3,6-hemiketals from the class of 9A-azalides

Details 3,6-hemiketals from the class of 9A-azalides 3,6-hemiketals from the class of 9A-azalides

2000-04-17

2002-04-09

Peselev, Elli (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C536S007400

Reexamination Certificate

active

06369035

ABSTRACT:

TECHNICAL FIELD OF THE INVENTION
A61 K 31/70, C 07 H 17/08
TECHNICAL PROBLEM
The invention relates to novel compounds from the class of macrolide antibiotics. Particularly, the invention relates to novel 3,6-hemiketals from the class of 9a-azalides, to their pharmaceutically acceptable addition salts with inorganic or organic acids, to a process for their preparation and to the use thereof as antibiotics or as intermediates for the synthesis of other macrolide antibiotics.
PRIOR ART
Macrolide antibiotic erythromycin A has been for more than 40 years considered as a safe and efficient agent for the treatment of respiratory and genital infections caused by Gram-positive and by some Gram-negative bacteria, some species of Legionella, Mycoplasma, Chlamidia and Helicobacter. Noticed changes in bioavailability after oral administration, gastric intolerance in many patients and loss of activity in an acidic medium whereat the inactive metabolite anbydroerythromycin is formed are basic disadvantages in the clinical use of eiythromycin. However, the spirocyclization of the aglycone ring is successfully inhibited by a chemical transformation of C-9 ketone or hydroxyl groups in C-6 and/or C-12 positions. Thus, e.g by oximation of C-9 ketone and subsequent Beckmann rearrangement and reduction, 9-deoxo-9a-aza-9a-homoerythromycin A, the first 15-membered macrolide antibiotic with 9a-amino group incorporated in the aglycone ring, is obtained (Kobrehel G. et al., U.S. Pat. No. 4,328,334; May 1982). By reductive methylation of 9-amines according to Eschweiler-Clark process, 9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin (AZITHROMYCIN), a prototype of a novel class of macrolide antibiotics, namely azalides, is synthesized (Kobrehel G. et al., BE 892357; July 1982). In addition to a broad antimicrobial spectrum including also Gram-negative bacteria, azithromycin is also characterized by a long biological half-life, a specific transport mechanism to the place of use and a short therapy period. Azithromycin easily penetrates and it accumulates inside human phagocyte cells resulting in an improved action upon intracellular pathogenic micro-organisms from the classes of Legionella, Chlamidia and Helicobacter.
Further, it is known that C-6/C-12 spirocyclization of erythromycin A is successfully inhibited by O-methylation of C-6 hydroxyl group of the aglycone ring (Watanabe Y. et al., U.S. Pat. No. 4,331,803; May 1982). By the reaction of erythromycin with benzyloxycarbonyl chloride and subsequent methylation of the obtained 2′-O,3′-N-bis(benzyloxycarbonyl) derivative, by elimination of the protecting groups and by 3′-N-methylation, there are formed, in addition to 6-O-methylerythromycin (CLARITHROMYCIN), also significant amounts of 11-O-methylerythromycin and of multiple-substituted analogs (Morimoto S., et al., J. Antibiotics, 1984, 37, 187). With respect to erytlromycin A, clarithromycin is considerably more stable in an acidic medium and exhibits better in vitro action with respect to Gram-positive bacteria strains (Kirst H. A. et al., Antimicrobial Agents and Chemoter., 1989, 1419). In a similar manner also a series of O-methyl-derivatives of azithromycin (Kobrehel G. et al., U.S. Pat. No. 5,250,518; October 1993) was synthesized. Although the main products of O-methylation of azithromycin, namely 11-O-methyl-azithromycin (Example 8) and 6-O-methyl-azithromycin (Example 6) exhibit significant activity against standard bacteria strains and clinical isolates and pharmacokinetic properties similar to those of azithromycin, the obtaining of products in larger quantities represents an additional technical problem due to nonselectivity of O-methylation. The determination of the structure of O-methyl-derivatives of azithromycin was based on analysis of
1
H-
1
H and
1
H-
13
