CN102702116A - 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 the chemical synthetic drug technical field, be specifically related to an organic micromolecule 4-(3-chloro-4-anisole amido)-6-(3-aminocarbonyl phenyl) quinazoline compounds or its pharmacy acceptable salt, their preparation method and the application in the preparation antitumor drug.
Background technology
Cancer is one of principal disease of serious harm human health, and the number of dying from cancer every year is cumulative year after year trend.Cancer has become the human second largest killer who is only second to cardiovascular diseases.Capture cancer is the research topic of attracting attention in the world always.Mainly contain methods such as operative treatment, radiotherapy, chemotherapy at present for treatment for cancer, wherein chemotherapy is accounting for critical role in treatment for cancer.
Traditional cancer therapy drug mainly is a cytotoxic drug; This kind anti-cancer drugs owner will act on the key ingredients such as DNA, RNA and microcosmic albumen of cell; And great majority are nonselective; When killing and wounding cancer cells, also can kill and wound the normal cell of body, have the shortcomings such as strong, the easy generation resistance of poor selectivity, toxic side effect that are difficult to avoid.
For overcome traditional cancer therapy drug these are significantly not enough, human very active for the research and development of the organic molecule PTS with target characteristic.The organic molecule PTS utilizes the target property of its molecule or structural points, reaches the selectivity that significantly improves cancer therapy drug, the toxic purpose that reduces cancer therapy drug.
In recent years; These contain the listing successively or the entering clinical experimental stage of the PTS of amido quinazoline structural unit along with ZD1939 (Gefitinib), Tarceva (Erlotinib), lapatinibditosylate (Lapatinib), PD 183805 and PD 153035 etc., and good antitumour activity and highly selective that the amido quinazoline structural unit shows cause extensive concern.Though it is domestic, abroad utilizing existing many documents aspect the amido quinazoline mechanical development PTS to comprise the report of patent documentation; But; The kind of existing organic molecule class target anticancer new drug is limited; And since the amino-quinazoline compound of chemical structures in vivo distribution and the bioavailability in the different tissues be not quite similar, therefore, they are still undesirable to the restraining effect of dissimilar cancer cells.
Although the amino-quinazoline compound of report demonstrates many advantages in the supernormal growth of anticancer and the aspects such as selectivity that improve cancer cells at present, but still a lot of unsatisfactory parts are arranged.Therefore, utilize the polytropy of amido quinazoline structure, further research and development amino-quinazoline PTS more, better effects if is significant.
Summary of the invention
The objective of the invention is to the kind of existing organic molecule class targeted anticancer medicine limited; The still unfavorable shortcoming of cancer therapy effect provides one type of 4-(3-chloro-4-anisole amido)-6-(3-aminocarbonyl phenyl) quinazoline compounds or its pharmacy acceptable salt with better antitumour activity.
Another object of the present invention provides the preparation method of above-mentioned 4-(3-chloro-4-anisole amido)-6-(3-aminocarbonyl phenyl) quinazoline compounds or its pharmacy acceptable salt.
Another object of the present invention provides above-mentioned 4-(3-chloro-4-anisole amido)-6-(3-aminocarbonyl phenyl) quinazoline compounds or the application of its pharmacy acceptable salt in the preparation cancer therapy drug.
