CN102558235B - Method for preparing arsanilic acid by diazotizing trimethoprim - Google Patents

Abstract

The invention discloses a method for preparing arsanilic acid by diazotizing trimethoprim, which is characterized in that trimethoprim is subjected to diazotization reaction under the existence of HCl and HNO2 to generate trimethoprim diazo salt; trimethoprim diazo salt is subjected to coupling reaction with arsanilic acid to generate molecules which are combined with azo bond and possess bifunctional groups. According to the invention, water-soluble side chain (TMP) is covalently bound to a medicine (arsanilic acid) which is insoluble in water; the arsanilic acid is conversed to the water-soluble medicine, thereby the disadvantages of low medicine dissolvability and low bioavailability caused by poor absorption can be solved.

Description

A kind of method being prepared arsanilic acid by diazotizing trimethoprim

Technical field

The present invention relates to a kind of method being prepared arsanilic acid by diazotizing trimethoprim, belong to beast bird field of pharmaceutical preparations.

Background technology

Based on fodder industry and intensive modern farming enterprise's aquaculture, be not only society and provide very abundant animal derived food, and greatly promoted the fast development of veterinary drug (fodder additives) industry.Under high feed nutrition concentration, high-density breeding condition, beast fowl resistibility is poor, makes the risk of mass-producing livestock-raising constantly increase; in order to reduce case fatality rate; pursue high efficiency, have to use veterinary drug and fodder additives in a large number, comprise various microbiotic, chemical synthetic drug etc.

Using with overdose on a large scale of multi items, high dosage veterinary drug (fodder additives), its drawback shows especially day by day.The consequence of abuse veterinary drug, one is cause veterinary drug in animal food residual; Two is that veterinary drug utilization ratio is low, and the veterinary drug used is about 70-80% and is discharged in environment by fecaluria, causes ecological pollution and affects human food prods by food chain; Three is cause producing a large amount of multidrug resistant disease pathogenic microorganism.

All veterinary drugs (comprising the fodder additives of prevention), all should make certain formulation, be applied to treatment with the form of preparation, prevent or diagnose the illness, and the validity of preparation, security, reasonableness and accuracy etc., then reflect the level of veterinary drug (fodder additives), determine the effect of veterinary drug.The curative effect of formulation to medicine plays a part very important, and now having broken " chemical structure " is the traditional concept uniquely determining curative effect.Be embodied in formulation and can change pharmaceutically-active character; Formulation energy regulating drug speed of action; The change of formulation can reduce or eliminate poisonous side effect of medicine; Formulation can determine the stability of medicine and the effect of Some dosage forms location target.It is exactly control medicine in the course of medicament phase and pharmacokinetics phase that the bioavailability of medicine controls.A molecule having optimum structure configuration and a physico-chemical property, can cause the curative effect of expectation at target site.But it may not have the molecular form and character that are transferred to final effect target.Usually, give in dosage and only have sub-fraction drug molecule to arrive target area, and major part interacts with non-target site, and this invalid transmission may cause side effect, so the structure of drug molecule needs further optimization.Optimize the chemical structure of medicine by pharmaceutical chemical principle, the physico-chemical property of medicine can be improved, more reasonably play the pharmacological action of medicine, improve bioavailability.Research both at home and abroad in people's medicine preparation has suitable development, as solid dispersion technology, inclusion technique, emulsifying technology, liposome preparatory techniques, microencapsulation and miniature balling-up technology and nanoparticle etc., physical chemistry and pharmaceutical chemical principle is mainly utilized to study pharmaceutical preparation, due to cost reason, the method of a lot of people's medicine preparation can not be implanted in veterinary drug preparation completely to be applied, and, veterinary formulations particularly requires to be worked at gi tract by oral as fodder additives mostly, being characterized in should be both safe and efficient, low price again.

For a long time, veterinary drug preparation still rests in the level of pin, sheet, the conventional formulation such as loose, although preparation process level is also in improve, but the veterinary drug preparation of these routines can not meet the development of high-efficiency agriculture of current high benefit, high production, can not adapt to the high request that intensive culture industry is prevented and treated diseases of bird and livestock.

How improved bioavailability and the result of use of veterinary drug by formulation process, reduce the usage quantity of veterinary drug, thus reduce resistance and drug residue, research and development new veterinary medicine becomes and improves veterinary drug production aggregate level problem demanding prompt solution.

Up to the present, no matter be people's medicine or veterinary drug, chemical synthetic drug has 30% to be insoluble drug.The medicine particularly main veterinary drug of oral administration, the insoluble of fodder additives causes the reduction of bioavailability, is therefore one of key of preparation to veterinary drug solubilising.

