CN109734768A - Go acetyl cedilanid glucosyl group modified compound composite lipidosome and its application - Google Patents
Go acetyl cedilanid glucosyl group modified compound composite lipidosome and its application Download PDFInfo
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Abstract
The invention discloses one kind to remove acetyl cedilanid glucosyl group modified compound composite lipidosome and its application.Mainly it is transformed from cedilanid glucosyl group, it is connected again with end 3- hydroxyl of digoxin using glucose and 2- Glucosamine as the part modification that raw material carries out molecule and generates the glucosyl group modified product for removing acetyl cedilanid, selects the molecule to meet the requirements under activity guiding.By synthesizing deacetylation cedilanid glucosyl group modified compound (2-O- benzyl-β-D- glucopyranoside-remove acetyl cedilanid etc.); to reinforce the antitumaous effect of such compound; improve potency; extend half-life period; modified compound is prepared into liposome simultaneously; the effect of its Liver targeting is improved, cardiac toxic is reduced.
Description
Technical field
The present invention relates to modified compound, specifically a kind for the treatment of heart failure conventional medicament goes acetyl cedilanid chemical modification to obtain
To noval chemical compound, and the application after Lipidosome is transformed in anticancer, i.e., it will remove acetyl cedilanid chemical modification Cheng Quyi
Acyl cedilanid glucosyl group modified compound (2-O- benzyl-β-D- glucopyranoside-remove acetyl cedilanid) is simultaneously prepared into liver
Application of the target liposomes in medicines resistant to liver cancer.
Background technique
In whole world common cancer, onset of liver cancer rate ranking the 7th, Chinese morbidity example is more than the 50% of whole world sum,
Although taking including tumor resection, liver transplant, the treatment methods such as Sorafenib and local treatment (radio-frequency ablation procedure), liver cancer
The death rate have not yet to see decline, therefore, research and development high-efficiency low-toxicity medicines resistant to liver cancer it is significant.
Cardiac glycoside is a kind of drug with selective cardiac effect, molecule by an alcohol radical or alcohol sample group (aglucon,
Aglycon or glucoside member) it is incorporated into glycan molecule in varying numbers and constitutes.If core containing sterol (steroid nucleus) in aglucon, 17 carbon atoms connect
With a unsaturated lactone ring, 3 carbon atoms are connected with glycan molecule, and this glycosides is cardiac glycoside.Its is many kinds of, including plants
Object source and vertebrate origin.Cardiac glycoside can be specifically bound with eukaryotic cell membrane na-k-atp enzyme, for treating the congested heart
The diseases such as force failure and arrhythmia cordis have more than 200 years history.In recent years, cardiac glycoside compounds are in prevention and treatment tumour side
Face is increasingly taken seriously.More optimistic, many researchs confirm that it has to malignant cell preference at present
Lethal effect does not influence the proliferation of normal cell.In view of this, cardiac glycoside is made to become a kind of novel medicine of targeting therapy on tumor
Object becomes possible.
Experiment in vitro finds that cardiac glycoside is invalid to rodent tumors cell.Equally, it is difficult to prove same base all the time
How to play a role to these cardiac glycoside compounds in these animal bodies of cause.However, more and more researchs confirm
Cardiac glycoside is to human tumor cell line extremely sensitive.Such as ouabain and Bu Falin.It is thin that Han Ke-Qi etc. establishes human liver cancer
Born of the same parents' strain (BEL-7402) orthotopic transplantation nude mice model, and give Bu Falin abdominal cavity treating.They have found this toad derivative
Cardiac glycoside significantly reduces gross tumor volume, and extends animal lifespan, and preliminary pathological study does not find the heart, lung, brain and kidney yet
Damage.Being one about semi-synthetic alkene lactone UNBS-1450 treatment orthotopic transplantation non-small cell lung cancer (A549) animal has
The report of interest.UNBS-1450 is the cardiac glycosides using African plant mudar extract as raw material by semi-artificial synthesis
Close object.Mijatovic T etc. carries out Long-term Oral UNBS-1450 to transplantability non-small cell lung carcinoma animal model, significant in efficacy.
