CN104817519A - CA-4 derivatives as well as preparation method and medical application of CA-4 derivatives - Google Patents
CA-4 derivatives as well as preparation method and medical application of CA-4 derivatives Download PDFInfo
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- CN104817519A CN104817519A CN201510235806.3A CN201510235806A CN104817519A CN 104817519 A CN104817519 A CN 104817519A CN 201510235806 A CN201510235806 A CN 201510235806A CN 104817519 A CN104817519 A CN 104817519A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D295/155—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/38—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino groups bound to acyclic carbon atoms and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
Abstract
The invention relates to the field of medicinal chemistry and particularly relates to Combretastatin A-4 derivatives (I), a preparation method of the Combretastatin A-4 derivatives and application of the Combretastatin A-4 derivatives to inhibition of tumor angiogenesis. A pharmacological experiment result shows that the compounds have a relatively strong effect on inhibiting MCF-7 human breast cancer cell proliferation, and meanwhile, parts of the compounds also have a relatively good effect on inhibiting the proliferation of human umbilical vein endothelial cells and the generation of new chick chorioallantoic membrane vessels. Therefore, the compounds provided by the invention can be used for treating various diseases related to angiogenesis, and the diseases include various cancers and chronic inflammations as well as other vascular diseases. The compounds provided by the invention have favorable water solubility.
Description
Technical field
The present invention relates to medicinal chemistry art, be specifically related to the derivative of a class Combretastatin A-4 (CA-4), they preparation method and to tumor vascular restraining effect.
Background technology
CA-4 is small molecules vascular disrupting agents (the Vascular Disrupting Agents separated from the Combretum Caffnom bark in South Africa, VDA), the colchicine binding site of its energy combining with vascular endothelial cell tubulin β subunit, cause the polymerization of tubulin, and then change skeleton structure and the form of its endotheliocyte, strengthen its vascular permeability, upset blood flow, thus cause tumor vascular endothelial cell apoptosis, cause secondary death of neoplastic cells.Although CA-4 has potential biological activity, its low water solubility and low bioavailability limit further application.
Summary of the invention
The invention discloses the compound of a class general formula I.Compound of the present invention has good water-soluble.The pharmacological results shows, compound of the present invention has stronger restraining effect to MCF-7 human breast cancer cell propagation, simultaneously, the generation of part of compounds to the propagation of Human umbilical vein endothelial cells and chick chorioallantoic membrane (Chicken chorioallactoic membrane, CAM) new vessel also has good restraining effect.Therefore, formula I of the present invention may be used for treating the various disease relevant to vasculogenesis, and these diseases comprise the angiogenic disease of various cancer and chronic inflammatory diseases and other.
Compound formula I of the present invention is as follows:
R represents: H, halogen, nitro, amino or trifluoromethyl.
R is preferred: H or nitro.
Wherein Y representative:
Y is preferred:
The compound of formula I can form acid salt with pharmaceutically acceptable acid, and described acid comprises hydrochloric acid, Hydrogen bromide, sulfuric acid, carbonic acid, citric acid, succsinic acid, tartrate, phosphoric acid, lactic acid, pyruvic acid, acetic acid, toxilic acid, methylsulfonic acid, Phenylsulfonic acid, tosic acid or forulic acid.
Part of compounds of the present invention is:
4-((4-methylpiperazine-1-yl) methyl) phenylformic acid-(Z)-2-methoxyl group-5-(3,4,5-trimethoxy styryl) phenyl ester (I-1)
4-(morpholine methyl) phenylformic acid-(Z)-2-methoxyl group-5-(3,4,5-trimethoxy styryl) phenyl ester (I-2)
4-(piperidin-1-yl methyl) phenylformic acid-(Z)-2-methoxyl group-5-(3,4,5-trimethoxy styryl) phenyl ester (I-3)
4-(pyrrolidin-1-yl methyl) phenylformic acid-(Z)-2-methoxyl group-5-(3,4,5-trimethoxy styryl) phenyl ester (I-4)
4-(diethylamine-1-ylmethyl) phenylformic acid-(Z)-2-methoxyl group-5-(3,4,5-trimethoxy styryl) phenyl ester (I-5)
4-((4-methylpiperazine-1-yl) methyl)-3-nitrobenzoic acid-(Z)-2-methoxyl group-5-(3,4,5-trimethoxy styryl) phenyl ester (I-6)
4-(morpholine methyl)-3-nitrobenzoic acid-(Z)-2-methoxyl group-5-(3,4,5-trimethoxy styryl) phenyl ester (I-7)
4-(piperidin-1-yl methyl)-3-nitrobenzoic acid-(Z)-2-methoxyl group-5-(3,4,5-trimethoxy styryl) phenyl ester (I-8)
4-(pyrrolidin-1-yl methyl)-3-nitrobenzoic acid-(Z)-2-methoxyl group-5-(3,4,5-trimethoxy styryl) phenyl ester (I-9)
4-(diethylamine methyl)-3-nitrobenzoic acid-(Z)-2-methoxyl group-5-(3,4,5-trimethoxy styryl) phenyl ester (I-10)
The preparation method of general formula compound of the present invention (I) is as follows:
Preparing compound 3 by 3,4,5-trimethoxy phenyl acetic acid (1) and 3-hydroxy-4-methyl phenyl aldehyde (2), is reactant condensation under triethylamine and aceticanhydride effect obtained.
Preparing 4 by compound 3, is obtained in quinoline/copper powder and 200 DEG C of high temperature decarboxylation by reactant.
Preparing 6 by compound 5, is be dissolved in chloroform by reactant, adds NBS and initiator benzoyl peroxide is obtained by reacting.
Preparing 7 by compound 6, is be dissolved in solvent by 6, under acid binding agent effect with
condensation obtains.Acid binding agent is selected from triethylamine, diisopropyl ethyl amine, pyridine, salt of wormwood, saleratus, sodium carbonate, sodium bicarbonate, preferred salt of wormwood.Solvent is selected from toluene/water, tetrahydrofuran (THF)/water, acetone/water, acetonitrile/water, preferred toluene/water.
Preparing 8 by compound 7, is reactant is placed in 20% concentrated hydrochloric acid backflow to obtain.
Preparing 9 by compound 8, is compound 12 and chlorizating agent are carried out chloro obtain.Wherein chlorizating agent is selected from sulfur oxychloride, oxalyl chloride, phosphorus oxychloride, preferred sulfur oxychloride.
Prepare target compound I by compound 9, be by compound 13 under acid binding agent effect with compound 4 in a solvent condensation obtain.Acid binding agent is selected from triethylamine, diisopropyl ethyl amine, pyridine, salt of wormwood, saleratus, sodium carbonate, sodium bicarbonate, preferred triethylamine.Solvent is selected from methylene dichloride, tetrahydrofuran (THF), acetonitrile, acetone, DMF, preferred methylene dichloride.
Another object of the present invention is to provide a kind of pharmaceutical composition, it comprises the compound or its salt of the present invention of medicine effective dose and pharmaceutically acceptable carrier.
Compound of the present invention can add pharmaceutically acceptable carrier and make common medicinal preparations, as tablet, capsule, pulvis, syrup, liquor, suspension agent, injection, the common medicinal supplementary material such as spices, sweeting agent, liquid or solid filler or thinner can be added.
Compound of the present invention administering mode clinically can adopt the modes such as oral, injection.
Usually, when CA-4 derivative of the present invention is used for the treatment of, people's dosage range is 1mg ~ 1000mg/ days.Also can according to the difference of formulation and disease severity, using dosage exceeds this scope.
Below pharmacological testing and the result of part of compounds of the present invention.
