CN103554091B - Quinazoline derivant and its production and use - Google Patents
Quinazoline derivant and its production and use Download PDFInfo
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- 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
Abstract
The invention belongs to pharmaceutical chemistry technical field, relate to general formula (I) quinazoline derivant and preparation method thereof, and the physiologically acceptable salt forming with inorganic or organic acid or alkali, the pharmaceutical composition that contains them, and at the medicine of preparation treatment disease, be particularly characterized as the application on the disease medicament of the PTK of abnormal erbB family activity. Described compound has valuable pharmacological properties, particularly to having inhibition because of the caused signal transduction of EGFR-TK.
Description
Technical field
The invention belongs to the synthetic field of medicine, specifically a kind of preparation method of quinazoline derivant and as medicineThing preparation purposes.
Background technology
Tyrosine inhibitors of kinases (TyrosineKinaseInhibitor), Main Function in epithelial cell growth because ofSub-acceptor (EpidermalGrowthFactorReceptor, EGFR). EGFR has important impact to the growth of cancer cellWith control dependence. If acceptor overexpression or the overactivity of cancer cell, cancer cell will raised growth, thereby relatedGround increases the probability of curing degree of difficulty and sending out. EGFR acceptor can be divided into four kinds of human epithelial growth factor acceptor (HumanEpidermalReceptor). The first type is commonly referred to EGFR, and Second-Type is called HER2, and other separately have the 3rd and the 4thType. In this four type, whether important the existence of Second-Type acceptor is, because excessive performance and the overactivity of Second-Type acceptorBe inversely proportional to patient with breast cancer's healing probability, if patient's cancer cell is with Second-Type acceptor, its cure rate is got over soLow, recurrence rate is higher, estimates that life span is shorter. People ErbB acceptor belongs to I receptor EGFR-TK (TK) family. CompriseErbB1 (EGFR), ErbB2 (HER2), ErbB3 (HER3) and ErbB4 (HER4). Cancer patient ErbB-1 (EGFR) and ErbB-2(HER-2) the common overexpression of acceptor or other change occurs.
The biological action of the PTK of ErbB family and tie up to for example United States Patent (USP) 5773476 with the pass of various diseases; InternationalPatent application WO99/35146; M.C.Hung etc., Seminarsinoncology, 26:4, Suppl.12,1999,51-59;Ullri etc., Cell, 61:203-212,20,1990; Modjtahedi etc., Int ' l.J.ofOncology, 13:335-342,1998; And J.R.Wooburn, Pharmacol.Ther., 82:2-3,241-250, existing discussion in 1999.
Known human epidermal growth factor acceptor-2 (ErbB-2, HER-2) be at present understanding comparatively clearly with breast cancerHuman carcinomas gene in close relations, its high expressed in breast cancer is often indicating easily lymphatic metastasis and Tumor DifferentiationPoor. Along with going deep into that HER-2 is studied, it has become one of target molecule of breast cancer specific treatment.
Many synthetic compounds have the activity of inhibition epidermal growth factor recipient tyrosine kinase (EGFR-PTK), outstandingIt is the most deep with quinazoline compounds research, and wherein Lapatinib was got permission listing treatment mammary gland in the U.S. in 2007Cancer, and obtain the approval with good conditionsi of European medicine administrative organ in December.
By to before Lapatinib clinical and analysis and the contrast of clinical data, Patent etc., establish with itFor lead compound, then, according to reporting compound and biological activity test data, utilize the means of CAD,The autotelic structure to Lapatinib designs, synthetic and screening, finds novel structure, high special, active better with itNovel targeted antitumoral compounds.
Summary of the invention
Goal of the invention:
The object of this invention is to provide a kind of compounds quinazoline derivant and dynamic isomer and its esters, outstandingIt is the physiologically acceptable salt of itself and inorganic or organic acid or alkali, and provides and contain on this pharmacology effectively chemical combinationThe pharmaceutical preparation of thing and application thereof.
Technical scheme:
The present invention is achieved through the following technical solutions.
