WO2022228218A1 - Application of quinazoline compound and pharmaceutical composition - Google Patents

Application of quinazoline compound and pharmaceutical composition Download PDF

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Publication number
WO2022228218A1
WO2022228218A1 PCT/CN2022/087761 CN2022087761W WO2022228218A1 WO 2022228218 A1 WO2022228218 A1 WO 2022228218A1 CN 2022087761 W CN2022087761 W CN 2022087761W WO 2022228218 A1 WO2022228218 A1 WO 2022228218A1
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Prior art keywords
day
pharmaceutical composition
cell lymphoma
weight
formula
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PCT/CN2022/087761
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French (fr)
Chinese (zh)
Inventor
许祖盛
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上海璎黎药业有限公司
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Publication of WO2022228218A1 publication Critical patent/WO2022228218A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61K47/30—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
    • A61K9/2022—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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • 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
    • A61K9/2806—Coating materials
    • A61K9/282—Organic compounds, e.g. fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
    • C07D239/84—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention relates to the application of a quinazoline compound and a pharmaceutical composition.
  • Peripheral T-cell lymphoma is a group of highly heterogeneous malignant proliferative diseases derived from mature T cells, accounting for about 25% to 30% of non-Hodgkin lymphomas in China, with strong invasiveness and poor prognosis.
  • peripheral T-cell lymphoma there is no standard first-line treatment regimen for peripheral T-cell lymphoma. Most of them choose chemotherapy regimens containing anthracyclines and/or etoposide, including CHOP, CHOPE, etc.
  • the pathological subtype is less effective in treatment, with a 5-year survival rate of only 30%.
  • NK/T cell lymphoma is a malignant tumor of the lymphatic system originating from mature NK/T cells. Infection is closely related, and has the characteristics of strong invasiveness, insensitivity to chemotherapy, and poor prognosis. NK/T-cell lymphomas can occur in all age groups, but are mainly seen in adults. NK/T-cell lymphoma is a kind of T-cell lymphoma with a low incidence in Western countries, but is common in China, accounting for about 30.1% of T-cell non-Hodgkin lymphoma (T-NHL), and the median survival time is about 12. -38 months. At present, there is no standard chemotherapy regimen for NK/T cell lymphoma, and it is recommended to participate in clinical research.
  • T-NHL T-cell non-Hodgkin lymphoma
  • 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 associated with cancer.
  • PI3K ⁇ inhibitor drugs have been successfully launched in the world, such as Idelalisib, Copanlisib and Duvelisb, all of which are used to treat circulatory system cancers. However, it has not been approved for use in peripheral T-cell lymphoma indications.
  • 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), 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 there is no standard first-line treatment scheme for the treatment of peripheral T-cell lymphoma and NK/T-cell lymphoma in the prior art, and the existing chemotherapy schemes have defects such as low effective rate and large side effects.
  • the application of a quinazoline compound and a pharmaceutical composition is provided.
  • the quinazoline compound or pharmaceutical composition of the present invention has good therapeutic effect on peripheral T-cell lymphoma and NK/T-cell lymphoma, high efficiency and good safety, and is expected to be applied to peripheral T-cell lymphoma and NK/T-cell lymphoma Treatment of lymphoma.
  • the present invention provides the use of a substance X or a pharmaceutical composition in the preparation of a medicine, wherein the substance X is a quinazoline compound represented by formula A, a pharmaceutically acceptable salt thereof, a solvate thereof or a pharmaceutical thereof
  • the pharmaceutical composition includes the substance X and pharmaceutical excipients
  • the drug is a drug for the treatment of peripheral T-cell lymphoma and NK/T-cell lymphoma;
  • the peripheral T-cell lymphoma is relapsed and/or refractory peripheral T-cell lymphoma, eg, relapsed or refractory peripheral T-cell lymphoma.
  • the NK/T cell lymphoma is relapsed and/or refractory NK/T cell lymphoma, eg, relapsed or refractory NK/T cell lymphoma.
  • the peripheral T-cell lymphoma is peripheral T-cell lymphoma unspecified, angioimmunoblastic T-cell lymphoma, ALK-positive anaplastic large cell lymphoma, ALK-negative anaplastic large cell lymphoma
  • lymphoma and monomorphic epithelial T-cell lymphoma eg, angioimmunoblastic T-cell lymphoma.
  • the NK/T cell lymphoma is an extranodal NK/T cell 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 based on the content of the quinazoline compound represented by formula A, the administration dose of the drug is 0.33 mg/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/day, 2 times/day, 3 times/day, 4 times/day, or 5 times/day, 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
  • the course of treatment 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 of treatment, for another example, 12 courses of treatment.
  • the medicament is a tablet or capsule, eg, a tablet.
  • the content of the quinazoline compound represented by formula A is 5mg-500mg, preferably 10mg-200mg, most preferably 20mg, 100mg, such as 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.
  • the drug is administered in histologically confirmed relapsed and/or refractory peripheral T-cell lymphocytes that have failed or are intolerable to at least one systemic systemic therapy and/or currently have no effective standard therapy.
  • tumor PTCL
  • NKTCL NK/T cell lymphoma
  • 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 thereof;
  • the disease is peripheral T-cell lymphoma and NK/T-cell lymphoma;
  • the substance X is a quinazoline compound represented by formula A, a pharmaceutically acceptable salt thereof, a solvate thereof or a pharmaceutically acceptable compound thereof.
  • the pharmaceutical composition comprising the substance X and a pharmaceutical excipient;
  • the peripheral T-cell lymphoma is relapsed and/or refractory peripheral T-cell lymphoma, eg, relapsed or refractory peripheral T-cell lymphoma.
  • the NK/T cell lymphoma is relapsed and/or refractory NK/T cell lymphoma, eg, relapsed or refractory NK/T cell lymphoma.
  • the peripheral T-cell lymphoma is peripheral T-cell lymphoma unspecified, angioimmunoblastic T-cell lymphoma, ALK-positive anaplastic large cell lymphoma, ALK-negative anaplastic large cell lymphoma
  • lymphoma or monomorphic epithelial T-cell lymphoma eg, angioimmunoblastic T-cell lymphoma.
  • the NK/T cell lymphoma is an extranodal NK/T cell 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 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 dose administered is 20-200 mg/day, eg, 20 mg/day, 30 mg/day, 40 mg/day, 50 mg, based on the content of the quinazoline compound of formula A /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 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 times/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 , for another example, 28 days/course.
  • 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, another example, 12 courses of treatment.
  • the substance X or pharmaceutical composition is a tablet or capsule, eg, a tablet.
  • the specification of the substance X or the pharmaceutical composition is 10-120mg/tablet, for example, 20-100mg/tablet, another example, 20mg/tablet, 30mg/tablet, 40mg/tablet, 50mg/tablet 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 histologically confirmed relapsed and/or refractory peripheral T-cell lymphoma who has failed or cannot tolerate at least one systemic systemic therapy and/or currently has no effective standard therapy (PTCL) and/or NK/T cell lymphoma (NKTCL).
  • PTCL standard therapy
  • NKTCL NK/T cell lymphoma
  • the quinazoline compound represented by formula A is the free base form of
  • free base form 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 the crystalline form I of the quinazoline compound represented by formula A, wherein the quinazoline compound represented by formula A
  • the crystal form I of can be defined in any way described in Chinese Patent Publication No. CN110950844A.
  • the pharmaceutical excipient includes a filler, and the filler is one, two or more 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, mannitol and corn starch.
  • 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, 10%-90% by weight, preferably 30%-70% by weight of the total weight of the pharmaceutical composition, 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 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 6:1-2:1, 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 hydroxypropylcellulose.
  • 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%, preferably 4%-8% by weight of the total weight of the pharmaceutical composition.
  • the pharmaceutical excipient further includes a lubricant.
  • the lubricant is calcium stearate, glycerol monostearate, glyceryl behenate, magnesium stearate, palmitic acid, poloxamer, polyethylene glycol, One or more of potassium benzoate, 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, 0.1%-5.0% by weight of the total weight of the pharmaceutical composition.
  • the lubricant is magnesium stearate, 0.3%-2.0% by weight, preferably 0.8%-1.4% by weight of the total weight of the pharmaceutical composition.
  • the pharmaceutical composition comprises the following components by weight:
  • 45%-55% filler which is one, two or more of microcrystalline cellulose, mannitol and cornstarch, preferably a mixture of microcrystalline cellulose and mannitol, most preferably microcrystalline cellulose
  • the mixture of crystalline cellulose and mannitol, and its mass ratio is 4:1-3:1;
  • disintegrant which is crospovidone and/or croscarmellose sodium, 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 medicament is 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 for the film-coated tablet is based on hydroxypropyl methylcellulose as the main film-forming polymer film coating premix.
  • 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 2%-5%, preferably 2.5%-4.5%, most preferably 3.5%, compared to the weight of the tablet core .
  • the pharmaceutical composition comprises two parts, a core tablet and a coating, and each contains the following components by weight:
  • the weight gain of the coating agent is 3.5% compared to the core weight.
  • 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 acid includes 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.
  • the pharmaceutically acceptable acid includes organic acids including, but 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, gluconic acid, sugar acid, formic acid,
  • the compounds of the present invention When the compounds of the present invention contain relatively acidic and relatively basic functional groups, they can be converted into base addition salts or acid addition salts.
  • base addition salts For details, see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66:1-19 (1977), or Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl and Camille G. Wermuth, ed. ., Wiley-VCH, 2002).
  • 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, and 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.
  • patient refers to any animal, preferably a mammal, and most preferably a human, who has been or is about to receive 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 term "specification" refers to the mass of active ingredient substance X.
  • the specification of the pharmaceutical composition is 20 mg, which means that the mass of the active ingredient substance X is 20 mg.
  • the reagents and raw materials used in the present invention are all commercially available.
  • the quinazoline compound or pharmaceutical composition of the present invention has good therapeutic effect on peripheral T-cell lymphoma and NK/T-cell lymphoma, high effective rate and good safety, and is expected to be applied to peripheral T-cell lymphoma and NK/T-cell lymphoma. Treatment of cell lymphomas and NK/T cell lymphomas.
  • 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.
  • 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 tablet press with 11*5.5mm upper punched Half wire bond die to tablet the blended material to form quinazoline containing 20 mg or 100 mg, respectively, of formula A 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 produced by the process described above were coated to a coating weight gain ranging from 2% to 5% to form film-coated tablets comprising 20 mg or 100 mg of the quinazoline compound of formula A, respectively.
  • test compound concentrations in and calculate pharmacokinetic parameters The results are shown in Table 1.
  • 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 that 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.
  • Three peripheral T-cell lymphoma-related cells were selected and tested for cell proliferation inhibitory activity.
  • Leukemia, acute T cells, T lymphocytes leukem I, acute T cell, T lymphocyte;
  • Leukemia acute T cells, T lymphocytic lymphoma, Sézary syndrome, cutaneous T lymphocytes: lymphoma, Sézary syndrome, cutaneous T lymphocyte;
  • Lymphoma cutaneous T lymphocyte: lymphoma, cutaneous T lymphocyte.
  • Patient recruitment criteria were: histologically confirmed patients with relapsed and/or refractory peripheral T-cell lymphoma (PTCL) who had failed or were intolerant of at least one systemic systemic therapy and/or currently have no effective standard therapy and NK/T cell lymphoma patients.
  • PTCL peripheral T-cell lymphoma
  • the patient takes the quinazoline compound tablet as shown in formula A prepared according to the method of Preparation Example 2, once a day, orally, 4 tablets each time (tablet specification is 20mg/tablet), until disease progression or Toxicity is not tolerated.
  • the curative effect was evaluated using the revised International Working Group (IRWG) curative effect evaluation criteria, and the evaluation indicators were ORR (CR+PR) and DCR (CR+PR+SD).
  • ORR Overall response rate
  • DCR Disease control rate
  • CR complete response
  • PR partial response
  • SD stable disease
  • PD progressive disease.
  • the quinazoline compound tablet of formula A showed good antitumor activity in patients with relapsed and/or refractory peripheral T-cell lymphoma and NK/T-cell lymphoma.
  • a total of 43 patients were enrolled, of which 41 were Efficacy evaluation has been completed, including 16 cases of peripheral T-cell lymphoma unspecified, 16 cases of angioimmunoblastic T-cell lymphoma, 4 cases of ALK-negative anaplastic large cell lymphoma, and 3 cases of extranodal NK/T cell lymphoma cases, 1 case of ALK-positive anaplastic large cell lymphoma, and 1 case of monomorphic epithelial T-cell lymphoma.
  • the patient inclusion criteria were histologically or cytologically confirmed patients with relapsed or refractory B-cell hematological tumors, and a total of 25 patients were included.
  • 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.
  • the quinazoline compound represented by formula A is safe and can be tolerated by oral administration in the range of 20mgQD to 200mgQD in patients with relapsed or refractory B-cell hematological tumors.
  • Duvelisib is an oral PI3K ⁇ and ⁇ small molecule inhibitor in a phase I clinical study (NCT01476657) in 16 patients with PTCL: ORR was 53%, CR was 13%, and PR was 40%.
  • Copanlisib (BAY-80-6946), an intravenously administered PI3K ⁇ and PI3K ⁇ inhibitor, was enrolled in a phase II study (CHRONOS-1, NCT01660451) in 84 patients with relapsed/refractory indolent or aggressive lymphoma, including 14 cases of PTCL; PTCL patients were evaluated for efficacy, 2 cases (14.3%) CR, 1 case (7.1%) PR, ORR was 21.4%.
