CN100393731C - Water soluble phosphate ester salt of(Z)-3'-hydroxy-3,4',5-trimethoxydiphenyl ethylene, and its preparation method ,pharmaceutical composition and uses - Google Patents

Water soluble phosphate ester salt of(Z)-3'-hydroxy-3,4',5-trimethoxydiphenyl ethylene, and its preparation method ,pharmaceutical composition and uses Download PDF

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CN100393731C
CN100393731C CNB2006100337881A CN200610033788A CN100393731C CN 100393731 C CN100393731 C CN 100393731C CN B2006100337881 A CNB2006100337881 A CN B2006100337881A CN 200610033788 A CN200610033788 A CN 200610033788A CN 100393731 C CN100393731 C CN 100393731C
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CN1807435A (en
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邹永
王志新
张学景
周玥
何树杰
林慧贞
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Guangzhou General Pharmaceutical Research Institute
Guangzhou Chemical Co Ltd of CAS
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Guangzhou Institute of Chemistry of CAS
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Abstract

The present invention relates to a compound disclosed in a formula (1), wherein M stands for K<+> and Na<+> or NH4 <+>. The present invention also relates to a method for preparing the compound, a medical composition and an application thereof in the treatment for resisting tumor endothelial cells and resisting blood vessel hyperplasia. The preparation method comprises: (Z)-3'-hydroxy-3, 4', 5-trimethoxy stilbene reacts with a phosphorylation reagent to produce a phosphorylation intermediate compound under the existence of an acid-binding agent, and then, the phosphorylation intermediate compound flows back to obtain a product. The compound in the formula (1) not only has favorable inhibitory activity for the growth of various tumor cell strains, but also can be combined with microtubulin in tumor vessel endothelial cells for inhibiting the polymerization of the tumor vessel endothelial cells and avoiding mitosis to block the blood vessels which supply oxygen gas and nutrition for tumors, and performs a target anti blood vessel resistance function to cause the death of the tumor cells from lack of blood. In addition, the compound with low concentration can drop abnormally proliferous endothelial cells off by morphological change. Thus, the compound in the formula (1) can be used for controlling tumors and resisting blood vessel hyperplasia.

Description

(Z)-3 '-and hydroxyl-3,4 ', water soluble phosphate ester salt of 5-trimethoxy toluylene and preparation method thereof, pharmaceutical composition and purposes
Technical field
The present invention relates to a kind of derivative of toluylene, relate to (Z)-3 '-hydroxyl base-3 of following formula (1) specifically, 4 ', the water soluble phosphate ester salt of 5-trimethoxy toluylene, and preparation method thereof, pharmaceutical composition and its be in antitumor endotheliocyte and anti-angiogenic hyperplasia treatment Application for Field.
Figure C20061003378800051
Formula (1)
Wherein M represents K +, Na +Or NH 4 +
Background technology
(Z)-3 '-and hydroxyl-3,4 ', 5-trimethoxy toluylene:
Figure C20061003378800052
Formula (2)
Being one is substituent diphenylethylene compounds with hydroxyl and methoxyl group.People such as M.Roberti (J.Med.Chem, 2003,46,3546) studies confirm that, this compound has very strong inhibition HL-60 cell-proliferation activity (IC 50Be 0.03 μ M) and induce HL-60 apoptosis activity (AC 50Be 0.04 μ M); HL-60R cell to multidrug resistance also has very strong inhibition activity (IC 50Be 0.025 μ M, AC 50Be 0.03 μ M); The inhibition HL-60 of this compound and HL-60R cells growth activity are higher than trans-resveratrol correlated with it and antitumor drug that some are classical far away, as etoposide, Citarabine, 5 FU 5 fluorouracil, cis-platinum etc., are only second to daunorubicin; What is more important, it is higher than etoposide, citarabine and daunorubicin far away to having chemical sproof HL-60R cell inhibiting activity.But the compound water soluble of formula (2) is extremely low, is unfavorable for vascular drug delivery.
Goal of the invention
The objective of the invention is to develop a kind of water-soluble higher diphenyl ethylene derivatives.Another object of the present invention is to develop the preparation method of this diphenyl ethylene derivatives.Another purpose of the present invention is to develop the pharmaceutical composition of this diphenyl ethylene derivatives.A further object of the present invention is to develop the application of this diphenyl ethylene derivatives in antitumor endotheliocyte of preparation and anti-angiogenic hyperplasia medicine.
