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WO2015043487A1 - Composé quinazoline, son procédé de préparation et son application - Google Patents

Composé quinazoline, son procédé de préparation et son application Download PDF

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Publication number
WO2015043487A1
WO2015043487A1 PCT/CN2014/087440 CN2014087440W WO2015043487A1 WO 2015043487 A1 WO2015043487 A1 WO 2015043487A1 CN 2014087440 W CN2014087440 W CN 2014087440W WO 2015043487 A1 WO2015043487 A1 WO 2015043487A1
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Prior art keywords
group
dimethoxyquinazolin
dihydroquinolin
carboxamide
yloxy
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Chinese (zh)
Inventor
李进
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SUZHOU HIGHTECHBIO BIOTECHNOLOGY Co Ltd
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SUZHOU HIGHTECHBIO BIOTECHNOLOGY Co Ltd
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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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

  • the invention relates to the technical field of medicine, in particular to a class of quinazoline tyrosine kinase inhibitors, a preparation method thereof and application thereof in preparing antitumor drugs.
  • Angiogenesis refers to the development of a new vascular system from an existing blood vessel. Normal angiogenesis occurs only in certain short-term, specific physiological processes, such as reproduction, wound healing, and the like. Abnormal angiogenesis is one of the pathological manifestations of malignant diseases such as tumors, rheumatoid arthritis, and diabetic retinopathy. Since Folkman's hypothesis that angiogenesis is closely related to the development of tumors, a large number of clinical practice and experimental studies have confirmed that inhibition of tumor-mediated angiogenesis can effectively inhibit tumor growth and metastasis.
  • the VEGF receptor is an important target for anti-angiogenesis.
  • studies on small molecule inhibitors targeting VEGF receptors have been very active, and a large number of structurally diverse inhibitors have been reported.
  • these inhibitors are all competitive inhibitors of ATP, and the concentration of ATP in cells, especially cancer cells, can reach 5mmol/L or more, so the inhibitor activity should be at least nanomolar.
  • the VEGF receptor belongs to the tyrosine kinase superfamily, and members of this family are widely involved in the transmission of biological signals in vivo. Due to the homology of the sequences, the three-dimensional structure of their ATP binding sites is highly conserved.
  • the invention uses computer-aided drug design technology and chemical synthesis means to design and synthesize novel VEGFR1, VEGFR2 based on comprehensive detection of the properties of VEGFR1, VEGFR2, VEGFR3 receptor active cavity and in-depth study of the mode of action of receptors and inhibitors.
  • the VEGFR3 receptor inhibitor series of compounds have found high-efficiency, low-toxic VEGFR1, VEGFR2, and VEGFR3 receptor-specific inhibitors.
  • R is selected from the group consisting of H, C 1-10 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 carbonyl, C 1-6 alkoxycarbonyl, carbonylamino, substituted carbonylamino, sulfonylamino, phenyl, substituted phenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, heteroaryl or Substituting a heteroaryl group.
  • substituted means that one or more hydrogen atoms are substituted with a substituent selected from the group consisting of C1-10 alkyl, halogenated C1-10 alkyl, C1-6 alkenyl, C1-6 alkynyl. , C1-6 alkoxy, halogenated C1-6 alkoxy, halogen, nitro, C1-6 alkylcarbonyl.
  • the halogenated C1-10 alkyl group comprises a trifluoromethyl group
  • the halogenated C1-6 alkoxy group comprises a trifluoromethoxy group
  • alkyl group refers to from 1 to 10 carbon atoms.
  • Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl.
  • alkoxy group refers to an oxygen-containing alkyl group.
  • the alkyl group referred to in the alkoxy group, alkylthio group, alkylcarbonyl group, alkoxycarbonyl group or the like is as defined above.
  • alkenyl group means a straight or branched hydrocarbon group of 2 to 6 carbon atoms containing one or more carbon-carbon double bonds. These include, but are not limited to, vinyl, propenyl, and butenyl.
  • aryl group refers to a monocyclic aromatic hydrocarbon having 6 carbon atoms, a bicyclic aromatic hydrocarbon having 10 carbon atoms, a tricyclic aromatic hydrocarbon having 14 carbon atoms, and 1 ring per ring. - 4 substituents.
  • Aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl.
  • cycloalkyl refers to a saturated or partially unsaturated cyclic hydrocarbon containing from 3 to 8 carbon atoms.
  • Cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl.
  • heteroaryl means a monocyclic aromatic hydrocarbon of 5-8 atoms, a bicyclic aromatic hydrocarbon of 8-12 atoms or a tricyclic aromatic hydrocarbon of 11-14 atoms, and contains one or more hetero atoms ( For example, N, O, S).
  • Heteroaryl groups include, but are not limited to, pyridinyl, furyl, imidazolyl, benzimidazolyl, pyrimidinyl, thienyl, quinolyl, fluorenyl.
  • heterocycloalkyl group means a monocyclic non-aromatic alkyl group having 3 to 8 atoms, a bicyclic ring of 8 to 12 atoms or a tricyclic hydrocarbon group of 11 to 14 atoms, and contains one or more A hetero atom (eg N, O, S).
  • Heterocycloalkyl groups include, but are not limited to, piperazinyl, pyrrolidinyl, dietyl, morpholinyl, tetrahydrofuranyl.
  • the invention also includes all corresponding pharmaceutically acceptable salts, hydrates or prodrugs of the above compounds.
  • These salts may be formed by a positively charged moiety of the compound with a negatively charged opposite charge; or by a negatively charged moiety of the compound with a positive charge.
  • the compounds of the invention may contain a non-aromatic double bond with one or more asymmetric centers. Therefore, these compounds may exist as racemic mixtures, individual enantiomers, individual diastereomers, diastereomeric mixtures, cis or trans isomers. All of these isomers are expected.
  • prodrug of structural formula I generally refers to a substance which, when administered by a suitable method, can be converted to a compound of formula I or a salt thereof by metabolic or chemical reaction in a subject.
  • R in the formula I is selected from the group consisting of H, C 1-10 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, C 1-6 alkoxy, C 1-6 An alkylthio group, a C 1-6 carbonyl group, a C 1-6 alkoxycarbonyl group, a carbonylamino group, a sulfonylamino group, a phenyl group which may have a substituent selected from the substituent group A, may have a substituent selected from the substituent group A a saturated or partially unsaturated cycloalkyl group of 3 to 8 carbon atoms of the group, a heteroaromatic hydrocarbon having 5 to 14 atoms and having 1 or more hetero atoms, or a substituent selected from the substituent group A a heterocycloalkyl group having 3 to 14 atoms and having 1 or more hetero atoms selected from the substituent of the substituent group A;
  • substituent group A is a group consisting of (1) C 1-10 alkyl group, (2) C 1-6 alkenyl group, (3) C 1-6 alkynyl group, (4) C 1-6 alkoxy, (5) halogen, (6) nitro, (7) trifluoromethyl, (8) trifluoromethoxy or (9) C 1-6 alkylcarbonyl.
  • R group in formula I is selected from the group consisting of H, C 1-10 alkyl, C 1-6 alkoxy, or selected from the following structural units:
  • R 1 and R 2 are each independently selected from the group consisting of H, halogen, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, C 1-6 alkoxy, nitro, trifluoro Methyl, trifluoromethoxy or C 1-6 carbonyl.
  • the R is
  • R 1 is hydrogen and R 2 is a meta substitution.
  • the R group is selected from each of the R groups in the compounds of Table 1.
  • the compound of formula (I) of the invention is selected from the group consisting of:
  • the compound of the present invention can be prepared in the form of a pharmaceutically acceptable salt according to a conventional method; including organic acid salts and inorganic acid salts thereof: inorganic acids including, but not limited to, hydrochloric acid, sulfuric acid, phosphoric acid, diphosphoric acid, hydrobromic acid, nitric acid, etc.
  • organic acids include, but are not limited to, acetic acid, maleic acid, fumaric acid, tartaric acid, succinic acid, lactic acid, p-toluenesulfonic acid, salicylic acid, oxalic acid, and the like.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable excipient or carrier, and the above-mentioned compound or each optical isomer thereof, each crystal form, a pharmaceutically acceptable inorganic or organic salt, Hydrate, solvate or prodrug.
  • the invention also provides the use of a compound according to the invention, or each of its optical isomers, each crystalline form, a pharmaceutically acceptable inorganic or organic salt, hydrate, solvate or prodrug, which is used A tyrosine kinase inhibitor is prepared.
