HK1036457B - 15-membered lactams ketolides with antibacterial activity - Google Patents

Description

15-membered lactam ketolides with antibacterial activity

Technical Field

The international patent classification: A61K31/70, C07H17/08

Technical problem

The present invention relates to novel compounds of the erythromycin a macrolide antibiotic class. In particular, the present invention relates to novel 15-membered ring ketoazalides (ketoazalides) of the 6-O-methyl-8 a-aza-8 a-homo-and 6-O-methyl-9 a-aza-9 a-homoerythromycin a (homoerythromycin) class, to intermediates and processes for their preparation, to pharmaceutically acceptable addition salts thereof with inorganic or organic acids, to processes for the preparation of pharmaceutical compositions and to the use of pharmaceutical compositions for the treatment of bacterial infections.

Prior Art

Erythromycin is a macrolide antibiotic characterized structurally by a 14-membered lactone ring with a C-9 ketone and two sugars, L-cladinose and D-desosamine, wherein the sugars are glycosidically bound at the C-3 and C-5 positions to the aglycone part of the molecule (McGuire: "antibiotic chemotherapy" (Antibiott. Chemotherm.) 1952, 2: 281). Erythromycin A has been recognized for over 40 years as a safe and effective antimicrobial agent for the treatment of respiratory and genital infections caused by gram-positive bacteria such as strains of Legionella, Mycoplasma, Chlamydia and helicobacter. The observed changes in bioavailability, gastric intolerance in many patients and loss of activity in acidic media following the use of oral formulations are major drawbacks in the use of erythromycin a therapy. The spirocyclization of the aglycon ring is successfully inhibited by chemical transformation of the C-9 ketone or the hydroxyl group in the C-6 and/or C-12 position. Thus, for example, 9-deoxo-9 a-aza-9 a-homoerythromycin A, which is the first semi-synthetic macrolide with a 15-membered azalide ring, is obtained by oximation of the C-9 ketone in erythromycin A with hydroxylamine hydrochloride, Beckmann rearrangement of the resulting 9(E) -oxime and reduction of the 6, 9-iminoether thus formed (6-deoxo-9 a-aza-9 a-homoerythromycin A6, 9-cycloiminoether) (KobrehelG et al, U.S. Pat. Nos. 4,328,334, 5/1982). 9-deoxo-9 a-methyl-9 a-aza-9 a-homoerythromycin A (azithromycin), a prototype of a novel azalide (azalide) antibiotic class, was synthesized by reductively methylating the newly introduced endocyclic 9 a-amino group according to the Escherrer-Crick reaction (Kobrehel G. et al, BE 892357, 7/1982). In addition to having a broad antimicrobial spectrum, including resistance to gram-negative bacteria, azithromycin is characterized by a long biological half-life, a specific mechanism of delivery to the site of administration, and a short treatment period. Azithromycin is able to penetrate and accumulate in human phagocytes, resulting in an improvement in intracellular pathogenic microorganisms of Legionella, Chlamydia and helicobacter strains.

Furthermore, it is known that C-6/C-12 spiro cyclization of erythromycin A is also inhibited by O-methylation of the C-6 hydroxyl group in the aglycone ring (Watanabe Y. et al, U.S. Pat. No. 4,331,803, 5/1982). 6-O-methyl-erythromycin A (clarithromycin) is formed by reacting erythromycin A with benzyloxycarbonyl chloride followed by methylation of the resulting 2 ' -0, 3 ' -N-bis (benzyloxycarbonyl) -derivative, elimination of the protecting group and 3 ' -N-methylation (Morimoto S. et al, J.antibiotics 1984, 37, 187). Clarithromycin is significantly more stable in acidic media and exhibits increased activity in vitro against gram-positive bacterial strains if compared to erythromycin A (Kirst H.A. et al, antibacterial Agents and chemotherapy 1989, 1419).

Recent studies on 14-membered macrolides have led to novel macrolide antibiotics, ketolides (ketolides), characterized by the substitution of the neutral sugar L-cladinose by the 3-keto group, the latter being known to be unstable even in weakly acidic media (Agourida C. et al, EP 596802A 1, 5/1994; Le Martret O., FR 2697524A 1, 5/94). Ketolides exhibit significantly enhanced activity in vitro against MLS (macrolides, lincosamides and streptogramins B) induced by resistant organisms (Jamjian c. antibacterial chemotherapy 1997, 41, 485).

EP-A-0507595 discloses 8 ｃA-azｃA-8 ｃA-homoerythromycin lactams which differ from the compounds according to the invention in that they do not carry ｃA methoxy group in position 6, which significantly changes the chemical and biological properties of the molecule.

According to the known and established prior art, 15-membered ring ketoazalides from the class of 6-O-methyl-8 a-aza-8 a-homo-and 6-O-methyl-9 a-aza-9 a-homoerythromycin A and their pharmaceutically acceptable addition salts with inorganic or organic acids, processes for their preparation and intermediates thereof, as well as processes for the preparation of pharmaceutical compositions and uses thereof have not been described so far.

The object of the invention is represented by the following steps: subjecting the 9(E) -and 9(Z) -oximes of 6-O-methylerythromycin A to Beckmann rearrangement, hydrolysis of cladinose in the 8 a-and 9 a-lactams thus obtained, protection of the hydroxyl group at the 2' -position in the desosamine, oxidation of the 3-hydroxyl group and removal of the protecting group, thereby obtaining novel 15-membered ring ketoazalides from the classes 6-O-methyl-8 a-aza-8 a-homo-and 6-O-methyl-9 a-aza-9 a-homoerythromycin A which have not been described so far.

Technical scheme

Novel 15-membered ring ketoazalides (ketoazalides) from the class of 6-O-methyl-8 a-aza-8 a-homo-and 6-O-methyl-9 a-aza-9 a-homoerythromycin A having the general formula (I) and their pharmaceutically acceptable addition salts with inorganic and organic acids are obtained as follows:wherein A represents an NH group and B simultaneously represents a C ═ O group; or A represents a C ═ O group and B simultaneously represents an NH group; r¹Represents OH group, L-cladinosyl group of the general formula (II)Or with R²Together represent a ketone; r²Represents hydrogen or with R¹Together represent a ketone; r³Represents hydrogen or C₁-C₄Alkanoyl of (1);

step 1:

