CN104961743A - Carbonyl/oxime-containing coumarinopyrazole compounds and preparation thereof, and application of compounds in inhibiting tumor cells - Google Patents
Carbonyl/oxime-containing coumarinopyrazole compounds and preparation thereof, and application of compounds in inhibiting tumor cells Download PDFInfo
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- CN104961743A CN104961743A CN201510416327.1A CN201510416327A CN104961743A CN 104961743 A CN104961743 A CN 104961743A CN 201510416327 A CN201510416327 A CN 201510416327A CN 104961743 A CN104961743 A CN 104961743A
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- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 241000244269 Peucedanum Species 0.000 description 1
- 244000226566 Psoralea corylifolia Species 0.000 description 1
- 241001093501 Rutaceae Species 0.000 description 1
- 241000208292 Solanaceae Species 0.000 description 1
- 241001602561 Stolephorus tri Species 0.000 description 1
- QTENRWWVYAAPBI-YZTFXSNBSA-N Streptomycin sulfate Chemical compound OS(O)(=O)=O.OS(O)(=O)=O.OS(O)(=O)=O.CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@H]1[C@H](N=C(N)N)[C@@H](O)[C@H](N=C(N)N)[C@@H](O)[C@@H]1O.CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@H]1[C@H](N=C(N)N)[C@@H](O)[C@H](N=C(N)N)[C@@H](O)[C@@H]1O QTENRWWVYAAPBI-YZTFXSNBSA-N 0.000 description 1
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000010100 anticoagulation Effects 0.000 description 1
- 239000001138 artemisia absinthium Substances 0.000 description 1
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 description 1
- KGNDCEVUMONOKF-UGPLYTSKSA-N benzyl n-[(2r)-1-[(2s,4r)-2-[[(2s)-6-amino-1-(1,3-benzoxazol-2-yl)-1,1-dihydroxyhexan-2-yl]carbamoyl]-4-[(4-methylphenyl)methoxy]pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate Chemical compound C1=CC(C)=CC=C1CO[C@H]1CN(C(=O)[C@@H](CCC=2C=CC=CC=2)NC(=O)OCC=2C=CC=CC=2)[C@H](C(=O)N[C@@H](CCCCN)C(O)(O)C=2OC3=CC=CC=C3N=2)C1 KGNDCEVUMONOKF-UGPLYTSKSA-N 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 235000004883 caffeic acid Nutrition 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- PMOWTIHVNWZYFI-WAYWQWQTSA-N cis-2-coumaric acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1O PMOWTIHVNWZYFI-WAYWQWQTSA-N 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 229940125797 compound 12 Drugs 0.000 description 1
- 229940126543 compound 14 Drugs 0.000 description 1
- 229940125758 compound 15 Drugs 0.000 description 1
- 229940126142 compound 16 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940125810 compound 20 Drugs 0.000 description 1
- 229940126086 compound 21 Drugs 0.000 description 1
- 229940126208 compound 22 Drugs 0.000 description 1
- 229940125833 compound 23 Drugs 0.000 description 1
- 229940125961 compound 24 Drugs 0.000 description 1
- 229940125846 compound 25 Drugs 0.000 description 1
- 229940125851 compound 27 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 150000004775 coumarins Chemical class 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000003255 drug test Methods 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000009036 growth inhibition Effects 0.000 description 1
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 1
- 241000411851 herbal medicine Species 0.000 description 1
- 238000005805 hydroxylation reaction Methods 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- BXENDTPSKAICGV-UHFFFAOYSA-N inophyllum-P Natural products C=1C(=O)OC2=C3C(O)C(C)C(C)OC3=C3C=CC(C)(C)OC3=C2C=1C1=CC=CC=C1 BXENDTPSKAICGV-UHFFFAOYSA-N 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- PMOWTIHVNWZYFI-UHFFFAOYSA-N o-Coumaric acid Natural products OC(=O)C=CC1=CC=CC=C1O PMOWTIHVNWZYFI-UHFFFAOYSA-N 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 235000021251 pulses Nutrition 0.000 description 1
- 150000003214 pyranose derivatives Chemical group 0.000 description 1
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- BXENDTPSKAICGV-RXSFTSLZSA-N soulattrolide Chemical compound O([C@H]([C@@H]([C@H](O)C1=C2OC(=O)C=3)C)C)C1=C1C=CC(C)(C)OC1=C2C=3C1=CC=CC=C1 BXENDTPSKAICGV-RXSFTSLZSA-N 0.000 description 1
- 238000005556 structure-activity relationship Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
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
- C07D491/02—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 two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
Abstract
The invention discloses carbonyl/oxime-containing coumarinopyrazole compounds disclosed as the following general formula, wherein R is disclosed in the specification. The experiment proves that the carbonyl/oxime-containing coumarinopyrazole compounds have different inhibiting actions on human colon cancer cell strain (HCT-116), human lung cancer cell strain (A549), liver cancer cell (Huh7) and human spinal cord leukaemia M3 cell strain (HL60), and thus, can be possibly used for preparing anticancer drugs. The invention also discloses a preparation method of the carbonyl/oxime-containing coumarinopyrazole compounds.
Description
Technical field
The present invention relates to tonka bean camphor containing carbonyl or oxime and pyrazole compound and preparation thereof and the application in inhibition tumor cell.
Background technology
Tonka bean camphor is the general name of a class natural compounds with benzene a pair of horses going side by side pyrone parent nucleus, structurally can be regarded as the lactone along coumarinic acid dehydration.Coumarin kind compound is distributed widely in vegitabilia, minority is only had to come from animal and microorganism, distribute in the plants such as Rutaceae, umbelliferae, composite family, pulse family, thymelaeceae, Solanaceae wider, a lot of herbal medicine such as the bark of ash, Psoralea corylifolia, the root of Dahurain angelica, the root of purple-flowered peucedanum, levisticum, oriental wormwood and Fructus Cnidii etc. all contain coumarin kind compound.Research shows, coumarin kind compound has obvious pharmacologically active, as AntiHIV1 RT activity, anticancer, on cardiovascular impact, anti-inflammatory and smooth muscle loosening, anticoagulation etc.
AIDS (acquired immune deficiency syndrome (AIDS)) be caused by HIV-1 (human immunodeficiency virus) one immunity and central nervous system degenerative disorders.Through effort for many years, a series of coumarin kind compound such as calanolide and inophyllum is successively separated from natural product, and experiment in vitro shows, natural calanolide and inophyllum tonka bean camphor has high degree of specificity to HIV-1-RT.The people such as Patil summarize the structure activity relationship of natural calanolide and inophyllum tonka bean camphor and analogue thereof and find: 1. the stereochemical structure of dihydropyrane alcohol ring C-10 and 11 two methyl is most important, when both are in trans pair of orthostatism of dihydropyrane alcohol ring, activity is the strongest, and the compound with this configuration has calanolide A and B; InophyllumB and P; Costatolide and soulattrolide.2. 12-hydroxyl configuration and replace also have considerable influence to activity, the activity with 12 β-hydroxylation compounds is greater than the isomer of α configuration.3. the compound activity that the open loop of tonka bean camphor lactonic ring or pyranose ring structure change almost disappears.Calanolide A is the focus primer of current anti-AIDS, and the U.S. tries out in clinical study, and likely becomes the non-nucleotide class medicine of new generation for the treatment of AIDS
The present invention is based on the antitumour activity of tonka bean camphor, different substituents is introduced to it and modifies, synthesize a series of containing containing the tonka bean camphor of carbonyl or oxime and pyrazole compound, and antitumour activity test is carried out to them.