In addition, experiment in vitro, which demonstrates digoxin, inhibits human nerve's fiber tumor cell growth.And in vivo in zoopery, also at
Function reduces the lump for being transplanted to mouse.
Research finds that cardiac glycoside can be used for the prevention or treatment of malignant disease by complicated Signal Transduction Mechanism.
Mijatovic T etc. has carried out the modification in chemical structure to cardiac glycoside, successfully eliminates effect of the cardiac glycoside to cardiac muscle, discovery
It is in time dependence apoptosis that these compounds of no cardiac activity, which cause T lymphoblast,.Enhance Anti-tumor angiogenesis.But
Peripheral blood mononuclear cells (peripheral blood mononuclear cells, PBMC) is influenced little.Make cardiac glycoside
The specificity antineoplastic drug for being expected to be transformed into acardia toxicity becomes a reality.Cardiac glycoside and as traditional cardiac drug
Chemotherapeutics known such as taxol, carboplatin, adriamycin, vincristine and cyclophosphamide etc. has different anticancer mechanisms, such as
Fruit can be shared with these chemotherapeutics there may be cooperate with, mitigate adverse reaction even resist cells resistance effect.Even if mesh
It is preceding to be still in external or animal experiment stage, but it will be from now on, the optimism unquestionable for the treatment prospect of tumour.Recent research
It is acted on it was found that cedilanid and tumor necrosis factor have shared anti-Gliblastoma, there is antihepatocarcinoma effect and suppression cancer in vitro
PTEN Gene state and caused by protein kinase C δ apoptosis-related, is found in our early stage research work, cardiac glycosides
Drug go acetyl cedilanid (English name: Deslanoside, also known as: Deslanoside, deaetyldigilanid C) have in vitro
Compared with the antihepatocarcinoma effect of strong selectivity, to SMMC-7721 human liver cancer cell (half-inhibitory concentration) IC50For 0.18 μ g/ml, to people
The IC of normal liver cell system LO250For 75.70 μ g/ml, 420 times are differed.But acetyl cedilanid (cedilanid) is gone in vivo may be used
Glucose and acetic acid are lost through hydrolysis, into the digoxin almost without antihepatocarcinoma effect, makes the internal anticancer of acetyl cedilanid
Active potency reduces and the maintenance effect time (timeliness) shortens.Further, since the Amplatzer duct occluder that cardiac glycoside compounds are generally existing
Property causes its anti-cancer applications risk larger.
Summary of the invention
The purpose of the present invention is being directed to go acetyl cedilanid that can lose glucose and acetic acid through hydrolysis in vivo, become almost
The deficiency of digoxin without antihepatocarcinoma effect, and provide a kind of deacetylation cedilanid glucosyl group modified compound composite lipidosome and
It is applied.By synthesizing deacetylation cedilanid glucosyl group modified compound (2-O- benzyl-β-D- glucopyranoside-go
Acetyl cedilanid etc.), to reinforce the antitumaous effect of such compound, potency is improved, extends half-life period, while by modificationization
It closes object and is prepared into liposome, improve the effect of its Liver targeting, reduce cardiac toxic.
An object of the present invention is: open one kind removes acetyl cedilanid glucosyl group modified compound (2-O- benzyl-β-
D- glucopyranoside-removes acetyl cedilanid etc.) synthetic method.
The second object of the present invention is to: the open preparation for removing acetyl cedilanid glucosyl group modified compound Liposomal formulation
Method.
The third object of the present invention is: open to go acetyl cedilanid glucosyl group modified compound Liposomal formulation in anti-liver
Application in cancer drug.
The structural formula of the present invention for removing acetyl cedilanid are as follows:
Due to going the glucosyl group of acetyl cedilanid to be easy to be fallen by enzyme hydrolysis, digoxin is hydrolyzed into lose related work
Property, and digoxin severe toxicity, so maintaining the stabilization of glucosyl group becomes critically important.Due to going the activity of acetyl cedilanid and dividing
Minor structure is closely related, it is contemplated that the modification transformation of part-structure is carried out in the case where keeping molecular bulk structure constant, thus
Reach and glucosyl group is maintained to be stabilized for the purpose of keeping or improve molecular activity.We mainly change from glucosyl group
It makes, is connected again with end 3- hydroxyl of digoxin using the part modification that glucose and 2- Glucosamine carry out molecule as raw material
The glucosyl group modified product for removing acetyl cedilanid is delivered a child into, selects the molecule to meet the requirements under activity guiding.
