CN101074189A - Styrene acid derivative and use in preparation of various blood-vessels target agent medicine - Google Patents

Styrene acid derivative and use in preparation of various blood-vessels target agent medicine Download PDF

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CN101074189A
CN101074189A CNA2006100208185A CN200610020818A CN101074189A CN 101074189 A CN101074189 A CN 101074189A CN A2006100208185 A CNA2006100208185 A CN A2006100208185A CN 200610020818 A CN200610020818 A CN 200610020818A CN 101074189 A CN101074189 A CN 101074189A
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medicine
acid derivative
alkyl
hydroxyl
acid
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CN101074189B (en
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雍智全
徐小平
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Dongguan peace pharmaceutical science and Technology Co Ltd
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雍智全
徐小平
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Abstract

A styrene acid derivative can be used to prepare vascular target agent medicine including antineoplastic medicine and medicine for inhibiting eyeground production. In formula, R1, R2, R3, R4 and R5 are hydrogen, alkyl, hydroxyl, alkoxy, amino, fluorine, chlorine or bromine; R11 is sodium, potassium, lithium, magnesium, calcium or ammonia or organic carboxy-contained ammonium including amino-acid or peptide or glyceryl, hydroxyl, glycosyl containing glucose, multi-hydroxy naphthenic acid containing kinic acid.

Description

Vinylbenzene acid derivative and the application in the preparation blood-vessels target agent medicine thereof
Technical field
What the present invention relates to is the salt of a quasi-styrene acid and the derivative of ester, can be applied to preparing blood-vessels target agent medicine.
Background technology
CA-4 P (CA4P) is the disodic alkaliine of a kind of diphenylethylene compounds combretastatin, and structure is suc as formula shown in the A.
Figure A20061002081800041
Combretastatin is George R.Pettit, the compounds that Ph.D. finds from a kind of dwarf willow tree in Africa (Combretum Caffrum) and separation obtains.CA4P is an OXiGENE company from the phosphoric acid ester sintetics of the natural compounds combretastatin A4 (CA4) of separation screening wherein.CA4P is that at present unique a kind of what developing is mechanism to destroy the tumor vessel system, utilize jejune blood vessel in its target tumor, enter endotheliocyte and destroy its inner skeleton after converting combretastatin to, change its form and block capillary vessel, break off the oxygen supply of tumour.It is shown at tumor vascular selectively targeted and destroy the tumor vascular effect that has generated, the potent attack vivo tumor of energy, cause tumour thoroughly dead from inside to outside, can be used as the injection type anticarcinogen, be used for the treatment of advanced solid tumor such as lung cancer, liver cancer, cervical cancer.
US 4,996, and 237 and US 5,561,122, and J.Org.Chem, 2001,66,8135-8138 and Journal ofMedicinal Chemistry, 1995 Jul 21; 38 (15): 2994 documents such as grade are introduced to some extent to correlative studys such as CA4, CA4P and synthetic methods thereof respectively.Wherein, in the preparation method to CA4 and analogue thereof, it is the report that intermediate obtains through reduction reaction that vinylbenzene acid or its methyl esters with corresponding precursor structure were once arranged.
Summary of the invention
Only report CA4P in view of present document and have, and the present inventor finds that its some precursor compound can have the blood-vessels target effect equally at tumor vascular specific target tropism effect.In view of the above, the present invention's purpose at first provides the salt and/or the ester derivative of this quasi-styrene acid with blood-vessels target effect.On this basis, further aim of the present invention provides these vinylbenzene acid derivatives and is used for the treatment of in preparation and comprises antitumor and suppress application aspect the blood-vessels target medicine of diseases such as optical fundus blood vessel hyperplasia.
Vinylbenzene acid derivative of the present invention comprises its corresponding salt derivative and ester derivative.
The structure of the said vinylbenzene Barbiturates of the present invention derivative is shown in (I).
Figure A20061002081800051
M in the formula (I) is sodium, potassium, lithium, magnesium, calcium, ammonium or the organic amine that contains carboxyl that comprises amino acid, dipeptides, tripeptides, polypeptide etc.; R 1, R 2, R 3, R 4, R 5For amidos such as alkoxyl groups such as alkyl such as hydrogen, methyl, ethyl, sec.-propyl, the tertiary butyl, hydroxyl, methoxyl group, oxyethyl group, butoxy, amino, methylamino, dimethylin, diethylin, fluorine, chlorine or bromine etc., wherein in particular for hydroxyl, methoxyl group or amido.
When the M in the above-mentioned salt derivative was the form of ammonium salt, its structure can be as shown in the formula shown in (II).
