CN102153544B - Preparation method and application of novel tyrosine kinase inhibitors - Google Patents
Preparation method and application of novel tyrosine kinase inhibitors Download PDFInfo
- Publication number
- CN102153544B CN102153544B CN201010109992.3A CN201010109992A CN102153544B CN 102153544 B CN102153544 B CN 102153544B CN 201010109992 A CN201010109992 A CN 201010109992A CN 102153544 B CN102153544 B CN 102153544B
- Authority
- CN
- China
- Prior art keywords
- base
- compound
- acid
- solvent
- azetidine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 0 **c(c1c2)ncnc1ccc2-c1c[n](*)nn1 Chemical compound **c(c1c2)ncnc1ccc2-c1c[n](*)nn1 0.000 description 1
Abstract
The invention relates to a preparation method and application of novel tyrosine kinase inhibitors. Specifically, the invention relates to novel tyrosine kinase inhibitors shown as a formula I, wherein the definition of each substituent group is expressed in the specification. The invention also relates to the preparation method of the tyrosine kinase inhibitors and the application of the tyrosine kinase inhibitors to preparation of medicaments for treating tumors.
Description
Technical field
The invention belongs to pharmacology, pharmaceutical chemistry and area of pharmacology, more specifically, relate to the preparation method of a class Novel tyrosine kinase inhibitors and the purposes in preparation tumor.
Background technology
According to the data presentation of urban and rural residents of China major causes of death in 2006 that the Ministry of Health announces, malignant tumour, cerebro-vascular diseases and heart trouble are the cause of the death of city resident's front three, urban residents' front three cause of the death is then respectively malignant tumour, cerebro-vascular diseases and respiratory system disease, and wherein the mortality ratio of malignant tumour comparatively rises 18.6% and 23.1% in 2005 respectively.As can be seen here, malignant tumour has become the primary cause of death of China resident, and in accelerated development trend.
Protein tyrosine kinase (protein tyrosine kinases, PTKs) with the generation of tumour with develop closely related, the hyperactivity of Tyrosylprotein kinase, its downstream signaling pathway is caused to activate, thus cause cytodifferentiation, propagation, migration, inhibited apoptosis, finally lead oncogenic formation and transfer [Top Med Chem, 2007 (1): 83-132.].Therefore, tyrosine kinase inhibitor has become a development series antineoplastic medicament the most rapidly, several small molecule tyrosine kinase inhibitors such as lapatinibditosylate (lapatinib), Sutent (sunitimib) successively listing [Nature will be had to the end of the year 2008,2006,441,457-462].Compared with traditional cell toxicant series antineoplastic medicament, this kind of drug selectivity is good, and curative effect is high, toxic side effect is little, has become the focus of current antineoplastic medicine research.
But these marketed drug all exist some shortcomings, the Antitumor Activity of Drugs as gone on the market in early days needs to improve further, and imatinib occurs drug resistance problems after using.There are some side effects being difficult to overcome in Sunitinib malate, as: left ventricular dysfunction, hemorrhage, elevation of blood pressure, diarrhoea, feel sick, stomatitis, maldigestion, vomiting, skin disease, parageusia, [the Clin.Cancer Res. such as hand-foot syndrome, 2003,9 (1), 327-337.].Lapatinibditosylate is water-soluble poor, and oral administration biaavailability is lower.
Therefore, this area is in the urgent need to developing novel structure, active strong, the Novel tyrosine kinase inhibitors that toxic side effect is little.
Summary of the invention
The object of this invention is to provide the novel tyrosine kinase inhibitor of a class, its preparation method and application thereof.
In a first aspect of the present invention, provide the compound as general formula (I) represents and various optical isomer thereof, various crystal formation, pharmaceutically acceptable inorganic or organic salt, hydrate or solvate, and containing compound shown in formula (I) and said derivative thereof the pharmaceutical composition as main active ingredient.
In formula:
X is O or NH;
R
1having structure unit can be selected from:
Wherein R
4, R
5be H, F, Cl, Br, I, CH separately
3, OCH
3, NO
2, NH
2, SO
2nH
2, CF
3or OCF
3;
R
6be selected from:
(1) hydrogen, C
1-6alkyl and C
3-7cycloalkyl, described alkyl or cycloalkyl is unsubstituted or by one to three halogen substiuted;
(2) aryl methylene or hetero-aromatic ring methylene radical, its be unsubstituted or be independently selected from by one to three lower group group replace: halogen, OH, NH
2, NO
2, CH
3, C
2h
5, (CH
3)
2cH,
tbu, CN, CF
3, OCH
3, or OCF
3;
(3) aryl or heteroaryl, its be unsubstituted or be independently selected from by one to three lower group group replace: halogen, OH, NH
2, NO
2, CH
3, C
2h
5, (CH
3)
2cH,
tbu, CN, CF
3, OCH
3, or OCF
3;
R
2having structure unit can be selected from:
Wherein m, n, o are separately the integer of 1,2 or 3, and Y is independently selected from CO, CO
2, S, SO, SO
2, NHCO, NHSO
2, or Y is chemical bond;
R
9be selected from:
(1) hydrogen atom, C
1-6chain or C
3-7cyclic alkyl, described alkyl be unsubstituted or be independently selected from by one to three lower group group replace: halogen, OH, O, N, S, SO, SO
2or CN;
(2) aryl methylene or hetero-aromatic ring methylene radical, its be unsubstituted or be independently selected from by one to three lower group group replace: halogen, OH, NH
2, NO
2, CH
3, C
2h
5, (CH
3)
2cH,
tbu, CN, CF
3, OCH
3, or OCF
3;
(3) aryl or heteroaryl, its be unsubstituted or be independently selected from by one to three lower group group replace: halogen, OH, NH
2, NO
2, CH
3, C
2h
5, (CH
3)
2cH,
tbu, CN, CF
3, OCH
3, or OCF
3.
In another preference, R
1be selected from lower group: 3-chloro-4-(3-fluorine benzyloxy) phenyl, the chloro-4-fluorophenyl of 3-, the bromo-2-fluorophenyl of 4-, 4-((pyridine-2-base) methoxyl group)-3-chloro-phenyl-, 4-((pyridin-3-yl) methoxyl group)-3-chloro-phenyl-, 1-(pyridine-2-ylmethyl)-1H-indazole-5-base, 2-(3-luorobenzyl)-1H-indazole-5-base, 1-(pyridine-2-ylmethyl)-2H-indazole-5-base, 2-(3-luorobenzyl)-2H-indazole-5-base, 4-methyl-3-sulfonamido phenyl, (R)-1-phenylethyl, 5-chlorobenzene is [d] [1 also, 3] two oxapentyl-4-base, 2, the chloro-5-p-methoxy-phenyl of 4-bis-, 4-(6-picoline-3-base oxygen base)-3-aminomethyl phenyl.
In another preference, R
1for the chloro-4-of 3-(3-fluorine benzyloxy) phenyl.
In another preference, X is O or NH; And/or
R
2be selected from lower group: 1-cyclohexylpiperidine-4-base, 1-methyl piperidine-4-base, 1-cyclopentyl piperidin-4-yl, 1-isobutyl-piperidin-4-yl, 1-(amyl group-3-base) piperidin-4-yl, 1-tertiary amyl piperidin-4-yl, 1-sec.-propyl piperidin-4-yl, 1-cyclobutyl piperidin-4-yl, 1-benzyl piepridine-4-base, 1-(4-methoxy-benzyl) piperidin-4-yl, 1-((pyridin-4-yl) methyl) piperidin-4-yl, 1-((furans-2-base) methyl) piperidin-4-yl, 1-((thiophene-2-base) methyl) piperidin-4-yl, 1-(4-t-butylbenzyl) piperidin-4-yl, 1-tert-butylpiperidin-4-base, 1-cyclopropyl piperidine-4-base, 1-(4-(dimethyl amido) but-2-ene-1-carbonyl) piperidin-4-yl, 1-((2-(dimethyl amido) ethyl) formamyl) piperidin-4-yl, 1-(pentane-3-base) azetidine-3-base, 1-sec.-propyl azetidine-3-base, 1-cyclopentyl azetidine-3-base, 1-cyclobutyl azetidine-3-base, 1-(ring fourth oxygen-3-base) azetidine-3-base, 1-methyl azetidine-3-base, 1-(Cvclopropvlmethvl) azetidine-3-base, 1-(2-(methyl sulfuryl) ethyl) azetidine-3-base, 1-benzyl azetidine-3-base, 1-(4-t-butylbenzyl) azetidine-3-base, 1-(pyridin-4-yl) azetidine-3-base, 1-(furans-2-base) azetidine-3-base, 1-(thiophene-2-base) azetidine-3-base, 1-(5-methyl furan-2-base) azetidine-3-base, 1-cyclopropyl azetidine-3-base, 1-tert-butylazetidin-3-base, 2-(2-(first sulfo group) ethyl amido) ethyl, 2-(pyrroles-1-base) ethyl, 2-(4-Nmethanesulphonylpiperazine-1-base) ethyl, 2-(4-methylpiperazine-1-yl) ethyl, 2-(4-methylamino formyl piperazine-1-base) ethyl, 2-(4-formamyl piperazine-1-base) ethyl, 2-(N, N-diethyl amido) ethyl, 2-(piperidin-1-yl) ethyl, 2-(morpholinyl) ethyl, 2-(4-(N, N dimethylamine base) formyl piperazine-1-base) ethyl, 2-(4-(morpholinyl) formyl piperazine-1-base) ethyl, 2-(4-(tetramethyleneimine-1 base) formyl piperazine-1-base) ethyl, 2-hydroxyethyl, (R)-1-benzyl-pyrrole alkane-3-base, (S)-1-benzyl-pyrrole alkane-3-base, (R)-1-ethyl pyrrolidine-3-base.
In another preference, X is NH.
In another preference, R
2it is 1-tert-butylazetidin-3-base.
In another preference, described compound is the compound 1 to 84 in table 1.
In a second aspect of the present invention, provide above-mentioned there is anti-tumor activity novel benzo pyridine compound or the preparation method of its pharmaceutically acceptable inorganic or organic salt, hydrate or solvate.
