CN103626747A - N-(2, 3-dihydrobenzofuran-5-yl) benzopyran-4-amide and preparation method and application thereof - Google Patents
N-(2, 3-dihydrobenzofuran-5-yl) benzopyran-4-amide and preparation method and application thereof Download PDFInfo
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- CN103626747A CN103626747A CN201310498701.8A CN201310498701A CN103626747A CN 103626747 A CN103626747 A CN 103626747A CN 201310498701 A CN201310498701 A CN 201310498701A CN 103626747 A CN103626747 A CN 103626747A
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- dihydrobenzofuranes
- acid amides
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- 0 C*c1c2OC(C)(C)Cc2cc(*=CCCC(C2c3cc(**)c(*)c(**)*3OCC2)=O)c1 Chemical compound C*c1c2OC(C)(C)Cc2cc(*=CCCC(C2c3cc(**)c(*)c(**)*3OCC2)=O)c1 0.000 description 5
- BZZZBCGGSMADJV-UHFFFAOYSA-N C=[O]c(cc1)cc(OCCC2Br)c1C2=O Chemical compound C=[O]c(cc1)cc(OCCC2Br)c1C2=O BZZZBCGGSMADJV-UHFFFAOYSA-N 0.000 description 1
- KDNRHEMLULAYEA-UHFFFAOYSA-N CC(CCOc1c(C)cccc1C=O)Br Chemical compound CC(CCOc1c(C)cccc1C=O)Br KDNRHEMLULAYEA-UHFFFAOYSA-N 0.000 description 1
- OUJBKYIRXHBPRL-UHFFFAOYSA-N COc1c2OCCC(C(O)=O)c2ccc1 Chemical compound COc1c2OCCC(C(O)=O)c2ccc1 OUJBKYIRXHBPRL-UHFFFAOYSA-N 0.000 description 1
- QDASTOAATNRTDG-UHFFFAOYSA-N Cc(cc1OCCC2)ccc1C2=O Chemical compound Cc(cc1OCCC2)ccc1C2=O QDASTOAATNRTDG-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
The invention relates to N-(2, 3-dihydrobenzofuran-5-yl) benzopyran-4-amide shown in a chemical structural formula I, wherein X1-X1 is selected from H, C1-C2 alkyls, C3-C4 straight chain alkyls or branched alkyls, C1-C2 alkoxys, C3-C4 straight chain alkoxys or branched alkoxys, fluorine, chlorine, bromine or iodine; and the invention also provides an application of the N-(2, 3-dihydrobenzofuran-5-yl) benzopyran-4-amide in preparation of anti-cervical cancer drugs.
Description
Technical field
The present invention relates to the preparation and application of new compound, specifically the application of cancer therapy drug is prepared in N-(2,3-Dihydrobenzofuranes-5-yl) chromene-4-acid amides and preparation method thereof and conduct.
Background technology
Tubatoxin is the broad-spectrum natural flavonoids of a class, and Mammals is had to lower toxicity, and Recent study shows, tubatoxin all has good restraining effect to mammary cancer and liver cancer cell, its IC
50value is in 0.008～0.010 μ g/mL[J.Natural Products, 2005,69 (3): 397-399], be applicable to take it as primer exploitation low toxicity, efficient antitumor drug.Tubatoxin molecule is mainly comprised of chromene and cumarone building stone, and chromene and benzofuran derivative are the important heterocyclic compounds of two classes.
2009, [the J.Natural Products of Yu Dequan seminar, 2009,72 (5): 966-968] from the limb skin of hair mulberry, separation obtains two kinds of compounds 4 and 5 with anti-tumor activity, 4 couples of A549 of compound are found in research, Bel7402, it is active that tetra-kinds of tumor cell lines of BGC-823 and HCT-8 have nonselective inhibition; Compound 5 optionally suppresses A2780, the propagation of Bel7402 and HCT-8 cell strain.
2009, Nguyen etc. [Bioorganic & Medicinal Chemistry Letters, 2009,19 (23): 6745-6749] separation from the stem skin of E.abyssinica obtained compound 6; 6 couples of MCF7 of compound, MCF/TAMR, tetra-kinds of breast cancer cells of MCF/ADR and MDA-MB-231 all have growth-inhibiting effect, its IC
50value is 12.0～28.0 μ mol/L.Atta etc. [European J Medicinal Chemistry, 2010,45 (11): 4920-4927] have described the synthetic of a series of compounds containing cumarone and benzopyrone structure; Bioactivity research shows that this compounds all has good cytotoxicity to human breast cancer cell MCF-7; Wherein compound 7 activity are higher.
Zhou Zhongzhen etc. described the synthetic and desinsection of 2,3a-dihydro-chromene [4,3-c] pyrazoles-3-ketones derivant and fungicidal activity (organic chemistry, 2009,29:1774).China's invention granted patent has been described the preparation and application of tubatoxin derivative and analogue thereof; The structure of its relevant Chinese invention patent and compound thereof is as follows:
Summary of the invention
The object of the present invention is to provide the N-shown in chemical structural formula I (2,3-Dihydrobenzofuranes-5-yl) chromene-4-acid amides:
Wherein, X
1be selected from: H, C
1～C
2alkyl, C
3～C
4straight chained alkyl or branched-chain alkyl, C
1～C
2alkoxyl group, C
3～C
4straight chain alkoxyl group or branched alkoxy, fluorine, chlorine, bromine or iodine; X
2be selected from: H, C
1～C
2alkyl, C
3～C
4straight chained alkyl or branched-chain alkyl, C
1～C
2alkoxyl group, C
3～C
4straight chain alkoxyl group or branched alkoxy; X
3be selected from: H, C
1～C
2alkyl, C
3～C
4straight chained alkyl or branched-chain alkyl, C
1～C
2alkoxyl group, C
3～C
4straight chain alkoxyl group or branched alkoxy; X
4be selected from: H, C
1～C
2alkoxyl group, C
3～C
4straight chain alkoxyl group or branched alkoxy, fluorine, chlorine, bromine or iodine; X
1x
2be selected from :-CH=CH-CH=CH-; X
2x
3be selected from :-CH=CH-CH=CH-.
The present invention also provides N-(2, 3-Dihydrobenzofuranes-5-yl) chromene-4-acid amides is selected from N-(2, 2-dimethyl-7-methoxyl group-2, 3-Dihydrobenzofuranes-5-yl) chromene-4-acid amides, N-(2, 2-dimethyl-7-methoxyl group-2, 3-Dihydrobenzofuranes-5-yl)-8-methyl chromene-4-acid amides, N-(2, 2-dimethyl-7-methoxyl group-2, 3-Dihydrobenzofuranes-5-yl)-7-methyl chromene-4-acid amides, N-(2, 2-dimethyl-7-methoxyl group-2, 3-Dihydrobenzofuranes-5-yl)-6-methyl chromene-4-acid amides, N-(2, 2-dimethyl-7-methoxyl group-2, 3-Dihydrobenzofuranes-5-yl)-8-methoxyl group benzo pyrans-4-acid amides, N-(2, 2-dimethyl-7-methoxyl group-2, 3-Dihydrobenzofuranes-5-yl)-7-methoxyl group benzo pyrans-4-acid amides, N-(2, 2-dimethyl-7-methoxyl group-2, 3-Dihydrobenzofuranes-5-yl)-6-methoxyl group benzo pyrans-4-acid amides, N-(2, 2-dimethyl-7-methoxyl group-2, 3-Dihydrobenzofuranes-5-yl)-6-chlorine chromene-4-acid amides, N-(2, 2-dimethyl-7-methoxyl group-2, 3-Dihydrobenzofuranes-5-yl) benzo [h] chromene-4-acid amides or N-(2, 2-dimethyl-7-methoxyl group-2, 3-Dihydrobenzofuranes-5-yl) benzo [g] chromene-4-acid amides.