Figure A20061002081800052
R in the formula (II) 6, R 7, R 8, R 9Can be alkyl such as hydrogen, methyl, ethyl, sec.-propyl, the tertiary butyl, or have an alkyl such as hydroxyethyl, hydroxypropyl, amine ethyl of oxygen, nitrogen, or contain the chain base of carboxyl in the structures such as dipeptides such as amino acid, AQ, GA, GL, tripeptides, polypeptide such as glycine, L-Ala, leucine, arginine, or at R 6, R 7, R 8, R 9In three groups between form as cycloalkyl such as piperidines, morpholine, piperazines, have the cycloalkyl of oxygen, nitrogen, said each alkyl or cycloalkyl can also further have substituting groups such as amido, trolamine base, as methylpiperazine, meglumine etc.
The structure of the said vinylbenzene esters of gallic acid of the present invention derivative is shown in (III):
Figure A20061002081800053
R in the formula (III) 1, R 2, R 3, R 4, R 5Be hydrogen, alkyl, hydroxyl, alkoxyl group, amido, fluorine, chlorine, bromine substituent, wherein equally in particular for hydroxyl, methoxyl group, amido; R 10For alkyl such as hydroxyethyl, glycerine alkyl, methyl, ethyl, sec.-propyl, the tertiary butyls, comprise sugared alkyl such as glucose, pectinose, Xylitol or comprise poly-hydroxy cycloalkyl such as quinic acid, gluconic acid.
Comprise the vinylbenzene Barbiturates of the present invention of above-mentioned various structure formation compounds and the structure of ester derivative, can be shown in general formula (IV).R wherein 1, R 2, R 3, R 4, R 5Be above-mentioned hydrogen, alkyl, hydroxyl, alkoxyl group, amido, fluorine, chlorine or bromine, wherein in particular for hydroxyl, methoxyl group, amido; R 11For sodium, potassium, lithium, magnesium, calcium, ammonium or comprise amino acid or the organic amine that contains carboxyl of peptide, or hydroxyethyl, glyceryl, comprise methyl alkoxyl group, comprise glucose glycosyl, comprise the poly-hydroxy cycloalkyl of quinic acid.
Figure A20061002081800061
Vinylbenzene acid derivative with formula (IV) structure is the effective active composition, auxiliary added ingredients combination such as corresponding pharmaceutical excipient with acceptable in the medicine or carrier, and, can prepare the blood-vessels target agent medicine of corresponding forms such as becoming oral, injection or external application type by after the corresponding conventional pharmaceutical methods processing treatment.For example, with can received disintegrating agent in the oral drug preparation, after auxiliary interpolation composition that vehicle, lubricant, tackiness agent, weighting agent etc. are commonly used mixes, handle by corresponding common process method, promptly may be made in the oral pharmaceutical of the solid preparation forms such as sustained release dosage, control-released agent of tablet, pill, granule, capsule or appropriate form; Press in the injectable drug preparation and to allow the appropriate solvent that uses and after additives cooperate and corresponding technological operation handles, can be prepared into the injection agent medicine of muscle such as corresponding liquid drugs injection or powder pin or vein form; With commonly used solvent, stablely swash or lipophilicity matrix such as sodium polyacrylate, polyvinyl alcohol, polyoxyethylene glycol, glycerine, vegetables oil, Vaseline, lanolin and/or water-soluble base mix, handle by corresponding external medicine preparation, promptly may be made in eye drop or emplastrum, plaster, gelifying agent, ointment, liniment, liniment etc.Injection formulationss such as these injection liquids, aseptic powder injection, aseptic freeze-dried powder pin, oral preparations such as tablet, capsule, various sustained-release preparations, and as external preparation form medicines such as eye drop, ointment etc., can comprise antitumor drug for treatment respectively and suppress class diseases such as optical fundus blood vessel hyperplasia and use.
Embodiment by the following examples is described in further detail foregoing of the present invention again.But this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following example.Do not breaking away under the above-mentioned technological thought situation of the present invention, various replacements or change according to ordinary skill knowledge and customary means are made all should comprise within the scope of the invention.
Embodiment
Embodiment 1
(E)-3-(3 '-hydroxyl-4 '-methoxyphenyl)-2-(3 ", 4 ", 5 " and 2,4,5-trimethoxyphenyl)-2-vinylformic acid (abbreviation CA 4Synthesizing S)
With 3,4,5-trimethoxy toluylic acid 140g (610mmol), isovanillin 110g (724mmol), acetic anhydride 200ml and NEt 3100ml (717mmol) joins in the round-bottomed flask of 1000ml, and temperature was in 150 ℃ of stirring and refluxing 2.5 hours outside, and solvent is to the greatest extent steamed in decompression, get oily matter, add about 300 milliliters of 1N hydrochloric acid, stirred overnight at room temperature, get yellow solid, get faint yellow solid 125g with ethanol 400mL recrystallization, yield 56%.mp.228℃～232℃。
TLC detects: developping agent PE: EA=1: 1, and (2 of ice acetic acids) Rf=0.45.
