CN104817519B - The derivant of one class CA-4, its preparation method and medical usage thereof - Google Patents

The derivant of one class CA-4, its preparation method and medical usage thereof Download PDF

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CN104817519B
CN104817519B CN201510235806.3A CN201510235806A CN104817519B CN 104817519 B CN104817519 B CN 104817519B CN 201510235806 A CN201510235806 A CN 201510235806A CN 104817519 B CN104817519 B CN 104817519B
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acid
arh
compound
ethyl acetate
layer
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CN104817519A (en
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徐云根
刘坤
宋晓翰
陈泓竹
张宏波
张灵芝
朱启华
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China Pharmaceutical University
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D295/00Heterocyclic 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
    • C07D295/04Heterocyclic 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
    • C07D295/14Heterocyclic 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
    • C07D295/155Heterocyclic 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
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/38Compounds 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 present invention relates to medicinal chemistry art, be specifically related to the derivant (I) of a class Combretastatin A 4, their preparation method and the inhibitory action to tumor-blood-vessel growth.The pharmacological results shows, the compound of the present invention has stronger inhibitory action to MCF 7 human breast cancer cell propagation, meanwhile, part of compounds also has good inhibiting effect to the propagation of Human umbilical vein endothelial cells and the generation of chick chorioallantoic membrane new vessels.Therefore, the compounds of this invention may be used for treating the various disease relevant to angiogenesis, and these diseases include various cancer and chronic inflammatory disease and other angiogenic disease.The compound of the present invention has good water solublity.

Description

The derivant of one class CA-4, its preparation method and medical usage thereof
Technical field
The present invention relates to medicinal chemistry art, be specifically related to a class Combretastatin A-4 (CA-4) derivant, Their preparation method and to tumor vascular inhibitory action.
Background technology
CA-4 is the little molecule vascular disrupting agents separated from the Combretum Caffnom bark in South Africa (Vascular Disrupting Agents, VDA), the colchicine of its energy combining with vascular endothelial cell tubulin β subunit Binding site, causes the polymerization of tubulin, and then changes framing structure and the form of its endotheliocyte, strengthens its Vascular permeability Property, upset blood flow, thus cause tumor vascular endothelial cell apoptosis, cause secondary death of neoplastic cells.Although CA-4 has latent Biological activity, but its low aqueous solubility and low bioavailability limit further application.
Summary of the invention
The invention discloses a class compounds of formula I.The compound of the present invention has good water solublity.Pharmacological evaluation Result shows, the compound of the present invention has stronger inhibitory action, meanwhile, partization to MCF-7 human breast cancer cell propagation Compound is to the propagation of Human umbilical vein endothelial cells and chick chorioallantoic membrane (Chicken chorioallactoic Membrane, CAM) generation of new vessels also has good inhibiting effect.Therefore, the compound of formula I of the present invention may be used for Treating the various disease relevant to angiogenesis, these diseases include various cancer and chronic inflammatory disease and other is angiogenic Disease.
The 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 represents:
Y is preferred:
The compound of Formulas I can form acid-addition salts with pharmaceutically acceptable acid, and described acid includes hydrochloric acid, hydrobromic acid, sulfur Acid, carbonic acid, citric acid, succinic acid, tartaric acid, phosphoric acid, lactic acid, acetone acid, acetic acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, to first Benzenesulfonic acid or ferulic acid.
Part of compounds of the present invention is:
4-((4-methylpiperazine-1-yl) methyl) benzoic acid-(Z)-2-methoxyl group-5-(3,4,5-trimethoxy styryl) Phenyl ester (I-1)
4-(morpholine methyl) benzoic acid-(Z)-2-methoxyl group-5-(3,4,5-trimethoxy styryl) phenyl ester (I-2)
4-(piperidin-1-yl methyl) benzoic acid-(Z)-2-methoxyl group-5-(3,4,5-trimethoxy styryl) phenyl ester (I- 3)
4-(pyrrolidin-1-yl methyl) benzoic acid-(Z)-2-methoxyl group-5-(3,4,5-trimethoxy styryl) phenyl ester (I-4)
4-(diethylamine-1-ylmethyl) benzoic 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 benzene Vinyl) 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 styrene Base) 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:
By 3,4,5-trimethoxy phenyl acetic acid (1) and 3-hydroxy-4-methyl benzaldehyde (2) prepare compound 3, are to react Thing is condensed to yield under triethylamine and acetic anhydride effect.
Prepared 4 by compound 3, be that reactant is obtained in quinoline/copper powder and 200 DEG C of high temperature decarboxylation.
Prepared 6 by compound 5, be that reactant is dissolved in chloroform, add NBS and initiator benzoyl peroxide reacts Arrive.
Prepared 7 by compound 6, be to be dissolved in 6 in solvent, under acid binding agent effect with It is condensed to yield.Acid binding agent is selected from triethylamine, diisopropyl ethyl amine, pyridine, carbonic acid Potassium, potassium bicarbonate, sodium carbonate, sodium bicarbonate, preferably potassium carbonate.Solvent is selected from toluene/water, oxolane/water, acetone/water, second Nitrile/water, preferably toluene/water.
Prepared 8 by compound 7, be reactant to be placed in 20% concentrated hydrochloric acid backflow obtain.
Prepared 9 by compound 8, be compound 12 and chlorinating agent to be carried out chloro obtain.Wherein chlorinating agent is selected from protochloride Sulfone, oxalyl chloride, phosphorus oxychloride, preferably thionyl chloride.
Prepared target compound I by compound 9, be by compound 13 under acid binding agent effect with compound 4 in a solvent It is condensed to yield.Acid binding agent is selected from triethylamine, diisopropyl ethyl amine, pyridine, potassium carbonate, potassium bicarbonate, sodium carbonate, bicarbonate Sodium, preferably triethylamine.Solvent is selected from dichloromethane, oxolane, acetonitrile, acetone, DMF, preferably dichloromethane.
Another object of the present invention is to provide a kind of pharmaceutical composition, it includes the change of the present invention of medicine effective dose Compound or its salt and pharmaceutically acceptable carrier.
Compound of the present invention can add pharmaceutically acceptable carrier and make common pharmaceutical formulation, such as sheet Agent, capsule, powder, syrup, liquor, suspending agent, injection, can add spice, sweeting agent, liquid or solid filler or diluent Etc. common medicinal supplementary material.
Compound of the present invention administering mode clinically can be to use the modes such as oral, injection.
Usually, when the CA-4 derivant of the present invention is used for treating, people's dosage range is 1mg~1000mg/ days.Also may be used Difference according to dosage form and disease severity, using dosage exceeds this scope.
The following is pharmacological testing and the result of part of compounds of the present invention.
