CN105461708A - Quinazoline tyrosine kinase inhibitor, and preparation method and application thereof - Google Patents
Quinazoline tyrosine kinase inhibitor, and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a quinazoline tyrosine kinase inhibitor, and a preparation method and an application thereof. The quinazoline tyrosine kinase inhibitor is a compound represented by general formula (I), and various optical isomers or pharmaceutically acceptable salts thereof; and the preparation method is a routine compound preparation method. The quinazoline tyrosine kinase inhibitor has strong inhibition activity on tyrosine kinases, has excellent pharmacokinetic properties, is highly safe to the cardiovascular system, can substantially inhibit growth of tumors, and can be applied in the preparation of medicines for treating tyrosine kinase related diseases.
Description
Technical field
The present invention relates to tyrosine kinase inhibitor and Synthesis and applications thereof, particularly relate to quinazoline ditosylate salt tyrosine kinase inhibitor and Synthesis and applications thereof.
Background technology
Cancer is the malignant disease of serious threat general health.Most of tumor prognosis is poor, and survival time is short, lacks recoverable means, there is highly unsatisfied clinical demand, has in recent years progressively risen to and has caused dead first cause.Need new treatment means badly to find.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, 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.
In 10 years in the past, along with the progress of preclinical medicine, and the transformation of clinical treatment pattern, the discovery of some new antitumor drug target spots, the research and development of field of antineoplastic medicaments there occurs great variety, have turned to the targeted drug of non-cytotoxicity class to develop from traditional cytotoxic drug.Protein tyrosine kinase (proteintyrosinekinases, 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 [TopMedChem, 2007 (1): 83-132.].
Tyrosylprotein kinase is the class key enzyme in the middle of intracellular signal transduction pathway, receptor type tyrosine kinase (receptortyrosinekinase can be divided into by structure, and non-receptor tyrosine kinase (nonreceptortyrosinekinase, nRTK) two kinds RTK).A RTK normally class has the cell surface receptor of endogenous RTK activity, it has the outer ligand binding region of born of the same parents, a trans-membrane region and an intracellular kinase region. according to the difference of its extracellular ligand calmodulin binding domain CaM structure, for four subclass can be further divided into:
The first, EGF-R ELISA (epidermalgrowthfactorreceptor, EGFR) family, be that extracellular signal is delivered to intracellular important pivot, it plays an important role in signal transduction, cell proliferation and differentiation and various regulation mechanism; Its Major Members has EGFR (HER1/erbB1), HER2 (erbB2), HER3 (erbB3) and HER4 (erbB4);
The second, insulin receptor (insulinreceptor, INSR) family, comprises insulin receptor, IGF-1 (IGF1-R) etc., and in the middle of hemocyte tumour, the height of this receptoroid common is expressed;
Three, platelet derived growth factor receptor (plateletderivedgrowthfactorreceptor, PDGFR) family, mainly comprise platelet derived growth factor receptor hypotype (PDGFR α), platelet derived growth factor receptor β hypotype (PDGFR β), colony-stimulating factor-1 acceptor (CSF-1R) and stem cell factor receptor (stemcellfactorreceptor, c-kit);
Four, fibroblast growth factor acceptor (fibroblastgrowthfactorreceptor, FGFR) family, be made up of FGFR-1, FGFR-2, FGFR3-and FGFR-4, the processes such as their adjustable various kinds of cell growth, differentiation, play an important role in the processes such as vasculogenesis, wound healing and tumour generation.
In addition, also has the receptor type tyrosine kinase that a class is more common, i.e. vascular endothelial growth factor receptor (vascularendothelialgrowthfactorreceptor, VEGFR) family, comprise VEGFR-1 (FLT-1), VEGFR-2 (KDR/FLK-1) and VEGFR-3 (FLT-4), this receptoroid can promote to regulate vasculogenesis, has short division and chemotaxis to vascular endothelial cell.
Tyrosine kinase inhibitor has become a development series antineoplastic medicament the most rapidly, has lapatinibditosylate (lapatinib), Sutent (sunitimib), Ah method for multiple small molecule tyrosine kinase inhibitors such as Buddhist nun (afatinib) successively listing to the end of the year 2013.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.CancerRes.2003 such as hand-foot syndrome, 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, the Novel tyrosine kinase inhibitors that active strong, toxic side effect is little.
Summary of the invention
In view of the foregoing, the present inventor is through studying widely, synthesize and screened a large amount of compounds, shown in Late Cambrian general 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.
Therefore, the technical problem to be solved in the present invention is to provide the novel quinazoline ditosylate salt tyrosine kinase inhibitor of a class and Synthesis and applications thereof.
A first aspect of the present invention, provides the quinazoline ditosylate salt tyrosine kinase inhibitor that a class is novel, and it is the compound shown in general formula (I), its various optical isomer or its pharmacy acceptable salt (comprising: inorganic or organic salt).
In general formula (I), n is separately 1 or 2;
L is selected from CO, SO
2, NHCO or chemical bond;
X is selected from O, S or N-R
3, wherein, R
3for hydrogen or C
1-4alkyl (namely carbonatoms is the alkyl of 1 ~ 4);
Y and Z is all selected from C or N, and Y and Z may be the same or different;
R
1be selected from following group:
Wherein, R
4, R
5and R
6independently be selected from H, F, Cl, Br, I, CH
3, OCH
3, NO
2, CN, NH
2, SO
2nH
2, CF
3or OCF
3;
R
7be selected from following (1) ~ (3) any one:
(1) hydrogen, C
1-6alkyl (namely carbonatoms is the alkyl of 1 ~ 6) or C
3-7cycloalkyl (namely carbonatoms is the cycloalkyl of 3 ~ 7), wherein, described alkyl or cycloalkyl is unsubstituted or by one to three halogen substiuted;
(2) aryl methylene or heteroaryl 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, t-Bu, CN, CF
3, OCH
3or 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, t-Bu, CN, CF
3, OCH
3or OCF
3;
R
2be selected from hydrogen atom, C
1-6alkyl (namely carbonatoms is the alkyl of 1 ~ 6), C
2-6thiazolinyl (namely carbonatoms is the thiazolinyl of 2 ~ 6) or C
3-7cyclic alkyl (namely carbonatoms is the cyclic alkyl of 3 ~ 7), wherein, described alkyl be unsubstituted or be independently selected from by one to three lower group group replace:
Halogen, OH, CN, O, S, SO, SO
2, CO, R
8r
9n, R
8r
9nC (O)-, R
8c (O) N (R
9)-, R
8r
9nS (O
2)-or R
8s (O
2) N (R
9)-; Wherein, described R
8and R
9independently be selected from hydrogen atom, C
1-6alkyl (namely carbonatoms is the alkyl of 1 ~ 6) or can form 5-6 ring further, also can contain one or more nitrogen, oxygen or sulphur atom in this 5-6 ring.
In described quinazoline ditosylate salt tyrosine kinase inhibitor, preferably representational compound title and structural formula see the following form 1.
Table 1 representative compound of the present invention and structural formula thereof
In addition, in the present invention, unless otherwise specified, following term 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 7 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.The example of cycloalkyl has cyclopropyl, cyclobutyl, cyclopentyl, hexanaphthene, cyclohexadiene, diamantane, suberane, cycloheptatriene etc.
" thiazolinyl " refers to be selected from and has 2 to 6 carbon atoms and the straight chain and the non-cyclic hydrocarbon of side chain that comprise at least one carbon-to-carbon double bond.Representational straight chain and side chain C
2-C
6thiazolinyl comprises vinyl, allyl group ,-1-propenyl ,-1-butylene base ,-3-methyl-1-butene base ,-1-pentenyl ,-4-methyl-1-pentene base or 1-hexenyl 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 comprises: furyl, thienyl, pyridyl, pyrroles, N-alkyl pyrryl, pyrimidyl, pyrazinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazyl, indyl, triazinyl, purine radicals, quinolyl or 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 and single enantiomer, body.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.
Pharmacy acceptable salt
In the present invention, " pharmacy acceptable salt ", as long as refer to pharmaceutically acceptable salt, just there is no particular limitation, and can enumerate the salt that above-claimed cpd is formed with acid particularly, the acid being applicable to salify comprises: mineral acid, organic acid or acidic amino acid; Wherein, mineral acid comprises: hydrochloric acid, Hydrogen bromide, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid; Organic acid comprises: 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, p-methyl benzenesulfonic acid, ethyl sulfonic acid, Phenylsulfonic acid; Acidic amino acid comprises: aspartic acid or L-glutamic acid.
A second aspect of the present invention, provides the preparation method of above-mentioned quinazoline ditosylate salt tyrosine kinase inhibitor, can carry out, shown in specific as follows by compounds process for production thereof conveniently.Such as, but the condition of the method, the amount, temperature of reaction, reaction required time etc. of 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.
The preparation method of quinazoline ditosylate salt tyrosine kinase inhibitor of the present invention, its flow process can comprise:
(1) flow process I: the preparation of intermediate compound I-4a-I-4u
In formula (I-2a-I-2u), (I-3a-I-3u) and (I-4a-I-4u), R is the one in following group:
(I-1) Compound I-1 (US2005101617) is in polar solvent, and under neutral or basic conditions, carries out reaction 1 ~ 12 hour in-20 DEG C ~ 100 DEG C (or under reflux temperature) and amine, obtains formula intermediate compound I-2a-I-2u;
Wherein, Compound I-1 is preferably 1:0.8 ~ 1:1.2 with the mol ratio of amine;
Polar solvent is selected from methyl alcohol, ethanol, Virahol, the trimethyl carbinol, acetonitrile or DMF etc., and can be single solvent, also can be mixed solvent;
Alkali in alkaline condition be selected from mineral alkali, organic bases one or more, wherein, described mineral alkali comprises: sodium bicarbonate, sodium carbonate or salt of wormwood etc.; Organic bases comprises: 1,8-diazacyclo [5,4,0] hendecene-7, triethylamine, diisopropyl ethyl amine or N-methylmorpholine etc.;
Amine is selected from:
The top condition of reaction is take Virahol as polar solvent, under neutral or basic conditions, in 70 ~ 90 DEG C of reactions 1 ~ 5 hour;
(I-2) intermediate compound I-2a-I-2u is in polar aprotic solvent, at 20 ~ 120 DEG C, and under rare gas element (comprising: nitrogen or argon gas etc.) and suitable alkali exist, with palladium catalyst catalysis duplex pinacol borate, through linked reaction 1 ~ 48 hour, obtain a series of boric acid ester and replace intermediate compound I-3a-I-3u;
Wherein, intermediate compound I-2a-I-2u is preferably 1:1 ~ 1:2 with the mol ratio of duplex pinacol borate; Palladium catalyst consumption is preferably 1% ~ 10% of intermediate compound I-2a-I-2u molar weight, and alkali consumption is preferably 1 ~ 5 equivalent;
Polar aprotic solvent is selected from toluene, Isosorbide-5-Nitrae-dioxane, dimethyl formamide, N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone or methyl-sulphoxide etc., and can be single solvent, also can be mixed solvent;
Alkali is selected from sodium carbonate, salt of wormwood, cesium carbonate, potassium acetate or sodium acetate etc.;
Palladium catalyst is selected from [1,1'-two (diphenylphosphine) ferrocene] palladium chloride, three (dibenzalacetone) two palladium, tetrakis triphenylphosphine palladium, palladium or palladium carbon etc.