The present invention also provides N-(2, the 3-Dihydrobenzofuranes-5-yl) preparation method of chromene-4-acid amides, it is characterized in that the preparation method of N-(2,3-Dihydrobenzofuranes-5-yl) chromene-4-acid amides is as follows:
Wherein, X
1be selected from: H, C
1～C
2alkyl, C
3～C
4straight chained alkyl or branched-chain alkyl, C
1～C
2alkoxyl group, C
3～C
4straight chain alkoxyl group or branched alkoxy, fluorine, chlorine, bromine or iodine; X
2be selected from: H, C
1～C
2alkyl, C
3～C
4straight chained alkyl or branched-chain alkyl, C
1～C
2alkoxyl group, C
3～C
4straight chain alkoxyl group or branched alkoxy; X
3be selected from: H, C
1～C
2alkyl, C
3～C
4straight chained alkyl or branched-chain alkyl, C
1～C
2alkoxyl group, C
3～C
4straight chain alkoxyl group or branched alkoxy; X
4be selected from: H, C
1～C
2alkoxyl group, C
3～C
4straight chain alkoxyl group or branched alkoxy, fluorine, chlorine, bromine or iodine; X
1x
2be selected from :-CH=CH-CH=CH-; X
2x
3be selected from :-CH=CH-CH=CH-.
The object of the present invention is to provide the application of the N-shown in chemical structural formula I (2,3-Dihydrobenzofuranes-5-yl) chromene-4-acid amides in the anti-human cervical cancer medicine of preparation:
Wherein, X
1be selected from: H, C
1～C
2alkyl, C
3～C
4straight chained alkyl or branched-chain alkyl, C
1～C
2alkoxyl group, C
3～C
4straight chain alkoxyl group or branched alkoxy, fluorine, chlorine, bromine or iodine; X
2be selected from: H, C
1～C
2alkyl, C
3～C
4straight chained alkyl or branched-chain alkyl, C
1～C
2alkoxyl group, C
3～C
4straight chain alkoxyl group or branched alkoxy; X
3be selected from: H, C
1～C
2alkyl, C
3～C
4straight chained alkyl or branched-chain alkyl, C
1～C
2alkoxyl group, C
3～C
4straight chain alkoxyl group or branched alkoxy; X
4be selected from: H, C
1～C
2alkoxyl group, C
3～C
4straight chain alkoxyl group or branched alkoxy, fluorine, chlorine, bromine or iodine; X
1x
2be selected from :-CH=CH-CH=CH-; X
2x
3be selected from :-CH=CH-CH=CH-.
The present invention compared with prior art tool has the following advantages:
The present invention designs first and has prepared N-(2,3-Dihydrobenzofuranes-5-yl) chromene-4-acid amides, and it is active that it has higher anti-human cervical cancer.
Embodiment
Following examples are intended to illustrate the present invention rather than limitation of the invention further.
Embodiment 1
4-is bromo-3,4-dihydrobenzo [b] oxa-
the preparation of-5 (2H)-one (17a)
13.00g compound 16a, 100mL ethanol, reflux, and adds 35.70g cupric bromide in 30min in batches, continue reaction 30min, TLC monitoring reacts completely, and suction filtration, is spin-dried for, use 100mL acetic acid ethyl dissolution, 20mL10% hcl acidifying, adds 200mL frozen water, and suction filtration is removed bromize alpha ketone, filtrate is standing, the saturated NaHCO of 100mL for ethyl acetate layer
3washing, washing, anhydrous sodium sulfate drying, filters, and is spin-dried for, and short column is purified and is obtained the faint yellow oily mater 17a of 18.10g, yield 88.0%;
1h NMR (CDCl
3, 400MHz) δ: 2.47～2.54 (m, 1H, 3-H), 2.90～2.99 (m, 1H, 3-H), 4.11～4.18 (m, 1H, 2-H), 4.42～4.48 (m, 1H, 2-H), 4.99 (t, J=8.4Hz, 1H, 4-H), 7.07 (d, J=8.0Hz, 1H, 9-H), 7.12 (t, J=8.0Hz, 1H, 7-H), 7.46 (t, J=8.0Hz, 1H, 8-H), 7.76 (d, J=8.0Hz, 1H, 6-H).
Embodiment 2
9-methyl-4-is bromo-3,4-dihydrobenzo [b] oxa-
the preparation of-5 (2H)-one (17b)
Press embodiment 1 working method, 5.30g compound 16b reacts 0.8h with 13.50g cupric bromide, obtains faint yellow oily mater 17b, yield 95.8%;
1h NMR (CDCl
3, 400MHz) δ: 2.29 (s, 3H, 9-CH
3), 2.45～2.53 (m, 1H, 3-H), 2.87～3.01 (m, 1H, 3-H), 4.07～4.14 (m, 1H, 2-H), 4.46～4.53 (m, 1H, 2-H), 4.99 (t, J=8.4Hz, 1H, 4-H), 7.01 (t, J=8.0Hz, 1H, 7-H), 7.33 (d, J=8.0Hz, 1H, 6-H), 7.59 (d, J=8.0Hz, 1H, 8-H).
Embodiment 3
8-methyl-4-is bromo-3,4-dihydrobenzo [b] oxa-
the preparation of-5 (2H)-one (17c)
Press embodiment 1 working method, 6.90g compound 16c reacts 1.2h with 17.50g cupric bromide, obtains faint yellow oily mater 17c, yield 95.0%;
1h NMR (CDCl
3, 400MHz) δ: 2.36 (s, 3H, 8-CH
3), 2.45～2.53 (m, 1H, 3-H), 2.88～2.97 (m, 1H, 3-H), 4.09～4.16 (m, 1H, 2-H), 4.39～4.45 (m, 1H, 2-H), 4.97 (t, J=8.4Hz, 1H, 4-H), 6.68 (s, 1H, 9-H), 6.93 (d, J=8.0Hz, 1H, 7-H), 7.67 (d, J=8.0Hz, 1H, 6-H).
