Cetomacrogol class eritromicina and method of production thereof

 

(57) Abstract:

Describes new connections - cetomacrogol class eritromicina And General formula I, where the values of R1, R2, R3, Z, W, X, Y specified in paragraph 1 of the claims. They are potential intermediate compounds for new antibiotics - macrolides. Describes how they are received. 2 S. and 19 C.p. f-crystals.

The technical field to which the invention relates

A 61 K 31/70 C 07 H 17/08

Technical problem

The present invention relates to new compounds of the class of the well-known antibiotic of the macrolide erythromycin A. In particular, the present invention relates to new cetomacrogol - potential intermediate compounds for new macrolide antibacterial action, and the way they are received.

Prior art

Erythromycin is an antibiotic is a macrolide, whose structure is characterized by a 14-membered Laktionova ring with a keto group at C-9 position and two sugars - L-cladinose and D-desosamine attached by glycosidic linkages at positions C-3 and C-5 aglionby group of molecules (McGuire, Antibiot. Chemother. , 1952; 2:281). Over 40 years of operations of the genital organs, caused by gram-positive bacteria, some species of Legionella, Mycoplasma, chlamydia and Helicobacter. Significant changes in bioavailability after administration of oral medications, gastric intolerance to many patients and the loss of activity in the acidic environment due to the formation of inactive metabolites of anhydroerythromycin are the main disadvantages with therapeutic use of erythromycin A. However, spiritlessly aliceooa rings successfully inhibited by a chemical transformation of the C-9 ketone or hydroxyl groups at position C-6 and/or C-12. For example, aksamitowana C-9 ketone erythromycin A with hydroxylamine hydrochloride, Beckmann rearrangement received 9(E)-oxime and restoring the received simple 6,9-aminoether (6,9-cyclic aminoether 6-deoxy-9-desoxo-9a-utahamerican) received 9 desoxo-9a-Aza-9a-homoerythromycin A first semi-synthetic macrolide with a 15-membered azlactone ring (Kobrehel G. et al, U.S. patent 4328334, 5/1982). In accordance with the method of the Eschweiler-Clarke, by reductive methylation of the newly introduced endocycles 9a-amino synthesized 9-desoxo-9a-methyl-9a-Aza-9a-homoerythromycin A (AZITHROMYCIN) is a prototype of the new class and the including gram-negative bacteria, azithromycin is also characterized by a long biological half-time of existence, the specific mechanism of transfer to the place of use and short term treatment. Azithromycin easily penetrate human phagocytes and accumulates in them, resulting in improved activity against intracellular pathogens classes Leqionella, chlamydia and Helicobacter.

Recently described hydrolysis and alcoholysis C-1-lactone erythromycin A and B, whereby are formed corresponding linear scaricati and esters (Martin S., J. Am.Chem. Soc., 1991; 113: 5478). In addition, also described alkali catalyzed the transformation of erythromycin A, leading to the disclosure of the macrocyclic ring with the formation of C-1-carboxylate (Waddel S. T. and Blizzard T. A., PCT, WO 94/15617, 7/1994). Also described is a method of obtaining new macrolide and solidnyh rings by combining Eastern ("Oriental")-C-1/C-8-C-1/C-9-groups of the molecules 9 desoxo-8A-Aza-8A-homoerythromycin A and 9 desoxo-9a-Aza-9a-homoerythromycin A, respectively, with different fragments, which become the Western ("Western") is a group of molecules. Emphasized that the linear fragments C-1/C-9, thus obtained, are different from the corresponding fragment of azithromycin presence additionally the impact of hydroxylamine hydrochloride on simple 6,9-circular iminoethyl and subsequent alkali catalyzed intramolecular acylation of the newly formed C-10-amino and C-1-lactone. The structure thus obtained C-1-amides characterized by the Eastern fragment C-1/C-9, which is identical to the fragment in azitromicina and Western-fragment C-10/C-15 of erythromycin A, reversible associated with carbon atom C-1. However, when the effects of acids 6.9-circular iminoethyl the cleavage of the double bond C-9/9-a-N formed 6-deoxy-6,9-epoxy-8(R)-methyl-10-amino-9,10-securitiesin A terminal C-10 group. The object of the present invention is the synthesis of new cetomacrogol potential intermediates in the synthesis of biologically active chimeric macrolides, on the basis of 6-deoxy-6,9-epoxy-8(R)-methyl-10-amino-9,10-securitiesin A.

Summary of the invention

According to a well known and established technology is still not described cetomacrogol General formula (I)

< / BR>
where R1represents hydrogen, (C1-C4)-alkanoyloxy group, arylcarbamoyl group, or together with R2and carbon atoms to which they are linked, cyclic carbonyl or thiocarbonyl group;

R2represents hydrogen or together with R1and carbon atoms to which they are linked, cyclic carbonyl or thiocarbonyl group;

R3predstavleniya group of the formula (i).

< / BR>
where R4represents hydrogen or (C1-C4)-alkanoyloxy group;

W represents hydrogen or D-disseminating group of the formula (ii)

< / BR>
where R5represents hydrogen or (C1-C4)-alkanoyloxy or arylcarbamoyl group;

X and Y together represent lactone or X represents a group CH2OR6where R6represents hydrogen or (C1-C4)-alkanoyloxy group, Y represents a hydroxyl group.

The present invention also relates to pharmaceutically acceptable salts of the accession of inorganic or organic acids.

Detailed description of the invention

New cetomacrogol General formula (I)

< / BR>
where X, Y, Z and W have the foregoing meanings, and their pharmaceutically acceptable salts accession inorganic or organic acids get subjecting 6-deoxy-6,9-epoxy-8(R)-methyl-10-amino-9,10-securitiesin A (EP 0735041 A1, 2/1996) of the formula (II)

< / BR>
interaction with polar solvents within the time required in order by intramolecular acylation of the primary C-10-amino and C-1-lactone was formed compound of General formula (I), where R1, R2and R represents hydrogen, W is D-disseminules group of the formula (ii), where R5is hydrogen, and X and Y together represent lactone [compound (Ia)], which is further subjected to

A) interaction with acids under the conditions of hydrolysis of one or both sugars, receiving the compound of General formula (I), where R1, R2and R3are the same and represent hydrogen, Z is hydrogen, W is D-disseminules group of the formula (ii), where R5is hydrogen, and X and Y together represent lactone [compound (Ib)], and the compound of General formula (I), where R1, R2and R3are the same and represent hydrogen, Z, and W are the same and represent hydrogen, and X and Y together represent lactone [compound (Ic)], or

B) O-acylation with anhydrides or carboxylic acid anhydrides, getting

B1) when the O-acylation with anhydrides or acid chlorides (C1-C4)-alkylcarboxylic acid compound of General formula (I), where R1and R3are the same and represent (C1-C4)-alcoholnye group and R2is hydrogen, Z is L-klavesinnoj group of the formula (i), where R4is (C1-C4)-alkanoyloxy grow group, and X and Y together represent lactone, which is then, if necessary, is subjected to solvolysis reaction, obtaining the compound of General formula (I), where R1and R3are the same and represent (C1-C4)-alcoholnye group and R2is hydrogen, Z is L-klavesinnoj group of the formula (i), where R4is (C1-C4)-alkanoyloxy group, W is a D-disseminules group of the formula (ii), where R5is hydrogen, and X and Y together represent lactone, or getting

B2) when the O-acylation with anhydrides arylcarboxylic acids, when

BA) use at least 1,1 equimolar excess of the carboxylic acid, the compound of General formula (I), where R1, R2and R3are the same and represent hydrogen, Z is L-klavesinnoj group of the formula (i), where R4represents hydrogen, W is D-disseminules group of the formula (ii), where R5is arylcarbamoyl group, and X and Y together represent lactone, which, if required, subjected to O-acylation according to B1), obtaining the compound of General formula (I), where R1and R3are the same and represent (C1-C4)-alcoholnye group and RC4)-alkanoyloxy group, W is a D-disseminules group of the formula (ii), where R5is arylcarbamoyl group, and X and Y together represent lactone, or

