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CN103613580B - For 3-hydroxyindole-2-ketone compounds or its salt that pharmaceutically can accept of antitumor drug - Google Patents

For 3-hydroxyindole-2-ketone compounds or its salt that pharmaceutically can accept of antitumor drug Download PDF

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CN103613580B
CN103613580B CN201310636517.5A CN201310636517A CN103613580B CN 103613580 B CN103613580 B CN 103613580B CN 201310636517 A CN201310636517 A CN 201310636517A CN 103613580 B CN103613580 B CN 103613580B
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CN103613580A (en
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张磊
王京
陈永正
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Zunyi Medical University
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    • C07—ORGANIC CHEMISTRY
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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 present invention relates to medicinal chemistry art, be specifically related to the 3-hydroxyindole-2-ketone compounds (I) of a class for antitumor drug, its preparation method and the disease for preventing or treat abnormal cell proliferation, metamorphosis etc. to be correlated with thereof, grow and the purposes in the medicine of transfer in particular for treatment or prophylaxis of tumours.

Description

For 3-hydroxyindole-2-ketone compounds or its salt that pharmaceutically can accept of antitumor drug
Technical field
The present invention relates to medicinal chemistry art, be specifically related to the 3-hydroxyl-3-[2 that a class has anti-tumor activity, 3-dihydroquinoline-4-ketone-3-base] indole-2-ketone compound and pharmacy acceptable salt thereof or pharmaceutically acceptable solvate, its preparation method, comprise the pharmaceutical composition of this compound, and these compounds are in the disease of being correlated with for the preparation of prevention or treatment abnormal cell proliferation, metamorphosis etc., grow and the purposes in the medicine of transfer in particular for treatment or prophylaxis of tumours.
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 whole world every annual new cancer patient about 1,000 ten thousand people, the mortality ratio that the mankind cause because of cancer is only second to cardiovascular and cerebrovascular diseases.The World Health Organization predicts, to the year two thousand twenty, whole world cancer morbidity will than increasing by 50% now, and the annual newly-increased cancer patients in the whole world will reach 1,500 ten thousand people.At present, the antitumor drug used clinically is classic chemotherapy medicine mainly, this kind of medicine kills tumour cell by cytotoxicity, play a significant role in the complex therapy of some malignant tumour, but not good enough to most solid tumor curative effect, also there is the shortcoming such as poor selectivity, large, the easy generation resistance of toxic side effect being difficult to avoid simultaneously.This just develops the antitumor drug with novelty, low toxicity, selectivity high in the urgent need to medicine scholars.
3-hydroxyindole-2-ketone molecular skeleton is present in natural product, widely as TMC-95A, MaremycinB, ConvolutamydineA, CelogentinK, ParatunamideD, Arundaphine etc.Natural product containing 3-hydroxyindole-2-ketone skeleton has multiple biological activity, as antitumor, antiviral, the release of Maxi-K channel agonist, somatropin, 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 an oncogenic fusion protein EWS-FLI1 expresses.Because EWS-FLI1 is a dislocation albumen, the method design small molecules inhibition of conventional structure based cannot be used.In view of the combination of EWS-FLI1 and RNA helicase A is very important to its oncogenic function, American scientist HayriyeVE uses the method screening of surface plasma sub-resonance examination can be combined with EWS-FLI1 and can block itself and the interactional micromolecular compound of RHA.Wherein YK-4-279, chemical name: 4,7-bis-chloro-3-hydroxyl-3-[2-(4-methoxyl group)-2-ethyl oxide] indol-2-one, it is the effective lead compound obtained 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 made a variation to combine (NatureMedicine, 2009,7:756 ~ 757) with the cellular constituent needed for carcinogenic effect.2010, the people such as PenthalaNR have synthesized a series of 3-hydroxyl-3-(2-imino--3-methyl-5-oxo-imidazole alkane ketone-4-base) indol-2-one derivates, when active testing is carried out to 57 kinds of tumor cell lines, majority of compounds all has stronger anti-tumor activity, and wherein part of compounds is to the GI of the tumour cells such as A549, ATTC 50value is less than 1 μM, 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-base] indole-2-ketone compound (I).Pharmacological evaluation proves, the compounds of this invention has stronger restraining effect to various tumor cell strains; In experiment in vivo, the compounds of this invention can the propagation of Tumor suppression significantly, and gross tumor volume obviously diminishes, and inhibiting rate comparatively 5 FU 5 fluorouracil is strong, to main metabolic organ and immune organ without obvious toxicity.Therefore, general formula of the present invention (I) compound, can be used for the disease that the various abnormal cell proliferation of prevention and therapy, metamorphosis etc. are relevant, grows and the purposes in the medicine of transfer in particular for treatment or prophylaxis of tumours.