The condition optimization of reaction is:, react 3 ~ 24 hours under 100 DEG C of conditions using potassium acetate as alkali, using methyl-sulphoxide as polar aprotic solvent as catalyzer with [two (diphenylphosphine) ferrocene of 1,1'-] palladium chloride;
(I-3) in suitable solvent, 20 ~ 150 DEG C, under rare gas element (comprising: nitrogen or argon gas etc.) and suitable alkali, with palladium catalyst catalytic intermediary I-3a-I-3u and tertiary butyl 4-(5-bromo thiazole-2-base) piperazine-1-carboxylicesters, through linked reaction 1 ~ 48 hour, obtain intermediate compound I-4a-I-4u;
Wherein, intermediate compound I-3a-I-3u is preferably 1:1 ~ 2:1 with the mol ratio of tertiary butyl 4-(5-bromo thiazole-2-base) piperazine-1-carboxylicesters; Palladium catalyst consumption is preferably 1% ~ 10% of intermediate compound I-3a-I-3u molar weight; Alkali consumption is preferably 1 ~ 5 equivalent;
Solvent is selected from water, Isosorbide-5-Nitrae-dioxane, DMF, N,N-dimethylacetamide, methyl-sulphoxide, acetonitrile, toluene, benzene, dimethylbenzene, tetrahydrofuran (THF) or glycol dimethyl ether etc., and can be single solvent, also can be mixed solvent;
Alkali is selected from salt of wormwood, saleratus, sodium carbonate, sodium bicarbonate, Tripotassium phosphate, cesium carbonate, cesium fluoride, sodium hydroxide or potassium hydroxide etc.;
Palladium catalyst is selected from tetrakis triphenylphosphine palladium, palladium, two (dibenzalacetone) palladium, [two (diphenylphosphine) ferrocene of 1,1'-] palladium chloride, two (triphenylphosphine) palladium chlorides or two (cyano group benzene) palladium chloride etc.;
The optimum condition of reaction is: with volume ratio be the mixed solution of Isosorbide-5-Nitrae-dioxane and the water of 1:1 ~ 10:1 as solvent, salt of wormwood is alkali, and tetrakis triphenylphosphine palladium is catalyzer, reacts 3 ~ 24 hours at 80 DEG C;
(2) flow process II: the preparation of compound 1 and intermediate II-1a-II-1t
R ' in intermediate II-1a-II-1t is the one in following group:
In organic solvent, intermediate compound I-4a-I-4u reacts 1 ~ 24 hour with acid at 0 ~ 50 DEG C, sloughs tertbutyloxycarbonyl protecting group, obtains compound 1 and intermediate II-1a-II-1t;
Wherein, intermediate compound I-4a-I-4u is 1:1 ~ 1:20 with the mol ratio of acid;
Organic solvent is selected from methylene dichloride, chloroform, 1,2-ethylene dichloride, ethyl acetate, tetrahydrofuran (THF), ether, methyl tert-butyl ether, methyl alcohol or ethanol etc., and can be single solvent, also can be mixed solvent;
Acid is selected from hydrochloric acid, hydrogen chloride methanol solution (mixing solutions of hydrogenchloride and methyl alcohol, also known as hydrochloric acid methanol), sulfuric acid, trifluoroacetic acid, methanesulfonic or tosic acid etc.
The optimum condition of reaction was: be solvent with methyl alcohol, adds 1 ~ 8M hydrogen chloride methanol solution, 20 DEG C of reactions 1 ~ 5 hour;
(3) flow process III: the preparation of compound 2-28
R in compound 2-28 is selected from the one in following group:
In the presence of a base, compound 1 in a solvent in-20 DEG C ~ 100 DEG C (or under reflux temperature) and the halides containing the R group in above-claimed cpd 2-28 or sulphonate [as different chloro thing (N as chloro-in 2-, N-dimethylethyl amine, 2-chlor(o)acetamide, N-methyl-2-chlor(o)acetamide etc.), bromo-derivative is (as monobromethane, bromoethanol, isopropyl bromide, bromoacetonitrile etc.), iodo thing is (as methyl iodide, iodoethane), hydroxyl p-toluenesulfonic esters (2-fluoro ethyl p-toluenesulfonic esters, 2-methoxy ethyl p-toluenesulfonic esters etc.) and hydroxymethane sulfonic acid ester (as 2-fluorine cyclopentyl methanesulfonates etc.)] there is substitution reaction 1 ~ 48 hour, generate compound 2-28 respectively,
Wherein, halides containing the R group in above-claimed cpd 2-28 or sulphonate are respectively bromoethanol, methyl iodide, iodoethane, 2-N-PROPYLE BROMIDE, 2, 2-dimethyl N-PROPYLE BROMIDE, Cyclopropyl Bromide, 2-fluorine cyclopentyl methanesulfonates, 2-fluoro ethyl p-toluenesulfonic esters, 2, 2-bis-fluoro ethyl p-toluenesulfonic esters, 2, 2, 2-trifluoro iodoethane, 2-methoxy ethyl p-toluenesulfonic esters, 2-bromopropionitrile, bromoacetonitrile, 1-bromo-2-methylsulfonyl ethane, 1-bromo-2-first sulfoxide group ethane, 2-bromotrifluoromethane-1-dimethyl sulfide, 2-bromo-N-methyl ethyl-amine hydrobromate, the bromo-N of 2-, N-dimethyl amine hydrobromate, 2-chlor(o)acetamide, N-methyl-2-chlor(o)acetamide, the chloro-N of 2-, N-dimethylethyl amine, 2-chloro-1-morpholine ethyl ketone, N-ethanoyl-2-chlor(o)acetamide, the chloro-N-methylacetamide of N-ethanoyl-2-, 1-(2-chloroethyl)-piperidines-2-ketone, N-(2-chlorine 2-ethyl) Toluidrin and 2-chloro-N-methyl ethyl sulfonamide,
Compound 1: the halides containing the R group in above-claimed cpd 2-28 or the mol ratio of sulphonate are preferably 1:1 ~ 1:3, and alkali consumption is preferably 3 ~ 8 equivalents;
Alkali be selected from mineral alkali, organic bases one or more, described mineral alkali comprises: sodium carbonate, salt of wormwood, cesium carbonate, sodium hydroxide, potassium hydroxide or potassiumphosphate, organic bases comprises: 1,8-diazacyclo [5,4,0] hendecene-7, triethylamine, diisopropyl ethyl amine or N-methylmorpholine etc.;
Solvent selected from acetone, tetrahydrofuran (THF), acetonitrile, ethanol, methyl alcohol, Virahol, Isosorbide-5-Nitrae-dioxane, dimethyl formamide, N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone, methyl-sulphoxide or water etc. can be single solvents, also can mixed solvent;
The optimum condition of reaction is: take acetonitrile as solvent, salt of wormwood is alkali, reacts 3 ~ 24 hours under 80 DEG C of conditions.
(4) flow process IV: the preparation of compound 29-45
R ' in intermediate II-1a-II-1t and compound 29-45 is selected from the one in following group:
In the presence of base, intermediate II-1a-II-1t, in a solvent in-20 DEG C ~ 100 DEG C (or under reflux temperature) and 2-chloro-N-methylacetamide generation substitution reaction 1 ~ 48 hour, generates compound 29-45 respectively;
Wherein, intermediate II-1a-II-1t is preferably 1:1 ~ 1:4 with the mol ratio of the chloro-N-methylacetamide of 2-, and alkali consumption is preferably 4 ~ 8 equivalents;
Alkali be selected from mineral alkali, organic bases one or more, described mineral alkali comprises: sodium carbonate, salt of wormwood, cesium carbonate, sodium hydroxide, potassium hydroxide or potassiumphosphate, organic bases comprises: 1,8-diazacyclo [5,4,0] hendecene-7, triethylamine, diisopropyl ethyl amine or N-methylmorpholine etc.;
Solvent selected from acetone, tetrahydrofuran (THF), acetonitrile, ethanol, methyl alcohol, Virahol, Isosorbide-5-Nitrae-dioxane, dimethyl formamide, N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone, methyl-sulphoxide or water etc. can be single solvents, also can mixed solvent;
The optimum condition of reaction is: take acetonitrile as solvent, salt of wormwood is alkali, reacts 3 ~ 24 hours under 80 DEG C of conditions;
(5) flow process V: the preparation of compound 46-51
R ' in intermediate II-1a-II-1t and compound 46-51 is selected from the one in following group:
Under the effect of alkali, intermediate II-1a-II-1t separately in a solvent, in-20 DEG C ~ 100 DEG C (or under reflux temperature) and 2-fluoro ethyl-4-methyl p-toluenesulfonic esters generation substitution reaction 1 ~ 48 hour, generates compound 45-51 respectively.
Wherein, intermediate II-1a-II-1t is preferably 1:1 ~ 1:4 with the mol ratio of 2-fluoro ethyl-4-methyl p-toluenesulfonic esters, and alkali consumption is preferably 4 ~ 8 equivalents;
Alkali be selected from mineral alkali, organic bases one or more, described mineral alkali comprises: sodium carbonate, salt of wormwood, cesium carbonate, sodium hydroxide, potassium hydroxide or potassiumphosphate, organic bases comprises: 1,8-diazacyclo [5,4,0] hendecene-7, triethylamine, diisopropyl ethyl amine or N-methylmorpholine etc.;
Solvent selected from acetone, tetrahydrofuran (THF), acetonitrile, ethanol, methyl alcohol, Virahol, Isosorbide-5-Nitrae-dioxane, dimethyl formamide, N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone, methyl-sulphoxide or water etc. can be single solvents, also can mixed solvent;
The optimum condition of reaction is: take acetonitrile as solvent, salt of wormwood is alkali, reacts 3 ~ 24 hours under 80 DEG C of conditions;
(6) flow process VI: the preparation of compound 52-58
R in compound 52-58 is selected from the one in following group:
In the presence of a base, intermediate II-1e (preparing in flow process II) in a solvent in-20 DEG C ~ 100 DEG C (or under reflux temperature) and containing the halides of above R group or sulphonate [as different chloro things (2-chlor(o)acetamide, N-methyl-2-chlor(o)acetamide, N-methyl-3-chlorine propionic acid amide etc.), bromo-derivative (bromoacetonitrile, allyl bromide 98 etc.), hydroxyl p-toluenesulfonic esters (2-fluoro ethyl p-toluenesulfonic esters)] there is substitution reaction 1 ~ 48 hour, generate compound 52-58 respectively;
Wherein, the halides containing above R group or sulphonate are N-methyl-2-chlor(o)acetamide, 2-fluoro ethyl p-toluenesulfonic esters, 2-bromopropionitrile, bromoacetonitrile, 2-chlor(o)acetamide, N-methyl-3-chlorine propionic acid amide or allyl bromide 98;
Intermediate II-1e is preferably 1:1 ~ 1:4 with containing the halides of above R group or the mol ratio of sulphonate, and alkali consumption is preferably 3 ~ 8 equivalents;
Alkali be selected from mineral alkali, organic bases one or more, described mineral alkali comprises: sodium carbonate, salt of wormwood, cesium carbonate, sodium hydroxide, potassium hydroxide or potassiumphosphate, organic bases comprises: 1,8-diazacyclo [5,4,0] hendecene-7, triethylamine, diisopropyl ethyl amine or N-methylmorpholine etc.;
Solvent selected from acetone, tetrahydrofuran (THF), acetonitrile, ethanol, methyl alcohol, Virahol, Isosorbide-5-Nitrae-dioxane, dimethyl formamide, N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone, methyl-sulphoxide or water etc. can be single solvents, also can mixed solvent;
The optimum condition of reaction is: take acetonitrile as solvent, salt of wormwood is alkali, reacts 3 ~ 24 hours under 80 DEG C of conditions;
(7) flow process VII: the preparation of compound 59-61
R in compound 59-61 is selected from the one in following group:
In the presence of an organic base, intermediate II-1n (preparing in flow process II) in non-protonic solvent in-20 DEG C ~ 40 DEG C and containing R group acyl chlorides (as
) there is linked reaction 0.5 ~ 24 hour, generate compound 59-61 respectively;
Wherein, intermediate II-1n is preferably 1:1 ~ 1:4 with the mol ratio of the acyl chlorides containing R group, and alkali consumption is preferably 4 ~ 8 equivalents;
Organic bases is selected from 1,8-diazacyclo [5,4,0] hendecene-7, pyridine, triethylamine, diisopropyl ethyl amine or N-methylmorpholine etc.;
Non-protonic solvent is selected from methylene dichloride, tetrahydrofuran (THF), toluene, glycol dimethyl ether, ether or methyl tertiary butyl ether etc., can be single solvent, also can mixed solvent;
The optimum condition of reaction is: take methylene dichloride as solvent, triethylamine is alkali, reacts 1 ~ 5 hour under 0 DEG C of condition;
(8) flow process VIII: the preparation of compound 62
(VIII-1) in suitable solvent, at 20 ~ 150 DEG C, under rare gas element (comprising: argon gas, nitrogen etc.) and suitable alkali, with palladium catalyst catalytic cpd I-3a and tert-butyl 4-(5-bromo thiazole-2-base) homopiperazine-1-carboxylicesters, through linked reaction 1 ~ 48 hour, obtain intermediate III-1;
