CZ20001319A3 - Novel 3,6-hemiketals from the 9a-azalide class - Google Patents

Abstract

Compounds of formula (I) wherein R 1 denotes a hydroxyl or L-cladynosyl group according to the formula (II) wherein R 2 is hydrogen or a silyl group, R 3 is hydrogen or - together with the R 6 - ether group, R 4 represents hydrogen, A C 1 -C 4 acyl group or a -COO- (CH 2) n -Ar group, where n is 1-7 and Ar is unsubstituted or substituted aryl of up to 18 carbon atoms, R5 is hydrogen, methyl or -COO- (CH 2) n - Ar-, wherein n is 1-7 and Ar represents unsubstituted or substituted aryl of up to 18 carbon atoms, R6 is a hydroxyl group, or - together with R3 - is important ether groups, R 7 is hydrogen, C 1 -C 12 alkyl, silyl group, or - together with R8 and C-11 / C-12 carbon atoms are cyclic carbonate, R5 is hydrogen, C1-C12 an alkyl group, a silyl group, or - together with R 7 and C 11 / C 12 carbon atoms - denotes cyclic carbonate, and pharmaceutically acceptable addition salts thereof; inorganic or organic acids. Is described and a pharmaceutical composition useful for treatment bacterial infections in humans and animals.

Description

Technical field

The present invention relates to novel compounds from the group of macrolide antibiotics. In particular, the present invention relates to novel 3,6-hemiketals from the group of 9α-azalides, their pharmaceutically acceptable addition salts with organic or inorganic acids, their preparation and their use as antibiotics or as intermediates for the synthesis of other macrolide antibiotics.

BACKGROUND OF THE INVENTION

Macrolide antibiotic erythromycin A has been considered a safe and effective means for the treatment of respiratory and genital tract infections caused by Gram-positive and some Gram-negative bacteria, some Legionella, Mycoplasma, Chlamidia and Helicobacter for over 40 years. The main disadvantages of the clinical use of erythromycin are the observed changes in oral bioavailability, intestinal intolerance in many patients, and loss of activity in the acidic environment where the inactive metabolite anhydroerythromycin is formed. However, spirocyclization of the aglycone ring is successfully inhibited by chemical transformation of the C-9 ketone or hydroxyl group at the C-6 and / or C-12 positions. For example, oximation of ketone C-9 followed by Beckmann rearrangement and reduction yields 9-deoxo-9α-aza-9α-homoerythromycin A, the first 15-member macrolide antibiotic with 9α-amino group incorporated into the aglycone ring (Kobrehel G. et al.

US 4,328,334; 5/1982). By reductive methylation of 9-amines according to Eschweiler and Clark, 9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin (AZITHROMYCIN), a prototype of a new class of macrolide antibiotics, namely azalides (Kobrehel G. et al., BE 892357; / 1982). Azithromycin, in addition to its broad antimicrobial spectrum, including gram-negative bacteria, is also characterized by a long half-life, a specific mechanism of transport to the site of action, and a short duration of therapy. Azithromycin readily penetrates and accumulates within human phagocytic cells, thereby enhancing action on intracellular pathogenic microorganisms of the classes Legionella, Chlamidia and Helicobacter.

It is further known that C-6 / C-12 spirocyclization of erythromycin A is successfully inhibited by G-methylation of the hydroxyl group on the C-6 aglycone ring (Watanabe Y. et al., Watanabe Y. et al.).

US 4,331,803; 5/1982). Reaction of erythromycin with benzyloxycarbonyl chloride followed by methylation of the obtained 2 '- (3,3'-A-iso) (benzyloxycarbonyl) derivative, deprotection and 3'-N methylation produces, in addition to 6-O-methylerythromycin (CLARITHROMYCIN), significant amounts of II. -O-methylerythromycin and multiple substituted analogs (Morimoto S. et al., J. Antibiotics, 1984, 37, 187) Compared to erythromycin A, clarithromycin is substantially more stable in an acidic environment and shows better in vitro activity on Gram-positive bacteria strains ( Kirst HA et al., Antimicrobial Agents and Chemoter., 1989, 1419. A series of (9-methyl azithromycin derivatives (Kobrehel G. et al., US 5,250,518; 10/1993) was synthesized in a similar manner. azithromycin, namely 11-O-methylazithromycin (Example 8) and 6- <2-methylazithromycin (Example 6), show considerable activity against standard bacterial strains and clinical isolates, and having azithromycin-like pharmacokinetic properties, obtaining these products in larger amounts presents another technical problem due to the non-selectivity of O-methylation. The determination of the structure of the O-methyl derivatives of azithromycin was based on the analysis of Η- ¹ !! and ¹ H- ⁿ C 2D spectra (300 MHz). Additionally, long-range NMR spectroscopy revealed that azithromycin was erroneously attributed substitution at the hydroxyl group of C-6 and was in fact 12-O-methylazithromycin. Furthermore, it has been found that the use of suitable protecting groups on the hydroxyl groups at the 4 'and 11 positions (particularly silyl protecting groups such as trimethylsilyl groups) results in selective (? -Methylation) allowing easy preparation of 12-O-methylazithromycin (HR970051A; Irrespective of the latter patent application, Waddell ST et al (Biorg. Med. Chem. Letters 8 (1998), 549-555) later determined that O-methylation occurs at the hydroxyl group at the C-12 position.

It is also known that recent research into 14-membered macro people has led to the discovery of a new type of macrolide antibiotic, ketolides. Instead of the neutral sugar L-cladinose, known for its instability even in a weakly acidic environment, these compounds have a keto group at the C-3 position (Agouridas C. et al., EP 596802 A1, 5/1994; Le Martret O., FR 2697524 A1 , 5/1994). Ketolides show significantly better activity against organisms with MLS-induced resistance (macrolide, lincosamide and streptogramin B), as shown by Jamjian C. (Antimicrob. Agents Chemother., 1997, 41, 485). This significant discovery resulted in a large number of 3-ketoderivatives of clarithromycin, substituted predominantly at the C-11 / C-12 positions, which yielded numerous cyclic carbonates, carbamates, and more recently carbazates. The first step in the synthesis of ketolides involves the hydrolysis of clarithromycin to form the corresponding 3-decladinosyl derivative, namely the 3-de (2,6-dideoxy-3-C-methyl-3- (9-methyl-α-ribohexopyranosyl-oxy) derivative that is, after the removal of the 2'- protecting group after the removal of the 2'- protecting group hydroxyl groups (protected preferably by acylation with carboxylic acid chlorides or anhydrides), subjected to a 2 'oxidation and deprotection reaction. To our knowledge, C-11 / C-12 substituted ketolides from the 9α-azalide group of antibiotics have not been described. The first step, namely the synthesis of the 3-decladinosyl derivatives of 9-deoxo-9a-aza-9a-homoerythromycin and azithromycin, is described in US Patent 4,886,792, 12/1989. The intended oxidation of the C-3 hydroxyl group of the 3-decladinosylazithromycin and its 11- <9-methyl- and 12- <9-methyl derivatives by the transanular addition of the 6-hydroxyl group to the newly formed C-3 ketone yields a hitherto undescribed series of 6-hemiketals from the 9α-azalide group.

The synthesis of azithromycin 3,6-hemiketals and its 9 9 -methylderivatives includes the preparation of the corresponding 3-decladinosyl derivatives, protection of the 2'-hydroxyl group of the basic sugar, D-desosamine, selective acylation, oxidation of the hydroxyl group at C-3, cyclization of Cl 1 and C-12 hydroxyl groups. The present invention also provides pharmaceutically acceptable addition salts of 3,6-hemiketals of azithromycin and its (9-methyl derivatives with both organic and inorganic acids), processes and intermediates for their preparation, as well as the preparation and methods of administration of pharmaceutical compositions.

SUMMARY OF THE INVENTION

The invention relates

1) new 3,6-hemiketals from the 9α-azalide group,

2) a process for the preparation of new 3,6-hemiketals from the 9α-azalide group,

3) use of novel 3,6-hemiketals from the group 9a-azalides as antibiotics or as intermediates for the synthesis of other macrolide antibiotics.

New 3,6-hemiketals from the group 9a-azalides of general formula (I)

characterized in that the substituent R ¹ represents a hydroxyl or L-cladnosyl group according to formula (II)

where

R ² denotes hydrogen or a silyl group,

R ³ denotes hydrogen or - together with R ⁶ - an ether group,

R ⁴ represents hydrogen, a C 1 -C 4 acyl group or a -COO- (CH 2) _n -Ar group where n is 1 to 7 and Ar represents an unsubstituted or substituted aryl group having up to 18 carbon atoms,

R ⁵ denotes hydrogen, methyl or -COO- (CH 2) _n -Ar where n is 1 to 7 and Ar represents an unsubstituted or substituted aryl group of up to 18 carbon atoms,

R ⁶ denotes a hydroxyl group or - together with R ³ - denotes an ether group,

R ⁷ denotes hydrogen, C 1 -C 12 alkyl, silyl or - together with R ⁸ and C-11 / C-12 carbon atoms - denotes a cyclic carbonate,

R ⁸ denotes hydrogen, a C 1 -C 12 alkyl group, a silyl group, or - together with R ⁷ and C-11 / C-12 carbon atoms - denotes a cyclic carbonate, · ··· · ···· · ······ · · · · · · · · · · · · · · · · · · · · ·

and pharmaceutically acceptable inorganic or organic acid addition salts thereof are obtained by the following steps.

Step 1

Azithromycin of formula (I) wherein R ¹ is an L-Cladinosyl group of formula (II), R ² , R ³ , R ⁴ , R ⁷ and R ⁸ are the same and are hydrogen, R ⁵ is methyl and R ⁶ is hydroxyl group, is reacted with organic carboxylic acid chlorides of formula (IH)

ClCO (CH _{2) n} -Ar (ΠΙ) wherein n is 1-7 and Ar denotes unsubstituted or substituted aryl group having up to 18 carbon atoms, preferably with benzyloxycarbonyl chloride, in the presence of a base, preferably sodium bicarbonate, in an inert solvent preferably in benzene or toluene, to give 2'-O, 3'-N, N '- (benzyloxycarbonyl) -3'-N-demethylazithromycin (Kobrehel G. et al., US 5,250,518; 5/1993) of the general formula ( I), wherein R ¹ is an L-Cladinosyl group of formula (II), R ² , R ³ , R ⁷ and R ⁸ are the same and denote hydrogen, R ⁴ and R ⁵ are the same and denote a benzyloxycarbonyl group and R ⁶ is hydroxyl a group which is subsequently subjected to silylation

A) in the 4 'and 11 positions of a 2- to 5-fold molar excess of the silylating agent, in an organic inert solvent, at temperatures of 0 to 5 ° C for 5-8 hours, to give a new 4 "-11-G-bA (trimethylsilyl) - 2 '- <9.3' - N -A (benzyloxycarbonyl) -3'-N-demethyl azithromycin of formula (I) wherein R ¹ is an L-Cladinosyl group of formula (II), R ² and R ⁷ are the same and represent a benzyloxycarbonyl group and R ⁶ is a hydroxyl group, or

B) in the 4 'position with a 1.1- to 2-fold molar excess of the silylating agent, in an inert organic solvent, at 0 to 5 ° C for 1 hour, to give a new 4'-O-trimethylsilyl-2'-0, 3' - N - bA (benzyloxycarbonyl) -3'-N-demethylazithromycin of formula (I) wherein R is an L-Cladinosyl group of formula (II), R is a trimethylsilyl group, R ³ , R ⁷ and R ⁸ are the same and denote hydrogen R ⁴ and R ⁵ are the same and represent a benzyloxycarbonyl group and R ⁶ is a hydroxyl group.

As silylating agents, 1,1,1,3,3,3-hexamethyldisilazane, trimethylsilyl chloride, t-(trimethylsilyl) acetamide and the like intended to introduce a trimethylsilyl group, preferably a mixture of trimethylsilyl chloride and trimethylsilylimidazole, were used. A suitable solvent was 99 9 9 9 9 9 9 9 9 9 9

Pyridine, ethyl acetate, N, N-dimethylformamide, methylene chloride and the like, preferably pyridine.