1, srb assay detects test-compound to the proliferation function of MCF-7 and HUVECs cell
Passage, to logarithmic growth after date, through the digestion of pancreas enzyme-EDTA liquid, adjusts final concentration to be 5 × 10
4/ mL, is inoculated in 96 orifice plates, and every hole 200 μ L, the aseptic PBS of marginal pore fills, 5%CO
2, hatch for 37 DEG C.(be paved with (96 hole flat underside) at the bottom of hole to cell monolayer) after 24h, discard on plate original liquid in each hole, then change the cell culture fluid containing respective concentration medicine respectively, in 37 DEG C, 5%CO
2cultivate in incubator, the every concentration of various medicine establishes 5 parallel holes.SRB 1% acetic acid is made into 0.4% solution.Cell is cultivated end (48h) in dosing and is used Tricholroacetic Acid (TCA) to fix afterwards: the 50%TCA liquid 50uL (final concentration is 10%) that each aperture of attached cell adds precooling fixes; Must be added in nutrient solution surface gently when adding TCA, first leave standstill 5min and then flat board is moved to 4 DEG C and place 1h, this like cell is fixed on the bottom of culture hole.Outwell stationary liquid, aperture sterilizing tri-distilled water washes 5 times, dries, dry air.Every hole adds 0.4%SRB solution 100 μ L, lucifuge, places 10min in room temperature.Do not wash 5 times, dry air with protein bound SRB 1%TCA liquid.In conjunction with SRB with 150uL10mmol/L non-buffered Tris alkali lye (pH 10.5) dissolve, be placed on 5min on micro oscillator, lucifuge.Measuring OD value at enzyme-linked immunosorbent assay instrument, with blank zeroing, is the OD value that 490nm place measures each aperture at wavelength.Obtained growth of tumour cell inhibiting rate is defined as the extracorporeal inhibiting rate of drug on tumor cell and calculates IC
50value.Inhibiting rate=(without medicine cell control well OD value-medication hole OD value)/without medicine cell control well OD value × 100%
Table 1 compound to human breast cancer cell line Bcap-37 inhibited proliferation (
n=3)
From table 1 experimental result, we can find out the MCF-7 tumor cell proliferation inhibition activity comparatively positive drug CA-4 (IC of majority of compounds
50=0.058 μM) stronger, the comparatively strong order of magnitude of Zorubicin simultaneously, wherein Compound I-3 (IC
50=0.024 μM) activity be obviously better than CA-4.
Table 2 part of compounds to the restraining effect of cell proliferation of human umbilical vein (
n=3)
Experimental result shows, survey compound, to Human umbilical vein endothelial cells, there is strong restraining effect.
2, chick chorioallantoic membrane angiogenesis inhibitor experiment
6 days kind egg warm water is cleaned 2 times, soak 3min in 1:1000 bromogeramine after, puts into 37 DEG C of incubator relative humidity 65%, plant egg air chamber upwards, upset kind of egg 1 time/2h, to incubation the 6th day, under egg candler, observe kind of an egg growing state, reject unfertilized egg.Prick 1 duck eye with dissecting needle on air chamber top, the allantochorion of chicken embryo can be made to separate with the inner shell membrane of egg.Embryo head is found under egg candler, the square area of the chorion projection part mark 1.0cm × 1.0cm before zygote distance fetal head between 1cm two anterior vitelline veins, cut chorion with emery wheel along this region mill and go out indenture to eggshell surface scribing, gently take off recess egg skin, tear inner shell membrane gently, now visible this place CAM sink together with chicken embryo, and false air chamber forms (being different from the air chamber of self).With the false air chamber of sealed membrane sealing label, form transparent windows, continue to put into 37 DEG C of incubators and hatch 1 day.Take out egg in second day, reject rotten egg.Residue egg is divided into: blank group, DMSO group, positive drug group (10,2.5,1 μ g/), with candidate compound group (10 μ g/), often organize each 3, tear sealed membrane gently, cut-off footpath is about the cellulose mixture millipore filtration sheet (in advance autoclaving) of 0.5cm as carrier, be placed in just to the content-addressable memory face of viewing window, avoid great vessels, draw each group of corresponding liquid with aseptic sample injector and drip in carrier surface central authorities.After dosing 2d, remove adhesive tape, observe, record CAM around viewing window and take pictures.With Graph Pad 5.0 statistical software, tiny blood vessels quantity is added up.
We for positive control with angiogenesis inhibitor Revlimid, carry out the experiment of chick chorioallantoic membrane angiogenesis inhibitor with the compound of the dosage of 10 μ g/ eggs to synthesis, investigate compound angiogenesis inhibiting activity in animal body.The results are shown in Figure 1.
As can be seen from Fig. 1 we, under the dosage of 10 μ g/ eggs, survey target compound and all have CAM angiogenesis inhibitor in various degree active, wherein the activity of Compound I-1, I-2, I-3 and I-6 is better, suitable with positive drug Revlimid, and CA-4 demonstrates serious embryotoxicity under this dosage (10 μ g/ egg), chicken embryo cannot continue grow, prompting target compound toxicity comparatively CA-4 obviously reduce.
We with angiogenesis inhibitor Revlimid and CA-4 for positive control, with 1,2.5,10 μ g/ eggs, three dosage, the experiment of chick chorioallantoic membrane angiogenesis inhibitor is carried out to Compound I-1 and I-6, investigate them further to the inhibit activities of vasculogenesis.The results are shown in Figure 2.
As can be seen from Figure 2, under the dosage of 10 μ g/ eggs, it is active that Compound I-1 and I-6 show stronger CAM angiogenesis inhibitor.Namely CA-4 demonstrates embryotoxicity under 2.5 μ g/ egg dosage, and under 10 μ g/ egg dosage, embryotoxicity is larger, and chicken embryo cannot continue to grow.
Accompanying drawing explanation
Fig. 1 is that compound is active to CAM angiogenesis inhibitor
Fig. 2 is that compound is active to CAM angiogenesis inhibitor
Embodiment
Embodiment 1
(E)-3-(3 '-hydroxyl-4 '-methoxyl group) Ben Ji – 2-(3 ", 4 ", 5 "-trimethoxy) synthesis of phenyl-acrylic acid (3)
3,4,5-trimethoxy phenyl acetic acid (50.0g, 0.22mol), 3-hydroxyl-4-methoxybenzaldehyde (34.0g, 0.22mol), 62.5mL triethylamine and 150mL diacetyl oxide is added, N in 500mL three-necked bottle
2the lower stirring of protection is warming up to 140 DEG C, and reaction 12h, stops heating, be cooled to 10 DEG C, slowly drips concentrated hydrochloric acid 200mL, room temperature for overnight under ice bath.Have khaki color solid to separate out, stopped reaction filters out solid, and with about 200mL ethyl alcohol recrystallization, obtain 47.5g yellow needles 3, productive rate is 59.6%, m.p.184 ~ 186 DEG C.
1H NMR(300MHz,DMSO-d
6),δ(ppm):δ12.46(brs,1H,COOH),8.97(s,1H,OH),7.58(s,1H,＝CH),6.81(d,J＝8.5Hz,1H,ArH),6.61(dd,J
1＝8.5,J
2＝1.8Hz,1H,ArH),6.54(d,J＝1.8Hz,1H,ArH),6.44(s,2H,ArH),3.73(s,3H,OCH
3),3.71(s,3H,OCH
3),3.69(s,6H,2×OCH
3).
Embodiment 2
(Z)-3 ", 4 ', 4 ", 5 "-tetramethoxy-3 ' synthesis of-hydroxy stibene (CA-4,4)
3 (7.2g, 20mmol) are added, brand-new copper powder (6.6g, 0.103mol), quinoline 72mL, N in the 500mL three-necked bottle that thermometer, reflux condensing tube, drying tube are housed
2the lower reaction of protection is heated to 200 DEG C, stirs 4h.Be cooled to room temperature, add ether in right amount, use filtered off through Celite copper powder.With 300mL 5M HCl, quinoline is washed off, extract with ether 150mL, the water layer ether separated is washed (3 × 150mL), merge organic layer.Organic layer is washed once with 500mL respectively, saturated Na
2cO
3(2 × 300mL) washes twice, and saturated NaCl (2 × 300mL) washes twice, anhydrous Na
2sO
4dried overnight.Elimination sodium sulfate, decompression spins off the ether of 2/3 volume, has micro-yellow solid to separate out, leaches solid and use appropriate washed with diethylether, reclaims mother liquor, then remove portion solvent, is leached by the solid of precipitation, is total to obtain product 45.0g, productive rate 79.1%, m.p.116 ~ 117 DEG C.
1HNMR(300Hz,DMSO-d
6):δ8.94(s,1H,OH),6.83(d,J＝8.3Hz,1H,ArH),6.78(d,J＝1.8Hz,1H,ArH),6.68(dd,J＝8.2,1.8Hz,1H,ArH),6.57(s,2H,ArH),6.39(q,J＝12.3Hz,2H,HC＝CH),3.72(s,3H,OCH
3),3.63(s,3H,OCH
3),3.59(s,6H,2×OCH
3).
Embodiment 3
The synthesis of 4-bromomethyl-benzoic acid methyl ester (6a)
5a (15.0g, 0.1mol) is dissolved in chloroform (80mL), adds NBS (17.8g, 0.1mol) with BPO (45mg, 0.18mmol), be heated to backflow, stirring reaction 2.5h, white solid is separated out in cooling, suction filtration, and filtrate decompression is steamed and desolventized, obtain crude pale yellow oily liquids 14.50g, silica gel column chromatography (petrol ether/ethyl acetate=100/1), obtains colourless transparent liquid 6a 12.78g, yield 82.34%.