  • the invention also provides the use of a compound according to the invention, or each of its optical isomers, each crystalline form, a pharmaceutically acceptable inorganic or organic salt, hydrate, solvate or prodrug, which is used A medicament for inhibiting tyrosine kinase activity or for preparing a treatment, prevention, and alleviation of a disease associated with excessive tyrosine kinase activity.
  • the disease associated with excessive activity of tyrosine kinase is selected from the group consisting of a tumor, including but not limited to liver cancer, lung cancer, brain tumor, stomach cancer, kidney cancer, colon cancer, breast cancer, ovarian cancer. , prostate cancer, bone cancer, leukemia, skin cancer.
  • the VEGF receptor family is the most closely related to angiogenesis in the currently known members of the tyrosine kinase family, and those skilled in the art can expect to have a good inhibitory effect on VEGF receptor family members. Compounds should also have a good inhibitory effect on tumor angiogenesis.
  • the present invention also provides the use of the compound of the present invention, or each of its optical isomers, each crystalline form, a pharmaceutically acceptable inorganic or organic salt, hydrate, solvate or prodrug thereof. It is used to prepare angiogenesis inhibitors.
  • the invention also provides the use of a compound according to the invention, or each of its optical isomers, each crystalline form, a pharmaceutically acceptable inorganic or organic salt, hydrate, solvate or prodrug, which is used A medicament for preventing or treating a tumor is prepared.
  • the compounds of the present invention were tested at a molecular level for pharmacological activity, and the results showed that the compounds generally have good inhibitory activity against tyrosine kinases in vitro, particularly It has good inhibitory activity against three members of the VEGF receptor family, VEGFR1, VEGFR2 and VEGFR3.
  • Figure 1 is an X-ray single crystal diffraction pattern of the compound ZLZ-KZL-06.
  • the reaction solution was transferred to a separatory funnel, and the aqueous layer was separated.
  • the organic layer was washed twice with water (50 ml), and the organic layer was stood still, and pale yellow crystals were gradually separated and filtered to give a dry solid 28 g.
  • the butanone was purified to obtain 22 g of pure product. Yield: 65.3%.
  • the reaction solution was transferred to a separatory funnel, and the chloroform layer was washed twice with water and 10 ml, and the chloroform layer was washed once with 5 ml of a saturated sodium hydrogencarbonate solution, and then washed with water (10 ml) and washed twice, and the chloroform layer was anhydrous magnesium sulfate 1.5. After drying for 1 hour, the mixture was filtered, and then evaporated to dryness to give a yellow solid, and chloroform-n-decane was purified to yield 0.21 g. Yield: 28.1%.
  • the reaction solution was transferred to a separatory funnel, and the chloroform layer was washed twice with water and 10 ml, and the chloroform layer was washed once with 5 ml of a saturated sodium hydrogencarbonate solution, and then washed with water (10 ml) and washed twice, and the chloroform layer was anhydrous magnesium sulfate 1.5. g dry for 1 hour, filter, distill off most of the chloroform, add an appropriate amount of n-hexane, clarify, stand overnight, slowly precipitate the solid, and filter to give a solid. The solid was purified by chloroform-n-hexane to obtain a pure product (0.18 g). Yield: 24.3%.
  • the reaction solution was transferred to a separatory funnel, and the chloroform layer was washed twice with water and 10 ml, and the chloroform layer was washed once with 5 ml of a saturated sodium hydrogencarbonate solution, and then washed with water (10 ml) and washed twice, and the chloroform layer was anhydrous magnesium sulfate 1.5.
  • the mixture was dried for 1 hour, filtered, and evaporated to dryness to dryness crystals. Yield: 21.9%.
  • the reaction solution was transferred to a separatory funnel, and the chloroform layer was washed twice with water and 10 ml, and the chloroform layer was washed once with 5 ml of a saturated sodium hydrogencarbonate solution, and then washed with water (10 ml) and washed twice, and the chloroform layer was anhydrous magnesium sulfate 1.5.
  • the mixture was dried for 1 hour, filtered, and evaporated to dryness to dryness. Yield: 41.1%.
  • the reaction solution was transferred to a separatory funnel, and the chloroform layer was washed twice with water and 10 ml, and the chloroform layer was washed once with 5 ml of a saturated sodium hydrogencarbonate solution, and then washed with water (10 ml) and washed twice, and the chloroform layer was anhydrous magnesium sulfate 1.5.
  • the crystal structure of ZLZ-KZL-06 was measured on a Bruker APEX DUO (Double-Source Micro-Job Structure Analyzer).
