WO2021185234A1 - Combined pharmaceutical composition of compound as c-met kinase inhibitor and use thereof - Google Patents

Abstract

The present application relates to a combined pharmaceutical composition of a compound as a c-Met kinase inhibitor, comprising a compound of formula (I) or a pharmaceutically acceptable salt, hydrate or prodrug thereof, calcium folinate and 5-fluorouracil, and further comprising one of oxaliplatin or irinotecan or a pharmaceutically acceptable salt, hydrate or prodrug thereof, and use of the combined pharmaceutical composition for treating colorectal cancer.

Description

Combined pharmaceutical composition as a compound of c-Met kinase inhibitor and its use

Cross-references to related applications

This application claims the priority and rights of the Chinese patent application No. 202010183985.1 filed with the State Intellectual Property Office of China on March 16, 2020, and the content disclosed in the application is incorporated herein by reference in its entirety.

Technical field

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.

Background technique

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 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 confirmed that anti-HGF antibodies or HGF antagonists can also inhibit tumor metastasis.

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 ,

Summary of the invention

In one aspect, 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,

On the other hand, 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.

On the other hand, 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.

On the other hand, 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.

On the other hand, the application also provides the use of the above-mentioned combination pharmaceutical composition of the application for the treatment of colorectal cancer.

Detailed description of the invention

In one aspect, 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,

In one aspect, 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,

On the other hand, 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.

In some embodiments, 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.

In some embodiments, 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.

In some embodiments, 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.

In some embodiments, 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 One of the pharmaceutical composition containing oxaliplatin or the pharmaceutical composition containing irinotecan or its pharmaceutically acceptable salt, hydrate or prodrug.

In some embodiments, the combination pharmaceutical composition contains 90 mg-180 mg of the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or prodrug thereof.

In some embodiments, 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.

In some embodiments, 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. In some embodiments, 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.

In some embodiments, 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.

In some embodiments, 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.

In some embodiments, 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.

In some embodiments, 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.

In some embodiments, 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.

In some embodiments, 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.

In some embodiments, 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. In some embodiments, the combination pharmaceutical composition contains 400 mg/m ² calcium leucovorin based on the patient's body surface area and leucovorin.

In some embodiments, the content of calcium leucovorin in the combination pharmaceutical composition is a daily dose.

In some embodiments, based on folinic acid, the combination pharmaceutical composition contains a pharmaceutical composition of calcium folinate at a concentration of 10 mg/mL.

In some embodiments, the combination pharmaceutical composition contains 2800 mg/m ² of 5-fluorouracil based on the patient's body surface area.

In some embodiments, the content of 5-fluorouracil in the combination pharmaceutical composition is two daily doses.

In some embodiments, the combination pharmaceutical composition contains a pharmaceutical composition containing 5-fluorouracil at a concentration of 25 mg/mL.

In some embodiments, based on the patient's body surface area, the combination pharmaceutical composition contains 85 mg/m ² of oxaliplatin or 180 mg/m ² of irinotecan hydrochloride.

In some embodiments, the content of oxaliplatin or irinotecan or a pharmaceutically acceptable salt, hydrate or prodrug thereof in the combination pharmaceutical composition is a daily dose.

In some embodiments, the combination pharmaceutical composition contains a pharmaceutical composition containing oxaliplatin at a concentration of 5 mg/mL.

In some embodiments, the combination pharmaceutical composition contains a pharmaceutical composition containing irinotecan hydrochloride at a concentration of 20 mg/mL.

In some embodiments, 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 .

In some embodiments, 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 , A pharmaceutical composition of calcium folinate with a concentration of 10 mg/mL; a pharmaceutical composition of 5-fluorouracil with a concentration of 25 mg/mL; and a pharmaceutical composition of oxaliplatin with a concentration of 5 mg/mL or a concentration of 20 mg/mL 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.

The body surface area calculation formula of this application is: body surface area BSA (㎡)=0.00616×height (cm)+0.01286×weight (kg)-0.1529.

In some embodiments of the present application, 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. On the other hand, 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.

On the other hand, 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.

On the other hand, 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.

In some embodiments of the method or use, 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.

In some embodiments of the method or use, 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.

In some embodiments of the method or use, 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.

In some embodiments of the method or use, 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.

In some embodiments of the method or use, 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.

In some embodiments of the method or use, 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.

In some embodiments of the method or use, wherein the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or prodrug thereof is administered in the following manner: 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.

