CN102146059A - Quinazoline derivatives and preparation method and application thereof - Google Patents

Quinazoline derivatives and preparation method and application thereof Download PDF

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CN102146059A
CN102146059A CN2010101067320A CN201010106732A CN102146059A CN 102146059 A CN102146059 A CN 102146059A CN 2010101067320 A CN2010101067320 A CN 2010101067320A CN 201010106732 A CN201010106732 A CN 201010106732A CN 102146059 A CN102146059 A CN 102146059A
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quinazoline
egfr
pharmacy acceptable
acceptable salt
hydrogen
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姜勇
郭建辉
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Shanghai Allist Pharmaceuticals Inc
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Priority to PCT/CN2011/000160 priority patent/WO2011095053A1/en
Priority to CN201180008791.7A priority patent/CN102812010B/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen atoms

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Abstract

The invention discloses quinazoline derivatives serving as irreversible tyrosine kinase inhibitors, and use of the derivatives as inhibitors for human epidermal growth factor receptor (EGFR) mutant T790M and anticancer agents. The invention also relates to a preparation method for the quinazoline derivatives, and a medicinal composition containing the quinazoline derivatives.

Description

Quinazoline derivant, preparation method and application thereof
Technical field
The present invention relates to the quinazoline derivant of a class, and this analog derivative is as the inhibitor of EGF-R ELISA (EGFR) mutant T790M and the application of carcinostatic agent as tyrosine kinase inhibitor.The invention still further relates to its preparation method, and a kind of pharmaceutical composition that comprises quinazoline derivant.
Background technology
Cancer is considered to the disease of interior signal transducting system of cell or signal transduction mechanism.The most commonly encountered diseases of cancer is because of being a series of damaged, described damaged can be proteinic damaged (when it suddenlys change), or the adjusting of the amount of pair cell internal protein is damaged, thereby albumen is excessively produced or produces not enough.The sudden change of cell surface receptor (this sudden change passes the signal along in the cell by Tyrosylprotein kinase usually) can cause kinases to be activated under the condition that lacks part, and transmits in fact also non-existent signal.Perhaps, many receptor tyrosine kinases can cause the mistake of weak signal is responded by force in the cell surface overexpression.
Lung cancer is the first cause that causes cancer mortality in the industrial country.According to the performance of cell at microscopically, lung cancer is divided into two kinds of main types, nonsmall-cell lung cancer and small cell lung cancers.Nearly 80% lung cancer belongs to nonsmall-cell lung cancer (NSCLC).NSCLC is the U.S., Japan and the lethal major cause of West Europe cancer, and the early stage patient operation is difficult, and easily recurrence.Therefore chemotherapy can provide the help of appropriateness aspect survival rate, but toxicity is too big, presses for the therapeutical agent (Schiller JH etc., N.Engl.J.Med., 346:92-98,2002) that target specifically relates to tumor growth.
EGF-R ELISA (EGFR) is confirmed to be in vital driving factors in cell growth and the breeding.Epidermal Growth Factor Receptor Family is made up of EGFR (Erb-B1), Erb-B2 (HER-2/neu), Erb-B3 and Erb-B4.EGF-R ELISA is relevant with the disease process of most of cancer, as lung cancer, colorectal carcinoma, mammary cancer etc.The overexpression of EGFR and sudden change have been the primary hazard factor of the bad mammary cancer of prognosis by being unequivocally established.In addition, all four members that confirmed this receptor family all can be polymerized to heterodimer with other member of this family, form signal conduction mixture, if more than one member overexpression in malignant tumour is arranged in this family, just can cause the signal conduction of working in coordination with.
EGFR belongs to protein tyrosine kinase (PTK) family, and protein tyrosine kinase is a class is transferred to phosphate group the tyrosine residues that is positioned at protein substrate from ATP catalysis a enzyme.Protein tyrosine kinase works in normal cell growth.The overexpression of EGFR or sudden change cause acceptor to be activated under the condition that lacks part, make some albumen generation phosphorylation, have produced fissional signal.Therefore, EGFR has caused the excessive amplification of weak signal by the effect of self Tyrosylprotein kinase, has caused the excessive propagation of cell.
