CN102219811A - CA-4 derivatives and preparation method and medicinal application thereof - Google Patents
CA-4 derivatives and preparation method and medicinal application thereof Download PDFInfo
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Abstract
The invention relates to the field of pharmaceutical chemistry, in particular to CA-4 derivatives (I) and a preparation method thereof, and the inhibitory effect of the CA-4 derivatives on tumor blood vessels. Pharmacological experiments prove that the compounds can be used for treating angiogenesis-related diseases such as various cancers and chronic inflammation, and other angiogenic diseases.
Description
Technical field
The present invention relates to the pharmaceutical chemistry field, be specifically related to a class Combretastatin A-4 derivative, they the preparation method and to the tumor vessel restraining effect.
Background technology
Combretastatin A-4 (be called for short CA-4) is one of best material of anti-tumor activity in the Combretastatins compounds, it is separated from the trees Combretum Caffnom of South Africa, can utilize the differences of Physiological of tumor tissues and healthy tissues endotheliocyte, optionally suppress tumour tubulin activity, change the skeleton structure and the form of its endotheliocyte, strengthen its vascular permeability, upset blood flow, thereby cause the tumor vascular endothelial cell apoptosis, cause secondary death of neoplastic cells.Yet the water-soluble non-constant of CA-4 has limited its clinical application.And its water-soluble prodrug CA-4 disodic alkaliine (CA-4P) has entered III phase clinical stage.
According to mechanism of action, the antitumor drug of present clinical use mainly contains following four classes: the medicine that 1. directly acts on DNA; 2. disturb DNA synthetic medicine; 3. antimitotic medicine; 4. based on the medicine of tumor signal conduction path.The effect of preceding two kinds of medicines is strong, but lacks selectivity, and toxic side effect is big.Anti-mitosis medicine acts on tubulin, and Antitubulin (as: vinealeucoblastine(VLB) and taxanes) has been obtained good curative effect clinically as antitumor drug, and antitumor spectra is narrow, toxicity more greatly, more easily produces shortcomings such as resistance but also exist.But some Antitubulin is after using gap or drug withdrawal, the normal cell that originally is suppressed can recover the cell cycle in drug metabolism or after removing, and deactivation spindle body check point makes tumour cell stop division owing to sudden change damages prematurely at some tumour cell, thereby demonstrates certain selectivity.Antitumor drug based on tumor signal transmission mechanism (target) has advantages such as toxicity is low, few side effects.But, cause present existing single target spot or many target spots TAI easily to produce resistance, thereby influence their clinical result of use based on the tumor signal conduction path owing to exist vasculogenesis to rescue the liability and the complicacy of reaction and cancer transgenation.Therefore, exploitation is based on many target spots angiogenesis inhibitor of different mechanism of action, might obtain efficient, low toxicity, low chemical sproof new type antineoplastic medicine.
Summary of the invention
The invention discloses the compound and the hydrate thereof of a class general formula I, its constitutional features is that the hydroxyl in the CA-4 molecule passes through the amino coupled in Succinic Acid (or propanedioic acid, pentanedioic acid or hexanodioic acid) connecting arm and the aminosugar molecule, obtains many target spots angiogenesis inhibitor.Pharmacological evaluation shows that compound of the present invention has stronger restraining effect to Human umbilical vein endothelial cells propagation.Therefore, formula I compound of the present invention and the compound that contains crystal water thereof can be used for the treatment of the various diseases relevant with vasculogenesis, and these diseases comprise various cancers and chronic inflammatory diseases, and other angiogenic disease.
Compound general formula I of the present invention is as follows:
Wherein G-NH-represents following arbitrary structure:
Wherein G-NH-preferably represents following arbitrary structure:
The following arbitrary structure of the further preferred representative of G-NH-:
Wherein n representative: 0,1,2 or 3.
N preferably represents: 1 or 2.
The further preferred representative of n: 1.
The hydrate of The compounds of this invention also has the curative effect same with compound, and hydrate wherein exists with the form of crystal water, the molar equivalent of crystal water from 0.5 to 10.
