Title of Invention	3-DEOXY-DESMYCOSIN DERIVATIVES AND PROCESS FOR THEIR PREPARATION
Abstract	The present invention relates to derivatives of 3-deoxy desmycosin of formula (I), wherein, starting from triply protected desmycosin, there are performed an oxidation at C-3 in the first step and then, optionally, a hydrogenation of double bonds and an epoxidation followed by a reductive opening of the oxirane ring. The present invention also relates to derivatives of 3-deoxy-desmycosin of formula II, wherein in the first step triacetyl desmycosin is hydrogenated and then, via an intermediate mesylate, it is converted to a 2,3-didehydro derivative; or 2,3-didehydro-desmycosin is subjected to epoxidation reactions followed by a reductive opening of the oxirane ring.

Title of Invention

3-DEOXY-DESMYCOSIN DERIVATIVES AND PROCESS FOR THEIR PREPARATION

Abstract

The present invention relates to derivatives of 3-deoxy desmycosin of formula (I), wherein, starting from triply protected desmycosin, there are performed an oxidation at C-3 in the first step and then, optionally, a hydrogenation of double bonds and an epoxidation followed by a reductive opening of the oxirane ring. The present invention also relates to derivatives of 3-deoxy-desmycosin of formula II, wherein in the first step triacetyl desmycosin is hydrogenated and then, via an intermediate mesylate, it is converted to a 2,3-didehydro derivative; or 2,3-didehydro-desmycosin is subjected to epoxidation reactions followed by a reductive opening of the oxirane ring.

