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WO2022199373A1 - Composé de quinazoline et utilisation d'une composition pharmaceutique - Google Patents

Composé de quinazoline et utilisation d'une composition pharmaceutique Download PDF

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Publication number
WO2022199373A1
WO2022199373A1 PCT/CN2022/079678 CN2022079678W WO2022199373A1 WO 2022199373 A1 WO2022199373 A1 WO 2022199373A1 CN 2022079678 W CN2022079678 W CN 2022079678W WO 2022199373 A1 WO2022199373 A1 WO 2022199373A1
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day
formula
pharmaceutical composition
medicine
quinazoline compound
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PCT/CN2022/079678
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English (en)
Chinese (zh)
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许祖盛
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上海璎黎药业有限公司
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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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

Definitions

  • the present invention relates to the application of a quinazoline compound and a pharmaceutical composition.
  • PI3K Phosphatidylinositol 3-kinase (phosphatidylinositol 3-kinase), which is involved in the regulation of various cellular functions such as cell proliferation, differentiation, apoptosis and glucose transport.
  • PI3K can be divided into class I, class II and class III kinases, and the most widely studied is class I PI3K that can be activated by cell surface receptors.
  • Class I PI3Ks in mammalian cells are further divided into class Ia and class Ib according to their structure and receptors, which transmit signals from tyrosine kinase-coupled receptors and G protein-coupled receptors, respectively.
  • Class Ia PI3Ks include PI3K ⁇ , PI3K ⁇ , PI3K ⁇ isoforms, and class Ib PI3Ks include PI3K ⁇ isoforms (Trends. Biochem. Sci., 1997, 22, 267-272).
  • Class Ia PI3K is a dimeric protein composed of a catalytic subunit p110 and a regulatory subunit p85, with dual activities of lipid kinase and protein kinase (Nat. Rev. Cancer 2002, 2, 489-501), and is considered to be related to cell proliferation It is associated with cancer development, immune diseases and diseases involving inflammation.
  • FL Follicular lymphoma
  • NHL non-Hodgkin lymphoma
  • PI3Kdelta phosphoinositide 3-kinase-delta
  • PI3Kdelta is an intracellular signal transduction component, mainly expressed in blood cell lineages, including cell-induced or mediated malignant hematology sick.
  • PI3K ⁇ inhibitor drugs have been successfully launched in the world, namely Idelalisib, Copanlisib and Duvelisb, all of which are used for the treatment of circulatory system cancers.
  • results of the study showed that the median age of the subjects was 62 years (range 33-84 years), 54% were male and 90% were Caucasian. At inclusion, 92% of patients had a baseline ECOG performance status of 0 or 1; median disease duration was 4-7 years; and median number of prior treatments was 4 (range 2-12).
  • the most common prior regimens were R-CHOP (49%) (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), BR (50%) (bendamustine, tuximab), and R-CVP (28%) (rituximab, cyclophosphamide, vincristine, prednisone). At baseline, 33% of patients had extranodal metastases and 26% had bone marrow metastases.
  • CI confidence interval
  • CR complete response
  • PR partial response
  • the drugs currently on the market still have problems such as low efficiency and large side effects, and it is very necessary to develop new drugs including PI3K ⁇ inhibitors for the treatment of follicular lymphoma.
  • the quinazoline compound whose chemical structure is shown in formula A is a PI3K ⁇ small molecule inhibitor, which has been disclosed in the CN104557872A patent (compound 10), Compared with other existing PI3K ⁇ inhibitors, the selectivity to PI3K ⁇ is improved and the activity to PI3K ⁇ is eliminated.
  • Chinese patent CN110950844A discloses two polymorphs of the quinazoline compound represented by formula A.
  • the technical problem to be solved by the present invention is that the existing medicines for the treatment of FL in the prior art are relatively single, and the efficiency is not high and the side effects are large. Therefore, the present invention provides a quinazoline compound and a pharmaceutical composition.
  • the quinazoline compound has good therapeutic effect on B-cell hematoma, especially on follicular lymphoma, with high efficacy and good safety, and is expected to be applied to B-cell hematoma, especially follicular lymphoma. Treatment of lymphoma.
  • substance X is quinazoline compound as shown in formula A, its pharmaceutically acceptable salt, its solvate or its pharmacy
  • the solvate of the above acceptable salt the pharmaceutical composition comprises the substance X and pharmaceutical excipients
  • the drug is a drug for the treatment of B-cell hematoma
  • the B-cell hematoma is a B-cell lymphoma
  • the B-cell lymphoma is a non-Hodgkin's lymphoma
  • the non-Hodgkin's lymphoma is a filter Follicular lymphoma
  • the follicular lymphoma is relapsed and/or refractory follicular lymphoma, eg, relapsed or refractory follicular lymphoma.
  • the drug is administered orally.
  • the Substance X is in a therapeutically effective amount.
  • the administration dose of the drug can be determined according to the body weight of the patient, and in terms of the content of the quinazoline compound shown in formula A, the administration dose of the drug is 0.33 mg/time. kg-3.33mg/kg, for example, 0.66mg/kg-2.3mg/kg, another example, 1mg/kg, 1.2mg/kg, 1.3mg/kg, 1.33mg/kg, 1.4mg/kg, 1.5mg /kg, 1.6 mg/kg, 1.7 mg/kg, 1.8 mg/kg, 1.9 mg/kg, 2.0 mg/kg, 2.1 mg/kg, 2.2 mg/kg or 2.3 mg/kg.
  • the administration dose of the drug is 20 mg-200 mg/day, for example, 20 mg/day, 30 mg/day, 40 mg/day , 50mg/day, 60mg/day, 70mg/day, 80mg/day, 90mg/day, 100mg/day, 110mg/day, 120mg/day, 130mg/day, 140mg/day, 150mg/day, 160mg/day, 170mg /day, 180 mg/day, 190 mg/day or 200 mg/day, for another example, 80 mg/day.