The present invention goes the synthesis of acetyl cedilanid glucosyl group modified compound, with 2-O- benzyl-β-D- glucopyranose
Glycosides-goes for the synthesis of acetyl cedilanid to be specifically described:
(1) 2-O- benzyl-β-D- glucopyranoside-removes the structural formula of acetyl cedilanid are as follows:
(2) synthetic route is as follows:
(3) specific synthesis step is as follows:
1. the synthesis of compound 1: under ice bath, 140 milliliters of methanol being added in a dry reaction bottle equipped with drying tube, second
2.4 milliliters of acyl chlorides, stirring is stirred to be warming up to and is stirred at room temperature 20 minutes naturally after five minutes, and 10 grams of glucose (54.6mmol) is added,
It is heated to back flow reaction 2 hours.Cooling reaction solution is added Anhydrous potassium carbonate and is neutralized to neutrality, filter, being concentrated to get to room temperature
Close the crude product of object 1 (1-O- methylglycoside)；
2. the synthesis of compound 2: resulting 1 crude product of compound being dissolved in 34 milliliters of DMF, benzene dimethoxym ethane 16 is added dropwise
Milliliter (105.2mmol) is rapidly added 1.72 grams of p-methyl benzenesulfonic acid (9mmol), and overnight, TLC shows fully reacting for 50 DEG C of reactions,
Reactant is poured into the mixed liquor of 100 milliliters of ice water and 140 milliliters of petroleum ethers, acutely shaken, Off-white solid is precipitated, and takes out
Filter, dehydrated alcohol are recrystallized to give compound 2；
3. the synthesis of compound 3: compound 2, the Bu that will be obtained214 grams of SnO (44.8mmol) and 180 milliliters of toluene add
Enter in the round-bottomed flask equipped with water segregator, concentration of reaction solution adds back flow reaction to 60 milliliters until no moisture goes out within 3-4 hours
Enter 30 milliliters of anhydrous DMF, be added dropwise 7 milliliters of (58.4mmol) cylites, 100-110 DEG C reaction 5-6 hours, TLC, which is detected, to have reacted
Finish, reactant is diluted with 100 milliliters of ethyl acetate, successively uses suitable quantity of water, and saturated brine, each washing 2-3 times, organic layer is with anhydrous
Sodium sulphate dries, filters, and is concentrated under reduced pressure, and is purified by silica gel column chromatography (petroleum ether and ethyl acetate mixing elution), obtains chemical combination
Object 3；
4. the synthesis of compound 5: by gained compound 3,0.3 gram of the concentrated sulfuric acid, 90 milliliters of acetic acid, 30 milliliters of room temperatures of acetic anhydride
It is stirred to react -1 hour 30 minutes, TLC monitors end of reaction, obtains compound 4；11 milliliters of acetyl bromide are added, 7 milli of methanol
It rises, is protected from light 2 hours；Reaction mixture is diluted with 200 milliliters of methylene chloride, successively uses suitable quantity of water, and saturated sodium bicarbonate is molten
Liquid, saturated brine respectively wash 2-3 times, and organic layer anhydrous sodium sulfate dries, filters, and are concentrated under reduced pressure, obtain 5 crude product of compound；
5. the synthesis of compound 7: by 0.97 gram of (5mmol) digoxin compound, 6,0.17 gram of (5mmol) diphenyl chlorination
Tin is dissolved in 100 milliliters of acetonitriles, and room temperature, which is protected from light, to be stirred to react 10 minutes；1.74 grams of (7.5mmol) silver oxides of addition, 0.7 gram
5 dimethyl -2 5'- (3.75mmol), 2 '-bipyridyls, 4. compound 5 that 3 grams of (7.5mmol) steps of weighing obtain are added together
Reaction system, 35 DEG C high degree of agitation 24 hours, reaction mixture is cooled to room temperature, and is quenched with 1 milliliter of saturated aqueous ammonium chloride
Reaction system, chloroform: acetone=1:1 dilution filters out undissolved salt residue, and solution is concentrated under reduced pressure, and residue passes through
Column chromatographs to obtain the acetyl object of compound 7, and acetyl object is dissolved in 140ml methanol, and 40g sodium methoxide room temperature is added and handles to obtain
Compound 7.