In some embodiments of the method or use, wherein 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.

In some embodiments of the method or use, 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.

In some embodiments of the method or use, 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.

In some embodiments of the method or use, 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.

In some embodiments of the method or use, the calcium leucovorin is administered as an intravenous drip; in some embodiments, the intravenous drip is given for 2 hours.

In some embodiments of the method or use, 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.

In some embodiments of the method or use, 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.

In some embodiments of the method or use, wherein 5-fluorouracil is administered by pump-controlled infusion; in some embodiments, pump-controlled infusion is 46-48 hours.

In some embodiments of the method or use, wherein the 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.

In some embodiments of the method or use, 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.

In some embodiments of the method or use, wherein the oxaliplatin is administered by intravenous drip; in some embodiments, the oxaliplatin is administered by intravenous drip for 2 hours.

In some embodiments of the method or use, wherein 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.

In some embodiments of the method or use, wherein 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.

In some embodiments of the method or use, wherein 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.}

In some embodiments of the method or use, 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.

In some embodiments of the method or use, wherein 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.

In an embodiment of the method or use, 28 days is a treatment cycle, and 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.

In an embodiment of the method or use, 28 days is a treatment cycle, and 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.

In the embodiment of this application, as long as the disease is still under control and the protocol is clinically tolerable, the above-mentioned treatment cycle is repeated.

In some embodiments, 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.

In some embodiments, 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.

In some embodiments, 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.

In some embodiments, 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.

In some embodiments, 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.

In some embodiments, the aforementioned colorectal cancer is selected from advanced colorectal cancer.

In some embodiments, the aforementioned colorectal cancer is selected from metastatic colorectal cancer.

In some embodiments, the aforementioned colorectal cancer is selected from advanced metastatic colorectal cancer.

In some embodiments, the above-mentioned colorectal cancer is selected from infiltrating ulcer-type colorectal cancer.

In some embodiments, 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.

In some embodiments, the chemotherapy failure includes the failure of systemic standard chemotherapy or the failure of first-line or more than one-line chemotherapy.

In some embodiments, the chemotherapy failure includes treatment failure of a platinum-containing chemotherapy regimen.

In some embodiments, the chemotherapy failure includes a treatment regimen of fluoropyrimidines and oxaliplatin or irinotecan (with or without bevacizumab/cetuximab) and the treatment fails.

In some embodiments, 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.

In some embodiments, 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.

In some embodiments, the aforementioned colorectal cancer is selected from colorectal cancers that have previously been treated with oxaliplatin and/or capecitabine.

In some embodiments, 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.

In some embodiments, the aforementioned colorectal cancer is selected from colon cancer and/or rectal cancer.

In some embodiments, 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. In some embodiments, 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) or its pharmaceutically acceptable salt, hydrate or prodrug

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. For example, 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. For example, 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.

In some embodiments of the application, the compound of formula (I) is administered in its free base form.

Pharmaceutical 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.

In some embodiments, 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.

In some embodiments, 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.

In some embodiments, 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.

In some embodiments, 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.

In some embodiments, 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.

The pharmaceutical 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.

In some embodiments, 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.

In other embodiments, 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 .

Pharmaceutical composition containing calcium folinate

In some embodiments, the above-mentioned pharmaceutical composition containing calcium leucovorin further contains pharmaceutically acceptable excipients.

In some embodiments, the above-mentioned pharmaceutical composition containing calcium leucovorin is a water-soluble injection, and 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.

In some embodiments, 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.

Pharmaceutical composition containing 5-fluorouracil

In some embodiments, the above-mentioned 5-fluorouracil-containing pharmaceutical composition further contains pharmaceutically acceptable excipients.

In some embodiments, the above-mentioned 5-fluorouracil-containing pharmaceutical composition is a water-soluble injection, and 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.

In some embodiments, 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:

Pharmaceutical composition containing oxaliplatin

In some embodiments, the above-mentioned oxaliplatin-containing pharmaceutical composition further contains pharmaceutically acceptable excipients.

In some embodiments, the above-mentioned oxaliplatin-containing pharmaceutical composition is a water-soluble injection, and 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 .

In some embodiments, 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.

In some embodiments, the above-mentioned oxaliplatin-containing pharmaceutical composition is oxaliplatin injection, which is prepared by oxaliplatin for injection, or can be obtained commercially. In some embodiments, 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 or its pharmaceutically acceptable salts, hydrates and prodrugs

As used in this application, the chemical name of 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. For example, 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. In some embodiments of the application, irinotecan is administered in the form of irinotecan hydrochloride.

