CN105732476B - A kind of carbazole isatin type compound and its preparation method and purposes - Google Patents

A kind of carbazole isatin type compound and its preparation method and purposes Download PDF

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CN105732476B
CN105732476B CN201610081402.8A CN201610081402A CN105732476B CN 105732476 B CN105732476 B CN 105732476B CN 201610081402 A CN201610081402 A CN 201610081402A CN 105732476 B CN105732476 B CN 105732476B
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carbazole
isatin
bases
preparation
acethydrazide
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CN105732476A (en
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王广成
彭知云
李涓
李欣
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Power Intellectual Property Tianjin Co ltd
Tianjin Institute of Advanced Equipment of Tsinghua University
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Jishou University
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/82—Carbazoles; Hydrogenated carbazoles
    • C07D209/86—Carbazoles; Hydrogenated carbazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the ring system

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Abstract

The invention discloses a kind of carbazole isatin type compound and its preparation method and purposes.The compound has such as formula（I）Shown structure, preparation method is to obtain 2 (base of 9H carbazoles 9) ethyl acetate as raw material using carbazole and bromoacetate, react to obtain 2 (base of 9H carbazoles 9) acethydrazides through hydrazinolysis again, finally react to obtain target compound with various substitution isatin.The compound can be as the raw material of antineoplastic, and preparation method raw material is simple and easy to get, easy to operate.（I）.

Description

A kind of carbazole-isatin type compound and its preparation method and purposes
Technical field
Application the present invention relates to a kind of carbazole-isatin type compound and preparation method thereof and in antibacterials are prepared.
Background technology
At present, malignant tumour has turned into a kind of common disease and frequently-occurring disease for seriously endangering human health, and the whole world is new every year It was found that malignant tumor patient 7,600,000, is the second largest reason for causing human death, is only second to cardiovascular and cerebrovascular disease.And swell The trend risen year by year, the World Health Organization is presented in the incidence of disease of knurl（WHO）Prediction will have 1,200,000 people to die from cancer in 2030 Disease.In 27 kinds of tumor types, with dead most caused by lung cancer, stomach cancer, liver cancer, colon cancer and breast cancer.Due to constantly rising High tumor mortality rate is, it is necessary to find new, safe and efficient medicine to treat and prevent tumour.However, present many clinics On the antineoplastic that uses but have many shortcomings, for example higher toxicity, bioavilability be relatively low and drug resistance.Therefore, There is an urgent need to find the new medicine with the treatment tumour compared with high selectivity to solve the above problems.
Carbazole and its derivative are a kind of very important azaaromatics, are widely present in Calusena lansium and kamuning Deng in natural plants.In carbazoles natural products most it is representational be carbazole diindyl class antibiotic Staurosporin and Rebeccamycin, there is the good activity suppressed growth of microorganism with antitumor cell growth.Carbazole compound has Multiple biological activities, such as：With a variety of physiologically actives such as antitumor, antimicrobial, antihistamine, anti-oxidant and anti-inflammatories.Due to Carbazole analog derivative has such extensive physiologically active, therefore the synthesis of carbazole derivates and studies its potential new application Through as research field very active in the last few years, developing it has certain theory significance and actual value.
In addition isatin is a kind of endogenous active substance being present in mammalian tissues and body fluid.According to the literature, Isatin and its derivative have multiple biological activities, as anti-diabetic, anti-spasm, treating tuberculosis, antibacterium, it is antimycotic, antiviral, It is antitumor etc..Therefore the research tool that original new drug is carried out based on isatin is of great significance.Analyzed based on more than, I According to twin medicine principle, tonka bean camphor structure is connected with isatin structure, design has synthesized a kind of carbazole-isatin type compound.
The content of the invention
Technical scheme is as follows：
A kind of carbazole-isatin type compound, it is characterized in that they have such as formula（I）Shown general structure：
（I）
Wherein：R1For hydrogen, alkyl, benzyl or substituted benzyl, R2、R3、R4Or R5For hydrogen, halogen, alkyl, amino, alkoxy, Cyano group, nitro, hydroxyl or trifluoromethyl.
A kind of method for preparing above-mentioned carbazole-isatin type compound, it comprises the following steps：
Step 1：Carbazole, cesium carbonate are placed in round-bottomed flask, DMF is added, reacts 1 ~ 12 in 50-100 DEG C of water-bath H, then bromoacetate is added dropwise, 1-12 h are first reacted at room temperature, are then moved to reaction 1-12 h at 50-100 DEG C, are stopped reaction, Water is added, stirring separates out white solid, filters, obtains white solid powder 2- (9H- carbazole -9- bases) ethyl acetate；Described click Azoles, cesium carbonate, the mol ratio of bromoacetate are 1:（1~6）:（1~5）；
Step 2：2- (9H- carbazole -9- bases) ethyl acetate, hydrazine hydrate are placed in round-bottomed flask, add ethanol, backflow is anti- 5 ~ 24 h are answered, stops reaction, is cooled to room temperature, filters, obtains 2- (9H- carbazole -9- bases) acethydrazide；Described 2- (9H- carbazoles- 9- yls) ethyl acetate, hydrazine hydrate mol ratio be 1:（1~20）；
Step 3：2- (9H- carbazole -9- bases) acethydrazide, substitution isatin are placed in round-bottomed flask, add ethanol and ice second Acid, the h of back flow reaction 5 ~ 20, is cooled to room temperature, there is solid precipitation, filters to obtain carbazole-isatin type compound（I）；Described 2- (9H- carbazole -9- bases) acethydrazide, the mol ratio of substitution isatin are 1:（1~5）.
