CN103554121A - 3,3-spiro (2-tetrahydrofuranyl)-oxindole polycyclic compound and application thereof - Google Patents
3,3-spiro (2-tetrahydrofuranyl)-oxindole polycyclic compound and application thereof Download PDFInfo
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Abstract
The invention discloses a new 3,3-spiro (2-tetrahydrofuranyl)-oxindole polycyclic compound as shown in a formula (I). The new 3,3-spiro (2-tetrahydrofuranyl)-oxindole polycyclic compound is prepared by the following steps: performing (3+2) cycloaddition on isatin diazo, aldehyde and ortho-nitro-substituted phenylene under the catalysis of rhodium acetate to construct an intermediate containing a 3, 3-spiro (2-tetrahydrofuranyl)-oxindole structure, adding a base, and then performing intramolecular Michael addition to further perform ring-closure synthesis. The compound disclosed by the invention has the property of inhibiting the activity of aurora kinase A.
Description
Technical field
The invention belongs to medicine synthesising chemical technology field, relate to a kind of 3,3-spiral shell (2-tetrahydrofuran (THF)) Oxoindole polycyclic compound and application thereof.
Background technology
The naked ring skeleton of Oxoindole, as a kind of important structure monomer, is present in (Angew.Chem., Int.Ed.2007,46,8748-8758 in a lot of natural products and pharmaceutical activity intermediate; Tetrahedron Lett.2011,52,3945-3948).Wherein, the naked ring structure of Oxoindole and tetrahydrofuran (THF) is the intermediate fragments of a lot of natural products of conduct not only, also there is good biological activity, for example following I a-b is a kind of progesterone receptor inhibitor, and I c is used for the treatment of hypertension, and II a-b is used for the treatment of (the PCT Int.Appl.Patent2 such as skin pruritus and cancer, 000,066,167,2000; U.S.Patent4,226,860A, 1980; PCT Int.Appl.Patent2,006,110,917,2006).
The multi-component reaction of the diazoamines of Muthusamy professor first passage Rh in 2004 catalysis builds 3,3-spiral shell (2-tetrahydrofuran (THF)) Oxoindole compound (J.Org.Chem.2004,69,5631-5637), Schreiber seminar also attempts that silica reagent with Lewis acid induction participates in, and the method by isatin cyclisation builds 3,3-spiral shell (2-tetrahydrofuran (THF)) Oxoindole compound (J.Am.Chem.Soc.2007,129,1020-1021).But the defects such as substrate universality is low, severe reaction conditions that prior art all exists, the compound that makes to obtain new Oxoindole and the naked ring structure of tetrahydrofuran (THF) is very difficult.
Summary of the invention
The present invention proposes a kind of new 3,3-spiral shell (2-tetrahydrofuran (THF)) Oxoindole compound, shown in (I),
In formula (I), R
1for hydrogen, 5-methyl; 5-fluorine, 6-fluorine, 6-chlorine etc., R
2for methyl, ethanoyl, benzyl etc.; R
3for phenyl, a bromophenyl, to bromophenyl, p-methoxyphenyl, adjacent fluorophenyl, styryl, 2-thienyl, 2-furyl etc.; R
4for 5-chlorine, 5-bromine, hydrogen etc.
The compounds of this invention obtains by following preparation method, and its reaction formula is suc as formula shown in (II):
In formula (II), R
1for hydrogen, 5-methyl; 5-fluorine, 6-fluorine, 6-chlorine etc., R
2for methyl, ethanoyl, benzyl etc.; R
3for phenyl, a bromophenyl, to bromophenyl, p-methoxyphenyl, adjacent fluorophenyl, styryl, 2-thienyl, 2-furyl etc.; R
4for 5-chlorine, 5-bromine, hydrogen etc.
Wherein, the mol ratio of described isatin diazonium, aldehyde, nitro alkene, acetic acid rhodium, alkali is 1.5:1.5:1.0:0.02:0.2.
Wherein, described isatin diazonium is 5-methylisatin diazonium, 5-fluoro indigo red diazonium, 6-fluoro indigo red diazonium, 6-chlorisatide diazonium, nitrogen methylisatin diazonium, nitrogen ethanoyl isatin diazonium, nitrogen benzyl isatin diazonium etc.
Wherein, described aldehyde is phenyl aldehyde, p-bromobenzaldehyde, 3-bromobenzaldehyde, aubepine, o fluorobenzaldehyde, 2 furan carboxyaldehyde, 2 thiophene carboxaldehyde, phenylacrolein etc.
