HRP990192A2 - 4'-DEMICAROZYL-8a-AZA-8a-HOMOTHILOSINE DERIVATIVES - Google Patents

Description

The technical field to which the invention belongs

Int. Cl. A 61 K 31/70 C 07 H17/08

Technical problem

The invention relates to new compounds from the class of 17-membered azalides with antibacterial activity. In more detail, the invention relates to 4'-demicarosyl-8a-aza-8a-homotylosin derivatives of formula I

[image]

where R means CHO, CH(OCH3)2 or CH2N/CH2(C6H5)/2,

R1 means H or C1-C3 acyl,

R2 means OR6 and R6 means H or C1-C3 acyl,

R3 means H or R2 and R3 together mean =O,

R4 means OH,

R5 means H or R4 and R5 together mean =O,

and the procedure for obtaining them.

State of the art

4'-Demicarosyl-8a-aza-8a-homotylosin, a new semi-synthetic macrolide from the order of 17-membered azalides, was prepared by double transformation of the C-9 ketone of the 16-membered antibiotic 4'-demicarosyl-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 the 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) preparation of 4'-demicarosyl-20-deoxo- 20-dibenzylamino-8a-aza-8a-homotylosin (N. Lopotar., HR patent application P940962A 30.11.1994).

According to the known state of the art, C1-C3 acyl esters of 4'-demicarosyl-8a-aza-8a-homotylosin and 4'-demicarosyl-20-deoxo-20-dibenzylamino-8a-aza-8a-homo-tylosin have not yet been described, same as 4"-deoxy-4"-oxo- and 3-deoxy-3-oxo-derivatives of 4'-demicarosyl-8a-aza-8a-homotylosin and 4'-demicarosyl-20-deoxo-20-dibenzylamino-8a -aza-8a-homotylosin, their C1-C3-acyl esters, as well as the process for their preparation.

Detailed description of the invention

According to the present invention, 4'-demicarosyl-8a-aza-8a-homotylosin derivatives of formula I

[image]

where R means CHO, CH(OCH3)2 or CH2N/CH2(C6H5)/2,

R1 means H or C1-C3 acyl,

R2 means OR6 and R6 means H or C1-C3 acyl,

R3 means H or R2 and R3 together mean =O,

R4 means OH,

R5 is H or R4 and R5 together are =O

can be arranged like this,

that 4'-demicarosyl-8a-aza-8a-homotylosin 20-dimethylacetal of formula IIa and 4'-demicarosyl-20-deoxo-20-dibenzylamino-8a-aza-8a-homotylosin of formula IIb

[image]

undergo

A/O-acylation with anhydrides of C1-C3 carboxylic acids, primarily with acetic anhydride in methylene chloride, for 15 minutes to 1 hour, at room temperature, and the obtained compounds of formula I in which R has the meaning CH(OCH3)2 or CH2N /CH2(C6H5)/2,

R1 has the meaning COCH3, R2 has the meaning OR6 where R6 means H, R3 and R5 are the same and have the meaning H, and R4 has the meaning OH,

subject to choice

A1/O-acylation with anhydrides of C1-C3 carboxylic acids, primarily with acetic anhydride in methylene chloride, in the presence of an organic base, primarily triethylamine and 4-dimethylaminopyridine as a catalyst, for 30 hours at room temperature, and the obtained compounds of formula I in which R has the meaning CH(OCH3)2 or CH2N/CH2(C6H5)/2, R1 has the meaning COCH3, R2 has the meaning OR6 where R6 means COCH3, R3 and R5 are the same and have the meaning H, and R4 has the meaning OH,

subject to choice

B/ oxidation reaction with N(3-dimethylamino-propyl)-N'ethyl carbodiimide hydrochloride in the presence of dimethylsulfoxide and pyridine trifluoroacetate as a catalyst, in an inert solvent, primarily methylene chloride, for 2-6 hours at a temperature of 10°C to room temperature, and the obtained compounds of formula I in which R has the meaning CH(OCH3)2 or CH2N/CH2(C6H5)/2, R1 has the meaning COCH3, R2 has the meaning OR6 where R6 means COCH3, R3 has the meaning H, and R4 and R5 together mean =Oh,

subject to choice

C/ methanolysis at room temperature, for 2 days, and the obtained compounds of formula I in which R has the meaning CH(OCH3)2 or CH2N/CH2(C6H5)/2, R1 and R3 are the same and have the meaning H, R2 has the meaning OR6 where R6 means COCH3, and R4 and R5 together mean =O,

subject to choice

C 1/ to alkaline methanolysis in a mixture of methanol and 25% ammonia (4:11), at a temperature of 5°C to room temperature, during 20 to 60 hours, giving compounds of formula I in which R has the meaning CH(OCH3)2 or CH2N/CH2(C6H5)/2, R1 and R3 are the same and have the meaning H, R2 has the meaning OR6 where R6 means H, and R4 and R5 together mean =O;

or the compound obtained according to process C1

of formula I in which R has the meaning CH(OCH3)2, R1 and R3 are the same and have the meaning H, R2 has the meaning OR6 where R6 means H, and R4 and R5 together mean =O,

subject to choice

D/ acetal hydrolysis in a mixture of acetonitrile and 0.1 N hydrochloric acid (1:1l) for 2 hours at room temperature, giving the compound of formula I in which R has the meaning of the CHO group, R1 and R3 are the same and have the meaning H, R2 has the meaning OR6 where R6 means H, and R4 and R5 together mean =O;

or compounds obtained according to process A

of the formula I in which R has the meaning CH(OCH3)2 or CH2N/CH2(C6H5)/2, R1 has the meaning COCH3, R2 has the meaning OR6 where R6 means H, R3 and R5 are the same and have the meaning H, and R4 has the meaning OH,

optionally subjected to oxidation in the manner described in B,

and the obtained compounds of formula I in which R has the meaning CH(OCH3)2 or CH2N/CH2(C6H5)/2, R1 has the meaning COCH3, R2 and R3 together mean =O, R4 has the meaning OH, and R5 has the meaning H,

optionally subjected to methanolysis in the manner described in C,

giving compounds of formula I in which R has the meaning CH(OCH3)2 or CH2N/CH2(C6H5)/2, R1 and R5 are the same and have the meaning H, R2 and R3 together mean =O, and R4 has the meaning OH;

or the compound obtained according to process B

of formula I in which R has the meaning of the CH(OCH3)2 group, R1 has the meaning COCH3, R2 and R3 together mean =O, R4 has the meaning OH, and R5 has the meaning H,

optionally subjected to acetal hydrolysis in the manner described in D,

and the obtained compound of formula I in which R has the meaning of the CHO group, R1 has the meaning COCH3, R2 and R3 together have the meaning =O, R4 has the meaning OH, and R5 has the meaning H,

optionally subjected to methanolysis in the manner described in C,

giving a compound of formula I in which R has the meaning of the CHO group, R1 and R5 are the same and have the meaning H, R2 and R3 together mean =O, and R4 has the meaning OH;

or the compound obtained according to process A

of formula I in which R has the meaning CH(OCH3)2, R1 has the meaning COCH3, R2 has the meaning OR6 where R6 means H, R3 and R5 are the same and have the meaning H, and R4 has the meaning OH,

optionally subjected to acetal hydrolysis in the manner described in D,

giving a compound of formula I in which R has the meaning CHO, R1 has the meaning COCH3, R2 has the meaning OR6 where R6 means H, R3 and R5 are the same and have the meaning H, and R4 has the meaning OH;

or compounds obtained according to process A 1

of formula I in which R has the meaning CH(OCH3)2 or CH2N/CH2(C6H5)/2, R1 has the meaning COCH3, R2 has the meaning OR6 where R6 means COCH3, R3 and R5 are the same and have the meaning H, and R4 has the meaning OH,

optionally subjected to methanolysis in the manner described in C,

giving compounds of formula I in which R is CH(OCH3)2 or CH2N/CH2(C6H5)/2, R1, R3 and R5 are the same and are H, R2 is OR6 where R6 is COCH3 and R4 is OH ;

or the compound obtained according to process A 1

of formula I in which R has the meaning CH(OCH3)2 R1 has the meaning COCH3, R2 has the meaning OR6 where R6 means COCH3, R3 and R5 are the same and have the meaning H, and R4 has the meaning OH,

optionally subjected to acetal hydrolysis in the manner described in D, and the obtained compound of formula I in which R is CHO, R1 is COCH3, R2 is OR6 where R6 is COCH3, R3 and R5 are the same and have the meaning H, and R4 has the meaning OH,

optionally subjected to methanolysis in the manner described in C,

giving a compound of formula I in which R is CHO, R 1 , R 3 and R 5 are the same and are H, R 2 is OR 6 where R 6 is COCH 3 and R 4 is OH.