1, the srb assay detection test-compound proliferation function to MCF-7 and HUVECs cell
Passage, to logarithmic growth after date, digests through pancreas enzyme-EDTA liquid, adjusts final concentration of 5 × 104/ mL, is inoculated in 96 In orifice plate, every hole 200 μ L, edge hole fills with aseptic PBS, 5%CO2, hatch for 37 DEG C.(it is paved with at the bottom of hole to cell monolayer after 24h (96 hole flat underside)), discard on plate original liquid in each hole, then change the cell culture fluid containing respective concentration medicine respectively, In 37 DEG C, 5%CO2Cultivating in incubator, the every concentration of various medicines sets 5 parallel holes.It is molten that SRB is made into 0.4% with 1% acetic acid Liquid.Cell terminates (48h) in dosing cultivation to be fixed with trichloroacetic acid (TCA) afterwards: each aperture of attached cell adds the 50% of pre-cooling TCA liquid 50uL (final concentration of 10%) fixes;Culture fluid surface must be added in when adding TCA gently, first stand 5min and the most again will Flat board moves to 4 DEG C and places 1h, and this like cell is fixed on the bottom of culture hole.Outwelling fixative, aperture sterilizing tri-distilled water washes 5 Time, drying, air is dried.Every hole adds 0.4%SRB solution 100 μ L, lucifuge, places 10min in room temperature.Not with protein binding SRB 1%TCA liquid wash 5 times, air is dried.In conjunction with SRB with 150uL10mmol/L non-buffered Tris alkali liquor (pH 10.5) Dissolve, be placed on 5min on micro oscillator, lucifuge.Measure OD value at enzyme-linked immunosorbent assay instrument, return to zero with blank, at wavelength For measuring the OD value of each aperture at 490nm.Obtained growth of tumour cell suppression ratio is defined as the body of drug on tumor cell Outer suppression ratio also calculates IC50Value.Suppression ratio=(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)
The MCF-7 tumor cell proliferation inhibition activity of majority of compounds is we can see that relatively from table 1 experimental result Positive drug CA-4 (IC50=0.058 μM) higher, simultaneously compared with the strong an order of magnitude of amycin, wherein compound I-3 (IC50= 0.024 μM) activity be significantly stronger than CA-4.
Table 2 part of compounds to the inhibitory action of cell proliferation of human umbilical vein (N=3)
Experimental result shows, surveyed compound has strong inhibitory action to Human umbilical vein endothelial cells.
2, chick chorioallantoic membrane angiogenesis inhibitor experiment
6 days hatching egg warm water is cleaned 2 times, puts into 37 DEG C of incubators after soaking 3min in 1:1000 bromo geramine relative Humidity 65%, hatching egg air chamber upwards, overturns 1 time/2h of hatching egg, to incubation the 6th day, observes hatching egg growing state under egg candler, Reject unfertilized egg.Prick 1 duck eye with dissecting needle on air chamber top, the allantochorion of Embryo Gallus domesticus can be made to divide with the inner shell membrane of egg Open.Under egg candler find embryo head, germ cell before fetal head between two anterior vitelline veins of 1cm chorion projection part mark The square area of 1.0cm × 1.0cm, cuts through chorion with emery wheel along this region mill and goes out indenture to eggshell surface scribing, gently take off Recess egg skin, tears inner shell membrane gently, now visible at this CAM sink together with Embryo Gallus domesticus, false air chamber is formed and (is different from self Air chamber).With sealed membrane sealing label vacation air chamber, form transparent windows, continue to put into 37 DEG C of incubators and hatch 1 day.Took in second day Go out egg, reject rotten egg.Residue egg is divided into: blank group, DMSO group, positive drug group (10,2.5,1 μ g/), and waits Select compound group (10 μ g/), often organize each 3, tear sealed membrane gently, the cellulose mixture micropore filter of cut-off footpath about 0.5cm Diaphragm (autoclaving in advance), as carrier, is placed in the content-addressable memory face just to observation window, avoids big blood vessel, inhales with aseptic sample injector Take each group of corresponding medicinal liquid to drip in carrier surface central authorities.After dosing 2d, remove adhesive tape, observe, record around observation window CAM also takes pictures.With Graph Pad 5.0 statistical software, tiny blood vessels quantity is added up.
We are with angiogenesis inhibitor lenalidomide as positive control, with the dosage of the 10 μ g/ eggs compound to synthesis Carry out chick chorioallantoic membrane angiogenesis inhibitor experiment, investigate compound Agiogenesis inhibition in animal body and live Property.Result is shown in Fig. 1.
It will be seen that under the dosage of 10 μ g/ eggs, surveyed target compound all has CAM in various degree from Fig. 1 Angiogenesis inhibitor activity, wherein the activity of compound I-1, I-2, I-3 and I-6 is preferably, with positive drug lenalidomide phase When, and CA-4 demonstrates serious fetal toxicity under this dosage (10 μ g/ egg), Embryo Gallus domesticus cannot continue to grow, and points out targeted The toxicity of compound relatively CA-4 substantially reduces.
We are with angiogenesis inhibitor lenalidomide and CA-4 as positive control, with 1,2.5,10 three dosage of μ g/ egg Compound I-1 and I-6 is carried out chick chorioallantoic membrane angiogenesis inhibitor experiment, investigates them further raw to blood vessel The inhibitory activity become.Result is shown in Fig. 2.
Figure it is seen that under the dosage of 10 μ g/ eggs, compound I-1 and I-6 shows the new hemopoietic of stronger CAM Pipe generates inhibitory activity.CA-4 i.e. demonstrates fetal toxicity under 2.5 μ g/ egg dosage, and under 10 μ g/ egg dosage, fetal toxicity is more Greatly, Embryo Gallus domesticus cannot continue to grow.
Accompanying drawing explanation
Fig. 1 is that compound is to CAM angiogenesis inhibitor activity
Fig. 2 is that compound is to CAM angiogenesis inhibitor activity
Detailed description of the invention
Embodiment 1
(E)-3-(3 '-hydroxyl-4 '-methoxyl group) phenyl 2-(3 ", 4 ", 5 "-trimethoxy) conjunction of phenyl-acrylic acid (3) Become
3,4,5-trimethoxy phenyl acetic acid (50.0g, 0.22mol), 3-hydroxyl-4-methoxy is added in 500mL three-necked bottle Benzaldehyde (34.0g, 0.22mol), 62.5mL triethylamine and 150mL acetic anhydride, N2The lower stirring of protection is warming up to 140 DEG C, instead Answer 12h, stop heating, be cooled under 10 DEG C, ice bath be slowly added dropwise under concentrated hydrochloric acid 200mL, room temperature and be stirred overnight.There is khaki solid Body separates out, and stopped reaction filters out solid, with about 200mL ethyl alcohol recrystallization, obtains 47.5g yellow needles 3, and productivity is 59.6%, m.p.184~186 DEG C.1H NMR(300MHz,DMSO-d6),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, J1=8.5, J2=1.8Hz, 1H, ArH), 6.54 (d, J=1.8Hz, 1H, ArH), 6.44 (s, 2H, ArH), 3.73 (s, 3H, OCH3),3.71(s,3H, OCH3),3.69(s,6H,2×OCH3).