Full Text	NEW COMPOUNDS OF 3-DEOXY-DESMYCOSIN CLASS AND PROCESS FOR THE PREPARATION THEREOF Technical Field Intemationai Patent Classification: A 61 K 31/70, C 07 H 17/08 Technical Problem The present invention relates to new tylosin derivatives, new synthetic products of the macrolide class exhibiting antimicrobial activity. It particularly relates to 3-deoxy-3-oxo-desmycosin derivatives of the formula (I) wherein R represents CHO or CH(OCH3)2, R1 and R2 represent H or acetyl, R3 represents H or OH, R4 represents N(CH3)2 or N-O(CH3)2, the line represents a single or a double bond, the line represents or a double or a single bond, and the line represents a double or a single bond, and to derivatives of 3-deoxy-2,3-didehydro-desmycosin of the formula II wherein R represents CHO or CHCOCHB):. R1 represents H or OH. R2 represents N(CH3)2 or N-O(CH3)2, the line — represents a double or a single bond, the line represents or a single bond, and the line represents a double or a single bond, and to a process for the preparation thereof. Prior Art It is known that 13-hydroxy derivatives of tylosin have been prepared by a reductive opening of the oxirane ring (A. Narandja, SI 9700281). It is also known that 10-11,12,13-tetrahydro derivatives of tylosin have been prepared by catalytic hydrogenation of tylosin (A. Narandja, EP 287082 B3). It is also known that 3-deoxy-2,3-didehydro derivatives of tylosin (S.Kageyama, Bull. Chem. Jpn. 65, 3405,1992) as well as 3-deoxy-3-oxo derivatives of 6-0-methyl-erythromycin (A. Agouridas, J. Med. Chem. 41, 4080, 1998) have been prepared. According to the known prior art, however, neither 3-deoxy-3oxo-derivatives of tylosin class nor 3-deoxy-2,3-didehydro derivatives with exchanged left side of the molecule in C-10 to C-13 positions and processes for the preparation thereof have been described so far. Technical Solution It has been found that derivatives of 3-deoxy-3-oxo-desmycosin of the formula I wherein R represents CHO or CH(OCH3)2, R1 and R2 represent H or acetyl, R3 represents H or OH, R4 represents N(CH3)2 or N-O(CH3)2, the line ...... represents a single or a double bond, the line represents or a double or a single bond, and the line represents a double or a single bond, and 3-deoxy-2,3-didehydro-derivatives of the formula II wherein R represents CHO or CHCOCH3):, R1 represents H or OH, R2 represents N(CH3)2 or N-O(CH3)2, the line represents a double or a single bond, the line represents or a single bond, and the line represents a double or a single bond, can be prepared starting from a compound of the formula III wherein R represents H or SO2CH3 and the line represents a double or a single bond. 1 According to the present invention the compound of formula III, wherein R represents H and the line — represents a double bond, is subjected A/ to an oxidation reaction in a solution of methylene chloride in the presence of 15-28 equivalents of DMSO, 8-14 equivalents of N-(3-dimethylaminopropyl)-N'-ethyl carbodiimide hydrochloride and 8-14 equivalents of pyridine trifluoroacetate within 2-6 hours at a temperature of 10-25°C, whereupon the obtained compound of the formula I, wherein R represents CH(OCH3)2, R1 and R2 represent acetyl, R3 represents H, R4 represents N(CH3)2, the lines — and represent double bonds and the line represents a single bond, is optionally subjected B/ to a methanolysis at reflux temperature within 4-6 hours and the obtained compound of the formula I, wherein R represents CH(OCH3)2, R1 and R3 represent H, R" represents acetyl, R represents N(CH3)2, the lines— and represent double bonds and the line ^^'^^^ represents a single bond, is optionally subjected Bl/ to an alkaline methanolysis in a mixture of methanol and 25% NH4OH (2:1) at 5°C for a period of 48-60 hours, whereupon the obtained compound of the formula I, wherein R represents CH(OCH3)2, R1, R2 and R3 represent H, R4 represents N(CH3)2, the lines and represent double bonds and the line represents a single bond, is optionally subjected B2/ to a hydrolysis in a mixture of acetonitrile and 1% trifluoroacetic acid (2:3) within 2 hours at room temperature, giving a compound of the formula I, wherein R represents CHO, R, R2 and R3 represent H, R represents N(CH3)2, the lines and represent double bonds and the line represents a single bond, or optionally, a compound of the formula I, wherein R represents CH(OCH3)2, R1 and R2 represent acetyl, R3 represents H and R4 represents N(CH3)2, the lines and represent double bonds and the line represents a single bond, is subjected C/ to a catalytic hydrogenation reaction in the presence of 2-5% Pd/C (w/w) at room temperature within 5-8 hours at a hydrogen pressure of 0.3-0.5 MPa, whereupon the obtained compound of the formula I, wherein R represents CH(OCH3)2, R and R2 represent acetyl, R3 represents H, R4 represents N(CH3)2, and the lines , and represent single bonds, can be optionally subjected to methanolysis or alkaline methanolysis reactions in the manner described under B or Bl; or optionally, it is subjected D/ to an oxidation reaction in a methylene chloride solution in the presence of 3-6 equivalents of m-chloroperbenzoic acid within 6-10 hours at room temperature, giving a compound of the formula I, wherein R represents CH(OCH3)2, R1 and R2 represent acetyl, R3 represents H, R4 represents N-O(CH3)2, the line represents a double bond, the line represents — and the line ---- represents a single bond, or optionally, a compound of the formula I, wherein R represents CH(OCH3)2, R1 and R3 represent H, R2 represents acetyl, R represents N-(CH3)2, the lines - - - and represent double bonds and the line represents a single bond, is subjected to the oxidation reaction in the manner described under D, and the obtained compound of the formula I, wherein R represents CH(OCH3)2, R1 and R3 represent H, R2 represents acetyl, R4 represents N-O(CH3)2, the line — represents a double bond, the line represents and the line represents a single bond, is optionally subjected to the catalytic hydrogenation reaction in the manner described under C, giving a compound of the formula I, wherein R represents CH(OCH3)2, R1 and R3 represent H, R2 represents acetyl, R4 represents N(CH3)2, the line represents a single bond, the line represents and the line represents a single bond, is optionally subjected E/ to a reduction reaction with Zn-powder in a solution of EtOH and a 10% aqueous NH4OH solution (1:2) under maintaining the pH-value of 5.0-5.5, giving a compound of the formula I, wherein R represents CH(OCH3)2, R1 represents H, R2 represents acetyl, R3 represents OH, R4 represents N(CH3)2, the lines and represent single bonds and the line represents a double bond, or optionally, 1 ■) -i a compound of the formula I, wherein R represents CH(OCH3)2, R , R" and R represent H, R4 represents N(CH3)2, the lines and represent double bonds and the line represents a single bond, is subjected to the oxidation reaction in the manner described under D, and the obtained compound of the formula I, wherein R represents CH(OCH3)2, R1 R2 and R3 represent H, R4 represents N-O(CH3)2, the line - - - represents a double bond, the line represents and the line represents a single bond, is optionally subjected to the catalytic hydrogenation reaction in the manner described under C, giving a compound of the formula I, wherein R represents CH(OCH3)2, R1 , R2 and R3 represent H, R4 represents N(CH3)2, the line represents a single bond, the line represents and the line represents a single bond, or optionally, to the reduction with Zn-powder in the manner decribed under E, giving a compound of the formula I, wherein R represents CH(OCH3)2, R1 and R2 represent H, R3 represents OH, R4 represents N(CH3)25 the lines— and represent single bonds and the line represents a double bond. or optionally, a compound of the formula III, wherein R represents H and the line represents a double bond, is subjected to the catalytic hydrogenation reaction in the manner described under C and the obtained compound of the formula III, wherein R represents H and the line represents a single bond, is optionally subjected F/ to a mesylating reaction in a solution of pyridine under the addition of 3-5 equivalents of methanesulfochloride at 10°C within 3-5 hours and the obtained compound of the formula III, wherein R represents SO2CH3 and the line - - - represents a single bond, is subjected G/ to a reaction of elimination of mesylate in a mixture of methanol and 25% NH4OH (2:1) at room temperature within 5 hours and, subsequently, to the methanolysis in the manner described under Bl, and the obtained compound of the formula II, wherein R represents CH(OCH3)2, R1 represents H, R2 represents N(CH3)2, the lines , and represent single bonds, is subjected to the reaction of hydrolysis of acetal in the manner described under B2, or optionally, a compound of the formula II, wherein R represents CH(OCH3)2, R1 represents H, R2 represents N(CH3)2, the lines - - - and represent double bonds and the line represents a single bond, is subjected to the oxidation reaction in the manner describedunder D and the obtained compound of the formula II, wherein R represents CH(OCH3)2, R1 represents H, R2 represents N-O(CH3)2, the line represents a double bond, the line represents and the line represents a single bond, is optionally subjected to the reduction reaction in the manner described under E, giving a compound of the formula II, wherein R represents CH(OCH3)2. R represents OH, R2 represents N(CH3)2. the lines — and represent single bonds and the line represents a double bond. ■ •* According to the present invention the isolation of the products is performed by means of conventional extraction processes from alkaline aqueous solutions by the use of halogenated hydrocarbons such as methylene chloride, chloroform or tetrachloro-methane, followed by evaporation to a dry residue. The course of the reaction is followed by chromatography on a thin layer of silica gel (Merck 60 F254) in solvent systems methylene chloride-methanol-ammonium hydroxide 25% (90:9:1.5, system A), (90:9:0.5, system Al) or methylene chloride-acetone (8:2, system B) (7:3, system C). If appropriate, the separation of the reaction products and the purification of the products for the purpose of spectral analyses are performed on a silica gel column (Merck 60, 230-400 mesh/ASTM, or 60-230 mesh/ASTM in solvent systems A, B or C). The identification of the novel compounds is performed by UV and NMR spectroscopies and by mass analysis. The novel compounds show antibacterial activity, however, they can also be used as intermediates for the preparation of new derivatives. The present invention is illustrated but in no way limited by the following Examples. Preparation of 2',4-diacetyI-desmycosin 20-dimethylacetal Desmycosin 20-dimethylacetal (20 g, 24.4 mmol) was dissolved in methylene chloride (100 ml), acetanhydride (7.2 ml, 76.2 mmol) was added thereto and it was stirred at room temperature for 1 hour. The reaction mixture was poured into 400 ml of water, alkalized to a pH value of 8.5 and subsequently, after the removal of the organic layer, extracted once more with methylene chloride. The combined extracts were washed with a saturated NaHCO3 solution, dried and evaporated to a dry residue. Obtained: 19.6 g, 89.0%; Rf (A)0.68; Rf (B) 0.45; MH+902. Preparation of 2',4',4"-triacetyI-desmycosin 20-dimethylacetaI 2',4'-diacetyl-desmycosin 20-dimethylacetal (19.6 g, 21.7 mmol) was dissolved in methylene chloride (700 ml) and 4-(dimethylamino)pyridine (0.54 g, 3.7 mmol), triethylamine (27 ml) and acetanhydride (2.7 ml, 28.5 mmol) were added thereto. The reaction mixture was stirred at room temperature for 2 hours, poured into 1000 ml of water and, after the removal of the organic laver, it was extracted once more with methylene chloride. The combined extracts were dried and evaporated to a dry residue. Obtained: 19.5 g, 95.1%; Rf (A) 0.90; Rf (B) 0.60; MH+944. Preparation of 3-methansulfonyI-2',4',4"-triacetyl-desniycosin 20-dimethyIacetaI 2',4',4'-triacetyl-desmycosin 20-dimethylacetal (3 g, 3.18 mmol) was dissolved in pyridine (9.5 ml) and it was cooled to 10°C, whereupon methanesulfochloride (1.57 ml, 12.4 mmol) was gradually added thereto. The reaction solution was stirred for 3 hours at 10°C, whereupon it was poured into 250 ml of water, alkalized to a pH value of 9.2 and kept under stirring for 30 minutes. A thick white precipitate was separated by filtration and the still moist precipitate was dissolved in chloroform (60 ml) and washed with a saturated NaCl solution (120 ml). The extract was dried and evaporated to a dry residue. Obtained: 3.05 g, 94.1%; Rf (A) 0.95; Rf (B) 0.70; MH+ 1022. Preparation of 2,3-anhydro-desmycosin 20-dimethylacetal 3-methanesulfonyl-2',4',4"-triacetyl-desmycosin 20-dimethylacetal (3 g, 2.9 mmol) was dissolved in methanol (60 ml), 25% NH4OH (30 ml) was added thereto and it was stirred at room temperature for 3 hours. The reaction mixture was evaporated to 1/3 of its volume under reduced pressure, extracted with chloroform, dried and evaporated to a dry residue. The crude product was dissolved in methanol (160 ml) and heated at reflux temperature for 6 hours, whereupon methanol was evaporated and the product was dissolved in chloroform (150 ml), washed with a saturated NaHC03 solution and evaporated to a dry residue. Obtained: 2.22 g, 94.4%; Rf(A)0.50; MH+ 800. Example 1 3-deoxy-3-oxo-2',4',4"-triacetyl-desmycosin 20-dimethyIacetal (1) 2',4,4-triacetyl-desmycosin 20-dimethylacetal (10 g, 0.01 mmol) was dissolved in methylene chloride (230 ml), dimethylsulfoxide (16 ml, 0.22 mol) and, subsequently, N(3-dimethylaminopropyl)-N'-ethyl carbodiimide hydrochloride (20 g, 0.1 mol) were added thereto and the reaction mixture was cooled to 10°C. A solution of pyridine trifluoroacetate (20.2 g, 0.1 mol) in methylene chloride (115 ml) was added dropweise within 30 minutes. After 4 hours of stirring at room temperature the reaction solution was poured into 850 ml of water and the organic layer was separated and extracted once more with methylene chloride. The combined extracts were washed with a saturated NaCl solution and evaporated to a dry residue. Obtained: 9.73 g, 97.6%; Rf(A) 0.95, Rf(C) 0.65; MH+ 942; By chromatography on a silica gel column in the solvent system C, a product with the following characteristics demonstrating a product proportionated with its enol form (in proportion 1:1; determined according to the intensity of the characteristic signals) was obtained: 1H-NMR (CDCl3) 5 ppm: 12.04 (1H, s, 3-OH, enol, interchangeable with D2O), 7.14, 7.06 (1H, d, H-11), 6.25, 6,02 (1H, d, H-10), 5.82, 5.75 (1H, d, H-13), 4.89 (1H, dd, H-2'), 4.74 (1H, dd, H-4'), 4.72 (1H, s, H-2, enol), 4.65 (1H, d, H-1"), 4.44 (1H, dd, H-4"), 4.38 (1H, d, H-l'), 3.53 (3H, s, 3" -OMe), 3.47 (3H, s, T -OMe), 3.34 (3H, s, 20-OMe), 3.29 (3H, s, 20- OMe), 2.34 (6H, s, NMe2), 2.12 (3H, s, COMe), 2.06 (6H, s, 2xC0Me), 1.88(3H,s,H-22). 