CN102702116B - 4-(3-chloro-4-methoxylanilino)-6-(3-amidophenyl)quinazoline compound or pharmaceutically-acceptable salt thereof and preparation methods and applications thereof - Google Patents
4-(3-chloro-4-methoxylanilino)-6-(3-amidophenyl)quinazoline compound or pharmaceutically-acceptable salt thereof and preparation methods and applications thereof Download PDFInfo
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Abstract
The invention discloses a 4-(3-chloro-4-methoxylanilino)-6-(3-amidophenyl)quinazoline compound shown as a structure formula (I). In the structure formula (I), R is any one of -H, -COCH3, -COCF3, -COCH=CHCOOH, -COCH2Cl, -COCCl3, -COCH=CH2, -COC(CH3)3, -COCH2CH3 and -COHBrCH3. The invention further relates to a preparation method of the compound, a pharmaceutically-acceptable salt of the compound, and applications of the compound and the pharmaceutically-acceptable salt thereof to preparation of an antitumor medicament.
Description
Technical field
The present invention relates to chemical synthetic drug technical field, be specifically related to an organic micromolecule 4-(3-chloro-4-methoxy anilino)-6-(3-aminocarbonyl phenyl) quinazoline compounds or its pharmacy acceptable salt, their preparation method and preparing the application in antitumor drug.
Background technology
Cancer is one of principal disease of serious harm human health, and the number dying from cancer is every year cumulative year after year trend.Cancer has become the second largest killer of the mankind being only second to cardiovascular diseases.Capture cancer is the research topic attracted attention in the world always.Treatment at present for cancer mainly contains the methods such as operative treatment, radiotherapy, chemotherapy, and wherein chemotherapy accounts for very important status in the treatment of cancer.
Traditional cancer therapy drug mainly cytotoxic drug, this kind of cancer therapy drug mainly acts on the key ingredient such as DNA, RNA and tubulin of cell, and great majority are nonselective, while killing and wounding cancer cells, also can kill and wound the normal cell of body, there is the shortcoming such as poor selectivity, strong, the easy generation resistance of toxic side effect being difficult to avoid.
Significantly not enough in order to overcome these of conventional anti-cancer medicines, the mankind are very active for the research and development of the organic molecule PTS with target feature.Organic molecule PTS utilizes the targeting of its molecule or structural points, reaches the object of the selectivity significantly improving cancer therapy drug, the toxicity reducing cancer therapy drug.
In recent years, along with Gefitinib (Gefitinib), Tarceva (Erlotinib), lapatinibditosylate (Lapatinib), PD 183805 and PD 153035 etc., these contain the listing successively of the PTS of amido quinazoline structural unit or enter clinical experimental stage, and the high anti-cancer activity that amido quinazoline structural unit shows and highly selective cause extensive concern.Although domestic, abroad utilizing the report having many documents in amido quinazoline mechanical development PTS and comprise patent documentation, but, the limitednumber of existing organic molecule class target anticancer new drug, and because the distribution in vivo in different tissues of the amino-quinazoline compound of different chemical structures and bioavailability are not quite similar, therefore, they are still undesirable to the restraining effect of dissimilar cancer cells.
Although at present report amino-quinazoline compound anticancer abnormal growth and improve and demonstrate many advantages in the selectivity of cancer cells etc., but still have a lot of unsatisfactory part.Therefore, utilize the polytropy of amido quinazoline structure, research and development amino-quinazoline PTS that is more, better effects if is significant further.
Summary of the invention
The object of the invention is to the limitednumber for existing organic molecule class targeted anticancer medicine, the shortcoming that cancer therapy effect is still undesirable, the 4-providing a class to have better antitumour activity (3-chloro-4-methoxy anilino)-6-(3-aminocarbonyl phenyl) quinazoline compounds or its pharmacy acceptable salt.
Another object of the present invention is to provide the preparation method of above-mentioned 4-(3-chloro-4-methoxy anilino)-6-(3-aminocarbonyl phenyl) quinazoline compounds or its pharmacy acceptable salt.
Another object of the present invention is to provide above-mentioned 4-(3-chloro-4-methoxy anilino)-6-(3-aminocarbonyl phenyl) quinazoline compounds or its pharmacy acceptable salt is preparing the application in cancer therapy drug.
Above-mentioned purpose of the present invention is achieved by following scheme:
A kind of 4-(3-chloro-4-methoxy anilino)-6-(3-aminocarbonyl phenyl) quinazoline compounds or its pharmacy acceptable salt, its structural formula is as shown in formula I:
（Ⅰ）
In above-mentioned formula I, R takes from-H ,-COCH
3,-COCF
3,-COCH=CHCOOH ,-COCH
2cl ,-COCCl
3,-COCH=CH
2,-COC (CH
3)
3,-COCH
2cH
3,-COCHBrCH
3in any one.
