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CN103613580A - 3-hydroxyindole-2-ketone compounds for antitumor medicaments - Google Patents

3-hydroxyindole-2-ketone compounds for antitumor medicaments Download PDF

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CN103613580A
CN103613580A CN201310636517.5A CN201310636517A CN103613580A CN 103613580 A CN103613580 A CN 103613580A CN 201310636517 A CN201310636517 A CN 201310636517A CN 103613580 A CN103613580 A CN 103613580A
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CN103613580B (en
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张磊
王京
陈永正
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Zunyi Medical University
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

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Abstract

The invention relates to the field of medicinal chemistry, and specifically relates 3-hydroxy-3-[2,3-dihydroquinoline-4-keto-3-yl]indole-2-ketone compounds (I) and pharmaceutically acceptable salts thereof or pharmaceutically acceptable solvent mixtures thereof, a preparation method thereof, and uses of the compounds in preparing medicaments for preventing or treating diseases related to abnormal cell proliferation, morphologic change and the like, in particular medicaments for preventing or treating tumor growth and transfer.

Description

3-hydroxyindole-2-ketone compounds for antitumor drug
Technical field
The present invention relates to pharmaceutical chemistry field, be specifically related to a class and there is the 3-hydroxyl-3-[2 of anti-tumor activity, 3-dihydroquinoline-4-ketone-3-yl] indole-2-ketone compound and pharmacy acceptable salt or pharmaceutically acceptable solvate, its preparation method, the pharmaceutical composition that comprises this compound, and these compounds are for the preparation of relevant diseases such as prevention or treatment abnormal cell proliferation, metamorphosis, in particular for the purposes in treatment or prophylaxis of tumours growth and the medicine shifting.
Background technology
Tumour is a kind of common disease and frequently-occurring disease of serious threat human health, and statistic data nearly ten years shows: more than the new cancer patient of the every annual in the whole world approximately 1,000 ten thousand people, the mankind are only second to cardiovascular and cerebrovascular diseases because of the mortality ratio that cancer causes.World Health Organization's prediction, by 2020, whole world cancer morbidity will be than present increase by 50%, and the annual newly-increased cancer patients in the whole world will reach 1,500 ten thousand people.At present, the antitumor drug using is clinically mainly traditional chemotherapeutics, this class medicine kills tumour cell by cytotoxicity, in the complex therapy of some malignant tumour, play a significant role, but not good enough to most solid tumor curative effects, also there is the poor selectivity, the toxic side effect that are difficult to avoid simultaneously and greatly, easily produce the shortcomings such as resistance.This just in the urgent need to medicine scholars develop there is novelty, the antitumor drug of low toxicity, selectivity high.
3-hydroxyindole-2-ketone molecular skeleton is present in natural product widely, as TMC-95 A, Maremycin B, Convolutamydine A, Celogentin K, Paratunamide D, Arundaphine etc.The natural product that contains 3-hydroxyindole-2-ketone skeleton has multiple biological activity, as antitumor, antiviral, Maxi-K channel agonist, somatropin release, neurocyte protection effect, analgesic activity, antibacterial and tuberculosis effect.In the structure and drug discovery process in micromolecular compound storehouse, 3-hydroxyindole-2-ketone structure is also considered to a kind of advantage skeleton.
Many sarcomas and leukemia are with nonrandom chromosome translocation, and transcription factor is merged in the special variation of these transposition site codes for tumor.Ewing's sarcoma family tumor contains the characteristic t transposition that a carcinogenic fusion rotein EWS-FLI1 expresses.Because EWS-FLI1 is a dislocation albumen, cannot use the conventional method design small molecules inhibition based on structure.Very important to its oncogenic function in view of the combination of EWS-FLI1 and RNA helicase A, American scientist Hayriye V E is used the method screening of surface plasma sub-resonance examination be combined with EWS-FLI1 also to block itself and the interactional micromolecular compound of RHA.YK-4-279 wherein, chemical name: 4,7-bis-chloro-3-hydroxyls-3-[2-(4-methoxyl group)-2-ethyl oxide] indol-2-one, it is the effective lead compound obtaining in examination, can block the combination of RHA and EWS-FLI1, induction ESFT apoptosis also makes the orthotopic transplantation thing growth restriction of ESFT.Experimental result confirms that this compound can suppress the tomour specific transcription factor cellular constituent required with carcinogenic effect combine (Nature Medicine, 2009,7:756 ~ 757) of variation.2010, the people such as Penthala N R have synthesized a series of 3-hydroxyl-3-(2-imino--3-methyl-5-oxo-imidazole alkane ketone-4-yl) indol-2-one derivates, when 57 kinds of tumor cell lines are carried out to active testing, majority of compounds all has stronger anti-tumor activity, wherein the GI of part of compounds to tumour cells such as A549, ATTC 50value is less than 1 μ M, has certain researching value (Bioorg. Med. Chem. Lett, 2010,20:4468 ~ 4471).
