, purchased from Shanghai Lingchang Biotechnology Co., Ltd. Production license number: SCXK (Shanghai) 2013-0018; certificate number: 2013001802999.
  • Feeding environment SPF level.
  • Nude mice were subcutaneously inoculated with human esophageal cancer Eca-109 cells. After the tumor grew to 100-300 mm 3 , the animals were randomly divided into groups (D0). See Table 4 for dosing dosage and dosing schedule. Measure the tumor volume twice a week, weigh the mouse, and record the data.
  • BALB/cA-nude nude mice 6-7 weeks old, female, purchased from Shanghai Slack Laboratory Animal Co., Ltd. Production license number: SCXK (Shanghai) 2012-0002; animal certificate number 2007000570541.
  • Feeding environment SPF level.
  • Nude mice were subcutaneously inoculated with human non-small cell lung cancer HCC827 cells. After the tumor grew to 100-200 mm 3 , the animals were randomly divided into groups (D0). See Table 4 for dosing dosage and dosing schedule. The tumor volume was measured twice a week, the mouse was weighed, and the data was recorded.
  • V 1/2 ⁇ a ⁇ b 2 ; where a and b represent the length and width of the tumor, respectively.
  • the relative tumor volume (RTV) is calculated, and the formula is:
  • V 0 is the tumor volume measured during the caged administration (ie D0); V t is the tumor volume at each measurement.
  • T/C(%) (TT 0 )/(CC 0 ) ⁇ 100%;
  • T, C are the tumor volumes of the experimental group and the control group at the end of the experiment;
  • T 0 , C 0 are the start of the experiment
  • the tumor inhibition rate (%) 100%-(TT 0 )/T 0 ⁇ 100%.
  • Sample preparation method all prepared with 0.4% Tween-80/0.5% CMC.
  • D0 Randomized group, the time of first administration; D0-6 refers to 6 days of administration; D0-20 refers to 20 days of administration; PO: intragastric administration
  • LVEF left ventricular ejection fraction
  • contraceptive measures such as intrauterine device [IUD], contraceptives or condoms
  • IUD intrauterine device
  • condoms serum or urine pregnancy test within 7 days before study entry Negative, and must be a non-lactating patient
  • men should agree to use contraceptive measures during the study period and within 6 months after the end of the study period;
  • Formula (II) compound capsule provided by Chia Tai Tianqing Pharmaceutical Group Co., Ltd.
  • the second dose group is 0.5 mg/day
  • the third dose group is 1.0 mg/day
  • the fourth dose group is 1.5 mg/day
  • the fifth dose group is 2.0 mg/day
  • the sixth dose The group was 4.0 mg/day
  • the seventh dose group was 8.0 mg/day
  • the eighth dose group was 10.0 mg/day
  • the ninth dose group was 12.0 mg/day
  • the tenth dose group was 16.0 mg/day.
  • the doses taken in the first two dose groups refer to the doses of the first two dose groups of a single dose, that is, starting from 0.2 mg/day, the second dose group is 0.5 mg/day, and the third dose group is 1.0 mg/day.
  • the four dose group is 1.5 mg/day, the fifth dose group is 2.0 mg/day, the sixth dose group is 4.0 mg/day, the seventh dose group is 8.0 mg/day, and the eighth dose group is 10.0 mg/day.
  • the nine-dose group was 12.0 mg/day, and the tenth-dose group was 16.0 mg/day until DLT was reached.
  • Objective response rate Only calculate the objective tumor response rate of patients who can be measured according to the RECIST 1.1 version of the disease.
  • the objective response rate is defined as the proportion of patients in complete remission and partial remission. Patients who have not undergone tumor evaluation after baseline will be considered as having no objective response.
  • DCR Disease control rate
  • the period of remission is defined as the time between the initial appearance of complete or partial remission and the appearance of disease progression in patients with objective remission. If the patient has not died or progressed at the end of the study, or the patient has been lost to follow-up, the statistics of the remission period will be up to the time of the last tumor evaluation.
  • PFS Progression-free survival
  • the improvement or deterioration of the general condition is expressed by the change of the ECOG score before and after treatment.
  • Pleural effusion cytology a large number of malignant tumor cells were seen, which is considered adenocarcinoma. There were no signs of metastasis on MRI of the head.
  • the gene detection of pleural effusion cells showed: EGFR exon 20 S768I mutation, exon18 G719A mutation.
  • Re-examination of chest CT on July 3, 2018 showed: right hilar space-occupying lesions, diffuse multiple metastatic nodules in both lungs, thickening of the right pleura with effusion in the right pleural cavity.
  • the location of pleural effusion showed a medium effusion on the right side, and bevacizumab was injected into the pleural cavity to control the pleural effusion.
  • a reexamination indicated disease progression, and gefitinib treatment was discontinued.
  • Re-examination on August 31, 2018 showed that the nodules in the lung were larger than before, and the pleural fluid was more than before, suggesting PD.
  • Enhanced CT showed a right lower hilar mass, which was smaller than before; right upper lobe metastatic nodules were the same as before; liver S2 lesions were smaller than before; it was evaluated as PR according to RECIST1.1, target The total lesions were 37mm, which was 17mm smaller than the baseline.
  • the patient's adverse reactions are basically tolerable and continue to receive treatment.