The present invention gives the title of 10 kinds of concrete structures and corresponding 4-(3-chloro-4-methoxy anilino)-6-(3-aminocarbonyl phenyl) quinazoline compounds, shown in specific as follows:
In above-mentioned formula I, during R=-H, this 4-(3-chloro-4-methoxy anilino)-6-(3-aminocarbonyl phenyl) quinazoline compounds called after 4-(3-chloro-4-methoxy anilino)-6-(3-aminocarbonyl phenyl) quinazoline;
In above-mentioned formula I, R=-COCH
3time, this 4-(3-chloro-4-methoxy anilino)-6-(3-aminocarbonyl phenyl) quinazoline compounds called after 4-(3-chloro-4-methoxy anilino)-6-(3-acetamidophenyl) quinazoline;
In above-mentioned formula I, R=-COCF
3time, this 4-(3-chloro-4-methoxy anilino)-6-(3-aminocarbonyl phenyl) quinazoline compounds called after 4-(3-chloro-4-methoxy anilino)-6-(3-trifluoroacetyl amido phenyl) quinazoline;
In above-mentioned formula I, during R=-COCH=CHCOOH, this 4-(3-chloro-4-methoxy anilino)-6-(3-aminocarbonyl phenyl) quinazoline compounds called after 4-(3-chloro-4-methoxy anilino)-6-(the mono-maleic acylamino phenyl of 3-) quinazoline;
In above-mentioned formula I, R=-COCH
2during Cl, this 4-(3-chloro-4-methoxy anilino)-6-(3-aminocarbonyl phenyl) quinazoline compounds called after 4-(3-chloro-4-methoxy anilino)-6-(3-chloracetyl aminocarbonyl phenyl) quinazoline;
In above-mentioned formula I, R=-COCCl
3time, this 4-(3-chloro-4-methoxy anilino)-6-(3-aminocarbonyl phenyl) quinazoline compounds called after 4-(3-chloro-4-methoxy anilino)-6-(3-tribromo-acetyl amido phenyl) quinazoline;
In above-mentioned formula I, R=-COCH=CH
2time, this 4-(3-chloro-4-methoxy anilino)-6-(3-aminocarbonyl phenyl) quinazoline compounds called after 4-(3-chloro-4-methoxy anilino)-6-(3-acrylamido phenyl) quinazoline;
In above-mentioned formula I, R=-COC (CH
3)
3time, this 4-(3-chloro-4-methoxy anilino)-6-(3-aminocarbonyl phenyl) quinazoline compounds called after 4-(3-chloro-4-methoxy anilino)-6-(3-pivalyl aminocarbonyl phenyl) quinazoline;
In above-mentioned formula I, R=-COCH
2cH
3time, this 4-(3-chloro-4-methoxy anilino)-6-(3-aminocarbonyl phenyl) quinazoline compounds called after 4-(3-chloro-4-methoxy anilino)-6-(3-propionamido-phenyl) quinazoline;
In above-mentioned formula I, R=-COCHBrCH
3time, this 4-(3-chloro-4-methoxy anilino)-6-(3-aminocarbonyl phenyl) quinazoline compounds called after 4-(3-chloro-4-methoxy anilino)-6-(3-(2-bromine propionamido-) phenyl) quinazoline.
The present invention also provides the preparation method of 4-(3-chloro-4-methoxy anilino)-6-(3-aminocarbonyl phenyl) quinazoline compounds or its pharmacy acceptable salt, and this preparation method comprises the steps:
The preparation of step 1. 4-(3-chloro-4-methoxy anilino)-6-iodine quinazoline
With 4-chloro-6-iodine quinazoline and 3-chloro-4-methoxy aniline for raw material, in the presence of the solvent, react 1 ~ 12 hour at 40 ~ 100 DEG C, after reaction terminates, filter, precipitating solvent washing is to oyster, finally collect the oyster powder on filter paper, in 50 DEG C of vacuum-dryings, obtain 4-(3-chloro-4-methoxy anilino)-6-iodine quinazoline, its structure is as follows:
（Ⅱ）
In above-mentioned steps 1, the mol ratio of 4-chloro-6-iodine quinazoline and 3-chloro-4-methoxy aniline is 1:0.33 ~ 3.
In above-mentioned steps 1, one or more mixed solvents in solvent selected from methanol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol.
The chemical equation of above-mentioned steps 1 is as follows.
the preparation of step 2. 4-(3-chloro-4-methoxy anilino)-6-(3-aminocarbonyl phenyl) quinazoline
With the 4-of step 1 gained (3-chloro-4-methoxy anilino)-6-iodine quinazoline (II) and 3-amido phenylo boric acid hydrate for raw material; under the existence of nitrogen protection, catalyzer, acid binding agent and solvent; 40 ~ 100 DEG C of reactions 6 ~ 30 hours; after reaction terminates, reaction solution is concentrated; then silica gel column chromatography separating-purifying is used; collect the component containing product; pale yellow powder is obtained except after desolventizing; in 50 DEG C of vacuum-dryings; obtain 4-of the present invention (3-chloro-4-methoxy anilino)-6-(3-aminocarbonyl phenyl) quinazoline, its structural formula is as follows:
（Ⅲ）
In above-mentioned steps 2, the mol ratio of 4-(3-chloro-4-methoxy anilino)-6-iodine quinazoline and 3-amido phenylo boric acid hydrate is 1:0.33 ~ 3.
In above-mentioned steps 2, catalyzer is the mixture of triphenyl phosphorus and palladium or triphenyl phosphorus and Palladous chloride.
In above-mentioned steps 2, acid binding agent is selected from salt of wormwood, sodium carbonate, cesium carbonate, triethylamine, triethylenediamine, tetramethyl butane diamine, N, N-dimethyl benzylamine, N-ethylmorpholine, N, N-dimethyl cyclohexyl amine, N, N-methyl bicyclic is base amine, N-methylmorpholine, N, one or more mixtures in N-diethyl piperazine, N, N-lupetazin, salt of wormwood, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide.
In above-mentioned steps 2, solvent is selected from water, ethanol, tetrahydrofuran (THF), methylene dichloride, trichloromethane, 1, one or more mixed solvents in 2-ethylene dichloride, glycol dimethyl ether, ethylene glycol monomethyl ether, ether, acetone, butanone, cyclohexanone, benzene, toluene, dioxane, DMF, pyridine, ethyl acetate.
In above-mentioned steps 2, the moving phase of silica gel column chromatography is selected from one or more mixed solvents in ethyl acetate, normal hexane, cyclohexane, sherwood oil, methyl alcohol, ethanol, methylene dichloride, trichloromethane, ether, acetone, butanone.