B2B) using at least 5-equimolar excess of carboxylic acid, a mixture of compounds of General formula (I), where R1is arylcarbamoyl group, a R2and R3are the same and represent hydrogen, or R3is arylcarbamoyl group, and R1and R2are the same and represent hydrogen, Z is L-klavesinnoj group of the formula (i), where R4is hydrogen, and W is a D-disseminules group of the formula (ii), where R5is arylcarbamoyl group, and X and Y together represent lactone, and these compounds separated using column chromatography on silica gel, and then, if required, subjected to solvolysis reaction, obtaining the compound of General formula (I), where R1is arylcarbamoyl group, a R2and R3are the same and represent hydrogen, or R3is arylcarbamoyl group, and R1and R2are the same and represent hydrogen, Z is L-klavesinnoj group of the formula (i), where R
or

B) of the interesterification reaction with derivatives of carboxylic acids, receiving the compound of General formula (I), where R1and R2together with the carbon atoms to which they are linked, represent a cyclic carbonyl or thiocarbonyl group, and R3is hydrogen, Z is L-klavesinnoj group of the formula (i), where R4represents hydrogen, W is D-disseminules group of the formula (ii), where R5is hydrogen, and X and Y together represent lactone,

or

G) recovering, receiving connection of General formula (I), where R1, R2and R3are the same and represent hydrogen, Z is L-klavesinnoj group of the formula (i), where R4represents hydrogen, W is D-disseminules group of the formula (ii), where R5is hydrogen, and X represents a group CH2OR6where R6represents hydrogen and Y represents a hydroxyl group, which is optionally subjected to O-acylation according to B1), obtaining the compound of General formula (I), where R1and R3are the same and represent (C1-C4)-alcoholnye group, R2is hydrogen, Z is L-to the D-disseminules group of the formula (ii), where R5is (C1-C4)-alkanoyloxy group, X represents a group CH2OR6where R6represents hydrogen and Y represents a hydroxyl group.

Intramolecular acylation of the C-10-amino group of the C-1 lactone compound (II) is carried out in water or in a mixture of water and an organic solvent, preferably lower alcohols or acetone, at room temperature or at an elevated temperature to accelerate poreallashuone by a known method (J. March, Advanced Organic Chemistry: Reactions, Mechanisms and Structure; Third Ed., 1985, p. 375).

The hydrolysis of compounds (Ia) in accordance with (A) conduct a well-known manner in two stages. In the first stage, the interaction with diluted inorganic acids, preferably from 0.25 N hydrochloric acid at room temperature to carry out the splitting of the neutral sugar L-cladinose, resulting in the formation of 5-O-dessalinienne derivative (Ib), which is then, if necessary, expose more concentrated acids, preferably 2 to 6 N hydrochloric acid, in the presence of an inert organic solvent, preferably chloroform, at elevated temperature, preferably at the boiling PE ucaut compound (Ic).

The reaction of O-acylation of the compound (Ia) according to B1) is carried out with anhydrides or acid chlorides (C1-C4)-carboxylic acids well known manner in an inert reaction solvent at a temperature of from 0 to 30oC in the presence of suitable bases (Jones et al., J. Med.Chem., 1971, 15, 631, and Banaszek et ai., Rocy.Chem., 1969, 43, 763). As the inert solvent can be used methylene chloride, dichloroethane, acetone, pyridine, ethyl acetate, tetrahydrofuran, and other similar solvents. As suitable bases used sodium bicarbonate, sodium carbonate, potassium carbonate, triethylamine, pyridine, tributylamine and some other inorganic and organic bases. For example, acylation (Ia) with acetic anhydride in pyridine at room temperature for 3 nights get the leads to compounds, which (Id) (R1= R3= R4= R5= acetyl, R2is hydrogen, X and Y together represent lactone). The solvolysis received tetracyline derivatives is carried out in lower alcohols at room temperature or at an elevated temperature to accelerate the reaction, resulting is diallylamine in the 2' position. In this case, as the lower alcohol can be used for the Noah temperature for 3 days, formed triacetate (Ie) (R1= R3= R4= acetyl, R2= R5= hydrogen, X and Y together represent lactone). O-Acylation of the compound (Ia) with anhydrides arylcarboxylic acids in accordance with B2), where the term "aryl" means unsubstituted or substituted phenyl group, preferably - (C1-C4)-alkylphenyl or halogeniniu group, carried out preferably in an inert solvent, preferably in acetone, in the presence of inorganic or organic bases, preferably sodium bicarbonate, as a result, depending on equimolar ratio of reactants, reaction temperature and time acylation, are formed corresponding mono - or diarylpyrimidine derivatives. For example, acylation (Ia), at least from 1.1 equimolar excess 4-bromobenzonitrile in dry acetone at 0 to 5oC get 2'-mono-bromobenzoate (If) (R1= R2= R3= R4= H, R5= 4-bromobenzoyl and X and Y together represent lactone). The obtained 2'-monocrystalline derivatives, if required, On-acelerou method B1). For example, when interacting with acetic anhydride according to the above method are triacetate (Ig) (R1
= R5= 4-bromobenzoyl, R2= R3= R4= H, X and Y together represent lactone) and (Ii) (R3= R5= 4-bromobenzoyl, R1= R2= R4= H, X and Y together represent lactone), which is shared by chromatography on a column of silica gel, using, preferably, the solvent system CH2Cl2/CH3OH, 95:5, and then, if required, is subjected to solvolysis in the above-described method, as a result, when diallylamine complex 2'-esters, preferably 2'-O-(4-bromobenzoate), formed monobrominated (Ik) (R1= 4-bromobenzoyl, R2= R3= R4= R5= H, X and Y together represent lactone) and (Ij) (R3= 4-bromobenzoyl, R1= R2= R4= R5= H, X and Y together represent lactone).

The transesterification of compound (Ia) (B) is carried out with derivatives of carboxylic acids, preferably with 3-5 equimolar excess of ethylene carbonate resulting or 1,1-thiocarbonyldiimidazole the teli, for example in benzene, chlorinated hydrocarbons or lower alkylamino, for example ethyl acetate, at an elevated temperature, preferably at the boiling temperature of the reaction mixture within 3-9 hours, receiving a cyclic carbonate or thiocarbonate (R1and R2together represent a group C = O or C = S, R3= R4= R5= H, X and Y together represent lactone).

The reduction of compound (Ia) according to D) is carried out with a metal hydride complexes, preferably with sodium borohydride in the presence of tertiary alcohols, preferably tert-butanol, in an inert solvent, preferably lower alcohols, preferably methanol, at elevated temperature, preferably at the boiling temperature of the reaction mixture, receiving a mixture of isomeric 9-hydroxy-8(R)- (Im) and 9-hydroxy-8(S)-derivative (In) (R1= R2= R3= R4= R5= H, X represents a group CH2OR6where R6is hydrogen, and Y represents a hydroxyl group), which, if required, separated by column chromatography on silica gel and then, if required, subjected to O-acylation in accordance with B1).

Pharmaceutically acceptable salts prisoedini formula (I), at least equimolar amount of a suitable inorganic or organic acid, such as hydrochloric, itestosterone, sulfuric, phosphoric, acetic, propionic, triperoxonane, maleic, citric, stearic, succinic, Atlanterra, methansulfonate, benzolsulfonat, p-toluensulfonate, laurylsulphate acid and similar acid, in an inert reaction solvent. Salt accession acids are filtered if they are insoluble in the inert reaction solvent, by precipitation with a solvent in which the salt is insoluble, or by evaporation of the solvent, most often by lyophilization.

Using the series of reactions of 6-deoxy-6,9-epoxy-8(R)-methyl-10-amino-9,10-securitiesin A formula (II) receive a number of new, hitherto not described, linear derivatives with highly reactive terminal functional groups, which opens up the possibility of obtaining a number of new macrolides with modified macrocyclic aglycone. For simplicity, the numbering of the atoms of hydrogen and carbon in the data spectrometry new cetomacrogol in the experimental part of this patent application is the same as for Atami, which in no way limit its scope.