Part of compounds of the present invention is:
N-(2,3,4,6-four-O-ethanoyl-1-deoxidation-β-D-glucopyranosyl)-3-((Z) 2 '-methoxyl group-5 '-(and 3 ", 4 ", 5 "-the trimethoxy styryl) phenoxy group)-3-oxo propionic acid amide (I-1)
N-(2,3,4,6-four-O-ethanoyl-1-deoxidation-β-D-glucopyranosyl)-4-((Z) 2 '-methoxyl group-5 '-(and 3 ", 4 ", 5 "-the trimethoxy styryl) phenoxy group)-4-oxo butyramide (I-2)
N-(2,3,4,6-four-O-ethanoyl-1-deoxidation-β-D-glucopyranosyl)-5-((Z) 2 '-methoxyl group-5 '-(and 3 ", 4 ", 5 "-the trimethoxy styryl) phenoxy group)-5-oxo valeramide (I-3)
N-(2,3,4,6-four-O-ethanoyl-1-deoxidation-β-D-galactopyranose base)-3-((Z) 2 '-methoxyl group-5 '-(and 3 ", 4 ", 5 "-the trimethoxy styryl) phenoxy group) 3-oxo propionic acid amide (I-4)
N-(2,3,4,6-four-O-ethanoyl-1-deoxidation-β-D-galactopyranose base)-4-((Z) 2 '-methoxyl group-5 '-(and 3 ", 4 ", 5 "-the trimethoxy styryl) phenoxy group)-4-oxo butyramide (I-5)
N-(2,3,4,6-four-O-ethanoyl-1-deoxidation-β-D-galactopyranose base)-5-((Z) 2 '-methoxyl group-5 '-(and 3 ", 4 ", 5 "-the trimethoxy styryl) phenoxy group)-5-oxo valeramide (I-6)
N-(1,3,4,6-four-O-ethanoyl-2-deoxidation-β-D-glucopyranosyl)-4-((Z) 2 '-methoxyl group-5 '-(and 3 ", 4 ", 5 "-the trimethoxy styryl) phenoxy group)-4-oxo butyramide (I-7)
N-(1,3,4,6-four-O-ethanoyl-2-deoxidation-β-D-glucopyranosyl)-5-((Z) 2 '-methoxyl group-5 '-(and 3 ", 4 ", 5 "-the trimethoxy styryl) phenoxy group)-5-oxo valeramide (I-8)
N-(1,3,4,6-four-O-ethanoyl-2-deoxidation-β-D-glucopyranosyl)-6-((Z) 2 '-methoxyl group-5 '-(and 3 ", 4 ", 5 "-the trimethoxy styryl) phenoxy group)-6-oxo hexanamide (I-9)
N-(1,3,4,6-four-O-ethanoyl-2-deoxidation-β-D-galactopyranose base)-4-((Z) 2 '-methoxyl group-5 '-(and 3 ", 4 ", 5 "-the trimethoxy styryl) phenoxy group)-4-oxo butyramide (I-10)
N-(1,3,4,6-four-O-ethanoyl-2-deoxidation-β-D-galactopyranose base)-5-((Z) 2 '-methoxyl group-5 '-(and 3 ", 4 ", 5 "-the trimethoxy styryl) phenoxy group)-5-oxo valeramide (I-11)
N-(1,3,4,6-four-O-ethanoyl-2-deoxidation-β-D-galactopyranose base)-6-((Z) 2 '-methoxyl group-5 '-(and 3 ", 4 ", 5 "-the trimethoxy styryl) phenoxy group)-6-oxo hexanamide (I-12)
N-(6-deoxidation-β-D-glucopyranosyl)-4-((Z) 2 '-methoxyl group-5 '-(and 3 ", 4 ", 5 "-the trimethoxy styryl) phenoxy group)-4-oxo butyramide (I-13)
N-(6-deoxidation-α-D-galactopyranose base)-4-((Z) 2 '-methoxyl group-5 '-(and 3 ", 4 ", 5 "-the trimethoxy styryl) phenoxy group)-4-oxo butyramide (I-14)
N-(1-deoxidation-β-D-glucopyranosyl)-4-((Z) 2 '-methoxyl group-5 '-(and 3 ", 4 ", 5 "-the trimethoxy styryl) phenoxy group)-4-oxo butyramide (I-15)
N-(1-deoxidation-β-D-glucopyranosyl)-5-((Z) 2 '-methoxyl group-5 '-(and 3 ", 4 ", 5 "-the trimethoxy styryl) phenoxy group)-5-oxo valeramide (I-16)
N-(1-deoxidation-β-D-glucopyranosyl)-6-((Z) 2 '-methoxyl group-5 '-(and 3 ", 4 ", 5 "-the trimethoxy styryl) phenoxy group)-6-oxo hexanamide (I-17)
N-(1-deoxidation-β-D-galactopyranose base)-4-((Z) 2 '-methoxyl group-5 '-(and 3 ", 4 ", 5 "-the trimethoxy styryl) phenoxy group)-4-oxo butyramide (I-18)
N-(1-deoxidation-β-D-galactopyranose base)-5-((Z) 2 '-methoxyl group-5 '-(and 3 ", 4 ", 5 "-the trimethoxy styryl) phenoxy group)-5-oxo valeramide (I-19)
N-(2-deoxidation-β-D-glucopyranosyl)-4-((Z) 2 '-methoxyl group-5 '-(and 3 ", 4 ", 5 "-the trimethoxy styryl) phenoxy group)-4-oxo butyramide (I-20)
N-(2-deoxidation-β-D-glucopyranosyl)-5-((Z) 2 '-methoxyl group-5 '-(and 3 ", 4 ", 5 "-the trimethoxy styryl) phenoxy group)-5-oxo valeramide (I-21)
N-(2-deoxidation-β-D-galactopyranose base)-4-((Z) 2 '-methoxyl group-5 '-(and 3 ", 4 ", 5 "-the trimethoxy styryl) phenoxy group)-4-oxo butyramide (I-22)
N-(2-deoxidation-β-D-galactopyranose base)-5-((Z) 2 '-methoxyl group-5 '-(and 3 ", 4 ", 5 "-the trimethoxy styryl) phenoxy group)-5-oxo valeramide (I-23)
N-(1,2,3,4-four-O-ethanoyl-6-deoxidation-β-D-glucopyranosyl)-4-((Z) 2 '-methoxyl group-5 '-(and 3 ", 4 ", 5 "-the trimethoxy styryl) phenoxy group)-4-oxo butyramide (I-24)
N-(1,2,3,4-four-O-ethanoyl-6-deoxidation-α-D-galactopyranose base)-4-((Z) 2 '-methoxyl group-5 '-(and 3 ", 4 ", 5 "-the trimethoxy styryl) phenoxy group)-4-oxo butyramide (I-25)
The preparation method of general formula compound of the present invention (I) is as follows:
Wherein the preparation method of key intermediate 2 is as follows:
(a) solvent is a diacetyl oxide; Catalyzer is a triethylamine.