The compounds of this invention pharmacy acceptable salt, the salt of the mineral acid such as above-claimed cpd and hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid can be enumerated particularly, form salt with the acid of the organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, propanedioic acid, succsinic acid, fumaric acid, toxilic acid, lactic acid, oxysuccinic acid, tartrate, citric acid, picric acid, methylsulfonic acid, p-methyl benzenesulfonic acid, ethyl sulfonic acid and the acidic amino acid such as ASP, L-glutamic acid.
In another preference, described compound is mesylate, toluenesulfonate or hydrochloride.
In a third aspect of the present invention, provide a kind of pharmaceutical composition, it contains pharmacologically acceptable vehicle or carrier, and above-claimed cpd of the present invention (or its each optical isomer, each crystal formation) and pharmaceutically acceptable inorganic or organic salt, hydrate or solvate.
In a fourth aspect of the present invention, provide the purposes of compound of the present invention or its each optical isomer, each crystal formation, pharmaceutically acceptable inorganic or organic salt, hydrate or solvate, it is used to prepare tyrosine kinase inhibitor.
In a fifth aspect of the present invention, provide the purposes of compound of the present invention or its each optical isomer, each crystal formation, pharmacy acceptable salt, hydrate or solvate, it is used to prepare the medicine that suppresses tyrosine kinase activity or for the preparation for the treatment of, prevention and alleviate and the medicine of the too high relevant disease of tyrosine kinase activity.
In another preference, described is selected from tumour to the too high relevant disease of tyrosine kinase activity.
In a fifth aspect of the present invention, provide a kind of method of inhibition tumor cell growth of external non-therapeutic, described method comprises the steps: the contact by the compound described in described tumour cell and first aspect present invention or its each optical isomer, each crystal formation, pharmacy acceptable salt, hydrate or solvate, thus the growth of inhibition tumor cell.
In a sixth aspect of the present invention, provide a kind of method suppressing the growth of tumour cell of individuality, described method comprises the steps: the compound described in first aspect present invention or its each optical isomer, each crystal formation, pharmacy acceptable salt, hydrate or solvate to be applied to described individuality, thus the growth of inhibition tumor cell.
In a seventh aspect of the present invention, provide above-mentioned novel benzo pyridine compound or the application of its pharmacy acceptable salt in the medicine of preparation treatment tumor disease.
Should be understood that within the scope of the present invention, above-mentioned each technical characteristic of the present invention and in below (eg embodiment) specifically described each technical characteristic can combine mutually, thus form new or preferred technical scheme.
Embodiment
The present inventor, through studying widely, synthesizes and has screened a large amount of compounds, and Late Cambrian formula (I) compound has very high inhibit activities to Tyrosylprotein kinase and has very strong anti-tumor activity, is particularly suitable for preparing antitumor drug.The present inventor completes the present invention on this basis.
Preferably, the present invention is such as formula in compound shown in (I) structure, and representational compound title and structural formula see the following form 1.
Table 1 representative compound and structural formula thereof
Detailed description of the invention
Unless otherwise specified, following use term in the specification and in the claims has following implication:
" alkyl " refers to saturated aliphatic hydrocarbon group, comprises straight chain and the branched group of 1 to 6 carbon atom.Median size alkyl preferably containing 1 to 6 carbon atom, such as methyl, ethyl, propyl group, 2-propyl group, normal-butyl, isobutyl-, the tertiary butyl, amyl group etc.Low alkyl group more preferably containing 1 to 4 carbon atom, such as methyl, ethyl, propyl group, 2-propyl group, normal-butyl, isobutyl-, the tertiary butyl etc.
" cycloalkyl " refers to 3 to 8 yuan of full carbon monocycles, complete 5 yuan/6 yuan, carbon or 6 yuan/6 yuan fused rings or many rings fused ring group, and wherein one or more rings can contain one or more double bond, but neither one ring has the π-electron system of total conjugated.Examples of cycloalkyl has cyclopropyl, cyclobutyl, cyclopentyl, hexanaphthene, cyclohexadiene, diamantane, suberane, cycloheptatriene etc.
" aryl " refers to the group with at least one aromatic ring structure, namely has the aromatic ring of the π-electron system of conjugation, comprises isocyclic aryl, heteroaryl.
" heteroaryl " refers to have 1 to 3 heteroatoms as annular atoms, and remaining annular atoms is the aryl of carbon, and heteroatoms comprises oxygen, sulphur, nitrogen.Described ring can be 5 yuan or 6 rings.The example of heterocyclic aromatic groups includes but not limited to furyl, thienyl, pyridyl, pyrroles, N-alkyl pyrryl, pyrimidyl, pyrazinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazyl, indyl, triazinyl, purine radicals, quinolyl, isoquinolyl etc.
" halogen " refers to fluorine, chlorine, bromine or iodine.
Compound of the present invention can contain one or more asymmetric center, and therefore occurs with the form of raceme, racemic mixture, single enantiomer, diastereomeric compound and single diastereomer.The asymmetric center that can exist, depends on various substituent character on molecule.Each this asymmetric center will produce two optically active isomers independently, and all possible optically active isomer and non-enantiomer mixture and pure or partial-purified compound comprise within the scope of the present invention.The present invention means all this isomeric form comprising these compounds.
Compounds more described herein can exist with tautomeric forms, and it has the different hydrogen interface with one or more migration of the double bond.
Activeconstituents
As used herein, term " activeconstituents " refers to compound shown in formula (I)." activeconstituents " also comprises the various crystal formations of formula (I) compound, pharmaceutically acceptable inorganic or organic salt, hydrate or solvate.There is one or more unsymmetrical carbons in the compounds of this invention, therefore, shown in formula (I), compound comprises racemic modification thing, racemic mixture, single enantiomer, non-enantiomer mixture and single diastereomer.
Pharmacy acceptable salt
" pharmacy acceptable salt " used herein is as long as refer to that pharmaceutically acceptable salt is with regard to there is no particular limitation, the salt that the compounds of this invention is formed with acid can be enumerated particularly, the acid being applicable to salify includes, but is not limited to: hydrochloric acid, Hydrogen bromide, hydrofluoric acid, sulfuric acid, nitric acid, the mineral acids such as phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, trifluoroacetic acid, propanedioic acid, succsinic acid, fumaric acid, toxilic acid, lactic acid, oxysuccinic acid, tartrate, citric acid, picric acid, methylsulfonic acid, the organic acids such as p-methyl benzenesulfonic acid and aspartic acid, the acidic amino acids such as L-glutamic acid.
The synthetic method of the compounds of this invention
Describe the preparation method of general formula of the present invention (I) structural compounds below particularly, but these concrete grammars do not form any restriction to the present invention.
General formula of the present invention (I) structural compounds obtains by following method, but the condition of the method, the amount, temperature of reaction, reaction required time etc. of such as reactant, solvent, alkali, compound used therefor are not limited to explanation below.Various synthetic method that describe in this manual or known in the art can also optionally combine and obtain easily by the compounds of this invention, and such combination can be easy to carry out by those skilled in the art in the invention.
In the preparation process in accordance with the present invention, each reaction, usually in inert solvent, is carried out to solvent reflux temperature (preferred room temperature ~ 80 DEG C) at-30 DEG C.Reaction times is generally 0.1 hour ~ 60 hours, is preferably 0.5 ~ 48 hour.
The preparation method of general formula of the present invention (I) compound is prepared by following flow process, comprising:
Flow process I: the preparation of intermediate compound I-3a-I-3n
Flow process 1
In formula, representational R comprises following group:
(1) intermediate compound I-1 (US2005101617) is in polar solvent (inert solvent), under neutral or basic conditions, within 1-12 hour, intermediate compound I-2a-I-2n is obtained in-20 DEG C-100 DEG C (or under reflux temperatures) and the reaction of corresponding amine.Polar solvent can be methyl alcohol, ethanol, Virahol, the trimethyl carbinol, acetonitrile, DMF.Alkali can be selected from sodium bicarbonate, sodium carbonate, the mineral alkalis such as salt of wormwood or DBU, triethylamine, diisopropyl ethyl amine, the organic basess such as N-methylmorpholine.Optimum reaction condition is take Virahol as solvent, 70-90 DEG C of reaction 1-5 hour.(2) intermediate compound I-2a-I-2n is in polar aprotic solvent, at a suitable temperature, under rare gas element and suitable alkali exist, obtain a series of trimethylsilyl acetylene base with palladium/copper mixed catalyst catalysis trimethylsilyl acetylene and halogenide cross-coupling and replace intermediate.Polar aprotic solvent is selected from tetrahydrofuran (THF), ether, methylene dichloride, toluene, Isosorbide-5-Nitrae-dioxane, dimethyl formamide, N-Methyl pyrrolidone, acetonitrile etc.; Temperature range is between 20-120 DEG C; Alkali can be selected from sodium carbonate, salt of wormwood, cesium carbonate, triethylamine, Diisopropylamine, pyridine, N-methylmorpholine, morpholine, DIPEA etc.; Palladium catalyst optional two (triphenylphosphine) palladium chloride, two (cyano group benzene) palladium chloride, tetrakis triphenylphosphine palladium, palladium etc.; Copper catalyst selects cuprous iodide.Optimum condition is: with two (triphenylphosphine) palladium chlorides and cuprous iodide for catalyzer, triethylamine is alkali, and tetrahydrofuran (THF) is that solvent under reflux conditions reacts 6 hours.This serial trimethylsilyl acetylene base replaces the tetrahydrofuran solution of intermediate directly under fluorine reagent exists, and in-20 DEG C-50 DEG C reaction 0.1-4 hour, obtains intermediate compound I-3a-I-3n.Optimum reaction condition is that trifluoroacetic acid exists lower room temperature reaction 5-30 minute.