Summary of the invention
The invention discloses a class 3-hydroxyl-3-[2,3-dihydroquinoline-4-ketone-3-yl] indole-2-ketone compound (I).Pharmacological evaluation proves, the compounds of this invention has stronger restraining effect to various tumor cell strains; In experiment, the compounds of this invention can suppress the propagation of tumour significantly in body, and gross tumor volume obviously diminishes, and inhibiting rate is strong compared with 5 FU 5 fluorouracil, to main metabolic organ and immune organ without obvious toxicity.Therefore, general formula of the present invention (I) compound, can be used for prevention and treats the relevant diseases such as various abnormal cell proliferations, metamorphosis, in particular for the purposes in the medicine for the treatment of or prophylaxis of tumours growth and transfer.
3-hydroxyl-3-[2 of the present invention, 3-dihydroquinoline-4-ketone-3-yl] general structure of indole-2-ketone compound is as shown in following general formula (I):
R wherein 1the glycosyl of representative: H, C1 ~ C6 alkane, aryl, aralkyl, acyl group, aroyl, acyl group protection; Or as shown in the formula:
R 2, R 3, R 4, R 5, R 6, R 7, R 8and R 9represent independently H, halogen, hydroxyl, sulfydryl, C1 ~ C6 alkyl, nitro, amino, amido, amide group, C1 ~ C4 alkoxyl group, methylthio group, phenyl, phenoxy group, aryl, aralkyl, trifluoromethyl, acyl group, aroyl, sulfonic group, sulfamide groups, isocyanate group.
Described halogen is fluorine, chlorine, bromine or iodine.
According to the present invention, pharmacy acceptable salt comprises the acid salt that general formula (I) compound and following acid form: hydrochloric acid, Hydrogen bromide, sulfuric acid, citric acid, succsinic acid, tartrate, phosphoric acid, lactic acid, formic acid, acetic acid, Whitfield's ointment, propanedioic acid, fumaric acid, oxysuccinic acid, thionamic acid, xitix, nitric acid, propionic acid, oxalic acid, toxilic acid, methylsulfonic acid, Phenylsulfonic acid, tosic acid or forulic acid.
The pharmaceutically acceptable solvate of the compound that general formula of the present invention (I) represents comprises the compound of general formula (I) expression and the solvate of water, ethanol, Virahol, ether or acetone without limitation.
Pharmaceutical composition of the present invention, wherein contain significant quantity the compounds of this invention, its pharmacy acceptable salt or pharmaceutically acceptable solvate, formulation can be the pharmaceutically conventional formulation such as tablet, capsule, powder, granule, pill, suppository, oral liquid, suspensoid, injection.Wherein tablet for oral use and capsule contain traditional vehicle as: weighting material, thinner, lubricant, dispersion agent and tackiness agent, can be prepared according to method well known in the art.
The preparation method of general formula target compound of the present invention (I) is as follows:
Wherein a represents reaction conditions: catalyzer is diethylamine, triethylamine, piperidines, morpholine, sodium-acetate; Solvent is methyl alcohol, ethanol, Virahol.Wherein the preparation of compound 1-alkyl-isatin series intermediate (II) can reference literature (Chem. Central J, 2011, (replacement) isatin of 5:37), take is raw material, synthetic method is as follows:
Figure 434981DEST_PATH_IMAGE004
Compound 2,3-dihydroquinoline-4-ketone series intermediate (III) prepare reference literature (Tetrahedron, 2002,58:8475 ~ 8481; Aust. J. Chem, 2011,64:454 ~ 470), (replacement) phenyl-iodide of take is raw material, synthetic method is as follows:
Figure 356233DEST_PATH_IMAGE005
Below pharmacologically active testing method and the result of part of compounds of the present invention:
One, mtt assay test anti tumor activity in vitro
Material and instrument:
Cell strain: human liver cancer cell (HepG2), cervical cancer cell (HeLa), non-small cell lung cancer cell (A549), glioma cell (U251), gastric adenocarcinoma cells (SGC-7901) is purchased from Ke Xing bio tech ltd, Shanghai.