(b) solvent is a quinoline; Catalyzer is a copper powder.
(c) reactant is malonic anhydride, Succinic anhydried, Pyroglutaric acid or adipic anhydride; Solvent is acetone, acetonitrile or tetrahydrofuran (THF); Catalyzer is triethylamine, salt of wormwood, yellow soda ash, saleratus, sodium bicarbonate, potassium hydroxide, sodium hydroxide, sodium hydride or sodium amide.
The preparation method of target compound I is as follows:
(1) works as G-NH
2=G
1-NH
2～G
6-NH
2The time, synthetic route is as follows:
(d) reactant is an oxalyl chloride, or thionyl chloride, or triethylamine and EDCI/HOBt; Solvent is DMF.
(2) work as G-NH
2=G
7-NH
2～G
10-NH
2The time, synthetic route is as follows:
(e) reactant is sodium methylate or sodium ethylate; Solvent is methyl alcohol or ethanol.
(3) work as G-NH
2=G
11-NH
2～G
12-NH
2The time, synthetic route is as follows:
(f) reactant is an aceticanhydride, triethylamine and 4-DMAP; Solvent is pyridine or triethylamine.
Below be the pharmacological testing and the result of part of compounds of the present invention.
Part of compounds of the present invention suppresses active testing method to vascular endothelial cell proliferation under normal oxygen condition as follows:
Material: Human umbilical vein endothelial cells (HUVEC) cell strain.
Detect principle:
Succinodehydrogenase in the viable cell plastosome can make exogenous MTT be reduced to water-insoluble bluish voilet crystallization first a ceremonial jade-ladle, used in libation (Formazan) and be deposited in the cell, and dead cell does not have this function.First a ceremonial jade-ladle, used in libation in dimethyl sulfoxide (DMSO) (DMSO) the energy dissolved cell is measured its absorbance value with enzyme-linked immunosorbent assay instrument at 570nm wavelength place, can reflect viable cell quantity indirectly.It is strong more to Human umbilical vein endothelial cells (HUVEC) restraining effect that light absorption value is got over the bright test compound of novel, and activity is good more.
The solution preparation:
(1) PBS solution
NaCl 8.00g, KCl 0.20g, Na
2HPO
412H
2O 3.49g, KH
2PO
40.20g, add tri-distilled water dissolving after, be settled to 1000ml, 4 ℃ of preservations are standby behind the autoclaving.
(2) 0.25% trypsin solutions
Take by weighing trypsinase 0.25g, add PBS solution liquid, stirring is dissolved it fully on the magnetic stirring apparatus, is settled to 100ml, and-20 ℃ of preservations are standby after the filtration sterilization.
(3) Thiazolyl blue (MTT) solution
Take by weighing MTT 50mg, it is 10ml that adding PBS makes its final volume, after stirring is dissolved it fully on the magnetic stirring apparatus, and filtration sterilization, 4 ℃ keep in Dark Place, and use effective in two weeks.
Dilution process: with methyl-sulphoxide (DMSO) all test compound powder all are formulated as 10 before using
-2The mother liquor of the concentration of M faces with preceding and is made into desired concn with cell culture fluid.
Operating process:
Use Thiazolyl blue (MTT) method to measure, key step is as follows:
(1) gets and be in one bottle of people's venous endothelial cell (HUVEC) in good condition exponential phase of growth, add 0.25% tryptic digestive juice, digestion 1～2min, visible kytoplasm retraction under the inverted microscope, cell rounding, when the intercellular substance is clear, culturing bottle immediately overturns, add a little DMEM nutrient solution that contains 10% new-born calf serum and stop digestion, slowly blow down the cell of bottle wall, make cell suspension.
