CA2375812A1

CA2375812A1 - Derivatives of 4'-demycarosyl-8a-aza-8a-homotylosin

Info

Publication number: CA2375812A1
Application number: CA002375812A
Authority: CA
Inventors: Nevenka Lopotar; Stjepan Mutak; Amalija Narandja
Original assignee: Individual
Current assignee: Fidelta doo
Priority date: 1999-06-11
Filing date: 2000-06-06
Publication date: 2000-12-21
Also published as: WO2000077016A1; NO20016030L; HUP0201610A3; CZ20014362A3; AU5558300A; NO322424B1; HRP990192A2; NO20016030D0; YU87401A; EA200200026A1; HUP0201610A2; UA66930C2; AU767543B2; JP2003502338A; SK17572001A3; EP1189914A1

Abstract

The invention relates to derivatives of 4'-demycarosyl-8a-aza-8a-homotylosin of formula (I) wherein R represents CHO, CH(OCH3)2) or CH2N[CH2(C6H5)]2, R1 represents H or C1-C3 acyl, R2 represents OR6 and R6 represents H or C1-C3 acyl, R3 represents H or R2 and R3 together represent =O, R4 represents OH, R5 represents H or R4 and R5 together represent =O, and to a process for the preparation thereof. Novel derivatives show antibacterial action and may als o be used as intermediates for preparing novel 17-membered azalide antibiotics .

Description

DERIVATIVES OF 4'-DEMYCAROSYL-8a-AZA-8a-HOMOTYLOSIN
Technical Field IPC: A 61 K 31/70 Technical Problem The present invention relates to novel compounds from the class of 17-membered azalides having an antibacterial action. More particularly, the invention relates to derivatives of 4'-demycarosyl-8a-aza-8a-homotylosin of the formula I
~ O-NH CH3 8a R

R2 H3C N(CH3)2 H3C R1 ~ 2' 4 OR1 R3 4" ~ O \O O CH3 v ~ R4 OCH3 n R5 I
wherein R represents CHO, CH(OCH3)2 or CH2N[CH2(C6H5)]~, Rl represents H or C1-C3 acyl, R2 represents OR6 and R6 represents H or C1-C3 acyl, R3 represents H or RZ and R3 together represent =O, R4 represents OH, RS represents H or R4 and RS together represent =O, and to a process for the preparation thereof.
Pr~io~ Apt 4'-Demycarosyl-8a-aza-8a-homotylosin, a novel semisynthetic macrolide from the class of 17-membered azalides, was prepared by a double transformation of C-9 ketone of the 16-membered antibiotic 4'-demycarosyl-tylosin (R. L. Hamill, Antibiotics and Chemotherapy 11, 328 (1961); A. Narandja et al, EP 0 287 082 B1; N.
Lopotar et al, EP 0 410 433 B 1). By reductive amination of C-20 aldehyde group in the presence of formic acid (Wallach reaction, J. March: "Advanced Organic Chemistry", third ed. 6-15 p. 799 Wiley, New York, 1985) there was prepared 4'-demycarosyl-20-deoxo-20-dibenzylamino-8a-aza-8a-homotylosin (N. Lopotar, HR
Patent Application P940962A, 30.11.1994).
C1-C3 acyl esters of 4'-demycarosyl-8a-aza-8a-homotylosin and of 4'-demycarosyl-20-deoxo-20-dibenzylamino-8a-aza-8a-homotylosin as well as 4"-deoxy-4"-oxo-and 3-deoxy-3-oxo derivatives of 4'-demycarosyl-8a-aza-8a-homotylosin and of 4'-demycarosyl-20-deoxo-20-dibenzylamino-8a-aza-8a-homotylosin, C1-C3 acyl esters thereof and a process for the preparation thereof have hitherto not been disclosed in Prior Art.
Detailed Description of the Invention According to the present invention derivatives of 4'-demycarosyl-8a-aza-8a-homotylosin of the formula I

CO-8a \ R

R2 H3C N(CH3)2 H3C Rj p 2~ 4~ OR1 R3 4~~ ~ ) 4 O O CH3 I
wherein R represents CHO, CH(OCH3)2 or CH2N[CHZ(C6H5)]2, Rl represents H or C1-C3 acyl, R2 represents OR6 and R6 represents H or CI-C3 acyl, R3 represents H or R2 and R3 together represent =O, R4 represents OH, RS represents H or R4 and RS together represent =O, may be prepared in such a way that 4'-demycarosyl-8a-aza-8a-homotylosin 20-dimethylacetal of the formula IIa and 4'-demycarosyl-20-deoxo-20-dibenzylamino-8a-aza-8a-homotylosin of the formula IIb 8a R

