CN101492445A - Heteroaromatic compound, preparation method and uses thereof - Google Patents
Heteroaromatic compound, preparation method and uses thereof Download PDFInfo
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- CN101492445A CN101492445A CNA2008100008154A CN200810000815A CN101492445A CN 101492445 A CN101492445 A CN 101492445A CN A2008100008154 A CNA2008100008154 A CN A2008100008154A CN 200810000815 A CN200810000815 A CN 200810000815A CN 101492445 A CN101492445 A CN 101492445A
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- compound
- amine
- methylsulfonyl
- quinazoline
- amino
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/94—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Abstract
The invention relates to heteroaromatics with the formula (I), a preparation method and the usage thereof. In the formula (I), A, D and Y are defined as in the specification.
Description
Technical field
The present invention relates to a series of heteroaromaticss, their preparation method, the medicinal compositions that contains them and their purposes in medicine; The invention still further relates to the synthetic used intermediate of heteroaromatics.
Technical background
The phosphorylation of specific tyrosyl residue in the relevant various albumen of the adjusting of growth of protein tyrosine kinase catalysis and cell and differentiation.Protein tyrosine kinase can roughly be divided into acceptor (as EGFr, c-erbB-2, c-met, tie-2, PDGFr, FGFr) or non-acceptor (as c-src, lck, zap70) kinases.Shown many these type of kinase whose improper or uncontrolled activation of arriving, that is, for example can cause uncontrolled cells produce by the unusual protein tyrosine kinase activity due to overexpression or the sudden change.
Protein tyrosine kinase, relevant as the abnormal activity of c-erbB-2, c-src, c-met, EGFr, PDGFr with people's malignant tumour.For example, the EGFr of rising is active relevant with the neck cancer with nonsmall-cell lung cancer, bladder cancer and head, the c-erbB-2 activity of rising and the related to cancer of mammary gland, ovary, stomach and pancreas.Therefore, the arrestin Tyrosylprotein kinase should be able to provide above-mentioned tumor treatment.
The paraprotein tyrosine kinase activity is also relevant with other various diseases: psoriasis, fibroid degeneration, atherosclerosis, restenosis, autoimmune disorder, allergy, asthma etc. have shown by the effect of some receptor tyrosine kinases and can control these diseases.
Patent WO99/35146 has openly reported a series of compounds, and they have protein tyrosine kinase and suppress active, but active this type of new compound higher, that have more using value of exploitation also is very important.
Summary of the invention
The object of the present invention is to provide the new heteroaromatics shown in the general formula (I), their preparation method.
The object of the invention also is to provide a kind of pharmaceutical composition that contains the new heteroaromatics shown in effective dose, the general formula (I), and their application in diseases such as treatment cancer, malignant tumour and psoriasis;
Another object of the present invention is to provide the compound shown in general formula (II), (V), they are useful intermediates of preparation general formula (I) compound.
The objective of the invention is to reach, the invention discloses general formula (I) compound by following technical scheme:
Wherein,
A is CR
1With D be N; Or
A is CR
1With D be CR
2
R
1Expression CH
3SO
2[CH
2]
nCH (NH
2) [CH
2]
m-Ar-, wherein Ar is selected from and replaces or unsubstituted phenyl, furans, thiophene, pyrroles and thiazole, and substituting group is selected from halogen atom, C
1-4Alkyl or C
1-4Alkoxyl group, substituent number are 1 or 2; M, n=0,1,2;
R
2Be hydrogen, C
1-4The alkoxy or halogen atom;
Y is selected from optional by R
3, R
4The phenyl, pyridyl, 3H-imidazolyl, indyl, the 1H-indazolyl, 2 that replace, 3-dihydro-1H-indazolyl;
R
3Be selected from benzyl, halo-, dihalo-or three halogeno-benzyls, halo-, dihalo-or three halo benzyloxies, pyridylmethyl, pyridyl methoxyl group, 2-picoline oxygen base, benzyloxy;
R
4Be selected from hydrogen, hydroxyl, halogen atom, C
1-4Alkyl, C
1-4Alkoxyl group, amino, cyano group or trifluoromethyl.
In preferred version of the present invention, R
2Be selected from hydrogen or methoxyl group, more preferably hydrogen.
In preferred version of the present invention, Ar is selected from and replaces or unsubstituted furans, thiophene or thiazole, and substituting group is selected from halogen atom, C
1-4Alkyl or C
1-4Alkoxyl group, substituting group number are 1, preferred unsubstituted furans, thiophene or thiazole.
In preferred version of the present invention, m=0,1, n=1,2.
In preferred version of the present invention, Y is selected from optional by R
3, R
4The phenyl, pyridyl, the 1H-indazolyl, 2 that replace, 3-dihydro-1H-indazolyl; Preferred scheme is that Y is selected from optional by R
3, R
4The phenyl, the 1H-indazolyl that replace;
R
3Be selected from benzyl, halo-benzyl, halo-benzyloxy, pyridylmethyl, pyridyl methoxyl group, 2-picoline oxygen base, benzyloxy, preferred halo-benzyl, halo-benzyloxy, pyridyl methoxyl group;
R
4Be selected from hydrogen, halogen atom, C
1-4Alkyl or C
1-4Alkoxyl group.