The present invention goes the preparation of acetyl cedilanid glucosyl group modified compound composite lipidosome injection, including
(1) acetyl cedilanid glucosyl group modified compound liposome is gone to prepare
Capsule is prepared using back titration method, weighs the modified compound 7 of 100mg and the sodium alginate of 18mg/mL concentration
Solution 20mL mixing homogeneous, is extracted with container, is instilled 40mL dropwise and is contained in the beaker of CaCl2 solution of 37mg/mL, and 20 minutes
After filter, wash, complement antibody micro-capsule is obtained after freeze-drying, maximum capsule encapsulating rate reaches 70%.Pilot scale and industrial production
When scale up.
(2) preparation of modified compound liposome injection
Add 10% ethyl alcohol to dissolve modification of pharmaceutical liposome, is made into 0.1mg/1ml concentration, filtration sterilization, by every
1ml is either manually or mechanically filling, capping, shading, closed preservation.
The present invention has the advantages that
1, in vitro experiment, deacetylation cedilanid glucosyl group modified compound and cedilanid are to liver cancer cells toxicity
Quite, but 100 times higher than the potency of common drug 5-FU or more, and it is lower to normal cell toxicity；
2, in vivo in zoopery, deacetylation cedilanid glucosyl group modified compound is compared with cedilanid, to liver
The inhibiting rate of cancer is remarkably reinforced；Because deacetylation cedilanid glucosyl group modified compound is not easy in liver by enzyme hydrolysis at not having
There is the digoxin of antitumaous effect, to be obviously prolonged anticancer timeliness.
3, in cardiac toxic evaluation interior animal experiment, deacetylation cedilanid glucosyl group modified compound is prepared into
After liposome, compared with deacetylation cedilanid glucosyl group modified compound, the targeting to liver is improved, reduces heart tonifying
The cardiac toxic of glycosides compound reduces the generation of arrhythmia cordis, significantly improves the therapeutic index of drug.Pass through experiment, it was demonstrated that
Go acetyl cedilanid glucosyl group modified compound by be a kind of comparatively ideal high-efficiency low-toxicity medicines resistant to liver cancer.
Detailed description of the invention
Fig. 1 is that embodiment 2-O- benzyl-β-D- glucopyranoside-deacetylation cedilanid liposome cardiac toxic is real
It tests,
Changes in heart rate and arrhythmia cordis a situation arises electrocardiogram in unit time after mouse administration；
In figure, A:A group electrocardiogram；B:B group electrocardiogram；C:C group electrocardiogram.
Specific embodiment
Below by Cell culture invitro and the development said medicine inside and outside anticancer experiment of internal animal model is established, test
Method includes the following steps:
1. carrying out the culture of cancer cell and normal cell；
2. carrying out deacetylation cedilanid glucosyl group modified compound and the external anticancer of cedilanid and to normal cell
Toxicity comparative experiments；
3. establishing Liver Cancer Bearing Nude Mice animal model, carry out deacetylation cedilanid glucosyl group modified compound composite lipidosome and west
The internal anticancer comparative experiments of ground orchid liposome；
4. acetylation cedilanid glucosyl group modified compound composite lipidosome and cedilanid cardiac toxic are evaluated.
1. external anticancer experiment
By human tumor cell line be incubated at DMEM culture medium (containing 10% inactivation fetal calf serum, 100U/ml penicillin and
100 μ g/ml streptomysins), Human normal hepatocyte system HL-7702 is incubated at RPMI1640 culture medium (the tire ox blood containing 20% inactivation
Clearly, 100U/ml penicillin and 100 μ g/ml streptomysins).Six kinds of cell strains are placed in the CO2 saturated humidity incubator of 37 DEG C, 5%
Middle culture, two to three days are changed liquid and are passed on once, and logarithmic growth phase cell is for testing.
