CN1385417A - Polyasparacyl-L-arginine, its preparation and medical application - Google Patents
Polyasparacyl-L-arginine, its preparation and medical application Download PDFInfo
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- CN1385417A CN1385417A CN 02120900 CN02120900A CN1385417A CN 1385417 A CN1385417 A CN 1385417A CN 02120900 CN02120900 CN 02120900 CN 02120900 A CN02120900 A CN 02120900A CN 1385417 A CN1385417 A CN 1385417A
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Abstract
The present ivnention relates to a polyasparacyl-L-arginine, its preparation method and application of it as thrombosis-resisting agent. Said ivnention also provides its general formula.
Description
Invention field
The present invention relates to the DL-aspartic acid and generate polysuccinimide, further, obtain poly-asparagus fern acyl-L-arginine with the reaction of L-arginine through dehydration; Relate to the analytical procedure that comprises chromatogram and mass spectrum and characterize the poly-arginic molecular weight distribution of asparagus fern acyl; Relate to the application of poly-asparagus fern acyl-L-arginine oral administration administration as antithrombotic agent.
Background of the present invention
Poly-propylhomoserin compounds toxicity is low, good biocompatibility, and degraded easily, and meta-bolites can be absorbed by body.These characteristics make the polyamino acid compounds receive much attention as pharmaceutical polymers.For example, poly aspartic acid can carry out multiple derivative reaction (comprising amidation and esterification) because of carboxylic side-chain, be used for drug delivery system effectively, especially shown tangible hypotoxicity (1. Zunino F with daunorubicin or the covalently bound controlled release of methotrexate or targeting anti-tumor medicine, Savi G, Giuliani F, et al.Comparison of antitumoreffects of daunorubicin covalently linked to poly-L-amino acid carriers.Eur.J.Cancer Clin Oncol.1984,20 (3): 421～5 2. Zunino F, Giuliani F, Savi G et al.Anti-tumor activity of daunorubicin linked topoly-L-aspartic acid.Int J Cancer.1982,30 (4): 465～70).Poly aspartic acid self can also clearly protect the patient when accepting the aminoglycosides antibiotic therapy; do not produce renal toxicity and ototoxicity (Williams PD; Inhibition of membrane binding andnephrotoxicity of gentamicin by polyasparagine and polyaspartic acid inthe rat.Res Commun Chem Pathol Pharmacol.47:317～320. Swan SK; Long-term protection of polyaspartic acid in experimental gentamicinnephrotoxicity.Antimicrobial Agents and Chemotherapy.1991; 35:2591～2595.Laurent D; Reduction of gentamicin nephrotoxicity by theconcomitant administration of poly-L-aspartic acid and poly-L-asparginine in rats.Arch.Toxicol.1986,9:306～309).These results of study show that poly aspartic acid has tangible using value as the polymer medicinal materials.
The applicant is in the relevant drug research of L-arginine, once the L-arginine was covalently bound on malonyl and the succinyl, preparation vasodilator (Gu Mingdi, PengShiqi, Jiang Xiurong, Guo Xueqing, Cai Mengshen, EDRF-like actions ofhomoarginine.Progress in Natural Science.1993,3 (2): 155～159); Once the L-arginine derivative was covalently bound on the L-Methionin, prepared anti-septic shock agent (Zhao Ming, Wang Chao, Gu Mingdi, Peng Shiqi, Studies on thesynthesis of N
G-nitro-L-Arginine derivatives and their effects on septicshock.Prep.Biochem And Biotechnol.2000,30 (30): 241～246); Once according to stability (the Hughest P of the salt bridge that forms between the asparagicacid residue of thrombocyte Gp IIb/IIIa acceptor cytoplasmic domain and the arginine residues, Dia-Conzalez F, Brea-King theintegrin hinge, J Biol Chem.1990,271:6571～6574), L-arginine and L-aspartate salify, preparation antithrombotic agent (Wang Yinye, Wang Jingyan, Fu Yilong, Wang Chao, Peng Shiqi, the inhibition of L-arginine L-Aspartic Acid salt pair platelet function, Journal of physiology.2001，53(4)：303～306)。These results of study show that the L-arginine can show the cardiac vascular activity of expectation by assembling rationally.
Summary of the invention
The applicant finds, as pharmacophore, as drug-loading system, by the amido linkage bonding, can constitute the compound of general formula (1) to the L-arginine to poly aspartic acid, the compound exhibits of the general formula of acquisition (1) antithrombotic acitivity.