Flow process II: the preparation of intermediate II-3a-II-3d
Flow process 2
In formula, representational R comprises following group:
(1) intermediate compound I-1 is in polar solvent (inert solvent), in the basic conditions, within 1-24 hour, obtains intermediate II-2a-II-2d in-20 DEG C-100 DEG C and the reaction of corresponding phenolic compound.Polar solvent can be methyl alcohol, ethanol, Virahol, the trimethyl carbinol, acetonitrile, DMF.Alkali can be selected from sodium bicarbonate, sodium carbonate, the mineral alkalis such as salt of wormwood or DBU, triethylamine, diisopropyl ethyl amine, the organic basess such as N-methylmorpholine.Optimum reaction condition is be solvent with DMF, and salt of wormwood does alkali, room temperature reaction 4-16 hour;
(2) intermediate II-2a-II-2d is in polar aprotic solvent, at a suitable temperature, under rare gas element and suitable alkali exist, obtain a series of trimethylsilyl acetylene base with palladium/copper mixed catalyst catalysis trimethylsilyl acetylene and halogenide cross-coupling and replace intermediate.Polar aprotic solvent is selected from tetrahydrofuran (THF), ether, methylene dichloride, toluene, Isosorbide-5-Nitrae-dioxane, dimethyl formamide, N-Methyl pyrrolidone, acetonitrile etc.; Temperature range is between 20-120 DEG C; Alkali can be selected from sodium carbonate, salt of wormwood, cesium carbonate, triethylamine, Diisopropylamine, pyridine, N-methylmorpholine, morpholine, DIPEA etc.; Palladium catalyst optional two (triphenylphosphine) palladium chloride, two (cyano group benzene) palladium chloride, tetrakis triphenylphosphine palladium, palladium etc.; Copper catalyst selects cuprous iodide.Optimum condition is: with two (triphenylphosphine) palladium chlorides and cuprous iodide for catalyzer, triethylamine is alkali, and tetrahydrofuran (THF) is that solvent under reflux conditions reacts 6 hours.This serial trimethylsilyl acetylene base replaces the tetrahydrofuran solution of intermediate directly under fluorine reagent exists, and in-20 DEG C-50 DEG C reaction 0.1-4 hour, obtains intermediate II-3a-II-3d.Optimum reaction condition is that trifluoroacetic acid exists lower room temperature reaction 5-30 minute.
Flow process III: the preparation of intermediate III-3a-III-3n
Flow process 3
In formula, R
1r
2cH group is as follows:
(1) raw material II I-1 in polar solvent and corresponding aldehydes or ketones at-20 to 80 DEG C, under the existence of going back original reagent, carry out reductive amination process 1-24 hour obtain corresponding intermediate III-2a-III-2n.Polar solvent can be selected from methyl alcohol, ethanol, Virahol, tetrahydrofuran (THF), methylene dichloride, 1,2-ethylene dichloride, Isosorbide-5-Nitrae-dioxane, DMF, acetonitrile, glycol dimethyl ether etc.Reductive agent is selected from sodium borohydride, POTASSIUM BOROHYDRIDE, sodium cyanoborohydride, sodium triacetoxy borohydride etc.Optimum reaction condition is, methylene dichloride is solvent, and sodium triacetoxy borohydride is reductive agent, at room temperature reacts 4-16 hour.
(2) intermediate III-2a-III-2n under triphenylphosphine exists and azide reagent carry out Mitsunobu and be obtained by reacting intermediate III-3a-III-3n.Solvent can select tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane, methyl tert-butyl ether etc.; Azide reagent can be selected from sodiumazide, DPPA etc.Optimum reaction condition is, under triphenylphosphine exists, take tetrahydrofuran (THF) as solvent, DPPA is azide reagent, room temperature reaction 4-16 hour.
Flow process IV: intermediate compound IV-4a and the preparation of IV-4b
Flow process 4
(1) raw material IV-1 (J.Org.Chem., 2005,70 (5), 1930-1933) under vinylformic acid exists, in the basic conditions, do solvent and corresponding amine with water and within 2-24 hour, obtain intermediate compound IV-2a and IV-2b in room temperature-80 DEG C reaction.Alkali can be selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, the organic basess such as hydrated barta, and optimum reaction condition is take sodium hydroxide as alkali, at 40-70 DEG C of reaction 6-16 hour.
(2) raw material IV-2a and IV-2b is in polar aprotic solvent, to react obtain intermediate compound IV-3a and IV-3b in 2-12 hour with reductive agent at-20 DEG C to 50 DEG C.Polar aprotic solvent can be selected from methyl alcohol, ethanol, Virahol, the trimethyl carbinol etc., and reductive agent can be selected from sodium borohydride, lithium borohydride, POTASSIUM BOROHYDRIDE etc.Optimum reaction condition is that ethanol makees solvent, and sodium borohydride is reductive agent room temperature reaction 2-6 hour.
(3) intermediate compound IV-3a and IV-3b under triphenylphosphine exists and azide reagent carry out Mitsunobu and be obtained by reacting intermediate compound IV-4a and IV-4b.Solvent can select tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane, methyl tert-butyl ether etc.; Azide reagent can be selected from sodiumazide, DPPA etc.Optimum reaction condition is, under triphenylphosphine exists, take tetrahydrofuran (THF) as solvent, DPPA is azide reagent, room temperature reaction 6-16 hour.
Flow process V: the preparation of intermediate V-2b and V-3a
Flow process 5
(1) in polar aprotic solvent, at appropriate temperatures, V-1 (Tetrahrdron Lett., 2005,46 (16), 2911-2914) and corresponding acyl chlorides, react in the presence of base, obtain intermediate V-2a and V-2b.Polar aprotic solvent is selected from methylene dichloride, chloroform, 1,2-ethylene dichloride, ethyl acetate, tetrahydrofuran (THF), ether, methyl tert-butyl ether, Isosorbide-5-Nitrae-dioxane, dimethyl formamide, dimethyl sulfoxide (DMSO), acetonitrile etc.; Temperature range is between 0-100 DEG C; Alkali can be selected from imidazoles, triethylamine, pyridine, N-methylmorpholine, morpholine, DIPEA etc.; Optimum condition is: be alkali with triethylamine, and take tetrahydrofuran (THF) as solvent, room temperature reaction spends the night.
(2) intermediate V-2a is in non-polarity proton solvent, in the basic conditions and N
1, N
1-dimethyl-ethylenediamine reaction at appropriate temperatures reaction obtains intermediate V-3a in 1-24 hour.Polar aprotic solvent is selected from methylene dichloride, chloroform, 1,2-ethylene dichloride, ethyl acetate, tetrahydrofuran (THF), ether, methyl tert-butyl ether, Isosorbide-5-Nitrae-dioxane, dimethyl formamide, dimethyl sulfoxide (DMSO), acetonitrile etc.; Temperature range is between 0-100 DEG C; Alkali can be selected from sodium carbonate, salt of wormwood, imidazoles, triethylamine, pyridine, N-methylmorpholine, morpholine, N, N-diisopropylethylamine etc.; Optimum condition is: be alkali with salt of wormwood, and take dimethyl formamide as solvent, 30-60 DEG C of reaction is spent the night.
Flow process VI: the preparation of intermediate VI-3a-VI-3q
Flow process 6
In formula, R
1r
2cH group is as follows:
(1) raw material VI-1 (WO2006021881) in polar solvent and corresponding aldehydes or ketones at-20-80 DEG C, under the existence of going back original reagent, carry out reductive amination process 1-24 hour obtain corresponding intermediate VI-2a-VI-2o.Polar solvent can be selected from methyl alcohol, ethanol, Virahol, tetrahydrofuran (THF), methylene dichloride, and 1,2-ethylene dichloride, Isosorbide-5-Nitrae-dioxane, DMF, acetonitrile, glycol dimethyl ethers etc., reductive agent is selected from sodium borohydride, POTASSIUM BOROHYDRIDE, sodium cyanoborohydride, sodium triacetoxy borohydride etc.Optimum reaction condition is, methylene dichloride is solvent, and sodium triacetoxy borohydride is reductive agent, at room temperature reacts 2-16 hour.
(2) intermediate VI-2a-VI-2o, 1-cyclopropyl aza-cyclobutane-3-alcohol (SyntheticCommunications, 2003,22 (24), 4297-4302.), 1-tert-butylazetidin-3-alcohol (Synthetic Communications, 2003,22 (24), 4297-4302.) in polar aprotic solvent, at appropriate temperatures, react in the presence of base, and methylsulfonyl chloride is obtained by reacting corresponding mesylate intermediate.Polar aprotic solvent is selected from methylene dichloride, chloroform, 1,2-ethylene dichloride, ethyl acetate, tetrahydrofuran (THF), ether, methyl tert-butyl ether, Isosorbide-5-Nitrae-dioxane, dimethyl formamide, dimethyl sulfoxide (DMSO), acetonitrile etc.; Temperature range is between 0-100 DEG C; Alkali can be selected from imidazoles, triethylamine, pyridine, N-methylmorpholine, morpholine, DIPEA etc.; Optimum condition is: be alkali with triethylamine, take methylene dichloride as solvent, 0 DEG C-room temperature reaction 3 hours.The mesylate intermediate obtained is in polar aprotic solvent, and at appropriate temperatures, and azide reagent react obtains intermediate VI-3a-VI-3q, polar aprotic solvent is selected from methylene dichloride, chloroform, and 1,2-ethylene dichloride, ethyl acetate, tetrahydrofuran (THF), ether, methyl tert-butyl ether, 1,4-dioxane, dimethyl formamide, dimethyl sulfoxide (DMSO), acetonitrile etc.; Temperature range is between 0 DEG C-100 DEG C; Azide reagent, can be selected from sodiumazide, potassium azide etc.; Top condition is, take DMF as solvent, and sodiumazide is azide reagent, at 30-80 DEG C of reaction 2-8 hour.