Mtt assay detects anticancer drug to the effect of proliferative activity o f tumor.The cell of logarithmic growth phase, with 1 ×
104The density in the hole /k is inoculated in 96 orifice plates, every 180 μ l of hole.Test sets negative control group (PBS), positive controls (5-FU) (eventually
Concentration is 10-1Mmol/L), various concentration (2 × 10-2, 4 × 10-3, 8 × 10-4, 1.6 × 10-4, 3.2 × 10-5Mmol/L medicine)
Object group, every group sets 5 multiple holes, and 37 DEG C, overnight incubation in 5%CO2 saturated humidity incubator are separately added into 20 μ l of drug solution (eventually
Concentration is 2 × 10-2, 4 × 10-3, 8 × 10-4, 1.6 × 10-4, 3.2 × 10-5Mmol/L), 48h, every hole are cultivated after drug being added
MTT liquid (5mg/ml) 20 μ l is added, after cultivating 4h, inhales and abandons culture solution, every hole is added 150 μ l DMSO, gentle agitation 10min, molten
Solution crystallization sets survey OD value at microplate reader 490nm wavelength, inhibitory rate of cell growth is calculated according to the following formula:
Inhibitory rate of cell growth (%)=[1- (drug-treated group/negative control group)] × 100%.
Drug-treated group: culture medium containing cell, MTT, drug；
Negative control group: culture medium containing cell, MTT, PBS；
Blank group: culture medium, MTT without cell and drug；
Experiment is repeated 3 times.
2-O- benzyl-β-D- glucopyranoside-deacetylation cedilanid and the external anti-human liver cancer of deacetylation cedilanid
Cell (HepG2) and 1 is shown in Table to the exercising result of normal liver cell, table 2:
1. 2-O- benzyl-β-D- glucopyranoside of table-deacetylation cedilanid (A) and deacetylation cedilanid (B) body
Outer anti-human liver cancer cell (HepG2) exercising result (N=5)
Note: P < 0.05 *, compared with PBS control group；#P > 0.05, A group are compared with B group.
2. 2-O- benzyl-β-D- glucopyranoside of table-deacetylation cedilanid (A) and deacetylation cedilanid (B) body
Outside to Human normal hepatocyte (HL-7702) exercising result (N=5)
Note: * P > 0.05, A group, B group are compared with PBS control group；#P > 0.05, A group are compared with B group.
2. anti-tumor experiment in body
By human liver cancer cell (HCCLM3) routine culture 48 hours, 5 × 10 were made into PBS6It is spare.18~20g nude mice
(offer of the Guangdong BALB/c-nu Experimental Animal Center), aseptic condition is raised one week, using 5 × 106HCCLM3 cell nude mice back
0.1ml/ only inoculates modeling, starts grouping administration to tumor mass length to 0.5cm or so, animal is divided into 3 groups；Control group (PBS
Group), 2-O- benzyl-β-D- glucopyranoside-go acetyl cedilanid group (A) (1.0mg/kg) and cedilanid group (B)
(1.0mg/kg) intraperitoneal administration carries out intraperitoneal administration 1 time daily, is administered 9 times, puts to death animal in testing anesthesia in the 10th day, takes out
The weighing of lump electronics day chessboard.Statistical method: next day puts to death mouse after the last administration, and after weighing weight, stripping tumor weighing calculates tumor suppression
Rate (inhibition rate, IR), IR (%)=(the equal knurl weight of control group-administration group average knurl weight)/control group average knurl weight
× 100%.Statistical procedures are carried out to all data using 17.0 software of SPSS, are as a result indicated with mean ± standard deviation, two groups
Between mean compare and examined with t, mean compares using one-way analysis of variance between multiple groups, and P < 0.05 is to have significant difference.Data
Analysis: tumor average volume is indicated with ± s, the results are shown in Table 3:
3. 2-O- benzyl-β-D- glucopyranoside of table-deacetylation cedilanid (A) and deacetylation cedilanid body (B)
Influence to mouse subcutaneous implantation liver cancer cells tumour
| Group | Dosage (mg/kg) | Size of animal (n) | Tumor weight (g) | Tumour inhibiting rate (%) |
| PBS group | -- | 10 | 0.34±0.23 | -- |
| A | 1.0 | 10 | 0.11±0,02 | 67.64*# |
| B | 1.0 | 10 | 0.19±0.05 | 44.10* |
Note: P < 0.05 * is compared with PBS group；#P < 0.05 is compared with B group.