1H NMR(300MHz,CDCl
3)δ8.03(d,J＝8.0Hz,2H,ArH),7.47(d,J＝7.9Hz,2H,ArH),4.51(s,2H,CH
2),3.93(s,3H,OCH
3).MS(ESI(+)70eV,m/z):229.0[M+H]
+.
Embodiment 4
The synthesis of 4-brooethyl-3-nitrobenzene methyl (6b)
By 5a (19.50g, 0.1mol) be dissolved in chloroform (100mL), add NBS (17.8g, 0.1mol) and BPO (45mg, 0.18mmol), be heated to backflow, stirring reaction 2.5h, white solid is separated out in cooling, suction filtration, filtrate decompression steam desolventize, obtain crude pale yellow oily liquids 6b 22.50g, not purified direct throwing next step.
Embodiment 5
The synthesis of 4-((4-methylpiperazine-1-yl) methyl) benzoate hydrochlorate (7a)
Be equipped with in the 50mL eggplant type bottle of reflux condensing tube and add 6a (4.90g, 21.49mmol), N methyl piperazine (2.67g, 26.87mmol), salt of wormwood (2.31g, 16.74mmol), 10mL toluene and 6mL water, in 75 DEG C of stirring reactions 12 hours, it is complete that TLC monitors raw material reaction, stop heating and stir, separate toluene layer, aqueous layer with ethyl acetate extraction, to without product, merges organic layer.Organic layer with 10% salt acid elution to organic layer without product, combining water layer.Adjust pH to alkalescence with saturated sodium bicarbonate aqueous solution after water layer is washed till inclusion-free by ethyl acetate again, be extracted with ethyl acetate to water layer without product, combined ethyl acetate layer.Ethyl acetate washed with water washes three times, and saturated common salt washes three times, and anhydrous sodium sulfate drying spends the night.Suction filtration, removes solvent under reduced pressure, adds 20mL 20% hydrochloric acid in residuum, and temperature control spends the night in 100 DEG C of stirring reactions.Cooling, in low temperature low rate mixing, separate out white solid, suction filtration, obtains intermediate 7a 3.34g, yield 50.76%, m.p.310 ~ 311 DEG C.
1H NMR(300MHz,D
2O)δ7.90(d,J＝8.3Hz,2H,ArH),7.43(d,J＝8.3Hz,2H,ArH),4.32(s,2H,PhCH
2),3.44(m,8H,N(CH
2)
4),2.81(s,3H,CH
3).MS(ESI(+)70eV,m/z):235.1[M+H]
+.
Embodiment 6
The synthesis of 4-(4-morpholine methyl) benzoate hydrochlorate (7b)
Be equipped with in the 50mL eggplant type bottle of reflux condensing tube and add 6a (4.90g, 21.49mmol), morpholine (2.34g, 26.87mmol), salt of wormwood (2.31g, 16.74mmol), 10mL toluene and 6mL water, in 75 DEG C of stirring reactions 12 hours, it is complete that TLC monitors raw material reaction, stop heating and stir, separate toluene layer, aqueous layer with ethyl acetate extraction, to without product, merges organic layer.Organic layer with 10% salt acid elution to organic layer without product, combining water layer.Adjust pH to alkalescence with saturated sodium bicarbonate aqueous solution after water layer is washed till inclusion-free by ethyl acetate again, be extracted with ethyl acetate to water layer without product, combined ethyl acetate layer.Ethyl acetate washed with water washes three times, and saturated common salt washes three times, and anhydrous sodium sulfate drying spends the night.Suction filtration, removes solvent under reduced pressure, adds 20mL 20% hydrochloric acid in residuum, and temperature control spends the night in 100 DEG C of stirring reactions.Cooling, in low temperature low rate mixing, separate out white solid, suction filtration, obtains intermediate 7b 3.64g, yield 65.94%, m.p.295 ~ 297 DEG C.
1H NMR(300MHz,D
2O)δ7.84(d,J＝8.3Hz,2H,ArH),7.39(d,J＝8.3Hz,2H,ArH),4.23(s,2H,PhCH
2),3.88(d,J＝11.3Hz,2H,OCH
2),3.56(t,J＝12.1Hz,2H,OCH
2),3.23(d,J＝12.5Hz,2H,NCH
2),3.14–2.98(m,2H,NCH
2).MS(ESI(+)70eV,m/z):222.1[M+H]
+.
Embodiment 7
The synthesis of 4-(piperidin-1-yl methyl) benzoate hydrochlorate (7c)
Be equipped with in the 50mL eggplant type bottle of reflux condensing tube and add 6a (4.90g, 21.49mmol), piperidines (2.29g, 26.87mmol), salt of wormwood (2.31g, 16.74mmol), 10mL toluene and 6mL water, in 75 DEG C of stirring reactions 12 hours, it is complete that TLC monitors raw material reaction, stop heating and stir, separate toluene layer, aqueous layer with ethyl acetate extraction, to without product, merges organic layer.Organic layer with 10% salt acid elution to organic layer without product, combining water layer.Adjust pH to alkalescence with saturated sodium bicarbonate aqueous solution after water layer is washed till inclusion-free by ethyl acetate again, be extracted with ethyl acetate to water layer without product, combined ethyl acetate layer.Ethyl acetate washed with water washes three times, and saturated common salt washes three times, and anhydrous sodium sulfate drying spends the night.Suction filtration, removes solvent under reduced pressure, adds 20mL 20% hydrochloric acid in residuum, and temperature control spends the night in 100 DEG C of stirring reactions.Cooling, in low temperature low rate mixing, separate out white solid, suction filtration, obtains intermediate 7c 3.41g, yield 62.23%, m.p.282 ~ 284 DEG C.
1H NMR(300MHz,D
2O)δ7.86(d,J＝8.3Hz,2H,ArH),7.38(d,J＝8.3Hz,2H,ArH),4.13(s,2H,PhCH
2),3.26(d,J＝11.9Hz,2H,NCH
2),2.77(dd,J
1＝12.4,10.0Hz,J
2＝2H,NCH
2),1.82～1.13(m,6H,CH
2CH
2CH
2).MS(ESI(+)70eV,m/z):220.3[M+H]
+.
Embodiment 8
The synthesis of 4-(pyrrolidin-1-yl methyl) benzoate hydrochlorate (7d)
Be equipped with in the 50mL eggplant type bottle of reflux condensing tube and add 6a (4.90g, 21.49mmol), tetramethyleneimine (1.91g, 26.87mmol), salt of wormwood (2.31g, 16.74mmol), 10mL toluene and 6mL water, in 75 DEG C of stirring reactions 12 hours, it is complete that TLC monitors raw material reaction, stop heating and stir, separate toluene layer, aqueous layer with ethyl acetate extraction, to without product, merges organic layer.Organic layer with 10% salt acid elution to organic layer without product, combining water layer.Adjust pH to alkalescence with saturated sodium bicarbonate aqueous solution after water layer is washed till inclusion-free by ethyl acetate again, be extracted with ethyl acetate to water layer without product, combined ethyl acetate layer.Ethyl acetate washed with water washes three times, and saturated common salt washes three times, and anhydrous sodium sulfate drying spends the night.Suction filtration, removes solvent under reduced pressure, adds 20mL 20% hydrochloric acid in residuum, and temperature control spends the night in 100 DEG C of stirring reactions.Cooling, in low temperature low rate mixing, separate out white solid, suction filtration, obtains intermediate 7d 3.11g, yield 60.04%, m.p.278 ~ 281 DEG C.
1H NMR(300MHz,D
2O)δ7.81(d,J＝8.3Hz,2H,ArH),7.36(d,J＝8.3Hz,2H,ArH),4.21(s,2H,PhCH
2),3.28(dd,J＝10.6,5.3Hz,2H,NCH
2),2.97(dt,J
1＝10.7,J
2＝7.7Hz,2H,NCH
2),2.04–1.87(m,2H,CH
2),1.84～1.69(m,2H,CH
2).MS(ESI(+)70eV,m/z):206.1[M+H]
+.
Embodiment 9
The synthesis of 4-(diethylamine methyl) benzoate hydrochlorate (7e)
Be equipped with in the 50mL eggplant type bottle of reflux condensing tube and add 6a (4.90g, 21.49mmol), diethylamine (1.97g, 26.87mmol), salt of wormwood (2.31g, 16.74mmol), 10mL toluene and 6mL water, in 75 DEG C of stirring reactions 12 hours, it is complete that TLC monitors raw material reaction, stop heating and stir, separate toluene layer, aqueous layer with ethyl acetate extraction, to without product, merges organic layer.Organic layer with 10% salt acid elution to organic layer without product, combining water layer.Adjust pH to alkalescence with saturated sodium bicarbonate aqueous solution after water layer is washed till inclusion-free by ethyl acetate again, be extracted with ethyl acetate to water layer without product, combined ethyl acetate layer.Ethyl acetate washed with water washes three times, and saturated common salt washes three times, and anhydrous sodium sulfate drying spends the night.Suction filtration, removes solvent under reduced pressure, adds 20mL 20% hydrochloric acid in residuum, and temperature control spends the night in 100 DEG C of stirring reactions.Cooling, in low temperature low rate mixing, separate out white solid, suction filtration, obtains intermediate 7e 3.27g, yield 62.64%, m.p.285 ~ 288 DEG C.