Carbazole of the present invention-isatin type compound has preferable inhibitory activity to tubulin, is antineoplastic The development and application of thing provides new selection.
Brief description of the drawings
Fig. 1 is the syntheti c route figure of carbazole-isatin type compound.
Embodiment
Following embodiment is to describe the present invention in detail, is not intended to limit the present invention.
Embodiment one：The preparation of 2- (9H- carbazole -9- bases) ethyl acetate
By carbazole（5.00 g, 0.03 mmol）, cesium carbonate（16.29 g, 0.05 mmol）It is placed in round-bottomed flask, adds DMF, 2 h are reacted in 70 DEG C of water-baths, then bromoacetate is added dropwise, first react 2 h at room temperature, then move at 70 DEG C and react 5 h, TLC show that reaction finishes, and stop reaction, add water, and stirring separates out white solid, filters, obtains white solid powder, yield 87%。1H NMR (d6-DMSO, 400 MHz) δ: 1.24 (t, 3H), 3.61 (s, 2H), 3.86 (q, 2H), 7.12-7.85 (m, 8H); EIMS m/z = 254 [M+]。
Embodiment two：The preparation of 2- (9H- carbazole -9- bases) acethydrazide
By 2- (9H- carbazole -9- bases) ethyl acetate（1.00 g, 3.48 mmol）, hydrazine hydrate（1.96 mL, 34.8 mmol）It is placed in round-bottomed flask, adds 50 mL ethanol, 78 DEG C of back flow reactions 12 h, TLC show that reaction finishes, stop reacting, Room temperature is cooled to, filters, obtains white solid powder, the % of yield 69.1H NMR (d6-DMSO, 400 MHz) δ: 2.30 (s, 2H), 5.59 (s, 2H), 7.19 (d, 2H), 7.31 (m, 4H), 7.47 (m, 2H), 7.79 (s, 1H); EIMS m/z = 340 [M+]。
Embodiment three：(Z) -2- (9H- carbazole -9- bases)-N'- (5- methyl -2- oxindole -3- subunits) acethydrazide（1） Preparation
By 2- (9H- carbazole -9- bases) acethydrazide（239 mg, 1 mmol）, 5- methylisatins（161 mg, 1 mmol）It is placed in In round-bottomed flask, 10 mL ethanol and a drop glacial acetic acid are added, the h of back flow reaction 2, stops reaction, is cooled to room temperature, filters yellow Color solid powder, the % of yield 95.1H NMR (d6-DMSO, 400 MHz) δ: 2.30 (s, 3H), 5.80 (s, 2H), 6.40 (d, 1H), 7.22 (m, 2H), 7.35 (m, 1H), 7.47 (m, 2H), 7.57 (s, 1H), 7.60 (m, 2H), 7.80(d, 1H), 7.87 (m, 2H), 11.22 (s, 1H); EIMS m/z = 383 [M+]。
Example IV：(Z) -2- (9H- carbazole -9- bases)-N'- (5- methoxyl group -2- oxindole -3- subunits) acethydrazide （2）Preparation
Preparation method replaces with 5- methoxyl group isatin, the % of yield 75 with embodiment three, simply isatin.1H NMR (d6- DMSO, 400 MHz) δ: 3.82 (s, 3H), 5.81 (s, 2H), 6.42 (d, 1H), 7.21 (m, 2H), 7.40 (m, 1H), 7.49 (m, 2H), 7.56 (s, 1H), 7.62 (m, 2H), 7.81(d, 1H), 7.92 (m, 2H), 11.19 (s, 1H); EIMS m/z = 399 [M+]。
Embodiment five：(Z) -2- (9H- carbazole -9- bases)-N'- (6- methyl -2- oxindole -3- subunits) acethydrazide（3） Preparation
Preparation method replaces with 6- methylisatins, the % of yield 86 with embodiment three, simply isatin.1H NMR (d6-DMSO, 400 MHz) δ: 2.34 (s, 3H), 5.81 (s, 2H), 6.62 (d, 1H), 7.27 (m, 2H), 7.45 (m, 1H), 7.50 (m, 2H), 7.58 (s, 1H), 7.61 (m, 2H), 7.87(d, 1H), 7.96 (m, 2H), 11.36 (s, 1H); EIMS m/z = 383 [M+]。
Embodiment six：(Z) -2- (9H- carbazole -9- bases)-N'- (6- methoxyl group -2- oxindole -3- subunits) acethydrazide （4）Preparation
Preparation method replaces with 6- methoxyl group isatin, the % of yield 88 with embodiment three, simply isatin.1H NMR (d6- DMSO, 400 MHz) δ: 3.84 (s, 3H), 5.71 (s, 2H), 6.32 (d, 1H), 7.11 (m, 2H), 7.36 (m, 1H), 7.52 (m, 2H), 7.60 (s, 1H), 7.70 (m, 2H), 7.80 (m, 1H), 7.93 (m, 2H), 11.50 (s, 1H); EIMS m/z = 399 [M+]。
Embodiment seven：(Z) -2- (9H- carbazole -9- bases)-N'- (7- methyl -2- oxindole -3- subunits) acethydrazide（5） Preparation
