CN107089986A - 3,3 ' loop coil Oxoindoles containing difluoromethyl group and its preparation method and application - Google Patents

3,3 ' loop coil Oxoindoles containing difluoromethyl group and its preparation method and application Download PDF

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CN107089986A
CN107089986A CN201710371801.2A CN201710371801A CN107089986A CN 107089986 A CN107089986 A CN 107089986A CN 201710371801 A CN201710371801 A CN 201710371801A CN 107089986 A CN107089986 A CN 107089986A
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abdd
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loop coil
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CN107089986B (en
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韩文勇
赵佳
陈永正
崔宝东
万南微
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Zunyi Medical University
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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Abstract

The invention discloses it is a kind of containing difluoromethyl group 3,3' loop coil Oxoindoles and its preparation method and application, the present invention is with generated in-situ difluoromethyl diazomethane and 3 alkenyl Oxoindoles derived from isatin under without catalysts conditions, [3+2] reaction is carried out in organic solvent, a series of 3,3' loop coil Oxoindoles containing difluoromethyl group are synthesized.Such compound contains the difluoromethyl group and 3,3' loop coil Oxoindole skeleton of potential source biomolecule activity, chemical combination material resource can be provided for bioactivity screening, the screening and pharmaceutical industry to medicine have important application value.Meanwhile, the present invention has carried out tumor growth inhibiting activity screening for such compound to two kinds of tumor cell lines such as human prostate (PC 3) and human lung carcinoma cell (A549).Result of study finds that such compound has certain suppression tumor cell growth activity, it is contemplated that be used as antineoplastic use.

Description

3,3 '-loop coil Oxoindole containing difluoromethyl group and its preparation method and application
Technical field
The present invention relates to technical field of chemistry, especially a kind of 3,3'- loop coils Oxoindole containing difluoromethyl group and Its preparation method and application.
Background technology
Difluoromethyl (- CF2H), as an important fluoro-containing group, containing a low acidified c h bond, be hydroxyl, The isostere of sulfydryl and methylol, can adjust bioactivity, metabolic stability and lipophilicity of molecule etc., in doctor The fields such as medicine, agricultural chemicals play a part of and other fluoroalkyl no less importants.Therefore, it can be assigned by difluoromethyl being introduced in the molecule Many premium properties, while introducing or maintaining the crucial recognition element of biological targets.These determine it in biological medicine, life The great potential and scientific research value in the fields such as thing imaging.On the other hand, it is that many is faced to contain 3,3'- loop coil Oxoindole skeletons The core texture unit of bed drug molecule and natural alkaloid, the compound containing this skeleton often has good biology living Property and potential drug value.Such as MI-888, with good pharmacokinetic property and very strong internal antitumor work Property；3,3'- loop coil Oxoindoles containing tetrahydrochysene sulphur pyrans are a kind of new p53-MDM2 inhibitor.In view of 3,3'- loop coils Oxoindole has the important function of potential bioactivity and difluoromethyl in pharmaceutical chemistry, therefore, with difluoromethyl Diazomethane is building block, is reacted by [3+2] cyclization strategy and 3- alkenyls Oxoindole, synthesizes 3 containing difluoromethyl group, 3'- loop coils Oxoindole may produce a series of structures and the upper significant noval chemical compound of activity, and their synthesis can be Material base is set up in application of the 3,3'- loop coils Oxoindole of difluoromethyl substitution in drug discovery and druggability evaluation.
The content of the invention
It is an object of the invention to provide a kind of 3,3'- loop coil Oxoindoles containing difluoromethyl group and preparation method thereof And application, such compound is the important pharmaceutical activity molecule of a class, has important application to drug screening and pharmaceutical industry Value, and the synthesis of the quasi-molecule has the advantages that reaction condition is gentle, simple to operate, substrate universality is good.
What the present invention was realized in：Generated in-situ difluoromethyl diazomethane aoxidizes Yin with 3- alkenyls derived from isatin Diindyl carries out [3+2] reaction under without catalysts conditions, in organic solvent, obtains 3, the 3'- loop coil oxygen containing difluoromethyl group Change indoles.Such compound has the structure as shown in formula (I)：
In formula, R1For alkyl, alkoxy or halogen；R2For alkyl；R3For alkyl, aryl or acyl group.
Described organic solvent is dichloromethane, chloroform, carbon tetrachloride, acetonitrile, tetrahydrofuran, benzene, toluene, diformazan Benzene, mesitylene, 1,4- dioxane, glycol dimethyl ether, ethylene glycol diethyl ether or methyl tertiary butyl ether(MTBE).
The reaction temperature of generated in-situ difluoromethyl diazomethane and 3- alkenyls Oxoindole derived from isatin is 25- 100 DEG C, the reaction time is 1-48 hours.
The described 3,3'- loop coils Oxoindole containing difluoromethyl group is preparing the application of preventing and treating tumor disease medicine.
The reaction principle of the present invention is as follows：
Wherein, R1, R2, R3It is as described above with organic solvent.
By using above-mentioned technical proposal, difluoroethylamine (1) is positioned in reaction bulb, sequentially adds organic solvent, nitrous Tert-butyl acrylate and acetic acid, and reacted 10 minutes under the conditions of 70 DEG C, stop heating, you can original position obtains difluoromethyl diazomethane (2).Then 3- alkenyls Oxoindole (3) derived from isatin is added in reaction bulb, by [3+2] annulation, has synthesized one The serial 3,3'- loop coils Oxoindole (4) containing difluoromethyl group.Such compound contains the difluoromethyl of potential source biomolecule activity Group and 3,3'- loop coil Oxoindole skeleton, can be that material base is set up in drug discovery and druggability evaluation, with important Application value.Raw material of the present invention is easily obtained, and can be carried out in various organic solvents, with reaction condition is gentle, operation letter The good advantage of single, substrate universality.
Brief description of the drawings
Fig. 1 is embodiments of the invention compound 4a monocrystalline-X-ray diffraction structure.
Fig. 2 is embodiments of the invention compound 4k monocrystalline-X-ray diffraction structure.
Fig. 3 is embodiments of the invention compound 4t monocrystalline-X-ray diffraction structure.
Fig. 4-6 is embodiments of the invention compound 4a nmr spectrum.
