CN103012368A - Quinoline derivative - Google Patents
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- CN103012368A CN103012368A CN2011102829788A CN201110282978A CN103012368A CN 103012368 A CN103012368 A CN 103012368A CN 2011102829788 A CN2011102829788 A CN 2011102829788A CN 201110282978 A CN201110282978 A CN 201110282978A CN 103012368 A CN103012368 A CN 103012368A
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- WOEQSXAIPTXOPY-UHFFFAOYSA-N CC(C)(C)OC(N(CC1)CCC1OS(C)(=O)=O)=O Chemical compound CC(C)(C)OC(N(CC1)CCC1OS(C)(=O)=O)=O WOEQSXAIPTXOPY-UHFFFAOYSA-N 0.000 description 1
- WUQPBTWGWXJOPS-UHFFFAOYSA-N CC(Oc(c(OC)cc1ncc2C#N)cc1c2O)=O Chemical compound CC(Oc(c(OC)cc1ncc2C#N)cc1c2O)=O WUQPBTWGWXJOPS-UHFFFAOYSA-N 0.000 description 1
- QSYHJRNVHUODMU-UHFFFAOYSA-N CNC(CN(CC1)CCC1Oc(c(OC)cc1ncc2C#N)cc1c2Nc(cc1)cc(Cl)c1F)=O Chemical compound CNC(CN(CC1)CCC1Oc(c(OC)cc1ncc2C#N)cc1c2Nc(cc1)cc(Cl)c1F)=O QSYHJRNVHUODMU-UHFFFAOYSA-N 0.000 description 1
- JWLWWDOXMYIBAM-UHFFFAOYSA-N COC(c(c(N)c1)cc(OCc2ccccc2)c1OC)=O Chemical compound COC(c(c(N)c1)cc(OCc2ccccc2)c1OC)=O JWLWWDOXMYIBAM-UHFFFAOYSA-N 0.000 description 1
- SHQBNKDRVJNGDX-UHFFFAOYSA-N COC(c(c([N+]([O-])=O)c1)cc(OCc2ccccc2)c1OC)=O Chemical compound COC(c(c([N+]([O-])=O)c1)cc(OCc2ccccc2)c1OC)=O SHQBNKDRVJNGDX-UHFFFAOYSA-N 0.000 description 1
- IYWARKWWNJLZAS-UHFFFAOYSA-N COc(c(O)cc1c2Nc(cc3)cc(Cl)c3F)cc1ncc2C#N Chemical compound COc(c(O)cc1c2Nc(cc3)cc(Cl)c3F)cc1ncc2C#N IYWARKWWNJLZAS-UHFFFAOYSA-N 0.000 description 1
- NRBKRBAAWRIBKV-UHFFFAOYSA-N COc(c(O)cc1c2O)cc1ncc2C#N Chemical compound COc(c(O)cc1c2O)cc1ncc2C#N NRBKRBAAWRIBKV-UHFFFAOYSA-N 0.000 description 1
- 0 COc(c(OC1CC*CC1)cc1c2Nc(cc3Cl)ccc3F)cc1ncc2C#N Chemical compound COc(c(OC1CC*CC1)cc1c2Nc(cc3Cl)ccc3F)cc1ncc2C#N 0.000 description 1
Abstract
The invention discloses a compound represented by a formula (I), and a preparation method and an application thereof.
Description
The field
The application relates to the pharmaceutical chemistry field.
Background
At present the scheme of many diseases that unusually caused by regulation of cell proliferation such as psoriasis and cancer has been utilized the compound that suppresses the synthetic and cell proliferation of DNA.So far, the compound that is used for this treatment has cytotoxicity usually, pretends usefulness but they have for quick noble cells such as cancer cells, and this effect is favourable.Developed at present the method for replaceable these cell toxicant antitumour drugs, for example the selective depressant of Cell signal transduction pathway.The inhibitor of these types can show and strengthen selectively acting in the potentiality of antitumor cell, and therefore can reduce the probability of the adverse side effect that quality has.
As everyone knows, many Tyrosylprotein kinases sport the constitutive activity form and/or cause various human cells to transform after by overexpression.Kinase whose these sudden changes or overexpression form all exist in accounting for the human tumor of significant proportion.Owing to Tyrosylprotein kinase has vital role in the propagation of various tissues and differentiation, there is the research of a lot of development of new anti-cancer therapies all to concentrate on these enzymes.This family's enzyme is divided into two groups: receptor tyrosine kinase and nonreceptor tyrosine kinase, be respectively for example EGF acceptor and SRC family, from the large quantity research result of (comprising the Human Genome Project), about 90 kinds of Tyrosylprotein kinases in human genome, have been identified, wherein 58 kinds is receptor type, and 32 kinds is non-receptor type.They can be divided into 20 kinds of receptor tyrosine kinases and 10 kinds of nonreceptor tyrosine kinase subfamilies.
General introduction
On the one hand, the application relates to the compound shown in the formula (I),
On the other hand, the application relates to the intermediate of formula (I) compound shown in the formula (II),
Another aspect, the application relates to the intermediate of formula (I) compound shown in the formula (III),
(III)
On the one hand, the application relates to the pharmaceutical composition that comprises the compound shown in the formula (I) and medicine acceptable carrier again.
On the other hand, the application relates to the method for preparation formula (II) compound,
It comprises: with 4-chloro-3-formonitrile HCN-7-methoxy quinoline-6-base-ethyl acetate and the reaction of 3-chloro-4-fluoroaniline, obtain formula (II) compound.
Another aspect, the application relates to the method for preparation formula (III) compound,
It comprises: with (II) compound and alkali reaction, obtain formula (III) compound.
On the one hand, the application relates to the method for preparation formula (I) compound again,
It comprises:
(1) with formula (III) compound and 4-mesyloxy-N-tertiary butyloxycarbonyl phenylpiperidines reaction, obtain tertiary butyl 4-((4-(3-chloro-4-fluorophenyl) amino)-3-formonitrile HCN-7-methoxy quinoline-6-yl)-oxygen) piperidines-1-carboxylicesters;
(2) with tertiary butyl 4-((4-(3-chloro-4-fluorophenyl) amino)-3-formonitrile HCN-7-methoxy quinoline-6-yl)-oxygen) piperidines-1-carboxylicesters carries out deprotection reaction and obtains 4-((4-(3-chloro-4-fluorophenyl) amino)-7-methoxy quinoline-6-yl)-oxygen) piperidines-3-formonitrile HCN; And
(3) with 4-((4-(3-chloro-4-fluorophenyl) amino)-7-methoxy quinoline-6-yl)-oxygen) piperidines-3-formonitrile HCN and N-methyl-Haloacetamide reaction obtains formula (I) compound.