Specificity ptk inhibitor as potential anticancer therapy medicine receives much attention.The typical case of the EGFR reversible inhibitor of listing representative at present is the Gefitinib (Gefitinib of listing in 2003, commodity are called Iressa, by AstraZeneca UK Ltd. exploitation), the erlotinib (Erlotinib of listing in 2004, commodity are called Tarceva, by Genentech, Inc. and OSI Pharmaceuticals, Inc. exploitation), lapatinibditosylate (Lapatinib with listing in 2007, commodity are called Tykerb, by the GlaxoSmithKline exploitation), structure sees below.They all produce challenging clinical effectiveness, are respectively applied for treatment (Sordella R etc., Science, 305:1163-1167,2004 of NSCLC and mammary cancer; Pao, W. etc., Proc.Natl.Acad.Sci.U.S.A., 101:13306-13311,2004).Clinical study proves that Gefitinib, erlotinib have the good curing effect to the NSCLC patient that disappearance or point mutation (L858R) take place EGFR.Yet their limitation is that the patient produces resistance (Kobayashi, M. etc., N.Engl.J.Med., 352:786-792,2005) in the back of receiving treatment, and makes the further application clinically of this type of inhibitor be restricted.Existing studies show that, secondary sudden change (T790M) relevant (Pao, W. etc., Plos Med., 2:1-11,2005) take place with EGFR in 50% Gefitinib, the erlotinib treatment chemical sproof generation in back, and reversible inhibitor loses curative effect.
T790M is positioned at the inlet of EGFR and ATP binding pocket, and the size of its side chain directly influences the binding ability of EGFR and ATP.The T790M sudden change spatially hinders the effect of EGFR inhibitor and ATP-binding site, increase the avidity of EGFR, thereby make cell produce resistance (Cai-Hong Yun etc., Proc.Natl.Acad.Sci.U.S.A. the EGFR inhibitor to ATP, 105:2070-2075,2008).
Chinese patent CN100503580C has described the quinazoline compounds as tyrosine kinase irreversible inhibitor, and general structure is as shown in the formula shown in (a):
Figure GSA00000023874100021
Chinese patent CN1177833C discloses the quinazoline derivative that a class replaces, and the application in antineoplaston, and general structure is as shown in the formula shown in (b):
Figure GSA00000023874100022
Compare with reversibility EGFR inhibitor, irreversible EGFR inhibitor has very outstanding advantage.Irreversible EGFR inhibitor can suppress EGFR for a long time, only is subjected to the acceptor restriction of the normal speed of combination (being also referred to as recovery) again.Discover, irreversible EGFR inhibitor can be gone up cysteine residues (Cys797) covalent attachment by reversal of the Michael addition and EGFR, irreversible EGFR inhibitor and ATP-binding site are enlarged, thereby can overcome resistance (the Li D etc. that the T790M sudden change causes to a certain extent, Oncogene, 27:4702-4711,2008).At present comprise HKI-272 (Wyeth exploitation), EKB-569 (Wyeth exploitation), CI-1033 (Pfizer exploitation), BIBW2992 (Boehringer Ingelheim exploitation) and PF00299804 (Pfizer exploitation) etc. at the irreversible EGFR inhibitor that grinds.
Yet, can suppress the irreversible EGFR inhibitor of EGFR T790M, bring bigger toxic side effect usually, as diarrhoea, fash, feel sick, apocleisis, faint (Besse, B. etc., Eur.J.Cancer Suppl., 6,64, abstr.203,2008; Janne, P.A. etc., J.Clin.Oncol., 25:3936-3944,2007), interrupt drug development thus, as the CI-1033 of Pfizer.According to the literature, BIBW2992 and PF00299804 have anti-tumor activity significantly, can not only suppress the activity of EGFR, and can suppress the activity of EGFR T790M, test (Li D etc. carrying out clinical III phase and clinical II phase respectively at present, Oncogene, 27:4702-4711,2008; Andrea J.Gonzales etc., Mol.Cancer Ther., 7:1880-1889,2008).BIBW2992 can suppress EGFR1 and HER2 simultaneously, and PF00299804 can suppress HER-1, HER-2 and HER-4 acceptor simultaneously.