The general structure of 3-hydroxyl-3-of the present invention [2,3-dihydroquinoline-4-ketone-3-base] indole-2-ketone compound is as shown in following general formula (I):
Wherein R 1representative: the glycosyl of 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 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 independently.
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 are formed: 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 solvate of compound that general formula (I) represents and water, ethanol, Virahol, ether or acetone without limitation.
Pharmaceutical composition of the present invention, wherein containing significant quantity the compounds of this invention, its pharmacy acceptable salt or pharmaceutically acceptable solvate, formulation can be the formulation that tablet, capsule, powder, granule, pill, suppository, oral liquid, suspensoid, injection etc. are pharmaceutically conventional.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 (I) of the present invention is as follows:
Wherein a represents reaction conditions: catalyzer is diethylamine, triethylamine, piperidines, morpholine, sodium-acetate; Solvent is methyl alcohol, ethanol, Virahol.The preparation of wherein compound 1-alkyl-isatin series intermediate (II) can refer to document (Chem.CentralJ, 2011,5:37), and with (replacement) isatin for raw material, synthetic method is as follows:
Compound 2,3-dihydroquinoline-4-ketone series intermediate (III) prepare reference literature (Tetrahedron, 2002,58:8475 ~ 8481; Aust.J.Chem, 2011,64:454 ~ 470), with (replacement) phenyl-iodide for raw material, synthetic method is as follows:
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 (Gibco company of the U.S.), 0.25% trypsinase: (Amresco company of the U.S.), new-born calf serum, foetal calf serum (Hangzhou folium ilicis chinensis bio-engineering corporation product), methyl-sulphoxide (DMSO, analytical pure), Amresco company of the MTT(U.S.).
Sample: selected part 3-hydroxyl-3-[2,3-dihydroquinoline-4-ketone-3-base] indole-2-ketone compound.
Reference substance: 5 FU 5 fluorouracil (5-FU).
Experimental principle: in viable cell plastosome, the MTT of yellow can be reduced into water-fast bluish voilet Chan Wu formazan (MTTformazan) by desaturase, and be deposited in cell, the amount generated is directly proportional to number of viable cells, and dead cell does not have this function.DMSO can dissolve bluish voilet crystallisate, and shade is directly proportional to contained amount, therefore can reflect cell survival rate with the absorbance value that microplate reader measures.
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 respectively with 1,2,4,8,16 μm of ol/L process tumour cells and 15,18,21,24 μm of ol/L process tumour cells.The each concentration of experimental group establishes 5 multiple holes, compares with the nutrient solution of DMSO content corresponding to the highest administration concentration.After compound effects 48h, remove supernatant, every hole adds 100 μ lMTT (1mg/ml), continues to cultivate 4h, and abandon supernatant, every hole adds 100 μ lDMSO, and vibration mixing, measures absorbance by microplate reader at 570nm place.Calculate inhibiting rate, inhibiting rate (%)=(1-administration group absorbance/control group absorbance) × 100%.Draw regression equation with concentration-inhibiting rate curve, obtain half-inhibition concentration (IC 50).