13C-NMR (CDCl3) 5 ppm: 205.5 (s, C-3, keto), 205.2, 203.9 (s, C-9), 180.2 (s, C-3, enol), 172.9, 166.6 (s, C-1), 170.4, 170.1, 169.6 (s,3x COMe, 147.6, 146.5 (d, C-11), 140.5, 139.0 (d, C-13), 137.6, 136.8 (s,C-12), 124.2, 119.6 (d, C-10), 88.9 (d, C-2, enol), 46.5 (t, C-2, keto), 20.9, 20.8, 20.6 (q, 3x COMe). Example 2 3-deoxy-3-oxo-4"-acetyl-desmycosin 20-dimethylacetal (2) Compound 1 (9 g, 9,6 mmol) was dissolved in methanol (180 ml) and heated at reflux temperature for 4 hours, whereupon the reaction solution was evaporated to dryness and the product was dissolved in chloroform (90 ml) and washed with a saturated NaHC03 solution. The extract was dried and evaporated to a dry residue. Obtained: 8.1 g, 98%; Rf (A) 0.45; MH+ 858. By chromatography on a silica gel column in the alkali solvent system A, the keto-enol proportion was shifted in favour of the keto form (3:1). 1H-NMR (DMSO-d6) 5 ppm: 12.00 (1H, s, 3-OH, interchangeable with D2O), 6.99, 6.94 (1H, d, H-11), 6.47 (1H, d, H-10), 5.80, 5.68 (1H, d, H-13), 4.75 (1H, s, H-2, enol), 4.64 (1H, d, H-1"), 4.41 (1H, dd, H-4"), 4.38 (1H, d, H-1'), 3.39 (3H, s, 3"-0Me), 3.34 (3H, s, 2"-0Me), 3.25 (3H, s, 20 - OMe), 3.22 (3H, s, 20-OMe), 2.40 (6H, s, NMe2), 2.08 (3H, s, COMe), 1.81, 1.79 (3H, s, H-22). 13C-NMR (CDCl3) 5 ppm: 205.6 (s, C-3, keto), 205.4, 203.9 (s, C-9), 180.1 (s, C-3, enol), 172.5, 166.8 (s, C-1), 170.4 (s, COMe), 147.6. 146.8 (D, CA 1), 140.5, 139.01 (d, €-13), 136.8. 134.3 (s,C-12), 124.3, 119.8 (d, C-10), 46.3 (t, C-2), 20.5 (q, COMe). Example 3 3-deoxy-3-oxo-desmycosin 20-dimethyIacetal (3) Compound 2 (3.2 g, 3.72 mmol) was dissolved in methanol (64 ml), 25% NH4OH (32 ml) was added and it was left to stand at 5°C for a period of 60 hours. The reaction solution was evaporated to an oily product, which was dissolved in chloroform (60 ml), washed with a saturated NaHCO3 solution and evaporated to a dry residue. Obtained: 2.25 g, 74.0%; Rf(A)0.38; MH+816. By chromatography on a silica gel column in the solvent system A, a product with the following characteristics was obtained: 1H-NMR (CDCl3) 5 ppm: 7.16, 7.08 (1H, d, H-11), 6.25, 6.02 (1H, d, H-10), 5.81, 5.74 (1H, d, H-13), 4.74 (1H, s, H-2, enol), 4.64 (1H, d, H-1"), 4.38 (1H, d, H-1'), 3.53 (3H, s, 3"-0Me), 3.47 (3H, s, 2" - OMe), 3.29 (3H, s, 20-OMe), 3.22, (3H, s, 20-OMe), 2.34 (6H, s, NMe2), 1.78 (3H, s, H-22). Example 4 3-deoxy-3-oxo-desmycosin (4) Compound 3 (1 g. 1.22 mmol) was dissolved in acetonitrile (10 ml) and 1% trifluoro- acetic acid (12 ml), stirred for 2 hours at room temperature, chloroform (7 ml) was added thereto and it was alkalized to a pH value of 8.5. The organic layer was separated, extracted once more with chloroform and the combined extracts were dried and evaporated to a dry residue. Obtained: 0.79 g, 84.0%; Rf(A)0.32; MH+ 770. By chromatography on a silica gel column in the solvent system A, a product with the characteristics of a keto form was isolated. 1H-NMR (CDCl3) 5 ppm: 9.72 (1H, s, H-20), 7.30 (1H, d, H-l I), 6.04 (1H, d, H-10), 5.95 (1H, d. H-13X 4.64 (1H, d, H-l"), 4.38 (1H, d, H-1'), 3.53 (3H, s, 3"-0Me), 3.47 (3H, s, 2"-0Me), 2.34 (6H, s, NMe.), 1.78(3H,s,H-22). Example 5 2',4',4"-triacetyl-10,1142,13-tetrahydro-desmycosin 20-dimethylacetal (5) 2',4',4"-triacetyl-desmycosin 20-dimethylacetal (6 g, 6.3 mmol) was dissolved in ethanol (250 ml), 3 g of 10% Pd/C (w/vv) were added thereto and it was hydrogenated for 7 hours at room temperature and at a hydrogen pressure of 0.5 MPa. After the completion of the reaction the catalyst was separated by filtration and ethanol was evaporated under reduced pressure to a dry residue. Obtained: 5.8 g, 96.3%; Rf(A)0.88; Rf(B)0.45; MH+948; (does not adsorb in UV spectrum). By chromatography on a silica gel column in the solvent system B, a product with the following characteristics was obtained: 1H-NMR (CDCl3) 5 ppm: 4.89 (1H, dd, H-2'), 4.74 (1H, dd, H-4'), 4.58 (1H, d, H- 1"), 4.44 (1H, dd, H-4"), 4.38 (1H, d, H-r), 3.53 (3H, s, 3"-0Me), 3.47 (3H, s, 2"-0Me), 3.29 (3H, s, 20-OMe), 3.22 , (3H, s, 20-OMe), 2.34 (6H, s, NMe2), 2.12 (3H, s, COMe), 2.06 (6H, s 2x COMe), 0.94 (3H, d, H-22). 13C-NMR(CDCl3)δpm: 214.8, (s. C-9), 172.0, (s, C-1), 170.0, 169.7, 169.1 (s, 3x COMe), 39.2 (t, C-13), 34.8 (t, C-10), 29.7 (d, C-12), 29.4 (t, C-11), 20.8, 20.7, 20.06 (q, 3x COMe). Example 6 3-deoxy-3-oxo-2',4',4"-triacetyl-10,ll,12,13-tetrahydro-desmycosin 20-dimethylacetal (6) Process A Compound 5 (5 g, 5.3 mmol) was dissolved in methylene chloride (120 ml), dimethylsulfoxide (8 ml, 0.11 mol) and, subsequently, N(3-dimethylaminopropyl)-N'-ethyl carbodiimide hydrochloride (10 g, 50 mmol) were added thereto and the reaction mixture was cooled to 10°C. A solution of pyridine trifluoroacetate (10.2 g, 50 mmol) in methylene chloride (60 ml) was added dropwise within 30 minutes. After 4 hours of stirring at room temperature the reaction solution was poured into 430 ml of water and the organic layer was separated and extracted once more with methylene chloride. The combined extracts were washed with a saturated NaCl solution and evaporated to a dry residue. Obtained: 4.75 g, 95.2%; Rf(A) 0.93, Rf (B) 0.60; MH+ 946; (does not adsorb in UV spectrum). By chromatography on a silica gel column in the solvent system B, a keto-enol product (proportion 3:1 in favour of the keto form) with the following characteristics was obtained: 13C-NMR (CDCl3) 5 ppm: 216.4, 215.1 (s, C-9), 205.9 (s, C-3, keto), 178.2 (s, C-3, enol), 172.4, 166.7 (s, C-1), 170.0, 169.7, 169.1 (s, 3x COMe), 48.0 (t, C-2, keto), 39.6 (t, C-13), 33.8 (t, C-10), 29.9 (d, C-12), 29.4 (t, C-11), 20.8, 20.7, 20.6 (q, 3x COMe). Example 7 3-deoxy-3-oxo-4"-acetyl-10,1142,13-tetrahydro-desmycosin 20-dimethylacetal (7) Process A Compound 6 (9 g, 9.5 mmol) was dissolved in methanol (180 ml) and heated at reflux temperature for 4 hours, whereupon the reaction mixture was evaporated to dryness and the product was dissolved in chloroform (90 ml) and washed with a saturated NaHCOs solution. The extract was dried and evaporated to a dry residue. Obtained: 7.7 g, 93.9%; Rf(A)0.42; MH+ 862; (does not adsorb in UV spectrum). By chromatography on a silica gel column in the solvent system A, a keto-enol product (proportion 3:1 in favour of the keto form) with the following characteristics was obtained: 13C-NMR (CDCl3) 5 ppm: 216.6, 215,1 (s, C-9), 205.9 (s, C-3, keto), 178.2 (s, C-3, enol), 172.4 , 166.7 (s, C-1), 169.7, (s, COMe), 48.0 (t, C-2, keto), 39.6 (t, C-13), 33.8 (t, C-10), 29.9 (d, C-12), 29.4 (t, C-11), 20.8, 20.7, 20.6 (q, 3x COMe). Process B Compound 2 (6 g, 6.97 mmol) was dissolved in ethanol (250 ml), 3 g of 10% Pd/C (w/w) were added and it was hydrogenated for 6 hours at room temperature and at a hydrogen pressure of 0.5 MPa, After the completion of the reaction the catalyst was separated by filtration and ethanol was evaporated at a reduced pressure to a dry residue. Obtained: 5.7 s, 95.0%. By chromatography on a silica gel column in the solvent system A, a product with the same characteristics as the product obtained by process A was obtained. Example 8 3-deoxy-3-oxo-10,l 1,12,13-tetrahydro-desmycosin 20-dimethyIacetal (8) Process A Compound 7 (3.0 g, 3.48 mmol) was dissolved in methanol (60 ml), 25% NH4OH (30 ml) was added thereto and it was left to stand at 5°C for a period of 60 hours. The reaction solution was evaporated and processed in the manner described in Example 3. Obtained: 2.08 g, 73.0%; Rf(A)0.35; MH+ 820. By chromatography on a silica gel column in the solvent system A, a product with the following characteristics was obtained: 1H-NMR (CDCl3) 5 ppm 4.58 (1H, d, H-1"), 4.38 (1H, d, H-l'), 3.53 (3H, s, 3". OMe), 3.47 (3H, s, 2" -OMe), 3.29 (3H, s, 20-OMe), 3.22, (3H, s, 20-OMe), 2.34 (6H, s, NMe2), 0.95 (3H, d, H-22). 13C-NMR (CDCl3) 6 ppm:215.8 (s, C-9), 206.7 (s, C-3), 166.7 (s, C-1), 45.8 (t, C- 2), 39.4 (t, C-13), 34.8 (t, C-10), 29.7 (d. C-12), 29.4 (t, C-11). Process B Compound 3 (6 g, 7.35 mmol) was dissolved in ethanol (250 ml), 3 g of 10% Pd/C (vv/w) were added thereto and it was hydrogenated for 7 hours at room temperature at hydrogen pressure of 0.5 MPa. After the completion of the reaction the catalyst was separated by filtration and ethanol was evaporated at a reduced pressure to a dry residue. Obtained: 5.8 s, 96.2%. By chromatography on a silica gel column in the solvent system Al, a product with the same characteristics as the product obtained by process A was obtained. Example 9 12,13-epoxy-3-deoxy-3-oxo-2',4'4"-triacetyI-desmycosin (3'N-oxide) 20-dimethylacetaI (9) Compound 1 (2 g, 2.12 mmol) was dissolved in methylene chloride (40 ml), 71% m-chloroperbenzoic acid (2.05 g, 8.4 mmol) was added and it was stirred at room temperature for 8 hours. The reaction mixture was poured into 80 ml of water, alkalized to a pH value of 8.6, stirred for 30 minutes and the organic layer was separated. Subsequently, it was extracted once more with methylene chloride. The combined extracts were dried and evaporated to a dry residue. Obtained: 1.91 g, 94.0%; Rf (A) 0.23; MH+ 974; UVymax238 nm, s 14597. By chromatography on a silica gel column in the solvent system A, a keto-enol product (proportion 3:1 in favour of the keto form) with the following characteristics was obtained: 1H-NMR (CDCl3) 5 ppm: 11.91 (1H, s, 3-OH, interchangeable with D2O), 6.57, 6.55 (1H, d, H-11), 6.43, 6.41 (1H, d, H-10), 4.91 (IH. dd, H- 2'), 4.78 (1H, dd, H-4'), 4.64 (1H, d, H-1"), 4.45 (1H, dd, H-4"), 4.13 (1H, d, H-l'X 3.59 (3H, s, 3" -OMe), 3,46 (6H, s, N-Me, 2" -OMe), 3.31 (3H, s, 20-OMe), 3.29, (3H, s, 20-OMe), 3.25 (3H, s, NMe), 2.12 (9H, s, 3x COMe), 1.44 (3H, s, H-22). 13C-NMR (CDCl3) 5 ppm: 205.7 (s, C-3, keto), 200.8 (s, C-9), 179.2 (s, C-3, enol), 175.3, 166.2 (s,C-l), 171.6, 170.3, 170.1 (s, 3x COMe) 150.3, 147.3 (d, C-11), 124.2, 123.3 (d, C-10), 62.9 (s, C-12),48.3(t,C-2). Example 10 12,13-epoxy-3-deoxy-3-oxo-4"-acetyl-desmycosin (3'N-oxide) 20-dimethylacetal (10) Compound 2 (3 g, 3.5 mmol) was dissolved in methylene chloride (60 ml), 71% m- chloroperbenzoic acid (3.35 g, 14.0 mmol) was added thereto and it was stirred at room temperaure for 8 hours. The product was isolated from the reaction solution as described in Example 9. Obtained: 2.64 g, 85%; Rf (A) 0.22; MH+ 890; UVλmax.238 nm, s 15297. By chromatography on a silica gel column in the solvent system A, a keto-enol product (proportion 3:1 in favour of the keto form) with the following characteristics was obtained: 1H-NMR (CDCl3) 5 ppm 11.91 (1H, s, 3-OH, interchangeable with D2O), 6.57, 6.55 (1H, d, H-11), 6.43, 6.41 (1H, d, H-10), 4.64 (1H, d, H-1"), 4.44 (1H, dd, H-4"), 4.42 (1H, d, H-1'), 3.59 (3H, s,3" -OMe), 3.46 (6H, s, N-Me, 2" -OMe), 3,31 (3H, s, 20-OMe), 3.29, (3H, s, 20-OMe), 3.25 (3H, s, NMe), 2.12. (3H, s, COMe), 1.51 (3H, s, H-22). 13C-NMR (CDCl3) 5 ppm: 205,7 (s, C-3, keto), 200.8 (s, C-9), 179.2 (s, C-3, enol), 175.3, 166.2 (s,C-l), I70.1.(s, COMe), 150.4, 147.3 (d, C-11), 124.2, 123.3 (d C-10), 62.9 (s, C-12X 48.3 (t, C-2). Example 11 12,13-epoxy-3-deoxy-3-oxo-desmycosin (3'N-oxide) 20-dimethylacetal (11) Compound 3 (2 g, 2.45 mmol) was dissolved in methylene chloride (40 ml). 71% m- chloroperbenzoic acid (2.37 g, 9.8 mmol) was added thereto, whereupon the reaction and isolation in the manner described in Example 9 were performed. Obtained: 1.64 g, 79%; Rf(A)0.22; MH+ 848. By chromatography on a silica gel column in the solvent system A, a keto-enol product (proportion 3:1 in favour of the keto form) with the following characteristics was obtained: 1H-NMR (CDCl3) 5 ppm 11.91 (1H, s, 3-OH, interchangeable with D2O), 6.56, 6.53 (1H, d, H-11), 6.41, 6.40 (1H, d, H-10), 4.64 (1H, d, H-1"), 4.42 (1H, d, H-1'), 3.59 (3H, s, 3;-0Me), 3.46 (6H, s, N-Me, 2" -OMe), 3.31 (3 H, s, 20-OMe), 3.29, (3H, s, 20-OMe), 3.25 (3H, s, NMe), 1.51 (3H, s, H-22). Example 12 10,ll-dihydro-12,13-epoxy-3-deoxy-3-oxo-desmycosin 20-dimethylacetaI (12) Compound 11 (1 g, 1.18 mmol) was dissolved in ethanol (50 ml), 0.33 g of 10% Pd/C (w/w) were added thereto, whereupon the hydrogenation in the manner described in Example 5 was performed. Obtained: 0.95 g, 96.9%; Rf (A) 0.50; MH+ 834; (does not adsorb in UV-spectrum). By chromatography on a silica gel column in the solvent system A, a product with the following characteristics was obtained: 1H-NMR (CDCl3) 5 ppm 4.64 (1H, d, H-1"), 4.38 (1H, d, H-T), 3.59 (3H, s, 3" - OMe). 3.46 (3H, s, T -OMe), 3.31 (3H, s, 20-OMe), 3.29, (3H, s, 20-OMe), 2.50 (6H, s, NMe.), 1.34 (3H, s, H-22). Example 13 10,13-dihydro-13-hidroxy-3-deoxy-3-oxo-4"-acetyl-desinycosin 20-diinethylacetal (13) Compound 10 (1 g. 1.12 mmol) was dissolved in ethanol (20 ml), a 10% aqueous NH4CI solution (40 ml) and, gradually, Zn-povvder (2 g) were added thereto. It was stirred at room temperature for 6 hours, whereupon Zn was removed by filtration and the reaction solution was evaporated to 1/2 of its volume, chloroform (20 ml) was added and it was alkalized to a pH value of 8.5. The organic layer was separated and another extraction with chloroform was performed. The combined extracts were dried and evaporated to a dry residue, Obtained:0.64g,65%; Rf(A)0.45; MH+ 876. By chromatography on a silica gel column in the solvent system A, a keto-enol product (1:1) with the following characteristics was obtained: 1H-NMR (CDCl3) 6 ppm 12.04 (1H, s, 3-OH, enol, interchangeable with D2O), 5.38, 5.30 (1H, t, H-11), 4.78 (1H, s, H-2, enol), 4.49 (1H, d, H-1"), 4.38 (la d, H-r), 4.30 (1H, dd, H-4"), 3.59 (3H, s, 3" -OMe), 3.46 (3H, s, 2"-0Me), 3.31 (3H, s, 20 -OMe), 3.29 (3H, s, 20 -OMe), 2.39 (6H, s, NMe2), 2.12 (3H, s, COMe), 1.49(3H,s,H-22). Example 14 2,3-anhydro-12,13-epoxy-desmycosin (3'N-oxide) 20-dimethylacetaI (14) 2,3-anhydro-desmycosin 20-dimethylacetal (4 g, 5.00 mmol) was dissolved in methylene chloride (80 ml), 71% w-chloroperbenzoic acid (4.84 g, 0.02 mol) was added and then the oxidation in the manner described in Example 9 was performed. . Obtained: 2.83 g, 68%; Rf(A)0.20; MH+ 832; UVλmax.238 nm, e 12247, By chromatography on a silica gel column in the solvent system A, a product with the following characteristics was obtained: 1H-NMR (CDCl3) 5 ppm 6.66 (1H, m, H-3), 6.53 (1H, d, H-1 i), 6.36 (1H, d, H-10), 5.75 (1H, d, H-2), 4.58 (1H, d, H-1"), 4.41 (1H, d, H-l'), 3.59 (3H, s, 3" -OMe), 3.46 (6H, s, N-Me, T -OMe), 3.31 (3H, s, 20-OMe), 3.29, (3H, s, 20-OMe), 3.25 (3H, s, N-Me), 1.50(3H, s, H-22). Example 15 2,3-anhydro-10,13-dihydro-13-hydroxy-desmycosin 20-dimethylacetal (15) Compound 14 (1 g, 1.20 mmol) was dissolved in ethanol (12 ml), a 10% NH4OH solution (24 ml) and, gradually, Zn-powder (2.5 g) were added thereto. After stirring for 8 hours at room temperature, the isolation in the manner described in Example 14 was performed. Obtained: 0.95 g, 96.9%; Rf (A) 0.48; MH+ 818; (does not adsorb in UV-spectrum). 