  • phase Ib clinical study of the quinazoline compound tablet shown in formula A in the treatment of patients with relapsed and/or refractory peripheral T-cell lymphoma the phase Ib clinical study data showed that the best overall efficacy CR was 15 cases, PR There were 11 cases, SD was 10 cases, and PD was 5 cases.
  • the overall optimal curative effect ORR ratio was 63.41% (26/41), and the DCR ratio was 87.80% (36/41).
  • the quinazoline compound represented by formula A has obvious advantages over similar drugs.
  • phase Ib clinical study of the quinazoline compound tablet shown in formula A in the treatment of patients with relapsed or refractory NK/T cell lymphoma the phase Ib clinical study data showed that the best overall curative effect CR was 1 case, and PR was 1 case, SD was 0 case, PD was 1 case, the overall optimal response ORR ratio was 66.7% (2/3), and the DCR ratio was 66.7% (2/3). It is shown that in patients with relapsed or refractory NK/T cell lymphoma, the quinazoline compound represented by formula A also has good curative effect.

Abstract

An application of a quinazoline compound and a pharmaceutical composition. The quinazoline compound is the quinazoline compound shown in formula A, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of the pharmaceutically acceptable salt thereof; the pharmaceutical composition comprises the quinazoline compound and a pharmaceutical excipient. The quinazoline compound or the pharmaceutical composition has a good therapeutic effect on peripheral T cell lymphoma and NK/T cell lymphoma, having high efficiency and good safety.

Description

一种喹唑啉化合物及药物组合物的应用Application of a kind of quinazoline compound and pharmaceutical composition
本申请要求申请日为2021/4/30的中国专利申请2021104856675的优先权。本申请引用上述中国专利申请的全文。This application claims the priority of Chinese patent application 2021104856675 with the filing date of 2021/4/30. This application cites the full text of the above Chinese patent application.
技术领域technical field
本发明涉及一种喹唑啉化合物及药物组合物的应用。The present invention relates to the application of a quinazoline compound and a pharmaceutical composition.
背景技术Background technique
外周T细胞淋巴瘤是一组高度异质性来源于成熟T细胞的恶性增殖性疾病，在中国约占非霍奇金淋巴瘤的25％～30％，侵袭性强，预后差。外周T细胞淋巴瘤目前尚无标准一线治疗方案，多数选择含蒽环类和/或依托泊苷的化疗方案，包括CHOP、CHOPE等，然而上述方案对除ALK+间变大细胞淋巴瘤外的其它病理亚型的治疗疗效较差，5年生存率仅为30％。虽然自体造血干细胞移植可能改善部分患者的长期预后，但多数患者由于疾病状态或体能情况等原因无法接受造血干细胞移植。对于复发或难治性外周T细胞淋巴瘤患者，2018年美国国立综合癌症网络治疗指南建议不适用造血干细胞移植的患者，首先推荐参加临床试验。外周T细胞淋巴瘤的传统二线化疗方案疗效并不显著，尤其是对蒽环类耐药的患者。Peripheral T-cell lymphoma is a group of highly heterogeneous malignant proliferative diseases derived from mature T cells, accounting for about 25% to 30% of non-Hodgkin lymphomas in China, with strong invasiveness and poor prognosis. At present, there is no standard first-line treatment regimen for peripheral T-cell lymphoma. Most of them choose chemotherapy regimens containing anthracyclines and/or etoposide, including CHOP, CHOPE, etc. The pathological subtype is less effective in treatment, with a 5-year survival rate of only 30%. Although autologous hematopoietic stem cell transplantation may improve long-term outcomes for some patients, most patients are unable to receive hematopoietic stem cell transplantation due to disease status or physical performance. For patients with relapsed or refractory peripheral T-cell lymphoma, the 2018 National Comprehensive Cancer Network treatment guidelines recommend that patients who are not suitable for hematopoietic stem cell transplantation should first be recommended to participate in clinical trials. Conventional second-line chemotherapy regimens for peripheral T-cell lymphoma are not effective, especially in patients who are resistant to anthracyclines.
NK/T细胞淋巴瘤是起源于成熟NK/T细胞的淋巴***恶性肿瘤，属于T细胞淋巴肿瘤的一种特殊类型，多发生于结外部位，以发生于鼻部者为多，与EB病毒感染关系密切，具有侵袭性强、对化疗不敏感、预后差等特点。NK/T细胞淋巴瘤在各年龄段均可发病，但主要见于成年人。NK/T细胞淋巴瘤是一种在西方国家发病率低，但是中国常见的T细胞淋巴瘤，约占T细胞非霍奇金淋巴瘤(T-NHL)的30.1％，中位生存时间约12-38个月。NK/T细胞淋巴瘤目前尚无标准化疗方案，推荐参加临床研究。对于局限期(I期或II期)患者放化疗联合具有较好的疗效，对于III/IV期的患者化疗是其主要的治疗方法，对于晚期复发/难治的NK/T细胞淋巴瘤，综合治疗是最常用的方法，例如高强度的化疗联合放疗及L-门冬酰胺酶的使用可使患者受益，近年来有文献报道，大剂量化疗联合造血干细胞移植也可以作为治疗其晚期复发/难治的一种补救方法。NK/T cell lymphoma is a malignant tumor of the lymphatic system originating from mature NK/T cells. Infection is closely related, and has the characteristics of strong invasiveness, insensitivity to chemotherapy, and poor prognosis. NK/T-cell lymphomas can occur in all age groups, but are mainly seen in adults. NK/T-cell lymphoma is a kind of T-cell lymphoma with a low incidence in Western countries, but is common in China, accounting for about 30.1% of T-cell non-Hodgkin lymphoma (T-NHL), and the median survival time is about 12. -38 months. At present, there is no standard chemotherapy regimen for NK/T cell lymphoma, and it is recommended to participate in clinical research. For patients with limited stage (I or II), the combination of radiotherapy and chemotherapy has good curative effect. For patients with stage III/IV, chemotherapy is the main treatment method. For advanced relapsed/refractory NK/T cell lymphoma, comprehensive Treatment is the most commonly used method. For example, high-intensity chemotherapy combined with radiotherapy and the use of L-asparaginase can benefit patients. In recent years, it has been reported in the literature that high-dose chemotherapy combined with hematopoietic stem cell transplantation can also be used as a treatment for patients with advanced relapse/refractory disease. a remedy for treatment.
PI3K全称为Phosphatidylinositol 3-kinase(磷脂酰肌醇3-激酶)，其参与细胞增殖、分化、凋亡和葡萄糖转运等多种细胞功能的调节。PI3K可分为Ⅰ类、Ⅱ类和Ⅲ类激酶，而研究最广泛的是能被细胞表面受体所激活的Ⅰ类PI3K。哺乳动物细胞中Ⅰ类PI3K根据结构和受体又分为Ⅰa类和Ⅰb类，它们分别传递来自酪氨酸激酶-偶联受体和G蛋白-偶联受体 的信号。Ⅰa类PI3K包括PI3Kα、PI3Kβ、PI3Kδ亚型，Ⅰb类PI3K包括PI3Kγ亚型(Trends.Biochem.Sci.,1997,22,267-272)。Ⅰa类PI3K是由催化亚单位p110和调节亚单位p85所组成的二聚体蛋白，具有类脂激酶和蛋白激酶的双重活性(Nat.Rev.Cancer 2002,2,489-501)，被认为与细胞增殖和癌症发生相关。The full name of PI3K is 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 PI3Kα, PI3Kβ, PI3Kδ isoforms, and class Ib PI3Ks include PI3Kγ 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 associated with cancer.
目前全球已有多款PI3Kδ抑制剂药物成功上市，如Idelalisib、Copanlisib以及Duvelisb，均用于治疗血液循环***癌症。但是没有应用于外周T细胞淋巴瘤适应症获批上市。At present, a number of PI3Kδ inhibitor drugs have been successfully launched in the world, such as Idelalisib, Copanlisib and Duvelisb, all of which are used to treat circulatory system cancers. However, it has not been approved for use in peripheral T-cell lymphoma indications.
外周T细胞淋巴瘤和NK/T细胞淋巴瘤目前尚无标准一线治疗方案，已有的化疗方案存在有效率不高，副作用大等问题，非常需要开发新的药物包括PI3Kδ抑制剂用于治疗外周T细胞淋巴瘤和NK/T细胞淋巴瘤。There is currently no standard first-line treatment regimen for peripheral T-cell lymphoma and NK/T-cell lymphoma. The existing chemotherapy regimens have problems such as low efficacy and large side effects. It is very necessary to develop new drugs, including PI3Kδ inhibitors, for the treatment of peripheral T-cell lymphoma and NK/T-cell lymphoma.
化学结构如式A所示的喹唑啉化合物是一种PI3Kδ小分子抑制剂，已公开于CN104557872A专利中(化合物10)，
Figure PCTCN2022087761-appb-000001
中国专利CN110950844A公开了如式A所示的喹唑啉化合物的两种多晶型物。 The quinazoline compound whose chemical structure is shown in formula A is a PI3Kδ small molecule inhibitor, which has been disclosed in the CN104557872A patent (compound 10),
Figure PCTCN2022087761-appb-000001
Chinese patent CN110950844A discloses two polymorphs of the quinazoline compound represented by formula A.
发明内容SUMMARY OF THE INVENTION
本发明所要解决的技术问题是针对现有技术存在治疗外周T细胞淋巴瘤和NK/T细胞淋巴瘤尚无标准一线治疗方案，已有的化疗方案存在有效率不高，副作用大等缺陷，而提供了一种喹唑啉化合物及药物组合物的应用。本发明的喹唑啉化合物或药物组合物对外周T细胞淋巴瘤和NK/T细胞淋巴瘤治疗效果好，有效率高，安全性较好，有望应用于外周T细胞淋巴瘤和NK/T细胞淋巴瘤的治疗。The technical problem to be solved by the present invention is that there is no standard first-line treatment scheme for the treatment of peripheral T-cell lymphoma and NK/T-cell lymphoma in the prior art, and the existing chemotherapy schemes have defects such as low effective rate and large side effects. The application of a quinazoline compound and a pharmaceutical composition is provided. The quinazoline compound or pharmaceutical composition of the present invention has good therapeutic effect on peripheral T-cell lymphoma and NK/T-cell lymphoma, high efficiency and good safety, and is expected to be applied to peripheral T-cell lymphoma and NK/T-cell lymphoma Treatment of lymphoma.
本发明提供了一种物质X或药物组合物在制备药物中的应用，所述物质X为如式A所示的喹唑啉化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物；所述药物组合物包括所述物质X和药用辅料；所述药物为治疗外周T细胞淋巴瘤和NK/T细胞淋巴瘤的药物；The present invention provides the use of a substance X or a pharmaceutical composition in the preparation of a medicine, wherein the substance X is a quinazoline compound represented by formula A, a pharmaceutically acceptable salt thereof, a solvate thereof or a pharmaceutical thereof The solvate of the above acceptable salt; the pharmaceutical composition includes the substance X and pharmaceutical excipients; the drug is a drug for the treatment of peripheral T-cell lymphoma and NK/T-cell lymphoma;
Figure PCTCN2022087761-appb-000002
Figure PCTCN2022087761-appb-000002
在某一方案中，所述外周T细胞淋巴瘤为复发和/或难治性外周T细胞淋巴瘤，例如，复发或难治性外周T细胞淋巴瘤。In a certain aspect, the peripheral T-cell lymphoma is relapsed and/or refractory peripheral T-cell lymphoma, eg, relapsed or refractory peripheral T-cell lymphoma.
在某一方案中，所述NK/T细胞淋巴瘤为复发和/或难治性NK/T细胞淋巴瘤，例如，复发或难治性NK/T细胞淋巴瘤。In a certain aspect, the NK/T cell lymphoma is relapsed and/or refractory NK/T cell lymphoma, eg, relapsed or refractory NK/T cell lymphoma.
在某一方案中，所述外周T细胞淋巴瘤为外周T细胞淋巴瘤非特指型、血管免疫母细胞性T细胞淋巴瘤、ALK阳性间变大性细胞淋巴瘤、ALK阴性间变大性细胞淋巴瘤和单形性嗜上皮肠道T细胞淋巴瘤中的一种或多种，例如，血管免疫母细胞性T细胞淋巴瘤。In one embodiment, the peripheral T-cell lymphoma is peripheral T-cell lymphoma unspecified, angioimmunoblastic T-cell lymphoma, ALK-positive anaplastic large cell lymphoma, ALK-negative anaplastic large cell lymphoma One or more of lymphoma and monomorphic epithelial T-cell lymphoma, eg, angioimmunoblastic T-cell lymphoma.
在某一方案中，所述NK/T细胞淋巴瘤为结外NK/T细胞淋巴瘤。In a certain aspect, the NK/T cell lymphoma is an extranodal NK/T cell lymphoma.
在某一方案中，所述药物通过口服使用。In a certain regimen, the drug is administered orally.
在某一方案中，所述物质X为治疗有效量的。In one aspect, the Substance X is in a therapeutically effective amount.
在某一方案中，所述药物的施用剂量可以根据患者的体重来确定，以所述如式A所示的喹唑啉化合物的含量计，所述药物的施用剂量为一次0.33mg/kg-3.33mg/kg，例如，0.66mg/kg-2.3mg/kg，再例如，1mg/kg、1.2mg/kg、1.3mg/kg、1.33mg/kg、1.4mg/kg、1.5mg/kg、1.6mg/kg、1.7mg/kg、1.8mg/kg、1.9mg/kg、2.0mg/kg、2.1mg/kg、2.2mg/kg或2.3mg/kg。In a certain scheme, the administration dose of the drug can be determined according to the body weight of the patient, and based on the content of the quinazoline compound represented by formula A, the administration dose of the drug is 0.33 mg/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.