H3C N(CH3)2 H3C HO 2, 4~ OW
HO 4~ O ~Q O CH3 OCH3 ~ OH

IIa R = CH(OCH3)2 IIb R = CH2N[CHZ(C6H5)]2 are subjected to A) an O-acylation with anhydrides of Cl-C3 carboxylic acids, preferably with acetic acid anhydride in methylene chloride during 15 minutes to 1 hour at room temperature, and the obtained compounds of the formula I, wherein R represents CH(OCH3)~ or CH2N[CH2(C6H5)]2, R1 represents COCH3, R2 represents OR6, wherein R6 represents H, R3 and RS are the same and represent H and R4 represents OH, are optionally subjected to Al) an O-acylation with anhydrides of C1-C3 carboxylic acids, preferably with acetic acid anhydride in methylene chloride in the presence of an organic base, preferably triethyl amine and 4-dimethylaminopyridine as a catalyst during 30 hours at room temperature, and the obtained compounds of the formula I, wherein R represents CH(OCH3)2 or CH2N[CHZ(C6H5)]2, R1 represents COCH3, RZ represents OR6, wherein R6 represents COCH3, R3 and RS are the same and represent H and R4 represents OH, are optionally subjected to B) an oxidation reaction with N(3-dimethylamino-propyl)-N'ethyl carbodiimide hydrochloride in the presence of dimethylsulfoxide and pyridine trifluoroacetate as a catalyst in an inert solvent, preferably methylene chloride, during 2 to 6 hours at a temperature from 10°C to room temperature, and the obtained compounds of the formula I, wherein R represents CH(OCH3)2 or CH2N[CH2(C6H5)]2, R' represents COCH3, R2 represents OR6, wherein R6 represents COCH3, R3 represents H and R4 and RS together represent =O, are optionally subjected to C) methanolysis at room temperature for 2 days and the obtained compounds of the formula I, wherein R represents CH(OCH3)Z or CH2N[CH~(C6H5)]Z, R1 and R3 are the same and represent H, R2 represents OR6, wherein R6 represents COCH3, and R4 and RS together represent =O, are optionally subjected to C1) an alkaline methanolysis in a mixture of methanol and 25% ammonia (4:1) at a temperature from 5°C to room temperature during 20 to 60 hours to obtain compounds of the formula I, wherein R represents CH(OCH3)~ or CH2N[CH2(C6H5)]2, Rl and are the same and represent H, R2 represents OR6, wherein R6 represents H, and R4 and RS together represent =O;
or the compound obtained according to process C 1 of the formula I, wherein R represents CH(OCH3)~, R1 and R3 are the same and represent H, Rz represents OR6, wherein R6 represents H, and R4 and R' together represent =O, is optionally subjected to D) a hydrolysis of the acetal in a mixture of acetonitrile and 0.1 N
hydrochloric acid (1:l) for 2 hours at room temperature to obtain the compound of the formula I, wherein R represents a CHO group, Rl and R3 are the same and represent H, R2 represents OR6, wherein R6 represents H, and Ra and RS together represent =O;
or compounds obtained according to process A
of the formula I, wherein R represents CH(OCH3)~ or CH2N[CHZ(C6H5)]2, R1 represents COCH3, R2 represents OR6, wherein R6 represents H, R3 and R5 are the same and represent H and R4 represents OH, are optionally subjected to oxidation in the manner disclosed in B, and the obtained compounds of the formula I, wherein R represents CH(OCH3)2 or CH2N[CHZ(C6H5)]2, Rl represents COCH3, R2 and R3 together represent =O, R4 represents OH and RS represents H, are optionally subjected to methanolysis in the manner disclosed in C, to obtain compounds of the formula I, wherein R represents CH(OCH3)2 or CH2N(CH2(C6H5)]2, Rl and R5 are the same and represent H, R'' and R3 together represent =O and R4 represents OH;
or the compound obtained according to process B
of the formula I, wherein R represents a CH(OCH3)2 group, Rl represents COCH3, and R3 together represent =O, R'~ represents OH and RS represents H, is optionally subjected to a hydrolysis of acetal in the manner disclosed in D, and the obtained compound of the formula I, wherein R represents a CHO group, Rl represents COCH3, R2 and R3 together represent =O, R4 represents OH and R5 represents H, is optionally subjected to methanolysis in the manner disclosed in C, to obtain the compound of the formula I, wherein R represents a CHO group, Rl and R5 are the same and represent H, R2 and R3 together represent =O and R4 represents OH;
or the compound obtained according to process A
of the formula I, wherein R represents CH(OCH3)~, R1 represents COCH3, R'' represents OR6, wherein R6 represents H, R3 and RS are the same and represent H and R4 represents OH, is optionally subjected to a hydrolysis of acetal in the manner disclosed in D, to obtain a compound of the formula I wherein R represents CHO, Rl represents COCH3, R'' represents OR6, wherein R6 represents H, R3 and RS are the same and represent H and R4 represents OH;
or compounds obtained according to process Al of the formula I, wherein R represents CH(OCH3)2 or CH2N(CH2(C6H;)]2, Rl represents COCH3, R2 represents OR6, wherein R6 represents COCH3, R3 and RS
are the same and represent H and R4 represents OH, are optionally subjected to methanolysis in the manner disclosed in C, to obtain compounds of the formula I, wherein R represents CH(OCH3)2 or CH2N[CH2(C6H5)]2, Rl, R3 and R' are the same and represent H, R2 represents OR6, wherein R6 represents COCH3, and R4 represents OH;
or the compound obtained according to process Al of the formula I, wherein R represents CH(OCH3)2, Rl represents COCH3, Rz represents OR6, wherein R6 represents COCH3, R3 and RS are the same and represent H and R4 represents OH, is optionally subjected to a hydrolysis of acetal in the manner disclosed in D, and the obtained compound of the formula I, wherein R represents CHO, R' represents COCH3, R2 represents OR6, wherein R6 represents COCH3, R3 and RS
are the same and represent H and R4 represents OH, is optionally subjected to methanolysis in the manner disclosed in C, to obtain the compound of the formula I. wherein R represents CHO, Rl, R3 and RS
are the same and represent H, R2 represents OR6, wherein R~ represents COCH3, and R4 represents OH.
According to the present invention novel compouds are isolated by conventional processes of extraction from aqueous solutions of halogenated hydrocarbons such as methylene chloride or chloroform and by evaporating the organic solvent to a dry residue. Optionally, the separation of the reaction products or the purification of the products for spectral analyses is carried out by flash chromatography on a silica gel column (Merck & Co., Silicagel 60, 230-400 mesh/ASTM) in a solvent sistem:
CH2C12-CH30H-conc. NH40H (90:9:1.5, system A), CH2C12-CH30H (90:9, system B) or CHC13-CH3COCH3 (7:3, system C).
The structure of the novel compounds was confirmed by spectrometric methods and mass analysis.

The novel compounds show antibacterial action and may be also used as intermediates for preparing novel 17-membered azalide antibiotics.
The invention is illustrated and in no way limited by the following Examples.

