SK17572001A3 - Derivatives of 4'-demycarosyl-8a-aza-8a-homotylosin and process for producing same - Google Patents

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, R<1> represents H or C1-C3 acyl, R<2> represents OR<6> and R<6> represents H or C1-C3 acyl, R<3> represents H or R<2> and R<3> together represent =O, R<4> represents OH, R<5> represents H or R<4> and R<5> together represent =O, and to a process for the preparation thereof. Novel derivatives show antibacterial action and may also be used as intermediates for preparing novel 17-membered azalide antibiotics.

Description

4'-Demycarosyl-8a-aza-8a-homotylosins and a process for their preparation

PPMf'W

Technical field

The present invention relates to novel compounds of the 17-membered azalide group having antibacterial activity. More particularly, the present invention relates to the 4'-dicarosyl-8α-aza-8α-homotylosins of Formula I

in which

R is CHO, CH (OCH ₃ ) ₂ or CH ₂ N [CH ₂ (C ₆ H 5)] 2,

R ¹ is H or acyl having 1 to 3 carbon atoms,

R ² is OR ^6, wherein R ⁶ is H or acyl having 1 to 3 carbon atoms,

R ³ is H or R ² and R ³ together are = 0,

R ⁴ is hydroxyl and

R ⁵ represents a hydrogen atom or R ⁴ and R ⁵ together represent a group = O, and a process for their preparation.

BACKGROUND OF THE INVENTION

4 ^, -Demycarosyl-8a-aza-8a-homotylosin, a novel semisynthetic macrolide from the 17-membered azalide group, was prepared by a double transformation of the C-9 ketone 16r 2-membered antibiotic 4'-demycarosyl-tylosin (RL Hamill: Antibiotics and Chemotherapy 1961, 11, 328, A. Narandja et al .: European Patent No. 0 287 082 and N. Lopotar et al .: European Patent No. 0410433). Reductive amination of the C-20 aldehyde group in the presence of formic acid (Wallach reaction, J. March Advanced Organic Chemistry, third edition 6-15, page 799, Wiley, New York 1985) was prepared 4'-demy-carboxy-20 -deoxo-20-dibenzylamino-8α-aza-8α-homotylosin (N. Lopotar, HR patent application P940962A, Nov. 30, 1994).

The acyl esters having 1 to 3 carbon atoms of 4'-demycarosyl-8a-aza-8a-homotylosin and 4'-demycarosyl-20-deoxo-20dibenzylamino-8a-aza-8a-homotylosin of the same as 4 have not been described in the prior art. -deoxy-4-oxo- and 3-deoxy-3oxo-derivatives of 4-demycarosyl-8α-aza-8α-homotylosin and 4'-demycarosyl-20-deoxo-20dibenzylamino-8α-aza-8α-homotylosin, their acyl esters and a process for their preparation.

SUMMARY OF THE INVENTION

According to the present invention, the 4'-demycarosyl-8α-aza-8α-homotylosin derivatives of the general formula I

(Ktoromν which

R «« P f f * P P

P p P p p r p p * · r t r

í * - · p

R is CHO, CH (OCH 3) 2 or CH 2 N [CH 2 (C 6 H 5)] 2,

R ¹ is H or acyl having 1 to 3 carbon atoms,

R ² is OR ^6, wherein R ⁶ is H or acyl having 1 to 3 carbon atoms,

R ³ is H or R ² and R ³ together are = 0,

R ⁴ is hydroxyl and

R ⁵ represents a hydrogen atom or R ⁴ and R ⁵ together represent a group = O, can be prepared by the 20'-dimethylacetal of 4'-demycarosyl-8a-aza-8a-homotylosin of the formula IIa and 4'-demycarosyl-20-deoxo 20-dibenzylamino-8a-aza-8-ahomotylosin of general formula 11b

Ha, R = CH (OCH ₃ ) 2 Hb, R = CH ₂ N [CH ₂ (C ₆ H ₅ )] 2 is subjected to

a) O-acylation with carboxylic acid anhydrides of 1 to 3 carbon atoms, preferably acetic anhydride, in methylene chloride for 15 minutes to 1 hour at room temperature, and the obtained compound of formula I wherein R is CH (OCH 3) 2 or CH 2 N [CH 2 (C 6 H 5)] 2, R ¹ is COCH 3, R ² is OR ⁶ , where R ⁶ is hydrogen, R ³ and R ⁵ are the same and are hydrogen and R ⁴ is hydroxyl, optionally subjected to r 4, ·· .;

A1) O-acylation with C 1 -C 3 carboxylic anhydrides, preferably acetic anhydride, in methylene chloride in the presence of an organic base, preferably triethylamine and 4-dimethylaminopyridine as catalyst for 30 hours at room temperature and the compound of formula I obtained, wherein R is CH (OCH ₃ ) 2 or CH ₂ N [CH ₂ (C 6 H ₅ )] 2, R ¹ is COCH 3, R ² is OR ⁶ , where R ⁶ is hydrogen, R ³ and R ⁵ have and R &lt; ⁴ &gt; is hydroxyl, if appropriate

B) oxidation with N- (3-dimethylamino-propyl) -N'-ethylcarbodiimide hydrochloride in the presence of dimethylsulfoxide and trifluoroacetate with pyridine as a catalyst in an inert solvent, preferably methylene chloride, for 2 to 6 hours at a temperature of 10 ^e ) to room temperature and the compound of formula (I) in which R is CH (OCH 3) 2 or CH 2 N [CH 2 (C 6 H 5)] 2, R ¹ is COCH 3, R ² is OR ⁶ where R ⁶ is COCH ₃ , R ³ represents a hydrogen atom, and R ⁴ and R ⁵ together represent a group = O, optionally subjected to

C) methanolysis at room temperature for 2 days and the compounds of the formula I in which R is CH (OCH ₃ ) ₂ or CH ₂ N [CH ₂ (C ₆ H ₅ )] 2, R ¹ and R ³ have the same meaning and represent an atom hydrogen, R ² is OR ⁶ , where R ⁶ is COCH ₃ and R ⁴ and R ⁵ together are = O, optionally subjected to

C1) alkaline methanolysis in a mixture of methanol and 25% ammonia (4: 1) at a temperature of 5 ° C to room temperature for 20 to 60 hours to give compounds of formula I wherein R is CH (OCH ₃ ) ₂ or CH ₂ N [CH ₂ (C 6 H 5)] 2, R ¹ and R ³ have the same meaning and are hydrogen, R ² is OR ⁶ , where R ⁶ is hydrogen, and R ⁴ and R ⁵ together represent = O or the compound obtained according to method ad C1) of the general formula I, in which R represents CH (OCH ₃ ) 2, R ¹ and R ³ have the same meaning and represent hydrogen, R ² represents OR ⁶ , where R ⁶ represents hydrogen, and R ⁴ and R ⁵ together represent = O, r

eventually submit

D) hydrolysis of the acetal in a mixture of acetonitrile and 0.1 N hydrochloric acid (1: 1) for 2 hours at room temperature to give a compound of formula I wherein R is CHO, R ¹ and R ³ are the same and are hydrogen, R ² is OR ⁶ , where R ⁶ is hydrogen, and R ⁴ and R ⁵ together are = O, or compounds obtained according to method A) of formula I wherein R is CH (OCH 3) 12 or CH 2 N [CH 2 (C 6 H 5)] 2, R ¹ is COCH 3, R ² is OR ⁶ wherein R ⁶ is hydrogen, R ³ and R ⁵ are the same and are hydrogen and R ⁴ is hydroxyl, is optionally oxidized as described in (B) to give compounds of formula I wherein R is CH (OCH 3) 2 or CH ₂ N [CH ₂ (C ₆ H 5)] 2, R ¹ is COCH ₃ R ² and R ³ together represent = O, R ⁴ represents hydroxyl and R ⁵ represents a hydrogen atom, optionally subjected to methanolysis as described in C) to give compounds of formula I wherein R is CH (OCH 3) 2 or CH ₂ N [CH ₂ (C ₆ H ₅ )] 2, R ¹ and R ⁵ have the same meaning R @ ² and R @ ^{3 taken} together are = O and R @ ⁴ is hydroxyl, or the compound obtained according to process (B) of formula I wherein R is CH (OCH3) 2, R ^{@ 1} is COCH3, R @ ² and R @ ^{3 taken} together are = O, R @ ⁴ is hydroxyl and R @ ⁵ is hydrogen, optionally subjected to acetal hydrolysis in a manner similar to that described in