1H NMR(400MHz，DMSO)δ3.686(s，6H，3′，5′-OCH3)，3.712(s，3H，4′-OCH3)，3.731(s，3H，4-OCH3)，6.436(s，2H，2′，6′-ArH)，6.485(d，J＝2.0Hz，2-ArH)，6.603(dd，J＝2.0，8.4Hz，1H，5-ArH)，6.806(d，J＝8.4Hz，1H，6-ArH)，7.757(s，1H，C＝CH)，8.962(s，1H，OH)，12.435(s，1H，COOH)；
13C NMR (100MHz, DMSO) δ 55.659,56.148, and 60.299,107.055,111.743,117.391,123.098,127.255,132.276,137.262,139.254,146.059 149.064,153.257,168.727 totally 16 groups of carbon conform to product structure.ESI-MS：358.9(M-H，100)。
Embodiment 2
(E)-3-(2 ', 3 '-dihydroxyl-4 '-methoxyphenyl)-2-(3 ", 4 ", 5 " and 2,4,5-trimethoxyphenyl)-2-is acrylic acid synthetic
With 3,4,5-trimethoxy toluylic acid 140g (610mmol), 2,3-dihydroxyl-4-methoxybenzaldehyde 724mmol, acetic anhydride 200ml and NEt 3100ml (717mmol) joins in the round-bottomed flask of 1000ml, and 150 ℃ of following stirring and refluxing of temperature are 2.5 hours outside, and solvent is to the greatest extent steamed in decompression, get oily matter, add the about 300ml of 1N hydrochloric acid, stirred overnight at room temperature, get yellow solid, get faint yellow solid with ethanol 400ml recrystallization.
Embodiment 3
(E)-3-(3 '-amido-4 '-methoxyphenyl)-2-(3 ", 4 ", 5 " and 2,4,5-trimethoxyphenyl)-2-is acrylic acid synthetic
With 3,4,5-trimethoxy toluylic acid 140g (610mmol), 3-amido-4-methoxybenzaldehyde 724mmol, acetic anhydride 200ml and NEt 3100ml (717mmol) joins in the round-bottomed flask of 1000ml, 150 ℃ of following stirring and refluxing of temperature are 2.5 hours outside, solvent is to the greatest extent steamed in decompression, get oily matter, add the about 300ml of 1N hydrochloric acid, stirred overnight at room temperature, transferring pH with saturated sodium bicarbonate solution is 5-6, get yellow solid, get faint yellow solid with ethanol 400ml recrystallization.
Embodiment 4
(E)-3-(3 '-chloro-4 '-methoxyphenyl)-2-(3 ", 4 ", 5 " and 2,4,5-trimethoxyphenyl)-2-is acrylic acid synthetic
With 3,4,5-trimethoxy toluylic acid 140g (610mmol), 3-chloro-4-methoxybenzaldehyde 724mmol, acetic anhydride 200ml and NEt 3100ml (717mmol) joins in the round-bottomed flask of 1000ml, and 150 ℃ of following stirring and refluxing of temperature are 2.5 hours outside, and solvent is to the greatest extent steamed in decompression, get oily matter, add the about 300ml of 1N hydrochloric acid, stirred overnight at room temperature, get light yellow solid, get the off-white color solid with ethanol 400ml recrystallization.
Embodiment 5
(E)-3-(3 ', 5 '-dihydroxy phenyl)-2-(3 ", 4 ", 5 " and 2,4,5-trimethoxyphenyl)-2-is acrylic acid synthetic
With 3,4,5-trimethoxy toluylic acid 140g (610mmol), 3,5-Dihydroxy benzaldehyde 724mmol, acetic anhydride 200ml and NEt 3100ml (717mmol) joins in the round-bottomed flask of 1000ml, and 150 ℃ of following stirring and refluxing of temperature are 2.5 hours outside, and solvent is to the greatest extent steamed in decompression, get oily matter, add the about 300ml of 1N hydrochloric acid, stirred overnight at room temperature, get yellow solid, get faint yellow solid with ethanol 400ml recrystallization.
Embodiment 6
CA 4Synthesizing of S sodium salt
With each above-mentioned CA 4S 5.00g adds in the 100ml reaction flask, adds dehydrated alcohol 20ml, and carbonic acid gas-acetone is cooled to-50 ℃; under-50～-20 ℃ of protections at argon gas; stir and drip the ethanolic soln of equivalent sodium ethylate, about 20min dropwises, and is warming up to 20 ℃ of reactions 1 hour again.Be cooled to-20 ℃ then, filter and drying, get corresponding CA 4The sodium salt crystal product of S.
