Particularly, the invention relates to novel 3-decladinosyl derivatives from the class of 9a-N-carbamoyl-and 9a-N-thiocarbamoyl-9-deoxo-9-dihydro-9a-aza-9a- homoerythromycin A, to their pharmaceutically acceptable addition salts with inorganic or organic acids, to their hydrates, to the process for their preparation, to the process for preparation of their pharmaceutical compositions and to the use thereof as antibiotics or intermediates for the synthesis of other macrolide antibiotics.

3) Prior Art: Macrolides are well known agents for treating broad spectrum of infections.

Erythromycin A (McGuire J. M., Antibiot. Chemother. 1952; 2: 281) has been for more than 40 years considered as 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. By oximation of C-9 ketone of erythromycin and subsequent Beckmann rearrangement and reduction, 9-deoxo-9a-aza-9a-homoerythromycin A, the first 15-membered macrolide antibiotics with 9a-amino group incorporated in aglycone ring, is obtained (Kobrehel G. et al. , U. S.

4,328, 334 5/1982).

By 0-methylation of C-6 hydroxyl group of erythromycin clarithromycin is obtained (6-O-metil-erythromycin A) (Morimoto S. et al., J. Antibiotics 1984, 37,187). In comparison with erythromycin A, clarithromycin is more stable and shows enhanced in vitro activity against Gram-positive strains (Kirst H. A. et al., Antimicrob. Agents and Chemother. 1989,1419).

9a-N-carbamoyl i 9a-N-thiocarbamoyl derivatives of 9-deoxo-9-dihydro-9a-aza-9a- homoerythromycin A, who shoved significant antibacterial activity, are described.

(Kujundzic N. et. al., Eur. J. Med. Chem. 1995,30, 455).

It is known as well that recent research on 14-membered macrolides has lead to the discovery of new classes of macrolide antibiotics, ketolides and anhydrolides. Instead of the neutral sugar L-cladinose known for its instability even in a weakly acidic medium, ketolides possess a keto group on C-3 position (Agouridas C. et al. , EP 596802 Al 5/1994, Le Martret O., FR 2697524 Al 5/94). Anhydrolides are characterized by 2,3- anhydro group (Elliott R. et al., J. Med. Chez. 1998,41, 1651). Ketolides show a significantly better activity against MLS (macrolide, lincosamide and streptogramin B) induced-resistant organisms (Jamjian C., Antimicrob. Agents Chemother. 1997,41, 485).

Object of the present invention are 3-decladinosyl derivatives of 9a-N-carbamoyl-and 9a-N-thiocarbamoyl-9-deoxo-9-dihydro-9a-aza-9a-homoerythromy cin A, their pharmaceutically acceptable addition salts with inorganic or organic acids, their hydrates, methods and intermediates for their preparation as well as preparation and application methods of pharmaceutical preparations.

4) Description of technical problem with examples The invention relates to: i) novel 3-decladinosyl derivatives of 9a-N-carbamoyl-and 9a-N- thiocarbamoyl-9-deoxo-9-dihydro-9a-aza-9a-homoerythromycin A, their pharmaceutically acceptable addition salts with inorganic or organic acids and their hydrates, ii) methods for preparation of novel 3-decladinosyl derivatives of 9a-N- carbamoyl-and 9a-N-thiocarbamoyl-9-deoxo-9-dihydro-9a-aza-9a- homoerythromycin A, their pharmaceutically acceptable addition salts with inorganic or organic acids and their hydrates, iii) use of novel 3-decladinosyl derivatives of 9a-N-carbamoyl-and 9a-N- thiocarbamoyl-9-deoxo-9-dihydro-9a-aza-9a-homoerythromycin A, their pharmaceutically acceptable addition salts with inorganic or organic acids and their hydrates as antibiotics or iv) use of novel 3-decladinosyl derivatives of 9a-N-carbamoyl-and 9a-N- thiocarbamoyl-9-deoxo-9-dihydro-9a-aza-9a-homoerythromycin A, their pharmaceutically acceptable addition salts with inorganic or organic acids and their hydrates as intermediates for the synthesis of other macrolide antibiotics.

Novel 3-decladinosyl derivatives of 9a-N-carbamoyl-and 9a-N-thiocarbamoyl-9-deoxo- 9-dihydro-9a-aza-9a-homoerythromycin A of the general formula (I), their pharmaceutically acceptable addition salts with inorganic or organic acids and their hydrates, wherein Ri individually stands for hydrogen or together with R2 stands for double bond, R2 individually stands for hydrogen, hydroxyl or a group of the formula (II), (II) wherein Y individually stands for monocyclic aromatic ring unsubstituted or substituted with groups which are selected independently from halogen, OH, OMe, NO2, NH2 or R2 together with R3 stands for ketone or together with Rl stands for double bond, R3 individually stands for hydrogen or together with R2 stands for ketone or together with R4 stands for ether, R4 individually stands for hydroxyl, OCH3 group or together with R3 stands for ether, Rs stands for C1-C4 alkyl group, C2-C4 alkenyl grupe,-(CH2) m-Ar, wherein Ar individually stands for phenyl or phenyl substituted with one or two groups which are selected independently from halogen or halogen alkyl, and m is 0-3, R6 individually stands for hydrogen or hydroxyl protected group and X stands for oxygen or sulphur are subject of this invention.

Term « hydroxyl protected group » includes, but is not limited on benzoyl, benzyloxycarbonyl, acetyl or substituted silyl group in order to block the undesired reaction due the synthesis (Green T. H. and Wuts P. G. M., Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York, 1999). Compounds given by general formula (I), wherein RI, R2, R3, R4, Rs R6 X and Y have the meaning as defined above could be prepared by methods described in this invention. Methods of preparations, which also are subject of this invention, are illustrated by schemes 1. and 2.: Scheme 1.

Scheme 2.

Starting compound described in scheme 1. for synthesis of compounds, which are subject of this invention are prepared by methods described in patent Kobrehel G. et al. , U. S. 4,328, 334 5/1982 and in the article Denis A. and Agouridas C., Bioorg. Med.

Chez. Lett. 1998, 8, 2427 (compound of general formula 1).

Step 1.

Compounds of the formula 1., wherein R4 individually stands for hydroxyl or OCH3 group are subjected to a reaction with isocyanate or isothiocyanate of the formula Rs- N=C=X wherein R5 and X have the above meanings, in a reaction-inert solvent preferably toluene or acetonitril, at a temperature from room temperature to the reflux temperature of the solvent for 30 min to 50 hours, yielding 9a-N-carbamoyl and 9a-N- thiocarbamoyl derivatives of the formula 2. (scheme 1. ), wherein R4 individually stands for hydroxyl or OCH3 group and R5 and X have the above meanings.

9a-N-carbamoyl and 9a-N-thiocarbamoyl derivatives of the formula 2 wherein all substituents have the above meanings are subjected to a selective acylation of the hydroxyl group on 2'-position. Acylation is carried out with chlorides or anhydrides of carboxylic acids with up to 4 carbon atoms, preferably with acetic acid anhydrides, in the presence of inorganic or organic base, in a reaction-inert solvent at a temperature from 0-30°C, yielding 2'-O-acyl derivatives of the formula 3 (scheme 1. ), wherein R4 individually stands for hydroxyl or OCH3 group, Rs and X have the above meanings and R6 stands for hydroxyl protected group, preferably acetyl.

As suitable bases sodium hydrogencarbonate, sodium carbonate, potassium carbonate, triethylamine, pyridine, tributylamine are used. As a suitable inert solvent methylene chloride, dichlorethane, acetone, pyridine, ethyl acetate, tetrahydrofuran are used.

Step 2.

2'-O-Acetyl derivatives from the Step 1. are optionally subjected to a reaction with mixed anhydrides of carboxylic acids of the formula Z-COO-R', wherein Z individually stands for hydrogen or for group Y, which is defined above, R'stands for the group which is usually used for preparation of mixed anhydrides as pivaloyl-, p- toluensulphonyl-, isobutoxycarbonyl-, etoxycarbonyl-or isopropoxycarbonyl-group, in the presence of inorganic or organic base, in a reaction-inert solvent, preferably methylene chloride at a temperature from 0-30°C for 3-100 hours yielding compounds of the formula 4. (scheme 2. ), wherein R4 individually stands for hydroxyl or OCH3 group, R6 stands for acetyl and substituents RS, X and Y have the above meanings.

Formed compounds are subsequently subjected to deprotection with lower alcohols, preferably in methanol, at a temperature from room temperature to the reflux temperature of the solvent, yielding a compound of the formula 4. (scheme 2. ), wherein R6 stands for hydrogen and R4, Rs X and Y have the above meanings, or optionally 2'-O-acetyl derivatives from the Step 1., wherein R4 stands for the OCH3 group and all other substituents have the meanings as in the Step 1. are subjected to oxidation of the hydroxyl group in the C-3 position of an aglycone ring according to a modified Moffat- Pfitzner process with N, N-dimethylaminopropyl-3-ethyl-carbodiimide in the presence of dimethylsulfoxide and pyridinium trifluoracetate as a catalyst in a inert organic solvent, preferably in methylene chloride, at a temperature from 10 °C to room temperature, yielding compounds of the formula 5. (scheme 2. ), wherein R4 stands for the OCH3 group, R6 stands for acetyl and supstituents Rs and X have the above meanings. Formed compounds are subsequently subjected to deprotection with lower alcohols, preferably in methanol, at a temperature from room temperature to the reflux temperature of the solvent, yielding a compound of the formula 5. (scheme 2. ), wherein R6 stands for hydrogen and all other supstituents have the above meanings.

Alternatively it is possible to oxidize C-3 hydroxyl group using Dess Martin periodinane reagens or optionally 2'-O-acetyl derivatives from the Step 1., wherein R4 stands for hydroxyl and all other supstituents have the meanings as in the Step 1. are subjected to oxidation described to obtain compounds of the formula 5. (scheme 2. ), where compounds with 3, 6-hemiketal structure given by formula 6. (scheme 2. ), wherein R6 stands for acetyl and Rs and X have the above meanings are formed. Formed compounds are subsequently subjected to deprotection with lower alcohols, preferably in methanol, at a temperature from room temperature to the reflux temperature of the solvent, yielding a compound of the formula 6. (scheme 2. ), wherein R6 stands for hydrogen and Rs and X have the above meanings or optionally 2'-O-acetyl derivatives from the Step 1., wherein R4 stands for the OCH3 group and all other substituents have the meanings as in the Step 1., are subjected to the adequate reagents for dehydratation, preferably methylsulfonyl anhydride to transform hydroxyl group on position 3 in good leaving group, in an inert organic solvent, preferably in pyridine, at a temperature from room temperature to the reflux temperature of the solvent for 10-50 hours. Formed intermediate is subsequently subjected to reaction of elimination with adequate reagens, preferably sodium hydride, in a inert organic solvent, preferably in tetrahydrofuran, at a temperature from 10 °C to room temperature, yielding 2,3-anhydro derivatives of the formula 7. (scheme 2. ), R4 stands for the OCH3 group, R6 stands for acetyl and Rs and X have the above meanings. Formed compounds are subsequently subjected to deprotection with lower alcohols, preferably in methanol, at a temperature from room temperature to the reflux temperature of the solvent, yielding a compound of the formula 7. (scheme 2. ), wherein R6 stands for hydrogen and R4, Rs and X have the above meanings. or optionally 2'-O-acetyl derivatives from the Step 1., wherein R4 stands for the OH group and all other substituents have the meanings as in the Step 1., are subjected to adequate reagents for dehydratation, described to obtain compounds of the formula 7. (scheme 2. ), yielding 3,6 cyclic ethers of the formula 8. (scheme 2. ), wherein R6 stands for acetyl and Rs and X have the above meanings. Formed compounds are subsequently subjected to deprotection with lower alcohols, preferably in methanol, at a temperature from room temperature to the reflux temperature of the solvent, yielding a compound of the formula 8. (scheme 2. ), wherein R6 stands for hydrogen and Rs and X have the above meanings.