In the present invention, " C
1-4Alkyl " be selected from methyl, ethyl, propyl group, sec.-propyl, butyl etc.;
In general formula disclosed by the invention (I) compound, when having chiral carbon atom, compound is with racemic form or single (R) or (S) configuration existence.
General formula disclosed by the invention (I) compound, preferred following compound:
6-(2-(1-amino-2-(methylsulfonyl) ethyl) thiazole-4-yl)-N-(3-chloro-4-(pyridine-2-ylmethoxy) phenyl) quinazoline-4-amine;
6-(2-(2-amino-3-(methylsulfonyl) propyl group) thiazole-4-yl)-N-(3-chloro-4-(pyridine-2-ylmethoxy) phenyl) quinazoline-4-amine;
6-(4-(1-amino-2-(methylsulfonyl) ethyl) thiazol-2-yl)-N-(3-chloro-4-(pyridine-2-ylmethoxy) phenyl) quinazoline-4-amine;
6-(4-(2-amino-3-(methylsulfonyl) propyl group) thiazol-2-yl)-N-(3-chloro-4-(pyridine-2-ylmethoxy) phenyl) quinazoline-4-amine;
6-(5-(1-amino-2-(methylsulfonyl) ethyl) furans-2-yl)-N-(3-chloro-4-(pyridine-2-ylmethoxy) phenyl) quinazoline-4-amine;
6-(5-(2-amino-3-(methylsulfonyl) propyl group) furans-2-yl)-N-(3-chloro-4-(pyridine-2-ylmethoxy) phenyl) quinazoline-4-amine;
N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-(4-(1-amino-2-(methylsulfonyl) ethyl) thiazol-2-yl) quinazoline-4-amine;
N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-(4-(2-amino-3-(methylsulfonyl) propyl group) thiazol-2-yl) quinazoline-4-amine;
N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-(5-(1-amino-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine;
N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-(5-(2-amino-3-(methylsulfonyl) propyl group) furans-2-yl) quinazoline-4-amine;
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-amino-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine;
6-(5-(1-amino-2-(methylsulfonyl) ethyl) furans-2-yl)-N-(3-chloro-4-(6-picoline-3-oxygen) phenyl) quinazoline-4-amine;
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(2-amino-3-(methylsulfonyl) propyl group) furans-2-yl) quinazoline-4-amine;
6-(5-(2-amino-3-(methylsulfonyl) propyl group) furans-2-yl)-N-(3-chloro-4-(6-picoline-3-oxygen) phenyl) quinazoline-4-amine;
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(2-(1-amino-2-(methylsulfonyl) ethyl) thiazole-4-yl) quinazoline-4-amine;
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(2-(2-amino-3-(methylsulfonyl) propyl group) thiazole-4-yl) quinazoline-4-amine;
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(4-(1-amino-2-(methylsulfonyl) ethyl) thiazol-2-yl) quinazoline-4-amine;
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(4-(2-amino-3-(methylsulfonyl) propyl group) thiazol-2-yl) quinazoline-4-amine;
Or its salt or solvate.
Another object of the present invention is to provide the method for preparing general formula (I) compound,
Method one:
Method two:
Wherein,
A, D, Y are as defined above;
A ' is CR
1', R
1' expression CH
3SO
2[CH
2]
nCH (NH-R
5) [CH
2]
m-Ar-, R
5Be selected from hydrogen or amido protecting group; The various groups that " amido protecting group " is well known to those skilled in the art comprise but do not limit following group: tertbutyloxycarbonyl, carbobenzoxy-(Cbz), benzyl, formyl radical, ethanoyl, trifluoroacetyl group, 4-methoxy-benzyl, trityl; Preferred scheme is R
5Be selected from hydrogen or tertbutyloxycarbonyl.
Work as R
5During for different group, the method for used deprotection base is also inequality, for example works as R
5During for groups such as tertbutyloxycarbonyl, trityls, deprotection reaction carries out under existence conditions such as acidic conditions such as trifluoroacetic acid or hydrochloric acid; Work as R
5During for groups such as carbobenzoxy-(Cbz), benzyl, 4-methoxy-benzyls, deprotection reaction in the presence of catalyzer, hydrogenation and finishing; Work as R
5During for groups such as formyl radical, ethanoyl, trifluoroacetyl groups, deprotection reaction can carry out under acidity or alkaline condition.
General formula compound (II) and (III), (V) and (VI) condensation reaction takes place and all in the presence of catalyzer, carry out, catalyst system therefor is the composite palladium catalyzer, be selected from: two (triphenylphosphine) palladium chloride, four (triphenylphosphines) are changed palladium or two (cyano group benzene) palladium chloride, preferred two (triphenylphosphine) palladium chloride.
Another object of the present invention is to provide general formula (II) and (V) shown in compound, they are preparation general formula (I) compound useful as intermediates:
Wherein
Ar, m, n are as above-mentioned definition;
R
5, R
6, X is as above-mentioned definition.
