CN104177612A - New nonlinear polymer and preparation and use thereof - Google Patents

Abstract

The invention discloses a new nonlinear polymer containing a metal ion structure, and a preparation method and use thereof. A compound with a branch structure is used for construction of the new nonlinear polymer, and the new structure is used for testing in eczema animal models, and the new compound has excellent therapeutic effect on the treatment of eczema disease.

Description

A kind of new non-linear polymer and preparation and purposes

Technical field

The invention discloses preparation method and the purposes of a kind of non-linear polymer that contains metal ion structure and this polymkeric substance.

Background technology

Eczema has ear eczema, Hand and Foot Eczema, eczema mammae, anus eczema of external genitalia, legs eczema etc.Eczema can occur in any position, but taking exsertion part and side in the wrong as common; Fash often symmetry distributes.Eczema has a variety of classification, and more common classification is to damage characteristicness by skin to be divided into three kinds of acute, subacute and chronic eczemas.Wherein acute eczema is most grain grain large red papules, papulo-vesicle or blister, still has obvious point-like or strip erosion, sepage, incrustation.Infringement indefinite border.When concurrent infection, can occur that warts, purulence are oozed out and scab bits etc.; Subacute eczema is often dealt with improperly and is delayed to come because of acute phase infringement, and skin damages taking red papule, maculopapule or incrustation as main, has minority papulo-vesicle or blister and rotten to the corn sepage concurrently; That chronic eczema has more is acute, subacute eczema is not more transformed repeatedly, and skin damages as dark red or reddish brown color spot or maculopapule, and permelting is closed to thicken and is lichenification, and there is scab etc. on surface, is dispersed in minority papule, maculopapule etc. around.Treat with ointments such as glucocorticosteroid, zinc oxide, furoic acid momisones clinically, but result for the treatment of is limited, efficient not high.The inventor is surprised to find that a kind of compound has an unexpected effect on the medicine of preparation treatment eczema, there is no report at present for this base polymer treatment eczema.

Summary of the invention

Of the present invention theing contents are as follows:

The invention discloses the novel polymer structure shown in following formula, its structure is as follows:

Wherein the molecular weight polyethylene glycol in polymkeric substance is 100-200000, the integer between m=1-5000, the preferably integer between m=1-2000.

The preparation method of this compound, is characterized in that:

1) the structure A that contains nitrilotriacetic acid(NTA)-Methionin reacts and obtains Compound C with compd B in sodium hydrogen carbonate solution;

2) after Compound C and Compound D stirring reaction, obtain compd E;

3) compd E reacts to obtain product G with the compound F 17-hydroxy-corticosterone containing Y type polyoxyethylene glycol in solvent, and wherein the molecular weight polyethylene glycol in polymkeric substance is 100-200000;

4) compound G reacts to obtain compound H with Ni ionic compound;

Compd A;

Compd B;

Compound C;

Compound D;

Compd E;

Compound F 17-hydroxy-corticosterone;

Compound G;

End product H.

Wherein said chemical reaction step selects solvent to be selected from: one or more in acetic acid, formic acid, benzene, toluene, pyridine, tetrahydrofuran (THF), trifluoroacetic acid, chloroform, tetracol phenixin, methylene dichloride, methyl alcohol, ethanol, methylene dichloride, dimethyl sulfoxide (DMSO), DMF.Compound can be prepared into and be suitable for muscle, vein or the preparation of topical.Described preparation, it can be ordinary preparation, controlled release preparation, targeting preparation etc.Described part is percutaneous drug delivery or other mode administrations.Described compound and pharmacologically acceptable salt thereof the purposes in the medicine of preparation treatment eczema.

Preparation method of the present invention is specific as follows:

By compd A (being purchased) 10mg-10g and compd B (being purchased) 0.01g-5g as for 0.1-96 hour in solvent, cooling after 1-48 hour in 50 degree-100 degree heating, regulate PH to 2-5, after concentrating under reduced pressure, in ethanol, wash, after being dried, obtain Compound C, Compound D (being purchased) stirs 1-10 hour with C in phosphoric acid salt, concentrating under reduced pressure obtains compd E, and compd E reacts to obtain compound G, the NiCl of compound G and 1-5mol with the Y type compound F 17-hydroxy-corticosterone (being purchased) that contains polyoxyethylene glycol being purchased ₂react 1-48 hour to obtain final product compound H.Freeze-drying obtains the freeze-dried preparation of end product.

