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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- 230000000694 effects Effects 0.000 claims abstract description 17
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 30
- -1 oxoindole polycyclic compound Chemical class 0.000 claims description 22
- PCKPVGOLPKLUHR-UHFFFAOYSA-N OH-Indolxyl Natural products C1=CC=C2C(O)=CNC2=C1 PCKPVGOLPKLUHR-UHFFFAOYSA-N 0.000 claims description 13
- 102000003989 Aurora kinases Human genes 0.000 claims description 8
- 108090000433 Aurora kinases Proteins 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 3
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 3
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 3
- 125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 claims description 3
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 3
- CVICEEPAFUYBJG-UHFFFAOYSA-N 5-chloro-2,2-difluoro-1,3-benzodioxole Chemical group C1=C(Cl)C=C2OC(F)(F)OC2=C1 CVICEEPAFUYBJG-UHFFFAOYSA-N 0.000 claims description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 125000005504 styryl group Chemical group 0.000 claims description 3
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- 150000002431 hydrogen Chemical class 0.000 claims 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 14
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- 108090000461 Aurora Kinase A Proteins 0.000 abstract description 10
- SVOOVMQUISJERI-UHFFFAOYSA-K rhodium(3+);triacetate Chemical compound [Rh+3].CC([O-])=O.CC([O-])=O.CC([O-])=O SVOOVMQUISJERI-UHFFFAOYSA-K 0.000 abstract description 9
- 238000006555 catalytic reaction Methods 0.000 abstract description 5
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- 150000001299 aldehydes Chemical class 0.000 description 9
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- 238000002868 homogeneous time resolved fluorescence Methods 0.000 description 3
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- 238000012216 screening Methods 0.000 description 2
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- KJPRLNWUNMBNBZ-QPJJXVBHSA-N (E)-cinnamaldehyde Chemical compound O=C\C=C\C1=CC=CC=C1 KJPRLNWUNMBNBZ-QPJJXVBHSA-N 0.000 description 1
- QBCDBWLSKXWSCZ-UHFFFAOYSA-N 2,3-dioxoindole-1-diazonium Chemical compound N1(C(=O)C(=O)C2=CC=CC=C12)[N+]#N QBCDBWLSKXWSCZ-UHFFFAOYSA-N 0.000 description 1
- ZWDVQMVZZYIAHO-UHFFFAOYSA-N 2-fluorobenzaldehyde Chemical compound FC1=CC=CC=C1C=O ZWDVQMVZZYIAHO-UHFFFAOYSA-N 0.000 description 1
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- 102100032306 Aurora kinase B Human genes 0.000 description 1
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 1
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- 102000003923 Protein Kinase C Human genes 0.000 description 1
- 108090000315 Protein Kinase C Proteins 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- 241000187747 Streptomyces Species 0.000 description 1
- 238000010958 [3+2] cycloaddition reaction Methods 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 239000003719 aurora kinase inhibitor Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- HUMNYLRZRPPJDN-KWCOIAHCSA-N benzaldehyde Chemical group O=[11CH]C1=CC=CC=C1 HUMNYLRZRPPJDN-KWCOIAHCSA-N 0.000 description 1
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzenecarboxaldehyde Natural products O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
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- 229940117916 cinnamic aldehyde Drugs 0.000 description 1
- KJPRLNWUNMBNBZ-UHFFFAOYSA-N cinnamic aldehyde Natural products O=CC=CC1=CC=CC=C1 KJPRLNWUNMBNBZ-UHFFFAOYSA-N 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
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- 150000008049 diazo compounds Chemical class 0.000 description 1
- 239000012954 diazonium Substances 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-O diazynium Chemical compound [NH+]#N IJGRMHOSHXDMSA-UHFFFAOYSA-O 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
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- CNUDBTRUORMMPA-UHFFFAOYSA-N formylthiophene Chemical compound O=CC1=CC=CS1 CNUDBTRUORMMPA-UHFFFAOYSA-N 0.000 description 1
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- IMAKHNTVDGLIRY-UHFFFAOYSA-N methyl prop-2-ynoate Chemical compound COC(=O)C#C IMAKHNTVDGLIRY-UHFFFAOYSA-N 0.000 description 1
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- 239000000178 monomer Substances 0.000 description 1
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- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- 125000004095 oxindolyl group Chemical group N1(C(CC2=CC=CC=C12)=O)* 0.000 description 1
- ZRSNZINYAWTAHE-UHFFFAOYSA-N p-methoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C=C1 ZRSNZINYAWTAHE-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
- C07D491/20—Spiro-condensed systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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 the technical field of pharmaceutical synthetic chemistry, and relates to a 3, 3-spiro (2-tetrahydrofuran) oxoindole polycyclic compound and application thereof.
