CN104371099A - New polymer and preparation method and use thereof - Google Patents

Abstract

The invention discloses a new nonlinear multi block polymer, a preparation method of the polymer, preparation steps, reagents used for producing and new use of the prepared nonlinear multi block polymer.

Description

A kind of novel polymer and its preparation method and application

Technical field

The invention discloses the non-linear multi-block polymer that a class is new, and the preparation method of this polymkeric substance, preparation process, the medical use of the required reagent of preparation and the non-linear many block polymerizations compound after preparing.

Background technology

Aging is the degeneration change that body is respectively organized, organ dysfunction occurs with age, is the comprehensive embodiment of organism physiology, pathologic process and biochemical reaction.Day by day urgent along with the problem of an aging population, the harm of diseases associated with senescence also strengthens gradually, becomes social hotspots.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: the invention discloses the non-linear segmented copolymer shown in following formula, its structure is as follows:

Integer wherein between n=1-200; Integer wherein between W=1-500.Integer wherein between n=1-200; Preferred n=1-100, the integer wherein between W=1-500, preferred 1-300.Its preparation method is:

1) compd A is obtained by reacting with compd A 1 and compd A 2;

2) compd A and acetylating 1,6-two (to carboxyphenoxy) hexane are obtained by reacting polymer B, the wherein integer of n=1-200, preferred 1-100;

Compd A 1 is selected from:

Compd A 2 is selected from:

Compd A:

Polymer B:

Wherein compd A 1 also can be selected from:

，

Wherein compound second also can be selected from:

Wherein optionally use solvent in chemical reaction step, described in step 1, solvent is selected from: one or more in chloroform, tetracol phenixin, methylene dichloride, dimethyl sulfoxide (DMSO), DMF, methyl alcohol, ethanol, benzene, toluene, pyridine, tetrahydrofuran (THF), dicyclohexylcarbodiimide; Step 2 optionally uses solvent, described solvent be selected from tetracol phenixin, dimethyl sulfoxide (DMSO), DMF, toluene, pyridine, tetrahydrofuran (THF), chloroform, methyl alcohol, ethanol, methylene dichloride, tetracol phenixin, methylene dichloride, dicyclohexylcarbodiimide one or more.

Preparation method of the present invention is specific as follows:

1) two for 1,6-(to carboxyphenoxy) hexane is refluxed in diacetyl oxide, form acetylizad 1,6-two (to carboxyphenoxy) hexane (also can be purchased);

2) compd A 1 dissolves with compd A 2 and mixes in a solvent, and at room temperature reaction is spent the night, and drying obtains compd A;

3) acetylizad 1,6-two (to carboxyphenoxy) hexane is mixed with compd A, react at 100-200 DEG C, reaction times 20min to 2h; After the cooling of question response mixture, washing, drying obtains polymer B;

Its reaction equation is as follows:

+

↓

+

↓

Aging is the degeneration change that body is respectively organized, organ dysfunction occurs with age, is the comprehensive embodiment of organism physiology, pathologic process and biochemical reaction.Day by day urgent along with the problem of an aging population, the harm of diseases associated with senescence also strengthens gradually, becomes social hotspots.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.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.This polymkeric substance also by chemical bond coupling drug, or forms suitable nanometer formulation by packaging medicine, microball preparation, implant preparation, and the preparation of formation still possesses the function described in the claims in the present invention, and also can play the function of medicine carrying medicine.

accompanying drawing illustrates:

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

embodiment 1

1) the mixture backflow of 1,6-two (to carboxyphenoxy) hexane 25g in 500ml diacetyl oxide, to form acetylizad 1,6-two (to carboxyphenoxy) hexane;

2) compd A 1 is 3g, and compd A 2 is that 51mg, dicyclohexylcarbodiimide 165mg and pyridine 8mg mix, and at room temperature stirs and spends the night; Then washed with diethylether is used, and dry under vacuo, obtain polymkeric substance;

3) chemical step the 1st step and the 2nd step Product mix are put into flask, decompression melting polyreaction 1 hour at 180 DEG C; Thing to be polymerized is cooled to room temperature chloroform and dissolves, and also dry by petroleum ether;

embodiment 2

1) the mixture backflow of 1,6-two (to carboxyphenoxy) hexane 30g in 300ml diacetyl oxide, to form acetylizad 1,6-two (to carboxyphenoxy) hexane;

2) compd A 1 is 2.7g, and compd A 2 is that 29mg, dicyclohexylcarbodiimide 130mg and pyridine 5mg mix, and at room temperature stirs and spends the night; Then washed with diethylether is used, and dry under vacuo, obtain polymkeric substance;

3) chemical step the 1st step and the 2nd step Product mix are put into flask, decompression melting polyreaction 1 hour at 150 DEG C; Thing to be polymerized is cooled to room temperature chloroform and dissolves, and also dry by petroleum ether;

effect experimental is as follows:

The polyoxyethylene glycol (molecular weight is 20000) (buying in Sigma-Aldrich of the U.S.) of sample prepared by embodiment 1-2 and purchase, poly-(two (p-carboxyphenoxy) hexane of 1,6-) (buying in Sigma-Aldrich of the U.S.) is carried out effect and is implemented experiment.