Part of compounds pharmacology test result is as follows:
Table 1 part of compounds of the present invention checks it to the antiproliferative activity of kinds of tumor cells
Experimental result shows, and majority of compounds has good inhibit activities 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 couples of HepG2, SGC-7901 is better.
Two, sample compound I-7 anti-tumor in vivo active testing
Laboratory animal, cell:
ICR mouse (female), 18 ~ 20g, 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:
Instrument is dried in TEC-2500 drift: 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: Sai Duolisi instrument system company limited of BeiJing, China, China;
Ultralow Temperature Freezer: Xin Bulunzi Brunswick Scientific Instruments Corporation of the U.S., 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 model mouse, after ascitic tumor model mouse intraperitoneal cultivates 14 days (two generations), is put to death by ascitic tumor strain, bubble 75% ethanol 5min after putting to death, peritoneocentesis gets 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 0.2ml/ only (4 × 10 6individual/only) be inoculated in 21 ICR mouse oxters.After tumor growth 4 ~ 6d latent period, the subcutaneous visible tubercle of inoculation position, when tumor size is about 3 ~ 4mm to diameter, administration after 2 weeks.At random mouse is divided into 3 groups, often organize 7, model control group administration is solvent physiological saline, administration group: 5 FU 5 fluorouracil is abdominal injection (20mg/kg/d); Sample compound I-7 is gastric infusion (20mg/kg/d).Successive administration was weighed after 10 days, and mouse eyeground vein clump gets blood, after then cervical dislocation puts to death mouse, peeled off tumour.Often will organize mouse peel off tumour and rinse well, filter paper blots, and weighs, and calculates average knurl weight, tumour inhibiting rate.The average knurl of tumour inhibiting rate (%)=(control group average knurl weight-administration group average knurl weight)/control group heavy × 100%.
Detect toxicity index:
Each group of immune function of mice and metabolism organ index are detected.Mouse organs's weight: thymus gland, spleen, liver, kidney are weighed calculating:
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:
Table 2 sample compound I-7 is to the tumour inhibiting rate of mouse ascites knurl
Table 3 sample compound I-7 is on the impact of ascitic tumor mouse immune, metabolic organ's index
Obtain beneficial effect: drug sample Compound I-7 pairs of ascitic tumor mouse have obvious tumor-inhibiting action, and comparatively 5 FU 5 fluorouracil is remarkable, and when tumor suppression effective dose, the kidney,liver,spleen of ascitic tumor model mice and thymus index are not significantly affected, there is no the side effect that common chemotherapeutic has.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 fusing point of 3-hydroxyl-3-[2, the 3-dihydroquinoline-4-ketone-3-base] indole-2-ketone compound (I) obtained by the present invention measures with Mel-TEMP melting point apparatus, and temperature is not calibrated.ESI-MS HP1100LC/MSD mass spectrograph measures; 1hNMR BruckAV-300 type nmr determination, interior mark TMS; Ultimate analysis ElementarVarioEL III Instrument measuring.