Wherein, Compound I-3a is preferably 1:1 ~ 1:2 with the mol ratio of tert-butyl 4-(5-bromo thiazole-2-base) homopiperazine-1-carboxylicesters, and palladium catalyst consumption is preferably 1% ~ 10% of Compound I-3a molar weight; Alkali consumption is preferably 1 ~ 5 equivalent;
Solvent is selected from water, Isosorbide-5-Nitrae-dioxane, DMF, N,N-dimethylacetamide, methyl-sulphoxide, acetonitrile, water-toluene, benzene, dimethylbenzene, tetrahydrofuran (THF) or glycol dimethyl ether etc., and can be single solvent, also can be mixed solvent;
Alkali is selected from salt of wormwood, saleratus, sodium carbonate, sodium bicarbonate, Tripotassium phosphate, cesium carbonate, cesium fluoride, sodium hydroxide or potassium hydroxide etc.;
Palladium catalyst is selected from tetrakis triphenylphosphine palladium, palladium, two (dibenzalacetone) palladium, [two (diphenylphosphine) ferrocene of 1,1'-] palladium chloride, two (triphenylphosphine) palladium chlorides or two (cyano group benzene) palladium chloride etc.;
The optimum condition of reaction is: using the mixed solution of the Isosorbide-5-Nitrae-dioxane of volume ratio 1:1 ~ 10:1 and water as solvent, salt of wormwood is alkali, and tetrakis triphenylphosphine palladium is catalyzer, reacts 3 ~ 24 hours at 80 DEG C;
(VIII-2) in 0 ~ 50 DEG C and organic solvent, intermediate III-1 and suitable acid-respons 1 ~ 24 hour, slough tertbutyloxycarbonyl protecting group, obtain intermediate III-2;
Wherein, intermediate III-1 is 1:1 ~ 1:20 with the mol ratio of acid;
Organic solvent is selected from methylene dichloride, chloroform, 1,2-ethylene dichloride, ethyl acetate, tetrahydrofuran (THF), ether, methyl tert-butyl ether, methyl alcohol or ethanol etc., and can be single solvent, also can be mixed solvent; ;
Acid is selected from hydrochloric acid, hydrogen chloride methanol solution, sulfuric acid, trifluoroacetic acid, methanesulfonic or tosic acid etc.;
The optimum condition of reaction was: be solvent with methyl alcohol, adds 1 ~ 8M hydrogen chloride methanol solution, 20 DEG C of reactions 1 ~ 5 hour;
(VIII-3) in the presence of a base, intermediate III-2, in a solvent in-20 DEG C ~ 100 DEG C (or under reflux temperature) and 2-chloro-N-methylacetamide generation substitution reaction 1 ~ 48 hour, generates compound 62;
Wherein, intermediate III-2 is 1:1 ~ 1:5 with the mol ratio of the chloro-N-methylacetamide of 2-, and alkali consumption is preferably 3 ~ 8 equivalents;
Alkali be selected from mineral alkali, organic bases one or more, described mineral alkali comprises: sodium carbonate, salt of wormwood, cesium carbonate, sodium hydroxide, potassium hydroxide or potassiumphosphate, organic bases comprises: 1,8-diazacyclo [5,4,0] hendecene-7, triethylamine, diisopropyl ethyl amine or N-methylmorpholine etc.;
Solvent selected from acetone, tetrahydrofuran (THF), acetonitrile, ethanol, methyl alcohol, Virahol, Isosorbide-5-Nitrae-dioxane, dimethyl formamide, N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone, methyl-sulphoxide or water etc. can be single solvents, also can mixed solvent;
The optimum condition of reaction is: take acetonitrile as solvent, salt of wormwood is alkali, reacts 3 ~ 24 hours under 80 DEG C of conditions;
(9) flow process IX: the preparation of compound 63-71
(IX-1) in suitable solvent, at 20 ~ 150 DEG C, under rare gas element (comprising: argon gas, nitrogen etc.) and suitable alkali, with palladium catalyst catalytic cpd I-3a and tertiary butyl halo quinary heteroaryl piperazine-1-carboxylicesters, through linked reaction 1 ~ 48 hour, obtain intermediate compound IV-1a-IV-1i;
Wherein, Compound I-3a is preferably 1:1 ~ 1:2 with the mol ratio of tertiary butyl halo quinary heteroaryl piperazine-1-carboxylicesters, and palladium catalyst consumption is preferably 1% ~ 10% of I-3a molar weight, and alkali consumption is preferably 1 ~ 5 equivalent;
Solvent is selected from water, Isosorbide-5-Nitrae-dioxane, DMF, N,N-dimethylacetamide, methyl-sulphoxide, acetonitrile, water-toluene, benzene, dimethylbenzene, tetrahydrofuran (THF) or glycol dimethyl ether etc., and can be single solvent, also can be mixed solvent;
Alkali is selected from salt of wormwood, saleratus, sodium carbonate, sodium bicarbonate, Tripotassium phosphate, cesium carbonate, cesium fluoride, sodium hydroxide or potassium hydroxide etc.;
Palladium catalyst is selected from tetrakis triphenylphosphine palladium, palladium, two (dibenzalacetone) palladium, [two (diphenylphosphine) ferrocene of 1,1'-] palladium chloride, two (triphenylphosphine) palladium chlorides or two (cyano group benzene) palladium chloride etc.;
The optimum condition of reaction is: using the mixed solution of the Isosorbide-5-Nitrae-dioxane of volume ratio 1:1 ~ 10:1 and water as solvent, salt of wormwood is alkali, and tetrakis triphenylphosphine palladium is catalyzer, reacts 3 ~ 24 hours at 80 DEG C;
(IX-2) 0 ~ 50 DEG C, in organic solvent, intermediate compound IV-1a-IV-1i and acid-respons 1-24h, sloughs tertbutyloxycarbonyl protecting group, obtains intermediate compound IV-2a-IV-2i;
Intermediate compound IV-1a-IV-1i is preferably 1:1 ~ 1:20 with the mol ratio of acid;
Organic solvent is selected from methylene dichloride, chloroform, 1,2-ethylene dichloride, ethyl acetate, tetrahydrofuran (THF), ether, methyl tert-butyl ether, methyl alcohol or ethanol etc., and can be single solvent, also can be mixed solvent;
Acid can select hydrochloric acid, hydrogen chloride methanol solution, sulfuric acid, trifluoroacetic acid, methanesulfonic or tosic acid etc.;
The optimum condition of reaction is: be solvent with methyl alcohol, adds 1 ~ 8M hydrogen chloride methanol solution, reacts 1-5 hour at 20 DEG C;
(IX-3) in the presence of base, intermediate compound IV-2a-IV-2i, in a solvent in-20 DEG C ~ 100 DEG C (or under reflux temperature) and 2-chloro-N-methylacetamide generation substitution reaction 1 ~ 48 hour, generates compound 63-71 respectively;
Wherein, intermediate compound IV-2a-IV-2i is preferably 1:1 ~ 1:5 with the mol ratio of the chloro-N-methylacetamide of 2-, and alkali consumption is preferably 3 ~ 8 equivalents;
Alkali be selected from mineral alkali, organic bases one or more, described mineral alkali comprises: sodium carbonate, salt of wormwood, cesium carbonate, sodium hydroxide, potassium hydroxide or potassiumphosphate, organic bases comprises: 1,8-diazacyclo [5,4,0] hendecene-7, triethylamine, diisopropyl ethyl amine or N-methylmorpholine etc.;
Solvent selected from acetone, tetrahydrofuran (THF), acetonitrile, ethanol, methyl alcohol, Virahol, Isosorbide-5-Nitrae-dioxane, dimethyl formamide, N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone, methyl-sulphoxide or water etc. can be single solvents, also can mixed solvent;
The optimum condition of reaction is: take acetonitrile as solvent, salt of wormwood is alkali, reacts 3 ~ 24 hours under 80 DEG C of conditions.
(10) flow process X: the preparation of compound 72-76
In a solvent, compound 13 respectively under-20 DEG C ~ 100 DEG C condition reacts 1 ~ 48 hour with methylsulfonic acid, compound 55 with tosic acid with hydrochloric acid, compound 29 with fumaric acid, compound 21 with methylsulfonic acid, compound 14, direct precipitation solid or leave standstill and separate out solid or concentrated recrystallization, obtains compound 72 ~ 76.
Wherein, compound 13 is all preferably 1:1 ~ 1:10 with methylsulfonic acid, compound 55 with the mol ratio of tosic acid with hydrochloric acid, compound 29 with fumaric acid, compound 21 with methylsulfonic acid, compound 14;
Solvent selected from acetone, tetrahydrofuran (THF), acetonitrile, ethanol, methyl alcohol, Virahol, methylene dichloride, 1,4-dioxane, dimethyl formamide, N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone, methyl-sulphoxide or water etc., can be single solvent, also can mixed solvent;
The optimum condition of reaction is: volume ratio be the mixed solution of the methylene dichloride of 5:1 ~ 1:5 and methyl alcohol as solvent, react 3 ~ 24 hours at ambient temperature.
A third aspect of the present invention, the application of above-mentioned quinazoline ditosylate salt tyrosine kinase inhibitor is provided, the i.e. application of this quinazoline ditosylate salt tyrosine kinase inhibitor in the medicine of preparation treatment tyrosine kinase related disorder, the application especially in the medicine of preparation treatment tumor disease.
A fourth aspect of the present invention, provides a kind of pharmaceutical composition, and it contains the above-mentioned quinazoline ditosylate salt tyrosine kinase inhibitor (this quinazoline ditosylate salt tyrosine kinase inhibitor is as activeconstituents) for the treatment of significant quantity and pharmaceutically acceptable carrier.
Activeconstituents
In the present invention, " activeconstituents " refers to compound shown in general formula (I), and the various crystal formations of general 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 general formula (I), compound comprises racemic modification thing, single enantiomer.
In addition, as required, can by compound of the present invention in polar protic solvent, as methyl alcohol, ethanol, Virahol, and pharmaceutically acceptable acid-respons generation pharmacy acceptable salt prepares.Described pharmaceutically acceptable inorganic or organic acid can be: 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 etc.
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 pharmacy acceptable salt and pharmaceutically 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.
Pharmaceutical composition of the present invention (as compound and pharmacy acceptable salt thereof) can be made into various preparation, and the formulation of said preparation can be prepared according to the ordinary method of pharmaceutical field.Wherein comprise the compounds of this invention within the scope of safety, significant quantity or its pharmacy acceptable salt and pharmaceutically 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.
" pharmaceutically acceptable 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.Pharmaceutically acceptable carrier part example has: 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
), wetting agent (as sodium lauryl sulphate), tinting material, seasonings, stablizer, antioxidant, sanitas, apirogen water, vehicle etc.
When using the compounds of this invention, can oral, rectum, parenteral (intravenously, intramuscular or subcutaneous), topical etc.
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 excellent pharmacokinetic property;
(4) the compounds of this invention has good security to cardiovascular systems;
(5) growth of the significant Tumor suppression of the compounds of this invention energy.
Embodiment
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 addition, the reagent related in embodiment if not otherwise specified, can be commercially produced product.
The lapatinibditosylate used in following examples is the product prepared according to international publication WO2005120504, and it is two tosic acid monohydrates, purity HPLC:98.33%.
In all embodiments, fusing point X-4 melting point apparatus measures, and thermometer does not correct;
1hNMR VarianMercury400 nuclear magnetic resonance analyser record, chemical shift represents with δ (ppm); The mensuration Shimadzu LC-MS-2020 mass spectrograph of MS.Separation silica gel is undeclared is 200-300 order, and the proportioning of elutriant is volume ratio.
Embodiment 1N-(the chloro-4-of 3-(pyridine-2-ylmethoxy) phenyl)-6-iodine quinazoline-4-amine (I-2a)
Raw material I-1 (14.52g, 50.0mmol) is dissolved in Virahol (400mL), under stirring, adds the chloro-4-of 3-(pyridine-2-methoxyl group) aniline (11.73g, 50.0mmol), reflux 5h, 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 (23.4g, yield 96%).
