CN100415761C - Nucleophilic N0 donor of alkyl modified amido glucose, and synthetic method - Google Patents
Nucleophilic N0 donor of alkyl modified amido glucose, and synthetic method Download PDFInfo
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- CN100415761C CN100415761C CNB2006100283171A CN200610028317A CN100415761C CN 100415761 C CN100415761 C CN 100415761C CN B2006100283171 A CNB2006100283171 A CN B2006100283171A CN 200610028317 A CN200610028317 A CN 200610028317A CN 100415761 C CN100415761 C CN 100415761C
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Abstract
The present invention relates to an alkyl modified aminoglucose nucleophilic NO donor and a synthetic method thereof, which belongs to the technical field of medicine engineering. The method of the present invention comprises: the NH2 group of aminoglucose is treated by alkylation modification so that a nucleophilic NH group which can react with NO is produced; secondary amine NH groups of aminoglucose molecules react with NO gas molecules in a methanol solution of sodium methoxide under high pressureafter being treated by alkylation modification, wherein ratio of Na to NH is 2; the pressure is 5 atm; the reaction lasts 5 days at room temperature to produce [N(O)NO]<-> groups; the molecular structural formula of an obtained alkyl modified aminoglucose nucleophilic NO donor is disclosed in the right figure. A new nucleophilic NO donor of the present invention has different NO releasing rate and long half-life, overcomes the cytotoxicity of nucleophilic reagents (polyamine), and avoids the generation of a carcinogenic byproduct nitrosamine; the new nucleophilic NO donor has significant clinical application value and application prospect.
Description
Technical field
The present invention relates to a kind of medicine and synthetic method thereof of pharmaceutical engineering technical field, specifically is a kind of nucleophilic N 0 donor of alkyl modified amido glucose and synthetic method thereof.
Background technology
Contain [N (O) NO]
-The compound of functional group is a kind of most important NO donor medicine that grew up in recent years.It both can be under physiological condition spontaneous release NO molecule; After O2 replaces, can in target organ and target cell, be broken away from again, have the function of target by certain enzyme; It also has good Modulatory character; It can be prepared into various forms in addition, is applied to different medical fields as required.It can effectively prevent the moulding postoperative restenosis though a large amount of in vitro testss is verified, improve the antithrombotic property of medical treatment device, alleviate purposes such as lung's high pressure and vasospasm is right, but the generation of the cytotoxicity of nucleophilic reagent (polyamines) and carinogenicity by product nitrosamine is a main difficult problem that limits its clinical application.
In nearest 10 years, abroad to based on containing [N (O) NO]
-The NO donor controlled-release material of functional group has carried out a large amount of research.The nucleophic NO donor NONOate that initial research concentrates on ionic is scattered in the various hydrophobic polymers, strengthens the blood compatibility of these materials by the release of NO.Though these researchs have obtained considerable success, discover, hydrophilic NO donor can ooze out from polymkeric substance, forms the N-nitrosamine material of carinogenicity in blood.This class material is applied to clinical, also must consider following some: as the biocompatibility and the biodegradability of polymer matrix material.The cytotoxicity of nucleophilic reagent and biocompatibility.[N (O) NO] arranged
-Group carrier such as diethylenetriamine are found health harmful; Polymine (PEI) can be induced necrocytosis widely, and biocompatibility is relatively poor.Therefore select for use the nontoxic NO carrier that good biocompatibility is arranged to cause people's attention.One of terms of settlement wherein be exactly to adopt the harmless nucleophilic carrier with secondary amine group of health as (polyamino acid, micromolecule polypeptide).
D-glucosamine is the monose that is obtained by degradation of chitosan, not only has the synthetic isoreactivity of treatment of arthritis, anti-inflammatory, stimulatory protein(SP) polysaccharide, and can activate N K, LAK cell, has immunoregulation effect.D-glucosamine almost is distributed in human body institute in a organized way, participates in structure tissue and cytolemma, is protein-polysaccharide macromole synthetic intermediate material.Because this compounds has physiologically active, therefore use comparatively extensive at medicine, biological field.Because glucosamine and modified product thereof have good biological activity and pharmaceutical use, with its modification as a kind of nontoxic NO pharmaceutical carrier, can overcome the cytotoxic effect of polyamines carrier commonly used on the one hand, can overcome the inefficient problem of the chitin modified product load of macromole NO on the other hand, also can bring into play the D-glucosamine pharmacological action, be a kind of very promising novel NO donor therefore.