Background
The naked ring skeleton of the oxindole is an important structural monomer and exists in a plurality of natural products and pharmaceutical active intermediates (Angew. chem., int. Ed.2007, 46, 8748-. Among them, the naked ring structure of oxindole and tetrahydrofuran is not only an intermediate fragment of many natural products, but also has excellent biological activity, for example, I a-b below is a progestogen receptor inhibitor, I c is used for treating hypertension, and II a-b is used for treating skin itch and cancer, etc. (PCT int.appl.patent2,000, 066, 167, 2000; u.s.patent4,226, 860A, 1980; pct.appl.patent2,006, 110, 917, 2006).
The 3, 3-spiro (2-tetrahydrofuran) oxindole compound (J.org.chem.2004, 69, 5631-. However, the prior art has the defects of low substrate universality, harsh reaction conditions and the like, so that the new compound with the naked structure of the oxindole and tetrahydrofuran is difficult to obtain.
Disclosure of Invention
The invention provides a novel 3, 3-spiro (2-tetrahydrofuran) oxoindole compound which is shown as a formula (I),
in the formula (I), R1Is hydrogen, 5-methyl; 5-fluoro, 6-chloro, etc., R2Methyl, acetyl, benzyl, etc.; r3Is phenyl, m-bromophenyl, p-methoxyphenyl, o-fluorophenyl, styryl, 2-thienyl, 2-furyl, etc.; r45-chloro, 5-bromo, hydrogen, and the like.
The compound is obtained by the following preparation method, and the reaction formula is shown as the formula (II):
in the formula (II), R1Is hydrogen, 5-methyl; 5-fluoro, 6-chloro, etc., R2Methyl, acetyl, benzyl, etc.; r3Is phenyl, m-bromophenyl, p-methoxyphenyl, o-fluorophenyl, styryl, 2-thienyl, 2-furyl, etc.; r4Is 5-chloro, 5-bromoHydrogen, and the like.
Wherein the mol ratio of the isatin diazo to the aldehyde to the nitroene to the rhodium acetate to the alkali is 1.5: 1.5: 1.0: 0.02: 0.2.
wherein the isatin diazo is 5-methyl isatin diazo, 5-fluoro isatin diazo, 6-chloro isatin diazo, nitro methyl isatin diazo, nitro acetyl isatin diazo, nitro benzyl isatin diazo, etc.
Wherein the aldehyde is benzaldehyde, p-bromobenzaldehyde, m-bromobenzaldehyde, p-methoxybenzaldehyde, o-fluorobenzaldehyde, 2-furaldehyde, 2-thiophenecarbaldehyde, cinnamaldehyde and the like.
Wherein R of the ortho-substituted phenylnitroalkene (shown as the following formula 3)4Is 5-chloro, 5-bromo, hydrogen, etc.
The preparation method of the compound comprises the following steps: adding aldehyde, ortho-substituted phenyl nitroene, rhodium acetate,
Molecular sieve and organic solvent, wherein the addition amount of the organic solvent is 25-30 mL/mmol of ortho-substituted phenylnitroalkene; dissolving isatin diazo in an organic solvent to obtain a diazo solution, wherein the amount of the organic solvent for dissolving the isatin diazo is 25-30 mL/mmol; dropwise adding the diazo solution into a reaction bottle (0.7-1 mL/h) by a peristaltic pump at room temperature, after the dropwise adding of the diazo solution is finished, adding 20% mol of DBU, reacting for 2h, performing rotary evaporation to remove the solvent to obtain a crude product, and performing column chromatography to obtain the 3, 3-spiro (2-tetrahydrofuran) oxoindole polycyclic compound shown in the formula (I). Wherein, the isatin diazo is dripped for 1h, alkali is added for reaction for 2h, and the 3, 3-spiro (2-tetrahydrofuran) oxindole polycyclic compound can be quickly constructed after the reaction time is totally 3 h. The invention adopts a one-pot method at room temperature, and has short preparation routeNamely, the 3, 3-spiro (2-tetrahydrofuran) oxoindole polycyclic compound is efficiently constructed with a yield of more than 50%.
