CN105294578A - Quinazoline derivative having targeted antitumor activity - Google Patents
Quinazoline derivative having targeted antitumor activity Download PDFInfo
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- CN105294578A CN105294578A CN201410266829.6A CN201410266829A CN105294578A CN 105294578 A CN105294578 A CN 105294578A CN 201410266829 A CN201410266829 A CN 201410266829A CN 105294578 A CN105294578 A CN 105294578A
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Abstract
The present invention relates to an oxoquinazoline derivative having targeted antitumor activity, and particularly relates to a compound shown in a formula I and pharmaceutically acceptable salt thereof, a solvate and a prodrug, wherein R4 is selected from hydrogen, halogen, -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -C1-6 alkyl-phenyl, NH(CH2)mN [(CH2)nCH3]2; the alkyl, alkenyl, alkynyl and phenyl can be optionally substituted by halogen, nitro, cyano, hydroxy, -C1-6 alkoxyl and phenyl; m is an arbitrary integer of 2-8, and n is an arbitrary integer of 0-6; R7 is selected from halogen, -C1-6 alkoxyl, -C1-6 aryl alkoxyl and -C1-6 substituted aryl alkoxyl. The formula is as shown in the description.
Description
Technical field
The present invention relates to the quinazoline derivant that a class has targeting anti-tumor activity, also relate to the preparation method of this type of quinazoline derivant, and they are preparing the application in anti-tumor drugs targeting.
Background technology
Known quinazoline mother nucleus structure is the important feature integral part of many antitumor drugs, as in the chemical structure of the line antitumor drug such as small molecule, anti-tumor targeted drug Gefitinib, Tarceva, lapatinibditosylate based on epidermal growth factor recipient tyrosine kinase all containing quinazoline mother nucleus structure (as figure below).
This kind of medicine is used for clinical antineoplastic treatment with the form of oral capsule at present, clinical confirmation its have wider antitumor spectra, single medicine uses close with Combination chemotherapy curative effect, especially for advanced breast cancer and nonsmall-cell lung cancer more remarkable, obviously can extend lifetime, improve the quality of living, and it is slight to have toxic side effects, the bone marrow depression of anticarcinogen as none and immunosuppressive action, the feature of easy administration.
In addition, quinazoline compounds self antitumorly also has obvious synergistic function to the chemotherapy of tumor animal simultaneously.Recent study also confirms: find in process of clinical application, and the patient's curative effect when accepting radiotherapy taking quinazoline ditosylate salt medicine is also more obvious, analyzes the effect that simultaneously may possess radiation sensitivity.Quinazoline compounds Anticancer Effect and Mechanism is as ATP competitive inhibitor, the phosphorylation of retardance Tyrosylprotein kinase, suppresses bcrOabl to express, thus stops the propagation of cell and the formation of tumour.
Quinazoline ditosylate salt antineoplastic target small-molecule drug is the new variety of going on the market after calendar year 2001, the expansion of its mechanism of action, Mutiple Targets and security are still among Clinical Exploration, many medicine new indications be approved for clinical after, promoted the growth of market sale, and untoward reaction expose the fluctuation also making result in market gradually.Domestic target small molecules new drug development is started late, the domestic treatment lung cancer small molecules targeted drug Conmana listing only having Zhejiang shellfish to reach medicine company development at present.
Still need at present to find novel there is targeting and the antineoplastic compound of Mutiple Targets for clinical application.
Summary of the invention
Still need at present to find the novel quinazoline compounds with anti-tumor activity for clinical application.The present invention finds to have the anti-tumor activity that the compound shown in general formula I has desirable.The present invention is based on this find and be accomplished.
First aspect present invention provides with compounds of Formula I:
And pharmacologically acceptable salts, solvate, prodrug, wherein
R
4be selected from hydrogen, halogen ,-C
1-6alkyl ,-C
2-6thiazolinyl ,-C
2-6alkynyl ,-C
1-6alkyl-phenyl, NH (CH2) mN [(CH
2) nCH
3]
2, wherein said alkyl, thiazolinyl, alkynyl and phenyl can optionally be replaced by halogen, nitro, cyano group, hydroxyl ,-C1-6 alkoxyl group, phenyl; Wherein m is the arbitrary integer in 2-8, and n is the arbitrary integer in 0-6;
R
7be selected from halogen ,-C
1-6alkoxyl group ,-C
1-6aralkoxy ,-C
1-6replace aralkoxy.
Compound according to a first aspect of the present invention, wherein R
4be selected from hydrogen ,-C
1-6alkyl ,-C
2-6thiazolinyl ,-C
1-6alkyl-phenyl, wherein said alkyl, thiazolinyl and phenyl can optionally by halogen, nitro, cyano group, hydroxyl ,-C
1-6alkoxyl group.
Compound according to a first aspect of the present invention, wherein R
4be selected from hydrogen ,-C
1-6alkyl ,-C
2-6thiazolinyl ,-C
1-6alkyl-phenyl ,-C
1-6aralkoxy ,-C
1-6replace aralkoxy.。
Compound according to a first aspect of the present invention, wherein R
4be selected from hydrogen, methoxyl group, oxyethyl group, propoxy-, isopropoxy, allyloxy, propenyloxy group, benzene propoxy-, n-butoxy, benzyloxy, 4-fluorine benzyloxy, 4-chlorine benzyloxy.
Compound according to a first aspect of the present invention, it is be selected from following compound:
Compound title
The chloro-7-hydroxyquinazoline of 4-
4-chloro-7-oxyethyl group quinazoline
4-chloro-7-n-butoxy quinazoline
The positive hexyloxy quinazoline of the chloro-7-of 4-
4-chloro-7-allyloxy quinazoline
4-chloro-7-isopropoxy quinazoline
4-chloro-7-isobutoxy quinazoline
4-chloro-7-benzyloxy quinazoline
The chloro-7-of 4-(4-fluorine benzyloxy) quinazoline
The chloro-7-of 4-(3-benzene oxyethyl group) quinazoline
The chloro-7-of 4-(3-benzene propoxy-) quinazoline
N
1-(7-oxyethyl group quinazoline-4-base)-N
2, N
2-diethyl ethane-1,2-diamines
N
1, N
1-diethyl-N
2-(7-hexyloxy quinazoline-4-base) ethane-1,2-diamines
N
1-(7-allyloxy quinazoline-4-base)-N
2, N
2-diethyl ethane-1,2-diamines
N
1, N
1-diethyl-N
2-(7-isopropoxy quinazoline-4-base) ethane-1,2-diamines
N
1-(7-benzyloxy quinazoline-4-base)-N
2, N
2-diethyl ethane-1,2-diamines
N
1, N
1-diethyl-N
2-(7-(4-fluorine benzyloxy) quinazoline-4-base) ethane-1,2-diamines
N
1-(7-oxyethyl group quinazoline-4-base)-N
2, N
2-diethyl propane-1,2-diamines
N
1-(7-allyloxy quinazoline-4-base)-N
2, N
2-diethyl propane-1,2-diamines
N
1, N
1-diethyl-N
2-(7-(4-fluorine benzyloxy) quinazoline-4-base) propane-1,2-diamines
And their pharmacologically acceptable salts, solvate, prodrug.
Second aspect present invention relate to formula I, its tautomer, raceme or optical isomer described in any one of first aspect present invention, its pharmaceutical salts or solvate preparation can be used for preventing or treatment tumour medicine in purposes.
Third aspect present invention provides a kind of pharmaceutical composition, formula I wherein containing at least one first aspect present invention and hereinafter described formula II, formula III compound or its pharmacologically acceptable salts, solvate, prodrug, and optional pharmaceutical carrier or vehicle.According in this respect, the invention still further relates to described pharmaceutical composition as preventing or treating the application in the medicine of the diseases such as tumour.
Fourth aspect present invention provides the method preventing and/or treating tumour, and the method comprises formula I and hereinafter described formula II, formula III compound or its pharmacologically acceptable salts, solvate, prodrug to there being the experimenter of these needs to prevent and/or treat the first aspect of significant quantity.
The feature that any one of either side of the present invention or this either side has is equally applicable to any one of other either side or this other either side, as long as they can not be conflicting, certainly at where applicable each other, necessary words can be done suitably to modify to individual features.In the present invention, such as, when mentioning " any one of first aspect present invention ", the arbitrary sub-aspect that " any one " refers to first aspect present invention is somebody's turn to do; When other side is mentioned in a similar manner, also there is identical meanings.
Be further described with feature to various aspects of the present invention below.
All documents that the present invention quotes from, their full content is incorporated to herein by reference, and if the implication expressed by these documents and the present invention inconsistent time, be as the criterion with statement of the present invention.In addition, the various term that the present invention uses and phrase have and well known to a person skilled in the art general sense, nonetheless, the present invention still wishes to be described in more detail at this these terms and phrase and to explain, the term mentioned and phrase, if any inconsistent with common art-recognized meanings, are as the criterion with the implication that the present invention states.
