CN1309760C - Poly asparaginyl aminoacetic acid, alanine and lysine and its preparation method and medicament purpose - Google Patents
Poly asparaginyl aminoacetic acid, alanine and lysine and its preparation method and medicament purpose Download PDFInfo
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- CN1309760C CN1309760C CNB2003101004213A CN200310100421A CN1309760C CN 1309760 C CN1309760 C CN 1309760C CN B2003101004213 A CNB2003101004213 A CN B2003101004213A CN 200310100421 A CN200310100421 A CN 200310100421A CN 1309760 C CN1309760 C CN 1309760C
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Abstract
The present invention relates to poly asparagus acyl-amino acid in a general formula (1), wherein AA=Gly, L-Ala, L-Lys, n= 10-2000. The present invention also relates to a process for preparing medicinal salts and the application of the poly asparagus acyl-amino acid and compositions with the poly asparagus acyl-amino acid when used as anticonvulsant agent or thrombolytic.
Description
Technical field
The present invention relates to poly-asparagus fern acyl glycine, poly-asparagus fern acyl-L-L-Ala or poly-asparagus fern acyl-L-Methionin, the preparation method comprises allowing the DL-aspartic acid generate polysuccinimide through dehydrating condensation, further with glycine, L-L-Ala or the reaction of L-Methionin; Relate to poly-asparagus fern acyl glycine and poly-asparagus fern acyl-L-Methionin and they can be medicinal salt and contain they or they can be medicinal the medicinal use of composition of salt, especially as the application of anticonvulsive agent and thrombolytics.
Background technology
The polyamino acid compounds shows all that generally hypotoxicity, high-biocompatibility, readily degradable and meta-bolites can be absorbed by body.These advantages make the polyamino acid compounds receive publicity as pharmaceutical polymers.For example, the drug delivery system of the various derivative reactions preparation by the poly aspartic acid carboxylic side-chain, especially poly aspartic acid and gentle red enzyme element or the covalently bound control of methotrexate or targeting anti-tumor medicine are because of tangible hypotoxicity (the 1.Zunino F that comes into one's own, Savi G, Giuliani F, et al., Comparison of antitumor effects of daunorubicin covalently linked topoly-l-amino acid carriers, Eur.J.Cancer Clin Oncol, 1984,20 (3), 421-5; 2.ZuninoF, Guiliani F, Savi G, et al., Antitumor 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 (3.Williams PD, Inhibition of membrane binding and nephrotoxicity ofgentamicin by polyasparagine and polyaspartic acid in the rat, Res CommunChem Pathol Pharmacol, 1980,47,317-320; 4.Swam SK, Long-term protection ofpolyaspartic acid in experimental gentamicin nephrotoxicity, AntimicrobialAgents and Chemotherapy, 1991,35,2591-5; 5.Laurent D, Reduction ofgentamicin nephrotoxicity by the concomitant administration of poly-l-asparticacid and poly-l-asparginine in rats, Arch Toxicol, 1986,9,306-9).The contriver once was attached to the L-arginine on the carboxyl that poly aspartic acid is covalently bound to poly aspartic acid, preparation antithrombotic agent (Peng Shiqi, Zhao Ming, Wang Chao; Qin's Yang, Wang Yinye, Lv Weichuan, Liu Jiangyuan, poly-asparagus fern acyl-L-arginine, its preparation, and the application in medical science, Chinese patent application number: 02120900.6).These results of study show that poly aspartic acid has clear and definite prospect in medicine.
Epileptic seizures and neurotransmitter have substantial connection.Some amino acid is divided into inhibitory transmitter and related with anticonvulsion thing.Wherein glycine and L-Methionin often are seen in document as anticonvulsive agent.So, rationally assemble glycine and L-Methionin and provide the foundation for seeking anticonvulsive agent.Thrombosis has comprised the non-bonded interaction between a large amount of scleroproeins.Introduce other hydrophobic interaction in the thrombus and can cause thrombolysis.Some amino acid can provide this other hydrophobic interaction for thrombus.So, rationally assemble glycine and L-Ala and provide the foundation for seeking molten frightened suppository.