EXAMPLE 1. 1-N-(2,3,4-trihydroxy-1,3-dimethylpentyl)-amido-10,11,12,13,14,15-hexanor-6-deoxy-6,9-epoxy-9,10-securitiesin A (Ia)

Method 1

6-Deoxy-6,9-epoxy-8(R)-methyl-10-amino-9,10-securitiesin A (EP 0735041 A1, 02.10.1996) (15 g, 0.02 mol) is dissolved in 540 ml of a mixture of acetone-water (1:5) and heated under stirring for 2 hours at a temperature of 55-60oC. the Reaction mixture was evaporated under reduced pressure, added to aqueous residue CHCl3(100 ml) (pH was 7.45) and then, after alkalizing to pH 9,0 (10% NaOH), the layers separated and the aqueous layer was extracted two times with CHCl3(100 ml). The combined organic extracts dried over K2CO3and evaporated and get a solid residue (12.9 g). By column chromatography on silica gel using the solvent CHCl3/CH3OH/conc.NH4OH, 6: 1: 0.1 to of the crude product (2.5 g) receive chromatographically uniform substance (Ia) (1.48 g) with the following physical-chemical constants.

Rfof 0.337, EtAc/(h-C6H6)/NHEt2, 100:100:20.

Rf0,621, CH2Cl2/CH3OH/NH4OH, 90:9:1,5.

IR (CHCl3) cm-13400, 2980, 2950, 1770, 1660, 1540, 1460, 1390, 1270, 1110, 1050, 10), 3.20 (H-13), 2.79 (H-8), 2.46 (H-2), 2.27 /3'-N(CH3)2/, 2.20 (H-7a), 2.00 (H-4), 1.98 (H-7b), 1.59 (H-14a), 1.55 (6-CH3), 1.35 (H-14b), 1.28 (8-CH3), 1.26 (10-CH3), 1.14 (12-CH3), 1.11 (2-CH3), 1.09 (4-CH3), 1.05 (15-CH3).

13C NMR (75 MHz, CDCl3) : 179.4 (C-9), 174.5 (C-1), 105.6 (C-1'), 96.3 (C-1'), 86.4 (C-6), 86.2 (C-5), 83.3 (C-13), 79.5(C-3), 75.2 (C-11), 74.9 (C-12). 49.3 (3"-OCH3), 48.8 (C-10), 42.6 (C-2), 40.0 /3'-N(CH3)2/, 39.1 (C-7), 38.5 (C-4), 34.2 (C-8), 25.0 (C-14), 23.8 (6-CH3), 21.3 (12-CH3), 15.7 (10-CH3), 14.9 (8-CH3), 11.6 (15-CH3), 11.0 (4-CH3), 9.9 (2-CH3).

MS, PI (EI, electron impact), m/z 748.

Method 2

6-Deoxy-6,9-epoxy-8(R)-methyl-10-amino-9,10-securitiesin A (EP 0735041 A1, 02.10.1996) (1 g, 0,00134 mol) are suspended in 100 ml of water and leave to stand for 3 hours at room temperature. To the reaction mixture add CHCl3(30 ml) and pH adjusted to 9.0 by adding 10% NaOH, the layers separated and the aqueous layer was extracted two more times with CHCl3(60 ml). The combined organic extracts dried over K2CO3, evaporated on a rotary evaporator and then purified column chromatography on silica gel using the solvent CHCl3/CH3OH/conc.NH4OH, 6:1:0.1, the as described in method A.

EXAMPLE 2. 5-O-Desosamine-1-N-(2,3,4-trihydroxy-1,3 - dimethyl who hexyl)amido-10,11,12,13,14,15-hexanor-6-deoxy-6,9-epoxy-8(R)-methyl-9,10-securitiesin A (Ia) from example 1 (6 g, 0,008 mol) is dissolved in 300 ml of 0.25 N HCl and then stirred for 2 hours at room temperature. To the reaction mixture add CHCl3(40 ml) (pH of 2.0), the layers separated and the aqueous layer was again extracted twice CHCl3. After alkalizing to pH of 10.0 (20% NaOH) aqueous layer was again extracted with CHCl3. The combined organic extracts are dried at a pH of over 10 K2CO3, filtered and evaporated and get the crude product (1.3 g). By column chromatography on silica gel using a solvent system CH2Cl2/CH3OH/conc. NH4OH, 90:9:1, get a chromatographically homogeneous product (Ib) (0.85 grams) with the following physical-chemical constants.

So pl. 87-89oC.

Rf0,324, CH2Cl2/CH3OH/NH4OH, 90:9:1,5.

Rf0,222, CHCl3CH3OH, 7:3.

IR (CHCl3) cm-1, 3420, 2980, 2940, 2870, 1740, 1640, 1500, 1480, 1380, 1295, 1230, 1170, 1140, 1120, 980.

EXAMPLE 3. 1-N-(2,3,4-Trihydroxy-1,3-dimethylpentyl)amido-10,11,12,13,14,15-hexanor-6-deoxy-6,9-epoxy-8(R)-methyl-9,10 - securetraveler A (Ic)

5-O-Desosamine-1-N-(2,3,4-trihydroxy-1,3-dimethylpentyl)amido-10,11,12,13,14,15-hexanor-6-deoxy-6,9-epoxy-9,10-securitiesin A (Ib) from example 2 (4 g, 0,0068 mol) was dissolved in 20 the com within 2 hours. After cooling to room temperature, separated CHCl3layer and the aqueous layer was again extracted twice CHCl3(25 ml). The aqueous solution evaporated under reduced pressure, the solid residue add CH3OH (40 ml) and the reaction suspension is stirred for 1 hour at room temperature, filtered and the clear filtrate evaporated on a rotary evaporator to obtain a solid residue (3 g). By column chromatography on silica gel using the solvent CHCl3/CH3OH, 7:3, of the crude product (0.6 g) receive chromatographically uniform substance (Ic) (0.28 g) with the following physical-chemical constants.

Rf0,793, CHCl3/CH3OH, 7:3.

IR (CHCl3) cm-1, 3420, 2980, 2940, 2890, 1760, 1615, 1550, 1460, 1390, 1300, 1240, 1160, 1100, 970.

1H NMR (300 MHz, Py-d5) : 8.84 (CONH), 4.85 (H-10), 4.44 (H-3), 4.41 (H-11), 4.01 (H-5), 4.00 (H-13), 3.06 (H-2), 2.81 (H-8), 2.41 (H-4), 2.30 (H-7a), 2.10 (H-7b), 2.03 (H-14a), 1.72 (H-14b), 1.60 (2-CH3), 1.59 (10-CH3), 1.55 (12-CH3), 1.46 (4-CH3), 1.44 (6-CH3), 1.21 (8-CH3), 1.17 (15-CH3).

13C NMR (75 MHz, Py-d5) : 179.4 (C-9), 174.4 (C-1), 86.5 (C-6), 79.2 (C-5), 79.2 (C-13), 77.8 (C-3), 77.1 (C-11), 75.6 (C-12), 47.0 (C-10), 44.9 (C-2), 39.3 (C-7), 36.6 (C-4), 34.5 (C-8), 24.9 (C-14), 22.0 (6-CH3), 20.0 (12-CH3), 15.3 (10-CH3<4'-O-Diacetyl-1-N-(2,4-O-diacetyl-3-hydroxy-1,3-dimethylpentyl)amido-10,11,12,13,14,15-hexanor-6-deoxy-6,9-epoxy-9,10-securitiesin A (Id)

To a solution of the substance (Ia) (3,38 g, 0,0045 mol) from example 1 in pyridine (40 ml) is added acetic anhydride (12 ml) and then the reaction mixture is left to stand for 3 days at room temperature. The solution is poured into a mixture of ice water (pH of 4.8), adjusted pH of the mixture to 9.0 by adding 10% NaOH and the product extracted with CHCl3. The combined organic layers dried over K2CO3, filtered and evaporated and get the crude product (4.15 g). By column chromatography on silica gel using a solvent system CH2Cl2/CH3OH/conc. NH4OH, 90:9:1.5 points in the product (1.2 g) receive chromatographically homogeneous leads to compounds, which (Id) (0.65 g) with the following physical-chemical constants.

Rf0,622, EtAc/(h-C6H6)/NHEt2, 100:100:20.

IR (CHCl3) cm-1, 1745, 1720, 1650, 1515, 1450, 1370, 1240, 1165, 1110, 1060.