Hereafter illustrate for group definition that formula I is done, composition, usage description of use etc., if can not produce contradiction, then these descriptive explanations go for formula II compound and formula III compound equally.
The term " halogen " adopted in the present invention, " halogen ", " Hal " or " halo " refer to fluorine, chlorine, bromine and iodine.
The term " alkyl " adopted in the present invention, " alkenyl " and " alkynyl " have general sense well known in the art, they are hydrocarbyl groups of straight or branched, such as but not limited to methyl, ethyl, propyl group, sec.-propyl, normal-butyl, sec-butyl, the tertiary butyl, allyl group, propenyl, proyl etc., and described " alkyl ", " alkenyl " and " alkynyl " can be referred to as " alkyl " or " chain alkylene ".In the present invention's preferred embodiment, described " alkyl " refers to that alkyl comprises alkyl group and cycloalkyl, particularly alkyl group such as C1-C6 alkyl.
As used herein, term " aryl " is such as but not limited to phenyl, naphthyl.
As used herein, phrase " substituted or unsubstituted C1-C6 alkyl " refers to the substituted or unsubstituted alkyl group having and specify number carbon atom, and the example includes but not limited to: methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl, amyl group, neo-pentyl, hexyl.
In the present invention, group " C
1-C
6alkyl " and " C
1-6alkyl " the two has identical meanings, all represents the straight or branched alkyl with 1-6 carbon atom.Other situation also can do similar understanding.
In the method for synthetic compound of formula i of the present invention, the various starting material reacting used are that those skilled in the art can prepare according to existing knowledge, or can be obtained by the known method of document, or can be buied by business.Intermediate used in above reaction scheme, starting material, reagent, reaction conditions etc. all can have knowledge according to those skilled in the art can make appropriate change.Or those skilled in the art also method can synthesize other not specifically enumerated formula I of the present invention according to a second aspect of the present invention.
According to the present invention, the salt that the pharmaceutical salts of formula I can be acid salt or be formed with alkali.Acid salt citing says it can is that inorganic acid salt is such as but not limited to hydrochloride, vitriol, phosphoric acid salt, hydrobromate; Or organic acid salt is such as but not limited to acetate, oxalate, lemon salt, gluconate, succinate, tartrate, tosilate, mesylate, benzoate, lactic acid salt and maleate; Formula I and alkali formed salt illustrate say can be an alkali metal salt such as but be not limited to lithium, sodium and sylvite; Alkaline earth salt such as but be not limited to calcium and magnesium salts; Organic alkali salt is such as but not limited to diethanolamine salt and choline salt etc.; Or chirality alkali salt is such as but not limited to alkyl phenyl amine salt.
The solvate of compound of the present invention can be that hydrate or the recrystallisation solvent comprising other are as alcohols such as ethanol.
According to the present invention, can there is cis/trans isomer in formula I, the present invention relates to the mixture of cis form and trans forms and these forms.If needed, the preparation of single stereoisomers can split mixture according to conventional methods, or by such as Stereo-selective synthesis preparation.If there is motor-driven hydrogen atom, the present invention also relates to the tautomeric form of formula I.
Therefore the present invention also relates to containing at least one formula I as the effective dose of active ingredient, or the pharmaceutical composition of its pharmaceutical salts and/or its steric isomer and customary pharmaceutical excipients or assistant agent.Usual pharmaceutical composition of the present invention contains formula I and/or its physiologically acceptable salt of 0.1-90 % by weight.Pharmaceutical composition can be prepared according to methods known in the art.During for this object, if needed, formula I and/or steric isomer and one or more solids or liquid pharmaceutical excipients and/or assistant agent can be combined, make the suitable administration form or dosage form that can be used as people.
Formula I of the present invention or the pharmaceutical composition containing it can administrations in a unit, and route of administration can be enteron aisle or non-bowel, as oral, muscle, subcutaneous, nasal cavity, oral mucosa, skin, peritonaeum or rectum etc.Form of administration is tablet, capsule, dripping pill, aerosol, pill, pulvis, solution, suspensoid, emulsion, granule, liposome, transdermal agent, buccal tablet, suppository, lyophilized injectable powder etc. such as.Can be ordinary preparation, sustained release preparation, controlled release preparation and various particulate delivery system.In order to unit dosage forms for administration is made tablet, various carrier well known in the art can be widely used.Example about carrier is, such as thinner and absorption agent, as starch, dextrin, calcium sulfate, lactose, N.F,USP MANNITOL, sucrose, sodium-chlor, glucose, urea, calcium carbonate, white bole, Microcrystalline Cellulose, pure aluminium silicate etc.; Wetting agent and tackiness agent, as water, glycerine, polyoxyethylene glycol, ethanol, propyl alcohol, starch slurry, dextrin, syrup, honey, glucose solution, mucialga of arabic gummy, gelatine size, Xylo-Mucine, lac, methylcellulose gum, potassiumphosphate, polyvinylpyrrolidone etc.; Disintegrating agent, such as dry starch, alginates, agar powder, laminaran, sodium bicarbonate and Citric Acid, calcium carbonate, polyoxyethylene sorbitol fatty acid ester, sodium laurylsulfonate, methylcellulose gum, ethyl cellulose etc.; Disintegration inhibitor, such as sucrose, Tristearoylglycerol, theobroma oil, hydrogenation wet goods; Absorption enhancer, such as quaternary ammonium salt, sodium lauryl sulphate etc.; Lubricant, such as talcum powder, silicon-dioxide, W-Gum, stearate, boric acid, whiteruss, polyoxyethylene glycol etc.Tablet can also be made coating tablet further, such as sugar coated tablet, thin membrane coated tablet, ECT, or double-layer tablets and multilayer tablet.In order to administration unit is made pill, the known various carrier in ability city can be widely used.Example about carrier is, such as thinner and absorption agent, as glucose, lactose, starch, theobroma oil, hydrogenated vegetable oil, polyvinylpyrrolidone, Gelucire, kaolin, talcum powder etc.; Tackiness agent is as gum arabic, yellow work glue, gelatin, ethanol, honey, liquid sugar, rice paste or batter etc.; Disintegrating agent, as agar powder, dry starch, alginates, sodium laurylsulfonate, methylcellulose gum, ethyl cellulose etc.In order to administration unit is made suppository, various carrier well known in the art can be widely used.Example about carrier is, the ester of such as polyoxyethylene glycol, Yelkin TTS, theobroma oil, higher alcohols, higher alcohols, bright limb, semi-synthetic glyceryl ester etc.In order to administration unit is made capsule, effective constituent formula I or its steric isomer are mixed with above-mentioned various carriers, and the mixture obtained thus is placed in hard obviously capsule or soft capsule.Also effective constituent formula I or its steric isomer can be made microcapsule, be suspended in aqueous medium and form suspensoid, also can load in hard capsule or make injection application.In order to administration unit is made injection preparation, as solution, emulsion, lyophilized injectable powder and suspensoid, all thinners that this area is conventional can be used, such as, the isooctadecanol of water, ethanol, polyoxyethylene glycol, 1,3-PD, ethoxylation, polyoxygenated isooctadecanol, Polyoxyethylene Sorbitol Fatty Acid Esters etc.In addition, in order to prepare isotonic injection liquid, appropriate sodium-chlor, glucose or glycerine can be added in injection preparation, in addition, conventional solubility promoter, buffer reagent, pH adjusting agent etc. can also be added.
In addition, as needs, also tinting material, sanitas, spices, correctives, sweeting agent or other material can be added in pharmaceutical preparation.
Formula I, or the dosage of its isomer depends on many factors, such as, to prevent or the character of disease therapy and severity, the sex of patient or animal, age, body weight and individual reaction, particular compound used, route of administration and administration number of times etc.Above-mentioned dosage can single dose form or be divided into several, such as two, three or four dosage forms for administration.
Term used herein " composition " means to comprise the product of each appointment composition comprising specified amount, and any product directly or indirectly produced from the combination of each appointment composition of specified amount.
The active compound amount of gained the actual dose level of each activeconstituents in pharmaceutical composition of the present invention can be changed, so that effectively can obtain required therapeutic response for concrete patient, composition and administering mode.Dosage level must according to the activity of particular compound, route of administration, treat the severity of the patient's condition and the patient's condition of patient to be treated and medical history and select.But the way of this area is, the dosage of compound, from lower than for obtaining level that required result for the treatment of requires, increases dosage, gradually until obtain required effect.
