CN104910373A - New polymer, preparation and application thereof - Google Patents

Abstract

The invention discloses a new nonlinear multiblock polymer and a preparation method of the polymer, preparation steps, preparation required reagents and medical use of the prepared nonlinear multiblock polymeric compound.

Description

A kind of novel polymer and preparation thereof and purposes

Technical field

The invention discloses the non-linear multi-block polymer that a class is new, and the preparation method of this polymkeric substance and purposes.

Background technology

Ocular angiogenic diseases is a global difficult problem, current ocular angiogenesis common disease has age is macular degeneration related, proliferative diabetic retinopathy, proliferative vitreoretinopathy, retinopathy of prematurity, pathologic myopia, assuming that ocular histoplasmosis's syndrome, branch retinal vein occlusion, central retinal vein occlusion, Branch Retinal Artery blocks, central retinal artery occlusion, the retinal ischemia that new vessel is relevant to tumour.Current scientific circles are very limited for the treatment means of ocular angiogenesis class disease, day by day urgent along with the problem of an aging population, the increase day by day of the colony of ocular angiogenic diseases, and very harmful, gently then blurred vision, heavy then can cause blind.The seriousness of retina and choroidal neovascular disease manifests day by day, needs a kind of very effective medicine to go to treat this type of disease clinically.The sufferer of neovascular disease is very many, and a lot of disease pathology is all associated.Current scientific circles are very limited for the treatment means of ocular angiogenesis class disease.The seriousness of retina and choroidal neovascular disease manifests day by day, needs a kind of very effective medicine to go to treat this type of disease clinically, otherwise the disease producing multiple eye disease is sent out by this type of disease.The colony that age-related macular venereal disease becomes increases day by day, and very harmful, also becomes the important threat of mankind's eye health.

The present inventor is surprised to find that the polymerizable compound of new texture just can treat above-mentioned disease when not loading any medicine, and effect is very magical.Mostly be polymer drug-carried rear disease therapy in world wide, there is no report about the disease therapy of non-linear multi-block polymer own.

Summary of the invention

Content of the present invention is as follows, and as shown in the formula the nonlinear segmented copolymer shown in formula I, its structure is as follows:

Wherein S1 is one section of hydrophobic polymer fragment, and S2 is one section of hydrophilic polymer segment, and X is the integer between 3 to 30, S3 representative has the connection compound of racemosus structure,, there is chemical reaction between "-" representative structure, between structure, combination reaction occur in preferred Y-connection compound.Wherein S1 is selected from polyester, condensing model, polycaprolactone, or their multipolymer, wherein preferred condensing model.Wherein S2 is selected from polyvinyl alcohol, polyoxyethylene glycol, polypyrrole alkane ketone, polyethers, polyoxyethylene block copolymer, or their multipolymer, wherein preferred polyoxyethylene glycol.Wherein S3 is a kind of connector, is selected from the structure containing polyprotonic acid, is preferably as follows compound:

Preferred structure of the present invention is as follows:

(poly sebacic polyanhydride-polyoxyethylene glycol)_3-20-Y-connection thing.

The preparation method of compound of the present invention, is characterized in that:

1) sebacic acid is refluxed in diacetyl oxide, form acetylating sebacic acid (also can be purchased);

2) S3 and HO-PEG-NH2 reaction, the molecular weight of PEG is 1-40000, preferred 1-20000, obtains the star compound A with poly-hydroxy ending; Here the HO-PEG-NH2 that illustrates is, itself and S3 react, the integer between W=1-1000, the integer between preferred W=1-500, obtain the star compound A with poly-hydroxy ending;

3) compd A (star compound) mixes with acetylating sebacic acid, reacts, reaction times 20min to 2h at 100-200 DEG C; After the cooling of question response mixture, washing, drying obtains star polymer B;

4) by polymer B as 0.5-24 hour in solvent, in 0-is subzero 30 DEG C after ultrasonic reaction 2-20 minute, then homogenizer high-speed stirring 1-20 minute, rotate volatilization obtain crude product, rear collected by centrifugation process obtains the prolonged action preparation of finished product formula I.

Wherein said chemical step 1-4 selects solvent to be selected from: one or more in benzene, toluene, pyridine, trifluoroacetic acid, tetrahydrofuran (THF), chloroform, tetracol phenixin, methylene dichloride, methyl alcohol, ethanol, methylene dichloride, dimethyl sulfoxide (DMSO), DMF.Final compd B can be prepared into the nanometer formulation being suitable for topical, microball preparation, implant, and described local is intravitreal injection administration or other mode administrations of eye, and head, skin, in nose, waits part administration in ear.The purposes of compound of the present invention, purposes is the medicine that preparation treatment is fallen ill due to new vessel, especially for the medicine of retina and choroidal neovascularization disease is treated in preparation.The compound of brand-new of the present invention can be prepared into the nanometer formulation being suitable for topical, microball preparation.Purposes is preparation treatment neovascular relative disease, the medicine of the especially ocular angiogenesis class disease such as treatment of age-related macular degeneration disease.Polymkeric substance of the present invention also can connect medicine or packaging medicine as auxiliary material, but do not affect the drug action of this polymkeric substance and the drug action of medicine itself, Inventive polymers is as also possessing treatment proliferative diabetic retinopathy while excipient substance or coupling drug, proliferative vitreoretinopathy, retinopathy of prematurity, pathologic myopia, assuming that ocular histoplasmosis's syndrome, branch retinal vein occlusion, central retinal vein occlusion, Branch Retinal Artery blocks, central retinal artery occlusion, the effect of the retinal ischemia that new vessel is relevant to tumour.

accompanying drawing illustrates:

fig. 1the nuclear magnetic resonance map of the end product of embodiment 1.