Advantage and effect:
Quinazoline derivant of the present invention also has but is not limited to following beneficial effect:
(1), with respect to Lapatinib, quinazoline derivant provided by the present invention I-2 have good pharmacologically active and choosingSelecting property. For example, the active IC of inhibition of quinazoline derivant I-2 pair cultured cell in vitro growth50(μ g/ml) value is as follows respectively: rightThe inhibition activity of A-549 and MCF-7 is 0.18 and 0.27 μ g/ml, is 10.2 to the inhibition activity of PC-3; And Lapatinib is to bodyThe active IC of inhibition of outer cultured cell growth50(μ g/ml) value is as follows respectively: be 1.56 Hes to the inhibition activity of A-549 and MCF-73.15 μ g/ml are 7.28 to the inhibition activity of PC-3. As can be seen here, designed quinazoline derivant has better inhibitionActivity and selectivity.
(2) quinazoline derivant of the present invention I-2 have water-soluble preferably, through test confirm, it is at 0.1NHCl saltIn acid, solubility is 0.008mg/mL, and the solubility in water can reach 0.05mg/mlH2O (25 DEG C of temperature), and Lapatinib existsIn 0.1NHCl hydrochloric acid, solubility is 0.001mg/mL, and in water, solubility is 0.007mg/mL (25 DEG C of temperature), almost higher than oneThe individual order of magnitude. Thereby quinazoline derivant of the present invention I-2 have the bioavilability better or at least suitable compared with Lapatinib.
Brief description of the drawings:
Fig. 1 is the general formula of quinazoline derivant or its pharmaceutically acceptable salt;
Fig. 2 is the route map of the compound derivatives shown in synthesis type general formula (I).
Detailed description of the invention:
The compounds and dynamic isomer and its esters and the method for making thereof that the present invention relates to general formula (I), contain this medicineThe pharmaceutical preparation of active compound and application thereof in Neo-Confucianism.
Quinazoline derivant shown in general formula (I) or its pharmaceutically acceptable salt:
Wherein, R1 represents: hydrogen, C1-4Alkyl, C1-4Alkoxy or halogen; R2 represents: hydrogen, acetyl group, cyclopropane carbonyl, ringHexyl formoxyl, mesyl, benzoyl, to toluyl groups, benzenesulfonyl or p-toluenesulfonyl.
R1 is preferably from mono-substituted hydrogen, methyl, methoxyl group, fluorine, chlorine or bromine.
R1 is preferably from disubstituted hydrogen, methyl, methoxyl group, fluorine, chlorine or bromine.
Quinazoline derivant shown in above-mentioned general formula (I) or its pharmaceutically acceptable salt, the applicable acid of salify is: saltAcid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid, salicylic acid, methanesulfonic acid, butanedioic acid, horseCarry out sour or malic acid.
Above-mentioned arbitrary compound as preparation treatment taking the abnormal ErbB PTK of family activity in the medicine of the disease of featureApplication.
The described ErbB PTK of family is selected from EGFR, ErbB1 (EGFR) and ErbB2 (HER2).
Described compound has valuable pharmacological properties, particularly to having because of the caused signal transduction of EGFR-TKInhibition.
Compound shown in above-mentioned general formula (I) or salt and non-toxicity pharmaceutically acceptable salt thereof, and comprise general formulaCompound shown in (I) or salt and non-toxicity pharmaceutically acceptable salt thereof as the pharmaceutical composition of active component as systemThe purposes of standby cancer therapy drug.
Above-claimed cpd or salt are for the preparation of subcutaneous administration or oral pharmaceutical preparation.
Compound or pharmaceutically acceptable salt thereof of the present invention can be separately or with the form administration of pharmaceutical composition. The present inventionPharmaceutical composition can be made into various suitable dosage forms according to method of administration. Use acceptable carrier on one or more physiology,Comprise excipient and auxiliary agent, they are conducive to reactive compound to be processed into the preparation that can pharmaceutically use. Suitable systemAgent form depends on selected method of administration, can be prepared according to general knowledge well known in the art.