the first step of the present invention comprises reacting a compound of formula (III)The C-9 ketoxime of 6-O-methylerythromycin A (clarithromycin) is converted to the corresponding oxime. The conversion of ketones into oximes is a well known reaction which is generally carried out with hydroxylamine hydrochloride in the presence of suitable inorganic or organic bases in suitable protic or aprotic solvents. Hydroxylamine hydrochloride is used in a 1-15 equimolar excess, preferably in a 10-equimolar excess, relative to clarithromycin. Alkali metal hydroxides, carbonates, bicarbonates and acetates are used as suitable bases, and C₁-C₃The alcohol (2) is used as a solvent. The preferred base is sodium carbonate or sodium acetate and the preferred solvent is methanol. In general, the reaction is carried out at a temperature of from 0 to 80 ℃ and preferably at 65 ℃ for from 2 hours to several days, but is essentially complete within from 8 to 20 hours. The treatment is carried out in a conventional manner, for example by evaporation of the solvent in vacuo; adding a mixture of water and an organic solvent; followed by extraction in an alkaline medium, preferably at pH 8.0-10.0. Dichloromethane, chloroform, ethyl acetate, diethyl ether and toluene were used as extraction solvents for the product, chloroform being the preferred extraction solvent. By separating the organic layer andthe product is isolated by evaporation of the solvent, giving the general formula (IV) in a ratio of about 1: 1A mixture of 6-O-methylerythromycin A9(E) -and 9(Z) -oxime. The separation of the isomers is carried out, if necessary, by column chromatography on silica gel using a dichloromethane-methanol-ammonium hydroxide system 90: 9: 1.5, thus giving 6-O-methylerythromycin A9(E) -oxime of general formula (IVa) having an Rf value of 0.446, which is chromatographically homogeneous;and chromatographically homogeneous 6-O-methylerythromycin A9(Z) -oxime of the general formula (IVb) having an Rf value of 0.355.

Step 2:

the 6-O-methylerythromycin A9(E) -oxime of the formula (IVa) is converted into 6-O-methyl-erythromycin A of the formula (I) by means of a Beckmann rearrangement reaction (cf. Integrated organic chemistry, I.O. Sutherland (eds.), Pergamon Press, New York, 1979, Vol. 2, 398-400 and 967-968),

wherein A represents an NH group; b simultaneously represents a C ═ O group; r¹Represents L-cladinosyl group of general formula (II);R²and R³Identical and represents hydrogen. In general, beckmann rearrangement of ketoximes produces carboxamides or, in the case of ring systems, lactams. The mechanism of this rearrangement involves the pre-conversion of the oxime hydroxy group into a better leaving group which is cleaved by the simultaneous migration of the carbon atom which is located in the second reaction step opposite to the leaving group. In an aqueous medium, a nitrilium ion is formed as an intermediate product, which reacts with water to form a suitable amide.

The beckmann rearrangement reaction is carried out under acidic, neutral and basic conditions. Common acidic reagents for catalyzing rearrangement include concentrated sulfuric acid, polyphosphoric acid, tioyl chloride, phosphorus pentachloride, sulfur dioxide, and formazanAnd (4) acid. Due to the sensitivity of the macrolide molecule in acidic media and in particular to the easy cleavage of the neutral sugar L-cladinose, these reagents are not suitable for rearranging oximes of formula (IVa) into 6-O-methyl-9 a-aza-9 a-homoerythromycin A of formula (I), wherein A, B, R¹、R²And R³Have the above-mentioned meanings. Preferably, the Beckmann rearrangement of the oxime (IVa) is carried out by initially O-sulfonating the oxime hydroxy group with an alkyl sulfonyl halide, aryl sulfonyl halide or aryl sulfonyl anhydride. The intermediate oxime sulfonate is isolated or generally rearranged in situ to the desired product. In general, the sulfonation and rearrangement is carried out in the presence of organic or inorganic bases.

Preferred sulfonating agents which catalyze oxime (IVa) rearrangement include methanesulfonyl chloride, benzenesulfonyl chloride, 4-acetaminosulfonyl chloride, p-toluenesulfonyl chloride, benzenesulfonic acid and anhydrides of p-toluenesulfonic acid. The reaction is carried out in the presence of inorganic bases such as sodium bicarbonate or potassium carbonate or in the presence of organic bases such as pyridine, 4-dimethylaminopyridine, triethylamine and N, N-diisopropyl-amine. Suitable solvents include aqueous mixtures such as acetone-water mixtures and dioxane-water mixtures and organic solvents such as dichloromethane, chloroform, ethyl acetate, diethyl ether, tetrahydrofuran, toluene, acetonitrile and pyridine. In general, the reaction is carried out at a temperature of from-20 to 50 ℃ by using a 1-3 equimolar excess of the sulfonation reagent and using the same or a more equimolar amount of a base. Pyridine is generally used as a solvent and simultaneously as a base. Preferably, the beckmann rearrangement of oxime (IVa) is performed in an acetone-water mixture using double equimolar excess of p-toluenesulfonyl chloride and sodium bicarbonate. The product was purified, if necessary, by column chromatography on silica gel using a dichloromethane-methanol-ammonium hydroxide 90: 9: 1.5 solvent system to yield chromatographically homogeneous 6-O-methyl-9 a-aza-9 a-homoerythromycin A.

Beckmann rearrangement of 6-O-methylerythromycin a9(Z) -oxime of formula (IVb) to 6-O-methyl-8 a-aza-8 a-homoerythromycin a of general formula (I) wherein a represents a C ═ O group and B simultaneously represents an NH group is carried out in a similar manner to 9(E) -oxime (IVa); r¹Representational general medicineL-cladinosyl group of formula (II); and R is²And R³Identical and represents hydrogen.

And step 3:

if appropriate, 6-O-methyl-9 a-aza-9 a-homoerythromycin A or 6-O-methyl-8 a-aza-8 a-homoerythromycin A of the general formula (I) in step 2 is allowed to react with a strong acid, preferably 0.25 to 1.5N hydrochloric acid, at room temperature within 10 to 30 hours, wherein A, B, R¹、R²And R³Having the above-mentioned meaning, thereby yielding 3-O-decladinosyl-3-oxo-derivatives of 6-O-methyl-9 a-aza-9 a-homoerythromycin a or 6-O-methyl-8 a-aza-8 a-homoerythromycin a of general formula (I), wherein a represents an NH group and B simultaneously represents a C ═ O group; or A represents a C ═ O group and B simultaneously represents an NH group; r¹Represents an OH group; and R is²And R³Identical and represents hydrogen.