According to this invention, the new compounds are isolated by the usual methods of extraction from aqueous solutions with halogenated hydrocarbons, such as methylene chloride or chloroform, and by evaporation of the organic solvent to a dry residue. If necessary, separation of reaction products or cleaning of products for spectral analysis is carried out by flash chromatography on a silica gel column (Merck Co., Silicagel 60,230-400 mesh/ASTH) in the solvent system: CH2Cl2-CH3OH-conc.NH4OH (90:9:1.5, system A), CH2Cl2-CH3OH (90:9, system B) or CHCl3-CH3COCH3 (7:3, system C).

The structure of the new compounds was proven by spectrometric methods and mass analysis.

The new compounds show antibacterial activity and can be used as intermediates for the preparation of new 17-membered azalide antibiotics.

The invention is illustrated by the following examples, which in no way limit the scope of this invention.

Example 1

4'-Demicarosyl-2',4'-di-O-acetyl-8a-aza-8a-homotylosin20-dimethylacetal: (1)

4'-Demicarosyl-8a-aza-8a-homotylosin 20-dimethylacetal (5.0 g, 6.02 mmol) was dissolved in dry methylene chloride (50 ml), acetic anhydride (2.0 ml) was added and stirred for 15 minutes at room temperature. The reaction mixture is poured into a mixture of water and ice (500 ml) and extracted twice with methylene chloride at pH 8.5. The combined organic extracts are washed with saturated NaHCO3 solution and water, dried (K2CO3), and evaporated under reduced pressure, yielding 5.38 g (97.8%) of TLC homogeneous product (1).

TLC: Rf (B) 0.44; Rf (C) 0.22

IR(KBr)cm-1 1749, 1657, 1620, 1544, 1455, 1375, 1229, 1170, 1063.

1H NMR (CDCl3) δ ppm 7.16 (H-11), 5.69 (H-10), 5.66 (H-13), 4.96 (8a-NH) exchangeable with D2O, 4.88 (H-2'), 4.76 (H- 4'), 4.63 (H-20), 4.58 (H-1"), 4.33 (H-1'), 4.17 (H-8), 3.61 (3"-OCH3), 3.47 (2"-OCH3), 3.56 (2x20-OCH3), 2.33 (3'-N(CH3)2/, 2.05 (COCH3), 2.03 (COCH3), 1.74 (H-22), 1.17 (H-21).

13C NMR (CDCl3) δ ppm 179.1 (C-1), 169.8, 169.4 (2xCOCH3), 166.2 (9-CONH), 144.7(C-11), 138.2 (C-13), 134.9 (C-12), 119.2 (C-10), 103.5 (C-20), 102.0 (C-1'), 100.9 (C-1"), 72.5 (C-4"), 71.4 (C-4'), 70.3 (C-2 '), 65.6 (C-3), 61.5 (3"-OCH3), 59.4 (2"-OCH3), 50.4 (2x20-OCH3), 42.7 (C-8), 42.5 (C-4), 41.0 /3'-N(CH3)2/, 40.5 (C-2), 34.3 (C-19), 21.8, 20.9 (2xCOCH3), 21.9 (C-21), 12.6 (C-22), 8.3 (C- 18).

FAB (MH+) 917.

Example 2.

4'-Demicarosyl-2',4'-di-O-acetyl-20-deoxo-20-dibenzylamino-8a-aza-8a-homotylosin: (2)

4'-Demicarosyl-20-deoxo-20-dibenzylamino-8a-aza-8a-homotylosin (2.8g, 2.90 mmol) was dissolved in dry methylene chloride (30 ml), acetic anhydride (1.3 ml, 13.76 mmol) was added and stir for 15 minutes at room temperature. The reaction mixture is poured into a mixture of water and ice (300 ml) and extracted twice with methylene chloride at pH 6.5. The combined organic extracts were washed with saturated NaHCO3 solution and water, dried (K2CO3), and evaporated under reduced pressure, yielding 3.02 g (98.9%) of TLC homogeneous product (2).

TLC: Rf(B) 0.38; Rf(C) 0.23

IR(KBr)cm-1 1749, 1651, 1633, 1548, 1454, 1374, 1231, 1169, 1059.

1H NMR (CDCl3) 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 D2O, 4.84 (H-2 '), 4.74 (H-4'), 4.60 (H-1"), 4.15(H-1'), 3.62(3"-OCH3), 3.61 (20-N-CH2-phenyl), 3.58 (20- CH2 -phenyl), 3.51 (2"-OCH3), 2.32 (3'-N(CH3)2/, 2.06 (COCH3), 2.00 (COCH3), 1.72 (H-22), 1.12 (H-21).

13C NMR (CDCl3) δ ppm 173.4 (C-1), 169.9, 169.5 (2xCOCH3), 166.1 (9-CONH), 144.8 (C-11), 137.9 (C-13), 135.2 (C-12), 119.3 (C-10), 102.3 (C-1'), 101.0 (C-1"), 72.5 (C-4"), 71.4 (C-4'), 70.4 (C-2'), 66.0 (C- 3), 61.5 (3"-OCH3), 59.5 (2"- OCH3), 52.2 (C-20), 42.9 (C-8), 42.4 (C-4), 41.0 /3'-N(CH3)2 /, 38.7(C-2), 29.4 (C-19), 21.8 (C-21), 21.1, 21.0 (2xCOCH3), 12.7 (C-22), 8.4 (C-18),

20-N(CH2C6H5)2 139.8, 129.1, 128.0, 126.6, 57.9.

FAB (MH+)1052.

Example 3.

4'-Demicarosyl-2',4',4"-tri-O-acetyl-8a-aza-8a-homotylosine 20-dimethylacetal: (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 then the reaction solution let it stand for 26 hours at room temperature. Isolation of the product is carried out in the manner described in Example 1, giving 4.08 g (97.7 %) of TLC homogeneous product (3).

TLC: Rf (A) 0.65; Rf (C) 0.54

IR(KBr)cm-1 1749, 1655, 1618, 1546, 1454, 1374, 1233, 1171, 1052.

1H NMR (CDCl3) δ ppm 7.16 (H-11), 5.69 (H-10), 5.65 (H-13), 4.89 (8a-NH) exchangeable with D2O, 4.88 (H-2'), 4.76 (H- 4'), 4.64 (H-1"), 4.59 (H-20), 4.33 (H-1'), 4.18 (H-8), 3.52 (3"-OCH3), 3.46 (2"OCH3), 3.36 (20-OCH3), 3.35 (20-OCH3), 2.33 /3'-N(CH3)2/, 2.12 (COCH3), 2.05 (COCH3), 2.03 (COCH3), 1.74 (H-22), 1.16 ( H-21).

13C NMR(CDCl3) δ ppm 173.1 (C-1), 170.1, 169.8, 169.4 (3xCOCH3), 166.1 (9-CONH), 144.7 (C-11), 138.0 (C-13), 134.9 (C-12) , 119.2 (C-10), 103.7 (C-20), 102.1 (C-1'), 100.9 (C-1"), 74.5 (C-4"), 71.4 (C-4'), 70.3 (C -2'), 65.6 (C-3), 61.3 (3"-OCH3), 59.3 (2"-OCH3), 53.7 (20-OCH3), 50.6 (20-OCH3), 42.7 (C-8) , 42.6 (C-4), 41.0 /3'-N(CH3)2/, 40.5 (C-2), 34.5 (C-19), 21.9, (C-21), 21.1, 21.0, 20.7 (3xCCOH3) , 12.7 (C-22), 8.3 (C-18).