In some embodiments, irinotecan hydrochloride is in the form of irinotecan hydrochloride trihydrate, having the following structural formula:

Pharmaceutical composition containing irinotecan or its pharmaceutically acceptable salts, hydrates and prodrugs

In some embodiments, the above-mentioned pharmaceutical composition containing irinotecan and its pharmaceutically acceptable salts, hydrates and prodrugs further contains pharmaceutically acceptable excipients.

In some embodiments, the above-mentioned pharmaceutical composition containing irinotecan and its pharmaceutically acceptable salts, hydrates and prodrugs is a water-soluble injection, and 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.

In some embodiments, 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.

In some embodiments, 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 . In some embodiments, 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.

Method of application

The following content does not limit the administration mode of the drug combination of the application.

The components in the pharmaceutical composition 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.

Technical effect

Generally, the combined pharmaceutical composition of the present application has one or more of the following effects:

(1) Compared with administering any of the drugs in the combination alone, it produces a better curative effect in reducing tumor growth or even eliminating tumors;

(2) Compared with the single administration of any drug in the combination, it provides a smaller amount of administration;

(3) Provide a well-tolerated treatment in patients, which has fewer adverse reactions and/or complications compared with any single drug administered;

(4) Provide a better disease control rate among the treated patients;

(5) Provide a longer survival period (such as median survival, progression-free survival or overall survival) in the treated patients;

(6) Compared with standard chemotherapy, the treated patients have a longer survival period (such as median survival, progression-free survival or overall survival);

(7) Provide a longer duration of disease remission (DOR); and/or

(8) Compared with administering any of the drugs in the combination alone, it has a good activity in treating tumors or proliferative diseases, and shows a more excellent anti-tumor synergistic effect.

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.

Definition and description

As used in the text, 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.

As used herein, "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.

The word "comprise" or "comprise" and its English variants such as comprises or comprising should be understood as an open, non-exclusive meaning, that is, "including but not limited to".

The term "patient" or "subject" refers to a mammal, preferably a human. In some embodiments, the patient or subject is a patient or subject who has failed or lacks standard treatment.

The term "systemic therapy" refers to a treatment in which a drug substance is transported through the bloodstream to reach and affect cells throughout the body.

The term "systemic therapy" refers to systemic chemotherapy, systemic or local radiotherapy.

The term "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" (AE) 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. For example, 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.

The application of alternatives (for example, "or") should be understood to refer to any one, two, or any combination of the alternatives. The indefinite article "a" or "an" used herein should be understood to mean "one or more/one or more" of any listed or enumerated component.

The term "metastatic" 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.

In some embodiments, 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:

Disease progression during the first-line treatment, or disease progression confirmed by imaging after the end of treatment;

Recurrence or metastasis occurred during neoadjuvant or adjuvant therapy or within 6 months after the last administration.

The term "pharmaceutically acceptable" or "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.

The term "therapeutically 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.

The term "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:

(i) Suppress the disease or disease state, that is, curb its development;

(ii) Alleviate the disease or disease state, even if the disease or disease state subsides.

The term "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.

The term "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.

The use of the term "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).

The term "daily dose" refers to a daily dose administered to a patient.

The term "body surface area-based dose" mentioned herein refers to the dose calculated based on the patient's body surface area and administered to the patient.

The term "patient" is a mammal. In some embodiments, the patient is a human.

The term "single dose" refers to the smallest packaging unit containing a certain amount of medicine. For example, 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.

The term "multi-dose" consists of multiple single doses.

As used herein, "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.

The term "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.

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.

Implementation

The purpose of the following specific embodiments is to enable those skilled in the art to understand and implement the application more clearly. They should not be considered as limitations on the scope of this application, but merely exemplary descriptions and typical representatives of this application.

Example 1 Capsules of compound of formula (I)

Table 1 Formula (I) compound capsule prescription composition

Preparation:

(1) Mix the compound of formula (I), corn starch, carboxymethyl cellulose calcium, and hypromellose evenly.

(2) Add magnesium stearate to step (1) for total mixing.

(3) Fill the capsule.

Example 2 Capsules of compound of formula (I)

Table 2 Formula (I) compound capsule prescription composition

Preparation:

(1) Mix the compound of formula (I), lactose, microcrystalline cellulose, and sodium starch glycolate uniformly.