Embodiment
Embodiments of the invention 1：The preparation of 3,3'- loop coils Oxoindole (4) containing difluoromethyl group；Compound 4a： In round-bottomed flask, dichloromethane (15mL), difluoroethylamine (1,97.3mg, 1.2mmol), nitrite tert-butyl are sequentially added (148.5mg, 1.44mmol), acetic acid (14.5mg, 0.24mmol) reacts 10 minutes under the conditions of 70 DEG C, stops heating, you can Original position prepares difluoromethyl diazomethane (2).Add 3- alkenyls Oxoindole derived from isatin (3a, 92.5mg, 0.4mmol), and it is sufficiently stirred at room temperature 24 hours, thin-layer chromatography is detected after completion of the reaction, through being concentrated under reduced pressure, silica gel column layer Analyse (300-400 mesh) separation (petroleum ether：Ethyl acetate=5：1) white solid 108.6mg, yield 84%, fusing point, are obtained： 91.8-93.8 DEG C, nuclear magnetic resonance and high resolution mass spectrum Measurement results are as follows：99:1dr(determined by19F NMR analysis)；1H NMR(400MHz,CDCl3) δ 7.39 (t, J=7.8Hz, 1H), 7.00 (t, J=7.6Hz, 1H), 6.94 (d, J=7.8Hz, 1H), 6.80 (d, J=7.6Hz, 1H), 6.44 (td, J=4.0,54.4Hz, 1H), 5.82-5.73 (m, 1H), 3.90-3.73 (m, 2H), 3.57 (d, J=8.4Hz, 1H), 3.32 (s, 3H), 0.68 (t, J=7.2Hz, 3H)；13C NMR (100MHz,CDCl3) δ 171.0,167.9,144.7,131.5,124.9,123.4,121.6,112.9 (t, J=244.0Hz), (t, J=22.0Hz), 109.0,99.3,94.0 61.9,44.3 (t, J=3.0Hz), 27.2,13.5；19F NMR(376MHz, CDCl3) δ -122.74 (ABdd, J=8.9,54.3,294.8Hz), -126.64 (ABdd, J=16.2,55.4,294.6Hz)； HRMS(ESI-TOF)Calcd.for C15H15F2N3NaO3[M+Na]+:346.0974；found:346.0971.
Monocrystalline-X-ray diffraction structure chart and nmr spectrum are by prior art Software Create, art technology in accompanying drawing The characteristics of personnel can be by figure is that can be appreciated that each compound attribute, may not be very because submitting reason for the numeral in figure Clearly, the full disclosure of the present invention but is not influenceed.
Compound 4b~the 4u prepared by embodiment preparation method is with compound 4a, rate of charge and compound 4a phases Together, compound 4b~4u is can obtain, reaction yield is shown in Table 1, but it is emphasized that the compound of the present invention is not limited to represented by table 1 Content.
Table 1 is the chemical constitution of the 3,3'- loop coil Oxoindoles containing difluoromethyl group
Table 1：
The present embodiment prepare compound 4b：Yellow oil, yield 72%；Nuclear magnetic resonance and high resolution mass spectrum test analysis As a result it is as follows：95:5dr(determined by19F NMR analysis)；1H NMR(400MHz,CDCl3)δ(major+ Minor) 7.19 (d, J=7.8Hz, 0.95H), 7.14 (s, 0.05H), 7.11 (d, J=8.0Hz, 0.05H), 6.82 (d, J= 7.8Hz, 0.95H), 6.78 (d, J=8.0Hz, 0.05H), 6.60 (s, 0.95H), 6.43 (td, J=4.0,55.5Hz, 0.95H), 6.38 (td, J=7.0,54.5Hz, 0.05H), 5.83-5.73 (m, 1H), 4.23-4.08 (m, 0.10H), 3.92- 3.73 (m, 1.90H), 3.56 (d, J=8.2Hz, 1H), 3.32 (s, 2.85H), 3.24 (s, 0.15H), 2.31 (s, 0.15H), 2.24 (s, 2.85H), 1.21 (t, J=7.2Hz, 0.15H), 0.70 (t, J=7.0Hz, 2.85H)；13C NMR(100MHz, CDCl3)δ(major+minor)170.9,167.9,142.2,133.1,132.4,131.6,128.9,125.5,123.6, (t, J=243.6Hz), 121.5,113.0 108.8,108.3,99.4,93.8 (t, J=22.0Hz), 61.9,44.3 (t, J= 2.9Hz),27.2,26.9,21.3,21.0,14.2,13.5；19F NMR(376MHz,CDCl3)δ(major+minor)- 111.04 (ABdd, J=5.8,54.4,293.6Hz, minor), -115.85 (ABdd, J=6.8,55.8,294.5Hz, ), minor -121.63 (ABdd, J=9.4,54.4,294.7Hz, major), -125.51 (ABdd, J=16.1,55.3, 294.7Hz,major)；HRMS(ESI-TOF)Calcd.for C16H17F2N3NaO4[M+Na]+:360.1130；found: 360.1147.
The present embodiment prepare compound 4c：Red oil, yield 77%；Nuclear magnetic resonance and high resolution mass spectrum test analysis As a result it is as follows：85:15dr(determined by19F NMR analysis)；1H NMR(400MHz,CDCl3)δ(major+ Minor) 6.93 (d, J=2.5Hz, 0.15H), 6.90 (d, J=2.5Hz, 0.85H), 6.86 (s, 0.85H), 6.83 (s, 0.15H), 6.42 (td, J=4.1,55.0Hz, 1H), 6.40 (d, J=2.5Hz, 1H), 5.83-5.74 (m, 1H), 3.91- 3.78 (m, 2H), 3.76 (s, 0.45H), 3.70 (s, 2.55H), 3.56 (d, J=8.2Hz, 1H), 3.31 (s, 2.55H), 3.23 (s, 0.45H), 1.21 (t, J=7.1Hz, 0.45H), 0.74 (t, J=7.1Hz, 2.55H)；13C NMR(100MHz,CDCl3)δ (major+minor)170.6,167.9,156.3,156.1,137.9,125.2,122.5,116.0,113.4,113.0(t,J =243.6Hz), 112.0,110.0,109.5,108.9,99.7,94.0 (t, J=22.0Hz), 61.9,56.0,44.3 (t, J =2.8Hz), 27.2,26.9,14.1,13.6；19F NMR(376MHz,CDCl3)δ(major+minor)-111.06(ABdd,J =6.0,55.0,294.4Hz, minor), -115.87 (ABdd, J=7.2,55.8,294.3Hz, minor), -121.65 (ABdd, J=9.2,54.4,294.8Hz, major), -125.45 (ABdd, J=15.9,55.2,294.7Hz, major)； HRMS(ESI-TOF)Calcd.for C16H17F2N3NaO4[M+Na]+:376.1079；found:376.1085.
