CN100365000C - Combretastatin A-4 as phosphorylcholine precursor medicine and its synthesis and application - Google Patents

Combretastatin A-4 as phosphorylcholine precursor medicine and its synthesis and application Download PDF

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CN100365000C
CN100365000C CNB031358403A CN03135840A CN100365000C CN 100365000 C CN100365000 C CN 100365000C CN B031358403 A CNB031358403 A CN B031358403A CN 03135840 A CN03135840 A CN 03135840A CN 100365000 C CN100365000 C CN 100365000C
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acid
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combretastatin
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雍智全
徐小平
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Guangzhou Anhao Pharmaceutical Technology Co ltd
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Abstract

The present invention relates to a combretastatin A-4 phosphorylcholine precursor medicine, a synthetic method and the application thereof. The combretastatin A-4 phosphorylcholine precursor medicine is a compound with a general formula A and a common structure, wherein n is from 1 to 10; R1, R2 and R3 are hydrogen or alkyl, or naphthene bases are formed among the three base groups of R1, R2 and R3; the alkyl or the naphthenic bases can be replaced by other base groups; the general formula A can form a salt with mineral acid, organic acid or sulfonic acid and can form metal or an aminium salt or forms a salt with amine or organic amine. The compound with a general formula A and a common structure can enhance the biological availability of CA4, release natural CA4 in vivo and enhance the treatment concentration of CA4 in action sites while in the same dose; the compound does not generate or increase potential side effect while in release.