(2) Add magnesium stearate to step (1) for total mixing.

(3) Fill the capsule.

Example 3 Clinical trial

3.1 Selection criteria:

1) Patients with advanced metastatic colorectal cancer diagnosed by tissue and/or cytology;

2) Have only received first-line treatments for metastatic disease in the past, containing fluoropyrimidines and oxaliplatin or irinotecan (combined or not)

Bevacizumab/cetuximab) and the treatment failed;

Note: The definition of first-line standard chemotherapy failure must meet any one of the following criteria:

Disease progression during the first-line treatment, or disease progression confirmed by imaging after the end of treatment;

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;

3) There is at least one measurable lesion (according to RECIST 1.1);

4) 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;

5) 18 to 75 years old; ECOG (Eastern Cooperative Oncology Group, Eastern Cooperative Oncology Group) physical status: 0 to 1 point; expected survival time is more than 3 months;

6) The main organs are functioning normally, that is, they meet the following standards:

a) Routine blood examination (under 14 days without blood transfusion and no hematopoietic stimulating factor drugs for correction): hemoglobin (Hb) ≥ 90g/L; absolute neutrophil count (ANC) ≥ 1.5×109/L; platelets ( PLT)≥100×109/L;

b) Biochemical examination: Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5×ULN (for liver metastasis of tumor, ≤5×ULN); serum total bilirubin (TBIL) ≤1.5×ULN (for patients with Gilbert syndrome) ,≤3×ULN); Serum creatinine (Cr)≤1.5×ULN, and creatinine clearance ≥60mL/min;

c) Blood coagulation function: activated partial thromboplastin time (APTT), international normalized ratio (INR), prothrombin time (PT)≤1.5×ULN;

d) Doppler ultrasound evaluation: left ventricular ejection fraction (LVEF) ≥50%.

7) Women of childbearing age should agree to use contraceptive measures (such as intrauterine device [IUD], contraceptives or condoms) during the study period and 6 months after the end of the study; serum or urine within 7 days before study entry The pregnancy test is negative, and the patient must be a non-lactating patient; the male should agree to the patient who must use contraceptive measures during the study period and within 6 months after the end of the study period;

8) Patients voluntarily joined the study, signed an informed consent form, and had good compliance.

3.2 Test drugs

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);

Calcium folinate (LV) injection: 10mL:0.1g and 5mL:50mg (based on folinic acid), (commercially available, manufactured by Jiangsu Hengrui Pharmaceutical Co., Ltd.);

5-Fluorouracil (5-FU) injection: 10mL: 0.25g (commercially available, produced by Shanghai Xudong Haipu Pharmaceutical Co., Ltd.).

3.3 Dosing schedule

Scheme A: Formula (I) compound capsule + oxaliplatin injection + leucovorin injection + 5-fluorouracil injection;

Scheme B: Formula (I) compound capsule + irinotecan hydrochloride injection + leucovorin injection + 5-fluorouracil injection.

The basis for the selection of the two options: select the option that the patient may potentially benefit from.

3.4 Order of administration and principles of administration

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.

3.5 Dosage

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.

3.6 Evaluation Criteria

The main efficacy indicators were evaluated according to the RECIST1.1 standard.

3.7 Efficacy evaluation

PFS (Progressive Free Survival): First administration to disease progression or death (whichever comes first).

ORR (Objective Response Rate): The proportion of patients whose disease has been evaluated as CR+PR.

DCR (Disease Control Rate): The proportion of patients whose tumors have shrunk or stabilized for a certain period of time, including CR (complete remission), PR (partial remission) and SD (stable disease) cases.

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.

3.8 Evaluation of treatment effect

Implementation of this clinical trial study, up to now, a total of 9 patients have been enrolled, of which 1 case has no efficacy evaluation. The efficacy evaluation result of the combined administration group of the remaining 8 patients is: the objective response rate (ORR) is 12.5%, Among them, 1 patient had partial remission (PR), 7 patients had stable disease (SD), disease control rate (DCR) was 100%, and median PFS was 3.7 months. As a result, it is found that the combined drug composition of the present application has clinical benefits.

Among them, the cases of patients with partial remission (PR) are as follows:

Patient, male, 40 years old, pathological diagnosis: advanced rectal cancer: infiltrating ulcer type, low-moderately differentiated adenocarcinoma, no cancer at the stump, lymph node metastasis (2/6), pTNMIIIB (T4aN1bM0) stage.