1H NMR(300MHz,D
2O)δ7.83(d,J＝8.3Hz,2H,ArH),7.37(d,J＝8.3Hz,2H,ArH),4.17(s,2H,PhCH
2),3.26–2.72(m,4H,N(C
H 2CH
3)
2),1.09(t,J＝7.3Hz,6H,N(CH
2C
H 3)
2).MS(ESI(+)70eV,m/z):208.1[M+H]
+.
Embodiment 10
The synthesis of 4-((4-methylpiperazine-1-yl) methyl)-3-nitrobenzoic acid hydrochloride (7f)
Be equipped with in the 25mL eggplant type bottle of reflux condensing tube and add 6b (1.00g, 3.66mmol), N methyl piperazine (0.46g, 4.58 mmol), salt of wormwood (0.39g, 2.85mmol), 2mL toluene and 1.2mL water, in 75 DEG C of stirring reactions 12 hours, it is complete that TLC monitors raw material reaction, stop heating and stir, separate toluene layer, aqueous layer with ethyl acetate extraction, to without product, merges organic layer.Organic layer with 10% salt acid elution to organic layer without product, combining water layer.Adjust pH to alkalescence with saturated sodium bicarbonate aqueous solution after water layer is washed till inclusion-free by ethyl acetate again, be extracted with ethyl acetate to water layer without product, combined ethyl acetate layer.Ethyl acetate washed with water washes three times, and saturated common salt washes three times, and anhydrous sodium sulfate drying spends the night.Suction filtration, removes solvent under reduced pressure, adds 10mL 20% hydrochloric acid in residuum, and temperature control spends the night in 100 DEG C of stirring reactions.Cooling, in low temperature low rate mixing, separate out white solid, suction filtration, obtains intermediate 7f 0.95g, yield 73.64%, m.p.315 ~ 318 DEG C.
1H NMR(300MHz,D
2O)δ8.58(s,1H,ArH),8.16(d,J＝7.5Hz,1H,ArH),7.65(d,J＝7.8Hz,1H,ArH),4.56(s,2H,PhCH
2),3.88–3.15(m,8H,N(C
H 2)
4N),2.81(s,3H,CH
3).MS(ESI(+)70eV,m/z):280.1[M+H]
+.
Embodiment 11
The synthesis of 4-(morpholine methyl)-3-nitrobenzoic acid hydrochloride (7g)
Be equipped with in the 25mL eggplant type bottle of reflux condensing tube and add 6b (1.00g, 3.66mmol), morpholine (0.40g, 4.58mmol), salt of wormwood (0.39g, 2.85mmol), 2mL toluene and 1.2mL water, in 75 DEG C of stirring reactions 12 hours, it is complete that TLC monitors raw material reaction, stop heating and stir, separate toluene layer, aqueous layer with ethyl acetate extraction, to without product, merges organic layer.Organic layer with 10% salt acid elution to organic layer without product, combining water layer.Adjust pH to alkalescence with saturated sodium bicarbonate aqueous solution after water layer is washed till inclusion-free by ethyl acetate again, be extracted with ethyl acetate to water layer without product, combined ethyl acetate layer.Ethyl acetate washed with water washes three times, and saturated common salt washes three times, and anhydrous sodium sulfate drying spends the night.Suction filtration, removes solvent under reduced pressure, adds 10mL 20% hydrochloric acid in residuum, and temperature control spends the night in 100 DEG C of stirring reactions.Cooling, in low temperature low rate mixing, separate out white solid, suction filtration, obtains intermediate 7g 0.76g, yield 68.47%, m.p.303 ~ 305 DEG C.
1H NMR(300MHz,D
2O)δ8.61(d,J＝1.6Hz,1H,ArH),8.17(dd,J
1＝7.9,J
2＝1.7Hz,1H,ArH),7.66(d,J＝7.9Hz,1H,ArH),4.53(s,2H,PhCH
2),3.59(m,8H,N(C
H 2)
4O).MS(ESI(+)70eV,m/z):267.1[M+H]
+.
Embodiment 12
The synthesis of 4-((piperidin-1-yl) methyl)-3-nitrobenzoic acid hydrochloride (7h)
Be equipped with in the 25mL eggplant type bottle of reflux condensing tube and add 6b (1.00g, 3.66mmol), piperidines (0.39g, 4.58mmol), salt of wormwood (0.39g, 2.85mmol), 2mL toluene and 1.2mL water, in 75 DEG C of stirring reactions 12 hours, it is complete that TLC monitors raw material reaction, stop heating and stir, separate toluene layer, aqueous layer with ethyl acetate extraction, to without product, merges organic layer.Organic layer with 10% salt acid elution to organic layer without product, combining water layer.Adjust pH to alkalescence with saturated sodium bicarbonate aqueous solution after water layer is washed till inclusion-free by ethyl acetate again, be extracted with ethyl acetate to water layer without product, combined ethyl acetate layer.Ethyl acetate washed with water washes three times, and saturated common salt washes three times, and anhydrous sodium sulfate drying spends the night.Suction filtration, removes solvent under reduced pressure, adds 10mL 20% hydrochloric acid in residuum, and temperature control spends the night in 100 DEG C of stirring reactions.Cooling, in low temperature low rate mixing, separate out white solid, suction filtration, obtains intermediate 7h 0.81g, yield 73.64%, m.p.298 ~ 301 DEG C.
1H NMR(300MHz,D
2O)δ8.59(d,J＝1.6Hz,1H,ArH),8.15(dd,J
1＝7.9,J
2＝1.6Hz,1H,ArH),7.63(d,J＝7.9Hz,1H,ArH),4.41(s,2H,PhCH
2),3.44(d,J＝12.1Hz,2H,NCH
2),3.02(t,J＝12.0Hz,2H,NCH
2),1.75(d,J＝14.8Hz,2H C
H 2CH
2CH
2),1.66–1.44(m,2H CH
2CH
2C
H 2),1.34(dd,J＝16.2,8.2Hz,2HCH
2C
H 2CH
2).MS(ESI(+)70eV,m/z):265.1[M+H]
+.
Embodiment 13
The synthesis of 4-((pyrrolidin-1-yl) methyl)-3-nitrobenzoic acid hydrochloride (7i)
Be equipped with in the 25mL eggplant type bottle of reflux condensing tube and add 6b (1.00g, 3.66mmol), tetramethyleneimine (3.26g, 4.58mmol), salt of wormwood (0.39g, 2.85mmol), 2mL toluene and 1.2mL water, in 75 DEG C of stirring reactions 12 hours, it is complete that TLC monitors raw material reaction, stop heating and stir, separate toluene layer, aqueous layer with ethyl acetate extraction, to without product, merges organic layer.Organic layer with 10% salt acid elution to organic layer without product, combining water layer.Adjust pH to alkalescence with saturated sodium bicarbonate aqueous solution after water layer is washed till inclusion-free by ethyl acetate again, be extracted with ethyl acetate to water layer without product, combined ethyl acetate layer.Ethyl acetate washed with water washes three times, and saturated common salt washes three times, and anhydrous sodium sulfate drying spends the night.Suction filtration, removes solvent under reduced pressure, adds 10mL 20% hydrochloric acid in residuum, and temperature control spends the night in 100 DEG C of stirring reactions.Cooling, in low temperature low rate mixing, separate out white solid, suction filtration, obtains intermediate 7i 0.69g, yield 65.71%, m.p.293 ~ 296 DEG C.
1H NMR(300MHz,D
2O)δ8.59(d,J＝1.5Hz,1H,ArH),8.17(dd,J
1＝7.9,J
2＝1.6Hz,1H,ArH),7.66(d,J＝8.0Hz,1H,ArH),4.53(s,2H,PhCH
2),3.48(d,J＝5.1Hz,2H,NCH
2),3.32–3.00(m,2H,NCH
2),2.03(s,2H,CH
2),1.83(dd,J
1＝7.4,J
2＝5.1Hz,2H,CH
2).MS(ESI(+)70eV,m/z):251.1[M+H]
+.