And 4, step 4:

if appropriate, 3-O-descladinosyl-3-oxo-6-O-methyl-9 a-aza-9 a-homoerythromycin A or 6-O-methyl-8 a-aza-8 a-homoerythromycin A of the general formula (I) in step 3 is subjected to a selective acylation reaction with the hydroxyl group in the 2' -position of desosamine, wherein A, B, R¹、R²And R³Have the above-mentioned meanings. The acylation reaction is carried out at a temperature of 0-30 ℃ in an inert organic solvent by using anhydrides of carboxylic acids having up to 4 carbon atoms, preferably using acetic anhydride, in the presence of an inorganic or organic base to produce 3-descladinosyl-3-oxo-6-O-methyl-9 a-aza-9 a-homoerythromycin A2 '-O-acetate or 3-descladinosyl-3-oxo-6-O-methyl-8 a-aza-8 a-homoerythromycin A2' -O-acetate of the general formula (I) wherein a represents an NH group and B simultaneously represents a C ═ O group; or A represents a C ═ O group and B simultaneously represents an NH group; r¹Represents an OH group; r²Is hydrogen and R³Is an acetyl group. Sodium bicarbonate, sodium carbonate, potassium carbonate, triethylamine, pyridine, tributylamine are used as suitable bases, sodium bicarbonate being preferably used. Dichloromethane, dichloroethane, acetone, pyridine, ethyl acetate, tetrahydrofuran are used as suitable inert solvents, dichloromethane being preferably used.

And 5:

if appropriate, the oxidation of the hydroxyl group in the C-3 position of the aglycone ring of 3-descladinosyl-3-oxo-6-O-methyl-9 a-aza-9 a-homoerythromycin A-2 'O-acetate or 3-descladinosyl-3-oxo-6-O-methyl-8 a-aza-8 a-homoerythromycin A-2' O-acetate of the general formula (I) in step 4 with N, N-dimethylaminopropyl-ethyl-carbodiimide in an inert organic solvent, preferably in dichloromethane, is carried out at temperatures of from 10 ℃ to room temperature according to the modified Moffat-Pfitzner process in the presence of dimethyl sulfoxide and pyridinium trifluoroacetate as catalysts, a, B, R therein¹、R²And R³Having the above-mentioned meaning, to give 3-decladinosyl-3-oxo-6-O-methyl-9 a-aza-9 a-homoerythromycin A2 '-O-acetate or 3-decladinosyl-3-oxo-6-O-methyl-8 a-aza-8 a-homoerythromycin A2' -O-acetate of the general formula (I), wherein a represents an NH group and B simultaneously represents a C ═ O group; or A represents a C ═ O group and B simultaneously represents an NH group; r¹And R²Together represent a ketone and R³Represents an acetyl group.

Step 6:

followed by solvolysis of 3-descladinosyl-3-oxo-6-O-methyl-9 a-aza-9 a-homoerythromycin A2 '-O-acetate or 3-descladinosyl-3-oxo-6-O-methyl-8 a-aza-8 a-homoerythromycin A2' -O-acetate of general formula (I) in step 5 in lower alcohols, preferably in methanol, at room temperature to the reflux temperature of the solvent, wherein A, B, R¹、R²And R³3-descladinosyl-3-oxo-6-O-methyl-9 a-aza-9 a-homoerythromycin or 3-descladinosyl-3-oxo-6-O-methyl-8 a-aza-8 a-homoerythromycin a of general formula (I) wherein a represents NH group and B simultaneously represents C ═ O group; or A represents a C ═ O group and B simultaneously represents an NH group; r¹And R²Together represent a ketone and R³Represents hydrogen.

By reacting the novel compounds from the classes of 6-O-methyl-8 a-aza-8 a-homoerythromycin A and 6-O-methyl-9 a-aza-9 a-homoerythromycin A of the general formula (I) with at least equimolar amounts of suitable alcoholsOrganic or organic acids such as hydrochloric acid, hydroiodic acid, sulfuric acid, phosphoric acid, acetic acid, propionic acid, trifluoroacetic acid, maleic acid, citric acid, stearic acid, succinic acid, ethylsuccinic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and laurylsulfonic acid in solvents inert to the reaction to obtain pharmaceutically acceptable addition salts also belonging to the object of the invention, wherein A, B, R¹、R²And R³Have the above-mentioned meanings. If the addition salt is insoluble in a solvent inert to the reaction, said addition salt is isolated by filtration, in other cases by precipitation with a non-solvent or by evaporation of the solvent, in most cases by lyophilization.

The novel compounds of the general formula (I), in which A, B, R is determined by the microdilution method according to the NCCLS protocol (national Committee of clinical laboratory standards, documents M7-A2, Vol.10, No. 8, 1990 and M11-A2, Vol.10, 15, 1991)¹、R²And R³Having the above meaning) and pharmaceutically acceptable addition salts thereof with inorganic or organic acids, for the in vitro antibacterial action on a series of standard test microorganisms and clinical isolates. A control of the laboratory process was carried out according to the NCCLS protocol (document M7-A2, Table 3, M100-S4) with the aid of the control strain Staphylococcus aureus ATTC 29213 (American type culture Collection).

The in vitro antibacterial effect of 6-O-methyl-8 a-aza-8 a-homoerythromycin A from example 3 compared to azithromycin, erythromycin and clarithromycin against a series of standard test microorganisms is presented in Table 1. Table 1: comparison of the in vitro antibacterial Effect of 6-O-methyl-8 a-aza-8 a-homoerythromycin A (example 3) with those of Azithromycin (Az), erythromycin (Er) and clarithromycin (Cl) test microorganisms Az Er Cl example 3 Listeria monocytogenes < 0.125 ATCC 7644 Staphylococcus aureus ATCC 0.50.250.50.5

25923 Staphylococcus epidermidis ATCC 1.00.250.250.5

12228 enterococcus faecalis ATCC 355500.51.00.251.0 Streptococcus pneumoniae ATCC 6305 < 0.125 Streptococcus pyogenes ATCC < 0.125

19615 Clostridium perfringens 0.1250.50.1250.25 bacterium ATCC 13124 Moraxella catarrhalis ATCC < 0.125

25238 Campylobacter fetus ATCC < 0.125

19438 Campylobacter jejuni ATCC < 0.125

33291 Citrobacter freudenreichii 4.064.064.016.0 ATCC 8090 Escherichia coli ATCC 259222.032.032.08.0 Proteus mirabilis ATCC 64.0 > 128.0 > 128.032.0

12453 Proteus mirabilis ATCC 64.0 & gt 128.0 & gt 128.032.0

43071 Salmonella choleraesuis ATCC 2.064.032.08.0

13076 Shigella flexneri ATCC 1.032.032.04.0

12022 Yersinia enterocolitis 1.016.016.04.0 bacterium ATCC 9610 Haemophilus influenzae ATCC 0.52.04.01.0

49247 Haemophilus influenzae ATCC 1.04.08.01.0

49766 Pseudomonas aeruginosa ATCC 64.0 > 128.0 > 128.032.0

25619

The process is illustrated by the following examples, which are not intended to limit the invention in any way

The scope of the invention.