Step 2

Reaction of 4 ', 11-O 2 z, N (trimethylsilyl) -2' -0,3'-7'-z '(benzyloxycarbonyl) -3' -N-demethylazithromycin from step 1A) and 4 "-O-trimethylsilyl, respectively. -2'-O, 3'-N-OH (benzyloxycarbonyl) 3'-N-demethylazithromycin from step 1B) with 1.3 to 10 moles of the corresponding alkylating agent, preferably methylating agent, in the presence of 1.1 to 8, 5 moles of a suitable base, at temperatures from -15 ° C to room temperature, preferably at 0 to 5 ° C, in a suitable inert solvent, occurs

A) for selective alkylation, preferably methylation, of a C-12 hydroxyl group to form the new 4'-11-R-trimethylsilyl) -2 '- (9,3'-N-z5 (benzyloxycarbonyl) -3'-V-) demethyl-12- (9-methylazithromycin of formula (I) wherein R ¹ denotes an L-Cladinosyl group of formula (II), R ² and R ⁷ are the same and are trimethylsilyl, R ³ is hydrogen, R ⁴ and R ⁵ are the same and represents a benzyloxycarbonyl group, R ⁶ is a hydroxyl group and R ⁸ is a methyl group, respectively

B) for alkylation, preferably methylation, of a C-11 or C-12 hydroxyl group to form a mixture of the novel 4'-O-trimethylsilyl-2'-C, 3'-N '- (benzyloxycarbonyl) -3'-V- demethyl-11-O-methylazithromycin of formula (I) wherein R ¹ represents the L-Cladinosyl group of formula (II), R ² is trimethylsilyl, R ³ and R ⁸ are the same and denote hydrogen, R ⁴ and R ⁵

Of the 7, they are the same and denote a benzyloxycarbonyl group, R represents a hydroxyl group, and R is methyl, and 4'-O-trimethylsilyl-2'-O, 3'-N-benzyl (benzyloxycarbonyl) -3'-N-demethyl-12- O-methylazithromycin of formula (I) wherein R ¹ represents the L-Cladinosyl group of formula (II), R ² is trimethylsilyl, R ³ and R ⁷ are the same and denote hydrogen, R ⁴ and R ⁵ are the same and represent benzyloxycarbonyl, R ⁶ represents a hydroxyl group and R ⁸ represents methyl.

C 1 to C 12 alkyl halides, preferably methyl iodide, dimethyl sulfate, methyl methanesulfonate or methyl p-toluenesulfonate, preferably methyl iodide, have been used as suitable alkylating agents herein. Suitable bases are alkali metal hydrides (lithium hydride, sodium hydride or potassium hydride), alkali metal hydroxides (potassium or sodium hydroxide) or alkali metal methylamides (lithium amide, sodium amide or potassium amide), preferably sodium hydride. Suitable inert solvents are dimethylsulfoxide, N, N-dimethylformamide.

I · *

N, N -dimethylacetamide or hexamethylphosphoric triamide, preferably N, N -dimethylformamide, dimethylsulfoxide or a mixture thereof with tetrahydrofuran.

Step 3 '-11- <9-bL (trimethylsilyl) -2' -0,3 '- N' - (trans) - (benzyloxycarbonyl) -3'-N-demethyl-12-0-methylazithromycin from step 2A) or obtained mixture 4 ' -O-trimethylsilyl-2'-O, 3'-N '(benzyloxycarbonyl) -3'-N-demethyl-11-O-methylazithromycin and 4'-O-trimethylsilyl-2'0,3' - # - az ' The 6 '(benzyloxycarbonyl) -3'-N-ethyl-12-O-methylazithromycin from step 2B) is subjected to a hydrogenolytic reaction according to the method of EH Flynn et al. (J. Am. Chem. Soc., 77, 3104, 1950) for deprotection of protecting groups at positions 2 'and 3' and then desilylation in a conventional manner in lower alcohols, preferably isopropanol in the presence of formic acid

A) at the 4 'and 11 positions in step 2A) to give 3'-N-demethyl-12-99-methylazithromycin of formula (I) wherein R ¹ represents an L-cladinosyl group of formula (II), R ² , R ³ , R ⁴ , R ⁵ and R ⁷ are the same and denote hydrogen, R ⁶ is a hydroxyl group and R ⁸ is methyl, or

B) at the 4 'position in step 2B) to form a mixture of 3'-A'-demethyl-10-methylazithromycin of formula (I) wherein R ¹ is an L-cladinosyl group of formula (II), R ² , R ³ R ⁴ , R ⁵ and R ⁸ are the same and are hydrogen, R ⁶ is hydroxyl and R ⁷ is methyl, and 3'-N-demethyl-12-O-methylazithromycin of formula (I) wherein R ¹ is L- the cladinosyl group of formula (II), R, R, R, R and R are the same and denote hydrogen, R is a hydroxyl group and R is a methyl group.

Hydrogenolysis was carried out in solution in lower alcohols, preferably ethanol, in the presence of a NaOAc / HOAc buffer (pH 5) with a catalyst such as palladium black or palladium on charcoal, at a hydrogen pressure of 0.1 to 2.0 MPa, at room temperature.

Step 4

3'-N-demethyl-12-O-methyl-azithromycin from step 3A) or a mixture of 3'-N-demethyl-11- (9-methylazithromycin and 3'-N-demethyl-12- (9-methylazithromycin obtained from step 3B) is subjected to reductive 3'-N-methylation with one to three equivalents of formaldehyde (37%) in the presence of the same or twice as much formic acid (98 to 100%) and a hydrogenation catalyst or other hydrogen source, in an inert solvent such as halogenated hydrocarbons; lower alcohols or lower ketones, preferably in chloroform, at the reflux temperature of the reaction mixture, to form

- in the case of the compound of step 3A): 12-O-methylazithromycin of general formula (I) in which R ¹ represents an L-cladinosyl group of formula (II), R ² , R ³ , R ⁴ and R ⁷ are the same and represent hydrogen R ⁵ and R ⁸ are the same to denote methyl and R ⁶ is a hydroxyl group, or

- in the case of the products of step 3B): mixtures of 11-O-methylazithromycin of general formula (I) in which R ¹ represents the L-Cladinosyl group of formula (II), R ² , R ³ , R ⁴ and R ⁸ are the same and denote hydrogen, R ⁵ and R ⁷ are the same to denote methyl and R ⁶ is a hydroxyl group, and 12-O-methylazithromycin of formula (I) wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ R ⁷ and R ⁸ have the same meaning as in the case of 3'-A-methylation of the compound of step 3A).

Step 5

Azithromycin of formula (I) wherein R ¹ is an L-Cladinosyl group of formula (II), R ² , R ³ , R ⁴ , R ⁷ and R ⁸ are the same and are hydrogen, R ⁵ is methyl and R ⁶ is hydroxyl the group or its 11-O-methyl and 12-O-methyl derivatives of step 4 are optionally subjected to hydrolysis with strong acids, preferably 0.25 to 1.5 N hydrochloric or dichloroacetic acid in a mixture of water and an alcohol, preferably methanol, ethanol or isopropanol, for 10 to 30 hours at room temperature, to give 3-de (2,6-dideoxy-3-C-methyl-3-O-methyla-L-ribhexopyranosyloxy) -3-oxyazithromycin of formula (I), wherein R ¹ and R ⁶ are the same and represent a hydroxyl group, R ³ , R ⁴ , R ⁷ and R ⁸ are the same and denote hydrogen and R ⁵ is methyl, or 3-de (2,6-dideoxy -3-C-methyl-3-O-methyl- [alpha] -L-ribohexopyranosyl-oxy) -3-oxy-11-O-methyl-azithromycin of formula (I) wherein R &lt; ¹ &gt; and R &lt; ⁶ &gt; ³ , R ⁴ and R ⁸ are the same and denote hydrogen and R 8 ⁵ and R ⁷ are the same and denote methyl, or 3-de (2,6-dideoxy-3-C-methyl-3-O-methyl-2-L-ribohexopyranosyloxy) -3-oxy-12-O-methyl azithromycin of formula (I) wherein R ¹ and R ⁶ are the same and denote a hydroxyl group, R ³ , R ⁴ and R ⁷ are the same and represent hydrogen and R ⁵ and R ⁸ are the same and denote methyl.

Step 6

The 3-De (2,6-dideoxy-3-C-methyl-3-O-methyl-2H-L-ribohexopyranosyloxy) -3-oxyazithromycin and its 11-O-methyl and 12-O-methyl derivatives of step 5 are subjected to selective acylation of the hydroxyl group at the 2 'position. The acylation is carried out with chlorides or anhydrides

I A A 4 A A A 4

A · A A

A AAAA * A A AAA

AAAA AAA carboxylic acids having up to 4 carbon atoms, preferably acetic anhydride, in the presence of inorganic or organic bases, in an inert organic solvent, at temperatures of 0 to 30 ° C, to form 2'-O-acetate of 3-de (2, 6-dideoxy-3-C-methyl-3- (9-methyl-.alpha .- (L-Hibohexopyranosyloxy) -3-oxyazithromycin of formula (I) wherein R @ ¹ and R @ ⁶ are the same and represent hydroxyl, R, R and R 2 are the same and are hydrogen and R 2 and R are the same are methyl, or 2'-O-acetate of 3-de (2,6-dideoxy-3-C-methyl-3- <9-methyl-2 H -ribohexopyranosyl- oxy) -3-oxy-11-O-methylazithromycin of formula (I) wherein R ¹ and R ⁶ are the same and are hydroxyl, R ³ and R ⁸ are the same and are hydrogen, R ⁴ is acetyl and R ⁵ and R ⁷ are the same to denote methyl, or 2 '- (9-acetate) 3-de (2,6-dideoxy-3-C-methyl-3-n-methyl- (2-ribohexopyranosyloxy) -3- oxy-12-N-methylazithromycin of formula (I) wherein R ¹ and R ⁶ are the same and denote hydroxy R ³ and R ⁷ are the same to denote hydrogen, R ⁴ is acetyl and R ⁵ and R ⁸ are the same to denote methyl.

Suitable bases here are sodium bicarbonate, sodium carbonate, potassium carbonate, triethylamine, pyridine, tributylamine, preferably sodium bicarbonate. As suitable inert solvent, methylene chloride, dichloroethane, acetone, pyridine, ethyl acetate, tetrahydrofuran, preferably methylene chloride are used herein.

Step 7 '-O-acetate of 3-de (2,6-dideoxy-3-C-methyl-3-O-methyl-η-L-ribohexopyranosyloxy) -3-oxyazithromycin and its 11-O-methyl- and 12 - The <9-methyl derivatives of step 6 are subjected to oxidation of the hydroxyl group at the C-3 position by Jones reagent or diimides by modified Moffat-Pfitzner procedure [i.e. DMSO and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide in the presence of pyridine trifluoroacetate] to give 3,6-hemiketal-2'-O-acetate of 3-de (2,6-dideoxy-3-C-methyl-3-O-methyl-α-L 17 ribohexopyranosyloxy) azithromycin of formula (I) ), wherein R is a hydroxyl group, R together with R ⁶ represent an ether group, R ⁴ is acetyl, R ⁵ is methyl and R ⁷ and R ⁸ are the same and represent hydrogen, or 3,6-hemiketal-2'-19- 3-de (2,6-dideoxy-3-C-methyl-3- (p-methyl-α-L-hexohexopyranosyloxy) -1 H -methylazithromycin acetate of formula (I) wherein R ¹ represents a hydroxyl group, R ³ together with R ⁶ denote an ether group, R ⁴ is acetyl, R ⁵ and R ⁷ are the same and denote meth and R ⁸ is hydrogen, or 3,6-hemiketal-2'-O-acetate 3-de (2,6-dideoxy-3-C-methyl-3-R-methyl-α-ribohexopyranosyl-oxy) - 12-No> 10

Methylazithromycin of formula (I) wherein R ¹ represents a hydroxyl group, R ³ together with R ⁶ denotes an ether group, R ⁴ is acetyl, R ⁵ and R ⁸ are and R ⁷ is hydrogen.

Step 8

3,6-Hemiketal-2 '- <9-acetate 3-de (2,6-dideoxy-3 -C-methyl-3-O-methyl-.alpha.-Libibohexopyranosyloxy) azithromycin and its 11-O-methyl and the 12-O-methyl derivatives of step 7 are subjected to solvolysis with lower alcohols, preferably methanol, at temperatures from room temperature to the reflux temperature of the solvent to give 3,6-hemiketal 3-de (2,6-dideoxy-3-C) -methyl-3- (9-methyl-6i-L-ribohexopyranosyloxy) azithromycin of formula (I) wherein R represents a hydroxyl group, R together with R denote an ether group, R ⁴ , R ⁷ and R ⁸ are the same and denotes hydrogen and R ⁵ is methyl, or 3,6-hemiketal of 3-de (2,6-dideoxy-3-C-methyl-3- (9-methyl-α-ribohexopyranosyloxy) -11-) methylazithromycin of formula (I) wherein R ¹ represents a hydroxyl group, R ³ together with R ⁶ denotes an ether group, R ⁴ and R ⁸ are the same and denotes hydrogen and R ⁵ and R ⁷ are the same denotes methyl, or 3,6 3-de (2,6-dideoxy-3-C-methyl-3- (9-methyl-α-L-ribohexopyranosyloxy) -12-β-methylazithromycin hemiketal of formula (I) wherein R ¹ represents a hydroxyl group, R ³ together with R ⁶ are the same and denote hydrogen and R ⁵ and R ⁸ are the same denote methyl.