Embodiment 4
7-methyl-4-is bromo-3,4-dihydrobenzo [b] oxa-
the preparation of-5 (2H)-one (17d)
Press embodiment 1 working method, 5.30g compound 16d reacts 1.0h with 13.40g cupric bromide, obtains white solid 17d, yield 67.4%, m.p.80～82 ℃;
1h NMR (CDCl
3, 400MHz) δ: 2.33 (s, 3H, 7-CH
3), 2.43～2.52 (m, 1H, 3-H), 2.87～2.96 (m, 1H, 3-H), 4.08～4.15 (m, 1H, 2-H), 4.39～4.45 (m, 1H, 2-H), 4.98 (t, J=7.6Hz, 1H, 4-H), 6.97 (d, J=8.4Hz, 1H, 9-H), 7.26 (dd, J=2.0,8.4Hz, 1H, 8-H), 7.55 (d, J=2.0Hz, 1H, 6-H).
Embodiment 5
9-methoxyl group-4-is bromo-3,4-dihydrobenzo [b] oxa-
the preparation of-5 (2H)-one (17e)
Press embodiment 1 working method, 1.90g compound 16e reacts 0.6h with 4.50g cupric bromide, obtains white solid 17e, yield 76.0%, m.p.83～85 ℃;
1h NMR (CDCl
3, 400MHz) δ: 2.47～2.55 (m, 1H, 3-H), 2.92～3.02 (m, 1H, 3-H), 3.91 (s, 3H, 9-OCH
3), 4.13～4.20 (m, 1H, 2-H), 4.53～4.59 (m, 1H, 2-H), 4.99 (t, J=8.0Hz, 1H, 4-H), 7.05～7.07 (m, 1H, 6-H, 8-H), 7.31～7.34 (m, 1H, 7-H).
Embodiment 6
8-methoxyl group-4-is bromo-3,4-dihydrobenzo [b] oxa-
the preparation of-5 (2H)-one (17f)
Press embodiment 1 working method, 5.80g compound 16f reacts 1.0h with 13.40g cupric bromide, obtains faint yellow oily matter 17f, yield 94.4%;
1h NMR (CDCl
3, 400MHz) δ: 2.46～2.54 (m, 1H, 3-H), 2.87～2.97 (m, 1H, 3-H), 3.84 (s, 3H, 8-OCH
3), 4.12～4.19 (m, 1H, 2-H), 4.40～4.46 (m, 1H, 2-H), 4.97 (t, J=8.0Hz, 1H, 4-H), 6.55 (d, J=2.4Hz, 1H, 9-H), 6.68 (dd, J=2.4,8.8Hz, 1H, 7-H), 7.76 (d, J=8.8Hz, 1H, 6-H).
Embodiment 7
7-methoxyl group-4-is bromo-3,4-dihydrobenzo [b] oxa-
the preparation of-5 (2H)-one (17g)
Press embodiment 1 working method, 3.80g compound 16g reacts 0.7h with 8.90g cupric bromide, obtains faint yellow oily matter 17g, yield 96.7%;
1h NMR (CDCl
3, 400MHz) δ: 2.42～2.50 (m, 1H, 3-H), 2.85～2.94 (m, 1H, 3-H), 3.81 (s, 3H, 7-OCH
3), 4.05～4.12 (m, 1H, 2-H), 4.38～4.44 (m, 1H, 2-H), 4.99 (t, J=7.6Hz, 1H, 4-H), 6.98～7.04 (m, 2H, 8-H, 9-H), 7.22 (d, J=2.8Hz, 1H, 6-H).
Embodiment 8
The chloro-4-of 7-is bromo-3,4-dihydrobenzo [b] oxa-
the preparation of-5 (2H)-one (17h)
Press embodiment 1 working method, 3.90g compound 16h reacts 1.0h with 8.90g cupric bromide, obtains faint yellow oily matter 17h, yield 88.0%.
1H?NMR(CDCl
3，400MHz)δ：2.47～2.55(m，1H，3-H)，2.88～2.97(m，1H，3-H)，4.11～4.21(m，1H，2-H)，4.40～4.46(m，1H，2-H)，4.95(t，J=6.4Hz，1H，4-H)，7.03(d，J=8.8Hz，1H，9-H)，9.39(dd，J=2.8，8.8Hz，1H，8-H)，7.11(d，J=2.8Hz，1H，6-H)。
Embodiment 9
4-is bromo-3,4-dihydro-naphtho [1,2-b] oxa-
the preparation of-5 (2H)-one (17i)
Press embodiment 1 working method, 4.20g compound 16i reacts 0.8h with 8.90g cupric bromide, obtains white solid 17i, yield 85.3%, m.p.122～124 ℃ (document [125] value: 106 ℃);
1h NMR (CDCl
3, 400MHz) δ: 2.60～2.67 (m, 1H, 3-H), 3.06～3.12 (m, 1H, 3-H), 4.29～4.36 (m, 1H, 2-H), 4.67～4.73 (m, 1H, 2-H), 5.10 (t, J=8.4Hz, 1H, 4-H), 7.51～7.57 (m, 2H, 7-H, 9-H), 7.61 (dt, J=1.2,8.4Hz, 1H, 10-H), 7.77 (d, J=8.4Hz, 1H, 6-H), 7.81 (d, J=8.4Hz, 1H, 8-H), 8.36 (d, J=8.4Hz, 1H, 11-H).
Embodiment 10
4-is bromo-3,4-dihydro-naphtho [2,3-b] oxa-
the preparation of-5 (2H)-one (17j)
Press embodiment 1 working method, 4.20g compound 16j reacts 0.7h with 8.90g cupric bromide, obtains white solid 17j, yield 75.5%, m.p.109～111 ℃;
1h NMR (CDCl
3, 400MHz) δ: 2.45～2.53 (m, 1H, 3-H), 2.86～2.96 (m, 1H, 3-H), 4.22～4.29 (m, 1H, 2-H), 4.46～4.52 (m, 1H, 2-H), 5.07 (t, J=8.0Hz, 1H, 4-H), 7.44 (t, J=8.4Hz, 1H, 8-H), 7.48 (s, 1H, 11-H), 7.55 (t, J=8.4Hz, 1H, 9-H), 7.75 (d, J=8.4Hz, 1H, 10-H), 7.90 (d, J=8.4Hz, 1H, 7-H), 8.34 (s, 1H, 6-H).
Embodiment 11
The preparation of chroman-4-carboxylic acid (19a)
16.90g compound 17a, 23.10g1,2-propylene glycol, 1.50g tosic acid, 100mL toluene, return stirring 8.0h, it is complete that TLC follows the tracks of ketal reaction, obtains compound 18a, when ketal reaction liquid is cooled to 80～90 ℃, add 1.60g zinc oxide, heating distributes part toluene, makes a bottle interior temperature be increased to 126～130 ℃, insulation reaction 4.0h, it is complete that TLC follows the tracks of rearrangement reaction, suction filtration, toluene is removed in underpressure distillation, obtains incarnadine oily mater.Then add 60mL30% aqueous sodium hydroxide solution, 80mL methanol solution, back flow reaction 4.0h, TLC monitoring reacts completely, in reaction solution, add 100mL cold water, suction filtration, filtrate is used 50mL washed with dichloromethane, water layer is adjusted pH2 with dilute hydrochloric acid, the extraction of 100mL ethyl acetate, anhydrous sodium sulfate drying, is spin-dried for to obtain solid 11.2g, yield 83.9%, m.p.93～95 ℃;
1hNMR (CDCl
3, 400MHz) δ: 2.12～2.18 (m, 1H, 3-H), 2.30～2.35 (m, 1H, 3-H), 3.81 (t, J=4.8Hz, 1H, 4-H), 4.24～4.27 (m, 2H, 2-H), 6.85 (d, J=8.4Hz, 1H, 8-H), 6.89 (t, J=7.6Hz, 1H, 6-H), 7.17 (t, J=8.4Hz, 1H, 7-H), 7.27 (d, J=7.6Hz, 1H, 5-H).