1H-NMR (CDCl3) 5 ppm: 6.55 (1H, m, H-3), 5.61 (1H, t, H-11), 5.58 (1H, d, H-2), 4.61 (1H, d, H-1"), 4.32 (1H, d, H-T), 3.59 (3H, s, 3"-OMe), 3.46 (3H, s, T -OMe), 3.31 (3H, s, 20-OMe), 3.29, (3H, s, 20-OMe), 2.51 (6H, s, NMe.), 1.68 (3H, s, H-22). Example 16 3-methanesulfonyI-2',4',4"-triacetyl-10,1142,13-tetrahydro-desmycosin 20-dimethyIacetal (16) Compound 5 (3 g, 3.16 mmol) was dissolved in pyridine (9.15 ml) and cooled to 10°C, whereupon methanesulfochloride (1.57 ml, 12.4 mmol) was gradually added. The reaction solution was stirred for 3 hours at 10°C, poured into 250 ml of water. alkalized to a pH value of 9.2 and then left to stir for 30 minutes. A thick white precipitate was separated by filtration and the still moist precipitate was dissolved in chloroform (60 ml) and washed with a saturated NaCl solution (120 ml). The extract was dried and evaporated to a dry residue. Obtained: 2.95 g, 86.5%; Rf(C) 0.70; MH+ 1026; (does not adsorb in UV-spectrum), By chromatography on a silica gel column in the solvent system C, a product with the following characteristics was obtained: 1H-NMR (CDCl3) 5 ppm: 4.89 (1H, dd, H-2'), 4.76 (1H, dd, H-4'), 4.61 (1H, d, H- 1"), 4.43 (1H, dd, H-4"), 4.40 (1H, d, H-T), 3.53 (3H, s, 3" -OMe), 3.47 (3H, s, 2'-0Me), 3.29 (3H, s, 20-OMe), 3.22, (3H, s, 20-OMe), 3.10 (3H, s, SO2Me), 2.34 (6H, s, NMe.), 2.12. (3H, s, COMe), 2.06 (6H, s 2xC0Me), 0.96 (3H, d, H-22). Example 17 2,3-anhydro-10,l 1,12,13-tetrahydro-desmycosin 20-dimethylacetal (17) Compound 16 (2 g, 1.95 mmol) was dissolved in methanol (40 ml), a 25% NH4OH solution (20 ml) was added thereto and it was stirred at room temperature for 3 hours. The reactiom solution was evaporated at a reduced pressure to 1/3 of its volume, extracted with chloroform, dried and evaporated to a dry residue. The crude product was dissolved in methanol (80 ml) and it was heated at reflux temperature for 6 hours. Subsequently, methanol was evaporated and the product was dissolved in chloroform (40 ml), washed with a saturated NaHCO3 solution and evaporated to a dry residue. Obtained: 1.39 g, 89.0%; Rf (A) 0.45; MH+ 804. 1H-NMR (CDCl3) 5 ppm 6.82 (1H, m, H-3), 5.88 (1H, d, H-2), 4.61 (1H, d, H-1"), 4.41 (1H, d, H-r), 3.59 (3H, s, 3"-0Me), 3.46 (3H, s, T-OMe), 3.31 (3H, s, 20 OMe), 3.29 (3H, s, 20-OMe), 2.51 (6H, s, NMe2), 0.76 (3H, s, H-22). 13C-NMR (CDCl3) 5 ppm: 215.0 (s, C-9), 167.0 (s, C-1), 148.8 (d, C-3), 122.7 (d, C- 2). 40.9 (t, C-13), 31.5 (t, C-10), 30.1 (d, C-12), 28.3 (t, C-11), 20.4(q,C-22). Example 18 2,3-anhydro-10,l 1,12,13-tetrahydro-desmycosin (18) Compound 17 (1 g, 1.2 mmol) was dissolved in acetonitrile (10 ml) and in 1% trifluoroacetic acid (13 ml). The reaction solution was stirred for 2 hours at room temperature and then the isolation in the manner described in Example 4 was performed. Obtained: 0.80 g, 85.0%; Rf(A)0.35, MH+ 758. ' H-NMR (CDCl3) 6 ppm 9.74 (1H, s, H-20), 6.82 (1H, m, H-3), 5.88 (1H, d, H-2), 4.61 (1H, d, H-1"), 4.41 (1H, d, H-1'), 3.59 (3H, s, 3"- OMe), 3.46 (3H, s, 2"-0Me), 2.51 (6H, s, NMe:), 0.76 (3H, s, H-22). '^ C-NMR (CDCl3) 5 ppm: 215.2 (s, C-9), 202.0 (d, C-20), 167.2 (s, C-1), 148.8 (d, C- 3), 122.7 (d, C-2), 40.8 (t, C-13), 31.6 (t, C-10), 30.1 (d, C-12). 28.4 (t, C-11), 20.3 (q, C-22). Claims 1. Derivatives of 3-deoxy-3-oxo-desmycosin of the formula I wherein R represents CHO or CH(OCH3)2, R1 and R2 represent H or acetyl, R3 represents H or OH, R4 represents N(CH3)2 or N-O(CH3)2, the line represents a single or a double bond, the line represents or a double or a single bond, and the line represents a double or a single bond, and derivatives of 3-deoxy-2,3-didehydro-desmycosin of the formula II wherein R represents CHO or CH(OCH3)2, R1 represents H or OH, R2 represents NCCHs): or N-O(CH3)2. the line represents a double or a single bond, the line represents or a single bond, and the line represents a double or a single bond. 2. A compound according to claim 1 of the formula I, characterized in that R represents CH(OCH3)2, R1 and R2 represent acetyl R3 represents H, R represents N(CH3)2, the lines - - - and represent double bonds and the line represents a single bond. 3. A compound according to claim 1 of the formula I, characterized in that R represents CH(OCH3)2, R1 and R3 represent H, R2 represents acetyl, R4 represents N(CH3)2, the lines - - - and represent double bonds and the line represents a single bond. 4. A compound according to claim 1 of the formula I, characterized in that R represents CH(OCH3)2, R1 R2 and R3 represent H, R4 represents N(CH3)2, the lines — and represent double bonds and the line represents a single bond. 5. A compound according to claim 1 of the formula I, characterized in that R represents CHO, R1 R2 and R3 represent H, R4 represents N(CH3)2, the lines — and represent a double bond and the line represents a single bond. 6. A compound according to claim 1 of the formula I, characterized in that R represents CH(OCH3)2, R1 and R2 represent acetyl, R3 represents H, R4 represents N(CH3)2, and the lines , and represent single bonds. 7. A compound according to claim 1 of the formula I, characterized in that R represents CH(OCH3)2, R1 and R3 represent H, R2 represents acetyl, R4 represents N(CH3)2, and the lines — , and represent single bonds. 8. A compound according to claim 1 of the formula I, characterized in that R represents CH(OCH3)2, R1 R2 and R3 represent H, R4 represents NCCHs):, and the lines — , and represent single bonds. 9. A compound according to claim 1 of the formula I, characterized in that R represents CH(OCH3)2, R1 and R2 represent acetyl, R3 represents H, R4 represents N-O(CH3)2, the line — represents a double bond, the line represents and the line represents a single bond. 10. A compound according to claim 1 of the formula I, characterized in that R represents CH(OCH3)2, R1 and R3 represent H, R2 represents acetyl, R4 represents N-O(CH3)2, the line — represents a double bond, the line represents and the line 'VU' represents a single bond. 11. A compound according to claim 1 of the formula I, characterized in that R represents CH(OCH3)2, R1 R2 and R3 represent H, R4 represents N-O(CH3)2, the line represents a double bond, the line represents and the line represents a single bond. 12. A compound according to claim 1 of the formula I, characterized in that R represents CH(OCH3)2, R1R2 and R3 represent H, R4 represents N(CH3)2, the line - - - represents a single bond, the line represents and the line represents a single bond. 13. A compound according to claim 1 of the formula I, characterized in that R represents CH(OCH3)2, R1 and R3 represent H, R2 represents acetyl, R4 represents N(CH3)2, the line — represents a single bond, the line represents and the line represents a single bond. 14. A compound according to claim 1 of the formula I, characterized in that R A. represents CH(OCH3)2, R1 and R2 represent H, R 3 represents OH, R represents N(CH3)2, the lines — and represent single bonds and the line represents a double bond. 15. A compound according to claim 1 of the formula II, characterized in that R represents CH(OCH3)2, R1 represents H, R2 represents N-O(CH3)2, the line represents a double bond, the line represents and the line represents a single bond. 16. A compound according to claim 1 of the formula 11, characterized in that R represents CH(OCH3)2, R1 represents OH, R2 represents N(CH3)2, the lines and represent single bonds and the line represents a double bond. 17. A compound according to claim 1 of the formula II, characterized in that R represents CH(OCH3)2, R1 represents H, R2 represents N(CH3)2, and the lines - - -, and represent single bonds, 18. A compound according to claim 1 of the formula II, characterized in that R represents CHO, R1 represents H, R2 represents N(CH3)2, and the lines - - -, and represent single bonds. 19. Process for the preparation of derivatives of 3-deoxy-3-oxo-desmycosin of the formula I wherein R represents CHO or CH(OCH3)2, R1 and R2 represent H or acetyl, R3 represents H or OH, R4 represents N(CH3)2 or N-O(CH3)2, the line represents a double or a single bond, the line represents or a double or a single bond, and the line represents a double or a single bond, characterized in that a compound of the formula III wherein R represents H or SO2CH3 and the line - - - represents a double bond, is subjected Amended claims A/ to an oxidation reaction in a solution of methylene chloride in the presence of 15-28 equivalents of DMSO, 8-14 equivalents of N-(3-dimethylaminopropyl)-N'-ethyI carbodiimide hydrochloride and 8-14 equivalents of pyridine trifluoroacetate 'vithin 2-6 hours at a temperature of 10-25°C , whereupon the obtamed compound of formula I, wherein R represents CH(OCH3)2, R1 and R2 represent acetyl, R3 represents H, R'* represents N(CH3)2, the lines — and represent double bonds and the line represents a single bond, is optionally subjected B/ to methanolysis at reflux temperature within 4-6 hours and the obtained compound of formula I, wherein R represents CH(OCH3)2, R1 and R3 represent H, R2 represents acetyl, R4 represents N(CH3)2, the lines — and represent double bonds and the line represents a single bond, is optionally subjected Bl/ to an alkaline methanolysis in a mixture of methanol and 25% NH4OH (2:1) at 5°C within 48-60 hours, whereupon the obtained compound of formula I, wherein R represents CH(OCH3)2, R1 R2 and R3 represent H, R4 represents N(CH3)2, the lines — and represent double bonds and the line represents a single bond, is optionally subjected B2/ to a hydrolysis in a mixture of acetonitrile and 1% trifluoroacetic acid (2:3) within 2 hours at room temperature, giving a compound of formula I, wherein R represents CHO, R1 R2 and R3 represent H, R4 represents N(CH3)2, the lines and represent double bonds and the line represents a single bond, or optionally, a compound of the formula I, wherein R represents CH(OCH3)2, R1 and R2 represent acetyl, R3 represents H and R44^ represents N(CH3)2, the lines— and represent double bonds and the line represents a single bond, is subjected, Amended claims C/ to a catalytic hydrogenation reaction in the presence of 2-5% Pd/C (w/w) at room temperature within 5-8 hours at a hydrogen pressure of 0.3-0.5 MPa, whereupon the obtained compound of the formula I, wherein R represents CH(OCH3)2, R^ and R^ represent acetyl, R3 represents H, R4 represents N(CH3)2, and the lines , , and the line represent single bonds, can be optionally subjected to the methanolysis or alkaline methanolysis reactions in the manner described under BorBl; or optionally, it is subjected D/ to an oxidation reaction in a methylene chloride solution in the presence of 3-6 equivalents of m-chloroperbenzoic acid within 6-10 hours at room temperature, giving a compound of the formula I, wherein R represents CH(OCH3)2, R1 and R2 represent acetyl, R3 represents H, R4 represents N-O(CH3)2, the line - - - represents a double bond, the line represents and the line represents a single bond, or optionally, a compound of the formula I, wherein R represents CH(OCH3)2, R1 and R3 represent H, R2 represents acetyl, R4 represents N-(CH3)2, the lines - - - and represent double bonds and the line represents a single bond, is subjected to the oxidation reaction in the manner described under D, and the obtained compound of the formula I, wherein R represents CH(OCH3)2, R1 and R3 represent H, R2 represents acetyl, R4 represents N-O(CH3)2, the line — represents a double bond, the line represents and the line represents a single bond, is optionally subjected to the catalytic hydrogenation reaction in the manner described under C, giving a compound of the formula I, wherein R represents CH(OCH3)2, R1 and R3 represent H, Amended claims R2 represents acetyl, R4 represents N(CH3)2, the line — represents a single bond, the line represents and the line represents a single bond, is optionally subjected E/ to a reduction with Zn-powder in a solution of EtOH and 10% aqueous NH4OH solution (1:2) under maintaining the pH-value of 5.0-5.5, giving a compound of the formula I, wherein R represents CH(OCH3)2, R1 represents H, R2 represents acetyl, R3 represents OH, R4 represents N(CH3)2, the lines and represent single bonds and the line represents a double bond, or optionally, a compound of the formula I, wherein R represents CH(OCH3)2, R1 B2 and R3 represent H, R4 represents N(CH3)2, the lines — and represent double bonds and the line represents a single bond, is subjected to the oxidation reaction in the maimer described under D and the obtained compound of the formula I, wherein R represents CH(OCH3)2, R1 R2 and R3 represent H, R4 represents N-O(CH3)2, the line - - - represents a double bond, the line represents and the line represents a single bond, is optionally subjected to the catalytic hydrogenation reaction in the manner described under C, giving a compound of the formula I, wherein R represents CH(OCH3)2, R1 R2 and R3 represent H, R4 represents N(CH3)2, the line - - - represents a double bond, the line represents and the line represents a single bond, or optionally, to the reduction with Zn-powder in the manner decribed under E, giving a compound of the formula I, wherein R represents CH(OCH3)2, R1 and R2 represent H, R3 represents OH, R4 represents N(CH3)2, the lines— and represent single bonds and the line represents a double bond. Amended claims 20. Process for the preparation of derivatives of 3-deoxy-2,3"didehydro-desmycosin of the formula II wherein R represents CHO or CH(OCH3)2, R1 represents H or OH, R2 represents N(CH3)2 or N-O(CH3)2, the line — represents a double or a single bond, the line represents or a single bond, and the line represents a double or a single bond, characterized in that a compound of the formula III, wherein R represents H and the line - - - represents a double bond, is subjected to the catalytic hydrogenation reaction according to the process C of claim 19 and the obtained compound of the formula III, wherein R represents H and the line — represents a single bond, is optionally subjected F/ to a mesylating reaction in a solution of pyridine under the addition of 3-5 equivalents of methanesulfochloride at 10°C within 3-5 hours and the obtained compound of the formula III, wherein R represents SO2CH3, the line — represents a single bond, is subjected G/ to a reaction of elimination of mesylate in a mixture of methanol and 25% NH4OH (2:1) at room temperature within 5 hours and then to the methanolysis in the manner Amended claims described under Bl of claim 19, and the obtained compound of the formula II, wherein R represents CH(OCH3)2, R1 represents H, R2 represents N(CH3)2, and the lines , and represent single bonds, is subjected to the reaction of hydrolysis of acetal in the manner described under B2 of claim 19, or optionally, a compound of formula III, wherein R represents H, and the line - - - represents a double bond, is subjected to the mesylation reaction in the manner described under F, to the elimination reaction in the manner described under G and, subsequently, to the methanolysis reaction according to the process B of claim 19, and the obtained compound of the formula II, wherein R represents CH(OCH3)2, R' represents H, R^ represents N(CH3)2, the lines - - - and represent double bonds and the line represents a single bond, is subjected to the oxidation reaction in the manner described under D of claim 19, and the obtained compound of the formula II, wherein R represents CH(OCH3)2, R1 represents H, R2 represents N-O(CH3)2, the line represents a double bond, the line represents and the line represents a single bond, is optionally subjected to the reduction reaction with Zn powder in the manner according to process E of claim 19, giving a compound of the formula II, wherein R represents CH(OCH3)2, R^ represents OH, R2 represents N(CH3)2, the lines - - - and represent single bonds and the line represents a double bond. 21. Derivatives of 3-deoxy-3-oxo-desmycosin of the formula I substantially as hereinbefore described. 22. Process for the preparation of derivatives of 3-deoxy-2, 3-didehydro- desmycosin of the formula II substantially as hereinbefore described.

