CN104371099B

CN104371099B - A kind of polymer and its preparation method and application

Info

Publication number: CN104371099B
Application number: CN201410402416.6A
Authority: CN
Inventors: 张雅珍; 李铁力; 白毅
Original assignee: Individual
Current assignee: Individual
Priority date: 2013-08-16
Filing date: 2014-08-15
Publication date: 2019-02-19
Anticipated expiration: 2034-08-15
Also published as: CN104371099A

Abstract

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

Description

A kind of polymer and its preparation method and application

Technical field

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

Background technique

Aging be body respectively organize, organ dysfunction with age and occur degeneration variation, be organism physiology, disease Reason process and the comprehensive of biochemical reaction embody.With being increasingly urgent to for the problem of an aging population, the harm of diseases associated with senescence It is gradually increased, becomes social hotspots.Present inventors have surprisingly found that the polymerizable compound of new construction is being not loaded with any drug In the case of can treat above-mentioned disease, effect is very magical.Mostly in world wide is polymer drug-carried rear treatment disease, about Non-linear multi-block polymer itself, which treats disease, there is no report.

Summary of the invention

The contents of the present invention are as follows: the invention discloses non-linear segmented copolymer shown in following formula, structure is as follows:

The wherein integer between n=1-200；The wherein integer between W=1-500.The wherein integer between n=1-200；It is excellent N=1-100 is selected, wherein the integer between W=1-500, preferably 1-300.Preparation method are as follows:

1) it reacts to obtain compound A with compound A1 and compound A2；

2) bis- (to the carboxyphenoxy) hexanes of compound A and 1 acetylating, 6- react to obtain polymer B, wherein n=1- 200 integer, preferably 1-100；

Compound A1 is selected from:

Compound A2 is selected from:

Compound A:

Polymer B:

Wherein compound A1 is further selected from:

Wherein compound second is further selected from:

Solvent is wherein optionally employed in chemical reaction step, solvent described in step 1 is selected from: chloroform, carbon tetrachloride, dichloromethane Alkane, dimethyl sulfoxide, N,N-dimethylformamide, methanol, ethyl alcohol, benzene, toluene, pyridine, tetrahydrofuran, dicyclohexyl carbon two are sub- One of amine is a variety of；Step 2 optionally employs solvent, and the solvent is selected from carbon tetrachloride, dimethyl sulfoxide, N, N- dimethyl Formamide, toluene, pyridine, tetrahydrofuran, chloroform, methanol, ethyl alcohol, methylene chloride, carbon tetrachloride, methylene chloride, dicyclohexyl One of carbodiimide is a variety of.

Preparation method of the invention is specific as follows:

1) bis- (to the carboxyphenoxy) hexanes of 1,6- are flowed back in acetic anhydride, 1, the 6- for forming acetylation is bis- (to carboxyl Phenoxy group) hexane (can also be commercially available)；

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

3) bis- (to the carboxyphenoxy) hexanes of the 1 of acetylation, 6- are mixed with compound A, are reacted at 100-200 DEG C, Reaction time 20min to 2h；After reaction mixture is cooling, washing is dried to obtain polymer B；

Its reaction equation is as follows:

+

↓

+

↓

Aging be body respectively organize, organ dysfunction with age and occur degeneration variation, be organism physiology, disease Reason process and the comprehensive of biochemical reaction embody.With being increasingly urgent to for the problem of an aging population, the harm of diseases associated with senescence It is gradually increased, becomes social hotspots.Present inventors have surprisingly found that the polymerizable compound of new construction is being not loaded with any drug In the case of can treat above-mentioned disease, effect is very magical.Mostly in world wide is polymer drug-carried rear treatment disease, about Non-linear multi-block polymer itself, which treats disease, there is no report.Present inventors have surprisingly found that the polymerizable compound of new construction exists Above-mentioned disease can be treated in the case where being not loaded with any drug, effect is very magical.Mostly in world wide is polymer supported Disease is treated after medicine, treating disease about non-linear multi-block polymer itself there is no report.This polymer can also pass through chemistry Key coupling drug, or nanometer formulation appropriate is formed by packaging medicine, microball preparation is implanted into body preparation, the preparation of formation Still have function described in the claims in the present invention, and the function of carrying medicine drug can also be played.