Other aspects, the application relates to formula (I) compound for the preparation of the purposes in the medicine that treats and/or prevents with protein tyrosine kinase diseases related or morbid state,
Describe in detail
Following description comprises some detail so that the various disclosed embodiments of thorough.Yet various equivalent modifications should be appreciated that and can need not one or more these details, perhaps can use other method, composition, material etc. to put into practice embodiment.
Unless context has requirement in addition, in the following description book and claims, term " comprises " and synonym " comprises " and should be interpreted as implication open, that comprise, namely should be interpreted as " including, but are not limited to ".
Mentioned " embodiment " in the whole specification sheets, or " embodiment ", or " in another embodiment ", or " some embodiment ", or " in certain embodiments " refers to that the described feature that be specifically related to, structure or the characteristic relevant with described embodiment are included at least one embodiment.Therefore, phrase " in one embodiment ", " in embodiments ", " in another embodiment " or " in certain embodiments " of the local appearance of each in whole specification sheets needn't all refer to identical embodiment.In addition, specific features, structure or characteristic can combine in one or more embodiments in any suitable manner.
On the one hand, the application relates to the compound shown in the formula (I),
On the other hand, the application relates to the intermediate of formula (I) compound shown in the formula (II),
Another aspect, the application relates to the intermediate of formula (I) compound shown in the formula (III),
On the one hand, the application relates to the pharmaceutical composition that comprises the compound shown in the formula (I) and medicine acceptable carrier again.
The medicine acceptable carrier comprises itself does not induce producing the medicament to the harmful antibody of the individuality of accepting described composition, and can administration and do not have unsuitable toxicity.
The exemplary carrier that can be used in the application includes but not limited to particulate; Liquid, such as water, salt solution, glycerine and ethanol etc.; Aerosol.
On the other hand, the application relates to the method for preparation formula (II) compound,
It comprises: with 4-chloro-3-formonitrile HCN-7-methoxy quinoline-6-base-ethyl acetate and the reaction of 3-chloro-4-fluoroaniline, obtain formula (II) compound.
In certain embodiments, the method for preparation formula (II) compound is carried out in the amine aqueous solution of alcohols.
The exemplary alcohols that can be used in the application includes but not limited to Virahol.In certain embodiments, the method for preparation formula (II) compound is carried out in the amine aqueous solution of Virahol.
The exemplary amine that can be used in the application includes but not limited to triethylamine.In certain embodiments, the method for preparation formula (II) compound is carried out in the triethylamine solution of alcohols.
In certain embodiments, the method for preparation formula (II) compound is carried out in the triethylamine solution of Virahol.
In certain embodiments, the method for preparation formula (II) compound is carried out under take pyridine hydrochloride as auxiliary agent in the amine aqueous solution of alcohols.
In certain embodiments, the method for preparation formula (II) compound is carried out in the amine aqueous solution of alcohols, and temperature of reaction is 65-100 ℃.
In certain embodiments, the method for preparation formula (II) compound is carried out in the amine aqueous solution of alcohols, and temperature of reaction is 65-100 ℃, carries out under protection of inert gas 1.5-6 hour.
The exemplary rare gas element that can be used in the application includes but not limited to argon gas and nitrogen.
Another aspect, the application relates to the method for preparation formula (III) compound,
It comprises: with (II) compound and alkali reaction, obtain formula (III) compound.
The exemplary alkali that can be used in the application's preparation formula (III) compound includes but not limited to ammoniacal liquor.
On the one hand, the application relates to the method for preparation formula (I) compound again,
It comprises:
(1) with formula (III) compound and 4-mesyloxy-N-tertiary butyloxycarbonyl phenylpiperidines reaction, obtain tertiary butyl 4-((4-(3-chloro-4-fluorophenyl) amino)-3-formonitrile HCN-7-methoxy quinoline-6-yl)-oxygen) piperidines-1-carboxylicesters;
(2) with tertiary butyl 4-((4-(3-chloro-4-fluorophenyl) amino)-3-formonitrile HCN-7-methoxy quinoline-6-yl)-oxygen) piperidines-1-carboxylicesters carries out deprotection reaction and obtains 4-((4-(3-chloro-4-fluorophenyl) amino)-7-methoxy quinoline-6-yl)-oxygen) piperidines-3-formonitrile HCN; And
(3) with 4-((4-(3-chloro-4-fluorophenyl) amino)-7-methoxy quinoline-6-yl)-oxygen) piperidines-3-formonitrile HCN and N-methyl-Haloacetamide reaction obtains formula (I) compound.
In certain embodiments, tertiary butyl 4-((4-(3-chloro-4-fluorophenyl) amino)-3-formonitrile HCN-7-methoxy quinoline-6-yl)-oxygen) deprotection reaction of piperidines-1-carboxylicesters carries out in organic solvent and alkaline solution.
The exemplary organic solvent that can be used in the application includes but not limited to the mixture of methylene dichloride and trifluoroacetic acid.In certain embodiments, tertiary butyl 4-((4-(3-chloro-4-fluorophenyl) amino)-3-formonitrile HCN-7-methoxy quinoline-6-yl)-oxygen) deprotection reaction of piperidines-1-carboxylicesters carries out in the mixture of methylene dichloride and trifluoroacetic acid and alkaline solution.
In certain embodiments, the exemplary alkali solution that can be used in the application includes but not limited to sodium bicarbonate.In certain embodiments, tertiary butyl 4-((4-(3-chloro-4-fluorophenyl) amino)-3-formonitrile HCN-7-methoxy quinoline-6-yl)-oxygen) deprotection reaction of piperidines-1-carboxylicesters carries out in organic solvent and sodium hydrogen carbonate solution.
In certain embodiments, 4-((4-(3-chloro-4-fluorophenyl) amino)-7-methoxy quinoline-6-yl)-oxygen) reaction of piperidines-3-formonitrile HCN and N-methyl-Haloacetamide is carried out in the mixing solutions of anhydrous sodium carbonate and potassiumiodide.
In certain embodiments, the method for preparation formula (I) compound also comprises: (4) are with the mixing solutions of methylene dichloride and water extraction 4-((4-(3-chloro-4-fluorophenyl) amino)-7-methoxy quinoline-6-yl)-oxygen) piperidines-3-formonitrile HCN and N-methyl-Haloacetamide react and obtain formula (I) compound.
In certain embodiments, the method for preparation formula (I) compound also comprises: (5) use formula (I) compound that obtains behind the chromatographic column separating and extracting.In certain embodiments, the condition of chromatographic column is methylene dichloride: methyl alcohol=20: 1.