Illustrate: in vivo in zoopery, deacetylation cedilanid glucosyl group modified compound (A) and deacetylation west
Ground orchid (B) has inhibiting effect to tumour, and (A) is significantly stronger than (B) to liver cancer inhibiting rate.The reason is that: in vivo, remove acetyl
The glucosyl group for changing cedilanid is easy to be fallen by enzyme hydrolysis, generates digoxin to lose related anticancer activity, and deacetylation is western
Ground orchid glucosyl group modified compound (A) is maintained the stabilization of glucosyl group and keeps the steady of its anticancer activity by being modified
It is qualitative.
3. 2-O- benzyl-β-D- glucopyranoside-deacetylation cedilanid liposome cardiac toxic experiment
SPF grades of 18-20g Kunming mouses 30 are selected, male and female dual-purpose (offer of SPF animal housing, Medical Colleges Of Guilin) is divided into three
Group, Normal group (A)；2-O- benzyl-β-D- glucopyranoside-deacetylation cedilanid Liposomal delivery group (B group), 2-
O- benzyl-β-D- glucopyranoside-deacetylation cedilanid group (C group), every group 10, Yu Anjing, 22-26 DEG C of room temperature experiment
Under the conditions of room, yellow Jackets 45mg/kg intraperitoneal injection of anesthesia takes mouse to face upward position and fixes, and is injected intraperitoneally and gives after mouse is stable
Medicine 2mg/kg starts with electrocardiograph (single lead ECC-11A type, 0~90Hz of Hz-KHz for 10 minutes after administration；Chart speed is
50mmPs, standard II lead) record mouse electrocardiogram 10 minutes, arrhythmia cordis frequency of occurrence is calculated, as a result with mean ± standard
Difference indicates that mean compares between two groups is examined with t, the results are shown in Table 4, Fig. 1；
A situation arises with arrhythmia cordis for (10 minutes) changes in heart rate in the unit time after the administration of 4. mouse of table
Note: * P < 0.05, B group illustrates compared with C group, by 2-O- benzyl-β-D- glucopyranoside-deacetylation west
After liposome is made in ground orchid, its liver targeting is improved, cardiac toxic is reduced.
In Fig. 1, A:A group electrocardiogram is schemed；Scheme B:B group electrocardiogram, heart rate slightly slows down, and the rhythm and pace of moving things is normal, does not find that the rhythm of the heart loses
Often；Scheme C:C group electrocardiogram, heart rate obviously slows down, and has atrioventricular block, P-Q interval prolongation seen in figure, and QRS-T wave disappears,
There is obvious atrioventricular block arrhythmia cordis.