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Abstract

一种喹唑啉衍生物或其可药用盐、或其固体药物组合物的用途，具体而言涉及式(I)所示的N 6-(1-丙烯酰基氮杂环己烷-4-基)-N 4-(3-氯-4-氟苯基)-7-甲氧基喹唑啉-4,6-二胺或其可药用盐、或其固体药物组合物的用途。

Description

喹唑啉衍生物或其盐、或其药物组合物的用途
相关申请的交叉引用
本申请要求于2019年11月01日向中国国家知识产权局提交的第201911059471.9号中国专利申请的优先权和权益，所述申请公开的内容通过援引整体并入本文中。
技术领域
本申请属于医药技术领域，涉及喹唑啉衍生物或其可药用盐、或其药物组合物的用途，具体而言涉及包含N 6-(1-丙烯酰基氮杂环己烷-4-基)-N 4-(3-氯-4-氟苯基)-7-甲氧基喹唑啉-4,6-二胺或其可药用盐、或其药物组合物的用途。
背景技术
EGFR(epidermal growth factor receptor，上皮生长因子受体)是一种酪氨酸激酶受体，为HER/ErbB家族成员之一，该家族包括EGFR、HER2、HER3和HER4，由三部分组成：胞外的配体结合区、由单链构成的跨膜区以及胞内的酪氨酸激酶区。EGFR广泛分布于哺乳动物的上皮细胞、成纤维细胞、胶质细胞、角质细胞等细胞的表面。EGFR信号通路对细胞的生长、增殖和分化等生理过程发挥重要的作用。EGFR等蛋白酪氨酸激酶功能缺失或其相关信号通路中关键因子的异常活性或细胞定位异常，均会引起肿瘤、糖尿病、免疫缺陷及心血管疾病的发生。
WO2015043515A公开的式(I)化合物，为选择性表皮生长因子受体抑制剂，可通过竞争性结合胞内段酪氨酸激酶的磷酸化位点，阻断其与ATP的相互作用，抑制酪氨酸磷酸化及下游一系列的信号传导，继而抑制肿瘤细胞的生长，可用于治疗非小细胞肺癌和乳腺癌等多种恶性肿瘤。其中式(I)化合物化学名称为N 6-(1-丙烯酰基氮杂环己烷-4-基)-N 4-(3-氯-4-氟苯基)-7-甲氧基喹唑啉-4,6-二胺。
Figure PCTCN2020125384-appb-000001
发明内容
一方面，本申请提供了一种用于预防或治疗癌症的方法，包括向有需要的个体给予式(I)化合物或其可药用盐
Figure PCTCN2020125384-appb-000002
其中所述癌症选自肺腺癌、肺鳞癌、咽鳞癌或食管癌。
另一方面，本申请提供了式(I)化合物或其可药用盐在制备用于预防或治疗癌症的药物中的用途，其中所述癌症选自肺腺癌、肺鳞癌、咽鳞癌或食管癌。
又一方面，本申请提供了式(I)化合物或其可药用盐在预防或治疗癌症中的用途，其中所述癌症选自肺腺癌、肺鳞癌、咽鳞癌或食管癌。
还一方面，本申请提供了用于预防或治疗癌症的式(I)化合物或其可药用盐，其中所述癌症选自肺腺癌、肺鳞癌、咽鳞癌或食管癌。
在一些实施方案中，上述癌症选自肺腺癌。在一些实施方案中，上述癌症选自肺鳞癌。在一些实施方案中，上述癌症选自咽鳞癌。在一些实施方案中，上述癌症选自食管癌。
在一些实施方案中，上述肺腺癌含有突变型的EGFR。在一些实施方案中，上述突变型包括但不限于EGFR的18号外显子点突变(G719A)、EGFR的19号外显子缺失突变(Del19，例如E746-A750)、EGFR的20号外显子点突变(S768I)、EGFR的21号外显子点突变(L858R)。在一些实施方案中，上述EGFR突变型可以涉及一种或同时涉及多种突变类型，例如涉及一、二、三或四种突变。
再一方面，本申请提供了一种用于预防或治疗肺癌的方法，包括向有需要的个体给予式(I)化合物或其可药用盐，其中所述肺癌包含有一种或多种突变型的EGFR，所述突变型选自：EGFR 18号外显子点突变(G719A)、EGFR 19号外显子缺失突变(Del19，例如E746-A750)、EGFR 20号外显子点突变(S768I)、EGFR 21号外显子点突变(L858R)。
再一方面，本申请提供了式(I)化合物或其可药用盐，在制备用于预防或治疗肺癌的药物中的用途，其中所述肺癌包含有一种或多种突变型的EGFR，突变型选自：EGFR 18号外显子点突变(G719A)、EGFR 19号外显子缺失突变(Del19，例如E746-A750)、EGFR 20号外显子点突变(S768I)、EGFR 21号外显子点突变(L858R)。
再一方面，本申请提供了式(I)化合物或其可药用盐在预防或治疗肺癌的用途，其中所述肺癌包含有一种或多种突变型的EGFR，所述突变型选自：EGFR 18号外显子点突变(G719A)、EGFR 19号外显子缺失突变(Del19，例如E746-A750)、EGFR 20号外显子点突变(S768I)、EGFR 21号外显子点突变(L858R)。
再一方面，本申请提供了用于预防或治疗肺癌的式(I)化合物或其可药用盐，其中所述肺癌包含有一种或多种突变型的EGFR，所述突变型选自：EGFR 18号外显子点突变(G719A)、EGFR 19号外显子缺失突变(Del19，例如E746-A750)、EGFR 20号外显子点突变(S768I)、EGFR 21号外显子点突变(L858R)EGFR。
在一些实施方案中，上述EGFR突变型为EGFR 18号外显子点突变(G719A)。在一些实施方案中，上述EGFR突变型为EGFR 19号外显子缺失突变(Del19，例如E746-A750)。在一些实施方案中，上述EGFR突变型为EGFR 20号外显子点突变(S768I)。在一些实施方案中，上述EGFR突变型为EGFR 21号外显子点突变(L858R)。
在一些实施方案中，上述突变型为EGFR 18号外显子点突变(G719A)和EGFR 20号外显子点突变(S768I)的组合。
在一些实施方案中，上述肺癌选自非小细胞肺癌。
在一些实施方案中，上述肺癌选自肺腺癌或肺鳞癌。
在一些实施方案中，上述肺癌(例如肺腺癌或肺鳞癌)个体选自接受过先前治疗(例如先前化学药剂治疗)的患者。
在一些实施方案中，上述肺癌个体接受过选自吉非替尼、贝伐珠单抗、培美曲塞、铂类药物(例如卡铂)及其组合的先前治疗。