The present embodiment prepare compound 4d：Yellow solid, yield 77%；Fusing point:86.7–88.6℃；Nuclear magnetic resonance and height Resolution Mass Spectrometry Measurement results are as follows：84:16dr(determined by19F NMR analysis)；1H NMR (400MHz,CDCl3) δ 7.13 (t, J=8.6Hz, 1H), 6.90 (dd, J=3.5,8.4Hz, 1H), 6.59 (s, 1H), 6.45 (td, J=4.0,55.0,1H), 5.86-5.77 (m, 1H), 3.97-3.80 (m, 2H), 3.58 (d, J=8.0Hz, 1H), 3.34 (s, 3H), 0.79 (t, J=7.1Hz, 3H)；13C NMR(100MHz,CDCl3) δ 170.6,167.7,159.2 (d, J= 242.3Hz), 140.7,122.8 (d, J=8.2Hz), 117.8 (d, J=23.3Hz), 113.3 (d, J=25.5Hz), 112.8 (t, J=243.8Hz), 109.7 (d, J=8.0Hz), 99.4,94.5 (t, J=22.3Hz), 62.2,44.2 (t, J= 2.8Hz),27.4,13.7；19F NMR(376MHz,CDCl3) δ (major+minor) -111.09 (ABdd, J=6.0,54.6, 295.4Hz, minor), -116.01 (ABdd, J=7.5,55.7,295.3Hz, minor), (- 118.52)-(- 118.58) (m, ), major (- 119.44)-(- 119.50) (m, minor), -121.61 (ABdd, J=9.0,54.4,295.2Hz, major), - 125.52 (ABdd, J=16.2,55.3,295.3Hz, major)；HRMS(ESI-TOF)Calcd.for C15H14F3N3NaO3[M +Na]+:364.0879；found:364.0870.
The present embodiment prepare compound 4e：Red oil, yield 74%；Nuclear magnetic resonance and high resolution mass spectrum test analysis As a result it is as follows：87:13dr(determined by19F NMR analysis)；1H NMR(400MHz,CDCl3)δ(major+ Minor) 7.39 (dd, J=2.0,8.2Hz, 0.87H), 7.36 (d, J=2.0Hz, 0.13H), 7.29 (dd, J=2.0, 8.2Hz, 0.13H), 6.89 (d, J=8.2Hz, 0.87H), 6.82 (s, 0.13H), 6.80 (d, J=2.0,0.87H), 6.45 (td, J=4.0,55.0Hz, 0.87H), 6.36 (td, J=7.0,55.2Hz, 0.13H), 5.86-5.77 (m, 1H), 4.24- 4.11 (m, 0.26H), 3.96-3.81 (m, 1.74H), 3.57 (d, J=7.6Hz, 1H), 3.33 (s, 2.61H), 3.25 (s, 0.39H), 1.23 (t, J=7.0Hz, 0.39), 0.78 (t, J=7.0Hz, 2.61H)；13C NMR(100MHz,CDCl3)δ (major+minor)170.5,167.7,143.3,131.4,128.8,128.6,128.3,125.4,123.5,123.1, 112.8 (t, J=243.8Hz), 110.0,109.4,99.1,94.6 (t, J=22.2Hz), 62.2,44.2 (t, J=2.9Hz), 27.3,27.0,14.2,13.7；19F NMR(376MHz,CDCl3) δ (major+minor) -111.06 (ABdd, J=5.5, 55.8,296.0Hz, minor), -116.00 (ABdd, J=7.1,55.5,295.4Hz, minor), -121.69 (ABdd, J= 8.9,54.2,295.2Hz, major), -125.52 (ABdd, J=16.3,55.2,295.0Hz, major)；HRMS(ESI- TOF)Calcd.for C15H15ClF2N3O3[M+H]+:358.0765；found:358.0774.
The present embodiment prepare compound 4f：Chinese red grease, yield 72%；Nuclear magnetic resonance and high resolution mass spectrum test point Analyse result as follows：81:19dr(determined by19F NMR analysis)；1H NMR(400MHz,CDCl3)δ(major + minor) 7.54 (dd, J=2.0,8.4Hz, 0.81H), 7.49 (d, J=2.0Hz, 0.19H), 7.44 (dd, J=2.0, 8.4Hz, 0.19H), 6.93 (d, J=2.0Hz, 0.81H), 6.84 (d, J=8.4Hz, 0.81H), 6.77 (d, J=8.4Hz, 0.19H), 6.45 (td, J=4.0,54.8Hz, 0.81H), 6.36 (td, J=7.2,55.2Hz, 0.19H), 5.84-5.77 (m, 1H), 3.99-3.91 (m, 1H), 3.88-3.80 (m, 1H), 3.57 (d, J=8.0Hz, 1H), 3.33 (s, 2.43H), 3.25 (s, 0.57H), 1.25 (td, J=1.5,7.2Hz, 0.57H), 0.80 (t, J=7.2Hz, 2.43H)；13C NMR(100MHz, CDCl3)δ(major+minor)170.4,167.6,143.7,134.3,131.5,128.1,126.2,123.4,115.8, 112.8 (t, J=243.9Hz), 110.5,109.9,99.0,94.5 (t, J=22.2Hz), 62.3,60.5,44.2 (t, J= 2.8Hz), 27.3,27.0,21.2,14.3 (d, J=11.5Hz), 13.7；19F NMR(376MHz,CDCl3)δ(major+ Minor) -111.05 (ABdd, J=6.0,54.6,294.9Hz, minor), -116.00 (ABdd, J=7.2,55.7, 295.5Hz, minor), -121.71 (ABdd, J=9.0,54.3,295.2Hz, major), -125.50 (ABdd, J=16.3, 55.3,295.3Hz,major)；HRMS(ESI-TOF)Calcd.for C15H14BrF2N3NaO3[M+Na]+:424.0079； found:424.0070.