Full Text

NEW COMPOUNDS OF 3-DEOXY-DESMYCOSIN CLASS AND PROCESS FOR THE PREPARATION THEREOF
Technical Field
Intemationai Patent Classification: A 61 K 31/70, C 07 H 17/08
Technical Problem
The present invention relates to new tylosin derivatives, new synthetic products of the macrolide class exhibiting antimicrobial activity. It particularly relates to 3-deoxy-3-oxo-desmycosin derivatives of the formula (I)

wherein
R represents CHO or CH(OCH3)2, R1 and R2 represent H or acetyl, R3 represents H or OH, R4 represents N(CH3)2 or N-O(CH3)2, the line represents a single or a

double bond, the line represents or a double or a single bond, and the line
represents a double or a single bond, and

to derivatives of 3-deoxy-2,3-didehydro-desmycosin of the formula II

wherein
R represents CHO or CHCOCHB):. R1 represents H or OH. R2 represents N(CH3)2 or
N-O(CH3)2, the line — represents a double or a single bond, the line represents
or a single bond, and the line represents a double or a single bond,
and to a process for the preparation thereof.
Prior Art
It is known that 13-hydroxy derivatives of tylosin have been prepared by a reductive opening of the oxirane ring (A. Narandja, SI 9700281). It is also known that 10-11,12,13-tetrahydro derivatives of tylosin have been prepared by catalytic hydrogenation of tylosin (A. Narandja, EP 287082 B3). It is also known that 3-deoxy-2,3-didehydro derivatives of tylosin (S.Kageyama, Bull. Chem. Jpn. 65, 3405,1992) as well as 3-deoxy-3-oxo derivatives of 6-0-methyl-erythromycin (A. Agouridas, J. Med. Chem. 41, 4080, 1998) have been prepared.
According to the known prior art, however, neither 3-deoxy-3oxo-derivatives of tylosin class nor 3-deoxy-2,3-didehydro derivatives with exchanged left side of the

molecule in C-10 to C-13 positions and processes for the preparation thereof have been described so far.
Technical Solution
It has been found that derivatives of 3-deoxy-3-oxo-desmycosin of the formula I

wherein
R represents CHO or CH(OCH3)2, R1 and R2 represent H or acetyl, R3 represents H
or OH, R4 represents N(CH3)2 or N-O(CH3)2, the line ...... represents a single or a
double bond, the line represents or a double or a single bond, and the line
represents a double or a single bond, and
3-deoxy-2,3-didehydro-derivatives of the formula II

wherein
R represents CHO or CHCOCH3):, R1 represents H or OH, R2 represents N(CH3)2 or
N-O(CH3)2, the line represents a double or a single bond, the line represents
or a single bond, and the line represents a double or a single bond,
can be prepared starting from a compound of the formula III

wherein R represents H or SO2CH3 and the line represents a double or a single
bond.
1

According to the present invention the compound of formula III, wherein R represents H and the line — represents a double bond, is subjected
A/ to an oxidation reaction in a solution of methylene chloride in the presence of 15-28 equivalents of DMSO, 8-14 equivalents of N-(3-dimethylaminopropyl)-N'-ethyl carbodiimide hydrochloride and 8-14 equivalents of pyridine trifluoroacetate within 2-6 hours at a temperature of 10-25°C, whereupon the obtained compound of the formula I, wherein R represents CH(OCH3)2, R1 and R2 represent acetyl, R3 represents
H, R4 represents N(CH3)2, the lines — and represent double bonds and the line
represents a single bond, is optionally subjected
B/ to a methanolysis at reflux temperature within 4-6 hours and the obtained compound of the formula I, wherein R represents CH(OCH3)2, R1 and R3 represent H,
R" represents acetyl, R represents N(CH3)2, the lines— and represent double
bonds and the line ^^'^^^ represents a single bond,
is optionally subjected
Bl/ to an alkaline methanolysis in a mixture of methanol and 25% NH4OH (2:1) at
5°C for a period of 48-60 hours, whereupon the obtained compound of the formula I,
wherein R represents CH(OCH3)2, R1, R2 and R3 represent H, R4 represents N(CH3)2,
the lines and represent double bonds and the line represents a single
bond,
is optionally subjected
B2/ to a hydrolysis in a mixture of acetonitrile and 1% trifluoroacetic acid (2:3) within
2 hours at room temperature, giving a compound of the formula I, wherein R
represents CHO, R, R2 and R3 represent H, R represents N(CH3)2, the lines
and represent double bonds and the line represents a single bond,
or optionally,
a compound of the formula I, wherein R represents CH(OCH3)2, R1 and R2 represent
acetyl, R3 represents H and R4 represents N(CH3)2, the lines and represent
double bonds and the line represents a single bond,

is subjected
C/ to a catalytic hydrogenation reaction in the presence of 2-5% Pd/C (w/w) at room temperature within 5-8 hours at a hydrogen pressure of 0.3-0.5 MPa, whereupon the obtained compound of the formula I, wherein R represents CH(OCH3)2, R and R2
represent acetyl, R3 represents H, R4 represents N(CH3)2, and the lines , and
represent single bonds, can be optionally subjected
to methanolysis or alkaline methanolysis reactions in the manner described under B or Bl;
or optionally, it is subjected
D/ to an oxidation reaction in a methylene chloride solution in the presence of 3-6
equivalents of m-chloroperbenzoic acid within 6-10 hours at room temperature, giving
a compound of the formula I, wherein R represents CH(OCH3)2, R1 and R2 represent
acetyl, R3 represents H, R4 represents N-O(CH3)2, the line represents a double
bond, the line represents — and the line ---- represents a single bond,
or optionally,
a compound of the formula I, wherein R represents CH(OCH3)2, R1 and R3 represent
H, R2 represents acetyl, R represents N-(CH3)2, the lines - - - and represent
double bonds and the line represents a single bond, is subjected to the
oxidation reaction in the manner described under D, and the obtained compound of the
formula I, wherein R represents CH(OCH3)2, R1 and R3 represent H, R2 represents
acetyl, R4 represents N-O(CH3)2, the line — represents a double bond, the line
represents and the line represents a single bond,
is optionally subjected
to the catalytic hydrogenation reaction in the manner described under C, giving a
compound of the formula I, wherein R represents CH(OCH3)2, R1 and R3 represent H,

R2 represents acetyl, R4 represents N(CH3)2, the line represents a single bond,
the line represents and the line represents a single bond,
is optionally subjected
E/ to a reduction reaction with Zn-powder in a solution of EtOH and a 10% aqueous NH4OH solution (1:2) under maintaining the pH-value of 5.0-5.5, giving a compound of the formula I, wherein R represents CH(OCH3)2, R1 represents H, R2 represents
acetyl, R3 represents OH, R4 represents N(CH3)2, the lines and represent
single bonds and the line represents a double bond,
or optionally,
1 ■) -i
a compound of the formula I, wherein R represents CH(OCH3)2, R , R" and R
represent H, R4 represents N(CH3)2, the lines and represent double bonds
and the line represents a single bond, is subjected to the oxidation reaction in
the manner described under D, and the obtained compound of the formula I, wherein R represents CH(OCH3)2, R1 R2 and R3 represent H, R4 represents N-O(CH3)2, the
line - - - represents a double bond, the line represents and the line
represents a single bond,
is optionally subjected
to the catalytic hydrogenation reaction in the manner described under C, giving a
compound of the formula I, wherein R represents CH(OCH3)2, R1 , R2 and R3 represent
H, R4 represents N(CH3)2, the line represents a single bond, the line
represents and the line represents a single bond,
or optionally,
to the reduction with Zn-powder in the manner decribed under E, giving a compound
of the formula I, wherein R represents CH(OCH3)2, R1 and R2 represent H, R3
represents OH, R4 represents N(CH3)25 the lines— and represent single bonds
and the line represents a double bond.

or optionally,
a compound of the formula III, wherein R represents H and the line represents a
double bond, is subjected to the catalytic hydrogenation reaction in the manner
described under C and the obtained compound of the formula III, wherein R represents
H and the line represents a single bond,
is optionally subjected
F/ to a mesylating reaction in a solution of pyridine under the addition of 3-5
equivalents of methanesulfochloride at 10°C within 3-5 hours and the obtained
compound of the formula III, wherein R represents SO2CH3 and the line - - -
represents a single bond, is subjected
G/ to a reaction of elimination of mesylate in a mixture of methanol and 25% NH4OH
(2:1) at room temperature within 5 hours and, subsequently, to the methanolysis in the
manner described under Bl, and the obtained compound of the formula II, wherein R
represents CH(OCH3)2, R1 represents H, R2 represents N(CH3)2, the lines ,
and represent single bonds, is subjected to the reaction of hydrolysis of acetal
in the manner described under B2,
or optionally,
a compound of the formula II, wherein R represents CH(OCH3)2, R1 represents H, R2
represents N(CH3)2, the lines - - - and represent double bonds and the line
represents a single bond, is subjected to the oxidation reaction in the manner
describedunder D and the obtained compound of the formula II, wherein R represents
CH(OCH3)2, R1 represents H, R2 represents N-O(CH3)2, the line represents a
double bond, the line represents and the line represents a single
bond,
is optionally subjected

to the reduction reaction in the manner described under E, giving a compound of the formula II, wherein R represents CH(OCH3)2. R represents OH, R2 represents
N(CH3)2. the lines — and represent single bonds and the line represents
a double bond.
■ •*
According to the present invention the isolation of the products is performed by means of conventional extraction processes from alkaline aqueous solutions by the use of halogenated hydrocarbons such as methylene chloride, chloroform or tetrachloro-methane, followed by evaporation to a dry residue.
The course of the reaction is followed by chromatography on a thin layer of silica gel (Merck 60 F254) in solvent systems methylene chloride-methanol-ammonium hydroxide 25% (90:9:1.5, system A), (90:9:0.5, system Al) or methylene chloride-acetone (8:2, system B) (7:3, system C). If appropriate, the separation of the reaction products and the purification of the products for the purpose of spectral analyses are performed on a silica gel column (Merck 60, 230-400 mesh/ASTM, or 60-230 mesh/ASTM in solvent systems A, B or C). The identification of the novel compounds is performed by UV and NMR spectroscopies and by mass analysis.
The novel compounds show antibacterial activity, however, they can also be used as intermediates for the preparation of new derivatives.
The present invention is illustrated but in no way limited by the following Examples.
Preparation of 2',4-diacetyI-desmycosin 20-dimethylacetal
Desmycosin 20-dimethylacetal (20 g, 24.4 mmol) was dissolved in methylene chloride (100 ml), acetanhydride (7.2 ml, 76.2 mmol) was added thereto and it was stirred at room temperature for 1 hour. The reaction mixture was poured into 400 ml of water, alkalized to a pH value of 8.5 and subsequently, after the removal of the organic layer,

extracted once more with methylene chloride. The combined extracts were washed with a saturated NaHCO3 solution, dried and evaporated to a dry residue. Obtained: 19.6 g, 89.0%; Rf (A)0.68; Rf (B) 0.45; MH+902.
Preparation of 2',4',4"-triacetyI-desmycosin 20-dimethylacetaI
2',4'-diacetyl-desmycosin 20-dimethylacetal (19.6 g, 21.7 mmol) was dissolved in methylene chloride (700 ml) and 4-(dimethylamino)pyridine (0.54 g, 3.7 mmol), triethylamine (27 ml) and acetanhydride (2.7 ml, 28.5 mmol) were added thereto. The reaction mixture was stirred at room temperature for 2 hours, poured into 1000 ml of water and, after the removal of the organic laver, it was extracted once more with methylene chloride. The combined extracts were dried and evaporated to a dry residue. Obtained: 19.5 g, 95.1%; Rf (A) 0.90; Rf (B) 0.60; MH+944.
Preparation of 3-methansulfonyI-2',4',4"-triacetyl-desniycosin 20-dimethyIacetaI
2',4',4'-triacetyl-desmycosin 20-dimethylacetal (3 g, 3.18 mmol) was dissolved in pyridine (9.5 ml) and it was cooled to 10°C, whereupon methanesulfochloride (1.57 ml, 12.4 mmol) was gradually added thereto. The reaction solution was stirred for 3 hours at 10°C, whereupon it was poured into 250 ml of water, alkalized to a pH value of 9.2 and kept under stirring for 30 minutes. A thick white precipitate was separated by filtration and the still moist precipitate was dissolved in chloroform (60 ml) and washed with a saturated NaCl solution (120 ml). The extract was dried and evaporated to a dry residue. Obtained: 3.05 g, 94.1%; Rf (A) 0.95; Rf (B) 0.70; MH+ 1022.
Preparation of 2,3-anhydro-desmycosin 20-dimethylacetal
3-methanesulfonyl-2',4',4"-triacetyl-desmycosin 20-dimethylacetal (3 g, 2.9 mmol) was dissolved in methanol (60 ml), 25% NH4OH (30 ml) was added thereto and it was stirred at room temperature for 3 hours. The reaction mixture was evaporated to

