CN104341590A - A dendritic polymer compound, preparation thereof and uses of the dendritic polymer compound - Google Patents

Abstract

Preparation and uses of a novel dendritic polymer are disclosed. The dendritic polymer is a dendritic compound containing an ethacrynic acid structure and a polyethylene glycol structure. A preparing method and the uses of the dendritic polymer are also disclosed. Anti-ageing effects of the dendritic compound containing the ethacrynic acid structure and the polyethylene glycol structure are better than that of medicines or medicaments of other forms.

Description

A kind of dendrimer compound and preparation thereof and purposes

Technical field

The invention discloses a kind of preparation and purposes of dendrimer of novelty, it refers to containing Uregit structure and the dendrimer of polyethylene glycol structures and the preparation method of this compound and purposes.

Background technology

Anti-ageing is a global difficult problem, current scientific circles there is no final conclusion for the secret of aging, be known as and caused by many reasons, day by day urgent along with the problem of an aging population, the increase day by day of aging colony, and the seriousness of the various diseases produced after human senility manifests day by day, a kind of very effective medicine is needed to go to delay senility clinically, and the various relative disease produced due to aging of assisting therapy.

The present inventor is surprised to find that a kind of dendrimer containing Uregit structure of novelty has beyond thought outstanding effect on the antidotal medicine of preparation, there is no report at present for this compounds is anti-ageing.

Summary of the invention

Content of the present invention is as follows:

The invention discloses the dendrimer containing polyethylene glycol structures of the Uregit coupling shown in following formula, its structure is as follows:

Molecular weight polyethylene glycol wherein in compound is the integer between 100-200000, W=1-500, the integer between preferred W=1-300.It is characterized in that:

1) containing carboxyl and methoxyl group ending polyoxyethylene glycol B and dendrimer A be obtained by reacting C, the wherein integer of W=1-500, preferred 1-300;

2) one is decomposed into half dendrimer D with active group with the dendrimer C of polyoxyethylene glycol ending;

3) compd E and half dendrimer D are obtained by reacting the dendrimer F containing Uregit structure;

Dendrimer A;

Compd B;

Compound C;

Compound D;

Compd E;

Compound F 17-hydroxy-corticosterone.

Each step of wherein said chemical step selects solvent to be selected from: one or more in benzene, toluene, pyridine, tetrahydrofuran (THF), trifluoroacetic acid, chloroform, tetracol phenixin, 3-(2-pyridine dimercapto) propionic acid N-hydroxy-succinamide ester, tricresyl phosphate (2-chloroethyl) ester, methylene dichloride, methyl alcohol, ethanol, methylene dichloride, dimethyl sulfoxide (DMSO), DMF.Compd A, B, E are for being purchased, and end product F can be prepared into and be suitable for intravenous administration, administered intramuscular, oral administration, the nanometer formulation of topical, microball preparation or implant preparation.Described topical is head administration, local skin or organ administration, intravitreal injection administration or other mode administrations of eye.Purposes is the medicine that preparation has antisenility function.

Preparation method of the present invention is specific as follows:

1) dendrimer A and the polyoxyethylene glycol B containing carboxyl are reacted, obtain Compound C;

2) the dendrimer C of polyoxyethylene glycol ending is decomposed into half dendrimer D with active group;

3) Uregit compd E and half dendrimer, is under the condition of about 7 at PH, within normal-temperature reaction 1-3 hour, is obtained by reacting the dendrimer F containing Uregit structure;

4) by the solution ultrasonic reaction containing F after 1-30 minute, then homogenizer high-speed stirring 1-10 minute in 0-is subzero 30 DEG C, rotates volatilization and obtains crude product, and after centrifugal acquisition, freeze-drying both must preparation containing end product.