Pharmaceutically acceptable addition salts which are also subject of this invention are prepared by reaction of new compounds of the general formula (I) with at least one eqimolar amounts of suitable inorganic or organic acid as chloride, iodide, sulphate, phosphate, acetic, propionic, trifluoracetic, maleinic, citric, stearic, jantaric, ethyljantaric, mathansulphonic, p-toluensulphonic, laurylsulphonic and other acids in reaction inert solvent. Addition salts are isolated by filtration (if they are insoluble in used solvent), by precipitation, by evaporating the solvent or by liophilisation.

The process is illustrated by the following examples, which do not limit the scope of the invention in any way.

Example 1.

3-Decladinosyl-9-deoxo-9-dihydro-9a-N- (N-isopropylcarbamoyl)-9a-aza-9a- homoerythromycin A To a solution of 3-decladinosyl-9-deoxo-9-dihydro-9a-aza-9a-homoerythromycin A (1,00 g) in toluene (20 ml) isopropylisocyanate (0, 17 g) was added. Reaction mixture was stirred for 1 hour at room temperature. The solvent was evaporated and 1,15 g of crude product is obtained.

Crystallization from mixture acetone-petrol ether yielding 0,97 g of chromatographically homogenous title product with following physical-chemical constants: TLC Rf = 0,37 (CH2C12 : MeOH = 8 : 2) IR (KBr) [v/crri i] : 3498,3466, 2974, 2938, 2877,1726, 1618,1596, 1528,1458, 1373,1279, 1172,1111, 1082, 1036, 978, 956,932, 901,833, 776,689, 633.

MS m/z: (FAB) : Mlr = 662 1H NMR (300 MHz, CDC13) [S/ppm] 5.03 (13-H), 4.40 (1'-H), 4.37 (9a-NCON'I), 3.92 (1"-H), 3.89 (3-H), 3.50 (11-H), 3.69 (5'-H), 3.63 (5-H), 3.32 (2'-H), 2.60 (2-H), 2.54 (3'-H), 2.28 (3'-N (CH3) 2), 1.88 (14- Ha), 1.72 (4'-Ha), 1. 58 (14-Hb), 1.56 (4-H), 1.34 (4'-Hb), 1.29 (2-CH3), 1.27 (5'-CH3), 1.26 (10-CH3), 1.13 (1- (CH3) 2), 1.10 (12-CH3), 1.06 (8-CH3), 0.93 (4-CH3), 0. 89 (15- CH3).

13C NMR (75 MHz, CDCl3) [#/ppm] 177.3 (1-C), 158.8 (9a-NCONH), 105.8 (1'-C), 95.9 (5-C), 77.7 (13-C), 77.1 (12-C), 74.5 (11-C), 74.9 (3-C), 74.2 (6-C), 73.0 (9-C), 70.3 (5'-C), 69.2 (2'-C), 64.9 (3'-C), 44.6 (2-C), 42.4 (1"-C), 41.7 (7-C), 39.9 (3'-N (CH3) 2), 38.5 (4-C), 27.6 (4'-C), 25.8 (6- CH3), 23.1 (1''-(CH3) 2), 21.2 (14-C), 20.6 (5'-CH3), 19.4 (8-CH3), 16.6 (12-CH3), 15.9 (2-CH3), 12.2 (10-CH3), 10.0 (15-CH3), 7.7 (4-CH3).

Example 2.

3-Decladinosyl-9-deoxo-9-dihydro-9a-N- (N'-ethylcarbamoyl)-9a-aza-9a- homoerythromycin A To a solution of 3-decladinosyl-9-deoxo-9-dihydro-9a-aza-9a-homoerythromycin A (1,00 g) in toluene (20 ml) ethylisocyanate (0,175 g) was added. Reaction mixture was stirred for 1 hour at room temperature. The solvent was evaporated and 1,24 g of crude product is obtained.

Crystallization from mixture acetone-petrol ether yielding 0, 98 g of chromatographically homogenous title product with following physical-chemical constants: TLC Rf= 0,48 (CH2C12: MeOH = 8 : 2) IR (KBr) [v/cm-1] : 3433,2975, 2936,2878, 1730,1618, 1532,1458, 1382,1350, 1267,1172, 1111,1077, 1036,980, 956,933, 900,834, 764.

MS m/z: (FAB): MH+ = 648 H NMR (300 MHz, CDCl3) [8/ppm] 5.03 (13-H), 4.39 (1'-H), 4.56 (9a-NCON'H), 3. 86 (3-H), 3.57 (11-H), 3. 68 (5'-H), 3.62 (5-H), 3.43 (9-Ha), 3.31 (2'-H), 3.23 (N'CH2), 2.59 (2-H), 2.53 (3'-H), 2.47 (9-Hb), 2.27 (3'-N (CH3) 2), 1.90 (14-Ha), 1.71 (4'-Ha), 1.55 (14-Hb), 1.55 (4-H), 1.33 (4'-Hb), 1.28 (2-CH3), 1. 28 (15-CH3), 1.28 (10-CH3), 1.27 (5'-CH3), 1.11 (N'CH2CH3), 1.08 (12-CH3), 1.05 (8-CH3), 0.92 (4-CH3), 0.87 (15-CH3).

13C NMR (75 MHz, CDCl3) [8/ppm] 177.0 (1-C), 159.5 (9a-NCONH), 105. 7 (1'-C), 96.2 (5-C), 77.7 (13-C), 77.1 (12-C), 74.5 (11-C), 75.1 (3-C), 74.1 (6-C), 72.8 (9-C), 70.3 (5'-C), 69.2 (2'-C), 64.9 (3'-C), 44.7 (2-C), 41.1 (7-C), 39.9 [3-N- (CH3) 21, 3 8. 3 (4-C), 36.5 (N'CH2), 28.9 (8-C), 27.6 (4'-C), 25.6 (6-CH3), 21. 3 (14-C), 20.6 (5'-CH3), 19.3 (8-CH3), 16.6 (12-CH3), 15. 8 (2- CH3), 15.0 (N'CH2CH3), 12.1 (10-CH3), 10.3 (15-CH3), 7.6 (4-CH3).

Example 3.

3-Decladinosyl-9-deoxo-9-dihydro-9a-N- [N'-(t-butyl)carbamoyl]-9a-aza-9a- homoerythromycin A To a solution of 3-decladinosyl-9-deoxo-9-dihydro-9a-aza-9a-homoerythromycin A (1,00 g) in toluene (20 ml) t-buthylisocyanate (0,198 g) was added. Reaction mixture was stirred for 1 hour at room temperature. The solvent was evaporated and 1,20 g of crude product is obtained.

Crystallization from mixture acetone-petrol ether yielding 0,95 g of chromatographically homogenous title product with following physical-chemical constants: TLC Rf = 0,42 (CH2C12: MeOH = 8 : 2) IR (KBr) [v/cm-1] : 3497,2976, 2946,1725, 1626,1532, 1456,1364, 1346,1317, 1281,1175, 1112,1082, 1055,1034, 977,956, 931,901, 865, 776, 685, 634.

MS m/z: (FAB): MH = 676 tH NMR (300 MHz, CDC13) [8/ppm] 5.03 (13-H), 4.52 (9a-NCON'H), 4.41 (1'-H), 3.89 (3-H), 3. 68 (5'-H), 3.47 (11-H), 3.62 (5-H), 3.41 (9-Ha), 3.32 (2'-H), 2.59 (2-H), 2.54 (3'-H), 2. 28 (3'-N (CH3) 2), 1.88 (14- Ha), 1.72 (4'-Ha), 1.57 (14-Hb), 1.56 (4-H), 1.32 (4'-Hb), 1.31 (N'C(CH3)3), 1.30 (2- CH3), 1.28 (5'-CH3), 1.24 (10-CH3), 1.11 (12-CH3), 1.05 (8-CH3), 0.92 (4-CH3), 0. 88 (15-CH3), .

"C NMR (75 MHz, CDCl3) [#/ppm] 177.7 (1-C), 158.7 (9a-NCONH), 105.9 (1'-C), 95.7 (5-C), 77.9 (13-C), 77.1 (12-C), 74.6 (11-C), 74. 8 (3-C), 74.3 (6-C), 73.3 (9-C), 70.3 (5'-C), 69.2 (2'-C), 65.0 (3'-C), 50.8 (N'C (CH3) 3), 44.6 (2-C), 41.1 (7-C), 40.0 (3'N- (CH3) 2), 38. 6 (4-C), 29.1 (N'C(CH3. 3), 28.9 (8-C), 27.7 (4'-C), 26.2 (6-CH3), 21.2 (14-C), 20.6 (5'-CH3), 19.4 (8- CH3), 16.5 (12-CH3), 16.0 (2-CH3), 12.2 (10-CH3), 10.6 (15-CH3), 7. 8 (4-CH3).

Example 4.

3-Decladinosyl-9-deoxo-9-dihydro-9a-N- (N'-benzylcarbamoyl)-9a-aza-9a- homoerythromycin A To a solution of 3-decladinosyl-9-deoxo-9-dihydro-9a-aza-9a-homoerythromycin A (1,00 g) in toluene (20 ml) benzylisocyanate (0,25 g) was added. Reaction mixture was stirred for 1 hour at room temperature. Crude product (1.18 g) is obtained by filtration of precipitate from reaction mixture.

Crystallization from mixture acetone-petrol ether yielding 0,82 g of chromatographically homogenous title product with following physical-chemical constants: TLC Rf = 0,42 (CH2C12 : MeOH = 8 : 2) IR (KBr) [v/cm-l] : 3404,2975, 2936,1731, 1625, 1529, 1454, 1384, 1349, 1319, 1274,1172, 1111,1091, 1049, 978, 957,931, 900,865, 837,740, 700,635.

MS m/z: (ES): MH+ = 710,6 1H NMR (300 MHz, CDCl3) [8/ppm] 7.35 (4"-H, 6"-H), 7.30 (3"-H, 7-H), 7. 24 (5"-H), 5.03 (13-H), 4.55 (l-Ha), 4.48 (9a- NONE), 4.30 (1'-H), 4.30 (l-Hb), 3.89 (3-H), 3. 68 (5'-H), 3.51 (11-H), 3.62 (5-H), 3. 41 (9-Ha), 3.30 (2'-H), 2.62 (2-H), 2.30 (3'-H), 2.27 (3'-N (CH3) 2), 1.89 (14-Ha), 1.69 (4'-Ha), 1. 58 (14-Hb), 1.56 (4-H), 1.28 (4'-Hb), 1.30 (2-CH3), 1.27 (5'-CH3), 1.32 (10- CH3), 1.28 (6-CH3), 1. 10 (12-CH3), 1.04 (8-CH3), 0.93 (4-CH3), 0.89 (15-CH3), .

13C NMR (75 MHz, CDCl3) [S/ppm] 176.9 (1-C), 159.6 (9a-NCONH), 139.4 (2'C), 128.6 (4"-C, 6"-C), 127.3 (3"-C, 7"-C), 126.9 5"-C), 105.7 (1'-C), 96.4 (5-C), 77.7 (13-C), 77.1 (12-C), 75.0 (11-C), 75.0 (3- C), 74.2 (6-C), 74.4 (9-C), 70.2 5'-C), 69.2 (2'-C), 64.8 3'-C), 44.7 (2-C), 44.6 (1 =C), 44.6 (7-C), 40.0 (3'N-(CH3) 2), 38. 4 (4-C), 27.5 (4'-C), 25.3 (6-CH3), 21.3 (14-C), 20.7 (5'-CH3), 19.7 (8-CH3), 16.7 (12-CH3), 15.9 (2-CH3), 12.2 (10-CH3), 10.4 (15-CH3), 7.6 (4-CH3).