在某一方案中，以所述如式A所示的喹唑啉化合物的含量计，所述药物的施用剂量为20mg-200mg/天，例如，为20mg/天、30mg/天、40mg/天、50mg/天、60mg/天、70mg/天、80mg/天、90mg/天、100mg/天、110mg/天、120mg/天、130mg/天、140mg/天、150mg/天、160mg/天、170mg/天、180mg/天、190mg/天或200mg/天，再例如，为80mg/天。In a certain scheme, based on the content of the quinazoline compound represented by formula A, 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.
在某一方案中，所述药物的施用频率为1-5次/天，例如，1次/天、2次/天、3次/天、4次/天或5次/天，再例如，1次/天。In a certain regimen, the frequency of administration of the drug is 1-5 times/day, eg, 1/day, 2 times/day, 3 times/day, 4 times/day, or 5 times/day, for example, 1 time/day.
在某一方案中，所述药物的施用疗程为14-84天/疗程，例如，14天/疗程、28天/疗程、42天/疗程、56天/疗程、70天/疗程或84天/疗程，再例如，28天/疗程。In a certain regimen, 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 The course of treatment, for another example, is 28 days/course.
在某一个方案中，所述药物共计施用1-20个疗程，较佳地，为10-20个疗程，例如，为10、11、12、13、14、15、16、17、18、19或20个疗程，再例如，为12个疗程。In a certain scheme, 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 of treatment, for another example, 12 courses of treatment.
在某一方案中，所述药物为片剂或胶囊，例如，片剂。In one aspect, the medicament is a tablet or capsule, eg, a tablet.
在某一方案中，所述药物组合物的单位剂型中，所述如式A所示的喹唑啉化合物的含量为5mg-500mg，优选10mg-200mg，最优选20mg、100mg，例如20mg、30mg、40mg、50mg、60mg、70mg、80mg、90mg或100mg。以片剂为例，所述单位剂型中，所述如式A所示的喹唑啉化合物的含量为5mg-500mg。In a certain scheme, in the unit dosage form of the pharmaceutical composition, the content of the quinazoline compound represented by formula A is 5mg-500mg, preferably 10mg-200mg, most preferably 20mg, 100mg, such as 20mg, 30mg , 40mg, 50mg, 60mg, 70mg, 80mg, 90mg or 100mg. Taking a tablet as an example, in the unit dosage form, the content of the quinazoline compound represented by formula A is 5 mg-500 mg.
在某一方案中，所述药物施用在组织学确诊的接受过至少一次***性全身治疗失败或不能耐受的和/或目前尚无有效标准治疗的复发和/或难治性外周T细胞淋巴瘤(PTCL)和NK/T细胞淋巴瘤(NKTCL)患者身上。In a certain regimen, the drug is administered in histologically confirmed relapsed and/or refractory peripheral T-cell lymphocytes that have failed or are intolerable to at least one systemic systemic therapy and/or currently have no effective standard therapy. tumor (PTCL) and NK/T cell lymphoma (NKTCL).
在某一方案中，所述药物的施用对象为人类。In one aspect, the medicament is administered to a human.
本发明还提供了一种治疗疾病的方法，其包括向患者(例如人类)施用治疗有效量的物质X或其药物组合物；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 thereof;
所述疾病为外周T细胞淋巴瘤和NK/T细胞淋巴瘤；所述物质X为如式A所示的喹唑啉化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物；所述药物组合物包括所述物质X和药用辅料；The disease is peripheral T-cell lymphoma and NK/T-cell lymphoma; the substance X is a quinazoline compound represented by formula A, a pharmaceutically acceptable salt thereof, a solvate thereof or a pharmaceutically acceptable compound thereof. A solvate of the accepted salt; the pharmaceutical composition comprising the substance X and a pharmaceutical excipient;
Figure PCTCN2022087761-appb-000003
Figure PCTCN2022087761-appb-000003
在某一方案中，所述外周T细胞淋巴瘤为复发和/或难治性外周T细胞淋巴瘤，例如，复发或难治性外周T细胞淋巴瘤。In a certain aspect, the peripheral T-cell lymphoma is relapsed and/or refractory peripheral T-cell lymphoma, eg, relapsed or refractory peripheral T-cell lymphoma.
在某一方案中，所述NK/T细胞淋巴瘤为复发和/或难治性NK/T细胞淋巴瘤，例如，复发或难治性NK/T细胞淋巴瘤。In a certain aspect, the NK/T cell lymphoma is relapsed and/or refractory NK/T cell lymphoma, eg, relapsed or refractory NK/T cell lymphoma.
在某一方案中，所述外周T细胞淋巴瘤为外周T细胞淋巴瘤非特指型、血管免疫母细胞性T细胞淋巴瘤、ALK阳性间变大性细胞淋巴瘤、ALK阴性间变大性细胞淋巴瘤或单形性嗜上皮肠道T细胞淋巴瘤中的一种或多种，例如，血管免疫母细胞性T细胞淋巴瘤。In one embodiment, the peripheral T-cell lymphoma is peripheral T-cell lymphoma unspecified, angioimmunoblastic T-cell lymphoma, ALK-positive anaplastic large cell lymphoma, ALK-negative anaplastic large cell lymphoma One or more of lymphoma or monomorphic epithelial T-cell lymphoma, eg, angioimmunoblastic T-cell lymphoma.
在某一方案中，所述NK/T细胞淋巴瘤为结外NK/T细胞淋巴瘤。In a certain aspect, the NK/T cell lymphoma is an extranodal NK/T cell lymphoma.
在某一方案中，所述施用的方式为口服。In a certain regimen, the mode of administration is oral.
在某一方案中，所述施用的剂量可以根据患者的体重来确定，以所述如式A所示的 喹唑啉化合物的含量计，所述施用的剂量为一次0.33mg/kg-3.33mg/kg，例如，0.66mg/kg-2.3mg/kg，再例如，1mg/kg、1.2mg/kg、1.3mg/kg、1.33mg/kg、1.4mg/kg、1.5mg/kg、1.6mg/kg、1.7mg/kg、1.8mg/kg、1.9mg/kg、2.0mg/kg、2.1mg/kg、2.2mg/kg或2.3mg/kg。In a certain scheme, 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 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.
在某一方案中，以所述如式A所示的喹唑啉化合物的含量计，所述施用的剂量为20-200mg/天，例如，20mg/天、30mg/天、40mg/天、50mg/天、60mg/天、70mg/天、80mg/天、90mg/天、100mg/天、110mg/天、120mg/天、130mg/天、140mg/天、150mg/天、160mg/天、170mg/天、180mg/天、190mg/天或200mg/天，再例如，80mg/天。In a certain scheme, the dose administered is 20-200 mg/day, eg, 20 mg/day, 30 mg/day, 40 mg/day, 50 mg, based on the content of the quinazoline compound of formula A /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.
在某一方案中，所述施用的频率为1-5次/天，例如，1次/天、2次/天、3次/天、4次/天或5次/天，再例如，1次/天。In a certain regimen, 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 times/day.
在某一方案中，所述施用的疗程为14-84天/疗程，例如，14天/疗程、28天/疗程、42天/疗程、56天/疗程、70天/疗程或84天/疗程，再例如，28天/疗程。In a certain regimen, 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 , for another example, 28 days/course.
在某一方案中，所述患者共计接受1-20个疗程，较佳地，为10-20个疗程，例如，10、11、12、13、14、15、16、17、18、19或20个疗程，再例如，12个疗程。In a certain regimen, 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, another example, 12 courses of treatment.
在某一方案中，所述物质X或药物组合物为片剂或胶囊，例如，为片剂。In one aspect, the substance X or pharmaceutical composition is a tablet or capsule, eg, a tablet.
在某一方案中，所述物质X或药物组合物的规格为10-120mg/片，例如，为20-100mg/片，再例如为，20mg/片、30mg/片、40mg/片、50mg/片、60mg/片、70mg/片、80mg/片、90mg/片或100mg/片，再例如为，20mg/片、80mg/片或100mg/片。In a certain scheme, the specification of the substance X or the pharmaceutical composition is 10-120mg/tablet, for example, 20-100mg/tablet, another example, 20mg/tablet, 30mg/tablet, 40mg/tablet, 50mg/tablet Tablet, 60mg/tablet, 70mg/tablet, 80mg/tablet, 90mg/tablet or 100mg/tablet, another example is 20mg/tablet, 80mg/tablet or 100mg/tablet.
在某一方案中，所述患者为组织学确诊的接受过至少一次***性全身治疗失败或不能耐受的和/或目前尚无有效标准治疗的复发和/或难治性外周T细胞淋巴瘤(PTCL)和/或NK/T细胞淋巴瘤(NKTCL)患者。In a certain regimen, the patient is histologically confirmed relapsed and/or refractory peripheral T-cell lymphoma who has failed or cannot tolerate at least one systemic systemic therapy and/or currently has no effective standard therapy (PTCL) and/or NK/T cell lymphoma (NKTCL).
在本发明的如上的应用或治疗方法的某一些实施方案中(以下简称“在本发明的某一实施方案中”)，所述如式A所示的喹唑啉化合物为游离碱形式的如式A所示的喹唑啉化合物，应当理解的是，“游离碱形式”是指如式A所示的喹唑啉化合物不是处于盐的形式的情况。In certain embodiments of the above application or method of treatment of the present invention (hereinafter referred to as "in an embodiment of the present invention"), the quinazoline compound represented by formula A is the free base form of For the quinazoline compound represented by formula A, it should be understood that "free base form" refers to the case where the quinazoline compound represented by formula A is not in the form of a salt.
在本发明的某一实施方案中，所述如式A所示的喹唑啉化合物为如式A所示的喹唑啉化合物的晶型Ⅰ形式，其中如式A所示的喹唑啉化合物的晶型Ⅰ可以按中国专利公开号CN110950844A中所描述的任何方式来定义。In a certain embodiment of the present invention, the quinazoline compound represented by formula A is the crystalline form I of the quinazoline compound represented by formula A, wherein the quinazoline compound represented by formula A The crystal form I of can be defined in any way described in Chinese Patent Publication No. CN110950844A.
在本发明的某一实施方案中，所述药用辅料包括填充剂，所述填充剂为微晶纤维素、甘露醇和玉米淀粉中的一种、两种或多种。In a certain embodiment of the present invention, the pharmaceutical excipient includes a filler, and the filler is one, two or more of microcrystalline cellulose, mannitol and corn starch.
在本发明的某一实施方案中，所述填充剂为微晶纤维素。In one embodiment of the present invention, the filler is microcrystalline cellulose.
在本发明的某一实施方案中，所述填充剂为微晶纤维素和甘露醇的混合物。In one embodiment of the present invention, the filler is a mixture of microcrystalline cellulose and mannitol.
在本发明的某一实施方案中，所述填充剂为微晶纤维素和玉米淀粉的混合物。In one embodiment of the present invention, the filler is a mixture of microcrystalline cellulose and cornstarch.
在本发明的某一实施方案中，所述填充剂为微晶纤维素、甘露醇和玉米淀粉的混合物。In a certain embodiment of the present invention, the filler is a mixture of microcrystalline cellulose, mannitol and corn starch.
在本发明的某一实施方案中，所述填充剂以重量计为所述药物组合物总重量的10％-90％，优选30％-70％，最优选45％-55％。In a certain embodiment of the present invention, the filler is 10%-90% by weight of the total weight of the pharmaceutical composition, preferably 30%-70%, most preferably 45%-55%.
在本发明的某一实施方案中，所述填充剂为微晶纤维素和甘露醇的混合物，以重量计为所述药物组合物总重量的10％-90％，优选30％-70％，最优选45％-55％。In a certain embodiment of the present invention, the filler is a mixture of microcrystalline cellulose and mannitol, 10%-90% by weight, preferably 30%-70% by weight of the total weight of the pharmaceutical composition, Most preferably 45%-55%.
在本发明的某一实施方案中，所述填充剂为微晶纤维素和甘露醇的混合物，所述微晶纤维素和所述甘露醇的质量比为10：1-1：10。In a certain embodiment of the present invention, the filler is a mixture of microcrystalline cellulose and mannitol, and the mass ratio of the microcrystalline cellulose and the mannitol is 10:1-1:10.
在本发明的某一实施方案中，所述填充剂为微晶纤维素和甘露醇的混合物，所述微晶纤维素和所述甘露醇的质量比为6：1-2：1，优选4：1-3：1。In a certain embodiment of the present invention, the filler is a mixture of microcrystalline cellulose and mannitol, and the mass ratio of the microcrystalline cellulose and the mannitol is 6:1-2:1, preferably 4 :1-3:1.
在本发明的某一实施方案中，所述药用辅料还包括崩解剂。In a certain embodiment of the present invention, the pharmaceutical excipient further includes a disintegrant.
在本发明的某一实施方案中，所述崩解剂为交联聚维酮和/或交联羧甲基纤维素钠。In a certain embodiment of the present invention, the disintegrant is crospovidone and/or croscarmellose sodium.
在本发明的某一实施方案中，所述崩解剂为交联聚维酮。In a certain embodiment of the invention, the disintegrant is crospovidone.
在本发明的某一实施方案中，所述崩解剂为交联羧甲基纤维素钠。In one embodiment of the present invention, the disintegrant is croscarmellose sodium.