Flow process VII: the preparation of intermediate VII-2a-VII-2l
Flow process 7
(1) in polar aprotic solvent, at appropriate temperatures, VII-1 (Org.Lett., 2001,3 (25), 4091-4094) and corresponding amine, react in the presence of base, obtain intermediate VII-2a-VII-2l.Polar aprotic solvent is selected from methylene dichloride, chloroform, 1,2-ethylene dichloride, ethyl acetate, tetrahydrofuran (THF), ether, methyl tert-butyl ether, Isosorbide-5-Nitrae-dioxane, DMF, dimethyl sulfoxide (DMSO), acetonitrile etc.; Temperature range is between 0-100 DEG C; Alkali can be selected from imidazoles, triethylamine, pyridine, N-methylmorpholine, morpholine, DIPEA etc.; Optimum condition is: be alkali with triethylamine, take acetonitrile as solvent, and back flow reaction reaction is spent the night.
Flow process VIII: the preparation of compound 1-14
Flow process 8
Raw material I-3a-I-3n, in polar solvent, is catalyzer at α-benzoinoxime and sodium ascorbate, under protection of inert gas, carries out D-A reacting generating compound 1-14 at suitable temp and raw material VI-3q.Polar solvent can be selected from methyl alcohol, ethanol, Virahol, trimethyl carbinol isopolarity protonic solvent and methylene dichloride, chloroform, 1,2-ethylene dichloride, ethyl acetate, tetrahydrofuran (THF), ether, methyl tert-butyl ether, Isosorbide-5-Nitrae-dioxane, DMF, dimethyl sulfoxide (DMSO), acetonitrile polar aprotic solvent; α-benzoinoxime can be selected from anhydrous cupric sulfate, cupric sulfate pentahydrate, neutralized verdigris, cuprous iodide; Temperature is room temperature-120 DEG C, and the reaction times is 0.1-24 hour.Optimum reaction condition is, take DMF as solvent, with cupric sulfate pentahydrate and sodium ascorbate for catalyzer is under argon shield, is heated to 40-80 DEG C of reaction 0.2-4 hour.
Flow process IX: the preparation of compound 15-18
Flow process 9
Raw material II-3a-II-3d, in polar solvent, is catalyzer at α-benzoinoxime and sodium ascorbate, under protection of inert gas, carries out D-A reacting generating compound 15-18 at suitable temp and raw material VI-3q.Polar solvent can be selected from methyl alcohol, ethanol, Virahol, trimethyl carbinol isopolarity protonic solvent and methylene dichloride, chloroform, 1,2-ethylene dichloride, ethyl acetate, tetrahydrofuran (THF), ether, methyl tert-butyl ether, Isosorbide-5-Nitrae-dioxane, DMF, dimethyl sulfoxide (DMSO), acetonitrile polar aprotic solvent; α-benzoinoxime can be selected from anhydrous cupric sulfate, cupric sulfate pentahydrate, neutralized verdigris, cuprous iodide; Temperature is room temperature-120 DEG C, and the reaction times is 0.1-24 hour.Optimum reaction condition is, take DMF as solvent, with cupric sulfate pentahydrate and sodium ascorbate for catalyzer is under argon shield, is heated to 40-80 DEG C of reaction 0.2-4 hour.
Flow process X: the preparation of compound 19-68
Flow process 10
Raw material I-3a is in polar solvent, be catalyzer at α-benzoinoxime and sodium ascorbate, under protection of inert gas, at suitable temp and raw material II I-3a-3n, IV-4a, IV-4b, V-2b, V-3a, VI-3a-3p, VII-2a-2l, (R)-3-nitrine-1-benzyl-pyrrole (J.Med.Chem., 1992, 35 (22), 4205-4213.), (S)-3-nitrine-1-benzyl-pyrrole (WO2004056767), (S)-3-nitrine-1-N-ethyl pyrrole N-(J.Org.Chem., 1998, 63 (23), 8266-8275.) carry out D-A reacting generating compound 19-68.Polar solvent can be selected from methyl alcohol, ethanol, Virahol, trimethyl carbinol isopolarity protonic solvent and methylene dichloride, chloroform, 1,2-ethylene dichloride, ethyl acetate, tetrahydrofuran (THF), ether, methyl tert-butyl ether, Isosorbide-5-Nitrae-dioxane, DMF, dimethyl sulfoxide (DMSO), acetonitrile polar aprotic solvent; α-benzoinoxime can be selected from anhydrous cupric sulfate, cupric sulfate pentahydrate, neutralized verdigris, cuprous iodide; Temperature is room temperature-120 DEG C, and the reaction times is 0.1-24 hour.Optimum reaction condition is, take DMF as solvent, with cupric sulfate pentahydrate and sodium ascorbate for catalyzer is under argon shield, is heated to 40-80 DEG C of reaction 0.2-4 hour.
Flow process XI: the preparation of compound 69-76
Flow process 11
Raw material I-3b, in polar solvent, is catalyzer at α-benzoinoxime and sodium ascorbate, under protection of inert gas; at suitable temp and raw material II I-3e; IV-4a, VI-3a, VI-3b; VI-3j VII-2a; VII-2f, 2-azidoethyl alcohol (Org.Lett., 2001; 3 (25), 4091-4094) D-A reacting generating compound 69-76 is carried out.Polar solvent can be selected from methyl alcohol, ethanol, Virahol, trimethyl carbinol isopolarity protonic solvent and methylene dichloride, chloroform, 1,2-ethylene dichloride, ethyl acetate, tetrahydrofuran (THF), ether, methyl tert-butyl ether, Isosorbide-5-Nitrae-dioxane, DMF, dimethyl sulfoxide (DMSO), acetonitrile polar aprotic solvent; α-benzoinoxime can be selected from anhydrous cupric sulfate, cupric sulfate pentahydrate, neutralized verdigris, cuprous iodide; Temperature is room temperature-120 DEG C, and the reaction times is 0.1-24 hour.Optimum reaction condition is, take DMF as solvent, with cupric sulfate pentahydrate and sodium ascorbate for catalyzer is under argon shield, is heated to 40-80 DEG C of reaction 0.2-4 hour.
Flow process XII: the preparation of compound 77-80
Flow process 12
Raw material I-3d, in polar solvent, is catalyzer at α-benzoinoxime and sodium ascorbate, under protection of inert gas, carries out D-A reacting generating compound 77-80 at suitable temp and raw material II I-3e, IV-3a, VI-3a, VI-3b.Polar solvent can be selected from methyl alcohol, ethanol, Virahol, trimethyl carbinol isopolarity protonic solvent and methylene dichloride, chloroform, 1,2-ethylene dichloride, ethyl acetate, tetrahydrofuran (THF), ether, methyl tert-butyl ether, Isosorbide-5-Nitrae-dioxane, DMF, dimethyl sulfoxide (DMSO), acetonitrile polar aprotic solvent; α-benzoinoxime can be selected from anhydrous cupric sulfate, cupric sulfate pentahydrate, neutralized verdigris, cuprous iodide; Temperature is room temperature-120 DEG C, and the reaction times is 0.1-24 hour.Optimum reaction condition is, take DMF as solvent, with cupric sulfate pentahydrate and sodium ascorbate for catalyzer is under argon shield, is heated to 40-80 DEG C of reaction 0.2-4 hour.
Flow process XIII: the preparation of compound 81-84
Flow process 13
Raw material I-3g, in polar solvent, is catalyzer at α-benzoinoxime and sodium ascorbate, under protection of inert gas, carries out D-A reacting generating compound 81-84 at suitable temp and raw material II I-3e, IV-3a, VI-3a, VI-3b.Polar solvent can be selected from methyl alcohol, ethanol, Virahol, trimethyl carbinol isopolarity protonic solvent and methylene dichloride, chloroform, 1,2-ethylene dichloride, ethyl acetate, tetrahydrofuran (THF), ether, methyl tert-butyl ether, Isosorbide-5-Nitrae-dioxane, DMF, dimethyl sulfoxide (DMSO), acetonitrile polar aprotic solvent; α-benzoinoxime can be selected from anhydrous cupric sulfate, cupric sulfate pentahydrate, neutralized verdigris, cuprous iodide; Temperature is room temperature-120 DEG C, and the reaction times is 0.1-24 hour.Optimum reaction condition is, take DMF as solvent, with cupric sulfate pentahydrate and sodium ascorbate for catalyzer is under argon shield, is heated to 40-80 DEG C of reaction 0.2-4 hour.
As required, can by compound of the present invention in polar protic solvent, as methyl alcohol, ethanol, Virahol, and pharmaceutically acceptable acid-respons generates pharmacy acceptable salt and prepares.Described pharmaceutically acceptable inorganic or organic acid is: hydrochloric acid, Hydrogen bromide, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, propanedioic acid, succsinic acid, fumaric acid, toxilic acid, lactic acid, oxysuccinic acid, tartrate, citric acid, picric acid, methylsulfonic acid, ethyl sulfonic acid, p-methyl benzenesulfonic acid, aspartic acid or L-glutamic acid.
Pharmaceutical composition and application process
Because the compounds of this invention has excellent tyrosine kinase inhibitory activity, therefore the compounds of this invention and various crystal formation thereof, pharmaceutically acceptable inorganic or organic salt, hydrate or solvate, and can be used for treatment, prevention containing the pharmaceutical composition that the compounds of this invention is main active ingredient and alleviate tyrosine kinase related disorder.Particularly, the compounds of this invention can be used for the growth of Tumor suppression (cell).
Pharmaceutical composition of the present invention comprises the compounds of this invention within the scope of safety, significant quantity or its pharmacologically acceptable salt and pharmacologically acceptable vehicle or carrier.Wherein " safety, significant quantity " refers to: the amount of compound is enough to obviously improve the state of an illness, and is unlikely to produce severe side effect.Usually, pharmaceutical composition contains 1-1000mg the compounds of this invention/agent, preferably 5-500mg the compounds of this invention/agent, more preferably, containing 10-200mg the compounds of this invention/agent.
Compound of the present invention and pharmacologically acceptable salt can be made into various preparation, wherein comprise the compounds of this invention within the scope of safety, significant quantity or its pharmacologically acceptable salt and pharmacologically acceptable vehicle or carrier.Wherein " safety, significant quantity " refers to: the amount of compound is enough to obviously improve the state of an illness, and is unlikely to produce severe side effect.Safety, the significant quantity of compound are determined according to the particular case such as age, the state of an illness, the course for the treatment of of treatment target.