We generate phosphorylated intermediate with the phosphorus esterification reagent reaction by the compound with formula (2) under the condition that acid binding agent exists; in alkaline solution, reflux then and obtain the compound of formula (1); this water soluble phosphate ester salt has the good restraining tumor cell growth activity, tubulin polymerization suppresses activity and targeting anti-tumor vasoactive; mix the pharmaceutical composition that to make anticancer and anti-angiogenic proliferative effect with pharmaceutically acceptable carrier, thereby realized purpose of the present invention.
(Z) of the present invention-3 '-hydroxyl-3,4 ', the water soluble phosphate ester salt of 5-trimethoxy toluylene, its structure is represented by following formula (1):
Figure C20061003378800061
Formula (1)
Wherein M represents K +, Na +Or NH 4 +
(Z) of the present invention-3 '-hydroxyl-3,4 ', the preparation method of the water soluble phosphate ester salt of 5-trimethoxy toluylene is characterized in that comprising the steps:
(1) with the inert solvent be solvent, the following and phosphorus esterification reagent reaction with the existence of acid binding agent at normal temperatures of the compound of formula (2) obtains the phosphorylated intermediate;
(2) the phosphorylated intermediate that obtains is heated to 50~100 ℃ of reactions in alkaline solution, obtains the compound of formula (1) behind the purifying.
Optimum condition with the preparation method of the compound of following formula (1) is:
Inert solvent described in the step (1) is methylene dichloride, ethylene dichloride, benzene etc., its consumption is 15~40 times of compound mole number of formula (2), described acid binding agent can be pyridine, trialkylamine, triethylamine preferably, the consumption of acid binding agent are 4~8 times of mole number of the compound of formula (2); Described phosphorus esterification reagent can be (C 2H 5O) 2P (O) Cl, P (O) Cl 3Or P (O) Br 3Deng, P (O) Cl preferably 3, the consumption of phosphorus esterification reagent is 5~8 times of compound mole number of formula (2); Reaction times is 2~8h.
The described alkali of step (2) can be that concentration range is NaOH, KOH, ammoniacal liquor, volatile salt, sodium alkoxide or the potassium alcoholate etc. of 0.2~1.5mol/L, and the consumption of alkali is 2 times of compound mole number of formula (2); Reaction times is 6~15h; Described purifying can be mixed solvent or the mixed solvent recrystallization of water and acetone, preferably the mixed solvent recrystallization of water and acetone of mixed solvent, water and ethanol mixed solvent, methyl alcohol and the acetone of water, water and methyl alcohol.
The preparation of the compound of formula (2) can be adopted conventional method; promptly earlier hydroxyl is protected; the Wittig reaction obtains the toluylene framework compound; the cis-trans product of mixing that obtains obtains obtaining product (document: J Med Chem after cis-compound is taken off protecting group through separating; 2003,46:3546).Preferably adopt method provided by the invention, make up the toluylene skeleton, obtain through functional group's conversion again, it is characterized in that comprising the steps: by the Perkin condensation reaction
(1) compound of following formula (3) reacts under 0~20 ℃ temperature with bromine in acetic acid solution, the purified compound that obtains formula (4);
Figure C20061003378800071
Formula (3) formula (4)
(2) with the compound of the formula (4) that obtains with the compound of following formula (5) under triethylamine catalysis, in acetic anhydride, be heated to 80~120 ℃, reaction back acidifying, purifying obtain the compound of following formula (6);
Formula (5) formula (6)
(3) compound of formula (6) is in strong base solution, and cupric salt exists down, 100~120 ℃ of reactions, again through acidifying, purifying, obtains the compound of following formula (7);
Figure C20061003378800073
Formula (7)
(4) compound of formula (7) 210~240 ℃ of decarboxylations under the katalysis of organic bases and metal are through the compound that separates, purifying obtains formula (2).