Wherein, the R of described ortho position substituted-phenyl nitro alkene (shown in 3)
45-chlorine, 5-bromine, hydrogen etc.
The preparation method of the compounds of this invention comprises: in reaction flask, add aldehyde, ortho position substituted-phenyl nitro alkene, acetic acid rhodium,
molecular sieve, organic solvent, wherein, the add-on of organic solvent is 25-30mL/mmol ortho position substituted-phenyl nitro alkene; Isatin diazonium is dissolved in organic solvent and obtains diazonium solution, wherein, is 25-30mL/mmol for dissolving the amount of the organic solvent of isatin diazonium; At room temperature by peristaltic pump, diazonium solution is added drop-wise to (0.7-1mL/h) in reaction flask, after diazonium solution dropwises, add 20%mol DBU, reaction 2h revolves to boil off to desolventize and obtains thick product, through column chromatography, obtain suc as formula 3 shown in (I) 3-spiral shell (2-tetrahydrofuran (THF)) Oxoindole polynuclear compound.Wherein, isatin diazonium drips 1h, adds alkali reaction 2h, and the reaction times amounts to 3h and gets final product rapid build 3,3-spiral shell (2-tetrahydrofuran (THF)) Oxoindole polycyclic compound.The present invention at ambient temperature, adopts one kettle way, and syntheti c route is short, to be greater than 50% efficient 3,3-spiral shell (2-tetrahydrofuran (THF)) the Oxoindole polycyclic compound that builds of productive rate.
In the preparation method of the compounds of this invention, described organic solvent is methylene dichloride, trichloromethane etc.
The present invention 3, and 3-spiral shell (2-tetrahydrofuran (THF)) Oxoindole compound is by isatin diazonium, aldehyde, and phenyl nitro alkene is in the catalysis of acetic acid rhodium and add that alkali reaction is synthetic to be obtained.In preparation process, by isatin diazonium and aldehyde, under the catalysis of acetic acid rhodium, form carbonyl ylide, occur 1 with the dipolarophile body such as ortho position substituted-phenyl nitro alkene again, 3-Dipolar Cycloaddition, forms 3,3-spiral shell (2-tetrahydrofuran (THF)) Oxoindole structure intermediate 4, add after alkali, by reversal of the Michael addition in molecule, further close ring, and then build the polynuclear compound 5 (reaction mechanism is suc as formula shown in (III)) that comprises 3,3-spiral shell (2-tetrahydrofuran (THF)) Oxoindole.The present invention from the efficient rapid build of raw material simple and easy to get one step 3, the polynuclear compound of 3-spiral shell (2-tetrahydrofuran (THF)) Oxoindole, it is active that biological activity test finds that this compounds has good inhibition to aurora kinases A (AURKA), for oncotherapy provides novel method.
The present invention 3,3-spiral shell (2-tetrahydrofuran (THF)) Oxoindole polynuclear compound, that synthetic method cheap and easy to get by a kind of raw material, syntheti c route is short, simple to operate, free of contamination prepares, with diazonium compound, aldehyde and nitro alkene is synthetic 3,3-spiral shell (2-tetrahydrofuran (THF)) Oxoindole polynuclear compound in the catalysis of acetic acid rhodium and after adding alkali.First by isatin, in diazonium, under the catalysis of Rh (II), form carbonyl ylide with aldehyde effect, the phenyl nitro alkene replacing by ortho position again catches this active intermediate, by [3+2] cycloaddition, obtain 3,3-spiral shell (2-tetrahydrofuran (THF)) Oxoindole intermediate, further closes ring by Michael addition after alkali and constructs the polynuclear compound (reaction mechanism is as shown in above-mentioned formula (III)) suc as formula (I) thereby add.In preparation process, a step has built five chiral carbon simultaneously, and five rings comprise the naked ring of Oxoindole, tetrahydrofuran (THF) also pyranoid ring, synthetic 3,3-spiral shell (2-tetrahydrofuran (THF)) the Oxoindole polynuclear compound of preparation.
In preparation process, the raw material salicylic aldehyde of organic solvent used and preparation ortho position substituted-phenyl nitro alkene, Methyl propiolate and Nitromethane 99Min. (refer to Chem.Eur.J.2011,17,6484-6491), the synthetic (Eur.J.Org.Chem.2012 that refers to of isatin diazonium raw material, 12,2359-2366), methylene dichloride is before use through hydrolith processed, and other organic solvents all make in advance purifying before reaction and during column chromatography or distillation is processed.In preparation process, raw materials used isatin diazonium, aldehyde, ortho position substituted-phenyl nitro alkene and organic solvent are cheap and easy to get, synthetic with low cost, simple and fast is synthetic, adopt one kettle way one step to build the target product of five ring texturees, syntheti c route is short, simple to operate, reaction conditions is gentle, there is Atom economy, highly selective, high yield etc., non-environmental-pollution, meets the requirement of Green Chemistry.