  • the crystal structure data is as follows:
  • the R 1 value of all diffraction points is 0.1342, and the wR 2 value of all diffraction points is 0.2838;
  • the reaction solution was transferred to a separatory funnel, and the chloroform layer was washed twice with water and 10 ml, and the chloroform layer was washed once with 5 ml of a saturated sodium hydrogencarbonate solution, and then washed with water (10 ml) and washed twice, and the chloroform layer was anhydrous magnesium sulfate 1.5.
  • the reaction solution was transferred to a separatory funnel, and the chloroform layer was washed twice with water and 10 ml, and the chloroform layer was further saturated with sodium hydrogencarbonate.
  • the solution was washed once with 5 ml of water, and then washed with water (10 ml) and shaken twice, and the chloroform layer was dried over 1.5 g of anhydrous magnesium sulfate for 1 hour, filtered, and evaporated to dryness to give a yellow solid solid, which was stirred in 10 ml of methanol and left to give a solid.
  • Crude column chromatography, mobile phase: methylene chloride: petroleum ether 1 : 5 obtained white solid, dried to yield 0.15 g. Yield: 21.1%.
  • the reaction solution was transferred to a separatory funnel, and the chloroform layer was washed twice with water and 10 ml, and the chloroform layer was washed once with 5 ml of a saturated sodium hydrogencarbonate solution, and then washed with water (10 ml) and washed twice, and the chloroform layer was anhydrous magnesium sulfate 1.5. g dry for 1 hour, filter, and chloroform to give a yellow sticky solid. Add 10 ml of methanol and stir, and let stand to give a solid. The crude product is dissolved in 2 ml of dichloromethane, then 6 ml of petroleum ether, 4 ml of ethyl acetate, clarified, and allowed to stand. The crystals were gradually precipitated to obtain a white solid, which was dried to give a pure product of 0.18 g. Yield: 25.4%.
  • the reaction solution was transferred to a separatory funnel, and the chloroform layer was washed twice with water and 10 ml, and the chloroform layer was washed once with 5 ml of a saturated sodium hydrogencarbonate solution, and then washed with water (10 ml) and washed twice, and the chloroform layer was anhydrous magnesium sulfate 1.5.
  • the mixture was dried for 1 hour, filtered, and evaporated to dryness to give a yellow solid. Yield: 30%.
  • the reaction solution was transferred to a separatory funnel, and the chloroform layer was washed twice with water and 10 ml, and the chloroform layer was washed once with 5 ml of a saturated sodium hydrogencarbonate solution, and then washed with water (10 ml) and washed twice, and the chloroform layer was anhydrous magnesium sulfate 1.5.
  • the mixture was dried for 1 hour, filtered, and evaporated to dryness to give a yellow solid. Yield: 20.3%.
  • the reaction solution was transferred to a separatory funnel, and the chloroform layer was washed twice with water and 10 ml, and the chloroform layer was washed once with 5 ml of a saturated sodium hydrogencarbonate solution, and then washed with water (10 ml) and washed twice, and the chloroform layer was anhydrous magnesium sulfate 1.5.
  • the mixture was dried for 1 hour, filtered, and evaporated to dryness to give a yellow solid.
  • the reaction solution was transferred to a separatory funnel, and the chloroform layer was washed twice with water and 10 ml, and the chloroform layer was washed once with 5 ml of a saturated sodium hydrogencarbonate solution, and then washed with water (10 ml) and washed twice, and the chloroform layer was anhydrous magnesium sulfate 1.5. g dry for 1 hour, filter, and lyophilize chloroform to obtain a yellow solid.
  • the crude product was dissolved in 4 ml of chloroform, and then heated under reflux. 5 ml of n-hexane was added, clarified, and allowed to stand, crystals were gradually precipitated, filtered, and dried to obtain a pure product of 0.23 g. , Yield: 28.8%.
  • the reaction solution was transferred to a separatory funnel, and the chloroform layer was washed twice with water and 10 ml, and the chloroform layer was washed once with 5 ml of a saturated sodium hydrogencarbonate solution, and then washed with water (10 ml) and washed twice, and the chloroform layer was anhydrous magnesium sulfate 1.5.
  • the mixture was dried for 1 hour, filtered, and evaporated to dryness to give a yellow solid.