Embodiment 2
-3 ", 4 ', 4 ", (Z) 5 "-tetramethoxy-3 ' synthesis of-hydroxy stibene (CA-4,4)
Equipped with thermometer, reflux condensing tube, drying tube 500mL three-necked bottle in add 3 (7.2g, 20mmol), brand-new Copper powder (6.6g, 0.103mol), quinoline 72mL, N2The lower reaction of protection is heated to 200 DEG C, stirs 4h.It is cooled to room temperature, adds second Ether is appropriate, uses filtered off through Celite copper powder.With 300mL 5M HCl, quinoline is washed off, extract with ether 150mL, the water that will separate Layer ether is washed (3 × 150mL), merges organic layer.Organic layer is washed once with 500mL respectively, saturated Na2CO3(2×300mL) Washing twice, saturated NaCl (2 × 300mL) washes twice, anhydrous Na2SO4It is dried overnight.Filtering off sodium sulfate, decompression spins off 2/3 volume Ether, have slightly yellow solid to separate out, leach solid and wash with appropriate ether, reclaiming mother solution, then remove partial solvent, will analysis The solid gone out leaches, and there are product 45.0g, productivity 79.1%, m.p.116~117 DEG C.1HNMR(300Hz,DMSO-d6):δ 8.94 (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, OCH3),3.63 (s,3H,OCH3),3.59(s,6H,2×OCH3).
Embodiment 3
The synthesis of 4-bromomethyl-benzoic acid methyl ester (6a)
5a (15.0g, 0.1mol) is dissolved in chloroform (80mL), add NBS (17.8g, 0.1mol) and BPO (45mg, 0.18mmol), being heated to backflow, stirring reaction 2.5h, cooling separates out white solid, and sucking filtration, filtrate decompression is evaporated off solvent, obtains slightly Product pale yellow oily liquid body 14.50g, silica gel column chromatography (petrol ether/ethyl acetate=100/1), obtain colourless transparent liquid 6a 12.78g, yield 82.34%.1H NMR(300MHz,CDCl3) δ 8.03 (d, J=8.0Hz, 2H, ArH), 7.47 (d, J= 7.9Hz,2H,ArH),4.51(s,2H,CH2),3.93(s,3H,OCH3).MS(ESI(+)70eV,m/z):229.0[M+H]+.
Embodiment 4
The synthesis of 4-bromomethyl-3-nitrobenzene methyl (6b)
5a (19.50g, 0.1mol) is dissolved in chloroform (100mL), add NBS (17.8g, 0.1mol) and BPO (45mg, 0.18mmol), being heated to backflow, stirring reaction 2.5h, cooling separates out white solid, and sucking filtration, filtrate decompression is evaporated off solvent, obtains slightly Product pale yellow oily liquid body 6b 22.50g, the most purified direct throwing next step.
Embodiment 5
The synthesis of 4-((4-methylpiperazine-1-yl) methyl) benzoate hydrochlorate (7a)
Equipped with in the 50mL eggplant type bottle of reflux condensing tube add 6a (4.90g, 21.49mmol), N methyl piperazine (2.67g, 26.87mmol), potassium carbonate (2.31g, 16.74mmol), 10mL toluene and 6mL water, in 75 DEG C of stirring reactions 12 hours, TLC supervised Survey raw material reaction is complete, stops heating and stirring, separates toluene layer, and 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.Water layer is used full after being washed till free from admixture by ethyl acetate again Adjust pH to alkalescence with sodium bicarbonate aqueous solution, be extracted with ethyl acetate to water layer without product, combined ethyl acetate layer.Ethyl acetate Layer washes with water three times, and saturated common salt is washed three times, and anhydrous sodium sulfate is dried overnight.Sucking filtration, removes solvent under reduced pressure, adds in residue Entering 20mL 20% hydrochloric acid, temperature control is in 100 DEG C of stirring reactions overnight.Cooling, in low temperature low rate mixing, separates out white solid, takes out Filter, obtains intermediate 7a 3.34g, yield 50.76%, m.p.310~311 DEG C.1H NMR(300MHz,D2O) δ 7.90 (d, J= 8.3Hz, 2H, ArH), 7.43 (d, J=8.3Hz, 2H, ArH), 4.32 (s, 2H, PhCH2),3.44(m,8H,N(CH2)4),2.81 (s,3H,CH3).MS(ESI(+)70eV,m/z):235.1[M+H]+.
Embodiment 6
The synthesis of 4-(4-morpholine methyl) benzoate hydrochlorate (7b)
Equipped with in the 50mL eggplant type bottle of reflux condensing tube add 6a (4.90g, 21.49mmol), morpholine (2.34g, 26.87mmol), potassium carbonate (2.31g, 16.74mmol), 10mL toluene and 6mL water, in 75 DEG C of stirring reactions 12 hours, TLC supervised Survey raw material reaction is complete, stops heating and stirring, separates toluene layer, and 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.Water layer is used full after being washed till free from admixture by ethyl acetate again Adjust pH to alkalescence with sodium bicarbonate aqueous solution, be extracted with ethyl acetate to water layer without product, combined ethyl acetate layer.Ethyl acetate Layer washes with water three times, and saturated common salt is washed three times, and anhydrous sodium sulfate is dried overnight.Sucking filtration, removes solvent under reduced pressure, adds in residue Entering 20mL 20% hydrochloric acid, temperature control is in 100 DEG C of stirring reactions overnight.Cooling, in low temperature low rate mixing, separates out white solid, takes out Filter, obtains intermediate 7b 3.64g, yield 65.94%, m.p.295~297 DEG C.1H NMR(300MHz,D2O) δ 7.84 (d, J= 8.3Hz, 2H, ArH), 7.39 (d, J=8.3Hz, 2H, ArH), 4.23 (s, 2H, PhCH2), 3.88 (d, J=11.3Hz, 2H, OCH2), 3.56 (t, J=12.1Hz, 2H, OCH2), 3.23 (d, J=12.5Hz, 2H, NCH2),3.14–2.98(m,2H, NCH2).MS(ESI(+)70eV,m/z):222.1[M+H]+.
