FI63421B - TRANSMISSION OF ANTIBIOTIC VERTSAM TRANS-12,13-DESEPOXY-12,13-DEHYDROROSARAMICIN ELLER DESS ESTER - Google Patents

Description

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SSh c i4n Patentti eySnr.cUy 10 C6 1933 * jSfiSS W Patent issued ^^ (51) K ».ik? / I« .a.3 C 07 H 17/08 SUOMI — FINLAND <M), T60U73 2U.02.76 ' r ”(23) AilaiplM — Glklghstsdsf 2 ^ .02.76 (41) Tullut (ulkltafcsl - BIMt publHg 29. θθ. 76 ΓκίΜΙΙΙ js Reksterihalltai · / 44) NaMMUcsipMo * µ hwijuiBiiw p * · * .—

Htmt · and Reflective Management — In 1 AntefcM Exposed and Utilized pwMfcartd 28.02.83 (32) (33) (31) fyy4 «** y utwolkum-tuglrd prtorltat 28.02.75 28.02.75 USA (US) 55 ^ 250, 55 ^ 266 (71) Oy Koleter Ab, Lönnrotsgatan 19 B, 00120 Helsinki 12, Suomi-Finland (Fl) (72) Hans Reimann, Wayne, New Jersey, Robert Solomon Jaret, Livingston,

New Jersey, Mohammad Mehdi Nafissi-Varchei, North Caldwell, New Jersey, Ashit Kumar Ganguly, Upper Montclair, New Jersey, Olga Sarre, Verona, New Jersey, United States (US) (5M Procedure for Preparing a New Antibiotic Trans-12 The present invention relates to a process for the preparation of a novel process for the preparation of a novel antibiotic-12,13-desepoxy-12,13-dehydroroearamicin or its ester. antibiotic-active trans-12,13-desepoxy-12,13-dehydro-rosamicin or its ester, which compound has the formula CH = 0

PH 22 ti I I

CH3 ^^^ Jl3 CH3 ^ 8 jL.

JM O | 4 ^, κΛΛΛο,

16 0R

CH3 νΞγ

OR

wherein R and R 'are hydrogen or hydrocarbon carbonyl of 2 to 18 carbon atoms, and of the pharmaceutically acceptable acid addition salts of this compound.

The process according to the invention is characterized by reducing rosaramicin of the formula

O

H3C v X -CH_N (CH2),

Rosamicin, formerly known as antibiotic 67-694, which antibiotic and certain derivatives thereof are disclosed in British Patent Specification 1,302,142. Rosamicin is obtained by Micromonospora rosaria, which is also disclosed in said British Patent Specification. Rosamicin has the formula 0 03ε ^ Jl of CH3N (CH3J2 9 ° Ch3) As suggested in formula II, rosamicin is a dihydro compound with one hydroxy group at the 3-position of the macrolide ring and the other at the 2 'position of the glycosidally bonded sugar moiety moiety. However, it is necessary to esterify both hydroxy groups and to use a selective hydrolysis to eliminate the 2 'ester function. hydrolysis is described in South African Patent Specification 73/8630 (The new hydrolysis process is equally applicable to the 3,2 'diesters of the compounds of the invention).

The nontoxic, pharmaceutically acceptable acid addition salts refer to those which are generally useful in pharmaceutical practice. Said terms include those salts formed with inorganic acids, such as sulfuric acid, phosphoric acid and halogen acids (such as hydrochloric acid) and those formed with carboxylic acids having 2-18 carbon atoms, for example aliphatic, cycloaliphatic, aromatic and heterocyclic carboxylic carboxyl . dicarboxylic acids. Examples of such acids are Mr. Mttic acid, propionic acid, butyric acid, pivalic acid, valeric acid, hexanoic acid, octanoic acid, decanoic acid, stearic acid, hydrochloric acid, glutaric acid, malonic acid, tartaric acid, citric acid, cyclopropylcarboxylic acid, carboxylic acid, cyclopentylacetic acid, cyclopentylacetic acid , picolic acid, benzoic acid, phthalic acid, phenylacetic acid, monocalcium phosphoric acid and the like. A particularly suitable class of non-toxic pharmaceutically acceptable acid addition salts is Mr. alkyl sulfate salts, wherein the alkyl group contains 10-18 carbon atoms.