(2) obtained cell suspension is inoculated on 96 orifice plates, 100 μ l/ holes, and about 5000 cells in every hole are put in the constant temperature CO2 incubator and were cultivated 24 hours.
(3) with cell control group (DMEM that contains 10% foetal calf serum), dosing group (containing the DMEM of 10% foetal calf serum and the medicine to be detected that ultimate density is respectively 10-5mol/L, 10-6 μ mol/L, 10-7 μ mol/L), cultivated 24 hours in 100 μ l/ holes.
(4) every hole adds the MTT solution 20 μ l of 5mg/ml, hatches 4h for 37 ℃.
(5) supernatant liquor is removed in suction, adds DMSO, 150 μ l/ holes, and jolting is 5 minutes on the flat bed.
(6) be the light absorption value that the 570nm place measures every hole with enzyme-linked immunosorbent assay instrument at wavelength.
Table 1. part of compounds of the present invention suppresses the IC of Human umbilical vein endothelial cells (HUVEC) propagation
50(mol/L)
| Test compound | IC 50(mol/L) | Test compound | IC 50(mol/L) |
| CA-4 | 3.43×10 -6 | I-10 | 2.20×10 -6 |
| I-2 | 4.68×10 -7 | I-13 | 1.26×10 -7 |
| I-5 | 1.12×10 -6 | I-14 | 8.23×10 -7 |
| I-7 | 3.37×10 -7 |
The same embodiment of chemical structure of compound code name correspondence in the table 1.
The pharmacology test result shows, part of compounds of the present invention as I-2, I-5, I-7, I-10, I-13 and I-14 the propagation of Human umbilical vein endothelial cells (HUVEC) is had the obvious suppression effect, and drug effect is better than CA-4.
The present invention also provides the pharmaceutical composition of a kind of treatment disease relevant with vasculogenesis, wherein contains the compound of Formula I and the pharmaceutically acceptable carrier for the treatment of significant quantity.Described pharmaceutical composition can be a dosage form conventional on the technology of pharmaceutics such as conventional tablet or capsule, slow releasing tablet or capsule, controlled release tablet or capsule, oral liquid, injection.
Usually, when CA-4 derivative of the present invention was used for the treatment of, the human dosage range was 1mg～5000mg/ days.Also can be according to the difference and the disease severity of formulation, using dosage exceeds this scope.
Embodiment
Embodiment 1
N-(2,3,4,6-four-O-ethanoyl-1-deoxidation-β-D-glucopyranosyl)-4-((Z) 2 '-methoxyl group-5 '-(and 3 ", 4 ", 5 "-the trimethoxy styryl) phenoxy group)-preparation of 4-oxo butyramide (I-2)
(E)-3-(3 '-hydroxyl-4 '-methoxyl group) phenyl-2-(3 ", 4 ", 5 "-three-methoxyl group) phenyl-vinylformic acid (1)
In the 500ml three-necked bottle, add 3,4,5-trimethoxy toluylic acid (50g, 0.22mol), 3-hydroxyl-4-methoxybenzaldehyde (34g, 0.22mol), 62.5ml triethylamine and 150ml diacetyl oxide, stirring is warming up to 140 ℃, reaction 4h stops heating, is cooled to 10 ℃, slowly drip concentrated hydrochloric acid 200ml, spend the night under the room temperature.Have the khaki color solid to separate out, stopped reaction filters out solid, with about 100ml ethyl alcohol recrystallization, get the pure product 47.5g of yellow spicule, productive rate is 61%, m.p.184～186 ℃ (literature value: 184～186 ℃ of [Bioorg.Med.Chem., 2005,13 (11): 3853-3864])
1HNMR(300MHz，DMSO)，δ(ppm)：12.42(1H，s，COOH)，8.95(1H，s，OH)，7.57(1H，s，＝CH)，6.81(1H，d，J＝8.7Hz，5’-ArH)，6.61(1H，dd，J＝2.1Hz，J＝8.4Hz，6’-ArH)，6.54(1H，d，J＝2.1Hz，2’-ArH)，6.44(2H，s，2”&6”-ArH)，3.73(3H，s，OCH
3)，3.72(3H，s，OCH
3)，3.69(6H，s，2×OCH
3).
