CN104371095B

CN104371095B - A kind of novel polymer and its preparation method and application

Info

Publication number: CN104371095B
Application number: CN201410402381.6A
Authority: CN
Inventors: 张雅珍; 李铁力; 白毅
Original assignee: Individual
Current assignee: Individual
Priority date: 2013-08-15
Filing date: 2014-08-15
Publication date: 2018-05-08
Anticipated expiration: 2034-08-15
Also published as: CN104371095A

Abstract

The invention discloses a new class of non-linear multi-block polymer, and the preparation method of the polymer, preparation process, the medical application of reagent needed for preparation and non-linear more block polymerization compounds after preparing.

Description

A kind of novel polymer and its preparation method and application

Technical field

The invention discloses a new class of non-linear multi-block polymer, and the preparation method of the polymer, prepares step Suddenly, reagent needed for preparation and the medical application of non-linear more block polymerization compounds after preparation.

Background technology

The sufferer of neovascular disease is very more, and many disease pathologies are all associated.Scientific circles are new for eye at present The treatment means of green blood tubing disease are very limited, with increasingly urgent, the harm of diseases associated with senescence of the problem of an aging population Also it is gradually increased, becomes social hotspots.The seriousness of retina and choroidal neovascular disease increasingly shows, and clinically needs A kind of very effective medicine is wanted to go to treat such disease, otherwise such disease sends out the disease for producing a variety of eye diseases.Age The colony of Macular lesion increasingly increases, and very harmful, also as the important threat of mankind's eye health.

Present inventors have surprisingly found that the polymerizable compound of new construction can be controlled in the case where being not loaded with any medicine Above-mentioned disease is treated, effect is very magical.Mostly in world wide is polymer drug-carried rear treatment disease, is gathered on non-linear more blocks Compound treats disease and there is no report in itself.

The content of the invention

Present disclosure is as follows：

The invention discloses non-linear segmented copolymer shown in following formula, its structure are as follows：

Its structure can also be：

Integer between wherein n=1-500；Integer between wherein W=1-2000.

Integer between wherein n=1-500；Integer between wherein W=1-2000.Wherein preferred n=1-200, wherein W are excellent Select 1-500.Preparation method characteristic is：

1）React to obtain compound A with compound A1 and compound A2；

2）Compound A and acetylating decanedioic acid react to obtain polymer B, the wherein integer of n=1-500, preferably 1- 200；

Wherein compound A1 is further selected from：

Wherein compound second is further selected from：

Compound A is preferred：

Polymer B is preferred：

Compound A1A2 is commercially available, solvent is wherein optionally employed in chemical reaction step, solvent described in step 1 is selected from： Methanol, ethanol, benzene, toluene, pyridine, tetrahydrofuran, chloroform, carbon tetrachloride, dichloromethane, dimethyl sulfoxide (DMSO), N, N- dimethyl One or more in formamide, dicyclohexylcarbodiimide；Step 2 optionally employs solvent, and the solvent is selected from methanol, second Alcohol, dichloromethane, chloroform, carbon tetrachloride, dimethyl sulfoxide (DMSO), N,N-dimethylformamide, toluene, pyridine, tetrahydrofuran, two rings One or more in hexyl carbodiimide.

The preparation method of the present invention is specific as follows：

1）Decanedioic acid is flowed back in acetic anhydride, forms the decanedioic acid of acetylation（Can also be commercially available）；

2）Compound A1 is mixed in a solvent with compound A2 dissolvings, and reaction at room temperature overnight, is dried to obtain compound A；

3）The decanedioic acid of acetylation is mixed with compound A, is reacted at 100-200 DEG C, reaction time 20min to 2h； After the cooling of question response mixture, washing, is dried to obtain polymer B；

Its reaction equation is as follows by taking embodiment 1 as an example：

+

↓

+

↓

；

The sufferer of neovascular disease is very more, and many disease pathologies are all associated.Scientific circles are new for eye at present The treatment means of green blood tubing disease are very limited, with increasingly urgent, the harm of diseases associated with senescence of the problem of an aging population Also it is gradually increased, becomes social hotspots.The seriousness of retina and choroidal neovascular disease increasingly shows, and clinically needs A kind of very effective medicine is wanted to go to treat such disease.The colony that age-related macular venereal disease becomes increasingly increases, and very harmful, Also the important threat of mankind's eye health is become.