The esters of formula I include aliphatic, cycloaliphatic, aromatic and heterocyclic esters, incl. hemi esters formed with dicarboxylic acids, such as maleic acid, malic acid, malonic acid and the like. Oe acids which are usually used are those seeds having 2-10 carbon atoms, especially 2-5 carbon atoms. The cycloalkanecarboxylic acids which are usually used are Mr. seeds with 4-11 carbon atoms. In aryl and arylalkanecarboxylic acids, the aryl group IM may preferably be phenyl and the alkyl group in the arylalkanecarboxylic acids is lower alkyl.

In cases where a novel compound of formula I exhibits an esterified 2 'and 3-hydroxy group, the invention comprises Mven mixed esters. Thus, for example, 12,13-desepoxy-12,13-dehydro-rosamicin can be esterified in the 2'-position with an acylating agent derived from a hydrocarbon carboxylic acid and then esterified with an acylating agent derived from another hydrocarbon carboxylic acid .

Particularly applicable compounds of the esters Mr such as R and / or R 'Mr acetyl, propionyl, pivaloyl, stearoyl or benzyl.

The most important salts are often the stearate, lauryl sulfate, and potassium di-phosphate salts.

In Table I, specific compounds of formula I.

63421 5

Table I

R R 'Physical constants

H H m.p. 109 - 111 ° C

C-CH, H m.p. 120-121 ° C

II 3 0___

H C-CHsmp. 95 - 98 ° C

M «5 __o 0 _

C-1% H m.p. 108 - 111 ° C

C-C_H_H, m.p. 90 - 94 ° C

ii-b 0___ C-C17H35 Η / a / D = "9 ° (ethanol). -Q ____ C-C2H5 C" C2H5 1 <X = -12.5 (ethanol) Ö__O__ HC "C2H5 / Or / ^ 6 = - 8.4 _______0______

C-CH, C-CH, m.p. 105 - 107 ° C

The process of the invention can be carried out with alkali metal bromides or preferably alkali metal iodides in an organic acid at room temperature. The carboxylic acids preferably contain from 1 to 4 carbon atoms. This reaction can also be carried out in aromatic hydrocarbons, such as benzene, toluene or cylene, containing concentrated iodine hydrogen acid. Another possibility lies in the treatment of the starting material of Formula IV with precursor oxides, trialkylphosphines, triphenylphosphines or hexalkylphosphoimidates.

A particularly suitable medium for carrying out this reaction is potassium iodide in reflux acetic acid. The reaction product can advantageously be isolated by diluting the reaction mixture with ice water, extracting the product with a water-immiscible organic solvent, washing the extract and isolating the product thereof.

In carrying out the process according to the invention, it is usually necessary to heat the reaction mixture to return to flow temperature in an acidic medium, thereby risking decomposition of the starting material and / or the product. This process therefore provides about 30-50% and the product comprises substantial amounts of both the cis and trans isomers.

In the process of the invention, the compound of formula I is obtained in yields of about 85 - 95%, which compound is about 90% pure. This new process further provides a product which is enriched in the trans isomer and therefore non-chromatographic separation of the isomers is required.

The method according to the invention comprises reduction of a method; compound of formula III in a preferably dilute mineral acid solution containing chromium (II) ions in an oxygen-free atmosphere. The reducing agent, ie. The chromium (II) ions are advantageously provided in the form of a solution containing a chromium (II) salt, where the anion is derived from a mineral acid, such as chromium (II) chloride, chromium (II) sulfate, chromium (II) iodide. or similar. The most suitable reducing agent is chromium (II) -r chloride, which can be advantageously prepared according to Inorganic Synthesis, volume III, pp. 148-150, McGraw-Hill (1950). It is particularly convenient that the chromium (II) chloride solution is prepared immediately prior to its use to prevent chromium (III) ion formation.

63421 In order to achieve optimum yields of the desired product, the ratio of chromium (II) ions to starting materials must be within the range of 2.0 - 2.2 moles per mole. When the ratio of chromium (II) ions to starting material is below 2.0, a certain amount of starting material remains unreduced. On the other hand, when the ratio of chromium (II) ion to starting material is above 2.2, the desired product is reduced.