(Z)-3 ", 4 ', 4 ", 5 "-tetramethoxy-3 '-hydroxy stibene (CA-4)
In the 500mL three-necked bottle of thermometer, reflux condensing tube, drying tube is housed, add 1 (7.2g, 20mmol), copper powder 6.6g (0.103mol), quinoline 72ml, reaction is heated to 200 ℃, stirs 3h.It is an amount of to add ether after reaction finishes, with diatomite filtering copper powder.With 300ml 5MHCl pyridine is washed off, with ether 150ml extraction, with the water layer told with ether wash (3 * 150ml), merge organic layer.Organic layer is washed once with 500ml respectively, saturated Na
2CO
3(2 * 300ml) wash twice, and (2 * 300ml) wash twice to saturated NaCl, anhydrous Na
2SO
4Dried overnight.Elimination sodium sulfate, decompression spins off the ether of 2/3 volume, has little yellow solid to separate out, and leaches solid also with an amount of ether washing, reclaim mother liquor, remove partial solvent again, the solid of separating out leached, altogether product 5.0g, productive rate 79%, m.p.116～117 ℃ (literature value: 116 ℃ [J.Org.Chem., 2001,66 (24): 8135-8138])
1H?NMR(300Hz，CDCl
3)：δ6.92(1H，d，J＝2.1Hz，2’-ArH)，6.82(1H，dd，J＝8.4Hz，2.1Hz，6’-ArH)，6.74(1H，d，J＝8.1Hz，5’-ArH)，6.53(2H，s，2”&6”-ArH)，6.47(1H，d，J＝12.6Hz，1a-H)，6.41(1H，d，J＝12.6，1a’-H)，5.68(1H，s，OH)，3.87(3H，s，4’-ArOCH
3)，3.84(3H，s，4”-ArOCH
3)，3.70(6H，s，3”&5”-ArOCH
3).
(Z)-4 (2 '-methoxyl group-5 '-(and 3 ", 4 ", 5 "-the trimethoxy styryl) phenoxy group)-4-ketobutyric acid (2b)
Under the ice bath triethylamine 1.8ml (12.8mmol) is slowly splashed in the 8ml acetone, add again CA-4 (1g, 3.2mmol) and Succinic anhydried (1.2g, 12mmol), make temperature of reaction remain on 15 ℃, stir, reaction 24h, stopped reaction revolves acetone, adds an amount of ethyl acetate, wash organic layer with 1.0mol/L HCl (13ml), and with 20ml washing one time, (2 * 20ml) wash saturated NaCl, anhydrous MgSO
4Dry 2h filters, and is spin-dried for solvent, use the ether dissolution crude product, and the filtering insolubles revolves and desolvates, and with the solid filtering of separating out, washs with a small amount of ether, must off-white color pressed powder 0.8g, and productive rate 60.0%, m.p.107～110 ℃.
1H?NMR(300Hz，CDCl
3)：δ7.11(1H，dd，J＝8.4Hz，1.8Hz，4’-ArH)，6.97(1H，d，J＝1.2Hz，6’-ArH)，6.84(1H，d，J＝8.4Hz，3’-ArH)，6.46(2H，s，2”&6”-ArH)，6.42(2H，s，1a?&1a’-H)，3.91(3H，s，2’-ArOCH
3)，3.85(3H，s，4”-ArOCH
3)，3.71(6H，s，3”&5”-ArOCH
3)，2.85(2H，t，J＝6.0HzCOCH
2C
H 2 COOH)，2.76(2H，t，J＝6.0Hz?COC
H 2 CH
2COOH).
N-(2,3,4,6-four-O-ethanoyl-1-deoxidation-β-D-glucopyranosyl)-4-((Z) 2 '-methoxyl group-5 '-(and 3 ", 4 ", 5 "-the trimethoxy styryl) phenoxy group)-4-oxo butyramide (I-2)
With G
1-NH
2.HCl (0.77g 2mmol) is dissolved in DMF (7ml), slowly drip the exsiccant triethylamine (0.28ml, 2mmol), add successively then in batches 2b (0.83g, 2mmol), EDCI (0.38g, 2mmol), HOBt (0.27g, 2mmol), stirring at room 24h.Reaction solution adds methylene dichloride (70ml), and the saturated common salt washing (3 * 70ml), drying, suction filtration removes solvent under reduced pressure, and silica gel column chromatography (petrol ether/ethyl acetate=3/2) gets little yellow solid 0.86g, yield 57.7%, m.p.83-85 ℃;
1H-NMR(300MHz，CDCl