D), and the compound of formula I wherein R represents CHO, R ¹ is a group COCH 3, R ² and R ³ together represent = 0, R ⁴ is hydroxy and R ⁵ is H, are optionally subjected to methanolysis process as described in ad C) to give a compound of formula I wherein R is CHO, R ¹ and R ⁵ are the same and are hydrogen, R ² and R ³ together are = O and R ⁴ is hydroxyl, or the compound obtained according to method A) of the general formula I, in which R is CH (OCH 3) 2, R ¹ is COCH 3, R ² is OR ⁶ , where R ⁶ is hydrogen, R ³ and R ⁵ have the same and represent H and ^R4 represents hydroxyl, optionally by hydrolysis of the acetal as described in d D) to obtain a compound of formula I wherein R represents CHO, R ¹ is a group COCH 3, R ² is OR ⁶ , wherein R ⁶ is H, R ³ and R ⁵ are the same and represent H and ^R4 is OH or the compound obtained according to process d A1) of the formula I, wherein R represents CH _{(OCH3) 2} or CH ₂ N [ CH ₂ (C 6 H 5) 12, R ¹ is COCH 3, R ² is OR ⁶ , where R ⁶ is COCH 3, R ³ and R ⁵ are the same and are hydrogen and R ⁴ is hydroxyl, optionally subjected to methanolysis as described in (C) to give compounds of formula I wherein R is CH (OCH ₃ ) ₂ or CH ₂ N [CH ₂ (C ⁶ H ⁵ )] 2, R ¹ , R ³ and R ⁵ have the same meaning and are atom hydrogen, R ² is OR ⁶ , where R ⁶ is COCH 3, and R ⁴ is hydroxyl, or the compound obtained according to method A1) of formula I wherein R is CH (OCH ₃ ) ₂₁ R ¹ is COCH 3 R ² is OR ⁶ , where R ⁶ is COCH ^3, R ³ and R ⁵ have the same meaning and are hydrogen, and R ⁴ is hydroxyl, optionally subjected to hydrolysis of the acetal as described in D) and the compound of formula I obtained, wherein R is CHO, R ¹ is COCH 3, R ² is OR ⁶ , where R is ⁶ is COCH ₃ , R ³ and R ⁵ have the same meaning and are hydrogen and R ⁴ is hydroxyl, optionally subjected to methanolysis as described in C) to give rp a compound of formula I wherein R is CHO R ¹ , R ³ and R ⁵ have the same meaning and are hydrogen, R ² is OR ⁶ , where R ⁶ is COCH 3. and R ⁴ is hydroxyl.

According to the present invention, the novel compounds are isolated by a conventional method of extraction from aqueous halogenated hydrocarbon solutions such as methylene chloride or chloroform and evaporation of the organic solvent to a dry residue. Alternatively, by separating the reaction products or purifying the products for spectral analysis, flash chromatography on a silica gel column (Merck & Co., silica gel 60, size 0.063-0.037 mm) in a solvent system is performed: CH ₂ Cl ₂ -CH ₃ OH-conc. NH ₄ OH (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 C).

The structure of the novel compounds was confirmed by spectrometric methods and mass analysis.

The novel compounds have an antibacterial effect and can also be used as intermediates for the production of novel 17-membered azalide antiotics.

The invention is illustrated, and in no way limited, by the following examples.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

20-dimethyl acetal ^4, -demykarozyl-2 ', ^{4-di-O-acetyl-8a-aza-8a-homotylozínu} (1)

4'-Demycarosyl-8α-aza-8α-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 the mixture was stirred at room temperature for 15 minutes. Pour the reaction into ice-water (500 mL) and extract twice with methylene chloride at pH 8.5. The combined organic extracts were washed with saturated NaHCO ₃ solution and water, dried (K 2 CO 3) and evaporated under reduced pressure. There was thus obtained a product (1.58 g, 97.8% by weight) which was homogeneous by TLC. TLC: R f (B): 0.44, R f (C): 0.22. IR (KBr, cm &^lt; -1 & gt ^; ): 1749, 1657, 1620, 1544, 1455, 1375, 1229, 1170, and 1063.

1 H NMR (CDCl ₃ , δ, ppm): 7.16 (H-11), 5.69 (H-10), 5.66 (H-13), 4.96 (8aNH), exchangeable with D ₂ O, 4.88 (H-2 '), 4.76 (H-4 ^1), 4.63 (H-20), 4.58 (H-1), 4.33 (H-1') 4.17 (H-8), 3.61 (3-OCH 3), 3.47 (2-OCH 3), 3.56 (2 x 20-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, δ, ppm): 179.1 (C-1), 169.8, 169.4 (2 x COCH 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-1 '), 100.9 (C) -1),

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 (2 x 20-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 (2 x COCH 3), 21.9 (C-21), 12.6 (C-22), 8.3 (C-18). Mass Spectrum (FAB, MH ⁺ ) 917.

Example 2

^{4'-Demykarozyl-2,} 4'-di-0-acetyl-20-deoxo-20-dibenzylamino-8a-aza-8ahomotylosin (2)

4'-Demycarosyl-20-deoxo-20-dibenzylamino-8α-aza-8α-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 the mixture was stirred at room temperature for 15 minutes. Pour the reaction into ice-water (300 mL) and extract twice with methylene chloride at pH 6.5. The combined organic extracts were washed with saturated NaHCO ₃ solution and water, dried (K ₂ CO ₃ ) and evaporated under reduced pressure. There was thus obtained a product (2, 3.02 g, 98.9% by weight) which was homogeneous by TLC. TLC: Rf (B): 0.38, Rf (C): 0.23. IR spectrum (KBr, cm ^-1 ): 1749, 1651, 1633, 1548, 1454, 1374, 1231, 1169, and 1059. 1 H NMR spectrum (CDCl ₃ , δ, ppm): 7.25-7.41 (phenyl) ), 7.10 (H-11),

5.70 (H-13), 5.65 (H-10), 4.89 (8a-NH) exchangeable with D ₂ 0, 4.84 (H-2 ^1), 4.74 (H-4 '),

4.60 (H-1), 4.15 (H-1 '), 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 , δ, ppm): 173.4 (C-1), 169.9, 169.5 (2 x COCH ₃ ),

166.1 (9-CONH), 144.8 (C-11), 137.9 (C-13), 135.2 (C-12), 119.3 (C-10), 102.3 (C) -r)

101.0 (C-6), 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 (2 x COCH 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. Mass Spectrum (FAB, MH ⁺ ) 1052.