Intermediate compound I-2a's
1hNMR (DMSO-d6,400MHz): δ 5.34 (s, 2H), 7.33-7.43 (m, 2H), 7.60-7.68 (m, 3H), 7.90-7.95 (m, 3H), 8.34 (d, J=9.1Hz, 1H), 8.61 (d, J=3.6Hz, 1H), 8.93 (s, 1H), 9.20 (s, 1H).
Be similar to the synthesis of intermediate compound I-2a, the intermediate compound I-2b to I-2u in table 2 can be synthesized by raw material I-1 and various arylamine (amine as in (I-1) of the flow process I of summary of the invention) and obtains.
-2b is to I-2u's for table 2 intermediate compound I
1hNMR and yield
Embodiment 2:N-(the chloro-4-of 3-(pyridine-2-ylmethoxy) phenyl)-6-(4,4,5,5-tetramethyl--1,3,2-dioxy boron pentane-2-base) quinazoline-4-amine (I-3a)
I-2a (4.88g, 10.0mmol) is dissolved in DMSO (50.0mL), adds duplex pinacol borate (3.05g, 12.0mmol), Potassium ethanoate (5.88g, 60.0mmol), adds Pd (dppf) under stirring
2cl
2(0.82g, 1.0mmol), argon shield, is heated to 100 DEG C, reaction 4h.React complete, concentrated, column chromatography, obtains light yellow solid (I-3a) (1.89g, yield 39%).
Intermediate compound I-3a's
1hNMR (DMSO-d6,400MHz): δ 1.24 (s, 12H), 5.34 (s, 2H), 7.33-7.43 (m, 2H), 7.60-7.68 (m, 3H), 7.87-7.91 (m, 3H), 8.14 (d, J=9.1Hz, 1H), 8.39 (d, J=3.6Hz, 1H), 8.93 (s, 1H), 9.20 (s, 1H).
Be similar to the synthesis of intermediate compound I-3a, the intermediate compound I-3b to I-3u of table 3 can be synthesized with duplex pinacol borate respectively by the intermediate feed I-2b to I-2u in embodiment 1 and obtains.
-3b is to I-3u's for table 3 intermediate compound I
1hNMR and yield
Embodiment 3: tert-butyl 4-(5-(4-((the chloro-4-of 3-(pyridine-2-ylmethoxy) phenyl) is amino) quinazoline-6-base) thiazol-2-yl) piperazine-1-carboxylicesters (I-4a)
Intermediate compound I-3a (1.46g, 3.0mmol) is dissolved in 15mL1, in 4-dioxane/water (4:1), adds tert-butyl 4-(5-bromo thiazole-2-base) piperazine-1-carboxylicesters (1.04g, 3.0mmol), K
2cO
3(1.24g, 9.0mmol) and Pd (PPh
3)
4(347mg, 0.3mmol), Ar protects, 80 DEG C of stirring reaction 18h.Be poured into water, filter, with dichloromethane extraction, organic phase anhydrous sodium sulfate drying, column chromatography, obtains yellow solid (I-4a) (1.23g, yield 65%).
Intermediate compound I-4a's
1hNMR (400MHz, CDCl
3): δ 1.48 (s, 9H), 3.49 – 3.54 (m, 4H), 3.56 – 3.61 (m, 4H), 5.27 (s, 2H), 7.02 (d, J=8.9Hz, 1H), 7.48 – 7.55 (m, 3H), 7.66 (d, J=7.7Hz, 1H), 7.74 – 7.77 (m, 2H), 7.84 – 7.89 (m, 3H), 8.61-8.57 (m, 1H), 8.70 (s, 1H).
Be similar to the synthesis of intermediate compound I-4a, the intermediate compound I-4b to I-4u of table 4 is synthesized with tert-butyl 4-(5-bromo thiazole-2-base) piperazine-1-carboxylicesters respectively by raw material I-3b to I-3u and obtains.
-4b is to I-4u's for table 4 intermediate compound I
1hNMR and yield
Embodiment 4:N-(the chloro-4-of 3-(pyridine-2-ylmethoxy) phenyl)-6-(2-(piperidin-1-yl) thiazole-5-base) quinazoline-4-amine four hydrochloride (compound 1)
Intermediate compound I-4a (1.14g, 1.80mmol) is dissolved in methyl alcohol (15mL), at 20 DEG C, adds 4N hydrochloric acid methanol (5.0mL), reaction 2h, after completion of the reaction, concentrated, obtain light yellow solid Compound 1 (1.21g, yield 100%).
Compound 1
1hNMR (CD
3oD, 400MHz): δ 3.45 – 3.51 (m, 4H), 3.92 – 3.99 (m, 4H), 5.65 (s, 2H), 7.42 (d, J=8.9Hz, 1H), 7.80 (dd, J=8.9,2.5Hz, 1H), 7.89 (d, J=8.8Hz, 1H), 8.04-8.06 (m, 2H), 8.10-8.15 (m, 1H), 8.30-8.34 (m, 2H), 8.70-8.74 (m, 1H), 8.81 (s, 1H), 8.92-8.94 (m, 2H).
Ultimate analysis: C
27h
28cl
5n
7oS, theoretical value C, 47.98; H, 4.18; N, 14.51; S, 4.75; Measured value C, 47.90; H, 4.20; N, 11.51; S, 4.73.
Be similar to the synthesis of compound 1, the intermediate II-1a to II-1t of table 5 is synthesized with hydrochloric acid methanol respectively by raw material I-4b to I-4u and obtains.
-1a is to II-1t's for table 5 intermediate II
1hNMR and yield
Embodiment 5:N-(the chloro-4-of 3-(pyridine-2-ylmethoxy) phenyl)-6-(2-(4-methylpiperazine-1-yl) thiazole-5-base) quinazoline-4-amine (compound 2)
Compound 1 (169mg, 0.25mmol) is added in acetonitrile (5.0mL), add salt of wormwood (173mg, 1.25mmol), under agitation slowly add bromoethanol (63mg, 0.50mmol).Heat up 80 DEG C of reactions, reacts complete, concentrated, adds methylene dichloride and water, separatory, organic over anhydrous dried over sodium sulfate, and concentrated, column chromatography, obtains light yellow solid powder compounds 2 (102mg, yield 71%).
Compound 2
1hNMR (400MHz, DMSO) δ: 2.46 (t, 2H), 2.59-2.65 (m, 4H), 3.58 (t, 2H), 3.60-3.67 (m, 4H), 5.30 (s, 2H), 7.29 (d, J=8.9Hz, 1H), 7.34 – 7.40 (m, 1H), 7.59 (d, J=7.9Hz, 1H), 7.70-7.75 (m, 2H), 7.81 (s, 1H), 7.89 (t, J=7.7Hz, 1H), 7.99 (d, J=2.4Hz, 1H), 8.05 (d, J=9.9Hz, 1H), 8.43 (s, 1H), 8.52 (s, 1H), 8.60 (s, 1H), 9.81 (s, 1H).
The ESI-LR:574.17 [M+1] of compound 2
+.
Embodiment 6-31: the preparation of compound 3-28
Being similar to the synthesis of compound 2, there is substitution reaction by compound 1 and different chloro things, bromo-derivative, iodo thing, hydroxyl p-toluenesulfonic esters and hydroxymethane sulfonic acid ester etc. (specifically can see the flow process III of summary of the invention) and generates in the compound 3-28 of table 6.
Table 6
Embodiment 32:2-(4-(5-(4-((3-methyl-4-(pyridine-2-ylmethoxy) phenyl) is amino) quinazoline-6-base) thiazol-2-yl) piperazine-1-base)-N-methylacetamide (compound 29)
By Compound II per-1a (163mg, 0.25mmol) add in acetonitrile (5.0mL), add salt of wormwood (173mg, 1.25mmol), under agitation slowly add the chloro-N-methylacetamide (54mg, 0.50mmol) of 2-.Heat up 80 DEG C of reactions, reacts complete, concentrated, adds methylene dichloride and water, separatory, organic over anhydrous dried over sodium sulfate, and concentrated, column chromatography, obtains light yellow solid powder compounds 29 (97mg, yield 67%).
Compound 29
1hNMR (400MHz, DMSO) δ: 2.29 (s, 3H), 2.59-2.65 (m, 4H), 2.79 (s, 3H), 3.09 (s, 2H), 3.60-3.67 (m, 4H), 5.31 (s, 2H), 7.30 (d, J=8.9Hz, 1H), 7.34 – 7.40 (m, 1H), 7.55-7.59 (m, 2H), 7.71 – 7.76 (m, 1H), 7.81 (s, 1H), 7.89 (t, J=7.7Hz, 1H), 8.00 (d, J=2.4Hz, 1H), 8.05 (d, J=9.9Hz, 1H), 8.43 (s, 1H), 8.52 (s, 1H), 8.61 (s, 1H), 9.80 (s, 1H).
The ESI-LR:581.24 [M+1] of compound 29
+.
Embodiment 33-48: the preparation of compound 30-45
Be similar to the synthesis of compound 29, the compound 30-45 of table 7 is generated by respective intermediate (the flow process IV with reference in summary of the invention) and 2-chloro-N-methylacetamide generation substitution reaction.
Table 7
Embodiment 49:N-(the chloro-4-of 3-((3-benzyl) oxo) phenyl)-6-(2-(4-(2-fluoro ethyl) piperazine-1-base) thiazole-5-base) quinazoline-4-amine (compound 46)
By Compound II per-1c (173mg, 0.25mmol) add in acetonitrile (5.0mL), add salt of wormwood (173mg, 1.25mmol), under agitation slowly add 2-fluoro ethyl-4-toluene sulfonic acide ester (109mg, 0.50mmol).Heat up 80 DEG C of reactions, reacts complete, concentrated, adds methylene dichloride and water, separatory, organic over anhydrous dried over sodium sulfate, and concentrated, column chromatography obtains light yellow solid powder compounds 46 (84mg, yield 57%).
Compound 46
1hNMR (400MHz, DMSO) δ: 2.59-2.65 (m, 4H), 2.79-2.83 (m, 2H), 3.60-3.67 (m, 4H), 4.47-4.56 (m, 2H), 5.25 (s, 2H), 7.18-7.23 (m, 1H), 7.24 – 7.37 (m, 3H), 7.47-7.51 (m, 1H), 7.71 – 7.76 (m, 2H), 7.82 (s, 1H), 7.89 (s, 1H), (8.05 d, J=9.9Hz, 1H), 8.43 (s, 1H), 8.52 (s, 1H), 9.81 (s, 1H).
The ESI-LR:593.16 [M+1] of compound 46
+.
Embodiment 50-55: the preparation of compound 47-51
Be similar to the synthesis of compound 46, the compound 47-51 of table 8 is generated by respective intermediate (the flow process V with reference in summary of the invention) and 2-fluoro ethyl-4-toluene sulfonic acide ester generation substitution reaction.
Table 8
Embodiment 55:N-methyl-2-(4-(5-(4-((3-methyl-4-((6-picoline-3-base) oxo) phenyl) is amino) quinazoline-6-base) thiazol-2-yl) piperazine-1-base) ethanamide (compound 52)
By intermediate II-1e (164mg, 0.25mmol) add in acetonitrile (5.0mL), add salt of wormwood (173mg, 1.25mmol), under agitation slowly add the chloro-N-methylacetamide (54mg, 0.50mmol) of 2-.Heat up 80 DEG C of reactions, reacts complete, concentrated, adds methylene dichloride and water, separatory, organic over anhydrous dried over sodium sulfate, and concentrated, column chromatography, obtains light yellow solid powder compounds 52 (91mg, 63%).
Compound 52
1hNMR (400MHz, DMSO) δ: 2.45 (s, 3H), 2.55-2.61 (m, 4H), 2.63 (s, 3H), 2.99 (s, 2H), 3.51-3.59 (m, 4H), 7.23 (d, J=8.9Hz, 1H), 7.27 – 7.29 (m, 2H), 7.76 (d, J=8.8Hz, 1H), 7.78 – 7.84 (m, 2H), 7.84-7.89 (m, 1H), 8.08-8.11 (m, 1H), 8.23-8.28 (m, 1H), 8.45 (s, 1H), 8.60 (s, 1H), 9.91 (s, 1H).