Preparation method replaces with 7- methylisatins, the % of yield 81 with embodiment three, simply isatin.1H NMR (d6-DMSO, 400 MHz) δ: 2.17 (s, 3H), 5.88 (s, 2H), 7.14 (m, 1H), 7.22 (m, 2H), 7.34 (m, 1H), 7.58 (m, 2H), 7.60 (s, 1H), 7.65 (m, 2H), 7.80 (m, 1H), 7.98 (m, 2H), 11.43 (s, 1H); EIMS m/z = 383 [M+]。
Embodiment eight：(Z) -2- (9H- carbazole -9- bases)-N'- (7- methoxyl group -2- oxindole -3- subunits) acethydrazide （6）Preparation
Preparation method replaces with 7- methoxyl group isatin, the % of yield 87 with embodiment three, simply isatin.1H NMR (d6- DMSO, 400 MHz) δ: 3.87 (s, 3H), 5.90 (s, 2H), 7.12 (m, 1H), 7.29 (m, 2H), 7.38 (m, 1H), 7.52 (m, 2H), 7.64 (s, 1H), 7.66 (m, 2H), 7.70 (m, 1H), 7.88 (m, 2H), 11.31 (s, 1H); EIMS m/z = 399 [M+]。
Embodiment nine：(Z) -2- (9H- carbazole -9- bases)-N'- (5- ethyl-2-oxo indoles -3- subunits) acethydrazide（7） Preparation
Preparation method replaces with 5- ethyl isatin, the % of yield 78 with embodiment three, simply isatin.1H NMR (d6-DMSO, 400 MHz) δ: 1.30 (t, 3H), 2.60 (q, 2H), 5.89 (s, 2H), 6.42 (d, 1H), 7.20 (m, 2H), 7.32 (m, 1H), 7.43 (m, 2H), 7.47 (s, 1H), 7.50 (m, 2H), 7.60 (d, 1H), 7.83 (m, 2H), 11.40 (s, 1H); EIMS m/z = 397 [M+]。
Embodiment ten：(Z) -2- (9H- carbazole -9- bases)-N'- (6- ethyl-2-oxo indoles -3- subunits) acethydrazide（8） Preparation
Preparation method replaces with 6- ethyl isatin, the % of yield 82 with embodiment three, simply isatin.1H NMR (d6-DMSO, 400 MHz) δ: 1.35 (t, 3H), 2.66 (q, 2H), 5.87 (s, 2H), 6.60 (d, 1H), 7.20 (m, 2H), 7.40 (m, 1H), 7.46 (m, 2H), 7.52 (s, 1H), 7.59 (m, 2H), 7.77(d, 1H), 7.87 (m, 2H), 11.2 (s, 1H); EIMS m/z = 397 [M+]。
Embodiment 11：(Z) -2- (9H- carbazole -9- bases)-N'- (7- ethyl-2-oxo indoles -3- subunits) acethydrazide （9）Preparation
Preparation method replaces with 7- ethyl isatin, the % of yield 65 with embodiment three, simply isatin.1H NMR (d6-DMSO, 400 MHz) δ: 1.75 (t, 3H), 2.86 (q, 2H), 5.82 (s, 2H), 7.10 (m, 1H), 7.20 (m, 2H), 7.31 (m, 1H), 7.48 (m, 2H), 7.51 (s, 1H), 7.55 (m, 2H), 7.60 (m, 1H), 7.79 (m, 2H), 11.05 (s, 1H); EIMS m/z = 397 [M+]。
Embodiment 12：(Z) -2- (9H- carbazole -9- bases)-N'- (5- ethyoxyl -2- oxindole -3- subunits) acethydrazide （10）Preparation
Preparation method replaces with 5- ethyoxyl isatin, the % of yield 66 with embodiment three, simply isatin.1H NMR (d6- DMSO, 400 MHz) δ: 1.40 (t, 3H), 4.30 (q, 2H), 5.85 (s, 2H), 6.32 (d, 1H), 7.10 (m, 2H), 7.22 (m, 1H), 7.35 (m, 2H), 7.42 (s, 1H), 7.51 (m, 2H), 7.62 (d, 1H), 7.78 (m, 2H), 10.99 (s, 1H); EIMS m/z = 413 [M+]。
Embodiment 13：Embodiment ten：(Z) (6- ethyoxyl -2- oxindoles -3- is sub- by -2- (9H- carbazole -9- bases)-N'- Base) acethydrazide（11）Preparation
Preparation method replaces with 6- ethyoxyl isatin, the % of yield 63 with embodiment three, simply isatin.1H NMR (d6- DMSO, 400 MHz) δ: 1.45 (t, 3H), 4.36 (q, 2H), 5.67 (s, 2H), 6.50 (d, 1H), 7.10 (m, 2H), 7.30 (m, 1H), 7.49 (m, 2H), 7.56 (s, 1H), 7.62 (m, 2H), 7.70(d, 1H), 7.88 (m, 2H), 11.01 (s, 1H); EIMS m/z = 413 [M+]。
Embodiment 14：(Z) -2- (9H- carbazole -9- bases)-N'- (7- ethyoxyl -2- oxindole -3- subunits) acethydrazide （12）Preparation
Preparation method replaces with 7- ethyoxyl isatin, the % of yield 79 with embodiment three, simply isatin.1H NMR (d6- DMSO, 400 MHz) δ: 1.75 (t, 3H), 4.50 (q, 2H), 5.72 (s, 2H), 7.08 (m, 1H), 7.15 (m, 2H), 7.21 (m, 1H), 7.38 (m, 2H), 7.41 (s, 1H), 7.50 (m, 2H), 7.62 (m, 1H), 7.86 (m, 2H), 10.84 (s, 1H); EIMS m/z = 413 [M+]。
Embodiment 15：(Z) -2- (9H- carbazole -9- bases)-N'- (4- methyl -2- oxindole -3- subunits) acethydrazide （13）Preparation