The present embodiment prepare compound 4g：Yellow oil, yield 59%；Nuclear magnetic resonance and high resolution mass spectrum test analysis As a result it is as follows：90:10dr(determined by19F NMR analysis)；1H NMR(400MHz,CDCl3)δ(major+ Minor) 7.72 (dd, J=2.0,8.2Hz, 1.0H), 7.63 (s, 0.10H), 7.07 (s, 0.90H), 6.73 (d, J=8.2Hz, 0.90H), 6.67 (d, J=8.2Hz, 0.10H), 6.44 (td, J=3.2Hz, 0.90H), 6.35 (td, J=7.6,55.0Hz, 0.10H), 5.83-5.78 (m, 1.0H), 3.99-3.78 (m, 2H), 3.55 (d, J=8.0Hz, 0.90H), 3.46 (d, J= 7.2Hz, 0.10H), 3.31 (s, 2.7H), 3.23 (s, 0.3H), 1.19 (t, J=7.2Hz, 0.30H), 0.78 (t, J= 7.2Hz,2.7H)；13C NMR(100MHz,CDCl3)δ(major+minor)170.2,167.6,144.3,140.2,137.5, (133.4,131.6,123.7,112.8 t, J=243.8Hz), 111.0,110.5,98.8,94.4 (t, J=22.2Hz), (85.2,62.2,44.2 t, J=2.8Hz), 27.2,26.9,14.2,13.7；19F NMR(376MHz,CDCl3)δ(major+ Minor) -111.00 (ABdd, J=6.4,55.0,295.5Hz, minor), -115.94 (ABdd, J=7.8,55.8, 295.5Hz, minor), -121.74 (ABdd, J=9.3,54.3,294.6Hz, major), -125.44 (ABdd, J=16.4, 55.2,294.9Hz,major)；HRMS(ESI-TOF)Calcd.for C15H14IF2N3NaO3[M+Na]+:471.9940； found:471.9970.
The present embodiment prepare compound 4h：Yellow oil, yield 70%；Nuclear magnetic resonance and high resolution mass spectrum test analysis As a result it is as follows：76:24dr(determined by19F NMR analysis)；1H NMR(400MHz,CDCl3)δ(major+ Minor) 7.31 (d, J=8.6Hz, 0.76H), 7.28 (s, 0.24H), 7.20 (d, J=8.4HZ, 0.24), 6.96 (d, J= 8.6Hz, 0.76H), 6.88 (d, J=8.4Hz, 0.24H), 6.73 (s, 0.76H), 6.45 (td, J=4.0,54.8Hz, 0.76H), 6.38 (td, J=7.2,55.1Hz, 0.24H), 5.89-5.80 (m, 1H), 4.21-4.11 (m, 0.48H), 3.94- 3.78 (m, 1.52H), 3.58 (d, J=8.0Hz, 1H), 3.36 (s, 2.28H), 3.28 (s, 0.72H), 1.22 (t, J= 7.2Hz, 0.72H), 0.77 (t, J=7.2Hz, 2.28H)；13C NMR(100MHz,CDCl3)δ(major+minor)172.1, 170.7,167.6,166.5,144.9,144.8,143.4,142.9,125.5,124.7,12 2.9,121.9,120.5 (q, J= 256.0Hz), 119.2,117.3,113.1 (t, J=236.0Hz), 112.8 (t, J=243.8Hz), 109.6,108.9, (t, J=22.2Hz), 99.2,94.8 62.3,62.2,44.2 (t, J=2.9Hz), 27.4,27.0,14.1,13.5；19F NMR (376MHz,CDCl3) δ (major+minor) -58.49 (s, minor), -58.61 (s, major), -111.10 (ABdd, J= 5.7,54.7,295.5Hz, minor), -116.08 (ABdd, J=7.1,55.6,295.5Hz, minor), -121.79 (ABdd, J=8.9,54.2,295.2Hz, major), -125.53 (ABdd, J=16.4,55.5,295.4Hz, major)；HRMS(ESI- TOF)Calcd.for C16H14F5N3NaO4[M+Na]+:430.0797；found:430.0795.
The present embodiment prepare compound 4i：Yellow solid, yield 58%；Fusing point:75.4–77.4℃；Nuclear magnetic resonance and height Resolution Mass Spectrometry Measurement results are as follows：93:7dr(determined by19F NMR analysis)；1H NMR(400MHz, CDCl3) δ 6.99 (dd, J=1.9,8.0Hz, 1H), 6.96 (s, 1H), 6.72 (d, J=8.0Hz, 1H), 6.45 (td, J= 3.9,54.9Hz, 1H), 5.83-5.73 (m, 1H), 3.92-3.78 (m, 2H), 3.56 (d, J=10.6Hz, 1H), 3.33 (s, 3H), 0.78 (t, J=7.1Hz, 3H)；13C NMR(100MHz,CDCl3)δ170.9,167.7,145.8,137.5,125.8, (t, J=243.6Hz), 123.2,119.8,112.7 109.8,98.8,94.2 (t, J=22.2Hz), 62.1,44.1 (t, J= 2.8Hz),27.3,13.6；19F NMR(376MHz,CDCl3) δ (major+minor) -111.01 (ABdd, J=5.8,54.6, 294.8Hz, minor), -115.92 (ABdd, J=7.0,55.7,294.9Hz, minor), -121.92 (ABdd, J=8.9, 54.3,294.8Hz, major), -125.68 (ABdd, J=16.5,55.6,294.8Hz, major)；HRMS(ESI-TOF) Calcd.for C15H14ClF2N3NaO3[M+Na]+:380.0584；found:380.0573.
The present embodiment prepare compound 4j：Red solid, yield 53%；Fusing point:82.6–84.2℃；Nuclear magnetic resonance and height Resolution Mass Spectrometry Measurement results are as follows：72:28dr(determined by19F NMR analysis)；1H NMR (400MHz,CDCl3) δ (major+minor) 7.21 (dd, J=1.2,8.2Hz, 0.28H), 7.16 (d, J=8.0Hz, 0.28H), 7.15 (d, J=1.8,8.0Hz, 0.72H), 7.11 (d, J=1.5Hz, 0.72H), 7.04 (d, J=1.6Hz, 0.28H), 6.66 (dd, J=1.2,8.0HZ, 0.72H), 6.45 (td, J=4.0,55.4Hz, 0.72H), 6.36 (td, J= 7.2,55.2Hz,0.28H),5.83-5.73(m,1H),4.20-4.07(m,0.56H),3.90-3.80(m,1.44H),3.56 (dd, J=1.2,8.2Hz, 0.72H), 3.32 (d, J=1.4Hz, 2.16H), 3.24 (d, J=1.4Hz, 0.84H), 3.23 (dd, J=1.4,9.4Hz, 0.28H), 1.21 (td, J=1.5,7.2Hz, 0.84H), 0.79 (td, J=1.5,7.2Hz, 2.16H)；13C NMR(100MHz,CDCl3) δ (major+minor) 172.1,170.8,167.7,166.7 (d, J= 20.7Hz), 145.9,145.4,126.1 (d, J=3.5Hz), 125.6,125.4,124.2,122.9,122.4,120.4, (115.5,113.1,112.7 t, J=243.7Hz), 112.6,112.1,110.7,98.9,94.3 (t, J=22.1Hz), (62.1,44.1 t, J=2.8Hz), 27.3,27.0,14.1,13.6；19F NMR(376MHz,CDCl3)δ(major+minor)- 111.00 (ABdd, J=6.3,54.6,295.0Hz, minor), -115.93 (ABdd, J=7.3,55.6,295.2Hz, ), minor -121.85 (ABdd, J=8.5,54.3,295.0Hz, major), -125.68 (ABdd, J=16.4,55.2, 294.8Hz,major)；HRMS(ESI-TOF)Calcd.for C15H14BrF2N3NaO3[M+Na]+:424.0079；found: 424.0083.
