WO2013143319A1 - Dérivé de quinazoline et utilisation associée - Google Patents

Dérivé de quinazoline et utilisation associée Download PDF

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Publication number
WO2013143319A1
WO2013143319A1 PCT/CN2012/086251 CN2012086251W WO2013143319A1 WO 2013143319 A1 WO2013143319 A1 WO 2013143319A1 CN 2012086251 W CN2012086251 W CN 2012086251W WO 2013143319 A1 WO2013143319 A1 WO 2013143319A1
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quinazoline
isoxazole
phenyl
isoxazol
alkoxy
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PCT/CN2012/086251
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English (en)
Chinese (zh)
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卢灿忠
雍建平
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中国科学院福建物质结构研究所
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Publication of WO2013143319A1 publication Critical patent/WO2013143319A1/fr

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    • 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
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • 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
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a novel structure of a quinazoline derivative having a heterocyclic oxazole heterocyclic ring, a pharmaceutical composition containing the same, and a use thereof, and more particularly to inhibiting epidermal growth factor protein butter cracking EGFR-TK) active quinazoline compound or a pharmaceutical composition thereof, which inhibits colorectal cancer fineness & strain (HCT-116) and human lung cancer lintel (A549) activity, some compounds on epidermis
  • the growth factor receptor chromium oxyacid ( EGFR-TK ) has strong inhibitory activity, and can be used as a drug or a lead compound for treating diseases such as tumors and cancers associated with protein proline stimulating.
  • Epidermal growth factor binds to Epidermal Growth Factor Receptor (EGFR) to activate the activity of alanine kinase and thereby activate the response leading to cell proliferation.
  • EPF Epidermal growth factor
  • EGFR Epidermal Growth Factor Receptor
  • Overexpression and activity enhancement of EGFR Can eventually lead to uncontrollable cell division.
  • the epidermal growth factor receptor chrome-acid sensitizing enzyme (EGFR-TK) is the first discovered protein, which is widely distributed in the cell membrane of human tissues. It is mostly in 3 ⁇ 4Jit tumors (eg, bladder cancer, non-small). Overexpression in fine J ⁇ cancer, ovarian cancer, breast cancer, gastric cancer, esophageal cancer, etc., the intracellular region of EGFR has a binding site of three monuments (ATP), and EGFR inhibitors can compete with ATP binding sites. The combination of dots inhibits the phosphorylation of EGFR, blocks the signaling of downstream signals, and inhibits the growth, differentiation and metastasis of tumor cells. The treatment of tumors with EGFR receptors as a defect is very active in cancer therapy today. One of the fields. It has also achieved remarkable results in clinical research. Among them, the study of small molecule compounds with quinazoline as the mother core is the most prominent.
  • Patent Application Publication Nos. W096/33977, W096/33978, W096/33979, WO%/33980, W096/33981, WO97/30034, WO97/30035, W097/38994, W098/13354, WO00/55141, WO00/56720, WO02 /41882, WO03/82290, EP566226 and EP837063 disclose certain quinazoline compounds which carry an anilino group on 4 and carry a compound on 6- and/or 7 with an acid sulphate inhibitory activity All the above cited citations are for reference.
  • the invention is based on erlotinib and ectinib, introducing an isoxazole heterocycle into a quinazoline core, synthesizing a series of quinazoline compounds containing an isoxazole heterocycle, inhibiting epidermal growth factor protein tyrosine in vitro Acid kinase (EGFR-TK) activity indicates that the compound has strong anti-EGFR-TK activity and can be used as an antitumor drug or a lead compound.
  • EGFR-TK epidermal growth factor protein tyrosine in vitro Acid kinase
  • Activity studies have shown that the compound has an inhibitory effect on EGFR-TK activity as an active ingredient.
  • the compound is used as an active ingredient against the activity of colorectal cancer cell line (HCT-116) and human lung cancer cell line (A549), and can be used as a lead compound for antitumor.
  • the compound constitutes a pharmaceutical composition either alone or in combination with one or more pharmaceutically acceptable, inert, non-toxic excipients or carriers.