  • the frequency of administration of the drug is 1-5 times/day, eg, 1 time/day, 2 times/day, 3 times/day, 4 times/day, or 5 times/day, and then For example, 1 time/day.
  • the drug is administered for a course of 14-84 days/course, eg, 14 days/course, 28 days/course, 42 days/course, 56 days/course, 70 days/course, or 84 days/course Day/course, for another example, is 28 days/course.
  • the drug is administered for a total of 1-20 courses of treatment, preferably 10-20 courses of treatment, for example, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 courses, another example, 12 courses.
  • the medicine is a tablet or a capsule, preferably a tablet.
  • the content of the quinazoline compound represented by formula A is selected from 5mg-500mg, preferably 10mg-200mg, most preferably 20mg-100mg, for example 20mg, 30mg, 40mg, 50mg, 60mg, 70mg, 80mg, 90mg or 100mg.
  • the content of the quinazoline compound represented by formula A is 5 mg-500 mg/tablet.
  • the drug is administered to a patient with relapsed or refractory follicular lymphoma who has received one or more systemic therapy regimens, eg, relapsed after one or more systemic therapy regimens
  • the drug is administered to patients with relapsed or refractory follicular lymphoma who have received two or more systemic treatment regimens, for example, received two or more systemic treatment regimens.
  • the drug is administered to a patient who has progressed after receiving second-line or more systemic systemic therapy in the previous treatment regimen, and the second-line or more systemic therapy has received CD20 monoclonal antibody and at least one In patients with progression after treatment with alkylating agents, including but not limited to bendamustine, cyclophosphamide, ifosfamide, chlorphentermine, melphalan, busulfan, and nitroso one or more.
  • alkylating agents including but not limited to bendamustine, cyclophosphamide, ifosfamide, chlorphentermine, melphalan, busulfan, and nitroso one or more.
  • the drug administered in the previous treatment regimen is R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), BR (bendamustine) , rituximab), and R-CVP (rituximab, cyclophosphamide, vincristine, prednisone).
  • the medicament is administered to a human.
  • the present invention also provides a method of treating a disease comprising administering to a patient (eg, a human) a therapeutically effective amount of Substance X or a pharmaceutical composition;
  • the disease is B-cell hematoma;
  • the substance X is a quinazoline compound represented by formula A, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof;
  • the pharmaceutical composition includes the substance X and pharmaceutical excipients.
  • the B-cell hematoma is a B-cell lymphoma
  • the B-cell lymphoma is a non-Hodgkin's lymphoma
  • the non-Hodgkin's lymphoma is a filter Follicular lymphoma
  • the follicular lymphoma is relapsed and/or refractory follicular lymphoma, eg, relapsed or refractory follicular lymphoma.
  • the mode of administration is oral.
  • the administered dose can be determined according to the body weight of the patient, and based on the content of the quinazoline compound shown in formula A, the administered dose is 0.33 mg/kg-3.33 mg once /kg, for example, 0.66mg/kg-2.3mg/kg, another example, 1mg/kg, 1.2mg/kg, 1.3mg/kg, 1.33mg/kg, 1.4mg/kg, 1.5mg/kg, 1.6mg/kg mg/kg, 1.7 mg/kg, 1.8 mg/kg, 1.9 mg/kg, 2.0 mg/kg, 2.1 mg/kg, 2.2 mg/kg or 2.3 mg/kg.
  • the administered dose is 20-200 mg/day, for example, 20 mg/day, 30 mg/day, 40 mg/day, 50mg/day, 60mg/day, 70mg/day, 80mg/day, 90mg/day, 100mg/day, 110mg/day, 120mg/day, 130mg/day, 140mg/day, 150mg/day, 160mg/day, 170mg/day day, 180 mg/day, 190 mg/day or 200 mg/day, for another example, 80 mg/day.
  • the frequency of administration is 1-5 times/day, eg, 1 time/day, 2 times/day, 3 times/day, 4 times/day, or 5 times/day, for example, 1 time/day.
  • the course of administration is 14-84 days/course, eg, 14 days/course, 28 days/course, 42 days/course, 56 days/course, 70 days/course or 84 days/course
  • the course of treatment for another example, is 28 days/course of treatment.
  • the patient receives a total of 1-20 courses of treatment, preferably 10-20 courses of treatment, eg, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 Or 20 courses of treatment, for another example, 12 courses of treatment.
  • the Substance X or pharmaceutical composition is a tablet.
  • the strength of Substance X or the pharmaceutical composition is 10-120 mg/tablet, for example, 20-100 mg/tablet, another example, 20 mg/tablet, 30 mg/tablet, 40 mg/tablet, 50 mg/tablet, 60mg/tablet, 70mg/tablet, 80mg/tablet, 90mg/tablet or 100mg/tablet, another example is 20mg/tablet, 80mg/tablet or 100mg/tablet.
  • the patient is a patient with relapsed or refractory follicular lymphoma who has received one or more regimens of systemic therapy, eg, relapsed follicular lymphoma who has received one or more regimens of systemic therapy
  • one or more regimens of systemic therapy eg, relapsed follicular lymphoma who has received one or more regimens of systemic therapy
  • a patient with lymphoma preferably, the patient is a patient with relapsed or refractory follicular lymphoma who has received two or more systemic treatment regimens, for example, has received two or more systemic treatment regimens. Treatment options for patients with relapsed follicular lymphoma.
  • the patient is a patient who has progressed after receiving second-line or above systemic therapy, preferably, the patient is a patient who has progressed after receiving CD20 monoclonal antibody and at least one alkylating agent,
  • the alkylating agent includes, but is not limited to, one or more of bendamustine, cyclophosphamide, ifosfamide, chlorphentermine, melphalan, busulfan, and nitroso.