N=10-2000 wherein, preferred n=50-1000, more preferably 70-400.
In embodiments, the present invention with the polymerization of DL-aspartic acid, generates polysuccinimide by operation shown in Figure 1.The DL-aspartic acid is with after 85% phosphoric acid and distilled water mix, and the 2.5h that reduces pressure under 180 ℃ of airbaths can successfully be converted into polysuccinimide, and yield is 93.4%; The DL-aspartic acid 100h that refluxes in naphthane is converted into polysuccinimide, and yield is 44%; The DL-aspartic acid is converted into polysuccinimide at 200 ℃ of frit reaction 3h, and yield is 16.7%.In the presence of the L-arginine, the polysuccinimide that makes by three kinds of approach can open loop, is converted into the poly-asparagus fern acyl-L-arginine of general formula (1) with high yield, and productive rate is respectively 95%, 35% and 76%.The present invention adopts chromatography and liquid matter logotype instrument to measure the molecular weight distribution of general formula (1), and the molecular weight that characterizes it from different angles constitutes.Wherein gel filtration chromatography records and is prepared into polysuccinimide and L-arginine prepared in reaction by three kinds of conditions and must gathers asparagus fern acyl-L-arginine and get molecular weight and be respectively 117,600,30,200 and 30,000.As those skilled in the art are known, by control reaction conditions (for example changing temperature of reaction, reaction times etc.), can be with the synthetic different molecular weight of polymer poly of the present invention.
The present invention is with the poly-arginic antiplatelet aggregative activity of asparagus fern acyl-L-of platelet aggregation model evaluation in the rat halfbody.Under 15mg/kg, 30mg/kg and 60mg/kg dosage, once oral compound of the present invention can significantly reduce the thrombocyte MA of ADP, collagen and thrombin induction.Under 15mg/kg dosage, once oral compound of the present invention in 1～6 hour, can significantly suppress the effect of ADP inductive rat platelet aggregation.Adopt the anti-bolt model of rat arteriovenous shut intubate, under 15mg/kg, 60mg/kg and 120mg/kg dosage, 3 times/day oral compounds of the present invention can significantly suppress the thrombosis of rat.Adopt the anti-bolt model of rat carotid artery, under 15mg/kg, 30mg/kg and 60mg/kg dosage, once oral compound of the present invention can significantly suppress FeCl
3The carotid artery thrombosis that stimulates.Under 10mg/kg dosage, vein gives compound of the present invention, can obviously suppress electricity irritation inductive rat carotid artery thrombosis.Under 15mg/kg to 60mg/kg dosage, compound of the present invention is the prolong rats bleeding time obviously.
Under 30mg/kg dosage, compound of the present invention once irritates stomach, TXA in the rat plasma for rat
2And PGI
2Level do not have considerable change, and, then can urge the TXA in the rat plasma as the same dosage acetylsalicylic acid of positive control
2And PGI
2Level significantly reduces.This character of compound of the present invention is not laid a good foundation for it does not possess the side effect that causes the gi tract local tissue necrosis.
Accompanying drawing summary Fig. 1 is the arginic three kinds of synthetic routes of poly-asparagus fern acyl-L-of the present invention.
Embodiment
In order further to illustrate the present invention, provide a series of embodiment below.It must be noted that these embodiment are illustrative fully.The purpose that provides these embodiment is in order fully to express meaning of the present invention and content, never the present invention to be caused any type of restriction.
Embodiment 1 heating decompression legal system is equipped with polysuccinimide
The DL-aspartic acid of 5g porphyrize in the 250mL round-bottomed flask, is added 2ml 85% phosphoric acid and 2mL distilled water, thoroughly mixing.Under 180 ℃ of airbaths, decompression reaction 2.5 hours adds 20ml DMF while hot, after treating that product dissolves fully, reaction solution is splashed in the 100ml distilled water, washing precipitation is to neutral, toast 24hr under infrared lamp, getting product 3.4g. productive rate is 93.4%. ultimate analysis (C
4H
3NO
2) n:C:46.76, H:3.35, N:13.64.
The code name of product is PD1.
Embodiment 2 azeotropic water removing legal systems are equipped with polysuccinimide
The DL-aspartic acid monomer of 50g porphyrize is suspended in the chemical pure naphthane of 500ml, refluxed 100 hours, remove the water of generation in boiling point, be cooled to room temperature, filter, filter residue is washed with ether earlier, and it is inferior to give a baby a bath on the third day after its birth with saturated sodium bicarbonate aqueous solution then, each 100ml, grinding makes spherical product be needle prick shape repeatedly, and first water is washed repeatedly, high speed centrifugation, separate, use 1% salt pickling again, last water is washed repeatedly again, and high speed centrifugation separates, up to check not chloride ion-containing with Silver Nitrate, get the about 16g of dry glassy yellow polysuccinimide.Productive rate 43.9% ultimate analysis (C
4H
3NO
2) n:C:45.24, H:3.85, N:13.30.