The invention allows for suc as formula 3 shown in (I) application of 3-spiral shell (2-tetrahydrofuran (THF)) Oxoindole polycyclic compound in suppressing aurora kinases A activity.The present invention 3, and 3-spiral shell (2-tetrahydrofuran (THF)) oxoindole derivative and polynary ring compound, belong to natural product intermediate fragments, are conducive to further derivative.Biological activity test finds that the compounds of this invention has and suppresses active AURKA aurora kinases A (AURKA), and then can destroy the cell cycle, stop cell proliferation, cause very eurypalynous apoptosis of tumor cells, this provides novel method for oncotherapy undoubtedly, new medicament screen and pharmaceutical technology is had very important significance simultaneously.
Embodiment
In conjunction with following specific embodiment, the present invention is described in further detail, and protection content of the present invention is not limited to following examples.Do not deviating under the spirit and scope of inventive concept, variation and advantage that those skilled in the art can expect are all included in the present invention, and take appending claims as protection domain.Implement process of the present invention, condition, reagent, experimental technique etc., except the content of mentioning specially below, be universal knowledege and the common practise of this area, the present invention is not particularly limited content.
The present invention proposes new 3,3-spiral shell (2-tetrahydrofuran (THF)) Oxoindole polycyclic compound is to obtain by following preparation method, its reaction scheme is specially: first take in molar ratio aldehyde: aromatic nitro alkene: acetic acid rhodium=1.5:1.0:0.02, by aldehyde, ortho position substituted-phenyl nitro alkene, acetic acid rhodium and organic solvent add in reaction flask, water-retaining agent
molecular sieve 350-500mg/mmol ortho position substituted-phenyl nitro alkene.Wherein, the add-on of organic solvent is 5-10mL/mmol ortho position substituted-phenyl nitro alkene; Then, isatin diazonium is dissolved in organic solvent, isatin diazonium add-on is 1.5mmol/mmol ortho position substituted-phenyl nitro alkene, obtains diazonium solution.Wherein, for dissolving the amount of the organic solvent of diazonium, be 2-5mL/mmol isatin diazonium.Then at room temperature, by peristaltic pump, diazonium solution is added drop-wise in reaction flask, within 1 hour, dropwises, in reaction system, add DBU, add-on is 0.2mmol/mmol ortho position substituted-phenyl nitro alkene, and 40 ℃-50 ℃ revolve to boil off and desolventize, and obtain thick product; By thick product volume ratio, be that ethyl acetate: sherwood oil=1:50～1:10 solution carries out column chromatography, obtain 3,3-spiral shell (2-tetrahydrofuran (THF)) Oxoindole polynuclear compound sterling.
Embodiment 1 prepares the compounds of this invention 5a
Take 5-chloro-phenyl-nitro alkene 3a (0.20mmol), acetic acid rhodium (1.70mg, 0.004mmol), p-bromobenzaldehyde 2a (0.30mmol),
molecular sieve (70mg) is put into small test tube reactor by them, under room temperature condition, adds the 1.0mL methylene dichloride heavily steaming.N-methyl-isatin diazonium 1a (0.30mmol) is dissolved in the methylene dichloride that 0.7mL heavily steams, and within 1 hour, inject reaction system by peristaltic pump, after injection, add DBU (0.04mmol), continue reaction 2h, reaction finishes, and 40 ℃ revolve to boil off and desolventize, again by column chromatography (eluent: sherwood oil: ethyl acetate=1:50～1:20) isolate and obtain 3,3-spiral shell (2-tetrahydrofuran (THF)) Oxoindole polynuclear compound 5a.Yield 80%, d.r. is 91:9.In Table 1.
The present embodiment product 3, the sign of 3-spiral shell (2-tetrahydrofuran (THF)) Oxoindole polycyclic compound 5a:
1H?NMR(400MHz，CDCl
3，25℃，TMS)：δ7.88(d，J=7.3Hz，1H)，7.45(dd，J=12.7，8.1Hz，3H)，7.32-7.15(m，3H)，7.05(dd，J=8.7，2.0Hz，1H)，6.83(t，J=7.9Hz，2H)，6.34(s，1H)，6.17(s，1H)，5.51(d，J=6.5Hz，1H)，4.97(s，1H)，3.65(s，3H)，2.92(s，3H)，2.85-2.60(m，2H)；
13C?NMR(400MHz，CDCl
3，25℃，TMS)：δ=173.97，170.03，144.20，132.93，132.12，131.75，129.54，128.26，127.85，126.65，125.92，125.12，124.19，119.71，108.98，99.16，85.82，84.34，73.36，52.32，50.35，34.99，25.95.