Embodiment 7
CA 4Synthesizing of S calcium salt
With each above-mentioned CA 4S 5.00g adds in the 100ml reaction flask, adds dehydrated alcohol 20ml, is cooled to-20 ℃, under-20 ℃ of protections at argon gas, stirs and drip the aqueous solution of equivalent calcium hydroxide, and about 20min dropwises, and is warming up to 20 ℃ of reactions 1 hour.Be cooled to-20 ℃ then, filter and drying, obtain corresponding CA 4The calcium salt crystallization of S.
Embodiment 8
A kind of CA 4Synthesizing of S leucine salt
With each above-mentioned CA 4S 5.00g adds in the 100ml reaction flask, adds acetone 20ml, is cooled to-20 ℃, stirs under the protection of argon gas and the leucic acetone soln of dropping equivalent, and about 20min dropwises, and is warming up to 60 ℃ of reactions 1 hour.Concentrating under reduced pressure adds the 20ml ethyl acetate then, is heated to 80 ℃ of backflows, is cooled to 0 ℃, filters and drying, obtains corresponding CA 4The leucine salt crystallization of S.
Embodiment 9
CA 4Synthesizing of S triethanolamine salt
With each above-mentioned CA 4S 5.00g adds in the 100ml reaction flask, adds acetone 20ml, is cooled to-20 ℃, under-20 ℃ of protections at argon gas, stirs and drip the acetone soln of equivalent trolamine, and about 20min dropwises, and is warming up to 60 ℃ of reactions 1 hour then.Concentrating under reduced pressure adds the 20ml ethyl acetate then, is heated to 80 ℃ of backflows, is cooled to 0 ℃, filters and drying, obtains corresponding CA 4The triethanolamine salt crystallization of S.
Embodiment 10
CA 4Synthesizing of S meglumine salt
With each above-mentioned CA 4S 5.00g adds in the 100ml reaction flask, adds acetone 20ml, is cooled to-20 ℃, stirs and drip the acetone soln of equivalent meglumine under the protection of argon gas, and about 20min dropwises, and is warming up to 60 ℃ of reactions 1 hour.Concentrating under reduced pressure adds the 20ml ethyl acetate then, is heated to 80 ℃ of backflows, is cooled to 0 ℃, filters and drying, obtains corresponding CA 4The meglumine salt crystallization of S.
Embodiment 11
(E)-3-(2 ', 3 '-dihydroxyl-4 '-methoxyphenyl)-2-(3 ", 4 ", 5 " 2,4,5-trimethoxyphenyl)-2-vinylformic acid triethylamine salt synthetic
(E)-3-that embodiment 2 is obtained (2 '; 3 '-dihydroxyl-4 '-methoxyphenyl)-2-(3 "; 4 " 5 " 2,4,5-trimethoxyphenyl)-and 2-vinylformic acid 5.00g adds in the 100ml reaction flask; and add acetone 20ml, be cooled to 0 ℃, under 0 ℃ of protection, stir and drip the acetone soln of equivalent triethylamine; about 20min dropwises, be warming up to 20 ℃ and reacted 1 hour at argon gas.Concentrating under reduced pressure then adds the 20ml ethyl acetate, is heated to 80 ℃ of backflows, is cooled to 0 ℃, filter and dry, (E)-3-(2 ', 3 '-dihydroxyl-4 '-methoxyphenyl)-white crystals of 2-(3 ", 4 ", 5 " 2,4,5-trimethoxyphenyl)-2-vinylformic acid triethylamine salt.
Embodiment 12
(E)-3-(2 ', 3 '-dihydroxyl-4 '-methoxyphenyl)-2-(3 ", 4 ", 5 " 2,4,5-trimethoxyphenyl)-2-vinylformic acid piperazine salt synthetic
(E)-3-that embodiment 2 is obtained (2 '; 3 '-dihydroxyl-4 '-methoxyphenyl)-2-(3 "; 4 " 5 " 2,4,5-trimethoxyphenyl)-and 2-vinylformic acid 5.00g adds in the 100ml reaction flask; and add acetone 20ml, be cooled to 0 ℃, under 0 ℃ of protection, stir and drip the acetone soln of equivalent piperazine; about 20min dropwises, be warming up to 20 ℃ then and reacted 1 hour at argon gas.Concentrating under reduced pressure adds the 20ml ethyl acetate, is heated to 80 ℃ of backflows, is cooled to 0 ℃, filter and dry, (E)-3-(2 ', 3 '-dihydroxyl-4 '-methoxyphenyl)-white crystals of 2-(3 ", 4 ", 5 " 2,4,5-trimethoxyphenyl)-2-vinylformic acid piperazine salt.