When for above-mentioned treat and/or prevent or other treatment and/or prevention time, a kind of the compounds of this invention treating and/or preventing significant quantity can be applied in a pure form, or with the acceptable ester of pharmacy or prodrug forms (when there are these forms) application.Or described compound can accept the pharmaceutical composition administration of vehicle containing this object compound and one or more medicines.The compounds of this invention that word " prevents and/or treats significant quantity " refers to the compound of the q.s of the reasonable effect/Hazard ratio treatment obstacle being applicable to any medical prophylaxis and/or treatment.But it should be understood that total daily dosage portion of the compounds of this invention and composition must be maked decision within the scope of reliable medical judgment by attending physician.For any concrete patient, concrete treatment effective dose level must be determined according to many factors, and described factor comprises treated obstacle and the severity of this obstacle; The activity of the particular compound adopted; The concrete composition adopted; Age of patient, body weight, general health situation, sex and diet; The administration time of the particular compound adopted, route of administration and excretion rate; The treatment time length; The medicine combinationally using with adopted particular compound or use simultaneously; And the known similar factor of medical field.Such as, the way of this area is, the dosage of compound, from lower than for obtaining level that required result for the treatment of requires, increases dosage, gradually until obtain required effect.In general, formula I is used for the dosage of Mammals particularly people can between 0.001 ~ 1000mg/kg body weight/day, such as, between 0.01 ~ 100mg/kg body weight/day, such as, between 0.01 ~ 10mg/kg body weight/day.
Various disease of the present invention or illness effectively can be prevented and/or treated according to compound of the present invention.
Embodiment
The present invention is further illustrated by the following example, but these examples of implementation do not mean that any limitation of the invention, and the intermediate do not explained in the present invention or raw material are all bought by commercial sources.
Following synthetic route 1 depicts the general method of some intermediates and the compounds more of the present invention preparing the compounds of this invention.
synthetic route 1:
The General Synthetic Procedures of compound 8a-b: by chloro-for 7-4-(1H)-oxoquinazolin 6b or 7-methoxyl group-4-(1H)-oxoquinazolin 6d (10mmol) adds in round-bottomed flask, adds POCl subsequently
3(20ml), mixed solution reflux 1h.Cooling reaction solution, adds POCl
3(10ml), back flow reaction 1h is continued.React complete, cooling reaction solution is to room temperature.Reaction solution is slowly poured into (very exothermic) in frozen water, sodium hydroxide solution regulates pH to 9.0, separates out white fluffy solid, filters, washing, and dry (easily distilling), obtains pale solid.
embodiment 1: preparation 4,7-dichloroquinazoline (compound 8a)
With chloro-4 (the 1H)-oxoquinazolin 6b (10mmol) of 7-for raw material, obtain white solid (1.68g, 85%).ESI-MSm/z197[M]
+.
1HNMR(300MHz，CDCl
3)：δ8.74(1H，d，J＝4.8Hz)，8.09-8.15(2H，m)，7.54-7.58(1H，m)，7.45(1H，d，J＝4.8Hz).
13CNMR(75MHz，CDCl
3)δ151.0，149.4，142.8，136.7，128.8(2C)，125.7，125.1，121.6.
embodiment 2: the preparation chloro-7-methoxyquinazoline hydrochloride of 4-(compound 8b)
With 7-methoxyl group-4 (1H)-oxoquinazolin 6d (10mmol) for raw material, obtain white solid (1.7g, 88%).ESI-MSm/z194[M+H]
+.
1HNMR(300MHz，CDCl
3)：δ8.67(1H，d，J＝4.8Hz)，8.09(1H，d，J＝9.0Hz)，7.42(1H，d，J＝2.4Hz)，7.33(1H，d，J＝4.8Hz)，7.28(1H，dd，J＝9.0Hz，J＝2.4Hz)，3.97(3H，s).
13CNMR(75MHz，CDCl
3)δ161.3，151.0，150.2，142.4，125.3，121.7，120.8，119.3，107.7，55.9.
embodiment 3: preparation 7-chloro-4-methoxy quinazoline (compound 9a)
Anhydrous methanol (50ml) is added in 100ml round-bottomed flask, adds sodium Metal 99.5 (1.05g, 50mmol) subsequently, after sodium Metal 99.5 disappears, add the chloro-quinazoline of 4,7-mono-(10mmol), reflux 2h.React complete, cooling reaction solution is to room temperature, and decompression steams residue methyl alcohol, obtains white solid, adds 50ml water in bottle, filters, and washing is dry, obtains pale solid (1.66g, 84%).ESI-MSm/z194[M+H]
+.
1HNMR(300MHz，CDCl
3)：δ8.71(1H，d，J＝5.1Hz)，8.09(1H，d，J＝8.7Hz)，7.99(1H，d，J＝2.1Hz)，7.40(1H，dd，J＝8.7Hz，J＝2.1Hz)，6.70(1H，d，J＝5.1Hz)，4.03(3H，s).
13CNMR(75MHz，CDCl
3)δ162.4，152.7，149.7，135.8，128.0，126.7，123.6，120.0，100.6，56.1.
embodiment 4: preparation 7-chloro-4-oxyethyl group quinazoline (compound 9b)
Dehydrated alcohol (50ml) is added in 100ml round-bottomed flask, adds sodium Metal 99.5 (1.05g, 50mmol) subsequently, after sodium Metal 99.5 disappears, add 4,7-dichloro-quinazoline (10mmol), reflux 2h.React complete, cooling reaction solution is to room temperature, and decompression steams residue ethanol, obtains white solid, adds 50ml water in bottle, filters, and washing is dry, obtains pale solid (1.8g, 87%).ESI-MSm/z208[M+H]
+.
1HNMR(300MHz，CDCl
3)：δ8.68(1H，d，J＝5.1Hz)，8.11(1H，d，J＝9.0Hz)，7.98(1H，d，J＝2.1Hz)，7.39(1H，dd，J＝8.7Hz，J＝2.1Hz)，6.67(1H，d，J＝5.1Hz)，4.21(2H，q，J＝6.9Hz)，1.54(3H，t，J＝7.2Hz).
13CNMR(75MHz，CDCl
3)δ161.7，152.6，149.8，135.7，128.0，126.5，123.7，120.0，101.1，64.6，14.8.
embodiment 5: preparation 7-chloro-4-isopropoxy quinazoline (compound 9c)
Virahol (50ml) is added in 100ml round-bottomed flask, adds sodium Metal 99.5 (1.05g, 50mmol) subsequently, after sodium Metal 99.5 disappears, add 4,7-dichloro-quinazoline (10mmol), reflux 8h.TLC tracing detection, reacts complete, and cooling reaction solution is to room temperature, decompression steams residue Virahol, obtains yellow oil, adds water (50ml) in residue, dichloromethane extraction three times, washing, saturated salt is washed, anhydrous sodium sulfate drying, is evaporated to dry, silica gel column chromatography, methylene chloride/methanol=200: 1 wash-out, be evaporated to dry, obtain yellow oil (1.51g, 68%).ESI-MSm/z222[M+H]
+.
1HNMR(300MHz，CDCl
3)：δ8.68(1H，d，J＝5.1Hz)，8.12(1H，d，J＝8.7Hz)，7.98(1H，d，J＝2.1Hz)，7.41(1H，dd，J＝8.7Hz，J＝2.1Hz)，6.69(1H，d，J＝5.1Hz)，4.78-4.86(1H，m)，1.50(3H，s)，1.48(3H，s).
13CNMR(75MHz，CDCl
3)δ160.8，152.5，150.1，135.7，127.9，126.4，123.9，120.7，101.8，71.3，22.1.
embodiment 6: preparation 4,7-dimethoxyquinazoline (compound 9d)
Methyl alcohol (50ml) is added in 100ml round-bottomed flask, adds sodium Metal 99.5 (1.05g, 50mmol) subsequently, after sodium Metal 99.5 disappears, add the chloro-7-methoxyquinazoline hydrochloride (10mmol) of 4-, reflux 8h.TLC tracing detection, reacts complete, and cooling reaction solution is to room temperature, decompression steams residue methyl alcohol, obtains yellow oil, adds water (50ml) in residue, dichloromethane extraction three times, washing, saturated salt is washed, anhydrous sodium sulfate drying, is evaporated to dry, silica gel column chromatography, sherwood oil/acetone=4: 1 wash-out, be evaporated to dry, obtain white solid (1.66g, 88%).ESI-MSm/z190[M+H]
+.
1HNMR(300MHz，CDCl
3)：δ8.63(1H，d，J＝5.1Hz)，8.04(1H，d，J＝9.0Hz)，7.34(1H，d，J＝2.4Hz)，7.12(1H，dd，J＝9.0Hz，J＝2.4Hz)，6.60(1H，d，J＝5.1Hz)，4.00(3H，s)，3.93(3H，s).