1H NMR (300 MHz, CDCl3) : 6.87 (CONH), 4.86 (H-11), 4.86 (H-1"), 4.51 (H-2'). 4.81 (H-13), 4.66 (H-4"), 4.51 (H-1'), 4.43 (H-10), 3.95 (H-3), 3.75 (H-5), 3.37 (3"-OCH3), 2.75 (H-8), 2.23 (H-2), 2.29 /3'-N(CH3)2/, 2.16 (H-7a), 2.15, 2.07, 2.05 and 2.03 (COCH3), 1.90 (H-7b), 1.84 (H-14a), 1.66 (H-4), 1.58 (6-CH3), 1.56 (H-14b). 1.29 (12-CH3), 1.25 (8-CH3), 1.23 (5'-CH3), 1.21 (10-CH3), 1.12 (2-CH3), 1.11 (3"-CH3), 1.11 (5"-CH3), 1 3
), 101.0 (C-1'), 96.2 (C-1'), 85.5 (C - 6), 81.5 (C-5), 78.6 (C-4"), 78.1 (C-3), 76.8 (C-13), 76.0 (C-11), 74.9 (C-12). 62.7 (C-3'), 62.3 (C-5"), 49.4 (3"-OCH3), 45.1 (C-10), 44.7 (C-2), 40.3 /3'-N(CH3)2/, 39.8 (C-7), 39.8 (C-4), 33.3 (C-8), 30.6 (C-4'), 24.7 (6-CH3), 21.9 (C-14), 21.0, 20.7, 20.6, 20.5 (COCH3), 20.9 (3"-CH3), 20.7 (5'-CH3), 18.4 (12-CH3), 17.2 (5"-CH3), 16.0 (10-CH3), 14.5 (8-CH3), 11.3 (4-CH3), 10.7 (15-CH3), 10.5 (2-CH3).

MS, ES, m/z 916.

EXAMPLE 5. 4"-O-Acetyl-1-N-(2,4,-O-diacetyl-3-hydroxy-1,3-dimethylpentyl)amido-10,11,12,13,14,15-hexanor-6-deepoxy-6,9-epoxy-9,10-securitiesin A (Ie)

The solution of the substance (Id) (2 g, 0,00218 mol) from example 4 in CH3OH (50 ml), allowed to stand for 3 days at room temperature. By evaporation under reduced pressure, the reaction mixture was concentrated to about 1/4 volume, add water (100 ml) (pH of 6.9) and then the resulting product highlight extraction CH2Cl2at a pH of 9.0 (10% NaOH). The combined organic extracts dried over K2CO3, filtered and evaporated and get the crude product (1,72 g). By column chromatography on silica gel using a solvent system CH2Cl2/CH3OH, 85:15, get chromatographically homogeneous triacetate (Ie) (0.85 grams) with the following physical-chemical to which SUP>: 1740, 1710, 1665, 1515, 1460, 1380, 1240, 1170, 1130, 1060.

1H NMR (300 MHz, CDCl3) : 7.14 (CONH), 4.87 (H-13), 4.85 (H-1"), 4.77 (H-11), 4.65 (H-4"), 4.47 (H-10), 4.41 (H-1'), 4.37 (C-5"), 4.07 (H-3), 3.75 (H-5), 3.33 (3"- OCH3), 3.26 (H-2'), 2.75 (H-8), 2.50 (H-2), 2.32 /3'-N(CH3)2/, 2.13, 2.06, and 2.03. (COCH3), 2.09 (H-7a), 1.91 (H-4), 1.83 (H-14a), 1.58 (6-CH3), 1.54 (H-14b), 1.29 (12-CH3), 1.26 (8-CH3), 1.23 (5'-CH3, 1.18 (10-CH3), 1.15 (4-CH3), 1.12 (2-CH3), 1.10 (3"-CH3), 1.08 (5"-CH3), 0.90 (H-15).

13C NMR (75 MHz, CDCl3) : 179.1 (C-9), 173.8 (C-1), 170.4, 170.1 and 170.1 (PINES3), 103.4 (C-1'), 96.0 (C-1'), 85.6 (C-6), 79.4 (C-3). 82.8 (C-5), 78.2 (C-11), 75.5 (C-13), 74.5 (C-12), 69.9 (C-2'), 65.0 (C-3'), 62.1 (C-5"), 49.1 (3"-OCH3), 44.5 (C-10), 42.6 (C-2), 39.7 /3'-N(CH3)2/, 38.1 (C-7), 38.5 (C-4), 33.4 (C-8), 23.7 (6-CH3), 21.5 (C-14), 20.5, 20.3 and 20.2 (COCH3), 20.6 (3"-CH3and 5'-CH3), 18.1 (12-CH3), 16.7 (5"-CH3), 16.2 (4-CH3), 14.3 (8-CH3), 11.2 (10-CH3), 10.9 (2-CH3), 10.4 (C-15).

MS, ES, m/z 874.

EXAMPLE 6. 2-O-(4-Bromobenzoyl-1-N-(2,3,4-trihydroxy-1,3-dimethylpentyl)-amido-10,11,12,13,14,15-hexanor-6-deoxy-6,9-ethoxy-9,10-securitiesin A (If)

Compound (Ia) (2.0 g, 0,0027 mol) from example 1 is dissolved in dry acetone (10 ml), add NaHCO3(0.4 g, 0,00476 mol) and then, after stirring for 1 hour at 0-5oC, is added dropwise a solution of 4-bromobenzonitrile (0,8 what he is removed by distillation under reduced pressure and to the residue is added water (30 ml), after extraction CHCl3at pH 8.5 distinguish the product. After drying over K2CO3and evaporation of the combined organic extracts produce crude product (2.3 g). By column chromatography on silica gel with use of the system solvent CHCl3/CH3OH/conc. NH4OH, 90:9:1.5 to receive a chromatographic uniform 2'-(p-bromobenzoyl) derivative (If) (1,23 g) with the following physical-chemical constants.

Rf0,390, EtAc/(h-C6H6)/NHEt2, 100:100:20.

Rf0,814, CH2Cl2/CH3OH/NH4OH, 90:9:1,5.

IR (CHCl3), cm-1: 1740, 1710, 1650, 1580, 1500, 1450, 1390, 1370, 1340, 1265, 1165, 1160, 1120, 1100, 1055, 1010.

1H NMR (300 MHz, CDCl3) : 7.73 (Ph), 6.61 (CONH), 5.04 (H-2'), 4.86 (H-1"), 4.61 (H-1'), 4.02 (H-10), 3.98 (H-5"), 3.92 (H-3), 3.82 (H-11), 3.73 (H-5), 3.59 (H-5'), 3.36 (3"-och3), 3.26 (H-3'), 3.25 (H-13), 3.03 (H-4"), 2.87 (H-3'), 2.77 (H-8), 2.37 (H-2"), 2.30 /3'-N(CH3)2/, 2.20 (H-7a), 2.16 (H-2), 1.84 (H-4'a), 1.78 (H-7b), 1.56 (H-14a), 1.59 (6-CH3), 1.56 (H-4), 1.41 (H-14b), 1.27 (10-CH3), 1.57 (6-CH3), 1.23 (8-CH3), 1.13 (12-CH3), 0.83 (4-CH3), 1.05 (2-CH3), 1.04 (C-15).

13C NMR (75 MHz, CDCl3) : 180.6 (C-9), 175.6 (C-1), 164.7 (COBr), 131.7, 131.3, 129.2 and 128.1 (aryl), 101.1 (C 1'), 94.8 (C-1'), 86.1 (C-6), 79.9 (C-3), 82.2 (C-5), 81.2 (C-13), 78.0 (C-3), 75.9 (C-11), 74.3 (C-12), 73.0 (C-3"), 72.2 (C-2'), 65.4 (C3
), 24.9 (C-14), 21.7 (12-CH3), 18.1 (5"-CH3), 13.8 (10-CH3), 14.7 (8-CH3), 11.8 (4-CH3), 11.1 (C-15), 10.0 (2-CH3).

MS, ES, m/z 931.

EXAMPLE 7. 2'-O(4-Bromobenzoyl)-4"-O-acetyl-1-N-(2,4-O-diacetyl-3-hydroxy-1,3-dimethylpentyl)-amido-10,11,12,13,14,15-hexanor-6-deoxy-6,9-epoxy-9,10-securitiesin A (Ig)

To a solution of the substance (If) (0.50 g, 0,00054 mol) from example 6 in pyridine (10 ml) is added acetic anhydride (2.5 ml) and then the reaction mixture is left to stand for 3 days at room temperature. The solution is poured into a mixture of ice water, adjusted the pH of the mixture to 9.0 by adding 10% NaOH and the resulting product highlight extraction CHCl3. The combined organic extracts dried over K2CO3, filtered, evaporated under reduced pressure and get the crude product (or 0.57 g). By column chromatography on silica gel using a solvent system CH2Cl2/CH3OH/conc. NH4OH, 90: 9: 1.5 a, the obtained precipitate (1.2 g) receive chromatographically uniform substance (Ig) (0.18 g) with the following physical-chemical constants.