Embodiment 7
The synthesis of 4-(piperidin-1-yl methyl) benzoate hydrochlorate (7c)
Equipped with in the 50mL eggplant type bottle of reflux condensing tube add 6a (4.90g, 21.49mmol), piperidines (2.29g, 26.87mmol), potassium carbonate (2.31g, 16.74mmol), 10mL toluene and 6mL water, in 75 DEG C of stirring reactions 12 hours, TLC supervised Survey raw material reaction is complete, stops heating and stirring, separates toluene layer, and 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.Water layer is used full after being washed till free from admixture by ethyl acetate again Adjust pH to alkalescence with sodium bicarbonate aqueous solution, be extracted with ethyl acetate to water layer without product, combined ethyl acetate layer.Ethyl acetate Layer washes with water three times, and saturated common salt is washed three times, and anhydrous sodium sulfate is dried overnight.Sucking filtration, removes solvent under reduced pressure, adds in residue Entering 20mL 20% hydrochloric acid, temperature control is in 100 DEG C of stirring reactions overnight.Cooling, in low temperature low rate mixing, separates out white solid, takes out Filter, obtains intermediate 7c 3.41g, yield 62.23%, m.p.282~284 DEG C.1H NMR(300MHz,D2O) δ 7.86 (d, J= 8.3Hz, 2H, ArH), 7.38 (d, J=8.3Hz, 2H, ArH), 4.13 (s, 2H, PhCH2), 3.26 (d, J=11.9Hz, 2H, NCH2),2.77(dd,J1=12.4,10.0Hz, J2=2H, NCH2), 1.82~1.13 (m, 6H, CH2CH2CH2).MS(ESI(+) 70eV,m/z):220.3[M+H]+.
Embodiment 8
The synthesis of 4-(pyrrolidin-1-yl methyl) benzoate hydrochlorate (7d)
Equipped with in the 50mL eggplant type bottle of reflux condensing tube add 6a (4.90g, 21.49mmol), pyrrolidine (1.91g, 26.87mmol), potassium carbonate (2.31g, 16.74mmol), 10mL toluene and 6mL water, in 75 DEG C of stirring reactions 12 hours, TLC supervised Survey raw material reaction is complete, stops heating and stirring, separates toluene layer, and 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.Water layer is used full after being washed till free from admixture by ethyl acetate again Adjust pH to alkalescence with sodium bicarbonate aqueous solution, be extracted with ethyl acetate to water layer without product, combined ethyl acetate layer.Ethyl acetate Layer washes with water three times, and saturated common salt is washed three times, and anhydrous sodium sulfate is dried overnight.Sucking filtration, removes solvent under reduced pressure, adds in residue Entering 20mL 20% hydrochloric acid, temperature control is in 100 DEG C of stirring reactions overnight.Cooling, in low temperature low rate mixing, separates out white solid, takes out Filter, obtains intermediate 7d 3.11g, yield 60.04%, m.p.278~281 DEG C.1H NMR(300MHz,D2O) δ 7.81 (d, J= 8.3Hz, 2H, ArH), 7.36 (d, J=8.3Hz, 2H, ArH), 4.21 (s, 2H, PhCH2), 3.28 (dd, J=10.6,5.3Hz, 2H,NCH2),2.97(dt,J1=10.7, J2=7.7Hz, 2H, NCH2),2.04–1.87(m,2H,CH2), 1.84~1.69 (m, 2H,CH2).MS(ESI(+)70eV,m/z):206.1[M+H]+.
Embodiment 9
The synthesis of 4-(diethylamine methyl) benzoate hydrochlorate (7e)
Equipped with in the 50mL eggplant type bottle of reflux condensing tube add 6a (4.90g, 21.49mmol), diethylamine (1.97g, 26.87mmol), potassium carbonate (2.31g, 16.74mmol), 10mL toluene and 6mL water, in 75 DEG C of stirring reactions 12 hours, TLC supervised Survey raw material reaction is complete, stops heating and stirring, separates toluene layer, and 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.Water layer is used full after being washed till free from admixture by ethyl acetate again Adjust pH to alkalescence with sodium bicarbonate aqueous solution, be extracted with ethyl acetate to water layer without product, combined ethyl acetate layer.Ethyl acetate Layer washes with water three times, and saturated common salt is washed three times, and anhydrous sodium sulfate is dried overnight.Sucking filtration, removes solvent under reduced pressure, adds in residue Entering 20mL 20% hydrochloric acid, temperature control is in 100 DEG C of stirring reactions overnight.Cooling, in low temperature low rate mixing, separates out white solid, takes out Filter, obtains intermediate 7e 3.27g, yield 62.64%, m.p.285~288 DEG C.1H NMR(300MHz,D2O) δ 7.83 (d, J= 8.3Hz, 2H, ArH), 7.37 (d, J=8.3Hz, 2H, ArH), 4.17 (s, 2H, PhCH2),3.26–2.72(m,4H,N (CH 2CH3)2), 1.09 (t, J=7.3Hz, 6H, N (CH2CH 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 hydrochlorate (7f)
Equipped with in the 25mL eggplant type bottle of reflux condensing tube add 6b (1.00g, 3.66mmol), N methyl piperazine (0.46g, 4.58 mmol), potassium carbonate (0.39g, 2.85mmol), 2mL toluene and 1.2mL water, in 75 DEG C of stirring reactions 12 hours, TLC supervised Survey raw material reaction is complete, stops heating and stirring, separates toluene layer, and 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.Water layer is used full after being washed till free from admixture by ethyl acetate again Adjust pH to alkalescence with sodium bicarbonate aqueous solution, be extracted with ethyl acetate to water layer without product, combined ethyl acetate layer.Ethyl acetate Layer washes with water three times, and saturated common salt is washed three times, and anhydrous sodium sulfate is dried overnight.Sucking filtration, removes solvent under reduced pressure, adds in residue Entering 10mL 20% hydrochloric acid, temperature control is in 100 DEG C of stirring reactions overnight.Cooling, in low temperature low rate mixing, separates out white solid, takes out Filter, obtains intermediate 7f 0.95g, yield 73.64%, m.p.315~318 DEG C.1H NMR(300MHz,D2O)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, PhCH2),3.88– 3.15(m,8H,N(CH 2)4N),2.81(s,3H,CH3).MS(ESI(+)70eV,m/z):280.1[M+H]+.
Embodiment 11
The synthesis of 4-(morpholine methyl)-3-nitrobenzoic acid hydrochlorate (7g)
Equipped with in the 25mL eggplant type bottle of reflux condensing tube add 6b (1.00g, 3.66mmol), morpholine (0.40g, 4.58mmol), potassium carbonate (0.39g, 2.85mmol), 2mL toluene and 1.2mL water, in 75 DEG C of stirring reactions 12 hours, TLC supervised Survey raw material reaction is complete, stops heating and stirring, separates toluene layer, and 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.Water layer is used full after being washed till free from admixture by ethyl acetate again Adjust pH to alkalescence with sodium bicarbonate aqueous solution, be extracted with ethyl acetate to water layer without product, combined ethyl acetate layer.Ethyl acetate Layer washes with water three times, and saturated common salt is washed three times, and anhydrous sodium sulfate is dried overnight.Sucking filtration, removes solvent under reduced pressure, adds in residue Entering 10mL 20% hydrochloric acid, temperature control is in 100 DEG C of stirring reactions overnight.Cooling, in low temperature low rate mixing, separates out white solid, takes out Filter, obtains intermediate 7g 0.76g, yield 68.47%, m.p.303~305 DEG C.1H NMR(300MHz,D2O) δ 8.61 (d, J= 1.6Hz,1H,ArH),8.17(dd,J1=7.9, J2=1.7Hz, 1H, ArH), 7.66 (d, J=7.9Hz, 1H, ArH), 4.53 (s,2H,PhCH2),3.59(m,8H,N(CH 2)4O).MS(ESI(+)70eV,m/z):267.1[M+H]+.