Example 5.

3-Decladinosyl-9-deoxo-9-dihydro-9a-N- [N'-(3-trifluoromethylphenyl)carbamoyl]- 9a-aza-9a-homoerythromycin A To a solution of 3-decladinosyl-9-deoxo-9-dihydro-9a-aza-9a-homoerythromycin A (1,00 g) in toluene (20 ml) 3-trifluormetilphenylisocyanate (0,33 g) was added.

Reaction mixture was stirred for 30 min at room temperature. The solvent was evaporated and 1,30 g of crude product is obtained.

Crystallization from mixture ethyl ether-petrol ether yielding 0, 98 g of chromatographically homogenous title product with following physical-chemical constants: TLC Rf = 0,51 (CH2Cl2 : MeOH = 8 : 2) IR (KBr) fvlcm-1] : 3451,2975, 2935,1727, 1704,1659, 1548,1494, 1449,1384, 1336, 1258, 1167,1125, 1072,1049, 979,957, 933,901, 864, 835,794, 758, 699,659.

MS m/z : (ES) : MHs = 764,6 1H NMR (300 MHz, CDCl3) [S/ppmj 7.70 (2"-H), 7.58 (6"-H), 7.35 (5"-H), 7.23 (4"-H), 4.82 (13-H), 4.62 (9a-NCON'H), 4.35 (1'-H), 3. 87 (3-H), 3.62 (5'-H), 3.62 (5-H), 3. 51 (11-H), 3.41 (9-Ha), 3.30 (2'-H), 2.66 (2-H), 2.50 (3'-H), 2.26 (3'-N (CH3) 2), 1.88 (14-Ha), 1.71 (4'-Ha), 1. 58 (14-Hb), 1.56 (4-H), 1.28 (6-CH3), 1.28 (2-CH3), 1.31 (4'-Hb), 1.27 (5'-CH3), 1.24 (10-CH3), 1.10 (12-CH3), 1.04 (8-CH3), 0.92 (4-CH3), 0. 88 (15-CH3).

13C NMR (75 MHz, CDCl3) [8/ppm] 176. 8 (1-C), 156.6 (9a-NCONH), 140.0 (1"-C), 131.3 (3"-C), 129.2 (5&num -C), 122.3 (6"-C), 118.9 (4"-C), 115.8 (2"-C), 106.1 (1'-C), 96.5 (5-C), 78.8 (13-C), 77.1 (12-C), 75.7 (3- C), 74. 8 (9-C), 74.7 (6-C), 74.6 (11-C), 70.6 (5'-C), 69.4 (2'-C), 65.2 (3'-C), 45.2 (2-C), 40.2 (3vN-(CH3) 2), 38. 8 (4-C), 27.9 (4'-C), 21.5 (14-C), 20.9 (5'-CH3), 20.0 (8-CH3), 16.8 (12-CH3), 16.1 (2-CH3), 13.8 (10-CH3), 10.9 (15-CH3), 7.7 (4-CH3).

Example 6.

3-Decladinosyl-9-deoxo-9-dihydro-9a-N- [N'-(2-trifluoromethylphenyl)carbamoyl]- 9a-aza-9a-homoerythromycin A To a solution of 3-decladinosyl-9-deoxo-9-dihydro-9a-aza-9a-homoerythromycin A (1,00 g) in toluene (20 ml) 2-trifluormetilphenylisocyanate (0,35 g) was added.

Reaction mixture was stirred for 30 min at room temperature. The solvent was evaporated and 1,29 g of crude product is obtained.

Crystallization from mixture ethyl ether-petrol ether yielding 0,84 g of chromatographically homogenous title product with following physical-chemical constants: TLC Rf = 0,69 (CH2C12 : MeOH = 8 : 2) IR (KBr) [v/cm-1] : 3458, 2975,2940, 2879,2786, 1727, 1658, 1591,1536, 1457, 1384,1322, 1282, 1244,1171, 1112,1035, 979,956, 934,901, 864,834, 762,702.

MS m/z : (FAB): MH = 764,3 'H NMR (300 MHz, CDC13) [8/ppm] 8. 01 (6"H), 7.55 (3"H), 7.26 (4"-H), 7.16 (5"-H), 4.98 (13-H), 4.62 (9a-NCON'H), 4. 38 (1'-H), 3.90 (3-H), 3.65 (5'-H), 3.64 (5-H), 3.61 (11-H), 3.31 (2'-H), 2.64 (2-H), 2.52 (3'-H), 2.27 (3'-N (CH3) 2), 1.91 (14-Ha), 1.72 (4'-Ha), 1.57 (14-Hb), 1.56 (4-H), 1.35 (10-CH3), 1.32 (2-CH3), 1.28 (6-CH3), 1.31 (4'-Hb), 1.24 (5'-CH3), 1.15 (12-CH3), 1.10 (8-CH3), 0.96 (4-CH3), 0.91 (15-CH3).

13C NMR (75 MHz, CDCl3) [S/ppm] 177.3 (1-C), 157.0 (9a-NCONH), 136.4 (1"-C), 132.5 (3"-C), 125.7 (5"-C), 125.1 (4"-C), 123.4 (6 =C), 105.9 (1'-C), 82.9 (5-C), 77.9 (13-C), 74.4 (12-C), 75.2 (3-C), 74.4 (6-C), 73.8 (11-C), 70.4 (5'-C), 69.2 (2'-C), 64.9 (3'-C), 44.7 (2-C), 39. 9 (3'N-(CH3) 2), 38. 6 (4-C), 27.6 (4'-C), 21.3 (14-C), 20.7 (5'-CH3), 19.1 (8-CH3), 16.6 (12-CH3), 15.9 (2- CH3), 12.5 (10-CH3), 10.5 (15-CH3), 7.7 (4-CH3).

Example 7.

3-Decladinosyl-9-deoxo-9-dihydro-9a-N- [N'- (3- trifluoromethylphenyl) thiocarbamoyl]-9a-aza-9a-homoerythromycin A To a solution of 3-decladinosyl-9-deoxo-9-dihydro-9a-aza-9a-homoerythromycin A (1,00 g) in toluene (20 ml) 3-trifluormetilphenylisothiocyanate (0,35 g) was added.

Reaction mixture was stirred for 15 min at room temperature. Crude product (1.18 g) is obtained by and filtration of precipitate from reaction mixture.

Crystallization from mixture acetone-petrol ether yielding 0,92 g of chromatographically homogenous title product with following physical-chemical constants: TLC Rf= 0,60 (CH2Cl2 : MeOH=8 : 2) IR (KBr) [v/cm-1] : 3449,2975, 2937,1708, 1600,1547, 1494,1452, 1384,1328, 1255,1164, 1116,1073, 1019,980, 956,885, 862, 793,735, 696.

MS m/z: (FAB): MH = 780 1H NMR (300 MHz, CDCl3) [#/ppm] 7.68 (2"-H), 7.42 (6"-H), 7.26 (5"-H), 7.18 (4"-H), 4.82 (13-H), 4.61 (9a-NCON'H), 4.40 (1'-H), 3.90 (3-H), 3.66 (5'-H), 3.57 (5-H), 3.49 (11-H), 3.31 (2'-H), 2.69 (2-H), 2.52 (3'-H), 2.27 (3'-N (CH3) 2), 1.95 (14-Ha), 1.69 (4'-Ha), 1.62 (14-Hb), 1.53 (4-H), 1.34 (2-CH3), 1.28 (6-CH3), 1.34 (4'-Hb), 1.28 (5'-CH3), 1.25 (10-CH3), 1.21 (12-CH3), 1.08 (8-CH3), 0.98 (4-CH3), 0.94 (15-CH3).

13C NMR (75 MHz, CDCl3) [#/ppm] 183.2 (9a-NCONH), 177.6 (1-C), 140.4 (1"-C), 130.5 (3"-C), 130.2 (5"-C, 128. 1 (6"-C), 125.2 (4"-C), 123.6 (2"-C), 105.2 (1'-C), 94.9 (5-C), 79.3 (3-C), 77.7 (13-C), 77.2 (12- C), 73.5 (9-C), 73.6 (6-C), 73.4 (11-C), 70.6 (5'-C), 69.5 (2'-C), 65.2 (3'-C), 44.5 (2-C), 41. 1 (7-C), 40.2 (3'N-(CH3) 2), 38. 8 (4-C), 28.1 (8-C), 27.9 (4'-C), 25.9 (6-CH3), 21.0 (14-C), 21.0 (5'-CH3), 18.9 (8-CH3), 16.6 (12-CH3), 16.1 (2-CH3), 12.8 (10-CH3), 10.8 (15-CH3), 7.6 (4-CH3).

Example 8.

3-Decladinosyl-9-deoxo-9-dihydro-9a-N- (N'-benzylthiocarbamoyl)-9a-aza-9a- homoerythromycin A To a solution of 3-decladinosyl-9-deoxo-9-dihydro-9a-aza-9a-homoerythromycin A (1,00 g) in toluene (20 ml) benzylisothiocyanate (0,38 g) was added. Reaction mixture was stirred for 1 hour at room temperature. The solvent was evaporated and 1,35 g of crude product is obtained.

Crystallization from mixture ethyl ether-petrol ether yielding 1,06 g of chromatographically homogenous title product with following physical-chemical constants: TLC Rf= 0,40 (Ch2Cl2 : MeOH = 8 : 2) IR (KBr) [v/cm-1] : 3448,2974, 2938,1703, 1528,1456, 1384, 1323, 1283, 1178, 1109,1073, 1020,978, 955,934, 862, 825, 759,699.

MS m/z : (ES) : MH = 726.5 (300 NMR (300 MHz, CDCl3) [#/ppm] 7.34 (4"-H, 6"-H), 7.30 (3"-H, 7"-H), 7.27 (5"-H), 4.64 (9a-NCSM'H), 4.57 (13-H), 4.39 (1'-H), 3.89 (3-H), 3.67 (5'-H), 3.67 (5-H), 3.51 (11-H), 3.31 (2'-H), 2.64 (2-H), 2.55 (3'-H), 2.28 (3'-N (CH3) 2), 1.93 (14-Ha), 1.73 (4'-Ha), 1.62 (14-Hb), 1.56 (4-H), 1.34 (2-CH3), 1.27 (4'-Hb), 1.27 (5'-CH3), 1.27 (10-CH3), 1.25 (12-CH3), 0.94 (8-CH3), 0. 87 (4-CH3), 0.86 (15-CH3).

13C NMR (75 MHz, CDCl3) [8/ppm] 189.2 (9a-NCSNH), 179.5 (1-C), 137.5 (2"-C), 128. 6 (4"-C, 6"-C), 128.2 (3"-C, 7"C), 127.6 (5"-C), 105.9 (1'-C), 93.9 (5-C), 78.7 (13-C), 75.1 (12-C), 75.2 (6-C), 74.6 (3-C), 73.9 (11-C), 70.1 (5'-C), 69.5 (2'-C), 65.2 (3'-C), 50. 8 (1"-C), 44. 1 (2-C), 40.2 (3'N- (CH3) 2), 44.4 (4-C), 27.9 (4'-C), 21.1 (14-C), 20.9 (5'-CH3), 19.0 (8-Me), 16.7 (12- CH3), 16.5 (2-CH3), 12.3 (10-CH3), 11.3 (15-CH3), 8.3 (4-CH3).

Example 9.

