AU5558300A - Derivatives of 4'-demycarosyl-8a-aza-8a-homotylosin - Google Patents

Derivatives of 4'-demycarosyl-8a-aza-8a-homotylosin Download PDF

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AU5558300A
AU5558300A AU55583/00A AU5558300A AU5558300A AU 5558300 A AU5558300 A AU 5558300A AU 55583/00 A AU55583/00 A AU 55583/00A AU 5558300 A AU5558300 A AU 5558300A AU 5558300 A AU5558300 A AU 5558300A
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represent
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Nevenka Lopotar
Stjepan Mutak
Amalija Narandja
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Fidelta doo
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
    • C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

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Description

WO 00/77016 PCT/HROO/00018 1 DERIVATIVES OF 4'-DEMYCAROSYL-8a-AZA-8a-HOMOTYLOSIN Technical Field IPC: A 61 K 31/70 C 07 H 17/08 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 CO-NH CH3 8a R 20
H
3C
R
2 H3C RRN(H 3
)
2 OH H 3 3 R OCH O R5'
CH
3 wherein R represents CHO, CH(OCH 3
)
2 or CH 2
N[CH
2
(C
6
H
5
)]
2 , R' represents H or C 1
-C
3 acyl,
R
2 represents OR 6 and R 6 represents H or C 1
-C
3 acyl,
R
3 represents H or R 2 and R 3 together represent =0, R represents OH, R5 represents H or R 4 and R 5 together represent =0, and to a process for the preparation thereof. Prior Art WO 00/77016 PCT/HROO/00018 4'-Demycarosyl-8a-aza-8a-homotylosim, 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 B1). 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).
CI-C
3 acyl esters of 4'-demycarosyl-8a-aza-8a-homotylosin and of 4'-demycarosyl 20-deoxo-20-dibenzylamino-8 a-aza-8a-homotylosin as well as 4"-deoxy-4"-oxo- and 3-deoxy-3-oxo derivatives of 4'-demycarosyl-8 a-aza-8 a-homotylosin and of 4' demycarosyl-20-deoxo-20-dibenzylamino-8 a-aza-8 a-homotylosin, C 1
-C
3 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 WO 00/77016 PCT/HR0O/00018 3 CO-NH CH3 8a R 20
H
3C
R
2
H
3 0
N(CH
3
)
2
H
3 RZ0p OR1 411 0" 0OCH 3 3
OCH
3 00R 5
CH
3 wherein R represents CHO, CH(OCH 3
)
2 or CH 2
N[CH
2
(C
6
H
5
)]
2 ,
R
1 represents H or C 1
-C
3 acyl,
R
2 represents OR 6 and R 6 represents H or Ci-C 3 acyl,
R
3 represents H or R 2 and R 3 together represent =0, R represents OH, R5 represents H or R 4 and R 5 together represent =0, may be prepared in such a way that 4'-demycarosyl-8a-aza-8a-homotylosin 20-dimethylacetal of the formula Ila and 4' demycarosyl-20-deoxo-20-dibenzylamino-8a-aza-8a-homotylosin of the formula IIb CO-NH CH3 8a R
H
3 0
H
3 O 3 OH N(OH 3
)
2 HO 4'HO HO O 3 OH 3 OCH3 3 OH
CH
3 Ila R = CH(OCH 3
)
2 Ilb R = CH 2
N[CH
2
(C
6
H
5
)]
2 WO 00/77016 PCT/HROO/00018 4 are subjected to A) an O-acylation with anhydrides of C 1
-C
3 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 2 6
CH(OCH
3
)
2 or CH 2
N[CH
2
(C
6
H
5
)]
2 , R' represents COCH 3 , R2 represents OR , wherein R 6 represents H, R 3 and R' are the same and represent H and R 4 represents OH, are optionally subjected to Al) an O-acylation with anhydrides of C 1
-C
3 carboxylic acids, preferably with acetic acid anhydride in methylene chloride in the presence of an organic base, preferably triethyl amine and 4-dimethylaniminopyridine as a catalyst during 30 hours at room temperature, and the obtained compounds of the formula I, wherein R represents 2 6
CH(OCH
3
)
2 or CH 2
N[CH
2
(C
6
H
5
)]
2 , R' represents COCH 3 , R represents OR , wherein R 6 represents COCH 3 , R 3 and R 5 are the same and represent H and R 4 represents OH, are optionally subjected to B) an oxidation reaction with N(3-dimethylamino-propyl)-N'ethyl carbodilmide 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(OCH 3
)
2 or CH 2
N[CH
2
(C
6
H
5
)]
2 , R' represents 26 63
COCH
3 , R 2 represents OR , wherein R represents COCH 3 , R3 represents H and R 4 and R 5 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(OCH 3
)
2 or CH 2
N[CH
2
(C
6
H
5
)]
2 , R' and R 3 are the same and represent H, R 2 represents OR 6 , wherein R 6 represents COCH 3 , and R and
R
5 together represent =0, WO 00/77016 PCT/HROO/00018 5 are optionally subjected to Cl) 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(OCH 3
)
2 or CH 2
N[CH
2
(C
6
H
5
)]
2 , R' and R 3 are the same and represent H, R 2 represents OR 6 , wherein R 6 represents H, and R 4 and
R
5 together represent =0; or the compound obtained according to process C 1 of the formula I, wherein R represents CH(OCH 3