Embodiment 12
The synthesis of 4-((piperidin-1-yl) methyl)-3-nitrobenzoic acid hydrochlorate (7h)
Equipped with in the 25mL eggplant type bottle of reflux condensing tube add 6b (1.00g, 3.66mmol), piperidines (0.39g, 4.58mmol), potassium carbonate (0.39g, 2.85mmol), 2mL toluene and 1.2mL water, in 75 DEG C of stirring reactions 12 hours, TLC supervised Survey raw material reaction is complete, stops heating and stirring, separates toluene layer, and 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.Water layer is used full after being washed till free from admixture by ethyl acetate again Adjust pH to alkalescence with sodium bicarbonate aqueous solution, be extracted with ethyl acetate to water layer without product, combined ethyl acetate layer.Ethyl acetate Layer washes with water three times, and saturated common salt is washed three times, and anhydrous sodium sulfate is dried overnight.Sucking filtration, removes solvent under reduced pressure, adds in residue Entering 10mL 20% hydrochloric acid, temperature control is in 100 DEG C of stirring reactions overnight.Cooling, in low temperature low rate mixing, separates out white solid, takes out Filter, obtains intermediate 7h 0.81g, yield 73.64%, m.p.298~301 DEG C.1H NMR(300MHz,D2O) δ 8.59 (d, J= 1.6Hz,1H,ArH),8.15(dd,J1=7.9, J2=1.6Hz, 1H, ArH), 7.63 (d, J=7.9Hz, 1H, ArH), 4.41 (s,2H,PhCH2), 3.44 (d, J=12.1Hz, 2H, NCH2), 3.02 (t, J=12.0Hz, 2H, NCH2), 1.75 (d, J= 14.8Hz,2H CH 2CH2CH2),1.66–1.44(m,2H CH2CH2CH 2), 1.34 (dd, J=16.2,8.2Hz, 2HCH2CH 2CH2).MS(ESI(+)70eV,m/z):265.1[M+H]+.
Embodiment 13
The synthesis of 4-((pyrrolidin-1-yl) methyl)-3-nitrobenzoic acid hydrochlorate (7i)
Equipped with in the 25mL eggplant type bottle of reflux condensing tube add 6b (1.00g, 3.66mmol), pyrrolidine (3.26g, 4.58mmol), potassium carbonate (0.39g, 2.85mmol), 2mL toluene and 1.2mL water, in 75 DEG C of stirring reactions 12 hours, TLC supervised Survey raw material reaction is complete, stops heating and stirring, separates toluene layer, and 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.Water layer is used full after being washed till free from admixture by ethyl acetate again Adjust pH to alkalescence with sodium bicarbonate aqueous solution, be extracted with ethyl acetate to water layer without product, combined ethyl acetate layer.Ethyl acetate Layer washes with water three times, and saturated common salt is washed three times, and anhydrous sodium sulfate is dried overnight.Sucking filtration, removes solvent under reduced pressure, adds in residue Entering 10mL 20% hydrochloric acid, temperature control is in 100 DEG C of stirring reactions overnight.Cooling, in low temperature low rate mixing, separates out white solid, takes out Filter, obtains intermediate 7i 0.69g, yield 65.71%, m.p.293~296 DEG C.1H NMR(300MHz,D2O) δ 8.59 (d, J= 1.5Hz,1H,ArH),8.17(dd,J1=7.9, J2=1.6Hz, 1H, ArH), 7.66 (d, J=8.0Hz, 1H, ArH), 4.53 (s,2H,PhCH2), 3.48 (d, J=5.1Hz, 2H, NCH2),3.32–3.00(m,2H,NCH2),2.03(s,2H,CH2),1.83 (dd,J1=7.4, J2=5.1Hz, 2H, CH2).MS(ESI(+)70eV,m/z):251.1[M+H]+.
Embodiment 14
The synthesis of 4-(diethylamine methyl)-3-nitrobenzoic acid hydrochlorate (7j)
Equipped with in the 25mL eggplant type bottle of reflux condensing tube add 6b (1.00g, 3.66mmol), diethylamine (0.33g, 4.58mmol), potassium carbonate (0.39g, 2.85mmol), 2mL toluene and 1.2mL water, in 75 DEG C of stirring reactions 12 hours, TLC supervised Survey raw material reaction is complete, stops heating and stirring, separates toluene layer, and 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.Water layer is used full after being washed till free from admixture by ethyl acetate again Adjust pH to alkalescence with sodium bicarbonate aqueous solution, be extracted with ethyl acetate to water layer without product, combined ethyl acetate layer.Ethyl acetate Layer washes with water three times, and saturated common salt is washed three times, and anhydrous sodium sulfate is dried overnight.Sucking filtration, removes solvent under reduced pressure, adds in residue Entering 10mL 20% hydrochloric acid, temperature control is in 100 DEG C of stirring reactions overnight.Cooling, in low temperature low rate mixing, separates out white solid, takes out Filter, obtains intermediate 7j 0.78g, yield 73.58%, m.p.286~289 DEG C.1H NMR(300MHz,D2O) δ 8.63 (d, J= 1.7Hz,1H,ArH),8.17(dd,J1=7.9, J2=1.7Hz, 1H, ArH), 7.65 (d, J=8.0Hz, 1H, ArH), 4.49 (s,2H,PhCH2), 3.16 (q, J=7.3Hz, 4H, NCH2), 1.17 (t, J=7.3Hz, 6H, CH3).MS(ESI(+)70eV,m/ z):253.1[M+H]+.