在本发明的某一实施方案中，所述崩解剂不为低取代羟丙基纤维素。In a certain embodiment of the present invention, the disintegrant is not low-substituted hydroxypropylcellulose.
在本发明的某一实施方案中，所述崩解剂以重量计为所述药物组合物总重量的1％-20％；优选3％-15％，最优选4％-8％。In a certain embodiment of the present invention, the disintegrant is 1%-20% by weight of the total weight of the pharmaceutical composition; preferably 3%-15%, most preferably 4%-8%.
在本发明的某一实施方案中，所述崩解剂为交联羧甲基纤维素钠，以重量计为所述药物组合物总重量的1％-20％。In a certain embodiment of the present invention, the disintegrant is croscarmellose sodium, which is 1%-20% by weight of the total weight of the pharmaceutical composition.
在本发明的某一实施方案中，所述崩解剂为交联羧甲基纤维素钠，以重量计为所述药物组合物总重量的3％-15％，优选4％-8％。In a certain embodiment of the present invention, the disintegrant is croscarmellose sodium, which is 3%-15%, preferably 4%-8% by weight of the total weight of the pharmaceutical composition.
在本发明的某一实施方案中，所述药用辅料还进一步包括润滑剂。In a certain embodiment of the present invention, the pharmaceutical excipient further includes a lubricant.
本发明的某一实施方案中，所述润滑剂为硬脂酸钙、单硬脂酸甘油酯、山嵛酸甘油酯、硬脂酸镁、棕榈酸、泊洛沙姆、聚乙二醇、苯甲酸钾、苯甲酸钠、月桂基硫酸钠、硬脂酸钠、硬脂富马酸钠、硬脂酸、滑石粉、微粉硅胶和硬脂酸锌中的一种或多种。In one embodiment of the present invention, the lubricant is calcium stearate, glycerol monostearate, glyceryl behenate, magnesium stearate, palmitic acid, poloxamer, polyethylene glycol, One or more of potassium benzoate, sodium benzoate, sodium lauryl sulfate, sodium stearate, sodium stearyl fumarate, stearic acid, talc, micropowder silica gel and zinc stearate.
在本发明的某一实施方案中，所述润滑剂为硬脂酸镁。In one embodiment of the present invention, the lubricant is magnesium stearate.
在本发明的某一实施方案中，所述润滑剂以重量计为所述药物组合物总重量的0.1％-5.0％，优选0.3％-2.0％，最优选0.8％-1.4％。In a certain embodiment of the present invention, 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%.
在本发明的某一实施方案中，所述润滑剂为硬脂酸镁，以重量计为药物组合物总重量的0.1％-5.0％。In a certain embodiment of the present invention, the lubricant is magnesium stearate, 0.1%-5.0% by weight of the total weight of the pharmaceutical composition.
在本发明的某一实施方案中，所述润滑剂为硬脂酸镁，以重量计为药物组合物总重量的0.3％-2.0％，优选0.8％-1.4％。In a certain embodiment of the present invention, the lubricant is magnesium stearate, 0.3%-2.0% by weight, preferably 0.8%-1.4% by weight of the total weight of the pharmaceutical composition.
在本发明的某一实施方案中，所述药物组合物，包括以重量计的如下成分：In a certain embodiment of the present invention, the pharmaceutical composition comprises the following components by weight:
1)40％-50％的如式A所示的喹唑啉化合物；1) 40%-50% of the quinazoline compound shown in formula A;
2)45％-55％的填充剂，所述填充剂为微晶纤维素、甘露醇和玉米淀粉中的一种、两种或多种，优选微晶纤维素和甘露醇的混合物，最优选微晶纤维素和甘露醇混合物，且其质量比为4：1-3：1；2) 45%-55% filler, which is one, two or more of microcrystalline cellulose, mannitol and cornstarch, preferably a mixture of microcrystalline cellulose and mannitol, most preferably microcrystalline cellulose The mixture of crystalline cellulose and mannitol, and its mass ratio is 4:1-3:1;
3)4％-8％的崩解剂，所述崩解剂为交联聚维酮和/或交联羧甲基纤维素钠，优选交联羧甲基纤维素钠；3) 4%-8% disintegrant, which is crospovidone and/or croscarmellose sodium, preferably croscarmellose sodium;
4)0.8％-1.4％的润滑剂，所述润滑剂为硬脂酸镁。4) 0.8%-1.4% lubricant, the lubricant is magnesium stearate.
在本发明的某一实施方案中，所述如式A所示的喹唑啉化合物以重量计为所述药物组合物总重量的40％。In a certain embodiment of the present invention, the quinazoline compound represented by formula A is 40% by weight of the total weight of the pharmaceutical composition.
在本发明的某一实施方案中，所述填充剂以重量计为所述药物组合物总重量的52.8％。In a certain embodiment of the present invention, the filler is 52.8% by weight of the total weight of the pharmaceutical composition.
在本发明的某一实施方案中，所述崩解剂以重量计为所述药物组合物总重量的6％。In a certain embodiment of the present invention, the disintegrant is 6% by weight of the total weight of the pharmaceutical composition.
在本发明的某一实施方案中，所述润滑剂以重量计为所述药物组合物总重量的1.2％。In a certain embodiment of the present invention, the lubricant is 1.2% by weight of the total weight of the pharmaceutical composition.
在本发明的某一实施方案中，所述药物为片剂或者胶囊，优选片剂。In a certain embodiment of the present invention, the medicament is a tablet or a capsule, preferably a tablet.
在本发明的某一实施方案中，所述片剂为包衣片。In a certain embodiment of the invention, the tablet is a coated tablet.
在本发明的某一实施方案中，所述包衣片为薄膜包衣片。In a certain embodiment of the present invention, the coated tablet is a film-coated tablet.
在本发明的某一实施方案中，当所述包衣片为薄膜包衣片时，用于所述薄膜包衣片的包衣剂是基于羟丙基甲基纤维素为主要成膜聚合物的薄膜包衣预混剂。In a certain embodiment of the present invention, when the coated tablet is a film-coated tablet, the coating agent for the film-coated tablet is based on hydroxypropyl methylcellulose as the main film-forming polymer film coating premix.
在本发明的某一实施方案中，所述薄膜包衣片中，所述薄膜包衣片的包衣剂可以商购自卡乐康公司(Colorcon)，例如商标名
Figure PCTCN2022087761-appb-000004
的薄膜包衣预混剂。 In a certain embodiment of the present invention, in the film-coated tablet, the coating agent of the film-coated tablet can be purchased from Colorcon, for example, under the trade name
Figure PCTCN2022087761-appb-000004
film coating premix.
在本发明的某一实施方案中，所述薄膜包衣片中，与片芯重量相比，包衣剂的重量增重为2％-5％，优选2.5％-4.5％，最优选3.5％。In one embodiment of the present invention, in the film-coated tablet, the weight gain of the coating agent is 2%-5%, preferably 2.5%-4.5%, most preferably 3.5%, compared to the weight of the tablet core .
在本发明的某一实施方案中，所述药物组合物，其包括片芯和包衣两部分，并且各自含有以重量计的如下成分：In a certain embodiment of the present invention, the pharmaceutical composition comprises two parts, a core tablet and a coating, and each contains the following components by weight:
片芯：Chip:
1)40％的如式A所示的喹唑啉化合物；1) 40% of the quinazoline compound shown in formula A;
2)40％的微晶纤维素和12.8％的甘露醇；2) 40% microcrystalline cellulose and 12.8% mannitol;
3)6％的交联羧甲基纤维素钠；3) 6% croscarmellose sodium;
4)1.2％的硬脂酸镁；4) 1.2% magnesium stearate;
包衣：Coating:
5)与片芯重量相比，包衣剂的重量增重为3.5％。5) The weight gain of the coating agent is 3.5% compared to the core weight.
本发明中所使用的“填充剂”，也称“稀释剂”，是指在科学的背景下用于增加药物组合物产品剂型的体积和重量的一类辅料。因此，填充剂可以是，例如：碳酸钙、磷酸钙、磷酸氢钙、硫酸钙、乙酸纤维素、乙基纤维素、果糖、乳糖、乳糖醇、麦芽糖、麦芽糊精、麦芽糖醇、甘露醇、微晶纤维素、聚右旋糖、聚乙二醇、碳酸氢钠、碳酸钠、氯化钠、山梨糖醇、玉米淀粉、糊精、蔗糖、海藻糖和木糖醇。The "filler" 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. Thus, 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.
本发明中所使用的“崩解剂”，是指在科学的背景下用于促进药物组合物产品剂型在水环境中破裂成更小的碎片的一类辅料。因此，崩解剂可以是，例如：海藻酸、海藻酸钙、羧甲基纤维素钙、壳聚糖、胶体二氧化硅、交联羧甲基纤维素钠、交联聚维酮、羧甲基淀粉钠、低取代羟丙基纤维素、羟丙甲纤维素、甘氨酸、瓜尔胶、羟丙基纤维素、硅酸铝镁、甲基纤维素、聚维酮、海藻酸钠、羧甲基纤维素钠、羟基乙酸淀粉钠和淀粉。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. Thus, 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.
本发明中所使用的“润滑剂”，是指在科学的背景下用于改善药物组合物产品剂型加工过程的一类辅料。因此，润滑剂可以是，例如：硬脂酸钙、单硬脂酸甘油酯、山嵛酸甘油酯、硬脂酸镁、棕榈酸、泊洛沙姆、聚乙二醇、苯甲酸钾、苯甲酸钠、月桂基硫酸钠、硬脂酸钠、硬脂富马酸钠、硬脂酸、滑石粉、微粉硅胶和硬脂酸锌。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. Thus, 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.
本发明中所使用的“包衣剂”或“薄膜包衣预混剂”，是指在科学的背景下用于改善药物组合物产品剂型外观的一类辅料。因此，包衣剂可以是，例如：蔗糖、乳糖、羟丙基甲基纤维素、羟丙基乙基纤维素、醋酸纤维素酞酸酯、聚乙烯醇、聚醋酸乙烯邻苯二甲酸酯、邻苯二酸羟丙甲纤维素酯和丙烯酸树脂。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. Thus, 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.
术语“药学上可接受的盐”是指本发明化合物与相对无毒的、药学上可接受的酸或碱制备得到的盐。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的药学上可接受的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括但不限于：锂盐、钠盐、钾盐、钙盐、铝盐、镁盐、锌盐、铋盐、铵盐、二乙醇胺盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的药学上可接受的酸与这类化合物的中性形式接触的方式获得酸加成盐。所述药学上可接受的酸包括无机酸，所述无机酸包括但不限于：盐酸、氢溴酸、氢碘酸、硝酸、碳酸、磷酸、亚磷酸、硫酸等。所述药学上可接受的酸包括有机酸，所述有机酸包括但不限于：乙酸、丙酸、草酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、水杨酸、酒石酸、甲磺酸、异烟酸、酸式柠檬酸、油酸、单宁酸、 泛酸、酒石酸氢、抗坏血酸、龙胆酸、富马酸、葡糖酸、糖酸、甲酸、乙磺酸、双羟萘酸(即4,4’-亚甲基-双(3-羟基-2-萘甲酸))、氨基酸(例如谷氨酸、精氨酸)等。当本发明的化合物中含有相对酸性和相对碱性的官能团时，可以被转换成碱加成盐或酸加成盐。具体可参见Berge et al.,"Pharmaceutical Salts",Journal of Pharmaceutical Science 66:1-19(1977)、或Handbook of Pharmaceutical Salts:Properties,Selection,and Use(P.Heinrich Stahl and Camille G.Wermuth,ed.,Wiley-VCH,2002)。The term "pharmaceutically acceptable salts" refers to salts of compounds of the present invention prepared with relatively non-toxic, pharmaceutically acceptable acids or bases. When compounds of the present invention contain relatively acidic functional groups, 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. A salt. Pharmaceutically acceptable base addition salts include, but are not limited to, lithium, sodium, potassium, calcium, aluminum, magnesium, zinc, bismuth, ammonium, diethanolamine. When compounds of the present invention contain relatively basic functional groups, acid 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. The pharmaceutically acceptable acid includes 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. The pharmaceutically acceptable acid includes organic acids including, but 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, gluconic acid, sugar acid, formic acid, ethanesulfonic acid, pamoic acid (ie 4,4'-methylene-bis(3) -Hydroxy-2-naphthoic acid)), amino acids (eg glutamic acid, arginine) and the like. When the compounds of the present invention contain relatively acidic and relatively basic functional groups, they can be converted into base addition salts or acid addition salts. For details, see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66:1-19 (1977), or Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl and Camille G. Wermuth, ed. ., Wiley-VCH, 2002).
术语“溶剂合物”是指本发明化合物与化学计量或非化学计量的溶剂结合形成的物质。溶剂合物中的溶剂分子可以有序或非有序排列的形式存在。所述溶剂包括但不限于：水、甲醇、乙醇等。The term "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.
术语“药学上可接受的盐的溶剂合物”中的“药学上可接受的盐”和“溶剂合物”如上所述，是指本发明化合物与相对无毒的、药学上可接受的酸或碱制备得到的，与化学计量或非化学计量的溶剂结合形成的物质。"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.
术语“治疗有效量”是指给予患者的、足以有效治疗疾病的化合物的量。治疗有效量将根据化合物、疾病种类、疾病的严重度、患者的年龄等变化，但可由本领域技术人员视情况调整。The term "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.