Reaction scheme is:

Compd A

+

Compd B

Generate

Compound C;

Compound C

+

Compound D

Generate

Compd E;

Compd E

+

Compound F 17-hydroxy-corticosterone

Generate

Compound G

，

Compound G

+

Ni ionic compound

Generate

Compound H

The preparation that the end product of preparing at this patent is made treatment eczema relatively in, the medication effect of this patent new compound is very good, very good by the preparation for treating eczema effect of making of this patent.

brief description of the drawings:

fig. 1the nuclear magnetic resonance map of preparing 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 Example is as follows:

embodiment 1

Compd A (being purchased) 500mg is dissolved in 6ml water, with 600mg sodium bicarbonate and 500mg compd B (being purchased) as in same beaker 15 hours, cooling after heating 70 degree, acetic acid regulator solution PH to 3, after concentrating under reduced pressure, in ethanol, wash, crystallization obtains Compound C, filtering ethanol washs rear dry again, 400mg Compound D (being purchased) is dissolved in the phosphoric acid buffer of PH7.5, and stir 2 hours with Compound C, concentrating under reduced pressure, washing with alcohol, filter and wash again, the positive empty compd E that is dried to obtain, compd E and the Y type compound F 17-hydroxy-corticosterone that contains polyoxyethylene glycol being purchased, in methanol solution, stir 6 hours, react to obtain compound G, compound G reacts to obtain final product compound H with the NiCl2 of 2Mol.

embodiment 2

Compd A (being purchased) 1000mg is dissolved in 6ml water, with 900mg sodium bicarbonate and 1200mg compd B (being purchased) as in same beaker 24 hours, cooling after heating 75 degree, acetic acid regulator solution PH to 3.3, after concentrating under reduced pressure, in ethanol, wash, crystallization obtains Compound C, filtering ethanol washs rear dry again, 800mg Compound D (being purchased) is dissolved in the phosphoric acid buffer of PH7.5, and stir 2 hours with Compound C, concentrating under reduced pressure, washing with alcohol, filter and wash again, the positive empty compd E that is dried to obtain, compd E and the Y type compound F 17-hydroxy-corticosterone that contains polyoxyethylene glycol being purchased, in methanol solution, stir 8 hours, react to obtain compound G, the NiCl of compound G and 3Mol ₂react to obtain final product compound H.

effect experiment is as follows:

Sample prepared by embodiment 1-2 is compared with the experiment of the effect of other various medicines.Be specially:

First group is embodiment 1 sample sets;

Second group is embodiment 2 sample sets;

The 3rd group is polyoxyethylene glycol group;

The 4th group is Ni ionic group;

The 5th group of positive medicine furoic acid momisone group;

effect embodiment:

The therapeutic action of medicine to eczema

1, suppress swelling effect: 70 of rats, be divided at random 7 groups, every group 10, be divided at random 7 groups, normal group, model group, furoic acid momisone group, polyoxyethylene glycol group, Ni ionic group and medicine embodiment group, experiment is when daily liquid capacity method, measure the right back sufficient volume of each group of rat with homemade volume determination device, then (the painting dose of medicine embodiment group is 25ul to smear medicine to each group, polyoxyethylene glycol group (molecular weight is 8000), Ni ionic group (the NiCl2 solution of 2 moles), the painting dose of furoic acid momisone group is 30mg/), wherein normal group and model group are smeared distilled water, after 1 hour, the egg white (every injection 0.05ml) of the right back sufficient subcutaneous injection 10% of each group (except normal group).Then measure 1 hour with volumetric method, 2 hours, 4 hours, the right back sufficient volume of 6 hours, right back sufficient volume change value is worth being relatively swelling rate with first initial body machine, the swelling rate after the medication of relatively more each group, the action effect of evaluation medicine embodiment.