The mineral acids which can be used for carrying out the process are, for example, halo acids (such as hydrochloric acid), phosphoric acid, nitric acid, and preferably sulfuric acid. Furthermore, it is particularly desirable that the strength of the acid is about 0.5 - 3.0-n, preferably about 1-n. The concentration of the starting material in the reaction mixture. The range can be varied over a wide range, provided that the pH of the reaction mixture does not exceed 2.0 and the range is preferably maintained at a pH of 0.8 - 2, preferably at a pH of about 1.0, wherein, for example, rosamicin, which is basic, is reacted with one equivalent of acid per mole, thereby raising the pH of the reaction mixture. The most appropriate concentration of rosamicin in the reaction mixture is about 125 - 175 mg / ml.

The reaction proceeds at a temperature of about 10 - 40 ° C, with about 25 ° C being most suitable. The reaction may proceed for about 8-24 hours, with 15-20 hours being most appropriate.

When the transfer of the starting material is complete, the product is isolated by conventional means, preferably by extraction with water immiscible organic solvent, after which the reaction mixture is made basic and eats extracted with a water immiscible organic solvent. The product is then finally isolated by evaporation of the solvent.

The reduction of rosamicin is carried out at 25 ° C in 1-n sulfuric acid under argon with chromium (II) ions derived from chromium (II) chloride, where the molar ratio of chromium (II) chloride to rosamicin is 2.2 - 1, whereby the reduction expire about 18 hours.

Acylation can be carried out, for example, by means of the acid anhydride or an acid halide thereof, preferably the chloride. The reaction may be carried out in an organic solvent such as a ketone (preferably in acetone) or a tertiary amine (such as pyridine, dimethylamino-pyridine). As is known, an acid acceptor must be present in the reaction medium when the halide is used.

8 63421

In this process, it is particularly suitable to use the derivatives of an aliphatic hydrocarbon carboxylic acid containing from 2 to 18, preferably 2 to 5 carbon atoms, such as acetic acid, propionic acid, stearic acid, and pivalic acid, and aromatic carboxylic acids, such as benzoic acid.

Preferably, with said process, 2'-mono-esters, 3,2'-esters, 3,20,2'-triesters, 3,9,2'-triesters (where 'Z is preferably or 0) and 3.9 are prepared. , 20,2' tetraesters. The ester group in the 2 'position is first obtained under the usual reaction conditions. Mixed esters can also be prepared.

Esters containing a free hydroxy group at the 2 'position, especially the 3-monoesters, can be prepared by selective hydrolysis of the 2' ester group, as described in South African Patent 73/8630. The other ester groups may optionally be removed by known methods.

It is particularly advisable to use the free ester 1 in the free form (not in the form of its acid addition salt) for the solvolysis, especially with respect to the solvolysis of the 2 'ester group.

In preparing the acid addition salts of the free base and its esters of formula I, as starting material, acid addition salts can also be used. By applying the isolation procedures in question, it is possible to obtain the acid addition salt of the intended product. The free compounds (free base or esters of formula I) can be transferred to their acid addition salts by well known methods, such as by treating the compounds in an organic solvent (e.g. ethanol, acetone), which may also contain water, with the desired acid or its site, possibly in the presence of a small amount of acid, which makes the reaction mixture insignificantly acidic.

The new compounds of the formula are antibacterial agents. They differ from rosamicin in terms of activity, activity spectrum, and the mode of administration for which they are a clinical practitioner (especially oral, topical or parenteral administration).

The new compounds are more effective mother gram-positive organisms. However, they also exhibit activity against gram-negative species. Examples of the organisms against which the compounds of the invention can be used are strains of such species as Staphylococcus aureus, Streptococcus puogenes, Bacillus subtilis, Escheidia coli, Proteus vulgaris, Pseudomonas aeruginosa, Diplococcus pneumoniae, Proteus mirabilis, Proteus mirabilis .

For internal use, administration of approximately 5 to 50 mg of antibiotic (such as the free base) per kg body weight and day is appropriate. For topical application, a concentration of approximately 0.5-2% of antibacterial agent is required. The topical compositions are usually applied to the infected surface about 2-4 ginger daily.

The compounds of the invention are particularly suitable for the treatment of warm-blooded animals, but they can also be used for in vitro Sndamil as disinfectants for laboratory glass and dental and medical apparatus.

