DE1923964A1 - Tetracyclins derivs for use as antibiotics - Google Patents

Abstract

Derivs. are prepared by the action of peroxidase on tetracycline, 5-hydroxy-tetracycline or 6-demethyl-tetracycline, under aerobic conditions and in the presence of dihydroxyfumaric acid, at 15-37 degrees C, the 4-hydroxy cpds are produced, or tetracycline may be treated with a peracid, esp. m-chloroperbenzoic acid, to obtain secotetracycline derivs. or the action of H2O2 yields 4-hydroxy-4-dedimethyl-aminotetracyclin. The new derivs. have valuable antibiotic properties, and some may be used in cosmetic preparations for protection against sunlight.

Description

"Tetracycline [derivatives and processes for their preparation" the invention relates to new tetracycline and secotetracycline derivatives and a new process for the preparation of these derivatives and other known tetracycline derivatives.

The new compounds of the invention are (a) tetracycline derivatives of the general formula I. In which the radicals R are identical and represent hydrogen atoms or acyl radicals and the radical R 'represents a hydrogen atom or a methyl group; (b) Lactone derivatives of secotetracyolines of the general formula II in which R "denotes a hydrogen atom or a hydroxyl group and R 'has the meaning given above, and (c) 4-dedimethylamino-4-keto-4a, 12a-dehydro-12,12a-secotetracycline-12-carboxylic acid-0,12 -lactone of the formula III The new compounds of the invention of general formula I include 4-hydroxy-4-dedimethyaminotetracycline, 4-hydroxy-4-dedimethylamino-6-demethyltetracycline and their 4,12a-diesters, in particular the diesters of hydrocarbon carboxylic acids with fewer than 12 carbon atoms , æ§Be lower .. aliphatic. Carboxylic acids such as acetic acid, propionic acid, butyric acid and enanthic acid by a monocyclic aryl group. substituted lower aliphatic carboxylic acids such as phenylacetic acid and β-phenylpropionic acid, monocyclic aromatic carboxylic acids such as benzoic acid and p-toluic acid, lower aliphatic olefinically unsaturated fatty acids, lower aliphatic acetylenically unsaturated ferric acids, cycloalkanecarboxylic acids and cycloalkene carboxylic acids.

The new compounds of the invention of the general formula II include 4-dedimethylamino-12,12a-secotetracycline-12-carboxylic acid-6,12-lactone, 4-dedimethylamino-5-hydro-12,12a-secotetracycline-12-carboxylic acid-6-12-lactone and 4-dedimethylamino-6-demethyl-12, 12a-secotetracycline-12-carboxylic acid-6,12-lactone.

The new compounds of the invention of general formula I are valuable drugs as they have broad spectrum antibacterial activity showing the compounds to numerous gram-positive and gram-negative bacteria can be used orally in the same way as tetracycline to treat bacteria caused diseases can be used. Also show the connections the invention has a high activity against tetracycline-resistant microorganisms, like certain strains of Staphylococcus aureus. They are therefore used for treatment used by diseases2 caused by these microorganisms0 The new compounds of the invention of the general formula II and 4-dedimethylamino-4-keto-4a, 12a-dehydro-12,12a-secotetracycline-12-carboxylic acid-6,12-lactone are strong UV absorbers, used for the production of sun protection agents such as creams, lotions or oils will. In addition, 4-dedemethalamino-4-keto-4a, 12a-dehydro-12,12a-secotetracycline-12-carboxylic acid-6,12-lactone a strongly colored compound that is dark, mustard-yellow in color, and dager as a pigment together with a suitable carrier such as linseed oil, e.g. for paints can be used.

The invention also relates to a method of manufacturing neumes Compounds of the invention, which is characterized that one tetracycline, 6-demethyltetracycline or 5-hydroxytetracycline under aerobic Conditions of exposure to the enzyme peroxidase in the presence of dihydroxyfumaric acid suspends. The nature of the resulting products depends on the reaction conditions, These are discussed in more detail below.