Summary of the invention
The compound and the pharmacologically acceptable salts thereof that the purpose of this invention is to provide general formula (1):
Wherein AA is Gly, L-Lys or Ala, n=10-2000, preferred 70-400.
Another object of the present invention provides the preparation method of the compound of general formula (1), may further comprise the steps:
A, make the DL-aspartic acid generate polysuccinimide through dehydrating condensation (for example under 100 ℃-300 ℃, preferred 150-220 ℃) under the intensification condition;
B, allow polysuccinimide further with glycine, L-L-Ala or the reaction of L-Methionin, obtain poly-asparagus fern acyl glycine, poly-asparagus fern acyl-L-L-Ala or poly-asparagus fern acyl-L-Methionin respectively.
In a scheme, dehydrating condensation is to carry out under 150-200 ℃ temperature in the presence of phosphoric acid.
In another scheme, dehydrating condensation is to carry out under refluxing in inert solvent (for example naphthane, tetrahydrofuran (THF) etc.).
In another scheme, dehydrating condensation is realized by the frit reaction of DL-aspartic acid self.
Reaction times for example can be 1-10 hour, general 2-5 hour.
The molecular weight of polysuccinimide was controlled by temperature of reaction and reaction times, and temperature of reaction is low more or the reaction times is short more, and molecular weight is more little; Temperature of reaction is high more or the reaction times is long more, and molecular weight is big more.
A further object of the present invention provides wherein, and AA is above-mentioned general formula compound or the purposes of its pharmaceutical salts in the preparation anticonvulsant drug of Gly or L-Lys.
Also purpose of the present invention provides wherein, and AA is above-mentioned general formula compound or the purposes of its pharmaceutical salts in the preparation thrombolytics of Gly or L-Ala.
The applicant finds, glycine or L-Methionin as pharmacophore, poly aspartic acid as drug-loading system, by the amido linkage bonding, can constitute the compound of general formula (1), as AA=Gly and L-Lys, the compound exhibits of the general formula that obtains during n=10-2000 (1) anti-convulsant activity, as AA=Gly and L-Ala, the compound exhibits of the general formula that obtains during n=10-2000 (1) thrombolysis activity.
Another object of the present invention provides the pharmaceutical composition of the compound of the above-mentioned general formula (1) that contains pharmacy effective dose.Composition of the present invention can also comprise carrier and optional additive such as flavouring agent, sweeting agent etc.The content of compound in pharmaceutical composition of its formula of (1) for example can be 1-95%.
Pharmaceutical composition of the present invention can be made oral dosage form or injection or transfusion formulation.
The compound of general formula of the present invention (1) can use alone or use with the form of composition.
The dosage of the compound of general formula of the present invention (1) decides according to the factors such as weight of patient age, body weight, the course of disease, disease.For example, as a reference, under the situation of oral dosage form, the consumption of compound of the present invention can be 0.1-10mg/kg/d, and under the situation of injection type, compound amount of the present invention can be 0.1-5mg/kg/d.