13CNMR(75MHz，CDCl
3)δ162.3，160.9，151.8，151.1，123.1，118.3，116.1，107.3，98.9，55.7，55.6.
embodiment 7: preparation 4-oxyethyl group-7-methoxyquinazoline hydrochloride (compound 9e)
Dehydrated alcohol (50ml) is added in 100ml round-bottomed flask, adds sodium Metal 99.5 (1.05g, 50mmol) subsequently, after sodium Metal 99.5 disappears, add the chloro-7-methoxyquinazoline hydrochloride (10mmol) of 4-, reflux 2h.React complete, cooling reaction solution is to room temperature, and decompression steams residue ethanol, in residue, add 50ml water, extraction into ethyl acetate (100ml × 3), merge organic phase, washing, saturated salt is washed, anhydrous sodium sulfate drying, filter, be evaporated to dry, obtain pale yellow oil, silica gel column chromatography, sherwood oil/acetone=4: 1 wash-out, are evaporated to dry, obtain white solid (1.58g, 78%).ESI-MSm/z204[M+H]
+.
1HNMR(300MHz，CDCl
3)：δ8.60(1H，d，J＝5.4Hz)，8.06(1H，d，J＝9.3Hz)，7.33(1H，d，J＝2.4Hz)，7.11(1H，dd，J＝9.3Hz，J＝2.4Hz)，6.56(1H，d，J＝5.4Hz)，4.20(2H，q，J＝6.9Hz)，3.92(3H，s)，1.54(3H，t，J＝6.9Hz).
13CNMR(75MHz，CDCl
3)δ161.6，160.9，151.8，151.2，123.3，118.1，116.1，107.2，99.4，64.1，55.6，14.7.
Following synthetic route 2 depicts the general method of some intermediates and the compounds more of the present invention preparing the compounds of this invention.
synthetic route 2:
embodiment 8: the preparation chloro-7-hydroxyquinazoline of 4-(compound 22)
By chloro-for 4-7-methoxyquinazoline hydrochloride 8b (3.86g, 20mmol), 40%HBr (30mL) and acetic anhydride (20mL) are mixed and heated to 180-200 DEG C of successive reaction 50h.Solid precipitation again after cooling, add the dilution of 100mL water, regulate pH to 6.0, have a large amount of solid to separate out with NaOH, filter, washing, drying, obtains pale solid (3.53g, 98.6%).
embodiment 9: preparation 4-chloro-7-oxyethyl group quinazoline (compound 23a)
The chloro-7-hydroxyquinazoline of 4-(0.72g is added in the round-bottomed flask of 100ml, 4mmol), DMF (10ml) and 60%NaH (0.4g, 10mmol), stirring at room temperature 15min, add 1-monobromethane (20mmol) and continue reaction, TLC tracing detection, reaction 1h.React complete, be poured into water by reaction mixture, extraction into ethyl acetate, merge organic phase, washing, saturated common salt is washed, and anhydrous sodium sulfate drying, is evaporated to dry, column chromatography, obtains light yellow solid (0.56g, productive rate 67.2%).Mp70-71℃.MS(ESI)：m/z(M+H)
+207.8.
1HNMR(300MHz，CDCl
3)δ8.66(d，J＝4.7Hz，1H，ArH)，8.09(d，J＝9.2Hz，1H，ArH)，7.39(d，J＝1.8Hz，1H，ArH)，7.32(d，J＝4.7Hz，1H，ArH)，7.29-7.20(m，1H，ArH)，4.19(q，J＝6.9Hz，2H，CH
2)，1.50(t，J＝7.0Hz，3H，CH
3).
13CNMR(75MHz，CDCl
3)δ160.3，150.6，149.8，142.0，124.9，121.2，120.7，118.8，107.8，63.7，14.6.
embodiment 10: preparation 4-chloro-7-n-butoxy quinazoline (compound 23b)
The chloro-7-hydroxyquinazoline (0.89g, 5mmol) of 4-is added, acetone (40ml) and anhydrous K in the round-bottomed flask of 100ml
2cO
3(2.0g) stirring at room temperature refluxes 15 minutes, adds iodo and levy butane (20mmol) after something lost, reaction 24h.React complete, underpressure distillation removing acetone, adds 150mL water, extraction into ethyl acetate, merge organic phase, add concentrated hydrochloric acid acidifying, dehydrated alcohol band water, obtain yellow oil, acetone recrystallization, separates out white crystal, alkalization after filtering, obtain white solid (0.57g, productive rate 47.6%).Mp37-38℃.MS(ESI)：m/z(M+H)
+236.1.
1HNMR(300MHz，CDCl
3)δ8.65(d，J＝4.8Hz，1H，ArH)，8.08(d，J＝9.2Hz，1H，ArH)，7.39(d，J＝1.9Hz，1H，ArH)，7.31(d，J＝4.8Hz，1H，ArH)，7.29-7.23(m，1H，ArH)，4.12(t，J＝6.5Hz，2H，CH
2CH
2CH
2CH
3)，1.92-1.79(m，2H，CH
2CH
2CH
2CH
3)，1.62-1.47(m，2H，CH
2CH
2CH
2CH
3)，1.00(t，J＝7.3Hz，3H，CH
2CH
2CH
2CH
2).
13CNMR(75MHz，CDCl
3)δ160.5，150.7，149.8，142.0，124.9，121.2，120.8，118.8，108.0，68.0，31.0，19.2，13.8.
embodiment 11: the preparation just own chloroquinazoline of the chloro-7-of 4-(compound 23c)
The chloro-7-hydroxyquinazoline of 4-(0.36g is added in the round-bottomed flask of 100ml, 2mmol), DMF (10ml) and 60%NaH (0.2g, 5mmol), stirring at room temperature 10min, add isobutane bromide (3.5mmol) and continue reaction, TLC tracing detection, reaction 1.5h.React complete, be poured into water by reaction mixture, extraction into ethyl acetate, merge organic phase, washing, saturated common salt is washed, and anhydrous sodium sulfate drying, is evaporated to dry, column chromatography, obtains yellow oil (0.22g, productive rate 68.0%).Mpyellowoil.MS(ESI)：m/z(M+H)+263.9.
1HNMR(300MHz，CDCl
3)δ8.65(d，J＝4.8Hz，1H，ArH)，8.07(d，J＝9.2Hz，1H，ArH)，7.38(d，J＝2.4Hz，1H，ArH)，7.30(d，J＝4.8Hz，1H，ArH)，7.26(dd，J＝9.1，2.5Hz，1H，ArH)，4.11(t，J＝6.5Hz，2H，OCH
2(CH
2)
4CH
3)，1.94-1.79(m，1H，OCH
2CH
2(CH
2)
3CH
3)，1.49(dd，J＝14.4，7.2Hz，2H，O(CH
2)
2CH
2(CH
2)
2CH
3)，1.37(dt，J＝7.1，4.7Hz，4H，O(CH
2)
3CH
2CH
2CH
3)，0.91(t，J＝6.9Hz，3H，CH
3).
13CNMR(75MHz，CDCl
3)δ160.7，150.8，149.9，142.2，125.0，121.3，121.0，118.9，108.1，68.4，31.6，29.0，25.8，22.7，14.1.
embodiment 12: preparation 4-chloro-7-allyloxy quinazoline (compound 23d)
The chloro-7-hydroxyquinazoline of 4-(0.36g is added in the round-bottomed flask of 100ml, 2mmol), DMF (10ml) and 60%NaH (0.2g, 5mmol), stirring at room temperature 10min, add 1-bromine allyl alkane (3.5mmol) and continue reaction, TLC tracing detection, reaction 2h.React complete, be poured into water by reaction mixture, extraction into ethyl acetate, merge organic phase, washing, saturated common salt is washed, and anhydrous sodium sulfate drying, is evaporated to dry, column chromatography, obtains light yellow solid (0.37g, productive rate 78.4%).Mp36-37℃.MS(ESI)：m/z(M+H)
+219.8.
1HNMR(300MHz，CDCl
3)δ8.66(d，J＝4.6Hz，1H，ArH)，8.09(d，J＝9.1Hz，1H，ArH)，7.41(s，1H，ArH)，7.29(dd，J＝15.9，6.2Hz，2H，ArH)，6.10(ddt，J＝15.9，10.4，5.3Hz，1H，CH
2＝CH)，5.48(d，J＝17.2Hz，1H，CH
2＝CH)，5.34(d，J＝10.4Hz，1H，CH
2＝CH)，4.69(d，J＝4.8Hz，2H，OCH
2).