The ESI-LR:581.24 [M+1] of compound 52
+.
Embodiment 56-61: the preparation of compound 53-58
Being similar to the synthesis of compound 52, there is substitution reaction by intermediate II-1e and different chloro things, bromo-derivative, iodo thing, hydroxyl p-toluenesulfonic esters and hydroxymethane sulfonic acid ester etc. (specifically can see the flow process VI in summary of the invention) and generates in the compound 53-58 of table 9.
Table 9
Embodiment 62:1-(4-(5-(4-((the chloro-2-fluorophenyl of 3-) is amino) quinazoline-6-base) thiazol-2-yl) piperazine-1-base) ethyl ketone (compound 59)
Intermediate II-1n (137mg, 0.25mmol) is added in methylene dichloride (5.0mL), add triethylamine (127mg, 1.25mmol), under agitation slowly add Acetyl Chloride 98Min. (39mg, 0.50mmol).20 DEG C of reactions, react complete, add methylene dichloride and water, separatory, organic over anhydrous dried over sodium sulfate, and concentrated, column chromatography, obtains light yellow solid powder compounds 59 (83mg, 69%).
Compound 59
1hNMR (400MHz, DMSO) δ: 2.39 (s, 3H), 2.59-2.63 (m, 4H), 3.60-3.67 (m, 4H), 7.44 (s, 1H), 7.74-7.80 (m, 2H), 7.84 (s, 1H), 8.05-8.10 (m, 1H), 8.12-8.14 (m, 1H), 8.32-8.41 (m, 1H), 8.54 (s, 1H), 9.91 (s, 1H).
The ESI-LR:483.11 [M+1] of compound 59
+.
Embodiment 63-64: the preparation of compound 60-61
Be similar to the synthesis of compound 59, reacting generates with SULPHURYL CHLORIDE, isocyanic ester etc. (specifically can see the flow process VII in summary of the invention) respectively by intermediate II-1n for the compound 60-61 of table 10.
Table 10
Embodiment 65:2-(4-(5-(4-((the chloro-4-of 3-(pyridine-2-ylmethoxy) phenyl) is amino) quinazoline-6-base) thiazol-2-yl)-Isosorbide-5-Nitrae-diazo ring in heptan-1-base)-N-methylacetamide (compound 62)
(1) tert-butyl 4-(5-(4-((the chloro-4-of 3-(pyridine-2-ylmethoxy) phenyl) is amino) quinazoline-6-base) thiazol-2-yl)-Isosorbide-5-Nitrae-Diazesuberane-1-carboxylicesters (III-1)
By intermediate compound I-3a (486mg, 1.0mmol) be dissolved in 5mL1, in 4-dioxane/water (4:1), add tert-butyl 4-(5-bromo thiazole-2-base) 1,4-Diazesuberane-1-carboxylicesters (362mg, 1.0mmol), K
2cO
3(413mg, 3.0mmol) and Pd (PPh
3)
4(116mg, 0.1mmol), Ar protects, 80 DEG C of stirring reaction 18h.Be poured into water, filter, extraction, organic phase anhydrous sodium sulfate drying, column chromatography, obtains yellow solid III-1 (379mg, 59%).
Intermediate III-1
1hNMR (400MHz, CDCl
3): δ 1.48 (s, 9H), 1.73 – 1.81 (m, 2H), 3.49 – 3.54 (m, 4H), 3.56 – 3.61 (m, 4H), 5.27 (s, 2H), 7.02 (d, J=8.9Hz, 1H), 7.48 – 7.55 (m, 3H), 7.66 (d, J=7.7Hz, 1H), 7.74 – 7.77 (m, 2H), 7.84 – 7.89 (m, 3H), 8.61-8.57 (m, 1H), 8.70 (s, 1H).
(2) 6-(2-(Isosorbide-5-Nitrae-Diazesuberane-1-base) thiazole-5-base)-N-(the chloro-4-of 3-(pyridine-2-ylmethoxy) phenyl) quinazoline-4-amine four hydrochloride (III-2)
Intermediate III-1 (326mg, 0.60mmol) is dissolved in methyl alcohol (5mL), at 20 DEG C, adds 4N hydrochloric acid methanol (2mL), reaction 2h, after completion of the reaction, concentrated, obtain light yellow solid intermediate III-2 (414mg, 100%).
Intermediate III-2
1hNMR (CD
3oD, 400MHz): δ 1.67 – 1.71 (m, 2H), 3.45 – 3.51 (m, 4H), 3.92 – 3.99 (m, 4H), 5.65 (s, 2H), 7.42 (d, J=8.9Hz, 1H), 7.80 (dd, J=8.9,2.5Hz, 1H), 7.89 (d, J=8.8Hz, 1H), 8.04-8.06 (m, 2H), 8.10-8.15 (m, 1H), 8.30-8.34 (m, 2H), 8.70-8.74 (m, 1H), 8.81 (s, 1H), 8.92-8.94 (m, 2H).
(3) 2-(4-(5-(4-((the chloro-4-of 3-(pyridine-2-ylmethoxy) phenyl) is amino) quinazoline-6-base) thiazol-2-yl)-Isosorbide-5-Nitrae-diazo ring in heptan-1-base)-N-methylacetamide (compound 62)
By compound III-2 (173mg, 0.25mmol) add in acetonitrile (5.0mL), add salt of wormwood (173mg, 1.25mmol), under agitation slowly add the chloro-N-methylacetamide (54mg, 0.50mmol) of 2-.Heat up 80 DEG C of reactions, reacts complete, concentrated, adds methylene dichloride and water, separatory, organic over anhydrous dried over sodium sulfate, and concentrated, column chromatography, obtains light yellow solid powder compounds 62 (101mg, 66%).
Compound 62
1hNMR (400MHz, DMSO) δ: 1.73 – 1.81 (m, 2H), 2.59-2.65 (m, 4H), 2.79 (s, 3H), 3.09 (s, 2H), 3.60-3.67 (m, 4H), 5.29 (s, 2H), 7.30 (d, J=8.9Hz, 1H), 7.34 – 7.40 (m, 1H), 7.59 (d, J=7.9Hz, 1H), 7.71 – 7.76 (m, 2H), 7.81 (s, 1H), 7.89 (s, 1H), 8.00-8.05 (m, 1H), 8.05 (d, J=9.9Hz, 1H), 8.43 (s, 1H), 8.52 (s, 1H), 8.61 (s, 1H), 9.80 (s, 1H).
The ESI-LR:615.20 [M+1] of compound 62
+.
The preparation of embodiment 66-75: compound 63-compound 71
Be similar to the synthesis of compound 62, the compound 63-71 of table 11 can be prepared according to the method for embodiment 65.
Table 11
Embodiment 76:3-(4-(5-(4-((the chloro-4-of 3-(pyridine-2-ylmethoxy) phenyl) is amino) quinazoline-6-base) thiazol-2-yl) piperazine-1-base) propionitrile four mesylate (compound 72)
Compound 13 (1.46g, 2.5mmol) is dissolved in the mixed solvent of methylene dichloride (15mL) and methyl alcohol (8mL), after heating is entirely molten, drips methylsulfonic acid (0.96g, 10.0mmol), is heated to backflow.Cooling, has solid to separate out, and filters, and dries, obtains yellow solid compound 72 (1.95g, 80.5%), fusing point: 173-175 DEG C.
Ultimate analysis: C
34h
43clN
8o
13s
5, theoretical value C, 42.21; H, 4.48; N, 11.58; S, 16.57; Measured value C, 42.17; H, 4.51; N, 11.54; S, 16.59.
The preparation of embodiment 77-80: compound 73-compound 76
Be similar to the synthesis of compound 72, the compound 73-76 of table 12 can be prepared according to the method for embodiment 76.
Table 12
| Compound number | Acid | The mol ratio of acid | Salt fusing point (DEG C) | Yield |
| 73 | Fumaric acid | 1 | 145-146 | 90.2％ |
| 74 | Hydrochloric acid | 4 | 220-221 | 78.3％ |
| 75 | Methylsulfonic acid | 4 | 178-180 | 85.4％ |
| 76 | Tosic acid | 2 | 154-156 | 83.7％ |
Embodiment 81: the deliquescent mensuration of salt
Measuring method:
1) the configuration of the saturated solution: take a suitable amount of the product in 5 ml capacity calabash, add pH = 1.2 hydrochloric acid aqueous solution or supersaturated solution, purified water is made by the aperture of 0.22 um organic membrane filtering twice, quick.
2) the preparation of the reference substance solution: precision according to take the test 10 mg in 25 ml capacity calabash, add methanol solvent to dissolve the sample and the capacity to scale, and then shake well, for a quick.
3) preparation of sample solution: precision moving saturated solution 1 ml to 20 ml capacity in the calabash, add the capacity to scale the solvent of methanol, shake for a quick.
Testing method:
Chromatographic condition: be weighting agent with octadecylsilane chemically bonded silica; Test with the method detecting sample.
By sample solution and reference substance solution, each sample introduction 10 μ L, liquid phase is tested.
Wherein, C couple: reference substance solution concentration;
A sample: sample solution main peak peak area;
A couple: reference substance solution main peak peak area;
N: saturated solution extension rate.
The solvability result of table 13 salt-forming compound
| Compound number | Water solubility (mg/mL) | The hydrochloric acid water solubleness (mg/mL) of pH=1.2 |
| 72 | 15.89 | 27.93 |
| 73 | 1.49 | 2.51 |
| 74 | 3.02 | 7.95 |
| 75 | 13.08 | 7.78 |
| 76 | 1.82 | 4.66 |
| Lapatinibditosylate | 0.008 | 0.002 |
As can be seen from Table 13, part of compounds of the present invention solubleness after salify increases greatly than lapatinibditosylate, overcomes lapatinibditosylate this shortcoming poorly soluble.Wherein, the solvability of compound 72 in water can reach 15.89mg/mL, can make injection type administration.
Embodiment 82:HER-2 kinase inhibitory activity measures
Object:
Utilize the method for MobilityShiftAssay when KmATP, detection compound is screened the inhibit activities of kinases HER-2.
Background:
In this experiment, vitro kinase Her2 is carried out to the screening of compound, each compound is initial from 3 μMs, 3 times of dilutions, and 10 concentration point carry out detecting in (2 multiple hole).Adopt compound staurosporine (Sigma, >=95%) as standard control.
Experimental technique:
I. 1 × kinase buffer liquid and stop buffer is prepared
1.1 × kinase buffer liquid
50mMHEPES(Sigma),pH7.5
0.0015％Brij-35(Sigma)
10mMMgCl
2
2mMDTT (dithiothreitol (DTT))
2. stop buffer
100mMHEPES(Sigma),pH7.5
0.015％Brij-35(Sigma)
0.2%CoatingReagent#3 (caliper company)
50mMEDTA
II. compound preparation
1) diluted chemical compound
1, compound test final concentration is initial 3 μMs, is first configured to 50 times of concentration, namely 150 μMs.
2, in 96 orifice plates, capable 2nd hole of A adds the compound that 100 μ l are dissolved in 100%DMSO, 3 times of dilutions this compound, totally 10 concentration.Be operating as each hole except the 2nd hole and add 60 μ l100%DMSO, from the 2nd hole, get 30 μ l compounds to the 3rd hole, the like, be diluted to the 11st hole, totally 10 concentration.
2) transferase 45 times compound is to Sptting plate
1, get 10 μ l from each hole of above-mentioned 96 orifice plates to another block 96 orifice plate, add 90 μ l1 × kinase buffer liquid.Therefore, compound dissolution is in 10%DMSO.Vibration plate machine vibrates 10 minutes, mixing.
2, from above-mentioned 96 orifice plates, 5 μ l are taken out to one piece of 384 hole Sptting plate.Often row establishes negative control hole and each 2 of Positive control wells.In 96 orifice plates, the capable compound of A proceeds to the 384 capable 13-24 holes of orifice plate A with the form in multiple hole, left and right.Therefore, 5 times of compounds that the 10%DMSO of 5 μ l dissolves just are had in 384 hole Sptting plates.