  • And 11 7 are each independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 alkoxy, hydroxy C alkyl, hydroxy C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkoxy, C 3-8 cycloalkoxy, aryl optionally substituted by R 6 , optionally substituted heteroaryl , nitro, amino, C 1-6 alkyl di(C 1-6 alkyl) containing at least one heterocycloalkoxy selected from the group consisting of N, 0, S heteroatoms;
  • Z is -NR4-, C(R 5 ) 2 , S or -0-, wherein is hydrogen or C 1-3 pit group, R 5 is the same or different and is selected from hydrogen or C 1-3 alkyl;
  • R 3 is selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy or halogenated C 1-6 alkyl;
  • R6 is each independently selected from the group consisting of hydrogen, hydroxy, decyl, cyano, nitro, halogen, c1-6 alkyl, c1-6 alkoxy; C1-6 alkylthio, halo C 1-6 alkane a group, or a halogenated C 1-6 alkoxy group;
  • n is an integer from 0 to 5.
  • And 11 7 are each independently selected from the group consisting of hydrogen, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkoxy C 1-3 alkoxy, optionally substituted phenyl, a substituted pyridyl group, a nitro group, a C 3-8 heterocycloalkoxy group containing at least one hetero atom selected from N, O, S;
  • Z is -NH-, CH 2 or -0-;
  • R 3 is selected from hydrogen, fluorine, chlorine, bromine, methyl, decyloxy or trifluoromethyl, and n is preferably from 1 to 4, more preferably from 2 to 3.
  • And 11 7 are each independently selected from the group consisting of hydrogen, C 1-3 alkyl, C 1-3 alkoxy, C 1-6 alkoxy C 1-6 alkoxy, optionally substituted phenyl, nitrate base;
  • Z is -NH-, -CH 2 or -0-;
  • R6 is each independently selected from the group consisting of hydrogen, d-C 3 alkyl, hydroxy, halogen, C 1-3 alkoxy;
  • R 3 is selected from hydrogen, fluorine, chlorine, bromine, decyl, methoxy or trifluoromethyl, and n is preferably from 1 to 4, more preferably from 2 to 3.
  • Z is -NH- or -0-; and is hydrogen, C 1-3 alkoxy group,
  • R 7 is hydrogen or benzene;
  • R6 is each independently selected from the group consisting of hydrogen, pit, hydroxy, halogen, C 1-3 alkoxy; R 3 is ortho or para to the isoxazole ring, more preferably 4-fluoro, 4-chloro, 2-chloro 4-bromo, 2,4-dichloro, 4-indenyl, 4-methoxy, hydrogen, 4-trifluorodecyl or 2,4-dimethoxy.
  • Z is -NR4-, C(R 5 ) 2 , S or -0-, wherein is hydrogen or C 1-3 pit group, R 5 is the same or different and is selected from hydrogen or C 1-3 alkane Base
  • R 3 is selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, C w alkoxy or halogenated C 1-6 alkyl;
  • R6 is independently selected from hydrogen, a hydroxyl group, a mercapto group, a cyano group, J-, nitro, halo, C 1-6 alkyl, C 1-6 alkoxy; C 1-6 alkylthio group, halogeno C 1 -6 alkyl, or halogenated C 1-6 alkoxy; n is an integer from 0 to 5.
  • Z is -NR4-, C(R 5 ) 2 , S or -0-, wherein R 4 is hydrogen or d Cs), R 5 is the same or different and is selected from hydrogen or C 1-3 alkyl;
  • R 3 is selected from hydrogen, halogen, C w alkyl, C w alkoxy or halogenated C w alkyl; n is an integer from 0 to 5.
  • R 2 is hydrogen, a C 1-3 alkoxy group, a C 1-6 alkoxy C 1-6 alkoxy group, and at least one selected from the group consisting of N, a C 3-8 heterocycloalkoxy group of an O, S hetero atom;
  • Z is -NH-, CH 2 or -0-;
  • R 3 is selected from hydrogen, fluorine, chlorine, bromine, decyl, methoxy or trifluoromethyl, and n is preferably from 1 to 4, more preferably from 2 to 3.