The chemical equation of above-mentioned steps 2 is as follows.
the preparation of step 3. 4-(3-chloro-4-methoxy anilino)-6-(3-aminocarbonyl phenyl) quinazoline derivant
With the 4-of step 2 gained (3-chloro-4-methoxy anilino)-6-(3-aminocarbonyl phenyl) quinazoline (III) and acid anhydrides, a kind of compound in acyl chlorides or carboxylic acid (being called for short R-C (O)-X) is raw material, in nitrogen protection, under the existence of acid binding agent and solvent, react 2 ~ 24 hours at-5 DEG C ~ 100 DEG C, after reaction terminates, reaction solution is concentrated, then silica gel column chromatography separating-purifying is used, collect the component containing product, faint yellow or yellow powder is obtained except after desolventizing, in 50 DEG C of vacuum-dryings, obtain 4-of the present invention (3-chloro-4-methoxy anilino)-6-(3-aminocarbonyl phenyl) quinazoline derivant, its molecular structural formula is as shown in formula I.
In above-mentioned steps 3, the mol ratio of a kind of compound in 4-(3-chloro-4-methoxy anilino)-6-(3-aminocarbonyl phenyl) quinazoline and acid anhydrides, acyl chlorides or carboxylic acid (being called for short R-C (O)-X) is 1:0.25 ~ 4.
In above-mentioned steps 3, acid binding agent is selected from triethylamine, triethylenediamine, tetramethyl butane diamine, N, N-dimethyl benzylamine, N-ethylmorpholine, N, N-dimethyl cyclohexyl amine, N, N-methyl bicyclic is base amine, N-methylmorpholine, N, one or more mixtures in N-diethyl piperazine, N, N-lupetazin, salt of wormwood, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide.
In above-mentioned steps 3, one or more mixed solvents in solvent selected from ethanol, tetrahydrofuran (THF), methylene dichloride, chloroform, glycol dimethyl ether, ethylene glycol monomethyl ether, ether, acetone, toluene, dioxane, DMF, ethyl acetate.
In above-mentioned steps 3, the moving phase of silica gel column chromatography is selected from one or more mixed solvents in ethyl acetate, normal hexane, cyclohexane, sherwood oil, methyl alcohol, ethanol, methylene dichloride, trichloromethane, ether, acetone, butanone.
The chemical equation of above-mentioned steps 3 is as follows.
4-of the present invention (3-chloro-4-methoxy anilino)-6-(3-aminocarbonyl phenyl) quinazoline compounds or its pharmacy acceptable salt, described in it, pharmaceutically acceptable inorganic salt or organic salt comprise hydrochloride, vitriol, phosphoric acid salt, metilsulfate, sulfonate, formate, acetate, malate or lactic acid salt.
4-of the present invention (3-chloro-4-methoxy anilino)-6-(3-aminocarbonyl phenyl) quinazoline compounds or its pharmacy acceptable salt have good antitumor action through analysis of experiments, can separately for the preparation of antitumor drug when embody rule, or form composition with pharmaceutically acceptable carrier and prepare antitumor drug, as formed composition for oral administration or parenteral administration composition with pharmaceutically acceptable carrier.
Compared with prior art, the present invention has following beneficial effect:
The remarkable advantage of 4-(3-chloro-4-methoxy anilino)-6-(3-aminocarbonyl phenyl) quinazoline compounds prepared by the present invention has more significant restraining effect to the growth of Adenocarcinoma of lung cell line A549, hepatoma cell strain Bel-7402 and stomach cancer cell line SGC7901 tri-kinds of cancer cells, therefore, 4-(3-chloro-4-methoxy anilino)-6-(3-aminocarbonyl phenyl) quinazoline compounds that prepared by the present invention has the potential of the PTS being developed to treatment lung cancer, liver cancer and cancer of the stomach.
Embodiment
Below in conjunction with specific embodiment the present invention done and describe further, but specific embodiment does not do any restriction to the present invention.
embodiment 1 4-(3-chloro-4-methoxy anilino)-6-(3-aminocarbonyl phenyl) quinazoline compound
The preparation method of the present embodiment 4-(3-chloro-4-methoxy anilino)-6-(3-aminocarbonyl phenyl) quinazoline compound comprises the steps:
The preparation of step 1. 4-(3-chloro-4-methoxy anilino)-6-iodine quinazoline
With reflux condensing tube, in the 250ml there-necked flask of thermometer, add 4.00g(13.8 mmol successively) 4-chloro-6-iodine quinazoline, 6.51g(41.4 mmol) 3-chloro-4-methoxy aniline and 150ml Virahol, under agitation, react 1 hour at 100 DEG C, period monitors level of response with thin-layer chromatography, after reaction terminates, filter, precipitation methanol wash, until precipitation is in oyster, finally precipitation is placed in 50 DEG C of vacuum drying ovens dry, obtain oyster powder and be 4-(3-chloro-4-methoxy anilino)-6-iodine quinazoline, heavy 4.64g, productive rate 82%.Its structural formula as shown in formula II, its m.p. 243.6 DEG C;
1h-NMR(400 MHz, DMSO): δ 11.83(s, 1H), δ 9.40(s, 1H), δ 8.94(s, 1H), δ 8.35(d, 1H), δ 7.87(d, 1H), δ 7.78(d, 1H), δ 7.68(dd, 1H), δ 7.25(d, 1H), δ 3.89(s, 3H); ESI-MS m/e:414.5([M+1]
+); Ultimate analysis: theoretical value C 43.77%, H 2.69%, N 10.21%, test value C 43.37%, H 2.76%, N 10.48%.