The preparation that can in all sorts of ways of general formula (II), (V) compound is with compound
Be example, mainly contain following two kinds of synthetic methods:
Route one
Route two
Another purpose of the present invention provides a kind of medicinal preparations, and it contains general formula (I) compound or its pharmacy acceptable salt or the solvate and the acceptable accessories of effective dose.
Another purpose of the present invention provides general formula (I) compound or its pharmacy acceptable salt or solvate and is used for the treatment of purposes in the medicine of cancer and malignant tumour in preparation.
Another purpose of the present invention provides general formula (I) compound or its pharmacy acceptable salt or solvate and is used for the treatment of purposes in the psoriasic medicine in preparation.
Medicinal preparations involved in the present invention can exist with unit dosage form, and per unit dosage contains the activeconstituents of predetermined amount.Such unit can contain, 0.5mg-1g for example, and the age of how much depending on the disease, route of administration and the patient that receive treatment of concrete consumption, body weight, the state of an illness etc. are all multifactor.
Medicinal preparations can any suitable way give, and gives as approach such as oral, rectum, nasal cavity, part or parenteral (comprising subcutaneous, muscle, vein or transdermal).Above-mentioned various preparation can pass through the known any method of pharmacy field, for example, and by activeconstituents and carrier or mixed with excipients are prepared.
The compounds of this invention or its pharmacy acceptable salt or solvate can give separately or unite use with the other treatment agent of the above-mentioned disease of treatment.Especially, in antineoplastic treatment, should consider and other chemotherapeutics, hormone or antibody drug drug combination.
Embodiment:
In order to illustrate in greater detail the present invention, provide following example.But scope of the present invention is not to be defined in this.
Embodiment one
The preparation of 6-iodo-N-(3-chloro-4-(pyridine-2 ylmethoxy) phenyl) quinazoline-4-amine
Add 6-iodo-3H-quinazoline-4-one (100g) in the 2000mL flask, be dissolved in 1L thionyl chloride and N, in the mixed solvent of dinethylformamide (20ml), reflux is to the reaction solution clear.Steam thionyl chloride, do twice with the toluene band, standby.
Standby intermediate is dissolved in the Virahol (2L), adds 3-chloro-4-(pyridine-2 ylmethoxy)-anilinechloride (66g), add anhydrous K under the mechanical stirring
2CO
3(150g), reflux is spent the night, and be cooled to room temperature with reaction solution next day, and decompress filter, filter cake be with a little cold washed with isopropyl alcohol, after with filter cake water making beating flush away K
2CO
3To neutral, decompress filter, vacuum-drying obtains title product (95g, off-white color solid), productive rate: 95%.
m/z(M+1)
+：489
Press embodiment one same procedure, can prepare:
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-iodine quinazoline-4-amine;
m/z(M+1)
+：506
N-(1-(3-luorobenzyl)-1H-indazole-5 base)-6-iodine quinazoline-4-amine;
m/z(M+1)
+：496
6-iodo-N-(3-chloro-4-(6-picoline-3-base oxygen) phenyl) quinazoline-4-amine;
m/z(M+1)
+：489
Embodiment two
The preparation of 6-boric acid-N-(3-chloro-4-(pyridine-2 ylmethoxy) phenyl) quinazoline-4 amine
THF (20ml) after 6-iodo-N-(3-chloro-4-(pyridine-2 ylmethoxy) phenyl) quinazoline-4-amine (2.0g) and the drying treatment is put in the reaction flask, obtain yellow solution after the dissolving.Be cooled to 0 ℃, (1.0M 4.75ml), obtains bright yellow solution to add ethylmagnesium bromide/THF solution in reaction solution.
Be cooled to-78 ℃, add triisopropyl boron (3.73ml) fast in reaction solution, (2.5M, 3.95ml), insulation reaction is complete to add n-Butyl Lithium/hexane solution then.
In the reaction solution that reacts completely, add acetate (0.84ml), stir half an hour, add saturated sodium bicarbonate aqueous solution and transfer PH=8, fully extract, merge organic layer, saturated brine washing, drying with ethyl acetate.Filter, concentrated dry chromatography gets target compound.
m/z(M+1)
+：407
Press embodiment two identical methods, can prepare:
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-boric acid quinazoline-4-amine;
m/z(M+1)
+：424
N-(1-(3-luorobenzyl)-1H-indazole-5 base)-6-boric acid quinazoline-4-amine;
m/z(M+1)
+：414
6-boric acid-N-(3-chloro-4-(6-picoline-3-base oxygen) phenyl) quinazoline-4-amine;
m/z(M+1)
+：403
Embodiment three
The preparation of 1-(5-bromine furans-2-yl)-2-(methylsulfonyl) ethamine
Method A
With N-methoxyl group-N-methyl-2-(methylthio group) ethanamide (5.6g), 2,5-dibrom furan or 2-iodo-5-bromo-furans (10.6g or 12.8g) are dissolved among the THF (40ml) that handled, and vacuumize degassing is removed vacuum with nitrogen.Be cooled to-10～-20 ℃ under nitrogen protection, (2M, 40ml), the control rate of addition makes interior temperature≤-10 ℃ to add tertiary butyl chlorination magnesium/THF solution in this solution.Naturally rising to room temperature reaction after dripping off spends the night.