3)δ(ppm)：7.11(1H，dd，J＝8.4Hz，J＝1.8Hz，4’-ArH)，7.00(1H，d，J＝1.8Hz，6’-ArH)，6.82(1H，d，J＝8.7Hz，3’-ArH)，6.49(2H，s，2”&6”-ArH)，6.45(2H，s，1aH&1a’H)，6.34(1H，d，J＝9Hz，NH)，5.33～5.33(2H，m，H-1，H-3)，5.06(1H，t，J＝9.9Hz，H-2)，4.92(1H，t，J＝9.6Hz，H-4)，4.30(1H，dd，J＝4.2Hz，J＝12.6Hz，H-6a)，4.08(1H，dd，J＝1.2Hz，J＝12.3Hz，H-6b)，3.92～3，90(1H，m，H-5)，3.87(3H，s，2’-OCH
3)，3.84(3H，s，4”-OCH
3)，3.70(6H，s，3”&5”-OCH
3)，2.95～2.76(2H，m，NHCH
2C
H 2 COOH)，2.57～2.52(2H，m，CONHC
H 2 CH
2COOH)，2.17，2.07，2.05，2.03(each?3H，each?s，4×OAc)；
IR(cm
-1)：3357(NH)，2944(CH)，2360，2336，1754(ester，C＝O)，1680(amide，C＝O)，1509，1232(OCH
3)，1129(OAc)，1039(OCH
3)
MS(ESI(+)70eV，m/z)：763.4[M+NH
4]
+；
MS(ESI(-)70V，m/z)：780.5[M+Cl]
-
Embodiment 2
N-(2,3,4,6-four-O-ethanoyl-1-deoxidation-β-D-galactopyranose base)-4-((Z) 2 '-methoxyl group-5 '-(and 3 ", 4 ", 5 "-the trimethoxy styryl) phenoxy group)-preparation of 4-oxo butyramide (I-5)
With G
2-NH
2(0.8g 2.3mmol) is dissolved in DMF (12ml).Add successively then in batches 2b (0.92g, 2.3mmol), EDCI (0.44g, 2.3mmol), HOBt (0.31g, 2.3mmol), stirring at room 24h.Reaction solution adds methylene dichloride (80ml), washing (2 * 100ml), and the saturated common salt washing (3 * 100ml), drying, suction filtration removes solvent under reduced pressure, silica gel column chromatography (petrol ether/ethyl acetate=3/2), get little yellow solid 1.08g, yield 63.0%, m.p.85-87 ℃;
1H-NMR(300MHz，CDCl
3)δ(ppm)：7.12(1H，dd，J＝8.4Hz，J＝1.8Hz，4’-ArH)，7.01(1H，d，J＝1.8Hz，6’-ArH)，6.83(1H，d，J＝8.7Hz，3’-ArH)，6.50(2H，s，2”&6”-ArH)，6.45(2H，s，1aH&1a’H)，6.38(1H，d，J＝8.7Hz，NH)，5.44(1H，s，H-4)，5.30～5.13(3H，m，H-1，H-2and?H-3)，4.11～4.03(3H，m，H-5，H-6a?and?H-6b)，3.84(3H，s，2’-OCH
3)，3.80(3H，s，4”-OCH
3)，3.70(6H，s，3”&5”-OCH
3)，2.99～2.84(2H，m，NHCH
2C
H 2 COOH)，2.58～2.54(2H，m，CONHC
H 2 CH
2COOH)，2.07，2.04，1.99，1.98(each?3H，each?s，4×OAc)；
IR(cm
-1)：3369(NH)，2944(CH)，1751(ester，C＝O)，1699(amide，C＝O)，1508，1229(OCH
3)，1129(OAc)，1054(OCH
3)
MS(ESI(+)70eV，m/z)：763.4[M+NH
4]
+；
MS(ESI(-)70V，m/z)：780.6[M+Cl]
-
Embodiment 3
N-(1,3,4,6-four-O-ethanoyl-2-deoxidation-β-D-glucopyranosyl)-4-((Z) 2 '-methoxyl group-5 '-(and 3 ", 4 ", 5 "-the trimethoxy styryl) phenoxy group)-preparation of 4-oxo butyramide (I-7)
With G
3-NH
2.HCl (0.77g 2mmol) is dissolved in DMF (10ml).Slow dropping exsiccant triethylamine (0.28ml, 2mmol).Successively add then in batches 2b (0.83g, 2mmol), EDCI (0.38g, 2mmol), HOBt (0.27g, 2mmol), stirring at room 24h.Reaction solution adds methylene dichloride (80ml), washing (2 * 100ml), and the saturated common salt washing (3 * 100ml), drying, suction filtration removes solvent under reduced pressure, silica gel column chromatography (petrol ether/ethyl acetate=2/1), get white solid 0.82g, yield 55.0%, m.p.78-79 ℃;
1H-NMR(300MHz，CDCl
3)δ(ppm)：7.12(1H，dd，J＝8.4Hz，J＝1.8Hz，4’-ArH)，6.98(1H，d，J＝1.8Hz，6’-ArH)，6.82(1H，d，J＝8.4Hz，3’-ArH)，6.49(2H，s，2”&6”-ArH)，6.45(2H，s，1aH&1a’H)，5.73～5.68(2H，m，NH，H-1)，5.18～5.12(2H，m，H-3，H-4)，4.29～4.24(2H，m，H-2and?H-6a)，4.13～4.09(2H，m，H-6b?and?H-5)，3.84(3H，s，2’-OCH
3)，3.79(3H，s，4”-OCH
3)，3.70(6H，s，3”&5”-OCH
3)，2.89～2.85(2H，m，NHCH
2C
H 2 COOH)，2.49～2.42(2H，m，CONHC
H 2 CH
2COOH)，2.15，2.09，2.03，1.97(each?3H，each?s，4×OAc)；
IR(cm
-1)：3375(NH)，2944(CH)，1756(ester，C＝O)，1676(amide，C＝O)，1510，1225(OCH
3)，1129(OAc)，1075(OCH