Summary of the invention
The present invention relates to tonka bean camphor containing carbonyl or oxime and pyrazole compound and preparation thereof and the application in inhibition tumor cell.
Technical scheme of the present invention is as follows:
One class containing the tonka bean camphor of carbonyl or oxime and pyrazole compound, is characterized in that it has following general formula:
Wherein R is:
Prepare above-mentioned containing carbonyl or the tonka bean camphor of oxime and a method for pyrazole compound, it is characterized in that it is made up of the following step:
4 hydroxy coumarin 0.06mmol is dissolved in the anhydrous DMF of 46.2ml, this reaction solution is cooled to less than 0 DEG C.Below 0 DEG C under condition, slowly drip POCl while stirring
30.18mmol, treats POCl
3finish, after stirring 0.5h under reaction solution being slowly warming up to room temperature condition, be then warming up to 65-70 DEG C of stirring reaction 6h.With the reaction of TLC tracking monitor, when after completion of the reaction, reaction solution to be poured in the mixture of ice and water of 200g and vigorous stirring, have a large amount of light yellow solid 1 to separate out.By solid suction filtration, and with 5% Na
2cO
3solution washing, by gained solid drying, namely obtains intermediate.
Gained solid 1mmol in step one is dissolved in 10ml ethanol, adding stirring makes it dissolve fully, then 15-20 DEG C is cooled to, by the solution (the hydrazine hydrate 2mmol+ triethylamine 4mmol+60% ethanol 10ml of 85%) that configures under agitation, maintain the temperature at 15-20 DEG C, slowly drop in reaction solution.Drip and finish, keep temperature to be no more than 25 DEG C, stirring reaction 12h.React with TLC tracking monitor.By gained solid concentrating under reduced pressure, gained solid ethyl alcohol recrystallization, namely obtains intermediate 2.
Getting intermediate 23mmol and α-bromoacetophenone 3.6mmol is dissolved in the acetone of 20ml, triethylamine 6mmol is added under agitation condition, 0 DEG C of stirring reaction 15h, by TLC detection reaction progress, reaction is finished, reaction solution removes solvent under reduced pressure, adds water, is extracted by aqueous layer with ethyl acetate (3 × 100mL).Organic layer is merged, and with anhydrous sodium sulfate drying, and remove solvent under reduced pressure.Solid ethyl alcohol recrystallization, obtain pure compound 3.
Compound 31mmol previous step obtained and pyridine 3mmol is dissolved in 20ml dehydrated alcohol, add the sodium ethylate of 2mmol and the mixture of oxammonium hydrochloride 2mmol simultaneously, heated and stirred backflow 15-20h, after complete with TLC detection reaction, after cooling, poured into by mixture in trash ice, solid by filtration is collected.Solid is carried out silica gel chromatography and carry out column chromatography or the method with ethyl alcohol recrystallization, obtain final product.
Tonka bean camphor containing carbonyl or oxime of the present invention pyrazole compound has obvious restraining effect to tumour cell.Therefore the tonka bean camphor containing carbonyl or oxime of the present invention pyrazole compound can be applied to and prepare cancer therapy drug.
Embodiment
Further describe the present invention by following examples, but scope of the present invention is not by any restriction of these embodiments.
The preparation of embodiment one: 2-(2-oxo-2-styroyl) chromene also [4,3-c] pyrazoles-4 (2H)-one (compound 1)
4 hydroxy coumarin 0.06mmol is dissolved in the anhydrous DMF of 46.2ml, this reaction solution is cooled to less than 0 DEG C.Below 0 DEG C under condition, slowly drip POCl while stirring
30.18mmol, treats POCl
3finish, after stirring 0.5h under reaction solution being slowly warming up to room temperature condition, be then warming up to 65-70 DEG C of stirring reaction 6h.With the reaction of TLC tracking monitor, when after completion of the reaction, reaction solution to be poured in the mixture of ice and water of 200g and vigorous stirring, have a large amount of light yellow solid 1 to separate out.By solid suction filtration, and with 5% Na
2cO
3solution washing, by gained solid drying, namely obtains intermediate.
Gained solid 1mmol in step one is dissolved in 10ml ethanol, adding stirring makes it dissolve fully, then 15-20 DEG C is cooled to, by the solution (the hydrazine hydrate 2mmol+ triethylamine 4mmol+60% ethanol 10ml of 85%) that configures under agitation, maintain the temperature at 15-20 DEG C, slowly drop in reaction solution.Drip and finish, keep temperature to be no more than 25 DEG C, stirring reaction 12h.React with TLC tracking monitor.By gained solid concentrating under reduced pressure, gained solid ethyl alcohol recrystallization, namely obtains intermediate 2.
Getting intermediate 23mmol and α-bromoacetophenone 3.6mmol is dissolved in the acetone of 20ml, triethylamine 6mmol is added under agitation condition, 0 DEG C of stirring reaction 15h, by TLC detection reaction progress, reaction is finished, reaction solution removes solvent under reduced pressure, adds water, is extracted by aqueous layer with ethyl acetate (3 × 100mL).Organic layer is merged, and with anhydrous sodium sulfate drying, and remove solvent under reduced pressure.Solid ethyl alcohol recrystallization, namely obtain final product.Product is white powder, productive rate 60%.M.p.213-214℃.
1HNMR(400MHz，DMSO-d
6)：8.81(s，1H，ArH)，8.09(t，J＝4.2Hz，2H，ArH)，7.80-7.97(m，1H，ArH)，7.75(t，J＝7.40Hz，1H，ArH)，7.63(t，J＝7.72Hz，2H，ArH)，7.54-7.60(m，1H，ArH)，7.46(d，J＝8.08Hz，1H，ArH)，7.35-7.41(m，1H，ArH)，6.20(s，2H，-CH
2).MS(ESI)：305.03(C
18H
13N
2O
3，[M+H]
+).Anal.Calcd for C
18H
12N
2O
3：C，71.05；H，3.97；N，9.21％.Found：C，71.03；H，3.96；N，9.21％.
The preparation of embodiment two: 2-(2-oxo-2-(p-methylphenyl) ethyl) chromene also [4,3-c] pyrazoles-4 (2H)-one (compound 2)
Preparation method is with embodiment one.Product is white powdery solids.Productive rate 58%.M.p.216-218℃.