Plant cells and plant juices, animal tissue such as liver, body fluids such as saliva leukocytes (myeloperoxidase), Milk (lactoperoxidase) and a wide variety of microorganisms are used0 The preferred sources of peroxidase for the method of the invention are horseradish and the microorganism Myrothecium verrucariaO The peroxidase obtained from horseradish can be obtained by squeezing horseradish and the obtained Pressed juice used0 You can also use a purified preparation of horseradish peroxidase use. Peroxidase from M. verrucaria can be obtained by cultivating the microorganism on a suitable nutrient medium, separation of the mycelium formed and treatment of the mycelium for the isolation of purified peroxidase.

In addition to the enzyme peroxidase, hydroxyfumaric acid is used in the process of the invention used This compound can be used in practically any concentration however, it is preferably used in a molar ratio of from about 68: 1 to about 1030: 1, in particular from about 480: 1 to about 680 s 1, based on the amount used Tetracycline, used The reaction is carried out at a pH in the range of about 3 to 8, preferably at about 4.0 to about 6.0 and especially at about 4.5.

A buffer is added to the reaction medium to ensure that that the pH value remains in the desired range. Suitable buffer are e.g. Mollvaine's buffer, potassium citrate buffer, potassium acetate buffer, potassium phosphate buffer and potassium formate buffer.

The reaction is carried out in an aqueous medium under aerobic conditions conditions and at temperatures of about 15 to about 95 ° C, preferably at about 22 carried out up to about 37 ° C. The components of the medium, namely tetracycline, 6-demethyltetracycline or 5-hydroxytetracycline, the buffer that includes peroxidase and dihydroxyfumaric acid mixed with water, the pH value is adjusted by adding a base such as potassium hydroxide adjusted to the desired value, and the resulting mixture is about 10 to stirred or shaken for about 240 minutes, preferably about 30 to 120 minutes, to ensure adequate ventilation 0 The peroxidase acts as a catalyst and can therefore be in any proportion in order to maximize conversion of the tetracycline used to ensure the desired end product, the Peroxidase preferably in a weight ratio of about 0.1 to about 1.0 s 1, preferably in a weight ratio of 1.0: 1, based on the used Tetracycline used.

In the process of the invention, a mixture of products results can be separated from one another by chromatography. This is in the following Examples explained in more detail. When using tetracyoline as a starting material the known compounds 4-dedimethylaminotetracycline, 5a, 6-anhydrotetracycline, 5a, 6-anhydro-4-dedimethylaminotetracycline, 4-dedimethylamino-9-hydroxytetracycline as the new compounds 4-dedimethylamino-12,12a-secotetracycline-12-carboxylic acid-6,12-lactone, 4-dedimethylamino-4-hydroxytetracycline and 4-dedimethylamino-4-keto-4a, 12a-dehydro-12,12ase-cotetracycline-12-carboxylic acid-6,12-lactone educated. When using 5-hydroxytetracycline as the starting compound, the known compound 4-dedimethylamino-5-hydroxytetracycline and the new compound 4-Dedimethylamino-5-hydroxy-12,12a-secotetracycline -12-carboxylic acid-6,12-lactone formed, When using 6-demethyltetracycline as the starting compound, the following Compounds formed: 4-dedimethylamino-6-demethyltetracycline, 5a, 6-anhydro-6-demethyltetracycline, 5a, 6-anhydro-4-dedimethylamino-6-demethyltetracycline, 4-dedimethylamino-6-demethyl-9-hydroxytetracycline, 4-dedemethylamino-6-demethyl-12,12a-secotetracycline-12-carboxylic acid-6,12-lactone and 4-dedimethylamino-6-demethyl-4-hydroxytetracycline.

The 4 * 12a esters of the general formula I are obtained by reacting the 4-hydroxy-4-dedimethylamino derivatives of the corresponding tetracyclines with an acylating agent, e.g. the acid anhydride of a carboxylic acid with fewer than 12 O atoms of the aforementioned type produced in a non-aqueous medium.