(23ml) puts in another reaction flask with 5N hydrochloric acid, is cooled to 0 ℃, and above-mentioned reaction solution is added drop-wise in the hydrochloric acid, and the control rate of addition makes interior temperature≤5 ℃.Add t-butyl methyl ether (20ml), layering, organic layer is water and saturated brine washing successively, drying.Filter, concentrate and do, column chromatography purification gets 1-(5-bromine furans-2-yl)-2-(methylthio group) ethyl ketone.
To go up step intermediate (23.5g), pyridine (20ml), oxammonium hydrochloride (10g) and ethanol (100ml) and put in the reaction flask, back flow reaction is complete.Concentrating under reduced pressure is done, and adds entry and methylene dichloride, layering, and water layer is counter to be carried, and merges organic layer, saturated brine washing, drying.Filter, filtrate concentrating done, and is directly used in the next step.
To go up the step intermediate and be dissolved in the methyl alcohol (100ml), and be cooled to 0-5 ℃, gradation adds sodium borohydride reduction and reacts completely.In reaction solution, slowly add the unreacted sodium borohydride of water decomposition, concentrating under reduced pressure, dichloromethane extraction, organic layer merges, drying.Filter, filtrate decompression concentrates to be done, and gets intermediate 1-(5-bromine furans-2-yl)-2-(methylthio group) ethamine, is directly used in down to go on foot to feed intake.
To go up step intermediate (33.6g) be dissolved in methanol (7/3,250ml) in, be cooled to below 20 ℃, gradation adds oxone (50g) in reaction flask, add back insulation reaction 45 minutes, rises to room temperature reaction then 2 hours.Filter, filtrate is transferred PH=8 with saturated sodium bicarbonate solution, and dichloromethane extraction merges organic layer, drying.Filtrate concentrating done, and column chromatography purification gets target compound.
Method B
THF (200ml) after 5-bromo furfural (17.5g) and the drying treatment is put in the reaction flask, adds tertiary butyl sulfinyl amine (13.3g) again, dissolved clear after, add tetraisopropoxy titanium (70ml) rapidly, continue to stir and spend the night.Pour reaction solution in the water next day, dichloromethane extraction, the organic layer anhydrous sodium sulfate drying, concentrate product N-(5-bromine furans-2-yl) methylene radical)-2-methylpropane-2-sulfimide: 24g, yield 80%.
Dimethyl sulfone (28g) is dissolved among the exsiccant THF (700ml), is cooled to-40 ℃, insulation drips n-Butyl Lithium (150mmol), finishes nature and rises to room temperature 1.5 hours.Be cooled to-40 ℃ once more, add rapidly and go up step intermediate (18g), add nature and rise to room temperature.Reaction solution is poured in the water, washing, ethyl acetate extraction, organic layer concentrates, resistates adding capacity hydrochloric acid methanol, the stirring at room reaction is spent the night. and add ammonia methyl alcohol and transfer to neutrality, reaction solution concentrates the back column chromatography, gets title compound: 15g, yield: 93%.
Press embodiment three identical methods, can prepare:
1-(2-bromo thiazole-4-yl)-2-(methylsulfonyl) ethamine;
m/z(M+1)
+：286
1-(4-bromo thiazole-2-yl)-2-(methylsulfonyl) ethamine;
m/z(M+1)
+：286
1-(5-bromine furans-2-yl)-3-(methylsulfonyl) propyl group-2-amine;
m/z(M+1)
+：281
1-(2-bromo thiazole-4-yl)-3-(methylsulfonyl) propyl group-2-amine;
m/z(M+1)
+：300
1-(4-bromo thiazole-2-yl)-3-(methylsulfonyl) propyl group-2-amine;
m/z(M+1)
+：300
Embodiment four
The preparation of N-(tertbutyloxycarbonyl)-1-(5-boric acid furans-2-yl)-2-(methylsulfonyl) ethamine
Magnesium (0.27g) is placed anhydrous THF (25ml), add N-(tertbutyloxycarbonyl)-1-(5-boric acid furans-2-yl)-2-(methylsulfonyl) ethamine (2.8g), outgas nitrogen protection 3 times.Be heated to backflow, add an amount of glycol dibromide initiation reaction, keep backflow 0.5h, stop heating, about 1.5h reaction finishes, and obtains grignard reagent.
The grignard reagent for preparing is cooled to-20 ℃～15 ℃, slowly drips three isopropoxy boron (2.53ml).Dropwise insulation reaction 0.5h.Add entry (5ml), transfer pH=3～4, stir 0.5h with dilute hydrochloric acid.Solution of potassium carbonate is transferred pH=8, filters, and filter cake is washed 3 times with ethyl acetate, and filtrate adds water 50ml, and ethyl acetate (25ml * 2) is extracted, drying.Column chromatography (sherwood oil: ethyl acetate=10: 1 → 3: 1), get target compound: 0.87g.