1H NMR(400MHz，DMSO-d
6)：8.79(s，1H，ArH-d
6)，7.97-8.01(m，3H，ArH)，7.54-7.60(m，1H，ArH)，7.41-7.48(m，3H，ArH)，7.36-7.41(m，1H，ArH)，6.12(s，2H，-CH
2)，2.42(s，3H，-CH
3).MS(ESI)：319.24(C
19H
15N
2O
3，[M+H]
+).Anal.Calcd forC
19H
14N
2O
3：C，71.69；H，4.43；N，8.80％.Found：C，71.68；H，4.44；N，8.81％.
The preparation of embodiment three: 2-(2-(4-p-methoxy-phenyl)-2-oxoethyl) chromene also [4,3-c] pyrazoles-4 (2H)-one (compound 3)
Preparation method is with embodiment one.Product is white powdery solids.Productive rate 33%.Mp：261-263℃.
1H NMR(400MHz，DMSO)：8.75(s，1H，ArH)，7.97(d，J＝6.96Hz，1H，ArH)，7.55(t，J＝7.26Hz，1H，ArH)，7.44(d，J＝8.20Hz，1H，ArH)，7.38(t，J＝7.46Hz，1H，ArH)，7.14(t，J＝8.16Hz，1H，ArH)，6.57(d，J＝8.20Hz，1H，ArH)，6.50(s，1H，ArH)，6.41(dd，J
1＝8.08Hz，J
2＝1.56Hz，1H，ArH)，5.53(s，2H，-CH
2)，3.72(s，3H，-OCH
3)，3.68(s，2H，-CH
2)，3.62(s，2H，-CH
2)，3.26(s，2H，-CH
2)，3.16(s，2H，-CH
2).MS(ESI)：419.31(C
23H
23N
4O
4，[M+H]
+).Anal.Calcd for C
23H
22N
4O
4：C，66.02；H，5.30；N，13.39％.Found：C，66.04；H，5.31；N，13.36％.
The preparation of embodiment four: 2-(2-([1,1 '-biphenyl]-4-base)-2-oxoethyl) chromene also [4,3-c] pyrazoles-4 (2H)-one (compound 4)
Preparation method is with embodiment one.Product is white powdery solids.Productive rate 55%.M.p.216-217℃.
1H NMR(400MHz，DMSO-d
6)：8.83(s，1H，ArH)，8.18(d，J＝8.36Hz，2H，ArH)，7.98-8.02(m，1H，ArH)，7.94(d，J＝8.36Hz，2H，ArH)，7.81(d，J＝7.44Hz，2H，ArH)，7.51-7.61(m，3H，ArH)，7.46(t，J＝7.7Hz，2H，ArH)，7.39(t，J＝7.48Hz，1H，ArH)，6.23(s，2H，-CH
2).MS(ESI)：381.31(C
24H
17N
2O
3，[M+H]
+).Anal.Calcd forC
24H
16N
2O
3：C，75.78；H，4.24；N，7.36％.Found：C，75.76；H，4.25；N，7.35％.
The preparation of embodiment five: 2-(2-(4-fluorophenyl)-2-oxoethyl) chromene also [4,3-c] pyrazoles-4 (2H)-one (compound 5)
Preparation method is with embodiment one.Product is white powdery solids.Productive rate 62%.M.p.193-194℃.
1H NMR(400MHz，DMSO-d
6)：8.80(s，1H，ArH)，8.16-8.21(m，2H，ArH)，7.98(d，J＝7.68Hz，1H，ArH)，7.54-7.60(m，1H，ArH)，7.44-7.50(m，3H，ArH)，7.39(t，J＝7.50Hz，1H，ArH)，6.18(s，2H，-CH
2).MS(ESI)：322.15(C
18H
12FN
2O
3，[M+H]
+).Anal.Calcd for C
18H
11FN
2O
3：C，67.08；H，3.44；N，8.69％.Found：C，67.11；H，3.42；N，8.68％.
The preparation of embodiment six: 2-(2-(4-bromophenyl)-2-oxoethyl) chromene also [4,3-c] pyrazoles-4 (2H)-one (compound 6)
Preparation method is with embodiment one.Product is white powdery solids.Productive rate 59%.M.p.198-200℃.
1H NMR(400MHz，DMSO-d
6)：8.80(s，1H，ArH)，8.02(t，J＝4.30Hz，2H，ArH)，7.96-8.00(m，1H，ArH)，7.85(d，J＝8.60Hz，2H，ArH)，7.54-7.60(m，1H，ArH)，7.48(t，J＝4.16Hz，1H，ArH)，7.35-7.42(m，1H，ArH)，6.18(s，2H，-CH
2).MS(ESI)：383.23(C
18H
12BrN
2O
3，[M+H]
+).Anal.Calcd for C
18H
11BrN
2O
3：C，56.42；H，2.89；N，7.31％.Found：C，56.43；H，2.87；N，7.34％.
The preparation of embodiment seven: 2-(2-(2-chloro-phenyl-)-2-oxoethyl) chromene also [4,3-c] pyrazoles-4 (2H)-one (compound 7)
Preparation method is with embodiment one.Product is white powdery solids.Productive rate 52%.M.p.204-205℃.
1H NMR(400MHz，DMSO-d
6)：8.79(s，1H，ArH)，8.10(d，J＝8.60Hz，2H，ArH)，7.96-8.00(m，1H，ArH)，7.70(d，J＝8.56Hz，2H，ArH)，7.54-7.60(m，1H，ArH)，7.45(d，J＝8.08Hz，1H，ArH)，7.38(t，J＝7.50Hz，1H，ArH)，6.18(s，2H，-CH
2).MS(ESI)：339.65(C
18H
12ClN
2O
3，[M+H]
+).Anal.Calcd for C
18H
11ClN
2O
3：C，63.82；H，3.27；N，8.27％.Found：C，63.82；H，3.28；N，8.30％.
The preparation of embodiment eight: 2-(2-(3-chloro-phenyl-)-2-oxoethyl) chromene also [4,3-c] pyrazoles-4 (2H)-one (compound 8)
Preparation method is with embodiment one.Product is white powdery solids.Productive rate 61%.M.p.261-263℃.
1H NMR(400MHz，DMSO-d
6)：8.78(s，1H，ArH)，8.11(t，J＝1.74Hz，1H，ArH)，8.03(d，J＝7.92Hz，1H，ArH)，7.97-8.01(m，1H，ArH)，7.81-7.84(m，1H，ArH)，7.66(t，J＝7.92Hz，1H，ArH)，7.54-7.60(m，1H，ArH)，8.46(d，J＝7.68Hz，1H，ArH)，7.36-7.42(m，1H，ArH)，6.20(s，2H，-CH
2).MS(ESI)：339.78(C
18H
12ClN
2O
3，[M+H]
+).Anal.Calcd for C
18H
11ClN
2O
3：C，63.82；H，3.27；N，8.27％.Found：C，63.79；H，326；N，8.26％.
