WO2021185234A1 - Composition pharmaceutique combinée de composé en tant qu'inhibiteur de kinase c-met et son utilisation - Google Patents

Composition pharmaceutique combinée de composé en tant qu'inhibiteur de kinase c-met et son utilisation Download PDF

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Publication number
WO2021185234A1
WO2021185234A1 PCT/CN2021/081013 CN2021081013W WO2021185234A1 WO 2021185234 A1 WO2021185234 A1 WO 2021185234A1 CN 2021081013 W CN2021081013 W CN 2021081013W WO 2021185234 A1 WO2021185234 A1 WO 2021185234A1
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pharmaceutical composition
pharmaceutically acceptable
compound
hydrate
acceptable salt
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PCT/CN2021/081013
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English (en)
Chinese (zh)
Inventor
李许
张喜全
王训强
于鼎
黄云虎
刘津娜
许梦婕
侯雪
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正大天晴药业集团股份有限公司
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Priority to CN202180015738.3A priority Critical patent/CN115135326B/zh
Publication of WO2021185234A1 publication Critical patent/WO2021185234A1/fr

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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
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with 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

  • This application belongs to the field of medical technology, and relates to a combined pharmaceutical composition of a compound as a c-Met kinase inhibitor, and specifically relates to N-(4-((7-((1-(cyclopentylamino)cyclopropanyl) (Methoxy)-6-methoxyquinolin-4-yl)oxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dimethylamide
  • a pharmaceutical composition and its use for the treatment of colorectal cancer is a combined pharmaceutical composition of a compound as a c-Met kinase inhibitor, and specifically relates to N-(4-((7-((1-(cyclopentylamino)cyclopropanyl) (Methoxy)-6-methoxyquinolin-4-yl)oxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dimethylamide
  • c-Met kinase is a prototype member of the subfamily of heterodimeric receptor tyrosine kinases (RTKs).
  • RTKs include Met, Ron and Sea.
  • the anti-angiogenic and anti-proliferative activities of c-Met make it an attractive target.
  • the endogenous ligand of c-Met is hepatocyte growth factor (HGF), which is also known as scattering factor (SF) because it can interfere with colony formation in vitro.
  • HGF hepatocyte growth factor
  • SF scattering factor
  • HGF is a derivatized cytokine that induces receptor activation through autophosphorylation and increases receptor-dependent signals in normal cells and tumor cells (Sonnenberg et al., J. Cell Biol. 123:223-235, 1993; Matsumato et al. , Crit. Rev. Oncog. 3:27-54, 1992; Stoker et al., Nature 327:239-242, 1987). It has been
  • WO2012034055 discloses N-(4-((7-((1-(cyclopentylamino)cyclopropyl)methoxy)-6-methoxyquinolin-4 as c-Met kinase inhibitor -Yl)oxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dimethylamide (hereinafter referred to as formula I compound) and its use for inhibiting tyrosine kinase activity ,
  • the application provides a combined pharmaceutical composition, which includes a compound of formula (I) or a pharmaceutically acceptable salt, hydrate or prodrug thereof, calcium folinate and 5-fluorouracil, and also includes oxaliplatin or irinotecan Or one of its pharmaceutically acceptable salts, hydrates or prodrugs,
  • the present application provides a combined pharmaceutical composition for the treatment of colorectal cancer, which includes a compound of formula (I) or a pharmaceutically acceptable salt, hydrate or prodrug thereof, calcium folinate and 5-fluorouracil, and also includes Oxaliplatin or irinotecan or one of its pharmaceutically acceptable salts, hydrates or prodrugs.
  • the present application also provides a method for treating colorectal cancer, which comprises administering to a patient a therapeutically effective amount of the above-mentioned combination pharmaceutical composition of the present application.
  • the application also provides the use of the above-mentioned combination pharmaceutical composition of the application in the preparation of a medicament for the treatment of colorectal cancer.
  • the application also provides the use of the above-mentioned combination pharmaceutical composition of the application for the treatment of colorectal cancer.
  • the application provides a combined pharmaceutical composition, which includes a compound of formula (I) or a pharmaceutically acceptable salt, hydrate or prodrug thereof, calcium folinate and 5-fluorouracil, and also includes oxaliplatin or irinotecan Or one of its pharmaceutically acceptable salts, hydrates or prodrugs,
  • the present application provides a combination pharmaceutical composition, which includes a compound of formula (I), leucovorin and 5-fluorouracil, and also includes one of oxaliplatin or irinotecan,
  • the present application provides a combined pharmaceutical composition for the treatment of colorectal cancer, which includes a compound of formula (I) or a pharmaceutically acceptable salt, hydrate or prodrug thereof, calcium folinate and 5-fluorouracil, and also includes Oxaliplatin or irinotecan or one of its pharmaceutically acceptable salts, hydrates or prodrugs.
  • the combination pharmaceutical composition includes a compound of formula (I) or a pharmaceutically acceptable salt, hydrate or prodrug thereof, calcium leucovorin, 5-fluorouracil and oxaliplatin.