Above-mentioned purpose of the present invention is achieved through following scheme:
A kind of 4-(3-chloro-4-anisole amido)-6-(3-aminocarbonyl phenyl) quinazoline compounds or its pharmacy acceptable salt, its structural formula is shown in formula I:
（Ⅰ）
In the 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-anisole amido)-6-(3-aminocarbonyl phenyl) quinazoline compounds, specific as follows shown in:
In the above-mentioned formula I, R=-during H, this 4-(3-chloro-4-anisole amido)-6-(3-aminocarbonyl phenyl) quinazoline compounds called after 4-(3-chloro-4-anisole amido)-6-(3-aminocarbonyl phenyl) quinazoline;
In the above-mentioned formula I, R=-COCH
3The time, this 4-(3-chloro-4-anisole amido)-6-(3-aminocarbonyl phenyl) quinazoline compounds called after 4-(3-chloro-4-anisole amido)-6-(3-acetamido phenyl) quinazoline;
In the above-mentioned formula I, R=-COCF
3The time, this 4-(3-chloro-4-anisole amido)-6-(3-aminocarbonyl phenyl) quinazoline compounds called after 4-(3-chloro-4-anisole amido)-6-(3-trifluoroacetyl amido phenyl) quinazoline;
In the above-mentioned formula I, R=-during COCH=CHCOOH, this 4-(3-chloro-4-anisole amido)-6-(3-aminocarbonyl phenyl) quinazoline compounds called after 4-(3-chloro-4-anisole amido)-6-(the single maleoyl amido of 3-phenyl) quinazoline;
In the above-mentioned formula I, R=-COCH
2During Cl, this 4-(3-chloro-4-anisole amido)-6-(3-aminocarbonyl phenyl) quinazoline compounds called after 4-(3-chloro-4-anisole amido)-6-(3-chloracetyl amido phenyl) quinazoline;
In the above-mentioned formula I, R=-COCCl
3The time, this 4-(3-chloro-4-anisole amido)-6-(3-aminocarbonyl phenyl) quinazoline compounds called after 4-(3-chloro-4-anisole amido)-6-(3-tribromo-acetyl amido phenyl) quinazoline;
In the above-mentioned formula I, R=-COCH=CH
2The time, this 4-(3-chloro-4-anisole amido)-6-(3-aminocarbonyl phenyl) quinazoline compounds called after 4-(3-chloro-4-anisole amido)-6-(3-acrylamido phenyl) quinazoline;
In the above-mentioned formula I, R=-COC (CH
3)
3The time, this 4-(3-chloro-4-anisole amido)-6-(3-aminocarbonyl phenyl) quinazoline compounds called after 4-(3-chloro-4-anisole amido)-6-(3-pivalyl aminocarbonyl phenyl) quinazoline;
In the above-mentioned formula I, R=-COCH
2CH
3The time, this 4-(3-chloro-4-anisole amido)-6-(3-aminocarbonyl phenyl) quinazoline compounds called after 4-(3-chloro-4-anisole amido)-6-(3-propionamido-phenyl) quinazoline;
In the above-mentioned formula I, R=-COCHBrCH
3The time, this 4-(3-chloro-4-anisole amido)-6-(3-aminocarbonyl phenyl) quinazoline compounds called after 4-(3-chloro-4-anisole amido)-6-(3-(2-bromine propionamido-) phenyl) quinazoline.
The present invention also provides the preparation method of 4-(3-chloro-4-anisole amido)-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-anisole amido)-6-iodine quinazoline
With 4-chloro-6-iodine quinazoline and 3-chloro-4-anisidine is raw material, in the presence of solvent, reacts 1 ~ 12 hour down at 40 ~ 100 ℃; After reaction finishes, filter, precipitate with solvent wash to oyster; Collect the oyster powder on the filter paper at last; In 50 ℃ of vacuum-dryings, obtain 4-(3-chloro-4-anisole amido)-6-iodine quinazoline, its structure is following:
（Ⅱ）
In the above-mentioned steps 1, the mol ratio of 4-chloro-6-iodine quinazoline and 3-chloro-4-anisidine is 1:0.33～3.
In the above-mentioned steps 1, solvent is selected from one or more mixed solvents in methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, the isopropylcarbinol.
The chemical equation of above-mentioned steps 1 is as follows.
The preparation of
step 2. 4-(3-chloro-4-anisole amido)-6-(3-aminocarbonyl phenyl) quinazoline
4-(3-chloro-4-anisole amido)-6-iodine quinazoline (II) with step 1 gained is a raw material with 3-amido phenylo boric acid hydrate; In the presence of nitrogen protection, catalyzer, acid binding agent and solvent,, after reaction finishes reaction solution is concentrated 40 ~ 100 ℃ of reactions 6 ~ 30 hours; Separate with silica gel column chromatography then and purify; Collection contains the component of product, except that getting pale yellow powder after desolvating, in 50 ℃ of vacuum-dryings; Promptly get 4-of the present invention (3-chloro-4-anisole amido)-6-(3-aminocarbonyl phenyl) quinazolines, its structural formula is following:
（Ⅲ）
In the above-mentioned steps 2, the mol ratio of 4-(3-chloro-4-anisole amido)-6-iodine quinazoline and 3-amido phenylo boric acid hydrate is 1:0.33～3.
In the above-mentioned steps 2, catalyzer is the mixture of triphenyl phosphorus and palladium or triphenyl phosphorus and Palladous chloride.
In the above-mentioned steps 2; Acid binding agent is selected from salt of wormwood, yellow soda ash, cesium carbonate, triethylamine, triethylenediamine, tetramethyl butane diamine, N; N-dimethyl benzylamine, N-ethylmorpholine, N, N-dimethyl cyclohexyl amine, N, the basic amine of N-methyl bicyclic, N-methylmorpholine, N; N-diethylammonium piperazine, N, one or more mixtures in N-lupetazin, salt of wormwood, yellow soda ash, cesium carbonate, Pottasium Hydroxide, the sodium hydroxide.