The preparation of step 2. 4-(3-chloro-4-methoxy anilino)-6-(3-aminocarbonyl phenyl) quinazoline
With reflux condensing tube, in the 150ml there-necked flask of thermometer, add 0.5000g (1.215 mmol) 4-(3-chloro-4-methoxy anilino)-6-iodine quinazoline (II) successively, 0.5658g (3.645 mmol) 3-amino-benzene boric acid hydrate, the mixture of 0.0195g triphenyl phosphorus and palladium, 0.1458g sodium hydroxide and 100ml volume ratio are the tetrahydrofuran (THF)/water mixed solvent of 2/1, under agitation, react 30 hours at 40 DEG C, period monitors level of response with thin-layer chromatography, after reaction terminates, concentration of reaction solution, then separating-purifying is carried out with silica gel column chromatography, moving phase is the ethyl acetate/hexanaphthene mixed solvent of volume ratio 7/3.Collect the component containing product, obtain yellow powder after removing mixed solvent, in 50 DEG C of vacuum-dryings, obtain 4-(3-chloro-4-methoxy anilino)-6-(3-aminocarbonyl phenyl) quinazoline, heavy 0.2745g, productive rate 60%.Its structural formula as shown in formula III, its m.p. 267.3 DEG C;
1h-NMR(400 MHz, DMSO): δ 9.92(s, 1H), δ 8.73(s, 1H), δ 8.59(s, 1H), δ 8.04(d, 2H), δ 7.87(d, 1H), δ 7.81(dd, 2H), δ 7.20(t, 2H), δ 7.00(d, 2H), δ 6.66(d, 1H), δ 5.25(s, 2H), δ 3.88(s, 3H); ESI-MS m/e:376.9([M+1]
+); Ultimate analysis: theoretical value C 66.93%, H 4.55%, N 14.87%, test value C 66.38%, H 4.76%, N 14.36%.
embodiment 2 4-(3-chloro-4-methoxy anilino)-6-(3-acetamidophenyl) quinazoline compound
The preparation method of the present embodiment 4-(3-chloro-4-methoxy anilino)-6-(3-acetamidophenyl) quinazoline compound comprises the steps:
The preparation of step 1. 4-(3-chloro-4-methoxy anilino)-6-iodine quinazoline
With reflux condensing tube, in the 250ml there-necked flask of thermometer, add 12.00g(41.4mmol successively) 4-chloro-6-iodine quinazoline, 2.17g(13.8 mmol) 3-chloro-4-methoxy aniline and 150ml methyl alcohol, under agitation, react 12 hours at 40 DEG C, period monitors level of response with thin-layer chromatography, after reaction terminates, filter, precipitation methanol wash, until precipitation is in oyster, finally precipitation is placed in 50 DEG C of vacuum drying ovens dry, obtain oyster powder and be 4-(3-chloro-4-methoxy anilino)-6-iodine quinazoline, heavy 4.36g, productive rate 77%, its structural formula is as shown in formula II.
The preparation of step 2. 4-(3-chloro-4-methoxy anilino)-6-(3-aminocarbonyl phenyl) quinazoline
With reflux condensing tube, in the 150ml there-necked flask of thermometer, add 1.5000g(3.645 mmol successively) 4-(3-chloro-4-methoxy anilino)-6-iodine quinazoline (II), 0.1886g(1.215 mmol) 3-amino-benzene boric acid hydrate, the mixture of 0.0165g triphenyl phosphorus and Palladous chloride, 0.1363g triethylenediamine and 100ml volume ratio are the cyclohexanone/water mixed solvent of 2/1, under agitation, react 6 hours at 100 DEG C, period monitors level of response with thin-layer chromatography, after reaction terminates, concentration of reaction solution, then separating-purifying is carried out with silica gel column chromatography, moving phase is the butanone/sherwood oil mixed solvent of volume ratio 8/2.Collect containing product component, after removing mixed solvent, obtain yellow powder, in 50 DEG C of vacuum-dryings, obtain 4-(3-chloro-4-methoxy anilino)-6-(3-aminocarbonyl phenyl) quinazoline, heavy 0.2928g, productive rate 64%, its structural formula is as shown in formula III.
The preparation of step 3. 4-(3-chloro-4-methoxy anilino)-6-(3-acetamidophenyl) quinazoline
With reflux condensing tube, in the 150ml there-necked flask of thermometer, add 0.5000g(1.33 mmol successively) 4-(3-chloro-4-methoxy anilino)-6-(3-aminocarbonyl phenyl) quinazoline (III), 0.5426g(5.32mmol) diacetyl oxide, 0.5255g triethylenediamine and 100ml dioxane, under agitation, react 2 hours at 100 DEG C, period monitors level of response with thin-layer chromatography, after reaction terminates, concentration of reaction solution, then separating-purifying is carried out with silica gel column chromatography, moving phase is the trichloromethane/normal hexane mixed solvent of volume ratio 9/1.Collect the component containing product, obtain yellow powder after removing mixed solvent, in 50 DEG C of vacuum-dryings, obtain 4-(3-chloro-4-methoxy anilino)-6-(3-acetamidophenyl) quinazoline, heavy 0.4785g, productive rate 86%.Its structural formula is as shown in formula IV.