  • the combined pharmaceutical composition includes a compound of formula (I) or a pharmaceutically acceptable salt, hydrate or prodrug thereof, calcium folinate, 5-fluorouracil and irinotecan or a pharmaceutically acceptable salt thereof, Hydrate or prodrug.
  • the combination pharmaceutical composition is packaged in the same kit, and the kit further includes a compound of formula (I) or a pharmaceutically acceptable salt, hydrate or prodrug thereof, calcium leucovorin, 5- Instructions for the combined use of fluorouracil and oxaliplatin or irinotecan or its pharmaceutically acceptable salts, hydrates or prodrugs for the treatment of colorectal cancer.
  • the combination pharmaceutical composition includes a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt, hydrate or prodrug thereof, a pharmaceutical composition containing leucovorin, and 5-fluorouracil
  • a pharmaceutical composition containing oxaliplatin or the pharmaceutical composition containing irinotecan or its pharmaceutically acceptable salt, hydrate or prodrug is an effective pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt, hydrate or prodrug thereof.
  • the combination pharmaceutical composition contains 90 mg-180 mg of the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or prodrug thereof.
  • the combination pharmaceutical composition contains 90 mg-120 mg, 90 mg-150 mg, 120 mg-150 mg, 120 mg-180 mg, or 150 mg-180 mg of the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or pro- medicine.
  • the combination pharmaceutical composition contains 90 mg, 120 mg, 150 mg, or 180 mg of the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or prodrug thereof.
  • the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or prodrug thereof in the combination pharmaceutical composition is a single dose or multiple doses; in some embodiments, multiple doses. dose.
  • the combination pharmaceutical composition contains a single dose of 30 mg or 60 mg of the compound of formula (I) or a pharmaceutical composition of a pharmaceutically acceptable salt, hydrate or prodrug thereof.
  • the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or prodrug thereof in the combination pharmaceutical composition is a multiple dose, and the multiple dose is 30 mg or 30 mg from a single dose. 60 mg of the compound of formula (I) or a pharmaceutical composition of a pharmaceutically acceptable salt, hydrate or prodrug thereof.
  • the content of the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or prodrug thereof in the combination pharmaceutical composition is a daily dose.
  • the content of the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or prodrug thereof in the combination pharmaceutical composition is a once-a-day dose.
  • the content of the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or prodrug thereof in the combination pharmaceutical composition is a once-a-day dose, containing the compound of formula (I) or a pharmaceutically acceptable salt thereof
  • the pharmaceutical composition of hydrates or prodrugs is a single dose or multiple doses.
  • the combination pharmaceutical composition contains multiple doses of 90 mg, 120 mg, 150 mg or 180 mg of a compound of formula (I) or a pharmaceutical composition of a pharmaceutically acceptable salt, hydrate or prodrug thereof, wherein the formula ( I)
  • the content of the compound or its pharmaceutically acceptable salt, hydrate or prodrug is a once-a-day dose, and the multiple doses consist of a single dose of 30 mg or 60 mg of the compound of formula (I) or its pharmaceutically acceptable salt, hydrate or The pharmaceutical composition of the prodrug.
  • the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or prodrug thereof in the combination pharmaceutical composition is packaged in a kit, and the kit further contains the formula ( I) Instructions for the treatment of colorectal cancer with the compound or its pharmaceutically acceptable salts, hydrates or prodrugs.
  • the combination pharmaceutical composition contains 400 mg/m 2 calcium leucovorin based on the patient's body surface area and leucovorin.
  • the content of calcium leucovorin in the combination pharmaceutical composition is a daily dose.
  • the combination pharmaceutical composition contains a pharmaceutical composition of calcium folinate at a concentration of 10 mg/mL.
  • the combination pharmaceutical composition contains 2800 mg/m 2 of 5-fluorouracil based on the patient's body surface area.
  • the content of 5-fluorouracil in the combination pharmaceutical composition is two daily doses.
  • the combination pharmaceutical composition contains a pharmaceutical composition containing 5-fluorouracil at a concentration of 25 mg/mL.
  • the combination pharmaceutical composition contains 85 mg/m 2 of oxaliplatin or 180 mg/m 2 of irinotecan hydrochloride.
  • the content of oxaliplatin or irinotecan or a pharmaceutically acceptable salt, hydrate or prodrug thereof in the combination pharmaceutical composition is a daily dose.
  • the combination pharmaceutical composition contains a pharmaceutical composition containing oxaliplatin at a concentration of 5 mg/mL.
  • the combination pharmaceutical composition contains a pharmaceutical composition containing irinotecan hydrochloride at a concentration of 20 mg/mL.
  • the combination pharmaceutical composition includes: containing 90 mg, 120 mg, 150 mg or 180 mg of the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or prodrug thereof; based on the patient's body surface area, containing Calcium folinate with 400mg/m 2 in terms of folinic acid; 5-fluorouracil containing 2800mg/m 2 ; and oxaliplatin containing 85mg/m 2 or irinotecan hydrochloride containing 180mg/m 2 .