The advantage of the novel compounds of the invention produced by the following test results is: A) Acute toxicity in mouse LD5Q values (mg / kg) in subcutaneous administration: LDS0

Rosaramicin KH₂PO ^ 500 12,13-desepoxy-12,13-dehydro-rosaramicin (transform). K ^ PO ^ 850 2'-propionyl-rosaramicin H ^ PO ^ 750 2'-propionyl-12,13-desepoxy-12,13-dehydrorosaramicin.H ^ PO ^ 1100 B) In Vitro Actuity Data (MIC)

Minimum inhibitory concentration (MIC) was determined by conventional irradiation methods in Mueller-Hinton test medium at pH 7.2; incubation time 24 hours. The results are given in the following table.

63421 10

Chart.

Minimum inhibitory concentration (mg / ml)

Investigated compounds: A Rosaramicin B Rosaramicin. K 2 PO 2 C 2'-propionyl-rosaramicin D 12,13-desepoxy-12,13-dehydrorosaramicin (transform) E 12,13-desepoxy-12,13-dehydrorosaramicin (trans form) .kh2po4 F 12,13-desepoxy -12,13-dehydrorosaramicin-2'-propionate ~ Used bacterial strains ABCDEF Proteus mirabilis Hard. 7.5 17.5 17.5 0.75 3.0 3.0

Proteus justice Membel 17.5> 25 7.5 7.5 17.5 3.0

Andersson 17.5 17.5 17.5 7.5 7.57.5

Providencia 164 17.5 17.5 17.5 7.5 17.57.5 I, 3 *

Salmonella typhimurium j

Gr B 3.0 3.0 3.0 0.75j 3.0 '3.0

Serratia Dalton 3.0 7.5 3.0 0.7 5 j 3.0 3.0 _______________________ ____: _ »k - i!

The invention is further illustrated by the following examples, where the temperatures indicated are degrees Celsius. Example 1

12,13-desepoxi-12,13-dehydrorosamicin

Heat a solution of 15 g of potassium iodide in 30 ml of acetic acid to Sterflöä temperature. Add dropwise a solution of 6 g of rosamicin in 18 ml of acetic acid and continue the heating under 55 minutes of reflux. Cool the solution and pour it into about 180 g of ice and adjust the pH to about 9 with 10% aqueous sodium hydroxide solution. Extract with ethyl acetate and wash the organic extracts with alkaline sodium urate sulfate solution and with water. Concentrate the organic solution to a residue containing the title compound.

A. Chromatograph the ether on silica gel and elute with 3% methanol in chloroform. Combine fractions, containing a single compound, using thin layer chromatography, concentrate and crystallize from chloroform / hexane 63421 to form the compound of this example. Dry to constant weight, mp 109-111 °, / -7 ° -33 ° (ethanol) XMeOH 283 nm D max (8 21.700). On the basis of experiments with NMR and nuclear Overhauser effect, this compound is attributed to 12,13 trans stereochemistry.

B. Continue elution of the chromatography column with the same solvent system to form fractions containing the above-described compound in combination with a more polar component. Combine these fractions and chromatograph on silica gel using the same solvent system. Elute and combine the fractions on the basis of thin layer chromatography to give an additional amount of the above-described compound. Continue the elution to form fractions containing the less present, more polar component. Combine these fractions and concentrate to give a residue of the compound / ¾7 + 34 ° (ethanol), 288 nm (£ 14,300). On the basis of experiments with NMR and nuclear Offenhauser effect, this compound is attributed to 12,13-cis stereochemistry.

Example 2 12.13-desepoxy-12,13-dehydrorosamycin stearate salt Dissolve 100 ml of 12,13-desepoxy-12,13-dehydrorosamicin (trans isomer) in 5 ml of ethanol. Add a solution of 50 mg of stearic acid in 5 ml of ethanol with stirring. Concentrate the solution to a residue under reduced pressure and dry under high vacuum to give the compound of this example, n ~ 18 ° (ethanol), X MeOH 283 nm (£ 22,000).

Example 3 12.13-Decepoxy-12,13-dehydrorosamicin-potassium hydrogen phosphate salt Add 100 mg of 12,13-desepoxy-12,13-dehydrorosamicin (trans-isomer) to a solution of 24 mg of potassium dihydrogen phosphate in 25 ml of water.

