9A-N-(N&#39;-carbamoyl)and 9A-N-(N&#39;-thiocarbamoyl) derivatives of 9-deoxo-9A-aza-9A-homoerythromycin A
The present invention relates to 9a-N-(N&#39;-carbamoyl) and 9a-N-(N&#39;-thiocarbamoyl) derivatives of 9-deoxo-9a-aza-9a-homoerythromycin A, novel semisynthetic macrolide antibiotics of the azalide series having an antibacterial action of the general formula (I) ##STR2## wherein R represents a C 1  -C 3  alkyl, aryl or aralkyl group and X represents O or S, to pharmaceutically acceptable addition salts thereof with inorganic or organic acids, to a process for the preparation thereof, to a process for the preparation of the pharmaceutical compositions as well as to the use of pharmaceutical compositions obtained in the treatment of bacterial infections. 
     Erythromycin A is a macrolide antibiotic, whose structure is characterized by a 14-member macrolactone ring having a carbonyl group in C-9 position. It was found by McGuire in 1952 (Antibiot. Chemother., 1952; 2:281) and for over 40 years it has been considered as a reliable and effective antimicrobial agent in the treatment of diseases caused by Gram-positive and some Gram-negative microorganisms. However, in an acidic medium it is easily converted into anhydroerythromycin A, an inactive C-6/C-12 metabolite of a spiroketaI structure (Kurath P. et al., Experientia 1971; 27:362). It is well-known that spirocyclisation of aglycone ring of erythromycin A is successfully inhibited by a chemical transformation of C-9 ketones or hydroxy groups in a C-6 and/or C-12 position. By the oximation of C-9 ketones (Djokic S. et al., Tetrahedron Lett., 1967; 1945) and by subsequently modifying the obtained 9(E)-oxime into 9-[O-(2-methoxyethoxy)-methyloxime] erithromycin A (ROKSITROMICIN) (Ambrieres, G. S., FR 2,473,525/1981) or 9(S)-erithromycylamine (Egan R. S. et al., J. Org. Chem., 1974; 39:2492) or a more complex oxazine derivative thereof, 9-deoxo-11-deoxy-9,11-{imino[2-(2-methoxyethxyethylidene]-oxy}-9(S)-erythromycin A (DIRITROMICIN) (Lugar P. et al., J. Crist. Mol. Struct., 1979; 9:329), novel semisynthetic macrolides were synthetized, whose basic characteristic, in addition to a greater stability in an acidic medium, is a better pharmacokinetics and a long half-time with regard to the parent antibiotic erythromycin A. In a third way for modifying C-9 ketones use is made of Beckmann rearrangement of 9(E)-oxime and of a reduction of the obtained imino ether (Kobrehel G. et al., U.S. Pat. No. 4,328,334, 5/1982) into 11-aza-10-deoxo-10-dihydroerythromycin A (9-deoxo-9a-aza-9a-homoerythromycin A) under broadening the 14-member ketolactone ring into a 15-member azalactone ring. By reductive N-methylation of 9a-amino group according to Eschweiler-Clark process (Kobrehel G. et al., BE Pat. No. 892,357, 7/1982) or by a preliminary protection of amino group by means of conversion into the corresponding N-oxides and then by alkylation and reduction (Bright G. M., U.S. Pat. No. 4,474,768, 10/1984) N-methyl-11-aza-10-deoxo-10-dihydroerythromycin A (9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A, AZITROMICIN) was synthetized, a prototype of azalide antibiotics, which, in addition to a broad antimicrobial spectrum including Gram-negative bacteria and intracellular microorganisms, are characterized by a specific mechanism of transport to the application site, a long biological half-time and a short therapy period. In EP A 0 316 128 (Bright G. M.) novel 9a-allyl and 9a-propargyl derivatives of 9-deoxo-9a-aza-9a-homoerythromycin A are disclosed and in U.S. Pat. No. 4,492,688, 1/1985 (Bright G. M.) the synthesis and the antibacterial activity of the corresponding cyclic ethers are disclosed. In the Croatian patent application 381-03/93-05/041 (559-93-1) there are further disclosed the synthesis and the activity spectrum of novel 9-deoxo-9a-aza-11-deoxy-9a-homoerythromycin A 9a,11-cyclic carbamates and O-methyl derivatives thereof. 