The present embodiment prepare compound 4k：Chinese red solid, yield 65%；Fusing point:98.9–100.9℃；Nuclear magnetic resonance and High resolution mass spectrum Measurement results are as follows：97:3dr(determined by19F NMR analysis)；1H NMR (400MHz,CDCl3) δ 6.97-6.92 (m, 2H), 6.42 (td, J=4.1,54.9Hz, 1H), 6.37 (dd, J=2.2, 6.3Hz, 1H), 5.80-5.71 (m, 1H), 3.91-3.77 (m, 2H), 3.88 (s, 3H), 3.60 (s, 3H), 3.56 (d, J= 8.4Hz, 1H), 0.75 (t, J=7.2Hz, 3H)；13C NMR(100MHz,CDCl3)δ171.1,167.8,145.8,132.4, (124.0,122.8,117.2,115.1,113.0 t, J=243.6Hz), 99.4,93.8 (t, J=22.0Hz), 61.9,56.3, 44.5 (t, J=2.8Hz), 30.6,13.5；19F NMR(376MHz,CDCl3) δ (major+minor) -111.11 (ABd, J= 54.5,294.2Hz, minor), -116.01 (ABd, J=54.8,310.9Hz, minor), -121.75 (ABdd, J=9.5, 54.4,294.4Hz, major), -125.53 (ABdd, J=15.9,55.3,294.5Hz, major)；HRMS(ESI-TOF) Calcd.for C16H17F2N3NaO4[M+Na]+:376.1079；found:376.1079.
The present embodiment prepare compound 4l：Yellow solid, yield 64%；Fusing point:85.3–87.1℃；Nuclear magnetic resonance and height Resolution Mass Spectrometry Measurement results are as follows：91:9dr(determined by19F NMR analysis)；1H NMR(400MHz, CDCl3)δ(major+minor)7.18-7.12(m,1H),7.00-6.94(m,1H),6.60-6.57(m,1H),6.46(td,J =3.9,55.0Hz, 1H), 5.85-5.74 (m, 1H), 3.93-3.78 (m, 2H), 3.61-3.53 (m, 4H), 0.78 (td, J= 1.2,7.2Hz,3H)；13C NMR(100MHz,CDCl3) δ (major+minor) 170.6,167.7,147.9 (d, J= 244.2Hz), 131.4 (d, J=8.9Hz), 124.2 (d, J=3.2Hz), 124.1 (d, J=6.4Hz), 121.4,120.8 (d, ), J=3.4Hz 119.5 (d, J=19.0Hz), 112.8 (t, J=243.8Hz), 99.2,94.2 (t, J=22.2Hz), 65.1, (t, J=2.8Hz), 62.1,46.6,44.5 29.8 (d, J=5.8Hz), 13.8,13.7；19F NMR(376MHz,CDCl3)δ (major+minor) -111.08 (ABdd, J=5.3,53.7,296.0Hz, minor), -116.12 (ABdd, J=7.0, 55.5,295.0Hz, minor), -121.83 (ABdd, J=8.9,54.0,295.0Hz, major), -125.70 (ABdd, J= 16.4,55.2,294.9Hz,major),(-135.17)–(-135.23)(m,major),(-135.43)–(-135.48)(m, minor)；HRMS(ESI-TOF)Calcd.for C15H14F3N3NaO3[M+Na]+:364.0879；found:364.0878.
The present embodiment prepare compound 4m：Yellow solid, yield 67%；Fusing point:77.4–79.2℃；Nuclear magnetic resonance and height Resolution Mass Spectrometry Measurement results are as follows：94:6dr(determined by19F NMR analysis)；1H NMR(400MHz, CDCl3) δ 7.33 (d, J=8.2Hz, 1H), 6,93 (t, J=7.6Hz, 1H), 6.64 (J=7.4Hz, 1H), 6.46 (td, J= 3.2,54.4Hz, 1H), 5.81-5.73 (m, 1H), 3.93-3.78 (m, 2H), 3.71 (s, 3H), 3.59 (d, J=8.2Hz, 1H), 0.77 (t, J=7.1Hz, 3H)；13C NMR(100MHz,CDCl3)δ171.3,167.6,140.5,133.6,131.0, (124.1,123.3,116.5,112.7 t, J=243.7Hz), 98.7,94.1 (t, J=22.2Hz), 62.1,44.6 (t, J= 2.8Hz),30.7,13.6；19F NMR(376MHz,CDCl3) δ (major+minor) -111.07 (ABdd, J=5.8,54.5, 295.0Hz, minor), -114.68 (ABdd, J=7.0,55.0,292.6Hz, minor), -122.00 (ABdd, J=9.0, 54.1,294.7Hz, major), -125.77 (ABdd, J=16.4,55.2,294.9Hz, major)；HRMS(ESI-TOF) Calcd.for C15H14ClF2N3NaO3[M+Na]+:380.0584；found:380.0579.
The present embodiment prepare compound 4n：Yellow solid, yield 60%；Fusing point:91.4–93.2℃；Nuclear magnetic resonance and height Resolution Mass Spectrometry Measurement results are as follows：93:7dr(determined by19F NMR analysis)；1H NMR(400MHz, CDCl3) δ 7.51 (d, J=8.2Hz, 1H), 6.87 (t, J=8.2Hz, 1H), 6.68 (d, J=7.4Hz, 1H), 6.46 (td, J =4.0,55.5Hz, 1H), 5.82-5.73 (m, 1H), 3.93-3.77 (m, 2H), 3.73 (s, 3H), 3.59 (d, J=8.4Hz, 1H), 0.78 (t, J=7.2Hz, 3H)；13C NMR(100MHz,CDCl3)δ171.5,167.6,142.0,137.0,134.4, (t, J=243.8Hz), 124.4,123.9,112.7 103.2,98.7,94.2 (t, J=22.3Hz), 62.1,44.7 (t, J= 2.9Hz),31.0,13.6；19F NMR(376MHz,CDCl3) δ (major+minor) -111.07 (ABdd, J=6.5,54.4, 295.5Hz, minor), -116.05 (ABdd, J=6.9,55.8,295.3Hz, minor), -121.92 (ABdd, J=8.9, 54.2,295.0Hz, major), -125.78 (ABdd, J=16.5,55.3,294.9Hz, major)；HRMS(ESI-TOF) Calcd.for C15H15BrF2N3O3[M+H]+:402.0259；found:402.0264.
