CN105902529A - Preparation method of medicine for resisting cardiovascular and cerebrovascular diseases - Google Patents
Preparation method of medicine for resisting cardiovascular and cerebrovascular diseases Download PDFInfo
- Publication number
- CN105902529A CN105902529A CN201610327372.4A CN201610327372A CN105902529A CN 105902529 A CN105902529 A CN 105902529A CN 201610327372 A CN201610327372 A CN 201610327372A CN 105902529 A CN105902529 A CN 105902529A
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- China
- Prior art keywords
- preparation
- cardiovascular disease
- medicine
- medicament against
- against cardiovascular
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/275—Nitriles; Isonitriles
- A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
Abstract
The invention belongs to the technical field of medicines, and particularly relates to a preparation method of a medicine for resisting cardiovascular and cerebrovascular diseases. The method comprises the following steps: dissolving tert-Butyl phenyl carbonate and diallyl 2,2'-oxydiethyl dicarbonate into dichloromethane in a nitrogen environment; adding an initiator and dichloromethane solution of a catalyst after stirring, carrying out sealing polymerization, terminating reaction by glacial acetic acid, carrying out precipitation in ice diethyl ether, and carrying out filtration and vacuum drying to obtain a carbonate polymer; adding the compound to a buffer solution into which the carbonate polymer is dispersed, and magnetically stirring the buffer solution for half an hour; adding sucrose, and preparing a medicine suspension to obtain the medicine for resisting the cardiovascular and cerebrovascular diseases. The medicine provided by the invention is capable of inhibiting platelet activity and gathering performance and relatively effectively inhibiting thrombus formation, and is free of an effect on normal physiological activity; and the defects of KIF are relatively well overcome, so that the cardiovascular and cerebrovascular diseases can be resisted; and the method has a good clinical application prospect.
Description
Technical field
The invention belongs to medicinal chemistry art, be specifically related to a kind of resisting cardiovascular
The preparation method of disease medicament.
Background technology
Cardiovascular and cerebrovascular disease clinical onset mostly is falls forward suddenly dusk, syncope, and half
Body is unsuccessful, facial hemiparalysis and the symptom such as aphasia or hemiplegia, in time should
It is the key for the treatment of life for rescue patient with Western medicine, as antiplatelet gathers
Collection, neuroprotective, thromboembolism treatment, reduction intracranial pressure and prevent and treat complication
Deng.In Chinese Aged, cardiovascular and cerebrovascular disease sickness rate is up to 30%, heart and brain blood
It is the first that pipe disease occupies the cause of the death, is much higher than the ratio of Other diseases.Cardiovascular and cerebrovascular vessel
Disease is the most common with thromboembolism, and blood vessel internal membrane damage, blood flow slow down, blood
Liquid coagulability raises all can cause thrombosis, hematoblastic activation, is gathered in
The forming process of thrombosis plays an important role.Cardiovascular and cerebrovascular disease in recent years
Human health is had resulted in serious threat, according to the every annual in the WHO statistics whole world
17000000 people die from Cardial or cerebral vascular diseases, account for the 1/3 of the total death toll in the whole world,
Its cardiovascular disease and cerebrovascular respectively account for half.
The biodegradable polymer of synthesis is owing to its immunogenicity is relatively low, its property
Can conveniently obtain control wait and be particularly subject to pay close attention to, mainly have aliphatic polyester,
Merlon, polyamino acid, poly phosphate, condensing model, poe etc..
The antiplatelet drug used clinically at present mainly has Cycloxygenase-1 inhibitor
(aspirin), ADP P2Y12Acceptor inhibitor (clopidogrel), di-phosphate ester
Enzyme PDE inhibitor (cilostazol), Glycoprotein G P II b/ III a receptor antagonist
The big class of agent (abciximab) 4.KIF is oxygen propionitrile compounds, and pharmacological evaluation is demonstrate,proved
Real its has certain effect treating cardiovascular and cerebrovascular disease；But clinical effectiveness
Inconspicuous.It is thus desirable to find new similar compound on the basis of KIF, from
And develop the effective medicament against cardiovascular disease made new advances.
Summary of the invention
The goal of the invention of the present invention is to provide a kind of compound and is preparing anti-heart and brain blood
Application in pipe disease medicament, this compound has can resisting cardiovascular disease
Effect, toxicity is relatively low simultaneously.
To achieve the above object of the invention, the technical solution used in the present invention is:
The preparation method of a kind of medicament against cardiovascular disease, comprises the following steps,
In a nitrogen environment, tert-butyl-phenyl carbonic ester and allyl diglycol two carbonic ester
It is dissolved in dichloromethane, after stirring, adds the dichloromethane of the catalyst of initiator sum
Solution, seals polymerization, terminates reaction with glacial acetic acid, precipitates, mistake in ice ether
Filter, vacuum drying obtain carbonate polymer；Compound is added and is dispersed with carbonic acid
In the buffer of ester polymer, magnetic agitation half an hour, add sucrose, configuration
Become drug suspension, obtain medicament against cardiovascular disease；The change of described compound
Structural formula is as follows；
In the present invention, tert-butyl-phenyl carbonic ester rubs with allyl diglycol two carbonic ester etc.