Example 1 4'-Demycarosyl-2',4'-di-O-acetyl-8a-aza-8a-homotylosin 20-dimethylacetal (1) 4'-Demycarosyl-8a-aza-8a-homotylosin 20-dimethylacetal (5.0 g, 6.02 mmol) was dissolved in dry methylene chloride (50 ml), acetic anhydride (2.0 ml) was added and it was stirred for 15 minutes at room temperature. The reaction mixture was poured into a water/ice mixture (500 ml) and extracted twice with methylene chloride at pH
8.5. The combined organic extracts were washed with a saturated NaHC03 solution and water, dried (K2C03) and evaporated at reduced pressure to give a TLC
homogeneous product (1) (5.38 g; 97.8 %).
TLC: Rf (B) 0.44; Rf (C) 0.22.
IR (KBr) cm 1 1749, 1657, 1620, 1544, 1455, 1375, 1229, 1170, 1063.
1H NMR (CDC13) 8 ppm 7.16 (H-11), 5.69 (H-10), 5.66 (H-13), 4.96 (8a-NH) exchangeable with D20, 4.88 (H-2'), 4.76 (H-4'), 4.63 (H-20), 4.58 (H-1"), 4.33 (H-1'), 4.17 (H-8), 3.61 (3"-OCH3), 3.47 (2"-OCH3), 3.56 (2x20-OCH3), 2.33 /3'-N(CH3)2/, 2.05 (COCH3), 2.03 (COCH3), 1.74 (H-22), 1.17 (H-21).
isC NMR (CDC13) b ppm 179.1 (C-1), 169.8, 169.4 (2xCOCH3), 166.2 (9-CONH), 144.7 (C-11), 138.2 (C-13), 134.9 (C-12), 119.2 (C-10), 103.5 (C-20), 102.0 (C-1'), 100.9 (C-1"), 72.5 (C-4"), 71.4 (C-4'), 70.3 (C-2'), 65.6 (C-3), 61.5 (3"-OCH3), 59.4 (2"-OCH3), 50.4 (2x20-OCH3), 42.7 (C-8), 42.5 (C-4), 41.0 /3'-N(CH3)Z/, 40.5 (C-2), 34.3 (C-19), 21.8, 20.9 (2xCOCH3), 21.9 (C-21), 12.6 (C-22), 8.3 (C-18).
FAB (MH+) 917.
Example 2 4'-Demycarosyl-2',4'-di-O-acetyl-20-deoxo-20-dibenzylamino-8a-aza-8a-homotylosin (2) 4'-Demycarosyl-20-deoxo-20-dibenzylamino-8a-aza-8a-homotylosin (2.8 g, 2.90 mmol) was dissolved in dry methylene chloride (30 ml), acetic anhydride (1.3 ml, 13.76 mmol) was added and it was stirred for 15 minutes at room temperature.
The reaction mixture was poured into a water/ice mixture (300 ml) and extracted twice with methylene chloride at pH 6.5. The combined organic extracts were washed with a saturated NaHC03 solution and water, dried (KZC03) and evaporated at reduced pressure to give a TLC homogeneous product (2) (3.02 g; 98.9 %).
TLC: Rf (B) 0.38; Rf (C) 0.23.
IR (KBr) cm 1 1749, 1651, 1633, 1548, 1454, 1374, 123 l, 1169; 1059.
1H NMR (CDC13) 8 ppm 7.25 ~ 7.41 (phenyl), 7.10 (H-11), 5.70 (H-13), 5.65 (H-10), 4.89 (8a-NH) exchangeable with DSO, 4.84 (H-2'), 4.74 (H-4'), 4.60 (H-1"), 4.15 (H-1'), 3.62 (3"-OCH3), 3.61 (20-N-CH2-phenyl), 3.58 (20-CH2-phenyl), 3.51 (2"-OCH3), 2.32 /3'-N(CH3)2/, 2.06 (COCH3), 2.00 (COCH3), 1.72 (H-22), 1.12 (H-21).
i3C NMR (CDCl3) 8 ppm 173.4 (C-1), 169.9, 169.5 (2xCOCH3), 166.1 (9-CONH), 144.8 (C-11), 137.9 (C-13), 135.2 (C-12), 119.3 (C-10), 102.3 (C-1'), 101.0 (C-1"), 72.5 (C-4"), 71.4 (C-4'), 70.4 (C-2'), 66.0 (C-3), 61.5 (3"-OCH3), 59.5 (2"-OCH3), 52.2 (C-20), 42.9 (C-8), 42.4 (C-4), 41.0 /3'-N(CH3)2/, 38.7 (C-2), 29.4 (C-19), 21.8 (C-21), 21.1, 21.0 (2xCOCH3), 12.7 (C-22), 8.4 (C-18), 20-N(CH2C6H5)2, 139.8, 129.1, 128.0, 126.6, 57.9.
FAB (MH+) 1052.
Example 3 4'-Demycarosyl-2',4',4"-tri-O-acetyl-8a-aza-8a-homotylosin 20-dimethylacetal (3) Compound 1 (4.0 g, 4.37 mmol) was dissolved in dry methylene chloride (100 ml), triethyl amine (7.0 ml), 4-dimethylaminopyridine (0.12 g) and acetic anhydride (0.42 ml, 4.45 mmol) were added and then the reaction solution was left to stand for hours at room temperature. The isolation of the product was carried out in the manner disclosed in Example 1 to give a TLC homogeneous product (3) (4.08 g; 97.7 %).
TLC: Rf (A) 0.65; Rf (C) 0.54.
IR (KBr) cm 1 1749, 1655, 1618, 1546, 1454, 1374, 1233, 1171, 1052.
1H NMR (CDC13) 8 ppm 7.16 (H-11), 5.69 (H-10), 5.65 (H-13), 4.89 (8a-NH) exchangeable with D20, 4.88 (H-2'), 4.76 (H-4'), 4.64 (H-1"), 4.59 (H-20), 4.33 (H-1'), 4.18 (H-8), 3.52 (3"-OCH3), 3.46 (2"OCH3), 3.36 (20-OCH3), 3.35 (20-OCH3), 2.33 /3'-N(CH3)2/, 2.12 (COCH3), 2.05 (COCH3), 2.03 (COCH3), 1.74 (H-22), 1.16 (H-21).
i3C NMR (CDC13) 8 ppm 173.1 (C-1), 170.1, 169.8, 169.4 (3xCOCH3), 166.1 (9-CONH), 144.7 (C-11 ), 13 8.0 (C-13 ), 134.9 (C-12), 119.2 (C-10), 103 .7 (C-20), 102.1 (C-1'), 100.9 (C-1"), 74.5 (C-4"), 71.4 (C-4'), 70.3 (C-2'),.
65.6 (C-3), 61.3 (3"-OCH3), 59.3 (2"-OCH3), 53.7 (20-OCH3), 50.6 (20-OCH3), 42.7 (C-8), 42.6 (C-4), 41.0 /3'-N(CH3)2/, 40.5 (C-2), 34.5 (C-19), 21.9, (C-21), 21.1, 21.0, 20.7 (3xCOCH3), 12.7 (C-22), 8.3 (C-18).
FAB (MH+) 959.
Example 4 4'-Demycarosyl-2',4',4"-tri-O-acetyl-20-deoxo-20-dibenzylamino-8a-aza-8a-homotylosin (4) Compound 2 (2.8 g, 2.66 mmol) was dissolved in dry methylene chloride (60 ml), triethyl amine (3.7 ml), 4-dimethylaminopyridine (0.07 g) and acetic anhydride (0.25 ml, 1.64 mmol) were added and then the reaction solution was left to stand for hours at room temperature. The isolation of the product was carried out in the manner disclosed in Example 1 to give a TLC homogeneous product (4) (2.7 g; 92.9 %).
TLC: Rf (B) 0.55; Rf (C) 0.47.
IR (KBr) cm' 1747, 1651, 1632, 1538, 1453, 1372, 1233, 1170, 1051.
1H NMR (CDCl3) 8 ppm 7.22 ~ 7.41 (phenyl), 7.10 (H-11), 5.70 (H-13), 5.65 (H-10), 4.91 (8a-NH) exchangeable with D20, 4.86 (H-2'), 4.74 (H-4'), 4.66 (H-1"), 4.46 (H-4"), 4.15 (H-1'), 3.61 (2x20-N-CH2-phenyl), 3.53 (3"-OCH3), 3.50 (2"-OCH3), 2.32 /3'-N(CH3)2/, 2.12 (COCH3), 2.06 (COCH3), 2.00 (COCH3), 1.72 (H-22), 1.12 (H-21), 0.78 (H-18).
mC NMR (CDC13) b ppm 173.3 (C-1), 170.1, 169.9, 169.5 (3xCOCH3), 166.1 (9-CONH), 144.8 (C-11), 137.9 (C-13), 135.2 (C-12), 119.3 (C-10), 102.3 (C-1'), 101.0 (C-1"), 74.6 (C-4"), 71.4 (C-4'), 70.4 (C-2'), 66.0 (C-3), 61.5 (3"-OCH3), 59.3 (2"-OCH3), 52.2 (C-20), 42.9 (C-8), 42.4 (C-4), 41.0 /3'-N(CH3)2/, 38.7 (C-2), 29.4 (C-19), 21.8 (C-21), 21.1, 21.0, 20.7 (3xCOCH3), 12.7 (C-22), 8.4 (C-18), 20-N(CH~C6H5)2, 139.8, 129.1, 128.0, 126.6, 57.9.
FAB (MH+) 1094.
Example 5 4'-Demycarosyl-2',4'-di-O-acetyl-4"-deoxy-4"-oxo-8a-aza-8a-homotylosin 20-dimethylacetal (5) A solution of pyridine trifluoroacetate ( 1.0 g, 5.24 mmol) in methylene chloride ( 10 ml) was added drop by drop at 15°C to a solution of the compound 1 (1.0 g, 1.09 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.0 g, 5.22 mmol) and dimethyl sulfoxide ( 1.0 ml, 14.10 mmol) in methylene chloride (20 ml).
The reaction mixture was stirred for 3 hours at room temperature, then poured into water (150 ml) and after separating the organic layer, it was extracted two more times with methylene chloride. The combined organic extracts were washed with a saturated NaHC03 solution and water, dried (K2C03) and evaporated at reduced pressure to a dry residue. The obtained crude product (0.95 g) was purified by flash chromatography on a silica gel column using the solvent system B to give a TLC
homogeneous product (5) (0.45 g).
TLC: Rf (B) 0.52.
IR (KBr) cm 1 1749, 1657, 1620, 1542, 1455, 1375, 1230, 1172, 1060.