The exemplary N-methyl-Haloacetamide that can be used in the application includes but not limited to N-methyl-chlor(o)acetamide and N-methyl-bromoacetamide.
In certain embodiments, the method for preparation formula (I) compound comprises:
On the other hand, the application relates to formula (I) compound for the preparation of the purposes in the medicine that treats and/or prevents with protein tyrosine kinase diseases related or morbid state,
(I)
That in certain embodiments, can use the application's formula (I) compounds for treating and/or prevention is disease or the morbid state relevant with the epidermal growth factor receptor protein Tyrosylprotein kinase with protein tyrosine kinase diseases related or morbid state.
In certain embodiments, can use the disease relevant with the epidermal growth factor receptor protein Tyrosylprotein kinase of the application's formula (I) compounds for treating and/or prevention or morbid state to be the disease relevant with human epidermal growth factor receptor 2's protein tyrosine kinase.
In certain embodiments, can use the disease relevant with protein tyrosine kinase or the morbid state of the application's formula (I) compounds for treating and/or prevention to be solid tumor.
Can use the exemplary physical knurl of the application's formula (I) compounds for treating and/or prevention to include but not limited to nonsmall-cell lung cancer, mammary cancer, cancer of the stomach and maxicell lung cancer.
In certain embodiments, the disease relevant with Tyrosylprotein kinase or morbid state are selected from nonsmall-cell lung cancer and mammary cancer.
Other aspects, the application relates to the method that treats and/or prevents with protein tyrosine kinase diseases related or morbid state, and it comprises formula (I) compound for the treatment of significant quantity to the individuality of the described method of needs,
" individuality " refers to the animal as the object for the treatment of, observation or test." animal " comprises cold-blooded and homoiothermy vertebra and invertebrates, for example fish, Crustacean, Reptilia, and Mammals particularly." Mammals " includes but not limited to mouse, rat, rabbit, cavy, dog, cat, sheep, goat, cow, horse, primates, for example monkey, chimpanzee and ape, and people particularly.
" treatment " and " treatment " not necessarily means totally to treat or eliminate a disease or morbid state.On any degree, any any alleviation of not expecting the symptom of illness or disease or morbid state can both be considered to treatment.In addition, treatment can comprise the behavior that the comfort that makes patient's integral body or sign worsen.
" treatment significant quantity " is used for the amount of expression active compound or pharmaceutical preparation, and described amount causes biologically or the drug reaction of appointment.For example, the treatment significant quantity of compound can be prevention, alleviate or improve disease symptoms or prolongation and be treated the individual needed amount of survival.This reaction can occur in tissue, system, animal or human, and comprises that improvement is treated the symptom of disease.In the ability that is determined at those skilled in the art for the treatment of significant quantity, the detailed content that especially provides according to the application.Depend on the physical trait of the route of administration in the consideration, the type of animal that comprises the people that is treated and concrete animal as the come into the open treatment significant quantity of compound of the required the application of dosage.Can customize dosage with the realization desired effects, but can depend on such as following factor: the other factors that body weight, diet, drug combination and field of medicaments technician generally acknowledge.
The simple synthetic method of the disclosed formula of the application (I) compound and intermediate formula (II) thereof, formula (III) compound is easily gone.
In addition, the application's formula (I) compound not only can treat and/or prevent the disease relevant with protein tyrosine kinase or morbid state, and can treat and/or prevent disease or the morbid state relevant with the epidermal growth factor receptor protein Tyrosylprotein kinase, such as solid tumor.Formula (I) compound has good effect treating and/or preventing nonsmall-cell lung cancer and mammary cancer.
Hereinafter, the present invention will be explained in detail by following embodiment and better understand all respects of the present invention and advantage.But, should be appreciated that following embodiment is nonrestrictive and only is used for explanation certain embodiments of the present invention.
Embodiment
Embodiment 1
The preparation of 4-chloro-3-formonitrile HCN-7-methoxy quinoline-6-base-ethyl acetate
The preparation of 3-benzyloxy-4-methoxyl methyl benzoate (compound 2)
Be 3-hydroxyl-4-methoxyl methyl benzoate (9.11g with compound 1,50mmol), bromobenzyl (9.41g, 55mmol) and salt of wormwood (7.60g, 55mmol) be added in the 200mL acetonitrile, backflow 4h, suction filtration boils off acetonitrile while hot, obtain compound 2 with re-crystallizing in ethyl acetate, that is: 3-benzyloxy-4-methoxyl methyl benzoate is total to 12.12g, productive rate 89%.
3-hydroxyl-4-methoxyl methyl benzoate is available from West Asia, Shanghai reagent company, and bromobenzyl, acetonitrile and salt of wormwood are all available from the Beijing Chemical Plant.
The evaluation of compound 2
Compound 2 is carried out nucleus magnetic resonance and mass spectrometric detection, and the result is as follows:
1H NMR (300MHz, CDCl
3) δ 7.68 (dd, J=8.4,2.0Hz, 1H), 7.61 (d, J=2.0Hz, 1H), (7.47 d, J=7.2Hz, 2H), 7.43-7.27 (m, 3H), 6.90 (d, J=8.4Hz, 1H), 5.17 (s, 2H), 3.93 (s, 3H), 3.87 (s, 3H).MS(ESI+)m/z 273.1[M+H]
+。
The preparation of 5-benzyloxy-4-methoxyl group-2-nitro-methyl benzoate (compound 3)
With compound 2, that is: 3-benzyloxy-4-methoxyl methyl benzoate (0.82g, 3mmol) is added in the 7.5mL Glacial acetic acid, stir into suspension liquid, add again the 1.5mL concentrated nitric acid, 50 ℃ of lower reaction 2.5h, cooling adds the 50mL frozen water, suction filtration after stirring, be washed to neutrality, oven dry gets yellow solid 5-benzyloxy-4-methoxyl group-2-nitro-methyl benzoate, and namely compound 3,0.82g, productive rate 82%.