Preparation method replaces with 4- methylisatins, the % of yield 72 with embodiment three, simply isatin.1H NMR (d6-DMSO, 400 MHz) δ: 2.47 (s, 3H), 5.80 (s, 2H), 7.04 (m, 1H), 7.25 (m, 2H), 7.38 (m, 1H), 7.53 (m, 2H), 7.58 (s, 1H), 7.62 (m, 2H), 7.70 (m, 1H), 7.86 (m, 2H), 11.08 (s, 1H); EIMS m/z = 383 [M+]。
Embodiment 16：(Z) -2- (9H- carbazole -9- bases)-N'- (4- ethyl-2-oxo indoles -3- subunits) acethydrazide （14）Preparation
Preparation method replaces with 4- ethyl isatin, the % of yield 63 with embodiment three, simply isatin.1H NMR (d6-DMSO, 400 MHz) δ: 1.75 (t, 3H), 2.66 (q, 2H), 5.77 (s, 2H), 7.08 (m, 1H), 7.16 (m, 2H), 7.28 (m, 1H), 7.37 (m, 2H), 7.48 (s, 1H), 7.50 (m, 2H), 7.65 (m, 1H), 7.82 (m, 2H), 10.98 (s, 1H); EIMS m/z = 397 [M+]。
Embodiment 17：(Z) -2- (9H- carbazole -9- bases)-N'- (4- methoxyl group -2- oxindole -3- subunits) acethydrazide （15）Preparation
Preparation method replaces with 4- methoxyl group isatin, the % of yield 80 with embodiment three, simply isatin.1H NMR (d6- DMSO, 400 MHz) δ: 3.83 (s, 3H), 5.78 (s, 2H), 7.10 (m, 1H), 7.22 (m, 2H), 7.35 (m, 1H), 7.50 (m, 2H), 7.61 (s, 1H), 7.65 (m, 2H), 7.70 (m, 1H), 7.80 (m, 2H), 11.61 (s, 1H); EIMS m/z = 399 [M+]。
Embodiment 18：(Z) -2- (9H- carbazole -9- bases)-N'- (4- ethyoxyl -2- oxindole -3- subunits) acethydrazide （16）Preparation
Preparation method replaces with 4- ethyoxyl isatin, the % of yield 70 with embodiment three, simply isatin.1H NMR (d6- DMSO, 400 MHz) δ: 1.35 (t, 3H), 4.10 (q, 2H), 5.79 (s, 2H), 7.13 (m, 1H), 7.18 (m, 2H), 7.25 (m, 1H), 7.32 (m, 2H), 7.40 (s, 1H), 7.51 (m, 2H), 7.68 (m, 1H), 7.75 (m, 2H), 10.69 (s, 1H); EIMS m/z = 413 [M+]。
Embodiment 19：(Z) -2- (9H- carbazole -9- bases)-N'- (4- nitro -2- oxindole -3- subunits) acethydrazide （17）Preparation
Preparation method replaces with 4- Nitroisatoics, the % of yield 77 with embodiment three, simply isatin.1H NMR (d6-DMSO, 400 MHz) δ: 2.47 (s, 3H), 5.80 (s, 2H), 7.25 (m, 2H), 7.53 (m, 2H), 7.58 (s, 1H), 7.62 (m, 2H), 7.74 (m, 1H), 7.80 (m, 1H), 7.92 (m, 1H), 8.10 (m, 2H), 11.0 (s, 1H); EIMS m/z = 414 [M+]。
Embodiment 20：(Z) -2- (9H- carbazole -9- bases)-N'- (5- nitro -2- oxindole -3- subunits) acethydrazide （18）Preparation
Preparation method replaces with 5- Nitroisatoics, the % of yield 81 with embodiment three, simply isatin.1H NMR (d6-DMSO, 400 MHz) δ: 2.47 (s, 3H), 5.80 (s, 2H), 7.25 (m, 2H), 7.53 (m, 2H), 7.58 (s, 1H), 7.62 (m, 2H), 8.11 (d, 1H), 8.15 (m, 2H), 8.17 (m, 1H), 8.52 (d, 1H), 11.05 (s, 1H); EIMS m/z = 414 [M+]。
Embodiment 21：(Z) -2- (9H- carbazole -9- bases)-N'- (1,4- dimethyl -2- oxindole -3- subunits) second Hydrazides（19）Preparation
Preparation method replaces with Isosorbide-5-Nitrae-dimethylisatin, the % of yield 86 with embodiment three, simply isatin.1H NMR (d6- DMSO, 400 MHz) δ: 2.47 (s, 3H), 3.46 (s, 3H), 5.80 (s, 2H), 7.04 (m, 1H), 7.25 (m, 2H), 7.38 (m, 1H), 7.53 (m, 2H), 7.58 (s, 1H), 7.62 (m, 2H), 7.70 (m, 1H), 7.86 (m, 2H); EIMS m/z = 397 [M+]。
Embodiment 22：(Z) (4- methoxyl group -1- methyl -2- oxindoles -3- is sub- by -2- (9H- carbazole -9- bases)-N'- Base) acethydrazide（20）Preparation
Preparation method replaces with 4- methoxyl group -1- methylisatins, the % of yield 81 with embodiment three, simply isatin.1H NMR (d6-DMSO, 400 MHz) δ: 3.43 (s, 3H), 3.73 (s, 3H), 5.73 (s, 2H), 7.13 (m, 1H), 7.25 (m, 2H), 7.32 (m, 1H), 7.51 (m, 2H), 7.66 (s, 1H), 7.69 (m, 2H), 7.72 (m, 1H), 7.76 (m, 2H); EIMS m/z = 413 [M+]。
Embodiment 23：(Z) (4- ethyoxyl -1- methyl -2- oxindoles -3- is sub- by -2- (9H- carbazole -9- bases)-N'- Base) acethydrazide（21）Preparation
Preparation method replaces with 4- ethyoxyl -1- methylisatins, the % of yield 84 with embodiment three, simply isatin.1H NMR (d6-DMSO, 400 MHz) δ: 1.38 (t, 3H), 3.45 (s, 3H), 4.30 (q, 2H), 5.69 (s, 2H), 7.03 (m, 1H), 7.22 (m, 2H), 7.26 (m, 1H), 7.36 (m, 2H), 7.42 (s, 1H), 7.52 (m, 2H), 7.63 (m, 1H), 7.92 (m, 2H); EIMS m/z = 427 [M+]。