In the above-mentioned steps 2; Solvent is selected from water, ethanol, THF, methylene dichloride, trichloromethane, 1; 2-ethylene dichloride, glycol dimethyl ether, EGME, ether, acetone, butanone, cyclohexanone, benzene, toluene, dioxane, N, one or more mixed solvents in dinethylformamide, pyridine, the ETHYLE ACETATE.
In the above-mentioned steps 2, the moving phase of silica gel column chromatography is selected from one or more mixed solvents in ETHYLE ACETATE, normal hexane, cyclohexane, sherwood oil, methyl alcohol, ethanol, methylene dichloride, trichloromethane, ether, acetone, the butanone.
The chemical equation of above-mentioned steps 2 is as follows.
The preparation of
step 3. 4-(3-chloro-4-anisole amido)-6-(3-aminocarbonyl phenyl) quinazoline derivant
(a kind of compound that is called for short among the R-C (O)-X) is a raw material with acid anhydrides, acyl chlorides or carboxylic acid with 4-(3-chloro-4-anisole amido)-6-(3-aminocarbonyl phenyl) quinazoline (III) of step 2 gained; In the presence of nitrogen protection, acid binding agent and solvent, reacted 2 ~ 24 hours down at-5 ℃ ~ 100 ℃, after reaction finishes reaction solution is concentrated; Separate with silica gel column chromatography then and purify; Collection contains the component of product, except that getting faint yellow or yellow powder after desolvating, in 50 ℃ of vacuum-dryings; Promptly get 4-of the present invention (3-chloro-4-anisole amido)-6-(3-aminocarbonyl phenyl) quinazoline derivant, its molecular structural formula is shown in formula I.
In the above-mentioned steps 3, (mol ratio that is called for short a kind of compound among the R-C (O)-X) is 1:0.25～4 for 4-(3-chloro-4-anisole amido)-6-(3-aminocarbonyl phenyl) quinazoline and acid anhydrides, acyl chlorides or carboxylic acid.
In the 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, the basic amine of N-methyl bicyclic, N-methylmorpholine, N; N-diethylammonium piperazine, N, one or more mixtures in N-lupetazin, salt of wormwood, yellow soda ash, cesium carbonate, Pottasium Hydroxide, the sodium hydroxide.
In the above-mentioned steps 3; Solvent is selected from ethanol, THF, methylene dichloride, chloroform, glycol dimethyl ether, EGME, ether, acetone, toluene, dioxane, N, one or more mixed solvents in dinethylformamide, the ETHYLE ACETATE.
In the above-mentioned steps 3, the moving phase of silica gel column chromatography is selected from one or more mixed solvents in ETHYLE ACETATE, normal hexane, cyclohexane, sherwood oil, methyl alcohol, ethanol, methylene dichloride, trichloromethane, ether, acetone, the butanone.
The chemical equation of above-mentioned steps 3 is as follows.
4-of the present invention (3-chloro-4-anisole amido)-6-(3-aminocarbonyl phenyl) quinazoline compounds or its pharmacy acceptable salt have favorable anti-tumor effect through analysis of experiments; Can be used to prepare antitumor drug separately in the time of concrete the application; Perhaps form the preparation of compositions antitumor drug, as forming composition for oral administration or parenteral administration compsn with pharmaceutically acceptable carrier with pharmaceutically acceptable carrier.
Compared with prior art, the present invention has following beneficial effect:
The remarkable advantage of 4-(3-chloro-4-anisole amido)-6-(3-aminocarbonyl phenyl) quinazoline compounds of the present invention preparation is that the growth to lung adenocarcinoma cell line A549, hepatoma cell strain Bel-7402 and three kinds of cancer cells of stomach cancer cell line SGC7901 all has than significant inhibitory effect; Therefore, 4-(3-chloro-4-anisole amido)-6-(3-aminocarbonyl phenyl) quinazoline compounds of the present invention's preparation has the potential of the PTS that is developed to treatment lung cancer, liver cancer and cancer of the stomach.
Embodiment
Below in conjunction with specific embodiment the present invention is done description further, but specific embodiment is not done any qualification to the present invention.