You measure；Using organic zinc compound as catalyst, using pyridoxol as initiator,
Polymerization temperature is 55 DEG C, and the time is 30 hours；Catalyst amount is tert-butyl benzene
The 0.0015% of base carbonic ester mole；Initiator amount is tert-butyl-phenyl carbonic acid
The 0.2% of ester mole.
In the present invention, described buffer is phosphate buffer；In drug suspension, change
Compound concentration is 1wt%～5wt%.
In this application, medicament against cardiovascular disease is pharmaceutical composition, refers to
The compounds of this invention of effective dose and this area generally accept for biology is lived
Property compound is delivered to the preparation of the medium of mammal (such as people).This medium
Including pharmaceutically acceptable carrier.The purpose of pharmaceutical composition is to promote organism
Administration, beneficially active component absorption so that play biological activity.Pharmaceutically may be used
The biological activity referring to not affect the compounds of this invention accepted or the material of character
(such as carrier or diluent), and relative nontoxic, i.e. this material can be applied to individual
Body and do not cause bad biological respinse or comprise in compositions in bad mode
Any component interact.Pharmaceutically acceptable carrier includes but not limited to appoint
The government administration section license what is correlated with is for can accept for the mankind or domestic animal
Adjuvant, carrier, excipient, fluidizer, sweetener, diluent, preservative,
Dyestuff/coloring agent, correctives, surfactant, wetting agent, dispersant, help
Suspension, stabilizer, isotonic agent, solvent or emulsifying agent.The present invention's pharmaceutically may be used
The adjuvant accepted includes carbonate polymer and sucrose；Described carbonate polymer
It is polymerized with allyl diglycol two carbonic ester by tert-butyl-phenyl carbonic ester and obtains；System
During standby carbonate polymer, using organic zinc compound as catalyst, with pyridoxol
As initiator, polymerization temperature is 55 DEG C, and the time is 30 hours, can obtain
The biodegradable polymer carrier that molecular weight is controlled, it is possible to larger amount of loading medicine
Thing.
Effective dose, therapeutically effective amount or pharmacy effective dose refer to take metapedes with at certain
One or more symptoms of disease or the disease treated are alleviated extremely in the degree of kind
Few a kind of medicament or the amount of compound.Its result can be sign, symptom or the cause of disease
Abatement and/or alleviation, or other required change any of biosystem.Such as,
Effective dose for treatment is to provide significant remission effect institute clinically
The amount of the compositions comprising compound disclosed herein needed.Such as dosage can be used to pass
The technical measurement increasing test is suitable for the effective dose in any individual case.
Take, use, administration etc. refers to be delivered to compound or compositions
The method carrying out the required site of biological agent.These methods include but not limited to mouth
Take approach, through intraduodenal routes, parental injection (include intravenous, subcutaneous,
Intraperitoneal, intramuscular, intra-arterial injection or infusion), topical and per rectum give
Medicine；In the preferred embodiment of the invention, treatment cardiovascular disease medicine is injection
Medicine.
Compound structure disclosed by the invention is similar with KIF, is also existing compound,
It is low to normal physiological-toxicity, does not especially have function hematoblastic under physiological condition
Impact, can reach focus under the parcel of biodegradable polymer smoothly, enough
Effectively inhibition thrombosis, thus it is new to be expected to overcome the shortcoming of KIF to be developed into
Treatment cardiovascular and cerebrovascular diseases medicament.
Detailed description of the invention
Below in conjunction with embodiment, the invention will be further described；Relating to of the present embodiment
The chemical structural formula of compound is as follows；
In a nitrogen environment, equimolar tert-butyl-phenyl carbonic ester and pi-allyl two
Glycol two carbonic ester is dissolved in 10mL dichloromethane, adds 0.2mol% after stirring
Pyridoxol and catalyst double (double trimethyls are silica-based) amine zinc of 0.0015mol%
Dichloromethane solution, is sealed in 55 DEG C and reacts 30 hours, terminates anti-with glacial acetic acid
Should, precipitate in ice ether, filter, be vacuum dried and obtain carbonate polymer.
Being added by compound in the buffer being dispersed with carbonate polymer, magnetic force stirs
Mixing half an hour, add sucrose, being configured to drug level is 1wt%, 2wt%, 5wt%
Drug suspension, standby.
Take the mice 30 of body weight 28 ± 2g, male and female half and half；Suspension is pressed
5mg/20g gavage, Continuous Observation is the Survival of mice in 30 days, it was found that
In 30 days, all mice feeding activities are normal, do not have death, are not detected by LD50.