Embodiment 12
The preparation of 8-methyl chroman-4-carboxylic acid (19b)
Press embodiment 11 working method, 5.10g compound 17b and 5.00g1,2-propylene glycol and 0.50g tosic acid reaction 8.0h, obtain compound 18b, adds 1.00g zinc oxide, and reaction 2.0h, obtains incarnadine oily mater.Then add the 30mL30%NaOH aqueous solution, 40mL methanol solution reaction 4.0h, obtains compound 19b, yield 83.2%, m.p.103～104 ℃;
1h NMR (CDCl
3, 400MHz) δ: 2.09～2.17 (m, 1H, 3-H), 2.18 (s, 3H, CH
3), 2.28～2.34 (m, 1H, 3-H), 3.81 (t, J=6.0Hz, 1H, 4-H), 4.26～4.29 (m, 2H, 2-H), 6.79 (t, J=7.2Hz, 1H, 6-H), 7.04 (d, J=7.6Hz, 1H, 7-H), 7.11 (d, J=7.6Hz, 1H, 5-H).
Embodiment 13
The preparation of 7-methyl chroman-4-carboxylic acid (19c)
Press embodiment 11 working method, 10.20g compound 17c and 11.30g1,2-propylene glycol and 1.50g tosic acid reaction 8.0h, obtain compound 18b.Add 1.00g zinc oxide, reaction 2.0h, obtains incarnadine oily mater.Then add the 40mL30%NaOH aqueous solution, 60mL methanol solution reaction 4.0h, obtains compound 19c, yield 65.0%, m.p.110～111 ℃;
1h NMR (CDCl
3, 400MHz) δ: 2.10～2.18 (m, 1H, 3-H), 2.28 (s, 3H, 7-CH
3), 2.29～2.34 (m, 1H, 3-H), 3.78 (t, J=4.8Hz, 1H, 4-H), 4.21～4.25 (m, 2H, 2-H), 6.67 (s, 1H, 8-H), 6.72 (d, J=8.0Hz, 1H, 6-H), 7.15 (d, J=8.0Hz, 1H, 5-H).
Embodiment 14
The preparation of 6-methyl chromene-4-carboxylic acid (19d)
Press embodiment 11 working method, 5.10g compound 17d and 6.20g1,2-propylene glycol and 0.50g tosic acid reaction 8.0h, obtain compound 18d, adds 1.00g zinc oxide, and reaction 2.0h, obtains incarnadine oily mater.Then add the 40mL30%NaOH aqueous solution, 60mL methanol solution reaction 4.0h, obtains compound 19d, yield 91.9%, m.p.116～117 ℃;
1h NMR (CDCl
3, 400MHz) δ: 2.09～2.18 (m, 1H, 3-H), 2.26 (s, 3H, 6-CH
3), 2.28～2.34 (m, 1H, 3-H), 3.78 (t, J=8.4Hz, 1H, 4-H), 4.19～4.28 (m, 2H, 2-H), 6.75 (d, J=8.4Hz, 1H, 8-H), 6.98 (dd, J=2.0,8.4Hz, 1H, 7-H), 7.07 (d, J=2.0Hz, 1H, 5-H).
Embodiment 15
The preparation of 8-methoxyl group benzo pyrans-4-carboxylic acid (19e)
Press embodiment 11 working method, 2.70g compound 17e and 2.50g1,2-propylene glycol and 0.50g tosic acid reaction 8.0h, obtain compound 18e, adds 1.00g zinc oxide, and reaction 2.0h, obtains incarnadine oily mater.Then add the 40mL30%NaOH aqueous solution, 60mL methanol solution reaction 4.0h, obtains compound 19e, yield 34.8%, m.p.105～107 ℃;
1h NMR (CDCl
3, 400MHz) δ: 2.12～2.21 (m, 1H, 3-H), 2.31～2.37 (m, 1H, 3-H), 3.78 (t, J=4.8Hz, 1H, 4-H), 3.78 (s, 3H, 8-OCH
3), 4.29～4.39 (m, 2H, 2-H), 6.79 (dd, J=2.0,7.6Hz, 1H, 7-H), 7.17 (t, J=7.6Hz, 1H, 6-H), 6.89 (dd, J=2.0,7.6Hz, 1H, 5-H).
Embodiment 16
The preparation of 7-methoxyl group benzo pyrans-4-carboxylic acid (19f)
Press embodiment 11 working method, 8.10g compound 17f and 7.90g1,2-propylene glycol and 1.50g tosic acid, obtain compound 18f, adds 1.00g zinc oxide, and reaction 2.0h, obtains incarnadine oily mater.Then add the 40mL30%NaOH aqueous solution, 60mL methanol solution reaction 4.0h, obtains faint yellow oily matter compound 19f, yield 68.9%;
1h NMR (CDCl
3, 400MHz) δ: 2.09～2.14 (m, 1H, 3-H), 2.28～2.32 (m, 1H, 3-H), 3.76 (s, 3H, 7-OCH
3), 3.78 (t, J=4.8Hz, 1H, 4-H), 4.22～4.25 (m, 2H, 2-H), 6.39 (d, J=2.4Hz, 1H, 8-H), 6.50 (dd, J=2.4,8.8Hz, 1H, 6-H), 7.17 (d, J=8.8Hz, 1H, 5-H).
Embodiment 17
The preparation of 6-methoxyl group benzo pyrans-4-carboxylic acid (19g)
Press embodiment 11 working method, 5.40g compound 17g and 6.20g1,2-propylene glycol and 0.50g tosic acid, obtain compound 18g, adds 1.00g zinc oxide, and reaction 2.0h, obtains incarnadine oily mater.Add the 40mL30%NaOH aqueous solution, 60mL methanol solution reaction 4.0h, obtains compound 19g, yield 67.0%, m.p.103～104 ℃;
1h NMR (CDCl
3, 400MHz) δ: 2.09～2.18 (m, 1H, 3-H), 2.26～2.34 (m, 1H, 3-H), 3.75 (s, 3H, 6-OCH
3), 3.78 (t, J=4.8Hz, 1H, 4-H), 4.20～4.23 (m, 2H, 2-H), 6.77～6.82 (m, 3H, 7-H, 8-H, 5-H).