Embodiment 1 4-(3-chloro-4-anisole amido)-6-(3-aminocarbonyl phenyl) quinazoline compound
The preparation method of present embodiment 4-(3-chloro-4-anisole amido)-6-(3-aminocarbonyl phenyl) quinazoline compound comprises the steps:
The preparation of step 1. 4-(3-chloro-4-anisole amido)-6-iodine quinazoline
In having the 250ml there-necked flask of reflux condensing tube, TM, add 4.00g (13.8 mmol) 4-chloro-6-iodine quinazoline, 6.51g (41.4 mmol) 3-chloro-4-anisidine and 150ml Virahol successively, under agitation; In 100 ℃ of down reactions 1 hour, during with thin-layer chromatography monitoring reaction degree, after reaction finishes; Filter, deposition is used methanol wash, is oyster until deposition; Place 50 ℃ of vacuum drying ovens dry deposition at last; Obtain the oyster powder and be 4-(3-chloro-4-anisole amido)-6-iodine quinazoline, heavy 4.64g, productive rate 82%.Its structural formula shown in formula II, 243.6 ℃ of its m.p.;
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-anisole amido)-6-(3-aminocarbonyl phenyl) quinazoline
In having the 150ml there-necked flask of reflux condensing tube, TM; The mixture, 0.1458g sodium hydroxide and the 100ml volume ratio that add 0.5000g (1.215 mmol) 4-(3-chloro-4-anisole amido)-6-iodine quinazoline (II), 0.5658g (3.645 mmol) 3-amino-benzene boric acid hydrate, 0.0195g triphenyl phosphorus and palladium successively are THF/water mixed solvent of 2/1; Under agitation, in 40 ℃ of down reactions 30 hours, during with thin-layer chromatography monitoring reaction degree; After reaction finishes; Concentration of reaction solution separates purification with silica gel column chromatography then, and moving phase is the ETHYLE ACETATE/hexanaphthene mixed solvent of volume ratio 7/3.Collection contains the component of product, remove behind the mixed solvent yellow powder, in 50 ℃ of vacuum-dryings, promptly get 4-(3-chloro-4-anisole amido)-6-(3-aminocarbonyl phenyl) quinazoline, weight 0.2745g, productive rate 60%.Its structural formula shown in formula III, 267.3 ℃ of its m.p.;
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-anisole amido)-6-(3-acetamido phenyl) quinazoline compound
The preparation method of present embodiment 4-(3-chloro-4-anisole amido)-6-(3-acetamido phenyl) quinazoline compound comprises the steps:
The preparation of step 1. 4-(3-chloro-4-anisole amido)-6-iodine quinazoline
In having the 250ml there-necked flask of reflux condensing tube, TM, add 12.00g (41.4mmol) 4-chloro-6-iodine quinazoline, 2.17g (13.8 mmol) 3-chloro-4-anisidine and 150ml methyl alcohol successively, under agitation; In 40 ℃ of down reactions 12 hours, during with thin-layer chromatography monitoring reaction degree, after reaction finishes; Filter, deposition is used methanol wash, is oyster until deposition; Place 50 ℃ of vacuum drying ovens dry deposition at last, obtain the oyster powder and be 4-(3-chloro-4-anisole amido)-6-iodine quinazoline, heavy 4.36g; Productive rate 77%, its structural formula is shown in formula II.
The preparation of step 2. 4-(3-chloro-4-anisole amido)-6-(3-aminocarbonyl phenyl) quinazoline
In having the 150ml there-necked flask of reflux condensing tube, TM; The mixture, 0.1363g triethylenediamine and the 100ml volume ratio that add 1.5000g (3.645 mmol) 4-(3-chloro-4-anisole amido)-6-iodine quinazoline (II), 0.1886g (1.215 mmol) 3-amino-benzene boric acid hydrate, 0.0165g triphenyl phosphorus and Palladous chloride successively are cyclohexanone/water mixed solvent of 2/1; Under agitation, in 100 ℃ of down reactions 6 hours, during with thin-layer chromatography monitoring reaction degree; After reaction finishes; Concentration of reaction solution separates purification with silica gel column chromatography then, and moving phase is the butanone/sherwood oil mixed solvent of volume ratio 8/2.Collection contains the product component, remove behind the mixed solvent yellow powder, in 50 ℃ of vacuum-dryings, promptly get 4-(3-chloro-4-anisole amido)-6-(3-aminocarbonyl phenyl) quinazoline, weight 0.2928g, productive rate 64%, its structural formula is shown in formula III.