  • the crude product was dissolved in dichloromethane, and then purified and purified to yield a pure product of 0.19 g, yield: 24.8%.
  • the reaction solution was transferred to a separatory funnel, and the chloroform layer was washed twice with water and 10 ml, and the chloroform layer was washed once with 5 ml of a saturated sodium hydrogencarbonate solution, and then washed with water (10 ml) and washed twice, and the chloroform layer was anhydrous magnesium sulfate 1.5.
  • the mixture was dried for 1 hour, filtered, and evaporated to dryness to give a yellow solid.
  • the crude product was dissolved in methylene chloride.
  • the reaction solution was transferred to a separatory funnel, and the chloroform layer was washed twice with water and 10 ml, and the chloroform layer was washed once with 5 ml of a saturated sodium hydrogencarbonate solution, and then washed with water (10 ml) and washed twice, and the chloroform layer was anhydrous magnesium sulfate 1.5.
  • the mixture was dried for 1 hour, filtered, and evaporated to dryness to give a yellow solid.
  • the crude product was dissolved in dichloromethane.
  • the reaction solution was transferred to a separatory funnel, and the chloroform layer was washed twice with water and 10 ml, and the chloroform layer was washed once with 5 ml of a saturated sodium hydrogencarbonate solution, and then washed with water (10 ml) and washed twice, and the chloroform layer was anhydrous magnesium sulfate 1.5.
  • the mixture was dried for 1 hour, filtered, and evaporated to dryness to give a yellow solid.
  • the crude product was dissolved in methylene chloride.
  • the reaction solution was transferred to a separatory funnel, and the chloroform layer was washed twice with water and 10 ml, and the chloroform layer was washed once with 5 ml of a saturated sodium hydrogencarbonate solution, and then washed with water (10 ml) and washed twice, and the chloroform layer was anhydrous magnesium sulfate 1.5.
  • the mixture was dried for 1 hour, filtered, and evaporated to dryness to give a yellow solid.
  • the crude product was dissolved in dichloromethane, and then purified and purified to give a pure product (0.31 g, yield: 42.5%).
  • the reaction solution was transferred to a separatory funnel, and the chloroform layer was washed twice with water and 10 ml, and the chloroform layer was washed once with 5 ml of a saturated sodium hydrogencarbonate solution, and then washed with water (10 ml) and washed twice, and the chloroform layer was anhydrous magnesium sulfate 1.5.
  • the mixture was dried for 1 hour, filtered, and evaporated to dryness to give a yellow solid.
  • the crude product was dissolved in methylene chloride.
  • the reaction solution was transferred to a separatory funnel, and the chloroform layer was washed twice with water and 10 ml, and the chloroform layer was washed once with 5 ml of a saturated sodium hydrogencarbonate solution, and then washed with water (10 ml) and washed twice, and the chloroform layer was anhydrous magnesium sulfate 1.5.
  • the mixture was dried for 1 hour, filtered, and evaporated to dryness to give a yellow solid.
  • the crude material was dissolved in methylene chloride, and then purified to yield 0.21 g.
  • the reaction solution was transferred to a separatory funnel, and the chloroform layer was washed twice with water and 10 ml, and the chloroform layer was washed once with 5 ml of a saturated sodium hydrogencarbonate solution, and then washed with water (10 ml) and washed twice, and the chloroform layer was anhydrous magnesium sulfate 1.5. g drying for 1 hour, filtration, evaporation of chloroform to obtain a yellow solid, the crude product was dissolved in dichloromethane, and then purified by adding n-decane to a pure amount of 0.18 g. Yield: 23.4%.
  • the reaction solution was transferred to a separatory funnel, and the chloroform layer was washed twice with water and 10 ml, and the chloroform layer was washed once with 5 ml of a saturated sodium hydrogencarbonate solution, and then washed with water (10 ml) and washed twice, and the chloroform layer was anhydrous magnesium sulfate 1.5.
  • the mixture was dried for 1 hour, filtered, and evaporated to dryness to give a yellow solid.
  • the crude product was dissolved in methylene chloride, and then purified to yield 0.22 g.
  • the reaction solution was transferred to a separatory funnel, and the chloroform layer was washed twice with water and 10 ml, and the chloroform layer was washed once with 5 ml of a saturated sodium hydrogencarbonate solution, and then washed with water (10 ml) and washed twice, and the chloroform layer was anhydrous magnesium sulfate 1.5.