Method of administration can be oral, non-enteron aisle or topical, preferred oral and injection form administration. Can be oralPharmaceutical preparation comprises capsule and tablet etc. The compounds of this invention also can prepare for parenteral or cutaneous penetration orPerson's mucosal, or the mode administration of employing suppository or implants. It will be understood by those skilled in the art that of the present inventionizationCompound can adopt suitable drug delivery system (DDS) to obtain more favourable effect.
The present invention shows by external tetrazolium reducing process (mtt assay) test: the quinazoline with general formula (I) structure spreads outBiology is tied directly Human umbilical vein endothelial cells (HUVEC), human lung adenocarcinoma cell (A-549), people's marrow shape thyroid cell (TT), peopleEnteraden cancer cell (Colo205), Human Prostate Cancer Cells (PC-3), Proliferation of Human Ovarian Cell (SKOV-3), human breast cancer cell(MCF-7), human leukemia cell (HL-60) etc. has very strong cell inhibitory effect effect.
Below in conjunction with specific embodiment, the present invention is described further:
First the compound derivatives shown in bibliography (WO99/35146) method synthesis type (I):
Wherein R1And R2As defined above.
The 1 use ferrous acid reduction of nitro-phenoxy piperidones is obtained to compound 2, and compound 2 reacts with the quinazoline replacing againObtain compound 3, compound 3 obtains compound 4 with furans acid reaction under the catalysis of palladium carbon, and compound 4 is anti-with primary amine againShould obtain target compound I.
Embodiment 1
1-(4-((4-((6-(5-(((2-(mesyl) ethyl) amino) methyl) furans-2-yl) quinazoline-4-yl)Amino) phenoxy group) methyl) piperidin-1-yl) ethyl ketone (I-1) synthetic
500mL ethanol and 5mL sulfuric acid are added in 1000mL four-hole reaction bulb, then add 50g1-(4-((4-nitrobenzene oxygenBase) methyl) piperidin-1-yl) ethyl ketone 1, temperature rising reflux. Repeatedly add on a small quantity 60g reduced iron powder, add after iron powder in continuing and refluxReaction 3h. Be cooled to room temperature and drip ammoniacal liquor, regulate pH=9 left and right, filter, except de-iron mud, washing. Filtrate is adjusted pH=4 with hydrochloric acid,Separate out product, filter, filter cake is dried to obtain 36.8g1-(4-((4-amino-benzene oxygen) methyl) piperidin-1-yl) ethyl ketone 2.1HNMR(400MHz,DMSO):δ1.34-1.59(m,4H,CH2),2.00(m,1H,CH),2.36(s,3H,CH3),3.20-3.40(m,4H,CH2),3.90(d,2H,CH2),6.50-6.80(dd,4H,ArH)；ESI-MS:m/z249[M+H]+。
By chloro-4-6-iodine quinazoline (90.2g, 0.31mol) and 1-(4-((4-amino-benzene oxygen) methyl) piperidin-1-yl)Ethyl ketone 2 (76.9g, 0.31mol) is dissolved in isopropyl alcohol (500mL), adds hot reflux 2h. After solution is cooling, filter, isopropyl alcohol andEther is washed, and is dried to obtain 120.5g1-(4-((4-((6-iodine quinazoline-4-yl) amino) phenoxy group) methyl) piperidin-1-yl) secondKetone 3.1HNMR(400MHz,DMSO):δ1.34-1.59(m,4H,CH2),2.00(m,1H,CH),2.36(s,3H,CH3),3.20-3.40(m,4H,CH2),3.90(d,2H,CH2),6.74(d,2H,ArH),7.60(d,2H,ArH),7.93(d,1H,ArH),8.20(m,2H,ArH),8.60(s,1H,ArH)；ESI-MS:m/z503[M+H]+。