Claims (4)
1. the synthesis of deacetylation cedilanid glucosyl group modified compound, it is characterised in that: described to remove acetyl cedilanid grape
Glycosyl modified compound is that 2-O- benzyl-β-D- glucopyranoside-removes acetyl cedilanid, structural formula are as follows:
Its synthetic route is as follows:
2. the synthesis of deacetylation cedilanid glucosyl group modified compound according to claim 1, which is characterized in that tool
Body synthesis step is as follows:
1. the synthesis of compound 1: under ice bath, 140 milliliters of methanol being added in a dry reaction bottle equipped with drying tube, chloroacetic chloride
2.4 milliliters, stirring is stirred to be warming up to and is stirred at room temperature 20 minutes naturally after five minutes, is added 10 grams of glucose, is heated to back flow reaction
2 hours.Cooling reaction solution is added Anhydrous potassium carbonate and is neutralized to neutrality, filter, be concentrated to get 1-O- methylglycoside chemical combination to room temperature
The crude product of object 1；
2. the synthesis of compound 2: resulting 1 crude product of compound being dissolved in 34 milliliters of DMF, 16 milli of benzene dimethoxym ethane is added dropwise
It rises, is rapidly added 1.72 grams of p-methyl benzenesulfonic acid, overnight, TLC shows fully reacting for 50 DEG C of reactions, and reactant is poured into 100 milliliters
It in the mixed liquor of ice water and 140 milliliters of petroleum ethers, acutely shakes, Off-white solid is precipitated, and filters, and dehydrated alcohol is recrystallized to give
Compound 2；
3. the synthesis of compound 3: compound 2, the Bu that will be obtained214 grams and 180 milliliters of toluene of SnO are added the circle that water segregator is housed
In the flask of bottom, 30 milliliters of anhydrous DMFs are added to 60 milliliters in concentration of reaction solution to back flow reaction until no moisture goes out within 3-4 hours,
Be added dropwise 7 milliliters of cylites, 100-110 DEG C reaction 5-6 hours, TLC detects end of reaction, and reactant is with 100 milliliters of ethyl acetate
Suitable quantity of water is successively used in dilution, and saturated brine, each washing 2-3 times, organic layer is dried, filtered with anhydrous sodium sulfate, is concentrated under reduced pressure,
It is purified by silica gel column chromatography, obtains compound 3；
4. the synthesis of compound 5: by gained compound 3,0.3 gram of the concentrated sulfuric acid, 90 milliliters of acetic acid, 30 milliliters of acetic anhydride are stirred at room temperature
Hybrid reaction -1 hour 30 minutes, TLC monitored end of reaction, obtained compound 4；11 milliliters of acetyl bromide are added, 7 milli of methanol
It rises, is protected from light 2 hours；Reaction mixture is diluted with 200 milliliters of methylene chloride, successively uses suitable quantity of water, and saturated sodium bicarbonate is molten
Liquid, saturated brine respectively wash 2-3 times, and organic layer is dried, filtered with anhydrous sodium sulfate, are concentrated under reduced pressure, obtain 5 crude product of compound；
5. the synthesis of compound 7: by 0.97 gram of digoxin compound 6,0.17 gram of diphenyl stannic chloride is dissolved in 100 milliliters of acetonitriles
In, room temperature, which is protected from light, to be stirred to react 10 minutes；1.74 grams of silver oxides, 0.7 gram of dimethyl -2 55'-, 2 '-bipyridyls, weighing 3 is added
4. compound 5 that gram step obtains is added reaction system together, 35 DEG C high degree of agitation 24 hours, reaction mixture is cooled to room
Temperature, with 1 milliliter of saturated aqueous ammonium chloride quenching reaction system, chloroform: acetone=1:1 dilution filters out undissolved salt
Residue, solution are concentrated under reduced pressure, and residue chromatographs to obtain the acetyl object of compound 7 by column, and acetyl object is dissolved in 140ml first
In alcohol, 40g sodium methoxide room temperature is added and handles to obtain compound 7.
3. going the preparation of acetyl cedilanid glucosyl group modified compound composite lipidosome injection, feature made from claim 2
It is: including
(1) acetyl cedilanid glucosyl group modified compound liposome is gone to prepare
Capsule is prepared using back titration method, weighs the modified compound 7 of 100mg and the sodium alginate soln of 18mg/mL concentration
20mL mixing homogeneous, is extracted with container, instills the CaCl that 40mL contains 37mg/mL dropwise2In the beaker of solution, take out after twenty minutes
Filter, washing, obtains complement antibody micro-capsule, maximum capsule encapsulating rate reaches 70% after freeze-drying；
(2) preparation of modified compound liposome injection
Add 10% ethyl alcohol to dissolve modified compound liposome, is made into 0.1mg/1ml concentration, filtration sterilization, by every 1ml
It is either manually or mechanically filling, capping, shading, closed preservation.
4. prepared by claim 3 goes acetyl cedilanid glucosyl group modified compound composite lipidosome injection preparing anti-liver cancer drug
Application in object.
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| CN110530993B (en) * | 2019-08-30 | 2022-03-15 | 上海旭东海普药业有限公司 | Improved detection method of deacetylated hairy glycoside related substance |
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