1H NMR (CDC13) 8 ppm 7.16 (H-11), 5.71 (H-10), 5.64 (H-13), 4.97 (8a-NH) exchangeable with D20, 4.88 (H-2'), 4.76 (H-4'), 4.60 (H-20), 4.63 (H-1"), 4.33 (H-1'), 4.17 (H-8), 3.98 (H-5"), 3.78 (H-3"), 3.58 (3"-OCH3), 3.52 (2"-OCH3), 3.36 (20-OCH3), 3.35 (20-OCH3), 3.30 (H-2"), 2.33 /3'-N(CH3)2/, 2.05 (COCH3), 2.03 (COCH3), 1.76 (H-22), 1.34 (H-6"), 1.17 (H-21).
i3C NMR (CDC13) ~ ppm 202.4 (C-4"), 173.1 (C-1), 169.9, 169.5 (2xCOCH3), 166.1 (9-CONH), 144.6 (C-11), 137.6 (C-13), 135.3 (C-12), 119.5 (C-10), 103.6 (C-20), 103.0 (C-1"), 102.1 (C-1'), 85.3 (C-3"), 84.2 (C-2"), 73.3 (C-5"), 71.3 (C-4'), 70.3 (C-2'), 65.6 (C-3), 60.2 (3"-OCH3), 59.1 (2"-OCH3), 53.7 (20-OCH3), 50.5 (20-OCH3), 42.7 (C-8), 42.6 (C-4), 41.0 /3'-N(CH3)2/, 40.7 (C-2) 34.4 (C-19), 21.9 (C-21), 21.1, 21.0 (2xCOCH3), 14.0 (C-6"), C-12.7 (C-22), 8.3 (C-18).
FAB (MH+) 915.
Example 6 4'-Demycarosyl-2',4'-di-O-acetyl-4"-deoxy-4"-oxo-20-deoxo-20-dibenzylamino-8a-aza-8a-homotylosin (6) A solution of pyridine trifluoroacetate (0.6 g, 3.11 mmol) in methylene chloride (6 ml) was added drop by drop at 15°C to a solution of the compound 2 (0.6 g, 0.57 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.6 g, 3.14 mmol) and dimethyl sulfoxide (0.45 ml, 6.35 mmol) in methylene chloride (20 ml). The reaction mixture was stirred for 5 hours at room temperature. The isolation of the product was carried out in the manner disclosed in Example 5. The obtained crude product (0.54 g) was purified by flash chromatography on a silica gel column using the solvent system B to give a TLC homogeneous product (6) (0.28 g).
TLC: Rf (B) 0.48; Rf (C) 0.33.
IR (KBr) cm 1 1747, 1651, 1633, 1548, 1454, 1372, 1231, 1058.
1H NMR (CDC13) 8 ppm 7.25 ~ 7.41 (phenyl), 7.12 (H-11), 5.70 (H-13), 5.65 (H-10), 4.94 (8a-NH) exchangeable with D20, 4.82 (H-2'), 4.74 (H-4'), 4.65 (H-1"), 4.15 (H-1'), 3.98 (H-5"), 3.78 (H-3"), 3.62 (20-N-CH2-phenyl), 3.58 (20-CH2-phenyl), 3.55 (3"-OCH3), 3.49 (2"-OCH3), 2.32 /3'-N(CH3)2/, 2.06 (COCH3), 2.00 (COCH3), 1.74 (H-22), 1.36 (H-6"), 1.12 (H-21).
13C NMR (CDC13) 8 ppm 202.4 (C-4"), 173.4 (C-1), 169.8, 169.3 (2xCOCH3), 166.1 (9-CONH), 144.6 (C-11), 137.0 (C-13), 135.6 (C-12), 119.6 (C-10), 103.0 (C-1"), 102.2 (C-1'), 85.3 (C-3"), 84.8 (C-2"), 73.3 (C-5"), 71.4 (C-4'), 70.4 (C-2'), 65.9 (C-3), 60.3 (3"-OCH3), 59.1 (2"-OCH3), 52.2 (C-20), 42.9 (C-8), 42.4 (C-4), 40.9 /3'-N(CH3)2/, 38.7 (C-2), 29.4 (C-19), 21.8 (C-21), 21.1, 21.0 (2xCOCH3), 14.0 (C-6"), 12.8 (C-22), 8.4 (C-18), 20-N(CH2C6H5)2 139.6, 129.9, 128.0, 126.6, 57.8.
FAB (MH+) 1050.
Example 7 4'-Demycarosyl-2',4',4"-tri-O-acetyl-3-deoxy-3-oxo-8a-aza-8a-homotylosin 20-dimethylacetal (7) A solution of pyridine trifluoroacetate (3.0 g, 15.72 mmol) in methylene chloride (30 ml) was added drop by drop at 15°C to a solution of the compound 3 (2.0 g, 2.09 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.0 g, 15.66 mmol) and dimethyl sulfoxide (2.9 ml, 40.89 mmol) in methylene chloride (50 ml).
The reaction mixture was stirred for 3 hours at room temperature. The isolation of the product was carried out in the manner disclosed in Example 5. The obtained crude product ( 1.95 g) was purified by flash chromatography on a silica gel column using the solvent system C to give a TLC homogeneous product (7) (1.3 g).
TLC: Rf (C) 0.58.
IR (KBr) cm 1 1749, 1655, 1618, 1546, 1454, 1374, 1233, 1171, 1052.
'H NMR (CDC13) 8 ppm 6.90 (H-11), 5.76 (H-10), 5.43 (H-13), 4.96 (8a-NH) exchangeable with D20, 4.89 (H-2'), 4.79 (H-4'), 4.66 (H-1"), 4.40 (H-1'), 4.18 (H-8), 3.55, 3.32 (H-2), 3.52 (3"-OCH3), 3.49 (2"-OCH3), 3.30 (20-OCH3), 3.29 (20-OCH3), 2.34 /3'-N(CH3)2/, 2.12 (COCH3), 2.06 (COCH3), 2.03 (COCH3), 1.75 (H-22), 1.10 (H-21), 1.07 (H-18).
i3C NMR (CDCl3) ~ ppm 205.6 (C-3), 172.9 (C-1), 170.1, 169.8, 169.4 (3xCOCH3), 166.1 (9-CONH), 144.1 (C-11), 138.0 (C-13), 134.9 (C-12), 119.6 (C-10), 103 . 7 (C-20), 102.1 (C-1' ), 100. 9 (C-1 "), 74. 5 (C-4"), 71.4 (C-4' ), 70.
3 (C-2' ), 61.3 (3"-OCH3), 59.3 (2"-OCH3), 53.7 (20-OCH3), 50.6 (20-OCH3), 46.5 (C-2), 44.2 (C-4), 42.0 (C-8), 41.0 /3'-N(CH3)2/, 34.5 (C-19), 21.9, (C-21), 21.1, 21.0, 20.7 (3xCOCH3), 17.6 (C-18), 12.7 (C-22).
FAB (MH+) 957.
Example 8 4'-Demycarosyl-2',4',4"-tri-O-acetyl-3-deoxy-3-oxo-20-deoxo-20-dibenzylamino-8a-aza-8a-homotylosin (8) A solution of pyridine trifluoroacetate (2.0 g, 10.36 mmol) in methylene chloride (10 ml) was added drop by drop at 15°C to a solution of the compound 4 (1.0 g, 1.09 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.04 g, 10.44 mmol) and dimethyl sulfoxide (1.6 ml. 22.56 mmol) in methylene chloride (20 ml).
The reaction mixture was stirred for 6 hours at room temperature. The isolation of the product was carried out in the manner disclosed in Example 5. The obtained crude product (0.96 g) was purified by flash chromatography on a silica gel column using the solvent system B to give a TLC homogeneous product (8) (0.62 g).
TLC: Rf (B) 0.60.
IR (KBr) cm 1 1748, 1633, 1538, 1454, 1373, 1231, 1052.
1H NMR (CDC13) 8 ppm 7.22 ~ 7.40 (phenyl), 6.89 (H-11), 5.66 (H-10), 5.49 (H-13), 4.96 (8a-NH) exchangeable with D20, 4.81 (H-2'), 4.74 (H-4'), 4.66 (H-1"), 4.42 (H-4"), 4.15 (H-1'), 4.12 (H-8), 3.78, 3.38 (H-2), 3.51 (2x20-N-CHZ-phenyl, 3"-OCH3), 3.48 (2"-OCH3), 2.32 /3'-N(CH3)2/, 2.22 (H-4), 2.09 (COCH3), 2.06 (COCH3), 2.00 (COCH3), 1.72 (H-22), 1.10 (H-21), 1.08 (H-18).