  • the combination pharmaceutical composition includes: a pharmaceutical composition containing 90 mg, 120 mg, 150 mg, or 180 mg of a compound of formula (I) or a pharmaceutically acceptable salt, hydrate or prodrug thereof; calculated as leucovorin ,
  • One of the pharmaceutical compositions of irinotecan hydrochloride wherein the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or prodrug thereof is in a single dose or multiple dose form.
  • body surface area BSA (m2) 0.00616 ⁇ height (cm)+0.01286 ⁇ weight (kg)-0.1529.
  • the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or prodrug thereof, leucovorin and 5-fluorouracil, and oxaliplatin in the combination pharmaceutical composition Or irinotecan or one of its pharmaceutically acceptable salts, hydrates or prodrugs may be in the form of a pharmaceutical composition separately or together.
  • the present application also provides a method for treating colorectal cancer, which comprises administering to a patient a therapeutically effective amount of the above-mentioned combination pharmaceutical composition of the present application.
  • the present application also provides the use of the combination drug composition in the preparation of a medicament for the treatment of colorectal cancer, and the combination drug composition is the above-mentioned combination drug composition of the application.
  • the application also provides the use of a combination pharmaceutical composition for the treatment of colorectal cancer, and the combination pharmaceutical composition is the above-mentioned combination pharmaceutical composition of the application.
  • the combination pharmaceutical composition is administered in the following order: (1) a compound of formula (I) or a pharmaceutically acceptable salt, hydrate or prodrug thereof; (2) Austria Thaliplatin or irinotecan or its pharmaceutically acceptable salts, hydrates or prodrugs; (3) leucovorin; (4) 5-fluorouracil.
  • the combination pharmaceutical composition is administered in the following order: (1) a compound of formula (I); (2) oxaliplatin or irinotecan hydrochloride; (3) Leucovorin injection; (4) 5-Fluorouracil injection.
  • the combination pharmaceutical composition is administered in the following order: (1) a compound of formula (I) or a pharmaceutically acceptable salt, hydrate or prodrug thereof; (2) Austria Thaliplatin and leucovorin are administered simultaneously; (3) 5-Fluorouracil.
  • the combination pharmaceutical composition is administered in the following order: (1) a compound of formula (I); (2) oxaliplatin and calcium leucovorin are administered simultaneously; 3) 5-Fluorouracil injection.
  • the content of the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or prodrug thereof in the combination pharmaceutical composition is a daily dose, which is administered as follows: Medicine: The compound of formula (I) or its pharmaceutically acceptable salt, hydrate or prodrug is administered once a day.
  • the content of the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or prodrug thereof in the combination pharmaceutical composition is a daily dose, wherein the formula (I) The compound or its pharmaceutically acceptable salt, hydrate or prodrug is administered in a single dose or multiple doses. In some embodiments, wherein the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or prodrug thereof is administered in multiple doses.
  • the daily dose to the patient is 90 mg, 120 mg, 150 mg or 180 mg
  • the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or prodrug thereof is administered continuously every day.
  • the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or prodrug thereof is administered in the following manner: a treatment cycle of 28 days, a daily dose of 90 mg, 120mg, 150mg or 180mg, once a day.
  • the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or prodrug thereof is administered in an oral form; in some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof Take salts, hydrates or prodrugs orally on an empty stomach before breakfast.
  • the calcium leucovorin is administered in the following manner: administering 400 mg/m 2 of calcium leucovorin to the patient based on the patient’s body surface area and leucovorin at an interval of 14 days.
  • the calcium leucovorin is administered in the following manner: a 28-day treatment cycle is calculated based on the body surface area of the patient, and 400 mg/m 2 of leucovorin is administered to the patient. Leucovorin is administered on the 1st and 15th day of each cycle.
  • the calcium leucovorin is administered as an intravenous drip; in some embodiments, the intravenous drip is given for 2 hours.
  • the 5-fluorouracil is administered in the following manner: based on the patient's body surface area, 2800 mg/m 2 of 5-fluorouracil is administered to the patient at an interval of 14 days.
  • the 5-fluorouracil is administered in the following manner: taking 28 days as a treatment cycle, based on the patient's body surface area, administering 2800 mg/m 2 of 5-fluorouracil to the patient.
  • the administration starts on the 1st and 15th day of each cycle, and the duration of each administration is 46h-48h.
  • pump-controlled infusion is 46-48 hours.
  • oxaliplatin is administered by the following manner: administering 85 mg/m 2 of oxaliplatin to the patient based on the patient's body surface area, with an interval of administration of 14 days.
  • the oxaliplatin is administered in the following manner: taking 28 days as a treatment cycle, based on the patient's body surface area, administering 85 mg/m 2 of oxaliplatin to the patient , Administer on the 1st and 15th day of each cycle.
  • the oxaliplatin is administered by intravenous drip; in some embodiments, the oxaliplatin is administered by intravenous drip for 2 hours.
  • irinotecan or a pharmaceutically acceptable salt, hydrate or prodrug thereof is administered by the following method: administering 180 mg/m 2 of irinotecan based on the patient’s body surface area.
  • Rinotecan or its pharmaceutically acceptable salt, hydrate or prodrug the administration interval is 14 days.