After the reaction has ended, excess acid anhydride is dissolved with water decomposed in the usual way, the crystalline ester is from.

filtered, washed thoroughly with water and dried.

4-Dedimethylamino-4-keto-4a, 12a-dehydro-12,12a-seco-tetracycline-12-carboxylic acid-6,12-lactone and 4-hydroxy-4-dedimethylaminotetraoyolin can also be done by non-enzymatic routes from tetracycline by treatment with a peracid such as m-chloroperbenzoic acid, to the Formation of the first-mentioned compound and treatment with hydrogen peroxide to form the last-mentioned compound0 The examples illustrate The invention.

Example 1 A reaction mixture of the following composition is obtained prepared: volume components final concentration 1.0 ml Mollvaine's buffer, pH 4.5- (Handbook of Chemistry and Physics, 35th Ed. P. 1617) 1.0 tetracycline hydrochloride 500 µg / ml 1.0 horseradish peroxidase 50 µh / ml (Worthington, Quality D) 120 distilled Water 1.0 dihydroxyfumaric acid, adjusted to pH 4.5 with 10 mg / ml potassium hydroxide The reaction is carried out by adding the enzyme to the mixture of the other ingredients The mixture is put in motion in a test tube with dimensions 25 x 100 mm at 25 ° C on a rotary shaker with a stroke of about 5 cm at 280 RPM

incubated. After 60 minutes, the reaction products from the aqueous Solution extracted with SyO ml of ethyl acetate. The ethyl acetate extract is paper chromatographed analyzed. Samples of 20 μl are applied to Whatman No. 1 paper, which is labeled with 0.05 molar potassium citrate buffer is adjusted to 4.5 and closed by immersion an aqueous solution of 80% by volume of acetone hydrates and evaporates the acetone air dried will0 The g onatograms are in descending order with a mixture of equal parts by volume of hexane and ethyl acetate at room temperature developed. After development, the dried chromatograms are made with a UV lamp investigated, which has an emission maximum at 254 mµ, to absorbent and fluorescent Recognize connections. The spots are marked, the chromatogram is then displayed briefly exposed to ammonia vapor and examined again in UV light. Connections with antibacterial activity are commonly used by bicautography a 15-hour-old culture of Staphylococcus aureus strain 209P as a test organism established. The reaction products and some of their properties are shown below Given in the table. In the Inhibitory effect column, a + sign means that the connection possesses antibacterial activity, while a - sign indicates the compound shows no antibacterial activity towards the test organism used.

Table Pro- Rf Inhibit- Fluorescence Fluorescence Name of the compound effect before NH3 after NH3 A 0.78 + orange green 4-dedimethylaminotetracycline B 0.68 - orange orange 4-dedimethylamino-12,12a-secotetracycline-12-carboxylic acid-6,12-lactone C 0.68 - blue-green blue-green? D 0.81 + orange red-orange 5a, 6-anhydrotetracycline E 0.95 + yellow-orange orange-5a, 6-anhydro-4-dedimethylamino-tetracycline F 0.38 + orange green 4-dedimethylamino-4-hydroxytetracycline G 0.38 - red red 4-dedimethylamino-4-keto-4a, 12a-dehydro-12,12a-secotetracycline-12-carboxylic acid-6,12-lactone H 0.22 + (absorbed) 4-dedimethylamino-9-hydroxytetracycline 1 0.57 + orange green J 0g57 yellow orange K 0.26 - yellow yellow L 0.12 - orange orange M 0.46 - matt red matt rat N 0.62 - matt-red- matt-red-orange orange 0 0.85 - (absorbed) link B becomes in pure, crystalline form by preparative paper chromatography and subsequent countercurrent distribution in a mixture of hexane, ethyl acetate, methanol and water (ß s: 3: 4) (Ka10) and recrystallization from a mixture of ethanol and water-isolated properties of compound B [α] D20 -60 ° (c = 0.6; Methanol) C H N C 20 H 19 O 8 N; calc .: 59.69; 4.66 3.39; found .; 59.85; 4.77; 3.50.