Description

Combretastatin A-4 Phosphorylcholine class prodrug with and synthetic and application
Technical field
The present invention relates to medical compounds and synthetic method thereof and application.Particularly Combreta-statin A-4 Phosphorylcholine class prodrug with and synthetic and application.
Background technology
It is that blood vessel is dependent that Folkman in 1971 proposes tumor growth the earliest.Endothelial cell proliferation speed during the tumor vascular endothelial cell rate of propagation is more normally organized is approximately high more than 50 times.Therefore use the blood vessel supressor that tumor vessel is had the relative specificity effect, and can not cause obvious influence (may disturb the new vessel of gestation and menstruation) normal in-house blood vessel.Nineteen eighty-two first angiogenesis inhibitor discovery, finishing of a series of activities such as the proteic purifying of first angiogenic activity in 1984, above-mentioned viewpoint is supported by more and more evidences, and is made this field become the focus of tumor research and the New Policy of oncotherapy.
Combretastatin A-4 (CA4) is the diphenylethylene compounds with anti-tumor activity (United States Patent (USP), Feb, 22,1988 of extraction separation in the Combretum caffrum trunk of South Africa; 4,996,237).Because this compound dissolution is poor, produce precursor medicine Combretastatin A-4 sodium phosphate (CA4P) (United States Patent (USP), Jul, 23,1993 through phosphorylation; 5,561,122), its anti-tumor in vivo activity improves greatly, and CA4P is rapid in vivo, and dephosphorylation generates CA4, and be 30min plasma half-life.CA4 directly acts on endotheliocyte, induces the endothelial cell apoptosis of propagation, thereby suppresses vasculogenesis.
In mouse malignant tumour model, CA4P binding radioactivity therapy has been killed the cancer cells of mouse body interior 85%, and behind nine months of stopping to treat, has been found to have the sign of cancer return in the mouse body not yet.By studies confirm that CA4P can suppress to provide for cancer cells the growth of the vascular tissue of nutrient, but it can not destroy normal blood vessel.And utilize radiation treatment as a supplement, then may wipe out cancer cells, the side effect of this composite treatment simultaneously also very little (Clinical Cancer Research Vol.7,1052-1060, April2001).
OXiGENE in calendar year 2001 finish CA4P near 100 examples in the I at US and European three centers phase clinical study, in Irish cancer Clinical Research Center (25 example), nuclear magnetic resonance confirms significantly to reduce in the safe dose of CA4P the volume of blood flow of malignant tumour.The researchist also confirms, intravenous drip CA4P, and the tumor blood flow amount obviously reduces in 4-6h.Show equally that in the clinical study of Britain's 34 examples CA4P can reduce the tumor blood flow amount, dose limit toxicity shows slight ataxia.In this 37 routine clinical study of the University of Pennsylvania, observe dose limit cardiac toxic, there are 6 examples to present clinical related illness degree of stability, dose limit toxicity has the relaxing tumor pain phenomenon.
In the mouse of diabetes type proliferative retinopathy, CA4P is the dose-dependent inhibition vascularization, and does not have significant side effects.In cornea and retinoblastoma animal model, CA4P can suppress its vasculogenesis.In human breast carcinoma and ovarian cancer mouse model, CA4P and cis-platinum or endoxan share, and can suppress vasculogenesis and the necrosis of main body knurl widely fast.(Clinical?Cancer?ResearchVol.7，1052-1060，April?2001)
According to the statistics of U.S. eye association (NEI), make a definite diagnosis among the American of diabetes 1,050 ten thousand, the patient of about 40-50% suffers from diabetic retinopathy in various degree.The NEI cartogram condition of understanding is very serious, is enough to make 600,000 to 700,000 American's visual deprivations every year, and 2.4 ten thousand people are blind.The CA4P not only research on solid tumor makes progress, and also makes a breakthrough aspect the abnormal vascular formation under the various ophthalmic diseases situations of treatment, might become the newtype drug of treatment proliferative retinopathy,
The work of deriving from Combretastatin A-4 has comprised formation Combretastatin A-4 phosphate derivative.Such example such as United States Patent (USP) 5,561,122 and Chinese patent 01803140 described, though these prodrug salt have solved problems such as the solvability of natural Combretastatin A-4 and water absorbability, but do not improve the bioavailability of Combretastatin A-4, do not improve the biological effectively treatment concentration of medicine in other words at site of action.
Summary of the invention
The objective of the invention is provides a kind of medicine that can improve the bioavailability of Combretastatin A-4 in order to overcome above-mentioned weak point of the prior art, improve the CombretastatinA-4 medicine in other words at the Combretastatin of the biological effectiveness of site of action A-4 prodrug, can when same dose, improve the Combretastatin A-4 treatment concentration of site of action release in vivo, simultaneously, when discharging, do not produce or increase the prodrug of potential side effect.
The invention provides a kind of compound with general structure of general formula I:
Figure C0313584000051