  • the pharmaceutically acceptable salt of irinotecan is irinotecan hydrochloride and is administered by the following method: administering 180 mg/m 2 of irinotecan hydrochloride to the patient based on the patient's body surface area Kang, the dosing interval is 14 days.
  • irinotecan or a pharmaceutically acceptable salt, hydrate or prodrug thereof is administered in the following manner: a 28-day period is a treatment cycle, and the patient’s body surface area is calculated. Irinotecan or its pharmaceutically acceptable salts, hydrates or prodrugs at 180 mg/m 2 are administered to patients on the 1st and 15th days of each cycle.
  • irinotecan hydrochloride wherein the pharmaceutically acceptable salt of irinotecan is irinotecan hydrochloride and is administered in the following manner: a 28-day treatment period is used, and the patient’s body surface area is calculated based on the patient’s body surface area.
  • Irinotecan hydrochloride at 180 mg/m 2 was administered on the 1st and 15th days of each cycle.
  • irinotecan or a pharmaceutically acceptable salt, hydrate or prodrug thereof is administered by intravenous drip; in some embodiments, irinotecan or a pharmaceutically acceptable salt, hydrate or prodrug thereof Use salt, hydrate or prodrug intravenously for 0.5 to 1.5 hours.
  • 28 days is a treatment cycle
  • the administration mode is as follows: the compound of formula (I) or its pharmaceutically acceptable salt, hydrate or prodrug: the initial dose is 90 mg, 120 mg , 150mg or 180mg, orally on an empty stomach before breakfast, once a day for 28 consecutive days; Oxaliplatin: based on the patient’s body surface area, the starting dose is 85mg/m 2 , on the 1st and 15th day of each cycle Calcium folinate: based on the patient's body surface area, the initial dose is 400mg/m 2 , administered on the 1st and 15th day of each cycle; 5-fluorouracil: based on the patient's body surface area, the total amount is 2800mg /m 2 , pump-controlled infusion for 46-48 hours, and start administration on the 1st and 15th day of each cycle.
  • 28 days is a treatment cycle
  • the administration mode is as follows: the compound of formula (I) or its pharmaceutically acceptable salt, hydrate or prodrug: the initial dose is 90 mg, 120 mg , 150mg or 180mg, orally on an empty stomach before breakfast, once a day for 28 days;
  • Irinotecan hydrochloride based on the patient's body surface area, the starting dose is 180mg/m 2 , on the 1st and 15th days of each cycle Administration;
  • Leucovorin based on the patient's body surface area, the initial dose is 400mg/m 2 , administered on the 1st and 15th day of each cycle;
  • 5-fluorouracil based on the patient's body surface area, the total amount is 2800mg/ m 2 , pump-controlled infusion for 46-48 hours, and start the administration on the 1st and 15th day of each cycle.
  • the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or prodrug thereof is prepared to be suitable for 28 consecutive days, once a day, each time 90mg-180mg, or 90mg-150mg is administered to the patient , Or 90mg-120mg, or 120mg-150mg, or 120mg-180mg, or 150mg-180mg, or 90mg, or 120mg, or 150mg, or 180mg of formula (I) compound or its pharmaceutically acceptable salt, hydrate or prodrug Single dose or multiple doses.
  • the calcium leucovorin is prepared to be suitable for administration every 28 days as a treatment cycle, on the 1st and 15th days of each cycle, and each administration to the patient is 400 mg/m based on the patient’s body surface area. 2 single or multiple doses of leucovorin.
  • the 5-fluorouracil is prepared to be suitable for every 28 days as a treatment cycle, the administration starts on the 1st and 15th days of each cycle, and the duration of each administration is 46h-48h.
  • the patient is given a single dose or multiple doses of 5-fluorouracil at 2800 mg/m 2 based on the patient's body surface area.
  • the oxaliplatin is prepared to be suitable for administration every 28 days as a treatment cycle, on the 1st and 15th days of each cycle, and each administration to the patient is 85 mg per patient's body surface area. m 2 of single or multiple doses of oxaliplatin.
  • the pharmaceutically acceptable salt of irinotecan is irinotecan hydrochloride and is prepared to be suitable for administration every 28 days as a treatment cycle, on the 1st and 15th days of each cycle, each time to the patient A single dose or multiple doses of irinotecan hydrochloride of 180 mg/m 2 based on the patient's body surface area were given.
  • the aforementioned colorectal cancer is selected from advanced colorectal cancer.
  • the aforementioned colorectal cancer is selected from metastatic colorectal cancer.
  • the aforementioned colorectal cancer is selected from advanced metastatic colorectal cancer.
  • the above-mentioned colorectal cancer is selected from infiltrating ulcer-type colorectal cancer.
  • the above-mentioned colorectal cancer is selected from colorectal cancer that has failed chemotherapy, such as advanced colorectal cancer that has failed chemotherapy, and metastatic colorectal cancer that has failed chemotherapy; in some embodiments, the above-mentioned colorectal cancer is selected from chemotherapy Failed advanced metastatic colorectal cancer.