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. After that, 28 times of local rectal radiotherapy were performed. During the radiotherapy, capecitabine was orally administered 1500 mg early and 2000 mg late. Before enrollment, the lung CT showed small nodules in the left and right lower lobes. The larger ones had a long diameter of about 0.9cm. There were multiple small nodules in both lungs, some of which showed ground glass density; enhanced CT for the whole abdomen It shows a weakly strengthened nodule in the lower right anterior lobe of the liver, indicating the patient's disease progression.

The patient was enrolled in the clinical study of the combined pharmaceutical composition provided by this application, and the formula (I) compound + FOLFIRI regimen was combined for 6 cycles, specifically for each treatment cycle (28 days) given: formula (I) compound capsule , 120mg/day, once a day, fasting orally on d1-d28, irinotecan hydrochloride 335.4mg, d1 intravenous drip, leucovorin 745.4mg, d1 intravenous drip, 5-fluorouracil 5218.0mg, d1-d3 intravenous drip . Evaluation of the efficacy after 2 cycles indicates partial remission (PR) of the disease. The patient developed grade 3 diarrhea after medication, and was given irinotecan hydrochloride and 5-fluorouracil dose adjustment according to the study protocol. From the first day of the third cycle, the FOLFIRI protocol was reduced to: irinotecan hydrochloride 251.5 mg, intravenous infusion on d1 , Leucovorin calcium 745.4mg, d1 intravenous drip, 5-fluorouracil 3913.5mg, d1-d3 intravenous drip. After 6 cycles, the evaluation will maintain PR.

Claims (15)

A combined pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, hydrate or prodrug thereof, calcium leucovorin and 5-fluorouracil, and oxaliplatin or irinotecan or a pharmaceutically acceptable salt thereof , Hydrate or prodrug,

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, leucovorin and 5-fluorouracil, and also includes oxaliplatin or irinote Kang or one of its pharmaceutically acceptable salts, hydrates or prodrugs,