     According to the known and established Prior Art, 9a-N-(N&#39;-carbamoyl) and 9a-N-(N&#39;-thiocarbamoyl) derivatives of 9-deoxo-9a-aza-9a-homoerythromycin A and pharmaceutically acceptable addition salts thereof with inorganic or organic acids, a process for the preparation thereof as well as the preparation methods and use an pharmaceutical preparations have not been disclosed as yet. 
     It has been found and it is an object of the present invention that 9a-N-(N&#39;-carbamoyl) and 9a-N-(N&#39;-thiocarbamoyl) derivatives of 9-deoxo-9a-aza-9a-homoerythromycin A, novel semisynthetic macrolide antibiotics of the azalide series and pharmaceutically acceptable addition salts thereof with inorganic or organic acids may be prepared by reacting 9-deoxo-9a-aza-9a-homoerythromycin A with isocyanates or isothiocyanates and optionally by reacting the obtained 9a-N-(N&#39;-carbamoyl) and 9a-N-(N&#39;-thiocarbamoyl) derivatives of 9-deoxo-9a-aza-9a-homoerythromycin A with inorganic and organic acids. 
     It has been found that novel 9a-N-(N&#39;-carbamoyl) and 9a-N-(N&#39;-thiocarbamoyl) derivatives of 9-deoxo-9a-aza-9a-homoerythromycin A of the formula (I) ##STR3## wherein R represents a C 1  -C 3  alkyl, aryl or aralkyl group and X represents O or S, and pharmaceutically acceptable addition salts thereof with inorganic or organic acids may be prepared by reacting 9-deoxo-9a-aza-9a-homoerythromycin A with isocyanates or isothiocyanates of the general formula (II) 
     
         R-N═C═X(II) 
    
     wherein R and X have the above meanings, in toluene, xylene or some other aprotic solvent, at a temperature of 20° to 110° C., the isocyanates of the general formula (II) wherein R represents a phenyl group, 1-naphthyl group or unsubstituted or substituted aromatic 5-member and 6-member rings having one or two hetero atoms being prepared in situ by means of Curtius rearrangement of the corresponding acid azide at elevated temperature. 
     Pharmaceutically acceptable acid addition salts, which also represent an object of the present invention, are obtained by reacting 9a-N-(N&#39;-carbamoyl) and 9a-N-(N&#39;-thiocarbamoyl) derivatives of 9-deoxo-9a-aza-9a-homoerythromycin A with an at least equimolar amount of the corresponding inorganic or organic acid such as hydrochloric acid, hydroiodic acid, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, propionic acid, benzoic acid, benzene sulfonic acid, methane sulfonic acid, lauryl sulfonic acid, stearic acid, palmitic acid, succinic acid, ethylsuccinic acid, lactobionic acid, oxalic acid, salicylic acid and similar acids, in a solvent inert to the reaction. Addition salts are isolated by evaporating the solvent or, alternatively, by filtration after a spontaneous precipitation or a precipitation by the addition of a non-polar cosolvent. 
     9a-N-(N&#39;-carbamoyl) and 9a-N-(N&#39;-thiocarbamoyl) derivatives of 9-deoxo-9a-aza-9a-homoerythromycin A of the formula (I) and pharmaceutically acceptable addition salts with inorganic or organic acids thereof possess an antibacterial activity in vitro. Minimum inhibitory concentrations (MIC, mcg/ml) are determined by dilution method on microplates according to the recommendation of National Committee for Clinical Laboratory Standards (NCCLS, M7-A2). It is evident from Table 1 that standard strains and clinical isolates tested are susceptible to newly synthetised compounds. Thus they may be used for disinfection of rooms, chirurgical instruments and humans and as therapeutic agents in the treatment of infective diseases in animals, especially mammals and humans, caused by a broad spectrum of Gram-positive bacteria, mycoplasmas and generally patogenic microorganisms that are susceptible to the compounds of the formula (I). To this purpose the above compounds and pharmaceutically acceptable acid addition salts thereof may be administered orally in usual doses from 0.2 mg/kg body weight daily to about 250 mg/kg/day, most preferably from 5-50 mg/kg/day, or parenterally in the form of subcutaneous and intramuscular injections. 
