DD268951A1 - PROCESS FOR PREPARING ANTIBIOTICALLY EFFECTIVE GLYCOSIDE DERIVATIVES OF TETRACYCLINE - Google Patents

Abstract

The invention relates to the preparation of glucosidic tetracycline compounds which have better solubilities in water and organic solvents and, in the event of later hydrolysis, yield only physiologically acceptable degradation products and are therefore suitable for parenteral use as medicaments. The improved solubility in water and organic solvents coupled with no further increase in toxicity is achieved by linking the phenolic OH groups in the 3- and 10-position glycosidically with acylated sugars, preferably acetylglucose, to give compounds of general formula I arise.

Description

For this 1 page formulas

Field of application of the invention

The invention relates to a process for the preparation of antibiotically active glycoside derivatives of tetracyclines, in particular of oxytetracycline, which have improved solubility in water and organic solvents and provide only degradation products in the hydrolysis, which are physiologically harmless.

Characteristic of the known technical solutions

As is known, tetracyclines such as chlortetracycline, oxytetracycline are amphoteric substances which are very sparingly soluble in the physiological pH range.

The solubility of oxytetrncycline dihydrate in water is 0.0011 mg / ml. Salts of tetracyclines are more soluble, but aqueous solutions tend to hydrolyze and react strongly acidic or basic depending on the anionic or cationic counterions, so that their parenteral application encounters difficulties.

It is known that derivatives of tetracyclines having better solubility in polar inorganic solvents are obtained by aminoalkylation with formaldehyde or formaldehyde-donating compounds and suitable amines under Mannich reaction conditions (Brit. Pat. ,

It is also known that in addition to formaldehyde and higher carbonyl compounds react with primary or secondary amines and the tetracyclines to condensation products which have improved solubility in water (DDR-WP 30766).

However, in the case of hydrolysis, such Mannich derivatives give rise to degradation products which are foreign to the body and which, after application, have repeatedly led to serious incidents. Furthermore, diacetate compounds in C ₁₂ - and C ₆ -

Position and the formyl ester in C ₆ position described. However, no statement can be made about the biological activity (Lester A. Mitscher: The Chemistry of the Tetracyclines, New York, 1978).

Object of the invention

The aim of the invention is the preparation of antibiotically active compounds of the tetracyclines, preferably of oxytetracycline, which have an improved solubility in water, optionally promote resorption by increased lipophilicity and provide in a later hydrolysis only non-toxic degradation products.

Explanation of the essence of the invention

The object of the invention is the discovery of a process for the preparation of tetracyclines of the general formula I in which R) and R _{2 are} acylated sugars. It has been found that by glycosidic linkage of the phenolic OH groups with suitable sugars improved solubility in water, with appropriate derivatization of the OH groups of the sugar, but also an increased lipophilicity can be achieved.

Glucose is particularly well suited as a sugar component, since it is very readily accessible, but above all does not allow any unphysiological degradation products to be expected in the later metabolization.

For this reason, acylation with acetic acid is to be preferred for the derivatization of the OH groups of the sugar. The linking of the tetracyclines with the sugar to the glycoside is accomplished by reacting a tetracycline salt with an activated form of the sugar.

The tetracycline is reacted with a suitable solvent in the form of a metal or ammonium salt, preferably of the triethylammonium salt.

Suitable solvents are numerous polar solvents of the organic. Chemistry. For cost reasons, however, methanol is preferable.

As activated sugar component, a-2,3,4,6-tetraazetyl-glucose is available, which in good exploiter ι in a one-step reaction

accessible from glucose and is very reactive, ie mild conditions of implementation allows. The reaction can be carried out at ⁰ ° C.

be performed to 5O ⁰ C, but preferably at 10 ° C to 15 ⁰ C worked. The salt of tetracycline may be in one

be prepared separate reaction, it is advantageously further processed in situ. It is sufficient, the salt of tetracycline

with 2 moles of a base or of a hydroxide, e.g. B. triethylamine, implement. A change in the molar ratio brings no

Advantages. In principle, the same applies to the glycosidic sugar component, in front of - in an oversupply - even only 2 mol

be implemented.

It is known from the literature that tetracyclines have two acidic OH groups, which titrate and convert into a salt

to let. By IR spectroscopic studies it was found that the phenolic OH groups are in 3- and 10-position and the glycosidic linkage of these OH groups takes place.

The resulting reaction product of the oxytetracycline-di-tetraazetyl-glucose derivative has a solubility in water of

20mg / ml. The solubility in glycerol formal and in 1,2-propylene glycol is 200 mg / ml, in diethylacetamide 360 mg / ml, in DMF 800 mg / ml, in DMSO 350 mg / ml, in acetone 500 mg / ml and in the mixture 1,2 propylene glycol / water (2: 3 ) 120mg / ml.

According to elemental analysis, the reaction product in the above example contains 2MoI of water. The pH of a 2% saturated

aqueous solution is 4.8.

The compounds according to the invention are active against all types of germs, which usually belong to the tetracycline spectrum

belong. This affects among others:

E.coli

Enterobacter Klebsiella Proteus (indole positive) Proteus (indole negative) Staph.anreus Staph.epepiderdis enterococci Haemol.Streptococci of the serological group A The compounds of the invention show in their MIC values or MBK values the known antimicrobial Effects of the comparative substances doxycycline and OTC hydrochloride. It showed up against the tested Enterobacter Klebsiella strains have a better effect compared to the substances doxycycline and OTC hydrochloride

Compounds of the invention.

According to the experimental results obtained, the compounds according to the invention were Narrow-spectrum antibiotics whose qualitative effect is parallel to that of OTC hydrochloride and doxycycline, Jeren

quantitative effectiveness is above that of OTC hydrochloride.

exemplary Oxytetracycline-3,10-bis- (2,3,4,6-tetraazetyl-beta-glucoside)

4.955 g of oxytetracycline dihydrate are suspended in 30 ml of anhydrous methanol, and 2.024 g of triethylamine are added with cooling to give a clear solution. The solution is cooled to ⁰ ° C. to 5 ° C. and 8.224 g of acetoborne glucose dissolved in 20 ml of anhydrous methanol are added dropwise.

The reaction mixture is heated to a temperature of 10 ⁰ C to 15 ⁰ C, stirred for 3 hours and then the methanol

distilled off. The remaining solid is taken up in ethyl acetate, the insoluble constituents separated, the

Concentrated solution and precipitated in petroleum ether. This 9.5 g of a light yellow microcrystalline substance are obtained at

85 ⁰ C melts with decomposition.

analysis C 51.9% H 5,576% calculated for C ₆₀ HmN ₂ O ₂₇ 2H ₂ O: 51.30% 5.71% found: 51.73% 5.73% N 2.421% 2.60% found: 2.36%

IR analysis: Strong absorption bands at 1755cm, 1650cm " ¹ , 1618cm" ¹ .1585cm " ¹ , 1458cm, 1372cm" ¹ ,! 235cm

14 8 SSi 3

Claims (4)

1. A process for the preparation of novel ₍ antibiotically active derivatives of the tetracyclines of the formula I, in which R ₁ and R ₂ acylated sugars, characterized in that the tetracyclines are reacted in the form of their salts and in the presence of solvents with monosaccharides. 2. The method according to item 1, characterized in that is preferably used as tetracycline oxytetracycline. 3. The method according to item 1, characterized in that methanol is preferably used as the solvent. 4. The method according to item 1, characterized in that pentoses and hexoses, preferably glucose in its acylated form, are used for the reaction.