The evaluation of compound 3
Compound 3 is carried out nucleus magnetic resonance and mass spectrometric detection, and detected result is as follows:
1H NMR (300MHz, CDCl
3) δ 7.57-7.31 (m, 6H), 7.15 (s, 1H), 5.21 (s, 2H), 3.97 (s, 3H), 3.89 (s, 3H).MS(ESI+)m/z 317.9[M+H]
+。
The preparation of 5-benzyloxy-4-methoxyl group-2-Methyl anthranilate (compound 4)
With 5-benzyloxy-4-methoxyl group-2-nitro-methyl benzoate, be compound 3 (0.32g, 1mmol) be dissolved in the 10mL ethanol, add hydrated stannous chloride (0.90g, 4mmol), 50 ℃ of lower reaction 3h, pressure reducing and steaming ethanol, add 20mL ethyl acetate and 20mL water, with sodium hydroxide solution alkalize to pH be 8～9, suction filtration, separatory, water layer is with ethyl acetate extraction (20mL * 2), merge organic phase, saturated common salt washing (30mL * 2), anhydrous sodium sulfate drying, filter, concentrated, (sherwood oil: ethyl acetate=2: 1 → 1: 1) separate to get 5-benzyloxy-4-methoxyl group-2-amino-methyl benzoate, namely compound 4 to dodge post, be total to 0.24g, productive rate 84%.
Hydrated stannous chloride is available from the Beijing Chemical Plant.
The evaluation of compound 4
Compound 4 is carried out nucleus magnetic resonance and mass spectrometric detection, and detected result is as follows:
1H NMR (300MHz, CDCl
3) δ 7.50-7.26 (m, 6H), 6.15 (s, 1H), 5.62 (br s, 2H), 5.02 (s, 2H), 3.85 (s, 3H), 3.82 (s, 3H).MS(ESI+)m/z 288.1[M+H]
+。
The preparation of 6-benzyloxy-4-hydroxyl-7-methoxy quinoline-3-formonitrile HCN (compound 5)
With compound 4,5-benzyloxy-4-methoxyl group-2-amino-methyl benzoate (4.77g, 15mmol) and N, dinethylformamide dimethylacetal (3.57g, 30mmol) in 110 ℃ of lower backflow 3h, evaporated under reduced pressure then, the not purified direct use of gained intermediate.Nitrogen protection, is added to the 50mL tetrahydrofuran (THF) with the n-Butyl Lithium of 36.4mL 1.6M by-78 ℃; drip the tetrahydrofuran solution (50mL) of 3.02mL acetonitrile in the 15min, behind the insulation reaction 20min, drip the tetrahydrofuran solution (50mL) of intermediate; continue insulation reaction 30min; be warming up to-40 ℃ of reaction 1h, add 7.68mL acetic acid, rise to room temperature reaction 30min; add 200mL water; suction filtration after stirring, the filter cake methanol wash is dried; the gained crude product is with 200mL methanol eddy 30min; suction filtration, methanol wash, oven dry; get product 6-benzyloxy-4-hydroxyl-7-methoxy quinoline-3-formonitrile HCN; be compound 5, amount to 7.12g, productive rate 87.81%.
The DMF dimethylacetal is available from Wuhan Jia Kailong development in science and technology company limited, and n-Butyl Lithium is available from Beijing coupling Science and Technology Ltd., and tetrahydrofuran (THF) is available from the Beijing Chemical Plant.
The evaluation of compound 5
Compound 5 is carried out nucleus magnetic resonance and mass spectrometric detection, and detected result is as follows:
1H NMR (300MHz, DMSO-d
6) δ 12.59 (s, 1H), 8.60 (s, 1H), 7.57 (s, 1H), 7.53-7.29 (m, 5H), 7.08 (s, 1H), 5.21 (s, 2H), 3.90 (s, 3H).MS(ESI+)m/z307.1[M+H]
+。
The preparation of 4,6-dihydroxyl-7-methoxy quinoline-3-formonitrile HCN quinoline (compound 6)
With compound 5, namely 6-benzyloxy-4-hydroxyl-7-methoxy quinoline-3-formonitrile HCN (1.00g, 3.26mmol) is dissolved in the 150mL DMF, and adding Pd/C (10% content, 0.50g), 4 atm H
2, 50 ℃ of lower catalytic hydrogenation 3h.Suction filtration, evaporated under reduced pressure adds 25mL acetone, and is ultrasonic, refluxes, and suction filtration gets 4,6-dihydroxyl-7-methoxy quinoline-3-formonitrile HCN quinoline, and namely compound 6, product 0.65g, productive rate 92%.
Palladium carbon reaches company limited available from Shaanxi.
The evaluation of compound 6
Compound 6 is carried out nucleus magnetic resonance and mass spectrometric detection, and detected result is as follows:
1H NMR (300MHz, DMSO-d
6) δ 8.36 (s, 1H), 7.40 (s, 1H), 7.01 (s, 1H), 3.86 (s, 3H).MS(ESI+)m/z 217.1[M+H]
+。
The preparation of 3-formonitrile HCN-4-hydroxyl-7-methoxy quinoline-6-ethyl acetate (compound 7)
With compound 6, namely 4,6-dihydroxyl-7-methoxy quinoline-3-formonitrile HCN quinoline (2.14g, 10mmol) be added in the 16mL aceticanhydride 100 ℃ of lower reaction 2.5h, cooling with the 2mL pyridine, pour in the 100mL frozen water, stir 0.5h, suction filtration, washing, acetone is washed, oven dry, get 3-formonitrile HCN-4-hydroxyl-7-methoxy quinoline-6-ethyl acetate, namely compound 7, and this compound is yellow solid, 2.28g, productive rate 89%.
The evaluation of compound 7
Compound 7 is carried out nucleus magnetic resonance and mass spectrometric detection, and detected result is as follows:
1H NMR (300MHz, DMSO-d
6) δ 12.71 (s, 1H), 8.70 (s, 1H), 7.77 (s, 1H), 7.16 (s, 1H), 3.90 (s, 3H), 2.30 (s, 3H).MS(ESI+)：m/z 259.1[M+H]
+。
The preparation of 3-formonitrile HCN-4-chloro-7-methoxy quinoline-6-ethyl acetate (compound 8)
With compound 7, that is: 3-formonitrile HCN-4-hydroxyl-7-methoxy quinoline-6-ethyl acetate (2.44g, 10mmol) place the 100mL eggplant-shape bottle, add 25mL sulfur oxychloride and 0.5mL N, dinethylformamide, backflow 4h, then pressure reducing and steaming sulfur oxychloride, revolve to steam with toluene again and remove residual sulfur oxychloride (25mL * 2), obtain compound 8.