The preparation of embodiment nine: 2-(2-(4-chloro-phenyl-)-2-oxoethyl) chromene also [4,3-c] pyrazoles-4 (2H)-one (compound 9)
Preparation method is with embodiment one.Product is white powdery solids.Productive rate 51%.M.p.202-204℃.
1H NMR(400MHz，DMSO-d
6)：8.84(s，1H，ArH)，7.99(d，J＝7.68Hz，2H，ArH)，7.64(d，J＝4.04Hz，2H，ArH)，7.54-7.60(m，2H，ArH)，7.46(d，J＝8.32Hz，1H，ArH)，7.39(t，J＝7.52Hz，1H，ArH)，6.06(s，2H，-CH
2).MS(ESI)：339.68(C
18H
12ClN
2O
3，[M+H]
+).Anal.Calcd for C
18H
11ClN
2O
3：C，63.82；H，3.27；N，8.27％.Found：C，63.80；H，3.28；N，8.26％.
The preparation of embodiment ten: 2-(2-(2,4 difluorobenzene base)-2-oxoethyl) chromene also [4,3-c] pyrazoles-4 (2H)-one (compound 10)
Preparation method is with embodiment one.Product is white powdery solids.Productive rate 53%.M.p.198-200℃.
1H NMR(400MHz，DMSO-d
6)：8.73(s，1H，ArH)，7.99-8.07(m，1H，ArH)，7.91-7.96(m，1H，ArH)，7.50-7.58(m，2H，ArH)，7.42(d，J＝7.80Hz，1H，ArH)，7.27-7.37(m，2H，ArH)，5.97(d，J＝2.88，2H，-CH
2).MS(ESI)：341.13(C
18H
11F
2N
2O
3，[M+H]
+).Anal.Calcd for C
18H
10F
2N
2O
3：C，63.53；H，2.96；N，8.23％.Found：C，63.56；H，2.96；N，8.25％.
The preparation of embodiment 11: 2-(2-(2,4 dichloro benzene base)-2-oxoethyl) chromene also [4,3-c] pyrazoles-4 (2H)-one (compound 11)
Preparation method is with embodiment one.Product is white powdery solids.Productive rate 62%.M.p.165-167℃.
1H NMR(400MHz，DMSO-d
6)：8.82(s，1H，ArH)，8.04(d，J＝8.40Hz，1H，ArH)，7.97-8.01(m，1H，ArH)，7.84(d，J＝2.00Hz，1H，ArH)，7.66-7.70(m，1H，ArH)，7.54-7.60(m，1H，ArH)，7.45(t，J＝4.16Hz，1H，ArH)，7.36-7.41(m，1H，ArH)，6.06(s，2H，-CH
2).MS(ESI)：373.21(C
18H
11C
12N
2O
3，[M+H]
+).Anal.Calcd forC
18H
10Cl
2N
2O
3：C，57.93；H，2.70；N，7.51％.Found：C，57.91；H，2.72；N，7.52％.
The preparation of embodiment 12: 2-(2-(3,4-dichlorophenyl)-2-oxoethyl) chromene also [4,3-c] pyrazoles-4 (2H)-one (compound 12)
Preparation method is with embodiment one.Product is white powdery solids.Productive rate 63%.M.p.234-236℃.
1H NMR(400MHz，DMSO-d
6)：8.79(s，1H，ArH)，8.33(d，J＝1.88Hz，1H，ArH)，8.02-8.06(m，1H，ArH)，7.96-8.00(m，1H，ArH)，7.92(d，J＝8.40Hz，1H，ArH)，7.55-7.60(m，1H，ArH)，7.46(d，J＝8.24Hz，1H，ArH)，7.39(t，J＝7.52Hz，1H，ArH)，6.21(s，2H，-CH
2).MS(ESI)：373.06(C
18H
11Cl
2N
2O
3，[M+H]
+).Anal.Calcd forC
18H
10Cl
2N
2O
3：C，57.93；H，2.70；N，7.51％.Found：C，57.94；H，2.72；N，7.50％.
The preparation of embodiment 13: 2-(2-(3-nitrophenyl)-2-oxoethyl) chromene also [4,3-c] pyrazoles-4 (2H)-one (compound 13)
Preparation method is with embodiment one.Product is yellow powdery solid.Productive rate 56%.M.p.258-261℃.
1H NMR(400MHz，DMSO-d
6)：8.80(s，1H，ArH)，8.78(t，J＝1.84Hz，1H，ArH)，8.55-8.60(m，1H，ArH)，8.49-8.53(m，1H，ArH)，7.98-8.01(m，1H，ArH)，7.93(t，J＝8.02Hz，1H，ArH)，7.54-7.60(m，1H，ArH)，7.44-7.49(m，1H，ArH)，7.36-7.42(m，1H，ArH)，6.31(s，2H，-CH
2).MS(ESI)：350.36(C
18H
12N
3O
5，[M+H]
+).Anal.Calcdfor C
18H
11N
3O
5：C，61.89；H，3.17；N，12.03％.Found：C，61.90；H，3.19；N，12.05％.
The preparation of embodiment 14: 2-(2-oxo-2-(4-(trifluoromethyl) phenyl) ethyl) chromene also [4,3-c] pyrazoles-4 (2H)-one (compound 14)
Preparation method is with embodiment one.Product is white powdery solids.Productive rate 54%.M.p.208-211℃.
1H NMR(400MHz，DMSO-d
6)：8.81(s，1H，ArH)，8.28(d，J＝8.12Hz，2H，ArH)，8.03(s，1H，ArH)，7.97-8.02(m，2H，ArH)，7.55-7.61(m，1H，ArH)，7.47(d，J＝7.76Hz，1H，ArH)，7.36-7.42(m，1H，ArH)，6.27(s，2H，-CH
2).MS(ESI)：373.12(C
19H
12F
3N
2O
3，[M+H]
+).Anal.Calcd for C
19H
11F
3N
2O
3：C，61.30；H，2.98；N，7.52％.Found：C，61.32；H，2.97；N，7.53％.
Embodiment 15: the preparation of (E)-2-(2-(oxyimino)-2-styroyl) chromene also [4,3-c] pyrazoles-4 (2H)-one (compound 15)
4 hydroxy coumarin 0.06mmol is dissolved in the anhydrous DMF of 46.2ml, this reaction solution is cooled to less than 0 DEG C.Below 0 DEG C under condition, slowly drip POCl while stirring
30.18mmol, treats POCl
3finish, after stirring 0.5h under reaction solution being slowly warming up to room temperature condition, be then warming up to 65-70 DEG C of stirring reaction 6h.With the reaction of TLC tracking monitor, when after completion of the reaction, reaction solution to be poured in the mixture of ice and water of 200g and vigorous stirring, have a large amount of light yellow solid 1 to separate out.By solid suction filtration, and with 5% Na
2cO
3solution washing, by gained solid drying, namely obtains intermediate.