Example 3

20-dimethyl acetal ^{demykarozyl-4'-2, 4,} 4-tri-0-acetyl-8a-aza-8a-homotylozínu (3)

Compound 1 (4.0 g, 4.37 mmol) was dissolved in dry methylene chloride (100 mL). Triethylamine (7.0 mL), 4-dimethylaminopyridine (0.12 g) and acetic anhydride (0.42 mL, 4.45 mmol) were added and the reaction was allowed to stand at room temperature for 26 hours. Isolation of the product was carried out as described in Example 1. This gave a product (3, 4.08 g, 97.7% by weight) which was homogeneous by TLC. TLC: Rf (A): 0.65, Rf (C): 0.54. IR (KBr, cm ^{@ -1} ): 1749, 1655, 1618, 1546, 1454, 1374, 1233, 1171, and 1052. @ 1 H NMR Spectrum (CDCl3 .delta., Ppm): 7.16 (H-11), 5.69 (H10), 5.65 (H-13), 4.89 (8a-NH) exchangeable with D2 O, 4.88 (H-2 ^1), 4.76 (H-4 ^1), 4.64 ( H-1), 4.59 (H-20), 4.33 (H-1 '), 4.18 (H-8), 3.52 (3-OCH 3), 3.46 (2-OCH ₃₎ ), 3.36 (20OCH 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). ¹³ C NMR (CDCl ₃ , δ, ppm): 173.1 (C-1), 170.1, 169.8, 169.4 (3xCOCH ₃ ), 166.1 (9-CONH), 144.7 (0-11), 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 ¹⁾

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 (3 x COCH ₃ ), 12.7 (C-22), 8.3 ( C-18). Mass Spectrum (FAB, MH +) 959.

Example 4

^{4, -Demykarozyl-2,, 4,,} 4-tri-O-acetyl-20-deoxo-20-dibenzylamino-8a-aza-8ahomotylosin (4)

Compound 2 (2.8 g, 2.66 mmol) was dissolved in dry methylene chloride (60 mL).

Triethylamine (3.7 mL), 4-dimethylaminopyridine (0.07 g) and acetic anhydride (0.25 mL, 1.64 mmol) were added. The reaction mixture was then allowed to stand at room temperature for 26 hours. Isolation of the product was carried out as described in Example 1. This gave a product (4.2 g, 92.9% by weight) which was homogeneous by TLC. TLC: Rf (B): 0.55, Rf (C): 0.47. IR (KBr, cm ^-1 ): 1747, 1651, 1632, 1538, 1453, 1372, 1233, 1170 and 1051. ¹ H NMR Spectrum (CDCl ₃ , δ, ppm): 7.22-7.41 (phenyl) )

7.10 (H-11), 5.70 (H-13), 5.65 (H-10), 4.91 (8a-NH) exchangeable with D ₂ 0, 4.86 (H-2 ¹ )

4.74 (H-4 ^1), 4.66 (H-1), 4.46 (H-4), 4.15 (H-I '), 3.61 (2 * 20-N-CH2-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). ¹³ C NMR spectrum (CDCl 3, δ, 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 (3 x COCH ₃ ), 12.7 (C-22), 8.4 (C-18), 2-N (CH ₂ C ₆ H ₅ ), 139.8, 129.1, 128.0, 126.6, 57.9. Mass Spectrum (FAB, MH +) 1094.

Example 5

20-dimethyl acetal demykarozyl-4'-2 ', 4 ^{l-di-0-acetyl-4-deoxy-4-oxo-8a-aza-8a-homotylozínu} (5)

A solution of pyridine trifluoroacetate (1.0 g, 5.24 mmol) in methylene chloride (10 mL) was added dropwise at 15 ° C to a solution of compound 1 (1.0 g, 1.09 mmol), 1- (3-dimethylaminopropyl) -3 hydrochloride. -ethylcarbodiimide (1.0 g, 5.22 mmol) and dimethylsulfoxide (1.0 mL, 14.10 mmol) in methylene chloride (20 mL). The reaction mixture was stirred at room temperature for 3 hours, then poured into water (150 ml) and, after separation of the organic layer, extracted twice more with methylene chloride. The combined organic extracts were washed with saturated NaHCO ₃ solution and water, dried (K ₂ CO ₃ ) and evaporated to dryness under reduced pressure. This afforded the crude product (0.95 g) which was purified by flash column chromatography on silica gel, eluting with solvent system B. This gave the product (5, 0.45 g) which was homogeneous by TLC. TLC: Rf (B) 0.52. IR (KBr, cm &^lt; -1 & gt ^; ): 1749, 1657, 1620, 1542, 1455, 1375, 1230, 1172, and 1060.

¹ H NMR (CDCl 3, δ, ppm): 7.16 (H-11), 5.71 (H-10), 5.64 (H-13), 4.97 (8aNH), exchangeable with D 2 O, 4.88 (H-2 '), 4.76 (H-4 ^1), 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-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 ( _COCH3), 1.76 (H-22), 1.34 (H-6), 1.17 (H-21). ¹³ C NMR spectrum (CDCl ₃ δ, 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), 103.1 (C-1), 102.1 (C) -r)

85.3 (C-3), 84.2 (C-2), 73.3 (C-5), 71.3 (C-4 ^1), 70.3 (C-2 ^1), 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 (2 x COCH ₃ ), 14.0 (C-6), 12.7 (C-22), 8.34 (C-18). Mass Spectrum (FAB, MH +) 915.

Example 6

^{4, -Demykarozyl-2,} 4'-di-0-acetyl-4-deoxy-4-oxo-20-deoxo-20-dibenzylamino-8a-aza-8ahomotylosin (6)

A solution of pyridine trifluoroacetate (0.6 g, 3.11 mmol) in methylene chloride (6 mL) was added dropwise at 15 ° C to a solution of compound 2 (0.6 g, 0.57 mmol) of 1- (3-dimethylaminopropyl) hydrochloride. -3-ethylcarbodiimide (0.6 g, 3.14 mmol) and dimethylsulfoxide (0.45 mL, 6.35 mmol) in methylene chloride (20 mL). The reaction mixture was stirred at room temperature for 5 hours, isolating the product in the same manner as described in Example 5. This gave the crude product (0.54 g) which was purified by flash column chromatography on silica gel, eluting with the solvent system B. There was thus obtained a product (6, 0.28 g) which was homogeneous by TLC. TLC: Rf (B) 0.48, Rf (C) 0.33. IR spectrum (KBr, cm ^-1 ): 1747, 1651, 1633, 1548, 1454, 1372, 1231 and 1058. ¹ H NMR spectrum (CDCl ₃ , δ, 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 O, 4.82 (H-21 ⁾ 4.74 (H-4 '), 4.65 (H-1), 4.11 (H-1'),

3.98 (H-5), 3.78 (H-3), 3.62 _(20-N-CH2 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). ¹³ C NMR (CDCl ₃ , δ, 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-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 ^1), 65.9 (C-3), 60.3 _(3-OCH3), 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 (2 x COCH 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 and 57.8. Mass Spectrum (FAB, MH ⁺ ) 1050.