Experiment grouping is specially: first group blank healthy group, the second group model group, the 3rd group of embodiment 1 medication group, 4th group of embodiment 2 medication group, the 5th group of polyoxyethylene glycol medication group, the 6th group poly-(1, two (p-carboxyphenoxy) hexane of 6-) medication group, the 7th group of positive drug medication group.

The sample prepared by embodiment 1-2, the 3rd to the 6th group takes identical weight and tests.According to method described in former patent literature, carry out polymerizable compound of the present invention and to be correlated with pharmacodynamic experiment.

Experiment 1:

Aging is the degeneration change that body is respectively organized, organ dysfunction occurs with age, is the comprehensive embodiment of organism physiology, pathologic process and biochemical reaction.This research application β-tilactase staining detects the aging state of human embryonic lung diploid fibroblast, makes senile cell model, and furthers investigate the impact of cell growth from cellular signal transduction pathways, evaluate anti-aging effects.Use mouse to carry out in vivo test, every treated animal 10 (male and female half and half), experimental period is about 6 weeks simultaneously.Blank group does not do any special processing, and all the other administrations are respectively organized mouse and injected 0.5ml D-semi-lactosi (physiological saline is made into 5%) subcutaneous every day.Second group model group gavage 0.2ml every day physiological saline, the Ganoderma oral liquid (being purchased) of the 7th group of positive drug group gavage 3ml/kg every day, after the three to the six group of freeze-drying respectively according to the dosage of 0.5mg/kg first day intramuscular injection mouse.In experiment blood sampling after 6 weeks, centrifugal after antithrombotics anti-freezing, get supernatant for subsequent use.Put to death mouse after getting blood and open abdominal cavity, take liver and kidney.Make liver tissue homogenate and the kidney homogenate of 10%, centrifuging and taking supernatant is for subsequent use.After liver and kidney homogenate are diluted to 1%, according to test kit specification sheets method, application mda (MDA) test kit, superoxide-dismutase (SOD), nitricoxide synthase (NOS) test kit, Selenoperoxidase (GSH-PX) kit measurement plasma SOD and MDA, liver homogenate SOD and MDA, kidney homogenate GSH-PX and NOS.Experiment employment embryo lung diploid fibroblast strain comes from the Chinese Academy of Sciences, and after recovery, the sweet enzyme dyeing process of application beta galactose detects, and reaches the cell of more than 90% for aging model with positive cell ratio.On culturing cell and cell plate, instill isocyatic each group of medication respectively.In succeeding generations, adjustment cell density, on orifice plate, is examined under a microscope after beta-galactosidase enzymes dyeing and counts, deep green cell is positive cell, often organize counting 200 cells, calculate positive percentage, i.e. senile cell rate=deep green cell count/total cell count × 100%.

Experimental result:

Table 1 superoxide-dismutase Selenoperoxidase nitricoxide synthase mda Comparative result (n=10)

Each group of 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

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 is compared with model group

Table 2 β-tilactase stained positive rate reaches (n=10)

Each group of situation	Positive rate %
		First group	11.4±2.3
Second group	90.2±5.2
		3rd 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 (7)

1. the non-linear segmented copolymer be shown below, its structure is as follows:

Integer wherein between n=1-500; Preferred n=1-200, the integer wherein between W=1-2000, preferred 1-500.

2. the multipolymer of claim 1, its preparation method is:

1) compd A is obtained by reacting with compd A 1 and compd A 2;

2) compd A and acetylating 1,6-two (to carboxyphenoxy) hexane are obtained by reacting polymer B, the wherein integer of n=1-200, preferred 1-100;

Compd A 1 is selected from:

Compd A 2 is selected from:

Compd A:

Polymer B:

。

3. claim 1, the compd A 1 in 2 and A2, wherein compd A 1 also can be selected from:

，

Wherein compound second also can be selected from:

。

4. preparation method according to claim 2, wherein optional the following stated solvent in chemical reaction step, described in reaction 1, solvent is selected from: one or more in chloroform, tetracol phenixin, methylene dichloride, dimethyl sulfoxide (DMSO), DMF, methyl alcohol, ethanol, benzene, toluene, pyridine, tetrahydrofuran (THF), dicyclohexylcarbodiimide; Reaction 2 optionally uses solvent, one or more in described solvent selected from chloroform, methylene dichloride, methyl alcohol, ethanol, tetracol phenixin, dimethyl sulfoxide (DMSO), DMF, toluene, pyridine, tetrahydrofuran (THF), dicyclohexylcarbodiimide.

5. the purposes of the compound of claim 1-3, purposes is anti-ageing for animal.

6. the compound of claim 1-3 can be prepared into gastrointestinal administration preparation, intravenous administration formulation, intramuscular delivery preparation and be suitable for the nanometer formulation of topical, microball preparation, implant preparation.

7. claim 6, wherein said local is eye, ear, nose, the part administrations such as skin.