  • the patient's previous treatment regimen is R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), BR (bendamustine, tuximab), and R-CVP (rituximab, cyclophosphamide, vincristine, prednisone).
  • the pharmaceutical excipients are selected from conventional diluents, excipients, fillers, binders, wetting agents, disintegrants, absorption enhancers, surfactants, and adsorption carriers in the pharmaceutical field , one or more of lubricants.
  • the invention provides the application of a substance X in the preparation of a B-cell hematoma inhibitor
  • the substance X is a quinazoline compound represented by formula A, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof:
  • the B-cell hematoma is a B-cell lymphoma
  • the B-cell lymphoma is a non-Hodgkin's lymphoma
  • the non-Hodgkin's lymphoma is a filter Follicular lymphoma
  • the follicular lymphoma is relapsed and/or refractory follicular lymphoma, eg, relapsed or refractory follicular lymphoma.
  • the inhibitor in mammalian organisms; it can also be used in vitro, mainly for experimental purposes, such as: providing comparison as a standard sample or a control sample, or making a kit according to conventional methods in the art .
  • the substance X is the only active ingredient.
  • the substance X is in a therapeutically effective amount.
  • the quinazoline compound represented by formula A is the quinazoline compound represented by formula A in free base form, it should be understood that "free base form” is Refers to the case where the quinazoline compound represented by formula A is not in the form of a salt.
  • the quinazoline compound represented by formula A is preferably the crystal form I of the quinazoline compound represented by formula A, wherein the quinazoline compound represented by formula A
  • the crystal form I of the compound can be defined in any way described in Chinese Patent Publication No. CN110950844A.
  • the pharmaceutical excipients include fillers selected from one or more of microcrystalline cellulose, mannitol and corn starch.
  • the filler is preferably selected from one or two of microcrystalline cellulose, mannitol and corn starch.
  • the filler is microcrystalline cellulose.
  • the filler is a mixture of microcrystalline cellulose and mannitol.
  • the filler is a mixture of microcrystalline cellulose and cornstarch.
  • the filler is a mixture of microcrystalline cellulose and mannitol and cornstarch.
  • the filler is 10%-90% by weight of the total weight of the pharmaceutical composition, preferably 30%-70%, most preferably 45%-55%.
  • the filler is a mixture of microcrystalline cellulose and mannitol, which is 10%-90% by weight of the total weight of the pharmaceutical composition, preferably 30%-70% %, most preferably 45%-55%.
  • the filler is a mixture of microcrystalline cellulose and mannitol, and the mass ratio of the microcrystalline cellulose and the mannitol is selected from 10:1-1: 10.
  • the filler is a mixture of microcrystalline cellulose and mannitol, and the mass ratio of the microcrystalline cellulose and the mannitol is preferably 6:1-2: 1, most preferably 4:1-3:1.
  • the pharmaceutical excipient further includes a disintegrant.
  • the disintegrant is crospovidone and/or croscarmellose sodium.
  • the disintegrant is crospovidone.
  • the disintegrant is croscarmellose sodium.
  • the disintegrant is not low-substituted hydroxypropyl cellulose.
  • the disintegrant is 1%-20% by weight of the total weight of the pharmaceutical composition, preferably 3%-15%, most preferably 4%-8%.
  • the disintegrant is croscarmellose sodium, which is 1%-20% by weight of the total weight of the pharmaceutical composition.
  • the disintegrant is croscarmellose sodium, which is 3%-15% by weight of the total weight of the pharmaceutical composition, most preferably 4%- 8%.
  • the pharmaceutical excipients further include lubricants.
  • the lubricant is selected from calcium stearate, glycerol monostearate, glyceryl behenate, magnesium stearate, palmitic acid, poloxamer, polyethylene glycol, potassium benzoate , one or more of sodium benzoate, sodium lauryl sulfate, sodium stearate, sodium stearyl fumarate, stearic acid, talc, micropowder silica gel and zinc stearate.
  • the lubricant is magnesium stearate.
  • the lubricant is 0.1%-5.0% by weight of the total weight of the pharmaceutical composition, preferably 0.3%-2.0%, most preferably 0.8%-1.4%.
  • the lubricant is magnesium stearate, which is 0.1%-5.0% by weight of the total weight of the pharmaceutical composition.
  • the lubricant is magnesium stearate, which is 0.3%-2.0% by weight of the total weight of the pharmaceutical composition, most preferably 0.8%-1.4%.
  • the pharmaceutical composition comprises the following components by weight:
  • the filler is selected from one, two or more of microcrystalline cellulose, mannitol and corn starch, preferably a mixture of microcrystalline cellulose and mannitol, most preferably A mixture of microcrystalline cellulose and mannitol, and its mass ratio is 4:1-3:1;
  • disintegrant which is crospovidone and/or croscarmellose sodium, most preferably croscarmellose sodium;
  • the lubricant is magnesium stearate.
  • the quinazoline compound represented by formula A is 40% by weight of the total weight of the pharmaceutical composition.
  • the filler is 52.8% by weight of the total weight of the pharmaceutical composition.
  • the disintegrant is 6% by weight of the total weight of the pharmaceutical composition.
  • the lubricant is 1.2% by weight of the total weight of the pharmaceutical composition.
  • the pharmaceutical composition comprises the following components by weight:
  • the pharmaceutical composition is composed of the above components.
  • the pharmaceutical composition comprises the following components by weight:
  • the pharmaceutical composition is composed of the above components.
  • the pharmaceutical composition comprises the following components by weight:
  • the pharmaceutical composition is composed of the above components.
  • the pharmaceutical composition comprises the following components by weight:
  • the pharmaceutical composition is composed of the above components.
  • the pharmaceutical composition comprises the following components by weight:
  • the pharmaceutical composition is composed of the above components.