术语“药用辅料”是指生产药品和调配处方时使用的赋形剂和附加剂，是除活性成分以外，包括在药物制剂中的所有物质。具体参见中华人民共和国药典(2020年版)或Handbook of Pharmaceutical Excipients(Raymond C Rowe,2009)。The term "pharmaceutical excipients" refers to the excipients and additives used in the production of pharmaceuticals and the formulation of prescriptions, and are all substances included in pharmaceutical preparations except active ingredients. For details, please refer to the Pharmacopoeia of the People's Republic of China (2020 edition) or the Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009).
术语“治疗”指治疗性疗法。涉及具体病症时，治疗指：(1)缓解疾病或者病症的一种或多种生物学表现，(2)干扰(a)导致或引起病症的生物级联中的一个或多个点或(b)病症的一种或多种生物学表现，(3)改善与病症相关的一种或多种症状、影响或副作用，或者与病症或其治疗相关的一种或多种症状、影响或副作用，或(4)减缓病症或者病症的一种或多种生物学表现发展。The term "treatment" refers to therapeutic therapy. In relation to a specific disorder, 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.
术语“患者”指已经或即将接受治疗的任何动物，哺乳动物为优，人类最优。术语“哺乳动物”包括任何哺乳动物。哺乳动物的实例包括但不限于牛、马、羊、猪、猫、狗、小鼠、大鼠、家兔、豚鼠、猴、人等，以人类为最优。The term "patient" refers to any animal, preferably a mammal, and most preferably a human, who has been or is about to receive treatment. The term "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.
术语“规格”指活性成分物质X的质量。例如，药物组合物的规格为20mg，指的是活性成分物质X的质量为20mg。The term "specification" refers to the mass of active ingredient substance X. For example, the specification of the pharmaceutical composition is 20 mg, which means that the mass of the active ingredient substance X is 20 mg.
在不违背本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。On the basis of not violating common knowledge in the art, the above preferred conditions can be combined arbitrarily to obtain preferred examples of the present invention.
本发明所用试剂和原料均市售可得。The reagents and raw materials used in the present invention are all commercially available.
本发明的积极进步效果在于：本发明的喹唑啉化合物或药物组合物对外周T细胞淋巴瘤和NK/T细胞淋巴瘤治疗效果好，有效率高，安全性较好，有望应用于外周T细胞淋巴瘤和NK/T细胞淋巴瘤的治疗。The positive and progressive effects of the present invention are: the quinazoline compound or pharmaceutical composition of the present invention has good therapeutic effect on peripheral T-cell lymphoma and NK/T-cell lymphoma, high effective rate and good safety, and is expected to be applied to peripheral T-cell lymphoma and NK/T-cell lymphoma. Treatment of cell lymphomas and NK/T cell lymphomas.
具体实施方式Detailed ways
制备实施例1：如式A所示的喹唑啉化合物的合成路线Preparation Example 1: Synthetic route of the quinazoline compound shown in formula A
如式A所示的喹唑啉化合物按照专利CN104557872A中记载的化合物10的制备方法制备得到，并按照专利CN110950844A中实施例8的方法重结晶。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.
制备实施例2：如式A所示的喹唑啉化合物片的处方Preparation Example 2: The prescription of the quinazoline compound tablet shown in formula A
Figure PCTCN2022087761-appb-000005
Figure PCTCN2022087761-appb-000005
a：制造过程中按50％包衣效率计算，实际批处方使用量为0.264Kg。 a : Calculated according to 50% coating efficiency in the manufacturing process, the actual batch recipe usage is 0.264Kg.
b：制造过程中按50％包衣效率计算，实际批处方使用量为2.376Kg，纯化水在包衣过程中除去。 b : Calculated according to 50% coating efficiency in the manufacturing process, the actual batch recipe usage is 2.376Kg, and purified water is removed during the coating process.
按照以下方式进行制备：Prepare as follows:
片芯制备Chip preparation
按照设计的处方组成称取处方量的如式A所示的喹唑啉化合物和各辅料，将如式A所示的喹唑啉化合物、填充剂和崩解剂分别过30目筛网，润滑剂过60目筛网；将如式A所示的喹唑啉化合物与填充剂在混合机中混合均匀，得预混物1；将崩解剂加入到预混物1中，使用混合机混合均匀，得预混物2；使用整粒机过筛预混物2，得预混物3；将预混物3和润滑剂在混合机中进行混合，得总混物料；使用配备有5mm、D型圆型冲模或11*5.5mm、上冲刻Half线键型冲模的旋转式压片机对总混物料进行压片，以分别形成包括有20mg或100mg如式A所示的喹唑啉化合物的片芯。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 tablet press with 11*5.5mm upper punched Half wire bond die to tablet the blended material to form quinazoline containing 20 mg or 100 mg, respectively, of formula A Compound tablets.
薄膜包衣片制备Preparation of film-coated tablets
将薄膜包衣预混剂粉末加入到搅拌中的纯化水中，持续搅拌45分钟，配制成薄膜包衣预混剂固含量为10％(w/w)的包衣液，采用高效包衣机对上述所描述的工艺制造的片芯包衣至包衣增重范围为2％-5％，以分别形成包括20mg或100mg如式A所示的喹唑啉化合物的薄膜包衣片。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 produced by the process described above were coated to a coating weight gain ranging from 2% to 5% to form film-coated tablets comprising 20 mg or 100 mg of the quinazoline compound of formula A, respectively.
效果实施例1：如式A所示的喹唑啉化合物及其类似物对于PI3Kδ的体外抑制活性，以及对于其它亚型的选择性Effect Example 1: In vitro inhibitory activity of the quinazoline compound represented by formula A and its analogs on PI3Kδ, and selectivity for other subtypes
见CN104557872A说明书[0538]-[0549]段。See paragraphs [0538]-[0549] of the CN104557872A specification.
效果实施例2：如式A所示的喹唑啉化合物及其类似物的药代动力学评价Effect Example 2: Pharmacokinetic evaluation of the quinazoline compound represented by formula A and its analogs
实验方法：experimental method:
选择雄性SD大鼠，分为两组，静脉给药组(iv)剂量为2mg/kg，口服灌胃给药组(po)剂量为10mg/kg。给药后，两组分别在0h，0.083h，0.25h，0.5h，1h，2h，4h，8h，24h时间点采血，分离血浆，用LCMSMS法测定大鼠静脉和灌胃给药后，血浆中的受试化合物浓度，并计算药代动力学参数。结果见表1。Male SD rats were selected and divided into two groups, the dose of intravenous administration group (iv) was 2 mg/kg, and the dose of oral gavage administration group (po) was 10 mg/kg. After administration, blood was collected from the two groups at 0h, 0.083h, 0.25h, 0.5h, 1h, 2h, 4h, 8h, and 24h, respectively, and the plasma was separated. test compound concentrations in and calculate pharmacokinetic parameters. The results are shown in Table 1.
C max：药物达峰浓度，AUC last：0点到最后可测浓度对应时间点的浓度-时间曲线下面积，F％：生物利用度。 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.
表1：如式A所示的喹唑啉化合物及其类似物对PI3Kδ抑制活性以及选择性、药代动力学数据汇总表Table 1: Summary of PI3Kδ inhibitory activity, selectivity and pharmacokinetic data of quinazoline compounds and their analogs shown in formula A
Figure PCTCN2022087761-appb-000006
Figure PCTCN2022087761-appb-000006
Figure PCTCN2022087761-appb-000007
Figure PCTCN2022087761-appb-000007
---表示未测试。--- means not tested.
从结果上，尽管几个化合物在体外都表现了很好的PI3Kδ抑制活性，结构也比较接近，但是药代动力学上表现差异很大，如式A所示的喹唑啉化合物在相同剂量下的达峰浓度、0点到最后可测浓度对应时间点的浓度-时间曲线下面积以及生物利用度都更高。From the results, although several compounds showed good PI3Kδ inhibitory activity in vitro and their structures were relatively similar, their pharmacokinetics were quite different. The quinazoline compounds shown in formula A were at the same dose The peak concentration, the area under the concentration-time curve corresponding to the time point from 0 point to the last measurable concentration, and the bioavailability were all higher.
效果实施例3：如式A所示的喹唑啉化合物的药代动力学研究Effect Example 3: Pharmacokinetic study of the quinazoline compound represented by formula A
如式A所示的喹唑啉化合物在小鼠、大鼠和犬的药代动力学研究结果Results of pharmacokinetic studies of quinazoline compounds represented by formula A in mice, rats and dogs
如式A所示的喹唑啉化合物在小鼠、大鼠和犬的药代动力学研究结果显示，在药效剂量范围内口服吸收良好，口服生物利用度分别在90％、65％和60％以上。连续7天给药后大鼠和犬体内如式A所示的喹唑啉化合物的暴露量有一定升高，约为首次给药的1.28-2.20倍，提示药物严重蓄积的风险较小。如式A所示的喹唑啉化合物在大鼠体内的清除率为中等，而在小鼠和犬体内的清除率则较慢。如式A所示的喹唑啉化合物具有广泛的组织分布，除脑组织外，如式A所示的喹唑啉化合物在其他组织中的暴露量均高于其在血浆中的暴露量。如式A所示的喹唑啉化合物的组织分布存在一定性别差异。体外抑制、诱导试验和重组酶稳定性试验结果表明如式A所示的喹唑啉化合物对CYP酶没有明显抑制和诱导作用，CYP3A4是如式A所示的喹唑啉化合物的主要代谢酶，其次是CYP2C8。如式A所示的喹唑啉化合物在体内代谢广泛，但主要以原形药物通过尿液和粪便排出体外，约50％。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. After 7 consecutive days of administration, 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 that 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. There is a certain gender difference in the tissue distribution of the quinazoline compounds represented by formula A. The results of in vitro inhibition, induction and recombinase stability tests show that the quinazoline compound shown in formula A has no obvious inhibitory and induction effect on CYP enzymes, and CYP3A4 is the main metabolic enzyme of the quinazoline compound shown in formula A, Next is CYP2C8. The quinazoline compound represented by formula A is extensively metabolized in the body, but is mainly excreted in the original form through urine and feces, about 50%.
表2：ICR小鼠、SD大鼠、Beagle犬单次口服灌胃给药后的药代动力学结果Table 2: Pharmacokinetic results of ICR mice, SD rats, and Beagle dogs after a single oral gavage administration
Figure PCTCN2022087761-appb-000008
Figure PCTCN2022087761-appb-000008
Figure PCTCN2022087761-appb-000009
Figure PCTCN2022087761-appb-000009
吸收absorb
如式A所示的喹唑啉化合物灌胃给药后，在小鼠、大鼠和比格犬体内的吸收良好，口服生物利用度分别达到了90％，65％和60％以上。在不同剂量组的大鼠和犬试验中，如式A所示的喹唑啉化合物血浆暴露量以及达峰浓度的增加接近于剂量增加的比例，提示如式A所示的喹唑啉化合物随着剂量的增加，存在线性药代动力学的特征。After oral administration of the quinazoline compound represented by formula A, the absorption in mice, rats and beagle dogs is good, and the oral bioavailability reaches 90%, 65% and 60% or more, respectively. In different dose groups of rats and dogs, the increase in plasma exposure and peak concentration of the quinazoline compound represented by Formula A was close to the dose increase, suggesting that the quinazoline compound represented by Formula A increases with There is a linear pharmacokinetic profile with increasing dose.
分布distributed
体外血浆蛋白结合率试验结果表明，如式A所示的喹唑啉化合物在0.1-30μM浓度范围内其小鼠、大鼠、比格犬和人血浆的蛋白结合率均为中度(51.1-85.6％)；在猴血浆中，低中浓度下(0.1-2μM)其蛋白结合率为中度(89.3-89.6％)，而高浓度下(30μM)的蛋白结合率为高度(90.2％)。如式A所示的喹唑啉化合物在5个种属的血浆蛋白结合率由高到低依次为：食蟹猴>人>CD1小鼠>SD大鼠>比格犬，其中食蟹猴与人的结合率相似(85-90％)，SD大鼠和比格犬的结合率相似(50-65％)。The results of the in vitro plasma protein binding rate test showed that the quinazoline compounds represented by formula A had moderate protein binding rates in mouse, rat, beagle and human plasma in the concentration range of 0.1-30 μM (51.1-30 μM). 85.6%); in monkey plasma, protein binding was moderate (89.3-89.6%) at low and intermediate concentrations (0.1-2 μM) and high (90.2%) at high concentrations (30 μM). 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%).
ICR小鼠、SD大鼠和比格犬单次静脉注射分别给予10、10和1.0mg/kg剂量后，如式A所示的喹唑啉化合物的稳态表观分布容积(V ss，L/kg)分别为4.22(雄性小鼠)、4.55(雄性大鼠)、5.18(雌性大鼠)、4.70(雄性犬)和4.08(雌性犬)，分别是各动物体内体液总量的5.82(雄性小鼠)、6.80(雄性大鼠)、7.75(雌性大鼠)、7.79(雄性犬)和6.76(雌性犬)倍，提示如式A所示的喹唑啉化合物在各动物体内有较广泛的组织分布。 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.
灌胃给予SD大鼠60mg/kg后，如式A所示的喹唑啉化合物广泛分布至各组织和脏器中，除脑组织外，如式A所示的喹唑啉化合物在其他组织中的暴露量均明显高于其在血浆中的暴露量，约为后者的2-22倍。如式A所示的喹唑啉化合物的组织分布存在一定的性别差异。雄性大鼠在各时间点的血浆和组织药物浓度都高于雌性大鼠。如式A所示的喹唑啉化合物在雄性大鼠各组织中的暴露量约为雌性大鼠的1.49-3.70倍。如式A所示的喹唑啉化合物在雄性大鼠各组织中的半衰期约2.29-5.08hr，在雌性大鼠各组织中的半衰期约2.25-4.45hr(脑组织除外)。对雄性大鼠来说，如式A所示的喹唑啉化合物在胃中的暴露量最高，然后依次为小肠、肝、肾、肺、脾、大肠、胸腺、心、睾丸、骨骼 肌、脂肪、血浆和脑。对雌性大鼠来说，如式A所示的喹唑啉化合物的最高暴露量在小肠中，然后依次为胃、肝、脾、肾、肺、大肠、胸腺、卵巢、子宫、心、骨骼肌、脂肪、血浆和脑。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. There is a certain gender difference in the tissue distribution of the quinazoline compounds represented by formula A. 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). For male rats, 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. In female rats, 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.