Step 9

The 3,6-hemiketal 3-de (2,6-dideoxy-3-C-methyl-3-O-methyl-α-L-ribohexopyranosyl-oxy) azithromycin from step 8 is subsequently reacted with ethylene carbonate in the presence of inorganic or organic bases , preferably potassium carbonate, in an inert solvent, preferably ethyl acetate, to give the 3-de (2,6-dideoxy-3-C-methyl-3- <9-methyl) 11,12-cyclic carbonate of 3,6-hemiketal - α -L-ribohexopyranosyl-oxy) -azithromycin of formula (I) wherein R represents a hydroxyl group, R together with R represents an ether group, R ⁴ is hydrogen, R ⁵ is methyl and R ⁷ and R ⁸ together with C-carbon atoms -11 and C-12 denote cyclic carbonate.

Pharmaceutically compatible addition salts which are a further object of the present invention are obtained by reacting the novel compounds of formula (I) with at least an equimolar amount of the corresponding inorganic or organic acids, such as hydrochloric, hydroiodic, sulfuric, phosphoric, acetic, propionic, trifluoroacetic, · 4 · · f 9 9 · ······· 99 · I 99 9

9 9 9 9 9 9 9 9 • 99 9 9 · · 99 9 9 9 99 maleic, lemon, stearic, amber, ethylsuccinic, methanesulfonic, benzenesulfonic, μ-toluenesulfonic, laurylsulfonic and others, in an inert solvent. The addition salts are isolated by filtration (if insoluble in the inert solvent), precipitation with a precipitant, or evaporation of the solvent, but most often by lyophilization.

The antibacterial in vitro activity of these novel compounds of formula (I) and their pharmaceutically compatible salts with inorganic or organic acids against standard test microorganisms was determined in Mueller-Hinton medium (DifcoLaboratories, Detroit, MI) by conventional double dilution method in accordance with NCCLS recommendations ( The National Committee for Clinical Laboratory Standards). Each test microorganism was inoculated to a final concentration of ^{5 x} 10 ⁵ cfu / ml (cfu = colony forming unit) and incubated in an anaerobic manner at 37 ° C for 18 hours. The MIC in the liquid medium was defined as the lowest concentration of antibacterial agent that still inhibited visible growth in the micro-dilution tanks. Control organisms were obtained from ATCC (The American Type Culture Collection). All standards were identified by standard procedures and stored at -70 ° C. The results of the action of 12-O-methylazithromycin on standard test microorganisms and clinical isolates compared to azithromycin are shown in Table 1 and Table 2.

Table 1. Antibacterial in vitro activity of 12- (9-methylazithromycin) against standard strains compared to azithromycin

Organism MIC (gg / ml) azithromycin 12-O-methylazithromycin Staphylococcus aureus ATCC 6538 1 0.25 S. aureus ATCC 29213 0.25 0.25 5th epidermis ATCC 12228 0.5 0.03 Micrococcus flavius ATCC 10210 0.5 0.12 M. luteus ATCC 9341 0.06 0.03 Streptococcus faecalis ATCC 8043 0.5 0.25 Bacillus subtilis ATCC 6633 4 1 B. cereus ATCC 11778 1 0.25 Escherichia coli ATCC 10536 1 0.5

· / '· •?:.

* ·

Table 2. Antibacterial in vitro activity of 12-β-methylazithromycin against a number of clinical isolates compared to azithromycin

Organism' (strain number) Compound MIC (pg / ml) Range 50% 90% Staph. aureus (76) Azithromycin 0,25-8 1 4 12-O-Methylazithromycin 0,12-2 0.25 1 S. epidermis (21) Azithromycin 0,25-16 0.25 8 12-O-Methylazithromycin 0,12-8 0.25 4 Streptococcus pneumoniae (24) Azithromycin 0,03-0,25 0.06 0.12 12-O-Methylazi thromycin 0.03-0.12 0.03 0.12 Enterococcus sp. (35) Azithromycin 0,25-16 1 16 12-O-Methylazithromycin 0,12-8 0.5 8 Haemophilus influenzae (41) Azithromycin 0,12-0,5 0.25 0.5 12-O-Methylazithromycin 0,06-0,5 0.12 0.25

By determining the serum concentration of 12-O-methylazithromycin after a single oral dose of 20 mg / kg in a group of 36 male rats at time intervals of 0.25 to 24 hours, it was found that the new antibiotic was absorbed very rapidly into the serum. Peak analysis indicated the existence of enterohepatic circulation. Within 0.5 and 1 hours there was a rapid decrease in concentration, followed by an increase again. The maximum concentration of the substance was reached after two hours (c _max ~ 248.8 ng / ml). Secondary maximum was reached 4 hours after application. Half-life was

5.2 hours and total AUC was 1993.4 h.ng/ml.

The process for the preparation of novel 3,6-hemiketals from the 9α-azalide group is illustrated by the following examples, which in no way limit the scope of the invention.

9 9 9 9 9 9 9 9

9 ·· ·

9 »···· 9 9 · · 9 · 9 9

9 9 ·

9 9 · 9 9

9 9 9

9 99

DETAILED DESCRIPTION OF THE INVENTION

Preparation 1 -0 -0.3 ’---A (benzyloxycarbonyl) -3--A-demethylazithromycin A

To a solution of azithromycin (17 g, 0.0227 mol) in toluene (170 mL) was added NaHCO 3 (74.8 g, 0.890 mol) and the reaction mixture was heated to reflux (80-85 ° C) with stirring. 102 ml of 50% benzyloxycarbonyl chloride (104.04 g, 0.305 mol) in toluene were added dropwise with stirring to the reaction suspension over one hour. The reaction mixture was stirred at the same temperature for a further 2 hours and then allowed to stand overnight at room temperature. After filtration, the precipitate was washed with toluene (85 mL) and the toluene solution was extracted twice with 0.25 N HCl (170 mL) and twice with 1.5% aqueous NaCl (170 mL). To toluene was added water (340 mL) (pH 3.1), the pH of the reaction mixture was adjusted to 2.0 with 6 N HCl, the layers were separated and the organic layer was further extracted three times with water (340 mL) to pH was maintained at 2.0. To the combined aqueous extracts was added CH 2 Cl 2 (125 mL), the pH was adjusted to 10 with aqueous NaOH (20%), the layers were separated, and the aqueous layer was extracted again three times with CH 2 Cl 2 (125 mL). The combined organic extracts were dried over K 2 CO 3, filtered and evaporated under reduced pressure to give 16.5 g of a thick oily residue which was optionally purified by low pressure silica gel 60 (230-400 mesh ASTM) column. For this purpose, the crude product was dissolved in CH 2 Cl 2 (20 mL) and the solution was loaded onto a silica gel column (50 g) under a nitrogen overpressure of 0.05 MPa. To remove residual benzyl chloroformate and its decomposition products, the column was eluted with CH 2 Cl 2 (150 mL) and then - using a methylene chloride: methanol 9: 1 solvent system (200 mL) and evaporation of the fractions containing the chromatographically homogeneous title product - 11.53 g 2 '. &Lt; 9.3 &apos; -A-N (benzyloxycarbonyl) -N-demethylazithromycin, which was pure by TLC and whose physicochemical constants are described in U.S. Patent 5,250,518 of October 1993.

Example 1 ”, 11-O-cis (trimethylsilyl) -2 ´ -0,3 ´-N-ozo (benzyloxycarbonyl) -3 ´-N-demethylazithromycin

To a solution of 2'-O, 3'-A-tos' (benzyloxycarbonyl) -3'-A-demethylazithromycin (5.0 g, 0.005 mol) in pyridine (50 mL), cooled to 0-5 ° C, trimethylsilylimidazole (3.3 mL, 0.0226 mol) and trimethylsilyl chloride (3.0 mL, 0.0179 mol) were added under a stream of nitrogen. Reaction · 9 · 9 · 9 · 9 9 · 9 · 9 · 9 The mixture was stirred at the same temperature for 6 hours, then n-hexane (60 ml) and water (100 ml) were added, the layers were separated and the organic layer was washed with saturated NaHCO 3 solution (60 ml). . After drying over MgSO 4, filtering and evaporating the solvent under reduced pressure, 5.48 g of a white amorphous precipitate was obtained, which was optionally purified by low pressure silica gel column chromatography on a CH ₂ Cl ₂ : CH ₃ OH 9: 1 system. Combination and evaporation of chromatographically uniform fractions gave the product with the following physicochemical constants:

TLC, methylene chloride: methanol, 90: 1 ethyl acetate: n -hexane: diethylamine, 100: 100: 20

R _f 0.875 R _f 0.942

IR (KBr), cm ^-1 : 3524, 2969, 2692, 1754, 1732, 1708, 1498, 1456, 1382, 1335, 1252, 1168, 1116, 1060, 1005, 895, 841, 754, 696.

^! 1 HNMR (300 MHz, CDCl ₃ ), δ: 7.32-7.23 (Ph), 5.12, 4.98 (CH ₂ -Ph), 4.85 (H 1 "), 4.70 (H- 1 '), 4.65 (H-2'), 4.46 (H-3 '), 4.26 (H-5'), 4.42 (H-3), 3.72 (H-5 ') 3.66 (H-11), 3.49, 3.47 (H-5), 3.20 (H-4 '), 3.32, 3.18 (3'-OCH ₃ ), 2.83, 2.79 (3'-NCH ₃ ), 2.78 (H-2), 2.64 (H-10), 2.35 (H-9a), 2.33 (H-2 ") a), 2.11 (9a-NCH 3), 1.94 (H-9b), 1.91 (H-8), 1.64 (H-14a), 1.94 (H-4), 1, 50 (H-2 "b), 1.50 (H-14b), 1.27, 1.25 (6-CH 3), 1.24 (5" -CH ₃ ), 1.19 (5'-CH ₃ ) , 1.12 (3-CH ₃ ), 1.16 (12-CH ₃ ), 1.26 (2-CH ₃ ), 0.89 (10-CH ₃ ), 0.95 (8-CH 3) , 0.85 (14-CH ₃ ), 1.02 (4-CH ₃ ), 1.02 (4-CH ₃ ), 0.16 (11-OSi (CH ₃ ) ₃ ), and 0.13 ( 4 '-OSi (CH ₃ ) ₃ ).

¹³ C NMR (75 MHz, CDC1 ₃₎ δ: 176.2 (C), 156.2, 156.4 (OCO), 154.5, 154.4 (NCO), 136,7127,5 (Ph) 100.2 (C-1 '), 97.3 (C-1'), 83.9 (C-5), 80.7 (C-4 '), 75.0 (C-3), 75, 0 (C-2 '), 75.3 (C-6), 73.2 (C-3 "), 69.4, 69.2, 67.1, 66.8 (CH ₂ -Ph), 64 , 8 (C-5 '), 62.3 (C-10), 54.8 (C-3'), 49.4,

49.2 (3 '-OCH ₃ ), 46.2 (C-2), 38.5 (C-7), 39.4 (C-4), 34.2 (9a-NCH ₃ ), 35, 9, 35.6 (C-2 ”), 36.2,

36.1 (C-4 '), 29.0 (3'-NCH ₃ ), 25.6 (C-8), 27.8 (6-CH ₃ ), 21.9 (3 "-CH ₃ ), 21 , 5 (8-CH ₃ ), 20.7 (5'-CH ₃ ), 23.4 (C-14), 18.4 (5 "-CH ₃ ), 16.0 (2-CH ₃ ), 11.6 (14-CH ₃ ), 9.6, 9.5 (4-CH ₃ ), 8.3 (10-CH ₃ ), 1.2 (11-OSi (CH ₃ ) ₃ ) and O, 67 (4 "-OSi (CH3) _3).

· · Φ · · Φ · φ · · · · · · · · · · ·

1f φ Φ Φ φ Φ Φ Φ φ Φ Φ φ φ φ

Example 2 '-Y-Demethyl-12-O-methylazithromycin

Κ of a solution of the product of Example 1 (1.0 g, 0.0009 mol) in MM-dimethylformamide (20 ml) was gradually added over three hours at room temperature methyl iodide (0.43 ml, 0.0069 mol) and 60% hydride sodium (0.23 g, 0.0058 mol). The reaction mixture was stirred for another 30 minutes at the same temperature, quenched with triethylamine (2 mL) and then poured into a mixture of 10% aqueous NaHCO ₃ (50 mL) and water (50 mL) and extracted with ethyl acetate. The combined organic extracts were washed with saturated NaCl solution and water, dried over MgSO ₄ , filtered and evaporated under reduced pressure to give 0.93 g of a yellow precipitate [Rf 0.832 in methylene chloride: methanol 90: 1; IR (KBr), cm ^-1 : 3516, 1752, 1732, 1705, 1456, 1382, 1336, 1253, 1169, 1116, 1062,1004, 896, 840, 754, 696], The product was dissolved in ethanol (20 mL) ), followed by addition of NaOAc / HOAc buffer pH 5 (0.17 ml acetic acid, 0.263 g sodium acetate, 0.22 ml ethanol and 1 ml water) and Pd / C 10% (0.6 g), and reaction the mixture was hydrogenated with stirring for 5 hours in an autoclave at a hydrogen pressure of 0.5 MPa. The catalyst was filtered off, the filtrate was evaporated to a thick syrup to which CH 2 Cl 2 (10 mL) and water (15 mL) were added, the pH of the mixture was adjusted to 4 with 2 N HCl, the layers were separated and the aqueous layer was pH to 9.5 with 20% NaOH - extracted with CH 2 Cl 2 (3x10 mL). The combined organic extracts were dried over K 2 CO 3, filtered and evaporated. The precipitate was dissolved in isopropanol (10 mL), water (10 mL) and a few drops of formic acid were added, and the mixture was stirred at room temperature for 30 minutes, extracted with isopropyl acetate at pH 9.5 to give 0.50 after evaporation under reduced pressure. 43 g of the title product with the following physico-chemical constants:

IR (KBr), cm ^-1 : 3672, 3496, 2962, 1727, 1458, 1375, 1343, 1280, 1263, 1118, 1085, 1048, 1005, 998.