Reagent is commercially available chemical pure or analytical pure product, unless otherwise indicated, and not treated direct use
Embodiment 1
The preparation of 1-methyl-3-hydroxyl-3-[bromo-2, the 3-dihydroquinoline-4-ketone-3-bases of 6-] indol-2-one (I-1)
By 1-methyl-isatoic (1.61g, 10mmol) and bromo-2, the 3-dihydroquinoline-4-ketone (2.26g of 6-, 10mmol) be dissolved in dehydrated alcohol (10mL), add triethylamine (0.5mL) again, system is heated to 40 DEG C, stirring reaction 2h, by the solid suction filtration of separating out, dehydrated alcohol (2 × 1mL) washs, and vacuum-drying, obtains yellow solid 2.78g, yield 72%, m.p.189 ~ 191 DEG C. 1HNMR(DMSO-d6，300MHz)δ(ppm)：7.23~7.29(m，4H)，7.17(d，J=3.3Hz，1H)，6.94~6.99(m，2H)，6.75(d，J=8.4Hz，1H)，6.15(s，1H)，3.70~3.91(m，2H)，3.50-3.57(m，1H)，3.10(s，3H)；ESI-MSm/z：386.9[M+H] +；Anal.calcdforC 18H 15BrN 2O 3(387.23)：C55.83，H3.90，N7.23；found：C55.48，H4.10，N7.0。
Embodiment 2
The preparation of 1-methyl-3-hydroxyl-3-[chloro-2, the 3-dihydroquinoline-4-ketone-3-bases of 6-] indol-2-one (I-2)
By 1-methyl-isatoic (1.61g, 10mmol) and chloro-2, the 3-dihydroquinoline-4-ketone (1.81g of 6-, 10mmol) be dissolved in dehydrated alcohol (10mL), add triethylamine (0.5mL) again, system is heated to 40 DEG C, stirring reaction 2h, by the solid suction filtration of separating out, dehydrated alcohol (2 × 1mL) washs, and vacuum-drying, obtains yellow solid 2.56g, yield 75%, m.p.191 ~ 193 DEG C. 1HNMR(DMSO-d6，300MHz)δ(ppm)：7.23~7.28(m，4H)，7.15(d，J=3.3Hz，1H)，6.94~6.99(m，2H)，6.75(d，J=8.6Hz，1H)，6.14(s，H)，3.81~3.89(m，1H)，3.75(t，J=14.0Hz，1H)，3.50(dd，J=6.1and14.1Hz，1H)，3.10(s，3H)；ESI-MSm/z：365.1[M+Na] +；Anal.calcdforC 18H 15ClN 2O 3(342.78)：C63.07，H4.41，N8.17；found：C63.04，H4.56，N7.9。
Embodiment 3
The preparation of 1-ethyl-3-hydroxyl-3-[bromo-2, the 3-dihydroquinoline-4-ketone-3-bases of 6-] indol-2-one (I-3)
1-ethyl-isatin (1.75g, 10mmol) and bromo-2,3-dihydroquinoline-4-ketone (2.26g, 10mmol) of 6-are dissolved in
In dehydrated alcohol (10mL), then add triethylamine (0.5mL), system is heated to 40 DEG C, stirring reaction 2h, by the solid suction filtration of separating out, dehydrated alcohol (2 × 1mL) washs, and vacuum-drying, obtains yellow solid 2.84g, yield 71%, m.p.202 ~ 205 DEG C. 1HNMR(DMSO-d 6，300MHz)δ(ppm)：7.24~7.39(m，5H)，7.00(d，J=7.7Hz，1H)，6.88(t，J=7.4Hz，1H)，6.74(d,J=8.6Hz，1H)，6.24(s，1H)，3.89~3.95(m，1H)，3.62~3.78(m，3H)，3.23~3.30(dd，1H,J=5.7and13.6Hz，1H)，1.22(s，J=7.0Hz，3H)；ESI-MSm/z：401.0[M+H] +；Anal.calcdforC 19H 17BrN 2O 3(401.25)：C56.87，H4.27，N6.98；found：C56.77，H3.94，N6.8。
Embodiment 4
The preparation of 1-ethyl-3-hydroxyl-3-[chloro-2, the 3-dihydroquinoline-4-ketone-3-bases of 6-] indol-2-one (I-4)
1-ethyl-isatin (1.75g, 10mmol) and chloro-2,3-dihydroquinoline-4-ketone (1.81g, 10mmol) of 6-are dissolved in