Rf0,773, EtAc/(h-C6H6)/NHEt2, 100:100:20.

Rf0,938, CH2CI2/CH3OH/NH4OH, 90:9:1,5.

IR (CHCl7.73 (Ph), 6.83 (CONH), 3.38 (3"-OCH3), 2.28 /3'-N(CH3)2/, 2.17, 2.03 and 2.02 (COCH3).

EXAMPLE 8. 2'-O-(4-Bromobenzoyl)-1-N-[2-(4-bromobenzoyl)-3,4-dihydroxy-1,3-dimethylpentyl] amido-10,11,12,13,14,15-hexanor-6-deoxy-6,9-epoxy-9,10-securitiesin A (Ih) and

2'-O-(4-bromobenzoyl)-1-N-[4-(4-bromobenzoyl)-2,3-dihydroxy-1,3-dimethylpentyl] amido-10,11,12,13,14,15-hexanor-6-deoxy-6,9-epoxy-9,10-securitiesin A (Ii)

Compound (Ia) (7,8 g, 0,0104 mol) from example 1 is dissolved in dry acetone (200 ml) and added NaHCO3(23,55 g, 0,280 mol) and then the reaction suspension with stirring is heated to the boiling point. After stirring for 30 minutes is added dropwise a solution of 4-bromobenzonitrile (of 11.45 g, 0,052 mol) in acetone (80 ml), the reaction suspension is stirred for 30 hours at boiling under reflux, cooled to room temperature, filtered and evaporated under reduced pressure. The precipitate was dissolved in CH2Cl2(100 ml), add water (60 ml), followed by extraction with CHCl3at pH 9.0 to produce the product. The combined organic extracts washed with saturated solution of NaHCO3(80 ml) and water (40 ml) and dried over K2CO3. After removal of the solvent to obtain the compound (12.0 g) of dibromobenzoate (Ih) and (SUB>Cl2/CH3OH, 95:5 and receive a chromatographically homogeneous named in the title products (Ih) and (Ii) physico-chemical constants, below.

Compound (Ih)

Rf0,539, CH2Cl2/CH3OH/NH4OH, 90:9:0.5 in.

IR (CHCl3), cm-1: 1755, 1720, 1660, 1590, 1520, 1490, 1450, 1390, 1370, 1340, 1270, 1165, 1160, 1120, 1100, 1060, 1015, 850.

1H NMR (300 MHz, CDCl3) : 7.72 (Ph), 7.00 (CONH), 5.27 (H-11), 4.96 (H-2'), 4.72 (H-1"), 4.56 (H-1'), 4.53 (H-10), 3.93 (H-5"), 3.77 (H-3), 3.65 (H-5), 3.13 (H-13), 3.57 (H-5'), 3.25 (3"-och3), 3.05 (H-4"), 2.82 (H-3'), 2.42 (H-2"), 2.34 (H-8), 2.24 /3'N(CH3)2/, 2.02 (H-7a), 2.05 (H-2), 2.04 (H-2"a), 1.81 (H-4'a), 1.77 (H-7b), 1.71 (H-14a), 1.51 (H-2"b), 1.41 (H-14b), 1.50 (H-4), 1.41 (H-4'b), 1.36 (10-CH3), 1.27 (12-CH3), 1.30 (5"-CH3), 1.28 (5'-CH3), 1.24 (6-CH3), 1.23 (3"-CH3), 1.14 (8 - CH3), 1.01 (2-CH3), 0.98 (H-15), 0.83 (4-CH3), 0.80 (H-2"b).

13C NMR (75 MHz, CDCl3) : 180.3 (C-9), 174.6 (C-1), 166.4 and 164.5 (COBr), 131.6, 131.5, 129.1, 128.5, 128.2, 127.8 (Ph), 101.1 (C-1'), 96.3 (C-1'), 85.5 (C-6), 81.5 (C-5), 79.3 (C-11), 78.1 (C-3), 77.8 (C-4"), 77.0 (C-13), 75.7 (C-12), 72.6 (C-3"), 72.0 (C-2'), 68.9 (C-5'), 64.9 (C-5"), 63.0 (C-3'), 49.2 (3"-OCH3), 45.3 (C-10), 45.3 (C-2), 40.6 (C-4), 40.6 /3'N(CH3)2/, 36.9 (C-7), 33.1 (C-8), 34.5 (C-2'), 30.7 (C-4'), 24.3 (6-CH3), 22.6 (C-14), 21.3 (3"-CH3), 20.6 (5'-CH3), 17.8 (5"-CH3), 17.7 (12-CH3), 15.3 (10-CH3), 14.2 (8-CH3), 11.5 (4-CH3), 11.3 (C-15), 10.0 (2-CH3).
), cm-1: 3450, 2980, 2940, 1770, 1730, 1650, 1600, 1540, 1495, 1460, 1405, 1390, 1350, 1280, 1170, 1110, 1070, 1015, 850.

1H NMR (300 MHz, CDCl3) : 7.72 (Ph), 6.51 (CONH), 5.13 (H-13), 5.00 (H-2'), 4.55 (H-1'), 4.52 (H-1"), 4.09 (H-10), 3.92 (H-3), 3.85 (H-5"), 3.68 (H-5), 3.65 (H-11), 3.54 (H-5'), 3.28 (3"-och3), 3.00 (H-4"), 2.79 (H-3'), 2.69 (H-8), 2.25 /3'N(CH3)2/, 2.16 (H-7a), 2.10 (H-2), 2.04 (H-2"a), 2.00 (H-14a), 1.80 (H-4'a), 1.76 (H-7b), 1.62 (H-14b), 1.53 (H-4), 1.44 (H-4'b), 1.27 (5'-CH3), 1.27 (5'-CH3), 1.14 (3"-CH3), 1.04 (H-15), 0.80 (H-2"b).

13C NMR (75 MHz, CDCl3) : 180.1 (C-9), 174.9 (C-1). 165.8 and 164.7 (COBr), 131.8, 131.6, 131.5, 131.2, 131.0, 129.3, 129.1, 127.9 (Ph). 101.2 (C-1'), 94.1 (C-1'), 85.5 (C-6), 81.4 (C-5), 76.9 (C-3), 77.2 (C-4"), 78.3 (C-13), 74.6 (C-12), 72.6 (C-3"), 71.9 (C-2'), 70.2 (C-11), 69.0 (C-5'), 65.2 (C-5"), 63.3 (C-3'), 49.2 (3"-OCH3), 46.7 (C-10), 44.8 (C-2), 41.5 (C-4), 40.5 /3'N(CH3)2/, 36.9 (C-7), 33.3 (C-8), 33.2 (C-2'), 30.8 (C-4'), 25.0 (6-CH3), 21.7 (C-14), 21.3 (3"-CH3), 20.8 (5'-CH3), 17.5 (5"-CH3), 16.3 (12-CH3), 14.4 (8-CH3), 13.5 (10-CH3), 11.1 (C-15), 10.7 (4-CH3), 9.8 (2-CH3).

EXAMPLE 9. 1-N-[2,3-Dihydroxy-4-(4-bromobenzoyl)-1,3-di-etylhexyl] amido-10,11,12,13,14,15-hexanor-6-deoxy-6,9-epoxy-9,10-securitiesin A (Ij)

The product (Ii) (4.6 g) of example 8 was dissolved in methanol (50 ml), add water (10 ml) and then the reaction solution is left to stand for 24 hours at room temperature. Evaporation under reduced pressure to remove methanol, to which SUB>2CO3and evaporation of the combined organic extracts get the crude product (4.1 g). By column chromatography on silica gel using a solvent system CH2Cl2/CH3OH/conc. NH4OH, 90:9:0.5, and from raw product (1,90, g) allocate chromatographic (TLC) (0,72 g) homogeneous monobrominated (Ij) with physico-chemical constants, below.

Rf0,391, CH2Cl2/CH3OH/NH4OH, 90:9:0.5 in.