     
                       TABLE 1                                                     
______________________________________                                    
Antibacterial in vitro activity of novel 9a-N-(N&#39;-carbamoyl) and          
9a-N-(N&#39;-thiocarbamoyl) derivatives of 9-deoxo-9a-aza-9a-homo-            
erythromycin A in comparison with the starting amine                      
         MIC (mcg/ml)                                                     
Test       9a-                                                            
organism   NH*    1      4    5    6      7**                             
______________________________________                                    
Staphylococcus                                                            
           3.12   6.25   25.0 3.12 6.25   6.25                            
epidermidis ATCC                                                          
12228                                                                     
Staphylococcus                                                            
           3.12   1.56   12.5 6.25 3.12   3.12                            
aureus ATCC                                                               
6538P                                                                     
Micrococcus flavus                                                        
           1.56   3.12   12.5 6.25 3.12   1.56                            
ATCC 10240                                                                
Streptococcus                                                             
           3.12   3.12   6.25 3.12 3.12   1.56                            
faecalis ATCC                                                             
8043                                                                      
Bacillus subtilis                                                         
           12.5   1.56   25.0 6.25 3.12   1.56                            
NCTC 8236                                                                 
B. pumilus NCTC                                                           
           12.5   6.25   12.5 6.25 3.12   1.56                            
8241                                                                      
B. cererus ATCC                                                           
           3.12   6.25   12.5 12.5 6.25   6.25                            
11778                                                                     
Pseudomonas                                                               
           25.0   25.0   50.0 50.0 50.0   50.0                            
aeruginosa NCTC                                                           
10490                                                                     
Esherichia coli                                                           
           3.12   12.5   12.5 12.5 25.0   12.5                            
ATCC 10536                                                                
Salmonella 3.12   6.25   25.0 25.0 &gt;100.0 &gt;100.0                          
Panama 6117                                                               
BHS-A Strepto-                                                            
           3.12          12.5 3.12                                        
coccus pyogenes                                                           
J-21                                                                      
BHS-B Strepto-                                                            
           1.56          12.5 1.56                                        
coccus Agalactiae                                                         
J-22                                                                      
______________________________________                                    
 *9-deoxo-9a-aza-9a-homoerythromycin A                                    
 **numbers designate newly synthetised compounds from the corresponding   
 Examples                                                                 
 
    
     Process for the preparation of 9a-N-(N&#39;-carbamoyl) and 9a-N-(N&#39;-thiocarbamoyl) derivatives of 9-deoxo-9a-aza-9a-homoerythromycin A of this invention is illustrated by the following Examples which should in no way be construed as a limitation of the scope thereof. 
    
    
     EXAMPLE 1 
     9-deoxo-9a-N-(N&#39;-isopropyl-carbamoyl)-9a-aza-9a-homoerythromycin A 
     A mixture of 9-deoxo-9a-aza-9a-homoerythromycin A (7.27 g; 0.01 mole), isopropylisocyanate (0.94 g; 0.011 mole) and toluene (40 ml) was stirred for 1 hour at the temperature of 30° C. The reaction mixture was evaporated at reduced pressure (40° C.) to dryness to give crude 9-deoxo-9a-N-(N&#39;-isopropyl-carbamoyl)-9a-aza-9a-homoerythromycin A (7.0 g; 86.2%), m.p. 128°-136° C. By recrystallization of the obtained product from a methanol-water mixture a chromatographically homogenous substance having the following physico-chemical constants was obtained: 
     m.p. 135°-144° C. 
     TLC, EtAc-(n-C 6  H 6 )-NHEt 2  (100:100:20), Rf 0.351. 
     CHCl 3  --CH 3  OH-conc. NH 4  OH (6:1:0.1), Rf 0.553. 
     IR (KBr) cm -1  1730, 1625, 1515, 1455, 1380, 1270, 1165, 1050, 950. 
       1  H NMR (300 MHz, CDCl 3 )δ 5.00 (1H, H-13), 4.85 (1H, H-1&#34;), 4.47 (1H, H-1&#39;), 4.02 (1H, H-3), 3.91 (1H, --CH(CH 3 ) 2 ), 3.50 (1H, H-5), 3.43 (1H, H-9a), 3.28 (3H, 3&#34;-OCH 3 ), 2.49 (1H, H-9b), 2.32 [6H, 3&#39;-N(CH 3 ) 2 , 2.31 (1H, H-8), 1.62 (1H, H-7a), 1.29 (3H, 10-CH 3 ), 1.14 [6H,--CH(CH 3 ) 2  ], 1.13 (1H, H-7b), 1.04 (3H, 8-CH 3 ). 