  • Z is -NH- or -0-; and is hydrogen, C 1-3 alkoxy group,
  • R 3 is preferably ortho or para to the isoxazole ring, more preferably 4-fluoro, 4-chloro, 2-chloro, 4-bromo,
  • and 11 7 are each independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 alkoxy, hydroxy C 1-6 alkyl, hydroxy C 1-6 alkoxy, halo C 1-6 Alkyl, halo C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkoxy, C 3-8 cycloalkoxy, aryl optionally substituted by R 6 , optionally substituted Heteroaryl, nitro, amino, C 1-6 alkylamino, bis(C 1-6 alkyl)amino; heterocycloalkoxy containing at least one heteroatom selected from N, O, S;
  • Z is -NR4-, C(R 5 ) 2 , S or -0-, wherein is hydrogen or C 1-3 pit group, R 5 is the same or different and is selected from hydrogen or C 1-3 alkyl;
  • R 3 is selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy or halogenated C 1-6 alkyl;
  • R6 is each independently selected from the group consisting of hydrogen, hydroxy, decyl, cyano, nitro, halogen, c1-6 alkyl, c1-6 alkoxy; C1-6 alkylthio, halo C 1-6 alkane a group, or a halogenated C 1-6 alkoxy group;
  • n is an integer from 0 to 5.
  • R and R 7 are each independently selected from the group consisting of hydrogen, C 1-6 pit group, C 1-6 alkoxy group, halogenated C 1-6 alkyl group, halogenated C 1- 6 alkoxy, C 1-6 alkoxy C 1-6 alkoxy, C 3-8 cycloalkoxy, aryl optionally substituted by R 6 , heteroaryl optionally substituted by R 6 , nitro , amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino;
  • Z is -NR4-, C(R 5 ) 2 , -S- or -0-, wherein R 4 is hydrogen or a C 1-3 pit group, and R 5 is the same or different and is selected from hydrogen or C 1-3 alkyl;
  • R 3 is selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, C w alkoxy or halogenated C 1-6 alkyl;
  • R6 is independently selected from hydrogen, a hydroxyl group, a mercapto group, a cyano group, J-, nitro, halo, C 1-6 alkyl, C 1-6 alkoxy; C 1-6 alkylthio group, halogeno C 1 -6 alkyl, or halogenated C 1-6 alkoxy; n is an integer from 0 to 5.
  • R 7 and R 2 are each independently selected from the group consisting of hydrogen, C 1-3 alkyl, C 1-3 alkoxy, C 1-6 alkoxy C 1-6 alkoxy, phenyl optionally substituted by R 6 , nitro;
  • Z is -NH -, -CH 2 or -0-;
  • R 3 is selected from hydrogen, fluorine, chlorine, bromine, decyl, methoxy or trifluoromethyl, and n is preferably from 1 to 4, more preferably from 2 to 3.
  • Z is -NH- or -0-; R 7 is preferably hydrogen or benzene, and R 2 is preferably hydrogen or nitro,
  • R 3 is preferably ortho or para to the isoxazole ring, more preferably 4-fluoro, 4-chloro, 2-chloro, 4-bromo, 2,4-dichloro, 4-indenyl, 4-anthracene Base, hydrogen, 4-trifluorodecyl or 2,4-dimethoxy.
  • the quinazoline compound represented by the formula (I) is selected from any one of the following compounds or a pharmaceutically acceptable salt thereof:
  • the quinazoline compound represented by the formula (I) may be selected to form a pharmaceutically acceptable salt with a pharmaceutically acceptable acid, respectively.
  • pharmaceutically acceptable salts includes, but is not limited to, salts formed with inorganic acids, such as hydrochlorides, phosphates, diphosphates, hydrobromides, sulfates, sulfinates, nitrates, and Similar to salts; also includes salts with organic acids such as oxalates, malates, maleates, fumarates, tartrates, succinates, citrates, lactates, sulfonates , p-Toluenesulfonate, 2-hydroxyethylsulfonate, benzoate, salicylate, stearate, trifluoroacetic acid or amino acids and alkanoates such as acetate, HOOC-( CH2)n-COOH wherein n is a salt of 0-4, and the like.
  • pharmaceutically acceptable salts includes, but is not
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the quinazoline compound of the above formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable, inert , non-toxic excipients or carriers or diluents.
  • the present invention also provides a quinazoline derivative represented by the formula (I) according to any one of the above and one or more medically acceptable ones selected from the group consisting of a filler, a disintegrant, a lubricant, and a glidant
  • a pharmaceutical composition formed from an effervescent agent, a flavoring agent, a preservative, and a coating material.
