CN103172577B - 4-amido quinazoline and 4-aminoquinoline compounds and uses thereof - Google Patents
4-amido quinazoline and 4-aminoquinoline compounds and uses thereof Download PDFInfo
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- CN103172577B CN103172577B CN201210009825.0A CN201210009825A CN103172577B CN 103172577 B CN103172577 B CN 103172577B CN 201210009825 A CN201210009825 A CN 201210009825A CN 103172577 B CN103172577 B CN 103172577B
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- quinazoline
- diazanyl
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- methylene radical
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Abstract
Be applied to the compound of 4-amido quinazoline and 4-aminoquinoline compounds and uses thereof the general formula I in medical art, its configurational isomer and a configurational isomer mixture thereof, or its pharmacy acceptable salt and/or hydrate; Compound of Formula I, its configurational isomer and configurational isomer mixture thereof, or its pharmacy acceptable salt and/or hydrate; Compound of Formula I, its configurational isomer and configurational isomer mixture thereof, or its pharmacy acceptable salt and/or hydrate.This invention compound has significant anti-tumor activity, can be used for preparing the medicine treating and/or preventing tumor disease, and has that molecular weight is little, synthesis is simple, toxic side effect is little.
Description
Technical field
The invention belongs to medical art, relate to the 4-amino quinazoline derivative that a class is new, and this compounds and another kind of 4-aminoquinoline compounds are for the preparation of the purposes of antitumor drug, the pharmaceutical composition that also to relate to this compound be activeconstituents, and be used for the treatment of and/or prevent the purposes in the medicine of various cancer and proliferative disease.
Background technology
Malignant tumour is a kind of common disease and frequently-occurring disease of serious harm human health, and the antitumor drug used clinically is at present mostly cytotoxic drug, and this kind of medicine has inevitable shortcoming, as low selectivity, toxic side effect develop immunity to drugs by force and easily.Find that efficient, low toxicity, high specificity novel targeted cancer therapy drug has become the important directions of current antitumor drug research and development.
In human tumor cell, about have the tumour of 50% to contain the p53 gene of sudden change or disappearance, p53 gene is one of most important cancer suppressor gene found at present.In other 50% tumour cell containing normal p53 gene, also often there is the inactivation of p53 albumen.Nearly ten years, further investigation for p53 path makes people search out the novel targets of multiple antitumor drug, develops the small-molecule drug that many activity are outstanding, as (Science such as Nutlins class, MI-219 and CP-31398,2004,303 (5659): 844-848; SHANGARYS, QIND, MCEACHERND, etal.ProcNatlAcad SciUSA, 2008,105 (10): 3933-3938).Foster reports a series of 4-amino-quinazoline compound stablizing mutp53 activity conformation, and CP-31398 is one of them representative compound.Experimental study shows, and CP-31398 is 75% to the growth inhibition ratio of tumour, does not observe obvious toxic-side effects (Science, 1999,286 (5449): 2507-10; FOSTERBA, COFFEYHA, CONNELLRD.WO0032175,2000).
On the basis of 4-amino-quinazoline compound being carried out to extensively research, multiple structural points is modified and transformed, has synthesized the 4-amino-quinazoline compound of a series of novel structure.Anti tumor activity in vitro shaker test shows, this compounds has significant anti-tumor activity, and has the advantages such as molecular weight is little, synthesis is simple, toxic side effect is little.
4-aminoquinoline compounds carries out research report (Bioorganic & Medicinal Chemistry Letters as immunosuppressor at first, 1999 (9): 1819-1824), this compounds has immuno-stimulating antagonistic action, does not find the antitumor research report of being correlated with.By carrying out structure activity study to 4-amino-quinazoline compound, the a series of 4-aminoquinoline compounds of our design and synthesis, and anti tumor activity in vitro screening has been carried out to it, result of study shows this compounds and has outstanding anti-tumor activity, and this result shows that 4-aminoquinoline compounds has the purposes preparing antitumor drug.Therefore, a kind of 4-amido quinazoline is developed and 4-aminoquinoline compounds has vast potential for future development.
Summary of the invention
The object of the present invention is to provide a kind of 4-amido quinazoline and 4-aminoquinoline compounds and uses thereof, by carrying out structure activity study to 4-amino-quinazoline compound, the a series of 4-aminoquinoline compounds of our design and synthesis, and anti tumor activity in vitro screening has been carried out to it, result of study shows this compounds and has outstanding anti-tumor activity, this result shows that 4-aminoquinoline compounds has the purposes preparing antitumor drug, and has that molecular weight is little, synthesis is simple, toxic side effect is little.
The object of the present invention is achieved like this: a kind of 4-amino-quinazoline compound, the compound of general formula I, its configurational isomer and configurational isomer mixture thereof, or its pharmacy acceptable salt and/or hydrate,
Wherein:
R
1for any 1-3 is selected from hydrogen, hydroxyl, halo, cyano group, nitro, trifluoromethyl, trifluoromethoxy, C
1-C
6alkyl, C
1-C
6alkoxyl group, C
1-C
6alkylthio, C
1-C
6alkyloyl, C
1-C
4alkoxyl formyl, C
1-C
6alkyl sulphinyl, C
1-C
6alkyl sulphonyl, C
1-C
6alkylamidoalkyl, C
1-C
6alkylsulfonamido, list or two (C
1-C
6alkyl) substituting group of substituted-amino;
R
2and R
3identical or different, be separately selected from hydrogen, C
1-C
10alkyl, C
3-C
7cycloalkyl, 5-10 unit heterocyclic radical,
described C
1-C
10alkyl, C
3-C
7cycloalkyl and 5-10 unit heterocyclic radical can by the individual identical or different R of 1-3
6optional replacement;
N is the integer between 1-10;
R
4and R
5identical or different, be separately selected from hydrogen, C
1-C
10alkyl, C
3-C
7cycloalkyl, described C
1-C
10alkyl, C
3-C
7cycloalkyl can by the individual identical or different R of 1-3
6optional replacement;
Or R
4and R
5form 5-10 unit's heterocyclic radical or 5-10 unit heteroaryl together with its connected nitrogen-atoms, described heterocyclic radical and heteroaryl except with R
4and R