In the preparation method of the compound, the organic solvent is dichloromethane, trichloromethane and the like.
The 3, 3-spiro (2-tetrahydrofuran) oxindole compound is synthesized by the catalysis of isatin diazo, aldehyde and phenyl nitroene in rhodium acetate and the reaction of adding alkali. In the preparation process, isatin diazo and aldehyde form carbonyl ylide under the catalysis of rhodium acetate, then perform 1, 3-dipolar cycloaddition reaction with homophilic bodies such as ortho-substituted phenylnitroene and the like to form a 3, 3-spiro (2-tetrahydrofuran) oxoindole structure intermediate 4, after adding alkali, further close ring through intramolecular Michael addition reaction, and further construct a polycyclic compound 5 containing 3, 3-spiro (2-tetrahydrofuran) oxoindole (the reaction process is shown as formula (III)). The invention efficiently and quickly constructs the polycyclic compound of the 3, 3-spiro (2-tetrahydrofuran) oxoindole from simple and easily obtained raw materials by one step, and biological activity tests show that the compound has good inhibitory activity on aurora kinase A (AURKA), thereby providing a new method for treating tumors.
The 3, 3-spiro (2-tetrahydrofuran) oxindole polycyclic compound is prepared by a synthesis method which has the advantages of cheap and easily obtained raw materials, short preparation route, simple operation and no pollution, and is synthesized by diazo compounds, aldehyde and nitroene under the catalysis of rhodium acetate and after addition of alkali. Firstly, isatin reacts with aldehyde under the catalysis of Rh (II) to form carbonyl ylide, then ortho-substituted phenylnitroene is used for capturing the active intermediate, a 3, 3-spiro (2-tetrahydrofuran) oxoindole intermediate is obtained through [ 3+2 ] cycloaddition, and after alkali is added, the ring is further closed through Michael addition, so that the polycyclic compound shown in the formula (I) is constructed (the reaction process is shown in the formula (III)). Five chiral carbons and five rings including an oxindole ring and a tetrahydrofuran benzopyran ring are simultaneously constructed in one step in the preparation process, and the 3, 3-spiro (2-tetrahydrofuran) oxindole polycyclic compound is prepared and synthesized.
In the preparation process, the used organic solvent and raw materials of salicylaldehyde, methyl propiolate and nitromethane for preparing ortho-substituted phenylnitroene (please refer to chem.eur.j.2011, 17, 6484-. In the preparation process, the raw materials of isatin diazo, aldehyde, ortho-substituted phenyl nitroene and organic solvent are cheap and easy to obtain, the synthesis cost is low, the synthesis is simple and rapid, the five target products with the annular structures are constructed in one step by adopting a one-pot method, the preparation route is short, the operation is simple, the reaction condition is mild, the atom economy, the high selectivity, the high yield and the like are realized, the environment pollution is avoided, and the requirements of green chemistry are met.
The invention also provides application of the 3, 3-spiro (2-tetrahydrofuran) oxindole polycyclic compound shown as the formula (I) in inhibiting the activity of aurora kinase A. The 3, 3-spiro (2-tetrahydrofuran) oxoindole derivative and the multi-element cyclic compound belong to intermediate fragments of natural products and are beneficial to further derivation. Biological activity tests show that the compound has inhibitory activity on AURKA aurora kinase A (AURKA), further destroys cell cycle, prevents cell proliferation and causes apoptosis of many types of tumor cells, undoubtedly provides a new method for tumor treatment, and has very important significance on new drug screening and pharmaceutical technology.