       13  C NMR (75 MHz, CDCl 3 )δ (175.5 (C-1), 158.2 (9a-NCONH), 103.8 (C-1&#39;), 96.0 (C-1&#34;), 87.9 (C-5), 78.8 (C-3), 48.8 (3&#34;-OCH 3 ), 45.5 (C-2), 42.2 [--CH(CH 3 ) 2  ], 39.9 [3&#39;-N(CH 3 ) 2  ], 27.4 (C-8), 22.9 [--CH(CH 3 ) 2 , 20.5 (8-CH 3 ), 12.2 (10-CH 3 ). 
     EXAMPLE 2 
     9-deoxo-9a-N-{N&#39;-[(4-methyl-5-oxazole)-carbamoyl]}-9a-aza-9a-homoerythromycin A 
     A mixture of 9-deoxo-9a-aza-9a-homoerythromycin A (4.8 g; 0.0065 mole), 4-methyl-5-oxazole-carboxylic acid azide (1.0 g; 0.0066 mole) and dry toluene (30 ml) was heated for 15 minutes at the boiling temperature and then, by distillation at reduced pressure (40° C.), evaporated to dryness. The obtained residue was suspended in acetone (20 ml), stirred at room temperature and then the obtained crystals were filtered to give 9-deoxo-9a-N-{N&#39;-[(4-methyl-5-oxazole)-carbamoyl]}-9a-aza-9a-homoerythromycin A (5.4 g; 93.3%), m.p. 174°-177° C. By recrystallization from hot acetone, a chromatographically homogenous product having the following physico-chemical constants was obtained: 
     m.p. 181°-183° C. 
     TLC, EtAc-(n-C 6  H 6 )-NHEt 2  (100:100:20), Rf 0.149. 
     CHCl 3  --CH 3  OH-conc. NH 4  OH (6:1:0.1), Rf 0.491. 
     IR (KBr) cm -1  1730, 1680, 1655, 1490, 1460, 1380, 1170, 1050, 755, 660. 
       1  H NMR (300 MHz, Py d 5 , 50° C.)δ 9.02 (9a-N-CONH), 7.95 (--CH═N) 5.71 (1H, H-13), 5.15 (1H, H-1&#34;), 4.94 (1H, H-1&#39;), 4.77 (1H, H-3), 4.07 (1H, H-5), 3.96 (1H, H-9a), 3.44 (3H, 3&#34;-OCH 3 ), 2.50 (1H, H-9b), 2.32 [6H, 3&#39;-N(CH 3 ) 2  ], 2.34 (1H, H-8), 2.35 (1H, H-7a), 1.68 (3H, 10-CH 3 ), 1.97 (1H, H-7b), 1.09 (3H, 8-CH 3 ). 
       13  C NMR (75 MHz, Py d 5 , 50° C.)δ 177.2 (C-1), 157.2 (9a-NCONH), 104.2 (C-1&#39;), 96.9 (C-1&#34;), 86.6 C-5), 80.5 (C-3), 50.1 (3&#34;-OCH 3 ), 46.5 (C-2), 42.2 (C-4), 41.0 [3&#34;-N(CH 3 ) 2  ], 29.1 (C-8), 21.2 (8-CH 3 ), 14.1 (10-CH 3 ), 149.9, 142.2, 128.2 and 12.2 (4-methyl-5-oxazole). 
     EXAMPLE 3 
     9-deoxo-9a-N-[N&#39;-(2-furyl)-carbamoyl]-9a-aza-9a-homoerythromycin A 
     Analogously to the process disclosed in Example 2, from 9-deoxo-9a-aza-9a-homoerythromycin A (2.18 g; 0.003 mole), 2-furancarboxylic acid azide (0.5 g, 0.0036 mole) and toluene (15 ml) a resinous residue (2.1 g) was obtained, wherefrom by chromatography on a silica gel column using the solvent system CHCl 3  --CH 3  OH (7:3) 9-deoxo-9a-N-[N&#39;-(2-furyl)-carbamoyl]-9a-aza-9a-homoerythromycin A (1.7 g; 77.0%) having the following physico-chemical constants was obtained: 
     m.p. 155°-159° C. 