Stir the mixture for 30 minutes, filter and lyophilize to give the desired salt, m.p. 107-112 °, ^ 3 / D -17 ° (water),

Example 4 12,13-desepoxy-12,13-dehydrorosamicin-21-propionate Dissolve 100 mg of 12,13-desepoxy-12,13-dehydrorosamicin (trans-isomer) in 25 ml of acetone and add a total of 0.175 ml of propionic anhydride 12,63421 in several portions over a period of three days. Maintain the solution at room temperature for one more day, evaporate the effluent needle and triturate the ether residue with kail, dilute ammonium hydroxide. Isolate the product by filtration, purify by dissolving in chloroform and filter the solution through a short column of silica gel. Concentrate the eluate to a residue to give the compound of this example, mp 90-94 °, / ¾ MeOH 283 nm (620,800),

^ IUclX

mass spectrum M + 621.

Example 5 12.13-desepoxyl-12,13-dehydrorosamicin-2'-acetate Dissolve 1.13 g of 12,13-desepoxy-12,13-dehydrorosamicin (trans-isomer) in 15 ml of acetone and add 240 mg of acetic anhydride. Stir for 15 hours at room temperature, evaporate the solvent under reduced pressure and triturate the ether with dilute ammonium hydroxide solution. Extract with ethyl acetate, wash the extracts with water and dry over sodium sulfate. Evaporate the solvent under reduced pressure to give the crystalline title compound, mp 120-121 °, 5 ° (ethanol).

Similarly, using equivalent amounts of other anhydrides, such as the anhydrides of butyric acid, valeric acid, hexanoic acid, octanoic acid and the like, instead of acetic anhydride can be obtained from the corresponding esters.

Example 6 12,13-desepoxy-12,13-dehydrorosamicin-2'-benzoate Dissolve 100 mg of 12,13-desepoxy-12,13-dehydrorosamicin (trans-isomer) in 0.4 ml of acetone and add 45 mg of sodium hydrogen carbonate and 0.025 ml of benzoyl chloride. Stir the mixture for 3 days at room temperature, evaporate the solvent and triturate the residue with 1% ammonium hydroxide. Isolate the product by filtration and drying, melting point 108-111 °, -2.5 ° (ethanol) λ.JJeOH 228 nm (^ 16,300), 283 nm (£ 20,500), mass spectrum M + 669.

13 63421

Example 7 12.13-desepoxy-12,13-dehydrorosamicin-21-stearate Add a solution of 63 mg of stearoyl chloride in 0.5 ml of acetone, with 102 mg of 12,13-desepoxy-12,13-dehydrorosamicin and 50 mg of sodium hydrogen carbonate. Stir the mixture for two days at room temperature, remove the solids by filtration and evaporate the filtrate to an iterate. Triturate the iterate with dilute ammonium hydroxide and decant the aqueous phase from the sticky product formed. Absorb this in acetone and concentrate in vacuo to an iterate of the desired compound [0. -9 ° (ethanol), MeOH nm (20 400), mass spectrum M 832.

Example 8 12.13-desepoxy-12,13-dehydrorosamicin-3,2 * -diacetate Dissolve 744 mg of 12,13-desepoxy-12,13-dehydrorosamicin in 10 ml of pyridine and add 400 mg of acetic anhydride. Stir for 20 hours at room temperature, evaporate the solvent under reduced pressure and triturate the iterate with ammonium hydroxide. Take up the solids in ethyl acetate, wash with sodium hydrogen carbonate solution and dry over sodium sulfate. Concentrate the solution to an ether state of the desired compound, mp 105 - 107 ° C.

Similarly, using other acylating agents, such as propionic anhydride, benzoyl chloride and the like, in place of acetic anhydride in said procedure corresponding to esters, such as the 3,2'-dipropionate, 3,2'-dibenzoate and the like.

Example 9 12.13-desepoxl-12,13-dehydrorosamycin 3-acetate

Stir a solution of 720 mg of the 3,2'-diacetate from Example 8 in a mixture of 10 ml of methanol and 4 ml of water at room temperature for five hours. Replace the solvent with ethyl acetate, wash with water, dry and concentrate to an ether state of the desired compound, mp 95 - 98 ° C, 4 ° (ethanol).