5outside the nitrogen-atoms connected, the heteroatoms of N, O and S can also be selected from containing 1-4, except R
4and R
5outside the nitrogen-atoms connected, described heterocyclyl comprises 0-2 carbon-carbon double bond or three key, and described heterocyclic radical and heteroaryl can by the individual identical or different R of 1-3
6optional replacement;
R
6for hydrogen, halo, hydroxyl, cyano group, nitro, C
1-C
4alkoxyl formyl, trifluoromethyl and trifluoromethoxy, C
1-C
6alkyl, C
1-C
6alkoxyl group;
Y is-NH-N=CH-Ar
1;
Ar
1represent C
6-C
10aryl, 5-10 unit's heteroaryl or 5-10 unit heterocyclic radical, wherein, described heteroaryl and heterocyclic radical can be selected from the heteroatoms of N, O or S containing 1-3, described heterocyclyl comprises 0-2 carbon-carbon double bond or three key, and Ar
1can by the individual identical or different R of 1-3
7optional replacement;
R
7represent hydrogen, halo, hydroxyl, C
1-C
4alkoxyl formyl, cyano group, amino, trifluoromethyl, trifluoromethoxy, C
1-C
6alkyl, C
1-C
6alkoxyl group, C
1-C
6alkylthio, (C
1-C
3) alkylenedioxy group, C
1-C
6alkyl acyl, C
1-C
6alkylamidoalkyl, list or two (C
1-C
6alkyl) substituted-amino, C
1-C
6alkyl sulphonyl, C
1-C
6alkyl sulphinyl, C
1-C
6alkylsulfonamido, phenyl, benzyl or naphthyl, described phenyl, benzyl or naphthyl can by the individual identical or different R of 1-3
8optional replacement;
R
8for hydrogen, halo, hydroxyl, cyano group, C
1-C
4alkoxyl formyl, trifluoromethyl, trifluoromethoxy, C
1-C
6alkyl, C
1-C
6alkoxyl group, C
1-C
6alkylthio, C
1-C
6alkyl acyl, C
1-C
6alkylamidoalkyl, list or two (C
1-C
6alkyl) substituted amido, C
1-C
6alkyl sulphonyl, C
1-C
6alkyl sulphinyl or C
1-C
6alkylsulfonamido;
Compound of Formula I, its configurational isomer and configurational isomer mixture thereof, or its pharmacy acceptable salt and/or hydrate,
Wherein:
R
1for any 1-3 is selected from hydrogen, halo, C
1-C
6the substituting group of alkyl;
R
2and R
3identical or different, be separately selected from hydrogen, 5-10 unit heterocyclic radical,
described 5-10 unit heterocyclic radical can by the individual identical or different R of 1-3
6optional replacement;
N is the integer between 1-10;
R
4and R
5identical or different, be separately selected from hydrogen, C
1-C
10alkyl;
Or R
4and R
5formed together with its connected nitrogen-atoms 5-10 unit heterocyclic radical, described heterocyclic radical except with R
4and R
5outside the nitrogen-atoms connected, can also be selected from the heteroatoms of N, O and S containing 1-4, described heterocyclic radical can by the individual identical or different R of 1-3
6optional replacement;
R
6for hydrogen, C
1-C
6alkyl;
Y is-NH-N=CH-Ar
1;
Ar
1represent C
6-C
10aryl or 5-10 unit heteroaryl, wherein, described heteroaryl can be selected from the heteroatoms of N, O or S containing 1-3, and Ar
1can by the individual identical or different R of 1-3
7optional replacement;
R
7represent hydrogen, halo, hydroxyl, cyano group, amino, trifluoromethyl, trifluoromethoxy, C
1-C
6alkyl, C
1-C
6alkoxyl group, (C
1-C
3) alkylenedioxy group, C
1-C
6alkyl sulphonyl or benzyl, described benzyl can by the individual identical or different R of 1-3
8optional replacement;
R
8for hydrogen, halo, hydroxyl, cyano group, trifluoromethyl, trifluoromethoxy, C
1-C
6alkyl, C
1-C
6alkoxyl group, C
1-C
6alkyl sulphonyl;
Compound of Formula I, its configurational isomer and configurational isomer mixture thereof, or its pharmacy acceptable salt and/or hydrate,
Wherein:
R
1for hydrogen, halo;
R
2and R
3identical or different, be separately selected from hydrogen, 5-10 unit heterocyclic radical,
described 5-10 unit heterocyclic radical can by the individual identical or different R of 1-3
6optional replacement;
N is the integer between 2-4;
R
4and R
5identical or different, be separately selected from hydrogen, C
1-C
4alkyl;
Or R
4and R
5formed together with its connected nitrogen-atoms 5-10 unit heterocyclic radical, described heterocyclic radical except with R
4and R
5outside the nitrogen-atoms connected, the heteroatoms of N, O and S can also be selected from containing 1-4;
R
6for C
1-C
6alkyl;
Y is-NH-N=CH-Ar
1;
Ar
1represent the phenyl of phenyl or replacement, 5-10 unit heteroaryl, wherein, described heteroaryl can be selected from the heteroatoms of N, O or S containing 1-3, and Ar
1can by the individual identical or different R of 1-3
7optional replacement;
Compound of Formula I, its configurational isomer and configurational isomer mixture thereof, or its pharmacy acceptable salt and/or hydrate,
Wherein:
R
1for hydrogen;
R
2for hydrogen, R
3be selected from 5-10 unit heterocyclic radical,
described 5-10 unit heterocyclic radical can by the individual identical or different R of 1-3
6optional replacement;
N is 2 or 3;
R
4and R
5identical, be C
1-C
4alkyl;
Or R
4and R
5formed together with its connected nitrogen-atoms 5-6 unit heterocyclic radical, described heterocyclic radical except with R
4and R
5outside the nitrogen-atoms connected, the heteroatoms of N, O and S can also be selected from containing 1-2;
R
6for C
1-C
4alkyl;
Compound of Formula I, its configurational isomer and configurational isomer mixture thereof, or its pharmacy acceptable salt and/or hydrate,
Wherein:
R
2for hydrogen, R
3be selected from 6 yuan of heterocyclic radicals,
described 6 yuan of heterocyclic radicals can by the individual identical or different R of 1-3
6optional replacement;
N is 2 or 3;
R
4and R
5identical, be methyl or ethyl;
Or R
4and R
5form 6 yuan of heterocyclic radicals together with its connected nitrogen-atoms, described heterocyclic radical except with R
4and R
5outside the nitrogen-atoms connected, the heteroatoms of N, O and S can also be selected from containing 1-2;
R
6for methyl;
Compound of Formula I, its configurational isomer and configurational isomer mixture thereof, or its pharmacy acceptable salt and/or hydrate,
Wherein:
R
2for hydrogen, R
3for
Compound of Formula I, its configurational isomer and configurational isomer mixture thereof, or its pharmacy acceptable salt and/or hydrate,
Wherein:
Y is-NH-N=CH-Ar
1;
Ar
1represent indol-3-yl, benzimidazolyl-2 radicals-Ji, imidazoles-2-base or contain 1-3 R
8substituent phenyl, pyridin-4-yl, pyridin-3-yl, thiophene-2-base, pyrroles-2-base, 3,4-methylenedioxyphenyls, wherein, the 1-position of described indol-3-yl, benzimidazolyl-2 radicals-Ji, imidazoles-2-base is by containing 1-3 R
8substituent benzyl replaces;
Following general formula I derivative, its configurational isomer and configurational isomer mixture thereof, or its pharmacy acceptable salt and/or hydrate:
2-[2-(4-chlorobenzene methylene radical) diazanyl]-4-(2-dimethylamino-1-ethylamino) quinazoline;
2-[2-(4-fluorobenzylidene) diazanyl]-4-(2-dimethylamino-1-ethylamino) quinazoline;
2-[2-(the chloro-4-fluorobenzylidene of 2-) diazanyl]-4-(2-dimethylamino-1-ethylamino) quinazoline;
2-[2-(4-methyl benzylidene) diazanyl]-4-(2-dimethylamino-1-ethylamino) quinazoline;
2-[2-(4-chlorobenzene methylene radical) diazanyl]-4-(3-dimethylamino-1-third is amino) quinazoline;
2-[2-(the chloro-4-fluorobenzylidene of 2-) diazanyl]-4-(3-dimethylamino-1-third is amino) quinazoline;
2-[2-(3,4-methylene-dioxy α-tolylene) diazanyl]-4-(3-dimethylamino-1-third is amino) quinazoline;
2-[2-(2-phenol methylene) diazanyl]-4-(3-dimethylamino-1-third is amino) quinazoline;
2-[2-(1H-pyrroles-2-methylene radical) diazanyl]-4-[3-(morpholine-4-base)-1-third is amino] quinazoline;
2-[2-(4-chlorobenzene methylene radical) diazanyl]-4-[3-(morpholine-4-base)-1-third is amino] quinazoline;
2-[2-(thiophene-2-methylene radical) diazanyl]-4-[3-(morpholine-4-base)-1-third is amino] quinazoline;
2-[2-(4-hydroxyl-3,5-dimethylbenzylidene) diazanyl]-4-[3-(morpholine-4-base)-1-third is amino] quinazoline;
2-[2-(4-chlorobenzene methylene radical) diazanyl]-4-(N-methyl piperidine-4-is amino) quinazoline;
2-[2-(4-fluorobenzylidene) diazanyl]-4-(N-methyl piperidine-4-is amino) quinazoline;
2-[2-(the chloro-4-fluorobenzylidene of 2-) diazanyl]-4-(N-methyl piperidine-4-is amino) quinazoline;
2-[2-(2-phenol methylene) diazanyl]-4-(N-methyl piperidine-4-is amino) quinazoline;
2-[2-(3-methoxybenzylidene) diazanyl]-4-(N-methyl piperidine-4-is amino) quinazoline;
2-[2-(1-benzyl-1H-imidazoles-2-methylene radical) diazanyl]-4-(2-dimethylamino-1-ethylamino) quinazoline;
2-{2-[1-(4-methyl-benzyl)-1H-imidazoles-2-methylene radical] diazanyl }-4-(2-dimethylamino-1-ethylamino) quinazoline;
2-{2-[1-(4-luorobenzyl)-1H-imidazoles-2-methylene radical] diazanyl }-4-(2-dimethylamino-1-ethylamino) quinazoline;
2-{2-[1-(2,3-dichloro benzyl)-1H-imidazoles-2-methylene radical] diazanyl }-4-(2-dimethylamino-1-ethylamino) quinazoline;
2-{2-[1-(4-methyl-benzyl)-1H-imidazoles-2-methylene radical] diazanyl }-4-(3-dimethylamino-1-third is amino) quinazoline;
2-{2-[1-(2,3-dichloro benzyl)-1H-imidazoles-2-methylene radical] diazanyl }-4-(3-dimethylamino-1-third is amino) quinazoline;
2-{2-[1-(4-methyl-benzyl)-1H-imidazoles-2-methylene radical] diazanyl }-4-[3-(morpholine-4-base)-1-third is amino] quinazoline;
2-{2-[1-(4-luorobenzyl)-1H-imidazoles-2-methylene radical] diazanyl }-4-[3-(morpholine-4-base)-1-third is amino] quinazoline;
2-{2-[1-(2,3-dichloro benzyl)-1H-imidazoles-2-methylene radical] diazanyl }-4-[3-(morpholine-4-base)-1-third is amino] quinazoline;
2-{2-[1-(3-chlorobenzyl)-1H-imidazoles-2-methylene radical] diazanyl }-4-[3-(morpholine-4-base)-1-third is amino] quinazoline;
2-[2-(1-benzyl-1H-imidazoles-2-methylene radical) diazanyl]-4-(N-methyl piperidine-4-is amino) quinazoline;
2-{2-[1-(4-methyl-benzyl)-1H-imidazoles-2-methylene radical] diazanyl }-4-(N-methyl piperidine-4-is amino) quinazoline;
2-{2-[1-(4-luorobenzyl)-1H-imidazoles-2-methylene radical] diazanyl }-4-(N-methyl piperidine-4-is amino) quinazoline;
2-{2-[1-(2,3-dichloro benzyl)-1H-imidazoles-2-methylene radical] diazanyl }-4-(N-methyl piperidine-4-is amino) quinazoline;
2-{2-[1-(3-luorobenzyl)-1H-indoles-3-methylene radical] diazanyl }-4-(2-dimethylamino-1-ethylamino) quinazoline;
2-{2-[1-(4-chlorobenzyl)-1H-indoles-3-methylene radical] diazanyl }-4-(2-dimethylamino-1-ethylamino) quinazoline;
2-{2-[1-(4-t-butylbenzyl)-1H-indoles-3-methylene radical] diazanyl }-4-(2-dimethylamino-1-ethylamino) quinazoline;
2-{2-[1-(3-luorobenzyl)-1H-indoles-3-methylene radical] diazanyl }-4-(3-dimethylamino-1-third is amino) quinazoline;
2-{2-[1-(4-chlorobenzyl)-1H-indoles-3-methylene radical] diazanyl }-4-(3-dimethylamino-1-third is amino) quinazoline;
2-{2-[1-(3-trifluoromethyl benzyl)-1H-indoles-3-methylene radical] diazanyl }-4-(3-dimethylamino-1-third is amino) quinazoline;
2-{2-[1-(2-chlorobenzyl)-1H-indoles-3-methylene radical] diazanyl }-4-[3-(morpholine-4-base)-1-third is amino] quinazoline;
2-{2-[1-(2,3-dichloro benzyl)-1H-indoles-3-methylene radical] diazanyl }-4-[3-(morpholine-4-base)-1-third is amino] quinazoline;
2-{2-[1-(3-trifluoromethyl benzyl)-1H-indoles-3-methylene radical] diazanyl }-4-[3-(morpholine-4-base)-1-third is amino] quinazoline;
2-{2-[1-(2-luorobenzyl)-1H-indoles-3-methylene radical] diazanyl }-4-(N-methyl piperidine-4-is amino) quinazoline;
2-{2-[1-(4-chlorobenzyl)-1H-indoles-3-methylene radical] diazanyl }-4-(N-methyl piperidine-4-is amino) quinazoline;
2-{2-[1-(2,3-dichloro benzyl)-1H-indoles-3-methylene radical] diazanyl }-4-(N-methyl piperidine-4-is amino) quinazoline;
2-{2-[1-(4-cyanobenzyls)-1H-indoles-3-methylene radical] diazanyl }-4-(N-methyl piperidine-4-is amino) quinazoline;
2-{2-[1-(3-chlorobenzyl)-1H-benzimidazolyl-2 radicals-methylene radical] diazanyl }-4-(2-dimethylamino-1-ethylamino) quinazoline;
2-{2-[1-(3,4-dichloro benzyl)-1H-benzimidazolyl-2 radicals-methylene radical] diazanyl }-4-(2-dimethylamino-1-ethylamino) quinazoline;
2-{2-[1-(4-t-butylbenzyl)-1H-benzimidazolyl-2 radicals-methylene radical] diazanyl }-4-(2-dimethylamino-1-ethylamino) quinazoline;
2-{2-[1-(2,3-dichloro benzyl)-1H-benzimidazolyl-2 radicals-methylene radical] diazanyl }-4-(3-dimethylamino-1-third is amino) quinazoline;
2-{2-[1-(3-trifluoromethyl benzyl)-1H-benzimidazolyl-2 radicals-methylene radical] diazanyl }-4-(3-dimethylamino-1-third is amino) quinazoline;
2-{2-[1-(4-methyl-benzyl)-1H-benzimidazolyl-2 radicals-methylene radical] diazanyl }-4-(3-dimethylamino-1-third is amino) quinazoline;
2-{2-[1-(2-luorobenzyl)-1H-benzimidazolyl-2 radicals-methylene radical] diazanyl }-4-[3-(morpholine-4-base)-1-third is amino] quinazoline;
2-{2-[1-(4-chlorobenzyl)-1H-benzimidazolyl-2 radicals-methylene radical] diazanyl }-4-[3-(morpholine-4-base)-1-third is amino] quinazoline;
2-{2-[1-(2,3-dichloro benzyl)-1H-benzimidazolyl-2 radicals-methylene radical] diazanyl }-4-[3-(morpholine-4-base)-1-third is amino] quinazoline;
2-[2-(1-benzyl-1H-benzimidazolyl-2 radicals-methylene radical) diazanyl]-4-(N-methyl piperidine-4-is amino) quinazoline;
2-{2-[1-(3,4-dichloro benzyl)-1H-benzimidazolyl-2 radicals-methylene radical] diazanyl }-4-(N-methyl piperidine-4-is amino) quinazoline;
2-{2-[1-(4-methyl-benzyl)-1H-benzimidazolyl-2 radicals-methylene radical] diazanyl }-4-(N-methyl piperidine-4-is amino) quinazoline;