The preparation of step 3. 4-(3-chloro-4-anisole amido)-6-(3-acetamido phenyl) quinazoline
In having the 150ml there-necked flask of reflux condensing tube, TM; Add 0.5000g (1.33 mmol) 4-(3-chloro-4-anisole amido)-6-(3-aminocarbonyl phenyl) quinazoline (III), 0.5426g (5.32mmol) diacetyl oxide, 0.5255g triethylenediamine and 100ml dioxane successively; Under agitation, in 100 ℃ of down reactions 2 hours, during with thin-layer chromatography monitoring reaction degree; After reaction finishes; Concentration of reaction solution separates purification with silica gel column chromatography then, and moving phase is the trichloromethane/normal hexane mixed solvent of volume ratio 9/1.Collection contains the component of product, remove behind the mixed solvent yellow powder, in 50 ℃ of vacuum-dryings, promptly get 4-(3-chloro-4-anisole amido)-6-(3-acetamido phenyl) quinazoline, weight 0.4785g, productive rate 86%.Its structural formula is shown in formula IV.
（Ⅳ）
271.6 ℃ of the m.p. of present embodiment 4-(3-chloro-4-anisole amido)-6-(3-acetamido phenyl) 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 thus is C
23H
19ClN
4O
2H
2O.
Embodiment 3 4-(3-chloro-4-anisole amido)-6-(3-trifluoroacetyl amido phenyl) quinazoline compound
The preparation method of present embodiment 4-(3-chloro-4-anisole amido)-6-(3-trifluoroacetyl amido phenyl) quinazoline compound comprises the steps:
The preparation of step 1. 4-(3-chloro-4-anisole amido)-6-iodine quinazoline
In having the 250ml there-necked flask of reflux condensing tube, TM, add 4.00g (13.8 mmol) 4-chloro-6-iodine quinazoline, 3.26g (20.7 mmol) 3-chloro-4-anisidine and 150ml propyl carbinol successively, under agitation; In 60 ℃ of down reactions 8 hours, during with thin-layer chromatography monitoring reaction degree, after reaction finishes; Filter, deposition is oyster with the propyl carbinol washing until deposition; Place 50 ℃ of vacuum drying ovens dry deposition at last, obtain the oyster powder and be 4-(3-chloro-4-anisole amido)-6-iodine quinazoline, heavy 4.51g; Productive rate 80%, its structural formula is shown in formula II.
The preparation of step 2. 4-(3-chloro-4-anisole amido)-6-(3-aminocarbonyl phenyl) quinazoline
In having the 150ml there-necked flask of reflux condensing tube, TM; The volume ratio that adds mixture, 0.2454g triethylamine and the 100ml of 0.5000g (1.215 mmol) 4-(3-chloro-4-anisole amido)-6-iodine quinazoline (II), 0.2829g (1.823 mmol) 3-amino-benzene boric acid hydrate, 0.0165g triphenyl phosphorus and Palladous chloride successively is glycol dimethyl ether/water mixed solvent of 2/1; Under agitation, in 60 ℃ of down reactions 24 hours, during with thin-layer chromatography monitoring reaction degree; After reaction finishes; Concentration of reaction solution separates purification with silica gel column chromatography then, and moving phase is the butanone/normal hexane mixed solvent of volume ratio 8/2.Collection contains the component of product, remove behind the mixed solvent yellow powder, in 50 ℃ of vacuum-dryings, promptly get 4-(3-chloro-4-anisole amido)-6-(3-aminocarbonyl phenyl) quinazoline, weight 0.2836g, productive rate 62%, its structural formula is shown in formula III.
The preparation of step 3. 4-(3-chloro-4-anisole amido)-6-(3-trifluoroacetyl amido phenyl) quinazoline
In having the 150ml there-necked flask of reflux condensing tube, TM; Add 2.0000g (5.32mmol) 4-(3-chloro-4-anisole amido)-6-(3-aminocarbonyl phenyl) quinazoline, 0.1762g (1.33 mmol) trifluoroacetyl chloride, 0.1343g triethylamine and 100ml ETHYLE ACETATE successively; Under agitation, in-5 ℃ of down reactions 24 hours, during with thin-layer chromatography monitoring reaction degree; After reaction finishes; Concentration of reaction solution separates purification with silica gel column chromatography then, and moving phase is the methylene dichloride/sherwood oil mixed solvent of volume ratio 9/1.Collection contains the component of product, remove behind the mixed solvent the deep yellow powder, in 50 ℃ of vacuum-dryings, promptly get 4-(3-chloro-4-anisole amido)-6-(3-trifluoroacetyl amido phenyl) quinazoline, weight 0.5649g, productive rate 90%.Its structural formula is suc as formula shown in (V).