Detailed Description
The present invention will be described in further detail with reference to the following specific examples, but the present invention is not limited to the following examples. Variations and advantages that may occur to those skilled in the art may be incorporated into the invention without departing from the spirit and scope of the inventive concept, and the scope of the appended claims is intended to be protected. The procedures, conditions, reagents, experimental methods and the like for carrying out the present invention are general knowledge and common general knowledge in the art except for the contents specifically mentioned below, and the present invention is not particularly limited.
The novel 3, 3-spiro (2-tetrahydrofuran) oxoindole polycyclic compound provided by the invention is obtained by the following preparation method, and the reaction route is as follows: firstly, weighing aldehyde according to a molar ratio: aryl nitroenes: rhodium acetate = 1.5: 1.0: 0.02, adding aldehyde, ortho-substituted phenyl nitroene, rhodium acetate and organic solvent into a reaction bottle to obtain the water absorbentMolecular sieve 350-500 mg/mmol of ortho-substituted phenylnitroalkene. Wherein the addition amount of the organic solvent is 5-10 mL/mmol of ortho-substituted phenyl nitroene; next, isatin diazo was dissolved in an organic solvent in an amount of 1.5 mmol/mmol of ortho-substituted phenylnitroalkene to obtain a diazo solution. Wherein the amount of the organic solvent for dissolving the diazonium is 2-5 mL/mmol of isatin diazonium. Then at room temperature, dropwise adding a diazo solution into a reaction bottle through a peristaltic pump, after dropwise adding for 1 hour, adding DBU into the reaction system, wherein the addition amount is 0.2 mmol/mmol of ortho-substituted phenylnitroene, and removing the solvent through rotary evaporation at 40-50 ℃ to obtain a crude product; the crude product is prepared by mixing ethyl acetate: petroleum ether = 1: 50-1: performing column chromatography on the 10 solution to obtain a pure product of the 3, 3-spiro (2-tetrahydrofuran) oxoindole polycyclic compound.
EXAMPLE 1 preparation of Compound 5a of the present invention
5-chlorophenyl nitroene 3a (0.20mmol), rhodium acetate (1.70mg, 0.004mmol), p-bromobenzaldehyde 2a (0.30mmol) were weighed,
molecular sieves (70mg) they were placed in a small tube reactor and a redistilled 1.0mL of dichloromethane was added at room temperature. N-methylisatoic diazo 1a (0.30mmol) is dissolved in 0.7mL of redistilled dichloromethane and injected into the reaction system by a peristaltic pump for 1 hour, after the injection is finished, DBU (0.04mmol) is added, the reaction is continued for 2 hours, after the reaction is finished, the solvent is removed by rotary evaporation at 40 ℃, and then column chromatography (eluent: petroleum ether: ethyl acetate = 1: 50-1: 20) the 3, 3-spiro (2-tetrahydrofuran) oxoindole polycyclic compound 5a is separated. Yield 80%, d.r. 91: 9. see table 1.
Characterization of the product 3, 3-spiro (2-tetrahydrofuran) oxoindole polycyclic compound 5a of this example:
1H NMR(400MHz，CDCl3，25℃，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，CDCl3，25℃，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.
examples 2 to 16 preparation of Compounds (5b to 5p)
Examples 2-16 are the same as example 1. The change of the substituents in the reaction, the compound numbers, the d.r. values, the yields, etc., are shown in Table 1.
TABLE 1
Characterization of the products, 3-spiro (2-tetrahydrofuran) oxoindole polycyclic compounds 5 b-5 p, is as follows:
5b：
1H NMR(400MHz，CDCl3，25℃，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，CDCl3，25℃，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，CDCl3，25℃，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，CDCl3，25℃，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，CDCl3，25℃，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，CDCl3，25℃，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，CDCl3，25℃，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，CDCl3，25℃，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，CDCl3，25℃，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，CDCl3，25℃，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，CDCl3，25℃，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，CDCl3，25℃，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，CDCl3，25℃，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，CDCl3，25℃，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，CDCl3，25℃，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，CDCl3，25℃，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，CDCl3，25℃，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，CDCl3，25℃，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，CDCl3，25℃，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，CDCl3，25℃，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，CDCl3，25℃，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，CDCl3，25℃，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，CDCl3，25℃，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，CDCl3，25℃，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，CDCl3，25℃，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，CDCl3，25℃，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，CDCl3，25℃，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，CDCl3，25℃，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，CDCl3，25℃，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，CDCl3，25℃，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.