  • the present invention also provides a pharmaceutical preparation comprising the quinazoline compound of the above formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable, inert, Non-toxic excipient or carrier or diluent.
  • the pharmaceutical preparation according to the present invention is characterized in that the preparation is preferably a solid oral preparation, a liquid oral preparation or an injection.
  • the preparation is selected from the group consisting of a tablet, a tablet, an enteric tablet, a chewable tablet, an orally disintegrating tablet, a capsule, a granule, an oral solution, a water injection needle, a lyophilized powder for injection, and a large Infusion or small infusion.
  • the present invention also provides a quinazoline compound of the above formula (I), or a pharmaceutically acceptable salt thereof, for use as a medicament, in particular for the treatment of inhibiting EGFR transient expression and/or activity A highly effective tumor drug.
  • the present invention also provides the use of the quinazoline compound of the above formula (I) or a pharmaceutically acceptable salt thereof for the preparation of a medicament for antitumor or cancer.
  • the tumor or cancer is a cancer that is transiently expressed and/or active with EGFR. More preferably, the tumor or cancer is selected from the group consisting of: bladder cancer, non-small cell lung cancer, ovarian cancer, breast cancer, gastric cancer, esophageal cancer, lung cancer, head and neck cancer, colon cancer, pharyngeal cancer, and pancreatic cancer, etc. Application in cell lung cancer.
  • the present invention also provides the use of a quinazoline compound and/or a pharmaceutically acceptable salt of the formula (I) according to any of the preceding claims for the preparation of an inhibitor which inhibits the transient expression and/or activity of EGFR. .
  • the present invention also provides a process for producing an isoxazole heterocyclic-containing quinazoline compound represented by the formula (I), characterized in that the method comprises the following steps:
  • 2, 6, 7-trisubstituted-4-chloro-quinazoline (formula II) and 3-substituted phenyl-5-hydroxyindolyl-isoxazole (formula III) or 3-substituted phenyl-5- Amino-isoxazole (formula IV) is a starting material which is prepared by reaction in a dry organic solvent and a basic acid binding agent system.
  • the reaction temperature is from -20 ° C to reflux conditions, preferably from room temperature to reflux conditions.
  • the organic solvent is an aromatic hydrocarbon, a halogenated hydrocarbon, a C w lower alcohol, tetrahydrofuran or dimethyl sulfoxide (DMF).
  • the solvent is benzene, toluene, dinonylbenzene, dichlorodecane, chloroform, isopropanol, tetrahydrofuran or DMF, more preferably isopropanol.
  • the basic acid binding agent is an organic base or an inorganic base
  • the organic base is preferably triethylamine, tripropylamine, DMAP, potassium t-butoxide or the like
  • the inorganic base is preferably potassium carbonate or sodium hydride. , sodium carbonate, etc.
  • a preferred acid binding agent is triethylamine.
  • the present invention also provides a method for preparing an isoxazole heterocyclic-containing quinazoline compound represented by formula (IA), which is characterized in that The method includes the following steps:
  • 6,7-disubstituted 4-chloro-quinazoline (formula IIA) and 3-substituted phenyl-5-hydroxyindolyl-isoxazole (formula III) or 3-substituted phenyl-5-aminoindole - Isoxazole (Formula IV) is a starting material which is prepared by reaction in a dry organic solvent and a basic acid binding agent system.
  • the reaction temperature is from -20 ° C to reflux conditions, preferably from room temperature to reflux conditions.
  • the organic solvent is benzene, toluene, dinonylbenzene, dichlorodecane, chloroform, isopropanol, tetrahydrofuran or DMF, more preferably isopropanol.
  • the basic acid binding agent is an organic base or an inorganic base
  • the organic base is preferably triethylamine, tripropylamine, DMAP, potassium t-butoxide or the like
  • the inorganic base is preferably potassium carbonate or sodium hydride. , sodium carbonate, etc.
  • a preferred acid binding agent is triethylamine.