Reagent: DMEM/MEM/1640 substratum (U.S. Gibco company), 0.25 % trypsinase: (U.S. Amresco company), new-born calf serum, foetal calf serum (Hangzhou folium ilicis chinensis bio-engineering corporation product), methyl-sulphoxide (DMSO, analytical pure), MTT(U.S. Amresco company).
Sample: selected part 3-hydroxyl-3-[2,3-dihydroquinoline-4-ketone-3-yl] indole-2-ketone compound.
Reference substance: 5 FU 5 fluorouracil (5-FU).
Experimental principle: in viable cell plastosome, desaturase can be reduced into yellow MTT water-fast bluish voilet and produce thing formazan (MTT formazan), and is deposited in cell, and the amount of generation is directly proportional to viable cell number, and dead cell does not have this function.DMSO can dissolve bluish voilet crystallisate, and shade is directly proportional to contained amount, therefore with the absorbance value that microplate reader is measured, can reflect cell survival rate.
4 * 10 4the density of/ml is inoculated in 96 well culture plates, every hole 100 μ l.Cultivate after 24 hours, part of compounds of the present invention and 5-FU are respectively with 1,2, and 4,8,16 μ mol/L process tumour cell and 15,18, and 21,24 μ mol/L process tumour cell.Each concentration of experimental group is established 5 multiple holes, with the nutrient solution of DMSO content corresponding to the highest administration concentration, compares.After compound effects 48 h, remove supernatant, every hole adds 100 μ l MTT (1 mg/ml), continues to cultivate 4 h, abandons supernatant, and every hole adds 100 μ l DMSO, and vibration mixes, and by microplate reader, at 570 nm places, measures absorbance.Calculate inhibiting rate, inhibiting rate (%)=(1-administration group absorbance/control group absorbance) * 100%.With concentration-inhibiting rate curve, draw regression equation, obtain half-inhibition concentration (IC 50).
Part of compounds pharmacology test result is as follows:
Table 1 part of compounds of the present invention is checked its antiproliferative activity to kinds of tumor cells
Experimental result demonstration, majority of compounds has good inhibition active to tumour cell, but anti tumor activity in vitro is all weaker than positive drug 5 FU 5 fluorouracil.Wherein, the antiproliferative activity of Compound I-7 couple HepG2, SGC-7901 is better.
Two, sample compound I-7 anti-tumor in vivo active testing
Laboratory animal, cell:
ICR mouse (female), 18～20 g, purchased from Jiangsu University's animal center, conformity certification #:SYXK (Soviet Union) 2008-0024;
Ascitic Tumor Cells is derived from Jiangsu Prov. Tumour Hospital.
Key instrument:
TEC-2500 floats baking instrument: Changzhou Hao Si beautiful jade medical apparatus company limited, China;
Excellent general ultrapure water machine: Chinese Chengdu Ultra Pure Science & Technology Co., Ltd, China;
TE601-L electronic balance: BeiJing, China Sai Duolisi instrument system company limited, China;
Ultralow Temperature Freezer: U.S. Xin Bulunzi Brunswick scientific instrument company, the U.S..
Medicine and reagent:
5 FU 5 fluorouracil (5-FU): Hengrui Medicine Co., Ltd., Jiangsu Prov., the accurate word H12020959 of traditional Chinese medicines.