Embodiment 2-16 prepares compound (5b～5p)
Embodiment 2-16 is with embodiment 1.Substituent variation in reaction, compound number, d.r. value, productive rate etc., in Table 1.
Table 1
Product 3, the sign of 3-spiral shell (2-tetrahydrofuran (THF)) Oxoindole polycyclic compound 5b～5p, see following:
5b：
1H?NMR(400MHz，CDCl
3，25℃，TMS)：δ=8.21(d，J=8.2Hz，1H)，8.03(d，J=7.5Hz，1H)，7.47(dd，J=11.9，4.9Hz，1H)，7.42-7.33(m，1H)，7.24(d，J=8.5Hz，1H)，7.18(s，1H)，7.12(dd，J=8.7，2.4Hz，1H)，6.88(d，J=8.7Hz，1H)，6.49(d，J=2.2Hz，1H)，6.27(s，1H)，5.30(dd，J=9.1，2.8Hz，1H)，4.89(s，1H)，3.58(s，3H)，2.77-2.41(m，2H)，2.12(s，3H)；
13C?NMR(400MHz，CDCl
3，25℃，TMS)：δ=175.39，169.56，169.49，150.04，140.25，132.27，132.05，131.94，130.05，128.62，127.89，126.71，126.09，126.06，125.21，124.49，122.18，120.45，117.14，99.15，86.29，85.55，72.23，52.31，51.58，34.29，29.70，25.69.
5c：
1H?NMR(400MHz，CDCl
3，25℃，TMS)：δ=7.93(d，J=7.1Hz，1H)，7.53(t，J=5.5Hz，1H)，7.44-7.19(m，4H)，7.15(dd，J=8.7，2.5Hz，1H)，7.01(d，J=6.6Hz，1H)，6.92(d，J=8.7Hz，1H)，6.71(d，J=7.8Hz，1H)，6.44(d，J=2.2Hz，1H)，6.25(s，1H)，5.72(s，1H)，5.16(s，1H)，4.95(d，J=15.8Hz，1H)，4.43(d，J=15.9Hz，1H)，3.73(d，J=2.9Hz，3H)，2.93(d，J=4.8Hz，2H)；
13C?NMR(400MHz，CDCl
3，25℃，TMS)：δ=174.05，170.24，151.56，143.68，134.65，133.17，132.16，131.78，129.57，129.08，128.43，128.02，127.74，126.88，126.37，126.22，125.06，124.26，124.24，119.85，110.31，99.20，85.73，84.15，73.91，52.38，50.31，43.99，35.31.
5d：
1H?NMR(400MHz，CDCl
3，25℃，TMS)：δ=7.72(dd，J=7.3，2.3Hz，1H)，7.56(d，J=8.4Hz，1H)，7.42-7.21(m，3H)，7.18(dd，J=8.7，2.3Hz，1H)，7.06(ddd，J=22.7，11.3，4.7Hz，2H)，6.95(d，J=8.7Hz，1H)，6.64(dd，J=8.6，4.0Hz，1H)，6.49(d，J=1.9Hz，1H)，6.30(s，1H)，5.63(dd，J=7.6，3.2Hz，1H)，5.09(s，1H)，4.92(d，J=15.8Hz，1H)，4.41(d，J=15.9Hz，1H)，3.73(d，J=8.9Hz，3H)，2.87(d，J=7.6Hz，2H)；
13C?NMR(400MHz，CDCl
3，25℃，TMS)：δ=173.84，170.04，161.11，158.68，151.24，139.57，134.34，132.66，132.23，129.79，129.17，128.27，128.18，128.07，127.99，127.88，126.91，126.15，124.41，120.09，118.26，118.03，113.50，113.25，111.21，111.13，99.12，85.64，84.48，76.74，73.48，52.36，50.34，44.17，35.04，29.71.