)
2 , R' and R 3 are the same and represent H, R 2 represents OR 6 , wherein R 6 represents H, and R 4 and R together represent =0, is optionally subjected to D) a hydrolysis of the acetal in a mixture of acetonitrile and 0.1 N hydrochloric acid (1:1) for 2 hours at room temperature to obtain the compound of the formula I, wherein R represents a CHO group, R' and R 3 are the same and represent H, R 2 represents OR 6 , wherein R 6 represents H, and R 4 and R 5 together represent =0; or compounds obtained according to process A of the formula I, wherein R represents CH(OCH 3
)
2 or CH 2
N[CH
2
(C
6
H
5
)]
2 , R' represents COCH 3 , R 2 represents OR 6 , wherein R 6 represents H, R 3 and R 5 are the same and represent H and R 4 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(OCH 3
)
2 or
CH
2
N[CH
2
(C
6
H
5
)]
2 , R1 represents COCH 3 , R 2 and R 3 together represent =0, R 4 represents OH and R 5 represents H, are optionally subjected to methanolysis in the manner disclosed in C, WO 00/77016 PCT/HR0O/00018 6 to obtain compounds of the formula I, wherein R represents CH(OCH 3
)
2 or CH2N[CH 2
(C
6
H
5
)]
2 , RI and R 5 are the same and represent H, R 2 and R 3 together represent =O and R 4 represents OH; or the compound obtained according to process B of the formula I, wherein R represents a CH(OCH 3
)
2 group, R' represents COCH 3 , R 2 and R 3 together represent =O, R 4 represents OH and R 5 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, R1 represents COCH 3 , R 2 and R 3 together represent =O, R 4 represents OH and R 5 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, R' and R are the same and represent H, R 2 and R 3 together represent =O and R 4 represents OH; or the compound obtained according to process A of the formula I, wherein R represents CH(OCH 3
)
2 , R' represents COCH 3 , R 2 represents OR 6 , wherein R 6 represents H, R 3 and R 5 are the same and represent H and 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, R1 represents
COCH
3 , R 2 represents OR6, wherein R 6 represents H, R 3 and R 5 are the same and represent H and R 4 represents OH; or compounds obtained according to process Al of the formula I, wherein R represents CH(OCH 3
)
2 or CH 2
N[CH
2
(C
6
H
5
)]
2 , R1 represents COCH 3 , R 2 represents OR 6 , wherein R 6 represents COCH 3 , R 3 and R 5 are the same and represent H and R 4 represents OH, WO 00/77016 PCT/HROO/00018 7 are optionally subjected to methanolysis in the manner disclosed in C, to obtain compounds of the formula I, wherein R represents CH(OCH 3
)
2 or
CH
2
N[CH
2
(C
6
H
5
)]
2 , R1, R3 and R 5 are the same and represent H, R 2 represents OR , wherein R6 represents COCH 3 , and R4 represents OH; or the compound obtained according to process Al of the formula I, wherein R represents CH(OCH 3
)
2 , R 1 represents COCH 3 , R 2 represents OR 6 , wherein R6 represents COCH 3 , R 3 and R 5 are the same and represent H and R 4 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 1 represents COCH 3 , R2 represents OR 6 , wherein R 6 represents COCH 3 , R3 and R 5 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, R 1 , R 3 and R 5 are the same and represent H, R 2 represents OR 6 , wherein R 6 represents COCH 3 , and
R
4 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 meshi/ASTM) in a solvent sistem:
CH
2 Cl 2
-CH
3 OH-conc. NH40H (90:9:1.5, system A), CH 2 Cl 2
-CH
3 OH (90:9, system B) or CHCl 3
-CH
3
COCH
3 (7:3, system G). The structure of the novel compounds was confirmed by spectrometric methods and mass analysis.
WO 00/77016 PCT/HROO/00018 8 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.
WO 00/77016 PCT/HROO/00018 9 Example ] 4'-Demycarosyl-2',4'-di-O-acetyl-8a-aza-8a-homotylosin 20-dimethylacetal (1) 4'-Demycarosyl-8a-aza-8a-homotylosim 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 NaHCO 3 solution and water, dried (K 2 C0 3 ) 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. 'H NMR (CDCl 3 ) 5 ppm 7.16 (H-11), 5.69 (H-10), 5.66 (H-13), 4.96 (8a-NH) exchangeable with D 2 0, 4.88 (H-2'), 4.76 (H-4'), 4.63 (H-20), 4.58 (H-i"), 4.33 (H-l'), 4.17 (H-8), 3.61 (3"-OCH 3 ), 3.47 (2"-OCH 3 ), 3.56 (2x20-OCH 3 ), 2.33 /3'-N(CH 3
)
2 /, 2.05 (COCH 3 ), 2.03 (COCH 3 ), 1.74 (H-22), 1.17 (H-21). 13 C NMR (CDCl 3 ) 8 ppm 179.1 (C-1), 169.8, 169.4 (2xCOCH 3 ), 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-l'), 100.9 (C-i"), 72.5 (C-4"), 71.4 (C-4'), 70.3 (C-2'), 65.6 (C-3), 61.5 (3"-OCH 3 ), 59.4 (2"-OCH 3 ), 50.4 (2x20-OCH 3 ), 42.7 (C-8), 42.5 (C-4), 41.0 /3'-N(CH 3