Embodiment 13
(E)-3-(2 ', 3 '-dihydroxyl-4 '-methoxyphenyl)-2-(3 ", 4 ", 5 " 2,4,5-trimethoxyphenyl)-2-vinylformic acid isopropyl amine salt synthetic
(E)-3-that embodiment 2 is obtained (2 '; 3 '-dihydroxyl-4 '-methoxyphenyl)-2-(3 '; 4 '; 5 '-2,4,5-trimethoxyphenyl)-2-vinylformic acid 5.00g adds in the 100ml reaction flask; add acetone 20ml, be cooled to 0 ℃, under 0 ℃ of protection, stir and drip the acetone soln of equivalent Isopropylamine at argon gas; about 20min dropwises, and is warming up to 20 ℃ of reactions 1 hour then.Concentrating under reduced pressure adds the 20ml ethyl acetate, is heated to 80 ℃ of backflows, is cooled to 0 ℃, filter and dry, (E)-3-(2 ', 3 '-dihydroxyl-4 '-methoxyphenyl)-white crystals of 2-(3 ", 4 ", 5 " 2,4,5-trimethoxyphenyl)-2-vinylformic acid isopropyl amine salt.
Embodiment 14
(E)-3-(3 ', 5 '-dihydroxy phenyl)-2-(3 ", 4 ", 5 " 2,4,5-trimethoxyphenyl)-2-Hydroxyethyl acrylate synthetic
With (E)-3-(3 '; 5 '-dihydroxy phenyl)-2-(3 "; 4 " 5 " 2,4,5-trimethoxyphenyl)-and 2-vinylformic acid 5.00g adds in the 100ml reaction flask; and add ethylene glycol 20ml; be cooled to 0 ℃, under 0 ℃ of protection, stir and drip the 1ml vitriol oil, under the protection of argon gas, be warming up to 100 ℃ of reactions 1 hour at argon gas.Concentrating under reduced pressure then adds the 20ml ethyl acetate, is washed to neutrality, use anhydrous sodium sulfate drying, and concentrating under reduced pressure removes and desolvates, must (E)-3-(3 ', 5 '-dihydroxy phenyl)-white crystals of 2-(3 ", 4 ", 5 " 2,4,5-trimethoxyphenyl)-2-Hydroxyethyl acrylate.
Embodiment 15
(E)-3-(3 ', 5 '-dihydroxy phenyl)-2-(3 ", 4 ", 5 " 2,4,5-trimethoxyphenyl)-2-quinate synthetic
With (E)-3-(3 '; 5 '-dihydroxy phenyl)-2-(3 "; 4 " 5 " 2,4,5-trimethoxyphenyl)-and 2-vinylformic acid 5.00g adds in the 100ml reaction flask; and add 2-quinic acid 10g, be cooled to 0 ℃, ethyl acetate 50ml; under 0 ℃ of protection, stir and add DCC 6g, under the protection of argon gas, be warming up to room temperature reaction 1 hour at argon gas.Filter out the insoluble solid thing, add the 20ml ethyl acetate again, be washed to neutrality, use anhydrous sodium sulfate drying, concentrating under reduced pressure removes and desolvates, and gets product and uses column chromatography, (E)-3-(3 ', 5 '-dihydroxy phenyl)-white crystals of 2-(3 ", 4 ", 5 " 2,4,5-trimethoxyphenyl)-2-quinate.
Embodiment 16
The intravenous (IV) drug that contains vinylbenzene acid sodium-salt and 0.9% sodium-chlor:
Injection 1:
CA 4S sodium salt 1500g
Sodium-chlor 180g
Water for injection 20000ml
Make 1000 of the injections of 20ml altogether by the routine operation of injection, every contains CA 4S sodium salt 1.5 grams.
Injection 2:
CA 4S meglumine salt 3000g
Sodium-chlor 2250g
Water for injection 2000,000ml
Make 1000 bottles of the injections of 1000ml altogether by the routine operation of injection, every bottle contains CA 4S meglumine salt 3 grams.
Injection 3:
CA 4S sylvite 1.0g
Citric Acid 1.0g
Sodium Citrate 0.5g
Glucose 100g
Water for injection 2,000ml
Make 1000 of the injections of 2ml altogether by the routine operation of injection, every contains CA 41 milligram of S sylvite.
Injection 4:
CA 4S meglumine salt 1500g
Glucose 1000g
Water for injection 20,000ml
Make 1000 of the injections of 20ml altogether by the routine operation of injection, every contains CA 4S meglumine salt 1.5 grams.
Injection 5:
CA 4S triethanolamine salt 3000g
Glucose 10,000g
Water for injection 2,000,000ml
Make 1000 bottles of the injections of 1000ml altogether by the routine operation of injection, every bottle contains CA 4S triethanolamine salt 3 grams.