Embodiment 24：(Z) (4- ethyl -1- methyl -2- oxindoles -3- is sub- by -2- (9H- carbazole -9- bases)-N'- Base) acethydrazide（22）Preparation
Preparation method replaces with 4- ethyl -1- methylisatins, the % of yield 68 with embodiment three, simply isatin.1H NMR (d6-DMSO, 400 MHz) δ: 1.45 (t, 3H), 2.60 (q, 2H), 3.46 (s, 3H),5.73 (s, 2H), 7.09 (m, 1H), 7.13 (m, 2H), 7.32 (m, 1H), 7.39 (m, 2H), 7.44 (s, 1H), 7.53 (m, 2H), 7.66 (m, 1H), 7.89 (m, 2H); EIMS m/z = 411 [M+]。
Embodiment 25：(Z) -2- (9H- carbazole -9- bases)-N'- (the fluoro- 2- oxindoles -3- subunits of 4-) acethydrazide （23）Preparation
Preparation method replaces with 4- fluoro indigo reds, the % of yield 62 with embodiment three, simply isatin.1H NMR (d6-DMSO, 400 MHz) δ: 5.84 (s, 2H), 7.14 (m, 1H), 7.24 (m, 2H), 7.48 (m, 1H), 7.56 (m, 2H), 7.58 (s, 1H), 7.64 (m, 2H), 7.66 (m, 1H), 7.83 (m, 2H), 11.2 (s, 1H); EIMS m/z = 387 [M+]。
Embodiment 26：(Z) -2- (9H- carbazole -9- bases)-N'- (4- chloro-2-oxo indoles -3- subunits) acethydrazide （24）Preparation
Preparation method replaces with 4- chlorisatides, the % of yield 66 with embodiment three, simply isatin.1H NMR (d6-DMSO, 400 MHz) δ: 5.79 (s, 2H), 7.24 (m, 1H), 7.29 (m, 2H), 7.54 (m, 1H), 7.58 (m, 2H), 7.61 (s, 1H), 7.69 (m, 2H), 7.86 (m, 1H), 7.95 (m, 2H), 11.41 (s, 1H); EIMS m/z = 403 [M+]。
Embodiment 27：(Z) -2- (9H- carbazole -9- bases)-N'- (the bromo- 2- oxindoles -3- subunits of 4-) acethydrazide （25）Preparation
Preparation method replaces with 4- bromo-isatins, the % of yield 61 with embodiment three, simply isatin.1H NMR (d6-DMSO, 400 MHz) δ: 5.66 (s, 2H), 7.28 (m, 1H), 7.32 (m, 2H), 7.38 (m, 1H), 7.58 (m, 2H), 7.60 (s, 1H), 7.66 (m, 2H), 7.76(m, 1H), 7.85 (m, 2H), 11.0 (s, 1H); EIMS m/z = 448 [M+]。
Embodiment 28：(Z) -2- (9H- carbazole -9- bases)-N'- (the fluoro- 2- oxindoles -3- subunits of 5-) acethydrazide （26）Preparation
Preparation method replaces with 5- fluoro indigo reds, the % of yield 65 with embodiment three, simply isatin.1H NMR (d6-DMSO, 400 MHz) δ: 5.82 (s, 2H), 6.96 (s, 1H), 7.22-7.25 (m, 3H), 7.42-7.46 (m, 3H), 7.60 (d, 2H), 7.70 (d, 2H), 11.34 (s, 1H); EIMS m/z = 397 [M+]。
Embodiment 29：Embodiment ten：(Z) (the fluoro- 2- oxindoles -3- of 6- are sub- by -2- (9H- carbazole -9- bases)-N'- Base) acethydrazide（27）Preparation
Preparation method replaces with 6- fluoro indigo reds, the % of yield 63 with embodiment three, simply isatin.1H NMR (d6-DMSO, 400 MHz) δ: 5.64 (s, 2H), 7.08 (m, 2H), 7.25 (m, 1H), 7.45 (m, 2H), 7.52 (s, 1H), 7.63 (d, 1H), 7.68 (m, 2H), 7.75 (d, 1H), 7.81 (m, 2H), 10.80 (s, 1H); EIMS m/z = 387 [M+]。
Embodiment 30：(Z) -2- (9H- carbazole -9- bases)-N'- (the fluoro- 2- oxindoles -3- subunits of 7-) acethydrazide（28） Preparation
Preparation method replaces with 7- fluoro indigo reds, the % of yield 61 with embodiment three, simply isatin.1H NMR (d6-DMSO, 400 MHz) δ: 5.70 (s, 2H), 7.21 (m, 2H), 7.29 (m, 1H), 7.31 (m, 1H), 7.38 (m, 2H), 7.46 (s, 1H), 7.55 (m, 2H), 7.58 (m, 1H), 7.89 (m, 2H), 11.50 (s, 1H); EIMS m/z = 387 [M+]。
Embodiment 31：(Z) -2- (9H- carbazole -9- bases)-N'- (the bromo- 2- oxindoles -3- subunits of 5-) acethydrazide （29）Preparation
Preparation method replaces with 5-bromoisatin, the % of yield 63 with embodiment three, simply isatin.1H NMR (d6-DMSO, 400 MHz) δ: 5.85 (s, 2H), 7.10 (m, 2H), 7.22 (d, 1H), 7.35 (m, 2H), 7.42 (s, 1H), 7.51 (m, 2H), 7.58 (m, 1H), 7.72 (d, 1H), 7.85 (m, 2H), 10.99 (s, 1H); EIMS m/z = 413 [M+]。
Embodiment 32：Embodiment ten：(Z) (the bromo- 2- oxindoles -3- of 6- are sub- by -2- (9H- carbazole -9- bases)-N'- Base) acethydrazide（30）Preparation