13CNMR(75MHz，CDCl
3)δ159.9，150.5，149.9，142.1，132.2，125.1，121.4，120.8，119.0，118.1，108.4，68.9.
embodiment 13: preparation 4-chloro-7-isopropoxy quinazoline (compound 23e)
The chloro-7-hydroxyquinazoline of 4-(0.36g is added in the round-bottomed flask of 100ml, 2mmol), DMF (10ml) and 60%NaH (0.2g, 5mmol), stirring at room temperature 10min, add 1-bromine isopropyl alkane (3.5mmol) and continue reaction, TLC tracing detection, reaction 24h.React complete, be poured into water by reaction mixture, extraction into ethyl acetate, merge organic phase, washing, saturated common salt is washed, and anhydrous sodium sulfate drying, is evaporated to dry, column chromatography, obtains light yellow solid (0.28g, productive rate 54.6%).Mp65-66℃.MS(ESI)：m/z(M+H)
+221.8.
1HNMR(300MHz，CDCl
3)δ8.65(d，J＝4.7Hz，1H，ArH)，8.08(d，J＝9.2Hz，1H，ArH)，7.39(s，1H，ArH)，7.30(d，J＝4.7Hz，1H，ArH)，7.27-7.20(m，1H，ArH)，4.82-4.67(m，1H，CH)，1.43(d，J＝6.0Hz，6H，CH
3).
13CNMR(75MHz，CDCl
3)δ159.3，150.5，149.7，142.1，125.0，121.5，121.0，118.7，108.8，70.2，21.7.
embodiment 14: preparation 4-chloro-7-isobutoxy quinazoline (compound 23f
)
The chloro-7-hydroxyquinazoline of 4-(0.36g is added in the round-bottomed flask of 100ml, 2mmol), DMF (10ml) and 60%NaH (0.2g, 5mmol), stirring at room temperature 10min, add isobutane bromide (3.5mmol) and continue reaction, TLC tracing detection, reaction 8h.React complete, be poured into water by reaction mixture, extraction into ethyl acetate, merge organic phase, washing, saturated common salt is washed, and anhydrous sodium sulfate drying, is evaporated to dry, column chromatography, obtains white solid (0.26g, productive rate 88.7%).Mp57-58℃.MS(ESI)：m/z(M+H)
+235.8.
1HNMR(300MHz，CDCl
3)δ8.65(d，J＝4.8Hz，1H，ArH)，8.09(d，J＝9.2Hz，1H，ArH)，7.38(d，J＝2.4Hz，1H，ArH)，7.31(d，J＝4.8Hz，1H，ArH)，7.28(dd，J＝9.2，2.4Hz，1H，ArH)，3.88(d，J＝6.5Hz，2H，CH
2)，2.18(dp，J＝13.3，6.6Hz，1H，CH)，1.07(d，J＝6.7Hz，6H，CH
3).
13CNMR(75MHz，CDCl
3)δ160.7，150.8，149.9，142.2，125.0，121.3，121.0，118.9，108.1，74.7，28.1，19.3.
embodiment 15. prepares 4-chloro-7-benzyloxy quinazoline (compound 23g
)
The chloro-7-hydroxyquinazoline (0.89g, 5mmol) of 4-is added, acetone (40ml), cylite (7.5mmol) and anhydrous K in the round-bottomed flask of 100ml
2cO
3(2.0g), stirring at room temperature 16h.React complete, acetone is gone out in underpressure distillation, adds 150mL water, is extracted with ethyl acetate, and merges organic phase, add concentrated hydrochloric acid acidifying, dehydrated alcohol band water, obtains dark oil thing, acetone recrystallization, crystallize out, after filtering, alkalization, obtains white solid (0.63g, productive rate 46.8%).Mp87-88℃.MS(ESI)：m/z(M+H)
+269.8.
1HNMR(300MHz，CDCl
3)δ8.67(d，J＝4.7Hz，1H，ArH)，8.12(d，J＝9.2Hz，1H，ArH)，7.52-7.30(m，8H，ArH)，5.21(s，2H，CH
2).
13CNMR(75MHz，CDCl
3)δ160.2，150.7，150.0，142.2，135.9，128.5，128.1，127.5，125.2，121.6，120.9，119.2，108.7，70.3.
embodiment 16: preparation 4-chloro-7-(4-fluorine benzyloxy) quinazoline (compound 23h)
The chloro-7-hydroxyquinazoline of 4-(0.36g is added in the round-bottomed flask of 100ml, 2mmol), DMF (15ml) and 60%NaH (0.2g, 5mmol), stirring at room temperature 10min, then add 4-fluorobenzyl chloride (3.5mmol) and continue reaction, TLC tracing detection.React complete, reaction mixture is poured into water, extraction into ethyl acetate, merge organic phase, add concentrated hydrochloric acid acidifying, dehydrated alcohol band water, obtains yellow oil, re-crystallizing in ethyl acetate, separate out pale yellow crystals, after filtering, alkalization, obtains yellow solid (0.57g, productive rate 89.2%).Mp98-99℃.MS(ESI)：m/z(M+H)
+287.9.
1HNMR(300MHz，CDCl
3)δ8.67(d，J＝4.8Hz，1H，ArH)，8.12(d，J＝9.2Hz，1H，ArH)，7.49-7.42(m，3H，ArH)，7.36-7.30(m，2H，ArH)，7.08(t，J＝8.7Hz，2H，ArH)，5.17(s，2H，CH
2).
13CNMR(75MHz，CDCl
3)δ162.4(d，J＝246.4Hz)，159.9，150.6，150.0，142.2，131.7(d，J＝2.2Hz)，129.4(d，J＝8.1Hz)，125.2，121.6，120.8，119.2，115.44(d，J＝21.5Hz)，108.6，69.5.
embodiment 17: preparation 4-chloro-7-(3-benzene oxyethyl group) quinazoline (compound 23i)
The chloro-7-hydroxyquinazoline of 4-(0.36g is added in the round-bottomed flask of 100ml, 2mmol), DMF (10ml) and 60%NaH (0.2g, 5mmol), stirring at room temperature 10min, add 1-bromine 2-diphenylphosphino ethane (3.5mmol) and continue reaction, TLC tracing detection, reaction 24h.React complete, be poured into water by reaction mixture, extraction into ethyl acetate, merge organic phase, washing, saturated common salt is washed, and anhydrous sodium sulfate drying, is evaporated to dry, column chromatography, obtains light yellow solid (0.14g, productive rate 23.3%).Mp84-85℃.MS(ESI)：m/z(M+H)
+283.8.
1HNMR(300MHz，CDCl
3)δ8.64(d，J＝4.0Hz，1H，ArH)，8.07(d，J＝9.1Hz，1H，ArH)，7.40(s，1H，ArH)，7.36-7.19(m，7H，ArH)，4.34(t，J＝6.7Hz，2H，OCH
2CH
2)，3.18(t，J＝6.7Hz，2H，OCH
2CH
2).
13CNMR(75MHz，CDCl
3)δ160.1150.6，149.8，142.0，137.7，128.7，128.3，126.4，124.9，121.3，120.7，118.9，108.1，68.7，35.4.
embodiment 18: preparation 4-chloro-7-(3-benzene propoxy-) quinazoline (compound 23j)
The chloro-7-hydroxyquinazoline of 4-(0.45g is added in the round-bottomed flask of 100ml, 2.5mmol) with DMF (15ml), stirring at room temperature 10min, then 60%NaH (0.2g is added, 5mmol), stirring at room temperature 10min, adds 1-bromine 3-phenyl-propane (5mmol) and continues reaction, TLC tracing detection.React complete, reaction mixture is poured into water, extraction into ethyl acetate, merges organic phase, be evaporated to dry, obtain yellow oil, add concentrated hydrochloric acid acidifying, occur white solid, with 20mL acetone/sherwood oil=3: 1 recrystallization, use alkalization again after obtaining solid, obtain white crystal (0.03g, productive rate 53.6%).Mp51-52℃.MS(ESI)：m/z(M+H)
+297.9.
1HNMR(300MHz，CDCl
3)δ8.64(d，J＝4.3Hz，1H，ArH)，8.08(d，J＝9.1Hz，1H，ArH)，7.36(s，1H，ArH)，7.33-7.15(m，7H，ArH)，4.10(t，J＝6.0Hz，2H，OCH
2CH
2CH
2)，2.84(t，J＝7.4Hz，2H，OCH
2CH
2CH
2)，2.26-2.10(m，2H，OCH
2CH
2CH
2).
13CNMR(75MHz，CDCl
3)δ160.4150.6，149.8，142.0，140.9，128.2(C＝2)，125.8，124.9，121.3，120.7，118.9，108.0，67.2，32.1，30.5.