The preparation method's of the compound of above-mentioned formula (2) optimum condition is:
The compound of the described formula of step (1) (3) and the mol ratio of bromine are 1: 1, the consumption of acetate is 5~8 times of mole number of the compound of formula (3) or bromine, reaction times is 1~3h, described purifying can be with ethanol, the mixed solvent of second alcohol and water or the mixed solvent recrystallization of ethyl acetate and sherwood oil etc., preferably with the mixed solvent recrystallization of ethanol or second alcohol and water; The mol ratio of the compound of the compound of step (2) Chinese style (4) and formula (5) is 1: 1, the consumption of acetic anhydride is 8~10 times of mole number of the compound of formula (4) or (5), the consumption of triethylamine is 1.5~2.0 times of mole number of the compound of formula (4) or (5), reaction times is 6~8h, described purifying can be to remove impurity with ethyl acetate extraction, and adopt the recrystallizations such as mixed solvent of mixed solvent, chloroform and sherwood oil of mixed solvent, acetone and the sherwood oil of ethanol, second alcohol and water, preferably use ethyl alcohol recrystallization; The described strong base solution of step (3) can be that massfraction is 8%~20% NaOH or KOH solution etc., NaOH solution preferably, the consumption of alkali is 60~80 times of compound mole number of formula (6), the consumption of described cupric salt is 1~1.5 times of compound mole number of formula (6), described cupric salt can be a copper sulfate, cupric chloride, cupric nitrate or ventilation breather etc., copper sulfate preferably, reaction times is 48~72h, described purifying can be used the mixed solvent of chloroform and sherwood oil, the mixed solvent of ethyl acetate and sherwood oil, the mixed solvent of second alcohol and water, the recrystallizations such as mixed solvent of chloroform and sherwood oil are preferably used the mixed solvent recrystallization of ethyl acetate and sherwood oil; Organic bases described in the step (4) can be a pyridine, piperidines or quinoline woods etc., quinoline preferably, the consumption of organic bases is 20~25 times of compound mole number of formula (7), described metal can be Fe, Al, Zn or Cu etc., Cu preferably, the consumption of metal is 7.5~8 times of compound mole number of formula (7), reaction times is 2~8 hours, described purifying can adopt carrier commonly used to carry out column chromatography, and for example use volume ratio ethyl acetate-sherwood oil of 1: 4~1: 10 is that the column chromatography separation method of eluent or 30~50 times silica gel that quality is mixture quality to be separated are that carrier carries out column chromatography etc.
Adopt the compound of conventional Wittig prepared in reaction formula (2), the experiment condition harshness, cost height, product are the cis-trans mixture of almost equivalent, need further to separate, so yield are low.And adopt preparation method of the present invention raw materials used cheap and easy to get, all belong to the domestic industry raw material, the product yield height.
Be used for antitumor, anti-angiogenic outgrowth pharmaceutical composition, wherein contain the described compound of treatment significant quantity claim 1 and one or more pharmaceutically acceptable carriers.
Formula of the present invention (1) but compound per os or oral administration not.During the oral administration administration, this compound and conventional pharmaceutically acceptable carrier such as vehicle, disintegrating agent, tackiness agent, lubricant, antioxidant, Drug coating, tinting material, perfume compound, tensio-active agent etc. are mixed, be made into form administrations such as granule, capsule, tablet; Can injection liquid during non-oral administration, form administration such as infusion solution or suppository.When preparing above-mentioned preparation, can use conventional preparation technique.
The compound that experimental results show that formula of the present invention (1) can be used for treatment and prevention of tumour or auxiliary traditional tumour pharmacological agent; Also can be used for anti-angiogenic hyperplasia.
(Z) of the present invention-3 '-hydroxyl-3,4 ', the water soluble phosphate ester salt of 5-trimethoxy toluylene not only shows good inhibition activity to growth of various tumor cell strains, and can also combine with the tubulin in the tumor vascular endothelial cell, suppress its polymerization, stop mitotic division, cause the blood vessel blockage for tumour supply oxygen and nutrient, the anti-angiogenic effect of performance target makes tumour cell dead because of ischemic.Confirm that by the test of human umbilical vein's endothelial cell morphology its endotheliocyte genetic morphology that can make abnormality proliferation under low concentration change comes off in addition.Therefore, (Z) of the present invention-3 '-hydroxyl-3,4 ', the water soluble phosphate ester salt of 5-trimethoxy toluylene can be used for preparing the medicine of treatment and auxiliary for treating cancer and the medicine of preparation treatment blood vessel hyperplasia class disease, as is used for preparation treatment cancer, vascular tumor, the vocal cords neuroma, neurofibroma, hemangiofibroma, trachoma, the granuloma that suppurates, the telangiectasis of conjunctiva, psoriasis, scleroderma, arteriosclerosis, rheumatic arthritis, Ke Longshi disease, endometriosis, obesity, diabetic retinopathy, the blood vessel hyperplasia glaucoma, retinopathy of prematurity, hamartoplasia disease behind the crystal, granulomatosis, spider shape hemorrhoid, rendu-Osler-Weber disease, medicines such as von Willebrand disease.So compound of the present invention has good society and economic worth.