" pharmacologically acceptable vehicle or carrier " refers to: one or more biocompatible solid or liquid filler or gelatinous mass, and they are suitable for people and use, and must have enough purity and enough low toxicity." consistency " to referred to herein as in composition each component energy and compound of the present invention and they between mutually admix, and the drug effect of not obvious reduction compound.Pharmacologically acceptable vehicle or carrier part example have cellulose and its derivates (as Xylo-Mucine, ethyl cellulose sodium, cellulose ethanoate etc.), gelatin, talcum, solid lubricant (as stearic acid, Magnesium Stearate), calcium sulfate, vegetables oil (as soya-bean oil, sesame oil, peanut oil, olive wet goods), polyvalent alcohol (as propylene glycol, glycerine, N.F,USP MANNITOL, sorbyl alcohol etc.), emulsifying agent (as tween
), wetting agent (as sodium lauryl sulphate), tinting material, seasonings, stablizer, antioxidant, sanitas, apirogen water etc.
When using the compounds of this invention, can oral, rectum, parenteral (intravenously, intramuscular or subcutaneous), topical.
Solid dosage for oral administration comprises capsule, tablet, pill, powder and granule.In these solid dosages, active compound mixes with at least one conventional inert excipients (or carrier), as Trisodium Citrate or Si Liaodengji dicalcium phosphate feed grade, or mix with following compositions: (a) filler or expanding material, such as, starch, lactose, sucrose, glucose, N.F,USP MANNITOL and silicic acid; (b) tackiness agent, such as, Walocel MT 20.000PV, alginate, gelatin, Polyvinylpyrolidone (PVP), sucrose and gum arabic; (c) wetting Agent for Printing Inks, such as, glycerine; (d) disintegrating agent, such as, agar, calcium carbonate, yam starch or tapioca (flour), alginic acid, some composition silicate and sodium carbonate; (e) retarding solvent, such as paraffin; F () absorbs accelerator, such as, and quaternary ammonium compound; (g) wetting agent, such as hexadecanol and glyceryl monostearate; (h) sorbent material, such as, kaolin; (i) lubricant, such as, talcum, calcium stearate, Magnesium Stearate, solid polyethylene glycol, sodium lauryl sulphate, or its mixture.In capsule, tablet and 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 in this composition, the release of active compound or compound can discharge in certain part in a delayed fashion in digestive tube.The example of adoptable embedding component is polymeric material and Wax.If desired, active compound also can form microencapsulation form with one or more in above-mentioned vehicle.
Liquid dosage form for oral administration comprises pharmaceutically acceptable emulsion, solution, suspension, syrup or tincture.Except active ingredient beyond the region of objective existence, liquid dosage form can comprise the conventional inert diluent adopted in this area, as water or other solvent, solubilizing agent and emulsifying agent, example is known, the mixture etc. 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.
Except these inert diluents, composition also can comprise auxiliary agent, as wetting agent, emulsifying agent and suspension agent, sweeting agent, tender taste agent and spices.
Except active ingredient beyond the region of objective existence, suspension can comprise suspension agent, such as, and the mixture etc. of ethoxylation isooctadecane alcohol, polyoxyethylene sorbitol and Isosorbide Dinitrate, Microcrystalline Cellulose, aluminum methylate and agar or these materials.
Composition for parenteral injection can comprise physiologically acceptable sterile, aqueous or anhydrous solution, dispersion liquid, suspension or emulsion, and for being again dissolved into 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.
Formulation for the compounds of this invention of topical comprises ointment, powder, patch, propellant and inhalation.Activeconstituents aseptically with physiologically acceptable carrier and any sanitas, buffer reagent, or the propelling agent that may need if desired is mixed together.
The compounds of this invention can be individually dosed, or with other pharmaceutically acceptable compound Combined Preparation.
When making pharmaceutical composition, it is the Mammals (as people) being applicable to the compounds of this invention of safe and effective amount need treatment, when wherein using, dosage is the effective dosage pharmaceutically thought, for the people of 60kg body weight, day dosage is generally 1 ~ 1000mg, preferably 20 ~ 500mg.Certainly, concrete dosage also should consider the factor such as route of administration, patient health situation, and these are all within skilled practitioners skill.
Major advantage of the present invention comprises:
(1) the compounds of this invention is the tyrosine kinase inhibitor of a class recruit structure.
(2) the compounds of this invention has stronger inhibit activities to Tyrosylprotein kinase.
(3) the compounds of this invention has stronger inhibit activities to tumour cell.
(4) the compounds of this invention has excellent pharmacokinetic property.
More specifically explain the present invention in the following embodiments.But, should be appreciated that these embodiments are in order to demonstrate the invention, and be not limit the scope of the invention by any way.The experimental technique of unreceipted actual conditions in the following example, usually conveniently condition, or according to the condition that manufacturer advises.Unless otherwise indicated, otherwise number and per-cent are weight part and weight percent.
In all embodiments, fusing point X-4 melting point apparatus measures, and thermometer does not correct;
1h-NMR VarianMercury 300 or 400 nuclear magnetic resonance analyser record, chemical shift represents with δ (ppm); Separation silica gel is undeclared is 200-300 order, and the proportioning of elutriant is volume ratio.
Embodiment 1 N-(the chloro-4-of 3-(3-fluorine benzyloxy) phenyl)-6-iodine quinazoline-4-amine (I-2a)
Raw material I-1 (1.0g, 3.44mmol) is dissolved in Virahol (50mL), under stirring, adds the chloro-4-of 3-(3-fluorine benzyloxy) aniline (0.87g, 3.44mmol), reflux 3h, is cooled to room temperature, leaves standstill 6 hours, a large amount of solid is had to separate out, filter, a small amount of washed with isopropyl alcohol of filter cake, dry, obtain intermediate compound I-2a (yellow solid (1.7g, 98%).
1H NMR(DMSO-d
6，400MHz)：δ5.21(s，2H)，7.15(m，1H)，7.29(m，3H)，7.46(m，1H)，7.64(m，1H)，7.70(m，1H)，7.90(s，1H)，8.36(d，J＝6.30Hz，1H)，8.92(s，1H)，9.26(s，1H)，11.53(br s，1H).
Be similar to the synthesis of intermediate compound I-2a, following intermediate I-2b to I-2n can be synthesized by raw material I-1 and various arylamine and obtains.
Table 2
Embodiment 2 N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-ethynyl quinazoline-4-amine (I-3a)
I-2a (2.0g, 4.2mmol) is dissolved in THF (120mL), under stirring, adds CuI (70mg, 0.36mol), Pd (PPh
3)
2cl
2(164mg, 0.3mmol), Et
3n (1.42mL), trimethylsilyl acetylene (0.98mL, 4.2mmol), under the protection of argon gas; heating, backflow, control oil bath temperature at about 80 DEG C, reaction is spent the night; after TLC monitoring reacts completely, cool to room temperature, filter, filter cake THF washs.Filtrate is proceeded in 250mL there-necked flask, pass into argon gas, stir.Dissolve tetra-n-butyl Neutral ammonium fluoride (2.0g, 7.6mg) with a small amount of THF, add system fast, after reacting 5min under room temperature, react completely, reaction solution is poured in the Erlenmeyer flask that cold water (1200mL) is housed, have a large amount of brownish black solid to separate out, filter, consider cake to wash with water, dry, dissolve with a small amount of THF, silica gel mixed sample, column chromatography (V
pE:THF=5/1) yellow solid I-3a (yellow solid 530mg, 34%), is obtained.
1H NMR(400MHz，CDCl
3)：δ4.42(s，1H)，5.18(s，2H)，6.99-7.06(m，2H)7.21-7.26(m，2H)，7.34-7.40(m，2H)，7.52(dd，J
1＝2.7Hz，J
2＝8.8Hz，1H)，7.86(d，J＝3.2Hz，3H)，8.03(s，1H)，8.75(s，1H).
Be similar to the synthesis of intermediate compound I-3a, following intermediate I-3b to I-3n can carry out synthesis by raw material I-2b to I-2n and obtain.
Table 3
Embodiment 3 4-(the fluoro-2-Methyl-1H-indole of 4--5-base oxygen base)-6-iodine quinazoline (II-2a) adds I-1 (3.35g in DMF (50mL), 1mmol), the fluoro-2-Methyl-1H-indole of 4--5-phenol (2.0g, 1.05mmol), salt of wormwood (1.91g, 1.2mmol), 40h is reacted under stirring at room temperature.Add water dilution, ethyl acetate and the extraction of tetrahydrofuran (THF) mixed solution, organic layer washes 4 times again, anhydrous sodium sulfate drying, filtration, concentrates, mixes sample column chromatography (V
normal hexane: V
ethyl acetate=3/1).Obtain product II-2a (1.62g, 33%).
1H NMR(400MHz，DMSO-d
6)：δ2.42(s，3H)，6.24(s，1H)，7.01(t，J＝8.0Hz，1H)，7.16(d，J＝8.8Hz，1H)，7.78(d，J＝8.8Hz，1H)，8.30(dd，J＝8.8，2.0Hz，1H)，8.72(s，1H)，8.74(d，J＝1.4Hz，1H)，11.37(s，1H).
Be similar to the synthesis of intermediate II-2a, following intermediate II-2b to II-2d can be synthesized by raw material I-1 and various substituted phenol and obtains.
Table 4
Embodiment 44-(the fluoro-2-Methyl-1H-indole of 4--2--5-base oxygen base)-6-ethynyl quinazoline (II-3a)
In tetrahydrofuran (THF) (130mL), YF-50-184 (1.62g is added under argon gas, 3.86mmol), cuprous iodide (55mg, 0.286mmol), two (triphenylphosphine) palladium chloride (130mg, 0.278mmol), triethylamine (1.34mL), trimethyl silicane ethyl-acetylene (1.30mL) stir lower back flow reaction.Stopped reaction after 3h, suction filtration, a small amount of tetrahydrofuran solution is washed.In above-mentioned tetrahydrofuran solution (180mL), tetra-n-butyl Neutral ammonium fluoride (2.02g is added under argon gas, tetrahydrofuran solution (20mL) 7.72mmol), room temperature reaction 5min, pours in frozen water (800mL) and stirs, suction filtration, washing, oven dry.Obtain brownish black solids YF-50-190 (1.22g, 99%).