Press embodiment four same procedure, can prepare:
N-(tertbutyloxycarbonyl)-1-(2-boric acid thiazole-4-yl)-2-(methylsulfonyl) ethamine;
m/z(M+1)
+：351
N-(tertbutyloxycarbonyl)-1-(4-boric acid thiazol-2-yl)-2-(methylsulfonyl) ethamine;
m/z(M+1)
+：351
N-(tertbutyloxycarbonyl)-1-(5-boric acid furans-2-yl)-3-(methylsulfonyl) propyl group-2-amine;
m/z(M+1)
+：346
N-(tertbutyloxycarbonyl)-1-(2-boric acid thiazole-4-yl)-3-(methylsulfonyl) propyl group-2-amine;
m/z(M+1)
+：365
N-(tertbutyloxycarbonyl)-1-(4-boric acid thiazol-2-yl)-3-(methylsulfonyl) propyl group-2-amine;
m/z(M+1)
+：365
Embodiment five
The preparation of 6-(2-(1-amino-2-(methylsulfonyl) ethyl) thiazole-4-yl)-N-(3-chloro-4-(pyridine-2-ylmethoxy) phenyl) quinazoline-4-amine
Method A
6-boric acid-N-(3-chloro-4-(pyridine-2 ylmethoxy) phenyl) quinazoline-4 amine (4.2g) and 1-(4-bromo thiazole-2-yl)-2-(methylsulfonyl) ethamine (2.7g) are joined in the 200ml methyl alcohol; add triethylamine (3ml) again, bi triphenyl phosphine dichloride palladium (0.2g).Be heated to back flow reaction 4 hours.Concentrate, resistates is added to the water, ethyl acetate extraction, and organic layer concentrates the back column chromatography, gets target compound: 3.0g, is The compounds of this invention 1.
m/z(M+1)
+：581
Method B
6-iodo-N-(3-chloro-4-(pyridine-2 ylmethoxy) phenyl) quinazoline-4 amine (4.5g) and N-(tertbutyloxycarbonyl)-1-(4-boric acid thiazol-2-yl)-2-(methylsulfonyl) ethamine (3.0g) are joined in the 200ml methyl alcohol; add triethylamine 3ml again, bi triphenyl phosphine dichloride palladium 0.2g.Be heated to back flow reaction 4 hours.Concentrate, resistates is added to the water, ethyl acetate extraction, and organic layer concentrates the back column chromatography, gets 4.0g.
To go up step gained intermediate (3.5g) and join in the methylene dichloride (50ml), add trifluoroacetic acid (5.0ml), room temperature reaction 2 hours.In reaction solution, add entry, layering, organic layer is used saturated brine (50ml) and saturated sodium bicarbonate solution (50ml) washing, drying successively.Filter, concentrate and do, column chromatography gets target compound: 2.6g.
Embodiment six
The preparation of 6-(2-(2-amino-3-(methylsulfonyl) propyl group) thiazole-4-yl)-N-(3-chloro-4-(pyridine-2-ylmethoxy) phenyl) quinazoline-4-amine
The preparation method is The compounds of this invention 2 with embodiment five.
m/z(M+1)
+：595
Embodiment seven
The preparation of 6-(4-(1-amino-2-(methylsulfonyl) ethyl) thiazol-2-yl)-N-(3-chloro-4-(pyridine-2-ylmethoxy) phenyl) quinazoline-4-amine
The preparation method is The compounds of this invention 3 with embodiment five.
m/z(M+1)
+：581
Embodiment eight
The preparation of 6-(4-(2-amino-3-(methylsulfonyl) propyl group) thiazol-2-yl)-N-(3-chloro-4-(pyridine-2-ylmethoxy) phenyl) quinazoline-4-amine
The preparation method is The compounds of this invention 4 with embodiment five.
m/z(M+1)
+：595
Embodiment nine
The preparation of 6-(5-(1-amino-2-(methylsulfonyl) ethyl) furans-2-yl)-N-(3-chloro-4-(pyridine-2-ylmethoxy) phenyl) quinazoline-4-amine
The preparation method is The compounds of this invention 5 with embodiment five.
m/z(M+1)
+：564
Embodiment ten
The preparation of 6-(5-(2-amino-3-(methylsulfonyl) propyl group) furans-2-yl)-N-(3-chloro-4-(pyridine-2-ylmethoxy) phenyl) quinazoline-4-amine
The preparation method is The compounds of this invention 6 with embodiment five.
m/z(M+1)
+：578
Embodiment 11
The preparation of N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-(4-(1-amino-2-(methylsulfonyl) ethyl) thiazol-2-yl) quinazoline-4-amine
The preparation method is The compounds of this invention 7 with embodiment five.
m/z(M+1)
+：574
Embodiment 12
The preparation of N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-(4-(2-amino-3-(methylsulfonyl) propyl group) thiazol-2-yl) quinazoline-4-amine
The preparation method is The compounds of this invention 8 with embodiment five.
m/z(M+1)
+：588
Embodiment 13
The preparation of N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-(5-(1-amino-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine
The preparation method is The compounds of this invention 9 with embodiment five.
m/z(M+1)
+：557
Embodiment 14
The preparation of N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-(5-(2-amino-3-(methylsulfonyl) propyl group) furans-2-yl) quinazoline-4-amine
The preparation method is The compounds of this invention 10 with embodiment five.
