CN1111166C - Water soluble cephalotaxin phosphorus poly aminoacid ester or its salt, pharmaceutical compositions contg. same, and pharmaceutical use thereof - Google Patents

Water soluble cephalotaxin phosphorus poly aminoacid ester or its salt, pharmaceutical compositions contg. same, and pharmaceutical use thereof Download PDF

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CN1111166C
CN1111166C CN99118644A CN99118644A CN1111166C CN 1111166 C CN1111166 C CN 1111166C CN 99118644 A CN99118644 A CN 99118644A CN 99118644 A CN99118644 A CN 99118644A CN 1111166 C CN1111166 C CN 1111166C
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cephalotaxin
polyglutamic acid
sodium
acid esters
polyaspartate
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CN1288010A (en
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吴晓明
何彦萍
李松
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HANDE BIOLOGICAL TECHNOLOGY Co Ltd YUNNAN
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    • C07—ORGANIC CHEMISTRY
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    • C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
    • C07D305/14—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G69/00—Macromolecular compounds obtained by reactions forming a carboxylic amide link in the main chain of the macromolecule
    • C08G69/02—Polyamides derived from amino-carboxylic acids or from polyamines and polycarboxylic acids
    • C08G69/08—Polyamides derived from amino-carboxylic acids or from polyamines and polycarboxylic acids derived from amino-carboxylic acids
    • C08G69/10—Alpha-amino-carboxylic acids

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Abstract

The present invention relates to cephalotaxin phosphorus alkali polyamino acid ester with water solubility or salt thereof, particularly to cephalotaxin phosphorus alkali polyamino acid ester or alkaline-earth metal salt thereof, or cephalotaxin phosphorus alkali polyaspartic acid ester thereof or alkali metal salt thereof. The present invention also relates to a medical composition containing the cephalotaxin phosphorus alkali polyamino acid ester with water solubility or the salts thereof, particularly an application of the medical composition in tumor resistance.

Description

Water-soluble cephalotaxin polyamino acid ester or its salt contain their pharmaceutical composition and medicinal use thereof
The present invention relates to water-soluble cephalotaxin polyamino acid ester or its salt, especially cephalotaxin polyglutamic acid esters or its an alkali metal salt or cephalotaxin polyaspartate or its an alkali metal salt, the pharmaceutical composition and the medicinal use thereof that contain them, the especially purposes in antitumor.
Ramulus et folium taxi cuspidatae is a kind of rare plant, from Chinese yew, can extract a series of bearing taxanes and wherein major part have anti-tumor activity.Using at present and studying maximum bearing taxanes is taxol, and it now has been widely used in clinical demonstrating curative effect preferably aspect the treatment of cancer kinds such as mammary cancer, ovarian cancer, nonsmall-cell lung cancer, the esophageal carcinoma, incidence cancer.But, because the water-insoluble (solubleness of taxol in water is less than 0.004mg/ml) of taxol makes its application very inconvenient, simultaneously, the toxic side effect of existing taxol solubility promoter one Cremophor EL is more serious, brings out symptoms such as allergy easily.In addition, taxol is to except that mammary cancer, ovarian cancer have better curative effect, and low or the low or serious toxic side effect of cytotoxicity selectivity is subjected to very big restriction owing to curative effect to the effect of other tumor types.Cephalotaxin (having another name called taxol B) is separated from Ramulus et folium taxi cuspidatae as a bearing taxanes monomer, but it is water-soluble very poor, and it is water insoluble, so its medicinal exploitation is very limited.Therefore seeking has highly water-soluble more and the wide water-soluble taxane analog derivative of antitumor spectrum to be still very urgent and needs.
The objective of the invention is to seek and have good water-soluble and taxane derivatives that anticancer spectrum is wide.
The inventor has now found that polyamino acid ester or its salt of cephalotaxin after deliberation, especially cephalotaxin polyglutamic acid esters or polyaspartate or their an alkali metal salt or alkaline earth salt, demonstrate the water-soluble of obvious raising, widely the especially anti-nasopharyngeal carcinoma of anticancer spectrum, lung cancer and extremely low toxicity.The present invention is based on above discovery and finish.
The present invention's summary
What first aspect present invention related to is polyamino acid ester or its salt of general formula I cephalotaxin,
Figure C9911864400061
R wherein 1And R 2Can be polyamino acid residue or H identical or different and independently, M exist or exists and is basic metal or alkaline earth metal cation, and condition is R 1And R 2Can not be hydrogen simultaneously.
What the present invention related on the other hand is pharmaceutical composition, and it comprises at least a general formula I cephalotaxin-polyamino acid ester or its salt and pharmaceutical carrier, R wherein 1And R 2Can be polyamino acid residue or H identical or different and independently, M exist or exists and is basic metal or alkaline earth metal cation, and condition is R 1And R 2Can not be hydrogen simultaneously.
Further aspect of the present invention relate to the polyamino acid ester of at least a formula I cephalotaxin or its salt preparation be used for the treatment of cancer or with the medicine of autoimmunization defective diseases related in purposes,
Figure C9911864400071
R wherein 1And R 2Can be polyamino acid residue or H identical or different and independently, M exist or exists and is basic metal or alkaline earth metal cation, and condition is R 1And R 2Can not be hydrogen simultaneously.
The present invention describes in detail
The present invention relates to polyamino acid ester or its salt of formula I cephalotaxin,
R wherein 1And R 2Can be polyamino acid residue or H identical or different and independently, M exist or exists and is basic metal or alkaline earth metal cation, and condition is R 1And R 2Can not be hydrogen simultaneously.