The present embodiment prepare compound 4o：Yellow solid, yield 58%；Fusing point:93.9–95.0℃；Nuclear magnetic resonance and height Resolution Mass Spectrometry Measurement results are as follows：93:7dr(determined by19F NMR analysis)；1H NMR(400MHz, CDCl3) δ 7.41 (t, J=7.6Hz, 1H), 7.03 (t, J=7.6Hz, 1H), 6.96 (d, J=7.6Hz, 1H), 6.80 (d, J= 7.3Hz, 1H), 6.43 (td, J=3.6,55.1Hz, 1H), 5.89-5.79 (m, 1H), 3.59 (d, J=8.0Hz, 1H), 3.35 (s,3H),3.34(s,3H)；13C NMR(100MHz,CDCl3)δ170.8,168.6,144.5,131.5,124.7,123.4, (t, J=243.6Hz), 121.5,113.0 109.2,99.6,94.5 (t, J=22.2Hz), 52.9,44.1 (t, J=2.9Hz), 27.2；19F NMR(376MHz,CDCl3) δ (major+minor) -111.08 (ABdd, J=5.7,54.0,294.2Hz, ), minor -115.89 (ABdd, J=6.8,55.7,294.6Hz, minor), -121.36 (ABdd, J=9.0,54.5, 295.1Hz, major), -125.38 (ABdd, J=16.0,55.3,295.0Hz, major)；HRMS(ESI-TOF) Calcd.for C14H13F2N3NaO3[M+Na]+:332.0817；found:332.0813.
The present embodiment prepare compound 4p：Chinese red solid, yield 76%；Fusing point:43.2–45.0℃；Nuclear magnetic resonance and High resolution mass spectrum Measurement results are as follows：88:12dr(determined by19F NMR analysis)；1H NMR (400MHz,CDCl3)δ(major+minor)7.42-7.37(m,0.88H),7.34-7.31(m,0.12H),7.05-6.99 (m,1H),6.95-6.90(m,1H),6.81-6.78(m,1H),6.60-6.30(m,1H),5.84-5.75(m,1H),4.12- 3.98(m,0.24H),3.74-3.65(m,1.76H),3.62-3.59(m,0.88H),3.34(s,0.36H),3.33(s, 2.64H),3.27-3.26(m,0.12H),1.24-1.01(m,2H),0.87-0.82(m,0.36H),0.56-0.52(m, 2.64H)；13C NMR(100MHz,CDCl3)δ(major+minor)170.9,168.0,144.6,131.5,128.6,124.8, (d, J=3.2Hz), 123.4,122.8 121.5,112.9 (t, J=243.5Hz), 109.1,108.5,99.3,94.0 (t, J= 22.1Hz), 67.5,44.3 (t, J=2.8Hz), 27.1,26.9,21.9,21.4,10.3,9.9；19F NMR(376MHz, CDCl3) δ (major+minor) -111.03 (ABdd, J=5.8,54.8,294.0Hz, minor), -115.88 (ABdd, J= 6.8,55.7,294.1Hz, minor), -121.84 (ABdd, J=9.4,55.0,295.0Hz, major), -125.65 (ABdd, J=16.3,55.4,294.6Hz, major)；HRMS(ESI-TOF)Calcd.for C16H17F2N3NaO3[M+Na]+: 360.1130；found:360.1141.
The present embodiment prepare compound 4q：Yellow solid, yield 74%；Fusing point:58.1–60.1℃；Nuclear magnetic resonance and height Resolution Mass Spectrometry Measurement results are as follows：93:7dr(determined by19F NMR analysis)；1H NMR(400MHz, CDCl3) δ 7.40 (t, J=7.8Hz, 1H), 7.01 (t, J=7.6Hz, 1H), 6.95 (d, J=7.0Hz, 1H), 6.78 (d, J= 7.5Hz, 1H), 6.48 (td, J=3.6,55.0Hz, 1H), 5.65-5.55 (m, 1H), 3.56 (d, J=9.1Hz, 1H), 3.34 (s,3H),0.98(s,9H)；13C NMR(100MHz,CDCl3)δ171.3,166.4,144.7,131.4,125.1,123.4, (t, J=243.4Hz), 121.7,112.9 108.9,98.7,92.7 (t, J=22.0Hz), 82.9,45.6 (t, J=2.8Hz), 27.4,27.0；19F NMR(376MHz,CDCl3) δ (major+minor) -110.96 (ABdd, J=5.4,55.4,294.0Hz, ), minor -115.88 (ABdd, J=6.8,56.0,294.0Hz, minor), -122.87 (ABdd, J=9.8,54.3, 293.5Hz, major), -125.97 (ABdd, J=16.2,55.2,293.5Hz, major)；HRMS(ESI-TOF) Calcd.for C17H19F2N3NaO3[M+Na]+:374.1287；found:374.1284.
The present embodiment prepare compound 4r：Yellow solid, yield 76%；Fusing point:78.1–80.0℃；Nuclear magnetic resonance and height Resolution Mass Spectrometry Measurement results are as follows：94:6dr(determined by19F NMR analysis)；1H NMR(400MHz, CDCl3) δ 7.38 (t, J=7.8Hz, 1H), 7.01-6.95 (m, 2H), 6.78 (d, J=7.5Hz, 1H), 6.46 (td, J= 3.6,54.5Hz, 1H), 5.81-5.71 (m, 1H), 3.99-3.90 (m, 1H), 3.86-3.70 (m, 3H), 3.60 (d, J= 8.5Hz, 1H), 1.34 (t, J=7.2Hz, 3H), 0.68 (t, J=7.2Hz, 3H)；13C NMR(100MHz,CDCl3)δ170.6, (167.8,143.7,131.4,125.0,123.2,121.8,112.9 t, J=243.5Hz), 109.1,99.1,93.6 (t, J= 22.1Hz), 61.8,44.4 (t, J=2.8Hz), 35.7,13.5,12.6；19F NMR(376MHz,CDCl3)δ(major+ Minor) -111.06 (ABdd, J=5.8,54.5,294.2Hz, minor), -115.93 (ABdd, J=7.2,55.6, 294.2Hz, minor), -122.03 (ABdd, J=9.1,54.2,294.3Hz, major), -125.82 (ABdd, J=16.5, 55.3,294.4Hz,major)；HRMS(ESI-TOF)Calcd.for C16H17F2N3NaO3[M+Na]+:360.1130；found: 360.1120.