Gained solid 1mmol in step one is dissolved in 10ml ethanol, adding stirring makes it dissolve fully, then 15-20 DEG C is cooled to, by the solution (the hydrazine hydrate 2mmol+ triethylamine 4mmol+60% ethanol 10ml of 85%) that configures under agitation, maintain the temperature at 15-20 DEG C, slowly drop in reaction solution.Drip and finish, keep temperature to be no more than 25 DEG C, stirring reaction 12h.React with TLC tracking monitor.By gained solid concentrating under reduced pressure, gained solid ethyl alcohol recrystallization, namely obtains intermediate 2.
Getting intermediate 23mmol and α-bromoacetophenone 3.6mmol is dissolved in the acetone of 20ml, triethylamine 6mmol is added under agitation condition, 0 DEG C of stirring reaction 15h, by TLC detection reaction progress, reaction is finished, reaction solution removes solvent under reduced pressure, adds water, is extracted by aqueous layer with ethyl acetate (3 × 100mL).Organic layer is merged, and with anhydrous sodium sulfate drying, and remove solvent under reduced pressure.Solid ethyl alcohol recrystallization, obtain pure compound 3.
Compound 2-(2-oxo-2-styroyl) chromene that previous step is obtained also [4,3-c] pyrazoles-4 (2H)-one 1mmol and pyridine 3mmol is dissolved in 20ml dehydrated alcohol, add the sodium ethylate of 2mmol and the mixture of oxammonium hydrochloride 2mmol simultaneously, heated and stirred backflow 15-20h, after complete with TLC detection reaction, after cooling, poured into by mixture in trash ice, solid by filtration is collected.Solid is carried out silica gel chromatography and carry out column chromatography or the method with ethyl alcohol recrystallization, obtain final product.Product is white powdery solids.Productive rate 41%.M.p.262-264℃.
1H NMR(400MHz，DMSO-d
6)：12.02(s，1H，OH)，8.80(s，1H，ArH)，7.88-7.92(m，1H，ArH)，7.73-7.78(m，2H，ArH)，7.49-7.55(m，1H，ArH)，7.30-7.43(m，5H，ArH)，5.71(s，2H，CH
2).MS(ESI)：320.23(C
18H
14N
3O
3，[M+H]
+).Anal.Calcd for C
18H
13N
3O
3：C，67.71；H，4.10；N，13.16％.Found：C，67.72；H，4.10；N，13.19％.
Embodiment 16: the preparation of (E)-2-(2-(oxyimino)-2-(p-methylphenyl) ethyl) chromene also [4,3-c] pyrazoles-4 (2H)-one (compound 16)
Preparation method is with embodiment 15.Product is white powdery solids.Productive rate 35%.M.p.237-238℃.
1H NMR(400MHz，DMSO-d
6)：11.96(s，1H，OH)，8.83(s，1H，ArH)，7.88-7.92(m，1H，ArH)，7.64(d，J＝8.20Hz，2H，ArH)，7.49-7.55(m，1H，ArH)，7.40(t，J＝4.14Hz，1H，ArH)，7.31-7.36(m，1H，ArH)，7.19(d，J＝8.04Hz，2H，ArH)，5.69(s，2H，-CH
2)，2.27(s，3H，-CH
3).MS(ESI)：334.29(C
19H
16N
3O
3，[M+H]
+).Anal.Calcd forC
19H
15N
3O
3：C，68.46；H，4.54；N，12.61％.Found：C，68.49；H，4.53；N，12.60％.
Embodiment 17: the preparation of (E)-2-(2-(oxyimino)-2-(4-methoxyphenyl) ethyl) chromene also [4,3-c] pyrazoles-4 (2H)-one (compound 17)
Preparation method is with embodiment 15.Product is white powdery solids.Productive rate 33%.M.p.236-238℃.
1H NMR(400MHz，DMSO-d
6)：11.86(s，1H，OH)，8.82(s，1H，ArH)，7.87-7.93(m，1H，ArH)，7.70(d，J＝8.84Hz，2H，ArH)，7.52(t，J＝7.1Hz，1H，ArH)，7.39(t，J＝6.58Hz，1H，ArH)，7.33(t，J＝7.34Hz，1H，ArH)，6.94(d，J＝8.84Hz，2H，ArH)，5.68(s，2H，-CH
2)，3.74(s，3H，-OCH
3).MS(ESI)：350.18(C
19H
16N
3O
4，[M+H]
+).Anal.Calcd forC
19H
15N
3O
4：C，65.32；H，4.33；N，12.03％.Found：C，65.31；H，4.30；N，12.04％.
Embodiment 18: (E)-2-(2-([1,1 '-biphenyl]-4-base)-2-(oxyimino) ethyl) preparation of chromene also [4,3-c] pyrazoles-4 (2H)-one (compound 18)
Preparation method is with embodiment 15.Product is white powdery solids.Productive rate 44%.M.p.274-276℃.
1H NMR(400MHz，DMSO-d
6)：12.10(s，1H，OH)，8.86(s，1H，ArH)，7.93(d，J＝7.76Hz，1H，ArH)7.87(d，J＝8.40Hz，2H，ArH)，7.66-7.74(m，4H，ArH)，7.49-7.55(m，1H，ArH)
，7.46(t，J＝7.62Hz，1H，ArH)，7.31-7.41(m，4H，ArH)，5.75(s，2H，-CH
2).MS(ESI)：396.09(C
24H
18N
3O
3，[M+H]
+).Anal.Calcd for C
24H
17N
3O
3：C，72.90；H，4.33；N，10.63％.Found：C，72.93；H，4.34；N，10.65％.
Embodiment 19: the preparation of (E)-2-(2-(4-fluorophenyl)-2-(oxyimino) ethyl) chromene also [4,3-c] pyrazoles-4 (2H)-one (compound 19)
Preparation method is with embodiment 15.Product is white powdery solids.Productive rate 31%.M.p.242-243℃.
1HNMR(400MHz，DMSO-d
6)：12.05(s，1H，OH)，8.83(s，1H，ArH)，7.90(d，J＝7.72Hz，1H，ArH)，7.77-7.82(m，2H，ArH)，7.52(t，J＝7.8Hz，1H，ArH)，7.40(d，J＝8.28Hz，1H，ArH)，7.34(t，J＝7.52Hz，1H，ArH)，7.52(t，J＝8.86Hz，2H，ArH)，5.70(s，2H，-CH
2).MS(ESI)：338.31(C
18H
13FN
3O
3，[M+H]
+).Anal.Calcd for C
18H
12FN
3O
3：C，64.09；H，3.59；N，12.46％.Found：C，64.10；H，3.58；N，12.43％.
Embodiment 20: the preparation of (E)-2-(2-(4-bromophenyl)-2-(oxyimino) ethyl) chromene also [4,3-c] pyrazoles-4 (2H)-one (compound 20)
Preparation method is with embodiment 15.Product is white powdery solids.Productive rate 42%.M.p.268-270℃.