代谢metabolism
如式A所示的喹唑啉化合物在小鼠，大鼠，犬和人的肝微粒体中均较为稳定(半衰期>120分钟)，在猴的肝微粒体中为中等代谢(半衰期＝30-120分钟)。此外，如式A所示的喹唑啉化合物在小鼠、大鼠、犬、猴和人的体外肝细胞试验中都未见明显代谢(半衰期>120分钟)。The quinazoline compounds of formula A are stable in mouse, rat, canine and human liver microsomes (half-life > 120 min) and moderately metabolized in monkey liver microsomes (half-life = 30- 120 minutes). In addition, the quinazoline compounds of formula A were not significantly metabolized (half-life > 120 minutes) in in vitro hepatocyte assays in mice, rats, dogs, monkeys and humans.
从各种人重组酶介导下代谢物的生成来看，CYP3A4是如式A所示的喹唑啉化合物的主要代谢酶，其次是CYP2C8。虽然在CYP2C8孵育体系中如式A所示的喹唑啉化合物有20％-30％的减少，但在-NADPH和+抑制剂这两个孵育体系中也发生了同样的现象，故不能说明母药的代谢是依赖于重组酶CYP2C8。From the perspective of the generation of metabolites mediated by various human recombinases, CYP3A4 is the main metabolic enzyme of the quinazoline compound represented by formula A, followed by CYP2C8. Although 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.
如式A所示的喹唑啉化合物对人肝微粒体内的CYP 1A2、2B6、2C8、2C9、2C19、2D6及3A4无明显抑制作用(IC 50>10μM)。 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 μM).
如式A所示的喹唑啉化合物在0.4，4和40μM 3个测试浓度下，在CYP1A2，CYP2B6及CYP3A4方面，未表现出对酶活或mRNA表达的提高作用。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 μM.
ICR小鼠、SD大鼠和比格犬单次静脉注射分别给予10、10和1.0mg/kg的剂量后，如式A所示的喹唑啉化合物的总体清除率(CL，L/hr/kg)分别为1.25(雄性小鼠)、1.45(雄性大鼠)、2.18(雌性大鼠)、0.224(雄性犬)和0.191(雌性犬)，分别是各动物体内肝血流量的23.1％(雄性小鼠)、43.8％(雄性大鼠)、66.0％(雌性大鼠)、12.1％(雄性犬)和10.3％(雌性犬)，提示小鼠和犬对如式A所示的喹唑啉化合物的代谢清除能力较弱。The overall clearance of quinazoline compounds of formula A (CL, L/hr/ kg) were 1.25 (male mice), 1.45 (male rats), 2.18 (female rats), 0.224 (male dogs), and 0.191 (female dogs), which were 23.1% of the hepatic blood flow in each animal (male). mice), 43.8% (male rats), 66.0% (female rats), 12.1% (male dogs), and 10.3% (female dogs), suggesting that mice and dogs are more resistant to the quinazoline compound shown in formula A The metabolic clearance capacity is weak.
从肝微粒体中代谢物生成的种类及其相对含量，并结合如式A所示的喹唑啉化合物在肝微粒体的代谢稳定性判断，选择大鼠和犬作为啮齿和非啮齿类实验动物的安全性评价，符合药物临床前安全性评价的要求。Judging from the types of metabolites generated in liver microsomes and their relative contents, combined with the metabolic stability of the quinazoline compounds shown in formula A in liver microsomes, rats and dogs were selected as rodent and non-rodent experimental animals The safety evaluation of the drug meets the requirements of the preclinical safety evaluation of the drug.
***excretion
灌胃给予SD大鼠60mg/kg如式A所示的喹唑啉化合物后，如式A所示的喹唑啉化合物在雄性大鼠尿液、粪便及胆汁中0-72hr的***量分别为给药量的20.1±6.48％、24.5±11.1％和1.68±0.890％；而其在雌性大鼠尿液、粪便及胆汁中0-72hr的***量分别为给药量的8.11±2.62％、7.58±3.95％和10.9±1.29％。故灌胃给药后如式A所示的喹唑啉化合物在雄性和雌性SD大鼠尿粪和胆汁中的总***率分别为46.3％和26.6％。After 60mg/kg of quinazoline compound shown in formula A is given to SD rats by gavage, 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.
灌胃给予比格犬10mg/kg如式A所示的喹唑啉化合物后，如式A所示的喹唑啉化合物在雄性犬尿液和粪便中的***量分别为给药量的29.2±13.5％和19.5±16.2％，其在雌性犬尿液和粪便中的***量分别为给药量的41.4±12.4％和9.21±7.08％，故灌胃给药后如式A所示的喹唑啉化合物在雄性和雌性比格犬尿粪中的总***率分别为48.7％和50.6％。After oral administration of 10 mg/kg of the quinazoline compound shown in formula A to beagle dogs, 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.
效果实施例4：如式A所示的喹唑啉化合物对外周T细胞淋巴瘤相关细胞的抑制活性Effect Example 4: Inhibitory activity of the quinazoline compound represented by formula A on peripheral T-cell lymphoma-related cells
选择了三个外周T细胞淋巴瘤相关细胞，开展了细胞增殖抑制活性测试。Three peripheral T-cell lymphoma-related cells were selected and tested for cell proliferation inhibitory activity.
实验方法：experimental method:
分别向96孔板中(***孔除外)加入100μL待测细胞悬液。将培养板放置于二氧化碳培养箱中过夜。往各孔中加入配制好的如式A所示的喹唑啉化合物(50μM为起始浓度，通过3倍稀释，得到10个浓度梯度的如式A所示的喹唑啉化合物)。细胞板在二氧化碳培养箱中孵育72小时。向96孔板中加入25μL的CellTiter Glo试剂，避光震荡2分钟，室温避光静置10分钟，将培养板放入酶标仪中读取化学发光值，利用XLFit绘制药效抑制率曲线并计算IC 50值。 Add 100 μL of the cell suspension to be tested to the 96-well plate (except the peripheral wells). The plates were placed in a carbon dioxide incubator overnight. The prepared quinazoline compound represented by formula A (50 μM was the initial concentration, and 10 concentration gradients of the quinazoline compound represented by formula A were obtained by 3-fold dilution) were added to each well. Cell plates were incubated in a carbon dioxide incubator for 72 hours. Add 25 μL of CellTiter Glo reagent to the 96-well plate, shake it for 2 minutes in the dark, let it stand in the dark for 10 minutes at room temperature, put the culture plate into the microplate reader to read the chemiluminescence value, and use XLFit to draw the drug efficacy inhibition rate curve and analyze the results. IC50 values were calculated.
结果显示，如式A所示的喹唑啉化合物对外周T细胞淋巴瘤相关细胞没有明显的抑制活性。The results show that the quinazoline compound represented by formula A has no obvious inhibitory activity on peripheral T-cell lymphoma-related cells.
表3 如式A所示的喹唑啉化合物对外周T细胞淋巴瘤相关细胞细胞的抑制活性Table 3 Inhibitory activity of the quinazoline compounds represented by formula A on peripheral T-cell lymphoma-related cells
Figure PCTCN2022087761-appb-000010
Figure PCTCN2022087761-appb-000010
注：表中的细胞描述对应的英文如下：Note: The English corresponding to the cell descriptions in the table are as follows:
白血病，急性T细胞，T淋巴细胞：leukem Ⅰ,acute T cell,T lymphocyte；Leukemia, acute T cells, T lymphocytes: leukem Ⅰ, acute T cell, T lymphocyte;
白血病，急性T细胞，T淋巴细胞淋巴瘤，Sézary综合征，皮肤T淋巴细胞：lymphoma,Sézary syndrome,cutaneous T lymphocyte；Leukemia, acute T cells, T lymphocytic lymphoma, Sézary syndrome, cutaneous T lymphocytes: lymphoma, Sézary syndrome, cutaneous T lymphocyte;
淋巴瘤，皮肤T淋巴细胞：lymphoma,cutaneous T lymphocyte.Lymphoma, cutaneous T lymphocyte: lymphoma, cutaneous T lymphocyte.
效果实施例5：如式A所示的喹唑啉化合物的临床Ⅰb期和Ⅰa期结果Effect Example 5: Clinical Phase Ib and Phase Ia Results of Quinazoline Compounds Represented by Formula A
(1)Ⅰb期试验疗效及安全性结果(1) Efficacy and safety results of phase Ib trial
患者招募标准为：组织学确诊的接受过至少一次***性全身治疗失败或不能耐受的和/或目前尚无有效标准治疗的复发和/或难治性外周T细胞淋巴瘤(PTCL)患者和NK/T细胞淋巴瘤患者。Patient recruitment criteria were: histologically confirmed patients with relapsed and/or refractory peripheral T-cell lymphoma (PTCL) who had failed or were intolerant of at least one systemic systemic therapy and/or currently have no effective standard therapy and NK/T cell lymphoma patients.
患者服用按照制备实施例2的方法制备得到的如式A所示的喹唑啉化合物片，每日一次，口服给药，每次4片(片剂规格为20mg/片)，直到疾病进展或毒性不可耐受。The patient takes the quinazoline compound tablet as shown in formula A prepared according to the method of Preparation Example 2, once a day, orally, 4 tablets each time (tablet specification is 20mg/tablet), until disease progression or Toxicity is not tolerated.
采用修订的国际工作组(IRWG)疗效评价标准进行疗效评价，评价指标为ORR(CR+PR)及DCR(CR+PR+SD)。总缓解率(Overall response rate,ORR)；疾病控制率(Disease control rate,DCR)；CR＝完全缓解；PR＝部分缓解；SD＝病情稳定；PD＝疾病进展。The curative effect was evaluated using the revised International Working Group (IRWG) curative effect evaluation criteria, and the evaluation indicators were ORR (CR+PR) and DCR (CR+PR+SD). Overall response rate (ORR); Disease control rate (DCR); CR = complete response; PR = partial response; SD = stable disease; PD = progressive disease.
如式A所示的喹唑啉化合物片在复发和/或难治外周T细胞淋巴瘤患者和NK/T细胞淋巴瘤中展示了良好的抗肿瘤活性，共入组43例患者，其中41例已完成疗效评估，包括外周T细胞淋巴瘤非特指型16例、血管免疫母细胞性T细胞淋巴瘤16例、ALK阴性间变大性细胞淋巴瘤4例、结外NK/T细胞淋巴瘤3例、ALK阳性间变大性细胞淋巴瘤1例、单形性嗜上皮肠道T细胞淋巴瘤1例。The quinazoline compound tablet of formula A showed good antitumor activity in patients with relapsed and/or refractory peripheral T-cell lymphoma and NK/T-cell lymphoma. A total of 43 patients were enrolled, of which 41 were Efficacy evaluation has been completed, including 16 cases of peripheral T-cell lymphoma unspecified, 16 cases of angioimmunoblastic T-cell lymphoma, 4 cases of ALK-negative anaplastic large cell lymphoma, and 3 cases of extranodal NK/T cell lymphoma cases, 1 case of ALK-positive anaplastic large cell lymphoma, and 1 case of monomorphic epithelial T-cell lymphoma.
Figure PCTCN2022087761-appb-000011
Figure PCTCN2022087761-appb-000011
安全性结果：发生率高于5％且≥3级的治疗相关不良反应(TRAE)，有中性粒细胞计数降低(18.60％)、高甘油三酯血症(6.98％)、感染性肺炎(11.63％)，且均为临床可控。发生9例(20.90％)严重不良反应，结局均为“好转/恢复”，未发生结局为死亡的不良反应。Safety results: treatment-related adverse reactions (TRAEs) with an incidence rate higher than 5% and grade ≥3, including decreased neutrophil count (18.60%), hypertriglyceridemia (6.98%), infectious pneumonia ( 11.63%), and all were clinically controllable. Nine cases (20.90%) of serious adverse reactions occurred, and the outcome was "improvement/recovery", and no adverse reaction with the outcome of death occurred.
(2)Ⅰa期安全性效果(2) Phase Ia safety effect
Ⅰa期临床方案设计(爬坡和扩展方案)。Phase Ia clinical program design (climbing and expansion programs).
患者纳入标准为组织学或细胞学确诊的复发或难治B细胞血液肿瘤患者，共计纳入 患者25例。本研究分为两个阶段：剂量递增和剂量扩展；每个阶段均包括单次给药和多次给药研究。剂量递增阶段的剂量包括20mg/天、40mg/天、80mg/天、140mg/天、200mg/天。除20mg初始剂量组仅入组1例外，每个剂量组分别入组3-6例受试者，40mg剂量组入组3例，80mg剂量组入组3例，140mg剂量组入组3例，200mg剂量组入组4例。剂量扩展研究在80mg剂量组中进行。在28天观察期内均未发生剂量限制性毒性(DLT)，从不良事件的发生情况来看，如式A所示的喹唑啉化合物片单次和多次给药耐受性良好。The patient inclusion criteria were histologically or cytologically confirmed patients with relapsed or refractory B-cell hematological tumors, and a total of 25 patients were included. 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. Dose expansion studies were conducted in the 80 mg dose group. No dose-limiting toxicity (DLT) occurred during the 28-day observation period. In terms of the occurrence of adverse events, the single and multiple administrations of the quinazoline compound tablet shown in formula A were well tolerated.