  • the intermediate 6,7-disubstituted 4-chloro-quinazoline of the formula (IIA) can be produced by the following method: using 6,7-disubstituted-quinazolinone as a raw material, in dichloro Prepared by reflux in sulfoxide or phosphorus oxychloride system (R 1 ; R 2 as defined above):
  • the intermediate 3-substituted phenyl-5-hydroxymethyl-isoxazole of formula (III) or the intermediate 3-substituted phenyl-5-aminomethyl-isoxine of formula (IV) The azole can be prepared by the following method: Substituting benzoin as a raw material, by synthesizing ruthenium, 1,3-dipole Cycloaddition reaction, methanesulfonyl esterification reaction, azide, reduction reaction (R 3 as described above).
  • the intermediate 3-substituted phenyl-5-hydroxymethyl-isoxazole of the formula (III) is prepared by the following method: (1) by using a substituted benzaldehyde as a starting material, by reacting with hydroxylamine or hydroxylamine hydrochloride Synthesis of ruthenium (V); (2) ⁇ (V) and propargyl alcohol undergo 1,3-dipolar cycloaddition reaction under the action of N-chlorosuccinimide (NCS) and triethylamine, forming intermediate Body (111).
  • NCS N-chlorosuccinimide
  • the intermediate 3-substituted phenyl-5-aminoindolyl-isoxazole of formula (IV) is prepared by the following method:
  • the intermediate 3-substituted phenyl-5-hydroxyindolyl-isoxazole of the formula (III) is prepared by the following method: (1) Substituted benzaldehyde with hydroxylamine or hydroxylamine hydrochloride in methanol/ In the water system, the reaction is carried out under the catalysis of sodium carbonate to form the corresponding benzamidine;
  • the basic acid binding agent is selected from the group consisting of an organic base or an inorganic base
  • the organic base is selected from the group consisting of triethylamine, tripropylamine, DMAP, DMF, N-methylmorpholine, etc.
  • the inorganic base is selected from the group consisting of potassium carbonate, sodium hydride, sodium carbonate and the like.
  • a more preferred alkaline acid binding agent is triethylamine.
  • reaction temperature of the step (1) is from -20 ° C to reflux conditions, preferably room temperature (25 ° C) to reflux conditions.
  • reaction temperature of the step (2) is from -20 ° C to reflux conditions, preferably from 0 ° C to reflux conditions.
  • the intermediate 3-substituted phenyl 5-aminoindenyl-isoxazole of the formula (IV) is prepared by the following method:
  • the sulfonyl chloride is selected from the group consisting of: sulfonyl chloride, benzenesulfonyl chloride, substituted benzenesulfonyl chloride (such as halobenzenesulfonyl chloride, alkylbenzenesulfonyl chloride), and the like. More preferably, it is a methanesulfonyl chloride.
  • the reaction temperature is -5 degrees to the reflux temperature, preferably room temperature to reflux temperature.
  • the reaction solvent is selected from the group consisting of benzene, toluene, halogenated aromatic hydrocarbons, halogenated alkanes (e.g., chloroform or dichloromethane), tetrahydrofuran, acetonitrile, and ionic liquids. More preferably, the reaction is refluxed in a dichloromethane system.
  • a compound of the formula (VII) is catalytically reduced with ammonium chloride and zinc powder, iron powder or palladium carbon to prepare a compound of the formula (IV), preferably the catalyst is catalyzed under mineral acid conditions, preferably hydrochloric acid or sulfuric acid, The catalyst is preferably zinc powder and ammonium chloride.
  • the reaction temperature of the step (3) is from -20 ° C to reflux conditions, preferably from 0 ° C to room temperature.
  • reaction temperature of the step (4) is from -20 ° C to reflux conditions, preferably from 0 ° C to 80 ° C, more preferably from room temperature to 60 ° C.
  • the preferred reaction solvent in the step (5) is water or an organic solvent (e.g., an alcohol, a halogenated hydrocarbon, an aromatic hydrocarbon, etc.) or a mixture thereof, preferably a reaction system of ethanol and water.
  • the preparation method is as follows:
  • each substituent is as defined above.
  • Z is another substituent such as CH 2 , S, it can be prepared by using the corresponding propynyl chloride, propargyl mercaptan.