)
2 /, 40.5 (C-2), 34.3 (C-19), 21.8, 20.9 (2xCOCH 3 ), 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) WO 00/77016 PCT/HROO/00018 10 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 NaHCO 3 solution and water, dried (K 2 C0 3 ) 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' 1749, 1651, 1633, 1548, 1454, 1374, 1231, 1169, 1059. H NMR (CDC 3 ) 6 ppm 7.25 ~ 7.41 (phenyl), 7.10 (H- 11), 5.70 (H-13), 5.65 (H-10), 4.89 (8a-NH) exchangeable with D20, 4.84 (H-2'), 4.74 (H-4'), 4.60 (H-l"), 4.15 (H-l'), 3.62 (3"-OCH 3 ), 3.61 (20-N-CH 2 -phenyl), 3.58 (20-CH 2 -phenyl), 3.51 (2"-OCH 3 ), 2.32 /3'-N(CH 3
)
2 /, 2.06 (COCH 3 ), 2.00 (COCH 3 ), 1.72 (H 22), 1.12 (H-21). 13 C NMR (CDCl 3 ) 6 ppm 173.4 (C-1), 169.9, 169.5 (2xCOCH 3 ), 166.1 (9-CONH), 144.8 (C-11), 137.9 (C-13), 135.2 (C-12), 119.3 (C-10), 102.3 (C-l'), 101.0 (C-i"), 72.5 (C-4"), 71.4 (C-4'), 70.4 (C-2'), 66.0 (C-3), 61.5 (3"-OCH 3 ), 59.5 (2"-OCH 3 ), 52.2 (C-20), 42.9 (C-8), 42.4 (C-4), 41.0 /3'-N(CH 3
)
2 /, 38.7 (C-2), 29.4 (C-19), 21.8 (C-21), 21.1, 21.0 (2xCOCH 3 ), 12.7 (C-22), 8.4 (C-18), 20-N(CH 2
C
6
H
5
)
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 mil), 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 26 WO 00/77016 PCT/HROO/00018 11 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. 'H NMR (CDC 3 ) 8 ppm 7.16 (H-11), 5.69 (H-10), 5.65 (H-13), 4.89 (8a-NH) exchangeable with D 2 0, 4.88 (H-2'), 4.76 (H-4'), 4.64 (H-i"), 4.59 (H-20), 4.33 (H-l'), 4.18 (H-8), 3.52 (3"-OCH 3 ), 3.46 (2"OCH 3 ), 3.36 (20-OCH 3 ), 3.35 (20-OCH 3 ), 2.33 /3'-N(CH 3
)
2 /, 2.12 (COCH 3 ), 2.05 (COCH 3 ), 2.03
(COCH
3 ), 1.74 (H-22), 1.16 (H-21). 3 C NMR (CDCl 3 ) 6 ppm 173.1 (C-1), 170.1, 169.8, 169.4 (3xCOCH 3 ), 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-i'), 100.9 (C-i"), 74.5 (C-4"), 71.4 (C-4'), 70.3 (C-2'),. 65.6 (C-3), 61.3 (3"-OCH 3 ), 59.3 (2"-OCH 3 ), 53.7 (20-OCH 3 ), 50.6 (20-OCH 3 ), 42.7 (C-8), 42.6 (C-4), 41.0 /3'-N(CH 3
)
2 /, 40.5 (C-2), 34.5 (C-19), 21.9, (C 21), 21.1, 21.0, 20.7 (3xCOCH 3 ), 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 26 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-1 1747, 1651, 1632, 1538, 1453, 1372, 1233, 1170, 1051. 'H NMR (CDCl 3 ) 6 ppm 7.22 ~ 7.41 (phenyl), 7.10 (H-11), 5.70 (H-13), 5.65 (H-10), WO 00/77016 PCT/HROO/00018 12 4.91 (8a-NH) exchangeable with D 2 0, 4.86 (H-2'), 4.74 (H-4'), 4.66 (H-i"), 4.46 (H-4"), 4.15 (H-l'), 3.61 (2x20-N-CH 2 -phenyl), 3.53 (3"-OCH 3 ), 3.50 (2"-OCH 3 ), 2.32 /3'-N(CH 3
)
2 /, 2.12 (COCH 3 ), 2.06 (COCH 3 ), 2.00 (COCH 3 ), 1.72 (H-22), 1.12 (H-21), 0.78 (H-18). C NMR (CDCl 3 ) 6 ppm 173.3 (C-1), 170.1, 169.9, 169.5 (3xCOCH 3 ), 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"-OCH 3 ), 59.3 (2"-OCH 3 ), 52.2 (C-20), 42.9 (C-8), 42.4 (C-4), 41.0 /3'-N(CH 3
)
2 /, 38.7 (C-2), 29.4 (C-19), 21.8 (C-21), 21.1, 21.0, 20.7 (3xCOCH 3 ), 12.7 (C-22), 8.4 (C-18), 20-N(CH 2
C
6
H
5
)
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-dimethylamiinopropyl)-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 NaHCO 3 solution and water, dried (K2C0 3 ) 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.
WO 00/77016 PCT/HROO/00018 13 1H NMR (CDCl 3 ) 6 ppm 7.16 (H-11), 5.71 (H-10), 5.64 (H-13), 4.97 (8a-NH) exchangeable with D 2 0, 4.88 (H-2'), 4.76 (H-4'), 4.60 (H-20), 4.63 (H-i"), 4.33 (H-l'), 4.17 (H-8), 3.98 (H-5"), 3.78 (H-3"), 3.58 (3"-OCH 3 ), 3.52 (2"-OCH 3 ), 3.36 (20-OCH 3 ), 3.35 (20-OCH 3 ), 3.30 (H-2"), 2.33 /3'-N(CH 3
)
2 /, 2.05 (COCH 3 ), 2.03 (COCH 3 ), 1.76 (H-22), 1.34 (H-6"), 1.17 (H-21). 13 C NMR (CDCl 3 ) 6 ppm 202.4 (C-4"), 173.1 (C-1), 169.9, 169.5 (2xCOCH 3 ), 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-l'), 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"-OCH 3 ), 59.1 (2"-OCH 3 ), 53.7 (20-OCH 3 ), 50.5 (20-OCH 3 ), 42.7 (C-8), 42.6 (C-4), 41.0 /3'-N(CH 3
)
2 /, 40.7 (C-2) 34.4 (C-19), 21.9 (C-21), 21.1, 21.0 (2xCOCH 3 ), 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 pyridmie 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. H NMR (CDCl 3 ) 5 ppm 7.25 ~ 7.41 (phenyl), 7.12 (H-11), 5.70 (H-13), 5.65 (H-10), 4.94 (8a-NH) exchangeable with D 2 0, 4.82 (H-2'), 4.74 (H-4'), 4.65 (H-i"), WO 00/77016 PCT/HROO/00018 14 4.15 (H-l'), 3.98 (H-5"), 3.78 (H-3"), 3.62 (20-N-CH 2 -phenyl), 3.58 (20-CH 2 -phenyl), 3.55 (3"-OCH 3 ), 3.49 (2"-OCH 3 ), 2.32 /3'-N(CH 3
