CH630391A5 - Process for preparing derivatives of rosaramicin - Google Patents

Description

The invention relates to a process for the preparation of new 65 macrolide compounds which can be derived from antibiotic 67-694, which is also known as rosamicin or rosaramicin. The new compounds have antibacterial activity.

3rd

630 391

Rosaramicin, previously known as antibiotic 67-694, and certain derivatives of rosaramicin are described in British Patent No. 1 302 142. RosarEimicin is formed by the microorganism Micromonospora rosaria, which is also described in the aforementioned British patent. The structural formula does not stand for {pjR if the C atoms of the 2- and 3-positions are connected by a single bond and Q stands for O, W for OR ', characterized in that; that a correspondingly substituted compound of the general formula

N (ch3) 2

As the formula (III) shows, rosaramicin is a dihydroxy compound with a hydroxyl group in the 3-position of the macrolide ring and a further hydroxyl group in the 2'-position of the glycosidically bound sugar component. Both hydroxyl groups can be esterified, but the group in the 2 'position is the group that reacts first. To form a 3-monoester it is therefore necessary to esterify both hydroxyl groups and to remove the 2'-ester function use a selective hydrolysis. Such hydrolysis is described in South African patent 73/8630 (August 16, 1974). The new hydrolysis can also be applied to the 3,2'-diesters of the compounds according to the invention.

The invention relates to a process for the preparation of rosaramicin derivatives of the general formula

35

3 CH = Z

(I)

OR

in which the dashed line is an optional double bond, Q for O or (£ jR, Z for O or a group of the formula

(gR ', (8r ", <SR' '> NOH or NOR" is> R and R' are hydrogen, R "is hydrogen or an alkyl radical having 1 to 5 carbon atoms, W is OR ', where R' is the has the meaning given above, or hydrogen with the proviso that W is hydrogen when the 2 and 3 positions are connected by a double bond and with the further proviso that Z

where the dashed line is an optional double bond,

Q for O or (^ R, Z for O or a group of the formula

25 (£ jR, ('NOR' or NOR "is R, R and R 'are hydrogen or hydrocarboncarbonyl having 2 to 18 C atoms, R" is hydrogen or an alkyl radical having 1 to 5 C atoms, W is OR', where R 'has the meaning given above, or hydrogen with the proviso that when the 2- and 3-positions are connected by a double bond, W is hydrogen and with the further proviso that Z is not for < £ jR is when the C atoms of the 2- and 3-positions are connected by a single bond, Q is O, W is OR 'and R and R' have the meanings given above or non-toxic, pharmaceutically acceptable acid addition salts of these compounds is reduced by treatment with a reducing agent in the presence of acid, the 40 ester groups contained in the starting material are solvolysed, and the compounds thus obtained are isolated in free form or in the form of their pharmaceutically acceptable acid addition salts the compounds of formula I thus obtained are esterified according to claim 12. Compounds in which Z is O or the group (£ jR, (qr "or NOH are preferred. In these compounds, R and R 'are frequently acetyl or propionyl and in particular hydrogen and R" are methyl or preferably hydrogen .

For the preferred group of compounds in which W is hydrogen and the 2- and 3-positions are connected by a double bond, in particular those compounds in which Q and Z are O, 2,3; 12,13-bisdehydro- 55 3-deoxy-12,13-desepoxyrosaramicin to name as representative.

Compounds in which W for OR ', where R' has the meaning given above, in particular hydrogen, and the 2- and 3-positions are connected by a single bond, are also preferred. From this group of connections

60, those in which Q stands for (q ^, in which R 'has the meaning given above, in particular hydrogen, are to be emphasized. The preferred representative of this group is 9,9-dihydro-12,13-desepoxy-12, 13-Dehydrorosaramicin should be mentioned.65 Also of interest from this group are compounds in which Q is O. Particular mention should be made of compounds in which <qch3 or NOH.