（Ⅴ）
274.5 ℃ of the m.p. of present embodiment 4-(3-chloro-4-anisole amido)-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 thus is C
23H
16ClF
3N
4O
2H
2O.
Embodiment 4 4-(3-chloro-4-anisole amido)-6-(3-aminocarbonyl phenyl) quinazoline compounds or its pharmacy acceptable salt are to the restraining effect of cancer cells
Present embodiment adopts lung cancer cell line A549, hepatoma cell strain Bel-7402 and stomach cancer cell line SGC7901 as experimental subjects.With 4-(3-chloro-4-anisole amido)-6-(3-aminocarbonyl phenyl) quinazoline, 4-(3-chloro-4-anisole amido)-6-(3-acetamido phenyl) quinazoline, 4-(3-chloro-4-anisole amido)-6-(3-trifluoroacetyl amido phenyl) quinazoline, 4-(3-chloro-4-anisole amido)-6-(the single maleoyl amido of 3-phenyl) quinazoline, 4-(3-chloro-4-anisole amido)-6-(3-chloracetyl amido phenyl) quinazoline, 4-(3-chloro-4-anisole amido)-6-(3-tribromo-acetyl amido phenyl) quinazoline, 4-(3-chloro-4-anisole amido)-6-(3-acrylamido phenyl) quinazoline, 4-(3-chloro-4-anisole amido)-6-(3-pivalyl aminocarbonyl phenyl) quinazoline, 4-(3-chloro-4-anisole amido)-6-(3-propionamido-phenyl) quinazoline, 4-(3-chloro-4-anisole amido)-6-(3-(2-bromine propionamido-) phenyl) quinazoline is the experiment medicine; 4-of the present invention (3-chloro-4-anisole amido)-6-(3-aminocarbonyl phenyl) quinazoline compounds is to the research that experimentizes of the restraining effect of cancer cells, and concrete operations are as follows.
Adopt the MTT development process, the lung cancer cell line A549 in the vegetative period of taking the logarithm, hepatoma cell strain Bel-7402, stomach cancer cell line SGC7901 behind 0.25% tryptic digestion, add perfect medium and trypsinase, and piping and druming are prepared into single cell suspension repeatedly.On the tally counting after, with 5000 cell inoculations in every hole in 96 orifice plates.In 37 ℃, 5%CO
2Leave standstill in the incubator to cultivate and make cell attachment.Inhale behind the 24h and abandon original substratum,, add the fresh perfect medium that contains 10% newborn calf serum of 100 μ L with 150 μ L PBS washing 1 time; Add the experiment medicine then, simultaneously with the liquid medium hole of not dosing as negative control, only to add the nutrient solution hole as zeroing hole (not containing cancer cells); After cultivating 72h respectively; Sucking-off substratum and soup with PBS washing 1 time, add 200 μ L substratum and 20 μ L concentration are 5mgmL
-1MTT liquid, continue to cultivate 4h, inhale then and abandon the liquid in the orifice plate, add 150 μ L DMSO and blow and beat repeatedly, the bluish voilet crystallization is fully dissolved; Measure absorbance value (OD value), 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% with enzyme-linked immunosorbent assay instrument with the 490nm wavelength.
Adopt IC
50Value is as shown in table 1 to the antitumour activity evaluation result of 4-(3-chloro-4-anisole amido)-6-(3-aminocarbonyl phenyl) quinazoline compounds.Through the OD value of measuring in different time points, obtain the inhibiting rate changing conditions of different time points, the change curve that draws, as optimum time point, the best use of time that is drawn medicine by time curve is 36h with curve arrival that time point of plateau.
Table 1 4-(3-chloro-4-anisole the amido)-IC of 6-(3-aminocarbonyl phenyl) quinazoline compounds effect after 36 hours
50Value
Can find out that from table 1 4-of the present invention (3-chloro-4-anisole amido)-6-(3-aminocarbonyl phenyl) quinazoline compounds all demonstrates the good anticancer activity to lung adenocarcinoma cell line A549, hepatoma cell strain Bel-7402 and stomach cancer cell line SGC7901.