Figure GSA00000023874100031
Listing or the EGFR inhibitor that is grinding
Above-mentioned listing or be quinazoline compounds in the reversible or irreversible EGFR inhibitor major structural types of grinding.The quinazoline ditosylate salt EGFR inhibitor of having reported at present is the ATP state of conflict inhibitor of Wild type EGFR, and nonspecific action causes the generation of some side reactions thus in EGFR T790M.The specific effect that research report one class miazines is arranged recently is in the irreversible EGFR inhibitor of EGFR T790M, and structure is as shown in the formula shown in (c).Compare with existing aniline quinazoline class EGFR inhibitor, this type of pyrimidine compound has improved 30-100 doubly to the inhibition activity of EGFRT790M, and the inhibition activity of Wild type EGFR has been reduced by 100 times of (Wenjun Zhou etc., Nature, 462:1070-1074,2009).
Figure GSA00000023874100041
For overcoming the EGFR inhibitor class medicine that goes on the market, as the resistance problem that produces after Gefitinib, the erlotinib treatment tumour, the micromolecular inhibitor that the research specificity suppresses EGFR T790M has become pressing for of current antitumor field.Researchist of the present invention is in the process of research EGFR inhibitor, find pleasantly surprisedly, with the existing similar compounds of disclosed quinazoline compound, the energy specific effect is in EGFR L858R/T790M, the inhibition activity of EGFR L858R/T790M is significantly higher than inhibition activity to Wild type EGFR, shows good selectivity.Expect the curative effect that this type of inhibitor will have, and low toxic side effect is arranged, be expected to treat and overcome and use the resistance problem that produces behind Gefitinib, the erlotinib clinically.Be specific treatment preparation, have the excellent development prospect at the medicament-resistant mutation body.
Summary of the invention
The invention provides a kind of formula (I) compound, or its pharmacy acceptable salt,
Figure GSA00000023874100042
Wherein, R 1Be selected from hydrogen, halogen, C 1-C 4The C that alkyl, halogen replace 1-C 4Alkyl;
R 2Be selected from hydrogen, halogen, C 1-C 4The C that alkyl, halogen replace 1-C 4Alkyl, C 1-C 4The C that alkoxyl group, halogen replace 1-C 4Alkoxyl group;
R 3Be halogen.
In preferred scheme of the present invention, R 1Be selected from hydrogen or C 1-C 4Alkyl, in preferred scheme, R 1Be selected from hydrogen or methyl.
In another preferred scheme of the present invention, R 2Be selected from hydrogen or C 1-C 4Alcoxyl, in preferred scheme, R 2Be selected from hydrogen or methoxyl group.
In another preferred scheme of the present invention, R 3Be chlorine.
In the preferred scheme of the present invention, R 1Be selected from hydrogen or methyl, R 2Be selected from hydrogen or methoxyl group, R 3Be chlorine.
In the present invention, as the represented compound of general formula (I), the particular compound that is more preferably is:
N-[4-(3-chloro-4-hydroxyl-phenyl amido)-quinazoline-7-methoxyl group-6-base-]-crotonamide;
N-[4-(3-chloro-4-hydroxyl-phenyl amido)-quinazoline-6-base-]-crotonamide;
N-[4-(3-chloro-4-hydroxyl-phenyl amido)-quinazoline-6-base-]-acrylamide;
N-[4-(3-chloro-4-hydroxyl-phenyl amido)-quinazoline-7-methoxyl group-6-base-]-acrylamide, and their pharmacy acceptable salts.
Among the present invention, term " pharmacy acceptable salt " is meant the acid salt or the base addition salt of nontoxic relatively The compounds of this invention.Described acid salt is the salt that formula (I) compound and suitable mineral acid or organic acid form, these salt can prepare in last separation of compound and purification process, or the compound that makes purifying reacts with its free alkali form and suitable organic acid or mineral acid, the salt that forms separated again and makes.Representative acid salt comprises hydrobromate, hydrochloride, vitriol, sulphite, acetate, oxalate, valerate, oleate, palmitate, stearate, lauroleate, borate, benzoate, lactic acid salt, phosphoric acid salt, toluylate, Citrate trianion, maleate, fumarate, succinate, tartrate, mesylate, tosilate, gluconate, Lactobionate and lauryl sulfonate etc.