FAB (MH+) 959.

Example 4.

4'-Demicarosyl-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), triethylamine (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. Isolation of the product is carried out as described in Example 1, yielding 2.7 g (92.9%) of TLC homogeneous product (4).

TLC: Rf (B) 0.55; Rf (C) 0.47

IR(KBr)cm-1 1747, 1651, 1632, 1538, 1453, 1372, 1233, 1170, 1051.

1H NMR (CDCl3) 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 D2O, 4.86 (H-2 '), 4.74 (H-4'), 4.66 (H-1"), 4.46 (H-4"), 4.15 (H-1'), 3.61 (2x20-N-CH2 -phenyl), 3.53 (3" -OCH3), 3.50 (2"-OCH3), 2.32 /3'-N(CH3)2/, 2.12 (COCH3), 2.06 (COCH3), 2.00 (COCH3), 1.72 (H-22), 1.12 (H- 21), 0.78 (H-18).

13C NMR (CDCl3) δ ppm 173.3 (C-1), 170.1, 169.9, 169.5 (3xCOCH3), 166.1 (9-CONH), 144.8 (C-11), 137.9 (C-13), 135.2 (C-12) , 119.3 (C-10), 102.3 (C-1'), 101.0 (C-1"), 74.6 (C-4"), 71.4(C-4'), 70.4 (C-2'), 66.0 ( C-3), 61.5 (3"-OCH3), 59.3 (2"-OCH3), 52.2 (C-20), 42.9 (C-8), 42.4 (C-4), 41.0 /3'-N(CH3 )2/, 38.7 (C-2), 29.4 (C-19), 21.8 (C-21), 21.1, 21.0, 20.7 (3xCOCH3), 12.7 (C-22), 8.4 (C-18), 20- N(CH2C6H5)2 139.8, 129.1, 128.0, 126.6, 57.9.

FAB (MH+) 1094.

Example 5.

4'-Demicarosyl-2',4'-di-O-acetyl-4"-deoxy-4"-oxo-8a-aza-8a-homotylosin 20-dimethylacetal: (5)

To a solution of compound 1 (1.0 g, 1.09 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.0 g, 5.22 mmol) and dimethylsulfoxide (1.0 ml, 14.10 mmol) in 20 ml of methylene chloride was added dropwise to 15°C solution of pyridine trifluoroacetate (1.0 g, 5.24 mmol) in 10 ml of methylene chloride. The reaction mixture is stirred for 3 hours at room temperature, then poured into 150 ml of water and, after separating the organic layer, extracted two more times with methylene chloride. The combined organic extracts are washed with saturated NaHCO3 solution and water, dried (K2CO3), and evaporated under reduced pressure to a dry residue. The obtained crude product (0.95 g) is purified by flash chromatography on a silica gel column using solvent system B, yielding 0.45 g of TLC homogeneous product (5).

TLC: Rf(B) 0.52

IR(KBr)cm-1 1749, 1657, 1620, 1542, 1455, 1375, 1230, 1172, 1060.

1H NMR (CDCl3) δ ppm 7.16 (H-11), 5.71 (H-10), 5.64 (H-13), 4.97 (8a-NH) exchangeable with D2O, 4.88 (H-2'), 4.76 (H- 4'), 4.60 (H-20), 4.63 (H-1"), 4.33 (H-1'), 4.17 (H-8), 3.98 (H-5"), 3.78 (H-3"), 3.58 (3"-OCH3), 3.52 (2"-OCH3), 3.36 (20-OCH3), 3.35 (20-OCH3), 3.30 (H-2"), 2.33 /3'-N(CH3)2/, 2.05 (COCH 3 ), 2.03 (COCH 3 ), 1.76 (H-22), 1.34 (H-6"), 1.17 (H-21).

13C NMR (CDCl3) δ ppm 202.4 (C-4"), 173.1 (C-1), 169.9, 169.5 (2xCOCH3), 166.1 (9-CONH), 144.6 (C-11), 137.6 (C-13), 135.3 (C-12), 119.5 (C-10), 103.6 (C-20), 103.0 (C-1"), 102.1 (C-1'), 85.3 (C-3"), 84.2 (C-2 "), 73.3 (C-5"), 71.3 (C-4'), 70.3 (C-2'), 65.6 (C-3), 60.2 (3"-OCH3), 59.1 (2"-OCH3), 53.7 (20-OCH3), 50.5 (20-OCH3), 42.7 (C-8), 42.6 (C-4), 41.0 /3'-N(CH3)2/, 40.7 (C-2) 34.4 (C- 19), 21.9 (C-21), 21.1, 21.0 (2xCOCH3), 14.0 (C-6"), C-12.7 (C-22), 8.3 (C-18).

FAB (MH+) 915.

Example 6.

4'-Demicarosyl-2',4'-di-O-acetyl-4"-deoxy-4"-oxo-20-deoxo-20-dibenzylamino-8a-aza-8a-homotylosin: (6)

To a solution of compound 2 (0.6 g, 0.57 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.6 g, 3.14 mmol) and dimethylsulfoxide (0.45 ml, 6.35 mmol) in 20 ml of methylene chloride was added dropwise at 15°C. a solution of pyridine trifluoroacetate (0.6 g, 3.11 mmol) in 6 ml of methylene chloride. The reaction mixture is stirred for 5 hours at room temperature. Isolation of the product is carried out as described in Example 5. The obtained crude product (0.54 g) is purified by flash chromatography on a silica gel column using solvent system B, yielding 0.28 g of TLC homogeneous product (6).

TLC: Rf (B) 0.48; Rf(C) 0.33

IR(KBr)cm-1 1747, 1651, 1633, 1548, 1454, 1372, 1231, 1058.

1H NMR (CDCl3) 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 D2O, 4.82 (H-2 '), 4.74 (H-4'), 4.65 (H-1"), 4.15 (H-1'), 3.98 (H-5"), 3.78 (H-3"), 3.62 (20-N-CH2 -phenyl), 3.58 (20-CH2 -phenyl), 3.55 (3"-OCH3), 3.49 (2"-OCH3), 2.32 /3'-N(CH3)2/, 2.06 (COCH3), 2.00 (CCOH3) , 1.74 (H-22), 1.36 (H-6"), 1.12 (H-21).

13C NMR (CDCl3) δ ppm 202.4 (C-4"), 173.4 (C-1), 169.8, 169.3 (2xCOCH3), 166.1 (9-CONH), 144.6 (C-11), 137.0 (C-13), 135.6 (C-12), 119.6 (C-10), 103.0 (C-1"), 102.2 (C-1'), 85.3 (C-3"), 84.8 (C-2"), 73.3 (C- 5"), 71.4 (C-4'), 70.4 (C-2'), 65.9 (C-3), 60.3 (3"-OCH3), 59.1 (2"-OCH3), 52.2 (C-20), 42.9 (C-8), 42.4 (C-4), 40.9 /3'-N(CH3)2/, 38.7 (C-2), 29.4 (C-19), 21.8 (C-21), 21.1, 21.0 (2xCOCH3), 14.0 (C-6"), 12.8 (C-22), 8.4 (C-18), 20-N(CH2C6H5)2 139.6, 129.9, 128.0, 126.6, 57.8.

FAB (MH+) 1050.

Example 7.

4'-Demicarosyl-2',4',4"-tri-O-acetyl-3-deoxy-3-oxo-8a-aza-8a-homotylosin 20-dimethylacetal: (7)

A solution of compound 3 (2.0 g, 2.09 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.0 g, 15.66 mmol) and dimethylsulfoxide (2.9 ml, 40.89 mmol) in 50 ml of methylene chloride was added dropwise at 15° C solution of pyridine trifluoroacetate (3.0 g, 15.72 mmol) in 30 ml of methylene chloride. The reaction mixture is stirred for 3 hours at room temperature. Isolation of the product is carried out as described in Example 5. The obtained crude product (1.95 g) is purified by flash chromatography on a silica gel column using solvent system C, yielding 1.3 g of TLC homogeneous product (7).

