CN1047162C

CN1047162C - Acetylglutaminylzinc and its preparation and usage

Info

Publication number: CN1047162C
Application number: CN93104278A
Authority: CN
Inventors: 储亮侪; 夏小琳
Original assignee: Individual
Current assignee: Individual
Priority date: 1993-04-17
Filing date: 1993-04-17
Publication date: 1999-12-08
Anticipated expiration: 2013-04-17
Also published as: CN1094057A

Abstract

The present invention relates to a derivative of N-acetyl-L-glutamine, namely zinc salt disclosed in the specification, preparation thereof, and an application for using the zinc salt as an effective component of medicines for replenishing zinc or resisting ulcer. The compound is obtained by that N-acetyl-L-glutamine reacts with zinc carbonate hydroxide or zinc oxide in a polar solvent to form salt, and the decompressing concentration and the decompressing drying are carried out for the salt to obtain the compound. The compound has the functions of preventing and curing zinc deficiency of bodies and resisting ulcer.

Description

Acetylglutamide zn cpds and preparation thereof and application

The present invention relates to chemical substance N-acetyl-L-glutamine zinc and be aceglutamide zn cpds and preparation method thereof and aceglutamide zn cpds in pharmaceutically application.

Zinc is all life entity trace elements necessary, its content in human body is only second to iron and occupies second, zinc is present in 200 plurality of enzymes and the Regular Insulin, zinc is at accelerated wound healing, the aspects such as normal growth of retina location and bone all are essential, and particularly the g and D to children has vital role.Nearest many data show that peptide ulceration is a common disease, and sickness rate is very high, and recall rate is 19～33%.Zn cpds has the effect that stops or alleviate the experimentation on animals ulcer, simultaneously human body ulcer is had good therapeutic action.Cho C.H. has reported that zinc [sees DrugDevelopment Research 1989 to the pharmacological action of peptide ulceration; 17:185～197]; Ray T.K. has reported in the annual meeting of U.S. gi tract association that in 1989 zn cpds has the stomach of inhibition H ⁺, K ⁺The effect of-ATP enzyme [is seen Gastroenterology 1989; 96:A410].

The seventies just finds that zinc not only has prophylactic effect to experimental peptic ulcer, and the effect of zinc treatment ulcer is generally acknowledged, it is evident in efficacy that first is used for the treatment of peptide ulceration organic zinc compound zinc glycyrrhetate in the world, but because the acid group Potenlini of zinc glycyrrhetate has class steroid hormone structure, can occur untoward reactions such as the slide of water sodium pool, hypokalemia after taking, use is restricted.1978 Spain (Laboratorios Vinas S A) applied for kharophen caproic acid zinc organic zinc compound patent, the patent No. is ES466455.Spain's government permission in 1988 kharophen caproic acid zinc be used for the treatment of ulcer because the kharophen caproic acid is a hemostatic drug, cause cerebral vessels embolism easily, so there is the patient of thrombophilia to take.Just reported that as far back as nineteen sixty-eight Takagl and Okabe L-glutaminate has tangible prophylactic effect [to see Japanese pharmaceutical journal 1968 to the irritability gastric mucosa injury of rat; 18:9～18].Because the independent result of use of L-glutaminate is undesirable, is Mai Zilin so Japan is used for the treatment of the peptide ulceration medicine in recent years, Mai Zilin is the compound medicine that contains L-glutaminate and water-soluble Austria, has entered Chinese market at present.The N-acetyl-L-glutamine has the physiologically active of glutamine, and the both is intravital endogenous material, therefore Japan applied for the antiulcer compound patent of aceglutamide aluminum, patent No. JP81,113 in 1980,750, and be used for the clinical treatment peptide ulceration, effect is remarkable, along with the raising of research level, medical circle causes the harm of brain that further understanding has been arranged to aluminium, and acetylglutamide aluminium consumption clinically seldom.

In a word, the existing organic zinc chemical substance defectiveness that is used for the treatment of medicine for ulcer has certain restriction to the use of human body.