The code name of product is PD2.
Embodiment 3 scorifications prepare polysuccinimide
Evenly be tiled in the DL-aspartic acid of 30g porphyrize in the watch-glass, 200 ℃ of reacting by heating 3 hours, it is orange red that reaction product is. and it is inferior to give a baby a bath on the third day after its birth with saturated sodium bicarbonate aqueous solution, each 100ml, grinding makes spherical product be needle prick shape repeatedly, and first water is washed repeatedly, high speed centrifugation, separate, oven dry gets product 5g. ultimate analysis (C
4H
3NO
2) n:C:46.63, H:3.33, N:13.63.Yield 16.7%.
Amino acid composition analysis: aspartic acid: arginine=0.9: 0.6
The code name of product is PD3.
The embodiment 4 poly-arginic preparations of asparagus fern acyl-L-
In distilled water, will wait mole L-arginine and polysuccinimide (calculating as the unit) stirring at room by the aspartimide molecular weight, reaction end is judged by two indexs: 1. have excessive polysuccinimide to exist in the aqueous solution; 2. the aqueous solution is neutral.After-filtration is finished in reaction, and filtrate decompression is concentrated into dried, obtains title compound.The product code name that is obtained by PD1 is PDR1, and yield is 95%; The product code name that is obtained by PD2 is PDR2, and yield is 35%.The product code name that is obtained by PD3 is PDR3, and yield is 76%.
The embodiment 5 poly-arginic molecular weight characterizations of asparagus fern acyl-L-
Water-soluble GPC condition and parameter:
Instrument: the U.S. HP1100 of Hewlett-Packard company high performance liquid chromatograph, be furnished with
Diode-array detector (DAD) and automatic sampler.
Chromatographic column: Alltech Macrosphere GPC 100A 7u 250mmx4.6mm Seral
No.00110393.2
Agilent?Zorbax?BIO?SERIES?GF-250，4.6mmID×250mm
PART NO.884973701 (Agilent company provides)
Diol guard column, No820777.901 (Agilent company provides) moving phase: 0.2M dipotassium hydrogen phosphate solution, pH7.0 calibration standard: thyroglobulin (MW670000), IgG standard (MW150000), bovine serum albumin (MW67000), oralbumin (MW43000), N,O-Diacetylmuramidase (MW14300) molecular weight determination: with the elution volume of above-mentioned standard protein the respective compound molecular weight is made typical curve respectively, measure the elution volume of testing compound simultaneously, calculate the testing compound molecular weight by computer program.Flow velocity: 0.4ml/min column temperature: 40 ℃ are detected wavelength: 216nm, 230nm, 275nm
Result: relative molecular weight Mn:PDR1:117,600 PDR2:30,200 PDR3:30,000.
The embodiment 6 poly-arginic stability of asparagus fern acyl-L-
A gets two parts of 500ug PDR, uses 1ml deionized water and physiological saline solution respectively, every 20 hours sample introduction 20ul, measures the poly-arginic main peak area of asparagus fern acyl-L-with the HPLC method under the room temperature.The result shows that in 120 hours, peak area does not have obvious change.
B, configuration concentration are the PDR of 5mg/ml, add 2mol/L hydrochloric acid or 2mol/L NaOH, every 20 hours sample introduction 20ul, measure the poly-arginic main peak area of asparagus fern acyl-L-with the HPLC method under the room temperature.The result shows that in 120 hours, peak area does not have obvious change.
Embodiment 7 poly-asparagus fern acyl-L-arginine are to antiplatelet aggregative activity in the halfbody of rat
Animal: the Wistar rat, one-level, male, 270 ± 50g
Male rat, 220-320g is divided into five groups at random by weight average: solvent control group, positive drug (ASA) control group, three dosage groups of Compound P DR 15,30,60mg/kg.Overnight fasting before the experiment.Behind the administration 1hr, with Sodital sodium solution 40mg/kg intraperitoneal injection of anesthesia, abdominal aortic blood, 3.8% liquor sodii citratis anti-freezing with 1/10 volume, 1200rpm is centrifugal, and 10min prepares PRP, shifts supernatant PRP, and continuing to prepare PPP with the centrifugal 10min of 3000rpm is the aggregation inducing agent with collagen, the zymoplasm of ADP, dilution respectively, with turbidimetry for Determination platelet aggregation degree, compare between the work group.