Embodiment 15
4-((4-methylpiperazine-1-yl) methyl) benzoic acid-(Z)-2-methoxyl group-5-(3,4,5-trimethoxy styryl) Phenyl ester (I-1)
Adding 7a (0.27g, 1mmol) and 5mL thionyl chloride in equipped with the 25mL eggplant type bottle of reflux condensing tube, backflow is stirred Mixing reaction overnight, it is the most dry to remove solvent under reduced pressure, directly throws next step.CA-4 (0.316g, 1.0mmol) is dissolved in 5mL dichloromethane In alkane, it is subsequently poured into equipped with in the above-mentioned fresh eggplant type bottle preparing acyl chlorides, adds triethylamine (0.20g, 0.28mL, 2.0mmol), Reaction 2h, TLC monitoring reaction being stirred at room temperature complete, remove solvent under reduced pressure, residue adds saturated aqueous common salt, uses ethyl acetate Extraction is to water layer without product, and ethyl acetate washed with water is washed three times, and saturated common salt is washed three times, and organic layer anhydrous sodium sulfate is dried Night.Sucking filtration, filtrate is spin-dried for, and residue column chromatography (dichloromethane: methanol=200:1) is isolated and purified, obtains white solid I-1 0.23g, yield 43.40%, m.p.102~104 DEG C.IR(KBr,υcm-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,CDCl3) 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, OCH3),3.79(s,3H,OCH3),3.73(s,6H,2×OCH3),3.62(s,2H,PhCH2), 2.77~2.60 (m, 8H, piperazines Hydrogen), 2.48 (s, 3H, NCH3).HR-ESIMS m/z 533.2656[M+H]+(calcd for C31H37N2O6,533.2646).
I-1 (0.10g, 0.19mmol) is dissolved in 2mL dichloromethane, drips the diethyl ether solution of saturated HCl, stir 5 points Clock, separates out white solid, sucking filtration, obtains I-1 HCl 0.07g, yield 61.57%, m.p.234~236 DEG C.
Embodiment 16
4-(morpholine methyl) benzoic acid-(Z)-2-methoxyl group-5-(3,4,5-trimethoxy styryl) phenyl ester (I-2) hydrochloric acid Salt
Adding 7b (0.26g, 1mmol) and 5mL thionyl chloride in equipped with the 25mL eggplant type bottle of reflux condensing tube, backflow is stirred Mixing reaction overnight, it is the most dry to remove solvent under reduced pressure, directly throws next step.CA-4 (0.316g, 1.0mmol) is dissolved in 5mL dichloromethane In alkane, it is subsequently poured into equipped with in the above-mentioned fresh eggplant type bottle preparing acyl chlorides, adds triethylamine (0.20g, 0.28mL, 2.0mmol), Reaction 2h, TLC monitoring reaction being stirred at room temperature complete, remove solvent under reduced pressure, residue adds saturated aqueous common salt, uses ethyl acetate Extraction is to water layer without product, and ethyl acetate washed with water is washed three times, and saturated common salt is washed three times, and organic layer anhydrous sodium sulfate is dried Night.Sucking filtration, filtrate is spin-dried for, and residue column chromatography (dichloromethane: methanol=200:1) is isolated and purified, 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,CDCl3) δ 8.11 (d, J=8.2Hz, 2H, ArH), 7.47 (d, J =8.1Hz, 2H, ArH), 7.17 (dd, J1=8.4, J2=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, OCH3), 3.79(s,3H,OCH3),3.73(m,10H,PhCH2,2×OCH3and OCH2),3.58(m,2H,OCH2), 2.40~2.57 (m, 4H,N(CH2)2).13C NMR(75MHz,CDCl3)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 C30H34NO7,520.2330).
I-2 (0.10g, 0.19mmol) is dissolved in 2mL dichloromethane, drips the diethyl ether solution of saturated HCl, stir 5 points Clock, separates out white solid, sucking filtration, obtains I-2 HCl 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,CDCl3)δ 13.39 (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,PhCH2),4.27(m,2H,OCH2), 4.02~3.88 (m, 2H, OCH2),3.80(s,3H,OCH3),3.78(s, 3H,OCH3),3.72(s,6H,2×OCH3),3.35(m,2H,NCH2),2.92(m,2H,NCH2).
Embodiment 17
4-(piperidin-1-yl methyl) benzoic acid-(Z)-2-methoxyl group-5-(3,4,5-trimethoxy styryl) phenyl ester (I- 3) hydrochlorate
7c (255.1mg, 1mmol) and 5mL thionyl chloride, backflow is added in equipped with the 25mL eggplant type bottle of reflux condensing tube Overnight, it is the most dry to remove solvent under reduced pressure, directly throws next step in stirring reaction.CA-4 (0.316g, 1.0mmol) is dissolved in 5mL dichloro In methane, be subsequently poured into equipped with in the above-mentioned fresh eggplant type bottle preparing acyl chlorides, add triethylamine (0.20g, 0.28mL, 2.0mmol), reaction 2h, TLC monitoring reaction being stirred at room temperature complete, remove solvent under reduced pressure, residue adds saturated aqueous common salt, By ethyl acetate extraction to water layer without product, ethyl acetate washed with water is washed three times, and saturated common salt is washed three times, organic layer anhydrous slufuric acid Sodium is dried overnight.Sucking filtration, filtrate is spin-dried for, and residue column chromatography (dichloromethane: methanol=200:1) is isolated and purified, obtains I-3 white Solid 0.21g, yield 40.62%, m.p.100~102 DEG C.I-3 (0.10g, 0.193mmol) is dissolved in 2mL dichloromethane, Drip the diethyl ether solution of saturated HCl, stir 5 minutes, separate out white solid, sucking filtration, obtain I-3 HCl 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,CDCl3) δ 12.47 (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,PhCH2),3.82(s,3H,OCH3),3.80 (s,3H,OCH3),3.74(s,6H,2×OCH3),2.64(m,2H,NCH2),2.34(m,2H,NCH2),1.99(m,2H, CH 2CH2CH2),1.89(m,2H,CH2CH2CH 2), 1.88~1.77 (m, 2H, CH2CH 2CH2).13C NMR(75MHz,CDCl3)δ 163.23,152.45,149.78,138.80,133.02,131.98,131.38,131.30,130.52,130.38,129.55, 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 C31H36NO6,518.2537).
Embodiment 18
4-(pyrrolidin-1-yl methyl) benzoic acid-(Z)-2-methoxyl group-5-(3,4,5-trimethoxy styryl) phenyl ester (I-4) hydrochlorate
7d (241.1mg, 1mmol) and 5mL thionyl chloride, backflow is added in equipped with the 25mL eggplant type bottle of reflux condensing tube Overnight, it is the most dry to remove solvent under reduced pressure, directly throws next step in stirring reaction.CA-4 (0.316g, 1.0mmol) is dissolved in 5mL dichloro In methane, be subsequently poured into equipped with in the above-mentioned fresh eggplant type bottle preparing acyl chlorides, add triethylamine (0.20g, 0.28mL, 2.0mmol), reaction 2h, TLC monitoring reaction being stirred at room temperature complete, remove solvent under reduced pressure, residue adds saturated aqueous common salt, By ethyl acetate extraction to water layer without product, ethyl acetate washed with water is washed three times, and saturated common salt is washed three times, organic layer anhydrous slufuric acid Sodium is dried overnight.Sucking filtration, filtrate is spin-dried for, and residue column chromatography (dichloromethane: methanol=500:1) is isolated and purified, obtains I-4 white Solid 0.20g, yield 39.76%, m.p.98~100 DEG C.IR(KBr,υcm-1):3434,2938,2383,2348,2314, 1741,1612,1579,1509,1460,1420,1327,1265,1184,1125,1071,1019,860,797,769,703, I-4 (0.10g, 0.199mmol) is dissolved in 2mL dichloromethane by 582., drips the diethyl ether solution of saturated HCl, stirs 5 minutes, Separate out white solid, sucking filtration, obtain I-4 HCl 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,CDCl3)δ 12.86 (s, 1H), 8.22 (d, J=7.5Hz, 2H, ArH), 7.84 (d, J=7.6Hz, 2H, ArH), 7.19 (dd, J1=8.4, J2 =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, PhCH2),3.82(s,3H,OCH3),3.80(s,3H,OCH3), 3.73(s,6H,2×OCH3), 3.70~3.68 (m, 2H, NCH2),2.88(m,2H,NCH2),2.27(m,2H,CH2),2.08 (m,2H,CH2). 13C NMR(75MHz,CDCl3)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 C30H34NO6,504.2381).