Example 7

20-dimethyl acetal ^{demykarozyl-4'-2, 4,} 4-tri-O-acetyl-3-deoxy-3-oxo-8a-aza-8ahomotylozínu (7)

A solution of pyridine trifluoroacetate (3.0 g, 15.72 mmol) in methylene chloride (30 mL) was added dropwise at 15 ° C to a solution of compound 3 (2.0 g, 2.09 mmol), 1- (3-dimethylaminopropyl) -3 hydrochloride. -ethylcarbodiimide (3.0 g, 15.66 mmol) and dimethylsulfoxide (2.9 mL, 40.89 mmol) in methylene chloride (50 mL). The reaction mixture was stirred at room temperature for 3 hours. Isolation of the product was carried out as described in Example 5. This gave the crude product (1.95 g) which was purified by silica gel flash column chromatography, eluting with the solvent system C. This gave the product (7, 1.3 g) which was homogeneous by TLC. TLC: Rf (C) 0.58. IR (KBr, cm ^-1 ): 1749, 1655, 1618, 1546, 1454, 1374, 1233, 1171, and 1052. ¹ H NMR Spectrum (CDCl ₃ , δ, ppm):

6.90 (H-11), 5.76 (H-10), 5.43 (H-13), 4.96 (8a-NH) exchangeable with D ₂ 0, 4.88 (H-2 ¹ , 4.79 (H-4 '), 4.66 (H-1), 4.40 (H-1'), 4.18 (H-6), 3.55, 3.32 (H- 2), 3.52 (3-OCH 3), 3.49 (2-OCH 3), 3.30 (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) . ¹³ C NMR (CDCl 3, δ, ppm): 205.6 (C-3), 172.9 (C-1), 170.1, 169.8, 169.4 (3 x COCH 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-I '), 100.9 (C-1), 74.5 (C-4), 71.4 (C-4 ^1), 70.3 (C-2 ^1), 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 (3 x COCH ₃ ), 17.6 (C-18),

12.7 (C-22). Mass spectrum (FAB, MH ⁺ ) 597.

Example 8

^4, -Demykarozyl-2 ', ^4, 4-tri-O-acetyl-3-deoxy-3-oxo-20-deoxo-20-dibenzylamino-8a-aza-8a-homotylozínu (8)

A solution of pyridine trifluoroacetate (2.0 g, 10.36 mmol) in methylene chloride (10 mL) was added dropwise at 15 ° C to a solution of compound 4 (1.0 g, 1.09 mmol) 1- (3di-methylaminopropyl) hydrochloride -3-ethylcarbodiimide (2.04 g, 10.44 mmol) and dimethylsulfoxide (1.6 mL, 22.56 mmol) in methylene chloride (20 mL). The reaction mixture was stirred at room temperature for 6 hours. Isolation of the product was carried out in the same manner as described in Example 5. This gave the crude product (0.96 g) which was purified by flash chromatography on a silica gel column, eluting with the solvent system B. This afforded the product (8, 0.62). g) which is homogeneous by TLC. TLC: Rf (B) 0.60. IR (KBr, ^cm-1): 1748, 1633, 1538, 1454, 1373, 1231 and 1052. ^1H NMR _(CDCl3, δ, ppm):

7.22 to 7.40 (phenyl), 6.89 (H-11), 5.66 (H-10), 5.49 (H-13), 4.96 (8a-NH), exchangeable with D ₂ O , 4.81 (2 ^H-1), 4.74 (H-4 '), 4.66 (Η-Γ), 4.42 (H-4), 4.15 (H-L), 4, 12 (H-8), 3.78, 3.38 (H-2), 3.51 (2 x 20-N-CH 2 phenyl, 3-OCH 3), 3.48 (2 ^, -OCH 3), 2, 32 (3'-N _(CH3) 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). ¹³ C NMR (CDCl _3, δ, 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-1 '), 100.9 (C-1', 74.6 (C-4), 71.3 (C-4 '), 70.3 (C- ¹ ) 2 ^C-1), 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 (S'-NiCHah), 28.6 (C-19), 22.0 (C-21), 21.0, 20.7 (3x _COCH3), 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. Mass spectrum (FAB, MH +) 1092.

Example 9

20-dimethylacetal ^4, -demykarozyl-4-deoxy-4-oxo-8a-aza-8a-homotylozínu (9)

Compound 5 (0.65 g, 0.71 mmol) was dissolved in methanol (20 mL) and allowed to stand at room temperature for 48 hours. Saturated NaHCO ₃ solution was added to the reaction solution, and the solution was extracted twice with chloroform. The combined organic extracts were washed (K ₂ CO ₃ ) and evaporated to dryness under reduced pressure. This afforded the crude product (0.45 g) which was purified by flash column chromatography on silica gel, eluting with solvent system A. The product (9, 0.20 g) was homogeneous by TLC. TLC: Rf (A) 0.27. IR (KBr, cm @ ^-1 ): 1749, 1657, 1620, .delta.

- ecrr · * _r 'err

1542, 1455, 1375, 1230, 1172, and 1060. ¹ H NMR Spectrum (CDCl 3, δ, ppm): 7.16 (H-11), 5.72 (H-10), 5.67 (H-13) 4.99 (8a-NH), exchangeable with D2O, 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-OCH 3), 3.52 (2-OCH 3), 3.46 (H-2), 3.36, 3 , 35 (2 * 20-OCH 3), 3.30 (H-2), 3.06 (H-4 ^1), 2.33 (3'-N (CH3) _2), 1.76 (H-22 ), 1.34 (H-6), 1.17 (H-21). ¹³ C NMR (CDCl ₃ , δ, 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-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), 14.0 (C-6), 12.7 (C-6) C-22), 8.3 (C-18). Mass spectrum (FAB, MH ⁺ ) 831.

Example 10

4'-Demycarosyl-4-deoxy-4-oxo-20-deoxo-20-dibenzylamino-8α-aza-8α-homotylosin (10)

Compound 6 (0.30 g, 0.73 mmol) was dissolved in methanol (20 mL) and allowed to stand at room temperature for 30 hours. After addition of water (50 mL), the product was isolated by extraction with chloroform at pH 4.5 and 7.5. The combined chloroform extracts were taken at pH

7.5 dried (K ₂ CO ₃ ) and evaporated under reduced pressure. The product (0.17 g) was purified by flash column chromatography on silica gel, eluting with solvent system A. The product (10, 0.08 g) was homogeneous by TLC. TLC: Rf (A) 0.49. IR spectrum (KBr, cm ^-1 ): 1715, 1655, 1619, 1542, 1454, 1377, 1168, and 1082. ¹ H NMR spectrum (CDCl ₃ , δ, 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 O, 4.84 (H-2 ') ), 4.74 (H-4 '), 4.60 (H-1), 4.15 (H-1'), 3.98 (H-6), 3.78 (H-3), 3, 62 _(3-OCH3), 3.61 _(20-N-CH2 phenyl),

3.58 (20-CH ₂ -phenyl), 3.51 _(2-OCH3), 3.46 (H-2 '), 3.01 (H-4 ^1), 2.32 (3'-N (CH 3) 2), 1.72 (H-22), 1.12 (H-21). ¹³ C NMR (CDCl 3, δ, 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) ľ1), 103.0 (C-1), 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), 14.0 (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 and 58.0. Mass Spectrum (FAB, MH ⁺ ) 967.

~ r • r

Example 11

4'-Demycarosyl-4-O-acetyl-3-deoxy-3-oxo-8α-aza-8α-homotylosin 20-dimethylacetal (11)

Compound 7 (0.70 g, 0.73 mmol) was dissolved in methanol (50 mL) and allowed to stand at room temperature for 24 hours. The product was isolated as described in Example 9. This gave a crude product (0.62 g) which was purified by flash chromatography on silica gel, eluting with solvent system A. The product (11, 0.40 g) was homogeneous. according to TLC. TLC: Rf (A) 0.44. IR (KBr, ^cm-1): 1749, 1657, 1620, 1544, 1455, 1375, 1229, 1170 and 1063. Ή NMR (CDCl, δ, ppm): 6.87 (H-11), 5, 77 (H-10), 5.44 (H-13), 5.18 (8a-NH), exchangeable with D2O, 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 (H-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 · - Δ (0-3) 2), 2.12 (COCH 3), 1.75 (H-22), 1.25 (H-18). ¹³ C NMR (CDCl 3, δ, 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-1), 74.5 (C-4), 70.9 (C-21), 70.5 (C- ¹ ) 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 · -Ν (ΟΗ ₃ ) ₂ ), 33.8 (C-19), 22.0 (C-21), 20.7 (COCH ₃ ), 17.5 (C-18)

12.9 (C-22). Mass spectrum (FAB, MH ⁺ ) 873.