The present embodiment prepare compound 4s：Yellow solid, yield 78%；Fusing point:77.6–79.1℃；Nuclear magnetic resonance and height Resolution Mass Spectrometry Measurement results are as follows：93:7dr(determined by19F NMR analysis)；1H NMR(400MHz, CDCl3) δ 7.38-7.26 (m, 6H), 7.00-6.95 (m, 1H), 6.82-6.77 (m, 2H), 6.52 (td, J=3.8,54.7Hz, 1H), 5.86-5.77 (m, 1H), 5.25 (d, J=15.7Hz, 1H), 4.84 (d, J=15.7Hz, 1H), 3.89-3.81 (m, 1H), 3.77-3.69 (m, 2H), 0.54 (t, J=7.0Hz, 3H)；13C NMR(100MHz,CDCl3)δ171.3,167.8, 143.6,134.9,131.3,129.0,128.1,127.4,124.9,123.4,121.7,11 2.8 (t, J=243.6Hz), (t, J=22.1Hz), 110.1,99.2,93.8 62.0,44.6,44.5 (t, J=3.0Hz), 13.31；19F NMR(376MHz, CDCl3) δ (major+minor) -110.91 (ABdd, J=55.8,295.0Hz, minor), -116.02 (ABdd, J=7.9, 55.7,294.4Hz, minor), -122.11 (ABdd, J=9.0,54.0,294.2Hz, major), -125.92 (ABdd, J= 16.2,55.4,294.3Hz,major)；HRMS(ESI-TOF)Calcd.for C21H19F2N3NaO3[M+Na]+:422.1287； found:422.1291.
The present embodiment prepare compound 4t：Green solid, yield 67%；Fusing point:95.3–97.1℃；Nuclear magnetic resonance and height Resolution Mass Spectrometry Measurement results are as follows：86:14dr(determined by19F NMR analysis)；1H NMR (400MHz,CDCl3) δ (major+minor) 7.60-7.45 (m, 5H), 7.34 (t, J=8.0Hz, 1H), 7.06 (t, J= 7.2Hz, 1H), 6.92 (d, J=7.8Hz, 1H), 6.86 (d, J=7.8Hz, 1H), 6.49 (t, J=54.8Hz, 0.86H), 6.43 (td, J=54.8,7.2Hz, 0.14H), 5.87-5.79 (m, 1H), 4.25-4.11 (m, 0.28H), 3.96-3.81 (m, 1.72H), 3.71 (d, J=8.2Hz, 0.86H), 3.55 (d, J=8.2Hz, 0.14H), 1.12 (t, J=6.6Hz, 0.42H), 0.78 (t, J=6.6Hz, 2.58H)；13C NMR(100MHz,CDCl3)δ(major+minor)170.5,167.7,144.7, 144.2,134.0,133.7,131.4,130.0,129.8,129.7,128.9,128.6,126.7,126.5,125.0, (d, J=11.94Hz), 123.8,123.2 121.4,112.8 (t, J=243.6Hz), 110.3,110.1,109.8,99.3, 93.7 (t, J=22.2Hz), 62.1,62.0,45.0 (t, J=2.9Hz), 14.2,13.6；19F NMR(376MHz,CDCl3)δ (major+minor) -110.81 (ABdd, J=6.2,54.3,294.0Hz, minor), -115.92 (ABdd, J=7.0, 56.0,295.2Hz, minor), -121.97 (ABdd, J=8.8,54.5,294.8Hz, major), -125.73 (ABdd, J= 16.2,55.2,294.4Hz,major)；HRMS(ESI-TOF)Calcd.for C20H17F2N3NaO3[M+Na]+:408.1130； found:408.1129.
The present embodiment prepare compound 4u：Yellow solid, yield 31%；Fusing point:84.6–86.5℃；Nuclear magnetic resonance and height Resolution Mass Spectrometry Measurement results are as follows：93:7dr(determined by19F NMR analysis)；1H NMR(400MHz, CDCl3) δ 8.01 (d, J=8.2Hz, 1H), 7.44 (t, J=8.2Hz, 1H), 7.12 (t, J=7.6Hz, 1H), 6.78 (d, J= 7.6Hz, 1H), 6.49 (td, J=3.4,54.5Hz, 1H), 5.86-5.76 (m, 1H), 3.89-3.75 (m, 2H), 3.65 (dd, J =1.0,8.4Hz, 1H), 1.67 (s, 9H), 0.72 (td, J=1.0,7.2Hz, 3H)；13C NMR(100MHz,CDCl3)δ 169.4,167.5,148.7,140.9,131.7,125.1,124.5,120.7,115.9,11 2.6 (t, J=243.8Hz), (t, J=22.2Hz), 99.8,94.1 85.7,62.2,45.0 (t, J=2.5Hz), 28.2,13.5；19F NMR(376MHz, CDCl3) δ (major+minor) -110.69 (ABdd, J=5.8,54.9,296.3Hz, major), -112.80 (ABdd, J= 8.2,56.8,299.1Hz, minor), -114.77 (ABdd, J=7.5,53.3,299.0Hz, minor), -115.99 (ABdd, J=7.4,55.5,296.0Hz, major)；HRMS(ESI-TOF)Calcd.for C19H21F2N3NaO5[M+Na]+: 432.1341；found:432.1337.
Formula (1) compound of the present invention has important bioactivity, thin to human prostate (PC-3) and human lung cancer in vitro The cell toxicity test of born of the same parents (A549) totally two plants of tumour cells shows：The 3,3'- containing difluoromethyl group shown in such formula (1) Loop coil Oxoindole is inhibited to growth of tumour cell, it is possible to develop into new preventing and treating tumour medicine.
Formula (1) compound or pharmaceutically acceptable salt thereof and its solvate of the present invention can be with pharmaceutically conventional auxiliary material or load Body is combined, and is prepared with growth of tumour cell inhibitory activity so as to the pharmaceutical composition for anti-curing oncoma.It is above-mentioned Various kinds of drug composition can be solid form, such as tablet, capsule, granule, pulvis；It can also be liquid form, such as note Penetrate agent, suspending agent and emulsion etc..In addition to this it is possible to using controlled release agent or sustained release agent or nanometer well known to modern pharmaceutical circle Agent.