)
2 /, 2.06
(COCH
3 ), 2.00 (COCH 3 ), 1.74 (H-22), 1.36 (H-6"), 1.12 (H-21). "C NMR (CDCl 3 ) 6 ppm 202.4 (C-4"), 173.4 (C-1), 169.8, 169.3 (2xCOCH 3 ), 166.1 (9-CONH), 144.6 (C-11), 137.0 (C-13), 135.6 (C-12), 119.6 (C-10), 103.0 (C-i"), 102.2 (C-l'), 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"-OCH 3 ), 59.1 (2"-OCH 3 ), 52.2 (C-20), 42.9 (C-8), 42.4 (C-4), 40.9 /3'-N(CH 3
)
2 /, 38.7 (C-2), 29.4 (C-19), 21.8 (C-21), 21.1, 21.0 (2xCOCH 3 ), 14.0 (C-6"), 12.8 (C-22), 8.4 (C-18), 20-N(CH 2
C
6
H
5
)
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 pyridmie 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. 1H NMR (CDCl 3 ) 6 ppm 6.90 (H-11), 5.76 (H-10), 5.43 (H-13), 4.96 (8a-NH) exchangeable with D 2 0, 4.89 (H-2'), 4.79 (H-4'), 4.66 (H-i"), 4.40 (H-i'), 4.18 (H-8), 3.55, 3.32 (H-2), 3.52 (3"-OCH 3 ), 3.49 (2"-OCH 3 ), 3.30 WO 00/77016 PCT/HRO0/00018 15 (20-OCH 3 ), 3.29 (20-OCH 3 ), 2.34 /3'-N(CH 3
)
2 /, 2.12 (COCH 3 ), 2.06 (COCH 3 ), 2.03 (COCH 3 ), 1.75 (H-22), 1.10 (H-21), 1.07 (H-18). 1 3 C NMR (CDCl 3 ) 6 ppm 205.6 (C-3), 172.9 (C-1), 170.1, 169.8, 169.4 (3xCOCH 3 ), 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-l'), 100.9 (C-i"), 74.5 (C-4"), 71.4 (C-4'), 70.3 (C-2'), 61.3 (3"-OCH 3 ), 59.3 (2"-OCH 3 ), 53.7 (20-OCH 3 ), 50.6 (20-OCH 3 ), 46.5 (C-2), 44.2 (C-4), 42.0 (C-8), 41.0 /3'-N(CH 3
)
2 /, 34.5 (C-19), 21.9, (C-21), 21.1, 21.0, 20.7 (3xCOCH 3 ), 17.6 (C-18), 12.7 (C-22). FAB (MH) 957. Example 8 4'-Demycarosyl-2 ',4',4"-tri--acetyl-3-deoxy-3-oxo-20-deoxo-20-dibenzylamino 8a-aza-8a-homotylosin (8) A solution of pyridmie 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' 1748, 1633, 1538, 1454, 1373, 1231, 1052. 'H NMR (CDCl 3 ) 6 ppm 7.22 ~ 7.40 (phenyl), 6.89 (H- 11), 5.66 (H-10), 5.49 (H-13), 4.96 (8a-NH) exchangeable with D 2 0, 4.81 (H-2'), 4.74 (H-4'), 4.66 (H-1"), 4.42 (H-4"), 4.15 (H-l'), 4.12 (H-8), 3.78, 3.38 (H-2), 3.51 (2x20-N-CH 2 phenyl, 3"-OCH 3 ), 3.48 (2"-OCH 3 ), 2.32 /3'-N(CH 3
)
2 /, 2.22 (H-4), 2.09
(COCH
3 ), 2.06 (COCH 3 ), 2.00 (COCH 3 ), 1.72 (H-22), 1.10 (H-21), 1.08 (H-18).
WO 00/77016 PCT/HROO/00018 16 "C NMR (CDCl 3 ) 6 ppm 206.7 (C-3), 172.7 (C-1), 170.1, 169.9, 169.5 (3xCOCH 3 ), 166.1 (9-CONH), 144.0 (C-11),. 136.5 (C-12), 135.0 (C-13), 119.9 (C-10), 102.7 (C-i'), 100.9 (C-i"), 74.6 (C-4"), 71.3 (C-4'), 70.3 (C-2'), 61.3 (3"-OCH 3 ), 59.3 (2"-OCH 3 ), 51.7 (C-20), 47.7 (C-2), 44.5 (C-4)), 42.0 (C-8), 41.0 /3'-N(CH 3
)
2 /, 28.6 (C-19), 22.0 (C-21), 21.0, 20.7 (3xCOCH 3 ), 17.8 (C-18), 13.1 (C-22), 20-N(CH 2
C
6
H
2 ), 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 NaHCO 3 solution was added and it was extracted twice with chloroform. The combined organic extracts were dried (K 2 C0 3 ) 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' 1749, 1657, 1620, 1542, 1455, 1375, 1230, 1172, 1060. 1 H NMR (CDC1 3 ) 6 ppm 7.16 (H-11), 5.72 (H-10), 5.67 (H-13), 4.99 (8a-NH) exchangeable with D 2 0, 4.60 (H-20), 4.63 (H-i"), 4.33 (H-l'), 4.17 (H-8), 3.98 (H-5"), 3.78 (11-3"), 3.58 (3"-OCH 3 ), 3.52 (2"-OCH 3 ), 3.46 (H-2'), 3.36, 3.35 (2x20-OCH 3 ), 3.30 (H-2"), 3.06 (H-4'), 2.33 /3'-N(CH 3
)
2 /, 1.76 (H-22), 1.34 (H-6"), 1.17 (H-21). 1C NMR (CDCl 3 ) 6 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-i'), 85.3 (C-3"), 84.2 (C-2"), 73.3 (C-5"), 65.6 (C-3), 60.2 (3"-OCH 3 ), 59.1 (2"-OCH 3 ), 53.7 (20-OCH 3 ), 50.5 (20-OCH 3 ), 42.7 (C-8), 42.6 (C-4), 41.0 WO 00/77016 PCT/HR0O/00018 17 /3'-N(CH 3
)
2 /, 40.7 (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 (K 2 C0 3 ) 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-1 1715, 1655, 1619, 1542, 1454, 1377, 1168, 1082. H NMR (CDCl 3 ) 6 ppm 7.25 ~ 7.41 (phenyl), 7.12 (H-11), 5.70 (H-13), 5.65 (H-10), 4.94 (8a-NH) exchangeable with D 2 0, 4.84 (H-2'), 4.74 (H-4'), 4.60 (H-i"), 4.15 (H-i'), 3.98 (H-5"), 3.78 (H-3"), 3.62 (3"-OCH 3 ), 3.61 (20-N-CH 2 phenyl), 3.58 (20-CH 2 -phenyl), 3.51 (2"-OCH 3 ), 3.46 (H-2'), 3.01 (H-4'), 2.32 /3'-N(CH 3
)
2 /, 1.72 (H-22), 1.12 (H-21). 13C NMR (CDCl 3 ) 6 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-i'), 103.0 (C-i"), 85.4 (C-3"), 84.9 (C-2"), 73.3 (C-5"), 66.4 (C-3), 59.8 (3"-OCH 3 ), 58.6 (2"-OCH 3 ), 52.2 (C-20), 43.3 (C-8), 42.3 (C-4), 41.5 /3'-N(CH 3
)
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(CH 2
C
6
H
5
)
2 139.8, 129.1, 128.0, 126.6, 58.0. FAB (MH*) 967.