EXAMPLE 16 preparation of O-methyl erythromycin A9(E) -and 9(Z) -oxime method A

6-O-methylerythromycin A (2.0g, 0.003 mol) in methanol (100ml) was heated to reflux temperature, hydroxylamine hydrochloride (2.0g, 0.03 mol) and sodium carbonate (0.2g, 0.002 mol) were added and the system was heated under reflux conditions with stirring for 3 hours. Then the same amounts of hydroxylamine hydrochloride and sodium carbonate were added and the system was further heated under reflux conditions for 6 hours. Methanol was evaporated under reduced pressure and water (200ml) and chloroform (100ml) were added, the pH was adjusted to 9.8, the layers were separated and the aqueous layer was extracted twice more with chloroform. The combined organic extracts were dried over potassium carbonate, filtered and evaporated under reduced pressure to give 2.0g of a mixture of the title products. 0.63g of chromatographically homogeneous 6-O-methylerythromycin A9(E) -oxime having an Rf value of 0.446 and 0.61g of chromatographically homogeneous 6-O-methylerythromycin A9(Z) -oxime having an Rf value of 0.355 are obtained by column chromatography on silica gel using a dichloromethane-methanol-concentrated ammonium hydroxide system 90: 9: 1.5. 9(E) -oxime: rf 0.418, ethyl acetate- (n-hexane) -diethylamine, 100: 20IR (KBr) cm^-1：3449，2974，2939，2832，2788，1735，1638，1459，1379，1348，1169，1112，1054，1012，957，835，755.¹H NMR(300 MHz，CDCl₃)δ：5.11(H-13)，4.95(H-1″)，4.45(H-1′)，4.03(H-5″)，3.77(H-8)，3.76((H-3)，3.75(H-11)，3.66(H-5)，3.48(H-5′)，3.33(3″-OCH₃)，3.24(H-2′)，3.10(6-OCH₃)，3.03(H-4″)，2.89(H-2)，2.57(H-10)，2.45(H-3′)，2.37(H-2″a)，2.31/3′-N(CH₃)2/，1.93(H-4)，1.93(H-14a)，1.68(H-4′a)，1.58(H-2″b)，1.53(H-7a)，1.48(6-CH₃)，1.46(H-14b)，1.31(5″-CH₃)，1.25(3″-CH₃)，1.23(5′-CH₃)，1.20(2-CH₃)，1.13(10-CH₃)，1.13(12-CH₃)，1.08(4-CH₃)，1.00(8-CH₃)，0.86(15-CH₃).¹³C NMR(75 MHz，CDCl₃)δ：175.5(C-1)，169.2(C-9)，102.5(C-1′)，95.7(C-1″)，80.2(C-5)，78.4(C-6)，78.0(C-3)，77.8(C-4″)，76.5(C-13)，73.8(C-12)，72.4(C-3″)，71.1(C-2′)，70.0(C-11)，68.2(C-5′)，65.2(C-5″)，64.9(C-3′)，50.8(6-OCH₃)，49.1(3″-OCH₃)，44.7(C-2)，40.1/3′-N(CH₃)₂/，38.7(C-4)，37.0(C-7)，34.6(C-2″)，32.3(C-10)，29.4(C-4′)，24.9(C-8)，21.1(5′-CH₃)，21.0(3″-CH₃)，20.8(C-14)，19.6(6-CH₃)，18.3(5″-CH₃)，18.2(8-CH₃)，15.7(12-CH₃)，15.6(2-CH₃)，14.6(10-CH₃)，10.2(15-CH₃)，8.8(4-CH₃) 9(Z) -oxime: rf 0.300, ethyl acetate- (n-hexane) -diethylamine, 100: 20IR (KBr) cm^-1：3433，2973，2939，2832，1733，1638，1459，1379，1348，1286，1169，1114，1054，1011，958，892，755.¹H NMR(300 MHz，CDCl₃)δ：5.07(H-13)，4.93(H-1″)，4.43(H-1′)，4.03(H-5″)，3.98(H-11)，3.77(H-3)，3.62(H-5)，3.48(H-5′)，3.33(3″-OCH₃)，3.21(H-2′)，3.09(6-OCH₃)，3.06(H-4″)，2.88(H-2)，2.74(H-8)，2.65(H-10)，2.45(H-3′)，2.36(H-2″a)，2.30/3′-N(CH₃)₂/，1.96(H-4)，1.94(H-14a)，1.76(H-14b)，1.67(H-4′a)，1.59(H-2″b)，1.58(H-7a)，1.47(H-7b)，1.38(6-CH₃)，1.32(10-CH₃)，1.31(5″-CH₃)，1.25(3″-CH₃)，1.24(5′-CH₃)，1.19(2-CH₃)，1.14(12-CH₃)，1.07(4-CH₃)，1.06(8-CH₃)，0.84(15-CH₃).¹³C NMR(75 MHz，CDCl₃)δ：176.0(C-1)，167.4(C-9)，102.7(C-1′)，96.0(C-1″)，80.4(C-5)，78.7(C-6)，78.5(C-3)，77.8(C-4″)，76.9(C-13)，74.7(C-12)，72.6(C-3″)，70.9(C-2′)，70.3(C-11)，68.4(C-5′)，65.5(C-5″)，65.3(C-3′)，50.0(6-OCH₃)，49.3(3″-OCH₃)，45.0(C-2)，41.0/3′-N(CH₃)₂/，38.9(C-4)，37.0(C-7)，35.6(C-8)，34.7(C-2″)，34.1(C-10)，28.9(C-4′)，21.3(3″-CH₃)，21.2(5′-CH₃)，21.1(C-14)，19.7(6-CH₃)，19.6(8-CH₃)，18.5(5″-CH₃)，16.4(12-CH₃)，15.7(2-CH₃)，10.7(10-CH₃)，10.4(15-CH₃)，9.8(15-CH₃) Method B

6-O-methylerythromycin A (10.8g, 0.014 mol) in methanol (800ml) was heated to reflux temperature, and then hydroxylamine hydrochloride (27.0g, 0.388 mol) and anhydrous sodium acetate (15.2g, 0.183 mol) were added to the reaction solution in 4 portions over 10 hours and the system was heated under reflux conditions while further stirring for 8 hours. Methanol was evaporated under reduced pressure, water (1500ml) and dichloromethane (200ml) were added and the reaction system was extracted by gradient extraction at pH5.0 and 9.8. The combined organic extracts at pH 9.8 were dried over potassium carbonate, filtered and evaporated under reduced pressure to give 9.5g of a mixture of the title product. Chromatographic homogeneous 6-O-methylerythromycin A9(E) -oxime and 6-O-methylerythromycin A9(Z) -oxime were obtained by silica gel column chromatography using a dichloromethane-methanol-concentrated ammonium hydroxide system 90: 9: 1.5, with the same physicochemical constants as those in Process A.