1H NMR(400MHz，DMSO-d
6)：δ(ppm)2.41(s，3H)，4.50(s，1H)，6.26(d，J＝0.6Hz，1H)，7.01-7.05(m，1H)，7.17-7.20(m，1H)，7.55-7.65(m，1H)，8.00-8.09(m，2H)，8.49(d，J＝2.2Hz，1H)，8.73(s，1H)，11.38(s，1H).
Be similar to the synthesis of intermediate II-3a, following intermediate II-3b to II-3d can carry out synthesis by raw material II-2b to II-2d and obtain.
Table 5
Embodiment 5 1-cyclohexyl-4-hydroxy piperidine (III-2a)
4-hydroxy piperidine (4.05g, 40mmol) is dissolved in dry methylene dichloride (100mL), then adds pimelinketone (5.8g, 60mmol), add stirring 15 minutes, add NaBH (OAc)
3(16.93g, 80mmol), room temperature for overnight, TLC detection reaction is complete, add saturated sodium bicarbonate, methylene dichloride (80mL*3) extracts, anhydrous sodium sulfate drying, filter, evaporate to dryness filtrate obtains crude product YF-230-80 (2.1g, 40%).
MS(ESI-LR)m/z：184.2(M+1)
+.
Be similar to the synthesis of intermediate III-2a, following intermediate III-2b to III-2n can be obtained by reacting by raw material II I-1 and various amine.
Table 6
Embodiment 6 1-cyclohexyl-4-nitrine piperidines (III-3a)
III-2a (1.83g, 10mmol) is dissolved in the new THF (30mL) steamed, under stirring, adds PPh
3(3.94g, 15mmol), argon shield, DIAD (3mL is dripped under cryosel bath, 15mmol), DPPA (3.3mL, 15mmol), ice bath is shifted out after 10min, stirred overnight at room temperature, TLC monitoring reaction is complete, concentrated, remove solvent, add ethyl acetate (60mL), water (100mL) and dilute hydrochloric acid (18mL), separatory, aqueous phase methylene dichloride is washed, regulating by NaOH solution makes solution be strong basicity, extracting with methylene dichloride (100mL*3), anhydrous sodium sulfate drying, concentrated, obtain brown liquid YF-230-111 (0.89g, 46%).
1H NMR(400MHz，CDCl
3)：δ1.22-1.25(m，4H)，1.61-1.72(m，4H)，1.79-1.83(m，4H)，1.90-1.93(m，2H)，2.36-2.39(m，3H)，2.82-2.87(m，2H)，3.36(s，1H).
Be similar to the synthesis of intermediate III-3a, following intermediate III-3b to III-3n can be obtained by reacting by raw material II I-2b to III-2n.
Table 7
Embodiment 7 1-tert-butylpiperidin-4-ketone (IV-2a)
Vinylformic acid (34.5mL is added in water (100mL), 0.5mol) stir under be added dropwise to 10N sodium hydroxide (46mL), after add IV-1 (24.51g, 0.1mol), TERTIARY BUTYL AMINE (200mL), is warming up to back flow reaction and spends the night.Reaction terminates rear decompression removing low boilers, and resistates adds and is extracted with ethyl acetate, organic layer anhydrous sodium sulfate drying, and filter, concentrate, underpressure distillation obtains product IV-2a (5.05g, 32%).
1H NMR(300MHz，CDCl
3)：δ1.06(s，9H)，2.36(t，J＝6.0Hz，4H)，2.78(t，J＝6.0Hz，4H).
Embodiment 8 1-cyclopropyl piperidine-4-ketone (IV-2b)
The operation of similar embodiment 7, obtains intermediate compound IV-2b (4.8g, 40%).
1H NMR(400MHz，CDCl
3)：δ0.37-0.47(m，4H)，1.64-1.68(m，1H)，2.33-2.36(m，4H)，2.83-2.86(m，4H).
Embodiment 9 1-tert-butylpiperidin-4-alcohol (IV-3a)
In ethanol (100mL), add IV-2a (2.0g, 12.88mmol), add under water-bath under sodium borohydride (0.75g, 19.32mmol) stirs in batches and react 3.5h.Decompression removing ethanol, after resistates adds diluted hydrochloric acid dissolution, sodium carbonate solution neutralizes, dichloromethane extraction, organic layer anhydrous sodium sulfate drying, filters, concentrates.Obtain product IV-3a (1.875g, 92%).
1H NMR(300MHz，CDCl
3)：δ1.02(s，9H)，1.50-1.59(m，2H)，1.83-1.90(m，2H)，2.17-2.25(m，2H)，2.82-2.88(m，2H)，3.57-3.51(m，1H).
Embodiment 10 1-cyclopropyl piperidine-4-alcohol (IV-3b)
The operation of similar embodiment 9, obtains intermediate compound IV-3b (4.58g, 94%).
The embodiment 11 1-tertiary butyl-4-nitrine piperidines (IV-4a)
The operation of similar embodiment 6, can obtain intermediate compound IV-4a (2.6g, 95%).
1H NMR(400MHz，CDCl
3)：δ1.03(s，9H)，1.56-1.65(m，2H)，1.86-1.89(m，2H)，2.20-2.26(m，2H)，2.84-2.88(m，2H)，3.28-3.32(m，1H).
Embodiment 12 1-cyclopropyl-4-nitrine piperidines (YF-50-194)
The operation of similar embodiment 6, can obtain intermediate compound IV-4b (2.8g, 96%).
1H NMR(400MHz，CDCl
3)：δ0.32-0.39(m，4H)，1.51-1.59(m，3H)，1.80-1.83(m，2H)，2.25-2.31(m，2H)，2.81-2.87(m，2H)，3.30-3.34(m，1H).
Embodiment 13 4-nitrine piperidines-1 phenyl formate (V-2a)
Raw material V-1 (2.52g, 20mmol) is dissolved in tetrahydrofuran (THF) (50mL), adds triethylamine (3mL), cryosel bath cooling, adds rate phenyl formate (3.14g, 20mmol), add, room temperature reaction 3 hours, stopped reaction, be spin-dried for solvent, residue is dissolved in ethyl acetate (100mL), washing, saturated nacl aqueous solution is washed, anhydrous sodium sulfate drying, is spin-dried for, obtain intermediate V-2a (3.12g, 63%).
1H NMR(400MHz，CDCl
3)：δ1.42(m，2H)，1.63(m，2H)，3.36(m，4H)，3.78(m，1H)，7.10-7.23(m，5H).
Embodiment 14 (E)-1-(4-nitrine piperidin-1-yl)-4-(dimethyl amido)-but-2-ene-1-ketone (V-2b)
The operation of similar embodiment 13, can obtain intermediate V-2b (0.86g, 25%).
1H NMR(400MHz，CDCl
3)：δ1.41(m，2H)，1.63(m，2H)，2.28(s，6H)，3.14(d，J＝6.1Hz，2H)，3.34(m，4H)，3.75(m，1H)，6.25(d，J＝15.3Hz，1H)，6.54(m，1H).
Embodiment 15 4-nitrine-N-(2-(dimethyl amido) ethyl) piperidines-1-methane amide (V-3a)
Raw material V-2a (2.46g, 10mmol) is dissolved in dry DMF (20mL), adds salt of wormwood (2.76g, 20mmol), N
1, N
1-dimethyl-ethylenediamine (1.06g, 12mol), is heated to 50 DEG C of reactions and spends the night, stopped reaction, add water (100mL) dilution, and methylene dichloride (50mL*2) extracts, combined dichloromethane layer, and saturated common salt is washed, anhydrous sodium is dry, is spin-dried for, column chromatography (V
methylene dichloride/ V
methyl alcohol=20/1) intermediate V-3a (1.12g, 47%), is obtained.
1H NMR(400MHz，CDCl
3)：δ1.41(m，2H)，1.63(m，2H)，2.34(s，6H)，2.56(t，J＝6.5Hz，2H)，3.26(m，2H)，3.34(m，4H)，3.75(m，1H)，6.23(t，J＝6.10Hz，1H).
The synthesis (VI-2a) of embodiment 16 1-(pentane-3-base) aza-cyclobutane-3-alcohol
VI-1 (2.5g, 0.022mol) is dissolved in DCM (100mL), adds propione (1.9g, 0.022mol), sodium triacetoxy borohydride (7g, 0.033mol) is added under stirring, salt of wormwood (3.78g, 0.027mol) with a small amount of activated molecular sieve, room temperature reaction spends the night, and TLC raw material reaction is complete, add EA after filtering and concentrating to stir, again filter, after filtrate is concentrated, obtain intermediate VI-2a (1.6g, 49%).MS(ESI-LR)：142.2(M+1)
+.
Be similar to the synthesis of intermediate VI-2a, following intermediate VI-2b to VI-2o can be obtained by reacting from various different Carbonyl compounds by raw material VI-1.
Table 8
The synthesis (VI-3a) of embodiment 17 3-nitrine-1-(3-amyl group) ring butylamine
By VI-2a (1.6g, 0.011mol) be dissolved in dry DCM (25mL). add triethylamine (3mL, 0.022mol) under cryosel cooling, drip methane sulfonyl chloride (1mL, 0.013mol) and the mixed solution of DCM (10mL), drip Bi Fanying two hours TLC raw material reactions complete, add saturated sodium bicarbonate solution, layering also uses DCM aqueous phase extracted once, merge organic phase, saturated sodium bicarbonate and water respectively wash once, and dry concentrating obtains mesylate intermediate.Above-mentioned intermediate (1.7g, 0.0076mol) is added DMF (30mL), adds sodiumazide (1g, 0.015mol), under argon shield, be heated to 60 DEG C of reactions spend the night.After raw material reaction is complete, add water (100mL), DCM extracting twice, with using saturated sodium bicarbonate solution and water washing respectively once, VI-3a (0.25g, 19%) is obtained after evaporating column chromatography (hex-hex:EA=10/1) purifying after dry.