A kind of medicinal compositions, to comprise in claim 1-8 any one compound, its configurational isomer and configurational isomer mixture thereof, or its pharmacy acceptable salt and/or hydrate are as activeconstituents and pharmaceutically acceptable excipient; Any one compound, its configurational isomer and configurational isomer mixture thereof in claim 1-8, or its pharmacy acceptable salt and/or hydrate are for the preparation of the application treated and/or prevented in tumor disease medicine;
A kind of 4-aminoquinoline compounds, compound of Formula I, its configurational isomer and configurational isomer mixture thereof, or its pharmacy acceptable salt and/or hydrate, for the preparation of the application treated and/or prevented in tumor disease medicine,
Wherein:
R
1for any 1-3 is selected from hydrogen, hydroxyl, halo, cyano group, nitro, trifluoromethyl, trifluoromethoxy, C
1-C
6alkyl, C
1-C
6alkoxyl group, C
1-C
6alkylthio, C
1-C
6alkyloyl, C
1-C
4alkoxyl formyl, C
1-C
6alkyl sulphinyl, C
1-C
6alkyl sulphonyl, C
1-C
6alkylamidoalkyl, C
1-C
6alkylsulfonamido, list or two (C
1-C
6alkyl) substituting group of substituted-amino;
R
2and R
3identical or different, be separately selected from hydrogen or
N is the integer between 1-10;
R
4and R
5identical or different, be separately selected from hydrogen or C
1-C
10alkyl, described C
1-C
10alkyl can by the individual identical or different R of 1-3
6optional replacement;
Or R
4and R
5formed together with its connected nitrogen-atoms 5-10 unit heterocyclic radical, described heterocyclic radical except with R
4and R
5outside the nitrogen-atoms connected, can also be selected from the heteroatoms of N, O and S containing 1-4, described heterocyclic radical can by the individual identical or different R of 1-3
6optional replacement;
R
6for hydrogen, halo, hydroxyl, cyano group, nitro, C
1-C
4alkoxyl formyl, trifluoromethyl and trifluoromethoxy, C
1-C
6alkyl, C
1-C
6alkoxyl group;
Y is-CH=CH-Ar
1;
Ar
1represent C
6-C
10aryl or 5-10 unit heteroaryl, wherein, described heteroaryl can be selected from the heteroatoms of N, O or S containing 1-3, and Ar
1can by the individual identical or different R of 1-3
7optional replacement;
R
7represent hydrogen, halo, hydroxyl, C
1-C
4alkoxyl formyl, cyano group, amino, trifluoromethyl, trifluoromethoxy, C
1-C
6alkyl, C
1-C
6alkoxyl group, C
1-C
6alkylthio, (C
1-C
3) alkylenedioxy group, C
1-C
6alkyl acyl, C
1-C
6alkylamidoalkyl, list or two (C
1-C
6alkyl) substituted-amino, C
1-C
6alkyl sulphonyl, C
1-C
6alkyl sulphinyl, C
1-C
6alkylsulfonamido, phenyl, benzyl or naphthyl, described phenyl, benzyl or naphthyl can by the individual identical or different R of 1-3
8optional replacement;
R
8for hydrogen, halo, hydroxyl, cyano group, C
1-C
4alkoxyl formyl, trifluoromethyl, trifluoromethoxy, C
1-C
6alkyl, C
1-C
6alkoxyl group, C
1-C
6alkylthio, C
1-C
6alkyl acyl, C
1-C
6alkylamidoalkyl, list or two (C
1-C
6alkyl) substituted amido, C
1-C
6alkyl sulphonyl, C
1-C
6alkyl sulphinyl or C
1-C
6alkylsulfonamido;
Following general formula I I derivative, its configurational isomer and configurational isomer mixture thereof, or its pharmacy acceptable salt and/or hydrate:
(E) the fluoro-2-of-6-[2-(4-p-methoxy-phenyl) vinyl]-4-(2-dimethylamino-1-ethylamino) quinoline;
(E) the fluoro-2-of-6-[2-(4-fluorophenyl) vinyl]-4-(2-dimethylamino-1-ethylamino) quinoline;
(E) the fluoro-2-of-6-[2-(4-methylsulfonyl phenyl) vinyl]-4-(2-dimethylamino-1-ethylamino) quinoline;
(E) the fluoro-2-of-6-(2-thiophene-2-base-vinyl)-4-(2-dimethylamino-1-ethylamino) quinoline;
(E) the fluoro-2-of-6-[2-(3,4-methylenedioxyphenyl) vinyl]-4-(2-dimethylamino-1-ethylamino) quinoline;
(E) the fluoro-2-of-6-[2-(4-fluorophenyl) vinyl]-4-(3-dimethylamino-1-third is amino) quinoline;
(E) the fluoro-2-of-6-[2-(4-methylsulfonyl phenyl) vinyl]-4-(3-dimethylamino-1-third is amino) quinoline;
(E) the fluoro-2-of-6-(2-thiophene-2-base-vinyl)-4-(3-dimethylamino-1-third is amino) quinoline;
(E) the fluoro-2-of-6-[2-(4-p-methoxy-phenyl) vinyl]-4-[3-(morpholine-4-base)-1-third is amino] quinoline;
(E) the fluoro-2-of-6-[2-(4-fluorophenyl) vinyl]-4-[3-(morpholine-4-base)-1-third is amino] quinoline;
(E) the chloro-2-of-6-[2-(4-p-methoxy-phenyl) vinyl]-4-(2-dimethylamino-1-ethylamino) quinoline;
(E) the chloro-2-of-6-[2-(4-fluorophenyl) vinyl]-4-(2-dimethylamino-1-ethylamino) quinoline;
(E) the chloro-2-of-6-[2-(4-methylsulfonyl phenyl) vinyl]-4-(2-dimethylamino-1-ethylamino) quinoline;
(E) the chloro-2-of-6-(2-thiophene-2-base-vinyl)-4-(2-dimethylamino-1-ethylamino) quinoline;
(E) the chloro-2-of-6-(2-pyridin-4-yl-vinyl)-4-(2-dimethylamino-1-ethylamino) quinoline;
(E) the chloro-2-of-6-[2-(4-fluorophenyl) vinyl]-4-(3-dimethylamino-1-third is amino) quinoline;
(E) the chloro-2-of-6-[2-(4-methylsulfonyl phenyl) vinyl]-4-(3-dimethylamino-1-third is amino) quinoline;
(E) the chloro-2-of-6-(2-pyridin-4-yl-vinyl)-4-(3-dimethylamino-1-third is amino) quinoline;
(E) the chloro-2-of-6-[2-(3,4,5-trimethoxyphenyl) vinyl]-4-(3-dimethylamino-1-third is amino) quinoline;
(E) the chloro-2-of-6-[2-(4-p-methoxy-phenyl) vinyl]-4-[3-(morpholine-4-base)-1-third is amino] quinoline;
(E) the chloro-2-of-6-[2-(4-fluorophenyl) vinyl]-4-[3-(morpholine-4-base)-1-third is amino] quinoline;
(E) the chloro-2-of-6-(2-thiophene-2-base-vinyl)-4-[3-(morpholine-4-base)-1-third is amino] quinoline;
(E) the chloro-2-of-6-[2-(3,4-methylenedioxyphenyl) vinyl]-4-[3-(morpholine-4-base)-1-third is amino] quinoline;
(E) the chloro-2-of the fluoro-7-of-6-[2-(4-p-methoxy-phenyl) vinyl]-4-(3-dimethylamino-1-third is amino) quinoline;
(E) the chloro-2-of the fluoro-7-of-6-[2-(4-fluorophenyl) vinyl]-4-(3-dimethylamino-1-third is amino) quinoline;
(E)-6-methyl-2-{2-[1-(2-chlorobenzyl)-1H-indol-3-yl] vinyl }-4-(2-dimethylamino-1-ethylamino) quinoline;
(E)-6-methyl-2-{2-[1-(2,3-dichloro benzyl)-1H-indol-3-yl] vinyl }-4-(2-dimethylamino-1-ethylamino) quinoline;
(E) the fluoro-2-{2-of-6-[1-(2-chlorobenzyl)-1H-indol-3-yl] vinyl }-4-(3-dimethylamino-1-third is amino) quinoline;
(E) the fluoro-2-{2-of-6-[1-(2,3-dichloro benzyl)-1H-indol-3-yl] vinyl }-4-(3-dimethylamino-1-third is amino) quinoline;
(E) the chloro-2-{2-of-6-[1-(2-chlorobenzyl)-1H-indol-3-yl] vinyl }-4-(3-dimethylamino-1-third is amino) quinoline;
(E) the chloro-2-{2-of-6-[1-(2,3-dichloro benzyl)-1H-indol-3-yl] vinyl }-4-(3-dimethylamino-1-third is amino) quinoline;
(E) the fluoro-2-{2-of-6-[1-(2-chlorobenzyl)-1H-indol-3-yl] vinyl }-4-[3-(morpholine-4-base)-1-third is amino] quinoline;
(E) the fluoro-2-{2-of-6-[1-(2,3-dichloro benzyl)-1H-indol-3-yl] vinyl }-4-[3-(morpholine-4-base)-1-third is amino] quinoline;
(E) the chloro-2-{2-of the fluoro-7-of-6-[1-(2-chlorobenzyl)-1H-indol-3-yl] vinyl }-4-(3-dimethylamino-1-third is amino) quinoline.