Example 26 Beckmann rearrangement of O-methylerythromycin A9(E) -oxime

6-O-methylerythromycin A9(E) -oxime from example 1 (4.0g, 0.005 mol) was dissolved in acetone (130ml) and the solution was cooled to 0-5 ℃. Subsequently, a solution of p-toluenesulfonyl chloride (2.6g, 0.01 mol) in acetone (40ml) and sodium hydrogencarbonate (0.830g, 0.01 mol) were added dropwise thereto over 1 hour with stirringMole) of water (130 ml). The reaction mixture was stirred at room temperature for 8 hours, acetone was evaporated under reduced pressure and chloroform (40ml) was added to the aqueous solution, whereby the reaction system was extracted by gradient extraction at pH5.0 and 9.0. The combined organic extracts at pH9.0 were evaporated to give 2.8g of 6-O-methyl-9 a-aza-9 a-homoerythromycin A. Rf 0.218, ethyl acetate- (n-hexane) -diethylamine, 100: 20IR (KBr) cm^-1：3449，2974，2939，2834，1734，1706，1659，1534，1459，1379，1274，1169，1111，1053，1011，958.¹H NMR(300 MHz，CDCl₃)δ：6.12(9a-CONH)，4.85(H-1″)，4.68(H-13)，4.45(H-1′)，4.21(H-3)，4.16(H-10)，4.07(H-5″)，3.75(H-5)，3.49(H-5′)，3.34(3″-OCH₃)，3.32(6-OCH₃)，3.22(H-11)，3.20(H-2′)，3.04(H-4″)，2.83(H-2)，2.43(H-3′)，2.38(H-2″a)，2.30/3′-N(CH₃)₂/，2.22(H-8)，2.07(H-7a)，1.87(H-4)，1.87(H-14a)，1.67(H-4′a)，1.57(H-2″b)，1.57(H-14b)，1.36(6-CH₃)，1.33(H-7b)，1.32(5″-CH₃)，1.25(3″-CH₃)，1.24(H-4′b)，1.23(5′-CH₃)，1.23(2-CH₃)，1.18(12-CH₃)，1.16(10-CH₃)，1.09(8-CH₃)，1.02(4-CH₃)，0.89(15-CH₃).¹³C NMR(75 MHz，CDCl₃)δ：179.5(C-1)，177.3(C-9)，102.5(C-1′)，94.9(C-1″)，79.1(C-6)，78.5(C-5)，77.7(C-4″)，77.7(C-13)，75.9(C-3)，73.9(C-12)，72.5(C-3″)，72.6(C-11)，70.7(C-2′)，68.2(C-5′)，65.3(C-5″)，65.1(C-3′)，51.0(6-OCH₃)，49.1(3″-OCH₃)，45.1(C-10)，44.5(C-2)，41.3(C-4)，40.0/3′-N(CH₃)₂/，39.6(C-7)，35.4(C-8)，34.4(C-2″)，28.8(C-4′)，21.1(5′-CH₃)，21.0(3″-CH₃)，20.3(C-14)，20.2(6-CH₃)，19.1(8-CH₃)，18.1(5″-CH₃)，15.9(12-CH₃)，14.6(2-CH₃)，13.4(10-CH₃)，10.7(15-CH₃)，8.7(4-CH₃).

Example 36 Beckmann rearrangement of O-methylerythromycin A9(Z) -oxime

6-O-methylerythromycin A9(Z) -oxime (1.4g, 0.002 mol) from example 1 was dissolved in acetone (50ml) and the solution was cooled to 0-5 ℃. Subsequently, a solution of p-toluenesulfonyl chloride (1.84g, 0.014 mol) in acetone (56ml) and a solution of sodium hydrogencarbonate (1.16g, 0.014 mol) in water (180ml) were added dropwise thereto over 1 hour with stirring. The reaction mixture was stirred at room temperature for 2 hours, acetone was evaporated under reduced pressure and chloroform (70ml) was added to the aqueous solution, whereby the reaction system was extracted by gradient extraction at ph5.0 and 9.0. The combined organic extracts at pH9.0 are evaporated, giving 0.80g of product which, if appropriate, is purified by column chromatography on silica gel using a dichloromethane-methanol-concentrated ammonium hydroxide system 90: 9: 1.5, giving 6-O-methyl-8 a-aza-8 a-homoerythromycin A having the following physico-chemical constants: rf 0.152, ethyl acetate- (n-hexane) -diethylamine, 100: 20IR (KBr) cm^-1：3442，2974，2938，2833，1736，1648，1535，1459，1379，1284，1169，1110，1055，1013，960，902.¹H NMR(300 MHz，CDCl₃)δ：5.78(8a-CONH)，5.02(H-1″)，4.96(H-13)，4.41(H-1′)，4.19(H-8)，4.02(H-5″)，3.96(H-3)，3.69(H-5)，3.51(H-11)，3.47(H-5′)，3.32(3″-OCH₃)，3.18(H-2′)，3.16(6-OCH₃)，3.02(H-4″)，2.68(H-2)，2.44(H-3′)，2.35(H-2″a)，2.29/3′-N(CH₃)₂/，2.22(H-10)，1.92(H-4)，1.91(H-14a)，1.68(H-7a)，1.64(H-4′a)，1.56(H-2″b)，1.53(H-7b)，1.47(H-14b)，1.39(6-CH₃)，1.29(5″-CH₃)，1.24(3″-CH₃)，1.23(5′-CH₃)，1.20(2-CH₃)，1.18(10-CH₃)，1.13(12-CH₃)，1.13(8-CH₃)，1.07(4-CH₃)，0.88(15-CH₃).¹³C NMR(75 MHz，CDCl₃)δ：177.0(C-1)，174.3(C-9)，102.9(C-1′)，95.1(C-1″)，80.1(C-5)，78.6(C-6)，77.9(C-4″)，77.2(C-3)，76.7(C-13)，74.0(C-12)，72.6(C-3″)，70.4(C-2′)，70.1(C-11)，68.7(C-5′)，65.4(C-3′)，65.2(C-5″)，51.5(6-OCH₃)，49.1(3″-OCH₃)，45.4(C-2)，42.6(C-7)，42.1(C-4)，41.8(C-10)，40.6(C-8)，40.0/3′-N(CH₃)₂/，34.5(C-2″)，28.3(C-4′)，23.5(6-CH₃)，21.3(C-14)，21.2(12-CH₃)，21.1(5′-CH₃)，21.1(3″-CH₃)，17.9(5″-CH₃)，15.8(8-CH₃)，14.8(2-CH₃)，10.8(15-CH₃)，9.2(10-CH₃)，9.1(4-CH₃).