i3C NMR (CDC13) 8 ppm 206.7 (C-3), 172.7 (C-1), 170.1, 169.9, 169.5 (3xCOCH3), 166.1 (9-CONH), 144.0 (C-11),. 136.5 (C-12), 135.0 (C-13), 119.9 (C-10), 102.7 (C-1'), 100.9 (C-1"), 74.6 (C-4"), 71.3 (C-4'), 70.3 (C-2'), 61.3 (3"-OCH3), 59.3 (2"-OCH3), 51.7 (C-20), 47.7 (C-2), 44.5 (C-4)), 42.0 (C-8), 41.0 /3'-N(CH3)2/, 28.6 (C-19), 22.0 (C-21), 21.0, 20.7 (3xCOCH3), 17.8 (C-18), 13.1 (C-22), 20-N(CHZC6H2), 140.1, 128.9, 128.0, 126.4, 57.9.
FAB (MH+) 1092.
Example 9 4'-Demycarosyl-4"-deoxy-4"-oxo-8a-aza-8a-homotylosin 20-dimethylacetal (9) The compound 5 (0.65 g, 0.71 mmol) was dissolved in methanol (20 ml) and left to stand at room temperature for 48 hours. To the reaction solution a saturated NaHC03 solution was added and it was extracted twice with chloroform. The combined organic extracts were dried (K2C03) and evaporated at reduced pressure to a dry residue. The obtained crude product (0.45 g) was purified by flash chromatography on a silica gel column using the solvent system A to give a TLC homogeneous product (9) (0.20 g).
TLC: Rf (A) 0.27.
IR (KBr) cm 1 1749, 1657, 1620, 1542, 1455, 1375, 1230, 1172, 1060.
1H NMR (CDC13) ~ ppm 7.16 (H-11), 5.72 (H-10), 5.67 (H-13), 4.99 (8a-NH) exchangeable with D20, 4.60 (H-20), 4.63 (H-1"), 4.33 (H-1'), 4.17 (H-8), 3.98 (H-5"), 3.78 (H-3"), 3.58 (3"-OCH3), 3.52 (2"-OCH3), 3.46 (H-2'), 3.36, 3.35 (2x20-OCH3), 3.30 (H-2"), 3.06 (H-4'), 2.33 /3'-N(CH3)2/, 1.76 (H-22), 1.34 (H-6"), 1.17 (H-21).
i3C NMR (CDCl3) 8 ppm 202.4 (C-4"), 173.1 (C-1), 166.1 (9-CONH), 144.6 (C-11), 137.6 (C-13), 135.3 (C-12), 119.5 (C-10), 103.6 (C-20), 103.0 (C-1"), 102.1 (C-1'), 85.3 (C-3"), 84.2 (C-2"), 73.3 (C-5"), 65.6 (C-3), 60.2 (3"-OCH3), 59.1 (2"-OCH3), 53.7 (20-OCH3), 50.5 (20-OCH3), 42.7 (C-8), 42.6 (C-4), 41.0 /3'-N(CH3)2/, 4f.7 (C-2), 34.4 (C-19), 21.9 (C-21), 14.0 (C-6"), 12.7 (C-22), 8.3 (C-18).
FAB (MH+) 831.
Example 10 4'-Demycarosyl-4"-deoxy-4"-oxo-20-deoxo-20-dibenzylamino-8a-aza-8a-homotylosin (10) The compound 6 (0.30 g, 0.73 mmol) was dissolved in methanol (20 ml) and left to stand at room temperature for 30 hours. After addition of water (50 ml) the product was isolated by a gradient extraction with chloroform at pH 4.5 and 7.5. The combined chloroform extracts at pH 7.5 were dried (K2C03) and evaporated at reduced pressure and the obtained product (0.17 g) was purified by flash chromatography on a silica gel column using the solvent system A to give a TLC
homogeneous product (10) (0.08 g).
TLC: Rf (A) 0.49.
IR (KBr) cm I 1715, 1655, 1619, 1542, 1454, 1377, 1168, 1082.
'H NMR (CDC13) ~ ppm 7.25 ~ 7.41 (phenyl), 7.12 (H-11), 5.70 (H-13), 5.65 (H-10), 4.94 (8a-NH) exchangeable with D20, 4.84 (H-2'), 4.74 (H-4'), 4.60 (H-1"), 4.15 (H-1'), 3.98 (H-5"), 3.78 (H-3"), 3.62 (3"-OCH3), 3.61 (20-N-CH2-phenyl), 3.58 (20-CHZ-phenyl), 3.51 (2"-OCH3), 3.46 (H-2'), 3.01 (H-4'), 2.32 /3'-N(CH3)2/, 1.72 (H-22), 1.12 (H-21).
i3C NMR (CDC13) ~ ppm 202.4 (C-4"), 173.4 (C-1), 166.1 (9-CONH), 144.7 (C-11), 137.1 (C-13), 135.6 (C-12), 119.7 (C-10), 104.2 (C-1'), 103.0 (C-1"), 85.4 (C-3"), 84.9 (C-2"), 73.3 (C-5"), 66.4 (C-3), 59.8 (3"-OCH3), 58.6 (2"-OCH3), 52.2 (C-20), 43.3 (C-8), 42.3 (C-4), 41.5 /3'-N(CH3)2/, 38.7 (C-2), 29.4 (C-19), 22.0 (C-21), 14.1 (C-6"), 12.8 (C-22), 9.1 (C-18), 20-N(CH2C6H5)2 139.8, 129.1, 128.0, 126.6, 58Ø
FAB (MH+) 967.

Example 1l 4'-Demycarosyl-4"-O-acetyl-3-deoxy-3-oxo-8a-aza-8a-homotylosin 20-dimethylacetal (11) The compound 7 (0.70 g, 0.73 mmol) was dissolved in methanol (50 ml) and left to stand at room temperature for 24 hours. The isolation of the product was carried out in the manner disclosed in Example 9 and the obtained crude product (0.62 g) was purified by flash chromatography on a silica gel column using the solvent system A to give a TLC homogeneous product (11) (0.40 g).
TLC: Rf (A) 0.44.
IR (KBr) cm 1 1749, 1657, 1620, 1544, 1455, 1375, 1229, 1170, 1063.
1H NMR (CDC13) 8 ppm 6.87 (H-11), 5.77 (H-10), 5.44 (H-13), 5.18 (8a-NH) exchangeable with D20, 4.88 (H-2'), 4.64 (H-1"), 4.44 (H-4"), 4.30 (H-1'), 4.17 (H-8), 3.93 (H-5"), 3.89 (H-3"), 3.53 (3"-OCH3), 3.50, 3.26 (H-2), 3.48 (2"-OCH3), 3.30 (20-OCH3), 3.29 (20-OCH3), 2.53 /3'-N(CH3)2/, 2.12 (COCH3), 1.75 (H-22), 1.25 (H-18).
isC NMR (CDC13) ~ ppm 205.4 (C-3), 172.9 (C-1), 170.1 (COCH3), 167.4 (9-CONH), 143.4 (C-11), 136.2 (C-12), 134.6 (C-13), 120.7 (C-10), 104.2 ,(C-1'), 103.9 (C-20), 100.8 (C-1"), 74.5 (C-4"), 70.9 (C-2'), 70.5 (C-2'), 61.3 (3"-OCH3), 59.0 (2"-OCH3), 52.6 (20-OCH3), 52.1 (20-OCH3), 45.9 (C-2), 44.4 (C-4), 42.5 (C-8), 41.4 /3'-N(CH3)Z/, 33.8 (C-19), 22.0 (C-21), 20.7 (COCH3), 17.5 (C-18), 12.9 (C-22).
FAB (MH+) 873.
Example 12 4'-Demycarosyl-4"-O-acetyl-3-deoxy-3-oxo-20-deoxo-20-dibenzylamino-8a-aza-8a-homotylosin (12) The compound 8 ( 1.20 g, 10.99 mmol) was dissolved in methanol ( 100 ml) and left to stand at room temperature for 24 hours. To the reaction solution water ( 100 ml) was added and it was extracted with methylene chloride at pH 6.5. The combined organic extracts were dried (K2C03) and evaporated at reduced pressure and the obtained crude product ( 1.0 g) was purified by flash chromatography on a silica gel column using the solvent system A to give a TLC homogeneous product (12) (0.52 g).
TLC: Rf (A) 0.65.
IR (KBr) cm 1 1745, 1650, 1622, 1537, 1454, 1373, 1233, 1166, 1058.
1H NMR (CDC13) 8 ppm 7.25 ~ 7.41 (phenyl), 6.90 (H-11), 5.67 (H-10), 5.52 (H-13), 4.98 (8a-NH) exchangeable with DSO, 4.67 (H-1"), 4.45 (H-4"), 4.17 (H-1'), 4.02 (H-8), 3.61 (20-CH2-phenyl), 3.53 (3"-OCH3), 3.52 (20-CH,-phenyl), 3.50 (2"-OCH3), 3.76, 3.32 (H-2), 2.52 /3'-N(CH3)2/, 2.12 (COCH3), 1.73 (H-22), 1.21 (H-18), 1.08 (H-21).
isC NMR (CDC13) ~ ppm 205.3 (C-3), 172.5 (C-1), 170.1 (COCH3), 167.2 (9-CONH), 143.9 (C-11), 135.9 (C-12), 135.4 (C-13), 120.0 (C-10), 103.9 (C-1'), 100.9 (C-1"), 74.6 (C-4"), 70.7 (C-4'), 70.4 (C-2'), 61.3 (3"-OCH3), 59.3 (2"-OCH3), 51.6 (C-20), 46.1 (C-2), 44.5 (C-4), 43.3 (C-8), 41.5 /3'-N(CH3),/, 2s.s (C-19), 22.0 (C-21), 20.7 (COCH3), 17.g (C-18), 12.9 (C-22), 20-N(CH2C6H)2 139.9, 128.8, 128.0, 126.5, 58Ø
FAB (MH+) 1008.
Example 13 4'-Demycarosyl-4"-O-acetyl-8a-aza-8a-homotylosin 20-dimethylacetal (13) The compound 3 (0.5 g, 0.52 mmol) was dissolved in methanol (20 ml) and left to stand at room temperature for 24 hours. The isolation of the product was carried out in the manner disclosed in Example 9 and the obtained crude product (0.43 g) was purified by flash chromatography on a silica gel column using the solvent system A to give a TLC homogeneous product (13) (0.32 g).