According to the present invention, the polyamino acid ester of formula I cephalotaxin of the present invention or its salt have good water-solubility and in water solubility＞75mg/ml of 25 ℃, for example the water solubility of cephalotaxin polyglutamic acid esters sodium is 88mg/ml (25 ℃).
According to the present invention, the polyamino acid ester of formula I cephalotaxin of the present invention or the toxicity of its salt are very low, and they show their LD through intraperitoneal administration in acute toxicity test in mice 50(medium lethal dose) is 2000-3500mg/kg, for example, and the LD of cephalotaxin polyglutamic acid esters sodium 50Be 2900mg/kg.
According to the present invention, amino acid is selected from natural or alpha-non-natural amino acid in the term used herein " polyamino acid residue ", preferred L-glutamic acid and aspartic acid.Above-mentioned natural or non-natural propylhomoserin comprises its D-, L-or DL configuration.
According to the present invention, the molecular weight of used polyglutamic acid of the present invention or poly aspartic acid or their salt is 12,000-60, and 000, preferred 15,000-50,000, more preferably 22,000-40,000.
According to the present invention, " basic metal " is selected from lithium, sodium or potassium to term used herein.Used term " alkaline-earth metal " is selected from barium, calcium or magnesium.
According to the present invention, the preferred formula I compound of the present invention is selected from as follows:
Cephalotaxin 2 '-the polyglutamic acid esters,
Cephalotaxin 2 '-polyaspartate,
Cephalotaxin 2 ', 7-polyglutamic acid esters,
Cephalotaxin 2 ', the 7-polyaspartate,
Cephalotaxin 7-polyglutamic acid esters,
Cephalotaxin 7-polyaspartate,
Cephalotaxin 2 '-polyglutamic acid esters sodium,
Cephalotaxin 2 '-polyaspartate sodium,
Cephalotaxin 2 ', 7-polyglutamic acid esters sodium,
Cephalotaxin 2 ', 7-polyaspartate sodium,
Cephalotaxin 7-polyglutamic acid esters sodium,
Cephalotaxin 7-polyaspartate sodium.
According to the present invention, the compound that formula I compound of the present invention is more preferably following:
Cephalotaxin 2 '-polyglutamic acid esters sodium,
Cephalotaxin 2 ', 7-polyglutamic acid esters sodium,
Cephalotaxin 7-polyglutamic acid esters sodium.
According to the present invention, formula I cephalotaxin polyamino acid ester of the present invention or its salt can prepare by means known in the art.For example can be by with cephalotaxin (can from commercially available obtain or derive from Chinese yunnan Han De Bioisystech Co., Ltd) and polyamino acid or its basic metal or alkaline earth salt prepared in reaction formula I cephalotaxin of the present invention polyamino acid ester or its salt, or by cephalotaxin and polyamino acid reaction are made cephalotaxin polyamino acid ester, yet as required, oxyhydroxide with cephalotaxin polyamino acid ester and basic metal or alkaline-earth metal, carbonate or supercarbonate reaction make cephalotaxin amino acid ester basic metal or alkaline earth salt.
According to the present invention, pharmaceutical composition of the present invention comprises formula I cephalotaxin polyamino acid ester or its salt and pharmaceutical carrier.
According to the present invention, cephalotaxin polyamino acid ester or its salt are preferably following one group of compound in the pharmaceutical composition of the present invention:
Cephalotaxin 2 '-the polyglutamic acid esters,
Cephalotaxin 2 '-polyaspartate,
Cephalotaxin 2 ', 7-polyglutamic acid esters,
Cephalotaxin 2 ', the 7-polyaspartate,
Cephalotaxin 7-polyglutamic acid esters,
Cephalotaxin 7-polyaspartate,
Cephalotaxin 2 '-polyglutamic acid esters sodium,
Cephalotaxin 2 '-polyaspartate sodium,
Cephalotaxin 2 ', 7-polyglutamic acid esters sodium,
Cephalotaxin 2 ', 7-polyaspartate sodium,
Cephalotaxin 7-polyglutamic acid esters sodium,
Cephalotaxin 7-polyaspartate sodium.
According to the present invention, the compound that formula I compound of the present invention is more preferably following:
Cephalotaxin 2 '-polyglutamic acid esters sodium,
Cephalotaxin 2 ', 7-polyglutamic acid esters sodium,
Cephalotaxin 7-polyglutamic acid esters sodium.
According to the present invention, pharmaceutical composition of the present invention can prepare by means known in the art also can be by oral or parenteral route administration.Wherein oral administered dosage form can be tablet, capsule etc., and the parenterai administration formulation can be injection.
According to the present invention, cephalotaxin polyamino acid ester of the present invention or its salt can be used for preparing be used for the treatment of cancer or with the medicine of autoimmunization defective diseases related.One group of compound below wherein used cephalotaxin polyamino acid ester or its salt are preferred:
Cephalotaxin 2 '-the polyglutamic acid esters,
Cephalotaxin 2 '-polyaspartate,
Cephalotaxin 2 ', 7-polyglutamic acid esters,
Cephalotaxin 2 ', the 7-polyaspartate,
Cephalotaxin 7-polyglutamic acid esters,
Cephalotaxin 7-polyaspartate,
Cephalotaxin 2 '-polyglutamic acid esters sodium,
Cephalotaxin 2 '-polyaspartate sodium,
Cephalotaxin 2 ', 7-polyglutamic acid esters sodium,
Cephalotaxin 2 ', 7-polyaspartate sodium,
Cephalotaxin 7-polyglutamic acid esters sodium,
Cephalotaxin 7-polyaspartate sodium.
According to the present invention, the compound that formula I compound of the present invention is more preferably following:
Cephalotaxin 2 '-polyglutamic acid esters sodium,
Cephalotaxin 2 ', 7-polyglutamic acid esters sodium,
Cephalotaxin 7-polyglutamic acid esters sodium.