Preparation method of the present invention is simple to operate, and cost is low, the reaction conditions gentleness, and the yield height, aftertreatment is simple, adopts the solvent of environmental protection, and environmental pollution is little.
Embodiment:
The following example is to further specify of the present invention, but the invention is not restricted to following examples.
Embodiment 1:
Get homoanisic acid (being the compound of formula (3)) 30.0g (0.18mol) in there-necked flask, other adds the dissolving of 60mL (1.05mol) Glacial acetic acid, drip the bromine (0.18mol) of 9.5mL then, 45min drips off, under ice bath, stirred 1.5 hours again, pour in the frozen water, separate out solid, filter, drying makes product 41.0g, and yield is 92.6%, obtain the white plates crystal with the alcohol-water recrystallization, yield 70%, recording fusing point is 113~114 ℃ (literature value of 3-bromo-4-methoxyl group-toluylic acid is 114~115 ℃), MSm/z (%): 244,246 (typical bromine isotope peaks) therefore confirm that product is 3-bromo-4-methoxyl group-toluylic acid (being the compound of formula (4)).
Get the 3-bromo-4-methoxyphenylacetic acid 15.0g (0.06mol) that makes, other takes by weighing 3,5-dimethoxy benzaldehyde (being the compound of formula (5)) 10.2g (0.06mol) adds in the reaction flask, dissolve with 45.3mL (0.48mol) aceticanhydride, drip the triethylamine of 12.5mL (0.09mol), be heated to 115 ℃, reacted 6 hours.Separate out solid in the frozen water with pouring into after the concentrated hydrochloric acid acidification, the gained solid is with the dissolving of NaOH solution, and ethyl acetate extraction is removed impurity, and back acidifying water layer gets faint yellow solid, drying weigh 22.7g, yield is 94.3%; Get the 20.4g light yellow crystal with ethyl alcohol recrystallization, yield is 84.8%.Recording fusing point is 188~190 ℃, MSm/z (%): 393 (M +), 1H-NMR (CDCl 3): 3.56 (s, 6H, 2 * OMe), 3.89 (s, 3H, OMe), 6.26 (d, 2H, J=2.0Hz), 6.35 (t, 2H, J=2.0Hz), 6.89~6.91 (d, 1H, J AB=8.4Hz), 7.14~7.16 (d, 1H, J=8.4Hz), 7.47 (d, 1H, J=2.0Hz), 7.83 (s, 1H).Confirmation is 3-(3,4, the 5-trimethoxyphenyl)-2-(3 '-bromo-4 '-p-methoxy-phenyl)-vinylformic acid, i.e. compound of formula (6).
With the compound of 8.0g (0.02mol) formula (6), 62.0g (1.55mol) NaOH, the CuSO of 4.8g (0.03mol) 4Add and be equipped with in two mouthfuls of flasks of prolong, add the 350mL deionized water dissolving, stir and be heated to 110 ℃ (bathing temperature), reaction 72h, reacted after-filtration, use the concentrated hydrochloric acid acidifying, treat that solid all separates out after-filtration, ethyl acetate-sherwood oil recrystallization, get faint yellow solid 4.4g, yield 65.5%, recording fusing point is 178~191 ℃, MSm/z (%): 330 (M +), 1H-NMR (CDCl 3): 3.56 (s, 6H, 2 * OMe), 3.86 (s, 3H, OMe), 6.28~6.29 (d, 2H, J=2.0Hz), 6.33~6.34 (t, 1H, J=2.0Hz), 6.71~6.74 (d, 1H, J AB=8.4Hz), 6.83~6.84 (d, 1H, J=8.4Hz), 6.87 (s, 1H), 7.80 (s, 1H).Confirmation is the compound of formula (7).
With the compound 6.6g (0.02mol) of formula (7), Cu powder 9.9 (0.15mol) g, quinoline 47.3mL (0.40mol) was 210 ℃ of following stirring reactions 8 hours.Normal pressure filtered after reaction was finished, and with ethyl acetate washing reaction bottle and filter paper, filtrate is again with the dilute hydrochloric acid washing, and the organic layer dried over mgso concentrates and obtains dark oily liquids.Use the method for column chromatography to carry out purifying, eluent is 10: 1 a petroleum ether-ethyl acetate of volume ratio.Get white crystal 3.0g, yield is 52.4%.Confirm it is the compound of formula (2) by analysis, analytical data is as follows: Mp:91~93 ℃, MSm/z (%): 286 (M +). 1H-NMR (CDCl 3): 3.66 (s, 6H, 2 * OMe), 3.84 (s, 3H, OMe), 6.30 (s, 1H), 6.43 (s, 2H, J=4.0Hz), 6.42~6.45 (m, 2H, J AB=8.0Hz), 6.68~6.70 (d, 1H, J=8.0Hz), 6.75~6.76 (d, 1H, J=8.0Hz), 6.87 (s, 1H).