Main points structural formula of compound being it of the present invention and uses thereof.Its principle is, by carrying out structure activity study to 4-amino-quinazoline compound, the a series of 4-aminoquinoline compounds of our design and synthesis, and anti tumor activity in vitro screening has been carried out to it, result of study shows this compounds and has outstanding anti-tumor activity, and this result shows that 4-aminoquinoline compounds has the purposes preparing antitumor drug.
4-amido quinazoline and 4-aminoquinoline compounds and uses thereof are compared with prior art, there is this compounds and have significant anti-tumor activity, and there is the advantages such as molecular weight is little, synthesis is simple, toxic side effect is little, will be widely used in medical art.
Embodiment:
Embodiment is intended to set forth instead of limit the scope of the invention.The proton nmr spectra of compound measures with Bruker ARX-300, and mass spectrum Agilent 1100LC/MSD measures; Agents useful for same is analytical pure or chemical pure.
Ar
1the preparation of CHO intermediate
Partial aromatic aldehyde can commercially be buied; The preparation method of other aldehyde is as follows:
The preparation of method 1:1-substituted benzyl-indole-3-formaldehyde
Add in the DMF of 60mL by Anhydrous potassium carbonate (0.11mol), indole-3-formaldehyde (0.1mol), stirring at room temperature 20 minutes, adds ArCH in reaction solution
2cl (0.1mol).Drip and finish, room temperature reaction 6h, pours in 300mL water by reaction solution, stirs 0.5h, suction filtration, washing, dry 1-substituted benzyl-indoles-3 formaldehyde.
The preparation of method 2:1-substituted benzyl-benzimidazolyl-2 radicals-formaldehyde and 1-substituted benzyl-imidazoles-2-formaldehyde
Add in the DMF of 50mL by Anhydrous potassium carbonate (0.11mol), benzoglyoxaline (0.1mol), stirring at room temperature 20 minutes, adds ArCH
2cl (0.11mol), is warming up to 50 DEG C of reaction 2h.Be cooled to room temperature, reaction solution poured in 250mL water, stir 0.5h, suction filtration, washing repeatedly, dry 1-substituted benzyl benzoglyoxaline.
Add in the DMF of 50mL by Anhydrous potassium carbonate (0.11mol), imidazoles (0.1mol), stirring at room temperature 20 minutes, adds ArCH
2cl (0.11mol), is warming up to 50 DEG C of reaction 2h.Be cooled to room temperature, poured into by reaction solution in 250mL water, stir 0.5h, dichloromethane extraction, repeatedly, saturated common salt water washing, anhydrous sodium sulfate drying, removes the 1-substituted benzyl imidazoles that solvent obtains oily under reduced pressure, can be directly used in next step reaction in washing.
1-substituted benzyl benzoglyoxaline or 1-substituted benzyl imidazoles (0.03mol) are dissolved in the tetrahydrofuran (THF) that 60mL heavily steams; under nitrogen protection; be cooled to less than-78 DEG C; slow dropping n-Butyl Lithium (0.04mol); keep temperature of reaction not higher than-78 DEG C; drip and finish, rise to-60 DEG C of reaction 1h.Again be cooled to less than-78 DEG C, drip dry DMF (0.1mol), keep temperature of reaction not higher than-78 DEG C, drip and finish, insulation reaction 10 minutes 1h, rise to room temperature reaction 2h.Saturated aqueous ammonium chloride 50mL is added in reaction solution, stir 1h, ether extraction, successively with water, saturated common salt washing, anhydrous sodium sulfate drying, evaporated under reduced pressure solvent, crude product petrol ether/ethyl acetate column chromatography for separation, obtains 1-substituted benzyl-benzimidazolyl-2 radicals-formaldehyde or 1-substituted benzyl-imidazoles-2-formaldehyde.
The logical method 1 (route A) of preparation:
Steps A: R
1the preparation of-2,4-dihydroxyl quinazolines (A-1)
Will containing R
1substituent anthranilic acid (0.5mol) and urea (3.5mol) are mixed and heated to 160 DEG C and react 12h, reaction is cooled to 100 DEG C night, adds 250mL water, continue backflow 1h, be cooled to 60 DEG C, while hot suction filtration, washing repeatedly, dry R
1-2,4-dihydroxyl quinazolines (A-1), yield: 85%-90%.
Step B:R
1the preparation of-2,4-dichloroquinazolines (A-2)
Compd A-1 (0.3mol) is added in 200mL phosphorus oxychloride, drips DIPEA (0.6mol), drip and finish, be warming up to 90 DEG C of reaction 6h.Steam except most of phosphorus oxychloride, poured in frozen water by residue and stir 0.5h, suction filtration, washing, dry, methylene dichloride/acetone (2:1) recrystallization obtains compd A-2, yield: 90%-95%.
Step C:R
1the preparation of-2-chloro-4-substituted-amino quinazoline (A-3)
Compd A-2 (0.05mol) is added in 80mL tetrahydrofuran solution, under stirring, adds triethylamine (0.075mol) and NHR successively
2r
3(0.05mol), be warming up to 30 DEG C of reactions 15 minutes, solvent evaporated, add water and stir 0.5h, suction filtration, washing, dry compd A-3, yield: 80-100%.
Step D:R
1the preparation of-2-diazanyl-4-substituted-amino quinazoline (A-4)
Compd A-3 (0.02mol) is dissolved in 10mL ethanol, slowly be added drop-wise in the hydrazine hydrate solution of 80 DEG C 80%, finish, be warming up to 100 DEG C of reaction 1h, be cooled to room temperature, filter, filtrate adds water with n-butanol extraction, successively with water, saturated common salt washing, and anhydrous sodium sulfate drying, evaporate to dryness obtains compd A-4, yield: 82-88%.
Step e: R
1the preparation of-[2-(N'-substituted methylene)-diazanyl]-4-substituted-amino quinazoline (A-5)
Compd A-4 (1mmol) and replacement aldehyde (1mmol) are dissolved in reflux in toluene reaction 2h, solvent evaporated, add ether and stir 0.5h, filter, dry, methylene chloride/methanol column chromatography purification obtains compd A-5, yield: 65-80%
According to the logical method 1 of preparation, respectively obtained embodiment 1-73 compound (see table one).
Table one:
The logical method 2 (route B) of preparation:
Steps A: the preparation of (E)-3-substituted anilinic-2-butylene acetoacetic ester (B-1)
Will containing R
1substituent aniline (0.1mol) and methyl aceto acetate (0.12mol) mix to dissolving, add ceric ammonium nitrate (1mmol), and 40 DEG C are stirred 24h.Add 10ml ethanol and stir 0.5h, be cooled to room temperature, suction filtration, appropriate ice washing with alcohol, dry compd B-1, yield: 54-72%.
Step B:R
1the preparation of-2-methyl-4-hydroxyquinoline (B-2)
150ml phenyl ether is heated to 250 DEG C, add compd B-1 (0.1mol) in batches, keep temperature of reaction not higher than 255 DEG C, shoot until no longer include ethanol, reaction is cooled to 40 DEG C night, add 150ml ether, return stirring 20 minutes, slightly cold, suction filtration while hot, petroleum ether, dry compd B-2, yield: 89-95%.
Step C:R
1the preparation of-2-methyl-4-chloroquinoline (B-3)
Compd B-2 (0.05mol) is dissolved in 30ml phosphorus oxychloride, be warming up to 80 DEG C of reaction 1.5h, be cooled to room temperature, steam except most of solvent, residue is poured in frozen water and stirs 0.5h, filtering insolubles, filtrate adds ammoniacal liquor and adjusts PH8-9, suction filtration, washing and drying obtains intermediate B-3, yield: 88-95%.