（Ⅳ）
The m.p. 271.6 DEG C of the present embodiment 4-(3-chloro-4-methoxy anilino)-6-(3-acetamidophenyl) quinazoline;
1h-NMR(400 MHz, DMSO): δ 10.11(s, 1H), δ 9.94(s, 1H), δ 8.77(s, 1H), δ 8.60(s, 1H), δ 8.06(t, 1H), δ 8.01(s, 2H), δ 7.88(d, 1H), δ 7.77(d, 1H), δ 7.65(d, 1H), δ 7.59 ~ 7.32(m, 2H), δ 7.21(d, 1H), δ 3.88(s, 3H), δ 2.09(s, 3H); ESI-MS m/e:418.6([M+1]+); Ultimate analysis: molecular formula is C
23h
19clN
4o
2, theoretical value C 63.23%, H 4.84%, N 12.82%, test value C 63.02%, H 4.84%, N 11.98%, calculating molecular formula is thus C
23h
19clN
4o
2h
2o.
embodiment 3 4-(3-chloro-4-methoxy anilino)-6-(3-trifluoroacetyl amido phenyl) quinazoline compound
The preparation method of the present embodiment 4-(3-chloro-4-methoxy anilino)-6-(3-trifluoroacetyl amido phenyl) quinazoline compound comprises the steps:
The preparation of step 1. 4-(3-chloro-4-methoxy anilino)-6-iodine quinazoline
With reflux condensing tube, in the 250ml there-necked flask of thermometer, add 4.00g(13.8 mmol successively) 4-chloro-6-iodine quinazoline, 3.26g(20.7 mmol) 3-chloro-4-methoxy aniline and 150ml propyl carbinol, under agitation, react 8 hours at 60 DEG C, period monitors level of response with thin-layer chromatography, after reaction terminates, filter, precipitation propyl carbinol washs, until precipitation is in oyster, finally precipitation is placed in 50 DEG C of vacuum drying ovens dry, obtain oyster powder and be 4-(3-chloro-4-methoxy anilino)-6-iodine quinazoline, heavy 4.51g, productive rate 80%, its structural formula is as shown in formula II.
The preparation of step 2. 4-(3-chloro-4-methoxy anilino)-6-(3-aminocarbonyl phenyl) quinazoline
With reflux condensing tube, in the 150ml there-necked flask of thermometer, add 0.5000g(1.215 mmol successively) 4-(3-chloro-4-methoxy anilino)-6-iodine quinazoline (II), 0.2829g(1.823 mmol) 3-amino-benzene boric acid hydrate, the mixture of 0.0165g triphenyl phosphorus and Palladous chloride, the volume ratio of 0.2454g triethylamine and 100ml is the glycol dimethyl ether/water mixed solvent of 2/1, under agitation, react 24 hours at 60 DEG C, period monitors level of response with thin-layer chromatography, after reaction terminates, concentration of reaction solution, then separating-purifying is carried out with silica gel column chromatography, moving phase is the butanone/normal hexane mixed solvent of volume ratio 8/2.Collect the component containing product, after removing mixed solvent, obtain yellow powder, in 50 DEG C of vacuum-dryings, obtain 4-(3-chloro-4-methoxy anilino)-6-(3-aminocarbonyl phenyl) quinazoline, heavy 0.2836g, productive rate 62%, its structural formula is as shown in formula III.
The preparation of step 3. 4-(3-chloro-4-methoxy anilino)-6-(3-trifluoroacetyl amido phenyl) quinazoline
With in the 150ml there-necked flask of reflux condensing tube, thermometer, add 2.0000g(5.32mmol successively) 4-(3-chloro-4-methoxy anilino)-6-(3-aminocarbonyl phenyl) quinazoline, 0.1762g(1.33 mmol) trifluoroacetyl chloride, 0.1343g triethylamine and 100ml ethyl acetate, under agitation, react 24 hours at-5 DEG C, period monitors level of response with thin-layer chromatography, after reaction terminates, concentration of reaction solution, then carry out separating-purifying with silica gel column chromatography, moving phase is the methylene dichloride/sherwood oil mixed solvent of volume ratio 9/1.Collect the component containing product, obtain deep yellow powder after removing mixed solvent, in 50 DEG C of vacuum-dryings, obtain 4-(3-chloro-4-methoxy anilino)-6-(3-trifluoroacetyl amido phenyl) quinazoline, heavy 0.5649g, productive rate 90%.Its structural formula is such as formula shown in (V).
（Ⅴ）
The m.p. 274.5 DEG C of the present embodiment 4-(3-chloro-4-methoxy anilino)-6-(3-trifluoroacetyl amido phenyl) quinazoline;
1h-NMR(400 MHz, DMSO): δ 11.44(s, 1H), δ 9.94(s, 1H), δ 8.80(s, 1H), δ 8.61(s, 1H), δ 8.18 ~ 8.04(m, 2H), δ 8.00(d, 1H), δ 7.89(d, 1H), δ 7.76(d, 3H), δ 7.62(t, 1H), δ 7.22(d, 1H), δ 3.89(s, 3H); ESI-MS m/e:472.5([M+1]
+); Ultimate analysis: molecular formula is C
23h
16clF
3n
4o
2, theoretical value C 56.28%, H 3.70%, N 11.61%, test value C 59.30%, H 4.07%, N 10.90%, calculating molecular formula is thus C
23h
16clF
3n
4o
2h
2o.
embodiment 4 4-(3-chloro-4-methoxy anilino)-6-(3-aminocarbonyl phenyl) quinazoline compounds or its pharmacy acceptable salt are to the restraining effect of cancer cells
The present embodiment adopts lung cancer cell types, hepatoma cell strain Bel-7402 and stomach cancer cell line SGC7901 as experimental subjects.With 4-(3-chloro-4-methoxy anilino)-6-(3-aminocarbonyl phenyl) quinazoline, 4-(3-chloro-4-methoxy anilino)-6-(3-acetamidophenyl) quinazoline, 4-(3-chloro-4-methoxy anilino)-6-(3-trifluoroacetyl amido phenyl) quinazoline, 4-(3-chloro-4-methoxy anilino)-6-(the mono-maleic acylamino phenyl of 3-) quinazoline, 4-(3-chloro-4-methoxy anilino)-6-(3-chloracetyl aminocarbonyl phenyl) quinazoline, 4-(3-chloro-4-methoxy anilino)-6-(3-tribromo-acetyl amido phenyl) quinazoline, 4-(3-chloro-4-methoxy anilino)-6-(3-acrylamido phenyl) quinazoline, 4-(3-chloro-4-methoxy anilino)-6-(3-pivalyl aminocarbonyl phenyl) quinazoline, 4-(3-chloro-4-methoxy anilino)-6-(3-propionamido-phenyl) quinazoline, 4-(3-chloro-4-methoxy anilino)-6-(3-(2-bromine propionamido-) phenyl) quinazoline is Experimental agents, 4-of the present invention (3-chloro-4-methoxy anilino)-6-(3-aminocarbonyl phenyl) quinazoline compounds carries out experimental study to the restraining effect of cancer cells, concrete operations are as follows.