Preparation method replaces with 6- bromo-isatins, the % of yield 71 with embodiment three, simply isatin.1H NMR (d6-DMSO, 400 MHz) δ: 5.62 (s, 2H), 7.15 (m, 2H), 7.28 (m, 1H), 7.42 (m, 2H), 7.48 (s, 1H), 7.61 (d, 1H), 7.68 (m, 2H), 7.71 (d, 1H), 7.89 (m, 2H), 11.25 (s, 1H); EIMS m/z = 448 [M+]。
Embodiment 33：(Z) -2- (9H- carbazole -9- bases)-N'- (the bromo- 2- oxindoles -3- subunits of 7-) acethydrazide （31）Preparation
Preparation method replaces with 7- bromo-isatins, the % of yield 83 with embodiment three, simply isatin.1H NMR (d6-DMSO, 400 MHz) δ: 5. 72 (s, 2H), 7.18 (m, 2H), 7.22 (m, 1H), 7.30 (m, 1H), 7.39 (m, 2H), 7.44 (s, 1H), 7.52 (m, 2H), 7.57 (m, 1H), 7.87 (m, 2H), 11.33 (s, 1H); EIMS m/z = 447 [M+]。
Embodiment 34：(Z) -2- (9H- carbazole -9- bases)-N'- (5- chloro-2-oxo indoles -3- subunits) acethydrazide （32）Preparation
Preparation method replaces with 5- chlorisatides, the % of yield 84 with embodiment three, simply isatin.1H NMR (d6-DMSO, 400 MHz) δ: 5.84 (s, 2H) 7.00 (s, 1H), 7.23-7.27 (m, 3H), 7.44-7.48 (m, 3H), 7.61 (d, 2H), 7.85 (d, 2H), 11.43 (s, 1H); EIMS m/z = 403 [M+]。
Embodiment 35：Embodiment ten：(Z) (6- chloro-2-oxo indoles -3- is sub- by -2- (9H- carbazole -9- bases)-N'- Base) acethydrazide（33）Preparation
Preparation method replaces with 6- chlorisatides, the % of yield 77 with embodiment three, simply isatin.1H NMR (d6-DMSO, 400 MHz) δ: 5.64 (s, 2H), 7.11 (m, 2H), 7.31 (m, 1H), 7.48 (m, 2H), 7.52 (s, 1H), 7.58 (d, 1H), 7.65 (m, 2H), 7.70 (d, 1H), 7.82 (m, 2H), 11.15 (s, 1H); EIMS m/z = 403 [M+]。
Embodiment 36：(Z) -2- (9H- carbazole -9- bases)-N'- (7- chloro-2-oxo indoles -3- subunits) acethydrazide （34）Preparation
Preparation method replaces with 7- chlorisatides, the % of yield 86 with embodiment three, simply isatin.1H NMR (d6-DMSO, 400 MHz) δ: 5. 69 (s, 2H), 7.14 (m, 2H), 7.25(m, 1H), 7.31 (m, 1H), 7.37 (m, 2H), 7.45 (s, 1H), 7.51 (m, 2H), 7.62 (m, 1H), 7.79 (m, 2H), 11.23 (s, 1H); EIMS m/z = 403 [M+]。
Embodiment 37：(Z) -2- (9H- carbazole -9- bases)-N'- (the chloro- 1- methyl -2- oxindoles -3- subunits of 4-) Acethydrazide（35）Preparation
Preparation method replaces with the chloro- 1- methylisatins of 4-, the % of yield 67 with embodiment three, simply isatin.1H NMR (d6- DMSO, 400 MHz) δ: 3.45 (s, 3H), 5.74 (s, 2H), 7.26 (m, 1H), 7.29 (m, 2H), 7.53 (m, 1H), 7.58 (m, 2H), 7.61 (s, 1H), 7.71 (m, 2H), 7.76 (m, 1H), 7.90 (m, 2H); EIMS m/z = 417 [M+]。
Embodiment 38：(Z) -2- (9H- carbazole -9- bases)-N'- (the bromo- 1- methyl -2- oxindoles -3- subunits of 4-) Acethydrazide（36）Preparation
Preparation method replaces with the bromo- 1- methylisatins of 4-, the % of yield 62 with embodiment three, simply isatin.1H NMR (d6- DMSO, 400 MHz) δ: 3.47 (s, 3H), 5.83 (s, 2H), 7.20 (m, 1H), 7.41 (m, 2H), 7.52 (m, 1H), 7.59 (m, 2H), 7.65 (s, 1H), 7.70 (m, 2H), 7.82 (m, 1H), 7.92 (m, 2H); EIMS m/z = 462 [M+]。
Embodiment 39：(Z) -2- (9H- carbazole -9- bases)-N'- (1- methyl -4- trifluoromethyl -2- oxindoles - 3- subunits) acethydrazide（37）Preparation
Preparation method replaces with 1- methyl -4- (trifluoromethyl) isatin, the % of yield 60 with embodiment three, simply isatin.1H NMR (d6-DMSO, 400 MHz) δ: 3.41 (s, 3H), 5.78 (s, 2H), 7.22 (m, 1H), 7.26 (m, 2H), 7.51 (m, 1H), 7.57 (m, 2H), 7.65 (s, 1H), 7.70 (m, 2H), 7.80 (m, 1H), 7.88 (m, 2H); EIMS m/z = 451 [M+]。
Example IV ten：(Z) -2- (9H- carbazole -9- bases)-N'- (4- amino -1- methyl -2- oxindole -3- subunits) Acethydrazide（38）Preparation
Preparation method replaces with 4- amino -1- methylisatins, the % of yield 63 with embodiment three, simply isatin.1H NMR (d6-DMSO, 400 MHz) δ: 3.48 (s, 3H), 5.70 (s, 2H), 6.37 (s, 2H),7.18 (m, 1H), 7.22 (m, 2H), 7.48 (m, 1H), 7.53 (m, 2H), 7.61 (s, 1H), 7.72 (m, 2H), 7.82 (m, 1H), 7.90 (m, 2H); EIMS m/z = 398 [M+]。