Example 12

4´-Demycarosyl-4-O-acetyl-3-deoxy-3-oxo-20-deoxy-20-dibenzylamino-8α-aza-8ahomotylosin (12)

Compound 8 (1.20 g, 10.99 mmol) was dissolved in methanol (100 mL) and allowed to stand at room temperature for 24 hours. After addition of water (100 mL) to the reaction solution, the product was isolated by extraction of methylene chloride at pH 6.5. The combined organic extracts were dried (K ₂ CO ₃ ) and evaporated under reduced pressure. This afforded the crude product (1.0 g) which was purified by flash column chromatography on silica gel, eluting with solvent system A. This gave the product (12, 0.52 g) which was homogeneous by TLC. TLC:

Rf (A) 0.65. IR (KBr, cm ^-1 ): 1745, 1650, 1622, 1537, 1454, 1373, 1233, 1166, and 1058. ¹ H NMR Spectrum (CDCl 3, δ, 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 O, 4.67 (H-1 ', 4) , 45 (H-4 ¹ j, 4.17 (H-1 j, 4.02 (H-8), 3.61 (20-CH 2 -phenyl), 3.53 _(3-OCH3) 3, 52 _{(20-CH2-phenyl),} 3.50 _(2-OCH3), 3.76, 3.32 (H-2), 2.52 (3'-N _{(CH3) 2).} 2. 12 (COCH ₃ ), 1.73 (H-22), 1.21 (H-18), 1.08 (H-21) ¹³ C NMR Spectrum (CDCl ₃ , δ, 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-1 '), 100.9 (C-1'), 74.6 (C-4'j, 70.7 (C-1)) -4 '), 70.4 (C-2), 61.3 (3-OCH ₃ ),

59.3 _(2-OCH3), 51.6 (C-20), 46.1 (C-2), 44.5 (C-4), 43.3 (C-8), 41.0 ( 3'-N _{(CH3) 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. Mass Spectrum (FAB, MH ⁺ ) 1008.

Example 13

4'-Demycarosyl-4-O-acetyl-8α-aza-8α-homotylosin 20-dimethylacetal (13)

Compound 3 (0.5 g, 0.52 mmol) was dissolved in methanol (20 mL) and allowed to stand at room temperature for 24 hours. Isolation of the product was carried out as described in Example 9. The crude product (0.43 g) was purified by flash chromatography on a silica gel column, eluting with the solvent system A. This gave the product (13, 0.32 g) which was homogeneous by TLC. TLC: Rf (A) 0.32. IR (KBr, cm cm ¹ ): 1739, 1656, 1616, 1541, 1455, 1376, 1237, 1170 and 1062. a NMR Spectrum (CDCl ₃ , δ, ppm): 7.15 (H-11), δ , 71 (H-10), 5.66 (H-13), 4.97 (8a-NH) exchangeable with D ₂ 0, 4.64 (H-Lj), 4.62 (H-20), 4 44 (H-4), 4.24 (H-1, 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) Mass spectrum (FAB, MH +) 875.

Example 14

4'-Demykarozyl-4-O-acetyl-20-deoxo-20-dibenzylamino-8a-aza-8ahomotylosin (14)

Compound 4 (0.75 g, 0.69 mmol) was dissolved in methanol (20 mL) and allowed to stand at room temperature for 24 hours. The product was isolated as described in Example 12. The crude product obtained (0.66 g) was purified by silica gel flash column chromatography, eluting with solvent system A. This gave the product (14, 0.45 g) which was homogeneous by TLC. TLC: Rf (A) 0.50. IR (KBr, cm ^-1 ): 1740, 1657, 1621, 1538, 1454, 1373, 1236, 1169, and 1054. ¹ H NMR Spectrum (CDCl _3, δ, 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-1 ), 4.45 (H-4), 4.14 (H-8), 4.07 (H-I '), 3.59 _(20-N-CH2 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). Mass Spectrum (FAB, MH +) 1010.

Example 15

4'-Demycarosyl-3-deoxy-3-oxo-8α-aza-8α-homotylosin 20-dimethylacetal (15)

Compound 11 (0.40 g, 0.46 mmol) was dissolved in a mixture of methanol and concentrated ammonium hydroxide (4: 1, 50 mL) and allowed to stand at 5 ° C for 60 hours. The reaction solution was evaporated to an oily residue, and the product was then isolated as described in Example 9. The crude product (0.25 g) was purified by flash chromatography on silica gel, eluting with the solvent system A. 0.15 g) which is homogeneous by TLC. TLC: Rf (A) 0.39. IR (KBr, cm ^-1 ): 1739, 1714, 1650, 1620, 1544, 1455, 1375, 1170, and 1063.

¹ H NMR Spectrum (CDCl ₃ , δ, ppm): 6.87 (H-11), 5.77 (H-10), 5.44 (H-13), 5.18 (8a-NH), exchangeable D ₂ O, 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-OCH ₃ ), 3.50, 3.26 (H-2), 3.48 (2-OCH ₃ ), 3.30 (20-OCH ₃₎ ), 3.29 _(20-OCH3), 2.33 (3'-N _{(CH3) 2),} 1.75 (H-22), 1.25 (H-18). Mass spectrum (FAB, MH ⁺ ) 831.

Example 16

4'-Demycarosyl-3-deoxy-3-oxo-20-deoxo-20-dibenzylamino-8α-aza-8α-homotylosin (16)

Compound 12 (0.78 g, 0.77 mmol) was dissolved in a mixture of methanol and concentrated ammonium hydroxide (4: 1, 50 mL) and allowed to stand at room temperature for 24 hours. Water (80 mL) was added to the reaction solution and extracted twice with methylene chloride at pH 7.5. The combined organic extracts were dried (K 2 CO 3) and evaporated under reduced pressure. The product (0.66 g) was purified by flash column chromatography on silica gel, eluting with solvent system A. This gave the product (16, 0.32 g) which was homogeneous by TLC. TLC: Rf (A) 0.55. IR (KBr, cm ^-1 ): 1739, 1714, 1650, 1622, 1538, 1454, 1376, 1167 and 1082. ¹ H NMR Spectrum (CDCl 3, δ, 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 (Η-Γ), 4.16 (H-1 '), 4.03 (H-8), 3.62 (20-CH 2 -phenyl), 3.61 (3-OCH 3, 20-CH 2 -phenyl), 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). ¹³ C NMR (CDCl 3, δ, 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 '), 101.1 (C-1'), 72.5 (C-4) ), 70.7 (0-4 '),

70.4 (C-2 ^1), 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 (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. Mass Spectrum (FAB, MH ⁺ ) 967.