¹³ C NMR (75 MHz, CDCl ₃ ), δ: 177.4 (Cl), 102.7 (Cl), 95.5 (Cl "), 83.4 (C-5), 79.7 (C-12) , 78.0 (C-3), 76.6 (C-11), 74.0 (C-13), 73.9 (C-6), 74.3 (C-2 '), 73.0 (C-3 '), 68.8 (C-9), 65.7 (C-5'), 60.1 (C-3 '), 61.2 (C-10), 52.8 (12) -OCH ₃ ), 49.8 (3 "-OCH ₃ ), 45.5 (C-2), 41.5 (C-4), 33.1 (3'-NCH ₃ ), 36.8 (9a-NCH) ₃ ), 35.1 (C-2 '), 28.8 (C-4'), 27.0 (C-8).

EI-MS m / z 748;

····························· 9 9 · 9

Example 3

12-Ο-Methyl azithromycin

To a solution of 3'-Dimethyl-12-O-methyl azithromycin from Example 2 (0.43 g, 0.0006 mol) in CHCl 3 (20 mL) was added formaldehyde (37%) (0.017 mL, 0.0006 mol) and Formic acid (98-100%) (0.042 mL, 0.0011 mol). The reaction mixture was stirred at reflux for 3 hours, cooled to room temperature, poured into water (20 mL) and after adjusting the pH to 4.0, the layers were separated and the aqueous layer extracted twice more with CHCl 3. CHCl 3 was added to the aqueous layer, pH adjusted to 9.5 (with 2 N NaOH), the layers were separated and the aqueous layer was extracted twice more with CHCl 3. The combined organic extracts obtained at pH 9.5 were dried (K 2 CO 3) and evaporated to give 0.68 g of the title product which, if necessary, was purified by silica gel column chromatography using CH 2 Cl 2: CH 3 OH: conc. NH ₄ OH 90: 9: 1.

TLC, methylene chloride: methanol: conc. ammonia, 90: 9: 1 Rf 0.363 ethyl acetate: n-hexane: diethylamine 100: 100: 20 Rf 0.745

IR (KBr), cm ^-1 : 3499, 2972, 2940, 1736, 1633, 1460, 1381, 1259, 1168, 1110, 1059, 1082, 1054, 1013,999.

1 H NMR (300 MHz, CDCl 3), δ: 5.39 (H-13), 5.00 (H 1 '), 4.43 (H-1'), 4.32 (H-3), 4.06 (H-5 '), 3.68 (H-11), 3.65 (H-5), 3.51 (H-5'), 3.38 (12-OCH ₃ ), 3.32 (3 -OCH ₃ ), 3.24 (H-2 '), 3.02 (H-4 "), 2.73 (H-2), 2.69 (H-10), 2.49 (H- 3 '), 2.34 (H-2' a), 2.31 (H-9a), 2.29 (3'-N (CH ₃ ) ₂ ), 2.30 (9a-NCH ₃ ), 2 12 (H-9b), 2.04 (H-4), 2.01 (H-8), 1.73 (H-14a), 1.68 (H-4'a), 1.66 (H-4a) H-7a), 1.56 (H-2b), 1.52 (H-14b), 1.36 (H-7b), 1.29 (6-CH ₃ ), 1.21 (2- CH ₃ ), 1.30 (5 "-CH ₃ ), 1.24 (H-4'b), 1.23 (3" -CH ₃ ), 1.22 (5'-CH ₃ ), 1.09 ( _12-CH3), 1.29 _(4-CH3), 1.09 (10-CH _3), 0.92 (8-CH _3), 0.93 (14-CH _3).

¹³ C NMR (75 MHz, CDCl ₃ ), δ: 177.5 (Cl), 103.1 (C-1 '), 95.2 (Cl-1), 83.6 (C-5), 79.2 (C-12)

78.1 (C-3), 76.6 (C-11), 74.7 (C-13), 73.8 (C-6), 70.9 (C-2 '), 68.8 (C-2), C-9), 65.6 (C-5 "), 65.7 (C-3 '), 61.6 (C-10), 52.8 (12-OCH ₃ ), 49.4 (3" -OCH) ₃ ), 45.1 (C-2), 43.0 (C-7), 41.8 (C-4), 40.4 (3'N (CH ₃ ) ₂ ), 36.8 (9-). NCH ₃ ), 35.0 (C-2 "), 29.0 (C-4 '), 26.9 (C-8), 26.9 (6-CH ₃ ), 22.0 (8-CH 3) ), 22.0 (C-14), 21.6 (3'-CH ₃ ), 21.3 (5'-CH ₃ ), 18.1 (5'-CH ₃ ), 16.9 (12- CH ₃ ), 14.6 (2-CH ₃ ), 11.0 (14-CH ₃ ), 9.6 (4-CH ₃ ), 9.4 (10-CH ₃ ).

······························································································ ································

Example 4

3-De (2,6-dideoxy-3-C-methyl-3-n-methyl-α, L-ribohexopyranosyloxy) -3-oxy-12- (9-methylazithromycin)

12-O-methylazithromycin (1.7 g, 0.0022 mol) from Example 3 was dissolved in 0.25 N hydrochloric acid (80 mL) and the solution was allowed to stand at room temperature for 24 hours. CH 2 Cl 2 (pH 1.8) was added to the reaction mixture, the layers were separated and the aqueous was extracted twice more with CH 2 Cl 2. CH 2 Cl 2 was added again to the aqueous layer, the pH of the mixture was adjusted with conc. NH 4 OH to 9.0, the layers were separated and the aqueous layer was extracted with CH 2 Cl 2. The combined organic extracts obtained at pH 9.0 were washed with 10% aqueous NaHCO ₃ solution and water, dried over K 2 CO 3 and evaporated to give 1.25 g of the title product with the following physicochemical constants:

TLC, methylene chloride: methanol: conc. ammonia, 90: 9: 0.5 Rf 0.315 ethyl acetate: n-hexane: diethylamine, 100: 100: 20 Rf 0.594

IR (KBr), cm ^-1 : 3450, 2971, 2933, 1711, 1648, 1460, 1381, 1272, 1261, 1171, 1113, 1078, 1049.

* H NMR (300MHz, CDC1 ₃₎ δ: 5.32 (H-13), 4.47 (Η-Γ), 3.78 (H-3), 3.66 (H-ll}, 3.58 (H-5)

3.58 (H-5 '), 3.41 (12-OCH ₃ ), 3.28 (H-2'), 2.67 (H-2), 2.80 (H-10), 2.53 (H-10 ') H-3 '), 2.53 (H-9a), 2.27 (3'N (CH ₃ ) ₂ ), 2.37 (9a-NCH ₃ ), 2.07 (H-9b), 2, 27 (H-4), 1.9 (H-8), 1.74 (H-14a), 1.68 (H-4'a),

1.59 (H-7a), 1.63 (H-14b), 1.51 (H-7b), 1.31 (6-CH 3), 1.31 (2-CH ₃ ), 1.29 (H- 4'b), 1.26 (5'-CH ₃ ), 1.08 (12-CH 3), 1.05 (4-CH ₃ ), 1.19 (10-CH 3), 0.93 (8-CH 3) 0.92 (14-CH _3).

¹³ CNMR (75 MHz, CDCl 3), δ: 177.2 (Cl), 106.4 (C-1 '), 94.7 (C-5), 78.0 (C-12), 79.0 ( C-3),

78.3 (C-11), 75.1 (C-13), 72.9 (C-6), 70.2 (C-2 '), 70.3 (C-9), 65.3 (C- 3 '), 62.1 (C-10), 52.5 (12-OCH 3), 44.3 (C-2), 41.8 (C-7), 35.7 (C-4), 39 9 / 3'-N _{(CH3) 2),} 36.5 (9a-NCH _3), 27.9 (C-4 '),

26.4 (C-8), 25.5 (6-CH 3), 20.8 (8-CH 3), 20.7 (C-14), 20.8 (5'-CH ₃ ), 16.1 (12 -CH ₃ ), 15.7 (2-CH ₃ ), 10.3 (14-CH ₃ ), 7.6 (4-CH ₃ ), 7.2 (10-CH 3).

· 9 9 9 9 9

9 9 9 9 9 99 9 9 9 9 9 9 9 9

9 9 9 9 9

9999 9 99,999 9 · 99

Example 5

3-De (2,6-dideoxy-3-C-methyl-3-O-methyl-.alpha.-L-ribohexopyranosyl-oxy) -3-oxy-12-O-methyl azithromycin-2 &apos; -O-acetate

To a solution of 3-de (2,6-dideoxy-3-C-methyl-3-O-methyl-2-L-ribohexopyranosyloxy) -3-oxy-12-O-methylazithromycin (1.3 g, 0.0022 mol) of Example 4 in CH 2 Cl 2 (20 mL) was added NaHCl 3 (0.754 g, 0.009 mol) and acetic anhydride (0.221 mL, 0.0023 mol). The mixture was stirred for 10 hours at room temperature and then allowed to stand overnight. To the reaction mixture was added saturated NaHCO 3 solution, the layers were separated and the aqueous was extracted with CH 2 Cl 2. The combined organic extracts were washed with saturated NaHCO 3 solution and water, dried over K 2 CO 3, filtered and evaporated to give 1.29 g of a white amorphous precipitate.

TLC, methylene chloride: methanol: conc. ammonia, 90: 9: 0.5 Rf 0.489 ethyl acetate: n-hexane: diethylamine 100: 100: 20 Rf 0.661

IR (KBr), cm ^-1 : 3448, 2974, 1749, 1718, 1637, 1458, 1377, 1242, 1129, 1115, 1045.

1 HNMR (300 MHz, CDCl ₃ ), δ: 5.23 (H-13), 4.72 (H-2 '), 4.70 (H-1'), 3.59 (H-11), 3, 56 (H-5), 3.52 (H-3), 3.43 (H-5 '), 3.33 (12-OCH ₃ ), 2.72 (H-10), 2.71 (H) -3 '), 2.61 (H-2), 2.42 (H-9a), 2.30 (9a-NCH ₃ ), 2.20 (3'N (CH ₃ ) ₂ ), 2.12 (H-4), 1.99 (2'-COCtf ₅ ), 1.96 (H-9b), 1.80 (H-8), 1.67 (H-14a), 1.67 (H- 4'a), 1.58 (H-14b), 1.47 (H-7a), 1.31 (H-4'b), 1.21 (2-CH ₃ ), 1.18 (H- 7b), 1.16 (5'-CH ₃ ), 1.15 (6-CH 3), 1.10 (10-CH 3), 0.97 (12-CH ₃ ), 0.86 (14-CH ₃₎ ), 0.84 (8-CH 3), 0.81 (4-CH 3).

¹³ CNMR (75 MHz, CDCl 3), δ: 176.5 (Cl), 169.4 (2'-C <9CH 3), 98.6 (C-1 '), 84.3 (C-5), 77 , 3 (C-12), 78.3 (C-3), 76.7 (C-11), 74.6 (C-13), 72.4 (C-6), 70.7 (C- 2 '), 69.9 (C-9), 62.2 (C-3'), 62.3 (C-10), 51.9 (12-OCH 3), 43.0 (C-2), 40.1 (C-7), 35.2 (C-4), 39.6 (3 ^r N (CH 3) ₂ ), 35.9 (9a-NCH ₃ ), 30.0 (C-4 ') 25.4 (C-8), 25.2 (6-CH 3), 20.6 (2'-COC / Z ₃ ), 20.4 (8-CH 3), 20.0 (C-14),

20.2 (5'-CH ₃ ), 15.9 (12-CH ₃ ), 15.2 (2-CH ₃ ), 9.7 (14-CH ₃ ), 7.0 (4-CH ₃ ) 6.4 (10-CH 3).