Embodiment

Specific embodiment is described in further detail the present invention below, but the present invention not only limits to following examples.

Preparation embodiment is as follows:

embodiment 1

The mixture backflow of 1 sebacic acid 80g in 800ml diacetyl oxide, to form acetylating sebacic acid;

2 compound Ss 3:200mg withhO-PEG-NH₂2g puts into flask and reacts, that is:react with S3, put into dicyclohexylcarbodiimide 160mg and tetrahydrofuran (THF) 8mg simultaneously, mixing adds 15ml chloroform, at room temperature stirs and spends the night; Then washed with diethylether is used, and dry under vacuo, obtain the star compound A with the ending of poly-hydroxy base:

3 by A with acetylating-sebacic acid mixing, reducing pressure at 175 DEG C contains intermingle with (high vacuum melt phase polycondensation) and reacts 1 hour; Thing to be polymerized is cooled to room temperature chloroform and dissolves, and by petroleum ether and drying obtains star polymer B;

B：

Wherein Structure A is

The molecular weight of polyoxyethylene glycol is 5000, and the molecular weight of condensing model is 2000.

The 800mg polymkeric substance of 4 steps 3 puts into the dichloromethane solution 48 hours of 8ml dimethyl sulfoxide (DMSO) and 12ml; Ultrasonic 3 minutes; Then to insert in baking oven 1 hour; In subzero 10-20 degree, homogenizer ultra-high speed stirs 3 minutes, and the polyvinyl alcohol solution 600 turns then putting into 1% stirs 2 hours; Freeze-drying after collected by centrifugation, obtains the nanoparticle of end product.

Wherein Structure A is

N is the integer between 1-500, and w is the integer between 1-1000.

embodiment 2

The mixture backflow of 1 sebacic acid 100g in 900ml diacetyl oxide, to form ethanoyl-sebacic acid;

2 compound S 4 46mg withhO-PEG-NH₂3g puts into flask and reacts, and puts into dicyclohexylcarbodiimide 160mg and tetrahydrofuran (THF) 6mg simultaneously, and mixing adds 18ml methylene dichloride, at room temperature stirs and spends the night; Then washed with diethylether is used, and dry under vacuo, obtain the star compound A with poly-hydroxy ending;

3 ethanoyl-sebacic acid mixes with compd A, and at 180 DEG C, decompression contains intermingle with reaction 1 hour; Thing to be polymerized is cooled to room temperature chloroform and dissolves, and by petroleum ether and drying obtains star polymer B;

This polymkeric substance is put into the solution mixed by 5ml methyl alcohol and 5ml methylene dichloride by 4; Then to insert in baking oven 4 hours; In subzero 10-20 degree, ultrasonic 20 minutes; Product put into 3% cholic acid solution 400 turns stir 2 hours; Freeze-drying after collected by centrifugation, obtains the microball preparation of end product.

effect experimental is as follows:

(that is: poly-sebacic acid (molecular weight is 3000)-polyoxyethylene glycol (molecular weight 5000) polymkeric substance (does not connect the polymkeric substance of S3 to the non-star polymer made after the sample prepared by embodiment 1-2 and poly-sebacic acid-ethylene glycol connect, i.e. non-star compound) nanometer formulation, (molecular weight is 5000 to the polyoxyethylene glycol bought, buy in Sigma-Aldrich of the U.S.), poly-sebacic acid (molecular weight is 3000, buys in Sigma-Aldrich of the U.S.) carries out effect and implements experiment.

Be specially:

First group is embodiment 1 sample sets;

Second group is embodiment 2 sample sets;

3rd group is non-star polymer (that is: the nanometer formulation group of the polymkeric substance (not connecting the polymkeric substance of S3, i.e. non-star compound) of poly-sebacic acid-polyoxyethylene glycol made after poly-sebacic acid-ethylene glycol connects

4th group is polyoxyethylene glycol group;

5th group is poly-sebacic acid group

Carry out drug action test.

The sample prepared by embodiment 1-2, the 3rd group, the 4th group, the 5th group takes identical weight and tests.According to method described in patent documentation, carry out the pharmacodynamic experiment of compound on animals ocular angiogenic diseases

Medicine is tested the restraining effect of tela chorioidea's hyperplasia:

Get male rat 140, be divided into 7 groups at random, namely blank group (healthy, non-preparation model group), model control group (preparation model group), embodiment 1-2 group, the 3rd group, the 4th group and the 5th group.Each treated animal number is 20.Every rat random selecting is experimental eye at a glance, and another eye is contrast eye (comparing with blank group) simultaneously.Except model control group, respectively organize equal intraocular injection 10ug medicine or the preparation containing 10ug medicine, model control group gives isopyknic PBS solution.