  • the present invention also provides a method for preparing an isoxazole heterocyclic-containing quinazoline derivative represented by formula (IB), characterized in that the method comprises the following steps:
  • the base-isoxazole (formula IV) is prepared by reacting in a dry organic solvent and a basic acid binding agent system;
  • the reaction temperature is from -20 ° C to reflux conditions, preferably from room temperature to reflux conditions.
  • the organic solvent is an aromatic hydrocarbon or alkyl-substituted aromatic hydrocarbons, halogenated hydrocarbons, alcohols (e.g., C w - monoalcohols), tetrahydro-thiopyran bite, DMF or example of a liquid.
  • the organic solvent is preferably benzene, toluene, xylene, dichlorodecane, chloroform, isopropanol, tetrahydrofuran or DMF or an ionic liquid, more preferably isopropanol.
  • the basic acid binding agent is an organic base or an inorganic base
  • the organic base is preferably triethylamine, tripropylamine, DMAP, sodium hydride, potassium t-butoxide or the like
  • the inorganic base is preferably potassium carbonate. , sodium hydride, sodium carbonate, and the like.
  • a preferred acid binding agent is triethylamine.
  • the intermediate 2-phenyl-4-chloro-quinazoline of the formula (IIB) can be produced according to known methods or commercially available, for example, from Aladdin Reagent.
  • the intermediate 7-nitro-4-chloro-quinazoline of formula (IIB) can be prepared by the following method: 2-amino-4-nitro-benzoic acid and cesium acetate are used as raw materials by reaction in ethanol (The reaction temperature is preferably from -20 ° C to reflux conditions to obtain 7-nitroquinazolin-4(1H)-one, and then reacted in a thionyl chloride or phosphorus oxychloride system (preferably, the reaction temperature is 7-Nitro-4-chloro-quinazoline was prepared from -20 ° C to reflux conditions. A more specific reaction process is shown in the following scheme:
  • the compounds of formula I according to the invention include, but are not limited to, their optical isomers, racemates and mixtures thereof.
  • the cycloalkyl group in the cycloalkoxy group of the present invention may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, preferably cyclopropyl, cyclopentyl or a ring. Heji.
  • the C 3-8 heterocycloalkyl group may be a piperidinyl group, a piperidinyl group or a morpholinyl group. , pyrrolidinyl, homopiperazinyl, preferably a buffer ring, morpholinyl or piperidinyl.
  • an effective amount refers to an amount of the at least one compound and/or at least one pharmaceutically acceptable salt that is effective to "treat" a disease or condition in an individual.
  • an effective amount can reduce the number of cancer or tumor cells; reduce the size of the tumor; inhibit or prevent the invasion of tumor cells into peripheral organs, for example, tumors spread into soft tissues or bones; inhibit or prevent tumor metastasis; Or prevent the growth of tumors; to some extent alleviate one or more symptoms associated with cancer; reduce morbidity and mortality; improve quality of life; or a combination of the above effects.
  • An effective amount can be an amount that reduces the symptoms of the disease by inhibiting EGFR activity.
  • the effects of in vivo experiments can be measured by assessing, for example, survival, time to disease progression (TTP), response rate (RR), duration of response, and/or quality of life.
  • TTP time to disease progression
  • RR response rate
  • an effective amount can vary with the route of administration, the dosage of the excipient, and the combination with other drugs.
  • the term "effective amount” may also mean a dose effective to inhibit overexpression and/or hyperactivity of EGFR by said at least one compound and/or at least one pharmaceutically acceptable salt thereof.
  • the compound of the present invention has antitumor and anticancer activities, and particularly has strong inhibitory activity against human lung cancer cell line A549.
  • Compound P-26 at lxl (T 4 M concentration of human lung cancer cell ⁇ 549 beads inhibition rate 91.2%, ⁇ -24 at lxl (T 4 M concentration on A549 cells was suppressed beads 84.9%, P The inhibition rate of -22 on human lung cancer cell A549 beads was 81.5% at lxl (T 4 M concentration).
  • Some compounds also showed strong inhibitory activity against colorectal cancer cell line HCT-116: Compound P-27 at lxl (T inhibition rate of colorectal cancer cell line HCT-116 is 63.9% at a concentration of 4 M, P-25 compound in lxl (T 4 M concentration inhibitory rate of colorectal cancer cell line HCT-116 is 55.1%; the selectivity of the compound Inhibition activity was also shown for EGFR enzyme: Compound Q-15 inhibited EGFR activity at lxl (T 4 M concentration was 30.7%, compound Q-21 The inhibitory activity against EGFR enzyme at lxl (T 4 M concentration was 30.9%.