The evaluation of compound 8
Compound 8 is carried out nucleus magnetic resonance and mass spectrometric detection, and detected result is as follows:
1H NMR (300MHz, DMSO-d
6) δ 9.13 (s, 1H), 8.05 (s, 1H), 7.72 (s, 1H), 4.03 (s, 3H), 2.37 (s, 3H).MS(ESI+)：m/z 277.1[M+H]
+。
Embodiment 2
The preparation of 4-mesyloxy-N-tertiary butyloxycarbonyl phenylpiperidines
The preparation of 4-hydroxy-n-tertiary butyloxycarbonyl phenylpiperidines (compound 12)
With the 4-hydroxy piperidine, i.e. compound 11 (1.01g, 10mmol) and triethylamine (1.2g, 12mmol) be dissolved in the methylene dichloride (15mL) 0 ℃ of lower dichloromethane solution (2.58g, 12mmol that drips tert-Butyl dicarbonate, be dissolved in 5mL), rise to again room temperature reaction 1h, washing, the saturated common salt washing, anhydrous sodium sulfate drying filters, boil off solvent, get 4-hydroxy-n-tertiary butyloxycarbonyl phenylpiperidines, namely compound 12,1.92g, productive rate 91%.
The evaluation of compound 12
Compound 12 is carried out nucleus magnetic resonance and Mass Spectrometric Identification,
1H NMR (300MHz, CDCl
3) δ 3.86-3.83 (m, 3H), 3.07-2.98 (m, 2H), 1.88-1.83 (m, 4H), 1.46 (s, 9H).MS(ESI+)m/z 222.4[M+Na]
+。
The preparation of 4-sulfonyloxy methyl oxygen base-N-tertiary butyloxycarbonyl phenylpiperidines (compound 13)
With 4-hydroxy-n-tertiary butyloxycarbonyl phenylpiperidines, be compound 12 (2.01g, 10mmol) and triethylamine (1.2g, 12mmol) be dissolved in the tetrahydrofuran (THF) (15mL) 0 ℃ of lower Methanesulfonyl chloride (0.93mL that drips, 12mmol) and react 3h, add 50mL water, with ethyl acetate extraction (50mL * 2), merge organic phase, 1N salt pickling (30mL * 2), washing (30mL * 2), saturated sodium bicarbonate is washed (30mL * 2), saturated common salt washing (30mL * 2), filter, boil off solvent, get sulfonyloxy methyl oxygen base-N-tertiary butyloxycarbonyl phenylpiperidines, namely compound 13,2.57g, productive rate 92%.
The evaluation of compound 13
Compound 13 is carried out nucleus magnetic resonance and Mass Spectrometric Identification,
1H NMR (300MHz, CDCl
3) δ 4.88 (tt, J=7.7,3.8Hz, 1H), (3.80-3.62 m, 2H), 3.30 (ddd, J=12.2,8.0,3.8Hz, 2H), 3.04 (s, 3H), 2.04-1.90 (m, 2H), 1.83 (ddd, J=13.3,8.7,4.2Hz, 2H), 1.46 (s, 9H).MS(ESI+)m/z 302.0[M+Na]
+。
Embodiment 3
4-((4-fluoro-3-chloro-phenyl-)-amino)-3-formonitrile HCN-7-methoxy quinoline-6-guanidine-acetic acid ethyl ester (formula (III)
Compound) preparation
With 3-formonitrile HCN-4-chloro-7-methoxy quinoline-6-ethyl acetate, i.e. compound 8 (825mg, 3mmol); 3-chloro-4-fluoroaniline 9 (434mg, 3mmol)), pyridine hydrochloride (103mg; 0.9mmol) be dissolved in the 70mL Virahol argon shield, 85 ℃ of lower backflow 3h.Be cooled to room temperature, suction filtration, filter cake is with the isopropyl alcohol wash, ether is washed, dry 4-((4-fluoro-3-chloro-phenyl-)-amino)-3-formonitrile HCN-7-methoxy quinoline-6-guanidine-acetic acid ethyl ester that gets, namely formula (III) compound (compound 10) is total to 990mg, productive rate 86%.
The evaluation of formula (III) compound (compound 10)
Compound 10 is carried out nucleus magnetic resonance and mass spectrometric detection, and detected result is as follows:
1H NMR (300MHz, DMSO-d6) δ: 11.26 (br s, 1H), 9.04 (d, J=1.3Hz, 1H), 8.66～8.64 (m, 1H), (7.84 dd, J=2.3,6.6Hz, 1H), (7.66 d, J=1.8Hz, 1H), (7.56-7.46 m, 2H), 4.01 (s, 3H), 2.38 (s, 3H) .MS (ESI+) m/z:[M+H]
+, 386.0.
Embodiment 4
The preparation of formula (I) compound
The system of 4-((4-fluoro-3-chloro-phenyl-)-amino)-3-formonitrile HCN-7-methoxyl group-6-hydroxyquinoline (compound 14)
Standby
With 4-((4-fluoro-3-chloro-phenyl-)-amino)-3-formonitrile HCN-7-methoxy quinoline-6-guanidine-acetic acid ethyl ester, be compound 10,1.14g is dissolved in the 30mL methyl alcohol, adds 6mL ammoniacal liquor, stirring at room 2h, leach solid, water washing, oven dry, get compound 4-((4-fluoro-3-chloro-phenyl-)-amino)-3-formonitrile HCN-7-methoxyl group-6-hydroxyquinoline, be compound 14, be total to 700mg, productive rate 70%.
The evaluation of compound 14
Compound 14 is carried out nucleus magnetic resonance and Mass Spectrometric Identification, and qualification result is as follows:
1H NMR (300MHz, DMSO-d
6) δ: 9.92 (s, 1H), 9.43 (s, 1H), 8.48 (s, 1H), 7.57 (s, 1H), 7.43～7.36 (m, 2H), 7.20～7.16 (m, 1H), 3.99 (s, 3H) .MS (ESI+) m/z344.1[M+H]
+
Tertiary butyl 4-((4-(3-chloro-4-fluorophenyl) amino)-3-formonitrile HCN-7-methoxy quinoline-6-yl)-oxygen) piperidines
The preparation of-1-carboxylicesters (compound 15)
With 4-((4-fluoro-3-chloro-phenyl-)-amino)-3-formonitrile HCN-7 methoxyl groups-6-hydroxyquinoline; be compound 14 (0.765g; 2.2mmol); 4-mesyloxy-N-tertbutyloxycarbonyl piperidinyl-1 3 (0.88g; 3.3mmol) and cesium carbonate (1.1g; 3.3mmol) adding 6mL N; in the N-N,N-DIMETHYLACETAMIDE, argon shield, 100 ℃ of lower 2.5h that stir; stopped reaction; revolve and desolventize adding 20mL ethyl acetate, 20mL washing; water is with the 20mL ethyl acetate extraction; merge organic phase, saturated common salt washing, anhydrous sodium sulfate drying; revolve and desolventize; column chromatography (methylene dichloride: methyl alcohol=100: 1) separate, the gained crude product obtains tertiary butyl 4-((4-(3-chloro-4-fluorophenyl) amino)-3-formonitrile HCN-7-methoxy quinoline-6-yl)-oxygen with re-crystallizing in ethyl acetate again) piperidines-1-carboxylicesters, namely compound 15; product 650mg, productive rate 55%.