Purpose of the present invention, be to improve at above-mentioned the deficiencies in the prior art, provide a kind of new derivative of N-acetyl-L-glutamine ... N-acetyl-L-glutamine zinc is the acetylglutamide zn cpds, and can the purposes of product aspect prevention and the scarce zinc of treatment and prevention and treatment peptide ulceration be proposed simultaneously for the synthetic process of producing.

For realizing purpose of the present invention, the preparation method for making of acetylglutamide zinc is to be raw material with N-acetyl-L-glutamine and zinc subcarbonate or zinc oxide, zinc subcarbonate, zinc oxide joins in the aqueous solution of N-acetyl-L-glutamine by the chemical ratios amount, perhaps add 0～20% than chemical ratios amount, at 50～100 ℃, between best 60～80 ℃ behind the stirring reaction salify, cool to room temperature, be cooled to 4～5 ℃ again, filter, filtrate be no more than 60 ℃ be evaporated to dried, be lower than 80 ℃ down dry, be preferably lower than 80 ℃ of following drying under reduced pressure, must the product of falling white solid acetylglutamide zinc.

Reaction formula is:

The acetylglutamide zinc that must fall is a kind of white mass, has following physico-chemical property:

Fusing point: 148～152 ℃ (capillary tube technique);

MS m/z (FAB substrate: glycerine): 440 (M ⁺+ H), 189 (FAB-MS methods);

IR infrared absorpting light spectra (KBr pressed disc method): 3318cm ^-1, 1672cm ^-1, 1616cm ^-1, 1425cm ^-1, 1131cm ^-1, 575cm ^-1

Acetylglutamide zinc has certain physiologically active, can be absorbed by body after oral.Can be used for prevention and treatment body zinc deficiency; Give rat oral gavage in advance with it, can significantly improve the ulcer that dehydrated alcohol brings out rat stomach, have the cytoprotection of stomach simultaneously.

The experiment of acetylglutamide zn cpds pharmacological action is according to documents and materials [Esplugues etal:European Joumal Pharmacology.1985; 109:145～151] method give this compound to rat by the dosage of (one day, two days and three days) 100mg/kg, 200mg/kg and 300mg/kg, the ulcer that administration group dehydrated alcohol brings out rat stomach is 0, and blank group ulcer length is 6.14 ± 4.99 (cm).

Acetylglutamide zinc is compared with kharophen caproic acid zinc, can avoid because the danger of kharophen cerebral vessels embolism that caproic acid causes; Compare the detrimentally affect that this compound can avoid aluminum ion to produce IC accumulating with N-acetyl-L-glutamine aluminium; Compare with Zinc Gluconate, take this compound and not only can replenish zinc, and can absorb endogenous material N-acetyl-L-glutamine the nutritious effect of body.

Acetylglutamide zn cpds of the present invention, has certain physiologically active, can be used for preventing and treating the effective ingredient that lacks the zinc pharmaceutical preparation, can also be used to prevent and treat the effective ingredient of digestive ulcer medicament preparation, this compound does not add or add medicinal auxiliary material can be prepared into a series of oral preparations, compare with kharophen caproic acid zinc, can avoid the side effect that easily causes blood vessel inspection plug to cause; Compare with aceglutamide aluminum, can avoid the harm of aluminium brain.

Below in conjunction with embodiment compound and preparation method and the pharmacological effect of invention are further described:

Embodiment 1:

N-acetyl-L-glutamine and zinc subcarbonate prepared in reaction acetylglutamide zinc:

Get N-acetyl-L-glutamine 5g, after adding the water dissolution of 150ml, add zinc subcarbonate 0.9g, stirred one hour down for 37 ℃ in temperature, temperature is risen to 50～100 ℃ then, preferably 60～80 ℃, continuation is chilled to room temperature after stirring more than 30 minutes, be chilled to 4～5 ℃ then, kept 12 hours, and filtered, be evaporated to dried at 55～60 ℃, take out the back and be lower than 80 ℃ of following drying under reduced pressure, promptly get acetylglutamide zinc 5.1g, products obtained therefrom sampling and measuring fusing point carries out mass spectrum and Infrared spectroscopy.