Wherein:
1.n be 1～10;
2.R 1For hydrogen, alkyl, alkyl can be arbitrarily by hydroxyethyl, carboxyl substituted;
3.R 2For hydrogen, alkyl, alkyl can be arbitrarily by hydroxyethyl, carboxyl substituted;
4.R 3For hydrogen, alkyl, alkyl can be arbitrarily by hydroxyethyl, carboxyl substituted;
5.R 1, R 2, R 3Formed piperidyl with N;
6, general formula I can with many sour salifies, mineral acids such as example hydrochloric acid, sulfuric acid, phosphoric acid; Perhaps with the organic acid salify, for example aliphatic monocarboxylic acid or dicarboxylic acid, trifluoroacetic acid, acetate, propionic acid, oxyacetic acid, succsinic acid, maleic acid, anti--butene dioic acid, hydroxymaleic acid, oxysuccinic acid, tartrate, citric acid or oxalic acid, or amino acid such as arginine or Methionin for example, the carboxylic acid of aromatics, for example: phenylformic acid, 2-methoxy benzoic acid, 2-globentyl, salicylic acid, 4-aminosallcylic acid, amygdalic acid, styracin, the isomery carboxylic acid, for example: aliphatic sulfonic acid, for example: methylsulfonic acid, ethyl sulfonic acid or 2-hydroxyethylsulfonic acid, or aromatic sulfonic acid, Phenylsulfonic acid for instance, organic acids such as right-toluenesulphonic acids or 2-naphthene sulfonic acid;
7, general formula I and can form metal or ammonium salt, for example: the salt of basic metal or alkaline-earth metal etc., for instance with sodium, potassium, magnesium or calcium salify, perhaps with ammonia or suitable organic amine salify, for example: trisubstituted monoamine, triethylamine or three-(2-hydroxyl second)-amine for instance, or the amine of heterocyclic radical, the salt of amino acid etc., N-ethylpiperidine or N for instance, N-diethyl-piperazine.
The compound of the general structure of above-mentioned general formula I synthetic is the compound by general structure II, i.e. 2-chloro-2-oxo-1,3, and 2 phosphoric acid ester, wherein n is 1-10, Celsius
Figure C0313584000061
Subzero 50 spend 100 degree phosphorylated Combretastatin A-4 above freezing obtains compound as general structure III, and wherein n is 1-10:
The compound of general structure III and organic amine obtain the compound of general structure I at zero centigrade to 150 degree open loops above freezing, wherein:
Figure C0313584000071
(1) n is 1 to 10;
(2) R 1, R 2, R 3Be hydrogen or alkyl, its alkyl can be by hydroxyethyl, carboxyl substituted, or R 1, R 2, R 3Formed piperidyl with N;
(3) general formula I can with mineral acid, organic acid salify;
(4) general formula I can form metal or ammonium salt, perhaps with ammonia or organic amine salify.
The rapid in vivo dephosphorylation of the compound of general structure I generates Combretastatin A-4 (CA4), and be 30min plasma half-life.CA4 directly acts on endotheliocyte, induces the endothelial cell apoptosis of propagation, thereby suppresses vasculogenesis.
The present invention compared with prior art has following advantage: provide new, useful CombretastatinA-4 Phosphorylcholine class prodrug with and synthetic and application, has bigger solvability than natural Combretastatin A-4, simultaneously, many compounds that initiatively mediate tumor-targeting are arranged in human body, the many amine groups that all have of these compounds, Combretastatin A-4 is connected the compound that these initiatively mediate tumor-targeting by Phosphorylcholine class bridge, discharge Combretastatin A-4 easily in vivo, and when same dose, improve the concentration of Combretastatin A-4 at site of action, simultaneously, when discharging, do not produce or increase the potential side effect.So compound of the present invention provides the pharmaceutical use with quite big advantage.
Embodiment
The present invention is described in further detail below with reference to embodiment:
Synthesizing of embodiment 1 Combretastatin A-4 Phosphorylcholine
With Combretastin A-4 (5.00g; 15mmol, a great deal of) add in the 100ml reaction flask, add triethylamine 15mmol; dry toluene 15ml; carbonic acid gas-acetone is cooled to-50 ℃, under-50 to-20 ℃ of protections at argon gas, stirs and drip 2-chloro-2-oxo-1; 3; the dry toluene 15ml solution of 2 phosphoric acid glycol ester 15mmol, about 20min dropwises, and is warming up to 20 ℃ of reactions 1 hour then.Be cooled to-20 ℃ then, filter, filtrate decompression concentrates, add 15% sodium carbonate solution 15ml then, at the anti-stirring reaction 5min of stirring at room, with the ether extraction of 70ml, (2 * 20ml) wash ether layer with 10% sodium carbonate solution, dry also filtration, reduction vaporization falls solvent and gets yellow oil.
Above-mentioned oily matter with the dissolving of 50ml second cyanogen, is added the 10mmol Trimethylamine 99, and in 0 to 60 ℃ of reaction is spent the night, and reaction solution is cooled to below-20 ℃ 48 hours, separates out solid, and suction filtration, drying under reduced pressure get white crystals product, (δ 11200HZ, CDCL 3): 3.16 (9H), 3.69-3.96 (12H), 4.2 (4H), 6.42 (2H), 6.52 (2H), 6.81 (2H), 6.92 (1H).Its structure is as follows:
Figure C0313584000081
Synthesizing of embodiment 2.Combretastatin A-4 phosphinylidyne oxygen propyl group triethanol ammonium