m/z(M+1)
+：571
Embodiment 15
The preparation of N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-amino-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine
The preparation method is The compounds of this invention 11 with embodiment five.
m/z(M+1)
+：567
Embodiment 16
The preparation of 6-(5-(1-amino-2-(methylsulfonyl) ethyl) furans-2-yl)-N-(3-chloro-4-(6-picoline-3-oxygen) phenyl) quinazoline-4-amine
The preparation method is The compounds of this invention 12 with embodiment five.
m/z(M+1)
+：550
Embodiment 17
The preparation of N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(2-amino-3-(methylsulfonyl) propyl group) furans-2-yl) quinazoline-4-amine
The preparation method is The compounds of this invention 13 with embodiment five.
m/z(M+1)
+：581
Embodiment 18
The preparation of 6-(5-(2-amino-3-(methylsulfonyl) propyl group) furans-2-yl)-N-(3-chloro-4-(6-picoline-3-oxygen) phenyl) quinazoline-4-amine
The preparation method is The compounds of this invention 14 with embodiment five.
m/z(M+1)
+：564
Embodiment 19
The preparation of N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(2-(1-amino-2-(methylsulfonyl) ethyl) thiazole-4-yl) quinazoline-4-amine
The preparation method is The compounds of this invention 15 with embodiment five.
m/z(M+1)
+：584
Embodiment 20
The preparation of N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(2-(2-amino-3-(methylsulfonyl) propyl group) thiazole-4-yl) quinazoline-4-amine
The preparation method is The compounds of this invention 16 with embodiment five.
m/z(M+1)
+：600
Embodiment 21
The preparation of N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(4-(1-amino-2-(methylsulfonyl) ethyl) thiazol-2-yl) quinazoline-4-amine
The preparation method is The compounds of this invention 17 with embodiment five.
m/z(M+1)
+：584
Embodiment 22
The preparation of N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(4-(2-amino-3-(methylsulfonyl) propyl group) thiazol-2-yl) quinazoline-4-amine
The preparation method is The compounds of this invention 18 with embodiment five.
m/z(M+1)
+：600
Experimental example one
The anti tumor activity in vitro testing experiment
Experimental technique: SRB;
Cell strain: SK-BR-3;
Experimental design: cell and different concns compound incubation 5 days, the inhibition degree of employing SRB method assessing compound on cell proliferation is calculated inhibiting rate, adopts the Logit method to calculate IC50, the anti tumor activity in vitro of comparative compound according to inhibiting rate.
The inhibiting rate method of calculation:
Inhibiting rate (%)=(control group OD value-medication OD value)/control group OD value * 100%
Experimental result
| The compound title | IC50 |
| Lapatinibditosylate (Ge Lansu list a company product) | 0.044 |
| Invention compound 1 | 0.040 |
| Invention compound 3 | 0.036 |
| Invention compound 4 | 0.055 |
| Invention compound 5 | 0.030 |
| Invention compound 7 | 0.033 |
| Invention compound 9 | 0.042 |
| Invention compound 11 | 0.025 |
| Invention compound 12 | 0.100 |
| Invention compound 17 | 0.001 |
Experimental example two
Interior evaluating is to the curative effect of people's lung cancer Calu-3 Nude Mice
D0: administration time for the first time; Dn: after the administration 19 days for the first time; TV: gross tumor volume; RTV: relative tumour volume;
*P＜0.01vs contrast
Claims (21)
1, general formula (I) compound or its pharmacy acceptable salt or solvated compounds:
Wherein
A is CR
1With D be N; Or
A is CR
1With D be CR
2
R
1Expression CH
3SO
2[CH
2]
nCH (NH
2) [CH
2]
m-Ar-, wherein Ar is selected from and replaces or unsubstituted phenyl, furans, thiophene, pyrroles or thiazole, and substituting group is selected from halogen atom, C
1-4Alkyl or C
1-4Alkoxyl group, substituent number are 1 or 2; M, n are 0,1 or 2 independently of one another;
R
2Be hydrogen, C
1-4The alkoxy or halogen atom;
Y is selected from optional by R
3, R
4The phenyl, pyridyl, 3H-imidazolyl, indyl, the 1H-indazolyl or 2 that replace, 3-dihydro-1H-indazolyl;
Wherein, R
3Be selected from benzyl, halo-, dihalo-or three halogeno-benzyls, halo-, dihalo-or three halo benzyloxies, pyridylmethyl, pyridyl methoxyl group, 2-picoline oxygen base or benzyloxy; With
R
4Be selected from hydrogen, hydroxyl, halogen atom, C
1-4Alkyl, C
1-4Alkoxyl group, amino, cyano group or trifluoromethyl.
2, compound according to claim 1 or its pharmacy acceptable salt or solvated compounds is characterized in that R
2Expression hydrogen or methoxyl group.
3. compound according to claim 1 or its pharmacy acceptable salt or solvated compounds is characterized in that R
2Expression hydrogen.
4, compound according to claim 1 or its pharmacy acceptable salt or solvated compounds is characterized in that Ar is selected from replacement or unsubstituted furans, thiophene or thiazole, and substituting group is selected from halogen atom, C
1-4Alkyl or C
1-4Alkoxyl group, substituting group number are 1, preferred unsubstituted furans, thiophene or thiazole.