Test method: ascitic tumor strain is cultivated after 14 days (two generations) at ascitic tumor model mouse intraperitoneal, and ascitic tumor model mouse is put to death, bubble 75% ethanol 5 min after putting to death, peritoneocentesis is got the ascites of ascitic tumor model mouse, and normal saline dilution cell concn reaches 2 * 10 7individual/ml, under aseptic condition, gets Ascitic Tumor Cells suspension 0.2 ml/ only (4 * 10 6individual/only) be inoculated in 21 ICR mouse oxters.Tumor growth 4 ~ 6 d are after latent period, the subcutaneous visible tubercle of inoculation position, and when tumor size is about 3 ~ 4 mm to diameter, administration after 2 weeks.Mouse is divided into 3 groups at random, 7 every group, model control group administration is solvent physiological saline, administration group: 5 FU 5 fluorouracil is abdominal injection (20 mg/kg/d); Sample compound I-7 is gastric infusion (20 mg/kg/d).Successive administration was weighed after 10 days, and mouse eyeground vein clump is got blood, and then cervical vertebra dislocation is put to death after mouse, peels off tumour.Every group of mouse peeled off to tumour and rinse well, and filter paper blots, and weighs, and calculates average knurl weight, tumour inhibiting rate.The average knurl of tumour inhibiting rate (%)=(the average knurl weight of the average knurl weight-administration of control group group)/control group heavy * 100%.
Detect toxicity index:
Each group immune function of mice and metabolism organ index are detected.Mouse organ weight: thymus gland, spleen, liver, the kidney calculating of weighing:
Thymus index=thymic weight (mg)/body weight (g);
Index and spleen index=spleen weight (mg)/body weight (g);
Liver index=liver weight (mg)/body weight (g);
Renal index=kidney weight (mg)/body weight (g).
Sample compound I-7 pharmacology test result is as follows:
The tumour inhibiting rate of table 2 sample compound I-7 to mouse ascites knurl
The impact of table 3 sample compound I-7 on ascitic tumor mouse immune, metabolism organ index
Figure 2013106365175100002DEST_PATH_IMAGE002
Obtain beneficial effect: drug sample Compound I-7 pair ascitic tumor mouse has obvious tumor-inhibiting action, and remarkable compared with 5 FU 5 fluorouracil, and the kidney,liver,spleen of ascitic tumor model mice and thymus index are not significantly affected the side effect that does not have common chemotherapeutic to have when tumor suppression effective dose.And positive control 5-Fu shows larger toxic side effect, as the restraining effect to immune organs such as thymus gland.
Embodiment
Instrument and reagent
The prepared 3-hydroxyl-3-[2 of the present invention, 3-dihydroquinoline-4-ketone-3-yl] fusing point of indole-2-ketone compound (I) measures with Mel-TEMP melting point apparatus, and temperature is not calibrated.ESI-MS measures with HP1100LC/MSD mass spectrograph; 1bruck AV-300 type nmr determination for H NMR, interior mark TMS; Elementar Vario EL III Instrument measuring for ultimate analysis.
Reagent is commercially available chemical pure or analytical pure product, except special instruction, and not treated direct use
Embodiment 1