5e：
1H?NMR(400MHz，CDCl
3，25℃，TMS)：δ=7.93(dd，J=8.1，5.3Hz，1H)，7.55(d，J=8.2Hz，2H)，7.39-7.22(m，6H)，7.18(dd，J=8.7，1.9Hz，1H)，7.09-6.83(m，4H)，6.51(s，1H)，6.45(d，J=8.5Hz，1H)，6.28(s，1H)，5.62(dd，J=7.6，3.3Hz，1H)，5.10(s，1H)，4.92(d，J=15.8Hz，1H)，4.40(d，J=15.8Hz，1H)，3.72(s，3H)，2.87(d，J=7.6Hz，2H)；
13C?NMR(400MHz，CDCl
3，25℃，TMS)：δ=174.20，170.05，134.10，132.75，132.20，129.75，129.22，128.26，128.21，127.98，126.90，126.76，126.06，124.36，120.07，110.67，110.44，99.36，99.16，99.09，85.29，84.24，73.51，52.34，50.14，44.16，35.06.
5f：
1H?NMR(400MHz，CDCl
3，25℃，TMS)：δ=7.90(d，J=8.0Hz，1H)，7.55(d，J=8.4Hz，1H)，7.37-7.24(m，3H)，7.18(dd，J=8.7，2.3Hz，1H)，6.98(dd，J=27.8，7.8Hz，2H)，6.71(d，J=1.4Hz，1H)，6.52(d，J=1.9Hz，1H)，6.29(s，1H)，5.60(dd，J=7.8，3.0Hz，1H)，5.09(s，1H)，4.90(d，J=15.8Hz，1H)，4.39(d，J=15.9Hz，1H)，3.71(s，3H)，2.84(d，J=8.2Hz，2H)；
13C?NMR(400MHz，CDCl
3，25℃，TMS)：δ=173.94，170.01，151.14，144.89，137.63，134.10，132.64，132.21，129.82，129.24，128.28，128.24，127.98，126.87，126.32，126.08，124.85，124.39，124.20，121.20，120.14，110.87，99.20，85.25，84.38，73.39，52.36，50.10，44.11，34.99.
5g：
1H?NMR(400MHz，CDCl
3，25℃，TMS)：δ=7.71(s，1H)，7.55(d，J=8.3Hz，1H)，7.39-7.13(m，4H)，7.01(d，J=6.9Hz，1H)，6.92(d，J=8.7Hz，1H)，6.60(d，J=8.0Hz，1H)，6.45(d，J=1.6Hz，1H)，6.24(s，1H)，5.72(t，J=5.4Hz，1H)，5.15(s，1H)，4.93(d，J=15.8Hz，1H)，4.42(d，J=15.8Hz，1H)，3.74(s，3H)，2.95(d，J=5.3Hz，1H)，2.45(s，3H)；
13C?NMR(400MHz，CDCl
3，25℃，TMS)：δ=174.01，170.31，151.66，141.24，134.77，134.03，133.25，132.15，132.10，129.50，129.03，128.48，127.97，127.68，126.88，126.27，126.24，125.62，124.24，120.77，119.78，110.13，99.27，85.87，84.09，77.40，77.08，76.77，74.03，52.38，50.32，43.98，35.38，21.26.
5h：
1H?NMR(400MHz，CDCl
3，25℃，TMS)：δ=8.03-7.86(m，1H)，7.53-7.31(m，3H)，7.31-7.19(m，2H)，7.19-7.08(m，1H)，7.09-6.98(m，1H)，6.92(d，J=8.7Hz，1H)，6.72(d，J=7.7Hz，1H)，6.44(d，J=1.9Hz，1H)，6.26(s，1H)，5.79(dd，J=8.4，2.6Hz，1H)，5.21(s，1H)，4.96(d，J=15.8Hz，1H)，4.46(d，J=15.8Hz，1H)，3.75(s，3H)，2.99(dd，J=9.4，5.5Hz，2H)；
13C?NMR(400MHz，CDCl
3，25℃，TMS)：δ=174.18，170.45，151.79，143.68，134.70，134.17，131.68，130.02，129.45，129.05，128.93，127.88，127.70，126.88，126.56，126.23，125.03，124.20，119.75，110.25，99.19，85.68，84.84，74.18，52.35，50.39，43.96，35.41.