5, compound according to claim 1 or its pharmacy acceptable salt or solvated compounds is characterized in that m=0 or 1, n=1 or 2.
6, compound according to claim 1 or its pharmacy acceptable salt or solvated compounds, it is optional by R to it is characterized in that Y is selected from
3, R
4The phenyl, pyridyl, the 1H-indazolyl, 2 that replace, 3-dihydro-1H-indazolyl; Preferred phenyl, 1H-indazolyl;
R
3Be selected from benzyl, halo-benzyl, halo-benzyloxy, pyridylmethyl, pyridyl methoxyl group, 2-picoline oxygen base or benzyloxy;
R
4Be selected from hydrogen, halogen atom, C
1-4Alkyl or C
1-4Alkoxyl group.
7, compound according to claim 6 or its pharmacy acceptable salt or solvated compounds is characterized in that R
3Be selected from halo-benzyl, halo-benzyloxy or pyridyl methoxyl group.
8, compound according to claim 1 or its pharmacy acceptable salt or solvated compounds is characterized in that when having chiral carbon atom, and compound is with racemize or single (R) or (S) configuration existence.
9, compound according to claim 1 or its pharmacy acceptable salt or solvated compounds is characterized in that compound comprises:
6-(2-(1-amino-2-(methylsulfonyl) ethyl) thiazole-4-yl)-N-(3-chloro-4-(pyridine-2-ylmethoxy) phenyl) quinazoline-4-amine;
6-(2-(2-amino-3-(methylsulfonyl) propyl group) thiazole-4-yl)-N-(3-chloro-4-(pyridine-2-ylmethoxy) phenyl) quinazoline-4-amine;
6-(4-(1-amino-2-(methylsulfonyl) ethyl) thiazol-2-yl)-N-(3-chloro-4-(pyridine-2-ylmethoxy) phenyl) quinazoline-4-amine;
6-(4-(2-amino-3-(methylsulfonyl) propyl group) thiazol-2-yl)-N-(3-chloro-4-(pyridine-2-ylmethoxy) phenyl) quinazoline-4-amine;
6-(5-(1-amino-2-(methylsulfonyl) ethyl) furans-2-yl)-N-(3-chloro-4-(pyridine-2-ylmethoxy) phenyl) quinazoline-4-amine;
6-(5-(2-amino-3-(methylsulfonyl) propyl group) furans-2-yl)-N-(3-chloro-4-(pyridine-2-ylmethoxy) phenyl) quinazoline-4-amine;
N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-(4-(1-amino-2-(methylsulfonyl) ethyl) thiazol-2-yl) quinazoline-4-amine;
N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-(4-(2-amino-3-(methylsulfonyl) propyl group) thiazol-2-yl) quinazoline-4-amine;
N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-(5-(1-amino-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine;
N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-(5-(2-amino-3-(methylsulfonyl) propyl group) furans-2-yl) quinazoline-4-amine;
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-amino-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine;
6-(5-(1-amino-2-(methylsulfonyl) ethyl) furans-2-yl)-N-(3-chloro-4-(6-picoline-3-oxygen) phenyl) quinazoline-4-amine;
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(2-amino-3-(methylsulfonyl) propyl group) furans-2-yl) quinazoline-4-amine;
6-(5-(2-amino-3-(methylsulfonyl) propyl group) furans-2-yl)-N-(3-chloro-4-(6-picoline-3-oxygen) phenyl) quinazoline-4-amine;
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(2-(1-amino-2-(methylsulfonyl) ethyl) thiazole-4-yl) quinazoline-4-amine;
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(2-(2-amino-3-(methylsulfonyl) propyl group) thiazole-4-yl) quinazoline-4-amine;
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(4-(1-amino-2-(methylsulfonyl) ethyl) thiazol-2-yl) quinazoline-4-amine;
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(4-(2-amino-3-(methylsulfonyl) propyl group) thiazol-2-yl) quinazoline-4-amine.
10, preparation is as the method for general formula (I) compound of definition in the claim 1, and this method comprises:
1) in the presence of catalyzer, general formula (II) compound and the reaction of general formula (III) compound condensation are with preparation general formula (IV) compound
2) general formula (IV) compound deaminize protecting group prepares general formula (I) compound
Wherein,
A ' is CR
1', R
1' expression CH
3SO
2[CH
2]
nCH (NH-R
5) [CH
2]
m-Ar-, R
5Be selected from hydrogen or amido protecting group;
R
6Be selected from hydrogen or C
1-4The straight or branched alkyl;
X is a halogen atom.
11, method according to claim 10, wherein said X is a bromine or iodine.
12, preparation is as the method for general formula (I) compound of definition in the claim 1, and this method comprises:
1) in the presence of catalyzer, logical formula V compound and the reaction of general formula (VI) compound condensation are with preparation general formula (IV) compound
2) general formula (IV) compound deaminize protecting group prepares general formula (I) compound
Wherein,
A ' is CR
1', R
1' expression CH
3SO
2[CH
2]
nCH (NH-R
5) [CH
2]
m-Ar-, R
5Be selected from hydrogen or amido protecting group;
R
6Be selected from hydrogen or C
1-4The straight or branched alkyl;
X is a halogen atom.