Example IV 11：(Z) -2- (9H- carbazole -9- bases)-N'- (5- cyano group -2- oxindole -3- subunits) acethydrazide （39）Preparation
Preparation method replaces with 5- cyanoisatoics, the % of yield 68 with embodiment three, simply isatin.1H NMR (d6-DMSO, 400 MHz) δ: 5.80 (s, 2H) 7.01 (s, 1H), 7.24-7.29 (m, 3H), 7.46-7.50 (m, 3H), 7.62 (d, 2H), 7.83 (d, 2H), 11.23 (s, 1H); EIMS m/z = 394 [M+]。
Example IV 12：(Z) -2- (9H- carbazole -9- bases)-N'- (4- hydroxyl -2- oxindole -3- subunits) acetyl Hydrazine（40）Preparation
Preparation method replaces with 4- oxyphenisatins, the % of yield 62 with embodiment three, simply isatin.1H NMR (d6-DMSO, 400 MHz) δ: 5.45 (s, 1H),5.68 (s, 2H), 6.32 (s, 2H), 7.17 (m, 1H), 7.24 (m, 2H), 7.45 (m, 1H), 7.57 (m, 2H), 7.65 (s, 1H), 7.70 (m, 2H), 7.75 (m, 1H), 7.86 (m, 2H), 11.16 (s, 1H); EIMS m/z = 385 [M+]。
Example IV 13：(Z) (1- (3- luorobenzyls) -2- oxindoles -3- is sub- by -2- (9H- carbazole -9- bases)-N'- Base) acethydrazide（41）Preparation
Preparation method replaces with 1- (3- luorobenzyls) isatin, the % of yield 65 with embodiment three, simply isatin.1H NMR (d6- DMSO, 400 MHz) δ: 5.00 (s, 2H), 5.85 (s, 2H), 7.09-7.27 (m, 7H), 7.41-7.48 (m, 4H), 7.62-7.71 (m, 3H), 8.19 (d, 2H); EIMS m/z = 477 [M+]。
Example IV 14：(Z) -2- (9H- carbazole -9- bases)-N'- (1- (2- luorobenzyls) -5- methyl -2- oxos Yin Diindyl -3- subunits) acethydrazide（42）Preparation
Preparation method replaces with 1- (2- luorobenzyls) -5- methylisatins, the % of yield 74 with embodiment three, simply isatin.1H NMR (d6-DMSO, 400 MHz) δ: 5.03 (s, 2H), 5.55-5.82 (m, 2H), 6.91-6.96 (m, 1H), 7.13-7.27 (m, 5H), 7.36-7.38 (m, 1H), 7.43-7.46 (m, 3H), 7.61 (d, 2H), 8.18 (d, 2H); EIMS m/z = 491 [M+]。
Example IV 15：(Z) -2- (9H- carbazole -9- bases)-N'- (1- (3- luorobenzyls) -5- methyl -2- oxos Yin Diindyl -3- subunits) acethydrazide（43）Preparation
Preparation method replaces with 1- (3- luorobenzyls) -5- methylisatins, the % of yield 80 with embodiment three, simply isatin.1H NMR (d6-DMSO, 400 MHz) δ: 2.30 (s, 3H), 4.99 (s, 2H),5.78 (s, 2H), 6.95-6.97 (m, 1H), 7.11-7.25 (m, 6H), 7.36-7.46 (m, 4H), 7.60 (d, 2H), 8.17 (d, 2H); EIMS m/z = 491 [M+]。
Example IV 16：(Z) -2- (9H- carbazole -9- bases)-N'- (the chloro- 1- of 5- (2- luorobenzyls) -2- oxindoles -3- Subunit) acethydrazide（44）Preparation
Preparation method replaces with the chloro- 1- of 5- (2- luorobenzyls) isatin, the % of yield 55 with embodiment three, simply isatin.1H NMR (d6-DMSO, 400 MHz) δ: 5.05 (s, 2H), 5.87 (s, 2H), 7.06-7.08 (m, 1H), 7.16-7.28 (m, 5H), 7.35-7.46 (m, 5H), 7.61 (d, 2H), 8.17 (d, 2H); EIMS m/z = 511 [M+]。
Example IV 17：(Z) -2- (9H- carbazole -9- bases)-N'- (the chloro- 1- of 5- (3- luorobenzyls) -2- oxindoles -3- Subunit) acethydrazide（45）Preparation
Preparation method replaces with the chloro- 1- of 5- (3- luorobenzyls) isatin, the % of yield 60 with embodiment three, simply isatin.1H NMR (d6-DMSO, 400 MHz) δ: 5.02 (s, 2H), 5.82 (s, 2H), 7.09-7.12 (m, 1H), 7.21-7.27 (m, 5H), 7.39-7.49 (m, 5H), 7.61 (d, 2H), 8.17 (d, 2H); EIMS m/z = 511 [M+]。
Example IV 18：The antiproliferative activity test for the compound on tumor cell that embodiment is prepared：
This assay activity measure is carried out using 96 orifice plates, by tumor cell inoculation in 96 orifice plates, is cultivated 24 h, is sucked training Base is supported, adds candidate compound, blank control group adds isometric solvent, cultivates 24 h ~ 48h, sucks culture medium, per hole The mg/mL MTT solution of 200 μ L 0.5 is added, cultivates 4h, sucks supernatant, adds 150 μ L DMSO, concussion mixes, with enzyme mark Instrument（Wavelength is 570nm）Detect absorbance, processing data.Each experiment is repeated 3 times, and it is swollen in difference to measure each compound LC50 μM in oncocyte（IC50）.