According to the present invention, wherein term " cancer " can for example be nasopharyngeal carcinoma, lung cancer, mammary cancer, ovarian cancer, liver cancer, esophagus cancer, colorectal carcinoma, malignant melanoma, incidence cancer and leukemia etc.
According to the present invention, wherein term autoimmunization defective disease disease can for example be a rheumatoid arthritis, autoimmune nephrosis etc.
The following examples are used to further specify and describe the present invention, but and do not mean that the present invention only limits to this.
1: three class China fir of embodiment phosphorus alkali 2 '-preparation of polyglutamic acid esters
The 640mg cephalotaxin is dissolved in the 130ml acetonitrile, the adding molecular weight is 25000 polyglutamic acid 6.2g, add the 120mg dimethyl aminopyridine again, stirred 9 hours down at 25 ℃, under 50 ℃ of gauge pressure-0.05MPa, temperature, take out then in solvent, again silicagel column on the solid substance of gained is carried out chromatographic separation, with acetonitrile: the solution of water=25: 75 is eluent, final cephalotaxin 2 '-polyglutamic acid esters 6.1g.
Products obtained therefrom is through quantitative assay, and cephalotaxin content is 9.90%.
IR(KBr)cm -1：3450，2919，2360，1652，1558，1403，1230，650。
Uv-absorbing: λ max=230nm, ε=29800,
λmax＝275nm，ε＝1700。
1HNMR：δ(ppm)＝7.77-7.36，6.38，5.97，5.63，5.55-5.36，5.10，4.36，4.10，1.97，1.18-1.20。
Embodiment 2: cephalotaxin 2 '-preparation of polyglutamic acid esters
Take by weighing molecular weight and be 25000 PGA (polyglutamic acid) 500mg, be dissolved in 50mlDMF (dimethyl formamide), add cephalotaxin 150mg, add 50mgDCC (dicyclohexylcarbodiimide) and 10mgDMAP (dimethyl aminopyridine) again, reacted at ambient temperature 6 hours.Reacted solution is poured in the 120ml chloroform and is washed, the final reaction product 520mg that gets.
Detect through HPLC, cephalotaxin content is 18.8%.
IR(KBr)cm -1：3450，2919，2360，1652，1558，1403，1230，650。
Uv-absorbing: λ max=230nm, ε=29800,
λmax＝275nm，ε＝1700。
1HNMR：δ(ppm)＝7.77-7.36，6.38，5.97，5.63，5.55-5.36，5.10，4.36，4.10，1.97，1.18-1.20。
Embodiment 3: cephalotaxin 2 '-the polyaspartate preparation
The 625mg cephalotaxin is dissolved in the 120ml acetonitrile, the adding molecular weight is 24000 poly aspartic acid 6.1g, add the 115mg Dimethylamino pyridine again, stirred 8 hours down at 25 ℃, drain solvent under 50 ℃ of the gauge pressure-0.05MPa, temperature then, again silicagel column on the solid substance of gained is carried out chromatographic separation, with acetonitrile: the solution of water=25: 75 is eluent, final cephalotaxin 2 '-polyaspartate 6.05g.
Products obtained therefrom is through quantitative assay, and the content of cephalotaxin is 9.89%.
IR(KBr)cm -1：3450，2919，2360，1652，1558，1403，1230，650。
Uv-absorbing: λ max=231nm, ε=27900,
λmax＝275nm，ε＝160。
Embodiment 4: cephalotaxin 2 ' and, the preparation of 7-polyglutamic acid esters
The 530mg cephalotaxin is dissolved in the 130ml acetonitrile, the adding molecular weight is 26000 polyglutamic acid 8.8g, add 5.8ml dicyclohexylcarbodiimide and 185ml pyridine again, stirred 8 hours down at 25 ℃, drain solvent then under 50 ℃ of gauge pressure-0.05MPa, temperature, again silicagel column on the solid substance of gained is carried out chromatographic separation, with acetonitrile: the solution of water=25: 75 is eluent, final cephalotaxin 2 ', 7-polyglutamic acid esters 8.90g.
Products obtained therefrom is through quantitative assay, and the content of cephalotaxin is 5.50%.
IR(KBr)cm -1：3450，2919，2360，1652，1558，1403，1230，650。
Uv-absorbing: λ max=230nm, ε=29600,
λmax＝275nm，ε＝1680。
1HNMR：δ(ppm)＝7.77-7.36，6.38，5.97，5.63，5.55-5.36，5.10，5.18，4.10，1.97，1.18-1.20。
Embodiment 5: cephalotaxin 2 ' and, the preparation of 7-polyaspartate
The 520mg cephalotaxin is dissolved in the 5.6ml acetonitrile, the adding molecular weight is 25000 poly aspartic acid 8.6g, add 5.5ml dicyclohexylcarbodiimide and 180ml pyridine again, stirred 8 hours down at 25 ℃, drain solvent then under 50 ℃ of gauge pressure-0.05MPa, temperature, again silicagel column on the solid substance of gained is carried out chromatographic separation, with acetonitrile: the solution of water=25: 75 is eluent, final cephalotaxin 2 ', 7-polyaspartate 8.90g.
Products obtained therefrom is through quantitative assay, and the content of cephalotaxin is 5.80%.