Described base addition salt is the salt that formula (I) compound and suitable mineral alkali or organic bases form, for example comprise the salt that forms with basic metal, alkaline-earth metal, quaternary ammonium cation, as sodium salt, lithium salts, sylvite, calcium salt, magnesium salts, tetramethyl-quaternary ammonium salt, tetraethyl-quaternary ammonium salt etc.; Amine salt comprises and ammonia (NH 3), primary amine, secondary amine or the tertiary amine salt that forms, as methylamine salt, dimethylamine salt, front three amine salt, triethylamine salt, ethylamine salt etc.
Utilize compound or its pharmacy acceptable salt of gained of the present invention can deliver medicine to the people, can be oral, rectum, parenteral (intravenously, intramuscular or subcutaneous), topical (pulvis, ointment or drops).
The solid dosage that is used for oral administration comprises capsule, tablet, pill, powder and granule.In these solid dosages, active compound mixes with at least a conventional inert excipient (or carrier), as Trisodium Citrate or Lin Suanergai, or mixes with following compositions: (a) filler or expanding material, for example, starch, lactose, sucrose, glucose, N.F,USP MANNITOL and silicic acid; (b) tackiness agent, for example, Walocel MT 20.000PV, alginate, gelatin, Polyvinylpyrolidone (PVP), sucrose and gum arabic; (c) wetting Agent for Printing Inks, for example, glycerine; (d) disintegrating agent, for example, agar, lime carbonate, yam starch or tapioca (flour), alginic acid, some composition silicate and yellow soda ash; (e) retarding solvent, for example paraffin; (f) absorb accelerator, for example, quaternary ammonium compound; (g) wetting agent, for example hexadecanol and glyceryl monostearate; (h) sorbent material, for example, kaolin; (i) lubricant, for example, talcum, calcium stearate, Magnesium Stearate, solid polyethylene glycol, sodium lauryl sulphate, or its mixture.In capsule, tablet and the pill, formulation also can comprise buffer reagent.
Solid dosage such as tablet, sugar-pill, capsule, pill and granule can adopt dressing and the preparation of shell material, as casing and other material well known in the art.They can comprise opacifying agent, and, discharge in the mode that the release of active compound or compound can postpone in this composition certain part in digestive tube.The example of adoptable embedding component is polymeric material and Wax.In case of necessity, active compound also can with above-mentioned vehicle in one or more form microencapsulation form.
The liquid dosage form that is used for oral administration comprises pharmaceutically acceptable emulsion, solution, suspension, syrup or tincture.Except the active ingredient beyond the region of objective existence, liquid dosage form can comprise the conventional inert diluent that adopts in this area, as water or other solvent, solubilizing agent and emulsifying agent, example is known, the mixture of ethanol, Virahol, ethyl-carbonate, ethyl acetate, propylene glycol, 1,3 butylene glycol, dimethyl formamide and oil, particularly Oleum Gossypii semen, peanut oil, maize germ, sweet oil, Viscotrol C and sesame oil or these materials etc.
Except these inert diluents, composition also can comprise auxiliary agent, as wetting agent, emulsifying agent and suspension agent, sweeting agent, the agent of tender flavor and spices.
Except the active ingredient beyond the region of objective existence, suspension can comprise suspension agent, for example, and the mixture of ethoxylation isooctadecane alcohol, polyoxyethylene sorbitol and Isosorbide Dinitrate, Microcrystalline Cellulose, aluminum methylate and agar or these materials etc.
The composition that is used for parenteral injection can comprise physiologically acceptable aseptic moisture or anhydrous solution, dispersion liquid, suspension or emulsion and be used for being dissolved into again the aseptic Injectable solution or the sterilized powder of dispersion liquid.Suitable moisture and nonaqueous carrier, thinner, solvent or vehicle comprise water, ethanol, polyvalent alcohol and suitable mixture thereof.
The formulation that is used for the The compounds of this invention of topical comprises ointment, powder, propellant and inhalation.Activeconstituents under aseptic condition with physiologically acceptable carrier and any sanitas, buffer reagent, or the propelling agent that may need in case of necessity is mixed together.
The present invention also provides a kind of pharmaceutical composition, and it contains the above-mentioned formula I compound of 0.05-50mg or its pharmacy acceptable salt, and pharmaceutically acceptable carrier, vehicle or thinner.