  • the chemotherapy failure includes the failure of systemic standard chemotherapy or the failure of first-line or more than one-line chemotherapy.
  • the chemotherapy failure includes treatment failure of a platinum-containing chemotherapy regimen.
  • the chemotherapy failure includes a treatment regimen of fluoropyrimidines and oxaliplatin or irinotecan (with or without bevacizumab/cetuximab) and the treatment fails.
  • the above-mentioned colorectal cancer is selected from colorectal cancer (such as advanced metastatic colorectal cancer) that has only received first-line treatment for metastatic disease in the past.
  • the above-mentioned colorectal cancer is selected from a treatment regimen that has only received first-line treatment for metastatic disease, fluoropyrimidines and oxaliplatin or irinotecan (with or without bevacizumab/western Tuximab) and the treatment of colorectal cancer failed.
  • the aforementioned colorectal cancer is selected from colorectal cancers that have previously been treated with oxaliplatin and/or capecitabine.
  • the above-mentioned colorectal cancer is selected from colorectal cancers that have been treated with oxaliplatin and/or capecitabine in the past and the treatment has failed.
  • the aforementioned colorectal cancer is selected from colon cancer and/or rectal cancer.
  • the patient is selected from a treatment regimen that has only received first-line treatment for metastatic disease, fluoropyrimidines and oxaliplatin or irinotecan (with or without bevacizumab/cetuximab) Anti-) treatment plan and treatment failure patients.
  • the components in the pharmaceutical combination of the present application may each independently, or part or all of them together contain pharmaceutically acceptable carriers and/or excipients.
  • the pharmaceutical composition of the present application may also contain additional therapeutic agents.
  • the additional therapeutic agent may be a cancer therapeutic agent known in the art, preferably a colorectal cancer therapeutic agent.
  • 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 pharmaceutically acceptable salts, hydrates and prodrugs, which are converted into the free base of the compound of formula (I) in vivo form.
  • the pharmaceutically acceptable salt of the 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 inorganic acid can be selected from hydrochloric acid, hydrobromic acid, Sulfuric acid, nitric acid or phosphoric acid
  • the organic acid can be selected from succinic acid, maleic acid, acetic acid, fumaric acid, citric acid, tartaric acid, benzoic acid, p-toluenesulfonic acid, methanesulfonic acid or naphthalenesulfonic acid.
  • the compound of formula (I) is administered in its free base form.
  • composition containing a compound of formula (I) or a pharmaceutically acceptable salt, hydrate or prodrug thereof
  • the "compound of formula (I) or its pharmaceutically acceptable salt, hydrate or prodrug” mentioned in this application may be a “pharmaceutical composition containing the compound of formula (I) or its pharmaceutically acceptable salt, hydrate or prodrug" ".
  • the method of administration can be comprehensively determined according to the activity, toxicity and patient tolerance of the drug.
  • the above-mentioned pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt, hydrate or prodrug thereof further contains pharmaceutically acceptable excipients.
  • the pharmaceutical composition of the present application containing a compound of formula (I) or a pharmaceutically acceptable salt, hydrate or prodrug thereof is administered orally.
  • each of the aforementioned pharmaceutical compositions containing a compound of formula (I) or a pharmaceutically acceptable salt, hydrate or prodrug thereof is a solid pharmaceutical composition.
  • the preparation form of the solid pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or prodrug thereof of the present application is a capsule.
  • the pharmaceutical composition of the compound of formula (I) or its pharmaceutically acceptable salt, hydrate or prodrug is a capsule of the compound of formula (I) or its pharmaceutically acceptable salt, hydrate or prodrug, and the specification is 30mg and 60mg.
  • composition containing the compound of formula (I) or its pharmaceutically acceptable salts, hydrates or prodrugs of the present application can be manufactured by methods well known in the art, such as conventional mixing methods, dissolution methods, granulation methods, sugar-coated pills Method, grinding method, emulsification method, freeze-drying method, etc.
  • the solid oral composition can be prepared by conventional mixing, filling or tableting 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.
  • the pharmaceutical composition of the compound of formula (I) may be a capsule of the compound of formula (I), which contains the compound of formula (I), corn starch, calcium carboxymethyl cellulose, hypromellose and hard Magnesium fatty acid.
  • the pharmaceutical composition of the compound of formula (I) may be a capsule of the compound of formula (I), which contains the compound of formula (I), lactose, microcrystalline cellulose, sodium starch glycolate and magnesium stearate .
  • the above-mentioned pharmaceutical composition containing calcium leucovorin further contains pharmaceutically acceptable excipients.
  • the above-mentioned pharmaceutical composition containing calcium leucovorin is a water-soluble injection
  • the water-soluble injection includes, but is not limited to, a water-soluble preparation that has not been lyophilized or a water-soluble preparation reconstituted by a lyophilized powder.
  • the above-mentioned pharmaceutical composition containing calcium leucovorin is calcium leucovorin injection with specifications of 10 mL: 0.1 g and 5 mL: 50 mg (calculated as leucovorin), which can be obtained commercially.
  • the above-mentioned 5-fluorouracil-containing pharmaceutical composition further contains pharmaceutically acceptable excipients.