3-Decladinosyl-9-deoxo-9-dihydro-9a-N-[N'-(2,4-dichloroph enyl) carbamoyl] -9a- aza-9a-homoerythromycin A To a solution of 3-decladinosyl-9-deoxo-9-dihydro-9a-aza-9a-homoerythromycin A (3,00 g) in toluene (50 ml) 2,4-dichlorphenylisocyanate (1,07 g) was added. Reaction mixture was stirred for 1 hour at room temperature. The solvent was evaporated and 3,80 g of crude product is obtained.

Crystallization from mixture ethyl ether-petrol ether yielding 4,26 g of chromatographically homogenous title product with following physical-chemical constants: TLC Rf = 0,63 (CH2C12 : MeOH = 8 : 2) IR (KBr) [v/cm-1] : 3428,2973, 2934, 2878, 1718,1659, 1580, 1517,1459, 1382, 1345, 1297, 1229,1176, 1110,1086, 1048, 978, 955,932, 901, 866,825, 759,731, 696,631.

MS m/z: (ES): MH+ = 764,5 1H NMR (300 MHz, CDCl3) [#/ppm] 8. 17 (6"-H), 7.33 (3"-H), 7. 17 (5"-H), 4,71 (13-H), 4.57 (9a-NCON'H), 4.40 (1'-H), 4.10 (5-H), 3. 89 (3-H), 3.89 (5'-H), 3.32 (2'-H), 2.62 (2-H), 2.60 (3'-H), 2.30 (3'-N (CH3) 2), 1.93 (14-Ha), 1.76 (4'-Ha), 1.57 (14-Hb), 1.56 (4-H), 1.53 (12-CH3), 1.36 (10-CH3), 1.31 (2-CH3), 1. 29 (4'-Hb), 1.29 (8-CH3), 1.27 (5'-CH3), 0. 94 (4-CH3), 0.90 (15-CH3).

13C NMR (75 MHz, CDcl3) [#/ppm] 177.2 (1-C), 156.4 (9a-NCONH), 134.7 (1"-C), 128. 4 (3"-C), 127.6 (2-C), 125.3 (5"-C), 123.2 (4"-C), 105.9 (1'-C), 78.2 (13-C), 75.9 (3-C), 70.5 (5'-C), 69.5 (2'-C), 65.2 (3'- C), 44.9 (2-C), 40.2 (3'N-(CH3) 2), 38. 8 (4-C), 28.1 (4'-C), 28.0 (8-C), 21.5 (14-C), 20.9 (5'-CH3), 19.4 (6-CH3), 16.8 (12-CH3), 16.2 (2-CH3), 12.9 (10-CH3), 10.9 (15-CH3), 8. 0 (4-CH3).

Example 10.

3-Decladinosyl-9-deoxo-9-dihydro-9a-N-[N'-allylthiocarbam oyl-9a-aza-9a- homoerythromycin A To a solution of 3-decladinosyl-9-deoxo-9-dihydro-9a-aza-9a-homoerythlomycin A (1,00 g) in toluene (20 ml) allylisothiocyanate (0,19 g) was added. Reaction mixture was stirred for 1 hour at room temperature. The solvent was evaporated and 1,20 g of crude product is obtained.

Crystallization from mixture ethyl ether-petrol ether yielding 0,72 g of chromatographically homogenous title product with following physical-chemical constants: TLC Rf = 0,68 (CH2C12 : MeOH =8 : 2) IR (KBr) [v/cm-1] : 3451,2974, 2938,2878, 1704,1644, 1520,1456, 1384,1321, 1286, 1178, 1110,1074, 1048,1019, 978,955, 934, 862, 833, 762,632.

MS m/z: (ES): MH = 676.4 'H NMR (300 MHz, CDCl3) [S/ppm] 5.94 (2"-H), 5.29 (3"-Ha), 5.20 (3"-Hb), 4.57 (13-H), 4.41 (1'-H), 4.37 (9a-NCSN'H), 4.34 (1"Ha), 4.21 (1"-Hb), 3.90 (3-H), 3.69 (5'-H), 3. 78 (5-H), 3.32 (2'-H), 2.64 (2-H), 2.54 (3'-H), 2.28 (3'-N(CH3)2), 1.92 (14-Ha), 1.70 (4'-Ha), 1.60 (14-Hb), 1.52 (4-H), 1.34 (4'-Hb), 1.35 (2-CH3), 1.28 (5'-CH3), 1. 28 (6-CH3), 1.26 (10-CH3), 1.24 (12-CH3), 1.12 (8-CH3), 0.95 (4-CH3), 0.94 (15-CH3).

13C NMR (75 MHz, CDCl3) [8/ppm] 189.3 (1-C), 179.7 (9a-NCSNH), 133.6 (2-C), 117.8 (3"-C), 106.0 (1'-C), 95.0 (5-C), 78. 6 (13-C), 75.1 (12-C), 75.1 (6-C), 74.8 (3-C), 73.8 (11-C), 70.4 (5'-C), 69.3 (2'-C), 65.4 (3'-C), 48.8 (1"-C), 44.2 (2-C), 39.9 (3oN-(CH3) 2), 38.9 (4-C), 27.6 (4'-C), 20.7 (14-C), 20.6 (5'-CH3), 18.7 (8-CH3), 16.4 (12-CH3), 16.2 (2-CH3), 12.1 (10-CH3), 10.9 (15-CH3), 7.9 (4-CH3).

Example 11.

2'-O-Acetyl-3-decladinosyl-9-deoxo-9-dihydro-9a-N- (N'-isopropylcarbamoyl)-9a- aza-9a-homoerythromycin A To a solution of 3-decladinosyl-9-deoxo-9-dihydro-9a-N- (N-isopropylcarbamoyl)-9a- aza-9a-homoerythromycin A (1, 00 g) in CH2C12 (20 ml), NaHC03 (1. 01 g) and acetic acid anhydride (173µl ) were added and it was then stirred for 24 hours at room temperature. Onto the reaction mixture a saturated NaHC03 solution was added, the layers were separated and the aqueous one was extracted two more times with CH2C12.

The combined organic extracts were rinsed with saturated NaHC03 solution and water and evaporated yielding the title product (1,10 g) with following physical-chemical constants: TLC Rf = 0.71 (CH2C12 : MeOH = 8 : 2).

IR (KBr) [vcm-1] : 3423,2974, 2938,2878, 1735,1624, 1560,1522, 1459,1376, 1252,1169, 1109,1058, 987,956, 901,834, 771,670.

MS m/z: (ES): Mu+ = 704, 2 Example 12.

2'-O-Acetyl-3-O-mesyl-3-decladinosyl-9-deoxo-9-dihydro-9a -N- (N'- isopropylcarbamoyl)-9a-aza-9a-homoerythromycin A To a solution of 2'-O-Acetyl-3-decladinosyl-9-deoxo-9-dihydro-9a-N-(N'- isopropylcarbamoyl)-9a-aza-9a-homoerythromycin A (1,00 g) in pyridine (5 ml) methylsulphonyl anhydride (0,30 g) was added and the reaction mixture was stirred at room temperature for 3 hours. The solvent was evaporated and the residue was dissolved in CH2C12 (20 ml). Saturated aqueous solution of NaHC03 (20 ml) was added, the layers were separated and the water layer was extracted two more times with CH2C12 Combined organic extracts were rinsed with NaHC03 and brine, dried over K2C03 and evaporated yielding 0,87 g of crude product with following physical-chemical constants TLC Rf = 0,43 (CHC13: MeOH : NH4OH=6 : 1: 0.1).

IR (KBr) [vcm-1] : 3422,3065, 2972, 2876, 1735,1637, 1618, 1535, 1487, 1459, 1377,1330, 1240,1206, 1193,1059, 1004, 785, 773,755, 682, 609.

MS m/z: (ES): MHF = 783,2 Example 13. <BR> <BR> <BR> <BR> <P>3-Decladinosyl-3, 6-hemiketal-9-deoxo-9-dihydro-9a-N- (N-isopropylcarbamoyl)- 9a-aza-9a-homoerythromycin A To a solution of 2'-O-Acetyl-3-decladinosyl-9-deoxo-9-dihydro-9a-N- (N- isopropylcarbamoyl)-9a-aza-9a-homoerythromycin A (1,50 g) from Example 11. in CH2C12 (30 ml) dimethylsulfoxide (2,00 ml) and N,N-dimethyl-aminopropyl-ethyl- carbodiimid (2,30 ml) were added. The reaction mixture was cooled to 15 °C, a then, keeping the temperature constant, solution of pyridinium trifluoracetate (2,30 g) in CH2C12 (10 ml) was added dropwise during 30 minutes. The reaction mixture was stirred at 15 °C to room temperature for additional 2 hours. To the reaction mixture saturated aqueous solution of NaCl (40 ml) was added and the pH value was adjusted to pH 9.5. The layers were separated and the water layer was extracted two more times with CH2C12. Combined organic extracts were rinsed with brine, NaHC03 and water, dried over K2C03 and evaporated yielding 1,36 g of the crude product which is dissolved in MeOH (50 ml) and stirred for 24 hours at room temperature. The solvent was evaporated and the residue purified by low pressure chromatography on a silica gel column using the system CH2C12 : MeOH : NH4OH = 90: 3: 0,3. The combining and evaporating of chromatographically homogenous fractions gave the title product (0,313 g) with following physical-chemical constants: TLC Ru= 0. 51 (CH2Cl2 : MeOH : NH4OH = 90: 9: 0.5).

IR (KBr) [vcm~l] : 3373,2968, 2936,2877, 1728,1716, 1615,1526, 1520,1456, 1384,1261, 1181,1099, 1031,961, 864,799, 737.

MS m/z: (ES): MH = 660,6 1H NMR (300 MHz, CDC13) [8/ppm] 4.91 (13-H), 4.21 (1'-H), 4.20 (9a-NCON'H), 3.96 (1"-H), 3.63 (11-H), 3.53 (5'-H), 3. 78 (5-H), 3.26 (2'-H), 2.64 (2-H), 2.59 (10-H), 2.54 (3'-H), 2.32 (3'-N (CH3) 2), 2.08 (4-H), 2.06 (8-H), 1. 82 (14-Ha), 1.73 (4'-Ha), 1.62 (14-Hb), 1. 48 (7-Ha), 1.39 (6-CH3), 1.36 (7-Hb), 1. 28 (10-CH3), 1.27 (4'-Hb), 1.24 (5'-CH3), 1.24 (4-CH3), 1.15 (12-CH3), 1.13 (1"-(CH3)2), 0.97 (8-CH3), 0.96 (2-CH3), 0. 87 (15-CH3).

13C NMR (75 MHz, CDCl3) [#/ppm] 176.4 (1-C), 157.4 (9a-NCONH), 103.7 (1'-C), 103.1 (3-C), 94.2 (5-C), 83. 8 (6-C), 83. 3 (11-C), 79.0 (13-C), 75. 4 (12-C), 69.7 (5'-C), 69.6 (2'-C), 65.4 (3'-C), 49.2 (2-C), 48.3 (4-C), 46.5 (10-C), 42.6 (1'=C), 41.4 (7-C), 40.4 (3'-N (CH3) 2), 29.0 (4'-C), 28. 8 (8-C), 26.3 (6-CH3), 23.6 (1"-(CH3)2), 21.6 (14-C), 21.2 (5'-CH3), 21.2 (8-CH3), 17.7 (12- CH3), 14.3 (10-CH3), 13.9 (2-CH3), 12.9 (4-CH3), 10. 8 (15-CH3), .

Example 14.