Embodiment 18
The preparation of 6-chlorine chromene-4-carboxylic acid (19h)
Press embodiment 11 working method, 5.50g compound 17h and 4.60g1,2-propylene glycol and 0.50g tosic acid, obtain compound 18h, adds 1.00g zinc oxide, and reaction 2.0h, obtains incarnadine oily mater.Then add the 40mL30%NaOH aqueous solution, 60mL methanol solution reaction 4.0h, obtains compound 19h, yield 70.2%, m.p.90～92 ℃;
1h NMR (CDCl
3, 400MHz) δ: 2.08～2.17 (m, 1H, 3-H), 2.29～2.36 (m, 1H, 3-H), 3.78 (t, J=8.4Hz, 1H, 4-H), 4.22～4.27 (m, 2H, 2-H), 6.78 (d, J=8.8Hz, 1H, 8-H), 7.13 (dd, J=2.4,8.8Hz, 1H, 7-H), 7.28 (d, J=2.4Hz, 1H, 5-H).
Embodiment 19
The preparation of 3,4-dihydro-2H-benzo [h] chromene-4-carboxylic acid (19i)
Press embodiment 11 working method, 5.80g compound 17i and 4.70g1,2-propylene glycol and 1.00g tosic acid, reaction 8.0h, obtains compound 18i, adds 1.00g zinc oxide, and reaction 2.0h, obtains incarnadine oily mater.Then add the 40mL30%NaOH aqueous solution, 60mL methanol solution reaction 4.0h, obtains compound 19i, yield 54.0%, m.p.173～174 ℃;
1h NMR (CDCl
3, 400MHz) δ: 2.19～2.28 (m, 1H, 3-H), 2.39～2.46 (m, 1H, 3-H), 3.91 (t, J=4.4Hz, 1H, 4-H), 4.38～4.51 (m, 2H, 2-H), 7.32～7.38 (m, 2H, 7-H, 6-H), 7.44～7.48 (m, 2H, 9-H, 10-H), 7.73～7.75 (m, 1H, 8-H), 8.16～8.19 (m, 1H, 11-H).
Embodiment 20
The preparation of 3,4-dihydro-2H-benzo [g] chromene-4-carboxylic acid (19j)
Press embodiment 11 working method, 2.90g compound 17j and 2.40g1,2-propylene glycol and 0.50g tosic acid, reaction 8.0h, obtains compound 18j, adds 1.00g zinc oxide, and reaction 2.0h, obtains incarnadine oily mater.Then add the 40mL30%NaOH aqueous solution, 60mL methanol solution reaction 4.0h, obtains compound 19j, yield 52.2%, m.p.170～171 ℃;
1h NMR (CDCl
3, 400MHz) δ: 2.21～2.30 (m, 1H, 3-H), 2.37～2.44 (m, 1H, 3-H), 4.07 (t, J=5.2Hz, 1H, 4-H), 4.28～4.32 (m, 1H, 2-H), 4.34～4.41 (m, 1H, 2-H), 7.24 (s, 1H, 10-H), 7.28 (t, J=8.0Hz, 1H, 7-H), 7.38 (t, J=8.0Hz, 1H, 8-H), 7.66 (d, J=8.0Hz, 1H, 9-H), 7.71 (d, J=8.0Hz, 1H, 6-H), 7.78 (s, 1H, 5-H).
Embodiment 21
The preparation of N-(2,2-dimethyl-7-methoxyl group-2,3-Dihydrobenzofuranes-5-yl) chromene-4-acid amides (23a)
(1) 2,2-dimethyl-7-methoxyl group-5-nitro-2, the preparation of 3-Dihydrobenzofuranes (21)
17.80g compound 21,50mL dichloromethane solution, stirs at-5 ℃, drip 10mL concentrated nitric acid, 30min dropwises, and temperature rises to 10 ℃, continue reaction 30min, TLC monitoring reacts completely, reaction solution washing, dichloromethane extraction, anhydrous sodium sulfate drying, dehydrated alcohol recrystallization obtains yellow solid 2,2-dimethyl-7-methoxyl group-5-nitro-2,3-Dihydrobenzofuranes (21) 19.20g, yield 92.6%, m.p.124～126 ℃;
1h NMR (CDCl
3, 400MHz) δ: 1.57 (s, 6H, 2 * CH
3), 3.11 (s, 2H, 3-H), 3.95 (s, 3H, 7-OCH
3), 7.70 (d, J=2.4Hz, 1H, 6-H), 7.77 (d, J=2.4Hz, 1H, 4-H).
(2) 2,2-dimethyl-7-methoxyl group-2, the preparation of 3-Dihydrobenzofuranes-5-amine (22)
6.00g compound 22 (27.00mmol), 60mL methyl alcohol, Raney's nickel, drips the hydrazine hydrate of 12.00g80% at 20 ℃, in 1.0h, drip and finish, continue reaction 30min, TLC monitoring reacts completely, and suction filtration reclaims Raney's nickel, filtrate is spin-dried for, with 50mL methylene dichloride, dissolve 100mL water washing, 50mL dichloromethane extraction 3 times, anhydrous sodium sulfate drying, filter, be spin-dried for, dry 2,2-dimethyl-7-methoxyl group-2,3-Dihydrobenzofuranes-5-amine (22) 4.92g, yield 94.5%, m.p.126～128 ℃;
1h NMR (CDCl
3, 400MHz) δ: 1.47 (s, 6H, 2 * CH
3), 2.94 (s, 2H, 3-H), 3.34 (s, 2H, NH
2), 3.81 (s, 3H, 7-OCH
3), 6.17 (s, 2H, 4-H, 6-H).
(3) preparation of N-(2,2-dimethyl-7-methoxyl group-2,3-Dihydrobenzofuranes-5-yl) chromene-4-acid amides (23a)
0.59g compound 19a, 0.66g compound 22,20mL methylene dichloride, 0.67g DCC, 0.09g DMAP, stirring at room 1.0h, TLC monitoring reacts completely; Suction filtration, is spin-dried for, and dehydrated alcohol recrystallization obtains 0.40g white solid 23a, yield 33.3%, m.p.178～180 ℃;
1h NMR (CDCl
3, 400MHz) δ: 1.48 (s, 6H, 2 * CH
3), 2.16～2.25 (m, 1H, 3-H), 2.54～2.60 (m, 1H, 3-H), 2.97 (s, 2H, 3 '-H), 3.77 (t, J=4.8Hz, 1H, 4-H), 3.84 (s, 3H, 7 '-OCH
3), 4.09～4.15 (m, 1H, 2-H), 4.29～4.34 (m, 1H, 2-H), 6.74 (d, J=2.0Hz, 1H, 6 '-H), 6.93 (dd, J=2.0,8.0Hz, 1H, 8-H), 6.94 (d, J=2.0Hz, 1H, 4 '-H), 6.95～6.99 (m, 1H, 7-H), 7.17 (s, 1H, NH), 7.19 (dd, J=2.0,8.0Hz, 1H, 5-H), 7.24～7.29 (m, 1H, 6-H).