EXAMPLE 17 inhibition of Aurora kinase Activity by 3, 3-Spiro (2-tetrahydrofuran) oxindole polycyclic Compounds 5 a-5 p of the present invention
Aurora kinase is necessary for mitosis, AURKA plays an important role in mitotic spindle formation and centrosome maturation, AURKB is necessary for chromosome segregation and cytoplasm migration, studies show that inhibition of Aurora kinase activity destroys cell cycle, prevents cell proliferation, causes apoptosis of many types of tumor cells, and has no influence on non-dividing cells, and search for specific inhibitors of Aurora kinase provides a new approach for tumor therapy.
The experimental method comprises the following steps:
Protocol id：3
Protocol name：Aurora A activity assay，HTRF
the instrument comprises the following steps: envision (PerkinElmer, USA).
Materials: AURKA, aurora kinase A (AURKA), which is obtained by expression in an escherichia coli expression system in the laboratory. Detection Kit, HTRF Kinase Assay Kit (Cisbio)
The process is as follows: the activity was measured using the HTRF kinase assay kit from Cisbio.
Sample treatment:
the samples were dissolved in DMSO and stored at low temperature, and the concentration of DMSO in the final system was controlled within a range that did not affect the detection activity.
Data processing and results description:
the activity of the sample is tested under a single concentration condition, e.g., 20. mu.g/ml, for primary screening. For samples that exhibit activity under certain conditions, e.g., an Inhibition% Inhibition of greater than 50, the activity dose dependence relationship, i.e., IC 50/EC 50 values, were tested by nonlinear fitting of sample activity to sample concentration, the software used for the calculation was Graphpad Prism4, the model used for the fitting was sigmoidal dose-response (variable slope), and for most inhibitor screening models, the bottom and top of the fitted curve were set at 0 and 100. In general, each sample was tested with multiple wells (n.gtoreq.2) and the results were expressed as Standard Deviation (SD) or Standard Error (SE). The results of activity under certain conditions are indicated by the activity column. The reported compounds were used as a reference for each test. The reference compound in this example is Staurosporine (Staurosporine), which is a carbazole alkaloid compound isolated from streptomyces, and has the following structure, and is a protein kinase c (pkc) inhibitor that can permeate cell membranes.
Reference compounds inhibit Aurora kinase activity, see table 2 below.
TABLE 2
The 3, 3-spiro (2-tetrahydrofuran) oxindole polycyclic compounds 5 a-5 p of the present invention inhibit Aurora kinase activity, as shown in table 3 below.
TABLE 3
| ID | Sample numbering | Concentration of | Type (B) | Unit of | Results | Error of the measurement | Remarks for note |
| 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 |
The above experimental results show that: compared with a reference compound, the 3, 3-spiro (2-tetrahydrofuran) oxindole polycyclic compounds 5a to 5p all show good inhibition on Aurora kinase activity, wherein the compounds 5a, 5e, 5g, 5o and 5p show better performance and can be used as effective Aurora kinase inhibitors in the field of medicine.
Claims (2)
1. A 3, 3-spiro (2-tetrahydrofuran) oxoindole polycyclic compound shown as a formula (I);
wherein,
R1is hydrogen, 5-methyl, 5-fluoro, 6-fluoro, or 6-chloro;
R2is methyl, acetyl, or benzyl;
R3is phenyl, m-bromophenyl, p-methoxyphenyl, o-fluorophenyl, styryl, 2-thienyl, or 2-furyl;
R4is 5-chloro, 5-bromo, or hydrogen.
2. Use of a 3, 3-spiro (2-tetrahydrofuran) oxindole polycyclic compound according to claim 1 for inhibiting Aurora kinase activity.
Priority Applications (1)
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| CN106565731A (en) * | 2016-11-01 | 2017-04-19 | 浙江师范大学 | Double-spiro isatin furan derivatives with antibacterial activity as well as synthesis method and application thereof |
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