1H NMR(400MHz，CDCl
3)：δ0.80-0.85(m，6H)，1.28-1.42(m，4H)，2.00-2.04(m，1H)，2.92-2.97(m，2H)，3.57-3.62(m，2H)，3.96-4.00(m，1H).
Be similar to the synthesis of intermediate VI-3a, following intermediate VI-3b to VI-3o can respectively by raw material VI-2b to VI-2o, 1-cyclopropyl aza-cyclobutane-3-alcohol, and 1-tert-butylazetidin-3-alcohol is obtained by reacting.
Table 9
Embodiment 18 N-(2-azidoethyl)-2-(methyl sulphonyl) ethamine (VII-2a)
Raw material VII-1 (2.46g, 20mmol) is dissolved in dry acetonitrile (30mL), adds Anhydrous potassium carbonate (2.76g; 20mmol); 2-(methyl sulphonyl) ethamine (4.82g, 20mmol), is heated to 50 DEG C of reactions and spends the night.Stopped reaction, TLC (CH
2cl
2/ MeOH=50/1) monitoring reaction, after question response completes, stopped reaction, filter, ethyl acetate is washed, concentrated, residue column chromatography (CH
2cl
2/ MeOH=50/1), obtain intermediate VII-2a (oily matter 1.48g, productive rate 39%).
1H NMR(400MHz，CDCl
3)：δ3.38(t，J＝5.6Hz，2H)，3.15(m，4H)，2.98(s，3H)，2.76(t，J＝5.6Hz，2H)，1.55(br s，1H)。
Be similar to the synthesis of intermediate VII-2a, following intermediate VII-2b-3f can be obtained by reacting from the amine of different replacement by raw material VII-1 respectively.
Table 10
Embodiment 19N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(1-(1-tert-butylazetidin-3-base)-1H-1,2,3-triazole-4-base) quinazoline-4-amine (compound 1)
I-3a (238mg, 0.5mmol) is dissolved in DMF (5mL), adds CuSO
4.5H
2o (38mg, 0.15mmol), L-(+) sodium ascorbate (50mg; 25mmol), then add VI-3q (155mg, 1.5mmol); 60 DEG C of reaction 0.5h, TLC detection reaction are heated to complete, cooling under the protection of argon gas; reaction solution is poured into ice to enter in water (50mL), separate out a large amount of solid, filter; washing, after solid drying, is dissolved in a small amount of methylene dichloride; add silica gel to be spin-dried for and to mix sample, column chromatography (V
methylene dichloride/ V
methyl alcohol=20/1) yellow solid YF-230-34 (178mg, 64%), is obtained.
1H NMR(300MHz，DMSO-d
6)：δ1.04(s，9H)，3.79-3.84(m，4H)，5.24(s，2H)，5.31-5.36(m，1H)，7.13-7.20(m，1H)，7.24-7.33(m，3H)，7.42-7.49(m，1H)，7.76(dd，J
1＝1.4Hz，J
2＝9.0Hz，1H)，8.03(d，J＝2.4Hz，1H)，8.32(s，1H)，8.82(s，1H)，9.12(s，H)，10.0(s，1H)；ESI-LR：558.2[M+1]
+.
Embodiment 20-32
The synthesis of similar compound 1, compound 2-14 can be obtained by reacting by raw material I-3b to I-3n and VI-3q respectively.
Table 11
Embodiment 33-46
The synthesis of similar compound 1, compound 5-18 can be obtained by reacting by raw material II-3a to II-3d and VI-3q respectively.
Table 12
Embodiment 47-96
The synthesis of similar compound 1, compound 19-68 can by raw material I-3a respectively with III-3a to III-3n, IV-4a, IV-4b, V-2b, V-3a, VI-3a-3p, VII-2a-21, (R)-3-nitrine-1-benzyl-pyrrole, (S)-3-nitrine-1-benzyl-pyrrole, (S)-3-nitrine-1-N-ethyl pyrrole N-is obtained by reacting.
Table 13
Embodiment 97-104
The synthesis of similar compound 1, compound 69-76 can by raw material I-3b respectively with III-3e, IV-4a, VI-3a, VI-3b, VI-3j VII-2a, VII-2f, 2-azidoethyl alcohol is obtained by reacting.
Table 14
Embodiment 105-108
The synthesis of similar compound 1, compound 77-80 can be obtained by reacting with III-3e, IV-3a, VI-3a, VI-3b respectively by raw material I-3d.
Table 15
Embodiment 109-112
The synthesis of similar compound 1, compound 81-84 can be obtained by reacting with III-3e, IV-3a, VI-3a, VI-3b respectively by raw material I-3g.
Table 16
The preparation of embodiment 113 compound salt
Compound 1 (5.58g, 10mmol) be dissolved in the mixed solvent of ethyl acetate (160mL) and methyl alcohol (40mL), after heating is entirely molten, drip methylsulfonic acid (0.96g, 10mmol), add, evaporated under reduced pressure solvent, residue dehydrated alcohol (100mL) heated suspension 0.5 hour, after being cooled to room temperature, filters, the a small amount of dehydrated alcohol of solid is washed, collect solid, vacuum-drying obtains the mesylate (faint yellow solid 5.98g, productive rate 91%) of compound 1.Fusing point: 208-209 DEG C, liquid phase purity: 99.602%.
Embodiment 114 pharmaceutical composition
According to a conventional method, after each component of aforementioned pharmaceutical compositions being mixed, load common gelatine capsule, obtain 1000 capsules.
By similar approach, the obtained capsule containing compound 25.
Embodiment 115: the preparation of capsule
According to a conventional method, after each component of aforementioned pharmaceutical compositions being mixed, load common gelatine capsule, obtain 1000 capsules.
By similar approach, the obtained capsule containing compound 25.
Test example
1. tumors inhibition activity (IC
50)
After the Non-small Cell Lung Cancer A 549 of logarithmic phase and human breast carcinoma SKBR3 cell dissociation, blow and beat into single cell suspension, be inoculated in 96 well culture plates respectively; Every hole 5 × 10
3individual cell, every hole adds substratum 100 μ L, 37 DEG C, 5%CO
2overnight incubation in incubator.After cell attachment, add test-compound and the lapatinibditosylate of high, medium and low three dosage respectively, the sample of configuration three kinds of different concns, with blank group for negative control group, is positive controls with lapatinibditosylate, in incubator, cultivates 72h again.Then, every hole adds the MTT liquid that 20 μ L mass concentrations are 5mg/mL, cultured continuously 4h.Suck supernatant liquor, every hole adds 100 μ L methyl-sulphoxides, culture plate is placed in 10min that microwell plate vibrator vibrates, crystallisate is dissolved.Survey absorbance A value at 570nm wavelength place by microplate reader, calculate inhibiting rate; IC is calculated by Bliss method
50.Test-results sees the following form 17.
Table 17 part of compounds is to the inhibit activities of Non-small Cell Lung Cancer A 549 and human breast carcinoma SKBR3 cell
As can be seen from the data in upper table, this compounds of this invention all has the anti-tumor activity stronger than contrast medicine lapatinibditosylate.
2. anti-tumor in vivo is active
A549 lung carcinoma cell is with containing 1640 of 10% foetal calf serum in 37 DEG C, 5%CO
2cellar culture in incubator, after going down to posterity, when cell reaches aequum, digestion collecting cell.By 3 × 10
6individual A549 human lung carcinoma cell is injected into oxter on the left of every nude mouse, treats tumor growth to 100 ~ 200mm
3after, animal random packet is started administration.Inoculate from 30 21 nude mouses selecting tumor growth more consistent A549 nude mouse in advance and be divided into 3 groups at random, be respectively 1) solvent control group, 7; 2) compound 1100mg/kg group, 7; 4) lapatinibditosylate 100mg/kg group, 7.Solvent control group gavage CMCNa every day solvent; The compound solution 0.1mL/10g of compound 1100mg/kg group gavage 10mg/mL every day; The lapatinibditosylate solution 0.1mL/10g of lapatinibditosylate 100mg/kg group gavage 10mg/mL every day.On every Mondays, three, five weigh and measure gross tumor volume, within 24th day, put to death nude mouse in administration, weigh, measure knurl block and amass, calculate relative tumour volume (RTV), Relative tumor appreciation rate (T/C) and tumor suppression percentage, do statistics and detect.Test-results sees the following form 18.
The experimental therapy effect of table 18. compound 1 pair of people lung cancer A549 Nude Mice
Compared with the control
*: P < 0.05;
*: P < 0.01;
* *: P < 0.001
D1: point cage administration time.RTV: relative tumour volume, calculation formula is: RTV=V
t/ V
0.
T/C (%)=T
rTV/ C
rTV× 100.T
rTV: be treatment group RTV; C
rTV: be negative control group RTV.
The standard of curative effect evaluation: T/C (%) > 60 is invalid; T/C (%)≤60, and be effective through statistical procedures P < 0.05.
Compound 1 has the anti-tumor in vivo activity stronger than contrast medicine lapatinibditosylate as can be seen from the above table, is significantly better than blank group.
3. pharmacokinetic
Compound 1 has carried out Pharmacokinetics in Rat research.
Compound 1 adopts gavage and quiet note two kinds of administering modes, and dosage is 15mg/kg, often organizes healthy SD rat 4, male and female half and half.Administration volume is 10ml/kg, and wherein gavage is prepared with 0.5%CMC-Na, and quiet note is with DMSO, tween 80 and normal saline.Before administration, fasting 12h, freely drinks water, 5min, 15min after administration, 0.5,1.0,2.0,3.0,4.0,5.0,7.0,9.0,24 and 48h through rat eye rear vein beard extracting vein blood 0.3mL, put in heparinised tubes, the centrifugal 10min of 3500rpm, separated plasma ,-20 DEG C of preservations are to be measured.With the concentration of compound 1 in LC-MS/MS blood plasma, obtain corresponding pharmacokinetic parameter according to plasma concentration v. time curve.See the following form 19.