Embodiment 22
The preparation of N-(2,2-dimethyl-7-methoxyl group-2,3-Dihydrobenzofuranes-5-yl)-8-methyl chromene-4-acid amides (23b)
Press the preparation method of embodiment 21,3.30mmol compound 19b, 3.40mmol compound 22, reaction 1.0h, obtains white solid 23b, yield 53.4%, m.p.190～192 ℃;
1h NMR (CDCl
3, 400MHz) δ: 1.48 (s, 6H, 2 * CH
3), 2.15～2.20 (m, 1H, 3-H), 2.22 (s, 3H, 8-CH
3), 2.54～2.60 (m, 1H, 3-H), 2.96 (s, 2H, 3 '-H), 3.76 (t, J=4.8Hz, 1H, 4-H), 3.83 (s, 3H, 7 '-OCH
3), 4.08～4.14 (m, 1H, 2-H), 4.34～4.39 (m, 1H, 2-H), 6.73 (d, J=2.0Hz, 1H, 6 '-H), 6.87 (t, J=7.6Hz, 1H, 6-H), 6.95 (d, J=2.0Hz, 1H, 4 '-H), 7.03 (d, J=7.6Hz, 1H, 7-H), 7.12 (d, J=7.6Hz, 1H, 5-H), 7.21 (s, 1H, NH).
Embodiment 23
The preparation of N-(2,2-dimethyl-7-methoxyl group-2,3-Dihydrobenzofuranes-5-yl)-7-methyl chromene-4-acid amides (23c)
Press the preparation method of embodiment 21,3.30mmol compound 19c, 3.40mmol compound 22, reaction 1.0h, obtains white solid 23c, yield 36.6%, m.p.195～197 ℃;
1h NMR (CDCl
3, 400MHz) δ: 1.48 (s, 6H, 2 * CH
3), 2.14～2.23 (m, 1H, 3-H), 2.33 (s, 3H, 7-CH
3), 2.51～2.56 (m, 1H, 3-H), 2.97 (s, 2H, 3 '-H), 3.73 (t, J=4.8Hz, 1H, 4-H), 3.84 (s, 3H, 7 '-OCH
3), 4.05～4.11 (m, 1H, 2-H), 4.26～4.32 (m, 1H, 2-H), 6.74 (s, 2H, 6 '-H, 8-H), 6.78 (d, J=8.0Hz, 1H, 6-H), 6.95 (d, J=2.0Hz, 1H, 4 '-H), 7.06 (d, J=8.0Hz, 1H, 5-H), 7.21 (s, 1H, NH).
Embodiment 24
The preparation of N-(2,2-dimethyl-7-methoxyl group-2,3-Dihydrobenzofuranes-5-yl)-6-methyl chromene-4-acid amides (23d)
Press the preparation method of embodiment 21,3.30mmol compound 19d, 3.40mmol compound 22, reaction 1.0h, obtains white solid 23d, yield 39.5%, m.p.208～209 ℃;
1h NMR (CDCl
3, 400MHz) δ: 1.48 (s, 6H, 2 * CH
3), 2.14～2.23 (m, 1H, 3-H), 2.33 (s, 3H, 6-CH
3), 2.51～2.56 (m, 1H, 3-H), 2.97 (s, 2H, 3 '-H), 3.73 (t, J=4.8Hz, 1H, 4-H), 3.84 (s, 3H, 7 '-OCH
3), 4.06～4.13 (m, 1H, 2-H), 4.26～4.32 (m, 1H, 2-H), 6.74 (s, 1H, 6 '-H), 6.78 (d, J=8.0Hz, 1H, 8-H), 6.96～6.97 (m, 1H, 5-H, 4 '-H), 7.06 (dd, J=2.0,8.0Hz, 1H, 7-H), 7.19 (s, 1H, NH).
Embodiment 25
The preparation of N-(2,2-dimethyl-7-methoxyl group-2,3-Dihydrobenzofuranes-5-yl)-8-methoxyl group benzo pyrans-4-acid amides (23e)
Press the preparation method of embodiment 21,3.30mmol compound 19e, 3.40mmol compound 22, reaction 0.7h, obtains white solid 23e, yield 51.8%, m.p.212～214 ℃;
1h NMR (CDCl
3, 400MHz) δ: 1.48 (s, 6H, 2 * CH
3), 2.17～2.26 (m, 1H, 3-H), 2.56～2.62 (m, 1H, 3-H), 2.97 (s, 2H, 3 '-H), 3.78 (t, J=4.8Hz, 1H, 4-H), 3.83 (s, 3H, 7 '-OCH
3), 3.92 (s, 3H, 8-OCH
3), 4.13～4.20 (m, 1H, 2-H), 4.43～4.48 (m, 1H, 2-H), 6.75 (d, J=1.2Hz, 1H, 6 '-H), 6.80 (dd, J=1.2,8.0Hz, 1H, 7-H), 6.86～6.96 (m, 3H, 6-H, 5-H, 4 '-H), 7.19 (s, 1H, NH).
Embodiment 26
The preparation of N-(2,2-dimethyl-7-methoxyl group-2,3-Dihydrobenzofuranes-5-yl)-7-methoxyl group benzo pyrans-4-acid amides (23f)
Press the preparation method of embodiment 21,3.30mmol compound 19f, 3.40mmol compound 22, reaction 0.3h, obtains white solid 23f, yield 55.4%, m.p.166～167 ℃;
1h NMR (CDCl
3, 400MHz) δ: 1.48 (s, 6H, 2 * CH
3), 2.15～2.22 (m, 1H, 3-H), 2.51～2.56 (m, 1H, 3-H), 2.97 (s, 2H, 3 '-H), 3.70 (t, J=4.4Hz, 1H, 4-H), 3.81 (s, 3H, 7 '-OCH
3), 3.84 (s, 3H, 7-OCH
3), 4.04～4.11 (m, 1H, 2-H), 4.28～4.32 (m, 1H, 2-H), 6.47 (d, J=2.8Hz, 1H, 8-H), 6.57 (dd, J=2.8,8.4Hz, 1H, 6-H), 6.76 (d, J=2.0Hz, 1H, 6 '-H), 6.94 (d, J=2.0Hz, 1H, 4 '-H), 7.07 (d, J=8.4Hz, 1H, 5-H), 7.20 (s, 1H, NH).
Embodiment 27
The preparation of N-(2,2-dimethyl-7-methoxyl group-2,3-Dihydrobenzofuranes-5-yl)-6-methoxyl group benzo pyrans-4-acid amides (23g)
Press the preparation method of embodiment 21,3.30mmol compound 19g, 3.40mmol compound 22, reaction 1.0h, obtains white solid 23g, yield 80.2%, m.p.173～174 ℃;
1h NMR (CDCl
3, 400MHz) δ: 1.48 (s, 6H, 2 * CH
3), 2.15～2.25 (m, 1H, 3-H), 2.49～2.56 (m, 1H, 3-H), 2.97 (s, 2H, 3 '-H), 3.73 (t, J=4.8Hz, 1H, 4-H), 3.78 (s, 3H, 6-OCH
3), 3.84 (s, 3H, 7 '-OCH
3), 4.05～4.12 (m, 1H, 2-H), 4.25～4.29 (m, 1H, 2-H), 6.70 (d, J=2.0Hz, 1H, 6 '-H), 6.75 (d, J=2.0Hz, 1H, 4 '-H), 6.83～6.88 (m, 2H, 7-H, 8-H), 6.95 (d, J=2.4Hz, 1H, 5-H), 7.20 (s, 1H, NH).