· 99 99

9 9 9 9 9

9 9 9 9 99

9999 98 9 999 98 9

9 9 9 9 9

9900 9 99 999 99 99

Example 6

3.6-Hemiketal-2 '-O-acetate 3-de (2,6-dideoxy-3-C-methyl-3-Ο-methyl- <x-L-ribohexopyranosyloxy) -12-O-methyl azithromycin

To a solution of 2'-O-acetate of 3-de (2,6-dideoxy-3-C-methyl-3-O-methyl-α-Lribohexopyranosyloxy) -3-oxy-12-O-methylazithromycin (1,3 g, 0.0020 mol) of Example 5 in CH 2 Cl 2 (15 mL) was added dimethylsulfoxide (4.35 mL) and N, N -dimethylaminopropylethylcarbodiimide (4.45 g). The reaction mixture was cooled to 15 ° C and then a solution of pyridinium trifluroacetate (4.61 g, 0.0234 mol) in CH 2 Cl 2 (10 mL) was added dropwise over 30 minutes while stirring and maintaining the temperature at 15 ° C. The temperature of the reaction mixture was gradually raised to room temperature, and the mixture was stirred for an additional two hours before quenching with saturated NaCl solution (25 mL). After alkalization with 2 N NaOH to pH 9.5, the reaction mixture was extracted with CH ₂ Cl ₂ , the organic extracts washed with saturated NaCl, NaHCO 3 and water and dried over K 2 CO 3. Evaporation of CH 2 Cl 2 under reduced pressure gave 1.78 g of an oily residue.

TLC, methylene chloride: methanol: conc. ammonia, 90: 9: 0.5 Rf 0.176 ethyl acetate: n-hexane: diethylamine, 100: 100: 20 Rf 0.861

Example 7

3.6-3-de-hemiketal (2,6-dideoxy-3-C-methyl-3-O-methyl-α-L-ribohexopyranosyloxy) -12-O-methylazithromycin

3-de (2,6-dideoxy-3-C-methyl-3-O-methyl-o: -L-ribohexopyranosyloxy) -1,2-O-methylazithromycin (1.78 g) solution from 2'-O-acetate of Example 6 in methanol (50 mL) was allowed to stand at room temperature for 24 hours. Methanol was evaporated under reduced pressure and the obtained residue (1.65 g) was purified by low pressure silica gel column chromatography using methylene chloride: methanol: conc. ammonia, 90: 9: 0.5. Evaporation of the combined extracts with _Rf 0.082 were obtained chromatographically uniform hemiketal 3,6-3-de (2,6-dideoxy-3-C-methyl-3-O-methyl-L-ribohexopyranosyl-oxy-O-methyl-with following physical chemical constants:

· ** ** f f f c c c c c c c f c c c c c c f f c c c c f f f f f · · * * * * * · * »» »»

TLC, methylene chloride: methanol: conc. ammonia, ethyl acetate: n-hexane: diethylamine,

90: 9: 0.5 _Rf 0.082

100: 100: 20 _Rf 0.624

IR (CDCl3) cm ^-1 : 3450, 2956, 2940, 1718, 1678, 1631, 1459, 1383, 1278, 1198, 1117, 1068, 1048, 1014, 963;

1 HNMR (300 MHz, CDCl ₃ ), δ: 5.49 (H-13), 4.21 (H-1 '), 3.83 (H-11), 3.75 (H-5), 3, 52 (H-5 ')

3.43 (12-OCH 3), 3.25 (H-2 '), 2.59 (H-2), 2.93 (H-10), 2.50 (H-3'), 2, 61 (H-9a), 2.29 (3'N (CH ₃ ) ₂ ), 2.40 (9a-NCH ₃ ), 2.10 (H-9b), 2.06 (H-4), 1 88 (H-8), 1.77 (H-14a), 1.67 (H-4'a), 1.61 (H-7a), 1.64 (H-14b), 1.33 (H-14a) H-7b), 1.31 (6-CH 3), 1.05 (2-CH ₃ ), 1.27 (H-4'b), 1.26 (5'-CH ₃ ), 1.08 ( _12-CH3), 1.05 _(4-CH3), 1.19 (IO-CH3), 0.92 (8-CH3), 0.93 (14-CH _3).

¹³ CNMR (75 MHz, CDCl 3), δ: 176.2 (Cl), 105.8 (C-1 '), 94.6 (C-5), 78.3 (C-12), 102.7 ( C-3),

71.2 (C-11), 74.8 (C-13), 82.9 (C-6), 69.6 (C-2 '), 64.5 (C-9), 65.1 ( C-3 '), 60.7 (C-10), 52.2 (12-OCH 3), 49.2 (C-2), 41.4 (C-7), 48.6 (C-4) , 40.0 (3'N (CH ₃ ) ₃ ), 40.5 (9a-NCH ₃ ), 28.2 (C-4 '), 29.1 (C-8), 26.5 (6- CH 3), 21.5 (8-CH 3), 21.6 (C-14), 20.8 (5'-CH ₃ ), 16.3 (12-CH ₃ ), 13.6 (2-CH ₃₎ ), 10.7 (M-CH 3), 12.8 (4-CH ₃ ), 10.7 (10-CH ₃ ).

Example 8

4 ´ ´-O-Trimethylsilyl-2 ´ - (9-3 ´-7 N-óz' (benzyloxycarbonyl) -3 -3 -7 N-demethylazithromycin

To a solution of 2'-O, 3'-7'-N '(benzyloxycarbonyl) -3'-7'-demethylazithromycin (5g,

Trimethylsilylimidazole (1.46 ml, 0.01 mol) and trimethylsilyl chloride (1.64 ml, 0.01 mol) were added under a stream of nitrogen. The reaction mixture was stirred at the same temperature for 1 hour, n-hexane (50 ml) and water (25 ml) were added, the layers were separated and the organic layer was washed with saturated NaHCO ₃ solution (25 ml) and water (25 ml). After drying over MgSO 4, filtering and evaporating the solvent under reduced pressure, an amorphous precipitate (3.65 g) was obtained, which was purified by low pressure silica gel column chromatography using methylene chloride: methanol: conc. ammonia, 90: 9: 0.5. Combine and evaporate the chromatographically uniform fractions with Rf 0.670 to give the title product with the following physicochemical constants:

# 9 9 9 9 9 9 9 9 10 11 12 13 14 15 16 17 18 19 20 · · · · · ♦ ♦ 94 94

TLC, methylene chloride: methanol, ethyl acetate: n-hexane; diethylamine

90: 1 _Rf 0.525

100: 100: 20 _Rf 0.862

IR (KBr), cm ^-1 : 3502, 2969, 2938, 1753, 1732, 1708, 1454, 1383, 1365, 1254, 1169, 1118, 1063, 1001, 897, 839, 754, 696;

1 H NMR (300MHz, CDCl ₃ ), δ: 7.34-7.26 (Ph), 5.13, 5.09 (CH ₂ -Ph), 5.07 (H 1 '), 4.78 (H- 1 '), 4.68 (H-13), 4.66 (H-2'), 4.55 (H-3 '), 4.22 (H-5'), 4.13 (H-3) 3.96 (H-5 '), 3.65 (H-11), 3.58,

3.54 (H-5), 3.15 (H-4 "), 3.37, 2.99 (3" -OCH ₃ ), 2.85, 2.81 (3'-NCH ₃ ), 2.70 (H-2), 2.68 (H-10),

2.54 (H-9a), 2.35 (H-2 'a), 2.31 (9a-NCH ₃ ), 2.04 (H-9b), 1.97 (H-8), 1.90 ( H-14a), 1.85 (H-4), 1.62 (H-7a), 1.50 (H-2 ”b), 1.44 (H-14b), 1.28, 1.27 (6-CH ₃ ), 1.23 (5 "-CH ₃ ), 1.16 (5'-CH ₃ ), 1.15 (H-7b), 1.04 (3" -CH ₃ ), 1 15 (12-CH ₃ ), 1.10 (2-CH ₃ ), 1.10 (10-CH ₃ ), 0.92 (8-CH ₃ ), 0.89 (14-CH ₃ ), 1 10 _(4-CH3).

¹³ C NMR (75 MHz, CDC1 ₃₎ δ: 178.8 (C), 156.6, 156.3 (OCC>) 154.7, 154.6 (NC0) 136,8127,5 (Ph) , 99.2 (C-1 '), 94.8 (Cl-1), 83.2, 83.1 (C-5), 80.5, 80.4 (C-4'), 77.3 ( C-3), 75.1, 75.0 (C-2 '), 74.1 (C-12), 73.8 (C-11), 73.2 (C-6), 73.2 ( C-3 "), 69.2, 69.0, 67.2, 66.8 (CH ₂ -Ph), 64.8 (C-5 '), 62.2 (C-10), 54.6 (C-3 '), 49.3, 48.8 (3'-OCH ₃ ), 44.7 (C-2), 41.5 (C-7), 41.1 (C-4), 36 , 1 (9a-NCH ₃ ), 35.1, 35.0 (C-2 "), 36.3, 35.7 (C-4 '), 28.4 (3'-NCH ₃ ), 26, 3 (C-8), 26.8 (6-CH ₃ ), 22.1 (3 "-CH ₃ ), 21.6 (8-CH ₃ ), 21.4 (5'-CH ₃ ), 21 , 0 (C-14), 18.7 (5-CH ₃ ), 15.9 (2-CH ₃ ), 14.5 (12-CH ₃ ), 11.0 (14-CH ₃ ), 8 5 (4-CH ₃ ), 7.1 (10-CH ₃ ), 0.63 (4'-OSi (CH ₃ ) ₃ ).

ES-MS 1075.

Example 9

11-O-methylazithromycin and 12-O-methylazithromycin

To a solution of the product of Example 8 (3.0 g, 0.0028 mol) in N, N -dimethylformamide (50 ml) was added methyl iodide (1.29 ml, 0.0207 mol) and 60 ml at room temperature over three hours. % sodium hydride (0.69 g, 0.0174 mol). The reaction mixture was stirred at the same temperature for 1 hour, quenched with triethylamine (5 mL), transferred to a mixture of 10% aqueous NaHCO ₃ (100 mL) and water (100 mL) and extracted with ethyl acetate. The combined organic extracts were washed with saturated NaCl solution and water, dried over MgSO 4, filtered and evaporated under reduced pressure to give 2.9 g of product mixture, which was optionally purified by low pressure silica gel column chromatography using methylene chloride system. : methanol 90: 1, yielding chromatographically uniform 4'-O-trimethylsilyl-2'-O-3'-7H-hL (benzyloxycarbonyl) -3'-N-demethyl-11-O-methylazithromycin s R _f 0.745 [IR ( KBr): 3452, 2969, 1752, 1736, 1706, 1455, 1382, 1332, 1254, 1169, 1117, 1063, 1002, 914, 897, 840, 754, 697] and 4'-O-trimethylsilyl-2'- 3'-O-Z> A (benzyloxycarbonyl) -3'-jVdemethyl-12-O-methyl-with _Rf 0.485 [IR (KBr) cm ^-1: 3450, 2958, 1754, 1718, 1708, 1458, 1383, 1252, 1168, 1068, 1010, 896, 842, 753, 695].

The resulting mixture was dissolved in ethanol (50 mL), NaOAc / HOAc pH 5 buffer (0.51 mL HOAc, 0.789 g NaOAc, 0.66 mL ethanol and 3 mL water) and 10% Pd / C (1 mL) were added. 5 g) and the mixture was hydrogenated under autoclave under a hydrogen pressure of 0.5 MPa for eight hours. The catalyst was filtered off and the filtrate was concentrated to a thick syrup. Water (50 mL) and CHCl 3 (50 mL) were added and the product was isolated by pH gradient extraction at pH 4.0 and 9.5. The combined organic extracts obtained at pH 9.5 were dried over K 2 CO 3 and evaporated to give an amorphous precipitate. This precipitate was dissolved in isopropanol (20 ml), water (20 ml) and a few drops of formic acid were added, the mixture was stirred for 30 minutes at room temperature, extracted with isopropyl acetate at pH 9.5, dried over sodium sulfate and evaporated under reduced pressure. . The obtained product was dissolved in CHCl 3 (50 mL) and to this was added 37% formaldehyde (0.24 mL) and 98-100% formic acid (0.22 mL). The reaction mixture was stirred at reflux for 3 hours, cooled to room temperature, poured into water (20 mL), after adjusting the pH to 4.0, the layers were separated and the aqueous was extracted twice more with CHCl 3. CHCl 3 was added to the aqueous layer, pH was adjusted to 9.5 (with 2 N NaOH), the layers were separated and the aqueous was extracted twice more with CHCl 3. The combined organic extracts obtained at pH 9.5 were dried (K 2 CO 3) and evaporated to give 1.25 g of a precipitate which was chromatographed on a silica gel column using methylene chloride: methanol: conc. ammonia 90: 9: 1, yielding 0.40 g of chromatographically uniform 11-O-methylazithromycin whose physicochemical constants corresponded to US Patent No. 5,250,518 of 10/1993, and 0.52 g of 12-O-methylazithromycin whose physicochemical constants are given in Example 3.