根据Ⅰa期临床结果，证明如式A所示的喹唑啉化合物在复发或难治B细胞血液肿瘤患者中，20mgQD～200mgQD范围内口服给药安全性良好，患者可耐受。According to the clinical results of Phase Ia, it is proved that the quinazoline compound represented by formula A is safe and can be tolerated by oral administration in the range of 20mgQD to 200mgQD in patients with relapsed or refractory B-cell hematological tumors.
基于Ⅰa临床结果，在复发和/或难治性外周T细胞淋巴瘤和NK/T细胞淋巴瘤患者中开展如式A所示的喹唑啉化合物单臂、开放Ⅰb期临床研究，如前述(1)Ⅰb期试验安全性结果所示，研究结果提示如式A所示的喹唑啉化合物在复发和/或难治性外周T细胞淋巴瘤和NK/T细胞淋巴瘤患者中，80mgQD口服安全性可控，耐受性良好。Based on clinical results in Ia, a single-arm, open-label phase Ib clinical study of the quinazoline compound of formula A in patients with relapsed and/or refractory peripheral T-cell lymphoma and NK/T-cell lymphoma was conducted, as previously described ( 1) As shown by the safety results of the Phase Ib trial, the research results suggest that the quinazoline compound represented by formula A is safe in patients with relapsed and/or refractory peripheral T-cell lymphoma and NK/T-cell lymphoma, 80 mg QD orally is safe. Controllable and well tolerated.
(3)上市同靶点药物数据对比(3) Data comparison of listed drugs with the same target
目前FDA批准上市的PI3kδ抑制剂尚没有获批用于外周T细胞淋巴瘤的治疗。Duvelisib是一种口服PI3Kδ和γ小分子抑制剂，一项Ⅰ期临床研究(NCT01476657)治疗16例PTCL：ORR为53％，CR为13％，PR为40％。Copanlisib(BAY-80-6946)是一种静脉给药的PI3Kα和PI3Kδ抑制剂，一项Ⅱ期研究(CHRONOS-1,NCT01660451)入组84例复发/难治惰性或侵袭性淋巴瘤患者，包括14例PTCL；对PTCL患者进行疗效评估，2例(14.3％)CR，1例(7.1％)PR，ORR为21.4％。Currently FDA-approved PI3kδ inhibitors have not been approved for the treatment of peripheral T-cell lymphoma. Duvelisib is an oral PI3Kδ and γ small molecule inhibitor in a phase I clinical study (NCT01476657) in 16 patients with PTCL: ORR was 53%, CR was 13%, and PR was 40%. Copanlisib (BAY-80-6946), an intravenously administered PI3Kα and PI3Kδ inhibitor, was enrolled in a phase II study (CHRONOS-1, NCT01660451) in 84 patients with relapsed/refractory indolent or aggressive lymphoma, including 14 cases of PTCL; PTCL patients were evaluated for efficacy, 2 cases (14.3%) CR, 1 case (7.1%) PR, ORR was 21.4%.
如式A所示的喹唑啉化合物片在治疗复发和/或难治性外周T细胞淋巴瘤患者的Ⅰb期临床研究中，Ⅰb期临床研究数据表明，最佳整体疗效CR为15例，PR为11例，SD为10例，PD为5例，整体最优疗效ORR比例为63.41％(26/41)，DCR比例为87.80％(36/41)。如式A所示的喹唑啉化合物较同类药物有较明显的优势。In the phase Ib clinical study of the quinazoline compound tablet shown in formula A in the treatment of patients with relapsed and/or refractory peripheral T-cell lymphoma, the phase Ib clinical study data showed that the best overall efficacy CR was 15 cases, PR There were 11 cases, SD was 10 cases, and PD was 5 cases. The overall optimal curative effect ORR ratio was 63.41% (26/41), and the DCR ratio was 87.80% (36/41). The quinazoline compound represented by formula A has obvious advantages over similar drugs.
如式A所示的喹唑啉化合物片在治疗复发或难治性NK/T细胞淋巴瘤患者的Ⅰb期临床研究中，Ⅰb期临床研究数据表明，最佳整体疗效CR为1例，PR为1例，SD为0例，PD为1例，整体最优疗效ORR比例为66.7％(2/3)，DCR比例为66.7％(2/3)。表明在复发或难治性NK/T细胞淋巴瘤患者中，如式A所示的喹唑啉化合物同样具有较好的疗效。In the phase Ib clinical study of the quinazoline compound tablet shown in formula A in the treatment of patients with relapsed or refractory NK/T cell lymphoma, the phase Ib clinical study data showed that the best overall curative effect CR was 1 case, and PR was 1 case, SD was 0 case, PD was 1 case, the overall optimal response ORR ratio was 66.7% (2/3), and the DCR ratio was 66.7% (2/3). It is shown that in patients with relapsed or refractory NK/T cell lymphoma, the quinazoline compound represented by formula A also has good curative effect.

Claims (10)

  1. 一种物质X或药物组合物在制备药物中的应用，其特征在于，所述物质X为如式A所示的喹唑啉化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物；所述药物组合物包括所述物质X和药用辅料；所述药物为治疗外周T细胞淋巴瘤和NK/T细胞淋巴瘤的药物；A kind of application of substance X or pharmaceutical composition in the preparation of medicine, it is characterized in that, described 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 includes the substance X and pharmaceutical excipients; the drug is a drug for the treatment of peripheral T-cell lymphoma and NK/T-cell lymphoma;
    Figure PCTCN2022087761-appb-100001
    Figure PCTCN2022087761-appb-100001
  2. 如权利要求1所述物质X或药物组合物在制备药物中的应用，其特征在于，所述外周T细胞淋巴瘤为外周T细胞淋巴瘤非特指型、血管免疫母细胞性T细胞淋巴瘤、ALK阳性间变大性细胞淋巴瘤、ALK阴性间变大性细胞淋巴瘤和单形性嗜上皮肠道T细胞淋巴瘤中的一种或多种；The application of substance X or the pharmaceutical composition in the preparation of medicine according to claim 1, wherein the peripheral T-cell lymphoma is peripheral T-cell lymphoma unspecified type, angioimmunoblastic T-cell lymphoma, One or more of ALK-positive anaplastic large cell lymphoma, ALK-negative anaplastic large cell lymphoma, and monomorphic epithelial T-cell lymphoma;
    和/或，所述NK/T细胞淋巴瘤为结外NK/T细胞淋巴瘤；And/or, the NK/T cell lymphoma is extranodal NK/T cell lymphoma;
    和/或，所述外周T细胞淋巴瘤为复发和/或难治性外周T细胞淋巴瘤；And/or, the peripheral T-cell lymphoma is relapsed and/or refractory peripheral T-cell lymphoma;
    和/或，所述NK/T细胞淋巴瘤为复发和/或难治性NK/T细胞淋巴瘤。And/or, the NK/T cell lymphoma is relapsed and/or refractory NK/T cell lymphoma.
  3. 如权利要求1所述物质X或药物组合物在制备药物中的应用，其特征在于，所述外周T细胞淋巴瘤为血管免疫母细胞性T细胞淋巴瘤；The use of substance X or the pharmaceutical composition in the preparation of a medicine according to claim 1, wherein the peripheral T-cell lymphoma is angioimmunoblastic T-cell lymphoma;
    和/或，所述物质X为治疗有效量的；and/or, the substance X is in a therapeutically effective amount;
    和/或，所述药物通过口服使用；and/or, the drug is administered orally;
    和/或，所述药物为片剂或胶囊。And/or, the medicament is a tablet or a capsule.
  4. 如权利要求1所述物质X或药物组合物在制备药物中的应用，其特征在于，所述药物施用在组织学确诊的接受过至少一次***性全身治疗失败或不能耐受的和/或目前尚无有效标准治疗的复发和/或难治性外周T细胞淋巴瘤和NK/T细胞淋巴瘤患者身上。The use of the substance X or the pharmaceutical composition in claim 1 in the preparation of a medicament, characterized in that, the medicament is administered in a histologically confirmed patient who has received at least one systemic systemic treatment failure or intolerance and/or is currently In patients with relapsed and/or refractory peripheral T-cell lymphoma and NK/T-cell lymphoma for whom no effective standard therapy exists.
  5. 如权利要求1所述物质X或药物组合物在制备药物中的应用，其特征在于，以所述如式A所示的喹唑啉化合物的含量计，所述药物的施用剂量为一次0.33mg/kg-3.33mg/kg；The application of substance X or pharmaceutical composition in the preparation of medicine according to claim 1, characterized in that, based on the content of the quinazoline compound shown in formula A, the administration dose of the medicine is 0.33 mg once /kg-3.33mg/kg;
    和/或，以所述如式A所示的喹唑啉化合物的含量计，所述药物的施用剂量为20mg-200mg/天；And/or, in terms of the content of the quinazoline compound shown in formula A, the administered dose of the drug is 20mg-200mg/day;
    和/或，所述药物的施用频率为1-5次/天；And/or, the frequency of administration of the drug is 1-5 times/day;
    和/或，所述药物的施用疗程为14-84天/疗程；And/or, the administration course of the medicine is 14-84 days/course;
    和/或，所述药物共计施用1-20个疗程；And/or, the medicine is administered for a total of 1-20 courses of treatment;
    和/或，所述药物的单位剂型中，所述如式A所示的喹唑啉化合物的含量为5mg-500mg；And/or, in the unit dosage form of the medicine, the content of the quinazoline compound shown in formula A is 5mg-500mg;
    和/或，所述药物的施用对象为人类；and/or, the medicament is administered to a human being;
    和/或，所述药用辅料包括填充剂，所述填充剂为微晶纤维素、甘露醇和玉米淀粉中的一种、两种或多种；And/or, the pharmaceutical adjuvant includes a filler, and the filler is one, two or more of microcrystalline cellulose, mannitol and corn starch;
    和/或，所述药用辅料包括填充剂，所述填充剂以重量计为所述药物组合物总重量的10％-90％；And/or, the pharmaceutical adjuvant includes a filler, and the filler is 10%-90% by weight of the total weight of the pharmaceutical composition;
    和/或，当所述药物为片剂或胶囊时，所述片剂为包衣片。And/or, when the medicament is a tablet or capsule, the tablet is a coated tablet.
  6. 如权利要求5所述物质X或药物组合物在制备药物中的应用，其特征在于，以所述如式A所示的喹唑啉化合物的含量计，所述药物的施用剂量为一次0.66mg/kg-2.3mg/kg；The application of substance X or the pharmaceutical composition in the preparation of medicine according to claim 5, characterized in that, based on the content of the quinazoline compound shown in formula A, the administration dose of the medicine is 0.66 mg once /kg-2.3mg/kg;
    和/或，以所述如式A所示的喹唑啉化合物的含量计，所述药物的施用剂量为20mg/天、30mg/天、40mg/天、50mg/天、60mg/天、70mg/天、80mg/天、90mg/天、100mg/天、110mg/天、120mg/天、130mg/天、140mg/天、150mg/天、160mg/天、170mg/天、180mg/天、190mg/天或200mg/天；And/or, in terms of the content of the quinazoline compound shown in formula A, the administration dose of the drug is 20 mg/day, 30 mg/day, 40 mg/day, 50 mg/day, 60 mg/day, 70 mg/day. day, 80mg/day, 90mg/day, 100mg/day, 110mg/day, 120mg/day, 130mg/day, 140mg/day, 150mg/day, 160mg/day, 170mg/day, 180mg/day, 190mg/day or 200mg/day;
    和/或，所述药物的施用频率为1次/天、2次/天、3次/天、4次/天或5次/天；And/or, the frequency of administration of the drug is 1 time/day, 2 times/day, 3 times/day, 4 times/day or 5 times/day;
    和/或，所述药物的施用疗程为14天/疗程、28天/疗程、42天/疗程、56天/疗程、70天/疗程或84天/疗程；And/or, the administration course of the medicine is 14 days/course, 28 days/course, 42 days/course, 56 days/course, 70 days/course or 84 days/course;
    和/或，所述药物共计施用10-20个疗程；And/or, the medicine is administered for a total of 10-20 courses of treatment;
    和/或，所述药物的单位剂型中，所述如式A所示的喹唑啉化合物的含量为10mg-120mg；And/or, in the unit dosage form of the medicine, the content of the quinazoline compound shown in formula A is 10mg-120mg;
    和/或，所述药用辅料还包括崩解剂；And/or, the pharmaceutical excipient also includes a disintegrant;
    和/或，所述药用辅料还包括润滑剂；And/or, the pharmaceutical excipients also include lubricants;
    和/或，当所述填充剂为微晶纤维素、甘露醇和玉米淀粉中的一种、两种或多种时，所述填充剂为微晶纤维素和甘露醇的混合物，或，微晶纤维素和玉米淀粉的混合物；And/or, when the filler is one, two or more of microcrystalline cellulose, mannitol and corn starch, the filler is a mixture of microcrystalline cellulose and mannitol, or, microcrystalline a mixture of cellulose and cornstarch;
    和/或，所述药用辅料包括填充剂，所述填充剂以重量计为药物组合物总重量的30％-70％；And/or, the pharmaceutical adjuvant includes a filler, and the filler is 30%-70% by weight of the total weight of the pharmaceutical composition;
    和/或，当所述片剂为包衣片时，所述包衣片为薄膜包衣片。And/or, when the tablet is a coated tablet, the coated tablet is a film-coated tablet.