Detailed description of the invention:

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

Embodiment 1

1) mixture reflux of bis- (to carboxyphenoxy) the hexane 25g of 1,6- in 500ml acetic anhydride, to form acetyl Bis- (to the carboxyphenoxy) hexanes of the 1,6- of change；

2) compound A1 is 3g, and compound A2 is 51mg, dicyclohexylcarbodiimide 165mg and pyridine 8mg mixing, It is stirred overnight at room temperature；Then it is washed, and is dried under vacuum with ether, obtain polymer；

3) chemical step step 1 and step 2 product mix are put into flask, the decompression melting polymerization reaction at 180 DEG C 1 hour；Object to be polymerized is cooled to room temperature to be dissolved with chloroform, and with petroleum ether and drying；

Embodiment 2

1) mixture reflux of bis- (to carboxyphenoxy) the hexane 30g of 1,6- in 300ml acetic anhydride, to form acetyl Bis- (to the carboxyphenoxy) hexanes of the 1,6- of change；

2) compound A1 is 2.7g, and compound A2 is 29mg, dicyclohexylcarbodiimide 130mg and pyridine 5mg mixing, It is stirred at room temperature overnight；Then it is washed, and is dried under vacuum with ether, obtain polymer；

3) chemical step step 1 and step 2 product mix are put into flask, the decompression melting polymerization reaction at 150 DEG C 1 hour；Object to be polymerized is cooled to room temperature to be dissolved with chloroform, and with petroleum ether and drying；

Effect experiment is as follows:

By the embodiment 1-2 sample prepared and the polyethylene glycol (molecular weight 20000) of purchase, (purchase is in the western lattice in the U.S. Ma aldrich company), poly- (1,6- bis- (p- carboxyphenoxy) hexanes) (purchase in Sigma-Aldrich of the U.S.) into Row effect implements experiment.

Experimental group specifically: first group of blank health group, the second group model group, 1 medication group of third group embodiment, the 4th Group 2 medication group of embodiment, the 5th group of polyethylene glycol medication group, the 6th group of poly- (1,6- bis- (p- carboxyphenoxy) hexanes) medication Group, the 7th group of positive drug medication group.

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

Experiment 1:

Aging be body respectively organize, organ dysfunction with age and occur degeneration variation, be organism physiology, disease Reason process and the comprehensive of biochemical reaction embody.This research is using β-galactosidase decoration method detection human embryo lung (HEL) diploid at fibre The aging state of cell is tieed up, makes senile cell model, and further investigate the shadow grown to cell from cellular signal transduction pathways It rings, evaluates anti-aging effects.In vivo studies is carried out with mouse simultaneously, every group animal 10 (half male and half female), experimental period is 6 weeks or so.Blank control group does not do any specially treated, remaining administration each group mouse subcutaneously injects 0.5ml D- gala daily Sugared (physiological saline is made into 5%).The daily stomach-filling 0.2ml physiological saline of second group model group, the 7th group of positive drug group fill daily The Ganoderma lucidum oral liquid (commercially available) of stomach 3ml/kg, respectively according to the dosage of 0.5mg/kg at first day after third to the 6th group of freeze-drying Mouse of intramuscular injection.It takes a blood sample after experiment 6 weeks, centrifugation after anti-coagulants is anticoagulant takes supernatant spare.Execution mouse after blood is taken to beat Abdominal cavity is opened, liver and kidney are taken.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 are homogenized GSH-PX and NOS.Employment embryo lung diploid fibroblast strain is tested in Institute of section reaches 90% or more cell as aging using positive cell ratio using beta galactose sweet enzyme dyeing method detection after recovery Model.It cultivates on cell and cell plates, is respectively dropped into each group medication of isoconcentration.In succeeding generations, cell density is adjusted in hole It on plate, observes and counts 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

Third group

67.7±12.2**

1.9±0.3**

368.6±41.9**

12.0±2.0**

0.8±0.1**

3.4±0.9**

4th group

65.3±13.3**

2.0±0.3**

364.3±42.2**

11.9±2.1**

0.8±0.1**

3.5±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

47.2±14.2

2.9±0.6

297.4±48.2

15.8±2.9

0.7±0.2

1.9±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*

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

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
		Third group	26.1±8.6
4th group	29.4±7.7
		5th group	76.5±8.3
6th group	85.1±8.2
		7th group	75.9±7.1

Claims

1. a kind of purposes of non-linear segmented copolymer being shown below in the drug of preparation treatment animal anti-aging, Structure is as follows:

The wherein integer between n=1-500；Wherein_WInteger between=1-2000.

2. a kind of gastrointestinal administration preparation, intravenous administration formulation, intramuscular delivery preparation and the nanometer formulation suitable for local administration, Microball preparation is implanted into body preparation, is prepared by the copolymer of claim 1.

3. preparation according to claim 2, the local administration is eye, and ear, nose, local skin position is given Medicine.