By compound 3 (130.52g, 0.26mol), acid chloride (58.4g, 0.26mol), triphenyl phosphorus (68.1g,0.26mol) be dissolved in the DMF of 350mL with triethylamine 20mL, dropping 5-formoxyl-2-furans boric acid (36.4g,0.26mol), add hot reflux 7 hours, obtain crude product and obtain 90.3g5-(4-((4-((1-acetyl group piperidines-4-through column chromatographyBase) methoxyl group) phenyl) amino) quinazoline-6-yl) furans-2-formaldehyde 4.1HNMR(400MHz,DMSO):δ1.34-1.59(m,4H,CH2),2.00(m,1H,CH),2.36(s,3H,CH3),3.20-3.40(m,4H,CH2),3.90(d,2H,CH2),6.39(d,1H,ArH),6.74(d,2H,ArH),7.35(d,1H,ArH),7.60(d,2H,ArH),7.93(d,1H,ArH),8.20(m,2H,ArH),8.60(s,1H,ArH),9.70(s,1H,CHO)；ESI-MS:m/z471[M+H]+。
Compound 4 (84.6g, 0.18mol) and 2-mesyl ethamine (22.4g, 0.18mol) are added to 200mL dichloroIn methane, stirring at room temperature 2 hours. Then add the 50mL acetic acid solution of triacetyl sodium borohydride (110.2g, 0.52mol),Continue reaction 6 hours. Be poured into water, carrene extracts, solvent evaporated, and crude product column chromatography obtains target compound 1-(4-((4-((6-(5-(((2-(mesyl) ethyl) amino) methyl) furans-2-yl) quinazoline-4-yl) amino) phenoxy group) firstBase) piperidin-1-yl) ethyl ketone (I-1) 80.2g.1HNMR(400MHz,DMSO):δ1.34-1.59(m,4H,CH2),2.00(m,1H,CH),2.36(s,3H,CH3),2.83(s,3H,CH3),3.11(m,2H,CH2),3.20-3.40(m,4H,CH2),3.53(m,2H,CH2),3.67(s,2H,CH2),3.90(d,2H,CH2),6.39(d,1H,ArH),6.74(d,2H,ArH),7.35(d,1H,ArH),7.60(d,2H,ArH),7.93(d,1H,ArH),8.20(m,2H,ArH),8.60(s,1H,ArH)；ESI-MS:m/z578[M+H]+。
Embodiment 2
Cyclopropyl 1-(4-((4-((6-(5-(((2-(mesyl) ethyl) amino) methyl) furans-2-yl) quinazoline-4-yl) amino) phenoxy group) methyl) piperidin-1-yl) ketone (I-2) synthetic
According to the identical method preparation of embodiment 1, by cyclopropyl (4-((4-nitrophenoxy) methyl) piperidin-1-yl) firstKetone obtains compound (4-((4-amino-benzene oxygen) methyl) piperidin-1-yl) cyclopropyl ketone under iron powder reducing, more chloro-with 4-The reaction of 6-iodine quinazoline, then, with 5-formoxyl-2-furans acid reaction, finally reacts and obtains target with 2-mesyl ethamineChemical compounds I-2,1HNMR(400MHz,DMSO):δ0.72-0.93(m,4H,CH2),1.15-1.17(m,1H,CH),1.34-1.59(m,4H,CH2),2.00(m,1H,CH),2.83(s,3H,CH3),3.11(m,2H,CH2),3.20-3.40(m,4H,CH2),3.53(m,2H,CH2),3.67(s,2H,CH2),3.90(d,2H,CH2),6.39(d,1H,ArH),6.74(d,2H,ArH),7.35(d,1H,ArH),7.60(d,2H,ArH),7.93(d,1H,ArH),8.20(m,2H,ArH),8.60(s,1H,ArH)；ESI-MS:m/z604[M+H]+。
Embodiment 3
6-(5-(((2-(mesyl) ethyl) amino) methyl) furans-2-yl)-N-(4-((1-(mesyl) piperazinePyridine-4-yl) methoxyl group) phenyl) quinazoline-4-amine (I-3) synthetic
According to the identical method preparation of embodiment 1, by 1-mesyl-(4-((4-nitrophenoxy) methyl) piperidines existsUnder iron powder reducing, obtain compound (4-((1-mesyl) piperidin-4-yl) aminoanisole, then with the chloro-6-iodine of 4-quinazolineReaction, then, with 5-formoxyl-2-furans acid reaction, finally reacts and obtains target compound I-3 with 2-mesyl ethamine，1HNMR(400MHz,DMSO):δ1.34-1.59(m,4H,CH2),2.00(m,1H,CH),2.83(s,3H,CH3),2.96(s,3H,CH3),3.11(m,2H,CH2),3.20-3.40(m,4H,CH2),3.53(m,2H,CH2),3.67(s,2H,CH2),3.90(d,2H,CH2),6.39(d,1H,ArH),6.74(d,2H,ArH),7.35(d,1H,ArH),7.60(d,2H,ArH),7.93(d,1H,ArH),8.20(m,2H,ArH),8.60(s,1H,ArH)；ESI-MS:m/z614[M+H]+。