In dehydrated alcohol (10mL), then add triethylamine (0.5mL), system is heated to 40 DEG C, stirring reaction 2h, by the solid suction filtration of separating out, dehydrated alcohol (2 × 1mL) washs, and vacuum-drying, obtains yellow solid 2.77g, yield 78%, m.p.218 ~ 219 DEG C. 1HNMR(DMSO-d 6，300MHz)δ(ppm)：7.36(d，J=7.4Hz，1H)，7.25~7.29(m，4H)，7.00(d，J=7.6Hz，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=5.7and13.7Hz，1H)，1.22(s，J=7.0Hz，3H)；ESI-MSm/z：357.1[M+H] +；Anal.calcdforC 19H 17ClN 2O 3·0.1H 2O(358.60)：C63.63，H4.83，N7.81；found：C63.42，H4.48，N7.5。
Embodiment 5
The preparation of 1-propyl group-3-hydroxyl-3-[bromo-2, the 3-dihydroquinoline-4-ketone-3-bases of 6-] indol-2-one (I-5)
1-propyl group-isatin (1.89g, 10mmol) and bromo-2,3-dihydroquinoline-4-ketone (2.26g, 10mmol) of 6-are dissolved in
In dehydrated alcohol (10mL), then add triethylamine (0.5mL), system is heated to 40 DEG C, stirring reaction 2h, by the solid suction filtration of separating out, dehydrated alcohol (2 × 1mL) washs, and vacuum-drying, obtains yellow solid 3.07g, yield 74%, m.p.205 ~ 208 DEG C. 1HNMR(DMSO-d 6，300MHz)δ(ppm)：7.35~7.38(m，2H)，7.30~7.32(m，1H)，7.21(t，J=7.7Hz，1H)，6.84~6.88(m，2H)，6.72(d,J=8.6Hz，1H)，6.28(s，1H)，5.80~5.93(m，1H)，5.38~5.41(dd，J=1.6and17.2Hz，1H)，5.18(dd，J=1.55and10.4Hz，1H)，4.18~4.36(m，2H)，3.88~3.95(m，1H)，3.74(t，J=13.3Hz，1H)，3.24~3.31(m，1H)；ESI-MSm/z：413.0[M+H] +；Anal.calcdforC 20H 17BrN 2O 3(413.26)：C58.13，H4.15，N6.78；found：C58.14，H3.90，N6.7。
Embodiment 6
The preparation of 1-propyl group-3-hydroxyl-3-[chloro-2, the 3-dihydroquinoline-4-ketone-3-bases of 6-] indol-2-one (I-6)
1-propyl group-isatin (1.89g, 10mmol) and chloro-2,3-dihydroquinoline-4-ketone (1.81g, 10mmol) of 6-are dissolved in
In dehydrated alcohol (10mL), then add triethylamine (0.5mL), system is heated to 40 DEG C, stirring reaction 2h, by the solid suction filtration of separating out, dehydrated alcohol (2 × 1mL) washs, and vacuum-drying, obtains yellow solid 2.81g, yield 76%, m.p.217 ~ 219 DEG C. 1HNMR(DMSO-d 6，300MHz)δ(ppm)：7.38(d，J=7.2Hz，1H)，7.22~7.38(m，3H)，6.87~6.91(m，2H)，6.81(d，J=9.6Hz，1H)，6.32(s，1H)，5.83~5.96(m，1H)，5.41(dd，J=1.6and17.4Hz，1H)，5.19(dd，J=1.5and10.5Hz，1H)，4.28~4.33(m，2H)，3.91~3.98(m，1H)，3.77(m，1H)，3.27~3.33(m，2H)；ESI-MSm/z：369.1[M+H] +；Anal.calcdforC 20H 17ClN 2O 3(368.81)：C65.13，H4.65，N7.60；found：C65.15，H4.73，N7.5……
Embodiment 7
The preparation of 1-benzyl-3-hydroxyl-3-[bromo-2, the 3-dihydroquinoline-4-ketone-3-bases of 6-] indol-2-one (I-7)
1-benzyl-isatin (2.37g, 10mmol) and bromo-2,3-dihydroquinoline-4-ketone (2.26g, 10mmol) of 6-are dissolved in