Present inventors have surprisingly found that the polymerizable compound of new construction can be controlled in the case where being not loaded with any medicine Above-mentioned disease is treated, effect is very magical.Mostly in world wide is polymer drug-carried rear treatment disease, is gathered on non-linear more blocks Compound treats disease and there is no report in itself.This polymer can also be formed by chemical bond coupling drug, or by packaging medicine Appropriate nanometer formulation, microball preparation are implanted into body preparation, and the preparation of formation still possesses the work(described in the claims in the present invention Can, and can also play the function of carrying medicine medicine.

Brief description of the drawings：

The nuclear magnetic resonance map of Fig. 1 embodiments 1.

The nuclear magnetic resonance map of Fig. 2 embodiments 2.

Embodiment 1

Mixture reflux of the 1 decanedioic acid 1.5g in 50ml acetic anhydrides, to form the decanedioic acid of acetylation；

2 compound A1 are 3g,

Compound A2 is 51mg,

Dicyclohexylcarbodiimide 165mg and pyridine 8mg mixing, is stirred at room temperature overnight；Then washed with ether, and It is dried under vacuum, obtains polymer；

3 are put into the 1st step of chemical step and the 2nd step product mix in flask, the decompression melting polymerisation 1 at 180 DEG C Hour；Thing to be polymerized is cooled to room temperature to be dissolved with chloroform, and with petroleum ether and drying；

It is following product to obtain structure

Embodiment 2

Mixture reflux of the 1 decanedioic acid 2g in acetic anhydride 20ml, to form acetyl group-decanedioic acid；

2 compound A1 are 2.5g,

Compound A2 is 42mg,

Dicyclohexylcarbodiimide 150mg and tetrahydrofuran mixing add 15ml chloroforms, are stirred at room temperature overnight；Then Washed, and be dried under vacuum with ether, obtain polymer；

3 are put into the 1st step and the 2nd step product mix in flask, when reaction 1 is small at 150 DEG C；Thing to be polymerized is cooled to Room temperature is dissolved with chloroform, and with petroleum ether and drying；

Obtaining structure is

Polymer.

Effect experiment is as follows：

By the embodiment 1-2 samples prepared and the polyethylene glycol of purchase（Molecular weight is 20000）（Buy in the western lattice in the U.S. Agate aldrich company）, poly- decanedioic acid（Buy in Sigma-Aldrich of the U.S.）Carry out effect and implement experiment.

Experiment packet is specially：First group of blank health group, the second group model group, the 3rd group of 1 medication group of embodiment, the 4th Group 2 medication group of embodiment, the 5th group of polyethylene glycol medication group, the 6th group of poly- decanedioic acid medication group, the 7th group of positive drug medication group.

Sample prepared by embodiment 1-2, the 3rd to the 6th group weighs identical weight and is tested.According to pervious patent Document report the method, carries out polymerizable compound correlation pharmacodynamic experiment of the present invention.

Experiment 1：

Male rat 120 is taken, is randomly divided into 6 groups, i.e. first group of blank group（Health, non-preparation model group）, second group Model control group（Prepare model group）, embodiment 1-2 groups（3rd group and the 4th group）, the 5th group and the 6th group.Each group number of animals It is 20.It is experimental eye at a glance that every rat, which randomly selects, and another eye is control eye（It is compared at the same time with blank group）.Remove The preparation of the outer equal intraocular injection 10ug medicines of each group of model control group or the medicine containing 10ug, model control group give isometric PBS Solution.

With laser irradiation in rats eyeball（Modeling）, light has bubble to produce or with hyporrhea (sometimes with light ring) after coagulating Mark breaks up Bruch films, is denoted as available point.After laser photocoagulation, each group medicine is injected to rat right eye eyeball.Light coagulates rear 14 My god, tissues observed hyperplasia area simultaneously carries out histological examination.As a result such as table 1 below：

1 retina of table and tela chorioidea's hyperplasia area compare（Unit：mm²）

Group	Retina	Choroid
			First group	0.89±0.21**	0.85±0.22**
Second group	6.07±0.13##	3.66±0.17##
			3rd group	0.99±0.31**	0.95±0.22**
4th group	0.98±0.30**	0.93±0.19**
			5th group	5.97±0.31##	3.70±0.25##
6th group	6.09±0.33##	3.67±0.33##

The * p compared with model control group<0.05, * * p<0.01, compared with healthy group^#p<0.05,^##p<0.01