3-Decladinosyl-3, 6-cyclic ether-9-deoxo-9-dihydro-9a-N- (N-isopropylcarbamoyl)- 9a-aza-9a-homoerythromycin A To a solution of 2'-O-Acetyl-3-O-mesyl-3-decladinosyl-9-deoxo-9-dihydro-9a-N- (N'- isopropylcarbamoyl) -9a-aza-9a-homoerythromycin A from Example 12. (0,80 g) in DMF/THF (3,5 ml/1 ml) suspension (60%) of NaH in mineral oil (163 mg) was added and the reaction mixture was stirred at 0 °C for 5 hours, and additional 20h at the room temperature. The reaction mixture was poured into saturated aqueos solution of NaHC03 (20 ml), EtOAc (20 ml) was added and the layers were separated. The water layer was extracted two more times with EtOAc. Combined organic extracts were rinsed with NaHC03 and brine, dried over K2C03 and evaporated yielding 0.53 g of product.

The obtained product was dissolved in MeOH (20 ml) was stirred for 24 hours at room temperature. The solvent was evaporated and the crude product was purified by chromatography on a silica gel column using the system CH2C12 : MeOH : NH4OH = 90 : 3: 0.3. The combining and evaporating of chromatographically homogenous fractions gave the title product (0.17 g) with following physical-chemical constants: TLC Rft= 0. 32 (CH2Cl2 : MeOH : NH4OH = 90: 9: 0.5).

IR (KBr) [vcm'] : 3428,2972, 2938, 2876, 1735,1619, 1528, 1459,1383, 1330, 1270,1179, 1144,1073, 1051,1030, 961, 893, 835, 799,759, 635.

MS m/z: (ES) : MHS-644, 2 1H NMR (300 MHz, CDCl3) [#/ppm] 4.90 (13-H), 4.24 (1'-H), 4.20 (9a-NCON'H), 3.95 (1"-H), 3. 83 (11-H), 3.64 (3-H), 3.55 (5--H), 3.57 (5-H), 3.33 (2'-H), 3.25 (9-Ha), 2.92 (9-Hb), 2.76 (3'-H), 2.57 (2-H), 2. 48 (3'-N (CH3) 2), 2.06 (8-H), 2.04 (4-H), 1.92 (4'-Ha), 1.83 (14-Ha), 1.64 (14-Hb), 1.64 (7- Ha), 1.33 (4'-Hb), 1.29 (7-Hb), 1. 28 (10-CH3), 1.26 (5'-CH3), 1.24 (4-CH3), 1.23 (6- CH3), 1.19 (2-CH3), 1.14 (12-CH3), 1.13 (1"- (CH3) 2), 0.96 (8-CH3), 0. 88 (15-CH3).

13C NMR (75 MHz, CDCl3) [8/ppm] 176.6 (1-C), 157.8 (9a-NCONH), 103.9 (1'-C), 93.4 (5-C), 84. 0 (6-C), 83. 6 (3-C), 78.7 (13-C), 75.5 (12-C), 69.5 (2'-C), 69.4 (5'-C), 65.4 (3'-C), 46.5 (2-C), 45.7 (4-C), 42.6 (1"-C), 40.5 (3'-N (CH3) 2), 40.3 (7-C), 30.1 (4'-C), 28.9 (8-C), 23.6 (1"-(CH3) 2), 23.1 (6- CH3), 21.7 (14-C), 21.3 (8-CH3), 21.1 (5'-CH3), 18. 0 (12-CH3), 18. 0 (4-CH3), 14.3 (2- CH3), 12.8 (10-CH3), 11.0 (15-CH3).

Example 15.

3-Decladinosyl-3-O- (4-nitrophenyl) acyl-9-deoxo-9-dihydro-9a-N- (N'- isopropylcarbamoyl)-9a-aza-9a-homoerythromycin A To a solution of 4-nitrophenylacetic acid (0. 85 g) in dry CH2C12 (25 ml) TEA (0.65 ml) was added and the reaction mixture was cooled to 2-5 °C. Pyvaloyl chloride (0.57 ml) was added and the reaction mixture was stirred at the same temperature for 30 minutes.

To a reaction mixture pyridine (1,27 ml) and the solution of 2'-O-Acetyl-3- decladinosyl-9-deoxo-9-dihydro-9a-N-(N-isopropylcarbamoyl)-9 a-aza-9a- homoerythromycin A from Example 11 (1,00 g) in dry CH2C12 (5 ml) were added and the reaction mixture was stirred at room temperature for 20 hours. Saturated aqueous solution of NaHC03 (30 ml) was added and the layers were separated. The water layer was extracted two more times with CH2C12. Combined organic extracts were rinsed with brine, dried over K2CO3 and evaporated yielding 1,429 g of oily product. The obtained product was dissolved in MeOH (50 ml) was stirred for 24 hours at room temperature.

The solvent was evaporated and the crude product was purified by chromatography on a silica gel column using the system CH2C12 : MeOH : NHtOH = 90: 3: 0.3. The combining and evaporating of chromatographically homogenous fractions gave the title product (0.45 g) with following physical-chemical constants: TLC Rf= 0. 40 (CH2C12 : MeOH : NH4OH = 90: 9: 0.5).

IR (KBr) [vcm-1] : 3449,2975, 2939, 2877, 2791, 1741,1626, 1604,1523, 1459, 1382,1347, 1255, 1167,1111, 1075,1051, 1032,984, 959, 856, 767,728, 687.

MS m/z : (ES) : MH+ = 825 H NMR (300 MHz, CDCl3) [#/ppm] 8.21 (4"'-H, 6'''-H), 7,54 (3"°-H, 7'''-H), 5.43 (3-H), 5.06 (13-H), 4. 42 (9a- NCONMH), 4.23 (1'-H), 3.92 (1'''-H), 3.60 (5-H), 3.49 (5'-H), 3.26 (2'-H), 2. 68 (2-H), 2.45 (3'-H), 2.29 (3'-N (CH3) 2), 2.20 (8-H), 1.95 (14-Ha), 1.90 (4-H), 1.66 (4'-Ha), 1.50 (14-Hb), 1.32 (6-CH3), 1.26 (4'-Hb), 1.29 (10-CH3), 1.22 (5'-CH3), 1.17 (12-CH3), 1.05 (4-CH3), 0.95 (2-CH3), 1.15 (1"-(CH3) 2), 1.08 (8-CH3), 0.87 (15-CH3).

13C NMR (75 MHz, CDC13) [8/ppm] 174.7 (1-C), 169.9 (1"-CO), 158. 7 (9a-NCONH), 147.1 (5"'-C), 141.5 (2"'-C), 130.5 (3"'-C, 7"'-C), 123.6 (2'''-C, 6"'-C), 103.4 (1'-C), 88. 3 (5-C), 78.1 (13-C), 74.5 (3- C), 74. 2 (6-C), 70.4 (2'-C), 69.8 (5'-C), 65.4 (3'-C), 44.6 (2-C), 41.3 (1'''-C), 38.4 (4- C), 48. 7 (1"-C), 41.3 (7-C), 40.2 (3'-N (CH3) 2), 28.7 (4'-C), 27.8 (8-C), 27.4 (6-CH3), 23.2 (1"-(CH3)2), 21.7 (14-C), 20.7 (8-CH3), 20.8 (5'-CH3), 16.9 (12-CH3), 15.2 (2- CH3), 12.5 (10-CH3), 11.0 (15-CH3), 8.9 (4-CH3).

Example 16.

2'-O-Acetyl-3-decladinosyl-9-deoxo-9-dihydro-9a-N-[N'-(2, 4- dichlorphenyl) carbamoyl]-9a-aza-9a-homoerythromycin A To a solution of 3-decladinosyl-9-deoxo-9-dihydro-9a-N-[N'-(2, 4- dichlorphenyl) carbamoyl]-9a-aza-9a-homoerythromycin A (6,60 g) in CH2C12 (250 ml), NaHC03 (3,25 g) and acetic acid anhydride (895go) were added and it was then stirred for 24 hours at room temperature. In to the reaction mixture a saturated NaHC03 solution was added, the layers were separated and the aqueous one was extracted two more times with CH2C12. The combined organic extracts were rinsed with saturated NaHC03 solution and water and evaporated yielding the title product (6,30 g) with following physical-chemical constants: TLC Rf = 0. 33 (CH2Cl2 : MeOH: NH4OH = 90 : 9: 1,5).

IR (KBr) fvcm-1] : 3545,3448, 3393,2972, 2940,2882, 2831,2787, 1727, 1638, 1586, 1522,1490, 1460,1382, 1335,1309, 1298, 1247, 1201 ; 1166,1100, 1057,1036, 1006, 985, 947, 893, 864, 817, 756,702, 669,620.

MS m/z: (ES): MH = 806, 16 Example 17.

2'-O-Acetyl-3-O-mesyl-3-decladinosyl-9-deoxo-9-dihydro-9a -N- [Ns-(2, 4- dichlorphenyl) carbamoyl]-9a-aza-9a-homoerythromycin A To a solution of 2'-O-Acetyl-3-decladinosyl-9-deoxo-9-dihydro-9a-N [N- (2, 4- dichlorphenyl) carbamoyl]-9a-aza-9a-homoerythromycin A (1,50 g) in pyridine (60 ml) methylsulphonyl anhydride (1, 16 g) was added and the reaction mixture was stirred at room temperature for 3 hours. The solvent was evaporated and the residue was dissolved in CH2Cl2 (50 ml). Saturated aqueous solution of NaHCO2 (50 ml) was added, the layers were separated and the water layer was extracted two more times with CH2Cl2 Combined organic extracts were rinsed with NaHC03 and brine, dried over K2CO3 and evaporated yielding 1,62 g of crude product with following physical-chemical constants TLC Rf = 0,69 (etihylacetate: hexane: diethylamine = 10: 10: 2).

IR (KBr) [vem-l] : 3448,3058, 2935,1735, 1655,1637, 1603, 1560, 1528, 1486, 1376, 1332,1240, 1208,1193, 1097,1059, 1001,916, 822, 785, 773,753, 681, 609.

MS m/z: (ES) : MH = 884,05 Example 18.

3-Decladinosyl-3, 6-hemiketal-9-deoxo-9-dihydro-9a-N- [N'- (2, 4- dichlorphenyl) carbamoyl]-9a-aza-9a-homoerythromycin A To a solution of 2'-O-Acetyl-3-decladinosyl-9-deoxo-9-dihydro-9a-N [N- (2, 4- dichlorphenyl) carbamoyl]-9a-aza-9a-homoerythromycin A (2,00 g) from Example 16. in CH2C12 (30 ml) dimethylsulfoxide (2,66 ml) and N, N-dimethyl-aminopropyl-ethyl- carbodiimid (2,85 ml) were added. The reaction mixture was cooled to 15 °C, a then, keeping the temperature constant, solution of pyridinium trifluoracetate (2,15 g) in CH2C12 (10 ml) was added drop wise during 30 minutes. The reaction mixture was stirred at 15 °C to room temperature for additional 2 hours. To the reaction mixture saturated aqueous solution of NaCl (40 ml) was added and the pH value was adjusted to pH 9. 5. The layers were separated and the water layer was extracted two more times with CH2C12 Combined organic extracts were rinsed with brine, NaHC03 and water, dried over K2CO3 and evaporated yielding 1,10 g of the crude product which is dissolved in MeOH (50 ml) and stirred for 24 hours at room temperature. The solvent was evaporated and the residue purified by low pressure chromatography on a silica gel column using the system CH2C12 : MeOH : NH40H = 90: 3: 0,3. The combining and evaporating of chromatographically homogenous fractions gave the title product (0,516 g) with following physical-chemical constants: TLC Rf= 0. 60 (CH2Cl2 : MeOH : NH4OH = 90: 9: 0.5).

IR (KBr) [vcm l] : 3448,2974, 2938,2877, 2782,1720, 1667, 1580, 1512,1460, 1384, 1324,1299, 1231,1195, 1115, 1099,1072, 1049,962, 862, 823.