在一些实施方案中，上述肺癌个体选自既往接受过吉非替尼和/或贝伐珠单抗治疗的患者。
在一些实施方案中，上述肺癌个体选自既往接受过培美曲塞、卡铂和贝伐珠单抗联合或培美曲塞和贝伐珠单抗联合治疗的患者。
在一些实施方案中，上述肺癌个体选自既往接受过口服吉非替尼0.25g qd靶向治疗的患者。
在一些实施方案中，上述肺癌个体选自既往接受过贝伐珠单抗100mg胸腔注射的患者。
在上述任一方面的一些实施方案中，上述肺腺癌是指非小细胞肺腺癌。
在上述任一方面的一些实施方案中，上述肺腺癌包括但不限于晚期的肺腺癌。
在上述任一方面的一些实施方案中，上述肺腺癌包括但不限于缺乏常规的有效治疗方法或常规方法治疗后失败或复发的肺腺癌。
在上述任一方面的一些实施方案中，上述肺鳞癌是指非小细胞肺鳞癌。
在上述任一方面的一些实施方案中，上述肺鳞癌包括但不限于晚期的肺鳞癌。
在上述任一方面的一些实施方案中，上述肺鳞癌包括但不限于缺乏常规的有效治疗方法或常规方法治疗后失败或复发的肺鳞癌。
给予式(I)化合物或其可药用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)化合物或其可药用盐的日剂量以式(I)化合物计算，为0.2毫克至60毫克、或为0.5毫克至40毫克、或为1.0毫克至40毫克、或为1.5毫克至40毫克、或为2毫克至40毫克、或为4毫克至40毫克、或为5毫克至40毫克、或为6毫克至40毫克、或为7毫克至40毫克、或为8毫克至40毫克、或为8毫克至30毫克、或为8毫克至25毫克、或为8毫克至20毫克、或为8毫克至16毫克。
在一个特定的实施方案中，给予式(I)化合物或其可药用盐的日剂量以式(I)化合物计算，选自0.2毫克、0.5毫克、1毫克、1.5毫克、2毫克、2.5毫克、3.0毫克、3.5毫克、4.0毫克、4.5毫克、5毫克、5.5毫克、6毫克、6.5毫克、7毫克、7.5毫克、8毫克、8.5毫克、9毫克、9.5毫克、10毫克、10.5毫克、11毫克、11.5毫克、12毫克、12.5毫克、13毫克、13.5毫克、14毫克、14.5毫克、15毫克、15.5毫克、16毫克、16.5毫克、17毫克、17.5毫克或18毫克。在一个特定的实施方案中，给予式(I)化合物或其可药用盐的日剂量以式(I)化合物计算为8毫克。在一个特定的实施方案中，给予式(I)化合物或其可药用盐的日剂量以式(I)化合物计算为10毫克。在一个特定的实施方案中，给予式(I)化合物或其可药用盐的日剂量以式(I)化合物计算为12毫克。在一个特定的实施方案中，给予式(I)化合物或其可药用盐的日剂量以式(I)化合物计算为16毫克。
式(I)化合物或其可药用盐可通过多种途径给药，该途径包括但不限于以下途径：口服、肠胃外、腹膜内、静脉内、动脉内、透皮、舌下、肌内、直肠、透颊、鼻内、经吸入、阴道、眼内、经局部给药、皮下、脂肪内、关节内、腹膜内和鞘内。在一个特定的实施方案中，通过口服给药。
式(I)化合物或其可药用盐可以每日施用一次或多次。在一些实施方案中，每天1次给予式(I)化合物或其可药用盐。式(I)化合物或其可药用盐也可以单剂量或多剂量形式给药。在一个实施方案中，以单剂量每天给药1次。
在一个实施方案中，以单剂量的口服固体制剂每天给药1次。在一个实施方案中，以多剂量每天给药1次。
给药的方法可根据药物的活性、毒性以及患者的耐受性等来综合确定。
在一个实施方案中，上述个体以8mg剂量的口服固体药物组合物每天给药一次，所述固体药物组合物的单剂量为2mg。在一些实施方案中，式(I)化合物或其可药用盐是作为唯一的活性成分单独给予患者的。
式(I)化合物或其可药用盐
本申请式(I)化合物可以以其游离碱形式给药，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)化合物可药用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。
本申请所述的可药用盐选自马来酸盐、盐酸盐、氢溴酸盐、硫酸盐、磷酸盐、硝酸盐、乙酸盐、乳酸盐、丙二酸盐、丁二酸盐、富马酸盐、苹果酸盐、扁桃酸盐、酒石酸盐、柠檬酸盐、抗坏血酸盐、棕榈酸盐、苯甲酸盐、苯乙酸盐、肉桂酸盐、水杨酸盐、甲磺酸盐、苯磺酸盐或甲基苯磺酸盐。
在一些实施方案中，所述的可药用盐选自马来酸盐、苹果酸盐、富马酸盐、酒石酸盐、柠檬酸盐、乳酸盐、磷酸盐或乙酸盐。
在一些实施方案中，所述的可药用盐选自马来酸盐。
关于本申请所述的式(I)化合物的可药用盐，式(I)化合物与形成可药用盐的酸根离子的摩尔比可选自1:1。
本申请所述的式(I)化合物的可药用盐，所述式(I)化合物或其可药用盐选自式(I)化合物或式(I)化合物的马来酸盐。
本申请所述的式(I)化合物的可药用盐为式(II)化合物
Figure PCTCN2020125384-appb-000003
本申请所述的“式(I)化合物或其可药用盐”可以替换为“式(II)化合物”；例如上述“向有需要的个体给予式(I)化合物或其可药用盐”可以替换为“向有需要的个体给予式(II)化合物”。
药物组合物
本申请所述的“式(I)化合物或其可药用盐”，可以是“包含式(I)化合物或其可药用盐的药物组合物”，进一步的，可以是“包含式(II)化合物的药物组合物”。例如上述“向有需要的个体给予式(I)化合物或其可药用盐”可以是“向有需要的个体给予包含式(I)化合物或其可药用盐的药物组合物”，进一步的，可以是“向有需要的个体给予包含式(II)化合物的药物组合物”。在一些实施方案中，上述药物组合物还含有药学上可接受的辅料。
在一些实施方案中，上述药物组合物，以式(I)化合物计算，该组合物单剂量为0.2毫克至60毫克、或为0.5毫克至40毫克、或为1.0毫克至40毫克、或为1.5毫克至40毫克、或为2毫克至40毫克、或为4毫克至40毫克、或为5毫克至40毫克、或为6毫克至40毫克、或为7毫克至40毫克、或为8毫克至40毫克、或为8毫克至30毫克、或为8毫克至25毫克、或为8毫克至20毫克、或为8毫克至16毫克。