Washing human blood platelets (1*108/ ml) incubate with the suspension 37 DEG C of variable concentrations
Educate 20 minutes, then with causing poly-agent collagen 1.5 μ g/mL and thrombin 0.03
μ g/mL stimulates, with platelet aggregation instrument record aggregate curve, result it can be seen that
Show that the compounds of this invention can suppress platelet aggregation.
Take 500 μ L platelet rich plasma PRP (7*108/ mL) join cuvette
In, hatch 30 minutes with suspension 8 μ L37 DEG C of variable concentrations, add and cause to gather
Agent thrombin 0.6 μ g/Ml, blood after observing 10,20,40 minutes with image technology
Platelet grumeleuse retraction situation, result shows that medicine of the present invention can substantially suppress blood little
The retraction reaction of plate grumeleuse.To sum up, it may be said that the medicine of the bright present invention can suppress
Biologically active pdgf with gather performance, more effectively suppress the formation of thrombosis, the most right
Normal physiological activity does not affect, the shortcoming preferably overcoming KIF；Such that it is able to
Resisting cardiovascular disease, has good potential applicability in clinical practice.
Claims (6)
1. a preparation method for medicament against cardiovascular disease, including following step
Suddenly, in a nitrogen environment, tert-butyl-phenyl carbonic ester and allyl diglycol two carbon
Acid esters is dissolved in dichloromethane, adds the dichloro of the catalyst of initiator sum after stirring
Dichloromethane, seals polymerization, terminates reaction with glacial acetic acid, precipitates in ice ether,
Filter, vacuum drying obtains carbonate polymer；Compound is added and is dispersed with carbon
In the buffer of acid ester polymer, magnetic agitation half an hour, add sucrose, join
It is set to drug suspension, obtains medicament against cardiovascular disease；Described compound
Chemical structural formula is as follows；
The preparation method of medicament against cardiovascular disease the most according to claim 1,
It is characterized in that: tert-butyl-phenyl carbonic ester and allyl diglycol two carbonic ester etc.
Mole.
The preparation method of medicament against cardiovascular disease the most according to claim 1,
It is characterized in that: using organic zinc compound as catalyst, using pyridoxol as drawing
Sending out agent, polymerization temperature is 55 DEG C, and the time is 30 hours.
The preparation method of medicament against cardiovascular disease the most according to claim 1,
It is characterized in that: catalyst amount is tert-butyl-phenyl carbonic ester mole
0.0015%；Initiator amount is the 0.2% of tert-butyl-phenyl carbonic ester mole.
The preparation method of medicament against cardiovascular disease the most according to claim 1,
It is characterized in that: described buffer is phosphate buffer.
The preparation method of medicament against cardiovascular disease the most according to claim 1,
It is characterized in that: in drug suspension, compound concentration is 1wt%～5wt%.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610327372.4A CN105902529A (en) | 2016-05-16 | 2016-05-16 | Preparation method of medicine for resisting cardiovascular and cerebrovascular diseases |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610327372.4A CN105902529A (en) | 2016-05-16 | 2016-05-16 | Preparation method of medicine for resisting cardiovascular and cerebrovascular diseases |
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| Publication Number | Publication Date |
|---|---|
| CN105902529A true CN105902529A (en) | 2016-08-31 |
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| CN201610327372.4A Pending CN105902529A (en) | 2016-05-16 | 2016-05-16 | Preparation method of medicine for resisting cardiovascular and cerebrovascular diseases |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104672199A (en) * | 2015-02-13 | 2015-06-03 | 苏州大学 | Double-iodine cyclic carbonate compound and preparation method thereof |
| WO2015114486A1 (en) * | 2014-01-29 | 2015-08-06 | Indian Institute Of Technology Kanpur | Polymeric nanocomposite films with embedded channels |
| CN104958288A (en) * | 2015-06-26 | 2015-10-07 | 苏州大学 | Platelet inhibitor and application of platelet inhibitor for preparing medicine for resisting platelet diseases |
-
2016
- 2016-05-16 CN CN201610327372.4A patent/CN105902529A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015114486A1 (en) * | 2014-01-29 | 2015-08-06 | Indian Institute Of Technology Kanpur | Polymeric nanocomposite films with embedded channels |
| CN104672199A (en) * | 2015-02-13 | 2015-06-03 | 苏州大学 | Double-iodine cyclic carbonate compound and preparation method thereof |
| CN104958288A (en) * | 2015-06-26 | 2015-10-07 | 苏州大学 | Platelet inhibitor and application of platelet inhibitor for preparing medicine for resisting platelet diseases |
Non-Patent Citations (2)
| Title |
|---|
| JOHN MCB. HODGSON ET AL.: "Late stent thrombosis: Considerations and practical advice for the use of drug-eluting stents: A report from the society for cardiovascular angiography and interventions drug-eluting stent task force", 《CATHETERIZATION AND CARDIOVASCULAR INTERVENTIONS》 * |
| 郭清奎等: "新型可完全降解材料聚外消旋乳酸-三亚甲基碳酸酯聚合物体内降解行为和组织相容性", 《中国组织工程研究与临床康复》 * |
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