Its reaction equation is as follows:

+

Compound C;

Half dendrimer compound containing sulfydryl is obtained after Compound C cracking reduction

。

Then rapid just cracking is opened be obtained by reacting end product containing half dendrimer of polyethylene glycol structures and Uregit:

+

The brand-new dendrimer containing Uregit structure and polyethylene glycol structures that the present invention obtains, is easy to dissolve in water, and its transformation period extends a lot than Uregit, and such new compound is at antidotal work highly significant.

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

1) dendrimer A5g and the polyoxyethylene glycol B3g containing carboxyl are reacted at methyl alcohol, obtain Compound C;

2) in the dendrimer C dimethyl sulphoxide solution of the polyoxyethylene glycol ending obtained, reduction decomposition is half dendrimer D with active group;

3) 3-(2-pyridine dimercapto) propionic acid N-hydroxy-succinamide ester 1g and Uregit E5g obtains the compound F 17-hydroxy-corticosterone containing Uregit structure for 1 hour in PH7 condition normal-temperature reaction;

4) by the solution ultrasonic reaction containing F after 5 minutes, then homogenizer high-speed stirring 3 minutes in subzero 5 DEG C, rotates volatilization and obtains crude product, after centrifugal acquisition freeze-drying both nanometer formulation.

 

embodiment 2

1) dendrimer A4g and the polyoxyethylene glycol B4g containing carboxyl are reacted in ethanolic soln, obtain Compound C;

2) dendrimer C reduction decomposition in dichloromethane solution of polyoxyethylene glycol ending is half dendrimer D with active group;

3) 3-(2-pyridine dimercapto) propionic acid N-hydroxy-succinamide ester 1g and Uregit F7g obtains the compound F 17-hydroxy-corticosterone containing Uregit structure for 3 hours in PH7.5 weak basic condition normal-temperature reaction;

4) by the solution ultrasonic reaction containing F after 15 minutes, then homogenizer high-speed stirring 1 minute in subzero 10 DEG C, rotates volatilization and obtains crude product, after centrifugal acquisition freeze-drying both nanometer formulation.

effect experimental is as follows:

The sample prepared by embodiment 1-2 and Uregit and Cys coupled product medication group, Uregit ordinary preparation (powder injection) according to method described in patent CN201210497052.5, carries out the antidotal pharmacodynamic experiment of compound on animals respectively

1.1 laboratory animal and grouping

Experiment Kunming small white mouse, about body weight 20g.By animal random packet: i.e. blank group; Model group; Embodiment 1 group, embodiment 2 groups, and Uregit and Cys coupled product medication group, Uregit ordinary preparation (powder injection), positive drug group.

The foundation of 1.2 animal models

According to method design experiment described in CN201210497052.5, every treated animal 10 (male and female half and half), sub-cage rearing, 6 weeks experimental periods.Blank group is normally taken food every day, is left intact, and all the other respectively organize mouse dorsal sc injection every day 0.5ml D-semi-lactosi (physiological saline is made into 5%).Model group gavage 0.2ml every day physiological saline, positive drug group gavage 2.5ml/kg every day Ganoderma tsugae oral liquid (positive drug of purchase), embodiment 1 group, embodiment 2 groups, Uregit and Cys coupled product medication group, Uregit ordinary preparation group respectively according to 0.5mg injection/kg dosage in first day intramuscular injection once.

1.3 experiment detection method

In experiment after 6 weeks, eyeball is taken a blood sample, and after antithrombotics anti-freezing, 2500r/min is centrifugal, gets supernatant liquor refrigerator cold-storage for subsequent use.Put to death mouse with dislocation method after getting blood and open abdominal cavity immediately, take liver and kidney.Hepatic and renal tissue block ice brine removing blood, filter paper examination is dry, takes 0.2g respectively, adds physiological saline, make liver tissue homogenate and the kidney homogenate of 10%, and with the centrifugal 15min of 3000r/min, getting supernatant liquor, to put refrigeration in refrigerator for subsequent use.After liver and kidney homogenate are diluted to 1%, according to specification sheets method (mda (MDA) test kit, superoxide-dismutase (SOD) test kit, nitricoxide synthase (NOS) test kit, Selenoperoxidase (GSH-PX) test kit is all bought and is built up Bioengineering Research Institute in Nanjing) apply microplate reader and measure the protein content of liver and kidney and record; Plasma SOD and MDA, liver homogenate SOD and MDA, kidney homogenate GSH-PX and NOS all carry out mensuration and calculation result according to method, step appended by test kit.