The combination pharmaceutical composition according to claim 1 or 2, wherein the combination pharmaceutical composition is packaged in the same kit, and the kit further comprises a compound of formula (I) or a pharmaceutically acceptable salt or hydrate thereof Or prodrugs, leucovorin, 5-fluorouracil and oxaliplatin, or irinotecan or its pharmaceutically acceptable salts, hydrates or prodrugs in combination for the treatment of colorectal cancer. The combination pharmaceutical composition according to any one of claims 1 to 3, wherein the combination pharmaceutical composition comprises a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt, hydrate or prodrug thereof, The pharmaceutical composition of calcium folinate, the pharmaceutical composition containing 5-fluorouracil, and the pharmaceutical composition containing oxaliplatin or the pharmaceutical composition containing irinotecan or its pharmaceutically acceptable salt, hydrate or prodrug A sort of. The combination pharmaceutical composition according to any one of claims 1 to 4, which contains 90mg-180mg of the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or prodrug thereof, or contains 90mg-120mg, 90mg-150mg , 120mg-150mg, 120mg-180mg or 150mg-180mg of formula (I) compound or its pharmaceutically acceptable salt, hydrate or prodrug, or containing 90mg, 120mg, 150mg or 180mg of formula (I) compound or its pharmaceutically acceptable Salt, hydrate or prodrug; and/or, wherein the pharmaceutical composition containing the compound of formula (I) or its pharmaceutically acceptable salt, hydrate or prodrug is in a single dose or multiple doses; and/or, wherein said The combined pharmaceutical composition contains a single dose of 30 mg or 60 mg of a compound of formula (I) or a pharmaceutically acceptable salt, hydrate or prodrug thereof; and/or, wherein the combined pharmaceutical composition in the formula (I) ) The content of the compound or its pharmaceutically acceptable salt, hydrate or prodrug is a daily dose, or a once-a-day dose. The combination pharmaceutical composition according to any one of claims 1 to 5, wherein, in terms of leucovorin, the combination pharmaceutical composition contains a pharmaceutical composition of calcium folinate at a concentration of 10 mg/mL; or based on the patient’s Body surface area, as leucovorin, containing 400 mg/m ² calcium leucovorin; and/or, wherein the combination pharmaceutical composition contains a pharmaceutical composition of 5-fluorouracil at a concentration of 25 mg/mL; or based on the patient’s Body surface area meter, containing 2800 mg/m ² of 5-fluorouracil; and/or, wherein the combination pharmaceutical composition contains a pharmaceutical composition containing oxaliplatin at a concentration of 5 mg/mL; or based on the patient’s body surface area, Containing 85 mg/m ² of oxaliplatin; and/or, wherein the combination pharmaceutical composition contains a pharmaceutical composition of irinotecan hydrochloride at a concentration of 20 mg/mL; or, based on the patient’s body surface area, containing 180 mg/ m ² of irinotecan hydrochloride. A method for treating colorectal cancer, which comprises administering to a patient a therapeutically effective amount of the combined pharmaceutical composition according to any one of claims 1-6. Use of the combined pharmaceutical composition according to any one of claims 1 to 6 in the preparation of a medicament for the treatment of colorectal cancer. Use of the combined pharmaceutical composition according to any one of claims 1-6 to treat colorectal cancer. The method according to claim 7, the use according to claim 8, or the use according to claim 9, wherein the order of administration of the combined pharmaceutical composition is as follows: (1) the compound of formula (I) or its Medicinal salt, hydrate or prodrug; (2) Oxaliplatin or irinotecan or its pharmaceutically acceptable salt, hydrate or prodrug; (3) leucovorin; (4) 5-fluorouracil; or give The order of medicine is as follows: (1) a compound of formula (I) or a pharmaceutically acceptable salt, hydrate or prodrug thereof; (2) simultaneous administration of oxaliplatin and calcium leucovorin; (3) 5-fluorouracil; or, wherein The order of administration of the combined pharmaceutical composition is as follows: (1) compound of formula (I); (2) oxaliplatin or irinotecan hydrochloride; (3) leucovorin injection; (4) 5-fluorouracil Injection; or the order of administration is as follows: (1) compound of formula (I); (2) simultaneous administration of oxaliplatin and calcium folinate; (3) 5-fluorouracil injection. The method according to claim 7, the use according to claim 8, or the use according to claim 9, wherein the compound of formula (I) in the combined pharmaceutical composition or a pharmaceutically acceptable salt or hydrate thereof Or the content of the prodrug is a daily dose, which is administered in the following manner: the compound of formula (I) or its pharmaceutically acceptable salt, hydrate or prodrug is administered once a day; and/or, the combination drug The calcium leucovorin in the composition 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; and/or, The 5-fluorouracil in the combination pharmaceutical composition is administered by the following method: administering 2800 mg/m ² of 5-fluorouracil to the patient based on the patient's body surface area at an interval of 14 days; and/or, the combination The oxaliplatin in the pharmaceutical composition is administered in the following manner: administering 85 mg/m ² of oxaliplatin to the patient based on the patient's body surface area at an interval of 14 days; and/or, the combination Irinotecan or its pharmaceutically acceptable salt, hydrate or prodrug in the pharmaceutical composition is administered by the following method: administering 180 mg/m ² of irinotecan or its pharmaceutically acceptable salt based on the patient's body surface area , Hydrate or prodrug, the dosing interval is 14 days; or, the pharmaceutically acceptable salt of irinotecan in the combination pharmaceutical composition is irinotecan hydrochloride and is administered in the following manner: based on the patient's body surface area , Give the patient 180mg/m ² of irinotecan hydrochloride at an interval of 14 days. The method according to claim 7, the use according to claim 8, or the use according to claim 9, wherein the compound (I) in the combined pharmaceutical composition or its pharmaceutically acceptable salt, hydrate or Prodrugs are administered in the form of oral administration, 5-fluorouracil is administered by pump-controlled infusion, and calcium leucovorin, oxaliplatin or irinotecan or its pharmaceutically acceptable salts, hydrates or prodrugs are administered by intravenous drip Way of administration. The method or use according to any one of claims 7-12, wherein 28 days is a treatment cycle. The method or use according to any one of claims 7-13, wherein the colorectal cancer is selected from advanced colorectal cancer; or the colorectal cancer is selected from advanced metastatic colorectal cancer. The method according to any one of claims 7 and 10-14, wherein the patient is selected from patients who have only received a first-line treatment plan for metastatic disease in the past and the treatment has failed; or the patient is selected from the past Patients who have only received fluoropyrimidines and oxaliplatin or irinotecan with or without bevacizumab/cetuximab treatment and the treatment has failed.