1.5h behind PDR 30 or the 60mg/kg gastrointestinal administration, the interior platelet aggregation rate of halfbody of ADP, collagen or thrombin induction is significantly descended, show that PDR can obviously suppress the rat platelet aggregation that these inductors cause, its action intensity with the ASA close (seeing Table 1) of dosage.
Table 1.PDR (P.O.) is to the effect (n=10) of platelet aggregation in the rat halfbody
| Group | Dosage mg/kg | MA (%) | ||
| ?ADP | Collagen | Zymoplasm | ||
| Contrast (H 2O) PDR ASA | ????- ????15 ????30 ????60 ????30 | ?80.8±11.5 ?66.2±22.6 ?22.6±14.6 ***?17.3±13.0 ***?28.3±18.4 *** | 64.5±13.4 27.3±23.1 **10.6±10.3 ***11.0±9.4 ***12.4±14.5 *** | 69.6±10.2 16.4±18.4 **11.0±10.5 ***15.4±12.0 ***7.4±7.1 *** |
Compare with control group
*P＜0.01;
* *P＜0.001
Embodiment 8 poly-asparagus fern acyl-L-arginine are to the effect of platelet aggregation-against in the rabbit halfbody
Overnight fasting before male rabbit (about the 2.5Kg) test, with 3.8% Sodium Citrate anti-freezing, the ear medium sized artery is got blood, preparation PRP, PPP.With ADP is that inductor is measured administration thromboblast aggregation rate.With the oral single-dose of 30mg/kg PDR, after administration, got blood respectively in 1 hour, 2 hours, 4 hours, 6 hours, measure different platelet aggregation degree constantly with condition identical before the administration, be calculated as follows thrombocyte and suppress percentage, draw Time-activity-curve.
Aggregation rate * 100 before I%=(aggregation rate after the preceding aggregation rate-administration of administration)/administration
PDR 30 mg/kg are oral all to have obvious suppression effect (seeing Table 2) to 1h, 2h, 4h, 6h behind the rabbit to ADP inductive platelet aggregation.
Table 2.PDR (P.O.) is to the effect (n=8) of platelet aggregation in the ADP inductive rabbit halfbody
| Group | Dosage mg/kg | Different time inhibiting rate (%) after the administration | ||||
| ?1h | ??2h | ??4h | ??6h | ??8h | ||
| Contrast PDR-4 | ????- ????15 | ?2.5±5.0 ?59.8±23.6 *** | ??15.9±14.3 ??65.7±21.7 *** | ??1.6±3.1 ??52.3±32.6 ** | ??25.0±34.2 ??54.8±34.5 ** | ??20.9±31.3 ??21.9±27.0 |
Compare with control group
*P＜0.01;
* *P＜0.001
Embodiment 9 poly-asparagus fern acyl-L-arginine are to the thrombotic influence of rat carotid artery
(220～320g) are divided into five groups by weight average to male Wistar rat: solvent control group, positive drug (ASA) control group, three dosed administration groups of Compound P DR 15,30,60mg/kg.Animal overnight fasting before the experiment, gastric infusion is after 1 hour, with Sodital 40mg/kg, intraperitoneal injection of anesthesia, dorsal position is fixed.Separate right common carotid artery, lining is with rectangular plastic paper, and (4 * 0.5cm) drip 300 μ l FeCl to the calico bar
3Behind the solution impregnation, the parcel artery behind the 15min, is clamped proximal part with bulldog clamp, cuts stimulation place blood vessel, cuts open on template, scrapes thrombus, and drying at room temperature 24hr claims thrombus weight, compares between the work group.