The compound 1.5g (0.005mol) of modus ponens (2) is dissolved in 6mL (0.094mol) CH 2Cl 2In, add POCl then 32.6mL (0.028mol) stir.Slowly drip 6mL (0.094mol) CH 2Cl 2Dissolved 3.3mL (0.024mol) triethylamine, stirring reaction 6h under the room temperature.After finishing, reaction washes with water repeatedly, till presenting slightly acidic pH and being 6~7.Organic layer with anhydrous magnesium sulfate drying after, concentrate yellow oily liquid.In concentrated solution, add massfraction and be about 1% NaOH solution 30mL (0.01mol), heating in water bath to 70~80 ℃, vigorous stirring reaction 8h.Reaction solution elimination insolubles is concentrated into driedly, and water-acetone recrystallization obtains white solid 1.8g, and yield is 87.8%.Confirm it is the compound of formula (1) by analysis, wherein M represents Na +Analytical data is as follows: Mp:236~238 ℃ .FAB-MSm/z (%): 410 (M +). 1H-NMR (CDCl 3): 3.59 (s, 6H, 2 * OMe), 3.73 (s, 3H, OMe), 6.32 (s, 1H), 6.44 (s, 2H), 6.41~6.45 (d, 1H, J=12.0Hz), 6.55-6.58 (d, 1H, J=12.0Hz), 6.69 (d, 1H, J=4.0Hz), 6.76 (d, 1H, J=4.0Hz), 7.28 (s, 1H).
Embodiment 2:
Get homoanisic acid (being the compound of formula (3)) 16.6g (0.10mol) in there-necked flask, other adds the dissolving of 46mL (0.80mol) Glacial acetic acid, the bromine of Dropwise 5 .1mL (0.10mol) then, 45min drips off, under ice bath, stirred 3 hours again, pour in the frozen water, separate out solid, filter drying, make product 21.8g, yield is 89.0%, obtains the white plates crystal with ethyl alcohol recrystallization, yield 74%, recording fusing point is 113~114 ℃ (literature value of 3-bromo-4-methoxyl group-toluylic acid is 114~115 ℃).Therefore confirm that product is 3-bromo-4-methoxyl group-toluylic acid (being the compound of formula (4)).
Take by weighing the 3-bromo-4-methoxyphenylacetic acid 15.0g (0.06mol) that makes, other takes by weighing 3, and 5-dimethoxy benzaldehyde 10.2g (0.06mol) adds in the reaction flask, dissolve with 56.7mL (0.60mol) aceticanhydride, drip the triethylamine of 16.6mL (0.12mol), be heated to 120 ℃, reacted 8 hours.Separate out solid in the frozen water with pouring into after the concentrated hydrochloric acid acidification, the gained solid is with the dissolving of NaOH solution, and ethyl acetate extraction is removed impurity, and back acidifying water layer gets faint yellow solid, drying weigh 21.4g, yield is 90.7%; Get 3-(3,4, the 5-trimethoxyphenyl)-2-(3 '-bromo-4 '-the p-methoxy-phenyl)-vinylformic acid of 18.4g light yellow crystal with acetone-sherwood oil recrystallization, yield is 78.0%.
With the compound of 10.0g (0.025mol) formula (6), the KOH solid of 84.0g (1.50mol), the CuCl of 3.4g (0.025mol) 2Add and be equipped with in two mouthfuls of flasks of prolong, add the 350mL deionized water dissolving, stir and be heated to 100 ℃ (bathing temperature), reaction 48h has reacted after-filtration, uses the concentrated hydrochloric acid acidifying, treat that solid all separates out after-filtration, chloroform-sherwood oil recrystallization, the compound 5.0g of formula (7) of faint yellow solid, yield 60.6%.