Claims (9)
1. a 4-(3-chloro-4-anisole amido)-6-(3-aminocarbonyl phenyl) quinazoline compounds or its pharmacy acceptable salt, its structural formula is shown in formula I:
（Ⅰ）
In the 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;
When R=-during H, this 4-(3-chloro-4-anisole amido)-6-(3-aminocarbonyl phenyl) quinazoline compounds is 4-(3-chloro-4-anisole amido)-6-(3-aminocarbonyl phenyl) quinazoline;
When R=-COCH
3The time, this 4-(3-chloro-4-anisole amido)-6-(3-aminocarbonyl phenyl) quinazoline compounds is 4-(3-chloro-4-anisole amido)-6-(3-acetamido phenyl) quinazoline;
When R=-COCF
3The time, this 4-(3-chloro-4-anisole amido)-6-(3-aminocarbonyl phenyl) quinazoline compounds is 4-(3-chloro-4-anisole amido)-6-(3-trifluoroacetyl amido phenyl) quinazoline;
When R=-during COCH=CHCOOH, this 4-(3-chloro-4-anisole amido)-6-(3-aminocarbonyl phenyl) quinazoline compounds is 4-(3-chloro-4-anisole amido)-6-(the single maleoyl amido of 3-phenyl) quinazoline;
When R=-COCH
2During Cl, this 4-(3-chloro-4-anisole amido)-6-(3-aminocarbonyl phenyl) quinazoline compounds is 4-(3-chloro-4-anisole amido)-6-(3-chloracetyl amido phenyl) quinazoline;
When R=-COCCl
3The time, this 4-(3-chloro-4-anisole amido)-6-(3-aminocarbonyl phenyl) quinazoline compounds is 4-(3-chloro-4-anisole amido)-6-(3-tribromo-acetyl amido phenyl) quinazoline;
When R=-COCH=CH
2The time, this 4-(3-chloro-4-anisole amido)-6-(3-aminocarbonyl phenyl) quinazoline compounds is 4-(3-chloro-4-anisole amido)-6-(3-acrylamido phenyl) quinazoline;
When R=-COC (CH
3)
3The time, this 4-(3-chloro-4-anisole amido)-6-(3-aminocarbonyl phenyl) quinazoline compounds is 4-(3-chloro-4-anisole amido)-6-(3-pivalyl aminocarbonyl phenyl) quinazoline;
When R=-COCH
2CH
3The time, this 4-(3-chloro-4-anisole amido)-6-(3-aminocarbonyl phenyl) quinazoline compounds is 4-(3-chloro-4-anisole amido)-6-(3-propionamido-phenyl) quinazoline;
When R=-COCHBrCH
3The time, this 4-(3-chloro-4-anisole amido)-6-(3-aminocarbonyl phenyl) quinazoline compounds is 4-(3-chloro-4-anisole amido)-6-(3-(2-bromine propionamido-) phenyl) quinazoline.
2. according to the said 4-of claim 1 (3-chloro-4-anisole amido)-6-(3-aminocarbonyl phenyl) quinazoline compounds or its pharmacy acceptable salt, it is characterized in that said pharmaceutically acceptable inorganic salt or organic salt comprise hydrochloride, vitriol, phosphoric acid salt, metilsulfate, sulphonate, formate, acetate, malate or lactic acid salt.
3. the preparation method of the said 4-of claim 1 (3-chloro-4-anisole amido)-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-anisole amido)-6-iodine quinazoline
With 4-chloro-6-iodine quinazoline and 3-chloro-4-anisidine is raw material, in the presence of solvent, reacts 1 ~ 12 hour down at 40 ~ 100 ℃; After reaction finishes, filter, precipitate with solvent wash to oyster; Collect the oyster powder on the filter paper at last; In 50 ℃ of vacuum-dryings, obtain 4-(3-chloro-4-anisole amido)-6-iodine quinazoline, its structure is following:
（Ⅱ）
The preparation of step 2. 4-(3-chloro-4-anisole amido)-6-(3-aminocarbonyl phenyl) quinazoline
4-(3-chloro-4-anisole amido)-6-iodine quinazoline (II) and 3-amido phenylo boric acid hydrate with step 1 gained are raw material; In the presence of nitrogen protection, catalyzer, acid binding agent and solvent,, after reaction finishes reaction solution is concentrated 40 ~ 100 ℃ of reactions 6 ~ 30 hours; Separate with silica gel column chromatography then and purify; Collection contains the component of product, except that getting pale yellow powder after desolvating, in 50 ℃ of vacuum-dryings; Promptly get 4-of the present invention (3-chloro-4-anisole amido)-6-(3-aminocarbonyl phenyl) quinazoline, its structural formula is following:
（Ⅲ）
The preparation of step 3. 4-(3-chloro-4-anisole amido)-6-(3-aminocarbonyl phenyl) quinazoline derivant
(a kind of compound that is called for short among the R-C (O)-X) is a raw material with acid anhydrides, acyl chlorides or carboxylic acid with 4-(3-chloro-4-anisole amido)-6-(3-aminocarbonyl phenyl) quinazoline (III) of step 2 gained; In the presence of nitrogen protection, acid binding agent and solvent, reacted 2 ~ 24 hours down at-5 ℃ ~ 100 ℃, after reaction finishes reaction solution is concentrated; Separate with silica gel column chromatography then and purify; Collection contains the component of product, except that getting faint yellow or yellow powder after desolvating, in 50 ℃ of vacuum-dryings; Promptly get 4-of the present invention (3-chloro-4-anisole amido)-6-(3-aminocarbonyl phenyl) quinazoline derivant, its molecular structure is shown in formula I.