5i：
1H?NMR(400MHz，CDCl
3，25℃，TMS)：δ=7.75(d，J=7.3Hz，1H)，7.48(d，J=1.0Hz，1H)，7.35(t，J=7.8Hz，1H)，7.30-7.18(m，5H)，7.13(dd，J=8.7，2.2Hz，1H)，6.99(d，J=6.4Hz，2H)，6.91(d，J=8.7Hz，1H)，6.71(d，J=7.8Hz，1H)，6.56(d，J=3.2Hz，1H)，6.42(dd，J=3.2，1.8Hz，1H)，6.35(d，J=1.8Hz，1H)，6.05(t，J=3.8Hz，2H)，5.17(s，1H)，5.01(d，J=15.8Hz，1H)，4.45(d，J=15.8Hz，1H)，3.81(s，3H)，3.19(d，J=17.0Hz，1H)，2.98(dd，J=17.1，9.4Hz，1H)；
13C?NMR(400MHz，CDCl
3，25℃，TMS)：δ=174.06，170.63，152.19，147.66，144.07，143.57，134.60，131.71，129.28，129.03，127.70，127.52，126.80，126.61，126.20，124.83，124.25，119.35，119.07，111.14，110.96，110.20，95.77，85.60，74.28，52.38，50.17，44.04，35.67.
5j：
1H?NMR(400MHz，CDCl
3，25℃，TMS)：δ=7.89(d，J=6.9Hz，1H)，7.50-6.84(m，8H)，6.71(d，J=7.5Hz，1H)，6.44(d，J=42.7Hz，1H)，5.83(s，1H)，5.20(s，1H)，4.98(d，J=15.8Hz，1H)，4.44(d，J=15.8Hz，1H)，3.76(s，3H)，3.11(s，2H)；
13C?NMR(400MHz，CDCl
3，25℃，TMS)：δ=174.04，170.57，152.03，143.66，136.18，134.64，131.78，129.44，129.06，129.00，127.84，127.72，127.30，127.21，127.17，126.91，126.87，126.31，126.18，125.04，124.29，119.68，110.27，98.39，85.52，81.19，74.35，52.38，50.41，43.99，35.55.
5k：
1H?NMR(400MHz，CDCl
3，25℃，TMS)：δ=7.79(d，J=7.3Hz，1H)，7.57-7.21(m，11H)，7.13(dd，J=8.6，1.8Hz，1H)，7.03(d，J=7.0Hz，2H)，6.98-6.82(m，2H)，6.71(d，J=7.8Hz，1H)，6.36(s，1H)，6.07(dd，J=15.7，7.9Hz，1H)，5.73(dd，J=21.7，8.2Hz，2H)，5.02(d，J=15.0Hz，2H)，4.45(d，J=15.8Hz，1H)，3.74(d，J=18.6Hz，3H)，3.14(dd，J=16.9，9.3Hz，1H)，2.97(d，J=16.5Hz，1H)；
13C?NMR(400MHz，CDCl
3，25℃，TMS)：δ=175.18，171.69，153.25，144.76，139.12，136.42，135.81，132.79，130.43，130.18，130.08，129.84，128.85，128.82，128.35，127.98，127.47，127.20，126.04，125.30，121.98，120.74，111.35，98.97，86.93，84.41，75.40，53.46，51.99，45.11，36.48.
5l：
1H?NMR(400MHz，CDCl
3，25℃，TMS)：δ=7.95(d，J=7.3Hz，1H)，7.63-7.50(m，2H)，7.38(d，J=4.3Hz，2H)，7.34-7.19(m，6H)，7.16(d，J=8.7Hz，1H)，7.02(d，J=7.2Hz，2H)，6.93(d，J=8.7Hz，1H)，6.73(d，J=7.8Hz，1H)，6.44(s，1H)，6.25(s，1H)，5.73(t，J=5.6Hz，1H)，5.16(s，1H)，4.95(d，J=15.8Hz，1H)，4.45(d，J=15.8Hz，1H)，3.75(s，3H)，2.94(d，J=5.6Hz，2H).
13C?NMR(400MHz，CDCl
3，25℃，TMS)：δ=174.00，170.20，151.50，143.67，136.35，134.63，133.12，131.78，130.39，129.85，129.56，129.06，128.02，127.72，126.87，126.30，126.19，125.57，125.13，124.25，122.99，119.84，110.28，99.17，85.75，83.88，73.86，52.36，50.30，43.98，35.31.
5m：
1H?NMR(400MHz，CDCl
3，25℃，TMS)：δ=7.93(d，J=7.3Hz，1H)，7.49-7.33(m，3H)，7.33-7.18(m，5H)，7.14(dd，J=8.7，2.3Hz，1H)，7.03(d，J=7.1Hz，2H)，6.92(dd，J=8.7，2.9Hz，3H)，6.71(d，J=7.8Hz，1H)，6.43(s，1H)，6.21(s，1H)，5.74(s，1H)，5.20(s，1H)，4.97(d，J=15.8Hz，1H)，4.46(d，J=15.8Hz，1H)，3.82(s，3H)，3.76(s，3H)，2.99(d，J=7.6Hz，2H)；
13C?NMR(400MHz，CDCl
3，25℃，TMS)：δ=174.19，170.51，160.82，143.67，134.70，131.62，129.39，129.04，128.20，127.83，127.68，126.86，126.64，126.21，125.99，124.98，124.16，119.71，114.33，110.21，99.01，85.44，84.72，74.24，55.29，52.33，50.35，43.94，35.43.