IR(KBr)cm -1：3450，2919，2360，1652，1558，1403，1230，650。
Uv-absorbing: λ max=230nm, ε=28190,
λmax＝275nm，ε＝1618。
Embodiment 6: the preparation of cephalotaxin 7-polyglutamic acid esters
The 220mg cephalotaxin is dissolved in the 60ml acetonitrile, under 0 ℃, with 23mlCH 3CH 2COCl reaction 1 hour adds molecular weight and is 28000 polyglutamic acid sodium 1.7g again, adds the 42mg dimethyl aminopyridine again, stirs 8 hours down at 25 ℃, adds 0.1M HAC down at 25 ℃ then and mixes and stirred 20 minutes, goes into CHCl more in addition 3Give a baby a bath on the third day after its birth time, drain, again silicagel column on the solid substance of gained is carried out chromatographic separation, with acetonitrile: the solution of water=25: 75 is eluent, final cephalotaxin 7-polyglutamic acid esters 1.8g.
Products obtained therefrom is through quantitative assay, and the content of cephalotaxin is 11.90%.
IR(KBr)cm -1：3450，2919，2360，1652，1558，1403，1230，650。
Uv-absorbing: λ max=230nm, ε=29400,
λmax＝275nm，ε＝1680。
1HNMR：δ(ppm)＝7.77-7.36，6.38，5.97，4.78，5.55-5.36，5.10，5.18，4.10，1.97，1.18-1.20。
Embodiment 7: the preparation of cephalotaxin 7-polyaspartate
The 210mg cephalotaxin is dissolved in the 57ml acetonitrile, under 0 ℃, with 20mlCH 3CH 2COCl reaction 1.2 hours adds molecular weight and is 28000 polyglutamic acid sodium 1.6g again, adds the 43mg dimethyl aminopyridine again, stirs 10 hours down at 25 ℃, adds 0.1M HAC down at 25 ℃ then and mixes and stirred 25 minutes, adds CHCl again 3Give a baby a bath on the third day after its birth time, drain, silica gel on the solid substance of gained is carried out chromatographic separation, with acetonitrile: the solution of water=25: 75 is eluent, final cephalotaxin 7-polyaspartate 1.9g.
Products obtained therefrom is through quantitative assay, and the content of cephalotaxin is 11.21%.
IR(KBr)cm -1：3450，2919，2360，1652，1558，1403，1230，650。
Uv-absorbing: λ max=230nm, ε=27880,
λmax＝275nm，ε＝1629。
Embodiment 8: cephalotaxin 2 '-preparation of polyglutamic acid esters sodium
The 1.2g cephalotaxin is dissolved in the 220ml acetonitrile, the adding molecular weight is 4000 polyglutamic acid sodium 9.3g, add the 210mg dimethyl aminopyridine again, stirred 8 hours down at 25 ℃, under 50 ℃ of gauge pressure-0.05MPa, temperature, drain solvent then, again silicagel column on the solid substance of gained is carried out chromatographic separation, with acetonitrile: the solution of water=25: 75 is eluent, final cephalotaxin 2 '-polyglutamic acid esters sodium 9.8g.
Products obtained therefrom is through quantitative assay, and the content of cephalotaxin is 10.20%.
IR(KBr)cm -1：3450，2919，2360，1652，1558，1403，1230，650。
Uv-absorbing: λ max=230nm, ε=29800,
λmax＝275nm，ε＝1700。
1HNMR：δ(ppm)＝7.77-7.36，6.38，5.97，5.63，5.55-5.36，5.10，4.36，4.10，1.97，1.18-1.20。
Embodiment 9: cephalotaxin 2 '-preparation of polyglutamic acid esters sodium
Take by weighing molecular weight and be 25000 PGA (polyglutamic acid) 540mg, be dissolved in 53mlDMF (dimethyl formamide), add cephalotaxin 158mg, add 52mgDCC (dicyclohexylcarbodiimide) and 107mgDMAP (dimethyl aminopyridine) again, reacted at ambient temperature 6.2 hours.Reacted solution is poured in the 120ml chloroform and is washed, and then solid substance is leached, and is dissolved in the NaHCO of 110ml0.1M 3Solution.This solution is with the deionized water liquid of dialysing.Finish the solution of dialysis, lyophilize, the final reaction product 520mg that gets.
Detect through HPLC, cephalotaxin content is 19.3%.
IR(KBr)cm -1：3450，2919，2360，1652，1558，1403，1230，650。
Uv-absorbing: λ max=230nm, ε=29780,
λmax＝275nm，ε＝1710。
1HNMR：δ(ppm)＝7.77-7.36，6.38，5.97，5.63，5.55-5.36，5.10，4.36，4.10，1.97，1.18-1.20。
Embodiment 10: cephalotaxin 2 '-preparation of polyaspartate sodium
The 1.0g cephalotaxin is dissolved in the 210ml acetonitrile, the adding molecular weight is 38000 polyglutamic acid sodium 9.1g, add the 200mg dimethyl aminopyridine again, stirred 9 hours down at 25 ℃, under 50 ℃ of gauge pressure-0.05MPa, temperature, drain solvent then, again silicagel column on the solid substance of gained is carried out chromatographic separation, with acetonitrile: the solution of water=25: 75 is eluent, final cephalotaxin 2 '-polyaspartate sodium 9.6g.
Products obtained therefrom is through quantitative assay, and the content of cephalotaxin is 10.01%.
IR(KBr)cm -1：3450，2919，2360，1652，1558，1403，1230，650。
Uv-absorbing: λ max=231nm, ε=28460,
λmax＝277nm，ε＝1670。
Embodiment 11: cephalotaxin 2 ' and, the preparation of 7-polyglutamic acid esters sodium
The 1.2g cephalotaxin is dissolved in the 220ml acetonitrile, the adding molecular weight is 36000 polyglutamic acid sodium 17.0g, add 12mg dicyclohexylcarbodiimide and 360ml pyridine again, stirred 8 hours down at 25 ℃, drain solvent then under 50 ℃ of gauge pressure-0.05MPa, temperature, again silicagel column on the solid substance of gained is carried out chromatographic separation, with acetonitrile: the solution of water=25: 75 is eluent, final cephalotaxin 2 ', 7-polyglutamic acid esters sodium 17.8g.