630 391 4

Up to 11 carbon atoms, for example, are used as representatives of these compounds. In the aryl and arylalk

12,13-desepoxy-12,13-dehydrorosaramicin-20-dimethylacetal carboxylic acids, the aryl radical is expediently a phenyl radical and and 12,13-desepoxy-12,13-dehydrorosaramicin-20-oxime to the alkyl radical in the arylalkane carboxylic acids is a lower alkyl

call. rest. Of the heterocyclic carboxylic acids,

A preferred group of compounds generally uses those in which the cyclic component 5 a formula (I), however, form those compounds in which up to 6 ring atoms, in particular a hetero atom (for example S or O), the 2- and 3 positions connected by a single bond and is unsaturated. Suitable acids are, for example, Q and Z are O and W is OR. Epoxy-12,13-dehydrorosaramicin was mentioned as being suitable for the preparation of pharmaceutically unrepresented persons of this group of compounds above, as 12,13-questionable acid addition salts. Preference is given exclusively to the trans form of this compound (repromicin) used to prepare the alkyl sulfate salts. detects acids. In cases in which the invention also relates to the preparation of a 2'- and a 3-hydroxyl group esterified in a compound according to the invention. Non-toxic pharmaceutically acceptable esters and acid addi, the invention also includes the preparation of mixed ion salts of these compounds . esters. For example, 1,23-desepoxy-12,13-dehydroro-pharmaceutically acceptable acid addition salts 15 saramicin at the 2'-position are esterified with an hydrocarbon-derived acylating agent, which is generally used in the pharmaceutical field, and are salts . This expression includes the acylating agents derived from another co-inorganic acid such as sulfuric acid, phosphoric acid and hydrocarbon acid, which are then in the 3-position, and which are hydrogenated with carbon esters.

acids with 2 to 18 carbon atoms, e.g. aliphatic, cycloaliphatic 2o Of the esters, compounds are preferred in which aromatic and heterocyclic carboxylic acids include R and / or R 'acetyl, propionyl, pivaloyl, stearoyl, or ben-

finally the salts formed dicarboxylic acids. As an example are zoyl.

such acids are mentioned: acetic acid, propionic acid, butter. The salts stearates, lauryl sulfates and ca

Acid, pivalic acid, valeric acid, hexanoic acid, octanoic acid, lium dihydrogen phosphate salts are preferred.

Decanoic acid, stearic acid, succinic acid, glutaric acid, malonic acid. According to the invention, the following table I lists the acid, tartaric acid, citric acid, maleic acid, cyclopropylcard compounds. This table applies to formula I. bonic acid, cyclopentylcarboxylic acid, adamantanoic acid (adamanic acid) In this table «s» stands for a single bond (between toic), furanoic acid, nicotinic acid, thenoic acid, picolinic acid, the carbon atoms in the 2- and 3- Positions) and «d» for a benzoic acid, phthalic acid, phenylacetic acid and monopotassium double bond.

phosphoric acid. A preferred class of nontoxic, pharmaceutical 30 The general formula (I) does not express stereochemically harmless acid addition salts form the alkyl assignment.- Some of the compounds of formula (I)

sulfate salts in which the alkyl radical contains 10 to 18 carbon atoms. men in the cis form as well as in the trans form, and some of the

The pharmaceutically acceptable esters include esters of the groups can be in the a- or β-position, such as, for example, the methyl radical in the 23-position used generally in the pharmaceutical field, the OR 'groups in acids. Here ™ include esters of carboxylic acids with 2 to 18 35 9 and 20 positions and the OR "and SR" groups in carbon atoms. The expression includes aliphatic, cycloalidic 20-position.

phatic, aromatic and heterocyclic esters including In the following Table I no reference to the stereo

given the half ester with dicarboxylic acids such as maleic acid, malic acid chemistry of these compounds. It should be noted that and malonic acid. Acids with 2 to 10, the compound 2, the trans isomer and the compound 17, the C atoms, in particular with 2 to 5 C atoms, are expediently used. Of 40 cis isomers of 12,13-desepoxy-12,13-dehydrorosaramicin in the cycloalkane carboxylic acids, those with 4 can be expedient.