In dehydrated alcohol (10mL), then add triethylamine (0.5mL), system is heated to 40 DEG C, stirring reaction 2h, by the solid suction filtration of separating out, dehydrated alcohol (2 × 1mL) washs, and vacuum-drying, obtains yellow solid 3.65g, yield 79%, m.p.200 ~ 202 DEG C. 1HNMR(DMSO-d 6，300MHz)δ(ppm)：7.47(d，J=7.2Hz，2H)，7.34~7.43(m，6H)，7.27(t，J=7.2Hz，1H)，7.17(t，J=7.6Hz，1H)，6.87(t，J=7.4Hz，1H)，6.77(t，J=8.5Hz，2H)，6.41(s，1H)，4.90(s，2H)，3.93~4.00(m，1H)，3.80(t，J=13.2Hz，1H)，3.36(m，1H)；ESI-MSm/z：463.0[M+H] +；Anal.calcdforC 24H 19BrN 2O 3(463.32)：C62.22，H4.13，N6.05；found：C62.15，H4.08，N5.86。
Embodiment 8
The preparation of 1-benzyl-3-hydroxyl-3-[chloro-2, the 3-dihydroquinoline-4-ketone-3-bases of 6-] indol-2-one (I-8)
1-benzyl-isatin (2.37g, 10mmol) and chloro-2,3-dihydroquinoline-4-ketone (1.81g, 10mmol) of 6-are dissolved in
In dehydrated alcohol (10mL), then add triethylamine (0.5mL), system is heated to 40 DEG C, stirring reaction 2h, by the solid suction filtration of separating out, dehydrated alcohol (2 × 1mL) washs, and vacuum-drying, obtains yellow solid 3.21g, yield 77%, m.p.211 ~ 212 DEG C. 1HNMR(DMSO-d 6，300MHz)δ(ppm)：7.47(d，J=7.2Hz，2H)，7.34~7.42(m，4H)，7.25~7.29(m，3H)，7.17(t，J=7.7Hz，1H)，6.82~6.90(m，2H)，6.74(d，J=7.7Hz，1H)，6.41(s，1H)，4.90(s，2H)，3.93~4.01(m，1H)，3.80(t，J=13.2Hz，1H)，3.33~3.40(m，1H)；ESI-MSm/z：419.1[M+H] +；Anal.calcdforC 24H 19ClN 2O 3(418.87)：C68.82，H4.57，N6.69；found：C68.76，H4.44，N6.42。

Claims (6)

1., for 3-hydroxyindole-2-ketone compounds or its salt that pharmaceutically can accept of antitumor drug, the general structure of described compound is as shown in the formula (I):
Wherein R 1representative: H, C1 ~ C6 alkane, R 2represent H, halogen;
Described halogen is fluorine, chlorine, bromine or iodine.
2. as claimed in claim 1 for 3-hydroxyindole-2-ketone compounds or its salt that pharmaceutically can accept of antitumor drug, it is characterized in that: pharmaceutically receptible salt is the acid salt that the compound of general formula (I) and following acid are formed: 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.
3.1-benzyl-3-hydroxyl-3-[bromo-2, the 3-dihydroquinoline-4-ketone-3-bases of 6-] indol-2-one or
1-benzyl-3-hydroxyl-3-[chloro-2, the 3-dihydroquinoline-4-ketone-3-bases of 6-] indol-2-one.
4. formula (I) compound of any one of claim 1-3 containing significant quantity or the pharmaceutical composition of its salt that pharmaceutically can accept, its formulation is tablet, capsule, powder, granule, pill, suppository, oral liquid, suspensoid, injection.
5. pharmaceutical composition as claimed in claim 4, the vehicle that wherein tablet for oral use and capsule contain is: weighting material, thinner, lubricant, dispersion agent and tackiness agent.
6. the application in antitumor drug prepared by the compound any one of claim 1-3 or its salt that pharmaceutically can accept.
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