With the compound 6.6g (0.02mol) of formula (7), Fe powder 8.9g (0.16oml), pyridine 40mL (0.50mol), stirring reaction is 2 hours under reflux state.Normal pressure filtered after reaction was finished, and with ethyl acetate washing reaction bottle and filter paper, filtrate is again with the dilute hydrochloric acid washing, and the organic layer dried over mgso concentrates and obtains dark oily liquids.Use the method for column chromatography to carry out purifying, eluent is 4: 1 a petroleum ether-ethyl acetate of volume ratio.Get light yellow solid 3.4g, yield is 59.4%.
Get the light yellow solid 1.5g (0.005mol) that previous step obtains and be dissolved in 6.4mL (0.10mol) CH 2Cl 2In, add POBr then 34.1mL (0.04mol) stir.Slowly drip 6.4ml (0.10mol) CH 2Cl 2Dissolved 3.2mL (0.04mol) pyridine, stirring reaction 2h under the room temperature.After finishing, reaction washes with water repeatedly, till presenting slightly acidic pH and being 6~7.Organic layer with anhydrous magnesium sulfate drying after, concentrate yellow oily liquid.In concentrated solution, add massfraction and be about 1% NaOH solution 30mL, heating in water bath to 100 ℃, vigorous stirring reaction 15h.Reaction solution elimination insolubles is concentrated into driedly, with methyl alcohol-acetone recrystallization, obtains white solid 1.5g, i.e. the compound of formula (1), and wherein M represents Na +, yield is 73.2%.
Embodiment 3:
The preparation of the compound of formula (2) is with embodiment 1.
The compound 1.5g (0.005mol) of modus ponens (2) is dissolved in 6mL (0.094mol) CH 2Cl 2In, add (C then 2H 5O) 2P (O) Cl3.6mL (0.025mol) stirs.Slowly drip 6mL (0.094mol) CH 2Cl 2Dissolved 1.4mL (0.02mol) Trimethylamine 99, stirring reaction 8h under the room temperature.After finishing, reaction washes with water repeatedly, till presenting slightly acidic pH and being 6~7.Organic layer with anhydrous magnesium sulfate drying after, concentrate yellow oily liquid.In concentrated solution, add KOH solution 30mL (0.01mol, heating in water bath to 50 ℃, vigorous stirring reaction 6h.Reaction solution elimination insolubles is concentrated into driedly, and water-recrystallizing methanol obtains white solid 1.8g, i.e. the compound of formula (1), and wherein M represents K +, yield is 81.4%.
Embodiment 4:
The preparation of the compound of formula (2) is with embodiment 1.
The compound 1.5g (0.005mol) of modus ponens (2) is dissolved in 6mL (0.075mol) ethylene dichloride, adds POCl then 32.6mL (0.028mol) stir.Slowly drip 6ml (0.075mol) CH 2Cl 2Dissolved 3.3mL (0.024mol) triethylamine, stirring reaction 4h under the room temperature.After finishing, reaction washes with water repeatedly, till presenting slightly acidic pH and being 6~7.Organic layer with anhydrous magnesium sulfate drying after, concentrate yellow oily liquid.The ammonia soln 30mL (0.01mol) that in concentrated solution, adds, heating in water bath to 70~80 ℃, vigorous stirring reaction 6h.Reaction solution elimination insolubles is concentrated into driedly, and the water recrystallization obtains white solid 1.4g, i.e. the compound of formula (1), and wherein M represents NH 4 +, yield is 70%.
Embodiment 5: extracorporeal anti-tumor cell-proliferation activity screening---external tetrazolium bromide (MTT) method
Get the low differentiation of the CNE-2 people nasopharyngeal carcinoma cell, KB-3-1 human oral squamous cell carcinoma, MCF-7 human breast cancer cell, MGC803 gastric carcinoma cells, LoVo human colon cancer cell, HepG2 human liver cancer cell, HL-60 people's acute promyelocytic leukemia cell, Jurkat human lymphoma cell, Romos human lymphoma cell, 293 HEKC that are in logarithmic phase and be prepared as cell suspension respectively, cell density about 2 * 10 5/ mL adds in 96 orifice plates, every porocyte number about 2000.After treating cell attachment, the compound of the formula (1) that embodiment 1 is obtained is pressed the final concentration doubling dilution and is added separately in the group, and every group is 4 parallel holes, and setting 0.1% dimethyl sulfoxide (DMSO) (DMSO) is solvent control.Still place 37 ℃, 5%CO after the dosing 2Cultivate 72h in the cell culture incubator.The every hole of 4h added the MTT solution of the 5mg/mL of 20 μ L before experiment stopped, cultivate 4h again, thoroughly discard the nutrient solution part before the mensuration, every hole adds 200 μ L DMSO, normal temperature is vibration 10min down, after purple crystal to be generated dissolves fully, use the MULTISKAN microplate reader to measure every hole OD value at the 570nm/630nm dual wavelength, numerical value utilizes following formula to calculate and obtains cell proliferation inhibition rate (IR): IR=1-OD T/ OD C, (OD C: control group OD value, OD T: medication group OD value), utilize the Bliss method to calculate IC again 50The result is the IC of CNE-2 50(nM)=31.61 ± 5.97, the IC of MGC803 50(nM)=414.08 ± 46.90, the IC of MCF-7 50(nM)=57.70 ± 6.04, the IC of HepG2 50(nM)=43.04 ± 2.55, the IC of LoVo 50(nM)=38.99 ± 3.22, the IC of HL-60 50(nM)=14.33 ± 5.70.