Step D:R
1the preparation of-2-methyl-4-substituted-amino quinoline (B-4)
Compd B-3 (0.05mol) is dissolved in NHR2R35 (0.25mol), is warming up to 110 DEG C of reaction 6-12h, is cooled to room temperature, adds 200ml water, stir 0.5h, suction filtration, washing repeatedly, dry compd B-4, yield: 95-99%.
Step e: R
1the preparation of-2-substituted ethylene base-4-substituted-amino quinoline (B-5)
Compd B-4 (0.01mol) is dissolved in 5mLDMF, adds catalytic amount zinc chloride, back flow reaction 1h, be cooled to room temperature, add 15mL methyl alcohol, backflow 0.5h, suction filtration, methanol wash column, dry compd B-5, yield: 74-92%.
According to the logical method 2 of preparation, respectively obtained embodiment 74-116 compound (see table two).
Table two:
The anti tumor activity in vitro research of product of the present invention
Carried out anti tumor activity in vitro screening to the 4-amino-quinazoline of above formula I provided by the invention or the 4-aminoquinoline compounds of formula II, result is as follows.
Adopting mtt assay, is that positive control drug, test compounds are to the In Vitro Anti proliferation activity of one or more tumour cells with CP-31398.The tumour cell of taking the logarithm vegetative period, centrifugal rear RPMI-1640 nutrient solution is diluted to 4 × 10
4individual/mL, is inoculated in 96 orifice plates, adds the sample of different concns, hatching 24h after 37 DEG C of cultivation 12h.Add MTT solution (5 μ gmL
-1), after hatching 4h, every hole adds the dimethyl sulfoxide (DMSO) of 100 μ L, measures and absorbs angle value (630nm is with reference to wavelength), calculate IC by Bliss method at 492nm place
50value, Activity Results is in table three, table four and table five.
Table three:
Table four:
Table five:
The effect of the compounds of this invention at anti-tumor aspect of above test-results preliminary proof, should have a good application prospect.
According to some usual methods in field belonging to the present invention, the 4-amino-quinazoline of above formula I of the present invention or the 4-aminoquinoline compounds of formula II can generate its pharmacy acceptable salt with acid.Acid can comprise mineral acid or organic acid, and the salt formed with following acid is particularly preferred: hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, methylsulfonic acid, ethyl sulfonic acid, toluenesulphonic acids, Phenylsulfonic acid, naphthalene disulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, toxilic acid, citric acid, fumaric acid, Tartaric acid, Phenylsulfonic acid, phenylformic acid or tosic acid etc.
The compounds of this invention can exist with stereoisomer form, and these stereoisomeric forms in any ratio can be configurational isomer or configurational isomer mixture.The present invention both related to configurational isomer, also related to their respective mixtures, according to self known method, isomer mixture can be separated into stereomeric one-component.
In addition, the present invention also comprises the prodrug of the compounds of this invention.According to the present invention, prodrug is the derivative of formula I or II compound, they self may have more weak activity or even not have activity, but (such as by metabolism, solvolysis or other mode) is converted to corresponding biologically active form upon administration, in physiological conditions.
Unless otherwise noted, term used herein " halo " refers to fluoro, chloro, bromo or iodo, " alkyl " refers to the alkyl of straight or branched, " cycloalkyl " refers to substituted or unsubstituted cycloalkyl, " thiazolinyl " refers to the thiazolinyl of straight or branched, " alkynyl " refers to the alkynyl of straight or branched, " aryl " refers to a hydrogen atom in removing aromatic hydrocarbons and the organic group that obtains, as phenyl, naphthyl, 5-10 unit heteroaryl comprises and is selected from N containing one or more, the heteroatoms of O and S, wherein the ring-type system of each heteroaryl can be monocycle or many rings, ring-type system is aromaticity, altogether containing 5-10 atom, such as imidazolyl can be enumerated, pyridyl, pyrimidyl, pyrazolyl, (1, 2, 3)-and (1, 2, 4)-triazolyl, pyrazinyl, tetrazyl, furyl, thienyl, isoxazolyl, oxazolyl, pyrazolyl, pyrryl, thiazolyl, benzothienyl, benzofuryl, benzimidazolyl-, benzothiazolyl, indyl, quinolyl etc., 5-10 unit heterocyclic radical comprises containing one or more heteroatoms being selected from N, O and S, wherein the ring-type system of each heterocyclic radical can be monocycle or many rings, but be nonaromatic, ring-type system is altogether containing 5-10 atom, optionally can comprise 1 or 2 carbon-carbon double bond or carbon-carbon triple bond, such as pyrrolidyl, morpholinyl, piperazinyl, piperidyl, thiazolinyl etc. can be enumerated.
Compound of the present invention has double bond structure, therefore exists with the form of different configurational isomers and isomer mixture.All configurational isomers that the present invention relates to the compounds of this invention and composition thereof.
Owing to having antitumor action according to the 4-amino-quinazoline of above formula I of the present invention or the 4-aminoquinoline compounds of formula II, therefore, it can be used as the medicine, particularly solid tumor that preparation treats and/or prevents tumor disease.
Compound according to the present invention can be used as activeconstituents for the preparation for the treatment of and/or preventing tumor disease, the present invention also provides treatment or prevents the method for above-mentioned disease, comprise the patient significant quantity suffering from or easily suffer from this disease according to compound of the present invention.
The present invention includes pharmaceutical composition, said composition contains the 4-amino-quinazoline of above formula I or the 4-aminoquinoline compounds of formula II or its pharmacy acceptable salt as activeconstituents, and pharmaceutically acceptable excipient.Described pharmaceutically acceptable excipient refers to any thinner, auxiliary and/or the carrier that can be used for pharmaceutical field.Compound of the present invention can use with other active ingredient combinations, such as, as long as they do not produce other disadvantageous effect, anaphylaxis.
Pharmaceutical composition of the present invention can be mixed with several formulation, wherein containing some vehicle conventional in pharmaceutical field; Such as, oral preparations (as tablet, capsule, solution or suspension); Injectable preparation (as injectable solution or suspension, or injectable dried powder, adding water for injection before the injection can use immediately); Topical formulations (such as ointment or solution).
Carrier for pharmaceutical composition of the present invention is available common type in pharmaceutical field, comprising: the tackiness agent, lubricant, disintegrating agent, solubility promoter, thinner, stablizer, suspension agent, non-pigment, correctives etc. of oral preparations; The sanitas, solubilizing agent, stablizer etc. of injectable formulation; The matrix, thinner, lubricant, sanitas etc. of topical formulations.Pharmaceutical preparation can oral administration or parenteral (such as intravenously, subcutaneous, intraperitoneal or local) administration, if some drugs is unstable under stomach condition, can be mixed with enteric coated tablets.
And, the 4-amino-quinazoline of above formula I or the 4-aminoquinoline compounds of formula II are used for the clinical dosage of patient can basis: the age of activeconstituents therapeutic efficiency in vivo and bioavailability, their metabolism and discharge rate and patient, sex, disease phase suitably adjust, but every per daily dose of adult generally should be 10-500mg, is preferably 50-300mg.Therefore, when pharmaceutical composition of the present invention is made into unit dosage, consider above-mentioned effective dose, per unit preparation should contain the 4-amino-quinazoline of 10-500mg above formula I or the 4-aminoquinolines of formula II, is preferably 50-300mg.According to the guidance of doctor or pharmacist, these preparations can divide several times administration (being preferably to six time) at certain intervals.
Synthetic route A-B describes the preparation of formula I of the present invention or formula II compound below, and all raw materials are all methods by describing in these schematic diagram, prepared by the method known by organic chemistry filed those of ordinary skill or commercially available.Whole finalization compound of the present invention is all method by describing in these schematic diagram or is prepared by similar method, and these methods are that organic chemistry filed those of ordinary skill is known.The whole variable factors applied in these schematic diagram are as definition hereafter or as the definition in claim.