The evaluation of compound 15
Compound 15 is carried out nucleus magnetic resonance and mass spectral:mass spectrographic evaluation, and qualification result is as follows:
1H NMR (300MHz, DMSO-d6) δ 9.47 (br s, 1H), 8.50 (s, 1H), 8.65 (t, 1H), 7.75 (s, 1H), 7.53 (dd, J=2.5,6.6Hz, 1H), 7.47 (t, J=9.0Hz, 1H), (7.37 s, 1H), 7.31-7.26 (m, 1H), 4.71-4.64 (m, 1H), (3.96 s, 3H), 3.70-3.63 (m, 2H), 3.24-3.17 (m, 2H), (1.93-1.90 m, 2H), 1.66-1.54 (m, 2H), 1.41 (s, 9H).MS(ESI)m/z：[M+H]
+，527.1。
4-((4-(3-chloro-4-fluorophenyl) amino)-3-formonitrile HCN-7-methoxy quinoline-6-yl)-oxygen) piperidines (chemical combination
Thing 16) preparation
With compound tertiary butyl 4-((4-(3-chloro-4-fluorophenyl) amino)-3-formonitrile HCN-7-methoxy quinoline-6-yl)-oxygen) piperidines-1-carboxylicesters, be compound 15 (315mg, 0.6mmol) be dissolved in the 2.5mL methylene dichloride, 0 ℃ of lower 2.5mL trifluoroacetic acid that adds, after stirring 5min, rise to room temperature and continue to stir 1h, add the dilution of 20mL methylene dichloride, and add saturated sodium bicarbonate solution and sodium bicarbonate solid and be weakly alkaline to water pH, saturated common salt is washed to neutrality, anhydrous sodium sulfate drying, revolve and desolventize to get 4-((4-(3-chloro-4-fluorophenyl) amino)-3-formonitrile HCN-7-methoxy quinoline-6-yl)-oxygen) piperidines, be compound 16, product 229mg, productive rate 90%.
The evaluation of compound 16
Compound 16 is carried out nucleus magnetic resonance and Mass Spectrometric Identification, and qualification result is as follows:
1H NMR (300MHz, DMSO-d
6) δ 9.67 (br s, 1H), 8.47 (br s, 1H), 7.75 (s, 1H), 7.50 (dd, J=2.5,6.6Hz, 1H), (7.43 t, J=9.0Hz, 1H), 7.34 (s, 1H), (7.30-7.25 m, 1H), 4.65-4.54 (m, 1H), 3.94 (s, 3H), 3.00-2.93 (m, 2H), 2.62-2.54 (m, 2H), (1.98-1.92 m, 2H), 1.56-1.44 (m, 2H).MS(ESI+)m/z427.1[M+H]
+。
The preparation of formula (I) compound
With 4-((4-(3-chloro-4-fluorophenyl) amino)-3-formonitrile HCN-7-methoxy quinoline-6-yl)-oxygen) piperidines, be compound 16 and N-methyl chloride ethanamide, it is compound 18, Anhydrous potassium carbonate (85mg, 0.62mmol) and potassiumiodide (25mg, 0.15mmol) add in the 10mL acetonitrile, 80 ℃ of lower backflow 1h revolve and desolventize, and adding methylene dichloride and water, extraction, separatory, organic phase is washed with saturated common salt, anhydrous sodium sulfate drying, column chromatography (methylene dichloride: methyl alcohol=20: 1) separate to get formula (I) compound, i.e. product 180mg, productive rate 71%.
The evaluation of formula (I) compound
Formula (I) compound that obtains is carried out nucleus magnetic resonance and mass spectroscopy, and analytical results is as follows:
1H NMR (300MHz, DMSO-d6) δ: 9.48 (s, 1H), 8.49 (br s, 1H), 7.75-7.69 (m, 2H), 7.53 (dd, J=2.5,6.5Hz, 1H), 7.6 (t, J=9.0Hz, 1H), 7.36 (s, 1H), (7.32-7.26 m, 2H), 4.58-4.49 (m, 1H), (3.95 s, 3H), 2.92 (s, 2H), (2.73-2.69 m, 2H), 2.62 (d, J=4.7Hz, 3H), 2.33 (t, J=9.1Hz, 2H), 2.00-1.96 (m, 2H), 1.82-1.72 (m, 2H).MS(ESI+)m/z 498.2[M+H]
+。
Embodiment 5
The preparation of N-methyl chloride ethanamide
In the 250mL there-necked flask, add 15.3g aqueous methylamine solution (25%-30%), water 25mL, system is cooled to-20 ℃, slowly drip the 7.5mL chloroacetyl chloride to system, then rise to stirring at room 15min, transfer PH to 5, dichloromethane extraction 3 times, anhydrous sodium sulfate drying filters, desolventize, get white solid, add the 10mL normal hexane, be spin-dried for, get N-methyl chloride ethanamide, namely compound 18,5.5g, productive rate 48%.
Chloroacetyl chloride is available from the Beijing Chemical Plant.
The evaluation of N-methyl chloride ethanamide
N-methyl chloride ethanamide is carried out nucleus magnetic resonance and mass spectral:mass spectrographic detection, and the result is as follows:
1HNMR (300MHz, CDCl
3) δ 6.63 (br s, 1H), 4.07 (s, 2H), 2.90 (d, J=6.0Hz, 3H).MS(ESI)m/z 108.1[M+H]
+。
Embodiment 6
Employed positive control is among the application: 4-(3-chloro-2-fluoroanilino)-6-{[1-(N-ethylamino formyl radical methyl) piperidin-4-yl] the oxygen base }-7-methoxyl group-3-itrile group-quinoline
Its preparation method is as follows: with 2-chloro-N-methyl-ethanamide (51mg, 0.47mmol) dropwise add 4-(3-chloro-2, the 4-difluorobenzene is amino)-7-methoxyl group-6-[(piperidin-4-yl) amino]-3-itrile group-quinoline (0.47mmol), potassiumiodide (79mg, 0.47mmol) and salt of wormwood (79mg, 0.57mmol) in the mixture of N,N-DIMETHYLACETAMIDE (5ml).Heated these mixtures 1 hour in 70 ℃, the cooled and filtered solid, filtrate is through the HPLC column purification (C18 of preparative HPLC-MS system, 5 microns, the 19mm diameter, 10mm length), use comprises 2g/l ammonium formiate water and acetonitrile mixture (gradient) wash-out generates described control compound (46mg), is white solid.
1.