     TLC, EtAc-(n-C 6  H 6 )-NHEt 2  (100:100:20), Rf 0.262. 
     CHCl 3  --CH 3  OH-conc. NH 4  OH (6:1:0.1), Rf 0.574. 
     IR (CHCl 3 ) cm -1  1730, 1655, 1520, 1460, 1380, 1270, 1165, 1050, 1000, 955, 900, 830, 730. 
       1  H NMR (300 MHz, DMSO)δ 8.51 (9a-N-CONH), 7.24 (--O--CH═) 6.34 (--O--CH═CH--), 6.00 (--CH═C--NH), 5.04 (1H, H-13), 4.77 (1H, H-1&#34;), 4.47 (1H, H-1&#39;), 4.01 (1H, H-3), 3.42 (1H, H-5), 3.47 (1H, H-9a), 3.35 (3H, 3&#39;-OCH 3 ), 3.25 (1H, H-9b), 2.50 [6H, 3&#39;-N(CH 3 ) 2  ], 2.07 (1H, H-8), 1.45 (1H, H-7a), 1.20 (1H, H-7b), 1.15 (3H, 10-CH 3 ), 0.90 (3H, 8-CH 3 ). 
       13  C NMR (75 MHz, DMSO)δ 175.5 (C-1), 155.4 (9a-NCONH), 101.9 (C-1&#39;), 95.3 (C-1&#34;), 84.4 (C-5), 78.6 (C-3), 48.8 (3&#34;-OCH 3 ), 44.6 (C-2), 40.0 (C-4), 40.1 [3&#39;-N(CH 3 ) 2  ], 27.7 (C-8), 19.7 (8-CH 3 ), 13.2 (10-CH 3 ), 147.7, 136.5, 118.9, 98.0 (5-furanoyl). 
     EXAMPLE 4 
     9-deoxo-9a-N-[N&#39;-(4-pyridyl)-carbamoyl]-9a-aza-9a-homoerythromycin A 
     Analogously to the process disclosed in Example 2, from 9-deoxo-9a-aza-9a-homoerythromycin A (2.18 g; 0.003 mole), isonicotinic acid azide (0.53 g, 0.0036 mole) and toluene (15 ml) a resinous residue (2.26 g) was obtained, wherefrom by recrystallization from a methanol-water mixture 9-deoxo-9a-N-[N&#39;-(4-pyridyl)-carbamoyl]-9a-aza-9a-homoerythromycin A (1.9 g; 74.8%) having the following physico-chemical constants was obtained: 
     m.p. 149°-153° C. 
     TLC, EtAc-(n-C 6  H 6 )-NHEt 2  (100:100:20), Rf 0.089. 
     CHCl 3  --CH 3  OH-conc. NH 4  OH (6:1:0.1), Rf 0.441. 
     IR (CHCl 3 ) cm -1  1730, 1650, 1590, 1510, 1460, 1380, 1330, 1280, 1165, 1050, 1000, 955, 900, 830, 730. 
       1  H NMR (300 MHz, DMSO)δ 8.66 (9a-N--CONH), 8.25, 7.35 (4-piridyl), 5.16 (1H, H-13), 4.89 (1H, H-1&#34;), 4.52 (1H, H-1&#39;), 4.15 (1H, H-3), 3.53 (1H, H-5), 3.51 (1H, H-9a), 3.33 (3H, 3&#34;-OCH 3 ), 3.28 (1H, H-9b), 2.34 [6H, 3&#39;-N(CH 3 ) 2  ], 2.28 (1H, H-8), 1.62 (1H, H-7a), 1.23 (1H, H-7b), 1.36 (3H, 10-CH 3 ), 1.04 (3H, 8-CH 3 ). 
       13  C NMR (75 MHz, DMSO)δ 176.1 (C-1), 155.5 (9a-NCONH), 102.2 (C-1&#39;), 95.5 (C-1&#34;), 84.3 (C-5), 78.7 (C-3), 48.9 (3&#34;-OCH 3 ), 44.8 (C-2), 40.2 (C-4), 40.4 [3&#39;-N(CH 3 ) 2  ], 27.8 (C-8), 20.2 (8-CH 3 ), 14.4 (10-CH 3 ), 149.8, 148.0, 113.9 (4-pyridyl). 
