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WO2022228218A1 - Application d'un composé quinazoline et composition pharmaceutique - Google Patents

Application d'un composé quinazoline et composition pharmaceutique 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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WIPO (PCT)
Prior art keywords
day
pharmaceutical composition
cell lymphoma
weight
formula
Prior art date
Application number
PCT/CN2022/087761
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English (en)
Chinese (zh)
Inventor
许祖盛
Original Assignee
上海璎黎药业有限公司
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Publication of WO2022228218A1 publication Critical patent/WO2022228218A1/fr

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Classifications

    • 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.

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Abstract

L'invention concerne une application d'un composé quinazoline et d'une composition pharmaceutique. Le composé quinazoline est le composé quinazoline représenté par la formule A, un sel pharmaceutiquement acceptable de celui-ci, un solvate de celui-ci, ou un solvate du sel pharmaceutiquement acceptable de celui-ci ; la composition pharmaceutique comprend le composé quinazoline et un excipient pharmaceutique. Le composé quinazoline ou la composition pharmaceutique possède un bon effet thérapeutique sur le lymphome à cellules T périphériques et le lymphome à cellules NK/T, avec une haute efficacité et une bonne inocuité.
PCT/CN2022/087761 2021-04-30 2022-04-19 Application d'un composé quinazoline et composition pharmaceutique WO2022228218A1 (fr)

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CN110950844A (zh) * 2018-09-27 2020-04-03 上海璎黎药业有限公司 吗啉基喹唑啉类化合物的晶型、其制备方法及应用

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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 *
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