Example 17

4'-Demycarosyl-3-deoxy-3-oxo-8α-aza-8α-homotylosin (17)

Compound 15 (0.5 g, 0.60 mmol) was dissolved in acetonitrile / 0.1N HCl (1: 1, 35 mL) and stirred at room temperature for 2 hours. Saturated NaHCO ₃ solution was added to the reaction solution, and the product was extracted twice with methylene chloride. The combined organic extracts were dried (K ₂ CO ₃ ) and evaporated under reduced pressure. The product (0.42 g) was purified by flash chromatography on silica gel, eluting with solvent system A. This gave the product (17, 0.25 g) which was homogeneous by TLC. TLC: Rf (A) 0.35. IR (KBr, cm ^-1 ): 1739, 1719, 1657, 1620, 1545, 1455, 1376, 1169, and 1082. ¹ H NMR Spectrum (CDCl 3, δ, ppm): 9.78 (H-20), 7 19 (H-11), 5.72 (H-10), 5.70 (H-13), 5.06 (8a-NH), exchangeable with D2O, 4.58 (H-1), 4, 18 (H-1 '), 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). ¹³ C NMR (CDCl 3, δ, 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-1) -4), 71.0 (C-4 ^1), 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 (CH ₃ ) ₂ ), 22.4 (C- 21), 17.8 (C-18), 12.9 (C-22). Mass Spectrum (FAB, MH ⁺ ) 785.

Example 18

4'-Demycarosyl-2 ', 4'-di-O-acetyl-8α-aza-8α-homotylosin (18)

Compound 1 (0.5 g, 0.55 mmol) was dissolved in a mixture of acetonitrile with 0.1 N HCl (1: 1, 35 mL). The mixture was stirred at room temperature for 2 hours. The product was isolated as described in Example 17. This gave a product (18, 0.34 g) which was homogeneous by TLC. TLC: Rf (B) 0.35. IR (KBr, cm ^-1 ): 1749, 1657, 1620, 1548, 1455, 1375, 1231, 1170, and 1059. ¹ H NMR Spectrum (CDCl 3, δ, ppm): 9.75 (H-20), 7 , 21 (H-11), 5.72 (H-I0), 5.71 (H-13), 5.08 (8a-NH) exchangeable with D20, 4.89 (2 ^H-1), 4 74 ⁽¹ H-4), 4.58 (H-1), 4.26 (H-I '), 3.61 (3-OCH 3), 3.49 _(2-OCH3), 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 , δ, ppm): 203.6 (C-20), 173.3 (C-1), 169.9, 169.5 (2 x COCH 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 ^1), 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 (2 x COCH 3), 12.7 (C-22), 8.1 (C-18). Mass spectrum (FAB, MH ⁺ ) 871.

Example 19

^{4, -Demykarozyl-2,} 4 ', 4-tri-0-acetyl-8a-aza-8ahomotylosin (19)

Compound 3 (0.5 g, 0.52 mmol) was dissolved in a mixture of acetonitrile with 0.1 N HCl (1: 1, 35 mL). The mixture was stirred at room temperature for 2 hours. The product was isolated as described in Example 17. This gave the product (19, 0.47 g) which was homogeneous by TLC. TLC: Rf (B): 0.60, Rf (C): 0.50. IR (KBr, cm ^-1 ): 1748, 1659, 1621, 1538, 1455, 1373, 1232, 1171, and 1052. ¹ H NMR Spectrum

P * (CDCl 3, δ, ppm): 9.74 (H-20), 7.16 (H-11), 5.69 (H-10), 5.65 (H-13), 4.89 (H-10) 8a-NH) exchangeable with _D2 O, 4.88 (H-2 '), 4.76 (H-4 ^1), 4.64 (H-1), 4.44 (H-4), 4 33 (H-1 '), 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, δ, ppm): 203.6 (C-20), 173.1 (C-1), 170.1, 169.8, 169.4 (3 x COCH 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-1 '),

100.9 (C-1), 74.5 (C-4), 71.4 (C-4 ^1), 70.3 (C-2 ^1), 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 (3 x COCH) ₃ ), 12.7 (C-22), 8.3 (C-18). Mass spectrum (FAB, MH ⁺ ) 913.

Example 20

^{4'-Demykarozyl-2, 4-di-0-acetyl-4-deoxy-4-oxo-8-aza-8ahomotylosin} (20)

Compound 5 (0.7 g, 0.77 mmol) was dissolved in a mixture of acetonitrile with 0.1 N HCl (1: 1, 50 mL). The mixture was stirred at room temperature for 1 hour. The product was isolated as described in Example 17. This gave the product (20, 0.36 g) which was homogeneous by TLC. TLC: Rf (B): 0.48. IR (KBr, cm ^1): 1749, 1656, 1619, 1543, 1458, 1375, 1230, 1172 and 1058. ¹ H NMR (CDCl _3, δ, 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 O .

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-OCH ₃ ), 3.48 (2-OCH ₃ ), 3.30 (H-2), 2.33 (3'-N (CH ₃ ) ₂ ), 2.05 (COCH ₃₎ 1), 2.03 (COCH 3), 1.76 (H-22), 1.34 (H-6), 1.17 (H-21). ¹³ C NMR (CDCl ₃ , δ, ppm): 203.0 (C-20), 202.4 (C-4), 173.1 (C-1), 169.9, 169.5 (2x COCH ₃ ), 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-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 (2 x COCH ₃ ), 14.0 (C-6), 12.7 (C-22), 8.3 (C-1). Mass spectrum (FAB, MH ⁺ ) 869.

Example 21

4-Demycarosyl-4-O-acetyl-8α-aza-8α-homotylosin (21)

Compound 19 (0.30 g, 0.33 mmol) was dissolved in methanol and the mixture was allowed to stand at room temperature for 24 hours. The product was isolated as described in Example 9. This gave a crude product (0.25 g) which was purified by flash chromatography on silica gel, eluting with the solvent system A. The product (21, 0.19 g) was homogeneous. according to TLC. TLC: Rf (A) 0.28. IR (KBr, ^cm-1): 1749, 1657, 1620, 1544, 1455, 1375, 1229, 1170 and 1063. ¹ H NMR (CDCl _third δ, 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-4), 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). Mass Spectrum (FAB, MH ⁺ ) 829.

Example 22

4 ^, -Demycarosyl-4-deoxy-4-oxo-8α-aza-8α-homotylosin (22)

Compound 20 (0.23 g, 0.27 mmol) was dissolved in methanol (20 mL) and allowed to stand at room temperature for 24 hours, isolation of the product as described in Example 9. The crude product (0.14 g) was obtained. ), which was purified by flash column chromatography on silica gel, eluting with solvent system A. This gave a product (22, 0.095 g) which was homogeneous by TLC. TLC: Rf (A) 0.30. IR (KBr, cm ^-1 ): 1717, 1655, 1625, 1542, 1454, 1378, 1170 and 1062. ¹ H NMR Spectrum (CDCl 3, δ, ppm): 9.76 (H-20), 7.20 (H-11), 5.72 (H-10), 5.70 (H-13), 5.12 (8a-NH), exchangeable with D2O, 4.64 (H-1), 4.33 ( H-1 ', 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 ^1), 2.33 (3'-N (CH3) _2), 1.74 (H-22);

1.34 (H-6), 1.16 (H-21). ¹³ C NMR (CDCl ₃ , δ, 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-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). Mass spectrum (FAB, MH +) 785.