Embodiment 28
The preparation of N-(2,2-dimethyl-7-methoxyl group-2,3-Dihydrobenzofuranes-5-yl)-6-chlorine chromene-4-acid amides (23h)
Press the preparation method of embodiment 21,3.30mmol compound 19h, 3.40mmol compound 22, reaction 0.6h, obtains white solid 23h, yield 64.0%, m.p.163～165 ℃;
1h NMR (CDCl
3, 400MHz) δ: 1.49 (s, 6H, 2 * CH
3), 2.12～2.22 (m, 1H, 3-H), 2.50～2.56 (m, 1H, 3-H), 2.99 (s, 2H, 3 '-H), 3.74 (t, J=4.4Hz, 1H, 4-H), 3.85 (s, 3H, 7 '-OCH
3), 4.12～4.19 (m, 1H, 2-H), 4.28～4.32 (m, 1H, 2-H), 6.78 (d, J=1.6Hz, 1H, 6 '-H), 6.86 (d, J=8.4Hz, 1H, 8-H), 6.96 (d, J=1.6Hz, 1H, 4 '-H), 7.16 (s, 1H, NH), 7.17 (d, J=2.8Hz, 1H, 5-H), 7.21 (dd, J=2.8,8.4Hz, 1H, 6-H).
Embodiment 29
The preparation of N-(2,2-dimethyl-7-methoxyl group-2,3-Dihydrobenzofuranes-5-yl) benzo [h] chromene-4-acid amides (23i)
Press the preparation method of embodiment 21,3.30mmol compound 19i, 3.40mmol compound 22, reaction 0.6h, obtains white solid 23i, yield 57.9%, m.p.245～247 ℃;
1h NMR (CDCl
3, 400MHz) δ: 1.47 (s, 6H, 2 * CH
3), 2.28～2.37 (m, 1H, 3-H), 2.63～2.67 (m, 1H, 3-H), 2.95 (s, 2H, 3 '-H), 3.81 (s, 3H, 7 '-OCH
3), 3.70 (t, J=4.4Hz, 1H, 4-H), 4.24～4.30 (m, 1H, 2-H), 4.54～4.59 (m, 1H, 2-H), 6.77 (d, J=2.0Hz, 1H, 6 '-H), 6.88 (d, J=2.0Hz, 1H, 4 '-H), 7.16 (s, 1H, NH), 7.24 (d, J=8.4Hz, 1H, 5-H), 7.46 (d, J=8.4Hz, 1H, 6-H), 7.52～7.56 (m, 2H, 8-H, 9-H), 7.80～7.82 (m, 1H, 7-H), 8.22～8.25 (m, 1H, 10-H).
Embodiment 30
The preparation of N-(2,2-dimethyl-7-methoxyl group-2,3-Dihydrobenzofuranes-5-yl) benzo [g] chromene-4-acid amides (23j)
Press the preparation method of embodiment 21,3.30mmol compound 19j, 3.40mmol compound 22, reaction 1.0h, obtains white solid 23j, yield 54.2%, m.p.208～210 ℃;
1h NMR (CDCl
3, 400MHz) δ: 1.47 (s, 6H, 2 * CH
3), 2.25～2.33 (m, 1H, 3-H), 2.65～2.71 (m, 1H, 3-H), 2.95 (s, 2H, 3 '-H), 3.81 (s, 3H, 7 '-OCH
3), 4.03 (t, J=4.4Hz, 1H, 4-H), 4.19～4.26 (m, 1H, 2-H), 4.36～4.41 (m, 1H, 2-H), 6.73 (s, 1H, 10-H), 6.91 (s, 1H, 5-H), 7.20 (s, 1H, NH), 7.32 (s, 1H, 6 '-H), 7.35 (t, J=8.0Hz, 1H, 7-H), 7.45 (t, J=8.0Hz, 1H, 8-H), 7.72～7.77 (m, 3H, 4 '-H, 6-H, 9-H).
Embodiment 31
The activity of the anti-human cervical cancer of N-(2,3-Dihydrobenzofuranes-5-yl) chromene-4-acid amides
1. anti-tumor activity principle
Mtt assay biological activity test claims again MTT colorimetry, is a kind of method that detects cell survival and growth.MTT analytical method is with viable cell metabolite reductive agent tetrazolium bromide [3-(4,5-dimethyl-2-thiazole)-2,5-phenylbenzene bromination tetrazole; 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, MTT] be basis.MTT is a kind of dyestuff that can accept hydrogen atom.Desaturase relevant to NADP in viable cell plastosome can change into yellow MTT insoluble hepatic first a ceremonial jade-ladle, used in libation (formazon) in cell, and dead cell is without this function.With DMSO, dissolve after formazon, under certain wavelength, by microplate reader, measure optical density value, both can quantitatively measure the survival rate of cell.According to the variation of optical density value, observe the restraining effect of sample to tumour cell.
2. anti-tumor activity experiment
Sample: N-(2,3-Dihydrobenzofuranes-5-yl) chromene-4-acid amides (I):
Wherein, X
1be selected from: H, C
1～C
2alkyl, C
3～C
4straight chained alkyl or branched-chain alkyl, C
1～C
2alkoxyl group, C
3～C
4straight chain alkoxyl group or branched alkoxy, fluorine, chlorine, bromine or iodine; X
2be selected from: H, C
1～C
2alkyl, C
3～C
4straight chained alkyl or branched-chain alkyl, C
1～C
2alkoxyl group, C
3～C
4straight chain alkoxyl group or branched alkoxy; X
3be selected from: H, C
1～C
2alkyl, C
3～C
4straight chained alkyl or branched-chain alkyl, C
1～C
2alkoxyl group, C
3～C
4straight chain alkoxyl group or branched alkoxy; X
4be selected from: H, C
1～C
2alkoxyl group, C
3～C
4straight chain alkoxyl group or branched alkoxy, fluorine, chlorine, bromine or iodine; X
1x
2be selected from :-CH=CH-CH=CH-; X
2x
3be selected from :-CH=CH-CH=CH-.
Clone: human cervical carcinoma Hela cell is (Xiangya Medical College, Zhongnan Univ cell bank provides).
Reagent: tetrazolium bromide (MTT), RPMI1640 nutrient solution, new-born calf serum, microbiotic (U.S. hero Life Technologies, Inc.); Pancreatin (U.S. AMRESCO company); 96 well culture plates (U.S. hero Life Technologies, Inc.); Dimethyl sulfoxide (DMSO) (U.S. Sigma company).
Instrument: HFsafe-1500 type Bechtop, HF151UV type CO
2incubator (Shanghai Lishen Scientific Equipment Co., Ltd.); XSP-15C type inverted microscope (Shanghai rectangular opticinstrument company limited); Multiskan MK3 type microplate reader (U.S. Thermo company); Ultrapure water preparing instrument (U.S. Milli-Q company).