3)，1038
MS(ESI(+)70eV，m/z)：763.4[M+NH
4]
+；
MS(ESI(-)70V，m/z)：780.7[M+C1]
-；
Embodiment 4
N-(1,3,4,6-four-O-ethanoyl-2-deoxidation-β-D-galactopyranose base)-4-((Z) 2 '-methoxyl group-5 '-(and 3 ", 4 ", 5 "-the trimethoxy styryl) phenoxy group)-preparation of 4-oxo butyramide (I-10)
With G
4-NH
2.HCl (0.77g 2mmol) is dissolved in DMF (10ml).Slow dropping exsiccant triethylamine (0.28ml, 2mmol).Successively add then in batches 2b (0.83g, 2mmol), EDCI (0.38g, 2mmol), HOBt (0.27g, 2mmol), stirring at room 24h.Reaction solution adds methylene dichloride (80ml), washing (2 * 100ml), and the saturated common salt washing (3 * 100ml), drying, suction filtration removes solvent under reduced pressure, silica gel column chromatography (petrol ether/ethyl acetate=2/1), get little yellow solid 0.65g, yield 43.6%, m.p.66-68 ℃;
1H-NMR(300MHz，CDCl
3)δ(ppm)：7.12(1H，dd，J＝8.4Hz，J＝1.8Hz，4’-ArH)，6.98(1H，d，J＝1.8Hz，6’-ArH)，6.82(1H，d，J＝8.7Hz，3’-ArH)，6.49(2H，s，2”&6”-ArH)，6.45(2H，s，1aH&1a’H)，5.80(1H，d，J＝9.3Hz，NH)，5.73(1H，d，J＝8.7Hz，H-1)，5.14(1H，s，H-4)，5.12(1H，dd，J＝8.7Hz，J＝2.7Hz，H-3)，4.46～4.36(1H，m，H-2)，4.20～4.08(3H，m，H-5，H-6a?and?H-6b)，3.84(3H，s，2’-OCH
3)，3.79(3H，s，4”-OCH
3)，3.70(6H，s，3”&5”-OCH
3)，2.87(2H，t，J＝6.3Hz，NHCH
2C
H 2 COOH)，2.46(2H，t，J＝6.3Hz，CONHC
H 2 CH
2COOH)，2.16(3H，s，OAc)，2.09(6H，s，2×OAc)，1.93(3H，s，OAc)；
IR(cm
-1)：3363(NH)，2944(CH)，1751(ester，C＝O)，1685(amide，C＝O)，1510，1224(OCH
3)，1128(OAc)，1075(OCH
3)，1042；
MS(ESI(+)70eV，m/z)：763.3[M+NH
4]
+；
MS(ESI(-)70V，m/z)：780.6[M+C1]
-；
Embodiment 5
N-(6-deoxidation-β-D-glucopyranosyl)-4-((Z) 2 '-methoxyl group-5 '-(and 3 ", 4 ", 5 "-the trimethoxy styryl) phenoxy group)-4-oxo butyramide (I-13)
With G
5-NH
2(0.5g 2.6mmol) is dissolved in DMF (10ml).Add successively then in batches 2b (1.08g, 2.6mmol), EDCI (0.50g, 2.6mmol), HOBt (0.35g, 2.6mmol), stirring at room 24h.Reaction solution removes solvent under reduced pressure under 80 ℃, residuum silica gel column chromatography (methylene chloride=20/1), white solid 0.55g, yield 35.9%, m.p.153～156 ℃.
Embodiment 6
N-(6-deoxidation-α-D-galactopyranose base)-4-((Z) 2 '-methoxyl group-5 '-(and 3 ", 4 ", 5 "-the trimethoxy styryl) phenoxy group)-4-oxo butyramide (I-14)
With G
6-NH
2(0.5g 2.6mmol) is dissolved in DMF (10ml).Add successively then in batches 2b (1.08g, 2.6mmol), EDCI (0.50g, 2.6mmol), HOBt (0.35g, 2.6mmol), stirring at room 24h.Reaction solution removes solvent under reduced pressure under 80 ℃, residuum silica gel column chromatography (methylene chloride=20/1), faint yellow solid 0.4g, yield 26%, m.p.136～139 ℃.
Embodiment 7
Tablet
Get gained compound 0.5g among the embodiment 7, starch 2g, dextrin 1g mixes, and makes wetting agent with an amount of 30% ethanol, granulates compressing tablet.
Claims (7)
1. the compound of general formula (I) or its hydrate:
Wherein G-NH-representative:
N represents 0,1,2 or 3.
2. the compound of claim 1 or its hydrate, wherein G-NH-representative:
N represents 1 or 2.
3. the compound of claim 2 or its hydrate, wherein G-NH-representative:
N represents 1.
4. each compound or its hydrate in the claim 1 to 3, hydrate wherein exists with the form of crystal water, the molar equivalent of crystal water from 0.5 to 10.