TLC: Rf (C) 0.58

IR(KBr)cm-1 1749, 1655, 1618, 1546, 1454, 1374, 1233, 1171, 1052.

1H NMR (CDCl3) δ ppm 6.90 (H-11), 5.76 (H-10), 5.43 (H-13), 4.96 (8a-NH) exchangeable with D2O, 4.89 (H-2'), 4.79 (H- 4'), 4.66 (H-1"), 4.40 (H-1'), 4.18 (H-8), 3.55, 3.32 (H-2), 3.52 (3"-OCH3), 3.49 (2"-OCH3 ), 3.30 (20-OCH3), 3.29 (20-OCH3), 2.34 /3'-N(CH3)2/, 2.12 (COCH3), 2.06 (COCH3), 2.03 (COCH3), 1.75 (H-22), 1.10 (H-21), 1.07 (H-18).

13C NMR(CDCl3) δ ppm 205.6 (C-3), 172.9 (C-1), 170.1, 169.8, 169.4 (3xCOCH3), 166.1 (9-CONH), 144.1 (C-11), 138.0 (C-13) , 134.9 (C-12), 119.6 (C-10), 103.7 (C-20), 102.1 (C-1'), 100.9 (C-1"), 74.5 (C-4"), 71.4 (C- 4'), 70.3 (C-2'), 61.3 (3"-OCH3), 59.3 (2"-OCH3), 53.7 (20-OCH3), 50.6 (20-OCH3), 46.5 (C-2), 44.2 (C-4), 42.0 (C-8), 41.0 /3'-N(CH3)2/, 34.5 (C-19), 21.9, (C-21), 21.1,21.0, 20.7 (3xCOCH3), 17.6 (C-18), 12.7 (C-22).

FAB (MH+) 957.

Example 8.

4'-Demicarosyl-2',4',4"-tri-O-acetyl-3-deoxy-3-oxo-20-deoxo-20-dibenzylamino-8a-aza-8a-homotylosin: (8)

To a solution of compound 4 (1.0 g, 1.09 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.04 g, 10.44 mmol) and dimethylsulfoxide (1.6 ml, 22.56 mmol) in 20 ml of methylene chloride was added dropwise at 15°C. a solution of pyridine trifluoroacetate (2.0 g, 10.36 mmol) in 10 ml of methylene chloride. The reaction mixture was stirred for 6 hours at room temperature. Isolation of the product is carried out as described in Example 5. The obtained crude product (0.96 g) is purified by flash chromatography on a silica gel column using solvent system B, yielding 0.62 g of TLC homogeneous product (8).

TLC: Rf(B) 0.60

IR(KBr)cm-1 1748, 1633, 1538, 1454, 1373, 1231, 1052.

1H NMR (CDCl3) δ ppm 7.22- 7.40 (phenyl), 6.89(H-11), 5.66 (H-10), 5.49 (H-13), 4.96 (8a-NH) exchangeable with D2O, 4.81 (H-2 '), 4.74 (H-4'), 4.66 (H-1"), 4.42 (H-4"), 4.15 (H-1'), 4.12 (H-8), 3.78, 3.38 (H-2) , 3.51 (2x20-N-CH2 -phenyl, 3"-OCH3), 3.48 (2"-OCH3), 2.32 /3'-N(CH3)2/, 2.22 (H-4), 2.09 (COCH3), 2.06 (COCH3), 2.00 (COCH3), 1.72 (H-22), 1.10 (H-21), 1.08 (H-18).

13C NMR (CDCl3) δ ppm 206.7 (C-3), 172.7 (C-1), 170.1, 169.9, 169.5 (3xCOCH3), 166.1 (9-CONH), 144.0 (C-11), 136.5 (C-12) , 135.0 (C-13), 119.9 (C-10), 102.7 (C-1'), 100.9 (C-1"), 74.6 (C-4"), 71.3 (C-4'), 70.3 (C -2'), 61.3 (3"-OCH3), 59.3 (2"-OCH3), 51.7 (C-20), 47.7 (C-2), 44.5 (C-4), 42.0 (C-8), 41.0 /3'-N(CH3)2/, 28.6 (C-19), 22.0 (C-21), 21.0, 20.7 (3xCOCH3), 17.8 (C-18), 13.1(C-22), 20- N(CH2C6H)2 140.1, 128.9, 128.0, 126.4, 57.9.

FAB (MH+) 1092.

Example 9:

4'-Demicarosyl-4"-deoxy-4"-oxo-8a-aza-8a-homotylosin 20-dimethylacetal: (9)

Compound 5 (0.65 g, 0.71 mmol) was dissolved in 20 ml of methanol and left to stand for 48 hours at room temperature. A saturated NaHCO3 solution was added to the reaction solution and extracted twice with chloroform. The combined organic extracts are dried (K2CO3) and evaporated under reduced pressure to a dry residue. The obtained crude product (0.45 g) is purified by flash chromatography on a silica gel column using solvent system A, giving 0.20 g of TLC homogeneous product (9).

TLC: Rf (A) 0.27

IR(KBr)cm-1 1749, 1657, 1620, 1542, 1455, 1375, 1230, 1172, 1060.

1H NMR (CDCl3) 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"-OCH3), 3.52 (2"-OCH3), 3.46 (H-2'), 3.36, 3.35 (2x20-OCH3), 3.30 (H-2"), 3.06 (H-4'), 2.33 /3'-N(CH3)2/, 1.76 (H-22 ), 1.34 (H-6"), 1.17 (H-21).

13C NMR(CDCl3) 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"-OCH3), 59.1 (2"-OCH3), 53.7 (20-OCH3), 50.5 (20-OCH3), 42.7 (C-8), 42.6 (C-4), 41.0 /3'-N(CH3)2/, 40.7 (C-2), 34.4 (C-19), 21.9 (C-21), 14.0 (C-6"), 12.7 ( C-22), 8.3 (C-18).

FAB (MH+) 831.

Example 10.

4'-Demicarosyl-4"-deoxy-4"-oxo-20-deoxo-20-dibenzylamino-8a-aza-8a-homotylosin: (10)

Compound 6 (0.30 g, 0.73 mmol) was dissolved in 20 ml of methanol and left to stand for 30 hours at room temperature. After adding water (50 ml), the product is isolated by gradient extraction with chloroform at pH 4.5 and 7.5. The combined chloroform extracts at pH 7.5 were dried (K2CO3) and evaporated under reduced pressure, and the resulting product (0.17 g) was purified by flash chromatography on a silica gel column using solvent system A, yielding 0.08 g of TLC homogeneous product (10).

TLC: Rf(A) 0.49

IR(KBr)cm-1 1715, 1655, 1619, 1542, 1454, 1377, 1168, 1082.

1H NMR (CDCl3) 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 D2O, 4.84 (H-2 '), 4.74 (H-4'), 4.60 (H-1"), 4.15 (H-1'), 3.98 (H-5"), 3.78 (H-3"), 3.62 (3"-OCH3) , 3.61 (20-N-C-H2 -phenyl), 3.58 (20-CH2 -phenyl), 3.51 (2"-OCH3), 3.46 (H-2'), 3.01 (H-4'), 2.32 /3'- N(CH3)2/, 1.72 (H-22), 1.12 (H-21).

13C NMR (CDCl3) 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-1'), 103.0 (C-1"), 85.4 (C-3"), 84.9 (C-2"), 73.3 (C-5"), 66.4 (C -3) 59.8 (3"-OCH3), 58.6 (2"-OCH3), 52.2 (C-20), 43.3 (C-8), 42.3 (C-4), 41.5 /3'-N(CH3)2 /, 38.7 (C-2), 29.4 (C-19), 22.0 (C-21), 14.1 (C-6"), 12.8 (C-22), 9.1 (C-18), 20-N(CH2C6H5 )2 139.8, 129.1, 128.0, 126.6, 58.0.