在一些实施方案中，本申请提供了一种预防或治疗肺腺癌、肺鳞癌、咽鳞癌及食管癌的式(I)化合物或其可药用盐的药物组合物，以式(I)化合物计算，该组合物单剂量为0.2毫克、0.5毫克、1毫克、1.5毫克、2毫克、2.5毫克、3.0毫克、3.5毫克、4.0毫克、4.5毫克、5毫克、5.5毫克、6毫克、6.5毫克、7毫克、7.5毫克、8毫克、8.5毫克、9毫克、9.5毫克、10毫克、10.5毫克、11毫克、11.5毫克、12毫克、12.5 毫克、13毫克、13.5毫克、14毫克、14.5毫克、15毫克、15.5毫克、16毫克、16.5毫克、17毫克、17.5毫克或18毫克。
在一些实施方案中，以式(I)化合物计算，所述药物组合物单剂量为8毫克、10毫克、12毫克或16毫克；在一些特定实施方案中，单剂量为8毫克；在一些特定实施方案中，单剂量为10毫克；在一些特定实施方案中，单剂量为12毫克；在一些特定实施方案中，单剂量为16毫克。
本申请的各药物组合物可以是固体药物组合物，所述固体药物组合物可以通过多种旨在形成为适合于口服给药至患者(例如人)的制剂形式，例如包括片剂、丸剂、胶囊剂、粉剂或颗粒剂等。
上述药物组合物可以每日施用一次或多次。在一些实施方案中，每天1次给予上述药物组合物。上述药物组合物也可以单剂量或多剂量形式给药。
在一个实施方案中，每天给药1次。
在一个实施方案中，以单剂量每天给药1次。在一个实施方案中，以多剂量每天给药1次。
给药的方法可根据药物的活性、毒性以及患者的耐受性等来综合确定。
在一些实施方案中，式(I)化合物或其可药用盐是作为唯一的活性成分单独给予患者的。
在一些实施方案中，上述药物组合物包含式(I)化合物或其可药用盐及聚甲基丙烯酸酯。
在一些实施方案中，上述药物组合物包含式(I)化合物或其可药用盐、聚甲基丙烯酸酯及酸。
在一些实施方案中，上述药物组合物包含式(I)化合物或其可药用盐、聚甲基丙烯酸酯及表面稳定剂。
在一些实施方案中，上述药物组合物包含式(I)化合物或其可药用盐、聚甲基丙烯酸酯、酸、表面稳定剂、分散剂及载体。
在一些实施方案中，上述药物组合物包含式(II)化合物、聚甲基丙烯酸酯、酸、表面稳定剂、分散剂及载体。
在一些实施方案中，上述聚甲基丙烯酸酯为
Figure PCTCN2020125384-appb-000004
在一些实施方案中，上述聚甲基丙烯酸酯选自
Figure PCTCN2020125384-appb-000005
Figure PCTCN2020125384-appb-000006
及其组合。
在一些实施方案中，上述聚甲基丙烯酸酯选自
Figure PCTCN2020125384-appb-000007
在一些实施方案中，上述药物组合物中聚甲基丙烯酸酯与式(I)化合物或其可药用盐重量比为50～0.5：1、或者45～1：1、或者40～1.5：1、或者35～2：1、或者30～3：1、或者25～4：1、或者20～5：1、或者18～5.5：1、或者16～5.7：1、或者14～5.9：1、或者12～6.1：1、或者10～6.3：1、或者8.5～6.5：1、或者8.5～7：1、或者8.5～7.5：1。
在一些实施方案中，上述药物组合物中聚甲基丙烯酸酯与式(II)化合物的重量比为8：1。
在一些实施方案中，上述酸选自马来酸、苹果酸、富马酸、酒石酸、柠檬酸、乳酸、磷酸、乙酸及其组合。
在一些实施方案中，上述酸为马来酸。
在一些实施方案中，上述药物组合物中式(I)化合物或其可药用盐相对于所述固体药物组合物的总质量为0.1～50wt％，或者为0.1～20wt％，或者为0.1～10wt％，或者为0.1～5wt％，或者为0.1～4wt％。
在一些实施方案中，上述表面稳定剂选自羟丙基纤维素、羧甲基纤维素钙、羧甲基纤维素钠、甲基纤维素、羟乙基纤维素、羟丙基甲基-纤维素、羟丙基甲基-纤维素邻苯二甲酸酯、非结晶纤维素及其组合。
在一些实施方案中，上述表面稳定剂选自羟丙基纤维素(例如HPC-SL型)。
在一些实施方案中，上述药物组合物中表面稳定剂与式(Ⅰ)化合物或其可药用盐的重量比为0.06～1:1、或者0.07～0.9：1、或者0.08～0.8：1、或者0.09～0.7：1、或者0.10～0.6：1、或者0.11～0.5：1、或者0.12～0.7：1、或者0.13～0.6：1、或者0.14～0.5：1、或者0.15～0.4：1、或者0.15～0.3：1、或者0.15～0.2：1。
在一些实施方案中，上述药物组合物中表面稳定剂与式(II)化合物的重量比为0.16：1。
在一些实施方案中，上述分散剂选自蔗糖、乳糖、或甘露醇。
在一些实施方案中，上述分散剂选自蔗糖。
在一些实施方案中，上述药物组合物中分散剂与式(Ⅰ)化合物或其可药用盐的重量比为0.5～50：1、或者0.8～45：1、或者1.1～40：1、或者1.4～35：1、或者1.7～30：1、或者2～25：1、或者2.3～20：1、或者2.8～15：1、或者3.1～10：1、或者3.4～9：1、或者3.7～8：1、或者4.0～7：1、或者4.3～6：1、或者4.5～5.5：1，
在一些实施方案中，上述药物组合物中分散剂与式(II)化合物的重量比为5：1。
在一些实施方案中，上述载体选自纤维素球、甘露醇丸芯、酒石酸丸芯、乳糖/微晶丸芯、蔗糖丸芯、淀粉丸芯及其组合。
在一些实施方案中，上述载体选自纤维素球或者蔗糖丸芯。
在一些实施方案中，上述载体选自蔗糖丸芯(例如0.6-0.8mm)。
在一些实施方案中，上述载体占药物组合物的比例范围选自0.1～99wt％、0.5～99wt％、1～99wt％、5～99wt％、10～99wt％、15～99wt％、20～99wt％、25～99wt％、30～99wt％、35～99wt％、40～99wt％、或45～99wt％。
在一些具体的实施方案中，上述药物组合物包含式(II)化合物、羟丙基纤维素(例如HPC-SL型)、蔗糖、聚甲基丙烯酸酯(例如
Figure PCTCN2020125384-appb-000008
)、马来酸、蔗糖丸芯(例如0.6-0.8mm)。
上述药物组合物，包含如下重量组份：
Figure PCTCN2020125384-appb-000009
在具体一些实施方案中，上述固体药物组合物，其中所述聚甲基丙烯酸酯、酸、表面稳定剂、分散剂及载体分别如上述定义。
上述药物组合物，包含如下重量组份：
Figure PCTCN2020125384-appb-000010