Find that through literature search people such as Smith are (USP6261594, Chitosan-based nitric oxide donor compositions, 2001 in United States Patent (USP) to prior art; USP645 1337, Chitosan-basednitric oxide donor compositions, 2002) proposed modified chitosan to synthesize serial chitosan-NO affixture as nucleophilic NO carrier.The concrete modification of chitosan is divided into two classes: (1) hydrophilic radical modification: N-carboxylic butyl chitosan, N-carboxyetbyl chitosan, N-cm-chitosan.(2) hydrophobic group modification: N-propyl group chitosan, N-carboxyetbyl chitosan methyl esters.Its weak point is that the loading level of NO is lower, and reason has 2 points: the substitution value of (1) amino of chitosan modification (carboxylation and alkylation) generally has only 25-27%, and low substitution value causes the charge capacity of NO very low.(2) chitin modified product is an inhomogeneous reaction with the reaction of NO, and NO can not fully be reacted.Therefore limited its purposes medically.
Summary of the invention
The objective of the invention is at the deficiencies in the prior art, a kind of nucleophilic N 0 donor of alkyl modified amido glucose and synthetic method thereof are provided.By glucosamine is carried out alkylation modification, produce NH nucleophilic site, after the NO reaction, obtaining a series of is contain [N (O) NO] of carrier with amino monose
-The novel NO donor of functional group.Solved present this type of nucleophic NO donor and be applied to the problem (cytotoxicity of polyamines) that exists when clinical, this type of novel nucleophilic NO donor medicine is not seen bibliographical information so far.
The present invention is achieved by the following technical solutions:
Nucleophilic N 0 donor of alkyl modified amido glucose of the present invention as body material, adopts alkylation modification to produce secondary amine nucleophilic site (NH group) with glucosamine, produces [N (O) NO] with the NO reaction
-Functional group, molecular structural formula is as follows:
N[N (O) NO wherein]
-Group is that the NH group forms with the NO reaction.And the NH group comes from alkyl-modified glucosamine;
R is the alkyl of straight or branched, comprises methyl, ethyl, propyl group, butyl, amyl group, and it comes from formaldehyde, acetaldehyde, propionic aldehyde, butyraldehyde, glutaraldehyde and NH
2The Schiff alkali reaction, or halohydrocarbon (as monobromethane, n-propylcarbinyl chloride) and NH
2Alkyl substitution.
Nucleophilic N 0 donor of alkyl modified amido glucose synthetic method of the present invention is to the NH on the glucosamine
2Group carries out alkylation modification, make its generation can with the nucleophilic NH group of NO reaction.The alkyl modified amido glucose molecule carries out reaction under high pressure with the NO gas molecule in the methanol solution of sodium methylate, require Na
+/ NH=1-3, pressure are 5-10atm, room temperature reaction 3-7 days, produce [N (O) NO]
-Group.Synthetic product is cleaned respectively repeatedly with the methyl alcohol ether, and room temperature vacuum-drying is stored in-20 ℃ the moisture eliminator.
Described to the NH on the glucosamine
2Group carries out alkylation modification, by a kind of carrying out in following two kinds of methods:
Method (1): adopt the same NH of alkyl aldehydes (formaldehyde, acetaldehyde, propionic aldehyde, butyraldehyde, glutaraldehyde etc.)
2Group carries out the Schiff alkali reaction, uses sodium borohydride reduction then.
(GS) is soluble in water for glucosamine, and (GS: aldehyde mol ratio=1: 1-2), room temperature reaction 12h is with the NaBH that is mixed with 15% aqueous solution to add quantitative aldehyde
4Reduction 12h concentrates reaction solution, adds acetone or alcohol and makes the system precipitation, and with the solution rotating evaporation, the product that obtains is further purified with methyl alcohol or ethanol.Perhaps, separate with the separation chromatography post with the crude product water dissolution.
Method (2): adopt halohydrocarbon (monobromethane, n-propylcarbinyl chloride) and NH
2Group carries out alkyl substitution in basic solution.