Adopt MTT development process, the lung cancer cell types in vegetative period of taking the logarithm, hepatoma cell strain Bel-7402, stomach cancer cell line SGC7901, after 0.25% tryptic digestion, add perfect medium and trypsinase, and piping and druming is prepared into single cell suspension repeatedly.On tally after counting, be inoculated in 96 orifice plates with 5000, every hole cell.In 37 DEG C, 5%CO
2in incubator, quiescent culture makes cell attachment.Inhale after 24h and abandon original substratum, 1 time is washed with 150 μ L PBS, add the perfect medium containing 10% newborn calf serum that 100 μ L are fresh, then add Experimental agents, simultaneously using the substratum fluid apertures of not dosing as negative control, cultivate fluid apertures as zeroing hole (not containing cancer cells) only to add, after cultivating 72h respectively, sucking-off substratum and liquid, wash 1 time with PBS, adds 200 μ L substratum and 20 μ L concentration are 5mgmL
-1mTT liquid, continue to cultivate 4h, then inhale the liquid abandoned in orifice plate, add 150 μ L DMSO and repeatedly blow and beat, bluish voilet crystallization is fully dissolved; Absorbance value (OD value) is measured with 490nm wavelength place with enzyme-linked immunosorbent assay instrument, cell survival rate (%)=(test group OD value/control group OD value) × 100%, cell inhibitory rate (%)=(1-test group OD value/control group OD value) × 100%.
Adopt IC
50be worth as shown in table 1 to the antitumour activity evaluation result of 4-(3-chloro-4-methoxy anilino)-6-(3-aminocarbonyl phenyl) quinazoline compounds.By the OD value measured in different time points, obtain the inhibiting rate changing conditions of different time points, draw change curve, using curve arrival that time point of plateau as optimum time point, show that the best use of time of medicine is 36h by time curve.
The IC of table 1 4-(3-chloro-4-methoxy anilino)-6-(3-aminocarbonyl phenyl) quinazoline compounds effect after 36 hours
50value
As can be seen from Table 1,4-of the present invention (3-chloro-4-methoxy anilino)-6-(3-aminocarbonyl phenyl) quinazoline compounds all demonstrates good antitumour activity to Adenocarcinoma of lung cell line A549, hepatoma cell strain Bel-7402 and stomach cancer cell line SGC7901.
Claims (9)
1. 4-(3-chloro-4-methoxy anilino)-6-(3-aminocarbonyl phenyl) quinazoline compounds or its pharmacy acceptable salt, its structural formula is as shown in formula I:
（Ⅰ）
In formula I, as R=-H, this 4-(3-chloro-4-methoxy anilino)-6-(3-aminocarbonyl phenyl) quinazoline compounds is 4-(3-chloro-4-methoxy anilino)-6-(3-aminocarbonyl phenyl) quinazoline;
As R=-COCH
3time, this 4-(3-chloro-4-methoxy anilino)-6-(3-aminocarbonyl phenyl) quinazoline compounds is 4-(3-chloro-4-methoxy anilino)-6-(3-acetamidophenyl) quinazoline;
As R=-COCF
3time, this 4-(3-chloro-4-methoxy anilino)-6-(3-aminocarbonyl phenyl) quinazoline compounds is 4-(3-chloro-4-methoxy anilino)-6-(3-trifluoroacetyl amido phenyl) quinazoline;
As R=-COCH=CHCOOH, this 4-(3-chloro-4-methoxy anilino)-6-(3-aminocarbonyl phenyl) quinazoline compounds is 4-(3-chloro-4-methoxy anilino)-6-(the mono-maleic acylamino phenyl of 3-) quinazoline;
As R=-COCH
2during Cl, this 4-(3-chloro-4-methoxy anilino)-6-(3-aminocarbonyl phenyl) quinazoline compounds is 4-(3-chloro-4-methoxy anilino)-6-(3-chloracetyl aminocarbonyl phenyl) quinazoline;
As R=-COCCl
3time, this 4-(3-chloro-4-methoxy anilino)-6-(3-aminocarbonyl phenyl) quinazoline compounds is 4-(3-chloro-4-methoxy anilino)-6-(3-tribromo-acetyl amido phenyl) quinazoline;
As R=-COCH=CH
2time, this 4-(3-chloro-4-methoxy anilino)-6-(3-aminocarbonyl phenyl) quinazoline compounds is 4-(3-chloro-4-methoxy anilino)-6-(3-acrylamido phenyl) quinazoline;
As R=-COC (CH
3)
3time, this 4-(3-chloro-4-methoxy anilino)-6-(3-aminocarbonyl phenyl) quinazoline compounds is 4-(3-chloro-4-methoxy anilino)-6-(3-pivalyl aminocarbonyl phenyl) quinazoline;
As R=-COCH
2cH
3time, this 4-(3-chloro-4-methoxy anilino)-6-(3-aminocarbonyl phenyl) quinazoline compounds is 4-(3-chloro-4-methoxy anilino)-6-(3-propionamido-phenyl) quinazoline;
As R=-COCHBrCH
3time, this 4-(3-chloro-4-methoxy anilino)-6-(3-aminocarbonyl phenyl) quinazoline compounds is 4-(3-chloro-4-methoxy anilino)-6-(3-(2-bromine propionamido-) phenyl) quinazoline.