Figure PCTCN2020125384-appb-000011
上述药物组合物，包含如下重量组份：
Figure PCTCN2020125384-appb-000012
上述药物组合物，包含如下重量组份：
Figure PCTCN2020125384-appb-000013
上述药物组合物，包含如下重量组份：
Figure PCTCN2020125384-appb-000014
上述药物组合物，包含如下重量组份：
Figure PCTCN2020125384-appb-000015
本申请的上述各药物组合物，式(Ⅰ)化合物或其可药用盐的粒径范围为D50<10μm，D90<20μm；或者D50<5μm，D90<10μm；或者D50<2μm，D90<4μm。
在一些实施方案中，式(Ⅰ)化合物或其可药用盐的粒径范围为D50<2μm，D90<4μm。
本申请的上述各药物组合物，其中所述的酸适量添加，例如使药物组合物在水中呈酸性。
在一些实施方案中，上述各药物组合物，其中所述的马来酸适量添加。在一些实施方案中，上述各药用组合物中，所述酸可作为pH调节剂，例如在固体药用组合物的制备过程中，用于调节pH的范围，例如在水溶液中处于酸性，更具体地，例如在水溶液的pH值在3.0-3.5或者2.0-3.0之间。
本申请的上述各药物组合物可以通过多种旨在形成为适合于口服给药至患者(例如人)的制剂形式，例如包括片剂、丸剂、胶囊剂、粉剂或颗粒剂等。
在一些实施方案中，本申请的药用组合物通过口服给药。
在一些实施方案中，上述各药物组合物为固体药物组合物。
在一些实施方案中，本申请的固体药用组合物的制剂形式为胶囊。
在一些实施方案中，上述胶囊由微丸颗粒填充，所述微丸颗粒包含如前所述的固体药物组合物。
在一些实施方案中，上述胶囊为硬胶囊或软胶囊。
胶囊可根据已知的方法，通过将前述的式(Ⅰ)化合物或其可药用盐的微丸颗粒装入由明胶、羟丙基甲基纤维素、聚乙烯醇等制得的硬胶囊中，或装入基于明胶的软胶囊中。
本申请的药物组合物可以采用本领域众所周知的方法制造，如常规的混合法、溶解法、制粒法、制糖衣药丸法、磨细法、乳化法、冷冻干燥法等。
可以通过常规的混合、填充或压片方法来制备固体口服组合物。例如，可通过下述方法获得：将所述的活性化合物与固体辅料混合，任选地碾磨所得的混合物，如果需要则加入其它合适的辅料，然后将该混合物加工成颗粒，得到了片剂或糖衣剂的核心。适合的辅料包括但不限于：粘合剂、稀释剂、崩解剂、润滑剂、助流剂、甜味剂或矫味剂等。
另一方面，本申请提供了固体组合物的制备方法，包括以下过程：
配制含有式(I)化合物或其可药用盐的混悬液；在混悬液中加入酸和聚甲基丙烯酸酯；将上述得到的混悬液在载体上进行流化床上药，得到含药微丸。
本申请的治疗方案，在治疗肺腺癌、肺鳞癌、咽鳞癌或食管癌具有较好的疗效。其中至少在ORR、DCR、DoR、PFS或OS中的至少一方面具有突出的效果数据；而且患者耐受性好，副作用小。
本申请提供的包含式(I)化合物及其可药用盐的固体药物组合物，最大单杂含量低，总杂少，有效成分及各个杂质含量不会发生明显变化，具有良好的稳定性，同时生物利用度高，具有较高的溶出度，适合工业化生产、贮存，及临床使用。
定义和说明
词语“包括(comprise)”或“包含(comprise)”及其英文变体例如comprises或comprising应理解为开放的、非排他性的意义，即“包括但不限于”。
术语“任选”或“任选地”是指随后描述的事件或情况可以发生或不发生，该描述包括发生所述事件或情况和不发生所述事件或情况。其表示作为一种选择，可与“或者”互换地使用。
术语"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。
术语“可药用”或"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。术语“可药用”和"药学上可接受的"在本文中可互换地使用。
术语"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。
术语“治疗”意为将本申请所述化合物或制剂进行给药以改善或消除疾病或与所述疾病相关的一个或多个症状，且包括：
(i)抑制疾病或疾病状态，即遏制其发展；
(ii)缓解疾病或疾病状态，即使该疾病或疾病状态消退。
术语“预防”意为将本申请所述化合物或制剂进行给药以预防疾病或与所述疾病相关的一个或多个症状，包括：预防疾病或疾病状态在哺乳动物中出现，特别是当这类哺乳动物易患有该疾病状态，但尚未被诊断为已患有该疾病状态时。
术语“药学上可接受的辅料”是指对有机体无明显刺激作用，而且不会损害该活性化合物的生物活性及性能的那些辅料。合适的辅料是本领域技术人员熟知的，例如碳水化合物、蜡、水溶性和/或水可膨胀的聚合物、亲水性或疏水性材料、明胶、油、溶剂、水等。
术语“单剂量”是指含有一定量药品的最小包装单元，例如一盒药有七粒胶囊，则每个胶囊为单剂量；或者每瓶注射液为单剂量。
本申请采用下列缩略词：
PD：疾病进展(progressive disease)，靶病灶最大径之和至少增加≥20％，或出现新病灶。
PR：部分缓解(partial response)，靶病灶最大径之和减少≥30％，至少维持4周。
OS：总生存(overall survival)，从随机化开始至(因任何原因)死亡的时间。
SD：疾病稳定(stable disease)，靶病灶最大径之和缩小未达PR，或增大未达PD。
PO：口服。
实施方式
下面的具体实施例的目的是使本领域的技术人员能更清楚地理解和实施本申请。它们不应该被认为是对本申请范围的限制，而只是本申请的示例性说明和典型代表。
实施例1
1)将羟丙基纤维素加入水 1中，溶清后在搅拌的条件下加入式(II)化合物，分散均匀，过筛；
2)将上述含药混悬液高压均质，式(II)化合物粒径控制：D50<2μm，D90<4μm；
3)配制0.5mol/L马来酸水 2溶液，取一半配制好的马来酸水溶液溶解处方量的
Figure PCTCN2020125384-appb-000016
溶清后加入步骤2)所得混悬液，然后用剩余马来酸水溶液调节混悬液pH值在3.0-3.5之间，得混悬液；