Following synthetic route 3 depicts the general method of some intermediates and the compounds more of the present invention preparing the compounds of this invention.
synthetic route 3:
embodiment 19: preparation N
1
-(7-oxyethyl group quinazoline-4-base)-N
2
, N
2
-diethyl ethane-1,2-diamines (compound
24a)
Compound 23a (0.35g, 1.7mmol) and N, N-diethyl ethylenediamine (4mL) is added, heating reflux reaction 3.5h, TLC tracing detection in 100mL flask.React complete, add about 100mL water, extraction into ethyl acetate, merge organic phase, washing, saturated common salt is washed, and anhydrous sodium sulfate drying, is evaporated to dry, column chromatography, obtains light yellow solid (0.36g, productive rate 73.7%).Mp84-85℃.MS(ESI)：m/z(M+H)
+287.9.
1HNMR(300MHz，CDCl
3)δ8.44(d，J＝5.2Hz，1H，ArH)，7.61(d，J＝9.1Hz，1H，ArH)，7.28(s，1H，ArH))，7.04(d，J＝9.0Hz，1H，ArH)，6.25(d，J＝5.3Hz，1H，ArH)，5.98(s，1H，NH)，4.13(q，J＝6.9Hz，2H，OCH
2CH
3)，3.20(dd，J＝10.1，5.1Hz，2H，NHCH
2CH
2)，2.75(t，J＝5.8Hz，2H，NHCH
2CH
2)，2.56(q，J＝7.0Hz，4H，N(CH
2CH
3)
2)，1.46(t，J＝6.9Hz，1H，OCH
2CH
3)，1.04(t，J＝7.1Hz，6H，N(CH
2CH
3)
2).
13CNMR(75MHz，CDCl
3)δ159.2，151.1，150.0，149.7，120.6，116.9，113.2，108.5，97.8，63.3，50.6，46.4，39.7，14.7，12.0.
embodiment 20: preparation N
1
, N
1
-diethyl-N
2
-(7-hexyloxy quinazoline-4-base) ethane-1,2-diamines (compound
24b)
23c (0.53g, 2mmol) and N, N-diethyl ethylenediamine (4mL) is added, heating reflux reaction 3.5h, TLC tracing detection in 100mL flask.React complete, add about 100mL water, extraction into ethyl acetate, merge organic phase, washing, saturated common salt is washed, and anhydrous sodium sulfate drying, is evaporated to dry, column chromatography, obtains yellow solid (0.59g, productive rate 85.4%).Mp92-93℃.MS(ESI)：m/z(M+H)
+344.0.
1HNMR(300MHz，CDCl
3)δ8.43(d，J＝5.3Hz，1H，ArH)，7.61(d，J＝9.1Hz，1H，ArH)，7.28(d，J＝2.0Hz，1H，ArH)，7.04(dd，J＝9.0，2.2Hz，1H，ArH)，6.26(d，J＝5.3Hz，1H，ArH)，5.98(s，1H，NH)，4.06(t，J＝6.5Hz，2H，OCH
2(CH
2)
4CH
3)，3.22(dd，J＝10.3，5.4Hz，2H，NHCH
2CH
2)，2.77(t，J＝5.8Hz，2H，NHCH
2CH
2)，2.57(q，J＝7.0Hz，4H，N(CH
2CH
3)
2)，1.89-1.76(m，2H，OCH
2CH
2(CH
2)
3CH
3)，1.54-1.42(m，2H，O(CH
2)
2CH
2(CH
2)
2CH
3)，1.34(d，J＝3.5Hz，4H，O(CH
2)
3(CH
2)
2CH
3，1.05(t，J＝7.1Hz，6H，N(CH
2CH
2)
2)，0.90(t，J＝6.5Hz，3H，O(CH
2)
5CH
3).
13CNMR(75MHz，CDCl
3)δ159.5，151.1，145.0，149.8，120.6，117.1，113.2，108.6，97.8，68.0，50.7，46.5，39.8，31.6，29.1，25.8，22.6，14.1，12.1.
embodiment 21: preparation N
1
-(7-allyloxy quinazoline-4-base)-N
2
, N
2
-diethyl ethane-1,2-diamines (chemical combination
thing 24c)
23d (0.33g, 1.5mmol) and N, N-diethyl ethylenediamine (4mL) is added, heating reflux reaction 4h, TLC tracing detection in 100mL flask.React complete, add about 100mL water, extraction into ethyl acetate, merge organic phase, washing, saturated common salt is washed, and anhydrous sodium sulfate drying, is evaporated to dry, column chromatography, obtains white solid (0.36g, productive rate 79.8%).Mpyellowoil.MS(ESI)：m/z(M+H)
+300.1.
1HNMR(300MHz，CDCl
3)δ8.43(d，J＝5.3Hz，1H，ArH)，7.62(d，J＝9.1Hz，1H，ArH)，7.30(d，J＝2.1Hz，1H，ArH)，7.08(dd，J＝9.2，1.9Hz，1H，ArH)，6.28(d，J＝5.3Hz，1H，ArH)，6.09(ddd，J＝15.8，10.5，5.2Hz，1H，CH
2＝CH)，5.97(s，1H，NH)，5.46(d，J＝17.2Hz，1H，CH
2＝CH)，5.31(d，J＝10.5Hz，1H，CH
2＝CH)，4.65(d，J＝5.0Hz，2H，OCH
2CH＝CH
2)，3.25(dd，J＝10.6，5.4Hz，2H，NHCH
2CH
2)，2.80(t，J＝5.8Hz，2H，NHCH
2CH
2)，2.59(q，J＝7.1Hz，4H，(CH
2CH
3)
2)，1.07(t，J＝7.1Hz，6H，(CH
2CH
3)
2).
13CNMR(75MHz，CDCl
3)δ158.4，150.4，149.5，149.3，132.2，120.8，117.1，116.3，113.1，108.2，97.2，68.1，50.3，46.0，39.5，11.4.
embodiment 22: preparation N
1
, N
1
-diethyl-N
2
-(7-isopropoxy quinazoline-4-base) ethane-1,2-diamines (chemical combination
thing 24d)
23e (0.20g, 0.9mmol) and N, N-diethyl ethylenediamine (4mL) is added, heating reflux reaction 5h, TLC tracing detection in 100mL flask.React complete, add about 100mL water, extraction into ethyl acetate, merge organic phase, washing, saturated common salt is washed, and anhydrous sodium sulfate drying, is evaporated to dry, column chromatography, obtains yellow oil (0.12g, productive rate 10.9%).Mpyellowoil.MS(ESI)：m/z(M+H)
+302.1.
1HNMR(300MHz，CDCl
3)δ8.42(d，J＝5.3Hz，1H，ArH)，7.61(d，J＝9.1Hz，1H，ArH)，7.29(d，J＝2.0Hz，1H，ArH)，7.01(dd，J＝9.1，2.1Hz，1H，ArH)，6.26(d，J＝5.3Hz，1H，ArH)，5.99(s，1H，NH)，4.80-4.62(m，1H，OCH(CH
3)
2)，3.24(dd，J＝10.5，5.3Hz，2H，NHCH
2CH
2)，2.79(t，J＝5.9Hz，2H，NHCH
2CH
2)，2.58(q，J＝7.1Hz，4H，N(CH
2CH
3)
2)，1.40(d，J＝6.0Hz，6H，OCH(CH
3)
2)，1.06(t，J＝7.1Hz，6H，N(CH
2CH
3)
2).
13CNMR(75MHz，CDCl
3)δ158.2，150.7，149.8，149.7，120.8，117.7，113.1，109.5，97.6，69.7，50.7，46.4439.8，21.8，12.0.
embodiment 23: preparation N
1
-(7-benzyloxy quinazoline-4-base)-N
2
, N
2
-diethyl ethane-1,2-diamines (compound
24e)
23g (0.12g, 0.4mmol) and N, N-diethyl ethylenediamine (2mL) is added, heating reflux reaction 2.5h, TLC tracing detection in 100mL flask.React complete, add dehydrated alcohol, high-temperature pressure-reduction distillation removing amine, column chromatography, obtains light yellow solid (0.09g, productive rate 57.7%).Mp93-94℃.MS(ESI)：m/z(M+H)
+349.9.
1HNMR(300MHz，CDCl
3)δ8.44(d，J＝4.7Hz，1H，ArH)，7.63(d，J＝9.0Hz，1H，ArH)，7.47(d，J＝7.3Hz，2H，ArH)，7.34(dd，J＝13.5，7.7Hz，4H，ArH)，7.13(d，J＝9.0Hz，1H，ArH)，6.28(d，J＝5.1Hz，1H，ArH)，5.99(s，1H，NH)，5.17(s，2H，OCH
2)，3.25(d，J＝4.7Hz，2H，NHCH
2CH
2)，2.80(t，J＝5.4Hz，2H，NHCH
2CH
2)，2.59(q，J＝6.8Hz，4H，N(CH
2CH
3)
2)，1.07(t，J＝6.9Hz，6H，N(CH
2CH
3)
2).