The compounds of this invention can be used for preparing antitumor drug, as lung cancer, ovarian cancer, mammary cancer.Especially the tumor type that sports methionine(Met) (EGFR T790M) for 790 Threonines of EGF-R ELISA has better application.Saying for example, The compounds of this invention can be used for the medicine of preparation treatment nonsmall-cell lung cancer (EGFR T790M).Can be used for overcoming and use the resistance problem that causes by EGFR T790M behind Gefitinib, the erlotinib clinically.
Compound of the present invention or its pharmacy acceptable salt can be individually dosed, perhaps with other pharmaceutically acceptable therapeutical agent Combined Preparation, particularly with other antitumor drug combinations.Described therapeutical agent includes but not limited to: the medicine antitumour drug such as the cis-platinum that act on the DNA chemical structure, influence nucleic acid synthetic antitumor drug such as methotrexate (MTX), 5 FU 5 fluorouracil (5FU) etc., influence the antitumor drug such as the Zorubicin of transcribed nucleic acid, pidorubicin, aclacinomycin, Plicamycin etc., act on tubulin synthetic antitumor drug such as taxol, vinorelbine etc., arimedex such as aminoglutethimide, Lan Telong, letrozole, auspicious Ningde etc., cell signal pathway inhibitor such as epidermal growth factor receptor inhibitor imatinib (Imatinib), Gefitinib (Gefitinib), erlotinib (Erlotinib) etc.Each composition to be made up can simultaneously or in a sequence give, and gives with the unitary agent form or with the form of different preparations.Described combination not only comprises the combination of compound of the present invention and a kind of other promoting agent, and comprises the combination of compound of the present invention and two or more other promoting agents.
By the kinase inhibition experiment, prove the specific inhibitory effect of The compounds of this invention to EGFR T790M.The evaluation method of kinase inhibition experiment is an enzyme-linked immunosorbent assay.
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment only to be used to the present invention is described and be not used in and limit the scope of the invention.The experimental technique of unreceipted actual conditions in the following example, usually according to normal condition, or the condition of advising according to manufacturer.Unless otherwise indicated, otherwise umber and per-cent are weight part and weight percent.
Embodiment
Embodiment 1
N-[4-(3-chloro-4-hydroxyl-phenyl amido)-7-methoxyl group-quinazoline-6-base-]-crotonamide
Figure GSA00000023874100071
In a flask that condensing works is housed, with raw material (Ia-1) 4-hydroxyl-3-chloroaniline 1.37g (5.6mmol) and (Ib-1) 6-nitro-7-methoxyl group-4-chloro-quinazoline 1.20g (5.7mmol) and be dissolved in the 80ml Virahol, back flow reaction 3h, separate out a large amount of yellow solids in the system, filter, solid washs to ph=8 with saturated sodium bicarbonate aqueous solution.Sample vacuum-drying is (Ic-1) through differentiating this compound.
In a flask that reflux condensate device is housed, add above-mentioned (Ic-1) compound 1.60g (3.77mmol), and reduced iron powder 1.05g (18.85mmol, 5eq), Glacial acetic acid 2ml, methyl alcohol 40ml behind the back flow reaction 2.5h, removes by filter iron powder under 85 ℃ of oil baths, filtrate is diluted with ethyl acetate, the sodium hydrogen carbonate solution washing, washing, organic phase is dry to be concentrated, obtain yellow solid, be (Id-1) through differentiating this compound.
In a 100ml flask, under ice bath, add above-mentioned (Id-1) compound 1.2g (3.04mmol), triethylamine 0.8ml (6.1mmol, 2eq), and crotonyl chloride 1.02ml (12.1mmol, 4eq), THF 40ml rises to room temperature reaction, behind the 3h gradually, stopped reaction filters, and solid water is washed till neutrality, dry, obtain solid 1.0g, be (1), yield 67% through differentiating this compound.