IR (CHCl3), cm-1: 3400, 2980, 2950, 1770, 1660, 1540, 1460, 1390, 1270, 1110, 1050, 1005.

1H NMR (300 MHz, CDCl3) : 7.72 (aryl), 7.26 (CONH), 5.13 (H-13), 4.54 (H-1"), 4.36 (H-1'), 4.20 (H-10), 4.14 (H-3), 3.87 (H-5"), 3.70 (H-5), 3.57 (H-5'), 3.54 (H-11), 3.29 (H-2'), 3.19 (3"-och3), 2.94 (H-4"), 2.53 (H-8), 2.53 (H-2), 2.45 (H-3'), 2.30 /3'N(CH3)2/, 2.15 (H-7a), 2.02 (H-14a), 2.00 (H-7b), 1.98 (H-2"a), 1.86 (H-4), 1.69 (H-4'a), 1.61 (H-14b), 1.50 (6-CH3), 1.33 (H-4'b), 1.29 (12-CH3), 1.26 (5'-CH3), 1.27 (3"-CH3), 1.26 (8-CH3), 1.25 (5"-CH3), 1.20 (10-CH3), 1.10 (3"-CH3), 1.02 (2-CH3), 0.99 (4-CH3), 0.92 (H-15), 0.88 (H-2"b).

13C NMR (75 MHz, CDCl3) : 179.3 (C-9), 174.4 (C-1), 165.9 (COBr), 131.8, 131.1, 129.0 and 128.1 (aryl), 104.9 (C-1'), 94.6 (C-1'), 86.1 (C-6), 84.5 (C-5), 76.9 (C-3), 78.1 (C-13), 74.6 (C-12), 70.5 (C-11), 70.2 (C-2'), 65.3 (C-5"), 65.8 (C-3'), 49.0 (3"- OCH3), 46.1 (C-10), 41.6 (C-2), 41.0 /3'N(CH3)2/, 39.1 (C-4), 38.7 (C-7), 33.9 (C-2"), 33.8 (13.6 (10-CH3), 9.9 (2-CH3), 10.6 (4-CH3), 10.9 (C-15).

EXAMPLE 10. 1-N-[2-(4-bromobenzoyl)-3,4-dihydroxy-1,3-dimethylpentyl] amido-10,11,12,13,14,15-hexanor-6-deoxy-6,9-epoxy-9,10-securitiesin A (Ik)

Of the product (Ih) (2.20 g) of example 8 by the method described in example 9, after purification of the crude product column chromatography on silica gel and evaporation of the fractions with Rf0,283 get chromatographically homogeneous, named the title product (Ik) (0.95 g).

Rf0,283, CH2Cl2/CH3OH/NH4OH, 90:9:0.5 in.

1H NMR (300 MHz, CDCl3) : 7.72 (Ph), 7.00 (CONH), 5.20 (H-11), 4.72 (H-1"), 4.36 (H-1'), 4.53 (H-10), 3.93 (H-5"), 3.77 (H-3), 3.65 (H-5), 3.23 (H-13), 3.59 (H-5'), 3.36 (H-2'), 3.25 (3"-och3), 3.05 (H-4"), 2.72 (H-3'), 2.42 (H-2"), 2.34 (H-8), 2.28 /3'N(CH3)2/, 2.02 (H-7a), 2.05 (H-2), 2.04 (H-2"a), 1.71 (H-4'a), 1.77 (H-7b), 1.71 (H-14a), 1.51 (H-2"b), 1.41 (H-14b), 1.50 (H-4), 1.26 (H-4'b), 1.36 (10-CH3), 1.27 (12-CH3), 1.26 (5"-CH3), 1.26 (5'-CH3), 1.64 (6-CH3), 1.20 (3"-CH3), 1.14 (8-CH3), 1.01(2-CH3), 0.98 (H-15), 0.83 (4-CH3), 0.80 (H-2"b).

EXAMPLE 11. 2,3-Cyclic carbonate 1-N-[4-hydroxy-1,3-dimethylpentyl] amido-10,11,12,13,14,15-hexanor-6-deoxy-6,9-epoxy-9,10-securitiesin A (Il)

Compound (Ia) from example 1 (10.0 g, 0,0134 mol) is dissolved in dry benzene (100 ml) and add ethylene carbonate resulting (5.0 g, 0,057 mol) and then is refluxed for 9 hours, leave to stand over night, evaporated under reduced pressure and get the crude product (Il) (11,0 g). By column chromatography on silica gel using a solvent system CH2Cl2/CH3OH/conc. NH4OH, 90: 9: -1,5 of the crude product (3.0 g) receive chromatographically uniform substance (Il) (1,25 d) physico-chemical constants, below.

IR (CHCl3), cm-1: 3540, 3300, 1790, 1760, 1660, 1530, 1450, 1380, 1300, 1280, 1230, 1165, 1000.

1H NMR (300 MHz, Py) : 8.46 (CONH), 5.26 (H-11), 5.18 (H-1"), 4.81 (H-1'), 4.61 (H-10), 4.54 (H-3), 4.52 (H-5"), 4.19 (H-5), 3.79 (H-13), 3.76 (H-5'), 3.60 (H-2'), 3.41 (3"-och3), 3.29 (H-4"), 3.07 (H-2), 2.88 (H-8), 2.61 (H-3'), 255 (H-7a), 2.50 (H-2"), 2.50 (H-4), 2.24 /3'N(CH3)2/, 2.20 (H-7b), 2.24 (H-4'a), 1.75 (6-CH3), 1.73 (H-14a), 1.65 (3"-CH3), 1.65 (3"-CH3), 1.58 (H-2"b), 1.55 (4-CH3), 1.55 (5"-CH3), 1.41 (10-CH3), 1.43 (2-CH3), 1.33 (12-CH3), 1.30 (8-CH3), 1.28 (5'-CH3), 1.16 (H-4'b), 1.16 (H-15).

13C NMR (75 MHz, Py) : 180.1 (C-9), 175.9 (C-1), 155.0 (CO carbonate), 105.2 (C-1'), 97.7 (C-1'), 88.9 (C-12), 87.1 (C-6), 83.0 (C-5), 82.2 (C-13), 80.8 (C-11), 79.1 (C-3), 70.2 (C-2'), 66.5 (C-5"), 66.2 (C-3'), 50.0 (3"-OCH3), 46.1 (C-10), 44.8 (C-2), 41.0 /3'N(CH3)2/, 40.5 (C-4), 39.3 (C-7), 36.4 (C-2"), 34.9 (C-8). 30.9 (C-4'), 25.2 (6 - CH3), 24.6 (C-14), 22.1 (5'-CH3), 21.9 (3"-CH3), 19.3 (5"-CH3), 17.2 (12-CH3), 16.8 (2-CH3), 15.7 (10-CHelexis]amido-10,11,12,13,14,15-hexanor-9 desoxo-9-hydroxy-8(R)-methyl-9,10-securitiesin A (Im) and

1-N-[2,3,4-Trihydroxy-1,3-dimethylpentyl] amido-10,11,12,13,14,15-hexanor-9 desoxo-9-hydroxy-8(S)-methyl-9,10-securitiesin A (In)

While boiling under reflux the solution of the substance (Ia) of example 1 (3.0 g, 0,004 mol) and NaBH4(2.4 g, 0,063 mol) in tert-butanol (32 mol), after stirring for 5 hours, added to it dropwise methanol (32 ml) and the solution refluxed for 2 hours. To the cooled mixture is added water (15 ml) and then extracted with CH2Cl2at a pH of 2.5. The combined organic extracts dried over K2CO3, filtered and evaporated under reduced pressure. The crude product (2.4 g) purified column chromatography on silica gel using the solvent CHCl3/CH3OH/conc. NH4OH, 6:1:0,1. Combining and pariva fractions with higher Rf(0,600) than the original 6,9-lactone (Ia)

(Rf0,553), get the mixture (0.45 g) of isomers (Im) and (In). Isomers share the repeated column chromatography on silica gel using system EtAc/n-C6H6)/Et2NH, 100:100:20. Viparita combined fractions with Rf0,158 get isomer (Im) (0.2 g), and viparita fraction with Rf0,197 get isomer (In) (0.05 g).