  • the compounds of the invention are useful as drug candidates or lead compounds for the treatment of tumors, cancers. detailed description
  • Chemical reagents are commercially available analytically pure or chemically pure reagents, RPMI1640 from Gibco, Sulforodamine B (SRB) from Sigma, trichloroacetic acid (TCA), acetic acid and Tris base unbuffer Domestic analytical pure reagents.
  • Tyrosine kinase was expressed by the insect baculovirus expression system and purified by affinity purification using ⁇ - ⁇ column. The test was in accordance with the experimental standard, and the kinase reaction substrate Poly(Glu, Tyr) 4:1 (Sigma). Anti-phosphotyrosine monoclonal antibody PY99 (Santa Cruz), horseradish peroxidase-labeled goat anti-mouse IgG (Calbiochem), ATP, DTT, OPD (Amresco), ELISA plate (Corning) Other reagents were commercially available analytical grades, which were not treated without prior treatment prior to use. Isopropanol was treated with dry molecular sieves prior to use.
  • Example 2 Synthesis of 7-Nitro-quinazolinone Add 46g (0.25 mol) of 2-J ⁇ -4-nitrobenzoic acid and 52g (0.5 mol) of lanthanum acetate to a 500mL single-mouth round bottom flask, add 200mL of absolute ethanol, and reflux for 4 ⁇ 6 hours. There will be a large amount of khaki precipitates. At this point, the heating is stopped, the system is cooled to about 50 ° C, some ethanol is removed by vacuum to about 50 mL of the system, 30 mL of water is added to the system, and the system is stirred for several minutes and then refrigerated for 1 h.
  • R 3 is H as an example:
  • the mother liquid was washed with water, washed with a 5% sodium hydrogen carbonate solution, washed with water, dried over anhydrous sodium sulfate, and then evaporated under reduced pressure to give the crude product, 5-indolesulfonic acid, 3-phenyl-isoxazole-5-
  • the sterol ester was obtained in a yield of 68.0%.
  • the crude product was directly subjected to the next step without purification.
  • R 2 -H 4-CH 3 P-22 2-phenyl-4- ⁇ [3-(4-methyl-phenyl)-isoxazol-5-yl]-methoxy+quinazoline
  • P-22 2.37(s, 3H, Ph-CH 3 ), 6.02(s, 2H, CH 2 ), 7.32(m, 2H), 7.34(s, IH, isoxazole-H), 7.56-7.59(m, 3H ), J-7.81(m, 3H), 8.01-8.03(m, 2H), 8.26-8.28(m, IH), 8.57-8.59(m, 2H).
  • the quinoline compound represented by the formula (I) or a pharmaceutically acceptable salt thereof is used as an EGFR enzyme inhibitor, and the exemplified compounds are assayed for inhibition of EGFR enzyme activity by an enzyme-linked immunosorbent assay.
  • the enzyme reaction substrate Poly(Glu, Tyr) 4:1 was diluted to 20 g/mL with PBS without potassium ions, coated with the enzyme plate, placed After reacting at 37 ° C for 12 to 16 hours, the liquid in the well was discarded.
  • test sample is added to the well of the coated ELISA plate (the test sample is first prepared with DMSO to prepare lxl (T 2 M stock solution, and then diluted with the reaction buffer to the required sample). The concentration was added to the experimental wells to achieve the corresponding final concentration in the ⁇ reaction system.
  • the inhibitory activity against the EGFR enzyme of the compound of the formula (I) or a salt thereof was measured by the above activity test method.
  • the compound represented by the formula (I) or a salt thereof of the present invention is subjected to the SRB method for screening the activity against the colorectal cancer cell line (HCT-116) and the human lung cancer cell line (A549), and the screening process reference document (Li MH; Miao ZH; Tan WF et al. Clin. Cancer Res. 2004, 10(24): 8266-8274).