C 2D NMR spectra (300 MHz). Subsequently, it was additionally determined by long-range NMR spectroscopy that substitution on C-6 hydroxyl group had been erroneously ascribed to azithromycin and that actually 12-O-methyl-azithromycin was in question. Further it has been found that the use of suitable protecting groups on hydroxyl groups in 4″- and 11-positions (especially of silyl protecting groups such as trimethylsilyl groups) results in selective O-methylation and makes possible a simple preparation of 12-O-methyl-azithromycin (HR 970051A; October 1997). Later, Waddell S. T. et al., (Biorg. Med. Chem. Letters 8 (1998), 549-555), independently of the latter patent application, established O-methylation of hydroxyl group in C-12 position.
It is known as well that recent research on 14-membered macrolides has lead to the discovery of a new type of macrolide antibiotics, namely ketolides. Instead of the neutral sugar L-cladinose known for its unstability even in a weakly acidic medium, these compounds possess a keto group on C-3 position (Agouridas C. et al., EP 596802 A1, May 1994; Le Martret O., FR 2697524 A1, May 1994). Ketolides show a significantly better action against MLS (macrolide, lincosamide and streptogramin B) induced-resistant organisms (Jamjian C., Antimicrob. Agents Chemother., 1997, 41, 485). This important discovery has led to a large number of 3-keto derivatives of clarithromycin, mostly substituted on C-11/C-12 positions, yielding numerous cyclic carbonates, carbamates and, recently, carbazates. The first step of the synthesis of ketolides includes the hydrolysis of clarithromycin under the formation of a corresponding 3-decladinosyl derivative, (3-de(2,6-dideoxy-3-C-methyl-3-O-methyl-&agr;-L-ribohexopyranosyl-oxy)-derivative), which is, after the removal of the protection of 2′-hydroxyl group (preferably by acylation with chlorides or anhydrides of carboxylic acids), subjected to a reaction of oxidation and deprotection of 2′- position. According to our knowledge C-11/C-12 substituted ketolides from the class of 9a-azalide antibiotics have hitherto not been described. The first step, namely the synthesis of 3-decladinosyl-derivatives of 9-deoxo-9a-aza-9a-homoerydiromycin and azithromycin, is described in U.S. Pat. No. 4,886,792, December 1989. With intention to oxidize C-3 hydroxyl group of 3-decladinosyl-azithromycin and its 11-O-methyl- and 12-O-methyl-derivatives by transannular addition of 6-hydroxyl group onto the newly formed C-3 ketone there has been obtained a hitherto not described series of bicyclic and tricyclic 3,6-hemiketals from the class of 9a-azalides.
The synthesis of 3,6-hemiketals of azithromycin and O-methyl derivatives thereof comprises the preparation of corresponding 3-decladinosyl derivatives, the protection of 2′-hydroxyl group of the basic sugar, D-desosamine, by selective acylation, the oxidation of the hydroxyl group in C-3 position, the deprotection of 2′-position and the cyclization of C-11 and C-12 hydroxyl groups. Objects of the present invention are also pharmaceutically acceptable addition salts of 3,6-hemiketals of azithromycin and its O-methyl derivatives with organic and inorganic acids, methods and intermediates for their preparation, as well as preparation and application methods of pharmaceutical preparations.
DESCRIPTION OF TECHNICAL PROBLEM WITH EXAMPLES
The invention relates to
i) novel 3,6-hemiketals from the class of 9a-azalides,
ii) a process for the preparation of novel 3,6-hemiketals from the class of 9a-azalides.
iii) use of novel 3,6-hemiketals from the class of 9a-azalides as antibiotics or as intermediates for the synthesis of other macrolide antibiotics.
Novel 3,6-hemiketals from the class of 9a-azalides of the general formula (I)
characterized in that
R
1
individually stands for hydroxyl, L-cladinosyl group of the formula (II)
wherein
R
2
individually stands for hydrogen or a silyl group,
R
3
individually stands for hydrogen or together with R
6
stands for an ether group,
R
4
individually stands for hydrogen, (C
1
-C
4
)acyl group or —COO—(CH
2
)
n
—Ar group, wherein n is 1-7 and Ar individually stands for an unsubstituted or substituted aryl group with up to 18 carbon atoms,
R
5
individually stands for hyd

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