H 1-NMR(400MHz，CDCl 3+DMSO)：
δ8.64(s，1H)，8.47(s，1H)，8.07(d，1H)，7.51(s，1H)，7.23(s，1H)，7.02-7.00(d，1H)，6.96-6.92(m，1H)，6.78-6.75(d，1H)，5.97-5.93(dd，1H)，3.57(s，3H)，1.84-1.82(d，3H)
ESI(+)：385
Embodiment 2
N-[4-(3-chloro-4-hydroxyl-phenyl amido)-quinazoline-6-base-]-crotonamide
Figure GSA00000023874100081
In a flask that condensing works is housed, with raw material (Ia-1) 4-hydroxyl-3-chloroaniline 1.37g (5.6mmol) and (Ib-2) 6-nitro-4-chloro-quinazoline 1.20g (5.7mmol) and be dissolved in the 80ml Virahol, back flow reaction 3h, separate out a large amount of yellow solids in the system, filter, solid washs to ph=8 with saturated sodium bicarbonate aqueous solution.Sample vacuum-drying is (Ic-2) through differentiating this compound.
In a flask that reflux condensate device is housed, add above-mentioned (Ic-2) compound 1.60g (3.77mmol), and reduced iron powder 1.05g (18.85mmol, 5eq), Glacial acetic acid 2ml, methyl alcohol 40ml behind the back flow reaction 2.5h, removes by filter iron powder under 85 ℃ of oil baths, filtrate is diluted with ethyl acetate, the sodium hydrogen carbonate solution washing, washing, organic phase is dry to be concentrated, obtain yellow solid, be (Id-2) through differentiating this compound.
In a 100ml flask, under ice bath, add above-mentioned (Id-2) compound 1.2g (3.04mmol), triethylamine 0.8ml (6.1mmol, 2eq), and crotonyl chloride 1.02ml (12.1mmol, 4eq), THF 40ml rises to room temperature reaction, behind the 3h gradually, stopped reaction filters, and solid water is washed till neutrality, dry, obtain solid 1.1g, be (2), yield 68% through differentiating this compound.
H 1-NMR(400MHz，CDCl 3+DMSO)：
δ8.69(s，1H)，8.57(s，1H)，8.10(s，3H)，7.71-7.64(d，2H)，6.99-6.94(s，1H)，6.78-6.75(d，1H)，5.84-5.80(d，1H)，1.84(d，3H)
ESI(+)：355
Embodiment 3
N-[4-(3-chloro-4-hydroxyl-phenyl amido)-quinazoline-6-base-]-acrylamide
Figure GSA00000023874100091
In a 100ml flask, under ice bath, add (Id-2) compound 1.2g (3.04mmol) of the foregoing description 2, triethylamine 0.8ml (6.1mmol, 2eq), and acrylate chloride 1.02ml (12.1mmol, 4eq), THF40ml rises to room temperature reaction, behind the 3h gradually, stopped reaction filters, and solid water is washed till neutrality, dry, obtain solid 1.1g, be (3), yield 68% through differentiating this compound.
H 1-NMR(400MHz，CDCl 3+DMSO)：
δ8.63(s，1H)，8.53(s，1H)，8.14(s，3H)，7.71-7.64(dd，2H)，7.23(s，1H)，7.06-7.02(m，2H)，6.78-6.76(d，1H)，5.92-5.89(d，1H)，5.54-5.48(m，1H)
ESI(+)：341
Embodiment 4
N-[4-(3-chloro-4-hydroxyl-phenyl amido)-7-methoxyl group-quinazoline-6-base-]-acrylamide
Figure GSA00000023874100092
In a 100ml flask, under ice bath, add (Id-1) compound 1.2g (3.04mmol) of the foregoing description 1, triethylamine 0.8ml (6.1mmol, 2eq), and acrylate chloride 1.02ml (12.1mmol, 4eq), THF40ml rises to room temperature reaction, behind the 3h gradually, stopped reaction filters, and solid water is washed till neutrality, dry, obtain solid 1.1g, be (4), yield 68% through differentiating this compound.