1/3 of its volume under reduced pressure, extracted with chloroform, dried and evaporated to a dry residue. The crude product was dissolved in methanol (160 ml) and heated at reflux temperature for 6 hours, whereupon methanol was evaporated and the product was dissolved in chloroform (150 ml), washed with a saturated NaHC03 solution and evaporated to a dry residue. Obtained: 2.22 g, 94.4%; Rf(A)0.50; MH+ 800.
Example 1
3-deoxy-3-oxo-2',4',4"-triacetyl-desmycosin 20-dimethyIacetal (1)
2',4,4-triacetyl-desmycosin 20-dimethylacetal (10 g, 0.01 mmol) was dissolved in methylene chloride (230 ml), dimethylsulfoxide (16 ml, 0.22 mol) and, subsequently, N(3-dimethylaminopropyl)-N'-ethyl carbodiimide hydrochloride (20 g, 0.1 mol) were added thereto and the reaction mixture was cooled to 10°C. A solution of pyridine trifluoroacetate (20.2 g, 0.1 mol) in methylene chloride (115 ml) was added dropweise within 30 minutes. After 4 hours of stirring at room temperature the reaction solution was poured into 850 ml of water and the organic layer was separated and extracted once more with methylene chloride. The combined extracts were washed with a saturated NaCl solution and evaporated to a dry residue. Obtained: 9.73 g, 97.6%; Rf(A) 0.95, Rf(C) 0.65; MH+ 942;

By chromatography on a silica gel column in the solvent system C, a product with the
following characteristics demonstrating a product proportionated with its enol form (in
proportion 1:1; determined according to the intensity of the characteristic signals) was
obtained:
1H-NMR (CDCl3) 5 ppm: 12.04 (1H, s, 3-OH, enol, interchangeable with D2O),
7.14, 7.06 (1H, d, H-11), 6.25, 6,02 (1H, d, H-10), 5.82, 5.75 (1H, d, H-13), 4.89 (1H, dd, H-2'), 4.74 (1H, dd, H-4'), 4.72 (1H, s, H-2, enol), 4.65 (1H, d, H-1"), 4.44 (1H, dd, H-4"), 4.38 (1H, d, H-l'), 3.53 (3H, s, 3" -OMe), 3.47 (3H, s, T -OMe), 3.34 (3H, s, 20-OMe), 3.29 (3H, s, 20-

OMe), 2.34 (6H, s, NMe2), 2.12 (3H, s, COMe), 2.06 (6H, s, 2xC0Me), 1.88(3H,s,H-22). 13C-NMR (CDCl3) 5 ppm: 205.5 (s, C-3, keto), 205.2, 203.9 (s, C-9), 180.2 (s, C-3,
enol), 172.9, 166.6 (s, C-1), 170.4, 170.1, 169.6 (s,3x COMe, 147.6, 146.5 (d, C-11), 140.5, 139.0 (d, C-13), 137.6, 136.8 (s,C-12), 124.2, 119.6 (d, C-10), 88.9 (d, C-2, enol), 46.5 (t, C-2, keto), 20.9, 20.8, 20.6 (q, 3x COMe).
Example 2
3-deoxy-3-oxo-4"-acetyl-desmycosin 20-dimethylacetal (2)
Compound 1 (9 g, 9,6 mmol) was dissolved in methanol (180 ml) and heated at reflux temperature for 4 hours, whereupon the reaction solution was evaporated to dryness and the product was dissolved in chloroform (90 ml) and washed with a saturated NaHC03 solution. The extract was dried and evaporated to a dry residue. Obtained: 8.1 g, 98%; Rf (A) 0.45; MH+ 858.
By chromatography on a silica gel column in the alkali solvent system A, the keto-enol proportion was shifted in favour of the keto form (3:1).
1H-NMR (DMSO-d6) 5 ppm: 12.00 (1H, s, 3-OH, interchangeable with D2O),
6.99, 6.94 (1H, d, H-11), 6.47 (1H, d, H-10), 5.80, 5.68 (1H, d, H-13), 4.75 (1H, s, H-2, enol), 4.64 (1H, d, H-1"), 4.41 (1H, dd, H-4"), 4.38 (1H, d, H-1'), 3.39 (3H, s, 3"-0Me), 3.34 (3H, s, 2"-0Me), 3.25 (3H, s, 20 - OMe), 3.22 (3H, s, 20-OMe), 2.40 (6H, s, NMe2), 2.08 (3H, s, COMe), 1.81, 1.79 (3H, s, H-22).
13C-NMR (CDCl3) 5 ppm: 205.6 (s, C-3, keto), 205.4, 203.9 (s, C-9), 180.1 (s,
C-3, enol), 172.5, 166.8 (s, C-1), 170.4 (s, COMe),

147.6. 146.8 (D, CA 1), 140.5, 139.01 (d, €-13), 136.8. 134.3 (s,C-12), 124.3, 119.8 (d, C-10), 46.3 (t, C-2), 20.5 (q, COMe).
Example 3
3-deoxy-3-oxo-desmycosin 20-dimethyIacetal (3)
Compound 2 (3.2 g, 3.72 mmol) was dissolved in methanol (64 ml), 25% NH4OH (32 ml) was added and it was left to stand at 5°C for a period of 60 hours. The reaction solution was evaporated to an oily product, which was dissolved in chloroform (60 ml), washed with a saturated NaHCO3 solution and evaporated to a dry residue. Obtained: 2.25 g, 74.0%; Rf(A)0.38; MH+816.
By chromatography on a silica gel column in the solvent system A, a product with the following characteristics was obtained:
1H-NMR (CDCl3) 5 ppm: 7.16, 7.08 (1H, d, H-11), 6.25, 6.02 (1H, d, H-10), 5.81,
5.74 (1H, d, H-13), 4.74 (1H, s, H-2, enol), 4.64 (1H, d, H-1"), 4.38 (1H, d, H-1'), 3.53 (3H, s, 3"-0Me), 3.47 (3H, s, 2" - OMe), 3.29 (3H, s, 20-OMe), 3.22, (3H, s, 20-OMe), 2.34 (6H, s, NMe2), 1.78 (3H, s, H-22).
Example 4 3-deoxy-3-oxo-desmycosin (4)
Compound 3 (1 g. 1.22 mmol) was dissolved in acetonitrile (10 ml) and 1% trifluoro-
acetic acid (12 ml), stirred for 2 hours at room temperature, chloroform (7 ml) was
added thereto and it was alkalized to a pH value of 8.5. The organic layer was
separated, extracted once more with chloroform and the combined extracts were dried
and evaporated to a dry residue.
Obtained: 0.79 g, 84.0%; Rf(A)0.32; MH+ 770.
By chromatography on a silica gel column in the solvent system A, a product with the
characteristics of a keto form was isolated.

1H-NMR (CDCl3) 5 ppm: 9.72 (1H, s, H-20), 7.30 (1H, d, H-l I), 6.04 (1H, d, H-10),
5.95 (1H, d. H-13X 4.64 (1H, d, H-l"), 4.38 (1H, d, H-1'), 3.53 (3H, s, 3"-0Me), 3.47 (3H, s, 2"-0Me), 2.34 (6H, s, NMe.), 1.78(3H,s,H-22).
Example 5
2',4',4"-triacetyl-10,1142,13-tetrahydro-desmycosin 20-dimethylacetal (5)
2',4',4"-triacetyl-desmycosin 20-dimethylacetal (6 g, 6.3 mmol) was dissolved in
ethanol (250 ml), 3 g of 10% Pd/C (w/vv) were added thereto and it was hydrogenated
for 7 hours at room temperature and at a hydrogen pressure of 0.5 MPa. After the
completion of the reaction the catalyst was separated by filtration and ethanol was
evaporated under reduced pressure to a dry residue.
Obtained: 5.8 g, 96.3%; Rf(A)0.88; Rf(B)0.45; MH+948;
(does not adsorb in UV spectrum).
By chromatography on a silica gel column in the solvent system B, a product with the
following characteristics was obtained:
1H-NMR (CDCl3) 5 ppm: 4.89 (1H, dd, H-2'), 4.74 (1H, dd, H-4'), 4.58 (1H, d, H-
1"), 4.44 (1H, dd, H-4"), 4.38 (1H, d, H-r), 3.53 (3H, s, 3"-0Me), 3.47 (3H, s, 2"-0Me), 3.29 (3H, s, 20-OMe), 3.22 , (3H, s, 20-OMe), 2.34 (6H, s, NMe2), 2.12 (3H, s, COMe), 2.06 (6H, s 2x COMe), 0.94 (3H, d, H-22).
13C-NMR(CDCl3)δpm: 214.8, (s. C-9), 172.0, (s, C-1), 170.0, 169.7, 169.1 (s, 3x
COMe), 39.2 (t, C-13), 34.8 (t, C-10), 29.7 (d, C-12), 29.4 (t, C-11), 20.8, 20.7, 20.06 (q, 3x COMe).
Example 6
3-deoxy-3-oxo-2',4',4"-triacetyl-10,ll,12,13-tetrahydro-desmycosin 20-dimethylacetal (6)
Process A

Compound 5 (5 g, 5.3 mmol) was dissolved in methylene chloride (120 ml), dimethylsulfoxide (8 ml, 0.11 mol) and, subsequently, N(3-dimethylaminopropyl)-N'-ethyl carbodiimide hydrochloride (10 g, 50 mmol) were added thereto and the reaction mixture was cooled to 10°C. A solution of pyridine trifluoroacetate (10.2 g, 50 mmol) in methylene chloride (60 ml) was added dropwise within 30 minutes. After 4 hours of stirring at room temperature the reaction solution was poured into 430 ml of water and the organic layer was separated and extracted once more with methylene chloride. The combined extracts were washed with a saturated NaCl solution and evaporated to a dry residue.
Obtained: 4.75 g, 95.2%; Rf(A) 0.93, Rf (B) 0.60; MH+ 946; (does not adsorb in UV spectrum).
By chromatography on a silica gel column in the solvent system B, a keto-enol product (proportion 3:1 in favour of the keto form) with the following characteristics was obtained:
13C-NMR (CDCl3) 5 ppm: 216.4, 215.1 (s, C-9), 205.9 (s, C-3, keto), 178.2 (s, C-3,
enol), 172.4, 166.7 (s, C-1), 170.0, 169.7, 169.1 (s, 3x COMe), 48.0 (t, C-2, keto), 39.6 (t, C-13), 33.8 (t, C-10), 29.9 (d, C-12), 29.4 (t, C-11), 20.8, 20.7, 20.6 (q, 3x COMe).
Example 7
3-deoxy-3-oxo-4"-acetyl-10,1142,13-tetrahydro-desmycosin 20-dimethylacetal
(7)
Process A
Compound 6 (9 g, 9.5 mmol) was dissolved in methanol (180 ml) and heated at reflux
temperature for 4 hours, whereupon the reaction mixture was evaporated to dryness
and the product was dissolved in chloroform (90 ml) and washed with a saturated
NaHCOs solution. The extract was dried and evaporated to a dry residue.
Obtained: 7.7 g, 93.9%; Rf(A)0.42; MH+ 862;
(does not adsorb in UV spectrum).

By chromatography on a silica gel column in the solvent system A, a keto-enol
product (proportion 3:1 in favour of the keto form) with the following characteristics
was obtained:
13C-NMR (CDCl3) 5 ppm: 216.6, 215,1 (s, C-9), 205.9 (s, C-3, keto), 178.2 (s, C-3,
enol), 172.4 , 166.7 (s, C-1), 169.7, (s, COMe), 48.0 (t, C-2, keto), 39.6 (t, C-13), 33.8 (t, C-10), 29.9 (d, C-12), 29.4 (t, C-11), 20.8, 20.7, 20.6 (q, 3x COMe).
Process B
Compound 2 (6 g, 6.97 mmol) was dissolved in ethanol (250 ml), 3 g of 10% Pd/C
(w/w) were added and it was hydrogenated for 6 hours at room temperature and at a
hydrogen pressure of 0.5 MPa, After the completion of the reaction the catalyst was
separated by filtration and ethanol was evaporated at a reduced pressure to a dry
residue.
Obtained: 5.7 s, 95.0%.
By chromatography on a silica gel column in the solvent system A, a product with the
same characteristics as the product obtained by process A was obtained.
Example 8
3-deoxy-3-oxo-10,l 1,12,13-tetrahydro-desmycosin 20-dimethyIacetal (8)
Process A
Compound 7 (3.0 g, 3.48 mmol) was dissolved in methanol (60 ml), 25% NH4OH (30
ml) was added thereto and it was left to stand at 5°C for a period of 60 hours. The
reaction solution was evaporated and processed in the manner described in Example 3.
Obtained: 2.08 g, 73.0%; Rf(A)0.35; MH+ 820.
By chromatography on a silica gel column in the solvent system A, a product with the
following characteristics was obtained:
1H-NMR (CDCl3) 5 ppm 4.58 (1H, d, H-1"), 4.38 (1H, d, H-l'), 3.53 (3H, s, 3".
OMe), 3.47 (3H, s, 2" -OMe), 3.29 (3H, s, 20-OMe), 3.22, (3H, s, 20-OMe), 2.34 (6H, s, NMe2), 0.95 (3H, d, H-22).