Example 43-Decaclidinosyl-3-oxo-6-O-methyl-9 a-aza-9 a-homoerythromycin A

The material from example 2 (1.5g, 0.002 mol) was dissolved in 0.25N hydrochloric acid (40ml) and the solution was left to stand stable for 24 hours at room temperature. To the reaction mixture was added dichloromethane (30ml) (pH1.8) and the pH of the mixture was adjusted to 9.0 with concentrated aqueous ammonia, the layers were separated and the aqueous layer was extracted twice with dichloromethane (301). The combined organic extracts are washed with 10% aqueous sodium bicarbonate solution and water and then evaporated to give 1.3g of crude product which is purified, if appropriate, by column chromatography on silica gel using a dichloromethane-methanol-concentrated ammonium hydroxide 90: 9: 1.5 system. 0.65g of chromatographically homogeneous 3-descladinosyl-3-oxo-6-O-methyl-9 a-aza-9 a-homoerythromycin A having the following physico-chemical constants were isolated from 0.9g of the crude product: rf 0.152, ethyl acetate- (n-hexane) -diethylamine, 100: 20IR (KBr) cm^-1：3438，2973，2939，2879，2788，1702，1658，1535，1458，1373，1329，1270，1173，1112，1050，985，958，937.¹H NMR(300 MHz，CDCl₃)δ：7.16(9a-CONH)，4.63(H-13)，3.81(H-5)，4.45(H-1′)，4.13(H-10)，3.78(H-3)，3.55(H-5′)，3.30(6-OCH₃)，3.25(H-2′)，3.16(H-11)，2.66(H-2)，2.51(H-3′)，2.39(H-8)，2.26/3′-N(CH₃)₂/，2.05(H-4)，1.92(H-14a)，1.84(H-7a)，1.68(H-4′a)，1.57(H-14b)，1.43(H-7b)，1.38(6-CH₃)，1.33(2-CH₃)，1.26(5′-CH₃)，1.26(H-4′b)，1.20(10-CH₃)，1.12(12-CH₃)，1.11(8-CH₃)，1.01(4-CH₃)，0.91(15-CH₃).¹³C NMR(75 MHz，CDCl₃)δ：179.3(C-1)，176.9(C-9)，106.4(C-1′)，88.1(C-5)，79.1(C-6)，78.7(C-13)，78.0(C-3)，73.8(C-12)，73.9(C-11)，70.2(C-2′)，69.7(C-5′)，65.4(C-3′)，49.9(6-OCH₃)，45.6(C-10)，43.9(C-2)，40.8(C-7)，39.9/3′-N(CH₃)₂，35.6(C-4)，32.8(C-8)，27.8(C-4′)，20.9(5′-CH₃)，20.5(C-14)，18.3(6-CH₃)，17.4(8-CH₃)，15.8(12-CH₃)，15.9(2-CH₃)，14.8(10-CH₃)，10.7(15-CH₃)，7.5(4-CH₃).

Example 53-Decaclidinosyl-3-oxo-6-O-methyl-8 a-aza-8 a-homoerythromycin A

1.2g of crude product are obtained from the material of example 3 (1.5g, 0.002 mol) according to the process described in example 4, which is purified, if appropriate, by column chromatography on silica gel using a dichloromethane-methanol-concentrated ammonium hydroxide system 90: 9: 1.5 to give chromatographically homogeneous 3-descladinosyl-3-oxo-6-O-methyl-8 a-aza-8 a-homoerythromycin A having the following physico-chemical constants: rf 0.195, chloroform-methanol-ammonium hydroxide, 6: 1: 0.1IR (KBr) cm^-1：3438，2974，2939，2788，1733，1648，1535，1458，1378，1263，1165，1113，1075，1050，985，958，937.¹H NMR(300 MHz，CDCl₃)δ：5.58(9a-CONH)，5.09(H-13)，4.38(H-1′)，3.76(H-5)，3.92(H-8)，3.80(H-3)，2.64(H-2)，3.54(H-5′)，3.47(H-1 1)，3.25(H-2′)，2.11(H-4)，3.12(6-OCH₃)，2.48(H-3′)，2.38(H-10)，2.25/3′-N(CH₃)₂/，1.94(H-14a)，2.11(H-7a)，1.66(H-4′a)，1.51(H-7b)，1.50(H-14b)，1.31(2-CH₃)，1.39(6-CH₃)，1.12(4-CH₃)，1.26(5′-CH₃)，1.26(H-4′b)，1.20(10-CH₃)，1.25(8-CH₃)，1.13(12-CH₃)，0.88(15-CH₃).¹³C NMR(75 MHz，CDCl₃)δ：176.0(C-1)，174.4(C-9)，106.1(C-1′)，89.6(C-5)，77.3(C-6)，75.8(C-13)，78.3(C-3)，74.3(C-12)，70.3(C-11)，69.9(C-2′)，69.4(C-5′)，64.9(C-3′)，49.7(6-OCH₃)，42.1(C-10)，43.8(C-2)，41.7(C-7)，39.9/3′-N(CH₃)₂/，35.2(C-4)，42.4(C-8)，27.4(C-4′)，22.3(5′-CH₃)，20.9(C-14)，20.4(6-CH₃)，20.5(8-CH₃)，15.7(12-CH₃)，15.2(2-CH₃)，9.5(10-CH₃)，10.1(15-CH₃)，7.50(4-CH₃).

Example 63-Decaclidinosyl-3-oxo-6-O-methyl-9 a-aza-9 a-homoerythromycin A2' -O-acetate

To a solution of 3-descladinosyl-3-oxo-6-O-methyl-9 a-aza-9 a-homoerythromycin A (0.750g, 0.0012 moles) from example 4 in dichloromethane (25ml) was added sodium bicarbonate (0.440g, 0.0052 moles) and acetic anhydride (0.128ml, 0.0013 moles) and stirred at room temperature for 3 hours. To the reaction mixture was added a saturated sodium bicarbonate solution (30ml), the layers were separated and the aqueous portion was extracted again with dichloromethane (2X 20 ml). The combined organic extracts were washed successively with saturated sodium bicarbonate solution and water and evaporated to give 0.750g of the crude title product, having the following physicochemical constants: rf 0.403, chloroform-methanol-concentrated ammonium hydroxide, 6: 1: 0.1IR (KBr) cm^-1：3455，2974，2940，2880，2787，1748，1702，1658，1540，1459，1376，1239，1173，1112，1061，986，958，937，904.