MS m/z: (ES): MW = 762,12 'H NMR (300 MHz, CDCl3) [8/ppm] 8. 14 (6"-H), 7.32 (3"-H), 7.19 (5"-H), 4.91 (13-H), 4.36 (9a-NCON'H), 4.21 (1'-H), 3. 80 (5-H), 3.63 (11-H), 3.51 (5'-H), 3.23 (2'-H), 2.59 (10-H), 2.56 (2-H), 2.49 (3'-H), 2.27 (3'-N (CH3) 2), 2.20 (8-H), 2.09 (4-H), 1.83 (14-Ha), 1. 68 (4'-Ha), 1. 62 (14-Hb), 1.55 (7- Ha), 1.47 (7-Hb), 1.42 (6-CH3), 1.30 (2-CH3), 1.26 (4'-Hb), 1.26 (5'-CH3), 1.24 (4- CH3), 1.21 (12-CH3), 1.19 (10-CH3), 1.07 (8-CH3), 0.88 (15-CH3).

13C NMR (75 MHz, CDC13) [8/ppm] 177.4 (1-C), 154.8 (9a-NCONH), 134.8 (1"-C), 128.3 (3"-C), 127.3 (5"-C), 127.1 (2-C), 122.7 (4"-C), 121. 9 (6"-C), 106.2 (1'-C), 103.3 (3-C), 94.2 (5-C), 83.6 (6-C), 83. 3 (11- C), 79. 0 (13-C), 75.6 (12-C), 69.7 (2'-C), 69.6 (5'-C), 65.5 (3'-C), 49.2 (2-C), 48.4 (4- C), 46.3 (10-C), 41. 4 (7-C), 40.3 (3'N-(CH3) 2), 28.6 (4'-C), 28. 4 (8-C), 21.6 (14-C), 23.3 (5'-CH3), 26.4 (6-CH3), 21.5 (8-CH3), 17.7 (12-CH3), 16.8 (12-CH3), 14.2 (10- CH3), 13. 8 (2-CH3), 12. 9 (4-CH3), 10.9 (15-CH3).

Example 19.

3-Decladinosyl-3, 6-cyclic ether-9-deoxo-9-dihydro-9a-N- [N'- (2, 4- dichlorphenyl) carbamoyl]-9a-aza-9a-homoerythromycin A To a solution of 2'-O-Acetyl-3-O-mesyl-3-decladinosyl-9-deoxo-9-dihydro-9a-N [N- (2,4-dichlorphenyl) carbamoyl] -9a-aza-9a-homoerythromycin A from Example 12. (1, 50 g) in DNWITBF (57 ml/19 ml) suspension (60%) of NaH in mineral oil (270 mg) was added and the reaction mixture was stirred at 0 °C for 5 hours, and additional 20h at the room temperature. The reaction mixture was poured into saturated aqueous solution of NaHC03 (30 ml), EtOAc (30 ml) was added and the layers were separated. The water layer was extracted two more times with EtOAc. Combined organic extracts were rinsed with NaHCO3 and brine, dried over K2CO3 and evaporated yielding 1,25 g of product. The obtained product was dissolved in MeOH (20 ml) was stirred for 24 hours at room temperature. The solvent was evaporated and the crude product was purified by chromatography on a silica gel column using the system CH2C12: MeOH : NAH = 90 : 3: 0.3. The combining and evaporating of chromatographically homogenous fractions gave the title product (0.27 g) with following physical-chemical constants: TLC Ru 0. 42 (CH2C12 : MeOH : NH40H = 90: 9: 0.5).

IR (KBr) [vcm-1] : 3448,2971, 2936,2875, 2782,1736, 1670,1579, 1510,1460, 1383,1327, 1299,1260, 1177,1142, 1115,1099, 1072,1047, 961,890, 861, 829,763, 670,630.

MS m/z: (ES): Ex-746, 02 'H NMR (300 MHz, CDCl3) [8/ppm] 8.17 (6"-H), 7.32 (3"-H), 7.18 (5"-H), 4.91 (13-H), 4.23 (9a-NCON'H), 4.20 (1'-H), 3.88 (11-H), 3.56 (5-H), 3.51 (5'-H), 3.18 (2'-H), 2.59 (2-H), 2. 52 (3'-H), 2.29 (3'-N (CH3) 2), 2. 18 (8-H), 2.06 (4-H), 1.84 (14-Ha), 1.71 (14-Hb), 1.69 (4'-Ha), 1.63 (7-Ha), 1.44 (4'- Hb), 1.28 (10-CH3), 1.27 (7-Hb), 1.25 (6-CH3), 1.23 (4-CH3), 1.21 (5'-CH3) 1.20 (2- CH3), 1.13 (12-CH3), 1.06 (8-CH3), 0. 89 (15-CH3).

13C NMR (75 MHz, CDCl3) [8/ppm] 176.1 (1-C), 154.2 (9a-NCONH), 134.4 (1&num -C), 127.6 (3"C), 127.1 (5"-C), 126.4 (2"-C), 122.1 (4"-C), 121.2 (6"-C), 104.3 (1'-C), 93.4 (5-C), 83.3 (11-C), 83. 2 (6-C), 82.8 (3- C), 79.1 (13-C), 74.9 (12-C), 69.1 (5'-C), 69.0 (2'-C), 64.9 (3'-C), 45.7 (2-C), 45.2 (4- C), 40.1 (7-C), 39.7 (3-N-(CH3) 2), 30.0 (4'-C), 29.2 (8-C), 21.2 (14-C), 21.0 (5'-CH3), 22.7 (6-CH3), 20.9 (8-CH3), 12.6 (4-CH3), 17.0 (12-CH3), 12. 8 (10-CH3), 13.7 (2- CH3), 10.4 (15-CH3).

Example 20.

3-Decladinosyl-3-O- (4-nitrophenyl)acyl-9-deoxo-9-dihydro-9a-N-[N'-(2,4- dichlorphenyl) carbamoyl]-9a-aza-9a-homoerythromycin A To a solution of 4-nitrophenylacetic acid (0.74 g) in dry CH2C12 (25 ml) TEA (0.57 ml) was added and the reaction mixture was cooled to 2-5 °C. Pyvaloyl chloride (0.50 ml) was added and the reaction mixture was stirred at the same temperature for 30 minutes.

To a reaction mixture pyridine (1,1 ml) and the solution of 2'-O-Acetyl-3-decladinosyl- 9-deoxo-9-dihydro-9a-N- [N- (2, 4-dichlorphenyl) carbamoyl]-9a-aza-9a- homoerythromycin A from Example 16 (1,00 g) in dry CH2C12 (5 ml) were added and the reaction mixture was stirred at room temperature for 20 hours. Saturated aqueous solution of NaHC03 (30 ml) was added and the layers were separated. The water layer was extracted two more times with CH2C12. Combined organic extracts were rinsed with brine, dried over K2CO3 and evaporated yielding 1, 14 g of oily product. The obtained product was dissolved in MeOH (50 ml) was stirred for 24 hours at room temperature.

The solvent was evaporated and the crude product was purified by chromatography on a silica gel column using the system CH2C12 : MeOH : NH4OH = 90: 3: 0.3. The combining and evaporating of chromatographically homogenous fractions gave the title product (0.52 g) with following physical-chemical constants: TLC Ri= 0. 55 (CH2C12: MeOH : NH4OH = 90: 9: 0.5).

IR (KBr) [vcm-l] : 3448,2975, 2938,2879, 2789,1741, 1665,1607, 1578,1522, 1459,1382, 1347, 1298, 1256,1229, 1165,1110, 1074,1050, 983,958, 857, 821, 731,685, 669.

MS m/z: (ES): Oh+ = 927,2 H NMR (300 MHz, CDCl3) [8/ppm] 8.18 (4°"-H, 6'''-H), 8.13 (6"-H), 7.51 (3"'-H, 7'''-H), 7,32 (3"-H), 7.18 (5"-H), 5.36 (3-H), 5.03 (13-H), 4.42 (9a-NCON'H), 4.23 (1'-H), 3. 80 (1'''-H), 3.69 (5-H), 3.49 (5'- H), 3.25 (2'-H), 2. 68 (2-H), 2.45 (3'-H), 2.32 (3'-N (CH3) 2), 2. 29 (8-H), 1. 92 (14-Ha), 1.92 (4-H), 1.66 (4'-Ha), 1.58 (7-Ha), 1.51 (14-Hb), 1. 38 (10-CH3), 1.32 (6-CH3), 1.26 (7-Hb), 1.18 (4'-Hb), 1.24 (12-CH3), 1.16 (5'-CH3), 1.07 (8-CH3), 0.95 (2-CH3), 0.94 (4-CH3), 0.85 (15-CH3).

13C NMR (75 MHz, CDCl3) [8/ppm] 174.9 (1-C), 169.9 (1"-CO), 154. 9 (9a-NCONH), 147.2 (5'''-C), 141,3 (2"'-C), 134. 8 (1"-C), 130.6 (3'''-C, 7'''-C), 128. 5 (3"-C), 127.4 (2"-C, 5"-C), 123.7 (2'''-C, 6'''-C), 122.6 (4"-C), 122.2 (6"-C), 103. 9 (1'-C), 88. 3 (5-C), 77.6 (13-C), 74.3 (3-C), 74.2 (6- C), 70.5 (2'-C), 69.8 (5'-C), 65.5 (3'-C), 47.3 (4-C), 44.6 (2-C), 41.2 (1'''-C), 41.2 (7- C), 40.5 (3'-N (CH3) 2), 29.1 (4'-C), 27.5 (8-C), 27.4 (6-CH3), 22. 0 (14-C), 21.1 (5'- CH3), 21.0 (8-CH3), 12.3 (12-CH3), 13.1 (10-CH3), 11.2 (15-CH3), 3.2 (4-CH3).

Example 21. <BR> <BR> <BR> <P>3-Decladinosyl-6-O-Me-9-deoxo-9-dihydro-9a-N- (N'-isopropylcarbamoyl)-9a-aza- 9a-homoerythromycin A To a solution of 3-decladinosyl-6-O-Me-9-deoxo-9-dihydro-9a-aza-9a- homoerythromycin A (0,20 g) in acetonitrile (20 ml) isopropylisocyanate (0,07 ml) was added. Reaction mixture was stirred for 2 hours at room temperature. The solvent was evaporated and 0,25 g of crude product is obtained. Crude product was purified by chromatography on a silica gel column using the system (CH2Cl2 : MeOH : NH4OH = 90: 5: 0.5). The combining and evaporating of chromatographically homogenous fractions gave the title product (0. 128 g) with following physical-chemical constants: TLC Rf= 0. 54 (CHC13 : MeOH : NH4OH = 6: 1: 0.1).

IR (KBr) [vcm-1] : 3424,2975, 2937,2877, 1732,1687, 1627,1562, 1525,1460, 1379,1270, 1166,1112, 1080,1053, 984, 958, 938,896, 828, 766.

MS m/z: (ES): MH+ = 676, 8 IH NMR (300 MHz, CDCl3) [8/ppm] 5.16 (13-H), 4.44 (1'-H), 3.91 (1"-H), 3.65 (3-H), 3.73 (5-H), 3. 53 (5'-H), 3.23 (2'-H), 3.14 (6-OCH3), 2. 61 (2-H), 2. 48 (3'-H), 2.25 (3'-N (CH3) 2,), 1.82 (4-H), 1.91 (14a-H), 2.03 (8-H), 1.66 (4'a-H), 1.49 (14b-H), 1.35 (18-CH3), 1.28 (16-CH3), 1.25 (20-CH3), 1.25 (5'-CH3) 1. 25 (4'b-H), 1.15 (1"-(CH3)2), 1.14 (21-CH3), 1.05 (17-CH3), 0.96 (19- CH3), 0. 88 (15-CH3).