13C-NMR (CDCl3) 6 ppm:215.8 (s, C-9), 206.7 (s, C-3), 166.7 (s, C-1), 45.8 (t, C-
2), 39.4 (t, C-13), 34.8 (t, C-10), 29.7 (d. C-12), 29.4 (t, C-11).
Process B
Compound 3 (6 g, 7.35 mmol) was dissolved in ethanol (250 ml), 3 g of 10% Pd/C
(vv/w) were added thereto and it was hydrogenated for 7 hours at room temperature at
hydrogen pressure of 0.5 MPa. After the completion of the reaction the catalyst was
separated by filtration and ethanol was evaporated at a reduced pressure to a dry
residue.
Obtained: 5.8 s, 96.2%.
By chromatography on a silica gel column in the solvent system Al, a product with the
same characteristics as the product obtained by process A was obtained.
Example 9
12,13-epoxy-3-deoxy-3-oxo-2',4'4"-triacetyI-desmycosin (3'N-oxide) 20-dimethylacetaI (9)
Compound 1 (2 g, 2.12 mmol) was dissolved in methylene chloride (40 ml), 71% m-chloroperbenzoic acid (2.05 g, 8.4 mmol) was added and it was stirred at room temperature for 8 hours. The reaction mixture was poured into 80 ml of water, alkalized to a pH value of 8.6, stirred for 30 minutes and the organic layer was separated. Subsequently, it was extracted once more with methylene chloride. The combined extracts were dried and evaporated to a dry residue. Obtained: 1.91 g, 94.0%; Rf (A) 0.23; MH+ 974; UVymax238 nm, s 14597.
By chromatography on a silica gel column in the solvent system A, a keto-enol product (proportion 3:1 in favour of the keto form) with the following characteristics was obtained: 1H-NMR (CDCl3) 5 ppm: 11.91 (1H, s, 3-OH, interchangeable with D2O), 6.57, 6.55
(1H, d, H-11), 6.43, 6.41 (1H, d, H-10), 4.91 (IH. dd, H-

2'), 4.78 (1H, dd, H-4'), 4.64 (1H, d, H-1"), 4.45 (1H, dd, H-4"), 4.13 (1H, d, H-l'X 3.59 (3H, s, 3" -OMe), 3,46 (6H, s, N-Me, 2" -OMe), 3.31 (3H, s, 20-OMe), 3.29, (3H, s, 20-OMe), 3.25 (3H, s, NMe), 2.12 (9H, s, 3x COMe), 1.44 (3H, s, H-22). 13C-NMR (CDCl3) 5 ppm: 205.7 (s, C-3, keto), 200.8 (s, C-9), 179.2 (s, C-3, enol),
175.3, 166.2 (s,C-l), 171.6, 170.3, 170.1 (s, 3x COMe)
150.3, 147.3 (d, C-11), 124.2, 123.3 (d, C-10), 62.9 (s, C-12),48.3(t,C-2).
Example 10
12,13-epoxy-3-deoxy-3-oxo-4"-acetyl-desmycosin (3'N-oxide) 20-dimethylacetal
(10)
Compound 2 (3 g, 3.5 mmol) was dissolved in methylene chloride (60 ml), 71% m-
chloroperbenzoic acid (3.35 g, 14.0 mmol) was added thereto and it was stirred at
room temperaure for 8 hours. The product was isolated from the reaction solution as
described in Example 9.
Obtained: 2.64 g, 85%; Rf (A) 0.22; MH+ 890; UVλmax.238 nm, s 15297.
By chromatography on a silica gel column in the solvent system A, a keto-enol
product (proportion 3:1 in favour of the keto form) with the following characteristics
was obtained:
1H-NMR (CDCl3) 5 ppm 11.91 (1H, s, 3-OH, interchangeable with D2O),
6.57, 6.55 (1H, d, H-11), 6.43, 6.41 (1H, d, H-10), 4.64 (1H, d, H-1"), 4.44 (1H, dd, H-4"), 4.42 (1H, d, H-1'), 3.59 (3H, s,3" -OMe), 3.46 (6H, s, N-Me, 2" -OMe), 3,31 (3H, s, 20-OMe), 3.29, (3H, s, 20-OMe), 3.25 (3H, s, NMe), 2.12. (3H, s, COMe), 1.51 (3H, s, H-22).

13C-NMR (CDCl3) 5 ppm: 205,7 (s, C-3, keto), 200.8 (s, C-9), 179.2 (s, C-3, enol),
175.3, 166.2 (s,C-l), I70.1.(s, COMe), 150.4, 147.3 (d, C-11), 124.2, 123.3 (d C-10), 62.9 (s, C-12X 48.3 (t, C-2).
Example 11
12,13-epoxy-3-deoxy-3-oxo-desmycosin (3'N-oxide) 20-dimethylacetal (11)
Compound 3 (2 g, 2.45 mmol) was dissolved in methylene chloride (40 ml). 71% m-
chloroperbenzoic acid (2.37 g, 9.8 mmol) was added thereto, whereupon the reaction
and isolation in the manner described in Example 9 were performed.
Obtained: 1.64 g, 79%; Rf(A)0.22; MH+ 848.
By chromatography on a silica gel column in the solvent system A, a keto-enol
product (proportion 3:1 in favour of the keto form) with the following characteristics
was obtained:
1H-NMR (CDCl3) 5 ppm 11.91 (1H, s, 3-OH, interchangeable with D2O),
6.56, 6.53 (1H, d, H-11), 6.41, 6.40 (1H, d, H-10), 4.64 (1H, d, H-1"), 4.42 (1H, d, H-1'), 3.59 (3H, s, 3;-0Me), 3.46 (6H, s, N-Me, 2" -OMe), 3.31 (3 H, s, 20-OMe), 3.29, (3H, s, 20-OMe), 3.25 (3H, s, NMe), 1.51 (3H, s, H-22).
Example 12
10,ll-dihydro-12,13-epoxy-3-deoxy-3-oxo-desmycosin 20-dimethylacetaI (12)
Compound 11 (1 g, 1.18 mmol) was dissolved in ethanol (50 ml), 0.33 g of 10% Pd/C (w/w) were added thereto, whereupon the hydrogenation in the manner described in Example 5 was performed.
Obtained: 0.95 g, 96.9%; Rf (A) 0.50; MH+ 834; (does not adsorb in UV-spectrum).
By chromatography on a silica gel column in the solvent system A, a product with the following characteristics was obtained:

1H-NMR (CDCl3) 5 ppm 4.64 (1H, d, H-1"), 4.38 (1H, d, H-T), 3.59 (3H, s, 3" -
OMe). 3.46 (3H, s, T -OMe), 3.31 (3H, s, 20-OMe), 3.29, (3H, s, 20-OMe), 2.50 (6H, s, NMe.), 1.34 (3H, s, H-22).
Example 13
10,13-dihydro-13-hidroxy-3-deoxy-3-oxo-4"-acetyl-desinycosin 20-diinethylacetal
(13)
Compound 10 (1 g. 1.12 mmol) was dissolved in ethanol (20 ml), a 10% aqueous NH4CI solution (40 ml) and, gradually, Zn-povvder (2 g) were added thereto. It was stirred at room temperature for 6 hours, whereupon Zn was removed by filtration and the reaction solution was evaporated to 1/2 of its volume, chloroform (20 ml) was added and it was alkalized to a pH value of 8.5. The organic layer was separated and another extraction with chloroform was performed. The combined extracts were dried and evaporated to a dry residue, Obtained:0.64g,65%; Rf(A)0.45; MH+ 876.
By chromatography on a silica gel column in the solvent system A, a keto-enol product (1:1) with the following characteristics was obtained:
1H-NMR (CDCl3) 6 ppm 12.04 (1H, s, 3-OH, enol, interchangeable with D2O), 5.38,
5.30 (1H, t, H-11), 4.78 (1H, s, H-2, enol), 4.49 (1H, d, H-1"), 4.38 (la d, H-r), 4.30 (1H, dd, H-4"), 3.59 (3H, s, 3" -OMe), 3.46 (3H, s, 2"-0Me), 3.31 (3H, s, 20 -OMe), 3.29 (3H, s, 20 -OMe), 2.39 (6H, s, NMe2), 2.12 (3H, s, COMe), 1.49(3H,s,H-22).
Example 14
2,3-anhydro-12,13-epoxy-desmycosin (3'N-oxide) 20-dimethylacetaI (14)
2,3-anhydro-desmycosin 20-dimethylacetal (4 g, 5.00 mmol) was dissolved in methylene chloride (80 ml), 71% w-chloroperbenzoic acid (4.84 g, 0.02 mol) was added and then the oxidation in the manner described in Example 9 was performed. .

Obtained: 2.83 g, 68%; Rf(A)0.20; MH+ 832; UVλmax.238 nm, e 12247,
By chromatography on a silica gel column in the solvent system A, a product with the
following characteristics was obtained:
1H-NMR (CDCl3) 5 ppm 6.66 (1H, m, H-3), 6.53 (1H, d, H-1 i), 6.36 (1H, d, H-10),
5.75 (1H, d, H-2), 4.58 (1H, d, H-1"), 4.41 (1H, d, H-l'), 3.59 (3H, s, 3" -OMe), 3.46 (6H, s, N-Me, T -OMe), 3.31 (3H, s, 20-OMe), 3.29, (3H, s, 20-OMe), 3.25 (3H, s, N-Me), 1.50(3H, s, H-22).
Example 15
2,3-anhydro-10,13-dihydro-13-hydroxy-desmycosin 20-dimethylacetal (15)
Compound 14 (1 g, 1.20 mmol) was dissolved in ethanol (12 ml), a 10% NH4OH
solution (24 ml) and, gradually, Zn-powder (2.5 g) were added thereto. After stirring
for 8 hours at room temperature, the isolation in the manner described in Example 14
was performed.
Obtained: 0.95 g, 96.9%; Rf (A) 0.48; MH+ 818;
(does not adsorb in UV-spectrum).
1H-NMR (CDCl3) 5 ppm: 6.55 (1H, m, H-3), 5.61 (1H, t, H-11), 5.58 (1H, d, H-2),
4.61 (1H, d, H-1"), 4.32 (1H, d, H-T), 3.59 (3H, s, 3"-OMe), 3.46 (3H, s, T -OMe), 3.31 (3H, s, 20-OMe), 3.29, (3H, s, 20-OMe), 2.51 (6H, s, NMe.), 1.68 (3H, s, H-22).
Example 16
3-methanesulfonyI-2',4',4"-triacetyl-10,1142,13-tetrahydro-desmycosin 20-dimethyIacetal (16)
Compound 5 (3 g, 3.16 mmol) was dissolved in pyridine (9.15 ml) and cooled to 10°C, whereupon methanesulfochloride (1.57 ml, 12.4 mmol) was gradually added. The reaction solution was stirred for 3 hours at 10°C, poured into 250 ml of water.

alkalized to a pH value of 9.2 and then left to stir for 30 minutes. A thick white
precipitate was separated by filtration and the still moist precipitate was dissolved in
chloroform (60 ml) and washed with a saturated NaCl solution (120 ml). The extract
was dried and evaporated to a dry residue.
Obtained: 2.95 g, 86.5%; Rf(C) 0.70; MH+ 1026;
(does not adsorb in UV-spectrum),
By chromatography on a silica gel column in the solvent system C, a product with the
following characteristics was obtained:
1H-NMR (CDCl3) 5 ppm: 4.89 (1H, dd, H-2'), 4.76 (1H, dd, H-4'), 4.61 (1H, d, H-
1"), 4.43 (1H, dd, H-4"), 4.40 (1H, d, H-T), 3.53 (3H, s, 3" -OMe), 3.47 (3H, s, 2'-0Me), 3.29 (3H, s, 20-OMe), 3.22, (3H, s, 20-OMe), 3.10 (3H, s, SO2Me), 2.34 (6H, s, NMe.), 2.12. (3H, s, COMe), 2.06 (6H, s 2xC0Me), 0.96 (3H, d, H-22).
Example 17
2,3-anhydro-10,l 1,12,13-tetrahydro-desmycosin 20-dimethylacetal (17)
Compound 16 (2 g, 1.95 mmol) was dissolved in methanol (40 ml), a 25% NH4OH solution (20 ml) was added thereto and it was stirred at room temperature for 3 hours. The reactiom solution was evaporated at a reduced pressure to 1/3 of its volume, extracted with chloroform, dried and evaporated to a dry residue. The crude product was dissolved in methanol (80 ml) and it was heated at reflux temperature for 6 hours. Subsequently, methanol was evaporated and the product was dissolved in chloroform (40 ml), washed with a saturated NaHCO3 solution and evaporated to a dry residue. Obtained: 1.39 g, 89.0%; Rf (A) 0.45; MH+ 804.
1H-NMR (CDCl3) 5 ppm 6.82 (1H, m, H-3), 5.88 (1H, d, H-2), 4.61 (1H, d, H-1"),
4.41 (1H, d, H-r), 3.59 (3H, s, 3"-0Me), 3.46 (3H, s, T-OMe), 3.31 (3H, s, 20 OMe), 3.29 (3H, s, 20-OMe), 2.51 (6H, s, NMe2), 0.76 (3H, s, H-22).

13C-NMR (CDCl3) 5 ppm: 215.0 (s, C-9), 167.0 (s, C-1), 148.8 (d, C-3), 122.7 (d, C-
2). 40.9 (t, C-13), 31.5 (t, C-10), 30.1 (d, C-12), 28.3 (t, C-11), 20.4(q,C-22).
Example 18
2,3-anhydro-10,l 1,12,13-tetrahydro-desmycosin (18)
Compound 17 (1 g, 1.2 mmol) was dissolved in acetonitrile (10 ml) and in 1%
trifluoroacetic acid (13 ml). The reaction solution was stirred for 2 hours at room
temperature and then the isolation in the manner described in Example 4 was
performed.
Obtained: 0.80 g, 85.0%; Rf(A)0.35, MH+ 758.
' H-NMR (CDCl3) 6 ppm 9.74 (1H, s, H-20), 6.82 (1H, m, H-3), 5.88 (1H, d, H-2),
4.61 (1H, d, H-1"), 4.41 (1H, d, H-1'), 3.59 (3H, s, 3"-
OMe), 3.46 (3H, s, 2"-0Me), 2.51 (6H, s, NMe:), 0.76
(3H, s, H-22). '^ C-NMR (CDCl3) 5 ppm: 215.2 (s, C-9), 202.0 (d, C-20), 167.2 (s, C-1), 148.8 (d, C-
3), 122.7 (d, C-2), 40.8 (t, C-13), 31.6 (t, C-10), 30.1 (d,
C-12). 28.4 (t, C-11), 20.3 (q, C-22).