FAB (MH+) 967.

Example 11.

4'-Demicarosyl-4"-O-acetyl-3-deoxy-3-oxo-8a-aza-8a-homotylosin 20-dimethylacetal: (11)

Compound 7 (0.70 g, 0.73 mmol) was dissolved in 50 ml of methanol and left to stand for 24 hours at room temperature. The isolation of the product is carried out as described in Example 9, and the obtained crude product (0.62 g) is purified by flash chromatography on a silica gel column using solvent system A, yielding 0.40 g of TLC homogeneous product (11).

TLC: Rf (A) 0.44

IR(KBr)cm-1 1749, 1657, 1620, 1544, 1455, 1375, 1229, 1170, 1063.

1H NMR (CDCl3) 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 (3"-OCH3), 3.50 , 3.26 (H-2), 3.48 (2"-OCH3), 3.30 (20-OCH3), 3.29 (20-OCH3), 2.53 /3'-N(CH3)2/, 2.12 (COCH3), 1.75 (H -22), 1.25 (H-18).

13C NMR (CDCl3) δ ppm 205.4 (C-3), 172.9 (C-1), 170.1 (COCH3), 167.4 (9-CONH), 143.4 (C-11), 136.2 (C-12), 134.6 (C -13), 120.7 (C-10), 104.2 (C-1'), 103.9 (C-20), 100.8 (C-1"), 74.5 (C-4"), 70.9 (C-2'), 70.5 (C-2'), 61.3 (3"-OCH3), 59.0 (2"-OCH3), 52.6 (20-OCH3), 52.1 (20-OCH3), 45.9 (C-2), 44.4 (C -4), 42.5 (C-8), 41.4 /3'-N(CH3)2/, 33.8 (C-19), 22.0 (C-21), 20.7 (COCH3), 17.5 (C-18), 12.9 (C-22).

FAB (MH+) 873.

Example 12.

4'-Demicarosyl-4"-O-acetyl-3-deoxy-3-oxo-20-deoxo-20-dibenzylamino-8a-aza-8a-homotylosin: (12)

Compound 8 (1.20 g, 10.99 mmol) was dissolved in 100 ml of methanol and left to stand for 24 hours at room temperature. Add 100 ml of water to the reaction solution and extract with methylene chloride at pH 6.5. The combined organic extracts are dried (K2CO3) and evaporated under reduced pressure and the resulting crude product (1.0 g) is purified by flash chromatography on a silica gel column using solvent system A, yielding 0.52 g of TLC homogeneous product (12).

TLC: Rf (A) 0.65

IR(KBr)cm-1 1745, 1650, 1622, 1537, 1454, 1373, 1233, 1166, 1058.

1H NMR (CDCl3) δ ppm 7.25- 7.41 (phenyl), 6.90 (H-l 1), 5.67 (H-10), 5.52 (H-13), 4.98 (8a-NH) exchangeable with D2O, 4.67 (H-1" ), 4.45 (H-4"), 4.17 (H-1'), 4.02 (H-8), 3.61 (20-CH2-phenyl), 3.53 (3"-OCH3), 3.52 (20-CH2-phenyl) , 3.50 (2"-OCH3), 3.76, 3.32 (H-2), 2.52 /3'-N(CH3)2/, 2.12 (COCH3), 1.73 (H-22), 1.21 (H-18), 1.08 (H-21).

13C NMR (CDCl3) δ ppm 205.3 (C-3) 172.5 (C-1), 170.1 (COCH3), 167.2 (9-CONH), 143.9 (C-11), 135.9 (C-12), 135.4 (C- 13), 120.0 (C-10), 103.9 (C-1'), 100.9 (C-1"), 74.6 (C-4"), 70.7 (C-4'), 70.4 (C-2'), 61.3 (3"-OCH3), 59.3 (2"-OCH3), 51.6 (C-20), 46.1 (C-2), 44.5 (C-4), 43.3 (C-8), 41.5 /3'-N (CH3)2/, 28.8 (C-19), 22.0 (C-21), 20.7 (COCH3), 17.8 (C-18), 12.9 (C-22), 20-N(CH2C6H)2139.9, 128.8, 128.0 , 126.5,58.0.

FAB (MH+) 1008.

Example 13.

4'-Demicarosyl-4"-O-acetyl-8a-aza-8a-homotylosin20-dimethylacetal: (13)

Compound 3 (0.5 g, 0.52 mmol) was dissolved in 20 ml of methanol and left to stand for 24 hours at room temperature. The isolation of the product is carried out in the manner described in Example 9, and the resulting crude product (0.43 g) is purified by flash chromatography on a silica gel column using solvent system A, yielding 0.32 g of TLC homogeneous product (13).

TLC: Rf (A) 0.32

IR(KBr)cm-1 1739, 1656, 1616, 1541, 1455, 1376, 1237, 1170, 1062.

1H NMR (CDCl3) δ ppm 7.15 (H-11), 5.71 (H-10), 5.66 (H-13), 4.97 (8a-NH) exchangeable with D2O, 4.64 (H-1"), 4.62 (H- 20), 4.44 (H-4"), 4.24 (H-11), 4.18 (H-8), 3.53 (3"-OCH3), 3.47 (2"-OCH3), 3.37 (20-OCH3), 3.36 ( 20-OCH3), 2.50 /3'-N(CH3)2/, 2.12 (COCH3), 1.75 (H-22), 1.17 (H-21).

FAB (MH+) 875.

Example 14.

4'-Demicarosyl-4"-O-acetyl-20-deoxo-20-dibenzylamino-8a-aza-8a-homotylosin: (14)

Compound 4 (0.75 g, 0.69 mmol) was dissolved in 20 ml of methanol and left to stand for 24 hours at room temperature. Isolation of the product is carried out as described in Example 12, and the resulting crude product (0.66 g) is purified by flash chromatography on a silica gel column using solvent system A, yielding 0.45 g of TLC homogeneous product (14).

TLC: Rf(A) 0.50

IR(KBr)cm-1 1740, 1657, 1621, 1538, 1454, 1373, 1236, 1169, 1054.

1H NMR (CDCl3) 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 D2O, 4.66 (H-1 "), 4.45 (H-4"), 4.14 (H-8), 4.07 (H-1'), 3.59 (20-N-CH2-phenyl), 3.56 (20-CH2-phenyl), 3.53 (3" -OCH3), 3.50 (2"-OCH3), 2.49 (3'-N(CH3)2/, 2.12 (COCH3), 1.73 (H-22), 1.11 (H-21), 0.94 (H-18).

FAB (MH+) 1010.

Example 15.

4'-Demicarosyl-3-deoxy-3-oxo-8a-aza-8a-homotylosin 20-dimethylacetal: (15)

Compound 11 (0.40 g, 0.46 mmol) was dissolved in 50 ml of a mixture of methanol and conc. NH4OH (4:1) and let stand for 60 hours at a temperature of 5°C. The reaction solution is evaporated to an oily residue and then the product is isolated as described in Example 9. The obtained crude product (0.25 g) is purified by flash chromatography on a silica gel column using solvent system A, yielding 0.15 g of TLC homogeneous product (15).

TLC: Rf (A) 0.39

IR(KBr)cm-1 1739, 1714, 1650, 1620, 1544, 1455, 1375, 1170, 1063.

1H NMR (CDCl3) δ ppm 6.87 (H-11), 5.77 (H-10), 5.44 (H-13), 5.18 (8a-NH) exchangeable with D2O, 4.60 (H-20), 4.64 (H-1 "), 4.33 (H-1'), 4.17 (H-8), 3.93 (H-5"), 3.89 (H-3"), 3.53 (3"-OCH3), 3.50, 3.26 (H-2) , 3.48 (2"-OCH3), 3.30 (20-OCH3), 3.29 (20-OCH3), 2.33 (3'-N(CH3)2/, 1.75 (H-22), 1.25 (H-18).