13CNMR(75MHz，CDCl
3)δ159.1，151.1，149.9，136.5，128.4，127.9，127.5，120.9，117.1，113.6，109.6，109.2，105.24，98.0，70.0，50.8，46.5，39.8，12.1.
embodiment 24: preparation N 1 ,
n 1 -diethyl-N 2 -(7-(4-fluorine benzyloxy) quinazoline-4-base) ethane-1,2-diamines (is changed compound 24f)
23h (0.14g, 0.5mmol) and N, N-diethyl ethylenediamine (4mL) is added, heating reflux reaction 3h, TLC tracing detection in 100mL flask.React complete, add about 100mL water, extraction into ethyl acetate, merge organic phase, washing, saturated common salt is washed, and anhydrous sodium sulfate drying, is evaporated to dry, column chromatography, obtains white solid (0.10g, productive rate 55.9%).Mp67-68℃.MS(ESI)：m/z(M+H)+367.7.
1HNMR(300MHz，CDCl
3)δ8.44(d，J＝5.3Hz，1H，ArH)，7.63(d，J＝9.1Hz，1H，ArH)，7.42(dd，J＝8.3，5.5Hz，2H，ArH)，7.36(d，J＝2.4Hz，1H，ArH)，7.10(dd，J＝9.1，2.5Hz，1H，ArH)，7.04(t，J＝8.6Hz，2H，ArH)，6.27(d，J＝5.3Hz，1H，ArH)，5.99(d，J＝2.5Hz，1H，NH)，5.11(s，2H，OCH
2)，3.23(dd，J＝10.4，5.4Hz，2H，NHCH
2CH
2)，2.78(t，J＝5.9Hz，2H，NHCH
2CH
2)，2.58(q，J＝7.1Hz，4H，NCH
2CH
3)，1.06(t，J＝7.1Hz，6H，NCH
2CH
3).
13CNMR(75MHz，CDCl
3)δ162.32(d，J＝246.0Hz)，159.0，151.0，149.9，149.8，132.3，129.32(d，J＝7.9Hz)，121.0，117.0，115.33(d，J＝21.5Hz)，113.6，109.1，98.0，69.3，50.8，46.6，39.9，12.1.
Following synthetic route 4 depicts the general method of some intermediates and the compounds more of the present invention preparing the compounds of this invention.
synthetic route 4:
embodiment 25. prepares N
1
-(7-oxyethyl group quinazoline-4-base)-N
2
, N
2
-diethyl propane-1,2-diamines (compound
25a)
23a (0.31g, 1.5mmol) and 3-diethyl amino propylamine (4mL) is added, heating reflux reaction 4.5h, TLC tracing detection in 100mL flask.React complete, add about 100mL water, extraction into ethyl acetate, merge organic phase, washing, saturated common salt is washed, and anhydrous sodium sulfate drying, is evaporated to dry, column chromatography, obtains yellow oil (0.34g, productive rate 75.2%).Mpyellowoil.MS(ESI)：m/z(M+H)
+302.1.
1HNMR(400MHz，CDCl
3)δ8.41(d，J＝5.3Hz，1H，ArH)，7.83(s，1H，NH)，7.64(d，J＝9.1Hz，1H，ArH)，7.30(s，1H，ArH)，7.02(d，J＝9.1Hz，1H，ArH)，6.23(d，J＝5.3Hz，1H，ArH)，4.16(q，J＝6.9Hz，2H，CH
2CH
3)，3.38(d，J＝4.5Hz，2H，NCH
2)，2.65(dt，J＝14.1，6.1Hz，6H，CH
2N(CH
2CH
3)
2)，1.97-1.83(m，2H，NHCH
2CH
2CH
2)，1.47(t，J＝6.8Hz，3H，CH
2CH
3)，1.09(t，J＝7.0Hz，6H，N(CH
2CH
3)
2).
13CNMR(100MHz，CDCl
3)δ159.0，150.5，150.3，149.5，121.4，116.0，113.1，107.8，96.5，62.9，52.5，46.4，43.5.
embodiment 26: preparation N
1
-(7-allyloxy quinazoline-4-base)-N
2
, N
2
-diethyl propane-1,2-diamines (chemical combination
thing 25b)
23d (0.33g, 2mmol) and 3-diethyl amino propylamine (4mL) is added, heating reflux reaction 2.5h, TLC tracing detection in 100mL flask.React complete, add about 100mL water, extraction into ethyl acetate, merge organic phase, washing, saturated common salt is washed, and anhydrous sodium sulfate drying, is evaporated to dry, column chromatography, obtains yellow oil (0.15g, productive rate 31.9%).Mpyellowoil.MS(ESI)：m/z(M+H)
+313.9.
1HNMR(300MHz，CDCl
3)δ8.40(d，J＝5.3Hz，1H，ArH)，7.83(s，1H，NH)，7.64(d，J＝9.1Hz，1H，ArH)，7.03(dd，J＝9.1，1.6Hz，1H，ArH)，6.20(d，J＝5.4Hz，1H，ArH)，6.08(ddd，J＝21.5，10.4，5.2Hz，1H，CH＝CH
2)，5.45(d，J＝17.2Hz，1H，CH＝CH
2)，5.29(d，J＝10.5Hz，1H，CH＝CH
2)，4.63(d，J＝5.2Hz，2H，OCH
2)，3.34(d，J＝3.9Hz，2H，NCH
2(CH
2)
2)，2.61(dd，J＝13.9，6.7Hz，6H，CH
2N(CH
2CH
3)
2)，1.94-1.81(m，2H，NCH
2CH
2CH
2)，1.07(t，J＝7.1Hz，6H，N(CH
2CH
3)
2).
13CNMR(75MHz，CDCl
3)δ158.8，151.0，150.5，149.8，132.8，121.7，117.7，116.5，113.6，108.7，97.0，68.7，53.4，47.0，44.4，24.5，11.6.
embodiment2
7: preparation N 1 ,
n 1 -diethyl-N 2 -(7-(4-fluorine benzyloxy) quinazoline-4-base) propane-1,2-diamines (is changed compound 25c)
23h (0.29g, 1mmol) and 3-diethyl amino propylamine (4mL) is added, heating reflux reaction 1.5h, TLC tracing detection in 100mL flask.React complete, add about 100mL water, extraction into ethyl acetate, merge organic phase, washing, saturated common salt is washed, and anhydrous sodium sulfate drying, is evaporated to dry, column chromatography, obtains yellow oil (0.26g, productive rate 67.5%).Mpyellowoil.MS(ESI)：m/z(M+H)
+382.4.
1HNMR(300MHz，CDCl
3)δ8.41(d，J＝5.2Hz，1H，ArH)，7.83(s，1H，NH)，7.66(d，J＝9.1Hz，1H，ArH)，7.45-7.36(m，2H，ArH)，7.34(s，1H，ArH)，7.13-6.95(m，3H，ArH)，6.20(d，J＝5.1Hz，1H，ArH)，5.08(s，2H，OCH
2)，3.32(s，2H，NHCH
2(CH
2)
2)，2.67-2.53(m，6H，CH
2N(CH
2CH
3)
2)，1.84(s，2H，NHCH
2CH
2CH
2)，1.06(t，J＝6.8Hz，6H，N(CH
2CH
3)
2).
13CNMR(75MHz，CDCl
3)δ162.0(d，J＝245.7Hz)，158.6，151.0，150.3，149.7，132.11(d，J＝2.0Hz)，129.0(d，J＝8.0Hz)，121.7，116.1，115.0(d，J＝21.4Hz)，113.6，108.8，96.8，68.9，53.0，46.7，44.1，24.3，11.4.
experimental example 1: anti tumor activity in vitro is tested
Quinazoline derivant of the present invention is as the pharmacological research preparing Therapeutic cancer pharmaceutical use.The compound of all tests is all prepared into hydrochloride form before the test, using antineoplastic target medicine-Gefitinib conventional clinically and lapatinibditosylate as positive control medicine.
Select Human Laryngeal Cancer Cell (Hep-2) respectively, breast cancer cell line (MCF-7), gastric carcinoma cell lines (BGC-823), hepatoma cell line (HepG2), colon carcinoma cell line (HCT-8), cervical cancer tumer line (Hela), the clones such as prostate cancer cell line (PC-3), adopt mtt assay to test.Concrete grammar is as follows: respectively by good for growth conditions, be in the cell strain of logarithmic phase with 5 × 10
4the concentration of individual/ml is inoculated in 96 orifice plates, 160 μ l are inoculated in every hole, subsequently 96 orifice plates are placed in 37 DEG C, cultivate 24 hours containing the incubator of 5%CO2, abandon old liquid, change fresh medium, add the oxoquinazolin derivative of sterilising treatment, continue cultivation after 48 hours, discard nutrient solution, every hole adds the RPMI-1640 nutrient solution of 20ul containing 5mg/mlMTT, continue cultivation 4 hours, after careful removing supernatant, every hole adds the DMSO of 200 μ l, and vibrate about 10min dissolution precipitation, OD value is detected, wavelength 490nm subsequently by microplate reader.The cell survival rate under each sample concentration is obtained: survival rate %=sample sets mean OD value/control group mean OD value × 100% with following formula.With cell survival rate to the mapping of drug level logarithm, obtain the IC of each sample by graphing method
50value, the results are shown in following table.