  • the mixture was dried for 1 hour, filtered, and evaporated to dryness to give a yellow solid.
  • the crude product was dissolved in methylene chloride, and then purified to yield purified product (0.35 g, yield: 46.7%).
  • the reaction solution was transferred to a separatory funnel, and the chloroform layer was washed twice with water and 10 ml, and the chloroform layer was washed once with 5 ml of a saturated sodium hydrogencarbonate solution, and then washed with water (10 ml) and washed twice, and the chloroform layer was anhydrous magnesium sulfate 1.5. g dry for 1 hour, filtered, and evaporated to dryness to give a yellow solid.
  • the crude product was added to methanol (8 ml) and heated to reflux for 10 minutes. After filtration, the filter cake was dissolved in dichloromethane, and then purified by adding proper amount of n-decane to obtain a pure product of 0.47 g, yield: 62.7%. .
  • the reaction solution was transferred to a separatory funnel, and the chloroform layer was washed twice with water and 10 ml, and the chloroform layer was washed once with 5 ml of a saturated sodium hydrogencarbonate solution, and then washed with water (10 ml) and washed twice, and the chloroform layer was anhydrous magnesium sulfate 1.5.
  • the mixture was dried for 1 hour, filtered, and evaporated to dryness to give a yellow solid.
  • the crude product was dissolved in methylene chloride.
  • the reaction solution was transferred to a separatory funnel, and the chloroform layer was washed twice with water and 10 ml, and the chloroform layer was washed once with 5 ml of a saturated sodium hydrogencarbonate solution, and then washed with water (10 ml) and washed twice, and the chloroform layer was anhydrous magnesium sulfate 1.5.
  • the mixture was dried for 1 hour, filtered, and evaporated to dryness crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj
  • Test Example 1 Inhibition of tyrosine kinase activity test in vitro
  • the EDTA was formulated to stop the buffer.
  • the test sample is formulated into a 10 mM storage solution, and diluted to the desired concentration with a buffer solution while ensuring a DMSO concentration of 10%; if only the inhibition rate at a certain concentration is measured, a concentration is used. If you need to determine the IC 50 value, the initial concentration is 10 mM, the dilution factor is 3, 10 concentrations are set, and each concentration is set.
  • kinase was added to the base buffer to prepare a kinase buffer; FAM-labeled peptide and ATP were added to the base buffer to prepare a peptide buffer.
  • VEGFR-1 FLT1
  • VEGFR-2 KDR
  • VEGFR-3 FLT4
  • VEGFR-1 FLT1
  • VEGFR-2 KDR
  • VEGFR-3 FLT4
  • VEGFR inhibition experiments showed that the compounds tested had certain inhibitory effects on VEGFR-1 (FLT1), VEGFR-2 (KDR) or VEGFR-3 (FLT4), and some of the compounds were strong against all three receptors. Inhibition.
  • Dissolution 1 mL of methanol was added and dissolved in 4 mL of DMSO to a final concentration of 0.6 mg/mL.
  • Nebulizer pressure 40 psig; drying gas temperature: 350 ° C
  • Nebulizer pressure 40 psig; drying gas temperature: 350 ° C
  • Nebulizer pressure 40 psig; drying gas temperature: 350 ° C
  • a series of concentrations of ZLZ-KZL-05, ZLZ-KZL-11 and ZLZ-KZL-27 are prepared: 20 ⁇ mol/L, 10 ⁇ mol/L, 5 ⁇ mol/L, 2 ⁇ mol/L, 1 ⁇ mol/L, 0.5 ⁇ mol/L, 0.2 ⁇ mol /L, 0.1 ⁇ mol/L.
  • Inoculated cells A single Caco-2 cell (derived from ATCC) suspension was formulated in MEM medium containing 10% fetal bovine serum, and seeded into 96-well plates at 5000 cells per well.
  • the Caco-2 cell absorption model was administered at a concentration of ⁇ 2% inhibition against Caco-2 cells, and the apparent permeability coefficient was measured. As a result, the three compounds 20 ⁇ mol/L, 10 ⁇ mol/L, and 5 ⁇ mol/L showed significant cytostatic effects on Caco-2 cells. Finally, the safe concentration of ZLZ-KZL-27 at a concentration of 0.5 ⁇ M was selected for Caco- 2 cell transmittance test.