Claims (24)

PATENT CLAIMS 1. 4'-Demycarosyl-8a-aza-8a-homotylozines of the general formula (D. in which R is CHO, CH (OCH 3) ₂ or CH ₂ N [CH 2 (C 6 H 5)] 2, R ¹ is H or acyl having 1 to 3 carbon atoms, R ² is OR ^6, wherein R ⁶ is H or acyl having 1 to 3 carbon atoms, R ³ is H or R ² and R ³ together are = 0, R ⁴ is hydroxyl and R ⁵ represents a hydrogen atom or R ⁴ and R ⁵ together represent = O. The 4'-demycarosyl-8α-aza-8α-homotylosin according to claim 1, wherein R is CH (OCH 3) 2. R ¹ is COCH ₃ , R ² is OR ⁶ , where R ⁶ is hydrogen, R ³ and R ⁵ have the same meaning and are hydrogen, and R ⁴ is hydroxyl. The 4'-demycarosyl-8a-aza-8a-homotyloosine of claim 1, wherein R is CH 2 N [CH 2 (C 6 H 5)] 2, R ¹ is COCH ₃ , R ² is OR ⁶ , where R ⁶ is R ³ and R ⁵ have the same meaning and are hydrogen and R ⁴ is hydroxyl. r p The 4'-demycarosyl-8α-aza-8α-homotylosin according to claim 1, wherein R is CH (OCH 3) 2. R ¹ is COCH 3, R ² is OR ⁶ wherein R ⁶ is COCH 3, R ³ and R ⁵ have the same meaning and are hydrogen and R ⁴ is hydroxyl. The 4'-demycarosyl-8a-aza-8a-homotylozine of claim 1, wherein R is CH ₂ N [CH ₂ (C 6 H 5)] ₂ , R ¹ is COCH 3, R ² is OR ⁶ , wherein R ⁶ R &lt; ³ &gt; and R &lt; ⁵ & gt ^; have the same meaning and are hydrogen and R &lt; ⁴ &gt; is hydroxyl. The 4'-demycarosyl-8α-aza-8α-homotylosin according to claim 1, wherein R is ΟΗ (ΟΟΗ ₃ ) 2, R ¹ is COCH ₃ , R ² and R ³ together represent = O, R ⁴ is hydroxyl and ^R5 is hydrogen. The 4'-demycarosyl-8α-aza-8α-homotylosin according to claim 1, wherein R is ΟΗ ₂ Ν [ΟΗ ₂ (Ο 6-5)] 2, R ¹ is COCH ₃ R ² and R ³ together are = R ⁴ is hydroxyl and R ⁵ is hydrogen. The 4'-demycarosyl-8α-aza-8α-homotylosin according to claim 1, wherein R is CH (OCH ₃ ) ₂ , R ¹ is COCH 3, R ² is OR ⁶ , where R ⁶ is COCH 3 R ³ represents a hydrogen atom and R ⁴ and R ⁵ together represent = O. The 4'-demycarosyl-8α-aza-8α-homotylosin according to claim 1, wherein R is CH ₂ N [CH ₂ (C 6 H ₅ )] ₂₁ R ¹ is COCH 3, R ² is OR ⁶ wherein R ⁶ R @ ³ represents a hydrogen atom and R @ ⁴ and R @ ⁵ together represent a group = O. 10.4'-Demycarosyl-8a-aza-8a-homotylozines according to claim 1, wherein R is CH (OCH ₃ ) ₂ , R ¹ and R ⁵ have the same meaning and are hydrogen, R ² and R ³ together represent = O and R ⁴ are hydroxyl. 11.4'-Demykarozyl-8a-aza-8ahomotylosin according to claim 1, wherein R is CH2 N [CH2 (C6H5)] _{2 l} R ¹ and R ⁵ are the same and represent H, R ² and R ³ together are = O and R ⁴ is hydroxyl. 12.4'-Demycarosyl-8a-aza-8a-homotylozines according to claim 1, wherein R is CH (OCH ₃ ) ₂ , R ¹ and R ³ have the same meaning and are hydrogen, R ² is OR ⁶ , where R is ⁶ represents COCH 3, and R ⁴ and R ⁵ together represent = O. 13.4'-Demycarosyl-8a-aza-8a-homotylozines according to claim 1, wherein R is CH ₂ N [CH ₂ (C ₆ H 5)] 2, R ¹ and R ³ have the same meaning and are hydrogen, R ² is OR ⁶ where R ⁶ is COCH ₃ , and R ⁴ and R ⁵ together represent = O. 14.4'-Demycarosyl-8a-aza-8a-homotylozines according to claim 1, wherein R is CH (OCH ₃ ) ₂ , R ¹ , R ³ and R ⁵ have the same meaning and are hydrogen, R ² is OR ⁶ wherein R ⁶ is COCH ₃ , and R ⁴ is hydroxyl. The compound according to claim 1, wherein R is CH ₂ N [CH ₂ (C 6 H ₅ )] 2. 15.4'-Demycarosyl-8a-aza-8a-homotylosin. R ¹ , R ³ and R ⁵ have the same meaning and are hydrogen, R ² is OR ⁶ , where R ⁶ is COCH ₃ , and R ⁴ is hydroxyl. 16.4'-Demycarosyl-8a-aza-8a-homotyloosines according to claim 1, wherein R is CH (OCH ₃ ) ₂ , R ¹ and R ³ have the same meaning and are hydrogen, R ² is OR ⁶ , where R is ⁶ represents a hydrogen atom, and R ⁴ and R ⁵ together represent = O. A compound according to claim 1, wherein R is CH ₂ N [CH ₂ (C 6 H 5)] 2, R ¹ and R ³ have the same meaning and are hydrogen, R ² is a group OR ⁶ wherein R ⁶ represents a hydrogen atom and R ⁴ and R ⁵ together represent = O. 18.4'-Demycarosyl-8a-aza-8a-homotylozines according to claim 1, wherein R is CHO, R ¹ and R ³ have the same meaning and are hydrogen, R ² is OR ⁶ , where R ⁶ is hydrogen, and R ⁴ and R ⁵ together represent = O. 19.4'-Demycarosyl-8a-aza-8a-homotyloinsine according to claim 1, wherein R is CHO, R ¹ is COCH ₃ , R ² is OR ⁶ , where R ⁶ is hydrogen, R ³ and R ⁵ have and R &lt; ⁴ &gt; is hydroxyl. 20.4'-Demycarosyl-8a-aza-8a-homotylozines according to claim 1, wherein R is CHO, R ¹ is COCH 3, R ² is OR ⁶ , where R ⁸ is COCH 3, R ³ and R ⁵ have the same and R @ 4 is hydrogen and R @ ⁴ is hydroxyl. 21.4'-Demycarosyl-8a-aza-8a-homotylozines according to claim 1, wherein R is CHO, R ¹ is COCH ₃ , R ² and R ³ together represent -O, R ⁴ is hydroxyl and R ⁵ is atom hydrogen. 22.4'-Demycarosyl-8a-aza-8a-homotylozines according to claim 1, in which R is CHO, R ¹ , R ³ and R ⁵ have the same meaning and are hydrogen, R ² is OR ⁶ , where R ⁶ is COCH ₃ , and R ⁴ is hydroxyl. 23.4'-Demycarosyl-8a-aza-8a-homotylozines according to claim 1, wherein R is CHO, R ¹ and R ⁵ have the same meaning and are hydrogen, R ² and R ³ together represent = O and R ⁴ represents hydroxyl. A process for the preparation of the 4'-demycarosyl-8α-aza-8α-homotylosins of the general formula I. (0th in which R is CHO, CH (OCH ₃ ) 2 or CH 2 N [CH 2 (C 6 H ₅ )] 2, R ¹ is H or acyl having 1 to 3 carbon atoms, R ² is OR ^6, wherein R ⁶ is H or acyl having 1 to 3 carbon atoms, R ³ is H or R ² and R ³ together are = 0, R ⁴ is hydroxyl and R ⁵ represents a hydrogen atom or R ⁴ and R ⁵ together represent a group = O, characterized in that the 4'-demycarosyl-8a-aza-8a homotylosin 20-dimethylacetal of the formula 11a and 4'-demycarosyl-20-deoxo-20dibenzyl amino-8a-aza-8a-homotylosin of formula IIb IIa, R = CH (OCH ₃ ) ₂ IIb, R = CH ₂ N [CH ₂ (C ₆ H ₅ )] 2 a) O-acylation with carboxylic acid anhydrides of 