Experiment 2：

Aging be body respectively organize, organ dysfunction with age and occur degeneration change, be organism physiology, disease The comprehensive embodiment of reason process and biochemical reaction.This research detects human embryo lung (HEL) diploid into fibre using β-galactosidase decoration method The aging state of cell is tieed up, makes senile cell model, and the shadow of cell growth is furtherd investigate from cellular signal transduction pathways Ring, evaluate anti-aging effects.It is with mouse progress in vivo studies, every group of animal 10 (half male and half females), experimental period at the same time 6 weeks or so.Blank control group does not do any specially treated, remaining administration each group mouse subcutaneously injects 0.5ml D- galas daily Sugared (physiological saline is made into 5%).The daily gavage 0.2ml physiological saline of second group model group, the 7th group of positive drug group fill daily The Ganoderma lucidum oral liquid of stomach 3ml/kg（It is commercially available）, the 3rd to the 6th group freeze after respectively according to the dosage of 0.5mg/kg at first day Mouse of intramuscular injection.Take a blood sample after testing 6 weeks, centrifuged after anti-coagulants anti-freezing, take supernatant spare.Execution mouse beats after taking blood Abdominal cavity is opened, takes liver and kidney.10% liver tissue homogenate and kidney homogenate is made, centrifuging and taking supernatant is spare.By liver and After kidney homogenate is diluted to 1%, according to kit specification method, using malonaldehyde (MDA) kit, superoxide dismutase Enzyme (SOD), nitricoxide synthase (NOS) kit, glutathione peroxidase (GSH-PX) kit measurement plasma SOD And MDA, liver homogenate SOD and MDA, kidney homogenate GSH-PX and NOS.During experiment employment embryo lung diploid fibroblast strain comes from Institute of section, using the detection of beta galactose sweet enzyme dyeing method after recovery, reaches more than 90% cell as aging using positive cell ratio Model.Cell is cultivated with cell plates, being respectively dropped into each group medication of isoconcentration.In succeeding generations, adjustment cell density is in hole On plate, observe and count under the microscope after beta galactosidase dyeing, dark green cytochrome is positive cell, every group of counting 200 A cell, calculates positive percentage, i.e. senile cell rate=bottle green cell number/total cell number × 100%.

Experimental result：

1 superoxide dismutase of table glutathione peroxidase nitricoxide synthase malonaldehyde Comparative result（n= 10）

Each group situation

Liver SOD

Liver MDA

Blood SOD

Blood MDA

NOS

GSH-PX

First group

69.8±11.0**

2.0±0.3**

374.0±52.3**

12.1±2.2**

0.8±0.1**

3.5±1.4**

Second group

47.0±13.6

2.9±0.9

297.1±38.2

15.6±2.7

0.6±0.3

1.9±1.0

3rd group

65.7±12.1**

1.9±0.3**

365.2±41.8**

11.9±2.0**

0.8±0.1**

3.4±1.1**

4th group

65.5±11.7**

1.9±0.3**

364.3±42.2**

11.8±1.9**

0.9±0.1**

3.4±1.0**

5th group

48.5±13.8

2.8±0.6

296.3±48.5

15.9±2.7

0.6±0.2

1.9±1.0

6th group

48.7±14.5

2.9±0.7

296.3±50.0

15.8±2.8

0.6±0.2

1.8±0.9

7th group

50.1±13.9*

2.6±0.9*

309.9±51.9*

14.7±2.3*

0.7±0.2*

2.2±1.2*

The * P compared with model group<0.05**P<0.01

2 β of table-galactosidase stained positive rate reaches（n=10）

Each group situation	Positive rate %
		First group	11.4±2.3
Second group	90.2±5.2
		3rd group	23.2±9.8
4th group	24.3±8.2
		5th group	76.5±8.3
6th group	82.0±7.2
		7th group	75.9±7.1

Claims

1. the polymer being shown below is preparing the medicine for the treatment of ocular angiogenesis class disease and is preparing treatment anti-aging Purposes in medicine,

Integer between wherein n=1-500；Integer between wherein W=1-2000.

2. purposes as claimed in claim 1, it is characterised in that：Polymer in claim 1 is prepared into gastrointestinal administration, Intravenously administrable, intramuscular delivery and the nanometer formulation suitable for local administration, microball preparation, is implanted into body preparation.

3. purposes as claimed in claim 2, it is characterised in that：The local administration is eye, ear, nose, local skin Regional administration.