Quantitative glucosamine joined in the aqueous isopropanol of 10% sodium hydroxide, stirred 30 minutes at 70 ℃, dropwise add halogenated alkane (monobromethane, n-propylcarbinyl chloride), wherein halohydrocarbon: the mol ratio of glucosamine is 1: 1-1.2, room temperature reaction 12h, with hydrochloric acid solution is neutralized to neutrality, rotary evaporation, the product that obtains methyl alcohol, ethanol and acetone solution, recrystallization, repeated multiple times obtains the light yellow crystal powder.
The preparation of nucleophilic N 0 donor of alkyl modified amido glucose
The alkyl modified amido glucose that obtains by aforesaid method (1) or (2) carries out reaction under high pressure with the NO gas molecule in the methanol solution of sodium methylate, require Na
+/ NH=1-3, pressure are 5-10atm, room temperature reaction 3-7 days, are contained [N (O) NO]
-The nucleophic NO donor of group.
The nucleophilic N 0 donor of alkyl modified amido glucose that the present invention obtains is white fluffy powder, is stored in-20 ℃ the moisture eliminator.At room temperature can stable existence, in acidity or neutral aqueous solution, can spontaneous decomposition discharge NO and glucosamine molecule.
The nucleophilic N 0 donor of alkyl modified amido glucose of the present invention's preparation, have stable chemical property and long release transformation period, can be widely used in the treatment cardiovascular system diseases, lung's high pressure, promote wound healing, effectively prevent the moulding postoperative restenosis, improve the antithrombotic property of medical treatment device.
Embodiment
Embodiment 1: propionic aldehyde (PA) modified amido glucose/NO's is synthetic
10g (0.0506mol) glucosamine hydrochloride (GS) joins in the methanol solution of 100ml, adding 50ml water is its dissolving, 5.5ml propionic aldehyde (GS: PA mol ratio 1: 1.5) join in the system room temperature reaction 12h, with 3.83 with 383g (0.1012mol, GS: NaBH
4Mol ratio=1: 2) NaBH
4Be dissolved in the 25ml water, be added dropwise in the solution slowly, reduction reaction 12h obtains yellow solution, with 100ml acetone precipitation viscous substance, filter, the filtrate rotary evaporation, the solid that obtains methyl alcohol heating for dissolving refilters, repeat to use the methanol purification product, oven dry at last obtains light yellow crystal powder 5g.
Above-mentioned reaction product 2.5g (0.01mol) is joined in the 100ml absolute methanol solution that contains 2 15g (0 02mol) sodium methylate, in autoclave, react with NO, keep pressure 5atm, reacted 3-7 days, after finishing, reaction washs with anhydrous methanol and ether respectively, room temperature vacuum-drying obtains the about 2g of white fluffy powder.
[N (O) NO]
-Functional group the most directly perceived and effectively characterizing method be ultraviolet characteristic absorbance at the 230-280 place, among the synthetic product GSPA NO [N (O) NO]
-The characteristic absorbance of functional group is at 262nm, measured in the PBS damping fluid its light absorption ratio over time, and obtaining its transformation period by the function match of release profiles is 18h.
Embodiment 2: glutaraldehyde modified amido glucose hydrochloride/NO's is synthetic
10g (0.0506mol) glucosamine hydrochloride (GS) joins in the methanol solution of 100ml, the glutaraldehyde water solution of 20.24g25% (GS: the mol ratio of glutaraldehyde=1: 1) join in the solution room temperature reaction 24h.With 3.83g (0.1012mol, GS: NaBH
4Mol ratio=1: 2) NaBH
4Be dissolved in the 25ml water, be added dropwise in the solution reduction reaction 12h slowly.Reaction is finished and is added 30ml water in the afterreaction liquid, places stirred in water bath reaction for some time of 50-60 ℃, and solution is bleach gradually, room temperature is placed and is produced white viscous precipitate, filter paper filtering, and filtrate adds 30ml acetone and precipitation occurs, 60 ℃ of oven dry of filtrate obtain the 8.1210g yellow powder.Again this product is added dissolve with methanol and filter, the filtrate oven dry obtains the 7.0g pale yellow powder.