5n：
1H?NMR(400MHz，CDCl
3，25℃，TMS)：δ=7.76(d，J=7.3Hz，1H)，7.51-6.98(m，14H)，6.98-6.75(m，3H)，6.63(d，J=7.7Hz，1H)，6.27(d，J=5.2Hz，2H)，5.98(d，J=9.1Hz，1H)，5.10(s，1H)，4.93(d，J=15.8Hz，1H)，4.37(d，J=15.8Hz，1H)，3.70(s，3H)，3.09(d，J=16.8Hz，1H)，2.80(dd，J=16.9，9.5Hz，1H)；
13C?NMR(400MHz，CDCl
3，25℃，TMS)：δ=174.22，170.59，152.17，143.71，134.62，131.81，131.60，131.51，129.35，129.04，129.00，128.57，127.70，127.65，126.96，126.80，126.38，126.26，124.84，124.81，124.77，124.26，122.81，122.69，119.52，116.04，115.83，110.29，98.60，85.86，79.32，74.72，52.34，50.09，43.96，35.62，35.58，29.71.
5o：
1H?NMR(400MHz，CDCl
3，25℃，TMS)：δ=7.93(d，J=7.0Hz，1H)，7.55(d，J=8.5Hz，1H)，7.45-7.17(m，5H)，7.03(d，J=7.0Hz，1H)，6.87(d，J=8.7Hz，1H)，6.73(d，J=7.8Hz，1H)，6.58(d，J=1.8Hz，1H)，6.25(s，1H)，5.81-5.61(m，1H)，5.15(s，1H)，4.93(d，J=15.8Hz，1H)，4.48(d，J=15.9Hz，1H)，3.76(d，J=10.2Hz，3H)，2.93(d，J=5.3Hz，2H)；
13C?NMR(400MHz，CDCl
3，25℃，TMS)：δ=174.08，170.21，143.67，134.62，133.14，132.46，132.15，131.75，129.16，129.12，128.40，127.71，126.87，126.36，125.03，124.23，120.21，115.34，110.28，99.12，85.76，84.17，52.35，50.26，44.01，35.30.
5p：
1H?NMR(400MHz，CDCl
3，25℃，TMS)：δ=7.96(d，J=7.3Hz，1H)，7.55(d，J=8.2Hz，1H)，7.47-7.11(m，5H)，6.99(t，J=7.2Hz，2H)，6.74(t，J=6.6Hz，1H)，6.44(d，J=7.7Hz，1H)，6.30(s，1H)，5.70(d，J=8.0Hz，1H)，5.19(s，1H)，4.86(d，J=15.7Hz，1H)，4.42(d，J=15.7Hz，1H)，3.74(s，3H)，2.93(d，J=9.0Hz，2H)；
13C?NMR(400MHz，CDCl
3，25℃，TMS)：δ=174.18，170.40，143.71，134.89，133.34，132.09，131.42，129.37，128.69，128.41，127.70，127.41，126.94，126.53，125.16，124.13，124.01，123.11，118.45，109.94，99.70，85.88，84.25，73.58，52.28，50.61，43.83，35.36.
Embodiment 17 the present invention 3, the inhibition of 3-spiral shell (2-tetrahydrofuran (THF)) Oxoindole polycyclic compound 5a～5p to Aurora A activity
Aurora A is that mitotic division process is essential, AURKA has played the part of important role in mitotic spindle formation and centrosome maturation process, it is necessary that AURKB moves for chromosome segregation and cytoplasm, research shows, suppressing the activity of Aurora A can destroy the cell cycle, stops cell proliferation, causes very eurypalynous apoptosis of tumor cells, simultaneously on the not impact of non-division cells, the specific inhibitor of finding Aurora A provides novel method for oncotherapy.
Experimental technique:
Protocol?id：3
Protocol?name：Aurora?A?activity?assay，HTRF
Instrument: Envision (PerkinElmer, USA).
Material: AURKA, aurora kinase A, aurora kinases A (AURKA), this laboratory utilizes escherichia expression system to express and obtains.Detection kit, HTRF Kinase Assay Kit (Cisbio)
Process: use the HTRF kinase assay test kit of Cisbio company, detection of active.