Formula (I) compound is to Tyrosylprotein kinase (EGFR) restraining effect
Method: use to carry out the refining EGF acceptor of part from the A431 cell strain that comes from people's squamous cell carcinoma, improved the tyrosine kinase activity assay method of Linda J.Pike etc., and carried out determination of activity, method detailed is as follows:
In containing the Dalbeck political reform EAGLE substratum (DMEM) of cowboy's serum (FBS) 10%, at 37 ℃, cultivate the A431 cell under the condition of 5% carbon dioxide, with the homogenate in the solution that contains N-2-hydroxyethyl piperidine subbase-N ' of 10mM-2-ethanesulfonic acid (Hepes) damping fluid (pH7.4), 0.25M sucrose, 0.1mM EDTA of this cell, then with 3000G centrifugal 5 minutes, and then with 100000G centrifuged supernatant 30 minutes, obtain A431 cytolemma part, the refining EGF acceptor of its part as the enzyme source is supplied and determination of activity.
Be dissolved in above-mentioned A431 cytolemma part (10-15 μ g), 30mM Hepes damping fluid (pH7.7), 2mM MnCl
2, 100mM Na
3VO
4After adding the EGF of 100ng in the reaction mixture (ultimate density 1%DMSO) of analyte in the dimethyl sulfoxide (DMSO), add synthetic substrate Angiotensin II (Asp-Arg-Val-Tyr-Ile-His-Pro-Phe) 50 μ g, adenosine triphosphate (contains Y
32P-marked body 37KBq) ultimate density 10mM makes the reaction beginning.The capacity of this moment is 60 μ L.
Reaction is 30 minutes in ice, adds 10mg/mL bovine serum albumin 6 μ L, 20% Tricholroacetic Acid, 25 μ L, and reaction is stopped, and then directly places 30 minutes in frozen water.
Then, after centrifugal 2 minutes, get supernatant liquor 40 μ L with 5000G, on the absorption P81 phosphorus cellulose paper.Be immersed in 0.75% phosphate aqueous solution 5 minutes, clean, repeats four dippings, cleaning operation after, taking-up paper is measured by the scintiscanning counter
32The counting of P is set as A with this value.
Also measure simultaneously the reaction of not adding measured matter, the counting of the reaction that measured matter and EGF do not add is set as respectively B, C.
Calculate the tyrosine-kinase enzyme inhibition rate by these values according to following formula.
Inhibiting rate (%)=100-{ (A-C)/(B-C) } * 100
According to the inhibiting rate of the interpolation concentration gained that changes measured matter, calculate IC
50Value (50% inhibition concentration)
Table 1
| Compound | IC 50 |
| Formula (I) compound | 1.3 |
| Positive control | 2.1 |
2.
Formula (I) compound is to human epidermal growth factor receptor 2 HER2 tyrosine kinase inhibitory activity
Cell uses the NIH3T3 mouse fibroblast strain of being out of shape by the 659th α-amino-isovaleric acid being substituted by variation c-erbB2 that L-glutamic acid has stabilizing active.Below be designated as the A4 cell.Utilize the DMEM/F12 mixed culture medium (hereinafter referred to as collective media) that adds 10%FBS, cultivated 2 hours with 37 ℃.After cleaning cell once with PBS, again outstanding turbid at molten born of the same parents' damping fluid (60mM Tutofusin tris Tris (pH6.8), 2% sodium lauryl sulphate SDS, 10% glycerine, 5% beta-mercaptoethanol, 0.001% tetrabromophenol sulfonphthalein) in, uses ultrasonication, be used for western Protein transfer as WCL and inhale the seal method.
After the WCL of protein content 25 μ g parts is used for 7.5%SDS-polypropylene phthalein amine electrophoresis, be replicated on the pvdf membrane.Behind this membrane closure, in the Tutofusin tris Tris damping fluid that adds 0.1% polysorbas20, hatch with Tyrosine O-phosphate, mouse monoclonal antibody, then, with 2 antibody treatment of the anti-mouse of HRP mark.Process film with chemical reagent, carry out the chemoluminescence shooting with luminous CCD camera, be recorded in the electronic medium.The optical density meter carries out quantification to the phosphoric acid signal of gained, and the signal when not adding compound is made as 100% inhibitor, and background signal is made as 0%, and the phosphorylation that suppresses to estimate based on compound with % suppresses.
Table 2
| Compound | % suppresses (0.1 μ M) | % suppresses (1 μ M) |
| Formula (I) compound | 46 | 5 |
| Positive control | 42 | 4 |
3.
Formula (I) compound is to IC that the extracorporeal anti-tumor cell is rised in value 50 Mensuration
3.1 experiment purpose
Detect fixed pattern (I) compound to the propagation half-inhibition concentration IC of BT474, SK-BR-3 and A549 cell strain by the CCK-8 detection kit
50
3.2 experiment material and method
Cell strain:
BT474 human breast cancer cell strain (source: cell biological institute of the Chinese Academy of Sciences)
SK-BR-3 human breast cancer cell strain (source: cell biological institute of the Chinese Academy of Sciences)
A549 Non-small cell lung carcinoma cell strain (source: cell biological institute of the Chinese Academy of Sciences)
3.3 experiment reagent and preparation
Reagent and consumptive material:
Test kit CCK-8 test kit is available from the easy sharp test kit in Shanghai departmentized specialty store
96 well culture plates (available from Beijing Suo Laibao Science and Technology Ltd.)
Australia blood relationship foetal calf serum FBS (inspiring Bioisystech Co., Ltd, product type 10099-141 available from Shanghai)
Substratum (available from the product type RPMI1640 of the great Bioisystech Co., Ltd in Shanghai and DMEM)
Desk-top microplate reader is available from U.S. molecule instrument company China office
The candidate compound: formula (I) compound, molecular weight is 497.95, purity＞95% is about 5mg, deepfreeze.
3.4 experimental procedure
1) reagent preparation
The preparation of substratum
The preparation of compound:
Making final concentration with the DMSO diluted compounds is 10mM.
2) cell cultures
(1) collect the logarithmic phase cell, counting, with perfect medium Eddy diffusion cell,
(2) adjust cell concn to suitable concn, inoculate 96 orifice plates, 100 μ l cell suspensions are inoculated in every hole.
(3) cell is at 37 ℃, 100% relative humidity, 5% CO
2Hatched in the incubator 24 hours.
3) IC
50Experiment
(a) collect the logarithmic phase cell, counting with perfect medium Eddy diffusion cell, is adjusted cell concn to suitable concn (determining according to cell density optimization Test result), inoculates 96 orifice plates, and every hole adds 100 μ l cell suspensions.Cell is at 37 ℃, 100% relative humidity, 5%CO
2After hatching 24 hours in the incubator.