Experimental implementation: sample is for human cervical carcinoma Hela cell's test.In an experimentation, per sample (p.s.) arranges 5 concentration gradients (1.00 μ mol/mL, 0.30 μ mol/mL, 0.10 μ mol/mL, 0.03 μ mol/mL and 0.01 μ mol/mL), four parallel samples of each concentration, test parallel 3 times for every group, and reach a conclusion by the contrast of blank group.Microplate reader detects each hole OD value, detects wavelength 570nm.
3. anti-tumor activity evaluation
1) cell inhibitory rate calculates:
2) IC
50value is calculated
Sample solution concentration logarithmic value and cell inhibitory rate linear regression, utilize the half-inhibition concentration IC of computed in software sample to cell
50value.N-(2, the 3-Dihydrobenzofuranes-5-yl) IC of chromene-4-acid amides to human cervical carcinoma Hela cell
50in Table 1.
Table 1N-(2, the 3-Dihydrobenzofuranes-5-yl) IC of chromene-4-acid amides to Hela cell strain
50(μ mol/mL)
| N-(2,3-Dihydrobenzofuranes-5-yl) chromene-4-acid amides | IC 50 |
| N-(2,2-dimethyl-7-methoxyl group-2,3-Dihydrobenzofuranes-5-yl) chromene-4-acid amides | 0.232 |
| N-(2,2-dimethyl-7-methoxyl group-2,3-Dihydrobenzofuranes-5-yl)-8-methyl chromene-4-acid amides | 0.063 |
| N-(2,2-dimethyl-7-methoxyl group-2,3-Dihydrobenzofuranes-5-yl)-7-methyl chromene-4-acid amides | 0.043 |
| N-(2,2-dimethyl-7-methoxyl group-2,3-Dihydrobenzofuranes-5-yl)-6-methyl chromene-4-acid amides | 0.202 |
| N-(2,2-dimethyl-7-methoxyl group-2,3-Dihydrobenzofuranes-5-yl)-8-methoxyl group benzo pyrans-4-acid amides | 0.143 |
| N-(2,2-dimethyl-7-methoxyl group-2,3-Dihydrobenzofuranes-5-yl)-7-methoxyl group benzo pyrans-4-acid amides | 0.142 |
| N-(2,2-dimethyl-7-methoxyl group-2,3-Dihydrobenzofuranes-5-yl)-6-methoxyl group benzo pyrans-4-acid amides | 0.278 |
| N-(2,2-dimethyl-7-methoxyl group-2,3-Dihydrobenzofuranes-5-yl)-6-chlorine chromene-4-acid amides | 0.156 |
| N-(2,2-dimethyl-7-methoxyl group-2,3-Dihydrobenzofuranes-5-yl) benzo [h] chromene-4-acid amides | 0.088 |
| N-(2,2-dimethyl-7-methoxyl group-2,3-Dihydrobenzofuranes-5-yl) benzo [g] chromene-4-acid amides | 0.114 |
The demonstration of active testing result, it is active that N-(2,3-Dihydrobenzofuranes-5-yl) chromene-4-acid amides antagonism human cervical carcinoma Hela cell has good inhibition, can be used for preparing anti-human cervical cancer medicine.
Claims (10)
1. the N-shown in chemical structural formula I (2,3-Dihydrobenzofuranes-5-yl) chromene-4-acid amides:
Wherein, X
1be selected from: H, C
1～C
2alkyl, C
3～C
4straight chained alkyl or branched-chain alkyl, C
1～C
2alkoxyl group, C
3～C
4straight chain alkoxyl group or branched alkoxy, fluorine, chlorine, bromine or iodine; X
2be selected from: H, C
1～C
2alkyl, C
3～C
4straight chained alkyl or branched-chain alkyl, C
1～C
2alkoxyl group, C
3～C
4straight chain alkoxyl group or branched alkoxy; X
3be selected from: H, C
1～C
2alkyl, C
3～C
4straight chained alkyl or branched-chain alkyl, C
1～C
2alkoxyl group, C
3～C
4straight chain alkoxyl group or branched alkoxy; X
4be selected from: H, C
1～C
2alkoxyl group, C
3～C
4straight chain alkoxyl group or branched alkoxy, fluorine, chlorine, bromine or iodine; X
1x
2be selected from :-CHCH-CH=CH-; X
2x
3be selected from :-CH=CH-CH=CH-.
2. N-claimed in claim 1 (2,3-Dihydrobenzofuranes-5-yl) chromene-4-acid amides is selected from N-(2,2-dimethyl-7-methoxyl group-2,3-Dihydrobenzofuranes-5-yl) chromene-4-acid amides.
3. N-claimed in claim 1 (2,3-Dihydrobenzofuranes-5-yl) chromene-4-acid amides is selected from N-(2,2-dimethyl-7-methoxyl group-2,3-Dihydrobenzofuranes-5-yl)-8-methyl chromene-4-acid amides.
4. N-claimed in claim 1 (2,3-Dihydrobenzofuranes-5-yl) chromene-4-acid amides is selected from N-(2,2-dimethyl-7-methoxyl group-2,3-Dihydrobenzofuranes-5-yl)-7-methyl chromene-4-acid amides.
5. described in claim 1, N-(2,3-Dihydrobenzofuranes-5-yl) chromene-4-acid amides is selected from N-(2,2-dimethyl-7-methoxyl group-2,3-Dihydrobenzofuranes-5-yl)-6-methyl chromene-4-acid amides.
6. N-(2 claimed in claim 1,3-Dihydrobenzofuranes-5-yl) chromene-4-acid amides is selected from N-(2,2-dimethyl-7-methoxyl group-2,3-Dihydrobenzofuranes-5-yl)-8-methoxyl group benzo pyrans-4-acid amides, N-(2,2-dimethyl-7-methoxyl group-2,3-Dihydrobenzofuranes-5-yl)-7-methoxyl group benzo pyrans-4-acid amides or N-(2,2-dimethyl-7-methoxyl group-2,3-Dihydrobenzofuranes-5-yl)-6-methoxyl group benzo pyrans-4-acid amides.
7. N-claimed in claim 1 (2,3-Dihydrobenzofuranes-5-yl) chromene-4-acid amides is selected from N-(2,2-dimethyl-7-methoxyl group-2,3-Dihydrobenzofuranes-5-yl)-6-chlorine chromene-4-acid amides.
8. N-(2 claimed in claim 1,3-Dihydrobenzofuranes-5-yl) chromene-4-acid amides is selected from N-(2,2-dimethyl-7-methoxyl group-2,3-Dihydrobenzofuranes-5-yl) benzo [h] chromene-4-acid amides or N-(2,2-dimethyl-7-methoxyl group-2,3-Dihydrobenzofuranes-5-yl) benzo [g] chromene-4-acid amides.
9. the preparation method of N-claimed in claim 1 (2,3-Dihydrobenzofuranes-5-yl) chromene-4-acid amides, is characterized in that the preparation feedback of N-(2,3-Dihydrobenzofuranes-5-yl) chromene-4-acid amides is as follows:
In formula, X
1～X
4definition as claimed in claim 1.
10. N-(2, the 3-Dihydrobenzofuranes-5-yl) application of chromene-4-acid amides in preparing medicament for resisting cervical cancer described in any one in claim 1～8.
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