III. kinase reaction
1) 2.5 times of enzyme solution are prepared
Kinases (Carna company, 45nM) is added 1 × kinase buffer liquid, forms 2.5 times of enzyme solution.
2) substrate solution of 2.5 times is prepared
The polypeptide (gill biochemical corp, 3 μMs) mark FAM and ATP (Sigma, 7.5 μMs) add 1 × kinase buffer liquid, form 2.5 times of substrate solutions.
3) in 384 orifice plates, enzyme solution is added
1,5 times of compounds that in 384 hole Sptting plates, the 10%DMSO of existing 5 μ l dissolves.
2, in 384 hole Sptting plates, add 2.5 times of enzyme solution of 10 μ l.
3, incubated at room temperature 10 minutes.
4) in 384 orifice plates, substrate solution is added
2.5 times of substrate solutions of 10 μ l are added in 384 hole Sptting plates.
5) kinase reaction and termination
1,1 hour is hatched at 28 DEG C.
2,25 μ l stop buffer termination reactions are added.
IV.Caliper reading of data
Caliper upper reading and converting rate data.
V.IC
50value calculates
1, conversion data is copied from Caliper.
2, conversion is become inhibiting rate data.Wherein max refers to that the transformation efficiency that DMSO contrasts, min refer to the transformation efficiency without enzyme contrast alive.
Inhibiting rate=(max-compound ratio transformation)/(max-min) * 100.
3, inhibiting rate data GraphPad5.0 (production of Caliper company of the U.S.) obtains IC
50value.
Y=minimum value+(maximum value-minimum value)/(1+10^ ((LogIC
50-X) * slope))
Table 14 the compounds of this invention is to HER-2 kinase inhibiting activity
| Compound | IC 50(nM) | Compound | IC 50(nM) |
| Compound 2 | 5.5 | Compound 29 | 6.4 |
| Compound 3 | 8.3 | Compound 32 | 5.8 |
| Compound 5 | 6.8 | Compound 36 | 12 |
| Compound 9 | 9.3 | Compound 52 | 6.9 |
| Compound 13 | 14 | Compound 53 | 13 |
| Compound 14 | 10 | Compound 55 | 12 |
| Compound 15 | 4.2 | Compound 57 | 9.0 |
| Compound 20 | 5.2 | Compound 62 | 9.6 |
| Compound 21 | 3.7 | Lapatinibditosylate | 14 |
As can be seen from the data in table 14, part of compounds HER-2 kinase activity of the present invention is better than contrast medicine lapatinibditosylate, and wherein part of compounds is stronger more than 3 times than contrast medicine.
Embodiment 83:EGFR and HER-4 kinase inhibitory activity measure
According to the method that embodiment 82 is identical, compd E GFR (Carna, 45nM) and HER-4 (Carna, 45nM) kinase inhibitory activity can be recorded.
Table 15 the compounds of this invention is to EGFR and HER-4 kinase inhibiting activity
As can be seen from the data in table 15, part of compounds EGFR of the present invention and HER-4 kinase activity are better than contrast medicine lapatinibditosylate, and wherein part of compounds is stronger more than 3 times than contrast medicine.Show that this series compound has very strong kinase activity.
Embodiment 84: compound 9,13,14,21,29,52,53 and 55 Pharmacokinetics in Rat is tested
Experimental technique:
Healthy SD rat 24, male, be divided at random 8 groups (often organizing 3), dosage is 5mg/kg.
Fasting 12h before test, freely drinks water.Administration volume is 10mL/kg, prepares with 5%DMSO+95% (0.5%MethylCellulose).Blood sampling time point and sample preparation: before giving tested material (0hr) and after giving tested material 15min, 30min, 1h, 2h, 4h, 6h, 8h and 24h every animal get 0.15mL blood by eye socket at every turn, EDTAK2 anti-freezing, put in heparinised tubes, the centrifugal 10min of 5000rpm, separated plasma ， Yu – 80 DEG C of refrigerator and cooled are frozen.With the concentration of compound in LC-MS/MS blood plasma, obtain corresponding pharmacokinetic parameter according to plasma concentration v. time curve.
Table 16 compound 9,13,14,21,29,52,53 and 55 rat oral gavage gives the pharmacokinetic parameters of 5mg/k
| Compound | T max(h) | C max(ng/mL) | AUC 0-t(ng.h/mL) | MRT(h) | t 1/2(h) |
| Compound 9 | 5.00 | 253 | 1923 | 6.15 | 2.66 |
| Compound 13 | 1.67 | 1043 | 9782 | 12.7 | 8.69 |
| Compound 14 | 1.50 | 1110 | 6430 | 4.11 | 2.13 |
| Compound 21 | 2.00 | 5290 | 18634 | 3.06 | 1.57 |
| Compound 29 | 1.00 | 1823 | 5338 | 2.52 | 2.62 |
| Compound 52 | 0.50 | 793 | 3335 | 4.20 | 4.07 |
| Compound 53 | 1.67 | 5113 | 53505 | 6.36 | 4.05 |
| Compound 55 | 2.00 | 988 | 6083 | 4.51 | 2.73 |
As can be seen from upper table data, the better pharmacokinetic property that above-claimed cpd all has, especially compound 13,21 and 53, its pharmacokinetic property is more excellent, this shows that the compounds of this invention has good druggability, probably develops into effective anti-tumor medicine.
Embodiment 85: compound is tested hERG potassium-channel restraining effect
The HEK-293 cell (French CreacellTM) of stably express hERG, at room temperature, with whole-cell patch-clamp recording technique record hERG potassium channel current.Tip resistance is that the glass microelectrode of 1-4M about Ω is connected to Axon200A patch clamp amplifier.Clamping voltages and data logging pass through conputer controlled by clampex9.2 software through AxonDigiData1322AA/D transmodulator, and cell clamp, built in-80mV, brings out hERG potassium current (I
hERG) step voltage give the depolarizing voltage of a 2s to+20mV from-80mV, then repolarization is to-40mV, gets back to-80mV after continuing 4s.Give this voltage step respectively before administration afterwards and induce hERG potassium current.
Data Analysis Services adopts PatchMaster, GraphPadPrism5 and Excel software.Different compound concentration is to the following formulae discovery of suppression degree of hERG potassium current (the hERG tail current peak value brought out during-50mV):
Fractionalblock％＝[1–(I/Io)]×100％
Wherein, Fractionalblock representation compound is to the inhibition percentage of hERG potassium current, I and Io is illustrated respectively in after dosing and the amplitude of hERG potassium current before dosing.
The IC of compound
50use following equation to carry out the Fitting Calculation to draw:
I/Io＝1/{1+([C]/IC
50)^n}
Wherein, Io and I represents before dosing and the amplitude of hERG potassium current after dosing respectively.The concentration that [C] is compound, n is Hill coefficient.
The suppression of table 17 compound 13,14 and 21 couples of hERG
| Compound | IC 50(μM) |
| Compound 13 | 87.3 |
| Compound 14 | 58.6 |
| Compound 21 | 68.9 |
Table 17 shows, the suppression IC of compound 13,14 and 21 pairs of hERG potassium currents
50all be greater than 50 μMs, show that the compounds of this invention has good security to cardiovascular systems.
Embodiment 86: compound is to the antitumous effect to SK-BR-III cell model of nude mice bearing tumor
Cell and animal: SK-BR-III cell purchased from ATCC, cell cultures in containing 10% foetal calf serum, in the RPMI1640 substratum of penicillin and Streptomycin sulphate (each 100U/ml); RPMI1640 substratum is purchased from Hyclone.6-8 week nude mouse female mouse purchased from Shanghai Si Laike Experimental Animal Center, animal rearing in SPF level Animal House, free diet.
The foundation of SK-BR-III model of nude mice bearing tumor: by 5 × 10
6cell and Matrigel (1:1) combined inoculation subcutaneous in nude mouse.After administration weekly 2 times long and once wide by vernier caliper measurement tumour, according to formula V=(the wide * of long * is wide)/2 calculating gross tumor volume.
Experimental design: adopt SK-BR-III lotus knurl nude mouse model, often organize 8, if negative control group, lapatinibditosylate group, compound 13 groups and compound 21 groups, treat that tumor growth is to about 100mm
3time, start gastric infusion, dosage is 100mg/kg/day (medicine adopts 0.5%CMC-Na to suspend), every day is administered once, negative control group is to 0.5%CMC-Na (Xylo-Mucine), and dosage period 28 days, measures gross tumor volume 2 times weekly.
Data analysis: all results all adopt Origin8.0 software analysis, numerical value adopts Means ± SEM to represent.
Result:
Relative tumour volume (relativetumorvolume, RTV) is calculated, RTV=V according to measuring result
t/ V
0.Wherein V
0for (d during point cage administration
0) measure gained gross tumor volume, V
tgross tumor volume during for measuring each time.
Antitumor activity evaluation index is Relative tumor proliferation rate T/C (%)
T/C％＝TRTV/CRTV×100％
TRTV: treatment group RTV; CRTV: negative control group RTV.
The antitumor result of table 18 compound 13 and compound 21
Table 18 shows, compound 13 is compared with blank with 21, can significantly Tumor suppression growth.Wherein, the effect of compound 21 pairs of Tumor suppression growths is stronger than control sample lapatinibditosylate 1.45 times, and the effect of the Tumor suppression of compound 13 growth is stronger 1.96 times than contrast lapatinibditosylate.
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 (8)
1. a quinazoline ditosylate salt tyrosine kinase inhibitor, is characterized in that: it is the compound shown in general formula (I), its various optical isomer or its pharmacy acceptable salt;
In general formula (I), n is separately 1 or 2;
L is selected from CO, SO
2, NHCO or chemical bond;
X is selected from O, S or N-R
3, wherein, R
3for hydrogen or C
1-4alkyl;
Y and Z is all selected from C or N, and Y and Z is identical or different;
R
1be selected from following group:
Wherein, R
4, R
5and R
6independently be selected from H, F, Cl, Br, I, CH
3, OCH
3, NO
2, CN, NH
2, SO
2nH
2, CF
3or OCF
3;
R
7be selected from following (1) ~ (3) any one:
(1) hydrogen, C
1-6alkyl or C
3-7cycloalkyl, wherein, described alkyl or cycloalkyl is unsubstituted or by one to three halogen substiuted;
(2) aryl methylene or heteroaryl 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, t-Bu, CN, CF
3, OCH
3or 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, t-Bu, CN, CF
3, OCH
3or OCF
3;
R
2be selected from hydrogen atom, C
1-6alkyl, C
2-6thiazolinyl or C
3-7cyclic alkyl, wherein, described alkyl be unsubstituted or be independently selected from by one to three lower group group replace:
Halogen, OH, CN, O, S, SO, SO
2, CO, R
8r
9n, R
8r
9nC (O)-, R
8c (O) N (R
9)-, R
8r
9nS (O
2)-or R
8s (O
2) N (R
9)-; Wherein, described R
8and R
9independently be selected from hydrogen atom, C
1-6alkyl or can form 5-6 ring further, can also contain one or more nitrogen, oxygen or sulphur atom in this 5-6 ring.
2. quinazoline ditosylate salt tyrosine kinase inhibitor as claimed in claim 1, is characterized in that: described pharmacy acceptable salt comprises: the salt that the compound shown in general formula (I) is formed with acid;
Wherein, acid comprises: mineral acid, organic acid or acidic amino acid;
Described mineral acid comprises: hydrochloric acid, Hydrogen bromide, hydrofluoric acid, sulfuric acid, nitric acid or phosphoric acid;
Organic acid comprises: 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, p-methyl benzenesulfonic acid, ethyl sulfonic acid or Phenylsulfonic acid;
Acidic amino acid comprises: aspartic acid or L-glutamic acid.