  7. 如权利要求6所述物质X或药物组合物在制备药物中的应用，其特征在于，以所述如式A所示的喹唑啉化合物的含量计，所述药物的施用剂量为一次1mg/kg、1.2mg/kg、1.3mg/kg、1.33mg/kg、1.4mg/kg、1.5mg/kg、1.6mg/kg、1.7mg/kg、1.8mg/kg、1.9mg/kg、2.0mg/kg、2.1mg/kg、2.2mg/kg或2.3mg/kg；The application of substance X or the pharmaceutical composition in the preparation of medicine according to claim 6, characterized in that, in terms of the content of the quinazoline compound shown in formula A, the administration dose of the medicine is 1 mg/time. kg, 1.2mg/kg, 1.3mg/kg, 1.33mg/kg, 1.4mg/kg, 1.5mg/kg, 1.6mg/kg, 1.7mg/kg, 1.8mg/kg, 1.9mg/kg, 2.0mg/ kg, 2.1 mg/kg, 2.2 mg/kg or 2.3 mg/kg;
    和/或，所述药物的施用疗程为28天/疗程；And/or, the administration course of the medicine is 28 days/course;
    和/或，所述药物组合物共计施用10、11、12、13、14、15、16、17、18、19或20个疗程；and/or, the pharmaceutical composition is administered for a total of 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 courses of treatment;
    和/或，所述药物的单位剂型中，所述如式A所示的喹唑啉化合物的含量为20-100mg；And/or, in the unit dosage form of the medicine, the content of the quinazoline compound shown in formula A is 20-100 mg;
    和/或，所述药用辅料还包括崩解剂，所述崩解剂为交联聚维酮和/或交联羧甲基纤维素钠；And/or, the pharmaceutical excipient also includes a disintegrating agent, and the disintegrating agent is crospovidone and/or croscarmellose sodium;
    和/或，所述药用辅料还包括崩解剂，所述崩解剂以重量计为所述药物组合物总重量的1％-20％；And/or, the pharmaceutical adjuvant further includes a disintegrant, and the disintegrant is 1%-20% by weight of the total weight of the pharmaceutical composition;
    和/或，所述药用辅料还包括润滑剂，所述润滑剂为硬脂酸钙、单硬脂酸甘油酯、山嵛酸甘油酯、硬脂酸镁、棕榈酸、泊洛沙姆、聚乙二醇、苯甲酸钾、苯甲酸钠、月桂基硫酸钠、硬脂酸钠、硬脂富马酸钠、硬脂酸、滑石粉、微粉硅胶和硬脂酸锌中的一种或多种；And/or, described pharmaceutical adjuvant also includes lubricant, and described lubricant is calcium stearate, glyceryl monostearate, glyceryl behenate, magnesium stearate, palmitic acid, poloxamer, One or more of polyethylene glycol, potassium benzoate, sodium benzoate, sodium lauryl sulfate, sodium stearate, sodium stearyl fumarate, stearic acid, talc, micronized silica gel and zinc stearate ;
    和/或，所述药用辅料还包括润滑剂，所述润滑剂以重量计为所述药物组合物总重量的0.1％-5.0％；And/or, the pharmaceutical excipient further includes a lubricant, and the lubricant is 0.1%-5.0% by weight of the total weight of the pharmaceutical composition;
    和/或，所述药用辅料还包括填充剂，所述填充剂以重量计为药物组合物总重量的45％-55％；And/or, the pharmaceutical excipient further includes a filler, and the filler is 45%-55% by weight of the total weight of the pharmaceutical composition;
    和/或，当所述填充剂为微晶纤维素和甘露醇的混合物时，所述微晶纤维素和所述甘露醇的质量比为10：1-1：10；And/or, when the filler is a mixture of microcrystalline cellulose and mannitol, the mass ratio of the microcrystalline cellulose and the mannitol is 10:1-1:10;
    和/或，当所述包衣片为薄膜包衣片时，所述薄膜包衣片中，与片芯重量相比，包衣剂的重量增重为2％-5％。And/or, when the coated tablet is a film-coated tablet, in the film-coated tablet, the weight gain of the coating agent is 2%-5% compared to the weight of the tablet core.
  8. 如权利要求7所述物质X或药物组合物在制备药物中的应用，其特征在于，所述药物组合物的单位剂型中，所述如式A所示的喹唑啉化合物的含量为20mg、30mg、40mg、50mg、60mg、70mg、80mg、90mg或100mg；The application of substance X or the pharmaceutical composition in the preparation of medicine according to claim 7, characterized in that, in the unit dosage form of the pharmaceutical composition, the content of the quinazoline compound shown in formula A is 20 mg, 30mg, 40mg, 50mg, 60mg, 70mg, 80mg, 90mg or 100mg;
    和/或，所述药物组合物共计施用12个疗程；And/or, the pharmaceutical composition is administered for a total of 12 courses of treatment;
    和/或，当所述药用辅料还包括崩解剂时，所述崩解剂以重量计为所述药物组合物总重量的3％-15％；And/or, when the pharmaceutical excipient further includes a disintegrant, the disintegrant is 3%-15% by weight of the total weight of the pharmaceutical composition;
    和/或，所述药用辅料还包括润滑剂，所述润滑剂为硬脂酸镁；And/or, described pharmaceutical adjuvant also includes lubricant, and described lubricant is magnesium stearate;
    和/或，所述药用辅料还包括润滑剂，所述润滑剂以重量计为所述药物组合物总重量的0.3％-2.0％；And/or, the pharmaceutical excipient further includes a lubricant, and the lubricant is 0.3%-2.0% by weight of the total weight of the pharmaceutical composition;
    和/或，当所述填充剂为微晶纤维素和甘露醇的混合物时，所述微晶纤维素和所述甘露醇的质量比为6：1-2：1，例如，4：1-3：1；And/or, when the filler is a mixture of microcrystalline cellulose and mannitol, the mass ratio of the microcrystalline cellulose and the mannitol is 6:1-2:1, for example, 4:1- 3:1;
    和/或，当所述包衣片为薄膜包衣片时，用于所述薄膜包衣片的包衣剂是基于羟丙基甲基纤维素为主要成膜聚合物的薄膜包衣预混剂；And/or, when the coated tablet is a film-coated tablet, the coating agent for the film-coated tablet is a film-coated premix based on hydroxypropyl methylcellulose as the main film-forming polymer agent;
    和/或，当所述包衣片为薄膜包衣片时，所述薄膜包衣片中，与片芯重量相比，包衣剂的重量增重为2.5％-4.5％；And/or, when the coated tablet is a film-coated tablet, in the film-coated tablet, the weight gain of the coating agent is 2.5%-4.5% compared with the weight of the tablet core;
    和/或，所述药物组合物由如下组分组成：所述物质X、填充剂、崩解剂和润滑剂。And/or, the pharmaceutical composition consists of the following components: the substance X, a filler, a disintegrant and a lubricant.
  9. 如权利要求8所述物质X或药物组合物在制备药物中的应用，其特征在于，所述药用辅料还包括崩解剂，所述崩解剂以重量计为所述药物组合物总重量的4％-8％；The application of substance X or the pharmaceutical composition in the preparation of medicine according to claim 8, wherein the pharmaceutical excipient further comprises a disintegrant, and the disintegrant is the total weight of the pharmaceutical composition by weight 4%-8% of ;
    和/或，所述药用辅料还包括润滑剂，所述润滑剂以重量计为所述药物组合物总重量的0.8％-1.4％；And/or, the pharmaceutical excipient further includes a lubricant, and the lubricant is 0.8%-1.4% by weight of the total weight of the pharmaceutical composition;
    和/或，所述药物组合物，含有以重量计的如下成分：And/or, the pharmaceutical composition contains the following components by weight:
    1)40％-50％的如式A所示的喹唑啉化合物；1) 40%-50% of the quinazoline compound shown in formula A;
    2)45％-55％的填充剂，所述填充剂为微晶纤维素、甘露醇和玉米淀粉中的一种、两种或多种；2) 45%-55% filler, which is one, two or more of microcrystalline cellulose, mannitol and corn starch;
    3)4％-8％的崩解剂，所述崩解剂为交联聚维酮和/或交联羧甲基纤维素钠；3) 4%-8% disintegrant, which is crospovidone and/or croscarmellose sodium;
    4)0.8％-1.4％的润滑剂，所述润滑剂为硬脂酸镁；4) 0.8%-1.4% lubricant, the lubricant is magnesium stearate;
    和/或，所述如式A所示的喹唑啉化合物以重量计为所述药物组合物总重量的40％；And/or, the quinazoline compound represented by formula A is 40% by weight of the total weight of the pharmaceutical composition;
    和/或，所述填充剂以重量计为所述药物组合物总重量的52.8％；And/or, the filler is 52.8% by weight of the total weight of the pharmaceutical composition;
    和/或，所述崩解剂以重量计为所述药物组合物总重量的6％；and/or, the disintegrant is 6% by weight of the total weight of the pharmaceutical composition;
    和/或，所述润滑剂以重量计为所述药物组合物总重量的1.2％；And/or, the lubricant is 1.2% by weight of the total weight of the pharmaceutical composition;
    和/或，当所述包衣片为薄膜包衣片时，用于所述薄膜包衣片的包衣剂为商购自卡乐康公司，商标名
    Figure PCTCN2022087761-appb-100002
    的薄膜包衣预混剂；     And/or, when the coated tablet is a film-coated tablet, the coating agent used for the film-coated tablet is commercially available from Colorcon Corporation under the trade name
    Figure PCTCN2022087761-appb-100002
    film coating premix;
    和/或，当所述包衣片为薄膜包衣片时，所述薄膜包衣片中，与片芯重量相比，包衣剂的重量增重为3.5％。And/or, when the coated tablet is a film-coated tablet, in the film-coated tablet, the weight gain of the coating agent is 3.5% compared to the weight of the tablet core.
  10. 如权利要求9所述物质X或药物组合物在制备药物中的应用，其特征在于，所述药物组合物由如下组分组成：The application of substance X or pharmaceutical composition in the preparation of medicine as claimed in claim 9, wherein the pharmaceutical composition is composed of the following components:
    片芯：Chip:
    1)40％的如式A所示的喹唑啉化合物；1) 40% of the quinazoline compound shown in formula A;
    2)40％的微晶纤维素和12.8％的甘露醇；2) 40% microcrystalline cellulose and 12.8% mannitol;
    3)6％的交联羧甲基纤维素钠；3) 6% croscarmellose sodium;
    4)1.2％的硬脂酸镁；4) 1.2% magnesium stearate;
    包衣：Coating:
    5)与片芯重量相比，包衣剂的重量增重为3.5％。5) The weight gain of the coating agent is 3.5% compared to the core weight.
PCT/CN2022/087761 2021-04-30 2022-04-19 Application of quinazoline compound and pharmaceutical composition WO2022228218A1 (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104557872A (en) * 2013-10-16 2015-04-29 上海璎黎药业有限公司 Condensed heterocyclic compound as well as preparation method, pharmaceutical composition and application thereof
CN110950844A (en) * 2018-09-27 2020-04-03 上海璎黎药业有限公司 Crystal form of morpholinyl quinazoline compound, preparation method and application thereof

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP7038263B2 (en) * 2019-01-16 2022-03-17 シャンハイ インリー ファーマシューティカル カンパニー リミテッド Method for Producing Morpholine Quinazoline Compound and its Intermediate

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104557872A (en) * 2013-10-16 2015-04-29 上海璎黎药业有限公司 Condensed heterocyclic compound as well as preparation method, pharmaceutical composition and application thereof
CN110950844A (en) * 2018-09-27 2020-04-03 上海璎黎药业有限公司 Crystal form of morpholinyl quinazoline compound, preparation method and application thereof

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
ANONYMOUS: "A single-arm, open-label, multicenter phase II clinical trial of the efficacy and safety of CTR20210333 YY-20394 in patients with relapsed and/or refractory peripheral T/NK-cell lymphoma", YAOZH, no. CTR20210333, 12 March 2021 (2021-03-12), pages 1 - 7, XP055981480 *
ANONYMOUS: "YINGLI PHARMACEUTICAL: Why did its Small Molecule Tumor-Targeted New Drug Obtain the "Breakthrough Therapy Variety"", SHANGHAI BIOMEDICINE INDUSTRY JOURNAL, vol. 2020, no. 9, 10 September 2020 (2020-09-10), CN, pages 10 - 12, XP009541149 *
DACHUAN HUANG; TAMMY LINLIN SONG; MAARJA‐LIISA NAIRISMÄGI; YURIKE LAURENSIA; WAN‐LU PANG; DARYL CHEAH MING ZHE; ESTHER KAM YIN WON: "Evaluation of the PIK3 pathway in peripheral T‐cell lymphoma and NK/T‐cell lymphoma", BRITISH JOURNAL OF HAEMATOLOGY, vol. 189, no. 4, 31 January 2020 (2020-01-31), Hoboken, USA, pages 731 - 744, XP071163101, ISSN: 0007-1048, DOI: 10.1111/bjh.16435 *
MULVEY ERIN, RUAN JIA: "Biomarker-driven management strategies for peripheral T cell lymphoma", JOURNAL OF HEMATOLOGY & ONCOLOGY, vol. 13, no. 1, 1 December 2020 (2020-12-01), pages 1 - 20, XP055981484, DOI: 10.1186/s13045-020-00889-z *

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