FAB (MH+) 831.

Example 16.

4'-Demicarosyl-3-deoxy-3-oxo-20-deoxo-20-dibenzylamino-8a-aza-8a-homotylosin: (16)

Compound 12 (0.78g, 0.77 mmol) was dissolved in 50 ml of a mixture of methanol and conc. NH4OH (4:1) and let stand for 24 hours at room temperature. Add 80 ml of water to the reaction solution and extract twice with methylene chloride at pH 7.5. The combined organic extracts are dried (K2CO3) and evaporated under reduced pressure, and the resulting product (0.66 g) is purified by flash chromatography on a silica gel column using solvent system A, yielding 0.32 g of TLC homogeneous product (16).

TLC: Rf (A) 0.55

IR(KBr)cm-1 1739, 1714, 1650, 1622, 1538, 1454, 1376, 1167, 1082.

1H NMR (CDCl3) 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 D2O, 4.61 (H-1 "), 4.16 (H-1'), 4.03 (H-8), 3.62 (20-N-CH2-phenyl), 3.61 (20-CH2-phenyl, 3"-OCH3), 3.51 (2"-OCH3) , 3.78, 3.38 (H-2), 2.5 /3'-N(CH3)2/, 2.38 (H-4), 1.72 (H-22), 1.21 (H-18), 1.08 (H-21).

13C NMR (CDCl3) 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'), 101.0 (C-1'), 72.5 (C-4"), 70.7 (C-4'), 70.4 (C-2'), 61.5 (3" -OCH3), 59.5 (2"-OCH3), 51.7 (C-20), 46.1 (C-2), 44.5 (C-4), 43.3 (C-8), 41.5 /3'-N(CH3)2 /, 28.8 (C-19), 22.0 (C-21), 17.8 (C-18), 12.9 (C-22), 20-N(CH2C6H)2 140.0, 128.8, 128.0, 126.5, 58.0.

FAB (MH+) 967.

Example 17.

4'-Demicarosyl-3-deoxy-3-oxo-8a-aza-8a-homotylosin: (17)

Compound 15 (0.5 g, 0.60 mmol) was dissolved in 35 ml of acetonitrile-0.1 N HCl mixture (1:1) and stirred for 2 hours at room temperature. A saturated solution of NaHCO3 is added to the reaction mixture and extracted twice with methylene chloride. The combined organic extracts are dried (K2CO3) and evaporated under reduced pressure, and the resulting product (0.42 g) is purified by flash chromatography on a silica gel column using solvent system A, yielding 0.25 g of TLC homogeneous product (17).

TLC: Rf(A) 0.35

IR(KBr)cm-1 1739, 1719, 1657, 1620, 1545, 1455, 1376, 1169, 1082.

1H NMR (CDCl3) 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"-OCH3), 3.49 (2"-OCH3), 2.49/3'-N( CH3)2/, 1.75 (H-22), 1.25 (H-18), 1.18 (H-21).

13C NMR (CDCl3) 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-4"), 71.0 (C-4'), 70.4 (C-2 '), 61.5 (3"-OCH3), 59.5 (2"-OCH3), 46.6 (C-19), 46.1 (C-2), 44.5 (C-4), 43.3 (C-8), 41.5 /3 -N(CH3)2/, 22.4 (C-21), 17.8 (C-18), 12.9 (C-22).

FAB (MH+) 785.

Example 18.

4'-Demicarosyl-2',4'-di-O-acetyl-8a-aza-8a-homotylosin: (18)

Compound 1 (0.5 g, 0.55 mmol) was dissolved in 35 ml of acetonitrile-0.1 N HCl mixture (1:1) and stirred for 2 hours at room temperature. Isolation of the product is carried out as described in Example 17, giving 0.34 g of TLC homogeneous product (18).

TLC: Rf(B) 0.35

IR(KBr)cm-1 1749, 1657, 1620, 1548, 1455, 1375, 1231, 1170, 1059.

1H NMR (CDCl3) δ ppm 9.75 (H-20), 7.21 (H-11), 5.72 (H-10), 5.71 (H-13), 5.08 (8a-NH) exchangeable with D2O, 4.89 (H-2 '), 4.74 (H-4'), 4.58 (H-1"), 4.26 (H-1'), 3.61 (3"-OCH3), 3.49 (2"-OCH3), 2.33 /3'-N( CH3)2/, 2.05 (COCH3), 2.03 (COCH3), 1.74 (H-22), 1.18 (H-21).

13C NMR (CDCl3) δ ppm 203.6 (C-20), 173.3 (C-1), 169.9, 169.5 (2xCOCH3), 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"-OCH3), 59.5 (2"-OCH3), 46.3 (C-19), 42.5 (C-8), 41.0 /3'-N(CH3)2 /, 38.5 (C-2), 21.6 (C-21), 21.1, 21.0 (2xCOCH3), 12.7 (C-22), 8.1 (C-18).

FAB (MH+) 871.

Example 19.

4'-Demicarosyl-2',4',4"-tri-O-acetyl-8a-aza-8a-homotylosin: (19)

Compound 3 (0.5 g, 0.52 mmol) was dissolved in 35 ml of acetonitrile-0.1 N HCl mixture (1:1) and stirred for 2 hours at room temperature. Isolation of the product is carried out as described in Example 17, giving 0.47 g of TLC homogeneous product (19).

TLC: Rf (B) 0.60; Rf (C) 0.50

IR(KBr)cm-1 1748, 1659, 1621, 1538, 1455, 1373, 1232, 1171, 1052.

1H NMR (CDCl3) δ ppm 9.74 (H-20), 7.16 (H-11), 5.69 (H-10), 5.65 (H-13), 4.89 (8a-NH) exchangeable with D2O, 4.88 (H-2 '), 4.76 (H-4'), 4.64 (H-1"), 4.44 (H-4"), 4.33 (H-1'), 4.18 (H-8), 3.52 (3"-OCH3), 3.46 (2"-OCH3), 2.33 (3'-N(CH3)2/, 2.12 (COCH3), 2.05 (COCH3), 2.03 (COCH3), 1.74 (H-22), 1.16 (H-21).

13C NMR(CDCl3) δ ppm 203.6 (C-20), 173.1 (C-1), 170.1, 169.8, 169.4 (3xCOCH3), 166.1 (9-CONH), 144.7 (C-11), 138.0 (C-13) , 134.9 (C-12), 119.2 (C-10), 103.7 (C-20), 102.1 (C-1'), 100.9 (C-1"), 74.5 (C-4"), 71.4 (C- 4'), 70.3 (C-2'), 65.6 (C-3), 61.3 (3"-OCH3), 59.3 (2"-OCH3), 46.3 (C-19), 42.7 (C-8) , 42.6 (C-4), 41.0 /3'-N(CH3)2/, 40.5 (C-2), 34.5 (C-19), 21.9, (C-21), 21.1, 21.0, 20.7 (3xCOCH3) , 12.7 (C-22), 8.3 (C-18).

FAB (MH+) 913.

Example 20.

4'-Demicarosyl-2',4'-di-O-acetyl-4"-deoxy-4"-oxo-8a-aza-8a-homotylosin: (20)

Compound 5 (0.7 g, 0.77 mmol) was dissolved in 50 ml of acetonitrile-0.1 N HCl mixture (1:1) and stirred for 1 hour at room temperature. Isolation of the product is carried out as described in Example 17, and the resulting crude product (0.52 g) is purified by flash chromatography on a silica gel column using solvent system B, yielding 0.36 g of TLC homogeneous product (20).

TLC: Rf (B) 0.48

IR(KBr)cm-1 1749, 1656, 1619, 1543, 1458, 1375, 1230, 1172, 1058.