In following examples, 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 decompression is 2.5 hours under 180 ℃ of airbaths, can successfully be converted into polysuccinimide, and yield is 93.4%; The DL-aspartic acid refluxed in naphthane 100 hours, was converted into polysuccinimide, and yield is 44%; The DL-aspartic acid is converted into polysuccinimide 200 ℃ of frit reactions 3 hours, and yield is 16.7%.The polysuccinimide open loop that makes by three kinds of approach in the presence of L-Lys is converted into the poly-asparagus fern acyl-L-Methionin of general formula (1), and productive rate is respectively 57%, 94% and 65%.In the presence of Gly, by the polysuccinimide open loop that three kinds of approach make, be converted into poly-asparagus fern acyl glycine, productive rate is respectively 47%, 98% and 78%.In the presence of the L-L-Ala, by the polysuccinimide open loop that three kinds of approach make, be converted into poly-asparagus fern acyl-L-L-Ala, productive rate is respectively 50%, 90% and 70%.The present invention adopts chromatography and LC-MS instrument to measure the molecular weight distribution of general formula (1), and the molecular weight that characterizes it from different perspectives constitutes.Wherein gel filtration chromatography records poly-asparagus fern acyl-L-Methionin that the polysuccinimide for preparing by three kinds of conditions and the reaction of L-Methionin make, molecular weight is respectively 27095,105462 and 26900, makes poly-asparagus fern acyl glycine molecule amount with glycine reactant and is respectively 19178,74648 and 19040.As those skilled in the art are known, by control reaction conditions (for example changing temperature of reaction and reaction times), can be with the molecular weight control of compound of the present invention in a certain scope.
The present invention with the model evaluation of mouse maximal electroshock the anticonvulsant action of poly-asparagus fern acyl glycine and poly-asparagus fern acyl-L-Methionin.Under 100mg/kg dosage, poly-asparagus fern acyl glycine can obviously suppress the electrofit of mouse, compares P＜0.01 with the blank group.Under same dose, poly-asparagus fern acyl-L-Methionin can obviously suppress the electrofit of mouse, compares P＜0.01 with the blank group.Under 25mg/kg dosage, have only poly-asparagus fern acyl-L-Methionin can obviously suppress the mouse electrofit, compare P＜0.01 with the blank group.The present invention has observed poly-sky acyl glycine and the poly-asparagus fern acyl-time-effect relationship of L-Methionin under 25mg/kg dosage.1 hour poly-asparagus fern acyl-L-Methionin of administration is relatively P＜0.01 of obvious restraining effect and blank group to the mouse electrofit, and this restraining effect does not see at 2 hours and 4 hours and go down that inhibiting rate was reduced to 30% (the blank group is 7.4%) in 8 hours.Poly-1 hour inhibiting rate of asparagus fern acyl glycine administration is 40% (the blank group is 7.4%), reaches peak value, and compares P＜0.01 with the blank group in 2 hours and 4 hours.Inhibiting rate reduced to for 40% (comparing P=0.069 with the blank group) in 8 hours.
The present invention with the model evaluation of mouse pentylenetetrazole convulsion the anticonvulsant action of poly-asparagus fern acyl glycine and poly-asparagus fern acyl-L-Methionin.Under 100mg/kg dosage, their anticonvulsion rate is 20%, the there was no significant difference of comparing with the blank group.
The present invention has estimated the external thrombolytic effect of poly-asparagus fern acyl glycine and poly-asparagus fern acyl-L-L-Ala with external Thrombolysis Model.Thrombolysis activity that poly-asparagus fern acyl-L-L-Ala, poly-asparagus fern acyl glycine demonstrate in 0.125mg/ml and 0.25mg/ml concentration in this model and blank water are than significant difference is all arranged, wherein poly-asparagus fern acyl glycine makes thrombus loss of weight 11.34 ± 1.46mg in 0.25mg/ml concentration, make thrombus loss of weight 7.20 ± 1.19mg in 0.125mg/ml concentration, make thrombus loss of weight 3.34 ± 1.01mg in 0.06mg/ml concentration, the result of treatment of three kinds of dosage has significant difference.
Description of drawings
Fig. 1 is the synthetic route chart of poly-asparagus fern acyl glycine, poly-asparagus fern acyl-L-L-Ala or poly-asparagus fern acyl-L-Methionin.
Fig. 2 is an electrofit instrument synoptic diagram, by voltage stabilized source output 220v alternating-current, transfers to required voltage through transformer, and by numerical control on-off control conduction time, output electrode is connected with mouse by a pair of crocodile clip, measures preceding correction output voltage at every turn.