Example 73-Decaclidinosyl-3-oxo-6-O-methyl-8 a-aza-8 a-homoerythromycin A2' -O-acetate

To a solution of 3-descladinosyl-3-oxo-6-O-methyl-9 a-aza-9 a-homoerythromycin A from example 5 (1.5g, 0.0024 moles) in dichloromethane (40ml) was added sodium bicarbonate (0.88g, 0.01 moles) and acetic anhydride (0.250ml, 0.0025 moles) and then 1.4g of the title product was obtained following the procedure described in example 6, with the following physicochemical constants: rf 0.423, chloroform-methanol-concentrated ammonium hydroxide, 6: 1: 0.1IR (KBr) cm^-1：3394，2972，2939，2784，1736，1649，1542，1459，1376，1262，1165，1085，1059，986，958，904.

Example 83-Decaclidinosyl-3-oxo-6-O-methyl-9 a-aza-9 a-homoerythromycin A

To a solution of 3-descladinosyl-3-oxo-6-O-methyl-9 a-aza-9 a-homoerythromycin A2' -O-acetate (0.760g, 0.0012 moles) from example 6 in dichloromethane (15ml) was added dimethyl sulfoxide (1.27ml) and N, N-dimethylaminopropyl-ethyl-carbodiimide (1.335g, 0.007 moles). The reaction mixture was cooled to 15 ℃ and then a solution of pyridinium trifluoroacetate (1.37g, 0.007 mole) in dichloromethane (5ml) was added dropwise in steps over 30 minutes with constant stirring and maintenance of the temperature. The temperature of the reaction mixture was gradually raised to room temperature, stirring was continued for further 3 hours and the reaction was stopped by adding a saturated NaCl solution (20ml) and dichloromethane (20 ml). After basifying the reaction mixture to pH 9.5 with 2N NaOH, it is treated with CH₂Cl₂Extracting the organic extract with saturated NaCl and NaHCO₃The solution and water are washed and then with K₂CO₃And (5) drying. After filtration and evaporation of the dichloromethane under reduced pressure, 0.800g of an oily residue is obtained. The oily residue was methanolyzed at room temperature over 24 hours (30ml methanol). Methanol was evaporated under reduced pressure and the residue (0.625g) was purified by low pressure silica gel column chromatography using a dichloromethane-methanol-concentrated ammonium hydroxide 90: 9: 0.5 solvent system. The chromatographically homogeneous title product was obtained by evaporation of the combined extracts with an Rf value of 0.235, with the following physicochemical constants: rf 0.235, methylene chloride-methanol-concentrated ammonium hydroxide, 90: 9: 0.5IR (KBr) cm^-1：3438，2975，2939，2878，2787，1744，1655，1530，1458，1380，1340，1304，1169，1111，1075，1051，986，959，940.¹H NMR(300 MHz，CDCl₃)δ：6，63(9a-CONH)，4.64(H-13)，4.49(H-5)，4.41(H-1′)，4.20(H-10)，3.90(H-2)，3.64(H-5′)，3.34(H-11)，3.20(H-2′)，3.07(6-OCH₃)，3.02(H-4)，2.51(H-3′)，2.30(H-8)，2.27/3′-N(CH₃)₂/，1.94(H-14a)，1.94(H-7a)，1.69(H-4′a)，1.63(H-14b)，1.42(H-7b)，1.40(2-CH₃)，1.30(5′-CH₃)，1.29(4-CH₃)，1.26(6-CH₃)，1.25(H-4′b)，1.22(12-CH₃)，1，19(10-CH₃)，1.10(8-CH₃)，0.91(15-CH₃).¹³C NMR(75 MHz，CDCl₃)δ 206.8(C-3)，177.3(C-1)，173.8(C-9)，102.6(C-1′)，79.3(C-13)，78.4(C-6)，74.4(C-5)，73.9(C-12)，73.1(C-11)，70.0(C-2′)，69.1(C-5′)，65.5(C-3′)，50.1(6-OCH₃)，49.0(C-2)，46.2(C-4)，45.3(C-10)，40.3(C-7)，40.0/3′-N(CH₃)₂/，34.6(C-8)，28.3(C-4′)，21.0(6-CH₃)，20.7(C-14)，19.6(5′-CH₃)，18.6(8-CH₃)，15.9(12-CH₃)，14.1(2-CH₃)，13.9(10-CH₃)，13.9(4-CH₃)，10.7(15-CH₃).

Example 93-Decaclidinosyl-3-oxo-6-O-methyl-8 a-aza-8 a-homoerythromycin A

To a solution of 3-descladinosyl-3-oxo-6-O-methyl-8 a-aza-8 a-homoerythromycin A2' -O-acetate (1.4g, 0.0022 moles) from example 7 in dichloromethane (30ml) was added dimethyl sulfoxide (2.5ml) and N, N-dimethylaminopropyl-ethyl-carbodiimide (2.7g, 0.014 moles). The reaction mixture was cooled to 15 ℃ and then a solution of pyridinium trifluoroacetate (2.7g, 0.014 mole) in dichloromethane (10ml) was added dropwise stepwise over 30 minutes with constant stirring and maintaining the temperature. 1.1g of the title product are obtained according to the method described in example 8, having the following physico-chemical constants: IR (KBr) cm^-1：3435，2975，2939，2879，2788，1746，1648，1542，1458，1379，1339，1302，1166，1111，1076，1052，989，960，918.¹H NMR(300 MHz，CDCl₃)δ：5.89(9a-CONH)，5.08(H-13)，4.42(H-1′)，4.27(H-5)，4.03(H-8)，3.78(H-2)，3.60(H-5′)，3.58(H-11)，3.1 8(H-2′)，3.05(H-4)，2.91(6-OCH₃)，2.49(H-3′)，2.39(H-10)，2.27/3′-N(CH₃)₂/，1.96(H-14a)，1.68(H-7a)，1.68(H-4′a)，1.50(H-14b)，1.41(2-CH₃)，1.32(6-CH₃)，1.30(4-CH₃)，1.25(5′-CH₃)，1.23(H-4′b)，1.20(10-CH₃)，1.19(8-CH₃)，1.17(12-CH₃)，0.88(15-CH₃).¹³C NMR(75 MHz，CDCl₃)δ：206.2(C-3)，170.0(C-9)，174.6(C-1)，103.1(C-1′)，78.2(C-6)，77.9(C-5)，77.5(C-13)，74.1(C-12)，70.6(C-11)，70.0(C-2′)，69.1(C-5′)，65.5(C-3′)，50.5(6-OCH₃)，50.4(C-2)，47.6(C-4)，42.2(C-10)，42.1(C-7)，41.6(C-8)，39.9/3′-N(CH₃)₂/，28.0(C-4′)，22.8(8-CH₃)，21.2(C-14)，20.8(5′-CH₃)，20.1(6-CH₃)，16.1(12-CH₃)，15.4(2-CH₃)，14.4(4-CH₃)，10.5(15-CH₃)，10.1(10-CH₃).