IR (Nujcl): 5.65 (γ-lactone), 6.03, 6.15, 6.36, 6.90 (6.90 also when using CHCl3 as solvent) UV spectrum (95% ethanol, 0.1 n HCl) 217 mµ (16 600), 270 (21 700), 345 (4 600) (0.1 N solution of NaOH in ethanol) 245 (19 700), 273 (15 900), 382 (6 800) (after 30 to 120 minutes of standing) 246 (22 900), 274 (18 700), 341 (7 600) (after acidification) 211 (20 900), 269 (19 800) example 2 Example 1 is repeated, but a reaction mixture of the following composition is obtained used volume components final concentration 1.0 ml potassium citrate buffer pH 5.0 0.1 molar 1.0 tetracycline hydrochloride 500 µg / ml 1.0 horseradish peroxidase 50 µg / ml (Worthington, quality D) 1.0 potassium or ammonium formate 5.0 mg / ml 1.0 dihydroxyfumaric acid, adjusted 10 mg / ml to pH 5.0 with potassium hydroxide The number and the relative concentration of the end products is different from that in Example 1 received products. In the table below, the + signs indicate an increase the amount of compound and a - sign means no increase in amount compared Example io The letters denote the same products as in Example 1.

Table Product Stimulation of formation by adding formate B C -D -E -F ++ G -H ++ 1 + J K L N O Example 3 The reaction is carried out according to Example 1, however, a reaction mixture of the following composition is used: volume 1.0 ml potassium acetate buffer, pH 4.5 0.1 molar 1.0 tetracycline hydrochloride 500 µg / ml 1.0 horseradish peroxidase 50 µg / ml (Worthington, quality D) 1.0 chloro-p-phenylenediamine 100 µg / ml.

dihydrochloride 1.0 dihydroxyfumaric acid, to 10 mg / ml pH 4.5 with potassium hydroxide set The result of this modification is a change in the number and the relative concentration of the end products compared to Example 1.

This can be seen in the table below.

Table Product Formation stimulated by the addition of chlorine-p-phenylenediamine dihydrochloride A ++++ B ++ C -D -E -F -G -H +++ I +++ J -K -L -M -N -O - example 4 Example 3 is repeated, but 1.0 ml of potassium formate with a final concentration of 0.1 molar used instead of the potassium acetate buffer. This buffer becomes the reaction medium adjusted to pH 4.0. The result of this modification in Comparison to Example 1 can be seen from the table below.

Table Product Stimulation of the formation by the addition of chlorophenylenediamine dihydrochloride and formate A ++++ B ++ C -D -E -F -G -H +++ I +++ J -K -L -M -N -O -Example 5 Example 2 is repeated, but a raw pressed juice of fresh horseradish root is used used instead of the partially purified peroxidase. It will practically be the obtained the same results as in Example 2.

Example 6 Example 1 is repeated, but a heavily sine-fermented one becomes Preparation of horseradish peroxidase (Worthington Biochemical Corporation, grade A) used. Practically the same results as in Example are obtained 1.

Example 7 Forty 500 ml Erlenmeyer flasks are each filled with 100 ml of the following reaction mixture charged: Volume of ingredients 20 ml of 0.5 molar potassium formate 0.1 molar buffer, pH 4.0 25 ml of distilled water -25 ml methanol -10 ml tetracycline hydrochloride 500 µg / ml 10 ml dihydroxyfumaric acid, adjusted to 5 mg / ml pH 4 with potassium hydroxide 10 ml horseradish peroxidase 50 µg / ml (Worthington, Grade D) The flasks are rotated for 60 minutes on a rotary shaker shaken at 25 ° C. Then the implementation is practically named. The main products are 4-hydroxy-4-dedimethylaminotetracycline and 4-dedimethylamino-4-keto-4a, 12a-dehydro-12-12a-secotetracycline-12-carboxylic acid-6-12-lactone. These compounds are mutually and in the manner described below from unreacted Tetracycll, soaked.