  • the pharmaceutical composition comprises the following components by weight:
  • the pharmaceutical composition is composed of the above components.
  • the pharmaceutical composition comprises the following components by weight:
  • the pharmaceutical composition may be a solid preparation, preferably a solid oral preparation.
  • the pharmaceutical composition may be a tablet or a capsule, preferably a tablet.
  • the tablet is a coated tablet.
  • the coated tablet is a film-coated tablet.
  • the coating agent used for the film-coated tablet is based on hydroxypropyl methylcellulose as the main film-forming agent Film coating premixes for polymers.
  • the coating agent of the film-coated tablet in the film-coated tablet, can be purchased from Colorcon, for example, under the trade name film coating premix.
  • the weight gain of the coating agent is selected from 2%-5%, preferably 2.5%-4.5%, most preferably 3.5%.
  • the pharmaceutical composition comprises two parts, a tablet core and a coating, and each contains the following components by weight:
  • the filler is selected from one, two or more of microcrystalline cellulose, mannitol and corn starch, preferably a mixture of microcrystalline cellulose and mannitol, microcrystalline
  • the mass ratio of cellulose and mannitol is preferably 4:1-3:1;
  • disintegrant which is selected from at least one of crospovidone and croscarmellose sodium, most preferably croscarmellose sodium;
  • the lubricant is magnesium stearate
  • the weight gain of the coating agent is selected from 2%-5%, preferably 2.5%-4.5%, most preferably 3.5%, compared to the tablet core weight.
  • the pharmaceutical composition comprises two parts, a tablet core and a coating, and each contains the following components by weight:
  • the filler is a mixture of microcrystalline cellulose and mannitol, and the mass ratio of microcrystalline cellulose and mannitol is 4:1-3:1;
  • the lubricant is magnesium stearate
  • the weight gain of the coating agent is 3.5% compared to the core weight.
  • described pharmaceutical composition it comprises tablet core and coating two parts, and each contains the following components by weight:
  • the weight gain of the film coating agent is 3.5% compared to the tablet core weight.
  • the pharmaceutical composition is prepared by the following preparation method, and the preparation method is powder direct compression.
  • the preparation method of the pharmaceutical composition comprises the following steps:
  • the quinazoline compound, filler and disintegrating agent shown in formula A are respectively passed through 30 mesh sieves, and lubricant is passed through 60 mesh sieves;
  • the quinazoline compound as shown in formula A obtained according to step 1) is mixed with the filler in a mixer to obtain a premix 1;
  • premix 1 and disintegrant in a mixer to obtain premix 2; use a granulator to sieve premix 2 to obtain premix 3;
  • step 3 compressing the total mixture material obtained according to step 2) to obtain tablet cores;
  • fillers used in the present invention, also called “diluent”, refers to a class of adjuvants used to increase the volume and weight of the pharmaceutical composition product dosage form in the scientific context.
  • fillers may be, for example, calcium carbonate, calcium phosphate, calcium hydrogen phosphate, calcium sulfate, cellulose acetate, ethyl cellulose, fructose, lactose, lactitol, maltose, maltodextrin, maltitol, mannitol, Microcrystalline cellulose, polydextrose, polyethylene glycol, sodium bicarbonate, sodium carbonate, sodium chloride, sorbitol, cornstarch, dextrin, sucrose, trehalose and xylitol.
  • the "disintegrant" used in the present invention refers to a class of excipients used in the scientific context to facilitate the breaking of the dosage form of the pharmaceutical composition product into smaller fragments in an aqueous environment.
  • the disintegrant may be, for example: alginic acid, calcium alginate, calcium carboxymethyl cellulose, chitosan, colloidal silicon dioxide, croscarmellose sodium, crospovidone, carboxymethyl cellulose Sodium starch base, low-substituted hydroxypropyl cellulose, hypromellose, glycine, guar gum, hydroxypropyl cellulose, magnesium aluminum silicate, methyl cellulose, povidone, sodium alginate, carboxymethyl Sodium cellulose, sodium starch glycolate and starch.
  • the "lubricant" used in the present invention refers to a class of adjuvants used to improve the processing of pharmaceutical composition product dosage forms under the scientific background.
  • the lubricant can be, for example, calcium stearate, glyceryl monostearate, glyceryl behenate, magnesium stearate, palmitic acid, poloxamer, polyethylene glycol, potassium benzoate, benzene Sodium formate, sodium lauryl sulfate, sodium stearate, sodium stearyl fumarate, stearic acid, talc, micronized silica gel and zinc stearate.
  • the "coating agent” or “film coating premix” used in the present invention refers to a class of adjuvants used to improve the appearance of the dosage form of the pharmaceutical composition product under the scientific background.
  • the coating agent may be, for example: sucrose, lactose, hydroxypropyl methylcellulose, hydroxypropylethylcellulose, cellulose acetate phthalate, polyvinyl alcohol, polyvinyl acetate phthalate , hypromellose phthalate and acrylic resin.
  • salts refers to salts of compounds of the present invention prepared with relatively non-toxic, pharmaceutically acceptable acids or bases.
  • base additions can be obtained by contacting neutral forms of such compounds with a sufficient amount of a pharmaceutically acceptable base in neat solution or in a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include, but are not limited to, lithium, sodium, potassium, calcium, aluminum, magnesium, zinc, bismuth, ammonium, diethanolamine.
  • acids additions can be obtained by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable acid in neat solution or in a suitable inert solvent.
  • a salt is not limited to, lithium, sodium, potassium, calcium, aluminum, magnesium, zinc, bismuth, ammonium, diethanolamine.
  • the pharmaceutically acceptable acids include inorganic acids, including but not limited to: hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, phosphoric acid, phosphorous acid, sulfuric acid, and the like.