Claims (23)

1. A compound represented by the general formula (I)And the pharmaceutically acceptable addition salts thereof with inorganic and organic acids, wherein A represents an NH group and B simultaneously represents a C ═ O group; or A represents a C ═ O group and B simultaneously represents an NH group; r¹Represents OH group, L-cladinosyl group of the general formula (II)Or with R²Together represent a ketone;

R²represents hydrogen or with R¹Together substitute forEpiketones;

R³represents hydrogen or C₁-C₄Alkanoyl group of (1).

2. A compound according to claim 1, characterized in that A represents an NH group, B represents a C ═ O group, R¹Represents L-cladinosyl of formula (II), R²And R³Identical and represents hydrogen.

3. A compound according to claim 1, characterized in that A stands for C ═ O group, B stands for NH group, R¹Represents L-cladinosyl of formula (II), R²And R³Identical and represents hydrogen.

4. A compound according to claim 1, characterized in that A represents an NH group, B represents a C ═ O group, R¹Represents an OH group and R²And R³Identical and represents hydrogen.

5. A compound according to claim 1, characterized in that A stands for C ═ O group, B stands for NH group, R¹Represents an OH group and R²And R³Identical and represents hydrogen.

6. A compound according to claim 1, characterized in that A represents an NH group, B represents a C ═ O group, R¹Represents an OH group, R²Is hydrogen and R³Represents C₁-C₄Alkanoyl group of (1).

7. A compound according to claim 6, characterized in that R³Represents an acetyl group.

8. A compound according to claim 1, characterized in that A stands for C ═ O group, B stands for NH group, R¹Represents an OH group, R²Is hydrogen and R³Represents C₁-C₄Alkanoyl group of (1).

9. A compound according to claim 8, characterized in that R³Represents an acetyl group.

10. A compound according to claim 1, characterized in that A represents an NH group, B represents a C ═ O group, R¹And R²Together represent a ketone, and R³Is hydrogen.

11. A compound according to claim 1, characterized in that A stands for C ═ O group, B stands for NH group, R¹And R²Together represent a ketone, and R³Is hydrogen.

12. Preparation of the Compounds of the general formula (I)And to the pharmaceutically acceptable addition salts thereof with inorganic and organic acids, wherein A represents an NH group and B simultaneously represents a C ═ O group; or A represents a C ═ O group and B simultaneously represents an NH group; r¹Represents OH group, L-cladinosyl group of the general formula (II)Or with R²Together represent a ketone;

R²represents hydrogen or with R¹Together represent a ketone;

R³represents hydrogen or C₁-C₄Alkanoyl of (1);

characterized in that 6-O-methylerythromycin A of the general formula (III)With hydroxylamine hydrochloride in the presence of suitable inorganic or organic bases to give a mixture of 6-O-methylerythromycin A9(E) -and 9(Z) -oximes of the general formula (IV),optionally, subjecting the above mixture to silica gel column separation using a dichloromethane-methanol-concentrated ammonium hydroxide system 90: 9: 1.5 to yield chromatographically homogeneous 6-O-methylerythromycin A9(E) -oxime of formula (IVa) having an Rf value of 0.446;and chromatographically homogeneous 6-O-methylerythromycin A9(Z) -oxime of formula (IVb) having an Rf value of 0.355;and then subjecting the product to a Beckmann rearrangement reaction with an arylsulfonyl halide in the presence of an inorganic base in a solvent or solvent mixture which is inert to the reaction, to give, in the case of 6-O-methylerythromycin A9(E) -oxime of the general formula (IVa), compounds of the general formula (I) in which A represents an NH group, B represents a C ═ O group, R represents a C ═ O group¹Represents L-cladinosyl and R²And R³Are the same and represent hydrogen; or with respect to 6-O-methylerythromycin A9(Z) -oxime of formula (IVb), to give compounds of formula (I) wherein a represents C ═ O group, B represents NH group, R represents NH group¹Represents L-cladinosyl, R²And R³Are the same and represent hydrogen;

and subsequently reacting the product with a dilute mineral acid at room temperature to give a compound of the general formula (I) in which A represents NH and B simultaneously represents C ═ O, or A represents C ═ O and B simultaneously represents NH, R¹Represents an OH group and R²And R³Are the same and represent hydrogen;

the product is then selectively acylated with carboxylic anhydrides having up to 4 carbon atoms in an inert organic solvent to give compounds of the general formula (I) in which A represents an NH group and B simultaneously represents a C ═ O group, or A represents a C ═ O group and B simultaneously represents an NH group, R represents¹Represents an OH group, R²Is hydrogen and R³Is an acetyl group;

and then subjecting the above product to an oxidation reaction with a bisimide in the presence of dimethylsulfoxide and pyridinium trifluoroacetate as catalyst in an inert organic solvent at room temperature to give a compound of the general formula (I) wherein A represents an NH group and B simultaneously represents a C ═ O group, or A represents a C ═ O group and B simultaneously represents an NH group, R represents¹And R²Together represent a ketone and R³Is an acetyl group;

followed by deacylation of the 2' -position of the product by solvolysis at room temperature in lower alcohols to give compounds of the general formula (I)In which A represents NH and B simultaneously represents C ═ O, or A represents C ═ O and B simultaneously represents NH, R¹And R²Together represent a ketone and R³Is hydrogen;

optionally, the product is then reacted with an inorganic or organic acid to produce a pharmaceutically acceptable addition salt thereof.

13. The process according to claim 12, wherein the arylsulfonyl halide is tosyl chloride.

14. A process according to claim 12 wherein the inorganic base used in the reaction with the aryl sulphonyl halide is sodium bicarbonate.

15. The process according to claim 12, wherein the solvent used in the reaction with the aryl sulfonyl halide is an acetone-water mixture.

16. The process according to claim 12, wherein the dilute mineral acid is 0.25N hydrochloric acid.

17. The process of claim 12, wherein the carboxylic acid anhydride is acetic anhydride.

18. The process according to claim 12, wherein the inert organic solvent used in the reaction with the carboxylic anhydride is dichloromethane.

19. The method of claim 12, wherein the diimide is N, N-dimethylaminopropyl-ethyl-carbodiimide.

20. The process according to claim 12, wherein the inert organic solvent used in the reaction with the diimides is dichloromethane.

21. The process according to claim 12, wherein the lower alcohol is methanol.

22. A pharmaceutical composition for the treatment of bacterial infections in the human and animal body, which composition comprises an antibacterially effective amount of a compound of formula (I) or a pharmaceutically acceptable addition salt thereof as claimed in claim 1, and a pharmaceutically acceptable carrier.

23. Use of a compound of general formula (I) according to claim 1 or a pharmaceutically acceptable addition salt thereof for the manufacture of a medicament for the treatment of bacterial infections in the human and animal body.