1H NMR (CDCl3) δ ppm 9.75 (H-20), 7.21 (H-11), 5.72 (H-10), 5.70 (H-13), 5.08 (8a-NH) exchangeable with D2O, 4.88 (H-2 '), 4.74 (H-4'), 4.58 (H-1"), 4.30 (H-1'), 4.17 (H-8), 3.98 (H-5"), 3.78 (H-3"), 3.58 (3"-OCH3), 3.48 (2"-OCH3), 3.30 (H-2"), 2.33 /3'-N(CH3)2/, 2.05 (COCH3), 2.03 (COCH3), 1.76 (H- 22), 1.34 (H-6"), 1.17 (H-21).

13C NMR (CDCl3) δ ppm 203.0 (C-20), 202.4 (C-4"), 173.1 (C-1), 169.9, 169.5 (2xCOCH3), 166.5 (9-CONH), 145.0 (C-11), 138.1 (C-13), 135.1 (C-12), 119.0 (C-10), 102.1 (C-1"), 100.9 (C-1'), 85.3 (C-3"), 84.2 (C-2 "), 73.3 (C-5"), 71.3 (C-4'), 70.3 (C-2'), 65.6 (C-3), 61.5 (3"-OCH3), 59.4 (2"-OCH3), 46.3 (C-19), 42.5 (C-8), 41.0 /3'-N(CH3)2/, 38.5 (C-2), 21.9 (C-21), 21.1, 21.0 (2xCOCH3), 14.0 (C -6"), 12.7 (C-22), 8.3 (C-1).

FAB (MH+) 869.

Example 21.

4'-Demicarosyl-4"-O-acetyl-8a-aza-8a-homotylosin: (21)

Compound 19 (0.30 g, 0.33 mmol) was dissolved in 20 ml of methanol and left to stand for 24 hours at room temperature. Isolation of the product is carried out as described in Example 9, and the resulting crude product (0.25 g) is purified by flash chromatography on a silica gel column using solvent system A, yielding 0.19 g of TLC homogeneous product (21).

TLC: Rf (A) 0.28

IR(KBr)cm-1 1749, 1657, 1620, 1544, 1455, 1375, 1229, 1170, 1063.

1H NMR (CDCl3) δ ppm 9.78 (H-20), 7.20 (H-11), 5.72 (H-10), 5.70 (H-13), 5.12 (8a-NH) exchangeable with D2O, 4.88 (H-2 '), 4.64 (H-1"), 4.44 (H-4"), 4.18 (H-1'), 4.12 (H-8), 3.93 (H-5"), 3.89 (H-3"), 3.53 (3"-OCH3), 3.48 (2"-OCH3), 2.49 (3'-N(CH3)2/, 2.12 (COCH3), 1.75(H-22).

FAB (MH+) 829.

Example 22.

4'-Demicarosyl-4"-deoxy-4"-oxo-8a-aza-8a-homotylosin: (22)

Compound 20 (0.23 g, 0.27 mmol) was dissolved in 20 ml of methanol and left to stand for 24 hours at room temperature. The isolation of the product is carried out in the manner described in Example 9, and the resulting crude product (0.14 g) is purified by flash chromatography on a silica gel column using solvent system A, yielding 0.095 g of TLC homogeneous product (22).

TLC: Rf (A) 0.30

IR(KBr)cm-1 1717, 1655, 1625, 1542, 1454, 1378, 1170, 1062.

1H NMR (CDCl3) 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"-OCH3), 3.46 (2"-OCH3), 3.30 (H-2"), 3.06 (H-4'), 2.33 (3'-N(CH3)2/, 1.74 (H-22), 1.34 (H-6"), 1.16(H-21).

13C NMR (CDCl3) 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"), 74.5 (C-4"), 71.4 (C-4'), 70.3 (C- 2'), 66.3 (C-3), 61.5 (3"-OCH3), 59.7 (2"-OCH3), 46.2 (C-19), 42.7 (C-8), 42.1 (C-4), 41.5 /3'-N(CH3)2/, 39.8 (C-2), 21.7 (C-21), 14.0 (C-6"), 12.7 (C-22), 8.7 (C-18).

FAB (MH+) 785.

Claims (24)

