The title compound (IV) can be obtained by Eschweiler‐Clarke methylation of the azaerythromycin derivative (I).

The synthesis of 10-dihydro-10-deoxo-l l -azaerythromycin A (1 1 ) by the Beckmann rearrangement of erythromycin A oxime (2) and reduction of the imino ether so obtained (5) is described. The structure elucidation of the new ring-expanded semisynthetic erythromycins (5) and (1 1 ) has been established on the basis of their analytical and spectral data and acid-catalysed degradation into the aglycones (7) and (1 3), respectively. Finally, the complete structure of ring-expanded erythronolides (7) and (13) has been determined by X-ray crystallography.Erythromycin A (1) 2-4 is a macrolide antibiotic characterized by a 14-membered lactone ring, erythronolide A,5.6 with a 9-OX0 group. In efforts to modify its biological and/or pharmacodynamic properties numerous derivatives of (1) have been prepared, including 9-imino derivatives7 Of the nucleophiles 0 ( 1 ) E r y t h r o m y c i n A Me Y R2 -L -C l o d i n o s y l H d Me bMewith low steric requirements which were allowed to react at the 9-carbonyl centre of (l), hydroxylamine was the most interesting8v9 in that it yielded erythromycin A oxime, a substrate with potential for further modification of the aglycone ring. On the basis of its configurational analysis it was suggested that the E-isomer (2) predominated in the p r~d u c t .~To develop a method for the efficient introduction of the nitrogen atom into the 14-membered ring we studied the Beckmann rearrangement of 9-oxime (2) and conversion of the product (5) so obtained into a secondary amine (ll)." Such erythromycin derivatives are the first of their kind in the literature. Results and DiscussionIt is well known that 0-arylsulphonyloximes, especially p-tosyl compounds, are very suitable precursors in the Beckmann rearrangement of ketoximes." By the reaction of the 9-oxime (2) with para-substituted arene sulphonyl chlorides in dry acetone in the presence of sodium hydrogen carbonate, a series of new erythromycin A 9-0-arylsulphonyloximes (3a-e) was prepared (Scheme 1).The structure of these compounds was assigned from their spectroscopic properties. In particular, the i.r. spectrum of (3a) ( Table 1) revealed new bands at 1 680 (C=N) and 1 600, 810, and 680 cm-' (p-Ph). The 'H n.m.r. spectrum displayed signals at 6 2.35 (s, 3 H, p-Me), 3.36 (s, 3 H, OMe), and 7.36 (4, 4 H, p-Ph). Apart from a typical chemical shift for dimethylamino protons of (1) (lit.," 2.29 p.p.m.), (3a) showed a signal at 6 2.83 (s, 6 H) which corresponded to the N-methyl hydrogens of the protonated dimethylamine; ' this indicated formation of the hydrochloric salt of (3a). Further characterization of (3a) was achieved by potentiometric titration which showed 4.07% (requires 3.77%) ionic bonded chlorine.Surprisingly, Beckmann rearrangement of 9-0-arylsulphonyloximes (3a-e) carried out by a literature 147' method for related systems gave none of the expected lactam (9). Instead, it afforded the new compound (5) (erythromycin A imino ether) in 70-87% yield. This structure was confirmed by spectroscopic analysis. The i.r. spectrum of (5) showed...

4'-Deoxy-10,l l ,12,1 3-tetrahydrodesmycosin was prepared in six-step reactions. Antibacterial screening shows retained antibacterial spectrum of tylosin with some improvementagainst tylosin-sensitive Staphylococci and Haemophilus influenze. However,pharmacokinetic data demonstrated rapid distribution from blood in tissues and prolonged maintenance in all tissues, especially in the lungs, in comparison with tylosin. 10,1 1,12,13-Tetrahydrodesmycosin, a 16-membered macrolide antibiotic is obtained by selective catalytic hydrogenation of desmycosin in the C-10, C-ll, C-12, C-13 position, or by mild acid hydrolysis of previously prepared 10, 1 l^n-tetrahydrotylosm1). 1 6-Membered macrolides: rosamycin2) and mycinami-cins3) with desosamine (4/-deoxy-mycaminose) in the C-5 position instead of mycaminose,were found to be active against some strains of Gram-negative and macrolide resistent Gram-positive bacteria. Deoxygenation of C-4' hydroxyl group of desmyco-sin40, 1 9-deformyl-desmycosin5) or related 1 6-membered macrolide, neospiramycin6), has already been accomplished. In preceding papers4'5) it was shown that the 4'-deoxy derivatives of desmycosin exhibit enhanced activity in comparison to those of corresponding 4'hydroxy compounds. Contrary to expectation C-4'

In the present studies the in vivo and in vitro effects of erythromycin A and azithromycin, a new type of macrolide (Fig. 2.), were investigated upon extracellular release of lysosomal enzymes, beta-glucuronidase (beta-Gluc) and beta-N-acetylglucosaminidase (beta-Glm) by using two experimental model systems: in vivo-adjuvant-induced arthritis in rats and in vitro- human polymorphonuclear leucocytes (PMNL) exposed to bovine serum albumin/anti-bovine serum albumin (BSA/anti-BSA), immune complex. Administrations of erythromycin A or azithromycin at doses of 5, 10 and 15 mg/kg into rats one day prior and 2, 4, 6, 8 and 10 days after a single subplantar injection of Freund's complete adjuvant significantly (p less than 0.01) inhibited extracellular release of lysosomal enzymes tested in the synovial fluid of injected left hind paw. These effects were dose-dependent. Further, erythromycin A and azithromycin at concentrations of 10(-7) M, 10(-6) M and 10(-5) M significantly (p less than 0.01) reduced excocytosis of both lysosomal enzymes, beta-Gluc and beta-Glm from human PMNL initiated by BSA/anti-BSA in a dose-related fashion. However, azithromycin was by far more effective (p less than 0.01) in decreasing extracellular release of beta-Gluc and beta-Glm either in the in vivo or in vitro experiments in comparison with erythromycin A. Appropriate control experiments excluded the possibilities that erythromycin A or azithromycin interfered with activities of lysosomal enzymes or with test reagents. Also, in no instances was there enhanced release of a cytoplasmic enzyme LDH.(ABSTRACT TRUNCATED AT 250 WORDS)

No abstract