4. according to the said preparation method of claim 3, it is characterized in that in the said step 1 that the mol ratio of 4-chloro-6-iodine quinazoline and 3-chloro-4-anisidine is 1:0.33～3; In the said step 2, the mol ratio of 4-(3-chloro-4-anisole amido)-6-iodine quinazoline and 3-amido phenylo boric acid hydrate is 1:0.33～3; In the said step 3, (mol ratio that is called for short a kind of compound among the R-C (O)-X) is 1:0.25～4 for 4-(3-chloro-4-anisole amido)-6-(3-aminocarbonyl phenyl) quinazoline and acid anhydrides, acyl chlorides or carboxylic acid.
5. according to the said preparation method of claim 3, it is characterized in that in the said step 1 that solvent is selected from one or more mixed solvents in methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, the isopropylcarbinol.
6. according to the said preparation method of claim 3, it is characterized in that in the said step 2 that catalyzer is the mixture of triphenyl phosphorus and palladium or triphenyl phosphorus and Palladous chloride; Acid binding agent is selected from salt of wormwood, yellow soda ash, cesium carbonate, triethylamine, triethylenediamine, tetramethyl butane diamine, N; N-dimethyl benzylamine, N-ethylmorpholine, N; N-dimethyl cyclohexyl amine, N; The basic amine of N-methyl bicyclic, N-methylmorpholine, N, N-diethylammonium piperazine, N, one or more mixtures in N-lupetazin, salt of wormwood, yellow soda ash, cesium carbonate, Pottasium Hydroxide, the sodium hydroxide; Solvent is selected from water, ethanol, THF, methylene dichloride, trichloromethane, 1; 2-ethylene dichloride, glycol dimethyl ether, EGME, ether, acetone, butanone, cyclohexanone, benzene, toluene, dioxane, N, one or more mixed solvents in dinethylformamide, pyridine, the ETHYLE ACETATE.
7. according to the said preparation method of claim 3; It is characterized in that in the said 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; The basic amine of N-methyl bicyclic, N-methylmorpholine, N, N-diethylammonium piperazine, N, one or more mixtures in N-lupetazin, salt of wormwood, yellow soda ash, cesium carbonate, Pottasium Hydroxide, the sodium hydroxide; Solvent is selected from ethanol, THF, methylene dichloride, chloroform, glycol dimethyl ether, EGME, ether, acetone, toluene, dioxane, N, one or more mixed solvents in dinethylformamide, the ETHYLE ACETATE.
8. according to the said preparation method of claim 3; It is characterized in that in the said step 2 and 3 that the moving phase of silica gel column chromatography is selected from one or more mixed solvents in ETHYLE ACETATE, normal hexane, cyclohexane, sherwood oil, methyl alcohol, ethanol, methylene dichloride, trichloromethane, ether, acetone, the butanone.
9. the said 4-of claim 1 (3-chloro-4-anisole amido)-6-(3-aminocarbonyl phenyl) quinazoline compounds or its pharmacy acceptable salt application in the preparation 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 |
|---|
| SIAVOSH MAHBOOBI,等: "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", 《J. MED. CHEM.》 * |
| 徐浩,等: "埃罗替尼衍生物的合成及抗肿瘤活性", 《中国药科大学学报》 * |
| 李铭东,等: "盐酸埃洛替尼的合成", 《中国医药工业杂志》 * |
| 王武伟,等: "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", 《化工中间体》 * |
| 金波，等: "吉非替尼的合成", 《中国药科大学学报》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103864750A (en) * | 2014-03-11 | 2014-06-18 | 清华大学 | Derivative of N-biphenyl dichloroacetamide as well as preparation method and applications thereof |
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