Products obtained therefrom is through quantitative assay, and the content of cephalotaxin is 5.60%.
IR(KBr)cm -1：3450，2919，2360，1652，1558，1403，1230，650。
Uv-absorbing: λ max=230nm, ε=28840,
λmax＝275nm，ε＝1690。
1HNMR：δ(ppm)＝7.77-7.36，6.38，5.97，5.63，5.55-5.36，5.10，5.18，4.10，1.97，1.18-1.20。
Embodiment 12: cephalotaxin 2 ' and, the preparation of 7-polyaspartate sodium
The 1.1g cephalotaxin is dissolved in the 210ml acetonitrile, the adding molecular weight is 32000 poly (sodium aspartate) 16.6g, add 10mg dicyclohexylcarbodiimide and 340ml pyridine again, stirred 8 hours down at 25 ℃, drain solvent then under 50 ℃ of gauge pressure-0.05MPa, temperature, again silicagel column on the solid substance of gained is carried out chromatographic separation, with acetonitrile: the solution of water=25: 75 is eluent, final cephalotaxin 2 ', 7-polyaspartate sodium 16.6g.
Products obtained therefrom is through quantitative assay, and the content of cephalotaxin is 5.80%.
IR(KBr)cm -1：3450，2919，2360，1652，1558，1403，1230，650。
Uv-absorbing: λ max=230nm, ε=28910,
λmax＝275nm，ε＝1705。
Embodiment 13: the preparation of cephalotaxin 7-polyglutamic acid esters sodium
The 500mg cephalotaxin is dissolved in the 100ml acetonitrile, under 0 ℃, with 60mlCH 3CH 2COCl reaction 1 hour adds molecular weight and is 36000 polyglutamic acid sodium 5.2g again, adds the 100mg dimethyl aminopyridine again, stirs 8 hours down at 25 ℃, adds 0.1M HAC down at 25 ℃ then and mixes and stirred 20 minutes, adds CHCl again 3Give a baby a bath on the third day after its birth time, drain, again silicon post glue on the solid substance of gained is carried out chromatographic separation, with acetonitrile: the solution of water=25: 75 is eluent, final cephalotaxin 7-polyglutamic acid esters sodium 5.4g.
Products obtained therefrom is through quantitative assay, and the content of cephalotaxin is 9.20%.
IR(KBr)cm -1：3450，2919，2360，1652，1558，1403，1230，650。
Uv-absorbing: λ max=230nm, ε=29710,
λmax＝275nm，ε＝1690。
1HNMR：δ(ppm)＝7.77-7.36，6.38，5.97，5.55-5.36，5.10，5.18，4.10，1.97，1.18-1.20。
Embodiment 14: the preparation of cephalotaxin 7-polyaspartate sodium
The 540mg cephalotaxin is dissolved in the 115ml acetonitrile, under 0 ℃, with 63mlCH 3CH 2COCl reaction 1.5 hours adds molecular weight and is 32000 poly (sodium aspartate) 5.5g again, adds the 110mg dimethyl aminopyridine again, stirs 8 hours down at 25 ℃, adds 0.1M HAC down at 25 ℃ then and mixes and stirred 20 minutes, adds CHCl again 3Give a baby a bath on the third day after its birth time, drain, again silicagel column on the solid substance of gained is carried out chromatographic separation, with acetonitrile: the solution of water=25: 75 is eluent, final cephalotaxin 7-polyglutamic acid esters sodium 5.50g.
Products obtained therefrom is through quantitative assay, and the content of cephalotaxin is 9.10%.
IR(KBr)cm -1：3450，2919，2360，1652，1558，1403，1230，650。
Uv-absorbing: λ max=231nm, ε=28848,
λmax＝276nm，ε＝1668。
The anti-tumor activity test test-compound of cephalotaxin polyglutamic acid esters sodium: five concentration (300,100,30,10,3 μ g/ml) cephalotaxin polyglutamic acid esters sodium (being called for short compd A from now on)
Material and method 1. cell strains: K562 (HRBC leukemia cell line) and CNE (human nasopharyngeal carcinoma cell line), Kunming Institute of Zoology, Chinese Academy of Sciences provides.2. reagent: (1) positive control drug: mitoxantrone, the mazarine injection liquid, Sichuan Sunnyhope Pharmaceutical Co., Ltd produces, lot number; 970613, approval number: (96) are defended the accurate word x-84 of medicine number; (2) MTT:Sigma produces, lot number: 9710; (3) three each composition of liquid: SDS: chemical reagent station, Shanghai packing factory (import packing), lot number: 960711; HCl: Chengdu chemical reagent factory, lot number: 8509061; Isopropylcarbinol: Shanghai chemical reagent purchasing and supply station combines pool centralization plant produced, lot number: 930613; (4) each composition of cell culture medium: RPMI1640:Hyclone produces, lot number: AFM5891F; Superfine blood serum of newborn calf without mycoplasma: the elegant blue or green biological engineering material in Hangzhou four institute produces Nat'l Pharmaceutical ﹠ Biological Products Control Institute's mirror system, lot number: 980224.3. the preparation of method (1) sample: sample is mixed with the mother liquor of 30mg/ml earlier with physiological saline, with physiological saline reagent is diluted to five concentration of 3000,1000,30,100,30 μ g/ml again.Sample dissolution is abundant, does not see and separates out.