3. quinazoline ditosylate salt tyrosine kinase inhibitor as claimed in claim 1, is characterized in that: described quinazoline ditosylate salt tyrosine kinase inhibitor is
4. a preparation method for quinazoline ditosylate salt tyrosine kinase inhibitor as claimed in claim 1, is characterized in that, its flow process comprises:
(1) flow process I: the preparation of intermediate compound I-4a-I-4u
In formula (I-2a-I-2u), (I-3a-I-3u) and (I-4a-I-4u), R is the one in following group:
(I-1) Compound I-1 is in polar solvent, and under neutral or basic conditions, under-20 DEG C ~ 100 DEG C or reflux temperature, carries out reaction 1 ~ 12 hour with amine, obtain formula intermediate compound I-2a-I-2u;
Wherein, polar solvent is selected from methyl alcohol, ethanol, Virahol, the trimethyl carbinol, acetonitrile or DMF;
Alkali in alkaline condition be selected from mineral alkali, organic bases one or more, wherein, described mineral alkali comprises: sodium bicarbonate, sodium carbonate or salt of wormwood; Organic bases comprises: 1,8-diazacyclo [5,4,0] hendecene-7, triethylamine, diisopropyl ethyl amine or N-methylmorpholine;
Amine is selected from:
(I-2) intermediate compound I-2a-I-2u is in polar aprotic solvent, at 20 ~ 120 DEG C, and under rare gas element and alkali exist, with palladium catalyst catalysis duplex pinacol borate, through linked reaction 1 ~ 48 hour, obtains intermediate compound I-3a-I-3u; Wherein, polar aprotic solvent is selected from toluene, Isosorbide-5-Nitrae-dioxane, dimethyl formamide, N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone or methyl-sulphoxide; Alkali is selected from sodium carbonate, salt of wormwood, cesium carbonate, potassium acetate or sodium acetate; Palladium catalyst is selected from [1,1'-two (diphenylphosphine) ferrocene] palladium chloride, three (dibenzalacetone) two palladium, tetrakis triphenylphosphine palladium, palladium or palladium carbon;
(I-3) in a solvent, 20 ~ 150 DEG C, under rare gas element and alkali, with palladium catalyst catalytic intermediary I-3a-I-3u and tertiary butyl 4-(5-bromo thiazole-2-base) piperazine-1-carboxylicesters, through linked reaction 1 ~ 48 hour, obtain intermediate compound I-4a-I-4u; Wherein, solvent is selected from water, Isosorbide-5-Nitrae-dioxane, DMF, N,N-dimethylacetamide, methyl-sulphoxide, acetonitrile, toluene, benzene, dimethylbenzene, tetrahydrofuran (THF) or glycol dimethyl ether; Alkali is selected from salt of wormwood, saleratus, sodium carbonate, sodium bicarbonate, Tripotassium phosphate, cesium carbonate, cesium fluoride, sodium hydroxide or potassium hydroxide; Palladium catalyst is selected from tetrakis triphenylphosphine palladium, palladium, two (dibenzalacetone) palladium, [two (diphenylphosphine) ferrocene of 1,1'-] palladium chloride, two (triphenylphosphine) palladium chlorides or two (cyano group benzene) palladium chloride;
(2) flow process II: the preparation of compound 1 and intermediate II-1a-II-1t
R ' in intermediate II-1a-II-1t is the one in following group:
In organic solvent, intermediate compound I-4a-I-4u reacts 1 ~ 24 hour with acid at 0 ~ 50 DEG C, obtains compound 1 and intermediate II-1a-II-1t;
Wherein, organic solvent is selected from methylene dichloride, chloroform, 1,2-ethylene dichloride, ethyl acetate, tetrahydrofuran (THF), ether, methyl tert-butyl ether, methyl alcohol or ethanol;
Acid is selected from hydrochloric acid, hydrogen chloride methanol solution, sulfuric acid, trifluoroacetic acid, methanesulfonic or tosic acid;
(3) flow process III: the preparation of compound 2-28
R in compound 2-28 is selected from the one in following group:
In the presence of a base, compound 1, in a solvent under-20 DEG C ~ 100 DEG C or reflux temperature, with the halides containing the R group in above-claimed cpd 2-28 or sulphonate generation substitution reaction 1 ~ 48 hour, generates compound 2-28 respectively;
Wherein, alkali be selected from mineral alkali, organic bases one or more, described mineral alkali comprises: sodium carbonate, salt of wormwood, cesium carbonate, sodium hydroxide, potassium hydroxide or potassiumphosphate, organic bases comprises: 1,8-diazacyclo [5,4,0] hendecene-7, triethylamine, diisopropyl ethyl amine or N-methylmorpholine;
Solvent selected from acetone, tetrahydrofuran (THF), acetonitrile, ethanol, methyl alcohol, Virahol, Isosorbide-5-Nitrae-dioxane, dimethyl formamide, N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone, methyl-sulphoxide or water;
(4) flow process IV: the preparation of compound 29-45
R ' in intermediate II-1a-II-1t and compound 29-45 is selected from the one in following group:
In the presence of base, intermediate II-1a-II-1t, in a solvent under-20 DEG C ~ 100 DEG C or reflux temperature, with 2-chloro-N-methylacetamide generation substitution reaction 1 ~ 48 hour, generates compound 29-45 respectively;
Wherein, alkali be selected from mineral alkali, organic bases one or more, described mineral alkali comprises: sodium carbonate, salt of wormwood, cesium carbonate, sodium hydroxide, potassium hydroxide or potassiumphosphate, organic bases comprises: 1,8-diazacyclo [5,4,0] hendecene-7, triethylamine, diisopropyl ethyl amine or N-methylmorpholine;
Solvent selected from acetone, tetrahydrofuran (THF), acetonitrile, ethanol, methyl alcohol, Virahol, Isosorbide-5-Nitrae-dioxane, dimethyl formamide, N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone, methyl-sulphoxide or water;
(5) flow process V: the preparation of compound 46-51
R ' in intermediate II-1a-II-1t and compound 46-51 is selected from the one in following group:
Under the effect of alkali, intermediate II-1a-II-1t separately in a solvent, under-20 DEG C ~ 100 DEG C or reflux temperature, with 2-fluoro ethyl-4-methyl p-toluenesulfonic esters generation substitution reaction 1 ~ 48 hour, generates compound 45-51 respectively;
Wherein, alkali be selected from mineral alkali, organic bases one or more, described mineral alkali comprises: sodium carbonate, salt of wormwood, cesium carbonate, sodium hydroxide, potassium hydroxide or potassiumphosphate, organic bases comprises: 1,8-diazacyclo [5,4,0] hendecene-7, triethylamine, diisopropyl ethyl amine or N-methylmorpholine;
Solvent selected from acetone, tetrahydrofuran (THF), acetonitrile, ethanol, methyl alcohol, Virahol, Isosorbide-5-Nitrae-dioxane, dimethyl formamide, N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone, methyl-sulphoxide or water;
(6) flow process VI: the preparation of compound 52-58
R in compound 52-58 is selected from the one in following group:
In the presence of a base, the intermediate II-1e prepared in flow process II in-20 DEG C ~ 100 DEG C (or under reflux temperature) with containing the halides of above R group or sulphonate generation substitution reaction 1 ~ 48 hour, generates compound 52-58 in a solvent respectively;
Wherein, alkali be selected from mineral alkali, organic bases one or more, described mineral alkali comprises: sodium carbonate, salt of wormwood, cesium carbonate, sodium hydroxide, potassium hydroxide or potassiumphosphate, organic bases comprises: 1,8-diazacyclo [5,4,0] hendecene-7, triethylamine, diisopropyl ethyl amine or N-methylmorpholine;
Solvent selected from acetone, tetrahydrofuran (THF), acetonitrile, ethanol, methyl alcohol, Virahol, Isosorbide-5-Nitrae-dioxane, dimethyl formamide, N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone, methyl-sulphoxide or water;
(7) flow process VII: the preparation of compound 59-61
R in compound 59-61 is selected from the one in following group:
In the presence of an organic base, the intermediate II-1n prepared in flow process II in-20 DEG C ~ 40 DEG C and acyl chlorides generation linked reaction 0.5 ~ 24 hour containing R group, generates compound 59-61 respectively in non-protonic solvent;
Wherein, the acyl chlorides containing R group is
organic bases is selected from 1,8-diazacyclo [5,4,0] hendecene-7, pyridine, triethylamine, diisopropyl ethyl amine or N-methylmorpholine; Non-protonic solvent is selected from methylene dichloride, tetrahydrofuran (THF), toluene, glycol dimethyl ether, ether or methyl tertiary butyl ether;
(8) flow process VIII: the preparation of compound 62
(VIII-1) in a solvent, at 20 ~ 150 DEG C, under rare gas element and alkali, with palladium catalyst catalytic cpd I-3a and tert-butyl 4-(5-bromo thiazole-2-base) homopiperazine-1-carboxylicesters, through linked reaction 1 ~ 48 hour, obtain intermediate III-1;
Wherein, solvent is selected from water, Isosorbide-5-Nitrae-dioxane, DMF, N,N-dimethylacetamide, methyl-sulphoxide, acetonitrile, water-toluene, benzene, dimethylbenzene, tetrahydrofuran (THF) or glycol dimethyl ether; Alkali is selected from salt of wormwood, saleratus, sodium carbonate, sodium bicarbonate, Tripotassium phosphate, cesium carbonate, cesium fluoride, sodium hydroxide or potassium hydroxide; Palladium catalyst is selected from tetrakis triphenylphosphine palladium, palladium, two (dibenzalacetone) palladium, [two (diphenylphosphine) ferrocene of 1,1'-] palladium chloride, two (triphenylphosphine) palladium chlorides or two (cyano group benzene) palladium chloride;
(VIII-2) in 0 ~ 50 DEG C and organic solvent, intermediate III-1 and acid-respons 1 ~ 24 hour, obtain intermediate III-2;
Wherein, organic solvent is selected from methylene dichloride, chloroform, 1,2-ethylene dichloride, ethyl acetate, tetrahydrofuran (THF), ether, methyl tert-butyl ether, methyl alcohol or ethanol; Acid is selected from hydrochloric acid, hydrogen chloride methanol solution, sulfuric acid, trifluoroacetic acid, methanesulfonic or tosic acid;
(VIII-3) in the presence of a base, intermediate III-2, in a solvent under-20 DEG C ~ 100 DEG C or reflux temperature, with 2-chloro-N-methylacetamide generation substitution reaction 1 ~ 48 hour, generates compound 62;
Wherein, alkali be selected from mineral alkali, organic bases one or more, described mineral alkali comprises: sodium carbonate, salt of wormwood, cesium carbonate, sodium hydroxide, potassium hydroxide or potassiumphosphate, organic bases comprises: 1,8-diazacyclo [5,4,0] hendecene-7, triethylamine, diisopropyl ethyl amine or N-methylmorpholine;
Solvent selected from acetone, tetrahydrofuran (THF), acetonitrile, ethanol, methyl alcohol, Virahol, Isosorbide-5-Nitrae-dioxane, dimethyl formamide, N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone, methyl-sulphoxide or water;
(9) flow process IX: the preparation of compound 63-71
(IX-1) in suitable solvent, at 20 ~ 150 DEG C, under rare gas element and alkali, with palladium catalyst catalytic cpd I-3a and tertiary butyl halo quinary heteroaryl piperazine-1-carboxylicesters, through linked reaction 1 ~ 48 hour, intermediate compound IV-1a-IV-1i is obtained;
Wherein, solvent is selected from water, Isosorbide-5-Nitrae-dioxane, DMF, N,N-dimethylacetamide, methyl-sulphoxide, acetonitrile, water-toluene, benzene, dimethylbenzene, tetrahydrofuran (THF) or glycol dimethyl ether;
Alkali is selected from salt of wormwood, saleratus, sodium carbonate, sodium bicarbonate, Tripotassium phosphate, cesium carbonate, cesium fluoride, sodium hydroxide or potassium hydroxide;
Palladium catalyst is selected from tetrakis triphenylphosphine palladium, palladium, two (dibenzalacetone) palladium, [two (diphenylphosphine) ferrocene of 1,1'-] palladium chloride, two (triphenylphosphine) palladium chlorides or two (cyano group benzene) palladium chloride;
(IX-2) 0 ~ 50 DEG C, in organic solvent, intermediate compound IV-1a-IV-1i and acid-respons 1-24h, obtains intermediate compound IV-2a-IV-2i;
Wherein, organic solvent is selected from methylene dichloride, chloroform, 1,2-ethylene dichloride, ethyl acetate, tetrahydrofuran (THF), ether, methyl tert-butyl ether, methyl alcohol or ethanol;
Hydrochloric acid, hydrogen chloride methanol solution, sulfuric acid, trifluoroacetic acid, methanesulfonic or tosic acid are selected in acid;
(IX-3) in the presence of base, intermediate compound IV-2a-IV-2i, in a solvent under-20 DEG C ~ 100 DEG C or reflux temperature, with 2-chloro-N-methylacetamide generation substitution reaction 1 ~ 48 hour, generates compound 63-71 respectively;
Wherein, alkali be selected from mineral alkali, organic bases one or more, described mineral alkali comprises: sodium carbonate, salt of wormwood, cesium carbonate, sodium hydroxide, potassium hydroxide or potassiumphosphate, organic bases comprises: 1,8-diazacyclo [5,4,0] hendecene-7, triethylamine, diisopropyl ethyl amine or N-methylmorpholine;
Solvent selected from acetone, tetrahydrofuran (THF), acetonitrile, ethanol, methyl alcohol, Virahol, Isosorbide-5-Nitrae-dioxane, dimethyl formamide, N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone, methyl-sulphoxide or water;
(10) flow process X: the preparation of compound 72-76
In a solvent, compound 13 respectively under-20 DEG C ~ 100 DEG C condition reacts 1 ~ 48 hour with methylsulfonic acid, compound 55 with tosic acid with hydrochloric acid, compound 29 with fumaric acid, compound 21 with methylsulfonic acid, compound 14, direct precipitation solid or leave standstill and separate out solid or concentrated recrystallization, obtains compound 72 ~ 76;
Wherein, solvent selected from acetone, tetrahydrofuran (THF), acetonitrile, ethanol, methyl alcohol, Virahol, methylene dichloride, Isosorbide-5-Nitrae-dioxane, dimethyl formamide, N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone, methyl-sulphoxide or water.