WO 00/77016 PCT/HROO/00018 18 Example ]] 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' 1749, 1657, 1620, 1544, 1455, 1375, 1229, 1170, 1063. 'H NMR (CDCl 3 ) 6 ppm 6.87 (H-11), 5.77 (H-10), 5.44 (H-13), 5.18 (8a-NH) exchangeable with D 2 0, 4.88 (H-2'), 4.64 (H-i"), 4.44 (H-4"), 4.30 (H-l'), 4.17 (H-8), 3.93 (H-5"), 3.89 (H-3"), 3.53 (3"-OCH 3 ), 3.50, 3.26 (H-2), 3.48 (2"-OCH 3 ), 3.30 (20-OCH 3 ), 3.29 (20-OCH 3 ), 2.53 /3'-N(CH 3
)
2 /, 2.12
(COCH
3 ), 1.75 (H-22), 1.25 (H-18). 1 3 C NMR (CDCl 3 ) 6 ppm 205.4 (C-3), 172.9 (C-1), 170.1 (COCH 3 ), 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-i"), 74.5 (C-4"), 70.9 (C-2'), 70.5 (C-2'), 61.3 (3"
OCH
3 ), 59.0 (2"-OCH 3 ), 52.6 (20-OCH 3 ), 52.1 (20-OCH 3 ), 45.9 (C-2), 44.4 (C-4), 42.5 (C-8), 41.4 /3'-N(CH 3
)
2 /, 33.8 (C-19), 22.0 (C-21), 20.7 (COCH 3 ), 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) WO 00/77016 PCT/HROO/00018 19 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 (K 2 C0 3 ) 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. 'H NMR (CDCl 3 ) 6 ppm 7.25 ~ 7.41 (phenyl), 6.90 (H-11), 5.67 (H-10), 5.52 (H-13), 4.98 (8a-NH) exchangeable with D 2 0, 4.67 (H-i"), 4.45 (H-4"), 4.17 (H-i'), 4.02 (H-8), 3.61 (20-CH 2 -phenyl), 3.53 (3"-OCH 3 ), 3.52 (20-CH 2 -phenyl), 3.50 (2"-OCH 3 ), 3.76, 3.32 (H-2), 2.52 /3'-N(CH 3
)
2 /, 2.12 (COCH 3 ), 1.73 (H 22), 1.21 (H-18), 1.08 (H-21). 13C NMR (CDCl 3 ) 6 ppm 205.3 (C-3), 172.5 (C-1), 170.1 (COCH 3 ), 167.2 (9 CONH), 143.9 (C-11), 135.9 (C-12), 135.4 (C-13), 120.0 (C-10), 103.9 (C-I'), 100.9 (C-i"), 74.6 (C-4"), 70.7 (C-4'), 70.4 (C-2'), 61.3 (3"-OCH 3 ), 59.3 (2"
OCH
3 ), 51.6 (C-20), 46.1 (C-2), 44.5 (C-4), 43.3 (C-8), 41.5 /3'-N(CH 3
)
2 /, 28.8 (C-19), 22.0 (C-21), 20.7 (COCH 3 ), 17.8 (C-18), 12.9 (C-22), 20
N(CH
2
C
6
H)
2 139.9, 128.8, 128.0, 126.5, 58.0. 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).
WO 00/77016 PCT/HROO/00018 20 TLC: Rf (A) 0.32. IR (KBr) cm- 1739, 1656, 1616, 1541, 1455, 1376, 1237, 1170, 1062. 1H NMR (CDCl 3 ) 6 ppm 7.15 (H-11), 5.71 (H-10), 5.66 (H-13), 4.97 (8a-NH) exchangeable with D 2 0, 4.64 (H-1"), 4.62 (H-20), 4.44 (H-4"), 4.24 (H-l'), 4.18 (H-8), 3.53 (3"-OCH 3 ), 3.47 (2"-OCH 3 ), 3.37 (20-OCH 3 ), 3.36 (20
OCH
3 ), 2.50 /3'-N(CH 3
)
2 /, 2.12 (COCH 3 ), 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 1740, 1657, 1621, 1538, 1454, 1373, 1236, 1169, 1054. 'H NMR (CDCl 3 ) 6 ppm 7.25 ~ 7.41 (phenyl), 7.10 (H-11), 5.69 (H-13), 5.65 (H-10), 4.96 (8a-NH) exchangeable with D 2 0, 4.66 (H-i"), 4.45 (H-4"), 4.14 (H-8), 4.07 (H-l'), 3.59 (20-N-CH 2 -phenyl), 3.56 (20-CH 2 -phenyl), 3.53 (3"-OCH 3 ), 3.50 (2"-OCH 3 ), 2.49 /3'-N(CH 3
)
2 /, 2.12 (COCH 3 ), 1.73 (H-22), 1.11 (H-21), 0.94 (H-18). FAB (MH) 1010. Example 15 4'-Demycarosyl-3-deoxy-3-oxo-8a-aza-8a-homotylosin 20-dimethylacetal (15) WO 00/77016 PCT/HROO/00018 21 The compound 11 (0.40 g, 0.46 mmol) was dissolved in a methanol/conc. NH 4 0H 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. 'H NMR (CDCl 3 ) 6 ppm 6.87 (H-11), 5.77 (H-10), 5.44 -(H-13), 5.18 (8a-NH) exchangeable with D 2 0, 4.60 (H-20), 4.64 (H-1"), 4.33 (H-l'), 4.17 (H-8), 3.93 (H-5"), 3.89 (H-3"), 3.53 (3"-OCH 3 ), 3.50, 3.26 (H-2), 3.48 (2"-OCH 3 ), 3.30 (20-OCH 3 ), 3.29 (20-OCH 3 ), 2.33 /3'-N(CH 3
)
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/cone. NH 4 0H 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 (K 2 C0 3 ) 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. 'H NMR (CDCl 3 ) 6 ppm 7.25 ~ 7.41 (phenyl), 6.90 (H-11), 5.66 (H-13), 5.53 (H-10), 5.28 (8a-NH) exchangeable with D 2 0, 4.61 (H-1"), 4.16 (H-l'), 4.03 (H-8), WO 00/77016 PCT/HROO/00018 22 3.62 (20-N-CH 2 -phenyl), 3.61 (20-CH 2 -phenyl, 3"-OCH 3 ), 3.51 (2"-OCH 3 ), 3.78, 3.38 (H-2), 2.5 /3'-N(CH 3
)
2 /, 2.38 (H-4), 1.72 (H-22), 1.21 (H-18), 1.08 (H-21). 1 3 C NMR (CDCl 3 ) 6 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-l'), 101.0 (C-l'), 72.5 (C-4"), 70.7 (C-4'), 70.4 (C-2'), 61.5 (3"-OCH 3 ), 59.5 (2"-OCH 3 ), 51.7 (C-20), 46.1 (C-2), 44.5 (C-4), 43.3 (C-8), 41.5 /3'-N(CH 3
)
2 /, 28.8 (C-19), 22.0 (C-21), 17.8 (C-18), 12.9 (C-22), 20-N(CH 2
C
6
H)