The embodiment 6:HUVEC experiment that comes off
With human umbilical cord's venous endothelial cell (HUVECs) is that model carries out active testing.HUVECs is coated on the plate that has all scribbled 0.2% gelatin in 12 holes, every porocyte number is 3 * 10 4Behind the 24h, when cell has 30% to merge approximately, then use the medicine to be measured (being the compound of the formula (1) that obtains of embodiment 1) of different concns to handle 40min.After the processing, the not cast-off cells that the cell detachment situation is removed behind the testing drug by counting are weighed, the method of removing testing drug and solvent be with the careful cleaning cell of HBSS to remove the cell that comes off, make trypsinized then, just count enable cast-off cells number not.The result is represented that by the cast-off cells percentage result is all in limit of error.The compound of the formula (1) of concentration 0.01 μ mol/L is 12% to the cell detachment percentage ratio of human umbilical cord's venous endothelial cell as a result, and the cell detachment percentage ratio of concentration 0.1 μ mol/L is 20%, and the cell detachment percentage ratio of concentration 1 μ mol/L is 22%.
Embodiment 7: tubulin is in conjunction with suppressing experiment
Test method is earlier under 37 ℃ condition the compound of the formula (1) of different concns to be injected microtubule, and reaction solution freezes with ice-cold then.Add GTP, use the 300nm Gliford infrared spectra registering instrument that electron temperature-control equipment is housed with turbidity test polymerization situation.Can determine extent of polymerization after injecting 20min.The compound test is each parallel carries out three groups, obtains statistical average value.
Result of experiment is: the IC of the compound of formula (1) 50=8 μ mol/L.
Embodiment 8:
The crystal powder of the compound of 86.5g formula (1) is mixed mutually with 1g glucose, 10g W-Gum and 1.5g 5% corn starch paste, make mixture forming particle with a wet grain method.Add the 1g Magnesium Stearate then, obtain oral preparation by pressed disc method.
Embodiment 9:
3.2mg the white powder of the compound of formula (1) forms solution in the physiological saline of adding 1.6mL.

Claims (9)

1. the compound of general formula (1):
Formula (1)
Wherein M represents K +, Na +Or NH 4 +
2. the preparation method of the described compound of claim 1 is characterized in that comprising the steps:
(1) with the inert solvent be solvent, the following and phosphorus esterification reagent reaction with the existence of acid binding agent at normal temperatures of the compound of formula (2) obtains the phosphorylated intermediate;
Figure C2006100337880002C2
Formula (2)
(2) the phosphorylated intermediate that obtains is heated to 50~100 ℃ of reactions in alkaline solution, obtains the described general formula of claim 1 (1) compound behind the purifying.
3. the preparation method of compound according to claim 2; it is characterized in that the inert solvent described in the step (1) is methylene dichloride, ethylene dichloride or benzene; its consumption is 15~40 times of compound mole number of formula (2); described acid binding agent is pyridine or trialkylamine; the consumption of acid binding agent is 4~8 times of mole number of the compound of formula (2), and described phosphorus esterification reagent is (Bu tO) 2P (O) Cl, P (O) Cl 3Or P (O) Br 3, the consumption of phosphorus esterification reagent is 5~8 times of compound mole number of formula (2), the reaction times is 2~8h; The described alkali of step (2) is that concentration range is NaOH, KOH, ammoniacal liquor, volatile salt, sodium alkoxide or the potassium alcoholate of 0.2~1.5mol/L, the consumption of alkali is 2 times of compound mole number of formula (2), reaction times is 6~15h, and described purifying is the mixed solvent of mixed solvent, water and ethanol mixed solvent, methyl alcohol and acetone of water, water and methyl alcohol or the mixed solvent recrystallization of water and acetone.