Embodiment 14
The synthesis of 4-(diethylamine methyl)-3-nitrobenzoic acid hydrochloride (7j)
Be equipped with in the 25mL eggplant type bottle of reflux condensing tube and add 6b (1.00g, 3.66mmol), diethylamine (0.33g, 4.58mmol), salt of wormwood (0.39g, 2.85mmol), 2mL toluene and 1.2mL water, in 75 DEG C of stirring reactions 12 hours, it is complete that TLC monitors raw material reaction, stop heating and stir, separate toluene layer, aqueous layer with ethyl acetate extraction, to without product, merges organic layer.Organic layer with 10% salt acid elution to organic layer without product, combining water layer.Adjust pH to alkalescence with saturated sodium bicarbonate aqueous solution after water layer is washed till inclusion-free by ethyl acetate again, be extracted with ethyl acetate to water layer without product, combined ethyl acetate layer.Ethyl acetate washed with water washes three times, and saturated common salt washes three times, and anhydrous sodium sulfate drying spends the night.Suction filtration, removes solvent under reduced pressure, adds 10mL 20% hydrochloric acid in residuum, and temperature control spends the night in 100 DEG C of stirring reactions.Cooling, in low temperature low rate mixing, separate out white solid, suction filtration, obtains intermediate 7j 0.78g, yield 73.58%, m.p.286 ~ 289 DEG C.
1H NMR(300MHz,D
2O)δ 8.63(d,J＝1.7Hz,1H,ArH),8.17(dd,J
1＝7.9,J
2＝1.7Hz,1H,ArH),7.65(d,J＝8.0Hz,1H,ArH),4.49(s,2H,PhCH
2),3.16(q,J＝7.3Hz,4H,NCH
2),1.17(t,J＝7.3Hz,6H,CH
3).MS(ESI(+)70eV,m/z):253.1[M+H]
+.
Embodiment 15
4-((4-methylpiperazine-1-yl) methyl) phenylformic acid-(Z)-2-methoxyl group-5-(3,4,5-trimethoxy styryl) phenyl ester (I-1)
In the 25mL eggplant type bottle that reflux condensing tube is housed, add 7a (0.27g, 1mmol) and 5mL sulfur oxychloride, return stirring reaction is spent the night, and it is dry to the greatest extent to remove solvent under reduced pressure, directly throws next step.CA-4 (0.316g, 1.0mmol) is dissolved in 5mL methylene dichloride, then pours into be equipped with and above-mentionedly freshly prepare in the eggplant type bottle of acyl chlorides, add triethylamine (0.20g, 0.28mL, 2.0mmol), in stirring at room temperature reaction 2h, TLC monitoring reaction is complete, and remove solvent under reduced pressure, residuum adds saturated aqueous common salt, extract to water layer without product by ethyl acetate, ethyl acetate washed with water washes three times, and saturated common salt washes three times, and organic layer anhydrous sodium sulfate drying spends the night.Suction filtration, filtrate is spin-dried for, and residuum column chromatography (methylene dichloride: methyl alcohol=200:1) separation and purification, obtains white solid I-1 0.23g, yield 43.40%, m.p.102 ~ 104 DEG C.IR (KBr, υ cm
-1): 3431,9277,2938,2794,2739,2504,2530,2497,1739,1611,1578,1504,1451,1415,1398,1384,1328,1263,1209,1126,1068,1035,1011,901,851,807,768,749,694,580,462.
1h NMR (300MHz, CDCl
3) δ 8.11 (d, J=8.0Hz, 2H, ArH), 7.44 (d, J=8.0Hz, 2H, ArH), 7.17 (d, J=8.6Hz, 1H, ArH), 7.13 (s, 1H, ArH), 6.90 (d, J=8.4Hz, 1H, ArH), 6.54 (s, 2H, ArH), 6.48 (d, J=2.8Hz, 2H, ArH), 3.81 (s, 3H, OCH
3), 3.79 (s, 3H, OCH
3), 3.73 (s, 6H, 2 × OCH
3), 3.62 (s, 2H, PhCH
2), 2.77 ~ 2.60 (m, 8H, piperazine hydrogen), 2.48 (s, 3H, NCH
3) .HR-ESIMS m/z 533.2656 [M+H]
+(calcd for C
31h
37n
2o
6, 533.2646).
Be dissolved in 2mL methylene dichloride by I-1 (0.10g, 0.19mmol), drip the diethyl ether solution of saturated HCl, stir 5 minutes, separate out white solid, suction filtration, obtains I-1HCl 0.07g, yield 61.57%, m.p.234 ~ 236 DEG C.
Embodiment 16
4-(morpholine methyl) phenylformic acid-(Z)-2-methoxyl group-5-(3,4,5-trimethoxy styryl) phenyl ester (I-2) hydrochloride
In the 25mL eggplant type bottle that reflux condensing tube is housed, add 7b (0.26g, 1mmol) and 5mL sulfur oxychloride, return stirring reaction is spent the night, and it is dry to the greatest extent to remove solvent under reduced pressure, directly throws next step.CA-4 (0.316g, 1.0mmol) is dissolved in 5mL methylene dichloride, then pours into be equipped with and above-mentionedly freshly prepare in the eggplant type bottle of acyl chlorides, add triethylamine (0.20g, 0.28mL, 2.0mmol), in stirring at room temperature reaction 2h, TLC monitoring reaction is complete, and remove solvent under reduced pressure, residuum adds saturated aqueous common salt, extract to water layer without product by ethyl acetate, ethyl acetate washed with water washes three times, and saturated common salt washes three times, and organic layer anhydrous sodium sulfate drying spends the night.Suction filtration, filtrate is spin-dried for, and residuum column chromatography (methylene dichloride: methyl alcohol=200:1) separation and purification, obtains white solid I-2 0.19g, yield 36.53%, m.p.50 ~ 52 DEG C.IR(KBr,υcm
-1):3456,3001,2936,2836,1739,1612,1578,1509, 1453,1415,1350,1328,1263,1208,1174,1116,1067,1007,912,867,797,768,749,719,693,623,580,526.
1H NMR(300MHz,CDCl
3)δ8.11(d,J＝8.2Hz,2H,ArH),7.47(d,J＝8.1Hz,2H,ArH),7.17(dd,J
1＝8.4,J
2＝2.0Hz,1H,ArH),7.14(d,J＝1.9Hz,1H,ArH),6.90(d,J＝8.4Hz,1H,ArH),6.54(s,2H,ArH),6.47(d,J＝3.2Hz,2H,ArH),3.81(s,3H,OCH
3),3.79(s,3H,OCH
3),3.73(m,10H,PhCH
2,2×OCH
3and OCH
2),3.58(m,2H,OCH
2),2.40～2.57(m,4H,N(CH
2)
2).
13C NMR(75MHz,CDCl
3)δ163.96,152.46,149.98,143.60,139.08,136.57,131.98,129.81,129.57,128.98,128.61,128.11,127.64,127.35,122.79,111.55,105.27,66.49,62.54,60.41,55.48,55.45,53.15.HR-ESIMS m/z 520.2330[M+H]
+(calcd for C
30H
34NO
7,520.2330).
Be dissolved in 2mL methylene dichloride by I-2 (0.10g, 0.19mmol), drip the diethyl ether solution of saturated HCl, stir 5 minutes, separate out white solid, suction filtration, obtains I-2HCl 0.08g, yield 74.77%, m.p.128 ~ 130 DEG C.IR(KBr,υcm
-1):3426,2936,2837,2536,2368,1742,1613,1578,1509,1455,1422,1327,1263,1209,1183,1125,1072,1020,974,911,870,797,757,698,581,526,459.
1H NMR(300MHz,CDCl
3)δ13.39(s,1H),8.22(d,J＝5.1Hz,2H,ArH),7.85(d,J＝4.5Hz,2H,ArH),7.17(d,J＝8.4Hz,1H,ArH),7.14(m,1H,ArH),6.90(d,J＝8.4Hz,1H,ArH),6.52(s,2H,ArH),6.47(s,2H,ArH),4.30(s,2H,PhCH
2),4.27(m,2H,OCH
2),4.02～3.88(m,2H,OCH
2),3.80(s,3H,OCH
3),3.78(s,3H,OCH
3),3.72(s,6H,2×OCH
3),3.35(m,2H,NCH
2),2.92(m,2H,NCH
2).