     EXAMPLE 5 
     9-deoxo-9a-N-(N&#39;-phenyl-carbamoyl)-9a-aza-9a-homoerythromycin A 
     Analogously to the process disclosed in Example 2, from 9-deoxo-9a-aza-9a-homoerythromycin A (2.0 g; 0.0027 mole), benzoic acid azide (0.5 g, 0.0034 mole) and toluene (15 ml) a resinous residue (2.43 g) was obtained, wherefrom by chromatography on a silica gel column using a solvent system CH 2  Cl 2  --CH 3  OH (85:15), 9-deoxo-9a-N-(N&#39;-phenyl-carbamoyl)-9a-aza-9a-homoerythromycin A (1.4 g; 61.4%) having the following physico-chemical constants was obtained: 
     m.p. 126°-130° C. 
     TLC, EtAc-(n-C 6  H 6 )-NHEt 2  (100:100:20), Rf 0.345. 
     CHCl 3  --CH 3  OH-conc. NH 4  OH (6:1:0.1), Rf 0.637. 
     IR (KBr) cm -1  1730, 1645, 1600, 1539, 1510, 1455, 1380, 1315, 1240, 1165, 1045,950, 895, 755, 690. 
       1  H NMR (300 MHz, DMSO)δ 8.11 (9a-N--CONH), 7.30, 7.35 (phenyl), 5.05 (1H, H-13), 4.79 (1H, H-1&#34;), 4.46 (1H, H-1&#39;), 4.04 (1H, H-3), 3.46 (1H, H-5), 3.28 (1H, H-9a), 3.23 (3H, 3&#34;-OCH 3 ), 3.16 (1H, H-9b), 2.34 [6H, 3&#39;-N(CH 3 ) 2  ], 2.16 (1H, H-8), 1.58 (1H, H-7a), 1.15 (1H, H-7b), 1.25 (3H, 10-CH 3 ), 0.90 (3H, 8-CH 3 ). 
       13  C NMR (75 MHz, DMSO)δ 175.6 (C-1), 156.1 (9a-NCONH), 102.0 (C-1&#39;), 95.4 (C-1&#34;), 84.4 (C-5), 78.5 (C-3), 48.9 (3&#34;-OCH 3 ), 44.6 (C-2), 39.4 (C-4), 40.1 [3&#39;-N(CH 3 ) 2  ], 27.3 (C-8), 20.0 (8-CH 3 ), 14.0 (10-CH 3 ), 140.6, 127.9 and 114.4 (phenyl). 
     EXAMPLE 6 
     9-deoxo-9a-N-(N&#39;-benzyl-carbamoyl)-9a-aza-9a-homoerythromycin A 
     Analogously to the process disclosed in Example 1, from 9-deoxo-9a-aza-9a-homoerythromycin A (7.27 g; 0.01 mole), benzylisocyanate (1.33 g, 0.01 mole) and toluene (15 ml) a resinous residue (8.4 g) was obtained, wherefrom by chromatography on a silica gel column using a solvent system CHCl 3  --CH 3  OH (7:3), 9-deoxo-9a-N-(N&#39;-benzyl-carbamoyl)-9a-aza-9a-homoerythromycin A (6.5 g, 75.6%) having the following physico-chemical constants was obtained: 
     m.p. 142°-144° C. 
     TLC, EtAc-(n-C 6  H 6 )-NHEt 2  (100:100:20), Rf 0.355. 
     CHCl 3  --CH 3  OH-conc. NH4OH (6:1:0.1), Rf 0.621. 
     IR (KBr) cm -1  1730, 1630, 1525, 1410, 1380, 1270, 1165, 1045, 950, 895, 755, 700. 