Substance (Im)

IR (CHC), 4.97 (H-1"), 4.36 (H-1'), 4.17 (H-10), 4.23 (H-3), 4.04 (H-5"), 3.76 (H-11), 3.70 (H-5'), 3.60 (H-9a), 3.46 (H-2'), 3.41 (H-5), 3.28 (3"-och3), 3.27 (H-9b), 3.19 (H-13), 2.93 (H-4"), 2.77 (H-3'), 2.50 (H-2), 2.38 (H-2"a), 2.30 /3'N(CH3)2/, 2.09 (H-8), 1.95 (H-4), 1.78 (H-4'a), 1.57 (H-14a), 1.40 (H-7b), 1.40 (H-2"b), 1.36 (H-4'b), 1.36 (H-14b), 1.33 (6-CH3), 1.28 (5'-CH3), 1.25 (10-CH3), 1.23 (5"-CH3), 1.18 (3"-CH3), 1.14 (12-CH3), 1.09 (2-CH3), 1.06 (4-CH3), 1.05 (H-15), 0.95 (8-CH3).

13C NMR (75 MHz, CDCl3) : 173.4 (C-1), 106.7 (C-1'), 96.4 (C-1'), 92.5 (C-5), 83.7 (C-13), 80.1 (C-3), 75.0 (C-6), 74.7 (C-11), 74.6 (C-12), 70.2 (C-2'), 69.0 (C-9), 65.4 (C-5"), 64.1 (C-3'), 50.0 (3"-OCH3), 49.0 (C-10), 44.1 (C-7), 41.3 (C-2), 39.5 /3'N(CH3)2/, 37.4 (C-4), 34.8 (C-2'), 31.0 (C-8), 27.8 (C-4'), 24.7 (C-14), 22.1 (6-CH3), 21.4 (12-CH3), 20.7 (5'-CH3), 21.1 (3"- CH3), 20.0 (8-CH3), 17.3 (5"-CH3), 16.0 (10-CH3), 10.1 (4-CH3), 11.3 (C-15), 8.4 (2-CH3).

Substance (In)

1H NMR (300 MHz, CDCl3) : 7.63 (CONH), 5.05 (H-1"), 4.34 (H-1'), 4.22 (H-10), 4.25 (H-3), 4.06 (H-5"), 3.74 (H-11), 3.71 (H-5'), 3.48 (H-9a), 3.34 (H-2'), 3.70 (H-5), 3.28 (3"-och3), 3.29 (H-9b), 3.14 (H-13), 2.93 (H-4"), 2.84 (H-3'), 2.50 (H-2), 2.32 (H-2"a), 2.28 /3'N(CH3)2/, 1.74 (H-8), 1.93 (H-4), 1.76 (H-4'a), 1.56 (H-14a), 1.74 (H-7a), 1.64 (H-7b), 1.41 (H-2"b), 1.32 (H-4'b), 1.36 (H-14b), 1.34 (6-CH3), 1.27 (5'-CH3), 1.25 (10-CH3), 1.23 (5"-CH3), 1.17 (3"-CH3), 1.15 (12-CH3), 1.11 (2-CH3), 1.07 (4-CH3), 1.46 (H-15), 0.89 (8-CH3).

13C NMR (75 MHz, CDCl3), 49.7 (C-10), 46.7 (C-7), 41.9 (C-2), 39.3 /3'N(CH3)2/, 37.4 (C-4), 34.7 (C-2'), 32.0 (C-8), 27.8 (C-4'), 26.2 (6-CH3), 24.9 (C-14), 21.9 (12-CH3), 21.1 (3"-CH3), 20.7 (5'-CH3), 19.6 (8-CH3), 17.4 (5"-CH3), 16.7 (10-CH3), 11.4 (C-15), 10.1 (4-CH3), 8.1 (2-CH3).

EXAMPLE 13. 2', 4"-O-Diacetyl-1N-[2,4-O-diacetyl-3-hydroxy-1,3-dimethylpentyl] amido-10,11,12,13,14,15-hexanor-9 desoxo-9-O-acetyl-8(R)-methyl-9,10-securitiesin A (Io)

Substance (Im) (0,70 g) from example 12 was dissolved in pyridine (10 ml), add acetic anhydride (5 ml) and left to stand for 2 days at room temperature. The reaction mixture was poured onto ice (50 ml) and extracted with CHCl3at pH 5 and pH 9. Drying over K2CO3and the process of evaporation of the combined organic extracts at pH 9 gives the crude product (0.87 g), which is suspended in petroleum ether, stirred for 30 minutes at 0-5oC, filtered and dried in a vacuum drying Cabinet at 50oC and get chromatographically homogeneous, named the title product (O) (0,61 g).

Rf0,473, EtAc/(h-C6H6)/Et2NH, 100:100:20.

IR (CHCl3), cm-1: 3510, 3395, 2980, 2950, 1740, 1660, 1535, 1460, 1370, 1240, 1170, 1045.

1H NMR (300 MHz, CDCl3) : 6.53 (CONH), 4.94 (H-13), 4.84 (H-1"), 4.83 (H-2'), 4.66 (H-4"). 4.65 (H-1'), .12, 2.07, 2.05 and 2.02 (PINES3), 1.92 (H-4), 1.83 (H-14a), 1.73 (H-4'a), 1.56 (H-2"b), 1.50 (H-7a), 1.44 (H-14b), 1.36 (H-4'b), 1.28 (6-CH3), 1.26 (H-7b), 1.22 (5'-CH3), 1.20 (12-CH3), 1.15 (2-CH3), 1.13 (10-CH3), 1.11 (3"-CH3), 1.11 (5"-CH3), 1.02 (8-CH3), 0.98 (4-CH3), 0.89 (15-CH3).

Remarks: In the above NMR spectra, the following words mean the following:

and - and,

aryl - aryl,

carbonate - carbonate.

1. Cetomacrogol class eritromicina General formula I

< / BR>
R1is hydrogen, (C1- C4)alcoolica group;

R2is hydrogen or R1and R2together with the carbon atoms to which they are linked, form a cyclic carbonyl group;

R3- (C1- C4)alcoolica group or arylcarbamoyl group;

Z is hydrogen or L-clavesilla group of the formula i

< / BR>
where R4is hydrogen or (C1- C4)alcoolica group;

W - D-dessalinienne group of the formula ii

< / BR>
where R5is hydrogen, (C1- C4)alcoolica or arylcarbamoyl group;

X and Y together represent lactone or X is CH2OR6group, where R6is (C1- C4)alkanoyl, and Y represents a hydroxyl,

or their formats the p. 1, in which R1, R2and R3are the same and represent hydrogen, Z is hydrogen or L-ladiesenjoy group of the formula (i), where R4represents hydrogen, W is D-disseminating group of the formula (ii), where R5is hydrogen and X and Y together represent lactone.

3. Connection on p. 2, in which Z is L-ladiesenjoy group of formula i, where R4is hydrogen, and W is D-disseminating group of formula ii, where R5represents hydrogen.

4. Connection on p. 2, in which Z is hydrogen, and W is D-disseminating group of formula ii, where R5represents hydrogen.

5. Connection on p. 2, in which Z is hydrogen.

6. Connection on p. 1, in which R1and R3are the same and represent (C1- C4)alkanoyloxy group, R2is hydrogen, Z is L-ladiesenjoy group of formula i, where R4is (C1- C4)alkanoyloxy group, W is D-disseminating group of formula ii, where R5represents hydrogen or (C1- C4)alkanoyloxy group, and X and Y together represent lactone.

7. The connection is oredom, Z is L-ladiesenjoy group of formula i, where R4represents acetyl group, W is D-disseminating group of formula ii, where R5represents hydrogen.

8. Connection on p. 6, in which R1and R3are the same and represent acetyl group, R2is hydrogen, Z is L-ladiesenjoy group of formula i, where R4represents acetyl group, W is D-disseminating group of formula ii, where R5represents acetyl group.

9. Connection on p. 1, in which R1and R3are the same or different and represent hydrogen, (C1- C4)alkanoyloxy group, R2is hydrogen, Z is L-ladiesenjoy group of formula i, where R4represents hydrogen or (C1- C4)alkanoyloxy group, W is D-disseminating group of formula ii, where R5represents hydrogen or arylcarbamoyl group, and X and Y together represent lactone.