  • the above-mentioned 5-fluorouracil-containing pharmaceutical composition is a water-soluble injection
  • the water-soluble injection includes, but is not limited to, a water-soluble preparation that has not been lyophilized or a water-soluble preparation reconstituted by a lyophilized powder.
  • the above-mentioned 5-fluorouracil-containing pharmaceutical composition is 5-fluorouracil injection with a specification of 10 mL: 0.25 g, which can be obtained commercially.
  • oxaliplatin As used in this application, the chemical name of oxaliplatin is (1R-trans)-(1,2-cyclohexanediamine-N,N')[oxalic acid(2-)O,O']platinum , which has the following structural formula:
  • the above-mentioned oxaliplatin-containing pharmaceutical composition further contains pharmaceutically acceptable excipients.
  • the above-mentioned oxaliplatin-containing pharmaceutical composition is a water-soluble injection
  • the water-soluble injection includes, but is not limited to, a water-soluble preparation that has not been lyophilized or a water-soluble preparation reconstituted by a lyophilized powder .
  • the above-mentioned oxaliplatin-containing pharmaceutical composition is oxaliplatin for injection, the specification is 50 mg/bottle, and when used, it is made up of 5 mg/mL injection with water for injection or 5% dextrose solution. Commercially available.
  • the above-mentioned oxaliplatin-containing pharmaceutical composition is oxaliplatin injection, which is prepared by oxaliplatin for injection, or can be obtained commercially.
  • the oxaliplatin injection is prepared by oxaliplatin for injection with a specification of 50 mg/bottle, and the preparation method is to prepare a 5 mg/mL injection with water for injection or a 5% glucose solution.
  • irinotecan is (+)-(4S)-4,11-diethyl-4-hydroxy-9-[(4-piperidinylpiperidine)carbonyl]-1H -Pyrano[3,4:6,7]indoleazine[1,2b]quinoline-3,14-(4H,12H)-dione, which has the following structural formula:
  • Irinotecan can be administered in the form of its free base, or in the form of its pharmaceutically acceptable salts, hydrates and prodrugs, which are converted into the free base form of the compound of formula (I) in vivo.
  • a pharmaceutically acceptable salt of irinotecan is within the scope of the present invention, and the salt can be produced from different organic acids and inorganic acids according to methods known in the art.
  • irinotecan is administered in the form of irinotecan hydrochloride.
  • irinotecan hydrochloride is in the form of irinotecan hydrochloride trihydrate, having the following structural formula:
  • composition containing irinotecan or its pharmaceutically acceptable salts, hydrates and prodrugs irinotecan or its pharmaceutically acceptable salts, hydrates and prodrugs
  • the above-mentioned pharmaceutical composition containing irinotecan and its pharmaceutically acceptable salts, hydrates and prodrugs further contains pharmaceutically acceptable excipients.
  • the above-mentioned pharmaceutical composition containing irinotecan and its pharmaceutically acceptable salts, hydrates and prodrugs is a water-soluble injection
  • the water-soluble injection includes, but is not limited to, a water-soluble preparation that has not been lyophilized Or lyophilized powder reconstituted water-soluble formulation.
  • the above-mentioned pharmaceutical composition containing irinotecan, its pharmaceutically acceptable salts, hydrates, and prodrugs is irinotecan hydrochloride for injection, the specification is 100 mg/bottle, and when used, it passes 100 mg/bottle of injection hydrochloric acid.
  • Irinotecan is formulated into an injection with a concentration of 20 mg/mL ( calculated as C 33 H 38 N 4 O 6 ⁇ HCl).
  • Irinotecan hydrochloride for injection can be obtained commercially.
  • the above-mentioned pharmaceutical composition containing irinotecan and its pharmaceutically acceptable salts, hydrates and prodrugs is irinotecan injection, which is prepared by irinotecan hydrochloride for injection, or can be obtained commercially .
  • the irinotecan injection is formulated into an injection with a concentration of 20 mg/mL ( calculated as C 33 H 38 N 4 O 6 ⁇ HCl) by irinotecan hydrochloride for injection with a specification of 100 mg/bottle.
  • the following content does not limit the administration mode of the drug combination of the application.
  • compositions of the present application can be administered independently, or part or all of them can be administered by various suitable routes, including, but not limited to, oral or parenteral (by intravenous, intramuscular, topical or Subcutaneous route).
  • the components in the pharmaceutical composition of the present application may be independently, or some or all of them may be a suitable dosage form together, including, but not limited to, tablets, troches, pills, capsules (such as hard capsules, soft capsules) , Enteric-coated capsules, microcapsules), elixirs, granules, syrups, injections (intramuscular, intravenous, intraperitoneal), granules, emulsions, suspensions, solutions, dispersions and for oral or non-oral
  • the dosage form of the sustained-release preparation for administration including, but not limited to, tablets, troches, pills, capsules (such as hard capsules, soft capsules) , Enteric-coated capsules, microcapsules), elixirs, granules, syrups, injections (intramuscular, intravenous, intraperitoneal), granules, emulsions, suspensions, solutions, dispersions and for oral or non-oral
  • the combined pharmaceutical composition of the present application has one or more of the following effects:
  • the treated patients have a longer survival period (such as median survival, progression-free survival or overall survival);
  • the use of the aforementioned combination drug composition of the application has clinical benefits, including but not limited to: clinical patient progression-free survival (PFS) prolonged, overall survival (OS) prolonged, objective response rate (ORR) ) Is improved, the disease control rate (DCR) is improved, the number and/or degree of adverse reactions is reduced, the rate of distant metastasis and the rate of local control are reduced.