Table connection Q R W C2 Z physical data I

C3

2 = 0 H OH s = 0 mp 109-111 ° C

[a] D - 33 ° (ethanol)

CCH3 II

5 = 0 O OH s = 0 mp 120-121 ° C

[a] D - 5 ° (ethanol)

OCCH3

II

9 = 0 H O s = 0 mp 95-98 ° C

[cc] D - 4 ° (ethanol)

10 = 0 H OH s = NOH mp 165-167 ° C

[a] D - 38 ° (ethanol)

(Continuation)

Connect Q R

dung

O

14 = 0 c

17 19

24th

25th

26

27th

28

29

cc2h5

15 = 0 o

16 = 0

= o = o

20 = 0

cci7h35 II

o h h

CC (CH3) 3 II

O

22 = 0 h

<

h h

V

h vOH

,H

'"OH

CC2H5 II

= o o

= 0 h oc2h5

<

h oh

<

H

O

h oh

5

W

C2 1

C3

z physical data

OH

s

= o

M.p. 108-111 ° C Md - 2.5 ° (ethanol)

OH

s

= o

Mp 90-94 ° C

OH

s

= o

[a] D - 9 ° (ethanol)

OH H

s d o o

Il II

[a] D + 34 ° (ethanol) [a] D - 21.9 ° (ethanol)

OH

s

= o

Mass spectrum (M + l] + m / e 649

OH

s

^ OCH3 \ OCH3

[a] D = 1.3 ° (ethanol)

OH

s

/ OCH3

nsoch3

[a] D = + 2.0 ° (ethanol)

OH

s

= o

[a] D = 3.2 ° (ethanol)

OCC2H5

II

II

O

s

= o

[a] D = - 12.5 ° (ethanol)

OCC2H5

II

11

o s

= o

[a] D = - 8.4 ° (ethanol)

OH

s

= o

^ max 238 nm

OCC2h5 m

ii o

s

- O

Mass spectrum (M + l) + m / e 623

630 391

cch3 occh3

Il II

30 = 0 O O s = 0 mp 105-107 ° C

The process can be carried out with alkali metal bromides or preferably with alkali metal iodides in an organic acid at a temperature above ambient. The carboxylic acids preferably contain 1 to 4 carbon atoms. This reaction can also take place in aromatic hydrocarbons, e.g. Benzene, toluene or xylene, which contain concentrated hydroiodic acid. Another possibility is the treatment of the starting material of the formula (II) with phosphoric acid trialkoxides, trialkylphosphines, triphenylphosphines or hexalkylphosphoimidates.

A preferred medium for carrying out this reaction is potassium iodide in acetic acid, which is kept under reflux. 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 from the extract.

When carrying out the above process, it is generally necessary to heat the reaction mixture to the reflux temperature in an acidic medium. As a result, there is a risk of decomposition of the starting material and / or decomposition of the product. Therefore, yields of about 30 to 50% of theory are obtained in this process, and this product consists of substantial amounts of both the ice and the trans isomer.

In the new embodiment of the process described below, the compounds of the general formula (II), in particular when used for the conversion of rosaramicin into 12,13-desepoxy-12,13-dehydrorosarami-cin, are obtained in yields of 85 to 95%, and these compounds are about 90% pure. Furthermore, this embodiment leads to a product which is rich in trans isomers and therefore does not require chromatographic separation of the isomers.

The new embodiment of the process is characterized in that the reduction of the compounds of the general formula (II) with a chromium (II) compound is carried out in a mineral acid solution under an inert atmosphere. Dilute mineral acid solution is preferably used.

The reduction mixture, i.e. the chromium (II) ions are advantageously supplied in the form of a solution containing a chromium (II) salt in which the anion is derived from a mineral acid, e.g. Chromium (II) chloride, chromium (II) sulfate or chromium (II) iodide. Chromium (II) chloride is preferred as the reducing agent, which can advantageously be preferably produced by the process described in Inorganic Synthesis, Volume III, pages 148-150, published by McGraw-Hill 1950 the chromium (II) chloride solution is freshly prepared immediately before use to prevent the formation of higher quality chromium ions.