PDR15,30 or the 60mg/kg gastrointestinal administration can significantly suppress FeCl
3Inductive carotid artery thrombosis (seeing Table 3).Table 3.PDR (P.O.) is to the thrombotic effect of rat carotid artery (n=10)
| Group | Dosage (mg/kg) | ??n | Thrombus dry weight (mg) |
| Blank (H 2O) ????PDR-4 ????ASA | ????- ????15 ????30 ????60 ????30 | ??11 ??10 ??11 ??10 ??12 | ??1.025±0.185 ??0.775±0.208 *??0.746±0.189 **??0.768±0.198 **??0.774±0.277 * |
Compare with control group:
*P＜0.05;
*P＜0.01
Embodiment 10 poly-asparagus fern acyl-L-arginine are to the thrombotic influence of rat arteriovenous shut
(300～350g) are divided into five groups, solvent control group (H by weight average to male Wistar rat
2O), positive drug (ASA) control group, 7.5mg/kg, 30mg/kg, three dosage groups of 120mg/kg PDR.Gastric infusion 3 times, 1 time/12h.Overnight fasting before the test.Behind the last administration 1.25h, with vetanarcol 40mg/kg intraperitoneal injection of anesthesia.Dorsal position is fixed, and separates right common carotid artery and left external jugular vein, puts a silk thread of having weighed with long 6cm in polyethylene tube, and (50 μ/ml) are full of polyethylene tube with heparin-saline solution.After one end of polyethylene tube inserted left external jugular vein, in pipe, accurately inject heparin (50 μ/kg) anti-freezing, and then the other end of polyethylene tube inserted right common carotid artery.Opened bulldog clamp in 2 hours after administration, blood flow to polyethylene tube, returns left external jugular vein from right common carotid artery again.Open blood flow interrupted after 15 minutes, took out silk thread rapidly and weighed, and gross weight deducts silk thread and heavily promptly gets wet weight of thrombus.Each is analyzed between organizing.
Continuous 3 gastrointestinal administrations of PDR 30 or 120mg/kg are (inferior/as 12h), can obviously to suppress arteriovenous shut thrombosis (seeing Table 4).Table 4.PDR is to the thrombotic influence of rat arteriovenous shut (n=10)
| Group | Dosage (mg/Kg) | Thrombus weight (mg) |
| Blank to (H 2O) PDR ASA | ????- ????7.5 ????30.0 ????120.0 ????30.0 | ????34.00±6.84 ????28.70±5.91 ????27.00±7.40* ????22.60±5.48*** ????17.44±7.25*** |
Compare with control group:
*P＜0.05;
* *P＜0.001
Embodiment 11 intravenous injections gather asparagus fern acyl-L-arginine to the thrombotic influence of rat carotid artery
SD rat (body weight 270～330g, male), and urethane anesthesia (ip, 1.5g/kg), separate left carotid, place stimulating electrode and thermosensitive probe, tongue intravenous injection PDR or NS (0.5ml/100g), after 5 minutes, with 3mA galvanism 3 minutes, the record thrombus formation time.
Intravenously administrable of PDR 10mg/kg, but significant prolongation electricity irritation rat carotid artery thrombus formation time, its action intensity and ASA close (seeing Table 5)
(single is iv) to the thrombotic influence of rat electricity irritation arteria carotis communis for table 5 PDR
| Grup | Dosage (mg/kg) | ????n | Thrombus formation time (s) |
| Solvent contrast ASA PDR | ????--- ????10 ????10 | ????14 ????10 ????10 | ????561.7±57.7 ????677.8±125.4* ????713.9±147.81** |
Compare with control group: * P＜0.05, * * P＜0.01
Embodiment 12 poly-asparagus fern acyl-L-arginine are to the influence in mouse tail bleeding time
(20～25g) are divided into five groups by body weight to kunming mice at random: solvent control group, positive drug (heparin) control group, three dosed administration groups of Compound P DR 15,30,60mg/kg.Except that heparin group, continuous irrigation stomach 7 times (2 times/d), test preceding fasting 12h, after last is irritated stomach 50min, positive control treated animal tongue intravenous injection heparin (200u/kg), behind the 10min, all animals are apart from tail point 3mm place's docking, timing, gently dip in docking place drop of blood every 30sec with filter paper, record does not occur time of bloodstain to the filter paper from cutting off the tail point, is the bleeding time, surpass 15min, press 15min calculating.
PDR 15,30 or 60mg/kg are like prolonging the mouse bleeding time (seeing Table 6)
Table 6.PDR is to the effect (n=10) in mouse bleeding time
| Group | Dosage | Bleeding time (min) |
| Blank (H 2O) PDR ASA | ????- ????15 ????30 ????60 ????30 | ????5.8±1.9 ????7.6±1.2 *????7.4±1.7 ????7.6±1.6 *????7.4±1.1 * |
Compare with control group:
*P＜0.05
Embodiment 13 poly-asparagus fern acyl-L-arginine are to rat plasma TXB
2And PGI
2The influence of level
Rat is divided into 3 groups by weight average: solvent control group, positive drug (ASA) group and 30mg/kg PDR group, and fasting 12h before the animals administer, 2h vetanarcol anesthesia after the administration, blood is got in the Trisodium Citrate anti-freezing, preparation blood plasma.Measure TXA in the blood plasma with putting the method for exempting from
2And PGI
2Stable meta-bolites TXB
2With PG F
1 αConcentration.Radioimmunological kit is an eastern refined biotechnology institute product.