Embodiment 17
4-(piperidin-1-yl methyl) phenylformic acid-(Z)-2-methoxyl group-5-(3,4,5-trimethoxy styryl) phenyl ester (I-3) hydrochloride
In the 25mL eggplant type bottle that reflux condensing tube is housed, add 7c (255.1mg, 1mmol) and 5mL sulfur oxychloride, return stirring reaction is spent the night, and it is dry to the greatest extent to remove solvent under reduced pressure, directly throws next step.CA-4 (0.316g, 1.0mmol) is dissolved in 5mL methylene dichloride, then pours into be equipped with and above-mentionedly freshly prepare in the eggplant type bottle of acyl chlorides, add triethylamine (0.20g, 0.28mL, 2.0mmol), in stirring at room temperature reaction 2h, TLC monitoring reaction is complete, and remove solvent under reduced pressure, residuum adds saturated aqueous common salt, extract to water layer without product by ethyl acetate, ethyl acetate washed with water washes three times, and saturated common salt washes three times, and organic layer anhydrous sodium sulfate drying spends the night.Suction filtration, filtrate is spin-dried for, and residuum column chromatography (methylene dichloride: methyl alcohol=200:1) separation and purification, obtains I-3 white solid 0.21g, yield 40.62%, m.p.100 ~ 102 DEG C.Be dissolved in 2mL methylene dichloride by I-3 (0.10g, 0.193mmol), drip the diethyl ether solution of saturated HCl, stir 5 minutes, separate out white solid, suction filtration, obtains I-3HCl 0.09g, yield 84.11%, m.p.132 ~ 135 DEG C.IR(KBr,υcm
-1):3426,2939,2837,2636,2536,2384,1742,1613,1579,1509,1454,1424,1327,1265,1210,1183,1125,1072,1020,946,902,859,796,768,754,698,576.
1H NMR(300MHz,CDCl
3)δ12.47(s,1H),8.22(d,J＝3.6Hz,2H,ArH),7.92–7.76(m,2H,ArH),7.19(dd,J＝8.4,1.8Hz,1H,ArH),7.14(d,J＝1.9Hz,1H,ArH),6.91(d,J＝8.5 Hz,1H,ArH),6.54(s,2H,ArH),6.48(s,2H,ArH),4.22(s,2H,PhCH
2),3.82(s,3H,OCH
3),3.80(s,3H,OCH
3),3.74(s,6H,2×OCH
3),2.64(m,2H,NCH
2),2.34(m,2H,NCH
2),1.99(m,2H,C
H 2CH
2CH
2),1.89(m,2H,CH
2CH
2C
H 2),1.88～1.77(m,2H,CH
2C
H 2CH
2).
13C NMR(75MHz,CDCl
3)δ163.23,152.45,149.78,138.80,133.02,131.98,131.38,131.30,130.52,130.38,129.55,129.03,128.01,127.61,122.55,111.59,105.21,60.42,59.91,55.49,55.44,52.53,22.06,21.50.HR-ESIMS m/z 518.2532[M+H]
+(calcd for C
31H
36NO
6,518.2537).
Embodiment 18
4-(pyrrolidin-1-yl methyl) phenylformic acid-(Z)-2-methoxyl group-5-(3,4,5-trimethoxy styryl) phenyl ester (I-4) hydrochloride
In the 25mL eggplant type bottle that reflux condensing tube is housed, add 7d (241.1mg, 1mmol) and 5mL sulfur oxychloride, return stirring reaction is spent the night, and it is dry to the greatest extent to remove solvent under reduced pressure, directly throws next step.CA-4 (0.316g, 1.0mmol) is dissolved in 5mL methylene dichloride, then pours into be equipped with and above-mentionedly freshly prepare in the eggplant type bottle of acyl chlorides, add triethylamine (0.20g, 0.28mL, 2.0mmol), in stirring at room temperature reaction 2h, TLC monitoring reaction is complete, and remove solvent under reduced pressure, residuum adds saturated aqueous common salt, extract to water layer without product by ethyl acetate, ethyl acetate washed with water washes three times, and saturated common salt washes three times, and organic layer anhydrous sodium sulfate drying spends the night.Suction filtration, filtrate is spin-dried for, and residuum column chromatography (methylene dichloride: methyl alcohol=500:1) separation and purification, obtains I-4 white solid 0.20g, yield 39.76%, m.p.98 ~ 100 DEG C.IR (KBr, υ cm
-1): 3434,2938,2383,2348,2314,1741,1612,1579,1509,1460,1420,1327,1265,1184,1125,1071,1019,860,797,769, I-4 (0.10g, 0.199mmol) is dissolved in 2mL methylene dichloride by 703,582., drips the diethyl ether solution of saturated HCl, stirs 5 minutes, separate out white solid, suction filtration, obtains I-4HCl 0.08g, yield 74.76%, m.p.110 ~ 112 DEG C.IR(KBr,υcm
-1):3422,2938,2837,2569,2469,2362,1747,1624,1578,1541,1508,1454,1427,1345,1327,1257,1207,1153,1126,1006,919,894,856,797,771,747,580,462.
1H NMR(300MHz,CDCl
3)δ12.86(s,1H),8.22(d,J＝7.5Hz,2H,ArH),7.84(d,J＝7.6Hz,2H,ArH),7.19(dd,J
1＝8.4,J
2＝2.0Hz,1H,ArH),7.14(d,J＝2.0Hz,1H,ArH),6.91(d,J＝8.5Hz,1H,ArH),6.54(s,2H,ArH),6.48(d,J＝1.7Hz,2H,ArH),4.30(s,2H,PhCH
2),3.82(s,3H,OCH
3),3.80(s,3H,OCH
3),3.73(s,6H,2×OCH
3),3.70～3.68(m,2H,NCH
2),2.88(m,2H,NCH
2),2.27(m,2H,CH
2),2.08(m,2H,CH
2).
13C NMR(75MHz,CDCl
3)δ163.25,152.43,149.77,138.83,136.46,134.65,131.98,130.59,130.33,130.16,129.55,129.03,128.03,127.54,122.57,111.58,105.22,102.77,60.41,57.32,55.48,55.43,52.81,22.68.HR-ESIMS m/z 504.2384[M+H]
+(calcd for C
30H
34NO
6,504.2381).
Embodiment 19
4-(diethylamine-1-ylmethyl) phenylformic acid-(Z)-2-methoxyl group-5-(3,4,5-trimethoxy styryl) phenyl ester (I-5) hydrochloride
In the 25mL eggplant type bottle that reflux condensing tube is housed, add 7e (243.1mg, 1mmol) and 5mL sulfur oxychloride, return stirring reaction is spent the night, and it is dry to the greatest extent to remove solvent under reduced pressure, directly throws next step.CA-4 (0.316g, 1.0mmol) is dissolved in 5mL methylene dichloride, then pours into be equipped with and above-mentionedly freshly prepare in the eggplant type bottle of acyl chlorides, add triethylamine (0.20g, 0.28mL, 2.0mmol), in stirring at room temperature reaction 2h, TLC monitoring reaction is complete, and remove solvent under reduced pressure, residuum adds saturated aqueous common salt, extract to water layer without product by ethyl acetate, ethyl acetate washed with water washes three times, and saturated common salt washes three times, and organic layer anhydrous sodium sulfate drying spends the night.Suction filtration, filtrate is spin-dried for, and residuum column chromatography (methylene dichloride: methyl alcohol=500:1) separation and purification, obtains white solid I-5 0.25g, yield 49.50%.Be dissolved in 2mL methylene dichloride by I-5 (0.10g, 0.198mmol), drip the diethyl ether solution of saturated HCl, stir 5 minutes, separate out white solid, suction filtration, obtains I-5-HCl 0.09g, yield 84.11%, m.p.115 ~ 118 DEG C.
1H NMR(300MHz,CDCl
3)δ12.66(s,1H),8.26(d,J＝7.5Hz,2H,ArH),7.83(d,J＝7.6Hz,2H,ArH),7.21(dd,J
1＝8.4,J
2＝2.0Hz,1H,ArH),7.16(d,J＝2.0Hz,1H,ArH),6.90(d,J＝8.5Hz,1H,ArH),6.51(s,2H,ArH),6.46(d,J＝1.7Hz,2H,ArH),4.27(s,2H,PhCH
2),3.86(s,3H,OCH
3),3.80(s,3H,OCH
3),3.65(s,6H,OCH
3),3.16(s,2H,NCH
2),3.02(s,2H,NCH
2),1.42(s,6H,N(CH
2C
H 3)
2).
13C NMR(75MHz,CDCl
3)δ163.49,152.15,146.88,136.40,135.96,132.35,132.03,131.04,129.68,129.01,128.65,127.32,126.75,124.38,120.14,109.07,105.48,60.30,55.48,55.34,54.95,45.72,8.05.HR-ESIMS m/z 506.2536[M+H]
+(calcd for C
30H
36NO
6,506.2537).