Quinazoline derivant extracorporeal anti-tumor result (IC of the present invention
50, μM
a)
| Compound | Hep-2 b | MCF-7 b | BGC-823 b | HCT-8 b | HepG2 b | HeLa b | PC-3 b |
| 8a | 3.2 | 4.9 | 1.5 | 6.4 | 5.4 | 6.5 | 1.5 |
| 8b | 2.3 | 8.4 | 2.8 | 8.5 | 7.6 | 1.8 | 0.8 |
| 9a | 4.0 | 3.6 | 4.0 | 5.1 | 7.8 | 3.6 | 2.5 |
| 9b | 6.3 | 3.2 | 4.0 | 1.2 | 1.8 | 6.2 | 2.5 |
| 9c | 1.2 | 5.4 | 2.5 | 3.0 | 4.8 | 5.0 | 4.8 |
| 9d | 6.4 | 5.8 | 1.0 | 7.8 | 2.3 | 4.8 | 5.3 |
| 9e | 1.5 | 8.0 | 4.1 | 19.7 | 27.4 | 2.3 | 2.2 |
| 23a | 3.16 | 2.66 | 3.91 | 3.34 | 3.46 | 2.56 | 2.7 |
| 23b | 2.59 | 2.05 | 2.63 | 2.31 | 3.06 | 1.98 | 2.10 |
| 23c | 2.57 | 2.77 | 2.93 | 2.28 | 4.03 | 3.68 | 2.78 |
| 23d | 2.74 | 2.64 | 3.61 | 2.57 | 4.13 | 4.25 | 2.52 |
| 23e | 2.49 | 2.25 | 3.03 | 2.10 | 3.19 | 3.48 | 4.26 |
| 23f | 2.44 | 2.42 | 2.38 | 2.08 | 3.26 | 2.58 | 2.13 |
| 23g | 2.82 | 2.64 | 4.30 | 3.24 | 4.30 | 3.45 | 4.67 |
| 23h | 2.47 | 2.68 | 5.17 | 2.72 | 5.17 | 5.42 | 3.27 |
| 23i | 2.07 | 3.01 | 2.78 | 2.23 | 2.78 | 3.85 | 4.50 |
| 23j | 2.18 | 3.31 | 2.01 | 2.30 | 2.01 | 2.85 | 2.35 |
| 24a | 1.23 | 0.98 | 1.56 | 1.89 | 1.58 | 2.03 | 1.51 |
| 24b | 0.98 | 1.25 | 0.89 | 0.92 | 0.77 | 1.05 | 1.42 |
| 24c | 0.86 | 1.66 | 1.36 | 0.93 | 1.36 | 0.78 | 1.23 |
| 24d | 1.26 | 1.85 | 1.37 | 2.11 | 2.26 | 1.56 | 1.95 |
| 24e | 0.78 | 0.85 | 0.92 | 0.48 | 1.16 | 0.87 | 1.38 |
| 24f | 0.37 | 0.79 | 0.89 | 0.18 | 0.89 | 0.56 | 0.57 |
| 25a | 1.22 | 0.98 | 0.78 | 0.84 | 1.56 | 1.35 | 0.86 |
| 25b | 0.52 | 0.89 | 1.26 | 0.72 | 1.48 | 0.69 | 0.78 |
| 25c | 0.22 | 0.19 | 0.46 | 0.32 | 0.48 | 0.39 | 0.46 |
| Gefitinib | 11.6 | 12.6 | 6.80 | 9.6 | 7.61 | 10.4 | 11.9 |
| Lapatinibditosylate | 12.2 | 18.6 | 16.8 | 24.8 | 18.6 | 12.2 | 8.63 |
aiC
50value represents the drug level required for growth of tumour cell of suppression 50%.
btumor cell line comprises people's Human Laryngeal Cancer Cell (Hep-2), breast cancer cell line (MCF-7), gastric carcinoma cell lines (BGC-823), hepatoma cell line (HepG2), colon carcinoma cell line (HCT-8), cervical cancer tumer line (Hela), prostate cancer cell line (PC-3).
cin table, each numerical value represents the mean value of three parallel test results.
Claims (6)
1. formula I:
And pharmacologically acceptable salts, solvate, prodrug, wherein
R
4be selected from hydrogen, halogen ,-C
1-6alkyl ,-C
2-6thiazolinyl ,-C
2-6alkynyl ,-C
1-6alkyl-phenyl, NH (CH2) mN [(CH
2) nCH
3]
2, wherein said alkyl, thiazolinyl, alkynyl and phenyl can optionally be replaced by halogen, nitro, cyano group, hydroxyl ,-C1-6 alkoxyl group, phenyl; Wherein m is the arbitrary integer in 2-8, and n is the arbitrary integer in 0-6;
R
7be selected from halogen ,-C
1-6alkoxyl group ,-C
1-6aralkoxy ,-C
1-6replace aralkoxy.
2. the compound of claim 1, wherein R
4be selected from hydrogen ,-C
1-6alkyl ,-C
2-6thiazolinyl ,-C
1-6alkyl-phenyl, NH (CH2) mN [(CH
2) nCH
3]
2, wherein m is the arbitrary integer in 1-4, and n is the arbitrary integer in 1-3; Such as, wherein R
4be selected from hydrogen, methyl, ethyl, propyl group, sec.-propyl, allyl group, propenyl, phenmethyl, hydrocinnamyl, normal-butyl, NH (CH2)
2n [CH
2cH
3]
2, NH (CH2)
2n [CH
3]
2, NH (CH2)
3n [CH
2cH
3]
2, NH (CH2)
3n [CH
3]
2.
3. the compound of claim 1, wherein R
7be selected from halogen ,-C
1-4alkoxyl group ,-C
1-6aralkoxy; Such as, wherein R
7be selected from fluorine, chlorine, bromine, methoxyl group, benzyloxy, to fluorine benzyloxy etc.
4., according to the compound of any one of claim 1-3, it is be selected from following compound:
Compound title
The chloro-7-hydroxyquinazoline of 4-
4-chloro-7-oxyethyl group quinazoline
4-chloro-7-n-butoxy quinazoline
The positive hexyloxy quinazoline of the chloro-7-of 4-
4-chloro-7-allyloxy quinazoline
4-chloro-7-isopropoxy quinazoline
4-chloro-7-isobutoxy quinazoline
4-chloro-7-benzyloxy quinazoline
The chloro-7-of 4-(4-fluorine benzyloxy) quinazoline
The chloro-7-of 4-(3-benzene oxyethyl group) quinazoline
The chloro-7-of 4-(3-benzene propoxy-) quinazoline
N
1-(7-oxyethyl group quinazoline-4-base)-N
2, N
2-diethyl ethane-1,2-diamines
N
1, N
1-diethyl-N
2-(7-hexyloxy quinazoline-4-base) ethane-1,2-diamines
N
1-(7-allyloxy quinazoline-4-base)-N
2, N
2-diethyl ethane-1,2-diamines
N
1, N
1-diethyl-N
2-(7-isopropoxy quinazoline-4-base) ethane-1,2-diamines
N
1-(7-benzyloxy quinazoline-4-base)-N
2, N
2-diethyl ethane-1,2-diamines
N
1, N
1-diethyl-N
2-(7-(4-fluorine benzyloxy) quinazoline-4-base) ethane-1,2-diamines
N
1-(7-oxyethyl group quinazoline-4-base)-N
2, N
2-diethyl propane-1,2-diamines
N
1-(7-allyloxy quinazoline-4-base)-N
2, N
2-diethyl propane-1,2-diamines
N
1, N
1-diethyl-N
2-(7-(4-fluorine benzyloxy) quinazoline-4-base) propane-1,2-diamines
And their pharmacologically acceptable salts, solvate, prodrug.
5. the pharmaceutical applications of formula I described in any one of claim 1-4 or its pharmacologically acceptable salts, solvate, prodrug, namely preparation can be used for preventing or treatment tumour medicine in purposes.
6. a pharmaceutical composition, wherein containing formula I or its pharmacologically acceptable salts, solvate, prodrug described in any one of at least one claim 1-4, and optional pharmaceutical carrier or vehicle.
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|---|---|---|---|---|
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2014
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| CN108299655A (en) * | 2018-03-05 | 2018-07-20 | 张逸强 | A kind of preparation method of molecular targeted anti-tumor agents Gefitinib intermediate |
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