13, method according to claim 12, wherein said X is a bromine or iodine.
14, each described preparation method of claim 10 to 13 is characterized in that catalyzer is the composite palladium catalyzer, is selected from two (triphenylphosphine) palladium chloride, four (triphenylphosphines) change palladium or two (cyano group benzene) palladium chloride.
15. preparation method according to claim 14, wherein said composite palladium catalyzer is two (triphenylphosphine) palladium chloride.
16, by the general formula (II) or (V) compound of representative, they are as the intermediate of synthetic general formula as claimed in claim 1 (I) compound:
Wherein
R
5Be selected from hydrogen or amido protecting group,
R
6Be selected from hydrogen or C
1-4The straight or branched alkyl,
X is a halogen atom.
17. compound according to claim 16, wherein X is a bromine or iodine.
18, the medicinal preparations that contains each described formula (I) compound among at least a claim 1-8 or its pharmacy acceptable salt or solvate and one or more pharmaceutically acceptable carriers, thinner or vehicle.
19, each described formula (I) compound or its pharmacy acceptable salt or the solvate purposes in the medicine of the disease that the preparation treatment is regulated by c-erbB-2 and/or EGF-R protein tyrosine kinase activity among the claim 1-8.
20, purposes according to claim 19, described purposes are the purposes for preparing on the medicine for the treatment of cancer and malignant tumour.
21, purposes according to claim 19, described purposes are the purposes that is used to prepare on the antipsoriatics thing.
Priority Applications (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2008100008154A CN101492445A (en) | 2008-01-22 | 2008-01-22 | Heteroaromatic compound, preparation method and uses thereof |
| TW97125507A TW201002704A (en) | 2008-01-22 | 2008-07-07 | Heteroaromatic compounds, and preparation method and use thereof |
| PCT/CN2008/002046 WO2009094831A1 (en) | 2008-01-22 | 2008-12-23 | Heteroaromatic compounds, the preparation method and the use thereof |
| CN2008800125739A CN101663303B (en) | 2008-01-22 | 2008-12-23 | Heteroaromatic compounds, the preparation method and the use thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2008100008154A CN101492445A (en) | 2008-01-22 | 2008-01-22 | Heteroaromatic compound, preparation method and uses thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101492445A true CN101492445A (en) | 2009-07-29 |
Family
ID=40912236
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2008100008154A Pending CN101492445A (en) | 2008-01-22 | 2008-01-22 | Heteroaromatic compound, preparation method and uses thereof |
| CN2008800125739A Expired - Fee Related CN101663303B (en) | 2008-01-22 | 2008-12-23 | Heteroaromatic compounds, the preparation method and the use thereof |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2008800125739A Expired - Fee Related CN101663303B (en) | 2008-01-22 | 2008-12-23 | Heteroaromatic compounds, the preparation method and the use thereof |
Country Status (3)
| Country | Link |
|---|---|
| CN (2) | CN101492445A (en) |
| TW (1) | TW201002704A (en) |
| WO (1) | WO2009094831A1 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010083720A1 (en) * | 2009-01-23 | 2010-07-29 | Cen Junda | Optical pure quinazoline compounds |
| CN102344445A (en) * | 2010-07-23 | 2012-02-08 | 岑均达 | Optical voidness quinazoline compound |
| CN101735200B (en) * | 2008-11-17 | 2013-01-02 | 岑均达 | Quinazoline compound |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL112249A (en) * | 1994-01-25 | 2001-11-25 | Warner Lambert Co | Pharmaceutical compositions containing di and tricyclic pyrimidine derivatives for inhibiting tyrosine kinases of the epidermal growth factor receptor family and some new such compounds |
| RS49779B (en) * | 1998-01-12 | 2008-06-05 | Glaxo Group Limited, | Byciclic heteroaromatic compounds as protein tyrosine kinase inhibitors |
-
2008
- 2008-01-22 CN CNA2008100008154A patent/CN101492445A/en active Pending
- 2008-07-07 TW TW97125507A patent/TW201002704A/en unknown
- 2008-12-23 CN CN2008800125739A patent/CN101663303B/en not_active Expired - Fee Related
- 2008-12-23 WO PCT/CN2008/002046 patent/WO2009094831A1/en active Application Filing
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101735200B (en) * | 2008-11-17 | 2013-01-02 | 岑均达 | Quinazoline compound |
| WO2010083720A1 (en) * | 2009-01-23 | 2010-07-29 | Cen Junda | Optical pure quinazoline compounds |
| CN102344445A (en) * | 2010-07-23 | 2012-02-08 | 岑均达 | Optical voidness quinazoline compound |
| CN102344445B (en) * | 2010-07-23 | 2015-11-25 | 岑均达 | Optical pure quinazoline compound |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2009094831A1 (en) | 2009-08-06 |
| CN101663303B (en) | 2012-06-27 |
| CN101663303A (en) | 2010-03-03 |
| TW201002704A (en) | 2010-01-16 |
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Open date: 20090729 |