Embodiment 20
4-((4-methylpiperazine-1-yl) methyl)-3-nitrobenzoic acid-(Z)-2-methoxyl group-5-(3,4,5-trimethoxy styryl) phenyl ester (I-6) hydrochloride
In the 25mL eggplant type bottle that reflux condensing tube is housed, add 7f (0.32g, 1mmol) and 5mL sulfur oxychloride, return stirring reaction is spent the night, and it is dry to the greatest extent to remove solvent under reduced pressure, directly throws next step.CA-4 (0.316g, 1.0mmol) is dissolved in 5mL methylene dichloride, then pours into be equipped with and above-mentionedly freshly prepare in the eggplant type bottle of acyl chlorides, add triethylamine (0.20g, 0.28mL, 2.0mmol), in stirring at room temperature reaction 2h, TLC monitoring reaction is complete, and remove solvent under reduced pressure, residuum adds saturated aqueous common salt, extract to water layer without product by ethyl acetate, ethyl acetate washed with water washes three times, and saturated common salt washes three times, and organic layer anhydrous sodium sulfate drying spends the night.Suction filtration, filtrate is spin-dried for, and residuum column chromatography (methylene dichloride: methyl alcohol=200:1) separation and purification, obtains I-6 white solid 0.23g, yield 39.86%, m.p.70 ~ 72 DEG C.IR (KBr, υ cm
-1): 3438,2937,2837,2796,1746,1618,1579,1537,1509,1455,1426,1355,1328,1282,1263,1241,1208,1127,1011,919,856,819,797,772,742,580,462.
1h NMR (300MHz, CDCl
3) δ 8.57 (d, J=1.3Hz, 1H, ArH), 8.29 (dd, J=8.0,1.5Hz, 1H, ArH), 7.74 (d, J=8.0Hz, 1H, ArH), 7.19 (dd, J=8.5,1.9Hz, 1H, ArH), 7.12 (d, J=1.9Hz, 1H, ArH), 6.91 (d, J=8.5Hz, 1H, ArH), 6.52 (s, 1H, ArH), 6.49 (s, 1H, HC=CH), 3.87 (s, 2H, PhC
h 2n), 3.82 (s, 3H, OCH
3), 3.80 (s, 3H, OCH
3), 3.73 (s, 6H, 2 × OCH
3), 2.70 – 2.38 (m, 8H, piperazine hydrogen), 2.33 (s, 3H, NCH
3).
13c NMR (75MHz, CDCl
3) δ 162.00,152.50,149.66,149.29,138.83,138.64,133.04,131.88,130.79,129.70,129.24,129.04,127.90,127.72,125.61,122.50,111.63,105.33,60.39,58.37,55.44,54.40,52.32,45.27.HR-ESIMS m/z 578.2488 [M+H]
+(calcd for C
31h
36n
3o
8, 578.2497).
Be dissolved in 2mL methylene dichloride by I-6 (0.10g, 0.173mmol), drip the diethyl ether solution of saturated HCl, stir 5 minutes, separate out white solid, suction filtration, obtains I-6HCl 0.08g, yield 75.47%, m.p.144 ~ 146 DEG C.IR(KBr,υcm
-1):3422,2938,2837,2647,2388,1747,1624,1579,1541,1509,1454,1426,1345,1327,1295,1261,1206,1182,1153,1124,1010,948,857,770,747,610,581.
Embodiment 21
4-(morpholine methyl)-3-nitrobenzoic acid-(Z)-2-methoxyl group-5-(3,4,5-trimethoxy styryl) phenyl ester (I-7) hydrochloride
In the 25mL eggplant type bottle that reflux condensing tube is housed, add 7g (0.30g, 1mmol) and 5mL sulfur oxychloride, return stirring reaction is spent the night, and it is dry to the greatest extent to remove solvent under reduced pressure, directly throws next step.CA-4 (0.316g, 1.0mmol) is dissolved in 5mL methylene dichloride, then pours into be equipped with and above-mentionedly freshly prepare in the eggplant type bottle of acyl chlorides, add triethylamine (0.20g, 0.28mL, 2.0mmol), in stirring at room temperature reaction 2h, TLC monitoring reaction is complete, and remove solvent under reduced pressure, residuum adds saturated aqueous common salt, extract to water layer without product by ethyl acetate, ethyl acetate washed with water washes three times, and saturated common salt washes three times, and organic layer anhydrous sodium sulfate drying spends the night.Suction filtration, filtrate is spin-dried for, and residuum column chromatography (methylene dichloride: methyl alcohol=300:1) separation and purification, obtains white solid 0.23g, yield 40.78%, m.p.82 ~ 84 DEG C.IR(KBr,υcm
-1):3467,2960,2932,2852,1745,1615,1578,1530,1511,1451,1426,1412,1351,1339,1322,1269,1243,1207,1115,1082,1027,1009,913,881,868,841,803,767,740,707,582.
1H NMR(300MHz,CDCl
3)δ8.58(s,1H,ArH),8.29(d,J＝7.1Hz,1H,ArH),7.77(d,J＝7.4Hz,1H,ArH),7.23–7.09(m,2H,ArH),6.91(d,J＝7.9Hz,1H,ArH),6.52(s,2H,ArH),6.49(s,2H,HC＝CH),3.86(s,2H,PhC
H 2N),3.82(s,3H,OCH
3),3.80(s,3H,OCH
3),3.73(s,6H,2×OCH
3),3.68(m,4H,O(C
H 2)
2),2.46(m,4H,N(C
H 2)
2).
13C NMR(75MHz,CDCl
3)δ161.94,152.50,149.64,149.32,138.60,138.43,133.06,131.89,130.83,129.68,129.24,129.13,127.88,127.76,125.65,122.46,111.63,105.31,66.38,60.37,58.85,55.43,53.05,29.18.HR-ESIMS m/z 565.2178[M+H]
+(calcd for C
30H
33N
2O
9,565.2181).
Be dissolved in 2mL methylene dichloride by I-7 (0.10g, 0.177mmol), drip the diethyl ether solution of saturated HCl, stir 5 minutes, separate out white solid, suction filtration, obtains I-7HCl 0.08g, yield 75.47%, m.p.216 ~ 219 DEG C.
Embodiment 22
4-(piperidin-1-yl methyl)-3-nitrobenzoic acid-(Z)-2-methoxyl group-5-(3,4,5-trimethoxy styryl) phenyl ester (I-8) hydrochloride
In the 25mL eggplant type bottle that reflux condensing tube is housed, add 7h (0.30g, 1mmol) and 5mL sulfur oxychloride, return stirring reaction is spent the night, and it is dry to the greatest extent to remove solvent under reduced pressure, directly throws next step.CA-4 (0.316g, 1.0mmol) is dissolved in 5mL methylene dichloride, then pours into be equipped with and above-mentionedly freshly prepare in the eggplant type bottle of acyl chlorides, add triethylamine (0.20g, 0.28mL, 2.0mmol), in stirring at room temperature reaction 2h, TLC monitoring reaction is complete, and remove solvent under reduced pressure, residuum adds saturated aqueous common salt, extract to water layer without product by ethyl acetate, ethyl acetate washed with water washes three times, and saturated common salt washes three times, and organic layer anhydrous sodium sulfate drying spends the night.Suction filtration, filtrate is spin-dried for, and residuum column chromatography (methylene dichloride: methyl alcohol=400:1) separation and purification, obtains white solid 0.19g, yield 33.80%, m.p.74 ~ 76 DEG C.IR(KBr,υcm
-1):3467,3002,2931,2853,2782,2747,2335,2330,1745,1615,1578,1528,1512,1464,1447,1424,1412,1348,1337,1320,1290,1274,1239,1222,1176,1158,1112,1081,1027,1012,994,978,912,881,867,841,803,766,740,582.
1H NMR(300MHz,CDCl
3)δ8.58(s,1H,ArH),8.29(d,J＝7.7Hz,1H,ArH),7.83(d,J＝7.4Hz,1H,ArH),7.19(d,J＝8.3Hz,1H,ArH),7.13(s,1H,ArH),6.91(d,J＝8.4Hz,1H,ArH),6.52(s,2H,ArH),6.48(s,2H,HC＝CH),3.81(d,J＝5.9Hz,8H,2×OCH
3and PhC
H 2N),3.73(s,6H,2×OCH
3),2.28–2.48(m,4H,N(C
H 2)
2),1.38–1.49(m,4H,C
H 2CH
2C
H 2),0.97–0.81(m,2H,CH
2C
H 2CH
2).