Claims
1. Derivatives of 3-deoxy-3-oxo-desmycosin of the formula I

wherein
R represents CHO or CH(OCH3)2, R1 and R2 represent H or acetyl, R3 represents H or
OH, R4 represents N(CH3)2 or N-O(CH3)2, the line represents a single or a double
bond, the line represents or a double or a single bond, and the line
represents a double or a single bond, and
derivatives of 3-deoxy-2,3-didehydro-desmycosin of the formula II

wherein
R represents CHO or CH(OCH3)2, R1 represents H or OH, R2 represents NCCHs): or
N-O(CH3)2. the line represents a double or a single bond, the line represents
or a single bond, and the line represents a double or a single bond.
2. A compound according to claim 1 of the formula I, characterized in that R
represents CH(OCH3)2, R1 and R2 represent acetyl R3 represents H, R represents
N(CH3)2, the lines - - - and represent double bonds and the line
represents a single bond.
3. A compound according to claim 1 of the formula I, characterized in that R
represents CH(OCH3)2, R1 and R3 represent H, R2 represents acetyl, R4 represents
N(CH3)2, the lines - - - and represent double bonds and the line
represents a single bond.
4. A compound according to claim 1 of the formula I, characterized in that R
represents CH(OCH3)2, R1 R2 and R3 represent H, R4 represents N(CH3)2, the lines
— and represent double bonds and the line represents a single bond.
5. A compound according to claim 1 of the formula I, characterized in that R
represents CHO, R1 R2 and R3 represent H, R4 represents N(CH3)2, the lines — and
represent a double bond and the line represents a single bond.
6. A compound according to claim 1 of the formula I, characterized in that R
represents CH(OCH3)2, R1 and R2 represent acetyl, R3 represents H, R4 represents
N(CH3)2, and the lines , and represent single bonds.
7. A compound according to claim 1 of the formula I, characterized in that R
represents CH(OCH3)2, R1 and R3 represent H, R2 represents acetyl, R4 represents
N(CH3)2, and the lines — , and represent single bonds.

8. A compound according to claim 1 of the formula I, characterized in that R represents CH(OCH3)2, R1 R2 and R3 represent H, R4 represents NCCHs):, and the lines — , and represent single bonds.
9. A compound according to claim 1 of the formula I, characterized in that R represents CH(OCH3)2, R1 and R2 represent acetyl, R3 represents H, R4 represents
N-O(CH3)2, the line — represents a double bond, the line represents and
the line represents a single bond.
10. A compound according to claim 1 of the formula I, characterized in that R
represents CH(OCH3)2, R1 and R3 represent H, R2 represents acetyl, R4 represents
N-O(CH3)2, the line — represents a double bond, the line represents and
the line 'VU' represents a single bond.
11. A compound according to claim 1 of the formula I, characterized in that R
represents CH(OCH3)2, R1 R2 and R3 represent H, R4 represents N-O(CH3)2, the line
represents a double bond, the line represents and the line
represents a single bond.
12. A compound according to claim 1 of the formula I, characterized in that R
represents CH(OCH3)2, R1R2 and R3 represent H, R4 represents N(CH3)2, the line - - -
represents a single bond, the line represents and the line represents
a single bond.
13. A compound according to claim 1 of the formula I, characterized in that R
represents CH(OCH3)2, R1 and R3 represent H, R2 represents acetyl, R4 represents
N(CH3)2, the line — represents a single bond, the line represents and the
line represents a single bond.

14. A compound according to claim 1 of the formula I, characterized in that R
A.
represents CH(OCH3)2, R1 and R2 represent H, R 3 represents OH, R represents
N(CH3)2, the lines — and represent single bonds and the line represents
a double bond.
15. A compound according to claim 1 of the formula II, characterized in that R
represents CH(OCH3)2, R1 represents H, R2 represents N-O(CH3)2, the line
represents a double bond, the line represents and the line represents
a single bond.
16. A compound according to claim 1 of the formula 11, characterized in that R
represents CH(OCH3)2, R1 represents OH, R2 represents N(CH3)2, the lines and
represent single bonds and the line represents a double bond.
17. A compound according to claim 1 of the formula II, characterized in that R
represents CH(OCH3)2, R1 represents H, R2 represents N(CH3)2, and the lines - - -,
and represent single bonds,
18. A compound according to claim 1 of the formula II, characterized in that R
represents CHO, R1 represents H, R2 represents N(CH3)2, and the lines - - -, and
represent single bonds.

19. Process for the preparation of derivatives of 3-deoxy-3-oxo-desmycosin of the formula I

wherein
R represents CHO or CH(OCH3)2, R1 and R2 represent H or acetyl, R3 represents H or
OH, R4 represents N(CH3)2 or N-O(CH3)2, the line represents a double or a single
bond, the line represents or a double or a single bond, and the line
represents a double or a single bond, characterized in that a compound of the formula III

wherein R represents H or SO2CH3 and the line - - - represents a double bond, is subjected
Amended claims

A/ to an oxidation reaction in a solution of methylene chloride in the presence of 15-28 equivalents of DMSO, 8-14 equivalents of N-(3-dimethylaminopropyl)-N'-ethyI carbodiimide hydrochloride and 8-14 equivalents of pyridine trifluoroacetate 'vithin 2-6 hours at a temperature of 10-25°C , whereupon the obtamed compound of formula I, wherein R represents CH(OCH3)2, R1 and R2 represent acetyl, R3 represents H, R'*
represents N(CH3)2, the lines — and represent double bonds and the line
represents a single bond,
is optionally subjected
B/ to methanolysis at reflux temperature within 4-6 hours and the obtained compound
of formula I, wherein R represents CH(OCH3)2, R1 and R3 represent H, R2 represents
acetyl, R4 represents N(CH3)2, the lines — and represent double bonds and the
line represents a single bond,
is optionally subjected
Bl/ to an alkaline methanolysis in a mixture of methanol and 25% NH4OH (2:1) at
5°C within 48-60 hours, whereupon the obtained compound of formula I, wherein R
represents CH(OCH3)2, R1 R2 and R3 represent H, R4 represents N(CH3)2, the lines
— and represent double bonds and the line represents a single bond,
is optionally subjected
B2/ to a hydrolysis in a mixture of acetonitrile and 1% trifluoroacetic acid (2:3) within
2 hours at room temperature, giving a compound of formula I, wherein R represents
CHO, R1 R2 and R3 represent H, R4 represents N(CH3)2, the lines and
represent double bonds and the line represents a single bond,
or optionally,
a compound of the formula I, wherein R represents CH(OCH3)2, R1 and R2 represent
acetyl, R3 represents H and R44^ represents N(CH3)2, the lines— and represent
double bonds and the line represents a single bond,
is subjected,
Amended claims

C/ to a catalytic hydrogenation reaction in the presence of 2-5% Pd/C (w/w) at room temperature within 5-8 hours at a hydrogen pressure of 0.3-0.5 MPa, whereupon the obtained compound of the formula I, wherein R represents CH(OCH3)2, R^ and R^
represent acetyl, R3 represents H, R4 represents N(CH3)2, and the lines , , and
the line represent single bonds,
can be optionally subjected
to the methanolysis or alkaline methanolysis reactions in the manner described under
BorBl;
or optionally, it is subjected
D/ to an oxidation reaction in a methylene chloride solution in the presence of 3-6 equivalents of m-chloroperbenzoic acid within 6-10 hours at room temperature, giving a compound of the formula I, wherein R represents CH(OCH3)2, R1 and R2 represent acetyl, R3 represents H, R4 represents N-O(CH3)2, the line - - - represents a double
bond, the line represents and the line represents a single bond,
or optionally,
a compound of the formula I, wherein R represents CH(OCH3)2, R1 and R3 represent
H, R2 represents acetyl, R4 represents N-(CH3)2, the lines - - - and represent
double bonds and the line represents a single bond, is subjected to the oxidation
reaction in the manner described under D, and the obtained compound of the formula
I, wherein R represents CH(OCH3)2, R1 and R3 represent H, R2 represents acetyl, R4
represents N-O(CH3)2, the line — represents a double bond, the line represents
and the line represents a single bond,
is optionally subjected
to the catalytic hydrogenation reaction in the manner described under C, giving a
compound of the formula I, wherein R represents CH(OCH3)2, R1 and R3 represent H,
Amended claims

R2 represents acetyl, R4 represents N(CH3)2, the line — represents a single bond,
the line represents and the line represents a single bond,
is optionally subjected
E/ to a reduction with Zn-powder in a solution of EtOH and 10% aqueous NH4OH solution (1:2) under maintaining the pH-value of 5.0-5.5, giving a compound of the formula I, wherein R represents CH(OCH3)2, R1 represents H, R2 represents acetyl, R3
represents OH, R4 represents N(CH3)2, the lines and represent single bonds
and the line represents a double bond,
or optionally,
a compound of the formula I, wherein R represents CH(OCH3)2, R1 B2 and R3
represent H, R4 represents N(CH3)2, the lines — and represent double bonds
and the line represents a single bond, is subjected to the oxidation reaction in
the maimer described under D and the obtained compound of the formula I, wherein R represents CH(OCH3)2, R1 R2 and R3 represent H, R4 represents N-O(CH3)2, the line
- - - represents a double bond, the line represents and the line
represents a single bond,
is optionally subjected
to the catalytic hydrogenation reaction in the manner described under C, giving a
compound of the formula I, wherein R represents CH(OCH3)2, R1 R2 and R3 represent
H, R4 represents N(CH3)2, the line - - - represents a double bond, the line
represents and the line represents a single bond,
or optionally,
to the reduction with Zn-powder in the manner decribed under E, giving a compound
of the formula I, wherein R represents CH(OCH3)2, R1 and R2 represent H, R3
represents OH, R4 represents N(CH3)2, the lines— and represent single bonds
and the line represents a double bond.
Amended claims

20. Process for the preparation of derivatives of 3-deoxy-2,3"didehydro-desmycosin of the formula II

wherein
R represents CHO or CH(OCH3)2, R1 represents H or OH, R2 represents N(CH3)2 or
N-O(CH3)2, the line — represents a double or a single bond, the line represents
or a single bond, and the line represents a double or a single bond,
characterized in that
a compound of the formula III, wherein R represents H and the line - - - represents a double bond, is subjected to the catalytic hydrogenation reaction according to the process C of claim 19 and the obtained compound of the formula III, wherein R represents H and the line — represents a single bond,
is optionally subjected
F/ to a mesylating reaction in a solution of pyridine under the addition of 3-5
equivalents of methanesulfochloride at 10°C within 3-5 hours and the obtained
compound of the formula III, wherein R represents SO2CH3, the line — represents a
single bond, is subjected
G/ to a reaction of elimination of mesylate in a mixture of methanol and 25% NH4OH
(2:1) at room temperature within 5 hours and then to the methanolysis in the manner
Amended claims

described under Bl of claim 19, and the obtained compound of the formula II, wherein
R represents CH(OCH3)2, R1 represents H, R2 represents N(CH3)2, and the lines ,
and represent single bonds, is subjected to the reaction of hydrolysis of
acetal in the manner described under B2 of claim 19,
or optionally,
a compound of formula III, wherein R represents H, and the line - - - represents a double bond, is subjected to the mesylation reaction in the manner described under F, to the elimination reaction in the manner described under G and, subsequently, to the methanolysis reaction according to the process B of claim 19, and the obtained compound of the formula II, wherein R represents CH(OCH3)2, R' represents H, R^
represents N(CH3)2, the lines - - - and represent double bonds and the line
represents a single bond, is subjected to the oxidation reaction in the manner
described under D of claim 19, and the obtained compound of the formula II, wherein
R represents CH(OCH3)2, R1 represents H, R2 represents N-O(CH3)2, the line
represents a double bond, the line represents and the line represents
a single bond,
is optionally subjected
to the reduction reaction with Zn powder in the manner according to process E of
claim 19, giving a compound of the formula II, wherein R represents CH(OCH3)2, R^
represents OH, R2 represents N(CH3)2, the lines - - - and represent single bonds
and the line represents a double bond.

21. Derivatives of 3-deoxy-3-oxo-desmycosin of the formula I substantially as
hereinbefore described.
22. Process for the preparation of derivatives of 3-deoxy-2, 3-didehydro-
desmycosin of the formula II substantially as hereinbefore described.

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Patent Number

209545

Indian Patent Application Number

IN/PCT/2001/1661/CHE

PG Journal Number

50/2007

Publication Date

14-Dec-2007

Grant Date

05-Sep-2007

Date of Filing

27-Nov-2001

Name of Patentee

M/S. PLIVA FARMACEUTISKA INDUSTRIJA,DIONICKO DRUSTVO

Applicant Address

Ulica grada Vukovara 49, HR-10000 Zagreb

Inventors:

#	Inventor's Name	Inventor's Address
1	NARANDJA, Amalija	Bartula Kaši&cacute;a 6, 10000 Zagreb

PCT International Classification Number

C07H 17/08

PCT International Application Number

PCT/HR2000/000012

PCT International Filing date

2000-05-02

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	P990129A	1999-05-03	Croatia