5. pharmaceutical composition wherein contains in the claim 1 to 3 each compound or its hydrate and pharmaceutically acceptable carrier.
6. each compound or its hydrate purposes in the medicine of preparation treatment angiogenic disease in the claim 1 to 3.
7. the purposes of claim 6, wherein angiogenic disease is tumour or chronic inflammatory diseases.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103288605A (en) * | 2013-06-06 | 2013-09-11 | 陕西师范大学 | Synthetic method of combretastatin |
| CN103421057A (en) * | 2013-08-14 | 2013-12-04 | 合肥医工医药有限公司 | Combretastatin amino sugar conjugate and preparation method and medical appliance thereof |
| CN104817519A (en) * | 2015-05-11 | 2015-08-05 | 中国药科大学 | CA-4 derivatives as well as preparation method and medical application of CA-4 derivatives |
| CN106727629A (en) * | 2016-12-16 | 2017-05-31 | 中国药科大学 | A kind of antitumor mechanism research of the derivatives of combretastatin A 4 of originating |
| CN115403483A (en) * | 2021-07-02 | 2022-11-29 | 河南省儿童医院郑州儿童医院 | CA-4 derivative containing stilbene or benzophenone skeleton, pharmaceutical composition, preparation method and application thereof |
| CN115887687A (en) * | 2022-11-23 | 2023-04-04 | 广东省科学院动物研究所 | Hyaluronic Acid (HA) -CA-4 conjugate and synthesis method and application thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1994005682A1 (en) * | 1992-08-31 | 1994-03-17 | Francesca Pelizzoni | Combretastatin derivatives with antitumoral activity and process for the preparation thereof |
| CN101591369A (en) * | 2008-05-30 | 2009-12-02 | 徐云根 | N-glycosyl-3-aryl acrylamide derivative, its method for making and medicinal use thereof |
-
2011
- 2011-04-14 CN CN 201110093276 patent/CN102219811B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1994005682A1 (en) * | 1992-08-31 | 1994-03-17 | Francesca Pelizzoni | Combretastatin derivatives with antitumoral activity and process for the preparation thereof |
| CN101591369A (en) * | 2008-05-30 | 2009-12-02 | 徐云根 | N-glycosyl-3-aryl acrylamide derivative, its method for making and medicinal use thereof |
Non-Patent Citations (4)
| Title |
|---|
| BROWN R. T. 等: "Synthesis of Water-soluble Sugar Derivatives of Combretastatin A-4", 《JOURNAL OF THE CHEMICAL SOCIETY. PERKIN TRANSACTIONS. I》 * |
| PETTIT, GEORGE R.等: "Antineoplastic agents. 322. Synthesis of combretastatin A-4 prodrugs", 《ANTI-CANCER DRUG DESIGN》 * |
| 曲峰,等: "氢化可的松氨基糖衍生物的合成", 《有机化学》 * |
| 李林鲜，等: "风车子抑素A4及其衍生物的研究进展", 《国际药学研究杂志》 * |
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| CN103288605A (en) * | 2013-06-06 | 2013-09-11 | 陕西师范大学 | Synthetic method of combretastatin |
| CN103288605B (en) * | 2013-06-06 | 2015-04-08 | 陕西师范大学 | Synthetic method of combretastatin |
| CN103421057A (en) * | 2013-08-14 | 2013-12-04 | 合肥医工医药有限公司 | Combretastatin amino sugar conjugate and preparation method and medical appliance thereof |
| CN103421057B (en) * | 2013-08-14 | 2016-03-30 | 合肥医工医药有限公司 | Combretastatin aminosugar conjugate, its method for making and medicinal use thereof |
| CN104817519A (en) * | 2015-05-11 | 2015-08-05 | 中国药科大学 | CA-4 derivatives as well as preparation method and medical application of CA-4 derivatives |
| CN104817519B (en) * | 2015-05-11 | 2016-11-16 | 中国药科大学 | The derivant of one class CA-4, its preparation method and medical usage thereof |
| CN106727629A (en) * | 2016-12-16 | 2017-05-31 | 中国药科大学 | A kind of antitumor mechanism research of the derivatives of combretastatin A 4 of originating |
| CN115403483A (en) * | 2021-07-02 | 2022-11-29 | 河南省儿童医院郑州儿童医院 | CA-4 derivative containing stilbene or benzophenone skeleton, pharmaceutical composition, preparation method and application thereof |
| CN115403483B (en) * | 2021-07-02 | 2024-01-26 | 河南省儿童医院郑州儿童医院 | CA-4 derivative containing stilbene or diphenyl ketone skeleton, pharmaceutical composition, preparation method and application thereof |
| CN115887687A (en) * | 2022-11-23 | 2023-04-04 | 广东省科学院动物研究所 | Hyaluronic Acid (HA) -CA-4 conjugate and synthesis method and application thereof |
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