2. 4-(3-chloro-4-methoxy anilino)-6-(3-aminocarbonyl phenyl) quinazoline compounds or its pharmacy acceptable salt according to claim 1, it is characterized in that, described pharmacy acceptable salt is hydrochloride, vitriol, phosphoric acid salt, metilsulfate, sulfonate, formate, acetate, malate or lactic acid salt.
3. the preparation method of 4-described in claim 1 (3-chloro-4-methoxy anilino)-6-(3-aminocarbonyl phenyl) quinazoline compounds or its pharmacy acceptable salt, is characterized in that this preparation method comprises the steps:
The preparation of step 1. 4-(3-chloro-4-methoxy anilino)-6-iodine quinazoline
With 4-chloro-6-iodine quinazoline and 3-chloro-4-methoxy aniline for raw material, in the presence of the solvent, react 1 ~ 12 hour at 40 ~ 100 DEG C, after reaction terminates, filter, precipitating solvent washing is to oyster, finally collect the oyster powder on filter paper, in 50 DEG C of vacuum-dryings, obtain 4-(3-chloro-4-methoxy anilino)-6-iodine quinazoline, its structure is as follows:
；
（Ⅱ）
The preparation of step 2. 4-(3-chloro-4-methoxy anilino)-6-(3-aminocarbonyl phenyl) quinazoline
With the 4-of step 1 gained (3-chloro-4-methoxy anilino)-6-iodine quinazoline (II) and 3-amido phenylo boric acid hydrate for raw material; under the existence of nitrogen protection, catalyzer, acid binding agent and solvent; 40 ~ 100 DEG C of reactions 6 ~ 30 hours; after reaction terminates, reaction solution is concentrated; then silica gel column chromatography separating-purifying is used; collect the component containing product; pale yellow powder is obtained except after desolventizing; in 50 DEG C of vacuum-dryings; obtain 4-of the present invention (3-chloro-4-methoxy anilino)-6-(3-aminocarbonyl phenyl) quinazoline, its structural formula is as follows:
；
（Ⅲ）
The preparation of step 3. 4-(3-chloro-4-methoxy anilino)-6-(3-aminocarbonyl phenyl) quinazoline derivant
With the 4-of step 2 gained (3-chloro-4-methoxy anilino)-6-(3-aminocarbonyl phenyl) quinazoline (III) and acid anhydrides, a kind of compound in acyl chlorides or carboxylic acid is raw material, in nitrogen protection, under the existence of acid binding agent and solvent, react 2 ~ 24 hours at-5 DEG C ~ 100 DEG C, after reaction terminates, reaction solution is concentrated, then silica gel column chromatography separating-purifying is used, collect the component containing product, faint yellow or yellow powder is obtained except after desolventizing, in 50 DEG C of vacuum-dryings, obtain 4-of the present invention (3-chloro-4-methoxy anilino)-6-(3-aminocarbonyl phenyl) quinazoline derivant, its molecular structure is as shown in formula I.
4. preparation method according to claim 3, it is characterized in that in described step 1, the mol ratio of 4-chloro-6-iodine quinazoline and 3-chloro-4-methoxy aniline is 1:0.33 ~ 3; In described step 2, the mol ratio of 4-(3-chloro-4-methoxy anilino)-6-iodine quinazoline and 3-amido phenylo boric acid hydrate is 1:0.33 ~ 3; In described step 3, the mol ratio of a kind of compound in 4-(3-chloro-4-methoxy anilino)-6-(3-aminocarbonyl phenyl) quinazoline and acid anhydrides, acyl chlorides or carboxylic acid is 1:0.25 ~ 4.
5. preparation method according to claim 3, is characterized in that in described step 1, one or more mixed solvents in solvent selected from methanol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol.
6. preparation method according to claim 3, it is characterized in that in described step 2, catalyzer is the mixture of triphenyl phosphorus and palladium or triphenyl phosphorus and Palladous chloride; Acid binding agent is selected from salt of wormwood, sodium carbonate, cesium carbonate, triethylamine, triethylenediamine, tetramethyl butane diamine, N, N-dimethyl benzylamine, N-ethylmorpholine, N, N-dimethyl cyclohexyl amine, N, N-methyl bicyclic is base amine, N-methylmorpholine, N, one or more mixtures in N-diethyl piperazine, N, N-lupetazin, salt of wormwood, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide; Solvent is selected from water, ethanol, tetrahydrofuran (THF), methylene dichloride, trichloromethane, 1, one or more mixed solvents in 2-ethylene dichloride, glycol dimethyl ether, ethylene glycol monomethyl ether, ether, acetone, butanone, cyclohexanone, benzene, toluene, dioxane, DMF, pyridine, ethyl acetate.
7. preparation method according to claim 3, it is characterized in that in described step 3, acid binding agent is selected from triethylamine, triethylenediamine, tetramethyl butane diamine, N, N-dimethyl benzylamine, N-ethylmorpholine, N, N-dimethyl cyclohexyl amine, N, N-methyl bicyclic one or more mixtures in base amine, N-methylmorpholine, N, N-diethyl piperazine, N, N-lupetazin, salt of wormwood, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide; One or more mixed solvents in solvent selected from ethanol, tetrahydrofuran (THF), methylene dichloride, chloroform, glycol dimethyl ether, ethylene glycol monomethyl ether, ether, acetone, toluene, dioxane, DMF, ethyl acetate.