The main pharmacokinetic parameter of table 19 compound 1
As can be seen from upper table data, the compounds of this invention 1 has the pharmacokinetic property more more excellent than contrast medicine lapatinibditosylate (prior art).The Oral Administration in Rats bioavailability of the compounds of this invention 1 is 62.7%, and lapatinibditosylate is 24.0%, and therefore, the compounds of this invention likely becomes better clinical antitumor agents.
In a word, this series compound has the anti-tumor activity stronger than contrast medicine lapatinibditosylate and more excellent pharmacokinetic property, the advantages such as meanwhile, compound has novel structure, and synthesis technique is simple.
The all documents mentioned in the present invention are quoted as a reference all in this application, are just quoted separately as a reference as each section of document.In addition should be understood that 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 limited range equally.
Claims (9)
1. the compound shown in formula (I), or its pharmaceutically acceptable inorganic or organic salt:
In formula:
X is O or NH;
R
1having structure unit can be selected from:
Wherein R
4, R
5be H, F, Cl, Br, I, CH separately
3, OCH
3, NO
2, NH
2, SO
2nH
2, CF
3or OCF
3;
R
2having structure unit can be selected from:
Wherein m, n, o be separately 1 or 2, Y be chemical bond;
R
9be selected from C
1-6chain or C
3-7cyclic alkyl, described alkyl be unsubstituted or be independently selected from by one to three lower group group replace: halogen or CN.
2. compound as claimed in claim 1, is characterized in that, R
1be selected from lower group: (R)-1-phenylethyl, 5-chlorobenzene is the two oxapentyl-4-base in [d] [1,3] also, the chloro-5-p-methoxy-phenyl of 2,4-bis-.
3. compound as claimed in claim 1, it is characterized in that, X is O or NH; And/or
R
2be selected from lower group: 1-cyclohexylpiperidine-4-base, 1-methyl piperidine-4-base, 1-cyclopentyl piperidin-4-yl, 1-isobutyl-piperidin-4-yl, 1-(amyl group-3-base) piperidin-4-yl, 1-tertiary amyl piperidin-4-yl, 1-sec.-propyl piperidin-4-yl, 1-tert-butylpiperidin-4-base, 1-cyclopropyl piperidine-4-base, 1-(pentane-3-base) azetidine-3-base, 1-sec.-propyl azetidine-3-base, 1-cyclopentyl azetidine-3-base, 1-cyclobutyl azetidine-3-base, 1-methyl azetidine-3-base, 1-cyclopropyl azetidine-3-base, 1-tert-butylazetidin-3-base, (R)-1-ethyl pyrrolidine-3-base.
4. compound as claimed in claim 1, it is characterized in that, described compound is mesylate, toluenesulfonate or hydrochloride.
5. compound as claimed in claim 1, it is characterized in that, described compound is 6-(1-(1-tert-butylazetidin-3-base)-1H-1, 2, 3-triazole-4-base)-N-((R)-1-phenylethyl) quinazoline-4-amine, 6-(1-(1-tert-butylazetidin-3-base)-1H-1, 2, 3-triazole-4-base) (5-chlorobenzene is [d] [1 also for-N-, 3] two oxapentyl-4-base) quinazoline-4-amine, or 6-(1-(1-tert-butylazetidin-3-base)-1H-1, 2, 3-triazole-4-base)-N-(2, the chloro-5-p-methoxy-phenyl of 4-bis-) quinazoline-4-amine.
6. a pharmaceutical composition, is characterized in that, it contains pharmacologically acceptable vehicle or carrier, and compound according to claim 1 or its pharmaceutically acceptable inorganic or organic salt.
7. a purposes for compound according to claim 1 or its pharmaceutically acceptable inorganic or organic salt, is characterized in that, for the preparation of tyrosine kinase inhibitor.
8. the purposes of a compound according to claim 1 or its pharmacy acceptable salt, it is characterized in that, for the preparation of the medicine of suppression tyrosine kinase activity or for the preparation for the treatment of, prevention and the alleviation medicine to the too high relevant disease of tyrosine kinase activity.
9. purposes as claimed in claim 8, it is characterized in that, described is selected from tumour to the too high relevant disease of tyrosine kinase activity.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201010109992.3A CN102153544B (en) | 2010-02-12 | 2010-02-12 | Preparation method and application of novel tyrosine kinase inhibitors |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201010109992.3A CN102153544B (en) | 2010-02-12 | 2010-02-12 | Preparation method and application of novel tyrosine kinase inhibitors |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102153544A CN102153544A (en) | 2011-08-17 |
| CN102153544B true CN102153544B (en) | 2015-04-29 |
Family
ID=44435256
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201010109992.3A Active CN102153544B (en) | 2010-02-12 | 2010-02-12 | Preparation method and application of novel tyrosine kinase inhibitors |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102153544B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10251863B2 (en) | 2014-06-19 | 2019-04-09 | Merial Inc. | Parasiticidal compositions comprising indole derivatives, methods and uses thereof |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103159748B (en) * | 2011-12-19 | 2016-12-21 | 天津市国际生物医药联合研究院 | The preparation of 2-(1H-1,2,3-triazole-4-bases) amino benzenes compounds and purposes |
| JP6577479B2 (en) * | 2014-02-27 | 2019-09-18 | メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツングＭｅｒｃｋ Ｐａｔｅｎｔ Ｇｅｓｅｌｌｓｃｈａｆｔ ｍｉｔ ｂｅｓｃｈｒａｅｎｋｔｅｒ Ｈａｆｔｕｎｇ | Heterocyclic compounds and their use as NAV channel inhibitors |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1996016960A1 (en) * | 1994-11-30 | 1996-06-06 | Zeneca Limited | Quinazoline derivatives |
| WO1998002434A1 (en) * | 1996-07-13 | 1998-01-22 | Glaxo Group Limited | Fused heterocyclic compounds as protein tyrosine kinase inhibitors |
| CN101003514A (en) * | 2006-01-20 | 2007-07-25 | 上海艾力斯医药科技有限公司 | Derivative of quinazoline, preparation method and usage |
-
2010
- 2010-02-12 CN CN201010109992.3A patent/CN102153544B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1996016960A1 (en) * | 1994-11-30 | 1996-06-06 | Zeneca Limited | Quinazoline derivatives |
| WO1998002434A1 (en) * | 1996-07-13 | 1998-01-22 | Glaxo Group Limited | Fused heterocyclic compounds as protein tyrosine kinase inhibitors |
| CN101003514A (en) * | 2006-01-20 | 2007-07-25 | 上海艾力斯医药科技有限公司 | Derivative of quinazoline, preparation method and usage |
| CN101103005A (en) * | 2006-01-20 | 2008-01-09 | 上海艾力斯医药科技有限公司 | Quinazoline derivatives, preparation methods and uses thereof |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10251863B2 (en) | 2014-06-19 | 2019-04-09 | Merial Inc. | Parasiticidal compositions comprising indole derivatives, methods and uses thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102153544A (en) | 2011-08-17 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105461695B (en) | Pyrimidine or pyrrolotriazine derivatives and its production and use | |
| CN108349981B (en) | Novel pyrazolo [3, 4-d ] pyrimidine compound or salt thereof | |
| CN108026101B (en) | Fused pyrimidine compound or salt thereof | |
| JP5719770B2 (en) | Icotinib hydrochloride, compound, crystallographic form, concomitant drug and its use | |
| JP6035423B2 (en) | Novel condensed pyrimidine compound or salt thereof | |
| JP6321821B2 (en) | 2,3,4,6-4-substituted benzene-1,5-diamine derivatives, their production and use in pharmaceuticals | |
| JP6139782B2 (en) | Substituted pyrazolopyrimidine compounds, and pharmaceutically acceptable salts thereof, and solvates, stereoisomers, and tautomers thereof, and pharmaceutical compositions containing them | |
| JP6469092B2 (en) | Imidazolidinedione compounds and drug compositions | |
| CN104736155B (en) | Inhibitor of the dicyclic compound as kinases | |
| JP7041821B2 (en) | Amino-substituted nitrogen-containing condensed ring compound, its preparation method and use | |
| CN104109166B (en) | Quinolines, its preparation method, intermediate, pharmaceutical composition and application | |
| WO2020211853A1 (en) | Novel egfr triple mutation inhibitor and application thereof | |
| CN105705493A (en) | Quinazoline derivative, preparation method therefor, and pharmaceutical composition and application thereof | |
| CN102153544B (en) | Preparation method and application of novel tyrosine kinase inhibitors | |
| CN110467616B (en) | Preparation and application of triazolopyrazine compound containing heteroaryl substituted pyridazinone structure | |
| CN103965175B (en) | 4 (substitution phenylamino) quinazoline compounds, its preparation method and applications | |
| CN102688234B (en) | Indolone derivatives is as the Synthesis and application of RSK2 inhibitor | |
| CN107383014A (en) | A kind of 1H pyrazolos [3,4 d] pyrimidines and its preparation method and application | |
| TWI670261B (en) | Heat shock protein 90 inhibitors | |
| CN106117182A (en) | Quinazoline N phenethyl tetrahydroisoquinolicompounds compounds and its preparation method and application | |
| CN106146515A (en) | The preparation of Azaindole kinase inhibitors and application | |
| CN110407839B (en) | Preparation and application of triazole heterocyclic compound containing heteroaryl amide structure | |
| CN105461708A (en) | Quinazoline tyrosine kinase inhibitor, and preparation method and application thereof | |
| CN104016983B (en) | Pyrrolo-triazine analog derivative and its preparation method and purposes | |
| CN102827160B (en) | PI3K or PI3K/m-TOR pathway inhibitor and the purposes in pharmacy thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20210819 Address after: No. 1, Hengfei Road, Xingang economic and Technological Development Zone, Nanjing, Jiangsu 210038 Patentee after: Nanjing Changao Pharmaceutical Science & Technology Co.,Ltd. Address before: 201203 Shanghai city Pudong New Area Cailun Road Lane 1690 Building No. 7 4/5F Patentee before: Shanghai Sun-Sail Pharmaceutical Science & Technology Co.,Ltd. |