13C NMR (75 MHz, CDCl3) [S/ppm] 175.8 (1-C), 155.1 (9a-NCONH), 106.6 (1'-C), 90.2 (5-C), 79.5 (6-C), 78.9 (3-C), 74.2 (I1-C), 74.7 (12-C), 70.5 (2'-C), 70.0 (5'-C), 65.7 (3'-C), 49.8 (6-OCH3), 44.8 (2-C), 42.7 (1"-C), 40.3 (3'N- (CH3) 2), 36.4 (4-C), 28.1 (4'-C), 27.5 (8-C), 23.6 (18-CH3), 23.3 (1"-(CH3) 2), 22.3 (14-C), 21.3 (5'-CH3), 20.6 (19-CH3), 16.9 (21-CH3), 15.5 (16-CH3), 12.6 (20-CH3), 11.2 (15-CH3), 7.7 (17-CH3).

Example 22.

2'-O-Acetyl-3-decladinosyl-6-O-Me-9-deoxo-9-dihydro-9a-N- (N'- isopropylcarbamoyl)-9a-aza-9a-homoerythromycin A To a solution of 3-decladinosyl-6-O-Me-9-deoxo-9-dihydro-9a-N-(N- isopropylcarbamoyl)-9a-aza-9a-homoerythromycin A (1,08 g) in CH2C12 (20 ml), NaHC03 (0,54 g) and acetic acid anhydride (166µl) were added and it was then stirred for 20 hours at room temperature. Onto the reaction mixture a saturated NaHC03 solution was added, the layers were separated and the aqueous one was extracted two more times with CH2C12. The combined organic extracts were rinsed with saturated NaHC03 solution and water and evaporated yielding the title product (0,68 g) with following physical-chemical constants: TLC Rf= 0. 57 (CHC13: MeOH : NH4OH = 6: 1: 0.1).

IR (KBr) [vcm-l] : 3431,2974, 2937, 2876, 1734,1629, 1524,1459, 1376,1243, 1167,1083, 1058, 985,957, 938,904, 806, 671.

MS m/z : (ES): MH+ = 718,22 Example 23.

2'-O-Acetyl-3-O-mesyl-6-O-Me-3-decladinosyl-9-deoxo-9-dih ydro-9a-N- (N- isopropylcarbamoyl)-9a-aza-9a-homoerythromycin A To a solution of 2'-O-Acetyl-3-decladinosyl-6-O-Me-9-deoxo-9-dihydro-9a-N-(N' - isopropylcarbamoyl) -9a-aza-9a-homoerythromycin A (0,35 g) in pyridine (15 ml) methylsulphonyl anhydride (0,30 g) was added and the reaction mixture was stirred at room temperature for 3 hours. The solvent was evaporated and the residue was dissolved in CH2C12 (20 ml). Saturated aqueous solution of NaHC03 (20 ml) was added, the layers were separated and the water layer was extracted two more times with CH2CI2 Combined organic extracts were rinsed with NaHC03 and brine, dried over K2CO3 and evaporated yielding 0,36 g of crude product with following physical-chemical constants TLC Ru= 0. 76 (CHC13 : MeOH : NH4OH = 6: 1: 0.1).

IR (ihr) [vcm-1] : 3427, 2975, 2932, 2877, 2854, 1739, 1628, 1524, 1462, 1375, 1342,1243, 1175,1112, 1060,958, 917, 830, 768,707, 669.

MS m/z : (ES): MH+ = 796, 28 Example 24.

3-keto-3-decladinosyl-6-O-Me-9-deoxo-9-dihydro-9a-N- (N'-isopropylcarbamoyl)- 9a-aza-9a-homoerythromycin A To a solution of 2'-O-Acetyl-3-decladinosyl-6-O-Me-9-deoxo-9-dihydro-9a-N-(N' - isopropylcarbamoyl) -9a-aza-9a-homoerythromycin A (0,18 g) in CH2Cl2 (10 ml) dimethylsulfoxide (0,21 ml) and N, N-dimethyl-aminopropyl-ethyl-carbodiimid (0, 28 ml) were added. The reaction mixture was cooled to 15 °C, a then, keeping the temperature constant, solution of pyridinium trifluoracetate (0,22 g) in CH2C12 (5 ml) was added drop wise during 30 minutes. The reaction mixture was stirred at 15 °C to room temperature for additional 2 hours. To the reaction mixture saturated aqueous solution of NaCl (20 ml) was added and the pH value was adjusted to pH 9.5. The layers were separated and the water layer was extracted two more times with CHzClz Combined organic extracts were rinsed with brine, NaHC03 and water, dried over K2CO3 and evaporated yielding 0,15 g of the crude product which is dissolved in MeOH (20 ml) and stirred for 24 hours at room temperature. The solvent was evaporated and the residue purified by low pressure chromatography on a silica gel column using the system CH2Cl2 : MeOH : NH4OH = 90: 3: 0,3. The combining and evaporating of chromatographically homogenous fractions gave the title product (0,074 g) with following physical-chemical constants: TLC Rf= 0. 32 (CH2C12 : MeOH : NH40H = 90: 9: 0.5).

IR (KBr) [vcm-l] : 3428,2936, 1741,1629, 1520, 1458, 1378, 1260, 1172, 1111, 1077,1050, 985,810.

MS m/z : (ES): MH+ = 674,27 tH NMR (300 MHz, CDCl3) [6/ppm] 5.11 (13-H), 4.42 (1'-H), 4.34 (5-H), 3.91 (1"-H), 3.82 (2-H), 3.63 (5'-H), 3.21 (2'-H), 3.12 (4-H), 2.99 (6-OCH3), 2.57 (3'-H), 2.33 (3'-N (CH3) 2, ), 2.04 (8-H), 1.94 (14a-H), 1.75 (4'a-H), 1.54 (14b-H), 1.38 (18-CH3), 1. 33 (16-CH3), 1.26 (20-CH3), 1.27 (5'- CH3), 1.27 (4'b-H), 1.16 (1"- (CH3) 2), 1.14 (21-CH3), 1.27 (17-CH3), 0.98 (19-CH3), 0.90 (15-CH3).

13C NMR (75 MHz, CDCl30 [#/ppm] 207.0 (3-C), 170.6 (1-C), 158.0 (9a-NCONH), 102.8 (1'-C), 75.8 (5-C), 79.4 (6-C), 74.4 (12-C), 74.2 (11-C), 70.3 (2'-C), 69. 2 (5'-C), 65. 8 (3'-C), 50.7 (2-C), 50.1 (6-OCH3), 45.7 (4-C), 42.8 (1"-C), 40.4 (3oN-(CH3) 2), 29.1 (4'-C), 27.4 (8-C), 23. 8 (18-CH3), 23.2 (1"-(CH3) 2), 22.4 (14-C), 21.2 (5'-CH3), 20. 8 (19-CH3), 16.8 (21-CH3), 14.0 (16-CH3), 13.2 (20-CH3), 12.5 (17-CH3), 11.3 (15-CH3).

Example 25.

2, 3-anhydro-3-decladinosyl-6-0-Me-9-deoxo-9-dihydro-9a-N- (N- isopropylcarbamoyl)-9a-aza-9a-homoerythromycin A To a solution of 2'-O-Acetyl-3-O-mesyl-3-decladinosyl-6-O-Me-9-deoxo-9-dihydr o-9a- N-(N'-isopropylcarbamoyl)-9a-aza-9a-homoerythromycin A (0,35 g) in DMF/THF (17 ml/5 ml) suspension (60%) of NaH in mineral oil (90 mg) was added and the reaction mixture was stirred at 0 °C for 5 hours. The reaction mixture was poured into saturated aqueos solution of NaHC03 (20 ml), EtOAc (20 ml) was added and the layers were separated. The water layer was extracted two more times with EtOAc. Combined organic extracts were rinsed with NaHC03 and brine, dried over K2CO3 and evaporated yielding 0.53 g of product. The obtained product was dissolved in MeOH (20 ml) was stirred for 24 hours at room temperature. The solvent was evaporated and the crude product was purified by chromatography on a silica gel column using the system (CH2Cl2 : MeOH : NH4OH = 90: 3: 0.3). The combining and evaporating of chromatographically homogenous fractions gave the title product (0.031 g) with following physical-chemical constants: TLC Rf= 0. 50 (CHC13 : MeOH : NU, OH = 6: 1: 0.1).

IR (KBr) [vcm-l] : 3439,2974, 2937,1735, 1628,1520, 1459, 1381, 1336,1270, 1175,1111, 1075,1051, 958,919, 832,766, 535.

MS m/z: (ES): MH+ = 658, 22 H NMR (300 MHz, CDC13) [8/ppm] 5.16 (13-H), 4.93 (3-H), 4.56 (1'-H), 3.90 (1"-H), 3.23 (5-H), 3.53 (5'-H), 3.27 (2'-H), 3.12 (6-OCH3), 2.70 (3'-H), 2.36 (3'-N (CH3) 2,), 1.52 (4-H), 1.91 (14a-H), 2.05 (8-H), 1.70 (4'a-H), 1.49 (14b-H), 1.36 (18-CH3), 1.30 (16-CH3), 1.25 (20-CH3), 1.25 (5'- CH3), 1.25 (4ob-H), 1.15 (1"- (CH3) 2), 1.12 (21-CH3), 1.06 (17-CH3), 0.96 (19-CH3), 0. 88 (15-CH3).

13C NMR (75 MHz, CDCl3) [#/ppm] 173.2 (1-C), 158.1 (9a-NCONH), 146.4 (2-C), 127. 4 (3-C), 106.7 (1'-C), 86.1 (5-C), 79.5 (6-C), 74.2 (11-C), 75.0 (12-C), 70.7 (2'-C), 68. 3 (5'-C), 65. 9 (3'-C), 50.7 (6- OCH3), 42.8 (1"-C), 39.0 (3'N-(CH3) 2), 40.4 (4-C), 29.1 (4'-C), 28.4 (8-C), 23.4 (18- CH3), 22.3 (14-C), 22.1 (1"- (CH3) 2), 20.9 (5'-CH3), 20.5 (19-CH3), 16. 8 (21-CH3), 14.2 (16-CH3), 12.5 (20-CH3), 11.4 (15-CH3), 8.8 (17-CH3).

Example 26.

3-Decladinosyl-6-O-Me-9-deoxo-9-dihydro-9a-N- [N- (2, 4- dichlorphenyl) carbamoyl] -9a-aza-9a-homoerythromycin A To a solution of 3-decladinosyl-6-O-Me-9-deoxo-9-dihydro-9a-aza-9a- homoerythromycin A (0,20 g) in acetonitrile (20 ml) 2,4-dichlorphenylisocyanate (0,064 6) was added. Reaction mixture was stirred for 30 min at room temperature. The solvent was evaporated and 0, 254 g of crude product is obtained. Crude product was purified by chromatography on a silica gel column using the system (CH2C12 : MeOH : NH4OH = 90: 5: 0.5). The combining and evaporating of chromatographically homogenous fractions gave the title product (0.169 g) with following physical-chemical constants: TLC Rf 0. 61 (CHC13: MeOH : NH4OH = 6 : 1: 0.1).

IR (KBr) [vcm-1] : 3448,2975, 2939,2879, 2787, 1729,1707, 1670,1582, 1517, 1459, 1382, 1328,1298, 1274,1165, 1112,1076, 1051,983, 956, 937, 897, 861, 822, 750,699.