With Combretastin A-4 (5.00g; 15mmol, a great deal of) add in the 100ml reaction flask, add triethylamine 15mmol; dry tetrahydrofuran 15ml; be cooled to-20 ℃ with carbonic acid gas-acetone, in-20 to 20 ℃ under the protection of argon gas, stir and also to drip 2-chloro-2-oxo-1; 3; the dry tetrahydrofuran 15ml solution of 2 propanediol phosphate ester 15mmol, about 20min dropwises, and is warming up to 50 ℃ of reactions 2 hours then.Be cooled to-20 ℃ then, filter, filtrate decompression concentrates, add 15% sodium carbonate solution 15ml then, at stirring at room reaction 5min, with the ether extraction of 70mi, (2 * 20ml) wash ether layer, dry and filter, and reduction vaporization falls solvent and gets yellow oil with 10% sodium carbonate solution.
Above-mentioned oily matter with the dissolving of 50ml second cyanogen, is added the 10mmol trolamine, spend the night in 100-120 ℃ of reaction, reaction solution was cooled to below 0 ℃ 12 hours, separate out solid, suction filtration, drying under reduced pressure get the white crystals product.Its knot thing is as follows:
Figure C0313584000082
Embodiment 3.CombretastatinA-4 phosphinylidyne oxygen ethyl is leucic synthetic
With Combretastin A-4 (5.00g; 15mmol, a great deal of) add in the 100ml reaction flask, add triethylamine 15mmol; dry tetrahydrofuran 15ml; be cooled to-50 ℃ with carbonic acid gas-acetone, under-50 to-20 ℃ of protections, stir and drip 2-chloro-2-oxo-1 at argon gas; 3; the dry tetrahydrofuran 15ml solution of 2 phosphoric acid second diester 15mmol, about 20min dropwises, and is warming up to room temperature reaction then naturally and spends the night.Be cooled to-20 ℃ then, filter, filtrate decompression concentrates, add 15% sodium carbonate solution 15ml then, at stirring at room reaction 5min, with the ether extraction of 70ml, (2 * 20ml) wash ether layer, dry and filter, and reduction vaporization falls solvent and gets yellow oil with 10% sodium carbonate solution.
Above-mentioned oily matter with the dissolving of 50ml second cyanogen, is added the 10mmol leucine, spend the night in 100-120 ℃ of reaction, reaction solution was cooled to below-0 ℃ 12 hours, separate out solid, suction filtration, drying under reduced pressure get the white crystals product.
Its structure is as follows
Synthesizing of embodiment 4.CombretastatinA-4 phosphinylidyne oxygen ethyl piperidine
Combretastin A-4 (5.00g, 15mmol, a great deal of) is added in the 100ml reaction flask; add triethylamine 15mmol; dry tetrahydrofuran 15ml is cooled to-50 ℃, in-50 to-20 ℃; under the protection of argon gas; stir and drip 2-chloro-2-oxo-1,3, the dry tetrahydrofuran 15ml solution of 2 phosphoric acid glycol ester 15mmol; about 20min dropwises, and is warming up to room temperature reaction then naturally and spends the night.Be cooled to-20 ℃ then, filter, filtrate decompression concentrates, add 15% sodium carbonate solution 15ml then, at stirring at room reaction 5min, with the ether extraction of 70ml, (2 * 20ml) wash ether layer, dry and filter, and reduction vaporization falls solvent and gets yellow oil with 10% sodium carbonate solution.
Above-mentioned oily matter with the dissolving of 50ml second cyanogen, is added the 10mmol piperidines, spend the night in 100-120 ℃ of reaction, reaction solution was cooled to below-0 ℃ 12 hours, separate out solid, suction filtration, drying under reduced pressure get the white crystals product.
Its structure is as follows:
Embodiment 5.CombretastatinA-4 phosphinylidyne oxygen is synthesizing Combretastin A-4 (5.00g, 15mmol of base (N, N-dimethyl) aniline; a great deal of) adds in the 100ml reaction flask, add triethylamine 15mmol, dry toluene 15ml; be cooled to 20 ℃; in 20 to 50 ℃, under the protection of argon gas, stir and drip 2-chloro-2-oxo-1; 3; the dry toluene 15ml solution of 2 phosphoric acid hexylene glycol ester 15mmol, about 20min dropwises, and is warming up to 100 ℃ of reaction 30min then.Be cooled to-20 ℃ then, filter, filtrate decompression concentrates, add 15% sodium carbonate solution 15ml then, at stirring at room reaction 5min, with the ether extraction of 70ml, (2 * 20ml) wash ether layer, dry and filter, and reduction vaporization falls solvent and gets yellow oil with 10% sodium carbonate solution.
With above-mentioned oily matter 50ml N, N dimethyl formamide (N, N dimethyl formamide) dissolving adds 10mmol N, accelerine spends the night in 100-150 ℃ of reaction, and reaction solution was cooled to below 0 ℃ 12 hours, separate out solid, suction filtration, drying under reduced pressure get the white crystals product.Its structure is as follows:
Figure C0313584000101
Synthesizing of the basic triethylamine of embodiment 6.CombretastatinA-4 phosphinylidyne oxygen
Combretastin A-4 (5.00g, 15mmol, a great deal of) is added in the 100ml reaction flask; add triethylamine 15mmol; exsiccant toluene 15ml is cooled to 20 ℃, in 20 to 50 ℃; under the protection of argon gas; stir and drip 2-chloro-2-oxo-1,3, the dry toluene 15ml solution of 2 phosphoric acid hexylene glycol ester 15mmol; about 20min dropwises, and is warming up to 100 ℃ of reaction 30min then naturally.Be cooled to-20 ℃ then, filter, filtrate decompression concentrates, add 15% sodium carbonate solution 15ml then, at stirring at room reaction 5min, with the ether extraction of 70ml, (2 * 20ml) wash ether layer, dry and filter, and reduction vaporization falls solvent and gets yellow oil with 10% sodium carbonate solution.
With above-mentioned oily matter 50ml N, N dimethyl formamide dissolving adds the 10mmol triethylamine, spends the night in 100-120 ℃ of reaction, and reaction solution was cooled to below 0 ℃ 12 hours, separated out solid, and suction filtration, drying under reduced pressure get the white crystals product.Its structure is as follows:
Figure C0313584000102