  • Described pharmaceutically acceptable acid includes organic acid, described organic acid includes but is not limited to: acetic acid, propionic acid, oxalic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid , fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, salicylic acid, tartaric acid, methanesulfonic acid, isonicotinic acid, acid citric acid, oleic acid , tannic acid, pantothenic acid, hydrogen tartrate, ascorbic acid, gentisic acid, fumaric acid, gluc
  • solvate refers to a substance formed by combining a compound of the present invention with a stoichiometric or non-stoichiometric amount of a solvent.
  • Solvent molecules in solvates can exist in ordered or non-ordered arrangements.
  • the solvent includes, but is not limited to, water, methanol, ethanol, and the like.
  • “Pharmaceutically acceptable salt” and “solvate” in the term “solvate of a pharmaceutically acceptable salt”, as described above, refer to a compound of the present invention with a relatively non-toxic, pharmaceutically acceptable acid A substance prepared by combining with a stoichiometric or non-stoichiometric amount of a solvent.
  • therapeutically effective amount refers to an amount of a compound administered to a patient sufficient to be effective in treating a disease.
  • the therapeutically effective amount will vary depending on the compound, the type of disease, the severity of the disease, the age of the patient, etc., but can be adjusted as appropriate by those skilled in the art.
  • pharmaceutical excipients refers to the excipients and additives used in the production of pharmaceuticals and the formulation of prescriptions, which are all substances included in pharmaceutical preparations except active ingredients.
  • pharmaceutical excipients refers to the Pharmacopoeia of the People's Republic of China (2020 edition) or the Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009).
  • treatment refers to therapeutic therapy.
  • treatment refers to: (1) ameliorating one or more biological manifestations of the disease or disorder, (2) interfering with (a) one or more points in the biological cascade leading to or causing the disorder or (b) ) one or more biological manifestations of the disorder, (3) amelioration of one or more symptoms, effects or side effects associated with the disorder, or one or more symptoms, effects or side effects associated with the disorder or its treatment, or (4) slowing the progression of the disorder or one or more biological manifestations of the disorder.
  • progressive means that the disease is not relieved or cured after treatment, or even worsens.
  • patient refers to any animal, preferably a mammal, and most preferably a human, who has been or is about to undergo treatment.
  • mammal includes any mammal. Examples of mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc., with humans being the most preferred.
  • the reagents and raw materials used in the present invention are all commercially available.
  • the positive improvement effect of the present invention is that: the quinazoline compound of the present invention has good therapeutic effect on B-cell hematoma, especially on follicular lymphoma, with high effective rate and good safety. It is expected to be applied to the treatment of B-cell hematoma, especially follicular lymphoma.
  • Fig. 1 is the dissolution curve diagram of the pharmaceutical composition of the quinazoline compound represented by formula A provided in the second part of Examples 4 and 5 in 0.1 mol/L hydrochloric acid solution.
  • Figure 2 is a graph showing the dissolution profiles of the pharmaceutical compositions of the quinazoline compounds represented by formula A provided in the second part of Examples 4 and 5 in pH 6.8 phosphate buffer containing 0.2% SDS.
  • the quinazoline compound represented by formula A is prepared according to the preparation method of compound 10 described in patent CN104557872A, and recrystallized according to the method of example 8 in patent CN110950844A.
  • C max peak drug concentration
  • AUC last area under the concentration-time curve from 0 point to the time point corresponding to the last measurable concentration
  • F% bioavailability
  • the pharmacokinetic studies of the quinazoline compound represented by formula A in mice, rats and dogs show that the oral absorption is good within the effective dose range, and the oral bioavailability is 90%, 65% and 60%, respectively. %above.
  • the exposure of the quinazoline compound represented by formula A in rats and dogs increased to a certain extent, which was about 1.28-2.20 times of the first administration, indicating that the risk of serious drug accumulation was small.
  • the quinazoline compounds of formula A are moderately cleared in rats and relatively slowly in mice and dogs.
  • the quinazoline compound represented by formula A has a wide tissue distribution, and the exposure amount of the quinazoline compound represented by formula A in other tissues is higher than that in plasma except brain tissue.
  • Table 2 Pharmacokinetic results of ICR mice, SD rats, and Beagle dogs after a single oral gavage administration
  • the plasma protein binding rates of the quinazoline compounds represented by formula A in the five species are in descending order: cynomolgus monkey>human>CD1 mouse>SD rat>Beagle dog, among which cynomolgus monkey and Binding was similar in humans (85-90%), SD rats and beagle dogs (50-65%).
  • V ss Steady-state apparent volume of distribution (V ss , L /kg) were 4.22 (male mice), 4.55 (male rats), 5.18 (female rats), 4.70 (male dogs) and 4.08 (female dogs), which were 5.82 (male) of the total body fluid of each animal. mice), 6.80 (male rats), 7.75 (female rats), 7.79 (male dogs), and 6.76 (female dogs) times, suggesting that the quinazoline compound represented by formula A has a wider range in various animals. tissue distribution.
  • the quinazoline compound shown in formula A After gavage administration of 60 mg/kg to SD rats, the quinazoline compound shown in formula A is widely distributed in various tissues and organs, except for brain tissue, the quinazoline compound shown in formula A is in other tissues.
  • the exposures of serotonin were significantly higher than their exposures in plasma, which were about 2-22 times the latter.
  • the plasma and tissue drug concentrations were higher in male rats than in female rats at all time points.
  • the exposure of the quinazoline compound represented by formula A in various tissues of male rats is about 1.49-3.70 times that of female rats.
  • the half-life of the quinazoline compound represented by formula A is about 2.29-5.08 hr in various tissues of male rats, and the half-life in various tissues of female rats is about 2.25-4.45 hr (except brain tissue).