Furthermore, in order to achieve optimum yields of the desired product, the ratio of chromium (II) ions to the starting material must be in the range from 2.0 to 2.2 moles per mole. If the ratio of chromium (II) ions to the starting material is less than 2.0, a certain amount of the starting material remains unreduced. Conversely, the desired product is reduced if the ratio of chromium (II) ion to starting material is above 2.2.

Suitable mineral acids for this embodiment of the process are, for example, hydrohalic acids (e.g. hydrochloric acid), phosphoric acid, nitric acid and preferably sulfuric acid. Furthermore, the strength of the acid is preferably about 0.5n to 0.3n, preferably about 1.0n. The concentration of the starting material in the reaction mixture can be varied within a wide range, provided that the pH of the reaction mixture does not exceed 2.0 and that the pH is preferably kept between 0.8 and 2, in particular, for example, around 1.0 . Since rosaramicin is basic, it reacts with 1 equivalent of acid per mole, which increases the pH of the reaction mixture. A rosaramicin concentration in the reaction mixture of about 125 5 to 175 mg / ml is preferred.

The reaction proceeds at temperatures of about 10 ° to 40 ° C, with a temperature of about 25 ° C being preferred. The reaction time can be about 8 to 24 hours, with about 15 to 20 hours being preferred.

After complete conversion of the starting material, the product is isolated by customary methods, preferably by extraction with a water-immiscible organic solvent, basification of the reaction mixture and renewed extraction with a water-immiscible organic solvent. The product is then finally isolated by evaporating off the solvent.

When using this process to convert rosaramicin to 12,13-desepoxy-12,13-dehydrorosaramicin, the rosaramicin is preferably at 25 C in l-sulfuric acid under argon with chromium (H) ions derived from chromium (II) -chloride, reduced, the molar ratio of chromium (II) chloride to rosamicin being 2.2: 1 and the reduction being carried out for about 18 hours.

In the process described above, the 25 ester groups contained in the starting material (in particular the ester group in the 2'-position) are at least partially sol-volysed during the reaction itself or during the isolation process. The extent of solvolysis often depends on the reaction conditions actually used, which can be varied to a certain extent. In many cases, however, the free base is preferably used as the starting material instead of an ester of the base, whereby a product is obtained which does not contain a large number of undesirable by-products (several types of esters).

35 The acylation can be carried out, for example, with the acid anhydride or acid halide, preferably with the chloride. The reaction can be carried out in an organic solvent, e.g. a ketone (preferably acetone), or in a tertiary amine (e.g. pyridine and dimethylaminopyridine) 40. As is known, when using the halide, an acid acceptor must be present in the reaction medium.

Preferably, the corresponding derivative of an aliphatic hydrocarbon carboxylic acid with 2 45 to 18 C atoms, preferably with 2 to 5 C atoms, e.g. Acetic acid, propionic acid, stearic acid and pivalic acid, and an aromatic carboxylic acid, e.g. Benzoic acid.

According to the process described above, 2'-monoesters, 3,2'-diesters, 3,20,2'-triesters, thus 3,9,2'-triesters, are preferably used (in which Z is preferably a group of the formula

(0CH3 or O and 3,9,20,2'-tetraesters. The

Ester group in the 2'-positions is first obtained under the usual reaction conditions. Mixed esters can also be made 55.

Esters which contain a free hydroxyl group in the 2'-position, in particular 3-monoesters, can be prepared by selective hydrolysis of the 2'-ester group, as described in the South African patent 73/8630. The other fio ester groups can optionally be removed by known methods.

The ester in question is preferably used in free form (not in the form of its acid addition salt) for the solvolysis, in particular in the case of the solvolysis of the 2'-ester group.

The simple derivatives, i.e. the acid addition salts of the free base and their esters of the general formula (I) also fall within the scope of the invention. For many the first

7

630 391

The processes described can also use acid addition salts of the starting materials. Using suitable isolation processes, it is possible to obtain the acid addition salt of the desired product. The free compounds (free base or ester of general formula (I)) can be prepared by known methods, e.g. by converting the compounds in an organic solvent (e.g. ethanol and acetone), which may also contain water, with the desired acid or its salt, optionally in the presence of a small amount of acid which slightly acidifies the reaction mixture, into its acid addition salts.