5. method as claimed in claim 4, is characterized in that: in described (I-1), and Compound I-1 is 1:0.8 ~ 1:1.2 with the mol ratio of amine; Reaction conditions is take Virahol as polar solvent, under neutral or basic conditions, in 70 ~ 90 DEG C of reactions 1 ~ 5 hour;
(I-2), in, intermediate compound I-2a-I-2u is 1:1 ~ 1:2 with the mol ratio of duplex pinacol borate; Palladium catalyst consumption is 1% ~ 10% of intermediate compound I-2a-I-2u molar weight, and alkali consumption is 1 ~ 5 equivalent; The condition of reaction is:, react 3 ~ 24 hours under 100 DEG C of conditions using potassium acetate as alkali, using methyl-sulphoxide as polar aprotic solvent as catalyzer with [two (diphenylphosphine) ferrocene of 1,1'-] palladium chloride;
(I-3), in, intermediate compound I-3a-I-3u is 1:1 ~ 2:1 with the mol ratio of tertiary butyl 4-(5-bromo thiazole-2-base) piperazine-1-carboxylicesters; Palladium catalyst consumption is 1% ~ 10% of intermediate compound I-3a-I-3u molar weight; Alkali consumption is 1 ~ 5 equivalent; Reaction conditions is: with volume ratio be the mixed solution of the Isosorbide-5-Nitrae-dioxane of 1:1 ~ 10:1 and water as solvent, salt of wormwood was alkali, and tetrakis triphenylphosphine palladium is catalyzer, 80 DEG C of reactions 3 ~ 24 hours;
In flow process II, intermediate compound I-4a-I-4u is 1:1 ~ 1:20 with the mol ratio of acid; Reaction conditions was: be solvent with methyl alcohol, adds 1 ~ 8M hydrogen chloride methanol solution, 20 DEG C of reactions 1 ~ 5 hour;
In flow process III, halides containing the R group in above-claimed cpd 2-28 or sulphonate are respectively bromoethanol, methyl iodide, iodoethane, 2-N-PROPYLE BROMIDE, 2, 2-dimethyl N-PROPYLE BROMIDE, Cyclopropyl Bromide, 2-fluorine cyclopentyl methanesulfonates, 2-fluoro ethyl p-toluenesulfonic esters, 2, 2-bis-fluoro ethyl p-toluenesulfonic esters, 2, 2, 2-trifluoro iodoethane, 2-methoxy ethyl p-toluenesulfonic esters, 2-bromopropionitrile, bromoacetonitrile, 1-bromo-2-methylsulfonyl ethane, 1-bromo-2-first sulfoxide group ethane, 2-bromotrifluoromethane-1-dimethyl sulfide, 2-bromo-N-methyl ethyl-amine hydrobromate, the bromo-N of 2-, N-dimethyl amine hydrobromate, 2-chlor(o)acetamide, N-methyl-2-chlor(o)acetamide, the chloro-N of 2-, N-dimethylethyl amine, 2-chloro-1-morpholine ethyl ketone, N-ethanoyl-2-chlor(o)acetamide, the chloro-N-methylacetamide of N-ethanoyl-2-, 1-(2-chloroethyl)-piperidines-2-ketone, N-(2-chlorine 2-ethyl) Toluidrin or 2-chloro-N-methyl ethyl sulfonamide,
In flow process III, compound 1: the halides containing the R group in compound 2-28 or the mol ratio of sulphonate are 1:1 ~ 1:3, alkali consumption is 3 ~ 8 equivalents; Reaction conditions is: take acetonitrile as solvent, and salt of wormwood is alkali, reacts 3 ~ 24 hours under 80 DEG C of conditions;
In flow process IV, intermediate II-1a-II-1t is preferably 1:1 ~ 1:4 with the mol ratio of the chloro-N-methylacetamide of 2-, and alkali consumption is preferably 4 ~ 8 equivalents; Reaction conditions is: take acetonitrile as solvent, and salt of wormwood is alkali, reacts 3 ~ 24 hours under 80 DEG C of conditions;
In flow process V, intermediate II-1a-II-1t is 1:1 ~ 1:4 with the mol ratio of 2-fluoro ethyl-4-methyl p-toluenesulfonic esters, and alkali consumption is 4 ~ 8 equivalents; Reaction conditions is: take acetonitrile as solvent, and salt of wormwood is alkali, reacts 3 ~ 24 hours under 80 DEG C of conditions;
In flow process VI, the halides containing above R group or sulphonate are N-methyl-2-chlor(o)acetamide, 2-fluoro ethyl p-toluenesulfonic esters, 2-bromopropionitrile, bromoacetonitrile, 2-chlor(o)acetamide, N-methyl-3-chlorine propionic acid amide or allyl bromide 98;
In flow process VI, intermediate II-1e be 1:1 ~ 1:4 containing the halides of above R group or the mol ratio of sulphonate, alkali consumption is 3 ~ 8 equivalents; Reaction conditions is: take acetonitrile as solvent, and salt of wormwood is alkali, reacts 3 ~ 24 hours under 80 DEG C of conditions;
In flow process VII, intermediate II-1n is 1:1 ~ 1:4 with the mol ratio of the acyl chlorides containing R group, and alkali consumption is 4 ~ 8 equivalents; Reaction conditions is: take methylene dichloride as solvent, and triethylamine is alkali, reacts 1 ~ 5 hour under 0 DEG C of condition;
In (VIII-1) of flow process VIII, Compound I-3a is 1:1 ~ 1:2 with the mol ratio of tert-butyl 4-(5-bromo thiazole-2-base) homopiperazine-1-carboxylicesters, and palladium catalyst consumption is 1% ~ 10% of Compound I-3a molar weight; Alkali consumption is 1 ~ 5 equivalent; Reaction conditions was: using the mixed solution of the Isosorbide-5-Nitrae-dioxane of volume ratio 1:1 ~ 10:1 and water as solvent, salt of wormwood is alkali, and tetrakis triphenylphosphine palladium is catalyzer, 80 DEG C of reactions 3 ~ 24 hours;
In (VIII-2) of flow process VIII, intermediate III-1 is 1:1 ~ 1:20 with the mol ratio of acid; Reaction conditions was: be solvent with methyl alcohol, adds 1 ~ 8M hydrogen chloride methanol solution, 20 DEG C of reactions 1 ~ 5 hour;
In (VIII-3) of flow process VIII, intermediate III-2 is 1:1 ~ 1:5 with the mol ratio of the chloro-N-methylacetamide of 2-, and alkali consumption is 3 ~ 8 equivalents; Reaction conditions is: take acetonitrile as solvent, and salt of wormwood is alkali, reacts 3 ~ 24 hours under 80 DEG C of conditions;
In (IX-1) of flow process IX, Compound I-3a is 1:1 ~ 1:2 with the mol ratio of tertiary butyl halo quinary heteroaryl piperazine-1-carboxylicesters, and palladium catalyst consumption is 1% ~ 10% of I-3a molar weight, and alkali consumption is 1 ~ 5 equivalent; Reaction conditions was: using the mixed solution of the Isosorbide-5-Nitrae-dioxane of volume ratio 1:1 ~ 10:1 and water as solvent, salt of wormwood is alkali, and tetrakis triphenylphosphine palladium is catalyzer, 80 DEG C of reactions 3 ~ 24 hours;
In (IX-2) of flow process IX, intermediate compound IV-1a-IV-1i is 1:1 ~ 1:20 with the mol ratio of acid; Reaction part is: be solvent with methyl alcohol, add 1 ~ 8M hydrogen chloride methanol solution, reacts 1-5 hour at 20 DEG C;
In (IX-3) of flow process IX, intermediate compound IV-2a-IV-2i is 1:1 ~ 1:5 with the mol ratio of the chloro-N-methylacetamide of 2-, and alkali consumption is 3 ~ 8 equivalents; Reaction conditions is: take acetonitrile as solvent, and salt of wormwood is alkali, reacts 3 ~ 24 hours under 80 DEG C of conditions;
In flow process X, compound 13 is 1:1 ~ 1:10 with methylsulfonic acid, compound 55 with the mol ratio of tosic acid with hydrochloric acid, compound 29 with fumaric acid, compound 21 with methylsulfonic acid, compound 14; Reaction conditions is: volume ratio be the mixed solution of the methylene dichloride of 5:1 ~ 1:5 and methyl alcohol as solvent, react 3 ~ 24 hours at ambient temperature.
6. an application for the quinazoline ditosylate salt tyrosine kinase inhibitor as described in any one in claims 1 to 3, is characterized in that: the application of described quinazoline ditosylate salt tyrosine kinase inhibitor in the medicine of preparation treatment tyrosine kinase related disorder.
7. apply as claimed in claim 6, it is characterized in that: the application of described quinazoline ditosylate salt tyrosine kinase inhibitor in the medicine of preparation treatment tumor disease.
8. a pharmaceutical composition, is characterized in that: the quinazoline ditosylate salt tyrosine kinase inhibitor as described in any one in claims 1 to 3 containing treatment significant quantity and pharmaceutically acceptable carrier.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110407865A (en) * | 2019-08-02 | 2019-11-05 | 山东师范大学 | Formula (I) compound and the preparation method and application thereof based on benzsulfamide structure |
| CN113851711A (en) * | 2020-06-28 | 2021-12-28 | 深圳市研一新材料有限责任公司 | Battery electrolyte and preparation method of benzene sulfonate compound in battery electrolyte |
| CN114380697A (en) * | 2021-11-30 | 2022-04-22 | 上海毕得医药科技股份有限公司 | Preparation process of N-methylethylamine hydrochloride |
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2014
- 2014-08-22 CN CN201410416034.9A patent/CN105461708A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110407865A (en) * | 2019-08-02 | 2019-11-05 | 山东师范大学 | Formula (I) compound and the preparation method and application thereof based on benzsulfamide structure |
| CN110407865B (en) * | 2019-08-02 | 2022-04-15 | 山东师范大学 | Benzene sulfonamide structure-based compound shown as formula (I) and preparation method and application thereof |
| CN113851711A (en) * | 2020-06-28 | 2021-12-28 | 深圳市研一新材料有限责任公司 | Battery electrolyte and preparation method of benzene sulfonate compound in battery electrolyte |
| CN113851711B (en) * | 2020-06-28 | 2023-06-30 | 深圳市研一新材料有限责任公司 | Battery electrolyte and preparation method of benzenesulfonate compound therein |
| CN114380697A (en) * | 2021-11-30 | 2022-04-22 | 上海毕得医药科技股份有限公司 | Preparation process of N-methylethylamine hydrochloride |
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