4. according to the preparation method of claim 2 or 3 described compounds, it is characterized in that the described acid binding agent of step (1) is a triethylamine, described phosphorus esterification reagent is P (O) Cl 3, the described purifying of step (2) is the mixed solvent recrystallization of water and acetone.
5. according to the preparation method of claim 2 or 3 described compounds, it is characterized in that the preparation of the compound of formula (2) comprises the steps:
(1) compound of following formula (3) reacts under 0~20 ℃ temperature with bromine in acetic acid solution, the purified compound that obtains formula (4);
Figure C2006100337880003C1
Figure C2006100337880003C2
Formula (3) formula (4)
(2) with the compound of the formula (4) that obtains with the compound of following formula (5) under triethylamine catalysis, in acetic anhydride, be heated to 80~120 ℃, reaction back acidifying, purifying obtain the compound of following formula (6);
Figure C2006100337880003C4
Formula (5) formula (6)
(3) compound of formula (6) is in strong base solution, and cupric salt exists down, 100~120 ℃ of reactions, again through acidifying, purifying, obtains the compound of following formula (7):
Figure C2006100337880003C5
Formula (7)
(4) compound of formula (7) 210~240 ℃ of decarboxylations under the katalysis of organic bases and metal are through the compound that separates, purifying obtains formula (2).
6. the preparation method of compound according to claim 5, it is characterized in that the compound of the described formula of step (1) (3) and the mol ratio of bromine are 1: 1, the consumption of acetate is 5~8 times of mole number of the compound of formula (3) or bromine, reaction times is 1~3h, and described purifying is with ethanol, the mixed solvent of second alcohol and water or the mixed solvent recrystallization of ethyl acetate and sherwood oil; The mol ratio of the compound of the compound of step (2) Chinese style (4) and formula (5) is 1: 1, the consumption of acetic anhydride is 8~10 times of mole number of the compound of formula (4) or (5), the consumption of triethylamine is 1.5~2.0 times of mole number of the compound of formula (4) or (5), reaction times is 6~8h, described purifying is to use ethyl acetate extraction, and adopts the mixed solvent of mixed solvent, acetone and sherwood oil of ethanol, second alcohol and water or the mixed solvent recrystallization of chloroform and sherwood oil; The described strong base solution of step (3) is that massfraction is 8%~20% NaOH or KOH solution, the consumption of alkali is 60~80 times of compound mole number of formula (6), the consumption of described cupric salt is 1~1.5 times of compound mole number of formula (6), described cupric salt is copper sulfate, cupric chloride, cupric nitrate or ventilation breather, reaction times is 48~72h, and described purifying is mixed solvent, the mixed solvent of second alcohol and water or the mixed solvent recrystallization of chloroform and sherwood oil with mixed solvent, ethyl acetate and the sherwood oil of chloroform and sherwood oil; Organic bases described in the step (4) is pyridine, piperidines or quinoline woods, the consumption of organic bases is 20~25 times of compound mole number of formula (7), described metal is Fe, Al, Zn or Cu, the consumption of metal is 7.5~8 times of compound mole number of formula (7), reaction times is 2~8 hours, and described purifying is to be that the column chromatography separation method of eluent or 30~50 times silica gel that quality is mixture quality to be separated are that carrier carries out column chromatography with ethyl acetate-sherwood oil of 1: 4~1: 10 of volume ratio.
7. according to the preparation method of claim 5 or 6 described compounds, it is characterized in that the described purifying of step (1) is the mixed solvent with ethanol or second alcohol and water, the described purifying of step (2) is to use ethyl alcohol recrystallization; The described strong base solution of step (3) is that massfraction is 8%~20% NaOH solution, and described cupric salt is a copper sulfate, and described purifying is the mixed solvent recrystallization with ethyl acetate and sherwood oil; Organic bases described in the step (4) is a quinoline, and described metal is Cu.
8. be used to prepare antineoplastic vascular endothelial and anti-angiogenic outgrowth pharmaceutical composition, wherein contain the described compound of treatment significant quantity claim 1 and one or more pharmaceutically acceptable carriers.
9. the described compound of claim 1 is in preparation antineoplastic vascular endothelial and anti-angiogenic hyperplasia treatment Application for Field.
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