PL90384B1 - - Google Patents

Description

The subject of the invention is a process for the preparation of tetaine oximes or hydrazones and their analogs of the general formula I, in which R1 is a hydroxyl group or a group of formula II, where R8 represents a hydrogen atom, an alkyl, aryl, aralkyl group, and X is an acyl or alkyl group, R2 is a hydrogen atom, an acyl group, preferably an α-aminoacyl or acylaminoacyl group, and Z is a hydroxylamino or hydrazine residue or their alkyl, aryl or aralkyl derivatives. The tetaine antibiotic being a mixture of two isomeric Tetaine substances A and B produced by the ft strain Bacillus pumilus, exhibits a number of interesting biological properties. It is characterized by a very high antimicrobial activity, including many gramm positive and gram negative bacteria, as well as a number of other microorganisms. A particularly valuable feature of tetaine is its low toxicity to animal organisms, resulting from its mechanism of action, which is based on the damaging of murein synthesis of the microbial cell wall by inhibiting the incorporation of the first amino acid - alanine into the N-acetylmuramic acid residue. Hitherto there are no known antibiotics which inhibit this enzymatic process. The study of a new mechanism of inhibition of murein synthesis opens up new possibilities of obtaining non-toxic chemotherapeutic agents by synthesizing structural analogs of tetaine. Obtaining such analogs is also expedient due to the fact that tetaine itself is susceptible to the action of a number of enzymes that cause its inactivation in living organisms. Tetaine oximes and hydrazones and its analogues are not known so far. also the way of holding them. logs of formula 1, in which R 1 is a hydroxyl group, or a group of formula 2, where R 3 is a hydrogen atom, an alkyl, a -cyl, aralkyl group, and X is an acyl or an alkyl group, R2 is a hydrogen atom, a -cyl group , preferably a-aminoacyl or acylaminoacyl residue, and Z is a hydroxylamino residue or the alkyl, aryl, or aralkyl derivatives thereof according to the invention in that the tetaine or its analogs of formula III are characterized in which R1, R2 and The meaning of Rs as defined above is hydroxylamine or its alkyl, aryl or aralkyl derivatives. A method for the preparation of tetaine hydrazones and its analogs of formula I, in which R1 is a hydroxyl group, or a moiety of formula II, where R8 is a hydrogen atom, alkyl, aryl, aralkyl and X is acyl or alkyl, R2 is hydrogen, acyl, preferably alpha-aminoacyl or acylaminoacyl, and Z is a hydrazine or an alkyl residue. The non-alkyl, aryl or aralkyl derivatives thereof according to the invention are characterized in that the tetaine or its analogs of formula III, in which R1, R2, R * have the meaning given above, are hydrazine or its alkyl, aryl or aralkyl compounds The advantage of the method according to the invention is the possibility of obtaining compounds with increased stability, it has been found that "chemical modifications of the tetaine molecule and its analogues do not cause a deterioration of the antibiotic activity. The method according to the invention is illustrated by the following examples. EXAMPLE 1 62 mg (0.75 mole) of O-methylhydroxylamine hydrochloride are dissolved in 10 ml of ethyl alcohol and neutralized with solid acid potassium carbonate until the evolution of carbon dioxide ceases. The alcoholic methoxyamine solution is drained from the salt and an aqueous solution containing 135 mg of tetaine in 20 ml of water is added. The reaction mixture is allowed to stand at room temperature for 8 hours. After this time, the solvents are evaporated off under reduced pressure, and the dry residue is dissolved in methyl alcohol and triturated with diethyl ether. The precipitated solid is centrifuged, washed with diethyl ether and dried under reduced pressure. 115 mg of tetaine O-methyloxime are obtained. Example II. A solution of 8 mg of phenylhydrazine in 5 ml of ethyl alcohol is added to 10 mg of desalanyltetaine dissolved in 3 ml of water. The reaction mixture is kept at room temperature for 24 hours. Then, after evaporation of the solvents under reduced pressure, the crude product is purified analogously to Example 1. 11 mg of desalanyltetaine phenylhydrazone are obtained. x Example III. To 50 mg of tetaine A dissolved in 10 ml of water, 0.0 (13 ml of 80% hydrazine hydrate) is added and left at room temperature for 1 day. Then, after evaporation of the solvent under reduced pressure, it is cleaned. tetaine A crude hydrazone by analogy to Example I. Yield 38 mg. Example IV To 10 mg of pivaloyloxymethyl ester B, dissolved in 4 ml of acetone, 2.5 mg of O-methylhydroxylamine in 4 ml of alcohol is added Then, after evaporating the solvents in vacuo, the obtained crude 0-methyloxymethyl palkyloxymethyl ester of desalylethetaine B is purified on a chromatographic column filled with silica gel in the system ethyl acetate: methanol: water 5: 1: 1. Yield 5 mg. Example 5 To 10 mg of tetaine B methoxymethyl ester dissolved in 4 ml of acetone are added 2 mg of 0-methylhydroxylamine in 4 ml of ethyl alcohol. the reaction residue is allowed to settle at room temperature for 1 day, and then the obtained 0-methyl tetaine oxime methoxymethyl ester B is isolated as in Example IV. Yield 6 mg. In the same way, a series of further oximes and nydrazones of desalanyltetaine and its derivatives were obtained, summarized in the table below: Item 1 2 3 4 6 7. 8 Oximes and hydrazones of desalanyltetaine and its derivatives O-methyl oxime of desalanyltetaine O-ethyl tetaine oxime O-propyl tetaine oxime Onbenzyl tetaine oxime Desalanyltetaine oxime Hydrazone of desalanyltetaine O-methylethanyloxime O-methylphenylethyl oxime O-methylethyl oxime May III. I IV. All the obtained substances were tested by thin-layer chromatography and biochromatography. * Their identity was confirmed by mass spectra using the "field desorption" technique. PL

Claims (2)

Claims 1. Process for the preparation of tetaine oximes and its analogs of formula I, in which R1 is a hydroxyl group, or a group of formula 2, where R3 is a hydrogen atom, an alkyl, aryl, aralkyl group, and X is an acyl or alkyl group , R2 is a hydrogen atom, an acyl group, preferably a-aminoacyl or acylaminoacyl group, and Z is a hydroxylamine residue or its alkyl, aryl or aralkyl derivatives, characterized in that the tetaine or its analogs of formula According to claim 3, in which R1, R2 and R3 are as defined above, hydroxylamine or its alkyl, aryl or aralkyl derivatives are treated. 2. The method of obtaining tetaine hydrazones and analogs of formula I, in which R1 is a hydroxyl group, or a group of formula z, where R3 is a hydrogen atom, an alkyl, aryl, aralkyl group, and X is an acyl or alkyl group, R2 is an acyl group, preferably a-aminoacyl or acylaminoacyl group, and Z is a hydrazine residue or its alkyl, aryl or aralkyl derivatives, characterized in that the tetaine or its analogs of formula III, in which R1, R2, R3 are given above meaning, hydrazine or its alkyl, aryl or aralkyl derivatives are acting. 90 384 R-HN-CH-COR1 formula 1 -0-CHR3-0X formula 2 CH2 R-HN-CH-COR 'formula 3