The contents of the flasks are combined, once with 500 ml and twice extracted with 250 ml of ethyl acetate. The ethyl acetate extracts are combined over dried anhydrous sodium sulfate and filtered. The filtrate is evaporated to dryness at a temperature below 35 ° C. under reduced pressure. The dry weight of the orange-brown solid obtained is about 1.15 g. This material is purified by column chromatography to the extent of: 500 g cellulose powder is slurried with Mollvaine's buffer, pH 4.6, and filtered and dried. The dried, buffered cellulose powder is made by moistening hydrated with 80% aqueous acetone and then to separate the Acetone ventilated. The moist powder is then in a mixture of n-hexane and Ethyl acetate (2: 1) and poured into a column measuring 6.7 x 41 cm poured. About 1.15 g of the orange-brown solid obtained are in a Mixture of hexane and ethyl acetate (2: 1) dissolved and applied to the column. the Elution with the same solvent is carried out at a rate of 0.5 ml / Min., With fractions being collected after every 20 minutes. Every Fraction is analyzed by chromatography on Whatman # 1 paper that is matched with Mollvaine's Buffer is adjusted to pH 4.6. The chromatograms are made with a mixture Hexane and ethyl acetate (1: 1) developed. Fractions that do not contain any tetracycline used are combined, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure at 35 ° C. There will be about 258 mg of a yellow Powder received. This yellow powder can no longer be chromatographically satisfactory but it will be in the manner outlined below 2 components separated.

The yellow powder is digested with methanol. A methanol-soluble powder is obtained and methanol-insoluble fraction. The portion insoluble in methanol (41 mg) is pure 4-dedimethylamino-4-keto-4a, 12a-dehydro-12, 12a-secotetracycline-12-carboxylic acid-6, 12 lactone. This compound has a mustard-yellow color. The soluble in methanol Product is chromatographed on Whatman paper # 1 using Mollvaine's buffer adjusted to pH 4.6 and developed with a mixture of hexane and ethyl acetate.

The UV light absorbing J3and at an Rf value of about 0.38 are cut out and eluted with methanol. The methanol solution is evaporated and the residue was partitioned between saturated ammonium sulfate solution and ethyl acetate. The ethyl acetate extract is dried, filtered and evaporated to dryness The residue is taken up in a little ethyl acetate and washed with excess hexane offset. A white, amorphous powder separates out, this product (14 mg) diets practically pure 4-hydroxy-4-dedimethylaminotetracycline.

The properties of the purified compounds are given below 4-hidroxy-4-dedi- 4-Dedimethylamino-4-keto methylaminotetra- 4a, 12a-dehydro-12, 12acyclin secotetracycline-12-carboxylic acid-6, 12-lactone Appearance white amorphous mustard-yellow powder Powder F., ° C - 225.5-227.5 (Decomposition) [α] D20 methanol - -74 ° # 11 ° UV spectrum (E 1%) (C2H5OH) 222 (360), 268 (428), 275 (543), 299 (459), 365 (300) 337 (116), 422 (12) (0.1 N HCl) same specktrum 244 (263), 274 (670), as in C2H5OH; 295 (400), 338 (124) via Stable for 20 hours (0v1 n NaOH) 243. (504), 270 (405), 384 356); when more than 1 hour Standing, decomposes to products with an uncharacteristic UV spectrum IR (KBr) 6.03, 6.21, 6.35, 6.90 (Nujol) - 2.95, 3.05, 5.62, 6.08, 6.17, 6.30.

Example 8 Example 1 is repeated, but a crude peroxidase preparation is used used by Myrothecium verrucaria ATCC 9095; and the incubation temperature is 25 ° C. The peroxidase is obtained by culturing the microorganism for 5 days at 25 ° C in a soybean meal-glucose medium of the following composition: Extracted Soybean meal 30 g glucose 50 g CaCO3 7 g distilled water to 1 liter.