  • PFS clinical patient progression-free survival
  • OS overall survival
  • ORR objective response rate
  • DCR disease control rate
  • DCR disease control rate
  • the number and/or degree of adverse reactions is reduced
  • the rate of distant metastasis and the rate of local control are reduced.
  • the term “combined pharmaceutical composition” refers to two or more active ingredients administered simultaneously or sequentially (administered in the form of the respective active ingredients themselves, or in their respective pharmaceutically acceptable salts). Or esters and other derivatives, hydrates, prodrugs, or combinations). In this document, the terms “combined pharmaceutical composition” and “drug combination” are used interchangeably.
  • combined use or “combined use” means that two or more active substances can be administered to a subject together in a mixture, simultaneously as a single formulation, or sequentially as a single formulation in any order.
  • patient refers to a mammal, preferably a human.
  • patient or subject is a patient or subject who has failed or lacks standard treatment.
  • systemic therapy refers to a treatment in which a drug substance is transported through the bloodstream to reach and affect cells throughout the body.
  • systemic therapy refers to systemic chemotherapy, systemic or local radiotherapy.
  • first-line treatment refers to treatment with drugs that can be selected first or standard-selected according to the patient's condition.
  • an "adverse event” as used herein is any unfavorable and usually unintentional or undesirable sign (including abnormal laboratory findings), symptom, or disease related to the application of medical treatment.
  • an adverse event may be related to the activation of the immune system or the expansion of immune system cells (e.g., T cells) in response to the treatment.
  • Medical treatments can have one or more related AEs, and each AE can have the same or different severity levels.
  • the reference to a method capable of "modifying adverse events” refers to a treatment plan that reduces the incidence and/or severity of one or more AEs related to the application of different treatment plans.
  • metalastatic cancer refers to cancer that has spread from one part of the body to another part of the body.
  • “Failure of a standard chemotherapy” is defined as: disease progression during treatment or after the last treatment, or intolerable toxic side effects during treatment.
  • “Failure of first-line or more than first-line chemotherapy” is defined as: disease progression during treatment or after the last treatment; or intolerable due to toxic side effects during treatment.
  • the patient or subject is a patient or subject who has failed first-line standard chemotherapy. "Failure of first-line standard chemotherapy” needs to meet any one of the following criteria:
  • pharmaceutically acceptable refers to its use in the preparation of a pharmaceutical composition that is generally safe, non-toxic and neither biologically or otherwise undesirable, and Including it is acceptable for human drug use.
  • terapéuticaally effective amount means an amount sufficient to achieve the 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:
  • 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.
  • administering refers to the physical introduction of a composition containing a therapeutic agent into a subject using any of a variety of methods and delivery systems known to those skilled in the art. In certain embodiments, it is administered orally.
  • dose refers to the dose administered to a patient regardless of the patient's weight or body surface area (BSA). For example, a 60 kg person and a 100 kg person will receive the same dose of the compound of formula (I).
  • daily dose refers to a daily dose administered to a patient.
  • body surface area-based dose refers to the dose calculated based on the patient's body surface area and administered to the patient.
  • patient is a mammal. In some embodiments, the patient is a human.
  • single dose refers to the smallest packaging unit containing a certain amount of medicine.
  • a box of medicines has seven capsules, and each capsule is a single dose; for example, a box of medicines has seven medicines, and each medicine is a single dose.
  • multi-dose consists of multiple single doses.
  • combined use or “combined use” means that two or more active substances can each be administered to a patient simultaneously as a single formulation, or each as a single formulation sequentially in any order.
  • pharmaceutical composition refers to a mixture of one or more of the active ingredients of the present application or their pharmaceutical combination and pharmaceutically acceptable excipients.
  • the purpose of the pharmaceutical composition is to facilitate the administration of the compound of the present application or its pharmaceutical combination to a patient.
  • day (day) When referring to a dosing regimen, the terms “day (day)”, “every day (daily)”, etc. refer to the time within a calendar day, starting at midnight and ending at the next midnight.
  • step (1) Add magnesium stearate to step (1) for total mixing.
  • step (1) Add magnesium stearate to step (1) for total mixing.