(2) testing method: improvement mtt assay (1)The K562 that takes the logarithm vegetative period, CNE cell strain behind the counting, are adjusted into 5 * 10 respectively with cell concn 4/ ml, 4 * 10 4/ ml adds in 96 orifice plates, 90 μ l/ holes.CNE must place 4h and treat to add testing sample again, every hole 10 μ l after adherent in incubator.Negative control is isopyknic physiological saline, and positive control is a mitoxantrone.Dosing group and control group are all established 4 multiple holes, and each concentration is all established parallel control.The final concentration of given the test agent is 300,100,30,10,3 μ g/ml; The final concentration of positive control is 10 -4, 10 -5, 10 -6, 10 -7Mol/L.Cell is at 37 ℃, 5%CO 2Hatch 48h (K562) in the incubator respectively, behind the 72h (CNE), add MTT 5mg/ml respectively, 10 μ l/ holes.After continuing to cultivate 4h, add three liquid [10%SDS-5% isopropylcarbinol-0.012ml/L HCL (w/v/v)], placed after 21 hours in 100 μ l/ holes, and at 570nm, the 630nm dual wavelength is measured the OD value in each hole down with microplate reader (Bioteck EL-340, the U.S.).4. data processing: the OD value of the OD value/negative control hole in cell survival rate=dosing hole; Cell inhibitory rate=100%-cell survival rate (2)Respectively be subjected to the IC of reagent with the GWBASIC computed in software 50And IC 5095% credibility interval.The experimental result given the test agent sees table 1, table 2 for details to the influence of K562 and CNE dynamics of cell proliferation.Table 1. compd A is to the restraining effect of K562 (human erythroleukemia) cell strain in-vitro multiplication
Group Dosage The OD value (X ± SD) Inhibiting rate (%) IC 50 IC 5095% credibility interval
Negative control group (physiological saline) Same solvent 1.571±0.081 - - -
Compd A 3μg/ml 10μg/ml 30μg/ml 100μg/ml 300μg/ml 1.029±0.013 1.035±0.172 0.936±0.066 0.873±0.030 0.859±0.022 56.46 57.90 66.38 71.98 73.66 0.99μg/ml 0.36～2.68μg/ml .
Positive control (mitoxantrone) 10 -7mol/L 10 -6mol/L 10 -5mol/L 10 -4mol/L 1.499±0.069 0.720±0.021 0.528±0.012 0.027±0.018 16.52 87.45 97.27 98.52 2.75×10 -7 mol/L 4.96×10 -8～1.53× 10 -6mol/L
Table 2. compound is to the restraining effect of CNE (human nasopharyngeal carcinoma) cell strain in-vitro multiplication
Group Dosage The OD value (X ± SD) Inhibiting rate (%) IC 50 IC 5095% credibility interval
Negative control group (physiological saline) Same solvent 0.587±0.057 - - -
Compd A 3μg/ml 10μg/ml 30μg/ml 100μg/ml 300μg/ml 0.660±0.025 0.646±0.010 0.622±0.018 0.611±0.021 0.586±0.026 75.97 81.26 83.13 84.49 90.37 0.01 μg/ml 7.23～2.68μg/ml
Positive control (mitoxantrone) 10 -7mol/L 10 -6mol/L 10 -5mol/L 10 -4mol/L 0.969±0.083 0.898±0.034 0.520±0.016 0.050±0.022 25.97 35.84 92.50 93.31 7.60×10 -7 mol/L 1.50×10 -7～ 3.86×10 -6mol/L
Conclusion
According to plant milk extract IC 50＜30 μ g/ml think that promptly the propagation to tumour cell has certain inhibiting standard, and in being tried concentration range, compd A is to the IC of K562 cell strain growth 50Value＜1 μ g/ml shows that the propagation to K562 has stronger restraining effect.
In being tried concentration range, compd A is to the IC of CNE cell strain growth 50Value＜0.1 μ g/ml shows that the propagation to K562 has stronger restraining effect.
In being tried concentration range, compd A is to the IC of CNE cell strain growth 50Value＜0.1 μ g/ml shows that the propagation to CNE has very strong restraining effect.
Compd A is to the restraining effect of GLC-82, TYK, CA and SGC-7901 cell strain in-vitro multiplication.