4)在流化床中用步骤3)制备的混悬液在蔗糖空白丸芯上进行包衣，得到含药微丸；
5)将含药微丸加入料斗混合机中混匀；
6)充填胶囊。
具体药物胶囊制剂的组成如下表1所示。
表1
Figure PCTCN2020125384-appb-000017
Figure PCTCN2020125384-appb-000018
水 1:26.67mg；水 2:20mg。
实施例2-5参照实施例1的过程，进行制备，具体药物胶囊制剂的组成如下表2所示。
表2
Figure PCTCN2020125384-appb-000019
注：
实施例2，水 1：66.67mg；水 2：50mg；
实施例3，水 1：266.68mg；水 2：200mg；
实施例4，水 1：666.7mg；水 2：500mg；
实施例5，水 1：1333.4mg；水 2：1000mg。
实施例6
参照实施例1的步骤1)-6)，除了步骤3)中调节混悬液的pH值在2.0≤pH<3.0，以及水 1：25mg；水 2：50mg。
具体药物胶囊制剂的组成如下表3所示。
表3
Figure PCTCN2020125384-appb-000020
实验例1 细胞活性
磺酰罗丹明B蛋白染色法(SRB法)
人咽鳞癌细胞(FaDu细胞)(购自中国科学院上海生命科学院细胞库)用含10％FBS的RPMI 1640培养液培养。
样品配制方法：以二甲基亚砜(DMSO)配制到10mM，于-80℃保存。
接种一定数量的对数生长期细胞于96孔培养板。贴壁生长24小时后，加入不同浓度的待测样品。药物作用结束后，用三氯乙酸固定细胞。然后SRB溶液(Sigma公司)染色；最后加入Tris溶液溶解SRB，酶标仪510nm波长下测定OD值，以下列公式计算细胞生长抑制率：
抑制率＝(OD值对照孔－OD值给药孔)/OD值对照孔×100％
根据各浓度抑制率，计算半数抑制浓度IC 50。
结果见下表4。
表4
Figure PCTCN2020125384-appb-000021
实验例2 小鼠体内药效
BALB/cA-nude裸小鼠，6-7周，雌性，购自上海斯莱克实验动物有限责任公司。生产许可证号：SCXK(沪)2012-0002；动物合格证号2007000570156。饲养环境：SPF级。裸小鼠皮下接种人咽鳞癌FaDu细胞，待肿瘤生长至80-150mm 3后，将动物随机分组(D0)。给药剂量和给药方案见表4。每周测2次瘤体积，称鼠重，记录数据。
BALB/cA-nude裸小鼠，6-7周，雌性，购自上海灵畅生物科技有限公司。生产许可证号：SCXK(沪)2013-0018；合格证编号：2013001802999。饲养环境：SPF级。裸小鼠皮下接种人食管癌Eca-109细胞，待肿瘤生长至100-300mm 3后，将动物随机分组(D0)。给药剂量和给药方案见表4。每周测2次瘤体积，称鼠重，记录数据。
BALB/cA-nude裸小鼠，6-7周，雌性，购自上海斯莱克实验动物有限责任公司。生产许可证号：SCXK(沪)2012-0002；动物合格证号2007000570541。饲养环境：SPF级。裸小鼠皮下接种人非小细胞肺癌HCC827细胞，待肿瘤生长至100-200mm 3后，将动物随机分组(D0)。给药剂量和给药方案见表4。每周测2次瘤体积，称鼠重，记录数据。
肿瘤体积(V)计算公式为：
V＝1/2×a×b 2；其中a、b分别表示肿瘤长、宽。
根据测量结果计算出相对肿瘤体积(relative tumor volume,RTV),公式为：
RTV＝V t/V 0；其中V 0为分笼给药时(即D0)所测得的肿瘤体积；V t为每次测量时的肿瘤体积。
T/C(％)＝(T-T 0)/(C-C 0)×100％；其中T、C为实验结束时实验组和对照组的肿瘤体积；T 0、C 0为实验开
始时实验组和对照组的肿瘤体积。
抑瘤率(％)＝100％-T/C(％)。
当肿瘤出现消退时，抑瘤率(％)＝100％-(T-T 0)/T 0×100％。
样品配制方法：均用0.4％Tween-80/0.5％CMC配制。
试验结果见表5。
表5
Figure PCTCN2020125384-appb-000022
Figure PCTCN2020125384-appb-000023
D0：随机分组，第一次给药时间；D0-6是指给药6天；D0-20是指给药20天；PO：灌胃
实验例3 疗效研究
3.1入选标准：
1.经病理和/或细胞学明确诊断的晚期恶性实体肿瘤患者，缺乏常规的有效治疗方法或常规方法治疗后失败或复发；病例扩展阶段，入组满足上述条件的EGFR阳性(包括18-21外显子常见突变和罕见突变)；
2. 18～70岁；ECOG体力状况：0～1分；预计生存期超过3月；
3.主要器官功能正常，即符合下列标准：
a)血常规检查：Hb≥90g/L(开始治疗前14天内未输血)；ANC≥1.5×109/L；PLT≥100×109/L
b)生化检查：.血清肌酐<1.5倍正常上限，总胆红素<1.5倍正常上限，天冬氨酸转氨酶(AST)或丙氨酸转氨酶(ALT)<3倍正常上限(ULN)(如果与肝转移相关，则为<5倍正常上限)
c)多普勒超声评估：左室射血分数(LVEF)≥50％；
4.女性应同意在研究期间和研究结束后6个月内必须采用避孕措施(如宫内节育器[IUD]，避孕药或避孕套)；在研究入组前的7天内血清或尿妊娠试验阴性，且必须为非哺乳期患者；男性应同意在研究期间和研究期结束后6个月内必须采用避孕措施的患者；
5.患者自愿加入本研究，签署知情同意书，依从性好。
3.2试验药
式(II)化合物胶囊：由正大天晴药业集团股份有限公司提供。
规格(以式(I)化合物计算)：0.2mg、0.5mg、2mg、5mg、10mg；遮光、密封、在20℃以下处保存，有效期：24个月。
(1)单次给药剂量递增方法：
从0.2mg/日开始，第二剂量组为0.5mg/日，第三剂量组为1.0mg/日，第四剂量组为1.5mg/日，第五剂量组为2.0mg/日，第六剂量组为4.0mg/日，第七剂量组为8.0mg/日，第八剂量组为10.0mg/日，第九剂量组为12.0mg/日，第十剂量组为16.0mg/日。
(2)连续给药剂量递增方法：