TLC: Rf (A) 0.32.
IR (KBr) cm 1 1739, 1656, 1616, 1541, 1455, 1376, 1237, 1170, 1062.
1H NMR (CDC13) 8 ppm 7.15 (H-11), 5.71 (H-10), 5.66 (H-13), 4.97 (8a-NH) exchangeable with D20, 4.64 (H-1"), 4.62 (H-20), 4.44 (H-4"), 4.24 (H-1'), 4.18 (H-8), 3.53 (3"-OCH3), 3.47 (2"-OCH3), 3.37 (20-OCH3), 3.36 (20-OCH3), 2.50 /3'-N(CH3)2/, 2.12 (COCH3), 1.75 (H-22), 1.17 (H-21).
FAB (MH+) 875.
Example 14 4'-Demycarosyl-4"-O-acetyl-20-deoxo-20-dibenzylamino-8a-aza-8a-homotylosin (14) The compound 4 (0.75 g, 0.69 mmol) was dissolved in methanol (20 ml) and left to stand at room temperature for 24 hours. The isolation of the product was carried out in the manner disclosed in Example 12 and the obtained crude product (0.66 g) was purified by flash chromatography on a silica gel column using the solvent system A to give a TLC homogeneous product (14) (0.45 g).
TLC: Rf (A) 0.50.
IR (KBr) cm 1 1740, 1657, 1621, 1538, 1454, 1373, 1236, 1169, 1054.
1H NMR (CDCl3) ~ ppm 7.25 ~ 7.41 (phenyl), 7.10 (H-11), 5.69 (H-13), 5.65 (H-10), 4.96 (8a-NH) exchangeable with DzO, 4.66 (H-1"), 4.45 (H-4"), 4.14 (H-8), 4.07 (H-1'), 3.59 (20-N-CH2-phenyl), 3.56 (20-CH2-phenyl), 3.53 (3"-OCH3), 3.50 (2"-OCH3), 2.49 /3'-N(CH3)2/, 2.12 (COCH3), 1.73 (H-22), 1.11 (H-21), 0.94 (H-18).
FAB (MH+) 1010.
Example I S
4'-Demycarosyl-3-deoxy-3-oxo-8a-aza-8a-homotylosin 20-dimethylacetal (15) The compound 11 (0.40 g, 0.46 mmol) was dissolved in a methanol/conc. NH40H
mixture (4:1, 50 ml) and left to stand for 60 hours at the temperature of 5°C. The reaction solution was evaporated to an oily residue and then a product was isolated in the manner disclosed in Example 9. The obtained crude product (0.25 g) was purified by flash chromatography on a silica gel column using the solvent system A to give a TLC homogeneous product (15) (0.15 g).
TLC: Rf (A) 0.39.
IR (KBr) cm 1 1739, 1714, 1650, 1620, 1544, 1455, 1375, 1170, 1063.
1H NMR (CDCl3) 8 ppm 6.87 (H-11), 5.77 (H-10), 5.44 (H-13), 5.18 (8a-NH) exchangeable with DzO, 4.60 (H-20), 4.64 (H-1"), 4.33 (H-1'), 4.17 (H-8), 3.93 (H-5"), 3.89 (H-3"), 3.53 (3"-OCH3), 3.50, 3.26 (H-2), 3.48 (2"-OCH3), 3.30 (20-OCH3), 3.29 (20-OCH3), 2.33 /3'-N(CH3)2/, 1.75 (H-22), 1.25 (H-18).
FAB (MH+) 831.
Example 16 4'-Demycarosyl-3-deoxy-3-oxo-20-deoxo-20-dibenzylamino-8a-aza-8a-homotylosin (16) The compound 12 (0.78 g, 0.77 mmol) was dissolved in a methanol/conc. NH40H
mixture (4:1, 50 ml) and left to stand for 24 hours at room temperature. To the reaction solution water (80 ml) was added and it was extracted twice with methylene chloride at pH 7.5. The combined organic extracts were dried (K2C03) and evaporated at reduced pressure and the obtained product (0.66 g) was purified by flash chromatography on a silica gel column using the solvent system A to give a TLC
homogeneous product (16) (0.32 g).
TLC: Rf (A) 0.55.
IR (KBr) cm 1 1739, 1714, 1650, 1622, 1538, 1454, 1376, 1167, 1082.
1H NMR (CDC13) 8 ppm 7.25 ~ 7.41 (phenyl), 6.90 (H-11), 5.66 (H-13), 5.53 (H-10), 5.28 (8a-NH) exchangeable with D20, 4.61 (H-1"), 4.16 (H-1'), 4.03 (H-8), 3.62 (20-N-CH2-phenyl), 3.61 (20-CH2-phenyl, 3"-OCH3), 3.51 (2"-OCH3), 3.78, 3.38 (H-2), 2.5 /3'-N(CH3)~/, 2.38 (H-4), 1.72 (H-22), 1.21 (H-18), 1.08 (H-21).
isC NMR (CDC13) 8 ppm 205.3 (C-3), 172.5 (C-1), 167.2 (9-CONH), 143.9 (C-11), 135.9 (C-12), 135.6 (C-13), 120.0 (C-10), 103.9 (C-1'), 101.0 (C-1'), 72.5 (C-4"), 70.7 (C-4'), 70.4 (C-2'), 61.5 (3"-OCH3), 59.5 (2"-OCH3), 51.7 (C-20), 46.1 (C-2), 44.5 (C-4), 43.3 (C-8), 41.5 /3'-N(CH3)2/, 28.8 (C-19), 22.0 (C-21), 17.8 (C-18), 12.9 (C-22), 20-N(CH2C6H)2 140.0, 128.8, 128.0, 126.5, 58Ø
FAB (MH+) 967.
Example 17 4'-Demycarosyl-3-deoxy-3-oxo-8a-aza-8a-homotylosin (17) The compound 15 (0.5 g, 0.60 mmol) was dissolved in an acetonitrile/0.1 N HCl mixture (1:1, 35 ml) and stirred for 2 hours at room temperature. To the reaction solution a saturated NaHC03 solution was added and it was extracted twice with methylene chloride. The combined organic extracts were dried (K~C03) and evaporated at reduced pressure and the obtained product (0.42 g) was purified by flash chromatography on a silica gel column using the solvent system A to give a TLC
homogeneous product (17) (0.25 g).
TLC: Rf (A) 0.35.
IR (KBr) cm 1 1739, 1719, 1657, 1620, 1545, 1455, 1376, 1169, 1082.
1H NMR (CDC13) b ppm 9.78 (H-20), 7.19 (H-11), 5.72 (H-10), 5.70 (H-13), 5.06 (8a-NH) exchangeable with D20, 4.58 (H-1"), 4.18 (H-1'), 4.23 (H-8), 3.68, 3.32 (H-2), 3.62 (3"-OCH3), 3.49 (2"-OCH3), 2.49 /3'-N(CH3)2/, 1.75 (H-22), 1.25 (H-18), 1.18 (H-21).
i3C NMR (CDCl3) ~ ppm 205.3 (C-3), 203.8 (C-20), 173.5 (C-1), 166.9 (9-CONH), 145.1 (C-11), 138.2 (C-13), 135.1 (C-12), 129.3 (C-10), 103.7 (C-1'), 101.1 (C-1'), 72.8 (C-4"), 71.0 (C-4'), 70.4 (C-2'), 61.5 (3"-OCH3), 59.5 (2"-OCH3), 46.6 (C-19), 46.1 (C-2), 44.5 (C-4), 43.3 (C-8), 41.5 /3'-N(CH3)2/, 22.4 (C-21), 17.8 (C-18), 12.9 (C-22).
FAB (MH+) 785.
Example 18 4'-Demycarosyl-2',4'-di-O-acetyl-8a-aza-8a-homotylosin (18) The compound 1 (0.5 g, 0.55 mmol) was dissolved in an acetonitrile/0.1 N HCl mixture (1:1, 35 ml) and stirred for 2 hours at room temperature. The isolation of the product was carried out in the manner disclosed in Example 17 to give a TLC