  • Caco-2 cells were cultured in MEM medium (containing 10% FBS, 1% NEAA, 100 U ⁇ mL-1 penicillin-streptomycin, 10 mmol ⁇ L-1 HEPES), and a 37 ° C 5% CO 2 incubator. After 21 days of cell culture, the cell model was verified, and cells with cell transmembrane resistance greater than 600 ⁇ cm 2 and sodium fluorescein permeability less than 0.6% ⁇ h -1 ⁇ cm -2 were selected for drug transport experiments.
  • MEM medium containing 10% FBS, 1% NEAA, 100 U ⁇ mL-1 penicillin-streptomycin, 10 mmol ⁇ L-1 HEPES
  • the cells were carefully washed three times with HBSS solution, and the last time was incubated in the incubator for 30 min, and the HBSS solution was blotted dry.
  • the blank control group was added with HBSS solution on both sides of AP and BL.
  • the administration group was added with 0.5 ⁇ M 2N-27 HBSS solution (AP side 0.5 ml, BL side 1.5 ml) on the administration side, and blank HBSS solution was added to the receiving side.
  • the culture plate was incubated in an incubator, and 100 ⁇ L of the solution on the BL side and the AP side at 0, 30, 60, 90 and 120 min were collected, and 100 ⁇ L of the blank HBSS solution was added after sampling, and the sample was frozen in a refrigerator at -20 ° C.
  • the chemical composition in the transport liquid was quantitatively analyzed by HPLC.
  • HBSS solution Take ZBZ-KZL-27 with HBSS solution to prepare HBSS solution with concentration of 1 ⁇ mol/mL, 0.5 ⁇ mol/mL, 0.25 ⁇ mol/mL, 0.125 ⁇ mol/mL, 0.0625 ⁇ mol/mL, 0.3125 ⁇ mol/mL; take 100 ⁇ L HBSS solution+ 300 ⁇ L (with internal standard) acetonitrile.
  • the linear sample was obtained by vortexing for 20 min to obtain the supernatant; the internal standard solution was prepared with acetonitrile: 100 ng/mL ZLZ-KZL-27.
  • the measured apparent permeability coefficient P app of the compound is greater than 10 -5 , and it is generally considered that the apparent permeability coefficient P app of more than 10 -6 indicates that the oral absorption of the compound is good. This indicates that the absorption characteristics of ZLZ-KZL-27 are very good. Since the compounds provided in the present application all have the same parent core and the chemical structure difference between them is small, those skilled in the art should be able to predict that the compound provided by the present application should Both have good absorption and it is expected to develop oral preparations with high bioavailability.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
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  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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Abstract

La présente invention concerne le domaine technique des médicaments, en particulier, un inhibiteur de quinazoline tyrosine kinase ainsi que son procédé de préparation et son application dans la préparation de médicaments anti-tumoraux. Le composé a une formule développée (I). Le composé selon la présente invention présente une excellente activité inhibitrice de tyrosine kinase, en particulier sur le VEGFR1, le VEGFR2 et le VEGFR3. Une recherche sur la vitesse de métabolisme de microsome hépatique et sur les caractéristiques d'absorption dans un modèle Caco-2 est également réalisée concernant certains des composés préférés.
PCT/CN2014/087440 2013-09-26 2014-09-25 Composé quinazoline, son procédé de préparation et son application Ceased WO2015043487A1 (fr)

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CN103509005B (zh) * 2013-09-26 2015-04-08 苏州海特比奥生物技术有限公司 喹唑啉类化合物及其制备方法与应用
CN106892898B (zh) * 2015-12-18 2021-02-05 陕西师范大学 氮杂糖衍生化的喹唑啉类化合物

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Publication number Priority date Publication date Assignee Title
WO2002032872A1 (fr) * 2000-10-20 2002-04-25 Eisai Co., Ltd. Composes a noyau aromatique azote
CN103509005A (zh) * 2013-09-26 2014-01-15 苏州海特比奥生物技术有限公司 喹唑啉类化合物及其制备方法与应用

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BRPI0017548B8 (pt) * 1999-02-10 2023-05-02 Astrazeneca Ab Composto

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002032872A1 (fr) * 2000-10-20 2002-04-25 Eisai Co., Ltd. Composes a noyau aromatique azote
CN103509005A (zh) * 2013-09-26 2014-01-15 苏州海特比奥生物技术有限公司 喹唑啉类化合物及其制备方法与应用

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