参加单次给药患者，用药3天后，确认安全可控情况下，开始使用单次用药剂量进行连续用药，每天一次。如果药物半衰期超过24小时，后续剂量组直接连续使用。前两个剂量组服用的剂量参照单次用药的前两个剂量组的剂量，即从0.2mg/日开始，第二剂量组为0.5mg/日，第三剂量组为1.0mg/日，第四剂量组为1.5mg/日，第五剂量组为2.0mg/日，第六剂量组为4.0mg/日，第七剂量组为8.0mg/日，第八剂量组为10.0mg/日，第九剂量组为12.0mg/日，第十剂量组为16.0mg/日直到达到DLT。
3.3评价标准
主要疗效指标按RECIST1.1标准评价疗效。
3.4疗效评估
客观缓解率(ORR)：仅计算根据RECIST1.1版疾病可测量的患者的肿瘤客观缓解率。客观缓解率定义为完全缓解和部分缓解病人的比例。基线后未进行过肿瘤评估的患者将被认为无客观缓解。
疾病控制率(DCR)：疾病控制率定义为完全缓解和部分缓解以及疾病稳定的病人的比例。
缓解期(DoR)：缓解期定义为在有客观缓解的患者中，从初次出现完全或部分缓解到出现疾病进展之间的时间。如果在研究结束时患者仍未死亡或出现疾病进展，或者患者失访，缓解期统计将截至最后一次肿瘤评价的时间。
无进展生存期(PFS)：PFS定义为患者接受首次研究治疗到出现疾病进展或死亡的时间。如果在研究结束时患者仍没有死亡或出现疾病进展，或者患者失访，PFS统计将截至最后一次肿瘤评价的时间。
对一般状况的好转或恶化，用治疗前后ECOG评分的变化来表示。
3.5治疗效果
3.5.1对非小细胞肺腺癌的疗效
一名58岁女性，2018年4月行胸腔穿刺，胸水细胞学：可见多量恶性肿瘤细胞，考虑为腺癌。头颅MRI未见转移征象。胸水细胞基因检测示：EGFR exon 20 S768I突变，exon18 G719A突变。
2018年04月25日起口服吉非替尼0.25g qd靶向治疗。2018年5月予第一次贝伐珠单抗100mg胸腔注射。2018年5月30日复查胸部CT(与2018年4月10日比较)：右肺门区团片影较前有所缩小，双肺多发结节大致同前，右侧胸腔膜转移较前减轻，右侧胸腔积液较前减少。2018年6月20日患者再次出现右侧胸闷、呼吸困难，伴咳嗽，咳白痰。2018年7月3日复查胸部CT示：右肺门占位性病变，双肺弥漫多发转移结节，右侧胸膜增厚伴右侧胸腔积液。2018年7月9日胸水定位示右侧中量积液，行胸腔注射贝伐珠单抗控制胸水。2018年8月2日复查提示疾病进展，停服吉非替尼治疗。2018年8月31日复查提示肺内结节较前增大，胸水较前增多，提示疾病PD。2018年9月20日至2018年12月21日行4周期培美曲塞+卡铂+贝伐珠单抗方案治疗，化疗后白细胞及中性粒细胞减低1度。2019年1月18日行1周期培美曲塞和贝伐珠单抗方案治疗，最佳疗效SD。后患者咳嗽，胸闷较前逐渐加重，综合评效考虑疾病进展。
2019年4月1日开始每日一次口服上述实施例中制备的8.0mg(以式(I)化合物计，2mg每粒，共4粒)的式(II)化合物胶囊(单次用药3天)，2019年4月4日开始每日一次口服8.0mg(以式(I)化合物计)的式(II)化合物胶囊(连续用药每28天为一个治疗周期)进行治疗。
2019年4月30日患者接受治疗1周期，增强CT提示右下肺门肿块，较前缩小；右上叶转移结节同前；肝S2病灶，较前缩小；按RECIST1.1评价为PR，靶病灶总和为37mm，较基线缩小17mm。
2019年6月27日患者增强CT提示右下肺门肿块，较前略缩小。靶病灶总和为28mm。
2019年8月22日增强CT提示病灶较前变化不大，靶病灶总和28mm。
2020年10月21日，日增强CT提示病灶较前变化不大，维持PR。
患者不良反应基本可耐受，仍在继续接受治疗。

Claims (15)

  1. 一种用于预防或治疗癌症的方法，包括向有需要的个体给予式(I)化合物或其可药用盐，
    Figure PCTCN2020125384-appb-100001
    其中所述癌症选自肺腺癌、肺鳞癌、咽鳞癌或食管癌。
  2. 式(I)化合物或其可药用盐在制备用于预防或治疗癌症的药物中的用途，
    Figure PCTCN2020125384-appb-100002
    其中所述癌症选自肺腺癌、肺鳞癌、咽鳞癌或食管癌。
  3. 权利要求1所述的方法或权利要求2所述的用途，其中：
    所述肺腺癌个体选自接受过先前治疗的患者，任选地，所述先前治疗包括先前化学药剂治疗；或者
    所述肺腺癌个体接受过选自吉非替尼、贝伐珠单抗、培美曲塞、铂类药物及其组合的先前治疗；或者
    所述肺腺癌个体选自既往接受过吉非替尼和/或贝伐珠单抗治疗的患者；或者
    所述肺腺癌个体选自既往接受过培美曲塞、卡铂和贝伐珠单抗联合或者培美曲塞和贝伐珠单抗联合治疗的患者；或者
    所述肺腺癌个体选自既往接受过口服吉非替尼0.25g qd靶向治疗的患者；或者
    所述肺腺癌个体选自既往接受过贝伐珠单抗100mg胸腔注射的患者；或者
    所述肺腺癌包括晚期的肺腺癌；所述肺鳞癌包括晚期的肺鳞癌；或者
    其中所述肺腺癌包括缺乏常规的有效治疗方法或常规方法治疗后失败或复发的肺腺癌；所述肺鳞癌包括缺乏常规的有效治疗方法或常规方法治疗后失败或复发的肺鳞癌。
  4. 权利要求1所述的方法或权利要求2所述的用途，其中肺腺癌含有突变型的EGFR；任选地，所述突变型的EGFR包括但不限于EGFR的18号外显子点突变、19号外显子缺失突变、20号外显子点突变、以及21号外显子点突变；任选地，上述EGFR突变型可以涉及一种或同时涉及多种突变类型。
  5. 一种用于预防或治疗肺癌的方法，包括向有需要的个体给予式(I)化合物或其可药用盐，其中肺癌包含有一种或多种选自以下的突变型的EGFR：EGFR18号外显子点突变、EGFR19号外显子缺失突变、EGFR20号外显子点突变和EGFR21号外显子点突变，
    Figure PCTCN2020125384-appb-100003
  6. 式(I)化合物或其可药用盐在制备用于预防或治疗肺癌的药物中的用途，其中肺癌包含有一种或多种选自以下的突变型的EGFR：EGFR18号外显子点突变、EGFR19号外显子缺失突变、EGFR20号外显子点突变、EGFR21号外显子点突变，