Example 10 12.13-desepoxl-12,13-dehydrorosamicin-3,2 * -proplonate

Prepare the title compound by subjecting 10 mg of 12,13-desepoxy-12,13-dehydrorosamicin to the action of 10 ml of propionic anhydride and 50 mg of dimethylaminopyridine in 30 ml of pyridine for four days at room temperature (25 ° C). Precipitate the product in 300 ml of 2.5% sodium! Carbonate solution. Stir the suspension for 15 minutes, filter, wash the precipitate with water and dry at 50 ° C in vacuo. Yield 10.1 g.

in Dissolve 4 g of the title compound in chloroform, for the solution through 50 g of silica gel and collect fractions of 60 ml. Combine fractions 8-16 and concentrate to an ether to form a purified sample of the title compound.

Yield - 1.5 g, = -12.5 (c = 0.3%, ethanol) / M + 1-7 = 676 ° C. J 28 ° H 283 nm (8 22 300).

Example 11 12.13-desepoxy-12,13-dehydrorosamicin-lauryl sulfate salt Dissolve 50 ml of 12,13-desepoxy-12,13-dehydrorosamicin in 0.5 ml of acetone and dissolve 25,5 mg of sodium lauryl sulfate in 5.0 ml of water. Add 0.01 ml of acetic acid and stir for about 45 minutes under nitrogen to evaporate the acetone. Cool the oily edible overnight and decant the water. Triturate the oily ester with hexane and refrigerate for two hours. Decant the hexane, triturate with ethanol and decant the solvent. Dry the formed product at about 40 ° C in vacuo to give the title compound. Yield 60 mg, mp 129-132 ° C, 10 ° C = 15.4 ° (c = 0.3%, ethanol), λ 283 nm (£ 21,000).

max

Example 12 12.13-desepoxy-12,13-dehydrorosamicin-3-proplonate Dissolve 7.4 g of 12,13-desepoxy-12,13-dehydrorosamicin-3,2'-dipropionate (prepared according to Example 10) in 150 ml of 80 -% methanol in water. Store the reaction mixture for three days at room temperature (25 ° C). Concentrate the reaction mixture to about 40 ml and precipitate the product in 400 ml of 5% sodium bicarbonate solution. Filter the suspension, wash with a small amount of water and dry the precipitate at 50 ° C in a vacuum. Dissolve the product in chloroform and chromatograph on 600 g of silica gel, elute with chloroform and collect the first 3.0 liters of chloroform and then convert to 4% methanol in chloroform. Combine fractions 168 - 320 and concentrate to a residue for imaging.

O CL

of the title association. Yield 3.0 g = (c = 0.3%, ethanol) (M + 1) + = 622.

63421 15

Example 13 12/13-desepoxy-12,13-dehydro-rosamicin Dissolve 50 g of rosamicin in 300 ml of 1-n sulfuric acid under argon. Add 51/5 g of chromium (III) chloride hexahydrate in 80 ml of water and 20 ml of sulfuric acid / which is dropped through a column of 100 g of aerated alloy zinc to form an equivalent amount of chromium (II) ions (see Inorganic Synthesis, voi. 3, pp. 148 - 150). At this point, the pH of the solution should be about 0.8 - 1.2. Store the reaction mixture overnight (18 hours) at room temperature (25 ° C) under argon. Extract the reaction mixture with 500 ml of ethyl ether. Adjust the reaction mixture to pH 8 with 8-n sodium hydroxide solution. Extract the reaction mixture with 2.0 liters of ethyl ether and filter the extract. Wash the extract with water and concentrate it to a residue. Dissolve the ether residue in ethanol / water (1: 2) and lyophilize. Yield 44.7 g (89.4%), δ x7p6'5 = 29.3 (c = 3%, CHCl

X ΙΠ clX

Claims (2)

16 63421 A process for the preparation of a new antibiotic-active trans-12,13-desepoxy-12,13-dehydro-rosamicin or its ester, the compound of which has the formula CH-0 to 10 Sp 20 CH 3 wherein R and R 'are hydrogen or hydrocarbon carbonyl of 2 to 18 carbon atoms, and of the pharmaceutically acceptable acid addition salts of this compound, characterized in that mad reduces rosamicin of the formula H-jC acid addition salt, and the acid is required, the transisomer is separated, and it is desirable to esterify such a obtained compound containing rainst a free hydroxyl group, or possibly a solubilized such compound containing at least one ester group, and / or the obtained compound. is converted to its acid addition salt. 2. A process according to claim 1, characterized in that raan produces a compound of formula I in which R and R * are hydrogen, i. trans-12,13-desepoxy-12,13-dehydro-rosaramicin (repromicini. 18 63421