  • quinazoline compounds of formula A had the highest exposure in the stomach, followed by small intestine, liver, kidney, lung, spleen, large intestine, thymus, heart, testis, skeletal muscle, fat , plasma and brain.
  • the highest exposure to quinazoline compounds of formula A was in the small intestine, followed by stomach, liver, spleen, kidney, lung, large intestine, thymus, ovary, uterus, heart, skeletal muscle , fat, plasma and brain.
  • CYP3A4 is the main metabolic enzyme of the quinazoline compound represented by formula A, followed by CYP2C8.
  • the quinazoline compound shown in formula A showed a 20%-30% reduction in the CYP2C8 incubation system, the same phenomenon also occurred in the two incubation systems of -NADPH and + inhibitor, so it cannot be explained that the mother Drug metabolism is dependent on the recombinase CYP2C8.
  • the quinazoline compounds represented by formula A have no significant inhibitory effect on CYP 1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A4 in human liver microsomes (IC 50 >10 ⁇ M).
  • the quinazoline compound represented by formula A did not show an enhancement effect on enzyme activity or mRNA expression in terms of CYP1A2, CYP2B6 and CYP3A4 at three tested concentrations of 0.4, 4 and 40 ⁇ M.
  • the excretion amounts of quinazoline compound shown in formula A in male rat urine, feces and bile in 0-72hr are respectively: 20.1 ⁇ 6.48%, 24.5 ⁇ 11.1% and 1.68 ⁇ 0.890% of the dose; the excretion in female rat urine, feces and bile from 0-72 hr was 8.11 ⁇ 2.62%, 7.58% of the dose, respectively ⁇ 3.95% and 10.9 ⁇ 1.29%. Therefore, the total excretion rates of the quinazoline compound represented by formula A in the urine, feces and bile of male and female SD rats after oral administration were 46.3% and 26.6%, respectively.
  • the excretion amounts of the quinazoline compound shown in formula A in male dogs' urine and feces were 29.2 ⁇ 29.2 ⁇ of the administration amount, respectively. 13.5% and 19.5 ⁇ 16.2%, and their excretion in female dogs’ urine and feces were 41.4 ⁇ 12.4% and 9.21 ⁇ 7.08% of the administered dose, respectively, so the quinazole shown in formula A after oral administration
  • the total excretion rates of morpholino compounds in male and female beagle dogs were 48.7% and 50.6%, respectively.
  • the effect of quinazoline compounds of formula A on cell proliferation was tested in different tumor cells.
  • the results show that the quinazoline compound represented by formula A has obvious inhibitory activity on some hematological tumor cells.
  • the IC50 value in SU-DHL-6 cells was 0.2337 ⁇ M
  • the IC50 value in SU-DHL-5 cells was 1.7683 ⁇ M.
  • CB17SCID mice female, weighing 18-22 grams.
  • SU-DHL-6 cells were cultured in vitro in suspension under RPMI1640 medium with 10% heat-inactivated fetal bovine serum, 100 U/ml penicillin and 100 ⁇ g/ml streptomycin at 37°C and 5% CO 2 . Passaging twice a week. When cells are in exponential growth phase, cells are harvested for seeding.
  • Group administration was started when the average tumor volume reached 95.79 mm 3 .
  • Grouping method animals were weighed before administration, and tumor volume was measured. According to tumor volume random grouping (random grouping design), grouping and dosing schedule are shown in Table 3 below.
  • the antitumor efficacy of the compounds was evaluated by TGI (%). TGI (%) reflects tumor growth inhibition rate.
  • TGI (%) [1-(tumor volume at the end of treatment group administration-tumor volume at the beginning of treatment group administration)/(tumor volume at the end of solvent control group administration-solvent control group administration Tumor volume at the start of the drug)] ⁇ 100%.
  • the results show that by the 15th day of administration, the CAL-101 (that is, Idelalisib) 50mg/kg BID treatment group, the quinazoline compound shown in formula A 60mg/kg QD group, and the quinazoline compound shown in formula A
  • the TGI of the compound 120 mg/kg QD group and the quinazoline compound 240 mg/kg QD group shown in formula A were 42.67%, 71.89%, 81.57% and 86.98%, respectively.
  • results for both tumor volume and weight show quinazoline compound as shown in formula A 60mg/kg QD treatment, quinazoline compound as shown in formula A 120mg/kg QD treatment and quinazoline compound as shown in formula A 240mg/kg QD treatment significantly inhibited the growth of SU-DHL-6 human lymphoma cell subcutaneous xenografts.
  • the patient inclusion criteria were patients with relapsed or refractory B-cell hematological tumors confirmed by histology or cytology. A total of 25 patients were included, including 10 patients with follicular lymphoma.
  • the study is divided into two phases: dose escalation and dose expansion; each phase includes single-dose and multiple-dose studies.
  • Doses in the dose escalation phase included 20 mg/day, 40 mg/day, 80 mg/day, 140 mg/day, 200 mg/day. Except for the 20mg initial dose group, which was only enrolled in 1 group, 3-6 subjects were enrolled in each dose group, 3 subjects were enrolled in the 40 mg dose group, 3 subjects were enrolled in the 80 mg dose group, and 3 subjects were enrolled in the 140 mg dose group. 4 cases were enrolled in the 200 mg dose group; among them, 1 case of follicular lymphoma was enrolled at 40 mg and 200 mg respectively, and 2 cases were enrolled in the 80 mg group.
  • a dose-expansion trial was conducted at a dose of 80 mg/day, and a total of 11 patients were enrolled, including 6 patients with follicular lymphoma. A total of 10 patients with follicular lymphoma were enrolled.
  • the mode of administration is: oral administration, once daily during the continuous administration period, until disease progression or intolerable toxicity.
  • the quinazoline compound tablet represented by formula A is a powder-mixing direct-compression coated tablet, which is prepared according to the process described in the second part of preparation example 1 and preparation example 2.