Claims (5)

1. Combretastatin A-4 Phosphorylcholine class prodrug is characterized in that having the compound of the general structure of general formula I:
Figure C031358400002C1
Wherein:
(1) n is 1 to 10;
(2) R 1, R 2, R 3Be hydrogen or alkyl, its alkyl can be by hydroxyethyl, carboxyl substituted, or R 1, R 2, R 3Formed piperidyl with N;
(3) general formula I can with mineral acid, organic acid salify;
(4) general formula I can form metal or ammonium salt, perhaps with ammonia or organic amine salify.
2. Combretastatin A-4 Phosphorylcholine class prodrug according to claim 1, it is characterized in that, described can with the salifiable mineral acid of general formula I, organic acid is: hydrochloric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, acetate, propionic acid, oxyacetic acid, succsinic acid, maleic acid, instead-butene dioic acid, hydroxymaleic acid, oxysuccinic acid, tartrate, citric acid, oxalic acid, arginine, Methionin, phenylformic acid, the 2-phenoxy benzoate, the 2-globentyl, salicylic acid, the 4-aminosallcylic acid, amygdalic acid, styracin, methylsulfonic acid, ethyl sulfonic acid, the 2-hydroxyethylsulfonic acid, Phenylsulfonic acid, right-toluenesulphonic acids or 2-naphthene sulfonic acid.
3. Combretastatin A-4 Phosphorylcholine class prodrug according to claim 1, it is characterized in that, describedly can form metal or ammonium salt with general formula I, perhaps with the organic amine salify, the alkali-metal salt that has sodium, potassium to form, the salt of the alkaline-earth metal that magnesium, calcium form, triethylamine or three-(2-hydroxyl second)-amine, N-ethylpiperidine, N, the salt of N-diethyl-piperazine.
4. prepare claim 1 Combretastatin A-4 Phosphorylcholine class prodrug; it is characterized in that; compound synthetic with general structure of general formula I is the compound by general structure II; it is 2-chloro-2-oxo-1; 3; 2 phosphoric acid ester, wherein n is 1-10, spends 100 degree phosphorylated above freezing Celsius subzero 50
Figure C031358400003C1
Combretastatin A-4 obtains the compound as general structure III, and wherein n is 1-10:
Figure C031358400003C2
The compound of general structure III and organic amine obtain general structure I's at zero centigrade to 150 degree open loops above freezing
Figure C031358400003C3
Compound, wherein:
(1) n is 1 to 10;
(2) R 1, R 2, R 3Be hydrogen or alkyl, its alkyl can be by hydroxyethyl, carboxyl substituted, or R 1, R 2, R 3Formed piperidyl with N;
(3) general formula I can with mineral acid, organic acid salify;
(4) general formula I can form metal or ammonium salt, perhaps with ammonia or organic amine salify.
5. the compound of claim 1-3 is used to prepare the purposes of vasoinhibitor.
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CN1319978C (en) * 2005-04-06 2007-06-06 西南合成制药股份有限公司 Combretastatin compound preparation method
CN101074189B (en) * 2006-05-15 2011-04-13 雍智全 Styrene acid derivative and use in preparation of various blood-vessels target agent medicine

Citations (2)

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Publication number Priority date Publication date Assignee Title
US5561122A (en) * 1994-12-22 1996-10-01 Arizona Board Of Regents Acting On Behalf Of Arizona State University Combretastatin A-4 prodrug
CN1392876A (en) * 2000-09-14 2003-01-22 布里斯托-美尔斯奎比公司 Combretastatin A-4 phosphate prodrug, mono-and di-organic amine salt, mono-and di-amino acids salts, and mono-and di-amino acid ester salt

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5561122A (en) * 1994-12-22 1996-10-01 Arizona Board Of Regents Acting On Behalf Of Arizona State University Combretastatin A-4 prodrug
CN1392876A (en) * 2000-09-14 2003-01-22 布里斯托-美尔斯奎比公司 Combretastatin A-4 phosphate prodrug, mono-and di-organic amine salt, mono-and di-amino acids salts, and mono-and di-amino acid ester salt

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Title
Medicinal Chemistry Letters,Vol.13 No.9. 2003 *
Synthesis, in vitro, and in vivo evaluation of phosphateesterderivatives of combretastatin A-4. Hadimani, Mallinath B.,et al.Bioorganic & Medicinal Chemistry Letters,Vol.13 No.9. 2003 *
Synthesis, in vitro, and in vivo evaluation of phosphateesterderivatives of combretastatin A-4. Hadimani, Mallinath B.,et al.Bioorganic &amp *

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