The following examples illustrate the best mode of operation for carrying out the processes according to the invention. (The old name rosamicin is retained in the examples).

example 1

12,13-desepoxy-12,13-dehydrorosamicin

A solution of 15 g of potassium iodide in 30 ml of acetic acid is heated to the reflux temperature. A solution of 6 g of rosamicin in 18 ml of acetic acid is added dropwise and the mixture is refluxed for a further 55 minutes. The solution is cooled and poured into about 180 g of ice and then adjusted to about pH 9 with 10% aqueous sodium hydroxide. It is extracted with ethyl acetate and the organic extracts are washed with alkaline sodium thiosulfate solution and then with water. The organic solution is concentrated to a residue which contains the desired compound.

A. Chromatograph the residue on silica gel and elute with 3% methanol in chloroform. The fractions, which according to thin layer chromatography contain a single compound, are concentrated, and crystallized from chloroform-hexane to give the desired compound. One dries to constant weight. Melting point 109-

MeOH

111 ° C. [a] D - 33 ° (ethanol), 1 - 283 nm (e 21,700).

Max

The 12.13-trans stereo configuration is assigned to this compound on the basis of the NMR spectrum and determinations of the Overhauser core effect.

B. The chromatography column is further eluted with the same solvent system to give fractions containing the compound described above in admixture with a more polar component. These fractions are combined and chromatographed again on silica gel using the same solvent system. Fractions based on thin layer chromatography are eluted and combined to give an additional amount of the compound described above. Elution continues and fractions are obtained which contain the smaller, more polar component. These fractions are pooled and concentrated to a residue of the compound. [a] D + 34 ° (ethanol), X j ^ pH 288 nm

(e 14,300). The 12.13-cis stereochemistry is assigned to this compound on the basis of the NMR spectrum and determinations of the Overhauser core effect.

Example 3

12,13-desepoxy-12,13-dehydrorosamicin potassium dihydrogen phosphate salt

100 mg of 12,13-desepoxy-12,13-dehydrorosamicin 5 (trans-isomer) are added to a solution of 24 mg of potassium dihydrogen-phosphate in 25 ml of water. The mixture is stirred for 30 minutes, filtered and freeze-dried, the desired salt having a melting point of 107 to 112 ° C. being obtained. [a] D - 17 °

10 (water), /, 283 nm (e 21,000).

Example 4

12,13-desepoxy-12,13-dehydrorosamicin-2 'propionate

100 mg of 12,13-desepoxy-12,13-dehydrorosamicin 15 (trans-isomer) are dissolved in 25 ml of acetone and a total of 0.175 ml of propionic anhydride is added in several portions within 3 days. The solution is obtained for a further day at room temperature, then the solvent is evaporated off and the residue is triturated with cold, dilute ammonium hydroxide. The product is filtered off and purified by dissolving it in chloroform and filtering the solution through a short column of silica gel. The eluate is concentrated to a residue and the desired compound of melting point 90-94 ° C. is obtained.

25th

X max *** 283 nm (e 20,800), mass spectrum M + 621.

Example 5

12,13-desepoxy-l 2,13-dehydrorosamicin-2 'acetate 30 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 . The mixture is stirred at room temperature for 15 hours, the solvent is then evaporated off under reduced pressure and the residue is triturated with dilute ammonium hydro-35x solution. It is extracted with ethyl acetate, the extracts are washed with water and dried over sodium sulfate. The solvent is evaporated off under reduced pressure and the desired crystalline product of melting point 120-121 ° C. is obtained. [a] D - 5 ° (ethanol).

40 In the same way, using equivalent amounts of other anhydrides such as butyric anhydride, valeric anhydride, hexanoic anhydride and octanoic anhydride instead of acetic anhydride, the corresponding esters are obtained in the process described above.

45

50

55

Example 2

12,13-desepoxy-l 2,13-dehydrorosamicin stearate salt

100 mg of 12,13-desepoxy-12,13-dehydrorosamicin (trans-isomer) are dissolved in 5 ml of ethanol. A solution of 50 mg of stearic acid in 5 ml of ethanol is added with stirring. The solution is concentrated under reduced pressure to a residue which is dried under high vacuum to give the desired compound. [a] D -18 ° (ethanol), X 283 nm (e 22,000).