1H NMR(400MHz，DMSO-d
6)：12.17(s，1H，OH)，8.85(s，1H，ArH)，7.89-7.92(m，1H，ArH)，7.71(d，J＝8.68Hz，2H，ArH)，7.60(d，J＝8.64Hz，2H，ArH)，7.50-7.54(m，1H，ArH)，739-7.42(m，1H，ArH)，7.31-7.36(m，1H，ArH)，5.70(s，2H，-CH
2).MS(ESI)：398.23(C
18H
13BrN
3O
3，[M+H]
+).Anal.Calcd for C
18H
12BrN
3O
3：C，54.29；H，3.04；N，10.55％.Found：C，54.27；H，3.02；N，10.54％.
Embodiment 21: the preparation of (E)-2-(2-(2-chloro-phenyl-)-2-(oxyimino) ethyl) chromene also [4,3-c] pyrazoles-4 (2H)-one (compound 21)
Preparation method is with embodiment 15.Product is white powdery solids.Productive rate 39%.M.p.266-267℃.
1H NMR(400MHz，DMSO-d
6)：12.15(s，1H，OH)，8.84(s，1H，ArH)，7.88-7.92(m，1H，ArH)，7.78(d，J＝7.60Hz，2H，ArH)，7.50-7.55(m，1H，ArH)，7.40(d，J＝8.56Hz，2H，ArH)，7.78(d，J＝8.20Hz，1H，ArH)，7.33(t，J＝7.54Hz，1H，ArH)，5.70(s，2H，-CH
2).MS(ESI)：354.93(C
18H
13ClN
3O
3，[M+H]
+).Anal.Calcd for C
18H
12ClN
3O
3：C，61.11；H，3.42；N，11.88％.Found：C，61.10；H，3.45；N，11.89％.
Embodiment 22: the preparation of (E)-2-(2-(3-chloro-phenyl-)-2-(oxyimino) ethyl) chromene also [4,3-c] pyrazoles-4 (2H)-one (compound 22)
Preparation method is with embodiment 15.Product is white powdery solids.Productive rate 44%.M.p.230-232℃.
1H NMR(400MHz，DMSO-d
6)：12.26(s，1H，OH)，8.87(s，1H，ArH)，7.89(d，J＝7.68Hz，1H，ArH)，7.81(s，1H，ArH)，7.70-7.74(m，1H，ArH)，7.53(t，J＝7.50Hz，1H，ArH)，7.39-7.45(m，3H，ArH)，7.34(t，J＝7.52Hz，1H，ArH)，5.71(s，2H，-CH
2).MS(ESI)：354.74(C
18H
13ClN
3O
3，[M+H]
+).Anal.Calcd for C
18H
12ClN
3O
3：C，61.11；H，3.42；N，11.88％.Found：C，61.12；H，3.40；N，11.87％.
Embodiment 23: the preparation of (E)-2-(2-(4-chloro-phenyl-)-2-(oxyimino) ethyl) chromene also [4,3-c] pyrazoles-4 (2H)-one (compound 23)
Preparation method is with embodiment 15.Product is white powdery solids.Productive rate 46%.M.p.254-255℃.
1H NMR(400MHz，DMSO-d
6)：12.18(s，1H，OH)，8.86(s，1H，ArH)，7.88-7.91(m，1H，ArH)，7.78(d，J＝8.64Hz，2H，ArH)，7.50-7.55(m，1H，ArH)，7.47(d，J＝8.64Hz，2H，ArH)，7.40(d，J＝7.84Hz，1H，ArH)，7.31-7.36(m，1H，ArH)，5.70(s，2H，-CH
2).MS(ESI)：354.58(C
18H
13ClN
3O
3，[M+H]
+).Anal.Calcd for C
18H
12ClN
3O
3：C，61.11；H，3.42；N，11.88％.Found：C，61.10；H，3.40；N，11.87％.
Embodiment 24: the preparation of (E)-2-(2-(2,4 difluorobenzene base)-2-(oxyimino) ethyl) chromene also [4,3-c] pyrazoles-4 (2H)-one (compound 24)
Preparation method is with embodiment 15.Product is white powdery solids.Productive rate 41%.M.p.215-217℃
1H NMR(400MHz，DMSO-d
6)：12.26(s，1H，OH)，8.80(s，1H，ArH)，7.87(d，J＝7.48Hz，1H，ArH)，7.50-7.60(m，2H，ArH)，7.39(d，J＝8.24Hz，1H，ArH)，7.34(t，J＝7.48Hz，1H，ArH)，7.21-7.28(m，1H，ArH)，7.06(t，J＝7.34Hz，1H，ArH)，5.66(s，2H，-CH
2).MS(ESI)：356.16(C
18H
12F
2N
3O
3，[M+H]
+).Anal.Calcd for C
18H
11F
2N
3O
3：C，60.85；H，3.12；N，11.83％.Found：C，60.83；H，3.14；N，11.82％.
Embodiment 25: the preparation of (E)-2-(2-(2,4 dichloro benzene base)-2-(oxyimino) ethyl) chromene also [4,3-c] pyrazoles-4 (2H)-one (compound 25)
Preparation method is with embodiment 15.Product is white powdery solids.Productive rate 31%.M.p.207-208℃.
1H NMR(400MHz，DMSO-d
6)：12.23(s，1H，OH)，8.79(s，1H，ArH)，7.85-7.89(m，1H，ArH)，7.60(d，J＝1.88Hz，1H，ArH)，7.50-7.54(m，1H，ArH)，7.34-7.41(m，4H，ArH)，5.57(s，2H，-CH
2).MS(ESI)：388.22(C
18H
12Cl
2N
3O
3，[M+H]
+).Anal.Calcd forC
18H
11Cl
2N
3O
3：C，55.69；H，2.86；N，10.82％.Found：C，55.70；H，2.87；N，10.79％.
Embodiment 26: the preparation of (E)-2-(2-(3,4-dichlorophenyl)-2-(oxyimino) ethyl) chromene also [4,3-c] pyrazoles-4 (2H)-one (compound 26)
Preparation method is with embodiment 15.Product is white powdery solids.Productive rate 37%.M.p.271-272℃.
1H NMR(400MHz，DMSO-d
6)：12.36(s，1H，OH)，8.89(s，1H，ArH)，8.01(d，J＝1.88Hz，1H，ArH)，7.87-7.90(m，1H，ArH)，7.73-7.77(m，1H，ArH)，7.68(d，J＝8.52Hz，1H，ArH)，7.50-7.55(m，1H，ArH)，7.40(d，J＝7.92Hz，1H，ArH)，7.34(t，J＝7.52Hz，1H，ArH)，5.71(s，2H，-CH
2).MS(ESI)：388.32(C
18H
12Cl
2N
3O
3，[M+H]
+).Anal.Calcd forC
18H
11Cl
2N
3O
3：C，55.69；H，2.86；N，10.82％.Found：C，55.70；H，2.88；N，10.82％.