Table 1 swelling rate test-results (n=10)

Group	4 hours swelling rates (%)	6 hours swelling rates (%)
			Normal group	0.0±1.9**	0.0±2.4**
Model group	54.0±12.3	53.2±16.4*
			Furoic acid momisone group	49.2±10.3	43.1±16.7
Polyoxyethylene glycol group	53.5±5.5	56.4±2.3
			Metal ion group	51.5±4.1	56.2±1.9
Embodiment 1	19.9±6.1**	14.5±7.3**
			Embodiment 2	20.5±7.0**	12.8±6.6**

With relatively * P<0.05**P<0.01 of model group

2, itching-relieving action: cavy is divided into 7 groups at random, normal group, model group, furoic acid momisone group and medicine embodiment group, 10 every group.Test first 24 hours by each group of Guinea Pig Left dorsal portion unhairing, the about 1cm of area ², and carry out coating the 1st time, and the painting dose of medicine embodiment group is 25ul, the painting dose of polyoxyethylene glycol group, Ni ionic group, furoic acid momisone group is to smear twice 30mg/ every day.Abrade unhairing place, left back instep with flint paper, coating 1 time is coating again after 1 hour then, after administration 3 hours, only smears 0.01% histamine phosphate 0.05mL/ at cavy surface of a wound place, observe 5min, after this use successively the concentration of 0.02%, 0.03%, 0.04% speed increase administration histamine phosphate every 5min, only be 50ul/ at every turn, until occur that cavy later licks left back foot, the cumulative histamine phosphate total amount of giving is itch-threshold, record more each treated animal itch-threshold.

The impact (n=10) of table 2 medicine on guinea pig skin itch due to histamine phosphate

Group	Itch-threshold (histamine phosphate total amount mg)
		Normal group	530.6±28.0**
Model group	110.2±29.6
		Furoic acid momisone group	208.1±49.3*
Polyoxyethylene glycol group	111.0±33.3
		Metal ion group	120.3±34.2
Embodiment 1	423.6±34.0**
		Embodiment 2	427.3±31.7**

With relatively * P<0.05**P<0.01 of model group.

Claims (9)

1. the new compound structure being shown below, its structure is as follows:

。

2. the polymkeric substance of claim 1, wherein the molecular weight polyethylene glycol in polymkeric substance is 100-200000, the integer between m=1-5000, the preferably integer between m=1-2000.

3. the preparation method of compound as claimed in claim 1, is characterized in that:

1) the structure A that contains nitrilotriacetic acid(NTA)-Methionin reacts and obtains Compound C with compd B in sodium hydrogen carbonate solution;

2) after Compound C and Compound D stirring reaction, obtain compd E;

3) compd E reacts to obtain product G with the Y type compound F 17-hydroxy-corticosterone containing polyoxyethylene glycol in solvent, and wherein the molecular weight polyethylene glycol in polymkeric substance is 100-200000;

4) compound G reacts to obtain compound H with Ni ionic compound;

Compd A;

Compd B;

Compound C;

Compound D;

Compd E;

Compound F 17-hydroxy-corticosterone;

Compound G;

End product H.

4. the method for claim 3, wherein said chemical step selects solvent to be selected from: one or more in acetic acid, formic acid, benzene, toluene, pyridine, tetrahydrofuran (THF), trifluoroacetic acid, chloroform, tetracol phenixin, methylene dichloride, methyl alcohol, ethanol, methylene dichloride, dimethyl sulfoxide (DMSO), DMF.

5. the compound of claim 1 can be prepared into and be suitable for muscle, vein or the preparation of topical.

6. the described preparation of claim 5, it can be ordinary preparation, controlled release preparation, targeting preparation etc.

7. topical described in claim 5 is the various preparations for the direct administration of skin.

8. the compound of claim 1, described compound and pharmacologically acceptable salt thereof the purposes in the medicine of preparation treatment eczema.

9. the purposes of claim 8, the treatment of described eczema contains the treatment to acute, subacute and chronic eczema.