H 1-NMR(400MHz，CDCl 3+DMSO)：
δ8.61(s，1H)，8.46(s，1H)，8.11(s，3H)，7.51(s，1H)，7.23-7.22(s，1H)，7.06-7.05(d，1H)，7.01-6.99(d，1H)，6.78-6.75(d，1H)，6.56-6.52(dd，1H)，5.92-5.89(dd，1H)，3.57(s，3H)
ESI(+)：371
Test implementation example 1 EGFR tyrosine-kinase enzyme inhibition activity detects
Enzyme reaction substrate Poly (Glu, Tyr) 4: 1 coated elisa plates, T-PBS are washed plate three times, and be dry in 37 ℃ of baking ovens; Every hole adds successively with the ATP solution of reaction buffer dilution, solvent control, testing compound or the positive control (Lapatinib of gradient concentration, GSK) and tried Tyrosylprotein kinase (Wild type EGFR or EGFRT790M/L858R), start reaction, put 37 ℃ of shaking table reactions 1 hour, T-PBS washes plate three times; Add antibody PY99 in 37 ℃ of reaction 1h, T-PBS washes plate three times, and the IgG of the sheep anti mouse of adding horseradish peroxidase-labeled is in 37 ℃ of reaction 1h, and T-PBS washes plate three times; Add OPD colour developing liquid, room temperature lucifuge reaction 1-10min; Add 2M H 2SO 4Stopped reaction is surveyed A with the wavelengthtunable orifice plate microplate reader VERSAmax that declines 492Value.The inhibiting rate of sample is tried to achieve by following formula:
Figure GSA00000023874100101
Obtain the IC of compound for Wild type EGFR or EGFR T790M/L858R by converting 50Value:
Compound Wild type EGFR IC 50(nM) EGFR?T790M/L858R?IC 50(nM)
Lapatinib (contrast) 1.5 ＞5000
Embodiment 3 compounds ＞100 ＜10
Test result shows: The compounds of this invention has very strong restraining effect to people EGFR T790M/L858R, and is very weak to the restraining effect of Wild type EGFR, has good selectivity.
All quote in this application as a reference at all documents that the present invention mentions, just quoted as a reference separately as each piece document.Should be understood that in addition those skilled in the art can make various changes or modifications the present invention after having read above-mentioned teachings of the present invention, these equivalent form of values fall within the application's appended claims institute restricted portion equally.

Claims (9)

1. as quinazoline derivant or its pharmacy acceptable salt of following general formula (I) expression,
Figure FSA00000023874000011
Mark in the formula is represented following implication
R 1: hydrogen, halogen, C 1-C 4The C that alkyl, halogen replace 1-C 4Alkyl;
R 2: hydrogen, halogen, C 1-C 4The C that alkyl, halogen replace 1-C 4Alkyl, C 1-C 4The C that alkoxyl group, halogen replace 1-C 4Alkoxyl group;
R 3Be halogen.
2. quinazoline derivant as claimed in claim 1 or its pharmacy acceptable salt is characterized in that, described R 1Be selected from hydrogen or C 1-C 4Alkyl.
3. quinazoline derivant as claimed in claim 1 or its pharmacy acceptable salt is characterized in that, described R 2Be selected from hydrogen or C 1-C 4Alkoxyl group.
4. quinazoline derivant as claimed in claim 1 or its pharmacy acceptable salt is characterized in that, described R 3Be chlorine.
5. quinazoline derivant as claimed in claim 1 or its pharmacy acceptable salt is characterized in that, described R 1Be selected from hydrogen or methyl, R 2Be selected from hydrogen or methoxyl group, R 3Be chlorine.
6. quinazoline derivant as claimed in claim 1 or its pharmacy acceptable salt is characterized in that it is selected from:
N-[4-(3-chloro-4-hydroxyl-phenyl amido)-quinazoline-7-methoxyl group-6-base-]-crotonamide;
N-[4-(3-chloro-4-hydroxyl-phenyl amido)-quinazoline-6-base-]-crotonamide;
N-[4-(3-chloro-4-hydroxyl-phenyl amido)-quinazoline-6-base-]-acrylamide;
N-[4-(3-chloro-4-hydroxyl-phenyl amido)-quinazoline-7-methoxyl group-6-base-]-acrylamide, or their pharmacy acceptable salts.
7. medical composition, it comprises the carrier that allows on the described quinazoline derivant of claim 1 or its pharmacy acceptable salt and the pharmacopedics.
8. the application of the formula I compound of claim 1 in preparation medicine for treating tumor thing, described tumour shows as 790 Threonines of EGF-R ELISA and sports methionine(Met) (EGFR T790M).
9. the application of the formula I compound of claim 1 in preparation treatment non-small cell lung cancer drug, described nonsmall-cell lung cancer shows as 790 Threonines of EGF-R ELISA and sports methionine(Met) (EGFRT790M).
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