Example 6

12,13-desepoxy-l 2,13-dehydrorosamicin-2 'benzoate

100 mg of 12,13-desepoxy-12,13-dehydrorosamicin (trans-isomer) are dissolved in 0.4 ml of acetone and 45 mg of sodium bicarbonate and 0.025 ml of benzoyl chloride are added. The mixture is stirred for 3 days at room temperature, then the solvent is evaporated off and the residue is triturated with 1% aqueous ammonium hydroxide. The product is isolated by filtration and dried. Melting point 108-111 ° C. [a] D - 2.5 ° (etha-

nol), X MeOH 228 nm (e 16.300), 283 nm (e 20.500), mass spectrum M + 669.

60 Example 7

12,13-desepoxy-12,13-dehydrorosamicin-2 'stearate

102 mg of 12,13-desepoxy-12,13-dehydrorosamicin and 50 mg of sodium bicarbonate are added to a solution of 63 mg of stearoyl chloride in 0.5 ml of acetone. The mixture is stirred for 2 days at room temperature, the solids are then removed by filtration and the filtrate is evaporated to a residue. The residue is triturated with dilute ammonium hydroxide and the aqueous phase is decanted from the gum formed. One takes

630 391

the latter in acetone and concentrated under reduced pressure to a residue consisting of the desired compound. [a] D - 9 ° (ethanol),

X 283 nm (e 20.400), mass spectrum M + 832.

Example 8

12,13-desepoxy-12,13-dehydrorosamicin-3,2'-diacetate

744 mg of 12,13-desepoxy-12,13-dehydrorosamicin are dissolved in 10 ml of pyridine and 400 mg of acetic anhydride are added. The mixture is stirred at room temperature for 20 hours, then the solvent is evaporated off under reduced pressure and the residue is triturated with ammonium hydroxide. The solid is taken up in ethyl acetate, washed with aqueous sodium bicarbonate and dried over sodium sulfate. The solution is concentrated to a residue which consists of the desired compound with a melting point of 105-107 ° C.

In the same way, by using other acylating agents such as propionic anhydride and benzoyl chloride instead of acetic anhydride in the process described above, the corresponding diesters, e.g. the 3,2'-di-propionate and 3,2'-dibenzoate.

Example 9

12,13-desepoxy-12,13-dehydrorosamicin-3-acetate

A solution of 720 mg of the 3,2'-diacetate prepared according to Example 8 is stirred for 5 hours at room temperature in a mixture of 10 ml of methanol and 4 ml of water. The solvent is replaced by ethyl acetate, washed with water, dried and concentrated to a residue which consists of the desired compound of melting point 95-98 ° C. [o] D - 4 ° (ethanol).

8th

point 129 to 132 ° C. [a] £ f = 15.4 °, C = 0.3% ethanol,

XmS? H 283 nm (8 = 21-000).

In the same manner, using a 5 equivalent amount of other sodium alkyl sulfates such as sodium tetradecyl sulfate, sodium hexadecyl sulfate and sodium octadecyl sulfate instead of sodium lauryl sulfate, the following compounds can be prepared in the manner described in Example 23:

10 12,13-desepoxy-12,13-dehydrorosamicin tetradecyl sulfate salt, 12,13-desepoxy-12,13-dehydrorosamicin hexadecyl sulfate salt and 12,13-desepoxy-12,13-dehydrorosamicinoctadecyl sulfate salt.

15 Example 12

12,13-desepoxy-12,13-dehydrorosamicin-3-propionate

7.4 g of 12,13-desepoxy-12,13-dehydrorosamicin-3,2'-dipropionate (prepared according to Example 16) are dissolved in 150 ml of 80% methanol-water. The reaction mixture is left to stand at room temperature (25 ° C.) for 3 days. The reaction mixture is concentrated to about 40 ml and precipitated in 400 ml of 5% sodium bicarbonate. The suspension is filtered, washed with a little water and the precipitate is dried at 50 ° C. under reduced pressure. The product is dissolved in chloroform and chromatographed on 600 g of silica gel, eluting with chloroform, collecting the first 3.01 chloroform and then converting to 4% methanol in chloroform. Fractions 168 to 320 are combined and concentrated to a residue, giving the desired compound.