Formula (1) compound or pharmaceutically acceptable salt thereof and its solvate of the present invention can be with the antineoplastic that has listed Such as platinum medicine cis-platinum (DDP), deoxidation born of the same parents' former times class medicine gemcitabine (Gemcitabine, Gemzar, gemzar), taxol (Paclitaxel), vinca alkaloids medicine carbon loss vinblastine (Vinorebine, NVB NVB), camptothecine she It is vertical to be used in combination for health (Irinatecan, CPT-11), etoposide (Etoposide) etc., prepare with tumour growth The cytotoxic composition of inhibitory activity, available for treatment tumor disease.Such pharmaceutical composition can be solid form, such as piece Agent, capsule, granule, pulvis；Can also be liquid form, such as injection, suspending agent and emulsion.In addition, may be used also With using the controlled release agent well known to modern pharmaceutical circle or sustained release agent or nanometer agent.
Pharmacological Examples 1：The cytotoxicity of compound 4e, 4h, 4k, 4q or 4r to PC-3 cells
Containing 10% hyclone in PC-3 (human prostata cancer) cell RPMI-1640 medium cultures, culture medium, The streptomysin of 100U/mL penicillin and 100U/mL.Cell is added in 96 holes with the concentration of every 5000 cells in hole, at 37 DEG C Containing 5%CO2Cultivated 24 hours in the incubator of humid air.
The measure of cell survival rate improvement mtt assay.Cell is after the incubation of 24 hours, respectively by the compound newly matched somebody with somebody 4e, 4h, 4k, 4q or 4r dimethyl sulphoxide solution are added in each hole with concentration gradient, make compound ultimate density point in hole Wei not 6.25 μm of ol/L, 12.5 μm of ol/L, 25 μm of ol/L, 50 μm of ol/L and 100 μm of ol/L.After 48 hours, 10 μ L are added per hole MTT (5mg/mL) phosphate buffer, is further continued for after 37 DEG C are cultivated 4 hours, and centrifugation removes unconverted MTT in 5 minutes, often 150 μ L dimethyl sulfoxide (DMSO)s are added in hole.With the MTT crystal formazan (formazan) of dissolving and reducing, with ELIASA in 490nm wavelength Determine OD values.Wherein compound 4e, 4h, 4k, 4q or 4r is to PC-3 cell 503nhibiting concentrations IC50By spss softwares (19 version) point Analysis is obtained.ICs of the compound 4e to PC-3 tumour cells50For 82.7 μm of ol/L；ICs of the compound 4h to PC-3 tumour cells50For 64.6μmol/L；ICs of the compound 4k to PC-3 tumour cells50For 73.9 μm of ol/L；Compound 4q is to PC-3 tumour cells IC50For 33.7 μm of ol/L；ICs of the compound 4r to PC-3 tumour cells50For 83.2 μm of ol/L；And positive control cis-platinum is to PC-3 The IC of tumour cell50For 23.7 μm of ol/L.
Experiment conclusion：PC-3 cells are that test compound refers to the effective tool of the cytotoxicity of tumour cell and evaluation Mark.This experiment shows that the 3,3'- loop coils Oxoindole containing difluoromethyl group shown in such formula (1) has one to PC-3 cells Fixed cytotoxicity, it is possible to develop into the new medicine with antitumor action.
Pharmacological Examples 2：The cytotoxicity of compound 4f, 4h, 4k, 4q or 4t to A549 cells
A549 (human lung carcinoma cell) is used in DMEM medium cultures, culture medium containing 10% hyclone, 100U/mL green grass or young crops Mycin and 100U/mL streptomysins.Cell is added in 96 holes with the concentration of every 4000 cells in hole, contains 5%CO at 37 DEG C2It is moist Cultivated 24 hours in the incubator of air.
The measure of cell survival rate improvement mtt assay.Specific method such as Pharmacological Examples 1.Compound 4f is to A549 tumours The IC of cell50For 55.1 μm of ol/L；ICs of the compound 4h to A549 tumour cells50For 78.2 μm of ol/L；Compound 4k is to A549 The IC of tumour cell50For 88.6 μm of ol/L；ICs of the compound 4q to A549 tumour cells50For 85.7 μm of ol/L；4t pairs of compound The IC of A549 tumour cells50For 89.9 μm of ol/L；And positive control cis-platinum is to the IC of A540 tumour cells50For 23.0 μm of ol/L.
Experiment conclusion：A549 cells are that test compound refers to the effective tool of the cytotoxicity of tumour cell and evaluation Mark.This experiment shows that the 3,3'- loop coils Oxoindole containing difluoromethyl group shown in such formula (1) has one to A549 cells Fixed cytotoxicity, it is possible to develop into the new medicine with antitumor action.
We can see that such compound is all shown necessarily to this two plants of tumour cells from above Pharmacological Examples Cytotoxicity.It can be seen that these compounds have the potentiality for being developed into antineoplastic, it is worth continuing deeper into research.

Claims (5)

1. a kind of 3,3'- loop coil Oxoindoles containing difluoromethyl group, it is characterised in that：The compound has such as formula (I) Shown structure：
In formula, R1For alkyl, alkoxy or halogen；R2For alkyl；R3For alkyl, aryl or acyl group.
2. a kind of preparation method of 3, the 3'- loop coil Oxoindoles as claimed in claim 1 containing difluoromethyl group, its feature It is：As 3- alkenyls Oxoindole derived from generated in-situ difluoromethyl diazomethane and isatin under without catalysts conditions, [3+2] reaction is carried out in organic solvent, obtains 3, the 3'- loop coil Oxoindoles containing difluoromethyl group.
3. the preparation method of 3, the 3'- loop coil Oxoindoles according to claim 2 containing difluoromethyl group, its feature exists In：Described organic solvent be dichloromethane, chloroform, carbon tetrachloride, acetonitrile, tetrahydrofuran, benzene,toluene,xylene, Trimethylbenzene, 1,4- dioxane, glycol dimethyl ether, ethylene glycol diethyl ether or methyl tertiary butyl ether(MTBE).
4. the preparation method of 3, the 3'- loop coil Oxoindoles according to claim 2 containing difluoromethyl group, its feature exists In：The reaction temperature of generated in-situ difluoromethyl diazomethane and 3- alkenyls Oxoindole derived from isatin is 25-100 DEG C, Reaction time is 1-48 hours.
5. a kind of 3,3'- loop coils Oxoindole as claimed in claim 1 containing difluoromethyl group is preparing anti-curing oncoma disease The application of medicine.
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