Pro-gen 90, i.e. atoxylic acid (p-ArsaniliAcid), it is a kind of organoarsenic medicine for animals, U.S. FDA approval is used for the feed of pig and chicken as fodder additives, its Main Function is the infection reducing the pathogenic bacteria such as intestinal bacteria, staphylococcus, effectively controls chicken necrotizing enterocolitis; The diseases such as treatment and prevention pig dysentery characterized by blood in the stool, enteritis, improve growth of animals or poultry speed and feed efficiency, promote livestock and poultry pigment deposition, improve skin color, make the ruddy light of skin, the recommendation consumption of U.S. FDA is pig 90ppm (feed per ton adds 90 grams), chicken 45ppm.Domestic consumption in feed is commonly pig 100-200ppm at present, and chicken is 100-150ppm.Pro-gen 90 must carry out interpolation with dosage form and use, domestic current using method is that feed and breeding enterprise enter former powder from raw material pharmaceutical factory and directly add use, its action effect greatly declines, this forces user to increase consumption in early stage on the one hand, not only increase drug cost but also strengthen pollution, on the other hand in the later stage because general resistance causes again user to yield the use of this medicine, and then pursue the alternative medicine upgraded, form vicious cycle.

Summary of the invention

The object of the invention is to overcome the shortcomings and deficiencies existed in prior art, a kind of method being prepared arsanilic acid by diazotizing trimethoprim is provided, the bioavailability powder raising more than 50% more former in current Pro-gen 90 of said preparation.

Prepared a method for arsanilic acid by diazotizing trimethoprim, it is characterized in that, comprise the following steps:

A) trimethoprim is at HCl and HNO ₂existence under there is diazotization reaction, generate trimethoprim diazonium salt;

B) trimethoprim diazonium salt and Pro-gen 90 generation linked reaction, generate such as formula while combining with azo bond shown in (1) with the molecule of bifunctional;

(1)。

Water soluble sidechains (TMP) is covalently attached on water-insoluble drug (Pro-gen 90) by the present invention, changes Pro-gen 90 into water soluble drug, thus the shortcoming that the bioavailability solving too low, the absorption difference of drug solubility and cause is low.

The present invention utilizes the amino group existed in Pro-gen 90 molecule, and in Pro-gen 90 (atoxylic acid) molecule, covalency introducing Trimethoprim trimethoprim (is commonly called as: trimethoprim; English Trimethoprim, is called for short TMP), make Pro-gen 90 and TMP covalent attachment form Pro-gen 90-TMP, enter into by enzymatic or non-enzymatic hydrolysis after in body, the water-soluble covalent groups that removing is introduced generates former medicine and works.The present invention makes full use of the characteristic of Pro-gen 90 and TMP, while increasing substantially antibacterial effect, greatly reduces medication quantity.

Further, described preparation method also comprises product formula (1) Suo Shi is carried out ultramicronising, makes the step of nanoparticulate dispersed preparation.

Arsanilic acid is made nanoparticulate dispersed preparation, expand medicine and amass in digestive tube action face, enhance its anti-microbial activity in digestive tube; And it is water-soluble to enhance medicine, digestive tube specific absorption is improved.

Embodiment

Embodiment 1:

Following methods is adopted to prepare arsanilic acid:

A) trimethoprim is at HCl and HNO ₂existence under there is diazotization reaction, generate trimethoprim diazonium salt;

B) trimethoprim diazonium salt and Pro-gen 90 generation linked reaction, generate such as formula while combining with azo bond shown in (1) with the molecule of bifunctional;

C) product formula (1) Suo Shi is carried out ultramicronising, make nanoparticulate dispersed preparation.

Obtained arsanilic acid antibacterial effect increases 50-60%, and dosage can be reduced to 40-60ppm by original 90-110ppm, can reach same effect.

Claims (2)

1. prepared a method for arsanilic acid by diazotizing trimethoprim, it is characterized in that, comprise the following steps:

A) trimethoprim is at HCl and NaNO ₂existence under there is diazotization reaction, generate trimethoprim diazonium salt;

B) trimethoprim diazonium salt and Pro-gen 90 generation linked reaction, generate such as formula while combining with azo bond shown in (1) with the molecule of bifunctional;

2. preparation method as claimed in claim 1, is characterized in that, described preparation method also comprises product formula (1) Suo Shi is carried out ultramicronising, makes the step of nanoparticulate dispersed preparation.