       1  H NMR (300 MHz, CDCl 3 )δ 7.30, 5.00, 4.40 (--CH 2  --C 6  H 5 ), 5.04 (1H, H-13), 4.83 (1H, H-1&#34;), 4.48 (1H, H-1&#39;), 4.00 (1H, H-3), 3.52 (1H, H-5), 3.48 (1H, H-9a), 3.28 (3H, 3&#34;-OCH 3 ), 2.51 (1H, H-9b), 2.56 [6H, 3&#39;-N(CH 3 ) 2  ], 2.34 (1H, H-8), 1.66 (1H, H-7a), 1.10 (1H, H-7b), 0.99 (3H, 10-CH 3 ), 1.36 (3H, 8-CH 3 ).  13  C NMR (75 MHz, CDCl 3 )δ 175.7 (C-1), 159.3 (9a-NCONH), 103.8 (C-1&#39;), 96.5 (C-1&#34;), 88.8 (C-5), 78.8 (C-3), 48.9 (3&#34;-OCH 3 ), 45.9 (C-2), 40.4 (C-4), 40.2 [3&#39;-N(CH 3 ) 2  ], 27.3 (C-8), 20.5 (8-CH 3 ), 12.3 (10-CH 3 ), 139.1, 128.3, 127.2 and 126.8, 45.9 (--CH 2  --C 6  H 5 ). 
     EXAMPLE 7 
     9-deoxo-9a-N-(N&#39;-benzyl-thiocarbamoyl)-9a-aza-9a-homoerythromycin A 
     Analogously to the process disclosed in Example 1, from 9-deoxo-9a-aza-9a-homoerythromycin A (7.27 g; 0.01 mole), benzylisothiocyanate (1.50 g, 0.01 mole) and toluene (30 ml) under stirring of the reaction mixture for 8 hours at the temperature of 30° C., a resinous residue (8.6 g) was isolated, wherefrom by chromatography on a silica gel column using the solvent system CHCl 3  --CH 3  OH (7:3), 9-deoxo-9a-N-(N&#39;-benzyl-thiocarbamoyl)-9a-aza-9a-homoerythromycin A (7.2 g; 82.1%) having the following physico-chemical constants was obtained: 
     m.p. 119°-122° C. 
     TLC, EtAc-(n-C 6  H 6 )-NHEt 2  (100:100:20), Rf 0.370. 
     CHCl 3  --CH 3  OH-conc. NH 4  OH (6:1:0.1), Rf 0.689. 
     IR (KBr) cm -1  1730, 1630, 1525, 1410, 1380, 1270, 1165, 1045, 950, 895, 755, 700. 
       1  H NMR (300 MHz, CDCl 3 )δ 7.36, 4.85, 4.72 (--CH 2  --C 6  H 5 ), 4.75 (1H, H-13), 4.87 (1H, H-1&#34;), 4.4 (1H, H-1&#39;), 4.10 (1H, H-3), 3.81 (1H, H-11), 3.49 (1H, H-5), 3.30 (3H, 3&#34;-OCH 3 ), 3.03 (1H, H-4&#34;), 2.34 [6H, 3&#39;-N(CH 3 ) 2  ], 2.31 (1H, H-8), 1.52 (1H, H-7a), 1.26 (1H, H-7b), 1.31 (3H, 10-CH 3 ), 0.96 (3H, 8-CH 3 ). 
     EXAMPLE 8 
     9-deoxo-9a-N-[N&#39;-(1-naphthyl)-carbamoyl]-9a-aza-9a-homoerythromycin A 
     Analogously to the process disclosed in Example 1, from 9-deoxo-9a-aza-9a-homoerythromycin A (7.27 g; 0.01 mole), 1-naphthylisocyanate (1.7 g, 0.01 mole) and toluene (40 ml) by stirring the reaction mixture for 1 hour at the temperature of 20° C. a resinous residue (9.0 g) was isolated, wherefrom by chromatography on a silica gel column using the solvent system CHCl 3  --CH 3  OH-conc. NH 4  OH (6:1:0.1) 9-deoxo-9a-N-[N&#39;-(1-naphthyl)-carbamoyl]-9a-aza-9a-homoerythromycin A (7.8 g; 86.6%) having the following physico-chemical constants was obtained: 
     m.p. 134°-137° C. 
     TLC, EtAc-(n-C 6  H 6 )-NHEt 2  (100:100:20), Rf 0.335. 
     CHCl 3  --CH 3  OH-conc. NH4OH (6:1:0.1), Rf 0.658. 
     IR (CHCl 3 ) cm -1  1740, 1635, 1530, 1500, 1455, 1380, 1340, 1265, 1160, 1050, 1010, 960, 890, 795, 775, 735; 700.