In each above-mentioned prescription, for improving CA 4The stability of S can also add stablizer commonly used in the medicine respectively, as cyclodextrin inclusion compound, polyvinylpyrrolidone etc.; Antioxidant is as S-WAT, sodium bisulfite, Sodium Pyrosulfite, Sulfothiorine, xitix, halfcystine etc.; PH value conditioning agent can be selected for use as citric acid, fumaric acid, L-glutamic acid, L-aspartic acid, lactic acid, lactobionic acid, galacturonic acid, glucuronic acid, xitix, hydrochloric acid, acetic acid etc.
Embodiment 17 contains the eye drop medicine of vinylbenzene acid sodium-salt and 0.9% sodium-chlor
CA 4S sodium salt 1.0g
Citric Acid 1.0g
Sodium Citrate 0.5g
Sodium-chlor 18g
Water for injection 2000ml.
Press the conventional preparation method preparation of eye drop, make 1000 of the injections of 2ml altogether, every contains CA 41 milligram in S sodium.
For improving CA 4The stability of S can also add respectively as the used form stablizer of above-mentioned injection medicine, antioxidant, and pH value conditioning agents etc. are used complementary composition always.
Embodiment 18 contains CA 4The sterile powder injection of S
Prescription 1:CA 4S leucine salt aseptic powder 1g
Sodium-chlor aseptic powder 18g
Make 1000 of 2ml powder injection altogether by the routine operation of sterile powder injection, every contains CA 41 milligram of S leucine salt.
Prescription 2:CA 4S glycinate aseptic powder 1500g
Sodium-chlor aseptic powder 180g
Make 1000 of 20ml powder injection altogether by the routine operation of sterile powder injection, every contains CA 4S glycinate 1.2 grams.
Prescription 3:CA 4S meglumine salt aseptic powder 3000g
Make 1000 of 5ml powder injection altogether by the routine operation of sterile powder injection, every contains CA 4S meglumine salt 3 grams.
Prescription 4:CA 4S glycinate 1g
Glucose aseptic powder 100g
Make 1000 of 2ml powder injection altogether by the routine operation of sterile powder injection, every contains CA 41 milligram of S glycinate.
Prescription 5:CA 4S leucine salt aseptic powder 1500g
Glucose aseptic powder 1000g
Make 1000 of 20ml powder injection altogether by the routine operation of sterile powder injection, every contains CA 4S leucine salt 1.2 grams.
Embodiment 19 CA 4The aseptic freeze-dried powder injection of S
Each formulation product among the embodiment 16 is made CA through the freeze-drier lyophilize 4The aseptic freeze-dried powder injection of S sodium-chlor.
Embodiment 20 CA 4The S tablet:
(E)-3-(3 ', 5 '-dihydroxy phenyl)-2-(3 ", 4 ", 5 "
2,4,5-trimethoxyphenyl)-2-Hydroxyethyl acrylate 1.00g
Starch 184.00g
Polyvinylpyrrolidone 5.00g
Magnesium Stearate (120 order) 10.00g
Amount to: 200.00g
Weighting agent wherein can be selected for use as starch, dextrin, Icing Sugar, pregelatinized Starch, lactose, glucose, Microcrystalline Cellulose, lime carbonate, calcium sulfate, Calcium hydrogen carbonate etc.; Tamanori can be selected for use as hypromellose, polyvidone, starch slurry, dextrin slurry, syrup, rubber cement, sodium alginate, polyoxyethylene glycol, peach gum, gum arabic etc.; Disintegrating agent can be selected for use commonly used as croscarmellose sodium, polyvinylpolypyrrolidone, sodium starch glycolate, hydroxypropylated starch, low-substituted hydroxypropyl cellulose citric acid, tartrate, acid anhydrides, sodium bicarbonate, yellow soda ash etc.
Make 1000 altogether, every (E)-3-(3 ', 5 '-dihydroxy phenyl)-2-(3 ", 4 ", 5 " and 2,4,5-trimethoxyphenyl)-2-Hydroxyethyl acrylate 1mg.
Embodiment 21 CA 4The S capsule:
(E)-3-(3 ', 5 '-dihydroxy phenyl)-2-(3 ", 4 ", 5 "
2,4,5-trimethoxyphenyl)-2-quinate 100.00g
Starch 85.00g
Polyvinylpyrrolidone 5.00g
Magnesium Stearate (120 order) 10.00g
Amount to: 200.00g
Weighting agent wherein can be selected for use as starch, dextrin, Icing Sugar, pregelatinized Starch, lactose, glucose, Microcrystalline Cellulose, lime carbonate, calcium sulfate, Calcium hydrogen carbonate etc.; Tamanori can be selected for use as hypromellose, polyvidone, starch slurry, dextrin slurry, syrup, rubber cement, sodium alginate, polyoxyethylene glycol, peach gum, gum arabic etc.