(b) with substratum testing compound is diluted to behind the 500 μ M gradient dilution 8 times.Add cell by 25 μ l/ holes.The compound final concentration is from 100 μ M to 0 μ M, 3 times of dilutions, totally 10 concentration point.
(c) cell places 37 ℃, and 100% relative humidity was hatched in the 5%CO2 incubator 72 hours.
(d) substratum is abandoned in suction, adds the perfect medium that contains 10%CCK-8 and places 37 ℃ of incubators to hatch 2-4 hour.
(e) measure the absorbancy at 450nm wavelength place after the light shaking at SpectraMax M5 Microplate Reader, with 650nm place absorbancy as reference, the calculating inhibiting rate.
(4) data processing
Be calculated as follows medicine to the inhibiting rate of growth of tumour cell: growth of tumour cell inhibiting rate %=[(Ac-As)/(Ac-Ab)] * 100%
As: the OA of sample (cell+CCK-8+ testing compound)
Ac: the OA of negative control (cell+CCK-8+DMSO)
Ab: the OA of positive control (substratum+CCK-8+DMSO)
3.5 experimental result
IC after the conclusion
50Value sees table 3 for details
Table 3
As can be seen from the above table, formula (I) compound is to the IC of human breast cancer cell strain BT474, human breast cancer cell strain SK-BR-3 and Non-small cell lung carcinoma cell line A549
50Value all is lower than the IC of positive control
50Value shows that it is better than positive control to the proliferation inhibiting effect of tumour cell BT474, SK-BR-3 and A549.
Although be appreciated that from the foregoing for the purpose of exemplary illustration and described specific embodiments of the present invention, under condit without departing from the spirit and scope of the present invention, the described technician in this area can make various distortion or improvement.These distortion or modification all should fall into the scope of the application's claims.
Claims (17)
1. the compound shown in the formula (I),
2. the intermediate of formula (I) compound shown in the formula (II),
3. the intermediate of formula (I) compound shown in the formula (III),
4. the pharmaceutical composition that comprises the compound shown in the formula (I) and medicine acceptable carrier.
5. the method for preparation formula (II) compound,
It comprises: with 4-chloro-3-formonitrile HCN-7-methoxy quinoline-6-base-ethyl acetate and the reaction of 3-chloro-4-fluoroaniline, obtain formula (II) compound.
6. method as claimed in claim 5, wherein said reaction is carried out in the preferred triethylamine solution of the amine of the preferred Virahol of alcohols, is to carry out under the auxiliary agent at pyridine hydrochloride preferably.
7. such as claim 5 or 6 described methods, wherein temperature of reaction is 65-100 ℃, carries out under protection of inert gas 1.5-6 hour.
8. the method for preparation formula (III) compound,
It comprises: with (II) compound and alkali reaction, obtain formula (III) compound.
9. the method for preparation formula (I) compound,
It comprises:
(1) with formula (III) compound and 4-mesyloxy-N-tertiary butyloxycarbonyl phenylpiperidines reaction, obtain tertiary butyl 4-((4-(3-chloro-4-fluorophenyl) amino)-3-formonitrile HCN-7-methoxy quinoline-6-yl)-oxygen) piperidines-1-carboxylicesters;
(2) with tertiary butyl 4-((4-(3-chloro-4-fluorophenyl) amino)-3-formonitrile HCN-7-methoxy quinoline-6-yl)-oxygen) piperidines-1-carboxylicesters carries out deprotection reaction and obtains 4-((4-(3-chloro-4-fluorophenyl) amino)-7-methoxy quinoline-6-yl)-oxygen) piperidines-3-formonitrile HCN; And
(3) with 4-((4-(3-chloro-4-fluorophenyl) amino)-7-methoxy quinoline-6-yl)-oxygen) piperidines-3-formonitrile HCN and N-methyl-Haloacetamide reaction obtains formula (I) compound.
10. method as claimed in claim 9, wherein said deprotection reaction carries out in organic solvent and alkaline solution, and preferred described organic solvent is the mixture of methylene dichloride and trifluoroacetic acid, and preferred described alkaline solution is sodium hydrogen carbonate solution.
11. method as claimed in claim 9, wherein the reaction of step (3) is carried out in the mixing solutions of anhydrous sodium carbonate and potassiumiodide.
12. method as claimed in claim 9, wherein said N-methyl-Haloacetamide are N-methyl-chlor(o)acetamide or N-methyl-bromoacetamide.
13. formula (I) compound is for the preparation of the purposes in the medicine that treats and/or prevents with protein tyrosine kinase diseases related or morbid state,
14. purposes as claimed in claim 13, wherein said and protein tyrosine kinase diseases related or morbid state are disease or the morbid state relevant with the epidermal growth factor receptor protein Tyrosylprotein kinase.
15. purposes as claimed in claim 14, the wherein said disease relevant with the epidermal growth factor receptor protein Tyrosylprotein kinase or morbid state are the disease relevant with human epidermal growth factor receptor 2's protein tyrosine kinase.
16. purposes as claimed in claim 13, the wherein said disease relevant with protein tyrosine kinase or morbid state are solid tumor.
17. purposes as claimed in claim 13, the wherein said disease relevant with Tyrosylprotein kinase or morbid state are selected from nonsmall-cell lung cancer and mammary cancer.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1882569A (en) * | 2003-09-19 | 2006-12-20 | 阿斯利康(瑞典)有限公司 | Quinazoline derivatives |
| CN101638383A (en) * | 2008-07-29 | 2010-02-03 | 北大方正集团有限公司 | Quinoline as well as pharmaceutical composition and use thereof |
| CN101659658A (en) * | 2008-08-29 | 2010-03-03 | 北大方正集团有限公司 | Quinoline substituted by cyan |
| CN101659657A (en) * | 2008-08-29 | 2010-03-03 | 北大方正集团有限公司 | Quinoline substituted by cyan and preparation method and applications thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1882569A (en) * | 2003-09-19 | 2006-12-20 | 阿斯利康(瑞典)有限公司 | Quinazoline derivatives |
| CN101638383A (en) * | 2008-07-29 | 2010-02-03 | 北大方正集团有限公司 | Quinoline as well as pharmaceutical composition and use thereof |
| CN101659658A (en) * | 2008-08-29 | 2010-03-03 | 北大方正集团有限公司 | Quinoline substituted by cyan |
| CN101659657A (en) * | 2008-08-29 | 2010-03-03 | 北大方正集团有限公司 | Quinoline substituted by cyan and preparation method and applications thereof |
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