  • the colon cancer cell line (HCT-116) in the logarithmic growth phase is inoculated into a 96-well culture plate, and after adhering for 24 hours, a drug of 1 ⁇ 1 ( ⁇ 4 ⁇ is added, The concentration was set to 3 replicate wells, and the corresponding concentration of physiological saline control and cell-free zero-adjustment were set, and the tumor/cancer cells were cultured for 72 hours at 37 ° C and 5% CO 2 .
  • TCA cold triacetic acid
  • the compound represented by the formula (I) or a salt thereof was measured for its activity of inhibiting colorectal cancer cell beads (HCT-116) and human lung cancer cell A549 at a concentration of 1 ⁇ 1 . table.

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Abstract

La présente invention concerne un composé de quinazoline représenté dans la formule (I), ou sel pharmaceutiquement acceptable de celui-ci. R1, R2 et R7 sont sélectionnés indépendamment et respectivement à partir d'hydrogène,C1-6 alkyl, C1-6 alkoxy, halogenate C1-6 alkyl, halogenate C1-6 alkoxy, hydroxyl C1-6 alkyl, hydroxyl C1-6 alkoxy, C1-6 alkoxy C1-6 alkoxy, C3-8 cycloalkyloxy, aryle éventuel ou hétéroaryle substitué par R6, nitryl, amino, C1-6 alkylamino, et di (C1-6 alkyl)amino ; il comprend au moins un C3 -8 hétérocycloalkyloxy sélectionné à partir de N, O, S hétéroatomes ; Z est-NR4-, C (R5) 2, S ou-O-, R4 étant l'hydrogène ou Cl -3 alkyl, et R5 étant choisi parmi de l'hydrogène ou Cl -3 alkyle ; R3 est choisi à partir d'hydrogène, halogène, Cl -6 alkyle, Cl -6 alcoxy ou d'halogénation de Cl -6 alkyle ; R6 est choisi à partir d'hydrogène, Cl -3 alkyle, hydroxyle, halogène, Cl -3 alcoxy ; et n est compris entre 0 et 5. La présente invention concerne également un procédé de préparation du composé représenté par la formule (I) ou le sel pharmaceutiquement acceptable et l'utilisation pharmaceutique de celui-ci, qui peut être utilisé en tant que médicaments ou composés au plomb de traitement de maladies notamment les tumeurs et le cancer liée à la protéine tyrosine kinase.
PCT/CN2012/086251 2012-03-26 2012-12-10 Dérivé de quinazoline et utilisation associée WO2013143319A1 (fr)

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CN103601762B (zh) * 2013-11-26 2018-09-28 中国科学院福建物质结构研究所 二茂铁衍生物、制备方法及其用途
CN103819467B (zh) * 2014-02-27 2019-03-08 中国科学院福建物质结构研究所 喹唑啉衍生物的制备方法及其用途
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CN107474043A (zh) 2017-09-13 2017-12-15 厦门稀土材料研究所 烟酸衍生物及其制备方法与用途

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004078733A1 (fr) * 2003-03-03 2004-09-16 Vertex Pharmaceuticals Incorporated Quinazolines utilisees comme modulateurs de canaux ioniques
WO2011028741A1 (fr) * 2009-09-03 2011-03-10 Bristol-Myers Squibb Company Quinazolines comme inhibiteurs des canaux ioniques potassiques

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9603095D0 (en) * 1996-02-14 1996-04-10 Zeneca Ltd Quinazoline derivatives
KR100735639B1 (ko) * 2004-12-29 2007-07-04 한미약품 주식회사 암세포 성장 억제 효과를 갖는 퀴나졸린 유도체 및 이의제조방법

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004078733A1 (fr) * 2003-03-03 2004-09-16 Vertex Pharmaceuticals Incorporated Quinazolines utilisees comme modulateurs de canaux ioniques
WO2011028741A1 (fr) * 2009-09-03 2011-03-10 Bristol-Myers Squibb Company Quinazolines comme inhibiteurs des canaux ioniques potassiques

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
YONG, JIANPING ET AL.: "Synthesis of Novel Isoxazole Ring Containing Quinazoline Deriva-tives and in vitro Inhibitory Activity Against PTPa and PTPs", CHINESE JOURNAL OF ORGANIC CHEMISTRY, vol. 28, no. 7, 2008, pages 1204 - 1208 *

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