  • Recurrence or metastasis during neoadjuvant or adjuvant therapy or within 6 months after the last administration is considered to be the failure of first-line systemic chemotherapy for advanced disease
  • Systemic chemotherapy or other anti-tumor treatments should be completed at least 4 weeks before enrollment (oral fluorouracil drugs should be stopped for at least 2 weeks); systemic or local palliative radiotherapy should be completed at least 4 weeks;
  • Hb hemoglobin
  • ANC absolute neutrophil count
  • PLT platelets
  • ALT Alanine aminotransferase
  • AST aspartate aminotransferase
  • TBIL serum total bilirubin
  • Tr Serum creatinine
  • Cr Serum creatinine
  • Blood coagulation function activated partial thromboplastin time (APTT), international normalized ratio (INR), prothrombin time (PT) ⁇ 1.5 ⁇ ULN;
  • LVEF left ventricular ejection fraction
  • Formula (I) compound capsules Specifications: 30mg and 60mg, provided by Zhengda Tianqing Pharmaceutical Group Co., Ltd.
  • Oxaliplatin injection Oxaliplatin for injection, the specification is 50mg/bottle (commercially available, produced by Zhengda Tianqing Pharmaceutical Group Co., Ltd.), mixed with water for injection or 5% glucose solution to make 5mg/mL injection ;
  • Irinotecan hydrochloride injection Irinotecan hydrochloride for injection, the specification is 100mg/bottle (commercially available, manufactured by Jiangsu Hengrui Pharmaceutical Co., Ltd.), formulated into an injection with a concentration of 20mg/mL (based on C 33 H 38 N 4 O 6 ⁇ HCl meter);
  • 5-Fluorouracil (5-FU) injection 10mL: 0.25g (commercially available, produced by Shanghai Xudong Haipu Pharmaceutical Co., Ltd.).
  • Scheme B Formula (I) compound capsule + irinotecan hydrochloride injection + leucovorin injection + 5-fluorouracil injection.
  • Formula (I) compound capsule ⁇ oxaliplatin or irinotecan hydrochloride injection ⁇ leucovorin injection (also can be instilled simultaneously with oxaliplatin) ⁇ 5-fluorouracil injection.
  • Oxaliplatin was injected intravenously for 2h ( ⁇ 10min)
  • irinotecan hydrochloride was injected intravenously for 0.5h ⁇ 1.5h
  • calcium folinate was injected intravenously for 2h ( ⁇ 10min)
  • the total amount of 5-fluorouracil was 2800mg/m 2
  • pump controlled The infusion is 46-48 hours.
  • the dosing time window is ⁇ 3 days, but within 72 hours before each dosing, the subject must complete various clinical examinations to evaluate the tolerability of continued medication, and start using the medication only when the basic conditions are met. It is also recommended that the subjects stay in the hospital for observation 72 hours after the first administration.
  • Formula (I) compound capsule the initial dose is 120mg, 150mg or 180mg. Take it orally on an empty stomach before breakfast, once a day, for 28 consecutive days.
  • Oxaliplatin injection starting dose 85mg/m 2 , administered on the 1st and 15th day of each cycle.
  • Irinotecan hydrochloride injection the initial dose is 180 mg/m 2 , administered on the 1st and 15th day of each cycle.
  • Leucovorin injection starting dose 400mg/m 2 , administered on the 1st and 15th day of each cycle.
  • 5-Fluorouracil injection total 2800mg/m 2 , pump-controlled infusion for 46-48 hours, and administration is started on the 1st and 15th days of each cycle.
  • Dosing cycle every 28 days is a treatment cycle, until the study termination criteria.
  • the main efficacy indicators were evaluated according to the RECIST1.1 standard.
  • PFS Progressive Free Survival
  • ORR Objective Response Rate
  • DCR Disease Control Rate
  • DoR Duration of Remission: For patients whose best remission is complete remission or partial remission, it is defined as the time from the first appearance of CR or PR to disease progression or recurrence or death from various causes; for remission, before analysis For patients with no disease progression, or relapse or death due to various causes, the time of the last disease assessment shall be the end.
  • the patient started treatment with the XELOX regimen for 3 cycles, specifically: oxaliplatin 120 mg d1, capecitabine 1500 mg early and 2000 mg late d1-d4.
  • the patient developed second-degree diarrhea on the 10th day after the third cycle of chemotherapy, and no clear signs of recurrence and metastasis were found in the reexamination after the third cycle.
  • 28 times of local rectal radiotherapy were performed.
  • capecitabine was orally administered 1500 mg early and 2000 mg late.
  • the lung CT showed small nodules in the left and right lower lobes. The larger ones had a long diameter of about 0.9cm.

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  • Chemical & Material Sciences (AREA)
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  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne une composition pharmaceutique combinée d'un composé en tant qu'inhibiteur de kinase C-Met, comprenant un composé de formule (I) ou un sel, hydrate ou promédicament pharmaceutiquement acceptable de celui-ci, du folinate de calcium et du 5-fluorouracile, et comprenant en outre l'un parmi l'oxaliplatine ou l'irinotécan ou un sel, hydrate ou promédicament pharmaceutiquement acceptable de celui-ci, et l'utilisation de la composition pharmaceutique combinée pour le traitement du cancer colorectal.
PCT/CN2021/081013 2020-03-16 2021-03-16 Composition pharmaceutique combinée de composé en tant qu'inhibiteur de kinase c-met et son utilisation WO2021185234A1 (fr)

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