10. Connection on p. 9, in which R1, R2and R3are the same and represent hydrogen, Z is L-ladiesenjoy group of formula i, where R4represents hydrogen, W is D-desos.9, in which R1and R3are the same and represent acetyl group, R2is hydrogen, Z is L-ladiesenjoy group of formula i, where R4represents acetyl group, W is D-disseminating group of formula ii, where R5is 4-bromobenzoyl group.

12. Connection on p. 9, in which R2and R3are the same and represent hydrogen, Z is L-ladiesenjoy group of formula i, where R4represents hydrogen, W is D-disseminating group of formula ii, where R5is 4-bromobenzoyl group.

13. Connection on p. 9, in which R2and R3are the same and represent hydrogen, Z is L-ladiesenjoy group of formula i, where R4represents hydrogen, W is D-disseminating group of formula ii, where R5represents hydrogen.

14. Connection on p. 9, in which R3is 4-bromobenzoyl group, R1and R2are the same and represent hydrogen, Z is L-ladiesenjoy group of formula i, where R4represents hydrogen, W is D-disseminating group of formula ii, where R5is 4-Brom1and R2are the same and represent hydrogen, Z is L-ladiesenjoy group of formula i, where R4represents hydrogen, W is D-disseminating group of formula ii, where R5represents hydrogen.

16. Connection on p. 1, in which R1and R2together with the carbon atoms to which they are linked, represent a cyclic carbonyl group, R3is hydrogen, Z is L-ladiesenjoy group of formula i, where R4represents hydrogen, W is D-disseminating group of formula ii, where R5is hydrogen and X and Y together represent lactone.

17. Connection on p. 16, in which R1and R2together with the carbon atoms to which they are linked, represent a cyclic carbonyl group, and R3represents hydrogen.

18. Connection on p. 1, in which R1and R3are the same and represent hydrogen, R2is hydrogen, Z is L-ladiesenjoy group of formula i, where R4represents hydrogen or (C1- C4)alkanoyloxy group, W is D-disseminating group of formula ii, where R5represents hydrogen or (C1- C4)alkanoyloxy GRU and Y represents a hydroxyl group.

19. Connection on p. 18, in which R1, R2and R3are the same and represent hydrogen, Z is L-ladiesenjoy group of formula i, where R4represents hydrogen, W is D-disseminating group of formula ii, where R5represents hydrogen, X represents a group CH2OR6and Y represents a hydroxyl group.

20. Connection on p. 18, in which R3represents acetyl group, R2is hydrogen, Z is L-ladiesenjoy group of formula i, where R4represents acetyl group, W is D-disseminating group of formula ii, where R5represents acetyl group, X represents a group CH2OR6where R6represents an acetyl group and Y represents a hydroxyl group.

21. The method of obtaining compounds of General formula I

< / BR>
where R1, R2, R3, R4, R5X, Y, Z and W are defined in paragraph 1,

or its pharmaceutically acceptable salts accession inorganic or organic acids, characterized in that the 6-deoxy-6,9-epoxy-8(R)-methyl-10-amino-9,10-securitiesin And General formula II

< / BR>
exposed to polar solvents, preferred poreallashuone formed compound of General formula I, where R1, R2and R3are the same and represent hydrogen, Z is L-klavesinnoj group of formula i, where R4represents hydrogen, W is D-disseminules group of formula ii, where R5is hydrogen and X and Y together represent lactoovo group that further, if you want, put

A) interaction with diluted inorganic acids, preferably from 0.25 N hydrochloric acid, at room temperature, with the formation of compounds of General formula I, where R1, R2and R3are the same and represent hydrogen, Z is hydrogen, W is D-disseminules group of formula ii, where R5is hydrogen, X and Y together represent lactone, or interaction with a more concentrated acid, preferably with 2N hydrochloric acid, in the presence of an inert solvent, preferably chloroform, at elevated temperature, preferably at the boiling temperature of the reaction mixture, with formation of compounds of General formula (I), where R1, R2and R3are the same and represent hydrogen, Z is hydrogen, and X and Y together represent lactone, or

B) O-allyouareretards (C1- C4)alkylcarboxylic acids, preferably acetic anhydride, in an inert reaction solvent, preferably pyridine, at a temperature of 0 - 30oC, preferably at room temperature, the compounds of General formula I, where R1and R3are the same and represent (C1- C4)alcoholnye group, and R2is hydrogen, Z is L-klavesinnoj group of formula i, where R4is (C1- C4)alkanoyloxy group, W is a D-disseminules group of formula ii, where R5is (C1- C4)alkanoyloxy group, and X and Y together represent lactone, which is then, if necessary, is subjected to solvolysis reaction in the lower alcohols, preferably methanol, at room temperature for 3 days, with the formation of compounds of General formula I, where R1and R3are the same and represent (C1- C4)alcoholnye group, and R2is hydrogen, Z is L-klavesinnoj group of formula i, where R4is (C1- C4)alkanoyloxy group, W is a D-disseminules group of formula ii, where R5is hydrogen, and X and Y together represent lactone, or t, at least, 1,1 - equimolar excess of carboxylic acid, preferably 4-bromobenzonitrile, in dry acetone at a temperature of 0 to 5oWith compounds of General formula I, where R1, R2and R3are the same and represent hydrogen, Z is L-klavesinnoj group of formula i, where R4represents hydrogen, W is D-disseminules group of formula ii, where R5is arylcarbamoyl group, and X and Y together represent lactone, which then, if required, subjected to O-acylation according to B1), with the formation of compounds of General formula I, where R1and R3are the same and represent (C1- C4)alcoholnye group, and R2is hydrogen, Z is L-klavesinnoj group of formula i, where R4is (C1- C4)alkanoyloxy group, W is a D-disseminules group of formula ii, where R5is arylcarbamoyl group, and X and Y together represent lactone, or

B2B) use at least 5-equimolar excess of carboxylic acid, preferably 4-bromobenzonitrile, at elevated temperature, preferably at the boiling temperature of the reaction mixture, a mixture of compounds of the General who predstavlyaet hydrogen, or where R3is arylcarbamoyl group, and R1and R2are the same and represent hydrogen, Z is L-klavesinnoj group of formula i, where R4is hydrogen, and W is a D-disseminules group of formula ii, where R5is arylcarbamoyl group, and X and Y together represent lactone, and these compounds separated using column chromatography on silica gel, and then, if required, subjected to solvolysis reaction, with the formation of compounds of General formula I, where R1, R2and R3are the same and represent hydrogen, or R3is arylcarbamoyl group, and R1and R2are the same and represent hydrogen, Z is L-klavesinnoj group of formula i, where R4is hydrogen, and W is a D-disseminules group of formula ii, where R5is hydrogen, and X and Y together represent lactone, or

In) of the interesterification reaction with derivatives of carboxylic acids, preferably with 3-5 equimolar excess of ethylene carbonate resulting, in an inert solvent, preferably benzene, at elevated temperature, preferably at the boiling temperature of the reaction mixture for 3 to 9 hours, which are closely linked, are cyclic carbonyl group, and R3is hydrogen, Z is L-klavesinnoj group of formula i, where R4represents hydrogen, W is D-disseminules group of formula ii, where R5is hydrogen, and X and Y together represent lactone, or

G) recovering metal hydride complexes, preferably with sodium borohydride in the presence of tertiary alcohols, preferably tert-butanol, in an inert solvent, preferably methanol, at elevated temperature, preferably at the boiling temperature of the reaction mixture, with formation of compounds of General formula I, where R1, R2and R3are the same and represent hydrogen, Z is L-klavesinnoj group of formula i, where R4represents hydrogen, W is D-disseminules group of formula ii, where R5is hydrogen, and X represents a group CH2OR6and Y represents a hydroxyl group, which then, if required, subjected to O-acylation according to B1), preferably acetic anhydride, to form compounds of General formula I, where R1and R3are the same and represent (C1- C4)alkalise (C1- C4)alkanoyloxy group, W is a D-disseminules group of formula ii, where R5is (C1- C4)alkanoyloxy group, X represents a group CH2OR6where R6is (C1- C4)alkanoyloxy group, and Y represents a hydroxyl group,

and then, if required, obtained cetomacrogol subjected to interaction with at least equimolar amounts of the corresponding inorganic or organic acid in a solvent inert to the reaction, with formation of the corresponding salts accession acid.

 

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