Sample preparation:
Sample dissolves with DMSO, and cryopreservation, within the concentration of DMSO in final system is controlled at the scope that does not affect detection of active.
Data processing and presentation of results:
Primary dcreening operation is selected under single concentration conditions, and for example 20 μ g/ml, test the activity of sample.For showing active sample under certain condition, for example inhibiting rate %Inhibition is greater than 50, test agents amount dependence, it is IC50/EC50 value, by sample activity, sample concentration is carried out Nonlinear Quasi and obtained, calculating software used is Graphpad Prism4, and the model that matching is used is sigmoidaldose-response (varible slope), for most of inhibitor screening models, matched curve bottom and top are set as to 0 and 100.Generally, each sample all arranges multiple hole (n >=2) in test, in result, with standard deviation (Standard Deviation, SD) or standard error (Standard Error, SE), represents.We think that activated result is all listed as with * and is marked in activity under certain condition.Each test all has the compound of having reported as reference.Reference compound in the present embodiment is staurosporine (Staurosporine), and it is that structure is as follows by the isolated carbazole alkaloid compounds of streptomycete, is a kind of protein kinase C (PKC) inhibitor that can penetrating cytolemma.
The inhibition of reference compound to Aurora A activity, is shown in following table 2.
Table 2
The present invention 3, and the inhibition of 3-spiral shell (2-tetrahydrofuran (THF)) Oxoindole polycyclic compound 5a～5p to Aurora A activity, is shown in following table 3.
Table 3
| ID | Sample number into spectrum | Concentration | Type | Unit | Result | Error | Remarks |
| 1 | 5a | 0.1ug／mL | ％Inhibition | percent | 99.28 | 0.29 | ? |
| 2 | 5b | 0.1ug／mL | ％Inhibition | percent | 90.57 | 0.43 | ? |
| 3 | 5c | 0.1ug／mL | ％Inhibition | percent | 89.90 | 0.54 | ? |
| 4 | 5d | 0.1ug／mL | ％Inhibition | percent | 99.00 | 0.87 | ? |
| 5 | 5e | 0.1ug／mL | ％Inhibition | percent | 99.37 | 1.82 | ? |
| 6 | 5f | 0.1ug／mL | ％Inhibition | percent | 90.03 | 1.01 | ? |
| 7 | 5g | 0.1ug／mL | ％Inhibition | percent | 99.87 | 0.15 | ? |
| 8 | 5h | 0.1ug／mL | ％Inhibition | percent | 99.07 | 0.94 | ? |
| 9 | 5i | 0.1ug／mL | ％Inhibition | percent | 98.99 | 1.32 | ? |
| 10 | 5j | 0.1ug／mL | ％Inhibition | percent | 88.54 | 0.56 | ? |
| 11 | 5k | 0.1ug／mL | ％Inhibition | percent | 54.23 | 0.77 | ? |
| 12 | 5l | 0.1ug／mL | ％Inhibition | Percent | 79.83 | 0.45 | ? |
| 13 | 5m | 0.1ug／mL | ％Inhibition | percent | 98.53 | 0.63 | ? |
| 14 | 5n | 0.1ug／mL | ％Inhibition | percent | 43.19 | 0.32 | ? |
| 15 | 5o | 0.1ug／mL | ％Inhibition | percent | 99.74 | 1.86 | ? |
| 16 | 5p | 0.1ug／mL | ％Inhibition | percent | 100.76 | 1.94 | ? |
Above experimental result shows: contrast with reference compound, the present invention 3,3-spiral shell (2-tetrahydrofuran (THF)) Oxoindole polycyclic compound 5a～5p all shows the good inhibition to Aurora A activity, compound 5a wherein, 5e, 5g, 5o, 5p performance is better, can be used as effective Aurora A inhibitor and is applied to field of medicaments.
Claims (2)
1. one kind suc as formula 3 shown in (I), 3-spiral shell (2-tetrahydrofuran (THF)) Oxoindole polycyclic compound;
Wherein,
R
1for hydrogen, 5-methyl, 5-fluorine, 6-fluorine, or 6-chlorine;
R
2for methyl, ethanoyl, or benzyl;
R
3for phenyl, a bromophenyl, to bromophenyl, p-methoxyphenyl, adjacent fluorophenyl, styryl, 2-thienyl, or 2-furyl;
R
4for 5-chlorine, 5-bromine, or hydrogen.
2. as claimed in claim 13, the application of 3-spiral shell (2-tetrahydrofuran (THF)) Oxoindole polycyclic compound in suppressing Aurora A activity.
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