1. Compounds represented by the general formula I, [image] indicated by that R stands for CHO or CH2N/CH2(C6H5)/2 R1 means H or C1-C3 acyl, R2 means OR6 and R6 means H or C1-C3 acyl, R3 means H or R2 and R3 together mean =O, R4 means OH, R5 is H or R4 and R5 together are =O. 2. The compound according to claim 1, characterized in that R has the meaning CH(OCH3)2, R1 has the meaning COCH3, R2 has the meaning OR6, where R6 is H, R3 and R5 are the same and have the meaning H, and R4 has the meaning OH . 3. The compound according to claim 1, characterized in that R has the meaning CH2N/CH2(C6H5)/2, R1 has the meaning COCH3, R2 has the meaning OR6, where R6 is H, R3 and R5 are the same and have the meaning H, and R4 has the meaning OH. 4. The compound according to claim 1, characterized in that R has the meaning CH(OCH3)2, R1 has the meaning COCH3, R2 has the meaning OR6, where R6 is COCH3, R3 and R5 are the same and have the meaning H, R4 and ma have the meaning OH . 5. The compound according to claim 1, characterized in that R has the meaning CH2N/CH2(C6H5)/2, R1 has the meaning COCH3, R2 has the meaning OR6, where R6 is COCH3, R3 and R5 are the same and have the meaning H, and R4 has the meaning OH. 6. The compound according to claim 1, characterized in that R has the meaning CH(OCH3)2, R1 has the meaning COCH3, R2 and R3 together mean =O, R4 has the meaning OH, and R5 has the meaning H. 7. The compound according to claim 1, characterized in that R has the meaning CH2N/CH2(C6H5)/2, R1 has the meaning COCH3, R2 and R3 together mean =O, R4 has the meaning OH, and R5 has the meaning H. 8. The compound according to claim 1, characterized in that R has the meaning CH(OCH3)2, R1 has the meaning COCH3, R2 has the meaning OR6, where R6 is COCH3, R3 has the meaning H, and R4 and R5 together mean =O. 9. The compound according to claim 1, characterized in that R has the meaning CH2N/CH2(C6H5)/2, R1 has the meaning COCH3, R2 has the meaning OR6, where R6 is COCH3, R3 has the meaning H, and R4 and R5 together mean = ON. 10. Compound according to claim 1, characterized in that R has the meaning CH(OCH3)2, R1 and R5 are the same and have the meaning H, R2 and R3 together mean =O, and R4 has the meaning OH. 11. The compound according to claim 1, characterized in that R has the meaning CH2N/CH2(C6H5)/2, R1 and R5 are the same and have the meaning H, R2 and R3 together mean = O, and R4 has the meaning OH. 12. The compound according to claim 1, characterized in that R has the meaning CH(OCH3)2, R1 and R3 are the same and have the meaning H, R2 has the meaning OR6, where R6 is COCH3, and R4 and R5 together mean =O. 13. The compound according to claim 1, characterized in that R has the meaning CH2N/CH2(C6H5)/2, R1 and R3 are the same and have the meaning H, R2 has the meaning OR6, where R6 is COCH3, and R4 and R5 together mean = O. 14. The compound according to claim 1, characterized in that R has the meaning CH(OCH3)2, R1, R3 and R5 are the same and have the meaning H, and R2 has the meaning OR6, where R6 is COCH3 and R4 has the meaning OH. 15. The compound according to claim 1, characterized in that R has the meaning CH2N/CH2(C6H5)/2, R1, R3 and R5 are the same and have the meaning H, R2 has the meaning OR6, where R6 is COCH3 and R4 has the meaning OH . 16. The compound according to claim 1, characterized in that R has the meaning CH(OCH3)2, R1 and R3 are the same and have the meaning H, R2 has the meaning OR6, where R6 is H, and R4 and R5 together mean =O. 17. The compound according to claim 1, characterized in that R has the meaning CH2N/CH2(C6H5)/2, R1 and R3 are the same and have the meaning H, R2 has the meaning OR6, where R6 is H, and R4 and R5 together mean = ON. 18. A compound according to claim 1, characterized in that R has the meaning CHO, R1 and R3 are the same and have the meaning H, R2 has the meaning OR6, where R6 is H, and R4 and R5 together mean =O. 19. Compound according to claim 1, characterized in that R has the meaning CHO, R1 has the meaning COCH3, R2 has the meaning OR6, where R6 is H, R3 and R5 are the same and have the meaning H, and R4 has the meaning OH. 20. Compound according to claim 1, characterized in that R has the meaning CHO, R1 has the meaning COCH3, R2 has the meaning OR6, where R6 is COCH3, R3 and R5 are the same and have the meaning H, and R4 has the meaning OH. 21. The compound according to claim 1, characterized in that R has the meaning CHO, R1 has the meaning COCH3, R2 and R3 together mean = O, R4 has the meaning OH, and R5 has the meaning H. 22. The compound according to claim 1, characterized in that R has the meaning CHO, R1, R3 and R5 are the same and have the meaning H, R2 has the meaning OR6, where R6 is COCH3 and R4 has the meaning OH. 23. The compound according to claim 1, characterized in that R has the meaning CHO, R1 and R5 are the same and have the meaning H, R2 and R3 together mean = O, and R4 has the meaning OH. 24. Process for the preparation of compounds of general formula I [image] where R means CHO, CH(OCH3)2 or CH2N/CH2(C6H5)/2, R1 means H or C1-C3 acyl, R2 means OR6 and R6 means H or C1-C3 acyl, R3 means H or R2 and R3 together mean = O, R4 means OH, R5 is H or R4 and R5 together are =O indicated by that 4'-demicarosyl-8a-aza-8a-homotylosin20-dimethylacetal of formula IIa and 4'-demicarosyl-20-deoxo-20-dibenzylamino-8a-aza-8a-homotylosin of formula IIb [image] undergo A/ O-acylation with anhydrides of C1-C3 carboxylic acids, primarily with acetic anhydride in methylene chloride, for 15 minutes to 1 hour, at room temperature, and the obtained compounds of formula I in which R has the meaning CH(OCH3)2 or CH2N /CH2(C6H5)/2, R1 has the meaning COCH3, R2 has the meaning OR6 where R6 means H, R3 and R5 are the same and have the meaning H, and R4 has the meaning OH, subject to choice A1/O-acylation with anhydrides of C1-C3 carboxylic acids, primarily with acetic anhydride in methylene chloride, in the presence of an organic base, primarily triethylamine and 4-dimethylaminopyridine as a catalyst, during 30 hours at room temperature, and the obtained compounds of the formula and in which R has the meaning CH(OCH3)2 or CH2N/CH2(C6H5)/2, R1 has the meaning COCH3, R2 has the meaning OR6 where R6 means COCH3, R3 and R5 are the same and have the meaning H, and R4 has the meaning OH, optionally subjected B/ oxidation reaction with N(3-dimethylamino-propyl)-N'ethyl carbodiimide hydrochloride in the presence of dimethylsulfoxide and pyridine trifluoroacetate as a catalyst, in an inert solvent, primarily methylene chloride, for 2-6 hours at a temperature of 10°C to room temperature, and the obtained compounds of formula I in which R has the meaning CH(OCH3)2 or CH2N/CH2(C6H5)/2, R1 has the meaning COCH3, R2 has the meaning OR6 where R6 means COCH3, R3 has the meaning H, and R4 and R5 together mean = Oh, subject to choice C/ methanolysis at room temperature, for 2 days, and the obtained compounds of formula I in which R has the meaning CH(OCH3)2 or CH2N/CH2(C6H5)/2, R1 and R3 are the same and have the meaning H, R2 has the meaning OR6 where R6 means COCH3, and R4 and R5 together mean = O, subject to choice C1/ to alkaline methanolysis in a mixture of methanol and 25% ammonia (4:1), at a temperature of 5°C to room temperature, during 20 to 60 hours, giving compounds of formula I in which R has the meaning CH(OCH3)2 or CH2N/CH2(C6H5)/2, R1 and R3 are the same and have the meaning H, R2 has the meaning OR6 where R6 means H, and R4 and R5 together mean = O; or the compound obtained according to process C1 of formula I in which R has the meaning CH(OCH3)2, R1 and R3 are the same and have the meaning H, R2 has the meaning OR6 where R6 means H, and R4 and R5 together mean = O, subject to choice D/ acetal hydrolysis in a mixture of acetonitrile and 0.1 N hydrochloric acid (1:1) for 2 hours at room temperature, giving the compound of formula I in which R has the meaning of the CHO group, R1 and R3 are the same and have the meaning H, R2 has the meaning OR 6 where R 6 means H, and R 4 and R 5 together mean = O; or compounds obtained according to process A of the formula I in which R has the meaning CH(OCH3)2 or CH2N/CH2(C6H5)/2, R1 has the meaning COCH3, R2 has the meaning OR6 where R6 means H, R3 and R5 are the same and have the meaning H, and R4 has the meaning OH, optionally subjected to oxidation in the manner described in B, and the obtained compounds of formula I in which R has the meaning CH(OCH3)2 or CH2N/CH2(C6H5)/2, R1 has the meaning COCH3, R2 and R3 together mean = O, R4 has the meaning OH, and R5 has the meaning H, optionally subjected to methanolysis in the manner described in C, giving compounds of formula I in which R has the meaning CH(OCH3)2 or CH2N/CH2(C6H5)/2, R1 and R5 are the same and have the meaning H, R2 and R3 together mean = O, and R4 has the meaning OH; or the compound obtained according to process B of the formula I in which R has the meaning of the CH(OCH3)2 group, R1 has the meaning COCH3, R2 and R3 together mean = O, R4 has the meaning OH, and R5 has the meaning H, optionally subjected to acetal hydrolysis in the manner described in D, and the resulting compound of formula I in which R has the meaning of the CHO group, R1 has the meaning COCH3, R2 and R3 together have the meaning = O, R4 has the meaning OH, and R5 has the meaning H, optionally subjected to methanolysis in the manner described in C, giving a compound of formula I in which R has the meaning of the CHO group, R1 and R5 are the same and have the meaning H, R2 and R3 together mean = O, and R4 has the meaning OH; or the compound obtained according to process A of formula I in which R has the meaning CH(OCH3)2, R1 has the meaning COCH3, R2 has the meaning OR6 where R6 means H, R3 and R5 are the same and have the meaning H, and R4 has the meaning OH, optionally subjected to acetal hydrolysis in the manner described in D, giving a compound of formula I in which R has the meaning CHO, R1 has the meaning COCH3, R2 has the meaning OR6 where R6 means H, R3 and R5 are the same and have the meaning H, and R4 has the meaning OH; or compounds obtained according to process A1 of formula I in which R has the meaning CH(OCH3)2 or CH2N/CH2(C6H5)/2, R1 has the meaning COCH3, R2 has the meaning OR6 where R6 means COCH3, R3 and R5 are the same and have the meaning H, and R4 has the meaning OH, optionally subjected to methanolysis in the manner described in C, giving compounds of formula I in which R is CH(OCH3)2 or CH2N/CH2(C6H5)/2, R1, R3 and R5 are the same and are H, R2 is OR6 where R6 is COCH3 and R4 is OH ; or the compound obtained according to process A1 of formula I in which R has the meaning CH(OCH3)2 R1 has the meaning COCH3, R2 has the meaning OR6 where R6 means COCH3, R3 and R5 are the same and have the meaning H, and R4 has the meaning OH, optionally subjected to acetal hydrolysis in the manner described in D, and the obtained compound of formula I in which R has the meaning CHO, R1 has the meaning COCH3, R2 has the meaning OR6 where R6 means COCH3, R3 and R5 are the same and have the meaning H, and R4 has the meaning OH, optionally subjected to methanolysis in the manner described in C, giving a compound of formula I in which R is CHO, R 1 , R 3 and R 5 are the same and are H, R 2 is OR 6 where R 6 is COCH 3 and R 4 is OH.