The mycelium is filtered off with anhydrous acetone in the usual manner dried and ground to a fine powder. The dry powder comes in one Stored desiccator at about 40 until use. Immediately before use the powder is extracted with distilled water0 The: solution is available as an Ensympreparat used. Practically the same results as in Example are obtained lo Example 9 Example 8 is repeated, but an enzyme solution is used which has been partially purified by ammonium sulphate precipitation0 Powdered ammonium sulphate is to the distilled water extract of the powder obtained in Example 8 of No verrucaria given up to 50% saturation. The precipitated protein is centrifuged off and redissolved in water. This concentrated solution of the protain can be used as such or after removal of residual ammonium sulfate by dialysis for 15 hours against water at 4; up to 60C0 The results are practically the same obtained as in Example lo Example 10 Preparation of 4-dedimethylamino-4-keto-4a, 12a-dehydro-12, 12ase-cotetracycline-12-carboxylic acid-6,12-lactone tetracycline is used with m-Chloroperbenzoic acid in dioxane is added at room temperature. The implementation will followed by taking samples which are placed in potassium iodide solution Iodine released is titrated with thiosulphate solution. It is found that at 24.5 ° C, 1 mole of the peracid is consumed within 12 seconds. To 90 seconds are 2.5 moles per acid consumed, then the Reaction speed.

A paper chromatographic study of the reaction via a Range of poric acid concentrations indicates that the optimal concentration is 1.5 moles Peracid to 1 mole of etraoyclin is.

For preparative purposes, 1.6 mol of m-chloroperbenzoic acid are mixed with 1 Mol tetracycline methanol implemented. The reaction mixture is at 24, 5 to 26 ° C let stand until a starch-iodide test shows that all the peracid has been consumed is. Then the methanol is distilled off and the red, oily residue several times extracted with boiling hexane. The residue is digested with ethyl acetate. It a brick-red powder forms. The product is prepared by means of preparative paper chromatography isolated and compared with the enzymatically produced product. The products are identical.

Example 11 Preparation of 4-Hidroxy-4-dedimethylaminotetracycline by non-enzymatic route tetracycline hydrochloride (0.5 to 5.0 mg / ml; preferably 1 to 3 mg / ml) are dissolved in 0.1 molar potassium formate buffer pH 4.0 and mixed with Dihydroxyfumaric acid in the form of potassium saline (10 to 60 mg / ml; preferably 10 mg / ml) offset. The reaction is carried out by adding a dilute solution of hydrogen peroxide (Final concentration 0.03 to 3.0%; preferred concentration 0.03%) set in motion. The reaction mixture is shaken in air at 250C until all traces of the dihydroxyfumaric acid suspension have disappeared and the medium clears up. This takes about 2 hours. Thereafter, the reaction products with Ethyl acetate extracted and chromatographed on the protruding characterized in the manner described, the aforementioned compound is the main product. It is identical to the product produced enzymatically, Example 12 Production of 4-hydroxy-4-dedimethylaminotetracycline-4, 12adiacetate OC10 g of 4-hydroxy-4-dedimethylaminotetracycline are mixed with 1 ml acetic anhydride after standing for 14 days at 25 to 30 ° C the solution is evaporated at a temperature below 35 ° C under reduced pressure. The last traces of acetic anhydride are decomposed by adding water Product is filtered off, washed with water and dried, in a similar manner can use other acid anhydrides instead of acetic anhydride 4, 12a-diesters are produced.

Example 13 - The reaction is carried out according to Example 1, however 5-Hydroxytetracycline is used as a substrate instead of tetracycline. The reaction products and some of their properties are summarized in the table below0 In the Inhibitory column, the + sign means antibacterial activity against Staphylococcus aureus strain 209-P 9 while a sign of no antibacterial Shows activity against this strain.