1 to 3 carbon atoms, preferably acetic anhydride, in methylene chloride for 15 minutes to 1 hour at room temperature and the compound of formula I in which R is CH (OCH 3) 2 or CH ₂ N [CH ₂ (C 6 H 5)] 2, R ¹ is COCH ₃ , R ² is OR ⁶ , where R ⁶ is hydrogen, R ³ and R ⁵ are the same and are hydrogen and R ⁴ is hydroxyl , if necessary, submit A1) O-acylation with carboxylic acid anhydrides of 1 to 3 carbon atoms, preferably acetic anhydride, in methylene chloride in the presence of an organic base, preferably triethylamine and 4-dimethylaminopyridine as catalyst for 30 hours at room temperature and the compound of formula I obtained, wherein R is CH (OCH 3) 2 or CH ₂ N [CH ₂ (C 6 H ₅ )] 2, R ¹ is COCH ₃ R ² is OR ⁶ wherein R ⁶ is hydrogen, R ³ and R ⁵ have and R &lt; ⁴ &gt; is hydroxyl, if appropriate B) oxidation with N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride in the presence of dimethyl sulfoxide and pyridine trifluroacetate as a catalyst in an inert solvent, preferably methylene chloride, for 2-6 hours at a temperature of 10 ° C to room temperature and the compounds of formula I obtained in which R is CH (OCH ₃ ) ₂ or CH ₂ N [CH ₂ (C 6 H ₅ ) 2, R ¹ is COCH ₃ , R ² is OR ⁶ , where R ⁶ is COCH 3 , R ³ represents a hydrogen atom and R ⁴ and R ⁵ together represent a group = O, optionally subjected to C) methanolysis at room temperature for 2 days and the compounds of formula I in which R is CH (OCH ₃ ) ₂ or CH ₂ N [CH ₂ (C 6 H ₅ )] 2, R ¹ and R ³ have the same meanings and mean hydrogen, R ² is OR ⁶ , where R ⁶ is COCH ₃ , and R ⁴ and R ⁵ together are = O, optionally subjected to C1) alkaline methanolysis in a mixture of methanol and 25% ammonia (4: 1) at a temperature of 5 ° C to room temperature for 20 to 60 hours to give compounds of formula I wherein R is CH (OCH ₃ ) 2 or CH ₂ N [CH ₂ (C 6 H ₅ )] 2, R ¹ and R ³ have the same meaning and are hydrogen, R ² is OR ⁶ where R ⁶ is hydrogen, and R ⁴ and R ⁵ together represent = 0, or the compound obtained according to process ad C1) of the general formula I, in which R represents a group CH (OCH ₃ ) _2, R ¹ and R ³ have the same meaning and represent a hydrogen atom, R ² represents an OR ⁶ group, wherein R ⁶ is H, and R ⁴ and R ⁵ together are = 0, optionally subjected D) hydrolysis of the acetal in a mixture of acetonitrile and 0.1 N hydrochloric acid (1: 1) for 2 hours at room temperature to give a compound of formula I wherein R is CHO, R ¹ and R ³ are the same and are hydrogen, R ² is oR ^6, wherein R ⁶ is H, and R ⁴ and R ⁵ together are = 0, or the compound obtained according to process d a) of the formula I, wherein R represents CH (OCH ₃ ) 2 or CH 2 N [CH ₂ (C 6 H 5) j 2, R ¹ is COCH ₃ , R ² is OR ⁶ , where R ⁶ is hydrogen, R ³ and R ⁵ are the same and are hydrogen and R ⁴ is hydroxyl, optionally subjected to an oxidation as described in (B) to give compounds of formula I wherein R is CH (OCH ₃ ) 2 or CH ₂ N [CH ₂ (C 6 H 5)] 2. R ¹ is a group COCH _3, R ² and R ³ together represent = 0, R ⁴ is hydroxy and R ⁵ is H, are optionally subjected to methanolysis as described in d C), to obtain a compound of formula I, wherein R is * f * p - _e '* - <* eri · rrr P / Γ CH (OCH 3) 2 or CH ₂ N [CH ₂ (C 6 H 5)] 2, R ¹ and R ⁵ have the same meaning and are hydrogen, R ² and R ³ together represent = O and R ⁴ represents hydroxyl, or the compound obtained according to process ad B) of the general formula I, in which R represents CH (OCH ₃ ) 2, R ¹ represents COCH ₃ , R ² and R ³ together represent = O, R ⁴ represents hydroxyl and R ⁵ represents hydrogen, optionally subjected to acetal hydrolysis in a manner similar to that described in (D), and the compound of formula I obtained wherein R is CHO, R ¹ is COCH ₃ , R ² and R ³ together represent = O, R ⁴ is hydroxyl and R ⁵ is hydrogen, optionally subjected to methanolysis as described in C) to give a compound of formula I wherein R is CHO, R ¹ and R ⁵ are the same and are hydrogen, R ² and R ³ together represent = O and R ⁴ represents hydroxyl, or a compound to be obtained according to process ad A) of the general formula I, in which R is CH (OCH ₃ ) ₂ , R ¹ is COCH ₃ , R ² is OR ⁶ , where R ⁶ is hydrogen, R ³ and R ⁵ have the same and represent H and ^R4 represents hydroxyl, optionally to hydrolysis of acetal as described in d D) to obtain a compound of formula I wherein R represents CHO, R ¹ is a group COCH _{3 l} R ² is OR ⁶ wherein R ⁶ is hydrogen, R ³ and R ⁵ have the same meaning and are hydrogen and R ⁴ is hydroxyl, or the compounds obtained according to process ad A1) of the general formula I, wherein R is CH (OCH ₃ ) ₂ or CH ₂ N [CH ₂ (C ₆ H 5)] 2, R ¹ is COCH 3, R ² is OR ⁶ , where R ⁶ is COCH 3, R ³ and R ⁵ have the same meaning and are hydrogen and R ⁴ is fr hydroxyl, optionally subjected to methanolysis as described in C), so that to give compounds of formula I wherein R is CH (OCH 3) 2 or CH 2 N [CH 2 (C ⁶ H ⁵ ) 2, R ¹ , R ³ and R ⁵ have the same meaning and are hydrogen, R ² is OR ⁶ , wherein R ⁶ is COCH 3, and R ⁴ is hydroxyl, or the compound obtained according to process ad A1) of formula I wherein R is CH (OCH ₃ ) 2, R ¹ is COCH 3, R ² is OR ⁶ , where R ⁶ is COCH 3, R ³ and R ⁵ have the same meaning and are hydrogen and R ⁴ is hydroxyl, optionally subjected to hydrolysis of the acetal as described in (D) to give a compound of formula I wherein R is CHO, R ¹ is COCH 3, R ² is OR ⁶ , where R ⁶ is COCH 3, R ³ and R ⁵ have the same meaning and are hydrogen and R ⁴ is hydroxyl, optionally subjected to methanolysis as described in (C), so that to give a compound of formula I, v wherein R is CHO, R ¹ , R ³ and R ⁵ have the same meaning and are hydrogen, R ² is OR ⁶ , where R ⁶ is COCH 3, and R ⁴ is hydroxyl.