The computational methods of inhibiting rate：
Inhibiting rate（%）=（Control group OD values-test group OD values）/ control group OD value × 100%
Sample is to the height of the antiproliferative activity activity of tumour cell with IC50To represent, IC50It is smaller, the work of this compound Property is higher, the results are shown in Table 1.
Antiproliferative activity test result of 1. carbazoles of the table-isatin type compound to 5 kinds of tumour cells（IC50）
Most of carbazole-isatin type compound all has preferable to the kinds of tumor cells of test as can be seen from Table 1 The activity of Inhibit proliferaton, the wherein activity of compound 4,7,8,13,14,16,19,25,28,29,32,36,39,44,45 are preferably.
Above-mentioned simply presently preferred embodiments of the present invention, not makees any formal limitation to the present invention.It is any to be familiar with sheet The technical staff in field, in the case where not departing from technical solution of the present invention scope, all using the technology contents of the disclosure above Many possible changes and modifications are made to technical solution of the present invention, or are revised as the equivalent embodiment of equivalent variations.Therefore, it is all It is the content without departing from technical solution of the present invention, any is simply repaiied to made for any of the above embodiments according to the technology of the present invention essence Change, equivalent variations and modification, all should fall in the range of technical solution of the present invention protection.

Claims (3)

  1. A kind of 1. carbazole-isatin type compound, it is characterised in that：The compound has such as formula（I）Shown structure：
    （I）
    Wherein：R1For hydrogen or benzyl, R2、R3、R4Or R5For hydrogen, halogen, amino, cyano group, nitro, hydroxyl or trifluoromethyl.
  2. 2. the preparation method of carbazole described in a kind of claim 1-isatin type compound, it is characterised in that including following step Suddenly：
    Step 1：Carbazole, cesium carbonate are placed in round-bottomed flask, DMF is added, reacts 1 ~ 12 h in 50-100 DEG C of water-bath, then drip Add bromoacetate, first react 1-12 h at room temperature, then move to reaction 1-12 h at 50-100 DEG C, stop reaction, add Water, stirring separate out white solid, filter, obtain white solid powder 2- (9H- carbazole -9- bases) ethyl acetate；Described carbazole, carbon Sour caesium, the mol ratio of bromoacetate are 1:1:1~1:6:5；
    Step 2：2- (9H- carbazole -9- bases) ethyl acetate, hydrazine hydrate are placed in round-bottomed flask, addition ethanol, back flow reaction 5 ~ 24 h, stop reaction, be cooled to room temperature, filter, obtain 2- (9H- carbazole -9- bases) acethydrazide；Described 2- (9H- carbazole -9- bases) Ethyl acetate, the mol ratio of hydrazine hydrate are 1:1~1:20；
    Step 3：2- (9H- carbazole -9- bases) acethydrazide, substitution isatin are placed in round-bottomed flask, ethanol and glacial acetic acid is added, returns Stream 5 ~ 20 h of reaction, are cooled to room temperature, there is solid precipitation, filter to obtain carbazole-isatin type compound（I）；Described 2- (9H- clicks Azoles -9- bases) acethydrazide, substitute isatin mol ratio be 1:1~1:5.
  3. A kind of 3. carbazole-application of the isatin type compound in antineoplastic is prepared described in claim 1.
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