Embodiment 2:

N-acetyl-L-glutamine and zinc oxide prepared in reaction acetylglutamide zinc:

Get N-acetyl-L-glutamine 5g, after adding the water dissolution of 150ml, add zinc oxide 2.5g, be warmed up to 50～100 ℃, stirring reaction is more than 30 minutes, be chilled to room temperature, be chilled to 4～5 ℃ then, under this temperature, kept 12 hours, filter, be evaporated to driedly at 58～60 ℃, take out the back and is being lower than 80 ℃ of following drying under reduced pressure, promptly get acetylglutamide zinc product 5.1g, sampling records 148～152 ℃ of product fusing points, (FAB-MS) does mass spectroscopy by fast-atom-bombardment mass spectrometry, and the KBr pressed disc method is done infrared absorption spectrum analysis, determines the chemical structure of product.

Fig. 1 is the mass spectrum of example 1,2 products obtained therefroms

Fig. 2 is the infrared spectrogram of example 1,2 products obtained therefroms

Mass spectrogram 1 condition is that bombarding gas is Ar, accelerating potential 8KV, Ar ion current 2mA, substrate Glycerine.

MS m/z (FAB substrate glycerine) as seen from Figure 1: 440 (M⁺+H)、189。

As shown in Figure 2,3318cm is arranged^-1、1672cm ^-1、1616cm ^-1、1425cm ^-1、1131cm ^-1、 575cm ^-1。

Determine that thus product is that N-acetyl-L-glutamine zinc compound is NacetylLglutamine Zinc.

Embodiment 3:

The pharmacological evaluation of NacetylLglutamine Zinc compound:

Method [European Journal Pharmcology.1985 according to Esplugues et al report; 109:145～151]: to the agent of rat by (a day, two days and three days) 100,200,300mg/kg Amount gives NacetylLglutamine Zinc, and compares with not giving the rat of NacetylLglutamine Zinc. The experiment knot Fruit is listed in table 1. The effect of the anti-absolute ethyl alcohol rat ulcer of table 1 NacetylLglutamine Zinc compound Rat control group (cm) administration group (cm) 1 8.36 0 2 2.60 0 3 0.60 0 4 10.31 0 5 3.0 0 6 12.0 0 7 1.2 0 8 0.8 0 9 13.4 0 10 9.12 0 X 6.14 0* SD 4.99 0 Annotate: * and control group be P＜0.01 relatively It is simple that the NacetylLglutamine Zinc compound possesses synthesis technique, can be applied to industrial production.

Claims

1. acetylglutamide zn cpds is characterized in that it being the compound with formula I structural formula:

Formula I

2. the preparation method of an acetylglutamide zn cpds, it is characterized in that the N-acetyl-L-glutamine and Duo the reaction after a hour in 37 ℃ of water earlier of 0～20% zinc subcarbonate than the chemical ratios amount, react more than 30 minutes at 50～100 ℃ again, cooling, filter, filtrate is at 55～60 ℃ of concentrating under reduced pressure then, and the resultant of collection is being lower than 80 ℃ of drying under reduced pressure.

3. the preparation method of an acetylglutamide zn cpds, it is characterized in that N-acetyl-L-glutamine and 0～20% the zinc oxide of Duoing than the chemical ratios amount react more than 30 minutes in 50～100 ℃ of water, cooling, filter, filtrate is at 58～60 ℃ of concentrating under reduced pressure then, and the resultant of collection is being lower than 80 ℃ of drying under reduced pressure.

4. the described acetylglutamide zinc of claim 1 application in the ZD medicine in preparation prevention or treatment body.

5. one kind is prevented or the interior ZD composition of treatment body, comprises the acetylglutamide zinc of the claim 1 for the treatment of significant quantity and acceptable carrier or vehicle on pharmacology.

6. the application of the described acetylglutamide zinc of claim 1 in the medicine of preparation prevention or treatment peptide ulceration.

7. a composition that prevents or treat peptide ulceration comprises the acetylglutamide zinc of the claim 1 for the treatment of significant quantity and acceptable carrier or vehicle on pharmacology.