1.4 experimental result

Experimental result is in table 1

SOD (u/ml) under table 1 each group drug treatment and MDA (nmol/ml) result (mmHg, n=10)

Group	Plasma SOD	Blood plasma MDA	Hepatic tissue SOD	Hepatic tissue MDA
					Normal group	370.81±50.82**	12.08±2.13**	69.08±10.81**	1.98±0.33**
Model group	298.27±41.65	15.90±2.69	48.00±14.60	2.90±0.69
					Embodiment 1	367.12±46.23**	11.97±1.68**	65.31±11.98**	1.91±0.34**
Embodiment 2	355.21±49.69**	11.98±1.97**	66.36±11.52**	1.90±0.36**
					Uregit-Cys	301.50±53.67*	12.22±1.83**	52.47±11.63*	2.75±0.53*
Uregit	310.93±71.46*	12.06±1.91**	52.52±12.47*	2.68±0.57*
					Positive drug group	307.42±60.21*	14.55±2.26*	52.09±14.38*	2.74±0.67*

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

GSH-PX and NOS (u/mgprot) result (n=10) under drug treatment respectively organized by table 2

Group	GSH-PX	NOS
			Normal group	3.67±1.22**	0.83±0.10**
Model group	1.90±0.87	0.60±0.12
			Embodiment 1	3.46±1.25**	0.83±0.09**
Embodiment 2	3.52±1.14**	0.82±0.10**
			Uregit-Cys	2.17±0.97*	0.70±0.12*
Uregit	2.20±0.96*	0.73±0.09*
			Positive drug group	2.18±1.23*	0.72±0.20*

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

Claims (8)

1. a kind of new dendrimer in the structure be shown below, its structure is as follows:

。

2. the compound of claim 1, the molecular weight polyethylene glycol wherein in compound is the integer between 100-200000, W=1-500, the integer between preferred W=1-300.

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

1) containing carboxyl and methoxyl group ending polyoxyethylene glycol B and dendrimer A be obtained by reacting C, the wherein integer of W=1-500, preferred 1-300;

2) one is decomposed into half dendrimer D with active group with the dendrimer C of polyoxyethylene glycol ending;

3) compd E and half dendrimer D are obtained by reacting the dendrimer F containing Uregit structure;

Dendrimer A;

Compd B;

Compound C;

Compound D;

Compd E;

Compound F 17-hydroxy-corticosterone.

4. the method for claim 3, wherein said chemical step 1-4 selects solvent to be selected from: one or more in benzene, toluene, pyridine, tetrahydrofuran (THF), trifluoroacetic acid, chloroform, tetracol phenixin, 3-(2-pyridine dimercapto) propionic acid N-hydroxy-succinamide ester, tricresyl phosphate (2-chloroethyl) ester, methylene dichloride, methyl alcohol, ethanol, methylene dichloride, dimethyl sulfoxide (DMSO), DMF.

5. the compound of claim 1 can be prepared into various preparation, and it can be ordinary preparation, controlled release preparation, targeting preparation.

6. the compound of claim 1 can be prepared into and be suitable for intravenously administrable, administered intramuscular, oral administration, the nanometer formulation of topical, microball preparation or implant preparation.

7. topical described in claim 6 comprises head administration, topical cutaneous administration, intravitreal injection administration.

8. the purposes of the compound of claim 1, purposes is the purposes prepared in antiaging agent.