Embodiment 4
6-(5-(((2-(mesyl) ethyl) amino) methyl) furans-2-yl)-N-(4-((1-(benzenesulfonyl) piperazinePyridine-4-yl) methoxyl group) phenyl) quinazoline-4-amine (I-4) synthetic
According to the identical method preparation of embodiment 1,4-((4-nitrophenoxy) methyl)-1-(benzenesulfonyl) piperidines is existedUnder iron powder reducing, obtain compound 4-((1-(benzenesulfonyl) piperidin-4-yl) methoxyl group) aniline, then with the chloro-6-iodine of 4-quinazolineReaction, then, with 5-formoxyl-2-furans acid reaction, finally reacts and obtains target compound I-4 with 2-mesyl ethamine，1HNMR(400MHz,DMSO):δ1.34-1.59(m,4H,CH2),2.00(m,1H,CH),2.83(s,3H,CH3),3.11(m,2H,CH2),3.20-3.40(m,4H,CH2),3.53(m,2H,CH2),3.67(s,2H,CH2),3.90(d,2H,CH2),6.39(d,1H,ArH),6.74(d,2H,ArH),7.35(d,1H,ArH),7.60(d,2H,ArH),7.93(d,1H,ArH),8.20-8.45(m,7H,ArH),8.60(s,1H,ArH)；ESI-MS:m/z676[M+H]+。
Embodiment 5
1-(4-((2-methyl-4-((6-(5-(((2-(mesyl) ethyl) amino) methyl) furans-2-yl) quinoline azolesQuinoline-4-yl) amino) phenoxy group) methyl) piperidin-1-yl) ethyl ketone (I-5) synthetic
According to the identical method preparation of embodiment 1, by 1-(4-((2-methyl-4-nitrophenoxy) methyl) piperidines-1-Base) ethyl ketone obtains compound 1-(4-((4-amino-2-methyl phenoxy group) methyl) piperidin-1-yl) ethyl ketone under iron powder reducing,React with the chloro-6-iodine of 4-quinazoline again, then with 5-formoxyl-2-furans acid reaction, last and 2-mesyl ethamine is anti-Should obtain target compound I-5,1HNMR(400MHz,DMSO):δ1.34-1.59(m,4H,CH2),2.00(m,1H,CH),2.18(s,3H,CH3),2.36(s,3H,CH3),2.83(s,3H,CH3),3.11(m,2H,CH2),3.20-3.40(m,4H,CH2),3.53(m,2H,CH2),3.67(s,2H,CH2),3.90(d,2H,CH2),6.39(d,1H,ArH),6.74(d,1H,ArH),7.35(d,1H,ArH),7.60(d,2H,ArH),7.93(d,1H,ArH),8.20(m,2H,ArH),8.60(s,1H,ArH)；ESI-MS:m/z592[M+H]+。
Embodiment 6
1-(4-((the fluoro-4-of 2-((6-(5-(((2-(mesyl) ethyl) amino) methyl) furans-2-yl) quinazoline-4-yl) amino) phenoxy group) methyl) piperidin-1-yl) ethyl ketone (I-6) synthetic
According to the identical method preparation of embodiment 1, by 1-(4-((the fluoro-4-nitro of 2-methoxyl group) methyl) piperidin-1-yl)Ethyl ketone obtains compound 1-(4-((4-amino-2-fluorophenoxy) methyl) piperidin-1-yl) ethyl ketone under iron powder reducing, then with 4-Chloro-6-iodine quinazoline reaction, then, with 5-formoxyl-2-furans acid reaction, finally reacts and obtains with 2-mesyl ethamineTarget compound I-6,1HNMR(400MHz,DMSO):δ1.34-1.59(m,4H,CH2),2.00(m,1H,CH),2.36(s,3H,CH3),2.83(s,3H,CH3),3.11(m,2H,CH2),3.20-3.40(m,4H,CH2),3.53(m,2H,CH2),3.67(s,2H,CH2),3.90(d,2H,CH2),6.39(d,1H,ArH),6.74(d,1H,ArH),7.35(d,1H,ArH),7.60(d,2H,ArH),7.93(d,1H,ArH),8.20(m,2H,ArH),8.60(s,1H,ArH)；ESI-MS:m/z596[M+H]+。
Embodiment 7
Method for preparing tablet thereof is as follows:
Technique: active component auxiliary material is crossed respectively to 100 mesh sieves, take main ingredient and auxiliary material (the half carboxymethyl shallow lake of recipe quantityPowder sodium) fully mix, add polyvinylpyrrolidone aqueous solution softwood processed in right amount, cross 24 mesh sieves, make wet granular in 50-60 DEG CIn baking oven, dry about 2-3 hour, mixes residue sodium carboxymethyl starch and dolomol with particle, and whole grain, in the middle of measuringBody burden, with the shallow stamping of Φ 8mm.
Embodiment 8
The preparation of parenteral solution
Technique: get water for injection 50ml, the citric acid, the sodium dihydrogen phosphate that take recipe quantity are stirred to dissolve, and add sampleStirring and dissolving, with hydrochloric acid or the NaOH adjust pH of 0.1mol/L be 4.0-5.0, add 20 points of 0.1% charcoal absorptionsClock. First filter with 0.45 μ m filter membrane, then filter with 0.22 μ m is smart. Press 5 milliliters of per ampoules filling, 105 DEG C of high-temperature sterilizations 30 minutes areObtain parenteral solution.
Embodiment 9
The anti tumor activity in vitro test of chemical compounds I
(1) material
Cell line: Human umbilical vein endothelial cells (HUVEC), human lung adenocarcinoma cell (A-549), people's marrow shape thyroid cell(TT), people ties Rectal Adenocarcinoma Cells (Colo205), Human Prostate Cancer Cells (PC-3), Proliferation of Human Ovarian Cell (SKOV-3), human milkAdenocarcinoma cell (MCF-7), human leukemia cell (HL-60).
Reagent: MTT, Amresco company; DMEM, DMEM/F12 culture medium, Gibco company; Calf serum, Lanzhou Min HaiBiological; Trypsase, Amresco company.
Instrument: superclean bench, Suzhou Decontamination Equipment Plant; CO2 incubator, Thermo company, model: HERACell150; Inverted microscope, CarlZeiss company, model: Axiovert200; Enzyme-linked immunosorbent assay instrument, TECAN company,Model: Sunrise; Centrifuge, Kerdro company, model: Heraeus.
(2) method
Cell is cultivated: cell is seeded in containing 10% calf serum, 100IU/ml penicillin G sodium salt and 100ug/ml sulfate chainIn the DMEM of mycin or DMEM/F12 complete culture solution, put 37 DEG C, 100% relative humidity, containing in the incubator of 5%CO2, go down to posterityFor subsequent use after 3 times.
MTT colorimetric determination: the cell in the growth period of taking the logarithm, (suspension cell need not after 0.25% Trypsin InducedDigestion), be suspended in containing in the nutrient solution of 10% calf serum, blow and beat into gently single cell suspension with glass dropper, under microscopeWith blood cell counts plate numeration living cells. (cell concentration is 3～6 × 10 to the 96 every hole of well culture plate inoculating cell suspension 90 μ l4Individual/mL), to put after incubator 24h, every hole adds 10 μ l liquids. In addition, each concentration is established negative control (isoconcentration DMSO) and blankBackground (not adding cell), all establishes 6 multiple holes for each group. Continuous Cultivation 48h again, it is molten that then every hole adds the MTT of 10 μ l5mg/mLLiquid, continues to cultivate after 4h, carefully sucks supernatant. Every hole adds 100 μ lDMSO, puts micro oscillator concussion 5min so that knotCrystalline substance dissolves completely, in the mono-wavelength colorimetric of ELIASA 492nm, measures OD value, and result of the test is in table 1.