  • the formulation was that of Example 5 in Part II, and 20 mg and 100 mg tablets were made.
  • the quinazoline compound tablet represented by formula A shows good antitumor activity in patients with relapsed or refractory B cell hematological malignancies, especially in follicular lymphoma.
  • the results are shown in the table below.
  • the best overall curative effect was CR in 5 cases, PR in 11 cases, SD in 2 cases, PD in 7 cases, and the overall optimal curative effect ORR ratio was 64% (16/25) ( 95% CI: 45.2-82.8%), the DCR ratio was 72% (18/25) (95% CI: 54.4-89.6%).
  • the ORR and DCR ratios of the best curative effect in follicular lymphoma were both 90.0% (9/10).
  • the efficacy evaluation criteria for B-cell lymphoma refer to "The efficacy evaluation criteria for lymphoma IRWG (excerpt), the revised criteria for the efficacy evaluation of malignant lymphomas”.
  • the patient inclusion criteria were patients with relapsed or refractory B-cell hematological tumors confirmed by histology or cytology. A total of 25 patients were included, including 10 patients with follicular lymphoma.
  • the study is divided into two phases: dose escalation and dose expansion; each phase includes single-dose and multiple-dose studies. Doses in the dose escalation phase included 20 mg/day, 40 mg/day, 80 mg/day, 140 mg/day, 200 mg/day. Except for the 20mg initial dose group, which was only enrolled in 1 group, 3-6 subjects were enrolled in each dose group, 3 subjects were enrolled in the 40 mg dose group, 3 subjects were enrolled in the 80 mg dose group, and 3 subjects were enrolled in the 140 mg dose group.
  • the quinazoline compounds represented by formula A are safe and tolerable in the dose range of 20-200 mg, and can alleviate and control the progression of relapsed or refractory B-cell malignancies, especially in follicular lymphoma. showed a very good effect.
  • the current FDA-approved PI3k ⁇ inhibitor Idelalisib has an objective response rate (ORR) of 39% in the treatment of refractory and relapsed follicular lymphoma, while the PI3K ⁇ , ⁇ inhibitor Duvelisib has an ORR of 42% in the treatment of refractory and relapsed follicular lymphoma
  • ORR objective response rate
  • the ORR of the quinazoline compound represented by formula A in the clinical phase I treatment of follicular lymphoma was 90.0% (9/10).
  • the quinazoline compound represented by formula A used in the following examples was prepared according to the preparation method of compound 10 described in patent CN104557872A, and recrystallized according to the method of example 8 in patent CN110950844A.
  • the dissolution methods were in accordance with the second method of the 2015 edition of "Chinese Pharmacopoeia", Part Four General Principles 0931, with 900 ml of pH 6.8 phosphate buffer solution containing 0.2% SDS at 37°C as the dissolution medium, The rotation speed was 75 rpm, sampling was performed at appropriate time intervals, the same volume of dissolution medium was replenished, filtered through a 0.45 ⁇ m filter membrane, and the content was determined by high-performance liquid phase to calculate the dissolution rate.
  • the quinazoline compound shown in formula A and each auxiliary material of the recipe quantity are weighed according to the designed prescription composition, and the quinazoline compound shown in formula A, filler and disintegrating agent are respectively passed through a 30-mesh sieve, lubricating pass through a 60-mesh sieve; mix the quinazoline compound shown in formula A and the filler in a mixer to obtain a premix 1; add the disintegrant to the premix 1, and use a mixer to mix uniformly, to obtain premix 2; use a granulator to sieve premix 2 to obtain premix 3; mix premix 3 and lubricant in a mixer to obtain a total mixture; use equipment equipped with 5mm, D-type round die or rotary tableting machine with 11*5.5mm upper punched Half wire bond die to tablet the blended material to form quinazoline containing 20 mg or 100 mg of formula A, respectively Compound tablets.
  • the film coating premix powder was added to the stirring purified water, and the stirring was continued for 45 minutes to prepare a coating liquid with a solid content of 10% (w/w) of the film coating premix.
  • the tablet cores manufactured by the process described in Preparation Example 1 above were coated to a coating weight gain ranging from 2% to 5% to form film-coated tablets containing 20 mg or 100 mg of the quinazoline compound represented by Formula A, respectively.
  • Embodiment 1 tablet core prescription F1-F8
  • the type and amount of disintegrant directly affects the disintegration of the tablet and the release rate of the active pharmaceutical ingredient.
  • the formulation compositions F1-F8 of crospovidone, croscarmellose sodium and low-substituted hydroxypropyl cellulose as disintegrants were screened respectively, and the dosage of disintegrants in the formulations was screened.
  • the pharmaceutical composition was manufactured by the process described in the above Preparation Example 1, and tablet cores containing 20 mg of the quinazoline compound represented by formula A were obtained respectively. Taking the smoothness of tableting and the dissolution rate during the tableting process as the investigation indicators, the formulation composition and results are shown in Table 5 below.
  • Embodiment 2 film-coated tablet prescription F9-F10
  • the amount of lubricant used will affect the smoothness of tableting and the dissolution rate of the active pharmaceutical ingredient.
  • the formulation compositions F9 and F10 of different dosages of magnesium stearate as lubricant were screened respectively.
  • the pharmaceutical composition was manufactured by the process described in the above Preparation Example 1, and tablet cores containing 20 mg of the quinazoline compound represented by formula A were obtained respectively.
  • Formulation of Film Coating Premixes A coating liquid with a solid content of 10% (w/w) was used to coat the tablet cores with a high-efficiency coating machine (BGB-5F, Zhejiang Xiaolun Pharmaceutical Machinery Co., Ltd.) to give the formulations F9 and F10, respectively.