Embodiment 19
4-(diethylamine-1-ylmethyl) benzoic acid-(Z)-2-methoxyl group-5-(3,4,5-trimethoxy styryl) phenyl ester (I-5) hydrochlorate
7e (243.1mg, 1mmol) and 5mL thionyl chloride, backflow is added in equipped with the 25mL eggplant type bottle of reflux condensing tube Overnight, it is the most dry to remove solvent under reduced pressure, directly throws next step in stirring reaction.CA-4 (0.316g, 1.0mmol) is dissolved in 5mL dichloro In methane, be subsequently poured into equipped with in the above-mentioned fresh eggplant type bottle preparing acyl chlorides, add triethylamine (0.20g, 0.28mL, 2.0mmol), reaction 2h, TLC monitoring reaction being stirred at room temperature complete, remove solvent under reduced pressure, residue adds saturated aqueous common salt, By ethyl acetate extraction to water layer without product, ethyl acetate washed with water is washed three times, and saturated common salt is washed three times, organic layer anhydrous slufuric acid Sodium is dried overnight.Sucking filtration, filtrate is spin-dried for, and residue column chromatography (dichloromethane: methanol=500:1) is isolated and purified, obtains white solid Body I-5 0.25g, yield 49.50%.I-5 (0.10g, 0.198mmol) is dissolved in 2mL dichloromethane, drips saturated HCl's Diethyl ether solution, stirs 5 minutes, separates out white solid, sucking filtration, obtains I-5-HCl 0.09g, yield 84.11%, m.p.115~118 ℃。1H NMR(300MHz,CDCl3) δ 12.66 (s, 1H), 8.26 (d, J=7.5Hz, 2H, ArH), 7.83 (d, J=7.6Hz, 2H,ArH),7.21(dd,J1=8.4, J2=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, PhCH2),3.86(s, 3H,OCH3),3.80(s,3H,OCH3),3.65(s,6H,OCH3),3.16(s,2H,NCH2),3.02(s,2H,NCH2),1.42 (s,6H,N(CH2CH 3)2).13C NMR(75MHz,CDCl3)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 C30H36NO6,506.2537).
Embodiment 20
4-((4-methylpiperazine-1-yl) methyl)-3-nitrobenzoic acid-(Z)-2-methoxyl group-5-(3,4,5-trimethoxy benzene Vinyl) phenyl ester (I-6) hydrochlorate
Adding 7f (0.32g, 1mmol) and 5mL thionyl chloride in equipped with the 25mL eggplant type bottle of reflux condensing tube, backflow is stirred Mixing reaction overnight, it is the most dry to remove solvent under reduced pressure, directly throws next step.CA-4 (0.316g, 1.0mmol) is dissolved in 5mL dichloromethane In alkane, it is subsequently poured into equipped with in the above-mentioned fresh eggplant type bottle preparing acyl chlorides, adds triethylamine (0.20g, 0.28mL, 2.0mmol), Reaction 2h, TLC monitoring reaction being stirred at room temperature complete, remove solvent under reduced pressure, residue adds saturated aqueous common salt, uses ethyl acetate Extraction is to water layer without product, and ethyl acetate washed with water is washed three times, and saturated common salt is washed three times, and organic layer anhydrous sodium sulfate is dried Night.Sucking filtration, filtrate is spin-dried for, and residue column chromatography (dichloromethane: methanol=200:1) is isolated and purified, obtains I-6 white solid 0.23g, yield 39.86%, m.p.70~72 DEG C.IR(KBr,υcm-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,CDCl3) 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,PhCH 2N),3.82(s,3H,OCH3),3.80(s,3H,OCH3),3.73(s,6H,2×OCH3),2.70–2.38 (m, 8H, piperazine hydrogen), 2.33 (s, 3H, NCH3).13C NMR(75MHz,CDCl3)δ162.00,152.50,149.66, 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 C31H36N3O8,578.2497).
I-6 (0.10g, 0.173mmol) is dissolved in 2mL dichloromethane, drips the diethyl ether solution of saturated HCl, stir 5 points Clock, separates out white solid, sucking filtration, obtains I-6 HCl 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) hydrochlorate
Adding 7g (0.30g, 1mmol) and 5mL thionyl chloride in equipped with the 25mL eggplant type bottle of reflux condensing tube, backflow is stirred Mixing reaction overnight, it is the most dry to remove solvent under reduced pressure, directly throws next step.CA-4 (0.316g, 1.0mmol) is dissolved in 5mL dichloromethane In alkane, it is subsequently poured into equipped with in the above-mentioned fresh eggplant type bottle preparing acyl chlorides, adds triethylamine (0.20g, 0.28mL, 2.0mmol), Reaction 2h, TLC monitoring reaction being stirred at room temperature complete, remove solvent under reduced pressure, residue adds saturated aqueous common salt, uses ethyl acetate Extraction is to water layer without product, and ethyl acetate washed with water is washed three times, and saturated common salt is washed three times, and organic layer anhydrous sodium sulfate is dried Night.Sucking filtration, filtrate is spin-dried for, and residue column chromatography (dichloromethane: methanol=300:1) is isolated and purified, 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,CDCl3)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, PhCH 2N),3.82(s,3H, OCH3),3.80(s,3H,OCH3),3.73(s,6H,2×OCH3),3.68(m,4H,O(CH 2)2),2.46(m,4H,N(CH 2)2) .13C NMR(75MHz,CDCl3)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 C30H33N2O9, 565.2181).