• · · · · · · · · · · · ·

Example 10

3-De (2,6-dideoxy-3-C-methyl-3-O-methyl-.alpha.-L-ribohexopyranosyloxy) -3-oxy-11-O-methylazithromycin

10-methylazithromycin (1.5 g) was dissolved in methanol (30 ml), 0.25 N hydrochloric acid (50 ml) was added and the mixture was allowed to stand at room temperature for 25 hours. Methanol was evaporated, CDCl ₃ (pH 1.9) was added to the reaction mixture, the layers were separated and the aqueous extracted twice more with CDCl 3. The aqueous solution was basified to pH 9.5 and extracted with CDCl ₃ . The combined organic extracts obtained at pH 9.5 were dried over K 2 CO 3 and evaporated to give 0.95 g of the title product. This was optionally purified by low pressure silica gel column chromatography using a methylene chloride: methanol: conc. ammonia 90: 9: 0.5 to give a chromatographically uniform title product with the following physicochemical constants:

TLC, methylene chloride: methanol: conc. ammonia, 90: 9: 0.5 Rf 0.382 ethyl acetate: n-hexane: diethylamine, 100: 100: 20 Rf 0.594

IR (KBr), cm ^-1 : 3448, 2972, 2937, 1730, 1638, 1458, 1377, 1165, 1113, 1078, 1050.

1 HNMR (300MHz, CDCl ₃ ), δ: 4.97 (H-13), 4.52 (H-1 '), 3.76 (H-3), 3.70 (II-OCH 3), 3, 59 (H-5), 3.54 (H-5 '), 3.42 (H-11), 3.29 (H-2'), 2.68 (H-2), 2.70 (H-2 ') -10), 2.58 (H-3 '), 2.46 (H-9a), 2.35 (H-4), 2.29 (3'N (CH ₃ ) ₂ ), 2.30 (H-3') 9a-NCH ₃ ), 2.11 (H-9b), 1.94 (H-14a), 1.89 (H-8), 1.70 (H-4'a), 1.66 (H- 7a), 1.54 (H-7b), 1.52 (H-14b), 1.33 (6-CH 3), 1.30 (2-CH ₃ ), 1.27 (H-4'b) 1.25 (5'-CH ₃ ), 1.12 (12-CH 3), 1.10 (4-CH ₃ ), 1.06 (10-CH 3), 0.92 (8-CH 3), 0 86 _(14-CH3).

¹³ CNMR (75 MHz, CDCl 3), δ: 175.7 (Cl), 106.1 (C-1 '), 94.7 (C-5), 74.2 (C-12), 78.1 ( C-3), 86.0 (C-11), 77.1 (C-13), 72.8 (C-6), 70.2 (C-2 '), 70.9 (C-9) 65.4 (C-3 '), 62.9 (C-10), 62.0 (II-OCH 3), 44.1 (C-2), 42.5 (C-7), 35.3 (C-4), 39.9 (3'N (CH ₃ ) ₂ ), 36.2 (9a-NCH ₃ ), 28.0 (C-4 '),

26.7 (C-8), 25.8 (6-CH 3), 20.9 (8-CH 3), 21.2 (C-14), 20.8 (5'-CH ₃ ), 16.8 (12-CH ₃ ), 15.6 (2-CH ₃ ), 10.3 (14-CH ₃ ), 7.7 (4-CH ₃ ), 6.8 (10-CH ₃ ).

·· ·

Example 11

3-de (2,6-dideoxy-3-C-methyl-3-O-methyl-α-L-ribohexopyranosyloxy) -3-oxy-11-O-methylazithromycin

To a solution of 3-de (2,6-dideoxy-3 -C-methyl-3-O-methyl- (2-ribohexopyranosyloxy) -3-oxy-11- (9-methylazithromycin) (0.89 g) from Example 10 in CH 2 Cl 2 (25 mL) was added NaHCl 3 (0.52 g) and acetic anhydride (0.15 mL), the reaction mixture was stirred at room temperature for 10 hours, allowed to stand overnight and then isolated by extraction with CH 2 Cl 2 as described in Example 5, yielding 0.65 g of a white amorphous precipitate.

TLC, methylene chloride: methanol: conc. ammonia, 90: 9: 0.5 Rf 0.426 ethyl acetate: n-hexane: diethylamine, 100: 100: 20 Rf 0.670

IR (KBr), cm ^-1 : 3525, 3475, 2968, 2937, 1724, 1647, 1458, 1376, 1265, 1168, 1113, 1081, 1050.

Example 12

3,6-Hemiketal-2'-O-acetate 3-de (2,6-dideoxy-3-C-methyl-3- <9-methyl-α-Libibohexopyranosyl-oxy) -11-? -Methylazithromycin

To a solution of 3-de (2,6-dideoxy-3-C-methyl-3-n-methyl-α-L-hexohexopyranosyl-oxy) -3-oxy-11- (9-methylazithromycin) 2'-n-acetate ( 0.65 g) of Example 11 in CH 2 Cl 2 (20 mL) were added dimethylsulfoxide (0.94 mL) and N, N -dimethylaminopropylethylcarbodiimide (1.16 g) The reaction mixture was cooled to 15 ° C and then stirred and maintained A solution of pyridinium trifluoroacetate (1.15 g) in CH 2 Cl 2 (5 mL) was added dropwise over 30 minutes, the reaction mixture was allowed to warm to room temperature, stirred for an additional 4 hours, and then isolated as described. of Example 6 to give 0.6 g of the title product.

TLC, methylene chloride: methanol: conc. ammonia, ethyl acetate: n-hexane: diethylamine,

90: 9: 0.5 _Rf 0.606

100: 100: 20 R _f 0.861 · 61 * * * * * * * * * * * 61 61 61 61 • 61 61

Example 13

3,6-Hemiketal 3-de (2,6-dideoxy-3-C-methyl-3-G-methyl-α-L-ribohexopyranosyloxy) -1,1-methylazithromycin

A solution of 3-de (2,6-dideoxy-3 -C-methyl-3-O-methyl-α-L-hexohexopyranosyloxy) 3,6-hemiketal-2'-O-acetate (11-G-methylazithromycin) (0 6 g) of Example 12 in methanol (40 ml) was allowed to stand at room temperature for 24 hours. Methanol was evaporated under reduced pressure, and the obtained residue (0.53 g) was purified by low pressure silica gel column chromatography using methylene chloride: methanol: conc. ammonia 90: 9: 1.5. Evaporation of the combined extracts with Rf 0.370 yielded 0.22 g of chromatographically uniform 3,6-hemiketal of 3-de (2,6-dideoxy-3C-methyl-3-O-methyl-.alpha.-ribohexopyranosyloxy) -11-G- methylazithromycin with the following physico-chemical constants:

IR (CDC1 ₃₎ ^cm-1: 3471.2975, 1715, 1638, 1458, 1382, 1196, 1117, 1049, 1013.963.

1 HNMR (300MHz, CDCl ₃ ), δ: 5.01 (H-13), 4.22 (H-1 '), 3.80 (H-5), 3.50 (H-5'), 3 .45 (II-OCH 3), 3.25 (H-2 '), 2.63 (H-2), 2.49 (H-3'), 2.77 (H-9a), 2.29 (H-2 ') 3'N (CH ₃ ) ₂ ), 2.20 (9a-NCH ₃ ), 2.24 (H-9b), 2.09 (H-4), 1.85 (H-8), 1.83 (H-14a), 1.66 (H-4'a), 1.73 (H-14b), 1.36 (6-CH 3), 1.31 (2-CH ₃ ), 1.26 (H) -4'b), 1.21 (5'-CH _3), 1.25 _(4-CH3), 1.01 (10-CH _3), 1.03 (8-CH _3), 0.81 (14-CH _3).

¹³ CNMR (75 MHz, CDCl ₃ ), δ: 177.0 (Cl), 106.2 (C-1 '), 102.1 (C-3), 93.9 (C-5), 86.1 (Cl 1), 81.9 (C-6), 69.7 (C-2 '), 64.9 (C-9), 65.8 (C-3'), 62.1 (C-10) ), 61.9 (11-OCH ₃ ), 49.6 (C-2), 43.3 (C-7), 40.1 (3'N (CH ₃ ) ₂ ), 28.1 (C- 4 '), 28.7 (C-8), 25.5 (6-CH ₃ ), 20.9 (5'-CH ₃ ), 14.0 (2-CH ₃ ),

11.7 (14-CH _3), 12.3 _(4-CH3), 8.5 (1 O-CH _3).

Example 14

3-De (2,6-dideoxy-3-C-methyl-3-G-methyl-E-Z-L-ribohexopyranosyloxy) -3-oxy-azithromycin

3-De (2,6-dideoxy-3 -C-methyl-3-O-methyl-α-L-ribohexopyranosyloxy) -3-oxyazithromycin was prepared from azithromycin by the method of Djokic et al. from U.S. Pat. No. 4,886,792 to 12/1989, Example 3. Separation on a silica gel column using a methylene chloride: methanol: conc. ammonia 90: 9: 0.5 yielded a chromatographically uniform product with the following physicochemical constants:

TLC, ethyl acetate: triethylamine, 95: 5 Rf 0.371

IR (KBr), cm ^-1 : 3438, 2973, 2938, 1713, 1655, 1459, 1378, 1350, 1260, 1172, 1113, 1078, 1044, 957.

1 H NMR (300MHz, CDCl ₃ ), δ: 4.72 (H-13), 4.47 (H-1 '), 3.78 (H-3), 3.58 (H-5), 3 56 (H-5 '), 3.65 (H-11), 3.27 (H-2'), 2.66 (H-2), 2.74 (H-10), 2.52 (H-10 ') H-3 '), 2.49 (H-9a), 2.28 (H-4), 2.26 (3'N (CH ₃ ) ₂ ), 2.37 (9a-NCH ₃ ), 2, 06 (H-9b), 1.90 (H-14a), 1.90 (H-8), 1.67 (H-4'a), 1.62 (H-7a), 1.47 (H) -7b), 1.53 (H-14b), 1.32 (6-CH ₃ ), 1.30 (2-CH ₃ ), 1.28 (H-4'b), 1.26 (5 ') CH _3), 1.07 (12-CH _3), l, 06 _(4-CH3), 1.12 (10-CH _3), 0.92 (8-CH3), 0.88 (M- CH3).

¹³ CNMR (75 MHz, CDCl 3), δ: 178.8 (Cl), 106.6 (C-1 '), 94.7 (C-5), 72.9 (C-12), 79.2 ( C-3),

75.5 (C-11), 77.1 (C-13), 74.0 (C-6), 70.3 (C-2 '), 70.6 (C-9), 65.4 (C- 3 '), 62.2 (C-10), 44.2 (C-2), 41.7 (C-7), 35.6 (C-4), 39.9 (3'N (CH _{3)) 12} ), 36.8 (9a-NCH ₃ ), 27.7 (C-4 '), 26.3 (C-8), 25.5 (6-CH 3), 20.8 (8-CH ₃₎ ), 20.5 (C-14), 20.9 _(5'-CH3), 15.7 _(12-CH3), 15.8 _(2-CH3), 10.5 (14-CH ₃ )

7.5 _(4-CH3), 7.3 (10-CH _3).

Example 15 '- (9-Acetate of 3-de (2,6-dideoxy-3 -C-methyl-3- (9-methyl- α-L-ribohexopyranosyloxy) -3-oxyazithromycin)

To a solution of 3-de (2,6-dideoxy-3-C-methyl-3- (9-methyl- <2 L-ribohexopyranosyl-oxy) -3-oxyazithromycinu (10 g) from Example 14 in CH ₂ C1 ₂ (150 mL) was added NaHCO ₃ (5.84 g) and acetic anhydride (1.68 mL) The reaction mixture was stirred at room temperature for 12 hours, allowed to stand overnight and then isolated as described in Example 5 to give 11.21 g of amorphous precipitate with the following physicochemical constants:

TLC, ethyl acetate: diethylamine, 95: 5 Rf 0.547

IR (KBr), cm ^-1 : 3485, 2973, 2937, 1748, 1716, 1648, 1459, 1376, 1240, 1170, 1114, 1081, 1045, 956.