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, 2ml phosphoric acid (85%) and 2ml distilled water is thorough mixing in the 250ml round-bottomed flask.Reaction mixture adds 20mlDMF in decompression reaction under 180 ℃ of airbaths after 2.5 hours while hot inward, treats that solution drips in the 100ml distilled water after clear and bright.Collecting precipitation is washed till neutrality with distilled water, and drying obtains 3.4g (93.4%) title compound.Ultimate analysis (C
4H
3NO
2)
N2: C, 46.76; H, 3.35:N, 13.64.
Embodiment 2 azeotropic water removing legal systems are equipped with polysuccinimide
The suspension returning of the DL-aspartic acid of 50g porphyrize and 500ml naphthane (chemistry alcohol) 100 hours is removed the water of generation by water trap.Reaction mixture is chilled to the room temperature after-filtration, and filter residue is washed with ether earlier, uses saturated NaHCO again
3The aqueous solution washes (3 * 100ml).Filter cake more successively water and dilute hydrochloric acid (1%) wash repeatedly, be washed till repeatedly with distilled water at last and use AgNO
3Detection is less than Cl
-Filtration cakes torrefaction obtains 16g (44%) title compound.Ultimate analysis (C
4H
3NO
2)
N3: C, 45.24; H, 3.85; N, 13.30.
Embodiment 3 scorifications prepare polysuccinimide
The DL-aspartic acid of 30g porphyrize evenly is layered on the vessel bottom that diameter is 30cm, and 200 ℃ were heated 3 hours, and it is orange red that reaction product is.The reactant cooling saturated NaHCO in back
3(3 * 100ml), the solid that obtains is used the distillation washing repeatedly, and is centrifugal, and precipitation is dried, and gets 5g (17%) title compound in aqueous solution grinding.Ultimate analysis: (C
4H
3NO
2)
N1: C, 46.63; H, 3.33; N, 13.63.
The preparation of embodiment 4 poly-asparagus fern acyl glycine
Press the succimide molecular weight and calculate, with etc. the suspension stirring at room of mole glycine and polysuccinimide and an amount of distilled water, make that a small amount of polysuccinimide suspension reaction mixture PH is arranged in the reaction solution is 7.5.Filter, filtrate decompression is concentrated into dried, obtains title compound.Productive rate is 98% during the reaction of the polysuccinimide of glycine and embodiment 1., and during with the polysuccinimide reaction of implementing 2., yield is 47%, and yield is 78% during with the succimide reaction of embodiment 3..Amino acid composition analysis: Asp: Gly=1.0: 0.9
The preparation of embodiment 5 poly-asparagus fern acyl-L-Methionins
According to the operation of embodiment 4., replace glycine with L-Methionin, obtain title compound.Productive rate is 94% during the reaction of the polysuccinimide of L-Methionin and embodiment 1., and yield is 57% during with the polysuccinimide reaction of embodiment 2., and during with the polysuccinimide reaction of embodiment 3., yield is 65%.Amino acid composition analysis: Asp: Lys=1.00: 0.95
The preparation of embodiment 6 poly-asparagus fern acyl-L-L-Ala
According to the operation of embodiment 4., replace glycine with the L-L-Ala, obtain title compound.Productive rate was 65% when the polysuccinimide of L-L-Ala and embodiment 1 reacted.
The preparation of embodiment 7. poly-asparagus fern acyl glycine salts
Poly-asparagus fern acyl glycine 0.1mmol with wait for example sodium hydroxide of alkali that mole can be medicinal, potassium hydroxide, basic aminoacids is arginine for example, the Methionin reaction makes corresponding poly-asparagus fern acyl glycine salt, yield is more than 95%.
The preparation of embodiment 8 poly-asparagus fern acyl-L-Methionin salts
Poly-asparagus fern acyl-L-Methionin 0.1mmol with wait for example sodium hydroxide of alkali that mole can be medicinal, potassium hydroxide, basic aminoacids is arginine for example, the Methionin reaction makes corresponding poly-asparagus fern acyl-L-Methionin salt, yield is more than 95%.