homogeneous product (18) (0.34 g).
TLC: Rf (B) 0.35.
IR (KBr) cm 1 1749, 1657, 1620, 1548, 1455, 1375, 1231, 1170, 1059.
1H NMR (CDC13) 8 ppm 9.75 (H-20), 7.21 (H-11), 5.72 (H-10), 5.71 (H-13), 5.08 (8a-NH) exchangeable with D20, 4.89 (H-2'), 4.74 (H-4'), 4.58 (H-1"), 4.26 (H-1'), 3.61 (3"-OCH3), 3.49 (2"-OCH3), 2.33 /3'-N(CH3)2/, 2.05 (COCH3), 2.03 (COCH3), 1.74 (H-22), 1.18 (H-21).
i3C NMR (CDCl3) 8 ppm 203.6 (C-20), 173.3 (C-1), 169.9, 169.5 (2xCOCH3), 166.5 (9-CONH), 145 .2 (C-11 ), 13 8 . 3 (C-13 ), 13 5 . 0 (C-12), 119. 0 (C-10), 101. 6 (C-1'), 100.9 (C-1"), 72.5 (C-4"), 70.6 (C-4'), 70.3 (C-2'), 65.6 (C-3), 61.5 (3"-OCH3), 59.5 (2"-OCH3), 46.3 (C-19), 42.5 (C-8), 41.0 /3'-N(CH3)2/, 38.5 (C-2), 21.6 (C-21), 21.1, 21.0 (2xCOCH3), 12.7 (C-22), 8.1 (C-18).
FAB (MH+) 871.
Example 19 4'-Demycarosyl-2',4',4"-tri-O-acetyl-8a-aza-8a-homotylosin (19) The compound 3 (0.5 g, 0.52 mmol) was dissolved in an acetonitrile/0.1 N HCl mixture (1:1, 35 ml) and stirred for 2 hours at room temperature. The isolation of the product was carried out in the manner disclosed in Example 17 to give a TLC
homogeneous product (19) (0.47 g).
TLC: Rf (B) 0.60; Rf (C) o.so.
IR (KBr) cm' 1748, 1659, 1621, 1538, 1455, 1373, 1232, 1171, 1052.
1H NMR (CDCl3) ~ ppm 9.74 (H-20), 7.16 (H-11), 5.69 (H-10), 5.65 (H-13), 4.89 (8a-NH) exchangeable with D20, 4.88 (H-2'), 4.76 (H-4'), 4.64 (H-1"), 4.44 (H-4"), 4.33 (H-1'), 4.18 (H-8), 3.52 (3"-OCH3), 3.46 (2"-OCH3), 2.33 /3'-N(CH3)2/, 2.12 (COCH3), 2.05 (COCH3), 2.03 (COCH3), 1.74 (H-22), 1.16 (H-21).
isC NMR (CDCl3) 8 ppm 203.6 (C-20), 173.1 (C-1), 170.1, 169.8, 169.4 (3xCOCH3), 166.1 (9-CONH), 144.7 (C-11), 138.0 (C-13), 134.9 (C-12), 119.2 (C-10), 103.7 (C-20), 102.1 (C-1'), 100.9 (C-1"), 74.5 (C-4"), 71.4 (C-4'), 70.3 (C-2'), 65.6 (C-3), 61.3 (3"-OCH3), 59.3 (2"-OCH3), 46.3 (C-19), 42.7 (C-8), 42.6 (C-4), 41.0 /3'-N(CH3)2/, 40.5 (C-2), 34.5 (C-19), 21.9 (C-21), 21.1, 21.0, 20.7 (3xCOCH3), 12.7 (C-22), 8.3 (C-18).
FAB (MH+) 913.
Example 20 4'-Demycarosyl-2',4'-di-O-acetyl-4"-deoxy-4"-oxo-8a-aza-8a-homotylosin (20) The compound 5 (0.7 g, 0.77 mmol) was dissolved in an acetonitrile/0.1 N HCl mixture (1:1, 50 ml) and stirred for 1 hour at room temperature. The isolation of the product was carried out in the manner disclosed in Example 17 to give a TLC
homogeneous product (20) (0.36 g).
TLC: Rf (B) 0.48.
IR (KBr) cm 1 1749, 1656, 1619, 1543, 1458, 1375, 1230, 1172, 1058.
1H NMR (CDCl3) 8 ppm 9.75 (H-20), 7.21 (H-11), 5.72 (H-10), 5.70 (H-13), 5.08 (8a-NH) exchangeable with D20, 4.88 (H-2'), 4.74 (H-4'), 4.58 (H-1"), 4.30 (H-1'), 4.17 (H-8), 3.98 (H-5"), 3.78 (H-3"), 3.58 (3"-OCH3), 3.48 (2"-OCH3), 3.30 (H-2"), 2.33 /3'-N(CH3)2/, 2.05 (COCH3), 2.03 (COCH3), 1.76 (H-22), 1.34 (H-6"), 1.17 (H-21).
i3C NMR (CDC13) 8 ppm 203.0 (C-20), 202.4 (C-4"), 173.1 (C-1), 169.9, 169.5 (2xCOCH3), 166.5 (9-CONH), 145.0 (C-11), 138.1 (C-13), 135.1 (C-12), 119.0 (C-10), 102.1 (C-1"), 100.9 (C-1'), 85.3 (C-3"), 84.2 (C-2"), 73.3 (C-5"), 71.3 (C-4'), 70.3 (C-2'), 65.6 (C-3), 61.5 (3"-OCH3), 59.4 (2"-OCH3), 46.3 (C-19), 42.5 (C-8), 41.0 /3'-N(CH3)2/, 38.5 (C-2), 21.9 (C-21), 21.1, 21.0 (2xCOCH3), 14.0 (C-6"), 12.7 (C-22), 8.3 (C-1).
FAB (MH+) 869.
Example 21 4'-Demycarosyl-4"-O-acetyl-8a-aza-8a-homotylosin (21) The compound 19 (0.30 g, 0.33 mmol) was dissolved in methanol (20 ml) and left to stand for 24 hours at room temperature. The isolation of the product was carried out in the manner disclosed in Example 9 and the obtained crude product (0.25 g) was purified by flash chromatography on a silica gel column using the solvent system A to give a TLC homogeneous product (21) (0.19 g).
TLC: Rf (A) 0.28.
IR (KBr) cm 1 1749, 1657, 1620, 1544, 1455, 1375, 1229, 1170, 1063.
' H NMR (CDCl3) 8 ppm 9.78 (H-20), 7.20 (H-11 ), 5.72 (H-10), 5.70 (H-13 ), 5.12 (8a-NH) exchangeable with D20, 4.88 (H-2'), 4.64 (H-1"), 4.44 (H-4"), 4.18 (H-1'), 4.12 (H-8), 3.93 (H-5"), 3.89 (H-3"), 3.53 (3"-OCH3), 3.48 (2"-OCH3), 2.49 /3'-N(CH3)2/, 2.12 (COCH3), 1.75 (H-22).
FAB (MH+) 829.
Example 22 4'-Demycarosyl-4"-deoxy-4"-oxo-8a-aza-8a-hornotylosin (22) The compound 20 (0.23 g, 0.27 mmol) was dissolved in methanol (20 ml) and left to stand for 24 hours at room temperature. The isolation of the product was carried out in the manner disclosed in Example 9 and the obtained crude product (0.14 g) was purified by flash chromatography on a silica gel column using the solvent system A to give a TLC homogeneous product (22) (0.095 g).
TLC: Rf (A) 0.30.
IR (KBr) cm 1 1717, 1655, 1625, 1542, 1454, 1378, 1170, 1062.
1H NMR (CDC13) 8 ppm 9.76 (H-20), 7.20 (H-11), 5.72 (H-10), 5.70 (H-13), 5.12 (8a-NH) exchangeable with DSO, 4.64 (H-1"), 4.33 (H-1'), 4.18 (H-8), 3.98 (H-5"), 3.78 (H-3"), 3.58 (3"-OCH3), 3.46 (2"-OCH3), 3.30 (H-2"), 3.06 (H-4'), 2.33 /3'-N(CH3)2/, 1.74 (H-22), 1.34 (H-6"), 1.16 (H-21).
isC NMR (CDC13) 8 ppm 203.7 (C-20), 202.5 (C-4"), 173.4 (C-1), 166.6 (9-CONH), 144.9 (C-11), 137.6 (C-13), 135.4 (C-12), 119.4 (C-10), 102.1 (C-1'), 100.9 (C-1"), 71.4 (C-4'), 70.3 (C-2'), 66.3 (C-3), 61.5 (3"-OCH3), 59.7 (2"-OCH3), 46.2 (C-19), 42.7 (C-8), 42.1 (C-4), 41.5 /3'-N(CH3)2/, 39.8 (C-2), 21.7 (C-21), 14.0 (c-6"), 12.7 (c-22), s.7 (c-18).
FAB (MH+) 785.