30 ne.

Yield 3.0 g [a] ^ = - 8.4 (c = 0.3% ethanol)

(M + 1) + = 622.

Example 10

12,13-desepoxy-12,13-dehydrorosamicin-3,2 'dipropionate

10 g of 12,13-desepoxy-12,13-dehydrorosamicin are subjected to the action of 10 ml of propionic anhydride and 50 mg of dimethylaminopyridine in 30 ml of pyridine at room temperature (25 ° C.). The product is precipitated in 300 ml of 2.5% sodium carbonate. The suspension is stirred for 15 minutes, filtered, the precipitate is washed with water and dried at 50 ° C. under reduced pressure. Yield 10.1 g.

4 g of this product are dissolved in chloroform and the solution is passed through 50 g of silica gel, collecting fractions of 60 ml each. Fractions 8 to 16 are combined and concentrated to a residue, giving the desired product in purified form.

Yield 1.5 g [a] - 12.5 (c = 0.3%, ethanol) [M + 1] = 676 X OH 283 nm (e = 22,300)

Example 11

12,13-desepoxy-12,13-dehydrorosamicin lauryl sulfate salt

50 mg of 12,13-desepoxy-12,13-dehydrorosamicin are dissolved in 0.5 ml of acetone and 25.5 mg of sodium lauryl sulfate are dissolved in 5.0 ml of water. 0.01 ml of acetic acid are added to the solution and the mixture is stirred under nitrogen for about 45 minutes, the acetone being allowed to evaporate. The oily residue is kept in the refrigerator overnight and then the water is decanted. The oily residue is triturated with hexane and cooled for 2 hours. The hexane is decanted and triturated with ethanol, after which the solvent is removed by decanting. The product obtained is dried at about 40 ° C. under reduced pressure, the desired compound being obtained. Yield 60 mg. Schmelz35 Example 13

12,13-desepoxy-12,13-dehydrorosamicin

50 g of rosamicin are dissolved in 300 ml of 1N sulfuric acid under argon. A mixture of 51.5 g of chromium (III) chloride hexahydrate, 80 ml of water and 20 ml of sulfuric acid is added. This mixture was previously trickled through a column of 100 g amalgamated zinc, which formed an equivalent amount of chromium (II) ions (see Inorganic Synthesis, Volume 3, pages 148-150). At this point, this solution should have a pH of about 0.8 to 1.2. The reaction mixture is allowed to stand under argon overnight (18 hours) at room temperature (25 ° C.). The reaction mixture is extracted with 500 ml of ethyl ether, adjusted to pH 8 with 8N sodium hydroxide, extracted with 2.01 ethyl ether and the extract is filtered. The extract is washed with water and concentrated to a residue. The residue is dissolved in ethanol / water (1: 2) and freeze-dried.

Yield 44.7 g (89.4%); [a] ^ 6> 5 = -29.3 (C = 3%

CHC13)

55

X CH3 ° h 283 nm (g = 20,420)

60 Some starting compounds which are used for the process according to the invention are new compounds. They can be produced from rosaramicin by processes known per se.

The compounds according to the invention are antibacterial agents. They differ more or less from rosamicin in terms of the effect, spectrum of action and type of administration for which they are best suited (in particular for oral, topical or parenteral administration).

9

630 391

In general, the compounds according to the invention are more effective against gram-positive microorganisms, but they also show activity against gram-negative species. As examples of microorganisms against which the compounds according to the invention can be used are strains of species such as Staphylococcus aureus, Streptococcus pyoge-nes, Bacillus subtilis, Escherichia coli, Proteus vulgaris, Pseudomonas aeruginosa, Diplococcus pneumoniae, Proteus mirabilii and Proteus morganii and Proteus morganii call.