2 140.0, 128.8, 128.0, 126.5, 58.0. 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 HCi mixture (1:1, 35 ml) and stirred for 2 hours at room temperature. To the reaction solution a saturated NaHC0 3 solution was added and it was extracted twice with methylene chloride. The combined organic extracts were dried (K 2 C0 3 ) 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' 1739, 1719, 1657, 1620, 1545, 1455, 1376, 1169, 1082. 1H NMR (CDC 3 ) 6 ppm 9.78 (H-20), 7.19 (H-11), 5.72 (H-10), 5.70 (H-13), 5.06 (8a-NH) exchangeable with D 2 0, 4.58 (H-i"), 4.18 (H-l'), 4.23 (H-8), 3.68, 3.32 (H-2), 3.62 (3"-OCH 3 ), 3.49 (2"-OCH 3 ), 2.49 /3'-N(CH 3
)
2 /, 1.75 (H-22), 1.25 (H-18), 1.18 (H-21). 13C NMR (CDCl 3 ) 6 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-l'), 101.1 (C-i'), 72.8 (C-4"), 71.0 (C-4'), 70.4 (C-2'), 61.5 (3"-OCH 3 ), 59.5 (2"-OCH 3
),
WO 00/77016 PCT/HROO/00018 23 46.6 (C-19), 46.1 (C-2), 44.5 (C-4), 43.3 (C-8), 41.5 /3'-N(CH 3
)
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 HCI 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' 1749, 1657, 1620, 1548, 1455, 1375, 1231, 1170, 1059. 'H NMR (CDCl 3 ) 5 ppm 9.75 (H-20), 7.21 (H-11), 5.72 (H-10), 5.71 (H-13), 5.08 (8a-NH) exchangeable with D 2 0, 4.89 (H-2'), 4.74 (H-4'), 4.58 (H-1"), 4.26 (H-i'), 3.61 (3"-OCH 3 ), 3.49 (2"-OCH 3 ), 2.33 /3'-N(CH 3
)
2 /, 2.05 (COCH 3 ), 2.03 (COCH 3 ), 1.74 (H-22), 1.18 (H-21). 13 C NMR (CDCl 3 ) 6 ppm 203.6 (C-20), 173.3 (C-1), 169.9, 169.5 (2xCOCH 3 ), 166.5 (9-CONH), 145.2 (C-11), 138.3 (C-13), 135.0 (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"-OCH 3 ), 59.5 (2"-OCH 3 ), 46.3 (C-19), 42.5 (C-8), 41.0 /3'-N(CH 3
)
2 /, 38.5 (C-2), 21.6 (C-21), 21.1, 21.0 (2xCOCH 3 ), 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 WO 00/77016 PCT/HROO/00018 24 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) 0.50. IR (KBr) cm 4 1748, 1659, 1621, 1538, 1455, 1373, 1232, 1171, 1052. H NMR (CDCl 3 ) 8 ppm 9.74 (H-20), 7.16 (H-11), 5.69 (H-10), 5.65 (H-13), 4.89 (8a-NH) exchangeable with D 2 0, 4.88 (H-2'), 4.76 (H-4'), 4.64 (H-i"), 4.44 (H-4"), 4.33 (H-l'), 4.18 (H-8), 3.52 (3"-OCH 3 ), 3.46 (2"-OCH 3 ), 2.33 /3'-N(CH 3
)
2 /, 2.12 (COCH 3 ), 2.05 (COCH 3 ), 2.03 (COCH 3 ), 1.74 (H-22), 1.16 (H-21). 13 C NMR (CDCl 3 ) 6 ppm 203.6 (C-20), 173.1 (C-1), 170.1, 169.8, 169.4 (3xCOCH 3 ), 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-l'), 100.9 (C-1"), 74.5 (C-4"), 71.4 (C-4'), 70.3 (C-2'), 65.6 (C-3), 61.3 (3"-OCH 3 ), 59.3 (2"-OCH 3 ), 46.3 (C-19), 42.7 (C-8), 42.6 (C-4), 41.0 /3'-N(CH 3
)
2 /, 40.5 (C-2), 34.5 (C-19), 21.9 (C-21), 21.1, 21.0, 20.7 (3xCOCH 3 ), 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. H NMR (CDCl 3 ) 5 ppm 9.75 (H-20), 7.21 (H-11), 5.72 (H-10), 5.70 (H-13), 5.08 (8a-NH) exchangeable with D 2 0, 4.88 (H-2'), 4.74 (H-4'), 4.58 (H-i"), 4.30 (H-l'), 4.17 (H-8), 3.98 (H-5"), 3.78 (H-3"), 3.58 (3"-OCH 3 ), 3.48 (2"-OCH 3
),
WO 00/77016 PCT/HRO/00018 25 3.30 (H-2"), 2.33 /3'-N(CH 3
)
2 /, 2.05 (COCH 3 ), 2.03 (COCH 3 ), 1.76 (H-22), 1.34 (H-6"), 1.17 (H-21). "C NMR (CDC1 3 ) 6 ppm 203.0 (C-20), 202.4 (C-4"), 173.1 (C-1), 169.9, 169.5 (2xCOCH 3 ), 166.5 (9-CONH), 145.0 (C-11), 138.1 (C-13), 135.1 (C-12), 119.0 (C-10), 102.1 (C-i"), 100.9 (C-i'), 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"-OCH 3 ), 59.4 (2"-OCH 3 ), 46.3 (C-19), 42.5 (C-8), 41.0 /3'-N(CH 3
)
2 /, 38.5 (C-2), 21.9 (C-21), 21.1, 21.0 (2xCOCH 3 ), 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. 1H NMR (CDC 3 ) 6 ppm 9.78 (H-20), 7.20 (H-11), 5.72 (H-10), 5.70 (H-13), 5.12 (8a-NH) exchangeable with D 2 0, 4.88 (H-2'), 4.64 (H-I"), 4.44 (H-4"), 4.18 (H-1'), 4.12 (H-8), 3.93 (H-5"), 3.89 (H-3"), 3.53 (3"-OCH 3 ), 3.48 (2"-OCH 3 ), 2.49 /3'-N(CH 3
)
2 /, 2.12 (COCH 3 ), 1.75 (H-22). FAB (MH) 829. Example 22 4'-Demycarosyl-4"-deoxy-4"-oxo-8a-aza-8a-homotylosin (22) WO 00/77016 PCT/HROO/00018 26 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. H NMR (CDCl 3 ) 6 ppm 9.76 (H-20), 7.20 (H-11), 5.72 (H-10), 5.70 (H-13), 5.12 (8a-NH) exchangeable with D 2 0, 4.64 (H-i"), 4.33 (H-i'), 4.18 (H-8), 3.98 (H-5"), 3.78 (H-3"), 3.58 (3"-OCH 3 ), 3.46 (2"-OCH 3 ), 3.30 (H-2"), 3.06 (H-4'), 2.33 /3'-N(CH 3
)
2 /, 1.74 (H-22), 1.34 (H-6"), 1.16 (H-21). 3 C NMR (CDC1 3 ) 6 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-l'), 100.9 (C-i"), 71.4 (C-4'), 70.3 (C-2'), 66.3 (C-3), 61.5 (3"-OCH 3 ), 59.7 (2"-OCH 3 ), 46.2 (C-19), 42.7 (C-8), 42.1 (C-4), 41.5 /3'-N(CH 3
)
2 /, 39.8 (C-2), 21.7 (C-21), 14.0 (C-6"), 12.7 (C-22), 8.7 (C-18). FAB (MH) 785.