13C NMR(75MHz,CDCl
3)δ162.10,152.50,149.69,149.22,139.84,138.69,133.01,131.89,130.76,129.70,129.23,128.65,127.92,127.68,125.50,122.54,111.62,105.33,77.04,76.62,76.19,60.38,59.14,55.44,54.17,29.21,25.47,23.61.HR-ESIMS m/z 563.2389[M+H]
+(calcd for C
31H
35N
2O
8,563.2388).
Be dissolved in 2mL methylene dichloride by I-8 (0.10g, 0.178mmol), drip the diethyl ether solution of saturated HCl, stir 5 minutes, separate out white solid, suction filtration, obtains I-8HCl 0.08g, yield 75.12%, m.p.202 ~ 204 DEG C.
Embodiment 23
4-(pyrrolidin-1-yl methyl)-3-nitrobenzoic acid-(Z)-2-methoxyl group-5-(3,4,5-trimethoxy styryl) phenyl ester (II-9) hydrochloride
In the 25mL eggplant type bottle that reflux condensing tube is housed, add 7i (286.1mg, 1mmol) and 5mL sulfur oxychloride, return stirring reaction is spent the night, and it is dry to the greatest extent to remove solvent under reduced pressure, directly throws next step.CA-4 (0.316g, 1.0mmol) is dissolved in 5mL methylene dichloride, then pours into be equipped with and above-mentionedly freshly prepare in the eggplant type bottle of acyl chlorides, add triethylamine (0.20g, 0.28mL, 2.0mmol), in stirring at room temperature reaction 2h, TLC monitoring reaction is complete, and remove solvent under reduced pressure, residuum adds saturated aqueous common salt, extract to water layer without product by ethyl acetate, ethyl acetate washed with water washes three times, and saturated common salt washes three times, and organic layer anhydrous sodium sulfate drying spends the night.Suction filtration, filtrate is spin-dried for, and residuum column chromatography (methylene dichloride: methyl alcohol=200:1) separation and purification, obtains white solid I-9 0.20g, yield 36.50%, m.p.56 ~ 58 DEG C.IR(KBr,υcm
-1):3447,2935,2835,2362,1746,1618,1579,1535,1508,1460,1426,1350,1328,1265,1240,1206,1126,1024,1006,915,892,854,795,739,578.
1H NMR(300MHz,CDCl
3)δ8.63(d,J＝1.5Hz,1H,ArH),8.31(d,J＝8.1Hz,1H, ArH),7.88(d,J＝8.1Hz,1H,ArH),7.19(dd,J＝8.5,2.1Hz,1H,ArH),7.13(d,J＝2.0Hz,1H,ArH),6.91(d,J＝8.5Hz,1H,ArH),6.53(s,2H,ArH),6.49(s,2H,ArH),4.01(s,2H,PhC
H 2N),3.82(s,3H,OCH
3),3.80(s,3H,OCH
3),3.73(s,6H,2×OCH
3),2.54(s,4H N(C
H 2)
2),1.80(s,4H,C
H 2C
H 2).
13C NMR(75MHz,CDCl
3)δ162.13,152.49,149.67,148.65,140.33,138.66,136.61,133.37,131.91,130.61,129.68,129.22,128.54,127.94,127.68,125.59,122.56,111.59,105.26,60.42,56.11,55.55,55.44,53.76,23.24.HR-ESIMS m/z 549.2234[M+H]
+(calcd for C
30H
33N
2O
8,549.2231).
Be dissolved in 2mL methylene dichloride by I-9 (0.10g, 0.182mmol), drip the diethyl ether solution of saturated HCl, stir 5 minutes, separate out white solid, suction filtration, obtains I-9HCl 0.08g, yield 75.47%, m.p.106 ~ 108 DEG C.IR(KBr,υcm
-1):3426,2938,2837,2564,1748,1624,1578,1541,1508,1454,1426,1412,1345,1327,1258,1207,1125,1006,856,797,771,747,581,461.
1H NMR(300MHz,CDCl
3)δ12.93(s,1H,ArH),8.73(m,2H,ArH),8.51(d,J＝6.3Hz,1H,ArH),7.18(dd,J
1＝8.4,J
2＝1.4Hz,1H,ArH),7.11(d,J＝1.4Hz,1H,ArH),6.90(d,J＝8.4Hz,1H,ArH),6.50(s,2H,ArH),6.47(s,2H,ArH),4.73(s,2H,PhC
H 2N),3.84～3.66(m,14H,4×OC
H 3,NC
H 2),3.17～2.94(m,2H,NC
H 2),2.21(m,4H,CH
2CH
2).
Embodiment 24
4-(diethylamine methyl)-3-nitrobenzoic acid-(Z)-2-methoxyl group-5-(3,4,5-trimethoxy styryl) phenyl ester (I-10) hydrochloride
In the 25mL eggplant type bottle that reflux condensing tube is housed, add 7j (288.1mg, 1mmol) and 5mL sulfur oxychloride, return stirring reaction is spent the night, and it is dry to the greatest extent to remove solvent under reduced pressure, directly throws next step.CA-4 (0.316g, 1.0mmol) is dissolved in 5mL methylene dichloride, then pours into be equipped with and above-mentionedly freshly prepare in the eggplant type bottle of acyl chlorides, add triethylamine (0.20g, 0.28mL, 2.0mmol), in stirring at room temperature reaction 2h, TLC monitoring reaction is complete, and remove solvent under reduced pressure, residuum adds saturated aqueous common salt, extract to water layer without product by ethyl acetate, ethyl acetate washed with water washes three times, and saturated common salt washes three times, and organic layer anhydrous sodium sulfate drying spends the night.Suction filtration, filtrate is spin-dried for, and residuum column chromatography (methylene dichloride: methyl alcohol=200:1) separation and purification, obtains white solid I-10 0.23g, yield 41.82%, m.p.96 ~ 98 DEG C.Be dissolved in 2mL methylene dichloride by I-10 (0.10g, 0.182mmol), drip the diethyl ether solution of saturated HCl, stir 5 minutes, separate out white solid, suction filtration, obtains I-10HCl 0.08g, yield 75.05%, m.p.104 ~ 106 DEG C.IR(KBr,υcm
-1):3431,2939,2838,2561,1748,1624,1578,1541,1508,1463,1426,1346,1327,1295,1260,1205,1125,1009,857,797,771,741,580.
1H NMR(300MHz,CDCl
3)δ12.89(s,1H),8.92(d,J＝5.1Hz,1H,ArH),8.76(s,1H,ArH),8.54(d,J＝6.1Hz,1H,ArH),7.21(dd,J＝8.5,1.8Hz,1H,ArH),7.13(d,J＝1.8Hz,1H,ArH),6.92(d,J＝8.5Hz,1H,ArH),6.52(s,2H,ArH),6.49(s,2H,HC＝CH),4.62(s,2H,PhC
H 2N),3.82(s,3H,OCH
3),3.81(s,3H,OCH
3),3.73(s,6H,2×OC
H 3),3.22(s,4H,N(C
H 2CH
3)
2),1.47(s,6H,N(CH
2C
H 3)
2).
13C NMR (75MHz,CDCl
3)δ161.18,152.49,149.47,149.33,138.42,134.87,134.84,131.89,131.86,129.69,129.31,128.12,127.93,127.80,126.34,122.30,111.66,105.28,77.02,76.59,76.17,60.39,55.46,55.43,50.54,46.26,8.14.HR-ESIMS m/z 551.2383[M+H]
+(calcd for C
30H
35N
2O
8,551.2388).
Embodiment 25
Tablet
In Example 20, gained compound 0.5g, starch 2.0g, dextrin 1.0g mix, and make wetting agent with appropriate 30% ethanol, granulate, compressing tablet.
Claims (7)
1. the compound of general formula (I) or its pharmacy acceptable salt:
Wherein R representative: H, halogen, nitro or trifluoromethyl;
Y represents:
2. the compound of claim 1 or its pharmacy acceptable salt, wherein R represents H or nitro.
3. the compound of claim 1 or its pharmacy acceptable salt, wherein Y representative
4. the compound of claim 1 or its pharmacy acceptable salt, wherein pharmacy acceptable salt is the acid salt that general formula (I) compound of claim 1 and following acid are formed: hydrochloric acid, Hydrogen bromide, sulfuric acid, carbonic acid, citric acid, succsinic acid, tartrate, phosphoric acid, lactic acid, pyruvic acid, acetic acid, toxilic acid, methylsulfonic acid, Phenylsulfonic acid, tosic acid or forulic acid.
5. a pharmaceutical composition, wherein containing general formula (I) compound of claim 1 or its pharmacy acceptable salt and pharmaceutically acceptable carrier.
6. the compound of claim 1 or the purposes of its pharmacy acceptable salt in angiogenic disease.
7. the purposes of claim 6, wherein angiogenic disease is tumour or chronic inflammatory diseases.
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