Claims (9)

630 391 2nd PATENT CLAIMS 1. Process for the preparation of rosaramicin derivatives of the general formula 3 CH = Z (I) the 2- and 3-positions are connected by a single bond, and Q is O, W is OR 'and R and R' have the meanings given above or non-toxic, pharmaceutically acceptable acid addition salts of these compounds by treatment with a reducing agent in the presence of Acid reduced, the ester groups contained in the starting material being solvolysed, and the compounds thus obtained isolated in free form or as acid addition salts. 2. The method according to claim 1, characterized in that the reduction is carried out with an alkali metal bromide or alkali metal iodide in an organic acid or in aromatic hydrocarbons which contain concentrated hydroiodic acid, or with a chromium (II) compound in a mineral acid solution under an inert atmosphere . 15 3. The method according to claim 1 or 2, characterized in that one produces a compound (I) in which Z represents O, or NOH stands. in which the dashed line is an optional double bond, Q is O or {Z is O or a group of the formula (or '(or ;; 5 (sr ;;) noh or nor ", round R' are hydrogen, R" Is hydrogen or an alkyl radical having 1 to 5 carbon atoms, W is or ', in which r' has the meaning given above, or hydrogen is provided that W is hydrogen when the 2 and 3 positions are connected by a double bond are, and with the further proviso that Z does not stand for {if the C atoms of the 2- and 3-positions are connected by a single bond in a compound, and Q stands for O, W for OR ', characterized in that a correspondingly substituted compound of the general formula in which the dashed line is an optional double bond Q for O or Z for O or a group of the formula <0r'î <8g :; , <sr '' 'nor' or nor ", r and r ' Are hydrogen or hydrocarboncarbonyl having 2 to 18 carbon atoms, r "is hydrogen or an alkyl radical having 1 to 5 carbon atoms, W is or ', in which r' has the meaning given above, or hydrogen is provided that, when the 2 and 3 positions are connected by a double bond, W is hydrogen, and with the further proviso that Z does not stand for {if the carbon atoms in a compound / OH / OR " \ H '* OR " 4. The method according to any one of claims 1 to 3, characterized in that one produces a compound (I) in which R "is hydrogen or methyl. 5. The method according to any one of claims 1 to 4, characterized in that a compound (I) is prepared in which W is hydrogen, the 2- and 3-positions by a double 25 bond and Q and Z stand for O. 6. The method according to any one of claims 1 to 4, characterized in that a compound (I) is prepared in which W stands for OH and the 2- and 3-positions are connected by a single bond. 30 7. The method according to claim 6, characterized in to prepare a compound (I) in which Q is (qjj. 8. The method according to claim 6, characterized in that a compound (I) is prepared in which Q is O. 35 9. The method according to any one of claims 1 and 2, characterized in that 2,3; 12,13-bisdehydro-3-deoxy-12,13-desepoxyrosaramicin, 9,9-dihydro-12,13-desepoxy-12 , 13-dehydrorosaramicin, 12,13-desepoxy-12,13-dehydrorosaramicin-20-dimethylacetal, 12,13-desepoxy-12,13-dehydro-40 rosaramicin-20-oxime or 12,13-desepoxy-12, 13-dehydroro-saramicin. 10. The method according to claim 9, characterized in that one produces trans-12,13-desepoxy-12,13-dehydrorosaramicin (repromicin). 45 11. The method according to claim 2, characterized in that rosaramicin is reduced at 25 ° C in l-sulfuric acid under argon with chromium (n) chloride, the molar ratio of chromium (II) chloride to rosaramicin being 2.2: 1 is. 12. A process for the preparation of rosaramicin derivatives of the formula I in which Q and Z are (H) OR 'and W is OR', wherein R and R 'are carbon-carbonyl having 2 to 18 carbon atoms, characterized in that the compounds of the formula I in which R and R' are hydrogen and the OH-containing therein are prepared by the process of claim 1 Groups esterified with an appropriate acylating agent. 13. The method according to claim 12, characterized in that rosaramicin derivatives are prepared in which R and R 'hydrocarboncarbonyl having 2 to 5 carbon atoms 60 interpret.