Claims (24)

1. Compounds of the general formula I CO-NH CH3 8a R 20 H 3C R 2 H 3 C N(CH 3 ) 2 O H 3 C R10 OR1 O0H 3 30 OCH3 R5 CH 3 I wherein R represents CHO, CH(OCH 3 ) 2 or CH 2 N[CH 2 (C 6 H 5 )] 2 , R represents H or C 1 -C 3 acyl, R2 represents OR and R 6 represents H or C 1 -C 3 acyl, R 3 represents H or R 2 and R 3 together represent =0, R represents OH, R 5 represents H or R 4 and R 5 together represent =0.
2. A compound according to claim 1, characterized in that R represents CH(OCH 3 ) 2 , R' represents COCH 3 , R2 represents OR wherein R 6 represents H, R 3 and R 5 are the same and represent H and R 4 represents OH.
3. A compound according to claim 1, characterized in that R represents CH 2 N[CH 2 (C 6 H 5 )] 2 , RI represents COCH 3 , R 2 represents OR 6 wherein R 6 represents H, R 3 and R 5 are the same and represent H and R represents OH.
4. A compound according to claim 1, characterized in that R represents CH(OCH 3 ) 2 , R' represents COCH 3 , R 2 represents OR 6 wherein R 6 represents COCH 3 , R 3 and R 5 are the same and represent H and R 4 represents OH. WO 00/77016 PCT/HROO/00018 28
5. A compound according to claim 1, characterized in that R represents CH 2 N[CH 2 (C 6 H 5 )] 2 , R' represents COCH 3 , R represents OR wherein R 6 represents COCH 3 , R 3 and R 5 are the same and represent H and R 4 represents OH.
6. A compound according to claim 1, characterized in that R represents CH(OCH 3 ) 2 , R' represents COCH 3 , R 2 and R 3 together represent =0, R 4 represents OH and R 5 represents H.
7. A compound according to claim 1, characterized .in that R represents CH 2 N[CH 2 (C 6 H 5 )] 2 , RI represents COCH 3 , R 2 and R 3 together represent =0, R 4 represents OH and R 5 represents H.
8. A compound according to claim 1, characterized in that R represents CH(OCH 3 ) 2 , R 1 represents COCH 3 , R2 represents OR wherein R 6 represents COCH 3 , R 3 represents H and R 4 and R 5 together represent =0.
9. A compound according to claim 1, characterized in that R represents CH 2 N[CH 2 (C 6 H 5 )] 2 , RI represents COCH 3 , R 2 represents OR 6 wherein R 6 represents COCH 3 , R 3 represents H and R 4 and R 5 together represent =0.
10. A compound according to claim 1, characterized in that R represents CH(OCH 3 ) 2 , R 1 and R 5 are the same and represent H, R 2 and R 3 together represent =0 and R 4 represents OH.
11. A compound according to claim 1, characterized in that R represents CH 2 N[CH 2 (C 6 H 5 )] 2 , R' and R 5 are the same and represent H, R2 and R 3 together represent =0 and R 4 represents OH.
12. A compound according to claim 1, characterized in that R represents CH(OCH 3 ) 2 , R' and R 3 are the same and represent H, R 2 represents OR 6 wherein R 6 represents COCH 3 , and R 4 and R 5 together represent =0. WO 00/77016 PCT/HROO/00018 29
13. A compound according to claim 1, characterized in that R represents CH 2 N[CH 2 (C 6 H 5 )] 2 , R1 and R 3 are the same and represent H, R 2 represents OR 6 wherein R 6 represents COCH 3 , and R 4 and R 5 together represent =0.
14. A compound according to claim 1, characterized in that R represents CH(OCH 3 ) 2 , R', R3 and R are the same and represent H, R2 represents OR 6 wherein R6 represents COCH 3 , and R 4 represents OH.
15. A compound according to claim 1, characterized .in that R represents CH 2 N[CH 2 (C 6 H 5 )] 2 , R', R 3 and R 5 are the same and represent H, R 2 represents OR 6 wherein R represents COCH 3 , and R 4 represents OH.
16. A compound according to claim 1, characterized in that R represents CH(OCH 3 ) 2 , R 1 and R 3 are the same and represent H, R 2 represents OR 6 wherein R 6 represents H, and R 4 and R 5 together represent =0.
17. A compound according to claim 1, characterized in that R represents CH 2 N[CH 2 (C 6 H 5 )] 2 , RI and R 3 are the same and represent H, R 2 represents OR 6 wherein R represents H, and R 4 and R 5 together represent =0.
18. A compound according to claim 1, characterized in that R represents CHO, R 1 and R3 are the same and represent H, K represents OR6 wherein R6 represents H, and R 4 and R 5 together represent =0.
19. A compound according to claim 1, characterized in that R represents CHO, R represents COCH 3 , R 2 represents OR 6 wherein R 6 represents H, R 3 and R 5 are the same and represent H and R 4 represents OH.
20. A compound according to claim 1, characterized in that R represents CHO, R represents COCH 3 , K 2 represents OR 6 wherein R 6 represents COCH 3 , R 3 and R 5 are the same and represent H and R 4 represents OH. WO 00/77016 PCT/HROO/00018 30
21. A compound according to claim 1, characterized in that R represents CHO, R' represents COCH 3 , R 2 and R 3 together represent =O, R 4 represents OH and R 5 represents H.
22. A compound according to claim 1, characterized in that R represents CHO, R', R3 and R are the same and represent H, R2 represents OR 6 wherein R6 represents COCH 3 , and R 4 represents OH.
23. A compound according to claim 1, characterized in that R represents CHO, R' and R' are the same and represent H, R2 and R3 together represent =0 and R 4 represents OH.