MS m/z : (ES): MH+ = 778, 6 'H NMR (300 MHz, CDCl3) [8/ppm] 8.13 (6"-H), 7.34 (3"-H), 7. 18 (5"-H), 5.11 (13-H), 4.39 (1'-H), 3. 81 (5-H), 3.72 (3-H), 3.52 (5'-H), 3.35 (6-OCH3), 3.18 (2'-H), 2.61 (2-H), 2.61 (10-H), 2.50 (3'-H), 2.27 (3'- N (CH3) 2), 2.04 (8-H), 1.93 (14a-H), 1. 89 (4-H), 1.68 (4'a-H), 1.52 (14b-H), 1.35 (6- CH3), 1.33 (4'b-H), 1.28 (2-CH3), 1.25 (10-CH3), 1.23 (5'-CH3), 1.18 (12-CH3), 1.04 (4-CH3), 1.02 (8-CH3), 0.89 (15-CH3).

3C NMR (75 MHz, CDCl3) [#/ppm] 176.3 (1-C), 155.0 (9a-NCONH), 134.9 (1"-C), 128. 4 (3r-C), 127.7 (5"-C), 127.1 (2"- C), 122.7 (4"-C), 122.1 (6"-C), 106.9 (1'-C), 90.3 (5-C), 79.7 (3-C), 79.1 (6-C), 76.1 (13-C), 73.6 (11-C), 73.6 (12-C), 70.5 (2'-C), 69.9 (5'-C), 65.7 (3'-C), 49.9 (6-O-CH3), 44.7 (2-C), 40.3 (3ÆN-(CH3) 2), 36.7 (4-C), 35.5 (7-C), 28.3 (4'-H), 28. 2 (8-C), 22.4 (14- C), 21.3 (5'-CH3), 20.6 (18-CH3), 16.9 (21-CH3), 15.4 (16-CH3), 20.5 (20-CH3), 11. 4 (15-CH3), 7.6 (17-CH3).

Example 27.

2'-O-Acetyl-3-decladinosyl-6-O-Me-9-deoxo-9-dihydro-9a-N- [N'-(2, 4- dichlorphenyl) carbamoyl]-9a-aza-9a-homoerythromycin A To a solution of 3-decladinosyl-6-O-Me-9-deoxo-9-dihydro-9a-N-[N'-(2, 4- dichlorphenyl) carbamoyl]-9a-aza-9a-homoerythromycin A (0,12 g) in CH2Cl2 (10 ml), NaHC03 (0,058 g) and acetic acid anhydride (151) were added and it was then stirred for 24 hours at room temperature. Onto the reaction mixture a saturated NaHC03 solution was added, the layers were separated and the aqueous one was extracted two more times with CH2C12. The combined organic extracts were rinsed with saturated NaHC03 solution and water and evaporated yielding the title product (0,115 g) with following physical-chemical constants: TLC Rf= 0.29 (CHC13 : MeOH : NH40H = 90: 9: 0.5).

IR (KBr) [vcm 3449,2973, 2939,1748, 1730,1668, 1582, 1517, 1459,1377, 1298, 1261,1239, 1165, 1098, 1050,985, 906,866, 809,764, 664,622, 584, 544,505, 483, 463,444, 386.

MS m/z: (ES): MH+ = 820, 19 Example 28.

2'-O-Acetyl-3-O-mesyl-6-O-Me-3-decladinosyl-9-deoxo-9-dih ydro-9a-N- [N- (2, 4- dichlorphenyl) carbamoyl]-9a-aza-9a-homoerythromycin A To a solution of 2'-O-Acetyl-3-decladinosyl-6-O-Me-9-deoxo-9-dihydro-9a-N-[N' -(2, 4- dichlorphenyl) carbamoyl]-9a-aza-9a-homoerythromycin A (1,50 g) in pyridine (60 ml) methylsulphonyl anhydride (1,16 g) was added and the reaction mixture was stirred at room temperature for 3 hours. The solvent was evaporated and the residue was dissolved in CH2C12 (50 ml). Saturated aqueous solution of NaHCO3 (50 ml) was added, the layers were separated and the water layer was extracted two more times with CH2C12 Combined organic extracts were rinsed with NaHCO3 and brine, dried over K2CO3 and evaporated yielding 1,57 g of crude product with following physical-chemical constants TLC Rf 0. 68 (etihylacetate: hexane: diethylamine = 10: 10: 2).

IR (KBr) [vcm-l] : 3434,3060, 2974,2935, 1736,1701, 1686, 1655,1637, 1560, 1528,1509, 1486, 1376, 1330,1240, 1208,1193, 1059,785, 773, 753,681, 609.

MS m/z : (ES): MH+ = 898, 09 Example 29.

3-keto-3-decladinosyl-6-O-Me-9-deoxo-9-dihydro-9a-N- [N- (2, 4- dichlorphenyl) carbamoyl]-9a-aza-9a-homoerythromycin A To a solution of 2'-O-Acetyl-3-decladinosyl-6-O-Me-9-deoxo-9-dihydro-9a-N-[N' -(2, 4- dichlorphenyl) carbamoyl]-9a-aza-9a-homoerythromycin A (0,73 g) in CH2Cl2 (20 ml) dimethylsulfoxide (1,00 ml) and N, N-dimethyl-aminopropyl-ethyl-carbodiimid (1,02 6) were added. The reaction mixture was cooled to 15 °C, a then, keeping the temperature constant, solution of pyridinium trifluoracetate (1,03 g) in CH2C12 (20 ml) was added drop wise during 30 minutes. The reaction mixture was stirred at 15 °C to room temperature for additional 10 hours. To the reaction mixture saturated aqueous solution of NaCI (20 ml) was added and the pH value was adjusted to pH 9.5. The layers were separated and the water layer was extracted two more times with CH2C12 Combined organic extracts were rinsed with brine, NaHC03 and water, dried over K2CO3 and evaporated yielding 0,63 g of the crude product which is dissolved in MeOH (20 ml) and stirred for 24 hours at room temperature. The solvent was evaporated and the residue purified by low pressure chromatography on a silica gel column using the system (CH2C12 : M : eOH : NH40H = 90: 5: 0,5. The combining and evaporating of chromatographically homogenous fractions gave the title product (0,253 g) with following physical-chemical constants: TLC Ru 0. 61 (CHCI3 : MeOH : NH4OH = 6: 1 : 0. 1).

IR (KBr) [vcm-1] : 3448, 2976, 2938, 2877, 2786, 1741,1719, 1665, 1580, 1515, 1459, 1381, 1298,1230, 1197,1167, 1147, 1110,1076, 1051, 986,957, 937,895, 859,821, 761,753, 622.

MS m/z: (ES) : MH = 776,6 1H NMR (300 MHz, CDCl3) [#/ppm] 8.10 (6°-H), 7.34 (3"-H), 7.18 (5"-H), 5.08 (13-H), 4.40 (1'-H), 4.31 (5-H), 3. 81 (2-H), 3.62 (5'-H), 3.44 (6-OCH3), 3.17 (4-H), 3.16 (2'-H), 2.75 (10-H), 2.49 (3'-H), 2. 28 (3'- N (CH3) 2), 2.19 (8-H), 1.94 (14a-H), 1.68 (4'a-H), 1.56 (14b-H), 1. 32 (6-CH3), 1.30 (2- CH3), 1.27 (7a-H), 1.24 (10-CH3), 1.23 (4'b-H), 1.23 (5'-CH3), 1.19 (12-CH3), 1.06 (4- CH3), 1.03 (7b-H), 1.02 (8-CH3), 0.91 (15-CH3).

13C NMR (75 MHz, CDCl3) [S/ppm] 207.1 (3-C), 171.1 (1-C), 155.6 (9a-NCONH), 135.1 (1"-C), 128.8 (3"-C), 128.2 (5"-C), 127.8 (2"-C), 123.1 (4"-C), 122.5 (6"-C), 103. 1 (1'-C), 79.9 (6-C), 79.5 (13-C), 76.2 (5- C), 73.9 (12-C), 73.4 (11-C), 70.8 (2'-C), 69.7 (5'-C), 65.9 (3'-C), 51.1 (2-C), 50.9 (4- C), 50.6 (6-O-CH3), 40. 8 (3'N- (CH3) 2), 39.0 (7-C), 29.3 (4'-H), 28.6 (8-C), 22.7 (14-C), 21.6 (5'-CH3), 21.3 (19-CH3), 17.2 (21-CH3), 13.6 (16-CH3), 12.8 (20-CH3), 11.6 (15- CH3), 7.6 (17-CH3).

Example 30.

2, 3-anhydro-3-decladinosyl-6-O-Me-9-deoxo-9-dihydro-9a-N- [N- (2,4- dichlorphenyl) carbamoyl]-9a-aza-9a-homoerythromycin A To a solution of 2'-O-Acetyl-3-O-mesyl-3-decladinosyl-6-O-Me-9-deoxo-9-dihydr o-9a- N [N- (2, 4-dichlorphenyl) carbamoyl] -9a-aza-9a-homoerythromycin A (1,00 g) in DMF/THF (45 ml/13 ml) suspension (60%) of NaH in mineral oil (400 mg) was added and the reaction mixture was stirred at 0 °C. The reaction mixture was poured into saturated aqueos solution of NaHCO3 (50 ml), EtOAc (50 ml) was added and the layers were separated. The water layer was extracted two more times with EtOAc. Combined organic extracts were rinsed with NaHC03 and brine, dried over K2CO3 and evaporated yielding 0.32 g of product. The obtained product was dissolved in MeOH (20 ml) was stirred for 24 hours at room temperature. The solvent was evaporated and the crude product was purified by chromatography on a silica gel column using the system (CH2C12 : MeOH : NH4OH = 90: 3: 0.3). The combining and evaporating of chromatographically homogenous fractions gave the title product (0.024 g) with following physical-chemical constants : TLC Rf= 0. 43 (etihylacetate: hexane: diethylamine = 10: 10: 2).

IR (KBr) [vcm-1] : 3452, 2981, 2941,1748, 1731,1662, 1582,1516, 1459,137, 1298, 1261,1243, 1165,1098, 1052,985, 906, 867,810, 764, 666,625, 587.

MS m/z : (ES): MH+ = 760,70 'H NMR (300 MHz, CDCl3) [8/ppm] 8. 12 (6"-H), 7.34 (3"-H), 7.18 (5"-H), 5.16 (13-H), 4.92 (3-H), 4.39 (1'-H), 3.20 (5-H), 3.52 (5'-H), 3.30 (6-OCH3), 3.18 (2'-H), 2.61 (10-H), 2.50 (3'-H), 2. 27 (3'-N (CH3) 2), 2.04 (8-H), 1.93 (14a-H), 1.68 (4'a-H), 1.55 (4-H), 1.52 (14b-H), 1.35 (6-CH3), 1.29 (2- CH3), 1.26 (4'b-H), 1.25 (10-CH3), 1.25 (5'-CH3), 1.13 (12-CH3), 1.04 (4-CH3), 0.97 (8-CH3), 0.89 (15-CH3).

13C NMR (75 MHz, CDCl3) [8/ppm] 176.3 (1-C), 156.0 (9a-NCONH), 146. 8 (2-C), 127.7 (3-C), 134.8 (1"-C), 128.3 (3"-C), 127.5 (5"-C), 127.0 (2"-C), 122.8 (4"-C), 122.1 (6"-C), 106.9 (1'-C), 86.3 (5-C), 79.1 (6-C), 76.1 (13-C), 73.4 (11-C), 73.5 (12-C), 70.7 (2'-C), 69.9 (5'-C), 65.7 (3'-C), 50.0 (6-O-CH3), 40.3 (3'N-(CH3) 2), 40.7 (4-C), 35.4 (7-C), 28.3 (4'-H), 28.2 (8-C), 22.4 (14- C), 21.3 (5'-CH3), 20.6 (8-CH3), 16.9 (21-CH3), 14.2 (2-CH3), 12.8 (20-CH3), llv4 (15- CH3), 7.6 (4-CH3).