Make 1000 capsules altogether, every capsules contain (E)-3-(3 ', 5 '-dihydroxy phenyl)-2-(3 ", 4 ", 5 " 2,4,5-trimethoxyphenyl)-2-quinate 100mg.
The test-results of the antitumor action that the above-mentioned vinylbenzene acid derivative of the present invention is carried out
Materials and methods
Clone and cell cultures A549 cell strain are human lung carcinoma cell, and adherent growth includes 10% calf serum (Chengdu Harry's biotechnology company limited) in RPMI1640 (GIBCO company) nutrient solution, 1mmol/L glutamine and 100 μ g/ml Streptomycin sulphates.In 37 ℃, 5%CO 2The saturated humidity incubator in cultivate, changed liquid and go down to posterity once in every 2-3 days.
Drug treating is made into mother liquor with the PBS dissolving, again with the dilution of 1640 complete culture solutions, filtration sterilization.
Instrument Heraeus CO 2Incubator, Olympus inverted microscope, BioRAO Model 550 enzyme-linked immunosorbent assay instruments.
Experimental technique
Cellular form observe take the logarithm vegetative period the A549 cell to transfer to cell concn with nutrient solution be 2 * 10 5Individual/ml, be divided into negative group of not dosing and administration group, the different concns drug treating is after 24 hours, observation of cell form under inverted microscope.
Cell growth condition is observed the logarithmic phase cell with cell concn 2 * 10 5Individual/ml is inoculated in the culturing bottle, treats that cell divides into groups after adherent fully again.Be divided into not dosing group, drug treating group (the isocyatic medicine of 5,10,40 μ g/ml adds cytositimulation), day by day each three bottles in the thing treatment group of getting it filled after the dosing and not dosing group cell, trypsin digestion cell, platform is expected blue dyeing, light microscopic is the meter viable count down, with three bottles of cell count averages, calculate growth inhibition ratio.
Mtt assay is surveyed take the logarithm vegetative period cell of inhibiting rate and is made 1.5 * 10 5, being inoculated in 96 well culture plates, every hole 100 μ l establish three multiple holes.Adding drug level is 0,1,2,4,8,16,32,64 μ g/ml and MTX0.5 μ g/ml control wells and zeroing hole add 100 μ l nutrient solutions, continue to cultivate 48h, 4h before finishing adds 10 μ l MTT, and the zeroing group does not add MTT (5mg/ml), continue to cultivate 4 hours, whole supernatant liquors are removed in suction, only stay a small amount of raffinate, and every hole adds 100 μ lDMSO and shakes up vibration.Crystallization is fully dissolved, on enzyme-linked immunosorbent assay instrument, survey each hole light absorption value, wavelength 490nm.Calculate inhibiting rate by following formula:
Inhibiting rate=(1-dosing holes absorbance value/control wells absorbance value) * 100%
Experimental result
Morphological observation
Form under the light microscopic: A549 cell and CA4-P, (E)-3-(3 '-hydroxyl-4 '-methoxyphenyl)-2-(3 "; 4 ", 5 " and 2,4,5-trimethoxyphenyl)-2-vinylformic acid glycinate (being called for short CAG), (E)-3-(3 '-amino-4 '-methoxyphenyl)-2-(3 ", 4 "; 5 "-2,4,5-trimethoxyphenyl)-2-vinylformic acid triethanolamine salt (being called for short CAS), (E)-3-(3 ', 5 '-dihydroxy phenyl)-2-(3 "; 4 ", 5 " and 2,4,5-trimethoxyphenyl)-2-quinate (be called for short CAK) hatched 24-48 hour jointly.Many cell suspension death under light microscopic, and cytomorphosis, cell rounding breaks away from adjacent cells, endochylema concentrates, and tumor giant cell is not obvious, and cavity appears in the part cell, and some cell volume dwindles, the after birth shrinkage, karyopyknosis, fragmentation, and have and transfer the corpusculum formation etc. of dying.
Growth and proliferation of cell is observed and is shown CA4-P, and CAG, CAS, CAK all can obviously suppress the propagation of A549 cell, and retarding effect increases with concentration increase.
Several compounds of table 1 are to A549 cell inhibitory effect effect (24h)
CA4-P CAG CAS CAK
Concentration (μ g/ml) 2 8 32 2 8 32 2 8 32 2 8 32
Inhibiting rate (%) 30 60 85 30 60 90 50 70 90 35 70 90
Mtt assay survey inhibiting rate medicine has obvious dependence to the growth inhibition ratio and the drug concentrations of A549 cell, and along with drug level increases, growth inhibition ratio increases.CA4P, CAG, CAS, CAK act on the IC of A549 cell 48h 50All approximately less than 16 μ g/ml.