Table Pro- Rf Inhibit- Fluorescence Fluorescence Name of the compound product looks before NH3 after NH3 kung P 0.72 + orange green 4-dedimethylamino-5-hydroxytetracycline Q 0.56 e orange orange 4-dedimethylamino-5 hydroxy-12, 12a-secotetracycline-12-carboxylic acid-69 l2-lactone R 0.90 + orange green S 0.22 + orange orange T 0.94 - orange orange U 0977 - orange orange V 0.32 - orange orange Example 14 The reaction is carried out according to the example 1, but instead of tetracycline, 6-demethyltetracycline is used as the substrate used. The reaction products and their properties are as follows Given in the table. In the Inhibitory column, a + sign means antibacterial Activity against SO aureua strain 209-P, while a - sign indicates that the Compound shows no antibacterial activity against this strain.

Table Pro- Rf Inhibit- Fluorescence Fluorescence Name of the compound product works before NH3 after NH3 kung A '0.94 + brown brown 4-dedimethylamino-5a, 6-anhydro-6-demethyltetracycline B '0.89 - matt red matt red? C '0.83 + yellow-orange orange 5a, 6-anhydro-6-demethyltetracycline D '0.77 + yellow-green green 4-dedimethylamino-6-demethyltetracycline E' 0.70 - pink pink 4-dedimethylamino-6-demethyl-12, 12a-secotetracycline-12-carboxylic acid-6, 12-lactone F '0.65 - orange orange? G '0.59 - white white? H '0.51 + red green 4-hydroxy-4-dedimethylamino-6-demethyltetracycline I '0.39 - pink pink? J '0.35 - (absorbed)? K '0.31 - red red? L '0.27 + (absorbed) 4-Dedimethylamino-6-demethyl-9-hydroxytetracycline M '0.18 - white pink? N '0.12 - (absorbed)? O '0.09 - red red?

Claims (1)

P a t e n t a n s p r ü c h e 1. Process for the preparation of tetracycline derivatives, d a -d u r c h e k e n n n z e i c, h n e t that one tetracycline, 6-demethyltetracycline or 5-hydroxytetracycline under aerobic conditions under the action of peroxidase in the presence of dihydroxyfumaric acid. 2. Process for the production of 4-Uydroxy-4-dedimethylamino tetracycline, d a d u r c b G e k e n n s e i c h n e t that one can use tetracycline under aerobic conditions the action of peroxidase in the presence of dihydroxyfumaric acid at a tea temperature in the range of about 15. to about 37 ° C. Compound of the general formula in which the radicals R are hydrogen or acyl radicals of a hydrocarbon carboxylic acid with fewer than 12 carbon atoms and R 'represents a hydrogen atom or a methyl group. 4. 4-Hydroxy-4-dedimethylaminotetracycline 5. 4-Hydroxy-4-dedimethylamino-6-demethyltetracycline. 6. 4-Hydroxy-4-dedimethylaminotetracycline-4, 12a-diacetate. 7. Lactone derivatives of secotetracyclines of the general formula In which R 'denotes a hydrogen atom or a methyl group and R "denotes a hydrogen atom or a hydroxyl group. 8. 4-Dedimethylamino-5-hydroxy-12, 2a-secotetracycline-12-carboxylic acid-6, 12-lactone. 9. 4-Dedimethylamino-4-keto-4a, 12a-dehydro-12, 2a-secotetracycline-12-carboxylic acid-6, 12-lactone. 10. 4-Dedimethylamino-5-hydroxy-12, 2a-secotetracycline-12-carboxylic acid-6, 12-lactone. 11. 4-Dedimethylamino-6-demethy-12, 2a-secotetracycline-12-carboxylic acid-6, 12-lactone. 12. Process for the preparation of 4-dedimethylamino-4-keto-4a, 12a-dehydro-12, 12a-secotetracycline-12-carboxylic acid-6, 12-lactone, d a d u r c h e k e n n n z e i c h n e t that tetracycline is treated with a peracid0 13o procedure Claim 12, d a d u r o h g e k e n n -z e i c h n e t that the peracid is n-chloroperbenzoic acid used0 14o process for the preparation of 4-hydroxy-4-dedimethylaminotetracycline, d u r c h e k e k e n n n z e i c h n e t that one can tetracycline with hydrogen peroxide treated