Above-mentioned reaction product 5g (0.02mol) is joined in the 100ml absolute methanol solution that contains 4.3g (0.04mol) sodium methylate, in autoclave, react with NO, keep pressure 5atm, reacted 3-7 days, after finishing, reaction washs with anhydrous methanol and ether respectively, room temperature vacuum-drying obtains the about 6g of white fluffy powder.
Among the synthetic product GSGA/NO [N (O) NO]
-The characteristic absorbance of functional group is at 262nm, and discharging the transformation period in the PBS damping fluid is 47h, and its transformation period significantly is longer than the small molecules nucleophic NO donor of known all ionics now, therefore has important clinical application value.Find that by the intensification infrared analysis this product decomposes molecular structure generation considerable change 80 ℃ the time.
Embodiment 3: n-propylcarbinyl chloride modified amido glucose hydrochloride/NO donor synthetic
10g (0.0506mol) glucosamine hydrochloride (GS) joins in 10% the isopropanol water solution of 100ml, stirred 30 minutes at 70 ℃, dropwise add n-propylcarbinyl chloride, wherein halohydrocarbon: the mol ratio of glucosamine hydrochloride is 1: 1-1.2, room temperature reaction 12h, with hydrochloric acid solution is neutralized to neutrality, rotary evaporation, the product that obtains is successively used methyl alcohol, dissolve with ethanol, collect filtrate, recrystallization, repeated multiple times obtains the about 5g of light yellow crystal powder.
Above-mentioned reaction product 1g (0.004mol) is joined in the 100ml absolute methanol solution that contains 0.86g (0.008mol) sodium methylate, in autoclave, react with NO, keep pressure 5atm, reacted 3 days, after finishing, reaction washs with anhydrous methanol and ether respectively, room temperature vacuum-drying obtains the about 1g of white fluffy powder.
Ultraviolet spectroscopy [N (O) NO]
-The specific absorption of functional group is at 262nm.Discharging the transformation period in the PBS damping fluid is 27h.
Claims (5)
1. a nucleophilic N 0 donor of alkyl modified amido glucose is characterized in that: as body material, adopt alkylation modification to produce secondary amine NH nucleophilic site with glucosamine, produce [N (O) NO] with the NO reaction
-Functional group, molecular structural formula is as follows:
N[N (O) NO wherein]
-Group is that the NH group forms with the NO reaction, and the NH group comes from alkyl-modified glucosamine;
R is methyl, ethyl, propyl group, butyl or amyl group.
2. the preparation method of a nucleophilic N 0 donor of alkyl modified amido glucose as claimed in claim 1 is characterized in that: to the NH on the glucosamine
2Group carries out alkylation modification, make its generation can with the nucleophilic NH group of NO reaction, the secondary amine NH group on the alkyl modified amido glucose molecule reacts in the methanol solution of sodium methylate with the NO gas molecule, wherein, Na
+/ NH=2, pressure are 5atm, and room temperature reaction 5 days produces [N (O) NO]
-Group is contained [N (O) NO]
-The nucleophic NO donor of group.
3. the preparation method of nucleophilic N 0 donor of alkyl modified amido glucose according to claim 2 is characterized in that, to the NH on the glucosamine
2Group carries out alkylation modification and adopts the same NH of alkyl aldehydes
2Group carries out the Schiff alkali reaction, makes with sodium borohydride reduction then.
4. the preparation method of nucleophilic N 0 donor of alkyl modified amido glucose according to claim 2 is characterized in that, to the NH on the glucosamine
2Group carries out alkylation modification and adopts halohydrocarbon and NH
2In basic solution, carry out alkyl substitution.
5. the preparation method of nucleophilic N 0 donor of alkyl modified amido glucose according to claim 2 is characterized in that, the NO donor that obtains is white fluffy powder, is stored in-20 ℃ the moisture eliminator.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6261594B1 (en) * | 1998-11-25 | 2001-07-17 | The University Of Akron | Chitosan-based nitric oxide donor compositions |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6261594B1 (en) * | 1998-11-25 | 2001-07-17 | The University Of Akron | Chitosan-based nitric oxide donor compositions |
| US6451337B1 (en) * | 1998-11-25 | 2002-09-17 | The University Of Akron | Chitosan-based nitric oxide donor compositions |
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