24. Process for the preparation of the compounds of the general formula I CO-NH CH3 8a R 20 H 3C R 2 H 3 C H 3 R N(CH 3 ) 2 3 H3 R 4'3'OR 1 4o 0 OT H 3 OCH 3 R5 CH 3 wherein R represents CHO, CH(OCH 3 ) 2 or CH 2 N[CH 2 (C 6 H 5 )] 2 , RI represents H or C 1 -C 3 acyl, R represents OR and R6 represents H or C 1 -C 3 acyl, R 3 represents H or R2 and R 3 together represent =0, R represents OH, R5 represents H or R 4 and R 5 together represent =0, characterized in that WO 00/77016 PCT/HROO/00018 31 4'-demycarosyl-8a-aza-8a-homotylosin 20-dimethylacetal of the formula Ila and 4' demycarosyl-20-deoxo-20-dibenzylamino-8 a-aza-8a-homotylosin of the formula IIb CO-NH CH3 8a R 20 H 3 0 H 3 C H 3 N(OH 3 ) 2 H HOC 3 H OCH 3 OCH 3 OH CH 3 Ila R = CH(OCH 3 ) 2 Ilb R = CH 2 N[CH 2 (C 6 H 5 )] 2 are subjected to A) an O-acylation with anhydrides of C 1 -C 3 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 1 2 6 CH(OCH 3 ) 2 or CH 2 N[CH 2 (C 6 H 5 )] 2 , R represents COCH 3 , R 2 represents OR , wherein R 6 represents H, R 3 and R 5 are the same and represent H and R 4 represents OH, are optionally subjected to Al) an O-acylation with anhydrides of C 1 -C 3 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(OCH 3 ) 2 or CH 2 N[CH 2 (C 6 H 5 )] 2 , R' represents COCH 3 , R2 represents OR 6 , wherein R 6 represents COCH 3 , R3 and R 5 are the same and represent H and R 4 represents OH, WO 00/77016 PCT/HRO0/00018 32 are optionally subjected to B) an oxidation reaction with N(3-dimethylaniino-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(OCH 3 ) 2 or CH 2 N[CH 2 (C 6 H 5 )] 2 , RI represents COCH 3 , R2 represents OR6, wherein R 6 represents COCH 3 , R3 represents H and R 4 and R 5 together represent =0, are optionally subjected to C) methanolysis at room temperature for 2 days and the obtained compounds of the formula I, wherein R represents CH(OCH 3 ) 2 or CH 2 N[CH 2 (C 6 H 5 )] 2 , R' and R 3 are the same and represent H, R 2 represents OR 6 , wherein R 6 represents COCH 3 , and R 4 and R 5 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(OCH 3 ) 2 or CH 2 N[CH 2 (C 6 H 5 )] 2 , R' and R 3 are the same and represent H, R 2 represents OR 6 , wherein R 6 represents H, and R 4 and R 5 together represent =0; or the compound obtained according to process C1 of the formula I, wherein R represents CH(OCH 3 ) 2 , RI and R 3 are the same and represent H, R 2 represents OR 6 , wherein R 6 represents H, and R 4 and R 5 together represent =0, is optionally subjected to D) a hydrolysis of the acetal in a mixture of acetonitrile and 0. 1 N hydrochloric acid (1:1) for 2 hours at room temperature to obtain the compound of the formula I, wherein R represents a CHO group, R' and R 3 are the same and represent H, R 2 represents OR 6 , wherein R 6 represents H, and R 4 and R 5 together represent =O; WO 00/77016 PCT/HROO/00018 33 or compounds obtained according to process A of the formula I, wherein R represents CH(OCH 3 ) 2 or CH 2 N[CH 2 (C 6 H 5 )] 2 , R' represents COCH 3 , R 2 represents OR 6 , wherein R 6 represents H, R 3 and R 5 are the same and represent H and R 4 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(OCH 3 ) 2 or CH 2 N[CH 2 (C 6 H 5 )] 2 , R' represents COCH 3 , R2 and R 3 together represent =0, R 4 represents OH and R 5 represents H, are optionally subjected to methanolysis in the manner disclosed in C, to obtain compounds of the formula I, wherein R represents CH(OCH 3 ) 2 or CH 2 N[CH 2 (C 6 H 5 )] 2 , R 1 and R 5 are the same and represent H, R 2 and R 3 together represent =0 and R 4 represents OH; or the compound obtained according to process B of the formula I, wherein R represents a CH(OCH 3 ) 2 group, R' represents COCH 3 , R 2 and R 3 together represent =0, R4 represents OH and R 5 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, R' represents COCH 3 , R 2 and R 3 together represent =O, R 4 represents OH and R 5 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, R' and R are the same and represent H, R 2 and R 3 together represent =0 and R 4 represents OH; or the compound obtained according to process A WO 00/77016 PCT/HROO/00018 34 of the formula I, wherein R represents CH(OCH 3 ) 2 , R. represents COCH 3 , R2 represents OR, wherein Re represents H, R 3 and R' are the same and represent H and R 4 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, R' represents COCH 3 , R2 represents OR 6 , wherein R 6 represents H, IR? and R5 are the same and represent H and R 4 represents OH; or compounds obtained according to process Al of the formula L wherein R represents CH(OCH 3 ) 2 or CH 2 N[CH 2 (C 6 Hs)] 2 , R' represents COCH 3 , R represents OR 6 , wherein R6 represents COCH 3 , R3 and R5 are the same and represent H and R 4 represents OH, are optionally subjected to methanolysis in the manner disclosed in C, to obtain compounds of the formula L wherein R represents CH(OCH 3 ) 2 or CH 2 N[CH 2 (C 6 H 5 )] 2 , R', R3 and R5 are the same and represent H, R 2 represents OR 6 , wherein Ri represents COCH 3 , and RW represents OH; or the compound obtained according to process Al of the formula I, wherein R represents CH(OCH 3 ) 2 , R' represents COCH 3 , R2 represents OR 6 , wherein Ri represents COCH 3 , R? and R 5 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 , wherein R represents CHO, R' represents COCH 3 , R2 represents OR, wherein R represents COCH 3 , R' and Rs are the same and represent H and R 4 represents OH, is optionally subjected to methanolysis in the manner disclosed in C, WO 00/77016 PCT/HROO/00018 35 to obtain the compound of the formula I, wherein R represents CHO, R', R 3 and R 5 are the same and represent H, R 2 represents OR 6 , wherein R 6 represents COCH 3 , and R 4 represents OH.
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