N HNMR (300 MHz, CDCl ₃ ), δ: 4.71 (H -13), 4.79 (H-2 '), 4.71 (H-1'), 3.84 (H-3), 3.61 (H-5), 3.50 (H-5 ') ), 3.68 (H-11), 2.73 (H-10), 2.70 (H-2), 2.70 (H-3 '), 2.48 (H-9a), 2.27 ( H-4), 2.26 (3'-N _{(CH3) 2),} 2.36 (9a-NCH _3), 2.07 (COC7%), 2.05 (H-9b), 1.90 ( H-14a), 1.90 (H-8), 1.78 (H-4'a), 1.56 (H-7a), 1.24 (H-7b), 1.54 (H-14b) ), 1.23 _(6-CH3), 1.29 _(2-CH3), 1.32 (H-4'b), 1.24 _(5'-CH3), 1.11 (1O- CH ₃ ), 1.06 (12-CH ₃ ), 0.90 (4-CH ₃ ), 0.89 (8-CH ₃ ), 0.88 (14-CH ₃ ).

Example 16

3-de (2,6-dideoxy-3-C-methyl-3-O-methyl-α-L-ribohexopyranosyloxy) 3,6-hemiketal-2'-O-acetate azithromycin

To a solution of 2 '- <9-acetate 3-de (2,6-dideoxy-3-C-methyl-3- (9-methyl-.alpha.) - (&lt; / RTI &gt; from Example 15 in CH 2 Cl 2 (100 mL) was added dimethylsulfoxide (12.34 mL) and ΛζΝ-dimethylaminopropylethylcarbodiimide (15.05 g). The reaction mixture was cooled to 15 ° C and then a solution of pyridinium trifluoroacetate (15.04 g) in CH ₂ Cl ₂ (30 mL) was gradually added dropwise over 30 minutes while stirring and maintaining the temperature at 15 ° C. The temperature of the reaction mixture was raised to room temperature, stirred for an additional 4 hours, and then the product was isolated according to the procedure described in Example 6 to give 5.26 g of the title product.

TLC, ethyl acetate: triethylamine, 95: 5 Rf 0.675

Example 17

3-de (2,6-dideoxy-3-C-methyl-3- (9-methyl-cis-L-ribohexopyranosyloxy)) azithromycin 3,6-hemiketal

A solution of 3-de (2,6-dideoxy-3-C-methyl-3- (p-methyl-α-L-ribohexopyranosyloxy) -azithromycin 3,6-hemiketal-2'-n-acetate acetate (5.2 g) ) from Example 16 in methanol (100 ml) was allowed to stand at room temperature for 16 hours, methanol was evaporated under reduced pressure and the product was purified by low pressure silica gel column chromatography using methylene chloride: methanol: conc. ammonia 90: 9: 1, 5. Evaporation of the combined fractions with an Rf of 0.480 yielded chromatographically uniform 3,6-hemiketal of 3-de (2,6-dideoxy-3-C-methyl-3-O-methyla-L-ribohexopyranosyloxy) azithromycin with the following physical: chemical constants:

• · · · φ · φ · · · · · · · · ·

TLC, ethyl acetate: triethylamine, 95: 5 Rf 0.447

IR (CDCl 3), cm ^-1 : 3468, 2976, 1713, 1638, 1459, 1382, 1197, 1116, 1068, 1049, 1014, 963.

1 HNMR (300 MHz, CDCl 3), δ: 4.94 (H-13), 4.21 (H-1 '), 3.74 (H-5), 3.51 (H-5'), 3 23 (H-2 '), 2.57 (H-2), 2.49 (H-3'), 2.23 (3'N (CH ₃ ) ₂ ), 2.06 (H-4) , 1.74 (H-8), 1.67 (H-4'a), 1.39 (6-CH ₃ ), 1.28 (2-CH ₃ ), 1.25 (H-4'b) ), 1.22 (5'-CH _3), 1.23 _(4-CH3), 1.10 (10-CH _3), 1.04 (8-CH _3), 0.92 (14-CH ₃ ).

¹³ CNMR (75 MHz, CDCl ₃ ), δ: 176.9 (Cl), 106.1 (C-1 '), 102.3 (C-3), 94.8 (C-5), 82.4 (C-6)

69.7 (C-2 '), 68.5 (C-11), 66.4 (C-9), 65.3 (C-3'), 61.6 (C-10), 49.3 (C-2), 41.6 (C-7), 40.1 (3'N (CH ₃ ) ₂ ), 31.0 (C-8), 28.2 (C-4 '), 26, 4 (6-CH ₃ ), 20.8 (5'-CH ₃ ), 13.6 (2-CH ₃ ), 12.6 (4-CH ₃ ), 11.4 (14-CH ₃ ).

FAB-MS m / z 589;

Example 18

3-de (2,6-dideoxy-3-C-methyl-3- (9-methyl-.alpha.-L-hexohexopyranosyl-oxy) -azithromycin 3,6-hemiketal-11,12-cyclic carbonate

To a solution of 3-de (2,6-dideoxy-3-C-methyl-3-O-methyl-.alpha.-L-hexohexopyranosyloxy) -azithromycin 3,6-hemiketal (1 g) from Example 17 in ethyl acetate (30 mL) ethylene carbonate (0.5 g) and potassium carbonate (0.5 g) were added. The reaction mixture was stirred at reflux for 10 hours, allowed to stand for 16 hours at room temperature and then filtered. The ethyl acetate solution was washed with saturated NaCl solution and water, dried over CaCl ₂ , filtered and evaporated to give 1.05 g of an oily residue. After separation on a silica gel column using methylene chloride: methanol: conc. ammonia 90: 9: 0.5 gave a chromatographically uniform title product with the following physicochemical constants:

TLC, ethyl acetate: triethylamine, 95: 5 Rf 0.514

IR (CDCl 3), cm ^-1 : 3498, 2975, 2941, 1812, 1724, 1638, 1459, 1381, 1359, 1333, 1292, 1234, 1113, 1115, 1082, 1045, 1015, 966.

9 »·

9 · »

9 · · ·

9 9

9 *

9 9 · · ··

H NMR (300MHz, CDC1 ₃₎ δ: 5.03 (H-13), 4.61 (H-ll), 4.23 (Η-Γ), 3.73 (H-5), 3.52 ( H-5 ')

3.25 (H-2 '), 3.18 (H-9a), 2.90 (H-10), 2.54 (H-2), 2.50 (H-3'), 2.28 (3'N (CH ₃ ) ₂ ), 2.10 (H-4), 2.07 (9a-NCH ₃ ), 1.76 (H-7a), 1.95 (H-8), 1, 86 (H-14a), 1.67 (H-4'a), 1.57 (H-9b),

1.55 (H-14b), 1.45 (12-CH ₃ ), 1.37 (6-CH 3), 1.30 (2-CH ₃ ), 1.28 (H-4'b), 1 23 (5'-CH ₃ ), 1.24 (4-CH ₃ ), 1.13 (H-7b), 1.18 (10-CH ₃ ), 0.90 (8-CH ₃ ), 0 92 _(14-CH3).

¹³ C NMR (75 MHz, CDCl ₃ ), δ: 176.1 (Cl), 153.5 (C = O carbonate), 106.1 (C-1 '), 101.6 (C-3), 93 , 6 (C-5), 83.7 (C-12), 82.7 (C-6), 78.9 (C-11), 77.9 (C-13), 69.6 (C- 2 '), 69.4 (C-5'), 63.6 (C-9), 65.3 (C-3 '), 60.1 (C-10), 49.9 (C-2) 46.6 (C-4), 41.8 (C-7), 40.0 (3'N (CH ₃ ) ₂ ), 33.4 (9a-CH ₃ ), 28.0 (C-4) 26.8 (C-8), 25.1 (6-CH ₃ ), 22.3 (C-14), 20.8 (5'-CH ₃ ), 19.4 (8-CH ₃₎ ), 14.1 (12-CH _3), 13.9 _(2-CH3), 12.1 (4-CH3), 12.9 (10-CH _3), 10.1 (14-CH ₃₎ .

Claims (23)