With laser radiation rat eye (modeling), there is bubble produce or break up Bruch film with hyporrhea (sometimes with light sound) mark after light is solidifying, be designated as available point.After laser photocoagulation, inject each group of medicine to rat right eye eyeball.Light coagulates latter 14 days, and tissues observed hyperplasia area also carries out histological examination.Result is as following table 1:

Table 1 retina and hyperplasia Area comparison (unit: mm of tela chorioidea²)

Group	Retina	Choroid
			Model control group	6.00±0.15##	3.59±0.22##
Healthy group	0.88±0.27**	0.84±0.25**
			First group	0.92±0.30**	0.87±0.22**
Second group	0.90±0.33**	0.86±0.20**
			3rd group	6.03±0.26##	3.65±0.33##
4th group	6.10±0.28##	3.52±0.31##
			5th group	6.11±0.24##	3.58±0.32##

Compare * p<0.05 with model control group, * * p<0.01, compares with healthy group^#p<0.05,^##p<0.01

The effect of product of the present invention to retinal vein occlusion disease is carried out according to the Salvia miltiorrhiza and Panax notoginseng mixed solution delivered on Chinese TCM Ophthalmology magazine 23 volume 2 phase of the people such as the Fan Xi method described in the experimental study of branch retinal vein occlusion remaining of preventing.Administration grouping is the same, and dosage is the same.Investigate the action effect of Inventive polymers embodiment 1 and embodiment 2.

Table 2 is on the impact (x ± s) of rat platelet adherence rate and platelet aggregation rate

Group	Platelet adhesion reaction rate %	Platelet aggregation rate 5 minutes %
			Control group	30.99±6.81	53.55±18.20
First group	27.62±5.34	34.86±10.25
			Second group	26.46±5.83	32.16±11.58
3rd group	31.48±8.87	55.67±16.46
			4th group	30.84±7.27	53.16±15.35
5th group	31.18±7.25	57.59±13.45

Claims (10)

1. be shown below possess pharmacologically active can the nonlinear segmented copolymer of grafting medicine, its structure is as follows:

Wherein S1 is one section of hydrophobic polymer segments, and S2 is one section of hydrophilic polymer segments, and X is the integer between 3 to 30, S3 represents the connection compound of racemosus structure,, there is chemical reaction between "-" representative structure, between structure, combination reaction occur in preferred Y-connection compound.

2. the polymkeric substance of claim 1, wherein S1 is selected from polyester, polycaprolactone, condensing model, and their multipolymer, wherein preferred condensing model, wherein S2 is selected from polyoxyethylene glycol, polypyrrole alkane ketone, polyvinyl alcohol, polyethers, polyoxyethylene block copolymer, and their multipolymer, wherein preferred polyoxyethylene glycol.

3. the polymkeric substance of claim 1, wherein S3 is a kind of connector, is a kind of branch-like compound, is selected from the structure containing polyprotonic acid, is preferably as follows compound:

。

4. the polymkeric substance of claim 1-3, its preferred structure is as follows:

(poly sebacic polyanhydride-polyoxyethylene glycol)_3-20-Y-connection thing.

5. the preparation method of compound according to claim 4, is characterized in that:

1) sebacic acid is refluxed in diacetyl oxide, form acetylating sebacic acid;

2) S3 and HO-PEG-NH2 reaction, the molecular weight of PEG is 1-40000, preferred 1-20000, obtains the star compound A with poly-hydroxy ending;

3) compd A and be obtained by reacting the radial block polymer B that ethanoyl ends up with acetylating sebacic acid;

4) polymer B makes nanometer, the suitable formulations such as microballoon or implant;

Wherein said chemical step 1-4 selects solvent to be selected from: one or more in benzene, toluene, pyridine, trifluoroacetic acid, tetrahydrofuran (THF), chloroform, tetracol phenixin, methylene dichloride, methyl alcohol, ethanol, methylene dichloride, dimethyl sulfoxide (DMSO), DMF.

In the preferred structure of 6. claim 4 most preferably:

Wherein Structure A is

N is the integer between 1-500, and w is the integer between 1-1000.

7. the purposes of the compound of claim 1-3, purposes is treatment new vessel class disease.

8. the purposes of the compound of claim 1-3, purposes is the medicine of preparation treatment ocular angiogenesis class disease, especially for the medicine of retina and choroidal neovascularization disease is treated in preparation.

9. the purposes of the compound of claim 1-3, purposes is treatment age-related maculopathy disease.

10. arbitrary compound of claim 1 can be prepared into the nanometer formulation being suitable for topical, microball preparation, implant, and described local is intravitreal injection administration or other mode administrations of eye, and head, skin, in nose, waits part administration in ear.