1-methyl-3-hydroxyl-3-[6-is bromo-2,3-dihydroquinoline-4-ketone-3-yl] preparation of indol-2-one (I-1)
1-methyl-isatin (1.61g, 10mmol) and 6-is bromo-2,3-dihydroquinoline-4-ketone (2.26g, 10mmol) be dissolved in dehydrated alcohol (10mL), add again triethylamine (0.5mL), system is heated to 40 ℃, stirring reaction 2h, by the solid suction filtration of separating out, dehydrated alcohol (2 * 1mL) washing, vacuum-drying, obtains yellow solid 2.78g, yield 72%, 189 ~ 191 ℃ of m.p.. 1H?NMR?(DMSO-d6，300MHz)?δ?(ppm)：7.23~7.29(m，4H)，7.17(d，J?=?3.3?Hz，1H)，6.94~6.99(m，2H)，6.75(d，J?=?8.4?Hz，1H)，6.15(s，1H)，3.70~3.91(m，2H)，3.50-3.57(m，1H)，3.10(s，3H)；ESI-MS?m/z：386.9?[M+H] +；Anal.?calcd?for?C 18H 15BrN 2O 3(387.23)：C55.83，H3.90，N7.23；found：C55.48，H4.10，N7.0。
Embodiment 2
1-methyl-3-hydroxyl-3-[6-is chloro-2,3-dihydroquinoline-4-ketone-3-yl] preparation of indol-2-one (I-2)
1-methyl-isatin (1.61g, 10mmol) and 6-is chloro-2,3-dihydroquinoline-4-ketone (1.81g, 10mmol) be dissolved in dehydrated alcohol (10mL), add again triethylamine (0.5mL), system is heated to 40 ℃, stirring reaction 2h, by the solid suction filtration of separating out, dehydrated alcohol (2 * 1mL) washing, vacuum-drying, obtains yellow solid 2.56g, yield 75%, 191 ~ 193 ℃ of m.p.. 1H?NMR?(DMSO-d6，300?MHz)?δ?(ppm)：7.23~7.28(m，4H)，7.15(d，J?=?3.3?Hz，1H)，6.94~6.99(m，2H)，6.75(d，J?=?8.6?Hz，1H)，6.14(s，H)，3.81~3.89(m，1H)，3.75(t，J?=?14.0?Hz，1H)，3.50(dd，J?=?6.1?and?14.1?Hz，1H)，3.10(s，3H)；ESI-MS?m/z：365.1?[M+Na] +；Anal.?calcd?for?C 18H 15ClN 2O 3(342.78)：C63.07，H4.41，N8.17；found：C63.04，H4.56，N7.9。
Embodiment 3
1-ethyl-3-hydroxyl-3-[6-is bromo-2,3-dihydroquinoline-4-ketone-3-yl] preparation of indol-2-one (I-3)
1-ethyl-isatin (1.75g, 10mmol) and 6-is bromo-2, and 3-dihydroquinoline-4-ketone (2.26g, 10mmol) is dissolved in
In dehydrated alcohol (10mL), then add triethylamine (0.5mL), system is heated to 40 ℃, stirring reaction 2h, by the solid suction filtration of separating out, dehydrated alcohol (2 * 1mL) washing, vacuum-drying, obtain yellow solid 2.84g, yield 71%, 202 ~ 205 ℃ of m.p.. 1H?NMR?(DMSO-d 6，300?MHz)?δ?(ppm)：7.24~7.39(m，5H)，7.00(d，J?=?7.7?Hz，1H)，6.88(t，J?=?7.4?Hz，1H)，6.74(d,?J?=?8.6?Hz，1H)，6.24(s，1H)，3.89~3.95(m，1H)，3.62~3.78(m，3H)，3.23~3.30(dd，1H,?J?=?5.7?and?13.6?Hz，1H)，1.22(s，J?=?7.0?Hz，3H)；ESI-MS?m/z：401.0?[M+H] +；Anal.?calcd?for?C 19H 17BrN 2O 3(401.25)：C56.87，H4.27，N6.98；found：C56.77，H3.94，N6.8。
Embodiment 4
1-ethyl-3-hydroxyl-3-[6-is chloro-2,3-dihydroquinoline-4-ketone-3-yl] preparation of indol-2-one (I-4)
1-ethyl-isatin (1.75g, 10mmol) and 6-is chloro-2, and 3-dihydroquinoline-4-ketone (1.81g, 10mmol) is dissolved in
In dehydrated alcohol (10mL), then add triethylamine (0.5mL), system is heated to 40 ℃, stirring reaction 2h, by the solid suction filtration of separating out, dehydrated alcohol (2 * 1mL) washing, vacuum-drying, obtain yellow solid 2.77g, yield 78%, 218 ~ 219 ℃ of m.p.. 1H?NMR?(DMSO-d 6，300?MHz)?δ?(ppm)：7.36(d，J?=?7.4?Hz，1H)，7.25~7.29(m，4H)，7.00(d，J?=?7.6?Hz，1H)，6.80~6.88(m，2H)，6.24(s，1H)，3.89~3.92(m，1H)，3.65~3.78(m，3H)，3.23~3.30(dd，J?=?5.7?and?13.7?Hz，1H)，1.22(s，J?=?7.0?Hz，3H)；ESI-MS?m/z：357.1?[M+H] +；Anal.?calcd?for?C 19H 17ClN 2O 3·0.1H 2O(358.60)：C63.63，H4.83，N7.81；found：C63.42，H4.48，N7.5。