I-7 (0.10g, 0.177mmol) is dissolved in 2mL dichloromethane, drips the diethyl ether solution of saturated HCl, stir 5 points Clock, separates out white solid, sucking filtration, obtains I-7 HCl 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) hydrochlorate
Adding 7h (0.30g, 1mmol) and 5mL thionyl chloride in equipped with the 25mL eggplant type bottle of reflux condensing tube, backflow is stirred Mixing reaction overnight, it is the most dry to remove solvent under reduced pressure, directly throws next step.CA-4 (0.316g, 1.0mmol) is dissolved in 5mL dichloromethane In alkane, it is subsequently poured into equipped with in the above-mentioned fresh eggplant type bottle preparing acyl chlorides, adds triethylamine (0.20g, 0.28mL, 2.0mmol), Reaction 2h, TLC monitoring reaction being stirred at room temperature complete, remove solvent under reduced pressure, residue adds saturated aqueous common salt, uses ethyl acetate Extraction is to water layer without product, and ethyl acetate washed with water is washed three times, and saturated common salt is washed three times, and organic layer anhydrous sodium sulfate is dried Night.Sucking filtration, filtrate is spin-dried for, and residue column chromatography (dichloromethane: methanol=400:1) is isolated and purified, 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,CDCl3) δ 8.58 (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 × OCH3and PhCH 2N),3.73(s, 6H,2×OCH3),2.28–2.48(m,4H,N(CH 2)2),1.38–1.49(m,4H,CH 2CH2CH 2),0.97–0.81(m,2H, CH2CH 2CH2). 13C NMR(75MHz,CDCl3)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 C31H35N2O8,563.2388).
I-8 (0.10g, 0.178mmol) is dissolved in 2mL dichloromethane, drips the diethyl ether solution of saturated HCl, stir 5 points Clock, separates out white solid, sucking filtration, obtains I-8 HCl 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 styrene Base) phenyl ester (II-9) hydrochlorate
7i (286.1mg, 1mmol) and 5mL thionyl chloride, backflow is added in equipped with the 25mL eggplant type bottle of reflux condensing tube Overnight, it is the most dry to remove solvent under reduced pressure, directly throws next step in stirring reaction.CA-4 (0.316g, 1.0mmol) is dissolved in 5mL dichloro In methane, be subsequently poured into equipped with in the above-mentioned fresh eggplant type bottle preparing acyl chlorides, add triethylamine (0.20g, 0.28mL, 2.0mmol), reaction 2h, TLC monitoring reaction being stirred at room temperature complete, remove solvent under reduced pressure, residue adds saturated aqueous common salt, By ethyl acetate extraction to water layer without product, ethyl acetate washed with water is washed three times, and saturated common salt is washed three times, organic layer anhydrous slufuric acid Sodium is dried overnight.Sucking filtration, filtrate is spin-dried for, and residue column chromatography (dichloromethane: methanol=200:1) is isolated and purified, obtains white solid Body 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,CDCl3) δ 8.63 (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,PhCH 2N),3.82(s,3H,OCH3),3.80(s,3H,OCH3),3.73(s,6H,2×OCH3),2.54(s,4H N (CH 2)2),1.80(s,4H,CH 2CH 2).13C NMR(75MHz,CDCl3)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 C30H33N2O8,549.2231).
I-9 (0.10g, 0.182mmol) is dissolved in 2mL dichloromethane, drips the diethyl ether solution of saturated HCl, stir 5 points Clock, separates out white solid, sucking filtration, obtains I-9 HCl 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,CDCl3)δ12.93(s,1H, ArH), 8.73 (m, 2H, ArH), 8.51 (d, J=6.3Hz, 1H, ArH), 7.18 (dd, J1=8.4, J2=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,PhCH 2N), 3.84~3.66 (m, 14H, 4 × OCH 3,NCH 2), 3.17~2.94 (m, 2H, NCH 2), 2.21(m,4H,CH2CH2).
Embodiment 24
4-(diethylamine methyl)-3-nitrobenzoic acid-(Z)-2-methoxyl group-5-(3,4,5-trimethoxy styryl) phenyl ester (I-10) hydrochlorate
7j (288.1mg, 1mmol) and 5mL thionyl chloride, backflow is added in equipped with the 25mL eggplant type bottle of reflux condensing tube Overnight, it is the most dry to remove solvent under reduced pressure, directly throws next step in stirring reaction.CA-4 (0.316g, 1.0mmol) is dissolved in 5mL dichloro In methane, be subsequently poured into equipped with in the above-mentioned fresh eggplant type bottle preparing acyl chlorides, add triethylamine (0.20g, 0.28mL, 2.0mmol), reaction 2h, TLC monitoring reaction being stirred at room temperature complete, remove solvent under reduced pressure, residue adds saturated aqueous common salt, By ethyl acetate extraction to water layer without product, ethyl acetate washed with water is washed three times, and saturated common salt is washed three times, organic layer anhydrous slufuric acid Sodium is dried overnight.Sucking filtration, filtrate is spin-dried for, and residue column chromatography (dichloromethane: methanol=200:1) is isolated and purified, obtains white solid Body I-10 0.23g, yield 41.82%, m.p.96~98 DEG C.I-10 (0.10g, 0.182mmol) is dissolved in 2mL dichloromethane In, drip the diethyl ether solution of saturated HCl, stir 5 minutes, separate out white solid, sucking filtration, obtain I-10 HCl 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,CDCl3) δ 12.89 (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, PhCH 2N),3.82(s,3H, OCH3),3.81(s,3H,OCH3),3.73(s,6H,2×OCH 3),3.22(s,4H,N(CH 2CH3)2),1.47(s,6H,N (CH2CH 3)2).13C NMR (75MHz,CDCl3)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 C30H35N2O8,551.2388).
Embodiment 25
Tablet
Gained compound 0.5g in Example 20, starch 2.0g, dextrin 1.0g mix, and moisten with appropriate 30% ethanol Agent, pelletizes, tabletting.

Claims (7)

1. lead to compound or its pharmaceutically acceptable salt of formula (I):
Wherein R represents: H, halogen, nitro or trifluoromethyl;
Y represents:
2. the compound of claim 1 or its pharmaceutically acceptable salt, wherein R represents H or nitro.
3. the compound of claim 1 or its pharmaceutically acceptable salt, wherein Y represents
4. the compound of claim 1 or its pharmaceutically acceptable salt, wherein pharmaceutically acceptable salt is claim 1 The acid-addition salts that logical formula (I) compound is formed with following acid: hydrochloric acid, hydrobromic acid, sulphuric acid, carbonic acid, citric acid, succinic acid, winestone Acid, phosphoric acid, lactic acid, acetone acid, acetic acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, p-methyl benzenesulfonic acid or ferulic acid.
5. a pharmaceutical composition, wherein contains the logical formula (I) compound of claim 1 or its pharmaceutically acceptable salt and medicine Acceptable carrier on.
6. the compound of claim 1 or its pharmaceutically acceptable salt are in the medicine of preparation treatment angiogenic disease Purposes.
7. the purposes of claim 6, wherein angiogenic disease is tumor or chronic inflammatory disease.
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