1h after the PDR 30mg/kg administration is to blood plasma TXB
2And 6-keto-PGF
1 αLevel does not have obvious influence, and ASA 30mg/kg can significantly reduce the blood plasma level (seeing Table 7) of the two.The anti thrombotic action mechanism of prompting PDR may be different from ASA.
Table 7.PDR is to rat plasma TXB2 and 6-keto-PGF
1 αThe influence of concentration (n=10)
| Group | Dosage (mg/Kg) | TXB 2(pg/ml) | 6-keto-PGF 1α????(pg/ml) |
| Blank (H 2O) PDR ASA | ????- ????30 ????30 | ??432±82 ??378±55 ??232±64 ** | ??433±253 ??700±549 ??143±87 ** |
Compare with control group:
*P＜0.01
Claims (9)
1, the poly-asparagus fern acyl-L-arginine of general formula (1):
N=10-2000 wherein.
2, according to poly-asparagus fern acyl-L-arginine, the wherein n=50-1000 of claim 1.
3, according to poly-asparagus fern acyl-L-arginine, the wherein n=70-400 of claim 2.
4, each the arginic preparation method of poly-asparagus fern acyl-L-among the claim 1-3 comprises the dehydration of DL-aspartic acid is generated polysuccinimide, further with the reaction of L-arginine, obtains poly-asparagus fern acyl-L-arginine.
5, the preparation method of claim 4 wherein generates DL-aspartic acid dehydration polysuccinimide and is by the DL-aspartic acid in the presence of phosphoric acid, and the decompression under 150-250 ℃ of airbath is reacted and realized.
6, the preparation method of claim 4 wherein refluxes by the DL-aspartic acid DL-aspartic acid dehydration generation polysuccinimide and realizes in naphthane.
7, the preparation method of claim 4, the frit reaction that wherein DL-aspartic acid dehydration is generated polysuccinimide and be by the DL-aspartic acid realizes.
8, each the poly-asparagus fern acyl-purposes of L-arginine in medical science among the claim 1-3.
9, according to each poly-asparagus fern acyl-L-arginine among the claim 1-3 in the application of preparation in the antithrombotic agent.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1309760C (en) * | 2003-10-16 | 2007-04-11 | 北京北医投资管理有限公司医药科技开发分公司 | Poly asparaginyl aminoacetic acid, alanine and lysine and its preparation method and medicament purpose |
| CN102786687A (en) * | 2011-05-19 | 2012-11-21 | 山东百因制药技术有限公司 | Polyasparaginyl-L-cysteine and polyasparaginyl-L-methionine with polymerization degree of 59, preparation method and application thereof |
| CN104211961A (en) * | 2013-06-05 | 2014-12-17 | 首都医科大学 | Polyaspartic acid derivatives, preparation, nano structure, lead removing activity, and applications thereof |
-
2002
- 2002-06-07 CN CNB021209006A patent/CN1171858C/en not_active Expired - Fee Related
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1309760C (en) * | 2003-10-16 | 2007-04-11 | 北京北医投资管理有限公司医药科技开发分公司 | Poly asparaginyl aminoacetic acid, alanine and lysine and its preparation method and medicament purpose |
| CN102786687A (en) * | 2011-05-19 | 2012-11-21 | 山东百因制药技术有限公司 | Polyasparaginyl-L-cysteine and polyasparaginyl-L-methionine with polymerization degree of 59, preparation method and application thereof |
| CN102786687B (en) * | 2011-05-19 | 2014-09-10 | 山东百因制药技术有限公司 | Polyasparaginyl-L-cysteine and polyasparaginyl-L-methionine with polymerization degree of 59, preparation method and application thereof |
| CN104211961A (en) * | 2013-06-05 | 2014-12-17 | 首都医科大学 | Polyaspartic acid derivatives, preparation, nano structure, lead removing activity, and applications thereof |
| CN104211961B (en) * | 2013-06-05 | 2016-12-28 | 首都医科大学 | Poly-aspartate derivant, it prepares, nanostructured, Plumbum removing activity and application |
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| Publication number | Publication date |
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| CN1171858C (en) | 2004-10-20 |
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