According to type I compound of the present invention, in route A, Y is-NH-N=CH-Ar
1, substituent R
1, R
2, R
3and Ar
1as claim 1 define, according to preferred version of the present invention, Ar
1can be indol-3-yl, benzimidazolyl-2 radicals-Ji, imidazoles-2-base or containing 1-3 R
8substituent phenyl, pyridin-4-yl, pyridin-3-yl, thiophene-2-base, pyrroles-2-base, 3,4-methylenedioxyphenyls, wherein, the 1-position of described indol-3-yl, benzimidazolyl-2 radicals-Ji, imidazoles-2-base is by containing 1-3 R
8substituent benzyl replaces.
By R
1the anthranilic acid and the urea that replace are mixed and heated to molten state, reacting generating compound 3,4-dihydroxyl quinazoline (A-1), obtain 2,4-dichloroquinazoline (A-2) through phosphorus oxychloride chloro, afterwards and NHR
2r
3in tetrahydrofuran (THF), stirring at room temperature obtains compound 2-chloro-4-substituted-amino quinazoline (A-3), then back flow reaction obtains 2-diazanyl-4-substituted-amino quinazoline (A-4) in hydrazine hydrate, last and various aldehyde Ar
1cHO condensation obtains the compd A-5 of formula I.
According to formula II compound of the present invention, in route B, substituent R
1, R
2, R
3and Ar
1as summary of the invention part define.
Under room temperature condition, containing substituent R
1aniline and methyl aceto acetate react under ceric ammonium nitrate catalysis and generate condensation intermediate (B-1), in phenyl ether, high temperature cyclization obtains 2-methyl-4-hydroxyquinoline (B-2), 2-methyl-4-chloroquinoline (B-3) is obtained again by phosphorus oxychloride chloro, react with various replacement amine afterwards and generate 2-methyl-4-substituted-amino quinoline (B-4), finally under Zinc Chloride Anhydrous catalysis with various aldehyde Ar
1cHO condensation obtains the compd B-5 of formula II.
Claims (8)
1. a 4-amino-quinazoline compound, is characterized in that: the compound of general formula I or its pharmacy acceptable salt,
Wherein:
R
1for any 1-3 is selected from hydrogen, halogen, C
1-C
6the substituting group of alkyl;
R
2and R
3identical or different, be separately selected from hydrogen, 5-10 unit heterocyclic radical,
described 5-10 unit heterocyclic radical can by the individual identical or different R of 1-3
6optional replacement;
N is 2 or 3;
R
4and R
5identical or different, be separately selected from hydrogen, methyl;
Or R
4and R
55-10 unit heterocyclic radical is formed together with its connected nitrogen-atoms;
R
6for hydrogen, methyl;
Y is-NH-N=CH-Ar
1;
Ar
1represent phenyl or 5-10 unit heteroaryl, wherein, described heteroaryl can be selected from the heteroatoms of N, O or S containing 1-3, and Ar
1can by the individual identical or different R of 1-3
7optional replacement;
R
7represent hydrogen, halogen, hydroxyl, cyano group, trifluoromethyl, C
1-C
6alkyl, (C
1-C
3) alkylenedioxy group, benzyl, described benzyl can by the identical or different R of 1-3
8optional replacement;
R
8for hydrogen, halogen, hydroxyl, cyano group, trifluoromethyl, C
1-C
6alkyl.
2. 4-amino-quinazoline compound according to claim 1, is characterized in that: compound of Formula I or its pharmacy acceptable salt,
Wherein:
R
1for hydrogen;
R
2for hydrogen, R
3be selected from 5-10 unit heterocyclic radical,
described 5-10 unit heterocyclic radical can by the individual identical or different R of 1-3
6optional replacement;
R
4and R
5identical, be methyl;
Or R
4and R
55-6 unit heterocyclic radical is formed together with its connected nitrogen-atoms;
R
6for methyl.
3. 4-amino-quinazoline compound according to claim 2, is characterized in that: compound of Formula I or its pharmacy acceptable salt,
Wherein:
R
2for hydrogen, R
3be selected from 6 yuan of heterocyclic radicals,
described 6 yuan of heterocyclic radicals can by the individual identical or different R of 1-3
6optional replacement;
R
4and R
5identical, be methyl;
Or R
4and R
5form 6 yuan of heterocyclic radicals together with its connected nitrogen-atoms, described heterocyclic radical except with R
4and R
5outside the nitrogen-atoms connected, the heteroatoms of N, O and S can also be selected from containing 1-2;
R
6for methyl.
4. 4-amino-quinazoline compound according to claim 3, is characterized in that: compound of Formula I or its pharmacy acceptable salt,
Wherein:
R
2for hydrogen, R
3for
5. 4-amino-quinazoline compound according to claim 4, is characterized in that: compound of Formula I or its pharmacy acceptable salt,
Wherein:
Y is-NH-N=CH-Ar
1;
Ar
1represent indol-3-yl, benzimidazolyl-2 radicals-Ji, imidazoles-2-base or contain 1-3 R
8substituent phenyl, pyridin-4-yl, pyridin-3-yl, thiophene-2-base, pyrroles-2-base, 3,4-methylenedioxyphenyls, wherein, the 1-position of described indol-3-yl, benzimidazolyl-2 radicals-Ji, imidazoles-2-base is by containing 1-3 R
8substituent benzyl replaces.
6. 4-amino-quinazoline compound according to claim 5, is characterized in that: following general formula I derivative or its pharmacy acceptable salt:
2-[2-(4-chlorobenzene methylene radical) diazanyl]-4-(2-dimethylamino-1-ethylamino) quinazoline;
2-[2-(4-fluorobenzylidene) diazanyl]-4-(2-dimethylamino-1-ethylamino) quinazoline;
2-[2-(the chloro-4-fluorobenzylidene of 2-) diazanyl]-4-(2-dimethylamino-1-ethylamino) quinazoline;
2-[2-(4-methyl benzylidene) diazanyl]-4-(2-dimethylamino-1-ethylamino) quinazoline;
2-[2-(4-chlorobenzene methylene radical) diazanyl]-4-(3-dimethylamino-1-third is amino) quinazoline;
2-[2-(the chloro-4-fluorobenzylidene of 2-) diazanyl]-4-(3-dimethylamino-1-third is amino) quinazoline;
2-[2-(3,4-methylene-dioxy α-tolylene) diazanyl]-4-(3-dimethylamino-1-third is amino) quinazoline;
2-[2-(2-phenol methylene) diazanyl]-4-(3-dimethylamino-1-third is amino) quinazoline;
2-[2-(1H-pyrroles-2-methylene radical) diazanyl]-4-[3-(morpholine-4-base)-1-third is amino] quinazoline;
2-[2-(4-chlorobenzene methylene radical) diazanyl]-4-[3-(morpholine-4-base)-1-third is amino] quinazoline;
2-[2-(thiophene-2-methylene radical) diazanyl]-4-[3-(morpholine-4-base)-1-third is amino] quinazoline;
2-[2-(4-hydroxyl-3,5-dimethylbenzylidene) diazanyl]-4-[3-(morpholine-4-base)-1-third is amino] quinazoline;
2-[2-(4-chlorobenzene methylene radical) diazanyl]-4-(N-methyl piperidine-4-is amino) quinazoline;
2-[2-(4-fluorobenzylidene) diazanyl]-4-(N-methyl piperidine-4-is amino) quinazoline;
2-[2-(the chloro-4-fluorobenzylidene of 2-) diazanyl]-4-(N-methyl piperidine-4-is amino) quinazoline;