Embodiment 5
1-propyl group-3-hydroxyl-3-[6-is bromo-2,3-dihydroquinoline-4-ketone-3-yl] preparation of indol-2-one (I-5)
1-propyl group-isatin (1.89g, 10mmol) and 6-is bromo-2, and 3-dihydroquinoline-4-ketone (2.26g, 10mmol) is dissolved in
In dehydrated alcohol (10mL), then add triethylamine (0.5mL), system is heated to 40 ℃, stirring reaction 2h, by the solid suction filtration of separating out, dehydrated alcohol (2 * 1mL) washing, vacuum-drying, obtain yellow solid 3.07g, yield 74%, 205 ~ 208 ℃ of m.p.. 1H?NMR?(DMSO-d 6，300?MHz)?δ?(ppm)：7.35~7.38(m，2H)，7.30~7.32(m，1H)，7.21(t，J?=?7.7?Hz，1H)，6.84~6.88(m，2H)，6.72(d,?J?=?8.6?Hz，1H)，6.28(s，1H)，5.80~5.93(m，1H)，5.38~5.41(dd，J?=?1.6?and?17.2?Hz，1H)，5.18(dd，J?=?1.55?and?10.4?Hz，1H)，4.18~4.36(m，2H)，3.88~3.95(m，1H)，3.74(t，J?=?13.3?Hz，1H)，3.24~3.31(m，1H)；ESI-MS?m/z：413.0?[M+H] +；Anal.?calcd?for?C 20H 17BrN 2O 3?(413.26)：C58.13，H4.15，N6.78；found：C58.14，H3.90，N6.7。
Embodiment 6
1-propyl group-3-hydroxyl-3-[6-is chloro-2,3-dihydroquinoline-4-ketone-3-yl] preparation of indol-2-one (I-6)
1-propyl group-isatin (1.89g, 10mmol) and 6-is chloro-2, and 3-dihydroquinoline-4-ketone (1.81g, 10mmol) is dissolved in
In dehydrated alcohol (10mL), then add triethylamine (0.5mL), system is heated to 40 ℃, stirring reaction 2h, by the solid suction filtration of separating out, dehydrated alcohol (2 * 1mL) washing, vacuum-drying, obtain yellow solid 2.81g, yield 76%, 217 ~ 219 ℃ of m.p.. 1H?NMR?(DMSO-d 6，300?MHz)?δ?(ppm)：7.38(d，J?=?7.2?Hz，1H)，7.22~7.38(m，3H)，6.87~6.91(m，2H)，6.81(d，J?=?9.6?Hz，1H)，6.32(s，1H)，5.83~5.96(m，1H)，5.41?(dd，J?=?1.6?and?17.4?Hz，1H)，5.19?(dd，J?=?1.5?and?10.5?Hz，1H)，4.28~4.33(m，2H)，3.91~3.98(m，1H)，3.77(m，1H)，3.27~3.33(m，2H)；ESI-MS?m/z：369.1?[M+H] +；Anal.?calcd?for?C 20H 17ClN 2O 3?(368.81)：C65.13，H4.65，N7.60；found：C65.15，H4.73，N7.5……
Embodiment 7
1-benzyl-3-hydroxyl-3-[6-is bromo-2,3-dihydroquinoline-4-ketone-3-yl] preparation of indol-2-one (I-7)
1-benzyl-isatin (2.37g, 10mmol) and 6-is bromo-2, and 3-dihydroquinoline-4-ketone (2.26g, 10mmol) is dissolved in
In dehydrated alcohol (10mL), then add triethylamine (0.5mL), system is heated to 40 ℃, stirring reaction 2h, by the solid suction filtration of separating out, dehydrated alcohol (2 * 1mL) washing, vacuum-drying, obtain yellow solid 3.65g, yield 79%, 200 ~ 202 ℃ of m.p.. 1H?NMR?(DMSO-d 6，300?MHz)?δ?(ppm)：7.47(d，J?=?7.2?Hz，2H)，7.34~7.43(m，6H)，7.27(t，J?=?7.2?Hz，1H)，7.17(t，J?=?7.6?Hz，1H)，6.87(t，J?=?7.4?Hz，1H)，6.77(t，J?=?8.5?Hz，2H)，6.41(s，1H)，4.90(s，2H)，3.93~4.00(m，1H)，3.80(t，J?=?13.2?Hz，1H)，3.36(m，1H)；ESI-MS?m/z：463.0?[M+H] +；Anal.?calcd?for?C 24H 19BrN 2O 3(463.32)：C62.22，H4.13，N6.05；found：C62.15，H4.08，N5.86。
Embodiment 8
1-benzyl-3-hydroxyl-3-[6-is chloro-2,3-dihydroquinoline-4-ketone-3-yl] preparation of indol-2-one (I-8)
1-benzyl-isatin (2.37g, 10mmol) and 6-is chloro-2, and 3-dihydroquinoline-4-ketone (1.81g, 10mmol) is dissolved in