Test-compound: compd A material and method 1. cell strains: the GLC-82 (human lung carcinoma cell line) and the CA (human hepatoma cell strain) of six concentration (100,30,10,3,1,0.3 μ g/ml), Kunming Institute of Zoology, Chinese Academy of Sciences provides; SGC-7901 (human stomach cancer cell line), Chinese Academy of Sciences's Shanghai medicine provides; TYK (human oophoroma cell line), Shandong Medical University provides.Reagent: (1) positive control drug: mitoxantrone, dark injection liquid, Sichuan Sunnyhope Pharmaceutical Co., Ltd produces, lot number: 970613, authentication code: (96) are defended the accurate word X-84 of medicine number; Paclitaxel api, Handa Biotechnology Co Ltd, Yunnan provides: (2) MTT:Sigma produces, lot number: 9710 (3) three each composition of liquid: SDS: chemical reagent station, Shanghai packing factory (import packing), lot number: 960711; HCL: Chengdu chemical reagent factory, lot number: 8509061; Isopropylcarbinol: Shanghai chemical reagent purchasing and supply station combines pool centralization plant produced, lot number: 930613; (4) each composition of cell culture medium: RPMI1640; Hyclone produces, lot number: AFM5891F; Superfine blood serum of newborn calf without mycoplasma: the elegant blue or green biological engineering material in Hangzhou four institute produces Nat'l Pharmaceutical ﹠ Biological Products Control Institute's mirror system, lot number: 980224.3. the preparation of method (1) sample: sample is mixed with 1mg/ml with physiological saline, with physiological saline reagent is diluted to five concentration of 300,100,30,10,3 μ g/ml again.Sample dissolution is abundant, does not see and separates out.Taxol is mixed with the mother liquor of 1mg/ml earlier with DMSO.With physiological saline reagent is diluted to five concentration of 100,10,1,0.1,0.01 μ g/ml again.Sample dissolution is abundant, does not see and separates out.(2) testing method: improvement mtt assay (1)The GLC-82 that takes the logarithm vegetative period, SGC-7901, CA, TYK cell strain behind the counting, are adjusted into 4 * 10 with cell concn 4/ ml adds in 96 orifice plates, and 90 μ l/ porocytes are placed 4h and treated to add testing sample again, every hole 10 μ l after adherent in incubator.The negative control that is subjected to reagent is isopyknic physiological saline, and the negative control of taxol is isopyknic physiological saline, 1%DMSO, 10%DMSO, and positive control is that each concentration of mitoxantrone is all established parallel control, and establishes 12 zeroing holes in addition.The final concentration of given the test agent is 100,30,10,3,1,0.3 μ g/ml; The final concentration of taxol is 10,1,0.1,0.01,0.001 μ g/ml; The final concentration of positive control is 10 -4, 10 -5, 10 -6Mol/L.Cell is at 37 ℃, 5%CO 2After hatching 72h in the incubator, add MTT5mg/ml respectively, 10 μ l/ holes.After continuing to cultivate 4h, add three liquid [10%SDS-5% isopropylcarbinol-0.012ml/L HCL (w/v/v)], placed after 12 hours in 100 μ l/ holes, and at 570nm, the 630nm dual wavelength is measured the OD value in each hole down with microplate reader (Bioteck EL-340, the U.S.).4. data processing: the OD value of the OD value/negative control hole in cell survival rate=dosing hole; Cell inhibitory rate=100%-cell survival rate.Respectively be subjected to the IC of reagent with the GWBASIC computed in software 50And IC 5095% credibility interval.The result of implementation given the test agent sees table 3, table 4, table 5 and table 6 for details to the influence of GLC-82, TYK, CA and SGC-7901 dynamics of cell proliferation.Table 3. compd A is to the restraining effect of GLC-82 (people's lung cancer) cell strain in-vitro multiplication
Group Dosage The OD value (X ± SD) Inhibiting rate (%) IC 50 IC 5095% credibility interval
Negative control group (physiological saline) Same solvent 0.742±0.029 - - -
Compd A 0.3μg/ml 1μg/ml 3μg/ml 10μg/ml 30μg/ml 100μg/ml 0.671±0.008 0.650±0.009 0.622±0.020 0.609±0.028 0.634±0.023 0.617±0.030 82.5010 100 100 100 100 100 1.31×10 -3 μg/ml 8.78×10 -8～19.53 μg/ml
Positive control (mitoxantrone) 10 -6mol/L 10 -5mol/L 10 -4mol/L 0.605±0.042 0.522±0.018 0.074±0.035 56.15 100 100 4.09×10 -7 mol/L 6.15×10 -9～ 2.72×10 -5mol/L
Table 4. compd A is stopped outer inhibition of proliferation effect to SGC-7901 (people's cancer of the stomach) cell strain
Group Dosage The OD value (X ± SD) Inhibiting rate (%) IC 50 IC 5095% credibility interval
Negative control group (physiological saline) Same solvent 1.063±0.011 - - -
Compd A 0.3μg/ml 1μg/ml 3μg/ml 10μg/ml 30μg/ml 100μg/ml 0.850±0.011 0.729±0.020 0.657±0.026 0.635±0.030 0.646±0.029 0.628±0.020 52.34 82.27 100 100 100 100 0.12 μg/ml 8.13×10 -3～1.88 μg/ml
10 -6mol/L 10 -5mol/L 10 -4mol/L 0.618+0.013 0.510+0.015 0.053+0.017 86.82 99.38 100 3.37 10 -7 mol/L 1.92 10 7 5.93 10 7mol/L
Table 5 compd A is to the restraining effect of CA (people's liver cancer) cell strain in-vitro multiplication
Group Dosage The OD value (X ± SD) Inhibiting rate (%) IC 50 IC 5095% credibility interval
Negative control group (physiological saline) Same solvent 1.098±0.035 - - -
Compd A 0.3μg/ml 1μg/ml 3μg/ml 10μg/ml 30μg/ml 100μg/ml 0.939±0.036 0.729±0.013 0.674±0.023 0.648±0.025 0.641±0.028 0.634±0.026 33.78 78.40 90.19 95.50 97.10 98.58 0.31 μg/ml 0.13～0.74 μg/ml
Positive control (mitoxantrone) 10 -6mol/L 10 -5mol/L 10 -4mol/L 0.686±0.048 0.516±0.023 0.058±0.017 71.10 98.72 98.72 1.39× 10 -7 mol/L 7.07×10 -10～ 2.74×10 -5 mol/L
Table 6 compd A is to the restraining effect of TYK (human ovarian cancer) cell strain in-vitro multiplication
Group dosage The OD value (X ± SD) Inhibiting rate (%) IC 50 IC 5095% credibility interval
Negative control Physiological saline DMSO With solvent 1% 10% 0.7±0.014 0.685±0.039 0.694±0.023 - - - - - - - - -
Compd A 0.3μg/ml 1μg/ml 3μg/ml 10μg/ml 30μg/ml 100μg/ml 0.688±0.010 0.664±0.016 0.630±0.019 0.023±0.018 0.602±0.026 0.596±0.020 22.12 68/27 100 100 100 100 0.23μg/ml 2.20×10 -2～ 2.44μg/ml
Taxol 0.001μg/ml 0.01μg/ml 0.1μg/ml 1μg/ml 10μg/ml 0.850±0.011 0.729±0.020 0.657±0.026 0.635±0.030 0.646±0.029 10.58 53.85 76.92 77.88 100 1.53×10 -2 μg/ml 1.49×10 -3～ 0.16μg/ml
Positive control (mitoxantrone) 10 -6mol/L 10 -5mol/L 10 -4mol/L 0.850±0.011 0.729±0/020 0.657±0/026 50.00 100 100 4.64×10 -7 mol/L 7.90×10 -7～ 2.73×10 -5mol/L
Conclusion
According to plant milk extract IC 50＜30 μ g/ml think that promptly the propagation to tumour cell has certain inhibiting standard, and in being tried concentration range, compd A is to the IC of GLC-82, SGC-7901, CA cell strain growth 50Value is respectively 1.31 * 10 -3μ g/ml, 0.12 μ g/ml, 0.31 μ g/ml show that compd A has very strong restraining effect to the propagation of this three strains cell.