  • Example 3A and 3B preparation of film-coated tablets (20 mg specification, 20,000 tablets)
  • the pharmaceutical composition was manufactured by the process described in the above-mentioned preparation example 1, and a tablet core containing 20 mg of the quinazoline compound represented by formula A was obtained.
  • Formulation of Film Coating Premixes
  • the coating liquid with a solid content of 10% (w/w) was used to coat the tablet cores with a coating weight gain range of 2%-5% by using a high-efficiency coating machine (BGB-5F, Zhejiang Xiaolun Pharmaceutical Machinery Co., Ltd.).
  • a powder direct compression process is used to manufacture pilot scale pharmaceutical compositions.
  • the quinazoline compound shown in formula A, the filler and the disintegrating agent were respectively passed through a 30-mesh sieve, and the lubricant was passed through a 60-mesh sieve; Mix evenly in the hopper mixer (HBD200, Nantong Better Pharmaceutical Machinery Co., Ltd.) to obtain premix 1; add the disintegrant to premix 1, and use the hopper mixer to mix evenly to obtain premix 2 ; Sieve premix 2 using a granulator (Comil U10, QUADRO, Canada) equipped with a 032R screen and square impeller to obtain premix 3; mix premix 3 and lubricant in a hopper mixer, The blend was obtained; the blend was tabletted using a rotary tablet press (P2020, Fette, Germany) equipped with a 5mm D-type circular die to form tablets containing 20 mg of the quinazoline compound of formula A core.
  • the pharmaceutical composition was manufactured by the method described in Preparation Example 1 above, and a tablet core containing 100 mg of the quinazoline compound represented by formula A was obtained.
  • Formulation of Film Coating Premixes A coating solution with a solid content of 10% (w/w) is used to coat the tablet core with a high-efficiency coating machine until the coating weight is increased by 3.5% to obtain a film containing 100 mg of the quinazoline compound represented by formula A Coated tablet.
  • the film-coated tablet batch formulations of Example 5 are shown in Table 10 below.
  • Test Example 1 Determination of key quality attributes of pharmaceutical compositions
  • the pharmaceutical composition manufactured in the above-mentioned embodiment 4 is carried out to measure the key quality attributes of the medicine, and the examination items include character, content uniformity, content, related substances, dissolution, and the examination results are shown in the following table 11.
  • Content uniformity Take 10 pieces of the test sample, and measure the relative content xi of each single dose with the labeled amount of 100 according to the high-performance liquid chromatography method under the content determination conditions. According to the content uniformity inspection method (2015 edition of "Chinese Pharmacopoeia” four general chapters 0941), calculate A+2.2S.
  • Dissolution According to the dissolution test method (2015 edition of "Chinese Pharmacopoeia” four general rules 0931 second method), take 900ml of pH6.8 phosphate buffer containing 0.2% SDS as the dissolution medium, the speed is 75 rpm, take 6 Take 1 tablet of the test sample, and put 1 tablet in each dissolution cup. After 30 minutes, take 10 ml of the solution, filter it with a 0.45 ⁇ m filter membrane, measure the content by high-performance liquid phase, and calculate the dissolution rate of the quinazoline compound shown in formula A.
  • Dissolution profile measurements were performed on the pharmaceutical compositions prepared in Examples 4 and 5 above, respectively.
  • the rotation speed is 75 rpm, with 0.1mol/L hydrochloric acid solution (9ml hydrochloric acid, add water to make 1000ml) or pH6 containing 0.2% SDS .8 900ml of phosphate buffer is the dissolution medium, take 6 pieces of the test sample from the film-coated tablets manufactured in each example, and put 1 piece in each dissolution cup, take samples at appropriate time intervals, and rehydrate with the same volume of dissolution medium , filtered through a 0.45 ⁇ m filter membrane, and the cumulative dissolution rate of the quinazoline compound shown in formula A was calculated by high-performance liquid phase determination.
  • the measurement results are shown in Table 12 below and accompanying drawings 1-2.
  • the pharmaceutical composition manufactured in Example 4 was exposed and placed under the influence factors of high temperature (60°C), high humidity (25 ⁇ 2°C, RH92.5%), and light (4500 ⁇ 500Lux) for 30 days.
  • high temperature 60°C
  • high humidity 25 ⁇ 2°C, RH92.5%
  • light 4500 ⁇ 500Lux
  • the test method in 1 assesses the stability of the pharmaceutical composition, and the assessment indicators include properties, related substances, dissolution rate and content. Specific results are shown in Tables 13-15 below.
  • Tables 13-15 show that the pharmaceutical composition of the quinazoline compound represented by the formula A provided by the present invention is measured after being exposed and placed for 5 days, 10 days and 30 days under the conditions of high temperature, high humidity and light influence factors, respectively. , there was no significant change in the evaluation indicators of the pharmaceutical composition compared with those before the influence factor test treatment. When placed under high humidity conditions for 30 days, the pharmaceutical composition has no obvious hygroscopic weight gain.

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Abstract

Un composé de quinazoline et l'utilisation d'une composition pharmaceutique sont divulgués. La substance X de la présente invention est le composé de quinazoline, tel que représenté par la formule A ; un sel pharmaceutiquement acceptable de celui-ci ; et un solvate de celui-ci, ou un solvate du sel pharmaceutiquement acceptable de celui-ci. La composition pharmaceutique de la présente invention comprend la substance X et un excipient pharmaceutique. La substance X ou la composition pharmaceutique fournie dans la présente invention a un bon effet de traitement sur les néoplasmes hématologiques à lymphocytes B, et en particulier a un bon effet de traitement sur le lymphome folliculaire, et a une efficacité élevée et un bon degré de sécurité.
PCT/CN2022/079678 2021-03-26 2022-03-08 Composé de quinazoline et utilisation d'une composition pharmaceutique WO2022199373A1 (fr)

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