Claims

1. Compounds of the general formula I

wherein R represents CHO, CH(OCH3)2 or CH2N[CH2(C6H5)]2, R1 represents H or C1-C3 acyl, R2 represents OR6 and R6 represents H or C1-C3 aryl, R3 represents H or R2 and R3 together represent =O, R4 represents OH, R5 represents H or R4 and R5 together represent =O.

2. A compound according to claim 1, characterized in that R represents CH(OCH3)2, R1 represents COCH3, R2 represents OR6 wherein R6 represents H, R3 and R5 are the same and represent H and R4 represents OH.

3. A compound according to claim 1, characterized in that R represents CH2N[CH2(C6H5)]2, R1 represents COCH3, R2 represents OR6 wherein R6 represents H, R3 and R5 are the same and represent H and R4 represents OH.

4. A compound according to claim 1, characterized in that R represents CH(OCH3)2, R1 represents COCH3, R2 represents OR6 wherein R6 represents COCH3, R3 and R5 are the same and represent H and R4 represents OH.

5. A compound according to claim 1, characterized in that R represents CH=N[CH2(C6H5)]2, R1 represents COCH3, R2 represents OR6 wherein R6 represents COCH3, R3 and R5 are the same and represent H and R4 represents OH.

6. A compound according to claim 1, characterized in that R represents CH(OCH3)2, R1 represents COCH3, R2 and R3 together represent =O, R4 represents OH and R5 represents H.

7. A compound according to claim 1, characterized in that R represents CH2N[CH2(C6H5)]2, R1 represents COCH3, R2 and R3 together represent =O, R4 represents OH and R5 represents H.

8. A compound according to claim 1, characterized in that R represents CH(OCH3)2, R1 represents COCH3, R2 represents OR6 wherein R6 represents COCH3, R3 represents H and R4 and R5 together represent =O.

9. A compound according to claim 1, characterized in that R represents CH2N[CH2(C6H5)]2, R1 represents COCH3, R2 represents OR6 wherein R6 represents COCH3, R3 represents H and R4 and R5 together represent =O.

10. A compound according to claim 1, characterized in that R represents CH(OCH3)2, R1 and R5 are the same and represent H, R2 and R3 together represent =O
and R4 represents OH.

11. A compound according to claim 1, characterized in that R represents CH2N[CH2(C6H5)]2, R1 and R5 are the same and represent H, R2 and R3 together represent =O and R4 represents OH.

12. A compound according to claim 1, characterized in that R represents CH(OCH3)2, R1 and R3 are the same and represent H, R2 represents OR6 wherein represents COCH3, and R4 and R5 together represent =O.

13. A compound according to claim 1, characterized in that R represents CH2N[CH2(C6H5)]2, R1 and R3 are the same and represent H, R2 represents OR6 wherein R6 represents COCH3, and R4 and R5 together represent =O.

14. A compound according to claim 1, characterized in that R represents CH(OCH3)2, R1 and R3 are the same and represent H, R2 represents OR6 wherein represents H, and R4 and R5 together represent =O.

15. A compound according to claim 1, characterized in that R represents CH2N[CH2(C6H5)]2, R1 and R3 are the same and represent H, R2 represents OR6 wherein R6 represents H, and R4 and R5 together represent =O.

16. A compound according to claim 1, characterized in that R represents CHO, and R3 are the same and represent H, R2 represents OR6 wherein R6 represents H, and R4 and R5 together represent =O.

17. A compound according to claim 1, characterized in that R represents CHO, represents COCH3, R2 represents OR6 wherein R6 represents H, R3 and R5 are the same and represent H and R4 represents OH.

18. A compound according to claim 1, characterized in that R represents CHO, represents COCH3, R2 represents OR6 wherein R6 represents COCH3, R3 and R5 are the same and represent H and R4 represents OH.

19. A compound according to claim 1, characterized in that R represents CHO, represents COCH3, R2 and R3 together represent =O, R4 represents OH and R5 represents H.

20. A compound according to claim 1, characterized in that R represents CHO, and R5 are the same and represent H, R2 and R3 together represent =O and R1 represents OH.