2-[2-(2-phenol methylene) diazanyl]-4-(N-methyl piperidine-4-is amino) quinazoline;
2-[2-(3-methoxybenzylidene) diazanyl]-4-(N-methyl piperidine-4-is amino) quinazoline;
2-[2-(1-benzyl-1H-imidazoles-2-methylene radical) diazanyl]-4-(2-dimethylamino-1-ethylamino) quinazoline;
2-{2-[1-(4-methyl-benzyl)-1H-imidazoles-2-methylene radical] diazanyl }-4-(2-dimethylamino-1-ethylamino) quinazoline;
2-{2-[1-(4-luorobenzyl)-1H-imidazoles-2-methylene radical] diazanyl }-4-(2-dimethylamino-1-ethylamino) quinazoline;
2-{2-[1-(2,3-dichloro benzyl)-1H-imidazoles-2-methylene radical] diazanyl }-4-(2-dimethylamino-1-ethylamino) quinazoline;
2-{2-[1-(4-methyl-benzyl)-1H-imidazoles-2-methylene radical] diazanyl }-4-(3-dimethylamino-1-third is amino) quinazoline;
2-{2-[1-(2,3-dichloro benzyl)-1H-imidazoles-2-methylene radical] diazanyl }-4-(3-dimethylamino-1-third is amino) quinazoline;
2-{2-[1-(4-methyl-benzyl)-1H-imidazoles-2-methylene radical] diazanyl }-4-[3-(morpholine-4-base)-1-third is amino] quinazoline;
2-{2-[1-(4-luorobenzyl)-1H-imidazoles-2-methylene radical] diazanyl }-4-[3-(morpholine-4-base)-1-third is amino] quinazoline;
2-{2-[1-(2,3-dichloro benzyl)-1H-imidazoles-2-methylene radical] diazanyl }-4-[3-(morpholine-4-base)-1-third is amino] quinazoline;
2-{2-[1-(3-chlorobenzyl)-1H-imidazoles-2-methylene radical] diazanyl }-4-[3-(morpholine-4-base)-1-third is amino] quinazoline;
2-[2-(1-benzyl-1H-imidazoles-2-methylene radical) diazanyl]-4-(N-methyl piperidine-4-is amino) quinazoline;
2-{2-[1-(4-methyl-benzyl)-1H-imidazoles-2-methylene radical] diazanyl }-4-(N-methyl piperidine-4-is amino) quinazoline;
2-{2-[1-(4-luorobenzyl)-1H-imidazoles-2-methylene radical] diazanyl }-4-(N-methyl piperidine-4-is amino) quinazoline;
2-{2-[1-(2,3-dichloro benzyl)-1H-imidazoles-2-methylene radical] diazanyl }-4-(N-methyl piperidine-4-is amino) quinazoline;
2-{2-[1-(3-luorobenzyl)-1H-indoles-3-methylene radical] diazanyl }-4-(2-dimethylamino-1-ethylamino) quinazoline;
2-{2-[1-(4-chlorobenzyl)-1H-indoles-3-methylene radical] diazanyl }-4-(2-dimethylamino-1-ethylamino) quinazoline;
2-{2-[1-(4-t-butylbenzyl)-1H-indoles-3-methylene radical] diazanyl }-4-(2-dimethylamino-1-ethylamino) quinazoline;
2-{2-[1-(3-luorobenzyl)-1H-indoles-3-methylene radical] diazanyl }-4-(3-dimethylamino-1-third is amino) quinazoline;
2-{2-[1-(4-chlorobenzyl)-1H-indoles-3-methylene radical] diazanyl }-4-(3-dimethylamino-1-third is amino) quinazoline;
2-{2-[1-(3-trifluoromethyl benzyl)-1H-indoles-3-methylene radical] diazanyl }-4-(3-dimethylamino-1-third is amino) quinazoline;
2-{2-[1-(2-chlorobenzyl)-1H-indoles-3-methylene radical] diazanyl }-4-[3-(morpholine-4-base)-1-third is amino] quinazoline;
2-{2-[1-(2,3-dichloro benzyl)-1H-indoles-3-methylene radical] diazanyl }-4-[3-(morpholine-4-base)-1-third is amino] quinazoline;
2-{2-[1-(3-trifluoromethyl benzyl)-1H-indoles-3-methylene radical] diazanyl }-4-[3-(morpholine-4-base)-1-third is amino] quinazoline;
2-{2-[1-(2-luorobenzyl)-1H-indoles-3-methylene radical] diazanyl }-4-(N-methyl piperidine-4-is amino) quinazoline;
2-{2-[1-(4-chlorobenzyl)-1H-indoles-3-methylene radical] diazanyl }-4-(N-methyl piperidine-4-is amino) quinazoline;
2-{2-[1-(2,3-dichloro benzyl)-1H-indoles-3-methylene radical] diazanyl }-4-(N-methyl piperidine-4-is amino) quinazoline;
2-{2-[1-(4-cyanobenzyls)-1H-indoles-3-methylene radical] diazanyl }-4-(N-methyl piperidine-4-is amino) quinazoline;
2-{2-[1-(3-chlorobenzyl)-1H-benzimidazolyl-2 radicals-methylene radical] diazanyl }-4-(2-dimethylamino-1-ethylamino) quinazoline;
2-{2-[1-(3,4-dichloro benzyl)-1H-benzimidazolyl-2 radicals-methylene radical] diazanyl }-4-(2-dimethylamino-1-ethylamino) quinazoline;
2-{2-[1-(4-t-butylbenzyl)-1H-benzimidazolyl-2 radicals-methylene radical] diazanyl }-4-(2-dimethylamino-1-ethylamino) quinazoline;
2-{2-[1-(2,3-dichloro benzyl)-1H-benzimidazolyl-2 radicals-methylene radical] diazanyl }-4-(3-dimethylamino-1-third is amino) quinazoline;
2-{2-[1-(3-trifluoromethyl benzyl)-1H-benzimidazolyl-2 radicals-methylene radical] diazanyl }-4-(3-dimethylamino-1-third is amino) quinazoline;
2-{2-[1-(4-methyl-benzyl)-1H-benzimidazolyl-2 radicals-methylene radical] diazanyl }-4-(3-dimethylamino-1-third is amino) quinazoline;
2-{2-[1-(2-luorobenzyl)-1H-benzimidazolyl-2 radicals-methylene radical] diazanyl }-4-[3-(morpholine-4-base)-1-third is amino] quinazoline;
2-{2-[1-(4-chlorobenzyl)-1H-benzimidazolyl-2 radicals-methylene radical] diazanyl }-4-[3-(morpholine-4-base)-1-third is amino] quinazoline;
2-{2-[1-(2,3-dichloro benzyl)-1H-benzimidazolyl-2 radicals-methylene radical] diazanyl }-4-[3-(morpholine-4-base)-1-third is amino] quinazoline;
2-[2-(1-benzyl-1H-benzimidazolyl-2 radicals-methylene radical) diazanyl]-4-(N-methyl piperidine-4-is amino) quinazoline;
2-{2-[1-(3,4-dichloro benzyl)-1H-benzimidazolyl-2 radicals-methylene radical] diazanyl }-4-(N-methyl piperidine-4-is amino) quinazoline;
2-{2-[1-(4-methyl-benzyl)-1H-benzimidazolyl-2 radicals-methylene radical] diazanyl }-4-(N-methyl piperidine-4-is amino) quinazoline.
7. a medicinal compositions, described medicinal compositions comprises compound any one of at least one claim 1-6 of the therapeutic dose mixed with pharmaceutically acceptable carrier or its pharmacy acceptable salt.
8. in claim 1-6 any one compound or its pharmacy acceptable salt for the preparation of the application treated and/or prevented in lung cancer, liver cancer, colorectal carcinoma, stomach cancer medicine.
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| CN101263124A (en) * | 2005-07-15 | 2008-09-10 | 先灵公司 | Quinazoline derivatives useful in cancer treatment |
| CN102250075A (en) * | 2010-05-21 | 2011-11-23 | 中国医学科学院药物研究所 | 2,4-disubstituted quinazoline compounds and preparation method, medicinal composition and application thereof |
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| CN101263124A (en) * | 2005-07-15 | 2008-09-10 | 先灵公司 | Quinazoline derivatives useful in cancer treatment |
| CN102250075A (en) * | 2010-05-21 | 2011-11-23 | 中国医学科学院药物研究所 | 2,4-disubstituted quinazoline compounds and preparation method, medicinal composition and application thereof |
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| Synthesis and in vitro cytotoxic evaluation of 2-hydrazinylpyrido[2,3-b]pyrazin-3(4H)-one derivatives;Guo Gang Zhang et al;《Chinese Chemical Letters》;20110720;第22卷(第10期);1223-1225，第1223页第2段第3行 * |
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