The preparation of embodiment 9. poly-asparagus fern acyl-L-L-Ala salts
Poly-asparagus fern acyl-L-L-Ala 0.1mmol is listed as sodium hydroxide with waiting alkali that mole can be medicinal, and potassium hydroxide, basic aminoacids is arginine for example, and the Methionin reaction makes corresponding poly-asparagus fern acyl-L-L-Ala salt, and yield is more than 95%.
Embodiment 10. preparation of compositions
The compounds of this invention 200mg, Magnesium Stearate 10mg, lactose 200mg, starch 140mg tablet producing technology routinely makes tablet.
The molecular weight characterization of embodiment 11. poly-asparagus fern acyl glycine
Instrument: the U.S. HP1100 of Hewlett-Packard company high performance liquid chromatograph, be furnished with diode-array detector and automatic sampler.
Chromatographic column: Alltech Macrosphere GPC 100A 7u 250mm * 4.6mm, SeralNo.0010393.2; Agilent Iorbax Bioseries GF-250,250mm * 4.6mm, PartNo.884973701; Diol guard Column, No.820777.901.
Moving phase: potassium dihydrogen phosphate (0.2mol/L, PH7.0)
Calibration standard: thyroglobulin (MW670000), IgG (MW150000), bovine serum albumin (MW67000), oralbumin (MW43000), N,O-Diacetylmuramidase (MW14300).
Flow velocity: 0.4ml/min
Column temperature: 40 ℃
Detect wavelength: 216nm, 230nm, 275nm.
Measuring method: with the proteinic elution volume of above-mentioned calibration standard molecular weight is made typical curve respectively.Measure the elution volume of poly-asparagus fern acyl glycine, use typical curve to calculate molecular weight by computer program.
The result: the product that the polysuccinimide reaction that is made by glycine and embodiment 1. obtains is 19178, and the product that obtains with the polysuccinimide reaction of embodiment 2. is 74648, and the product that obtains with the polysuccinimide reaction of embodiment 3. is 19040.
The molecule of embodiment 12 poly-asparagus fern acyl-L-Methionins is sign
Instrument and method according to embodiment 6., the product that records the polysuccinimide that is made by L-Methionin and embodiment 1. is 27095, the molecular weight of the polysuccinimide product that makes with embodiment 2. is 105462, and the molecular weight of the product of the polysuccinimide that makes with embodiment 3. is 26900.
The stability of embodiment 13 poly-asparagus fern acyl glycine
1. the solution that is made into of the poly-asparagus fern acyl glycine of 500ug and 1ml deionized water, room temperature is placed, every 20 hours sample introduction 20ul, with the main peak area of HPLC method mensuration title compound.The result showed in 120 hours, the peak area no change.
2. the poly-asparagus fern acyl glycine of 500ug is placed with the solution room temperature that 1ml physiological saline is mixed with, every 20 hours sample introduction 20ul, with the main peak area of HPLC method mensuration title compound.The result shows, peak area no change in 120 hours.
3. the poly-asparagus fern acyl glycine of 5mg is placed with the solution room temperature that 1ml hydrochloric acid (2mol/L) is made into, every 20 hours sample introduction 20ul, with the main peak area of HPLC method mensuration title compound.The result shows, peak area no change in 120 hours.
4. the poly-asparagus fern acyl glycine of 5mg is placed with the solution room temperature that 1mlNaOH (2mol/L) solution is made into, every 20 hours sample introduction 20ul, with the peak area of HPLC method mensuration title compound.The result shows, peak area no change in 120 hours.
The stability of embodiment 14. poly-asparagus fern acyl-L-Methionins
Operation uses poly-asparagus fern acyl-L-Methionin to replace poly-asparagus fern acyl glycine with content with embodiment 8..The result shows that title compound is stable in water, physiological saline, 2mol/L hydrochloric acid and 2mol/LnaOH solution in 120 hours.