A compound of general formula (I) wherein R 1 is ^: denotes a hydroxyl or L-cladnosyl group according to formula (II) wherein R ² denotes hydrogen or a silyl group, q z R is hydrogen or - together with R - an ether group, R ⁴ is hydrogen, a C 1 -C 4 acyl group, or a -COO- (CH 2) _n -Ar group, wherein _n is 1 to 7aAr is an unsubstituted or substituted aryl group having up to 18 carbon atoms, R ⁵ denotes hydrogen, methyl or -COO- (CH 2) _n -Ar where n is 1 to 7 and Ar represents an unsubstituted or substituted aryl group having up to 18 carbon atoms, R ⁶ denotes a hydroxyl group or - together with R ³ - denotes an ether group, R ⁷ denotes hydrogen, a C 1 -C 12 alkyl group, a silyl group or - together with R ⁸ and Cl 1 / C-12 carbon atoms - denotes a cyclic carbonate, R ⁸ denotes hydrogen, a C 1 -C 12 alkyl group, a silyl group, or - together with R ⁷ and C 1 / C-12 carbon atoms - denotes a cyclic carbonate, 9 · · ······ 9 And their pharmaceutically acceptable addition salts with inorganic or organic acids. A compound according to claim 1, wherein R ¹ is L-Cladinosyl, R ² and R ⁷ are the same and denote trimethylsilyl, R ³ and R ⁸ are the same and denote hydrogen, R ⁴ and R ⁵ are the same and denote benzyloxycarbonyl and R ⁶ is a hydroxyl group. The compound of claim 1, wherein R represents L-Cladinosyl, R trimethylsilyl, R, R and R are the same and denote hydrogen, R and R are the same and denote a benzyloxycarbonyl group, and R ⁶ is a hydroxyl group. A compound according to claim 1, wherein R ¹ represents L-Cladinosyl, R ² and R ⁷ are the same and denote trimethylsilyl, R ³ represents hydrogen R ⁴ and R ⁵ are the same denote benzyloxycarbonyl, R is hydroxyl and R is methyl. A compound according to claim 1, wherein R ¹ is an L-Cladinosyl group, R ² represents a trimethylsilyl group, R ³ and R ⁸ are the same and denote hydrogen, R ⁴ and R ⁵ are the same and denote a benzyloxycarbonyl group, R represents a hydroxyl group and R is methyl. A compound according to claim 1, wherein R ¹ is L-cladinosyl, R ^{2 is} trimethylsilyl, R ³ and R ⁷ are the same and denote hydrogen, R ⁴ and R ⁵ are the same and denote a benzyloxycarbonyl group, R ⁶ is a hydroxyl group and R ⁸ is methyl. A compound according to claim 1, wherein R ¹ represents L-cladinosyl, R ² , R ³ , R ⁴ , R ⁵ and R ⁷ are the same and denote hydrogen, R ⁸ is methyl and R ⁶ is hydroxyl. A compound according to claim 1, wherein R ¹ is an L-Cladinosyl group, R ² , R ³ , R ⁴ and R ⁷ are the same and denote hydrogen, R ⁵ and R ⁸ are the same denote methyl and R ⁶ is a hydroxyl group . A compound according to claim 1, wherein R ¹ and R ⁶ are the same and denote a hydroxyl group, R ³ , R ⁴ and R ⁸ are the same denote hydrogen and R ⁵ and R ⁷ are the same denote methyl. A compound according to claim 1, wherein R ¹ and R ⁶ are the same and denote a hydroxyl group, R ³ , R ⁴ and R ⁷ are the same and denote hydrogen and R ⁵ and R ⁸ are the same denote methyl. The compound of claim 1, wherein R ¹ and R ⁶ are the same and denote a hydroxyl group, R ³ , R ⁷ and R ⁸ are the same and denote hydrogen, R ⁴ is acetyl and R ⁵ is methyl. A compound according to claim 1, wherein R ¹ and R ⁶ are the same and denote a hydroxyl group, R ³ and R ⁸ are the same and denote hydrogen, R ⁴ is acetyl and R ⁵ and R ⁷ are the same denote methyl. A compound according to claim 1, wherein R ¹ and R ⁶ are the same and denote a hydroxyl group, R ³ and R ⁷ are the same and denote hydrogen, R ⁴ is acetyl and R ⁵ and R ⁸ are the same denote methyl. • · I ί ·· \ A compound according to claim 1, wherein R represents a hydroxyl group, R together with R 0 represent an ether group, R ⁴ is acetyl, R ⁵ is methyl, R ⁷ and R ⁸ are the same and denote hydrogen. A compound according to claim 1, wherein R ¹ represents a hydroxyl group, R ³ together with R ⁶ represent an ether group, R ⁴ is acetyl, R ⁵ and R ⁷ are the same and denote methyl, and R ⁸ is hydrogen. A compound according to claim 1, wherein R is a hydroxyl group, R together with R represent an ether group, R ⁴ is acetyl, R ⁵ and R ⁸ are the same and denote methyl and R ⁷ is hydrogen. A compound according to claim 1, wherein R ¹ represents a hydroxyl group, R ³ together with R ⁶ represent an ether group, R ⁴ , R ⁷ and R ⁸ are the same and denote hydrogen, and R ⁵ is methyl. A compound according to claim 1, wherein R ¹ represents a hydroxyl group, R ³ together with R ⁶ represent an ether group, R ⁴ and R ⁸ are the same and denote hydrogen and R ⁵ and R ⁷ are the same denote methyl. A compound according to claim 1, wherein R ¹ represents a hydroxyl group, R ³ together with R ⁶ represent an ether group, R ⁴ and R ⁷ are the same and denote hydrogen and R ⁵ and R ⁸ are the same denote methyl. A compound according to claim 1, wherein R represents a hydroxyl group, R together with R represents an ether group, R ⁴ is hydrogen, R ⁵ is methyl, and R ⁷ and R ⁸ together with the Cl 1 / C-12 carbon atoms denote a cyclic carbonate . A process for the preparation of compounds of formula (I) wherein R ¹ denotes a hydroxyl or L-cladnosyl group according to formula (II) (9) wherein R ² denotes hydrogen or a silyl group, R ³ denotes hydrogen or - together with R ⁶ - an ether group, R ⁴ represents hydrogen, a C 1 -C 4 acyl group or a -COO- (CH 2) _n -Ar group, wherein n is 1 to 7 and Ar represents an unsubstituted or substituted aryl group having up to 18 carbon atoms, R ⁵ denotes hydrogen, methyl or -COO- (CH ₂ ) _n -Ar where n is 1 to 7 and Ar represents an unsubstituted or substituted aryl group having up to 18 carbon atoms, R ⁶ denotes a hydroxyl group or - together with R ³ - denotes an ether group, R ⁷ denotes hydrogen, a C 1 -C 12 alkyl group, a silyl group or - together with R ⁸ and Cl 1 / C-12 carbon atoms - denotes a cyclic carbonate, R ⁸ denotes hydrogen, a C 1 -C 12 alkyl group, a silyl group or - together with R ⁷ and Cl 1 / C-12 carbon atoms - denotes a cyclic carbonate, and their pharmaceutically acceptable addition salts with inorganic or organic acids, characterized in that 1 9 (I) an azithromycin of formula (I) wherein R represents an L-Cladinosyl group of formula (II), R ³ , R ⁴ , R ⁷ and R ⁸ are the same and denote hydrogen, R ⁵ is methyl and R ⁶ is hydroxyl, it is reacted with organic carboxylic acid chlorides of formula (III) ClCOO (CH ₂ ) _n -Ar (III) wherein n is 1 to 7 and Ar represents an unsubstituted or substituted aryl group of up to 18 carbon atoms, preferably with benzyloxycarbonyl chloride, in the presence of bases, preferably sodium bicarbonate, in an inert solvent, with preferably in benzene or toluene, to form a compound of formula (I) wherein R ¹ represents an L-Cladinosyl group of formula (II), R ² , R ³ , R ⁷ and R ⁸ are the same and denote hydrogen, R ⁴ and R ⁵ are the same and denote a benzyloxycarbonyl group and R ⁶ is a hydroxyl group, and the compound is subjected to selective silylation of the hydroxyl groups a) in the 4 'and 11 positions, a two to five-fold molar excess of a silylating agent, preferably a mixture of trimethylsilyl chloride and trimethylsilylimidazole, in an inert organic solvent such as pyridine, ethyl acetate, N-dimethylformamide or methylene chloride, preferably pyridine, at 0-5 ° C over 5 to 8 hours to give a compound of general formula 9 Of formula (I) wherein R ¹ represents the L-Cladinosyl group of formula (II), R ² and R ⁷ are the same and denote trimethylsilyl, R ³ and R ⁸ are the same and denote hydrogen, R ⁴ and R ⁵ are the same denote a benzyloxycarbonyl group and R ⁶ is a hydroxyl group, or b) in the 4 'position, with a 1.1 to 2-fold molar excess of the silylating agent, in an inert organic solvent, at temperatures of 0 to 5 ° C, over one hour to give a compound of formula (I) wherein R represents L- a cladinosyl group of formula (II), R represents a trimethylsilyl group, R ³ , R ⁷ and R ⁸ are the same and denote hydrogen, R ⁴ and R ⁵ are the same denote a benzyloxycarbonyl group and R ⁶ denotes a hydroxyl group, then undergoes O-alkylation A 1.3 to 10-fold molar excess of the appropriate alkylating agent, preferably methylating agent, preferably methyl iodide, in the presence of 1.1 to 8.5 moles of a suitable alkali metal hydride base, preferably sodium hydride, in an inert solvent such as dimethylsulfoxide, tetrahydrofuran , N, N-dimethylformamide or a mixture thereof, at temperatures from -15 ° C to room temperature, preferably at 0 to 5 ° C, to form, in the case of (a), a compound of formula (I) wherein R ¹ represents an L-Cladinosyl group of formula (II), R ² and R ⁷ are the same and denote trimethylsilyl, R ³ is hydrogen, R ⁴ and R ⁵ are the same and denote benzyloxycarbonyl, R ⁶ is a hydroxyl group and R ⁸ is methyl or, in the case of b), a mixture of a compound of formula (I) wherein R ¹ represents an L-cladinosyl group of formula (Π), R ² represents trimethylsilyl, R ³ and R ⁸ are the same and denote hydrogen, R ⁴ and R ⁵ are the same denote a benzyloxycarbonyl group, R ⁶ represents a hydroxyl group and R ⁷ is a methyl group, and compounds of formula (I) wherein R ¹ represents an L-cladinosyl group of formula (Π) , R denotes trimethylsilyl, R and R are the same and denote hydrogen, R ⁴ and R ⁵ are the same denote benzyloxycarbonyl, R ⁶ represents the hydroxyl group and R ⁸ is methyl, which are then subjected to deprotection at the positions 2 'and 3' in diff flow in lower alcohols, preferably ethanol, in the presence of a NaOAc / HOAc buffer (pH 5) and a catalyst in a hydrogen atmosphere at a pressure of 0.1 to 2.0 MPa, and then, after isolation, desilylation at the 4 ”and 11 positions solution in lower alcohols, preferably isopropanol, in the presence of formic acid, which, in case of a), gave a compound of formula (I) wherein R ¹ represents an L-cladinosyl group of formula (II), R ² , R ³ , R ⁴ , R ⁵ and R ⁷ are the same to denote hydrogen, R ⁶ is a hydroxyl group, and R ⁸ is a methyl group, or, In the case of (b), a mixture of a compound of the general formula (II); of formula (I) wherein R ¹ represents an L-Cladinosyl group of formula (Π), R ² , R ³ , R ⁴ , R ⁵ and R ⁸ are the same and denote hydrogen, R ⁶ is a hydroxyl group and R ⁷ is a methyl group, and compounds of formula (I) wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁷ and R ⁸ have the same meaning as in the deprotection of a) that are subjected to reductive 3'-N-methylation with one up to three equivalents of formaldehyde (37%) in the presence of the same or twice as much formic acid (98-100%) and a hydrogenation catalyst or some other hydrogen source, in an inert solvent, preferably chloroform, at elevated temperature, preferably reflux temperature; to form, in case a), a compound of formula (I) wherein R ¹ has the meaning of the L-Cladinosyl group of formula (Π), R ² , R ³ , R ⁴ and R ⁷ are the same and denote hydrogen, R ⁵ and R ⁸ are the same and denote methyl and R ⁶ is a hydroxyl group, or, in the case of b), a mixture of a compound of formula (I) wherein R ¹ has the meaning of an L-cladinosyl group of formula (Π), R ² , R ³ , R ⁴ and R ⁸ are the same and denote hydrogen, R ⁵ and R ⁷ are the same and denote methyl and R ⁶ is hydroxyl and the compounds of formula (I) wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁷ and R ⁸ have the same meaning as in the 3'-N-methylation in case a), which mixture it is then optionally subjected to separation on a silica gel column to give a chromatographically uniform compound of formula (I) in which R is an L-cladmosyl group, R, R ³ , R ⁴ and R ⁸ are the same and denote hydrogen, R ⁵ and R ⁷ are the same and denote methyl and R ⁶ represents a hydroxyl group (10-methylazithromycin) and a compound of formula (I) wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ have the same meaning as in the 3'-N-methylation of (a) (12-O-azithromycin), or that II) azithromycin or its 11-O-methyl and 12-O-methyl derivatives obtained by method I) are optionally subjected to a hydrolytic reaction with dilute inorganic acids, preferably 0.25 N hydrochloric acid, to form a compound of formula (I), wherein R ¹ and R ⁶ are the same and denote a hydroxyl group, R ³ , R ⁴ , R ⁷ and R ⁸ are the same denote hydrogen and R ⁵ is methyl, or compounds of formula (I) wherein R ¹ and R 6 ⁶ are the same and denote a hydroxyl group, R ³ , R ⁴ and R ⁸ are the same and denote hydrogen, and R ⁵ and R ⁷ are the same denote methyl, or the compounds of formula (I) wherein R ¹ and R ⁶ are the same and denote a hydroxyl group, R ³ , R ⁴ and R ⁷ are the same and denote hydrogen, and R ⁵ and R ⁸ are the same denote methyl, which are then optionally subjected to a selective acylation reaction of the hydroxyl group at the 2'-position acids containing up to four carbon atoms, «· · Preferably acetic anhydride, in an inert organic solvent, preferably in methylene chloride to form a compound of formula (I) wherein R ¹ and R ⁶ are the same and denote a hydroxyl group, R ³ , R ⁷ and R ⁸ are the same denote hydrogen, R ⁴ is acetyl and R ⁵ is methyl, or compounds of formula (I) wherein R ¹ and R ⁶ are the same to denote a hydroxyl group, R ³ and R ⁸ are the same to denote hydrogen, R ⁴ is acetyl and R ⁵ and R ⁷ are the same to denote methyl, or compounds of formula (I) in which R ¹ and R ⁶ are the same and denote a hydroxyl group, R ³ and R ⁷ are the same and denote hydrogen, R ⁴ is acetyl and R ⁵ and R ⁸ are the same denote methyl which are then optionally subjected to Jones reagent oxidation or according to a modified Moffat-Pfitzner process, preferably ΛζΑ-dimethylaminopropylethylcarbo diimidern, in the presence of dimethylsulfoxide and pyridinium trifluoroacetate as a catalyst, in an inert organic solvent, preferably methylene chloride, at temperatures from 10 ° C to room temperature, to give a compound of formula (I) wherein R ¹ is hydroxyl, R ³ together with R ⁶ represent an ether group, R ⁴ is acetyl, R ⁵ is methyl, R ⁷ and R ⁸ are the same and denote hydrogen, or compounds of formula (I) wherein R ¹ is a hydroxyl group, R ³ together with R 6 R ⁶ is an ether group, R ⁴ is acetyl, R ⁵ and R ⁷ are the same to denote methyl and R ⁸ is hydrogen, or compounds of formula (I) wherein R ¹ represents a hydroxyl group, R ³ together with R ⁶ denotes an ether group R ⁴ is acetyl, R ⁵ and R ⁸ are the same and denote methyl and R ⁷ is hydrogen, which are then subjected to the deacylation reaction at the 2 'position by solvolysis in lower alcohols, preferably methanol, at room temperature to form compounds of formula (I) wherein R ¹ is a hydroxyl group, R ³ together with R ⁶ is an ether group, R ⁴ , R ⁷ and R ⁸ are the same and denote hydrogen and R ⁵ is methyl, or compounds of the formula (I) wherein R ¹ represents a hydroxyl group, R ³ together with R ⁶ represent an ether group, R ⁴ and R ⁸ are the same and denote hydrogen and R and R are the same denote methyl, or compounds of formula (I) wherein R 1 ¹ has the meaning of a hydroxyl group, R ³ together with R ⁶ denote an ether group, R ⁴ and R ⁷ are the same and denote hydrogen and R ⁵ and R ⁸ are the same denote methyl, and then the compounds of formula (I) wherein R ¹ denotes a hydroxyl group, R ³ together with R ⁶ represent an ether group, R ⁴ , R ⁷ and R ⁸ are the same and denote hydrogen and R ⁵ is methyl which are optionally reacted with ethylene carbonate in the presence of inorganic or organic bases, preferably carbonate potassium in an inert solvent, preferably in ethanol ethyl acetate, to give a compound of formula (I) wherein R ¹ is hydroxyl, R ³ together R ⁶ is ether, R ⁴ is hydrogen, R ⁵ is methyl, and R ⁷ and R ⁸ together with C-11 / C-12 carbon atoms mean cyclic carbonate. ···· · * A pharmaceutical composition useful in the treatment of bacterial infections in both humans and animals comprising antibacterially effective amounts of a compound of formula (I) or a pharmaceutically acceptable addition salt thereof according to claim 1 in combination with a pharmaceutically acceptable carrier. 23. A method of treating bacterial infections in humans and animals, comprising administering to the human or animal an antibacterially effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof with the inorganic or organic acids of claim 1 in combination with a pharmaceutically acceptable carrier.