Embodiment 27: the preparation of (E)-2-(2-(oxyimino)-2-(3-nitrophenyl) ethyl) chromene also [4,3-c] pyrazoles-4 (2H)-one (compound 27)
Preparation method is with embodiment 15.Product is yellow powdery solid.Productive rate 39%.M.p.262-264℃.
1H NMR(400MHz，DMSO-d
6)：12.46(s，1H，OH)，8.91(s，1H，NH)，8.63(s，1H，ArH)，7.18-7.24(m，2H，ArH)，7.89(d，J＝7.72Hz，1H，ArH)，7.71(t，J＝8.00Hz，1H，ArH)，7.50-7.55(m，1H，ArH)，7.40(d，J＝8.24Hz，1H，ArH)，7.33(t，J＝7.54Hz，1H，ArH)，5.78(s，2H，-CH
2).MS(ESI)：365.34(C
18H
13N
4O
5，[M+H]
+).Anal.Calcd forC
18H
12N
4O
5：C，59.34；H，3.32；N，15.38％.Found：C，59.33；H，3.35；N，15.39％.
Embodiment 28: the preparation of (E)-2-(2-(oxyimino)-2-(4-(trifluoromethyl) phenyl) ethyl) chromene also [4,3-c] pyrazoles-4 (2H)-one (compound 28)
Preparation method is with embodiment 15.Product is white powdery solids.Productive rate 42%.M.p.250-252℃.
1H NMR(400MHz，DMSO-d
6)：12.39(s，1H，OH)，8.90(s，1H，ArH)，7.99(d，J＝8.16Hz，2H，ArH)，7.89(d，J＝7.16Hz，1H，ArH)，8.82(d，J＝8.16Hz，2H，ArH)，7.50-7.55(m，1H，ArH)，7.39-7.42(d，J＝8.20Hz，1H，ArH)，7.33(t，J＝7.52Hz，1H，ArH)，5.75(s，2H，-CH
2).MS(ESI)：388.23(C
19H
13F
3N
3O
3，[M+H]
+).Anal.Calcd forC
19H
12F
3N
3O
3：C，58.92；H，3.12；N，10.85％.Found：C，58.91；H，3.15；N，10.88％.
Embodiment 29: containing the tonka bean camphor of carbonyl or oxime and pyrazole compound Anticancer Activities
1. experiment material and method
1.1 medicines and reagent
Adopt MTT [3-(4,5)-bis-methyl-2-thiazole-(2,5)-phenyl bromination tetrazole is blue] method measures Caffeic acids derivative to Breast cancer lines (MCF-7), the half-inhibition concentration (IC of Human Lung Cancer cell strain (A549) and mouse melanin tumor cell (B16-F10)
50).
(1) preparation of nutrient solution (often liter): 1. suspension cell: RPMI-1640 cultivates one bag, powder (10.4g), new-born calf serum 100ml, penicillin solution (200,000 U/ml) 0.5ml, Streptomycin Solution (200,000 U/ml) 0.5ml, after adding tri-distilled water dissolving, with the NaHCO of 5.6%
3solution adjusts pH value to 7.2-7.4, is finally settled to 1000ml.Filtration sterilization.2. attached cell: the same, then add NaHCO
32.00g, HEPES 2.38g.
(2) preparation of PBS damping fluid (often liter): NaCl 8.00g, KCl 0.40g, Na
2hPO
412H
2o0.06g, KH
2pO
40.06g, NaHCO
30.35g.Autoclaving.
(3) preparation of trypsin solution: utilizing PBS damping fluid to be made into concentration is 0.5% trypsin solution.Filtration sterilization.
(4) preparation of liquid is tested: dissolved by a small amount of tri-distilled water of test sample and be made into storing solution, generally 10 times of preparation storing solutions of empirically maximum concentration.Different according to compound dissolution, available tri-distilled water directly dissolves, or with a small amount of DMSO hydrotropy, then adds tri-distilled water and dissolve.The concentration of DMSO in nutrient solution is unsuitable excessive, and in the every porocyte suspension after dosing, the final concentration of DMSO is generally no more than 0.05%-0.1%.Storing solution is stored in-20 DEG C of refrigerators for subsequent use.
(5) cultivation of human colon cancer cell strain HCT-116: be adherent growth cell, cellar culture is (containing 10% calf serum, 100U/ml Streptomycin sulphate) in RPMI-1640 nutrient solution, puts 37 DEG C, 5%CO
2cultivate in incubator, went down to posterity once every 3-4 days.First discard original fluid when going down to posterity, then use PBS buffer solution; Then use 0.5% tryptic digestion about 30 seconds, add a small amount of fresh medium and stop digestion; Piping and druming, makes attached cell split away off from culturing bottle wall; Pipette appropriate in fresh culture bottle, then supplement fresh medium to original volume (nutrient solution volume is about 1/10 of culturing bottle capacity).
(6) cultivation of human lung cancer cell A549: be adherent growth cell, cellar culture is (containing 10% calf serum, 100U/ml Streptomycin sulphate) in RPMI-1640 nutrient solution, puts 37 DEG C, 5%CO
2cultivate in incubator, went down to posterity once every 3-4 days.First discard original fluid when going down to posterity, then use PBS buffer solution; Then use 0.5% tryptic digestion about 30 seconds, add a small amount of fresh medium and stop digestion; Piping and druming, makes attached cell split away off from culturing bottle wall; Pipette appropriate in fresh culture bottle, then supplement fresh medium to original volume (nutrient solution volume is about 1/10 of culturing bottle capacity).
(7) cultivation of liver cancer cell Huh7: be adherent growth cell, cellar culture is (containing 10% calf serum, 100U/ml Streptomycin sulphate) in RPMI-1640 nutrient solution, puts 37 DEG C, 5%CO
2cultivate in incubator, went down to posterity once every 3-4 days.First discard original fluid when going down to posterity, then use PBS buffer solution; Then use 0.5% tryptic digestion about 30 seconds, add a small amount of fresh medium and stop digestion; Piping and druming, makes attached cell split away off from culturing bottle wall; Pipette appropriate in fresh culture bottle, then supplement fresh medium to original volume (nutrient solution volume is about 1/10 of culturing bottle capacity).
(8) cultivation of people's myeloid leukaemia M3 cell strain (HL60): be suspension growth cell, cellar culture is (containing 10% calf serum, 100U/ml Streptomycin sulphate) in RPMI-1640 nutrient solution, puts 37 DEG C, 5%CO
2cultivate in incubator, went down to posterity once every 3-4 days.First discard original fluid when going down to posterity, then use PBS buffer solution; Then use 0.5% tryptic digestion about 30 seconds, add a small amount of fresh medium and stop digestion; Piping and druming, makes attached cell split away off from culturing bottle wall; Pipette appropriate in fresh culture bottle, then supplement fresh medium to original volume (nutrient solution volume is about 1/10 of culturing bottle capacity).