The anti-electrofit effect of embodiment 15. poly-asparagus fern acyl glycine and poly-asparagus fern acyl-L-Methionin
Instrument: She Ji electrofit instrument voluntarily, structural representation such as Fig. 2 transfer to required voltage by voltage stabilized source output 220v alternating-current through transformer, by numerical control on-off control conduction time, output electrode is connected with mouse by a pair of crocodile clip, proofreaies and correct output voltage before each the mensuration.
Animal: Kunming mouse (17-22g, male and female half and half, available from Department Of Medicine, Peking University laboratory animal portion, credit number, the moving word 01-3056 of doctor).
Method: Kunming mouse (male and female half and half) is divided into blank group (physiological saline at random, 3ml/kg), positive controls (25mg/kg in 3ml/kg physiological saline), poly-N base acid group (10mg/kg, 25mg/kg and 100mg/kg in 3ml/kg physiological saline), through gastric infusion.Soak into the mouse ears with physiological saline after 1 hour, crocodile clip is connected the positive and negative electrode of electrofit instrument output terminal respectively on the folder with the mouse ears.Connect power supply, make the 80v/50Hz alternating-current pass through for 0.3 second from the mouse health.The forelimb flexing appears in mouse, and the tetanic convulsions of stretching property of hind leg is considered as fainting from fear.
Data analysis: use exact propability, by formula calculate the P value:
Wherein a is the number of animals that the blank group is fainted from fear, and b is the blank group number of animals of not fainting from fear, and c is the number of animals that the medication group is fainted from fear, and d is the number of animals that the medication group is not fainted from fear, and N is a sample number.P＜0.05 has been considered as significant difference.The results are shown in Table 1.
The poly-N base acid of table 1. is to the influence of mouse maximal electroshock
| Compound | The anticonvulsion rate of various dose (%) | ||
| 10mg/kg | 25mg/kg | 100mg/kg | |
| The poly-asparagus fern acyl of the poly-asparagus fern acyl glycine of physiological saline phenytoin Sodium-L-Methionin | 10.0 30.0 | 7.4 100 * 40.0 70.0 * | 60.0 * 60.0 * |
N=10,
*With physiological saline group ratio, P＜0.01
Embodiment 16. poly-asparagus fern acyl glycine and poly-asparagus fern acyl-L-Methionin are to the time-effect relationship of the maximum shock of mouse
Instrument, animal and method are with embodiment 15, but only select 25mg/kg dosage, animal is divided into the physiological saline group, poly-asparagus fern acyl glycine 1 hour, 2 hours, 4 hours and 8 hours groups, and poly-asparagus fern acyl-L-Methionin 1 hour, 2 hours, 4 hours and 8 hours groups.The results are shown in Table.
The poly-N base acid of table 2 to the mouse maximal electroshock the time-the effect effect
| Compound | The anticonvulsion rate of different time (%) | |||
| 1 hour | 2 hours | 3 hours | 4 hours | |
| The poly-asparagus fern acyl of the poly-asparagus fern acyl glycine of physiological saline-L-Methionin | 40.0 70.0 * | 7.4 70.0 * 70.0 * | 60.0 * 60.0 * | 40.0 30.0 |
N=10, dosage=25mg/kg,
*With physiological saline group ratio, P＜0.01
Embodiment 17. poly-asparagus fern acyl glycine and the anti-penta 4 property convulsions effects of poly-asparagus fern acyl-L-Methionin
Animal: Kunming mouse (17-22g, male and female half and half, available from Department Of Medicine, Peking University laboratory animal portion, credit number, moving doctor's word 01-3056).
Method: Kunming mouse (male and female half and half) is divided into blank group (physiological saline at random, 3ml/kg), positive controls is (stable, 1.25mg/kg), negative control group (phenytoin Sodium, 25mg/kg), poly-asparagus fern acyl glycine group (100mg/kg) and poly-asparagus fern acyl-L-Methionin group (100mg/kg).After 1 hour, through the subcutaneous Yetrazol (85mg/kg) that gives, paroxysmal is twitched and is considered as fainting from fear by described dosage gastric infusion.Record convulsions time of origin and anticonvulsion rate.The results are shown in Table 3.