In being tried concentration range, compd A is to the IC of TYK cell strain growth 50Value is 0.23 μ g/ml, shows that the propagation to TYK has very strong restraining effect.

Claims (15)

1. the cephalotaxin polyamino acid ester of general formula I or its salt,
Wherein, R 1And R 2Can be the polyglutamic acid residue identical or different and independently, poly aspartic acid residue or H, M exist or exist and be alkalimetal ion, and condition is R 1And R 2Can not be hydrogen simultaneously.
2. the compound of claim 1, wherein R 1Be polyglutamic acid residue or poly aspartic acid residue, R 2Be H.
3. the compound of claim 1, wherein R 1Be H, R 2Be polyglutamic acid residue or poly aspartic acid residue.
4. the compound of claim 1, wherein R 1Be polyglutamic acid residue or poly aspartic acid residue, R 2Be polyglutamic acid residue or poly aspartic acid residue.
5. the arbitrary compound of claim 1-4, wherein said formula I compound is selected from:
Cephalotaxin 2 '-the polyglutamic acid esters,
Cephalotaxin 2 '-polyaspartate,
Cephalotaxin 2 ', 7-polyglutamic acid esters,
Cephalotaxin 2 ', the 7-polyaspartate,
Cephalotaxin 7-polyglutamic acid esters,
Cephalotaxin 7-polyaspartate,
Cephalotaxin 2 '-polyglutamic acid esters sodium,
Cephalotaxin 2 '-polyaspartate sodium,
Cephalotaxin 2 ', 7-polyglutamic acid esters sodium,
Cephalotaxin 2 ', 7-polyaspartate sodium,
Cephalotaxin 7-polyglutamic acid esters sodium,
Cephalotaxin 7-polyaspartate sodium.
6. the compound of claim 5, wherein said formula I compound is selected from:
Cephalotaxin 2 '-polyglutamic acid esters sodium,
Cephalotaxin 2 ', 7-polyglutamic acid esters sodium,
Cephalotaxin 7-polyglutamic acid esters sodium.
7. the arbitrary compound of claim 1-4, wherein said polyglutamic acid or poly aspartic acid comprise its D-, L-, or DL configuration.
8. the arbitrary compound of claim 1-4, wherein said polyglutamic acid molecular weight is 15,000-60,000.
9. the compound of claim 8, wherein said polyglutamic acid molecular weight is 25,000-50,000.
10. the arbitrary compound of claim 1-4, wherein said poly aspartic acid molecular weight is 12,000-50,000.
11. the compound of claim 10, wherein said poly aspartic acid molecular weight is 22,000-40,000.
12. pharmaceutical composition, it comprises at least a formula I cephalotaxin polyamino acid ester or its salt and pharmaceutical carrier, Wherein, R 1And R 2Can be the polyglutamic acid residue identical or different and independently, poly aspartic acid residue or H, M exist or exist and be alkalimetal ion, and condition is R 1And R 2Can not be hydrogen simultaneously.
13. the pharmaceutical composition of claim 12, its Chinese style I cephalotaxin polyamino acid ester or its salt are selected from:
Cephalotaxin 2 '-the polyglutamic acid esters,
Cephalotaxin 2 '-polyaspartate,
Cephalotaxin 2 ', 7-polyglutamic acid esters,
Cephalotaxin 2 ', the 7-polyaspartate,
Cephalotaxin 7-polyglutamic acid esters,
Cephalotaxin 7-polyaspartate,
Cephalotaxin 2 '-polyglutamic acid esters sodium,
Cephalotaxin 2 '-polyaspartate sodium,
Cephalotaxin 2 ', 7-polyglutamic acid esters sodium,
Cephalotaxin 2 ', 7-polyaspartate sodium,
Cephalotaxin 7-polyglutamic acid esters sodium,
Cephalotaxin 7-polyaspartate sodium.
14. the pharmaceutical composition of claim 13, its Chinese style I cephalotaxin polyamino acid ester or its salt are selected from:
Cephalotaxin 2 '-polyglutamic acid esters sodium,
Cephalotaxin 2 ', 7-polyglutamic acid esters sodium,
Cephalotaxin 7-polyglutamic acid esters sodium.
15. at least a formula (I) compound that claim 1 requires is used for preparing and is used for the treatment of the medicine purposes that is selected from nasopharyngeal carcinoma, lung cancer, cancer of the stomach, liver cancer, ovarian cancer or leukemia cancer.
CN99118644A 1999-09-10 1999-09-10 Water soluble cephalotaxin phosphorus poly aminoacid ester or its salt, pharmaceutical compositions contg. same, and pharmaceutical use thereof Expired - Fee Related CN1111166C (en)

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US5643575A (en) * 1993-10-27 1997-07-01 Enzon, Inc. Non-antigenic branched polymer conjugates
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* Cited by examiner, † Cited by third party
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