Inhibiting rate (%)=[(experimental group OD average-blank group OD average)/(OD is equal for control group OD average-blank group for 1-Value)] × 100%. Bliss method is calculated test-compound IC50Value.
(3) result
The IC of table 1. to cultured cell in vitro growth50(μg/ml)
Claims (7)
1. the quinazoline derivant shown in general formula (I) or its pharmaceutically acceptable salt:
Wherein, R1 represents: hydrogen, C1-4Alkyl, C1-4Alkoxy or halogen; R2 represents: hydrogen, acetyl group, cyclopropane carbonyl, cyclohexylFormoxyl, mesyl, benzoyl, to toluyl groups, benzenesulfonyl or p-toluenesulfonyl.
2. quinazoline derivant according to claim 1 or its officinal salt, is characterized in that: R1 is preferably from mono-substitutedHydrogen, methyl, methoxyl group, fluorine, chlorine or bromine.
3. quinazoline derivant according to claim 1 and 2 or its pharmaceutically acceptable salt, is characterized in that: be suitable forAcid be: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid, salicylic acid, methanesulfonic acid,Butanedioic acid, maleic acid or malic acid.
4. arbitrary compound described in claim 1 or 2 is treated the disease taking the abnormal ErbB PTK of family activity as feature as preparationApplication in sick medicine.
5. purposes claimed in claim 4, is characterized in that: the described ErbB PTK of family is selected from EGFR, ErbB1 and ErbB2.
6. arbitrary compound or salt described in claim 1 or 2, and contain this arbitrary compound or salt becomes as activityThe pharmaceutical composition dividing is as the application of preparing cancer therapy drug.
7. application according to claim 6, it is for the preparation of subcutaneous administration or oral pharmaceutical preparation.
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| EP1510221A1 (en) * | 2002-06-03 | 2005-03-02 | Mitsubishi Pharma Corporation | Preventives and/or remedies for subjects with the expression or activation of her2 and/or egfr |
| CN102060875A (en) * | 2009-11-18 | 2011-05-18 | 天津药物研究院 | Novel quinazoline derivative, and preparation method and application thereof |
| CN102532103A (en) * | 2010-12-20 | 2012-07-04 | 天津药物研究院 | Quinazolinyl aryl urea derivatives and preparation method and application thereof |
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2013
- 2013-11-05 CN CN201310542061.6A patent/CN103554091B/en not_active Expired - Fee Related
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| WO1998002434A1 (en) * | 1996-07-13 | 1998-01-22 | Glaxo Group Limited | Fused heterocyclic compounds as protein tyrosine kinase inhibitors |
| CN1292788A (en) * | 1998-01-12 | 2001-04-25 | 葛兰素集团有限公司 | Bicyclic heteroaromatic compounds as protein tyrosine kinase inhibitors |
| EP1510221A1 (en) * | 2002-06-03 | 2005-03-02 | Mitsubishi Pharma Corporation | Preventives and/or remedies for subjects with the expression or activation of her2 and/or egfr |
| CN102060875A (en) * | 2009-11-18 | 2011-05-18 | 天津药物研究院 | Novel quinazoline derivative, and preparation method and application thereof |
| CN102532103A (en) * | 2010-12-20 | 2012-07-04 | 天津药物研究院 | Quinazolinyl aryl urea derivatives and preparation method and application thereof |
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| Optimization and SAR for dual ErbB-1/ErbB-2 tyrosine kinase inhibition in the 6-furanylquinazoline series;Kimberly G. Petrov，等;《Bioorganic & Medicinal Chemistry Letters》;20060613;第16卷(第17期);第4686-4691页 * |
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