The poly-asparagus fern acyl glycine of table 3. and poly-asparagus fern acyl-L-Methionin are to the influence of pentylenetetrazole convulsion
| Compound (dosage, mg/kg) | Convulsions time of origin (min) | Anticonvulsion rate (%) |
| The poly-asparagus fern acyl-1B (100mg/kg) of the poly-asparagus fern acyl glycine (100mg/lg) of stable (1.25mg/kg) dilantin sodium (25mg/kg) of physiological saline (3ml/kg) | 5.0±110 - 5.5±3.4 6.0±1.7 6.8±2.7 | 0 100 20 20 20 |
n＝10
The poly-N base acid that 18. 3 kinds of methods of embodiment make is to the influence of mouse maximum by shock
Instrument, method is with embodiment 10., but select 25mg/kg dosage, animal is divided into the physiological saline group, the poly-asparagus fern acyl glycine group that makes with the polysuccinimide and the glycine of embodiment 1. preparation, the poly-asparagus fern acyl glycine group that makes with the polysuccinimide and the glycine of embodiment 2. preparation, the poly-asparagus fern acyl glycine group that makes with the polysuccinimide and the glycine of embodiment 3. preparation, the poly-asparagus fern acyl-L-Methionin group that makes with the polysuccinimide and the L-Methionin of embodiment 1. preparation, the poly-asparagus fern acyl-L-Methionin group that makes with the polysuccinimide of embodiment 2. preparation and L-Methionin, and poly-asparagus fern acyl-L-Methionin group of making of the polysuccinimide for preparing with embodiment 3. and L-Methionin.Irritate stomach and measure anticonvulsant action after 2 hours.
The result: all use the poly-asparagus fern acyl glycine of different path of preparing and the mouse anti convulsions rate of poly-asparagus fern acyl-L-Methionin treatment to be 70%, do not show difference.
The acute toxicity test of embodiment 19. poly-N base acid
Animal: Kunming mouse (17-22g, male, available from Department Of Medicine, Peking University laboratory animal portion, credit number, medical science word 01-3056).
Method: 20 Kunming mouses are once irritated stomach and are gathered asparagus fern acyl glycine or poly-asparagus fern acyl-L-Methionin, and dosage is 5.0g/kg, 0.5ml (aqueous solution)/only, observed continuously 8 days.The administration animal does not see dystropy, does not see death.Put to death also no abnormality seen of back important organ.
The external thrombolytic effect of embodiment 20. poly-asparagus fern acyl glycine and poly-asparagus fern acyl-L-L-Ala
Use the outer Thrombolysis Model of self-built solid poly-asparagus fern acyl glycine and poly-asparagus fern acyl-L-L-Ala are carried out external thrombolysis evaluation.
The thrombus preparation: male SD rat, 350～400g gets the back raising and more than 1 day, freely drinks water and diet in quiet thermostatic chamber.During experiment, vetanarcol (50mg/kg, i.p.) anesthesia, it is fixing to lie on the back, and separates right common carotid artery, the bulldog clamp folder closes proximal part, the long polyethylene tube of 30mm is inserted in bulldog clamp top, emits about 3～4ml blood earlier, immediately the blood of emitting is injected one by one with the 5ml syringe of silanization to prepare the Glass tubing that thrombus is used, a stainless steel spiral is put into, try not to put partially at once.Leave standstill 40min and make thrombosis, behind the 40min, Glass tubing is carefully taken off from base, with fine needle with around the thrombus and the Glass tubing inwall separate, removal of thromboses hangs on the rubber plug of reaction flask, add 8ml distilled water in the reaction flask, thrombus is suspended on leaves standstill 1 hour in the water, remove the floating blood in thrombus surface.