8. preparation method according to claim 3, it is characterized in that in described step 2 and 3, the moving phase of silica gel column chromatography is selected from one or more mixed solvents in ethyl acetate, normal hexane, cyclohexane, sherwood oil, methyl alcohol, ethanol, methylene dichloride, trichloromethane, ether, acetone, butanone.
9. 4-described in claim 1 (3-chloro-4-methoxy anilino)-6-(3-aminocarbonyl phenyl) quinazoline compounds or its pharmacy acceptable salt are preparing the application in antitumor drug.
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Citations (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1211240A (en) * | 1996-02-14 | 1999-03-17 | 曾尼卡有限公司 | Quinazoline derivatives as antitumor agents |
| WO2005105094A2 (en) * | 2004-04-16 | 2005-11-10 | Smithkline Beecham Corporation | Cancer treatment method |
| CN1950345A (en) * | 2004-04-28 | 2007-04-18 | 阿罗治疗有限公司 | Morpholinylanilinoquinazoline derivatives for use as antiviral agents |
| CN101003514A (en) * | 2006-01-20 | 2007-07-25 | 上海艾力斯医药科技有限公司 | Derivative of quinazoline, preparation method and usage |
| US20080194557A1 (en) * | 2007-01-18 | 2008-08-14 | Joseph Barbosa | Methods and compositions for the treatment of pain, inflammation and cancer |
| EP2060565A1 (en) * | 2007-11-16 | 2009-05-20 | 4Sc Ag | Novel bifunctional compounds which inhibit protein kinases and histone deacetylases |
| US20090285782A1 (en) * | 2006-07-20 | 2009-11-19 | Gilead Sciences, Inc. | 4,6-di- and 2,4,6-trisubstituted quinazoline derivatives useful for treating viral infections |
| WO2011082337A1 (en) * | 2009-12-31 | 2011-07-07 | Galenea Corp. | Therapeutic compounds and related methods of use |
| WO2011116634A1 (en) * | 2010-03-23 | 2011-09-29 | Scinopharm Taiwan Ltd. | Process and intermediates for preparing lapatinib |
| CN102321076A (en) * | 2011-07-07 | 2012-01-18 | 中国科学技术大学 | The preparation method of lapatinibditosylate midbody and analogue thereof |
| WO2012017448A2 (en) * | 2010-08-03 | 2012-02-09 | Hetero Research Foundation | Salts of lapatinib |
-
2012
- 2012-06-13 CN CN201210194142.7A patent/CN102702116B/en not_active Expired - Fee Related
Patent Citations (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1211240A (en) * | 1996-02-14 | 1999-03-17 | 曾尼卡有限公司 | Quinazoline derivatives as antitumor agents |
| WO2005105094A2 (en) * | 2004-04-16 | 2005-11-10 | Smithkline Beecham Corporation | Cancer treatment method |
| CN1950345A (en) * | 2004-04-28 | 2007-04-18 | 阿罗治疗有限公司 | Morpholinylanilinoquinazoline derivatives for use as antiviral agents |
| CN101003514A (en) * | 2006-01-20 | 2007-07-25 | 上海艾力斯医药科技有限公司 | Derivative of quinazoline, preparation method and usage |
| US20090285782A1 (en) * | 2006-07-20 | 2009-11-19 | Gilead Sciences, Inc. | 4,6-di- and 2,4,6-trisubstituted quinazoline derivatives useful for treating viral infections |
| US20080194557A1 (en) * | 2007-01-18 | 2008-08-14 | Joseph Barbosa | Methods and compositions for the treatment of pain, inflammation and cancer |
| EP2060565A1 (en) * | 2007-11-16 | 2009-05-20 | 4Sc Ag | Novel bifunctional compounds which inhibit protein kinases and histone deacetylases |
| WO2009063054A1 (en) * | 2007-11-16 | 2009-05-22 | 4Sc Ag | Novel bifunctional compounds which inhibit protein kinases and histone deacetylases |
| WO2011082337A1 (en) * | 2009-12-31 | 2011-07-07 | Galenea Corp. | Therapeutic compounds and related methods of use |
| WO2011116634A1 (en) * | 2010-03-23 | 2011-09-29 | Scinopharm Taiwan Ltd. | Process and intermediates for preparing lapatinib |
| WO2012017448A2 (en) * | 2010-08-03 | 2012-02-09 | Hetero Research Foundation | Salts of lapatinib |
| CN102321076A (en) * | 2011-07-07 | 2012-01-18 | 中国科学技术大学 | The preparation method of lapatinibditosylate midbody and analogue thereof |
Non-Patent Citations (5)
| Title |
|---|
| N-(3-氯-4-(3-氟苯甲氧基)苯基)-6-碘喹唑啉-4-胺盐酸盐的合成;王武伟,等;《化工中间体》;20081115(第11期);第28-30页 * |
| Novel Chimeric Histone Deacetylase Inhibitor s: A Series of Lapatinib Hybrides as Potent Inhibitors of Epidermal Growth Factor Receptor (EGFR ), Human Epidermal Growth Factor Receptor 2 (HER2),and Histone Deacetylase Activity;Siavosh Mahboobi,等;《J. Med. Chem.》;20101116;第53卷(第24期);第8546-8555页 * |
| 埃罗替尼衍生物的合成及抗肿瘤活性;徐浩,等;《中国药科大学学报》;20081225;第39卷(第06期);第487-490页 * |
| 盐酸埃洛替尼的合成;李铭东,等;《中国医药工业杂志》;20070410;第38卷(第04期);第257-259页 * |
| 金波,等.吉非替尼的合成.《中国药科大学学报》.2005,第36卷(第01期),第92-94页. * |
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