In dehydrated alcohol (10mL), then add triethylamine (0.5mL), system is heated to 40 ℃, stirring reaction 2h, by the solid suction filtration of separating out, dehydrated alcohol (2 * 1mL) washing, vacuum-drying, obtain yellow solid 3.21g, yield 77%, 211 ~ 212 ℃ of m.p.. 1H?NMR?(DMSO-d 6，300?MHz)?δ?(ppm)：7.47(d，J?=?7.2?Hz，2H)，7.34~7.42(m，4H)，7.25~7.29(m，3H)，7.17(t，J?=?7.7?Hz，1H)，6.82~6.90(m，2H)，6.74(d，J?=?7.7?Hz，1H)，6.41(s，1H)，4.90(s，2H)，3.93~4.01(m，1H)，3.80(t，J?=?13.2?Hz，1H)，3.33~3.40(m，1H)；ESI-MS?m/z：419.1?[M+H] +；Anal.?calcd?for?C 24H 19ClN 2O 3(418.87)：C68.82，H4.57，N6.69；found：C68.76，H4.44，N6.42。

Claims (5)

1. for 3-hydroxyindole-2-ketone compounds of antitumor drug, it is characterized in that: this ketone compounds component is 3-hydroxyl-3-[2,3-dihydroquinoline-4-ketone-3-yl] pharmaceutically receptible salt or hydrate or its mixture are as the pharmaceutical composition of active ingredient for indole-2-ketone structural compounds or its, and the general structure of described compound is as shown in the formula (I):
Figure 381207DEST_PATH_IMAGE001
R wherein 1the glycosyl of representative: H, C1 ~ C6 alkane, aryl, aralkyl, acyl group, aroyl, acyl group protection; Or as shown in the formula:
Figure 298347DEST_PATH_IMAGE002
R 2, R 3, R 4, R 5, R 6, R 7, R 8and R 9represent independently H, halogen, hydroxyl, sulfydryl, C1 ~ C6 alkyl, nitro, amino, amido, amide group, C1 ~ C4 alkoxyl group, methylthio group, phenyl, phenoxy group, aryl, aralkyl, trifluoromethyl, acyl group, aroyl, sulfonic group, sulfamide groups, isocyanate group; Described halogen is fluorine, chlorine, bromine or iodine.
2. 3-hydroxyindole-2-the ketone compounds for antitumor drug as claimed in claim 1, it is characterized in that: described ketone compounds or its be receptible salt pharmaceutically, wherein pharmaceutically receptible salt is the acid salt that above-mentioned general formula (I) compound and following acid form: hydrochloric acid, Hydrogen bromide, sulfuric acid, citric acid, succsinic acid, tartrate, phosphoric acid, lactic acid, formic acid, acetic acid, Whitfield's ointment, propanedioic acid, fumaric acid, oxysuccinic acid, thionamic acid, xitix, nitric acid, propionic acid, oxalic acid, toxilic acid, methylsulfonic acid, Phenylsulfonic acid, tosic acid or forulic acid.
3. 3-hydroxyindole-2-the ketone compounds for antitumor drug as claimed in claim 1, is characterized in that: the pharmaceutically receptible solvate of the compound that described general formula (I) represents comprises the compound of general formula (I) expression and the solvate of water, ethanol, Virahol, ether or acetone without limitation.
4. 3-hydroxyindole-2-the ketone compounds for antitumor drug as claimed in claim 1, it is characterized in that: described pharmaceutical composition, wherein contain this compound of significant quantity, its pharmaceutically receptible salt or pharmaceutically receptible solvate, formulation is tablet, capsule, powder, granule, pill, suppository, oral liquid, suspensoid, injection formulation pharmaceutically; Wherein tablet for oral use and capsule contain traditional vehicle as weighting material, thinner, lubricant, dispersion agent and tackiness agent.
5. as being applied in, the 3-hydroxyindole-2-ketone compounds for antitumor drug of each in claim 1 or 2 or 3 prepares antitumor drug.
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