    Figure PCTCN2020125384-appb-100004
  7. 权利要求1或5所述的方法或权利要求2或6所述的用途，其中：
    式(I)化合物或其可药用盐通过口服给药；或者
    式(I)化合物或其可药用盐可以每日施用一次或多次；或者
    式(I)化合物或其可药用盐可以单剂量或多剂量形式给药。
  8. 权利要求1或5所述的方法或权利要求2或6所述的用途，其中：
    式(I)化合物可以以其游离碱形式给药，也可以以其盐、水合物和前药的形式给药，所述前药在体内转换成式(I)化合物的游离碱形式；任选地，所述的可药用盐选自马来酸盐、盐酸盐、氢溴酸盐、硫酸盐、磷酸盐、硝酸盐、乙酸盐、乳酸盐、丙二酸盐、丁二酸盐、富马酸盐、苹果酸盐、扁桃酸盐、酒石酸盐、柠檬酸盐、抗坏血酸盐、棕榈酸盐、苯甲酸盐、苯乙酸盐、肉桂酸盐、水杨酸盐、甲磺酸盐、苯磺酸盐或甲基苯磺酸盐；任选地，所述的可药用盐选自马来酸盐、苹果酸盐、富马酸盐、酒石酸盐、柠檬酸盐、乳酸盐、磷酸盐或乙酸盐；任选地，所述的可药用盐选自马来酸盐；或者
    其中所述式(I)化合物的可药用盐中，式(I)化合物与形成可药用盐的酸根离子的摩尔比可为1:1。
  9. 权利要求1或5所述的方法或权利要求2或6所述的用途，其中所述的式(I)化合物的可药用盐为式(II)化合物
    Figure PCTCN2020125384-appb-100005
  10. 权利要求1或5所述的方法或权利要求2或6所述的用途，其中所述式(I)化合物或其可药用盐为包含 所述式(I)化合物或其可药用盐的药物组合物的形式；任选地，所述药物组合物为固体药物组合物。
  11. 权利要求1、5或10所述的方法或权利要求2、6或10所述的用途，其中所述式(I)化合物或其可药用盐、或所述药物组合物的日剂量以式(I)化合物计算，为0.2毫克至60毫克、或为0.5毫克至40毫克、或为1.0毫克至40毫克、或为1.5毫克至40毫克、或为2毫克至40毫克、或为4毫克至40毫克、或为5毫克至40毫克、或为6毫克至40毫克、或为7毫克至40毫克、或为8毫克至40毫克、或为8毫克至30毫克、或为8毫克至25毫克、或为8毫克至20毫克、或为8毫克至16毫克；或者
    其中所述式(I)化合物或其可药用盐、或所述药物组合物的日剂量以式(I)化合物计算，选自0.2毫克、0.5毫克、1毫克、1.5毫克、2毫克、2.5毫克、3.0毫克、3.5毫克、4.0毫克、4.5毫克、5毫克、5.5毫克、6毫克、6.5毫克、7毫克、7.5毫克、8毫克、8.5毫克、9毫克、9.5毫克、10毫克、10.5毫克、11毫克、11.5毫克、12毫克、12.5毫克、13毫克、13.5毫克、14毫克、14.5毫克、15毫克、15.5毫克、16毫克、16.5毫克、17毫克、17.5毫克或18毫克。
  12. 权利要求10或11所述方法或用途，其中：
    所述药物组合物包含式(I)化合物或其可药用盐、及聚甲基丙烯酸酯；或者
    所述药物组合物包含式(I)化合物或其可药用盐、聚甲基丙烯酸酯及酸；或者
    所述药物组合物包含式(I)化合物或其可药用盐、聚甲基丙烯酸酯、酸、表面稳定剂、分散剂及载体。
  13. 权利要求12所述的方法或用途，其中所述的药物组合物包含式(II)化合物、聚甲基丙烯酸酯、酸、表面稳定剂、分散剂及载体，
    Figure PCTCN2020125384-appb-100006
  14. 权利要求12或13所述的方法或用途，其中：
    所述药物组合物中的所述聚甲基丙烯酸酯为
    Figure PCTCN2020125384-appb-100007
    任选地，其中所述聚甲基丙烯酸酯选自
    Figure PCTCN2020125384-appb-100008
    Figure PCTCN2020125384-appb-100009
    Figure PCTCN2020125384-appb-100010
    或其组合；任选地，其中所述聚甲基丙烯酸酯选自
    Figure PCTCN2020125384-appb-100011
    或者
    其中所述药物组合物中的所述酸选自马来酸、苹果酸、富马酸、酒石酸、柠檬酸、乳酸、磷酸、乙酸及其组合；任选地，所述酸为马来酸；或者
    其中所述药物组合物中的所述表面稳定剂选自羟丙基纤维素、羧甲基纤维素钙、羧甲基纤维素钠、甲基纤 维素、羟乙基纤维素、羟丙基甲基-纤维素、羟丙基甲基-纤维素邻苯二甲酸酯、非结晶纤维素及其组合；任选地，所述表面稳定剂选自羟丙基纤维素；或者
    其中所述药物组合物中的所述分散剂选自蔗糖、乳糖、甘露醇及其组合；任选地，所述分散剂选自蔗糖；或者
    其中所述药物组合物中的所述载体选自纤维素球、甘露醇丸芯、酒石酸丸芯、乳糖/微晶丸芯、蔗糖丸芯或、淀粉丸芯及其组合；任选地，所述载体选自纤维素球或者蔗糖丸芯；任选地，所述载体选自蔗糖丸芯。
  15. 权利要求10-14中任一项所述方法或用途，其中所述药物组合物包含式(II)化合物、羟丙基纤维素、蔗糖、聚甲基丙烯酸酯、马来酸、蔗糖丸芯。
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WO2016150340A1 (zh) * 2015-03-20 2016-09-29 正大天晴药业集团股份有限公司 喹唑啉衍生物的盐及其制备方法
WO2018036539A1 (zh) * 2016-08-25 2018-03-01 正大天晴药业集团股份有限公司 喹唑啉衍生物的盐的晶体

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WO2016150340A1 (zh) * 2015-03-20 2016-09-29 正大天晴药业集团股份有限公司 喹唑啉衍生物的盐及其制备方法
WO2018036539A1 (zh) * 2016-08-25 2018-03-01 正大天晴药业集团股份有限公司 喹唑啉衍生物的盐的晶体

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