Above-mentioned experimental result shows, the vinylbenzene acid derivative CAG that the present invention proposes, and CAS, CAK can have the blood-vessels target effect with the CA4P basically identical, obviously suppresses the propagation of A549 cell, and retarding effect increases with concentration increase.Therefore, the vinylbenzene acid derivative that the present invention proposes has the blood-vessels target effect with the satisfaction of CA4P basically identical, be used to prepare blood-vessels target agent medicine, for example comprising aspects such as antitumor drug and inhibition optical fundus blood vessel hyperplasia medicine, having positive meaning and prospect.

Claims (10)

1. vinylbenzene acid derivative, structure is shown in (I):
Figure A2006100208180002C1
M is sodium, potassium, lithium, magnesium, calcium, ammonium in the formula, or comprises the organic amine that contains carboxyl of amino acid or peptide;
R 1, R 2, R 3, R 4, R 5Be hydrogen, alkyl, hydroxyl, alkoxyl group, amido, fluorine, chlorine or bromine.
2. vinylbenzene acid derivative as claimed in claim 1 is characterized in that said R 1, R 2, R 3, R 4, R 5Be hydroxyl, methoxyl group or amido.
3. vinylbenzene acid derivative as claimed in claim 1 is characterized in that structure when said M is ammonium is suc as formula shown in (II)
Figure A2006100208180002C2
R in the formula 6, R 7, R 8, R 9Be hydrogen, alkyl, or have the alkyl of oxygen, sulphur, phosphorus, or at R 6, R 7, R 8, R 9In three groups between the cycloalkyl that comprises piperazinyl, piperidyl, morpholinyl, the cycloalkyl that has oxygen, sulphur, phosphorus that form, or further have substituent said each cycloalkyl that comprises amido, trolamine base.
4. vinylbenzene acid derivative, structure is shown in (III):
Figure A2006100208180002C3
R in the formula 1, R 2, R 3, R 4, R 5Be hydrogen, alkyl, hydroxyl, alkoxyl group, amido, fluorine, chlorine, bromine substituent, R 10Be hydroxyethyl, glycerine alkyl, the alkyl except that methyl, sugared alkyl or poly-hydroxy cycloalkyl.
5. vinylbenzene acid derivative as claimed in claim 4 is characterized in that said R 1, R 2, R 3, R 4, R 5Be hydroxyl, methoxyl group, amido.
6. vinylbenzene acid derivative as claimed in claim 4 is characterized in that said glycosyl is a glucose.
7. vinylbenzene acid derivative as claimed in claim 4 is characterized in that said poly-hydroxy cycloalkanes acidic group is a quinic acid.
8. suc as formula the application of vinylbenzene acid derivative in the preparation blood-vessels target agent medicine of (IV) structure, said blood-vessels target agent medicine comprises antitumor drug and suppresses optical fundus blood vessel hyperplasia medicine
Figure A2006100208180003C1
R in the formula 1, R 2, R 3, R 4, R 5Be hydrogen, alkyl, hydroxyl, alkoxyl group, amido, fluorine, chlorine or bromine, R 11Be sodium, potassium, lithium, magnesium, calcium, ammonium, or comprise the organic amine that contains carboxyl of amino acid or peptide, can also be glyceryl, alkoxyl group, comprise glucose glycosyl, comprise the poly-hydroxy cycloalkyl of quinic acid.
9. the application in the preparation blood-vessels target agent medicine as claimed in claim 8 is characterized in that said R 1, R 2, R 3, R 4, R 5Be hydroxyl, methoxyl group, amido.
10. the application in the preparation blood-vessels target agent medicine as claimed in claim 8 is characterized in that said blood-vessels target agent medicine comprises the medicine of injection-type preparation, the medicine of oral type preparation and the medicine of external application type preparation.
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WO2009059448A1 (en) * 2007-11-05 2009-05-14 Zhiquan Yong Styrene-acid derivative and use in manufacturing blood-vessel targeted-agent drugs
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CN105566100A (en) * 2014-10-29 2016-05-11 东莞达信生物技术有限公司 Styrene acid compound, composition containing same and application of styrene acid compound
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US20180353449A1 (en) * 2016-08-26 2018-12-13 Dongguan Anhao Pharmaceutical Co., Ltd. Drug combination with antitumor effects
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WO2022100487A1 (en) * 2020-11-13 2022-05-19 义乌市华耀医药科技有限公司 Amino-combretastatin derivative and use thereof
WO2023019688A1 (en) * 2021-08-16 2023-02-23 海南鑫开源医药科技有限公司 Intravitreal injection agent, preparation method therefor and application thereof
CN116492323A (en) * 2022-01-19 2023-07-28 广州安好医药科技有限公司 New application of styreneic acid compound
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