Drug evaluation: after 1 hour, inhale the moisture on the bolt surface of dehematizing, accurately weigh one by one with filter paper.Refill the solution of testing compound in each reaction flask, thrombus is hung in the solution of testing compound again, 37 ℃ of constant temperature shaking tables were hatched 3 hours.After hatching end, draw surface water with filter paper and accurately weigh one by one again, calculate thrombus at the weight difference that adds solution to be measured front and back, as the index of weighing the testing sample thrombolytic effect.Weight difference before and after statistics sample sets and the control group thrombolysis also carries out the t check.The results are shown in Table 4.
The external thrombolysis result of the poly-asparagus fern acyl glycine of table 4. and poly-asparagus fern acyl-L-L-Ala:
| Compound | Concentration (mg/ml) | Loss of weight (mg) |
| Water gathers the poly-asparagus fern acyl glycine of asparagus fern acyl-L-L-Ala | - 0.125 0.25 0.06 0.125 0.25 | 0.35±1.68 7.21±2.87 a 9.38±2.33 b 3.20±1.10 7.20±1.19 b 11.34±1.46 b，c |
N=6, a: with water than P＜0.01, b: with water than P＜0.001, c:
With poly-asparagus fern acyl glycine (0.125mg/ml) than P＜0.001.
Thrombolysis activity that poly-asparagus fern acyl-L-L-Ala, poly-asparagus fern acyl glycine demonstrate in 0.125mg/ml and 0.25mg/ml concentration and blank water are than significant difference is all arranged, wherein poly-asparagus fern acyl glycine makes thrombus loss of weight 11.34 ± 1.46mg in 0.25mg/ml concentration, with make thrombus loss of weight 7.20 ± 1.19mg in 0.125mg/ml concentration, with make thrombus loss of weight 3.20 ± 1.10mg in 0.06mg/ml concentration, the result of treatment of three kinds of dosage has significant difference.
Claims (4)
1, the compound of general formula 1 or its pharmacologically acceptable salts:
Wherein AA is glycine, L-Methionin or L-L-Ala, n=10-2000.
2, the purposes of general formula 1 compound or pharmaceutically acceptable salt thereof of claim 1 in the preparation anticonvulsant drug, wherein AA is glycine or L-Methionin.
3, the purposes of the compound or pharmaceutically acceptable salt thereof of the general formula 1 of claim 1 in the preparation thrombolytics, wherein AA is glycine or L-L-Ala.
4, a kind of anticonvulsive pharmaceutical composition or thrombolytics, it contains the compound of claim 1 formula of 1 of pharmacy effective dose.
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| CN102477084B (en) * | 2010-11-30 | 2014-08-13 | 首都医科大学 | Polyaspartoyl-L-lysine with chain length of 59, and preparation method and application thereof |
| CN107686554B (en) * | 2016-08-05 | 2021-01-01 | 首都医科大学 | polyaspartic-K-estradiol, its preparation, anti-osteoporosis activity and use |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4699927A (en) * | 1981-11-04 | 1987-10-13 | Pharlyse | Anticonvulsant valproic acid salts |
| CN1369514A (en) * | 2001-11-12 | 2002-09-18 | 南京南大表面和界面化学工程技术研究中心有限责任公司 | Polyasparagine derivative containing high-activity hydroxy radical |
| CN1385417A (en) * | 2002-06-07 | 2002-12-18 | 华北制药集团有限责任公司 | Polyasparacyl-L-arginine, its preparation and medical application |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4699927A (en) * | 1981-11-04 | 1987-10-13 | Pharlyse | Anticonvulsant valproic acid salts |
| CN1369514A (en) * | 2001-11-12 | 2002-09-18 | 南京南大表面和界面化学工程技术研究中心有限责任公司 | Polyasparagine derivative containing high-activity hydroxy radical |
| CN1385417A (en) * | 2002-06-07 | 2002-12-18 | 华北制药集团有限责任公司 | Polyasparacyl-L-arginine, its preparation and medical application |
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