(9) cell incubation: the tumour cell in vegetative period of taking the logarithm, tune concentration of cell suspension is 1-1.5 × 10
5individual ml
-1.In 96 well culture plates, every hole adds cell suspension 100 μ l, puts 37 DEG C, 5%CO
224h is cultivated in incubator.After cultivating 24h, add liquid by design respectively.
(10) dosing: join in each hole by test liquid respectively according to the concentration gradient of ultimate density, each concentration establishes 6 parallel holes.Experiment is divided into drug test group (adding the test medicine of different concns respectively), control group (only add nutrient solution and cell, do not add test medicine) and blank group (only add nutrient solution, do not add cell and test medicine).96 orifice plates after dosing are placed in 37 DEG C, 5%CO
248h is cultivated in incubator.The activity of positive control medicine measures according to the method for test sample.
The mensuration of-(11) survivaling cell: in 96 orifice plates after having cultivated 48h, every hole adds MTT 40 μ l (being made into 4mg/ml with PBS damping fluid).After placing 4h at 37 DEG C, remove supernatant liquor.Every hole adds 150 μ lDMSO, and vibration 5min, makes formazan dissolving crystallized.Finally, automatic microplate reader is utilized to detect the optical density(OD) (OD value) in each hole at 570nm wavelength place.
The calculating of inhibiting rate: the inhibiting rate of Growth of Cells calculates according to the following formula:
Growth inhibition ratio=(1-survival rate) × 100%=[1-(OD
experiment-OD
blank)/(OD
contrast-OD
empty in vain)] × 100% (OD
experimentrepresent the average optical of testing drug group, OD
contrastrepresent the average optical of control group, OD
blankrepresent the average optical of control group).
Half-inhibition concentration (IC
50) be defined as drug level when the tumor cell survival of 50%.According to the optical density(OD) (OD value) measured, make the typical curve of inhibitory rate of cell growth, typical curve is tried to achieve the drug level of its correspondence.
The IC recorded
50be shown in Table 1.
2. experimental result
The listed tonka bean camphor containing carbonyl or oxime of table 1 the present invention pyrazole compound are to the suppression IC of cancer cells
50value.
Result shows: containing the tonka bean camphor of carbonyl or oxime and pyrazole compound to human colon cancer cell strain (HCT-116), Human Lung Cancer cell strain (A549), liver cancer cell (Huh7) and people's myeloid leukaemia M3 cell strain (HL60) have restraining effect in various degree.
Claims (4)
1. a class is containing the tonka bean camphor of carbonyl or oxime and pyrazole compound, it is characterized in that it has following general formula:
Wherein R is:
2. described in claim 1 containing carbonyl or the tonka bean camphor of oxime and a method for making for pyrazole compound, it is characterized in that it is made up of following steps:
4 hydroxy coumarin 0.06mmol is dissolved in the anhydrous DMF of 46.2ml, this reaction solution is cooled to less than 0 DEG C.Below 0 DEG C under condition, slowly drip POCl while stirring
30.18mmol, treats POCl
3finish, after stirring 0.5h under reaction solution being slowly warming up to room temperature condition, be then warming up to 65-70 DEG C of stirring reaction 6h.With the reaction of TLC tracking monitor, when after completion of the reaction, reaction solution to be poured in the mixture of ice and water of 200g and vigorous stirring, have a large amount of light yellow solid 1 to separate out.By solid suction filtration, and with 5% Na
2cO
3solution washing, by gained solid drying, namely obtains intermediate.
Gained solid 1mmol in step one is dissolved in 10ml ethanol, adding stirring makes it dissolve fully, then 15-20 DEG C is cooled to, by the solution (the hydrazine hydrate 2mmol+ triethylamine 4mmol+60% ethanol 10ml of 85%) that configures under agitation, maintain the temperature at 15-20 DEG C, slowly drop in reaction solution.Drip and finish, keep temperature to be no more than 25 DEG C, stirring reaction 12h.React with TLC tracking monitor.By gained solid concentrating under reduced pressure, gained solid ethyl alcohol recrystallization, namely obtains intermediate 2.
Getting intermediate 2 3mmol and α-bromoacetophenone 3.6mmol is dissolved in the acetone of 20ml, triethylamine 6mmol is added under agitation condition, 0 DEG C of stirring reaction 15h, by TLC detection reaction progress, reaction is finished, reaction solution removes solvent under reduced pressure, adds water, is extracted by aqueous layer with ethyl acetate (3 × 100mL).Organic layer is merged, and with anhydrous sodium sulfate drying, and remove solvent under reduced pressure.Solid ethyl alcohol recrystallization, obtain pure compound 3.
Compound 3 1mmol previous step obtained and pyridine 3mmol is dissolved in 20ml dehydrated alcohol, add the sodium ethylate of 2mmol and the mixture of oxammonium hydrochloride 2mmol simultaneously, heated and stirred backflow 15-20h, after complete with TLC detection reaction, after cooling, poured into by mixture in trash ice, solid by filtration is collected.Solid is carried out silica gel chromatography and carry out column chromatography or the method with ethyl alcohol recrystallization, obtain final product.
3. method for making according to claim 2, chromatography described in its step 4, be adopt 200-300 order silicagel column, eluent is a certain proportion of anhydrous ethyl acetate and sherwood oil.
4. the tonka bean camphor containing carbonyl or oxime according to claim 1 pyrazole compound and preparation thereof and the application in Tumor suppression medicine.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101076332A (en) * | 2004-10-13 | 2007-11-21 | Ptc医疗公司 | Pyrazole or triazole compounds and their use for the manufacture of a medicament for treating somatic mutation-related diseases |
| CN101970428A (en) * | 2007-12-28 | 2011-02-09 | 雅培股份有限两合公司 | Carboxamide compounds and their use as calpain inhibitors |
| WO2014013117A1 (en) * | 2012-07-18 | 2014-01-23 | Consejo Superior De Investigaciones Científicas (Csic) | Chromenopyrazole diones as cannabinoid quinone derivatives having anti-tumour activity |
-
2015
- 2015-07-10 CN CN201510416327.1A patent/CN104961743A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101076332A (en) * | 2004-10-13 | 2007-11-21 | Ptc医疗公司 | Pyrazole or triazole compounds and their use for the manufacture of a medicament for treating somatic mutation-related diseases |
| CN101970428A (en) * | 2007-12-28 | 2011-02-09 | 雅培股份有限两合公司 | Carboxamide compounds and their use as calpain inhibitors |
| WO2014013117A1 (en) * | 2012-07-18 | 2014-01-23 | Consejo Superior De Investigaciones Científicas (Csic) | Chromenopyrazole diones as cannabinoid quinone derivatives having anti-tumour activity |
Non-Patent Citations (1)
| Title |
|---|
| YONG YIN，等: "Discovery and synthesis of a novel series of potent, selective inhibitors of the PI3Kα: 2-alkyl-chromeno[4,3-c]pyrazol-4(2H)-one derivatives", 《ORGANIC & BIOMOLECULAR CHEMISTRY》 * |
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