9a-azalide fragments macrolide antibiotic class of azalides, method of their production and intermediate compounds for their production

 

(57) Abstract:

The invention relates to new compounds of the class of cetomacrogol and semisolids, potential intermediates in obtaining new macrolide and asamenew antibiotics, as well as the way they are received and intermediate compounds for their preparation. Describes 9a-azalide fragments macrolide antibiotic class of azalides General formula (I) in which R1and R2the same and represent H or CH3; R3and R4different and denote H or CH3; Y denotes 0, when Z represents CH3or Y is NH, when Z is CH(CH3)CH(OH)SON(CH3)CH(OH)C2H5or their pharmaceutically acceptable salts of inorganic or organic acids. 3 S. and 36 C.p. f-crystals.

The invention relates to new compounds of the class of cetomacrogol and semisolids, potential intermediates in obtaining new macrolide and asamenew antibiotics, as well as the way they are received and intermediate compounds for their preparation.

It is known that erythromycin A - valuable macrolide antibiotic, the structure of which contains a 14-membered cyclic lactone with a keto group at position 9 (McGuire, Antibiot, chemother, 1952, the deposits of infections, caused by gram-positive bacteria. The main disadvantage of the use of erythromycin A in the treatment of man limited his actions against strains of gram-negative bacteria, poor tolerance of his gastro-intestinal tract of some patients, as well as the loss of activity in an acid environment with formation of active metabolite of anhydroerythromycin. Spiritlessly aliceooa rings erythromycin prevent A chemical conversion of the ketone C-9 or hydroxyl groups at position C-6 and/or C-12. So, for example, by the reaction of the ketone C-9 with hydroxylamine-hydrochloride, followed Ekmanovskoe rearrangement of the resulting oxime 9(E)-erythromycin A and the restoration of the thus obtained 6,9-aminoether allocated 9 desoxo-9a-Aza-9a-homoerythromycin A, the first macrolide with 15-membered azlactone ring. (Kobrehel J. et al., U. S. Pat. 4, 328, 334, 5/1982). Reductive methylation 9a-amino group (the process of Eschweiler-Clarke) synthesized 9-desoxo-9a-methyl-9a-Aza-9a-homoerythromycin A (AZITHROMYCIN) (Kobrehel, J. et. BE Pat. 892357, 7/1982), the prototype of a new antibiotic class of azalides. In addition to broad-spectrum antimicrobial activity, including gram-negative bacteria and intracellular microorganisms, azithromycinjlm and short treatment times.

Recently described hydrolysis and alcoholysis of lactone C-1 of erythromycin A and B, resulting in a corresponding linear SECO-acids or esters (Martin S. F., J. Am. Chem. Soc., 1991, 113, 5478-5480). It also describes catalyzed by bases transformations, which lead to the disclosure of the macrocycle in the formation of the C-1 carboxylate (Waddel S. J., and Blizzar J. A., 94/15617, 7/1994). Describes the formation of new macrolide and azalide cycles by connecting the right ("East") 8a-Aza-C-1/c-8 and 9a-Aza-C-1/C-9) fragments 9 desoxo-8a-Aza-8a-homoerythromycin A and 9 desoxo-9a-Aza-9a-homoerythromycin A different fragments, which form the left (Western) part of the molecule. It should be emphasized that the above-mentioned linear fragment C-1/C-9 is different from the corresponding fragment of azithromycin presence incremental ethylene group at carbon atom C-9. In the literature it is not known linear 9a-azalide fragments macrolide antibiotic class of azalides General formula (1), which are the object of the present invention.

< / BR>
in which R1and R2equal and denote H or CH3,

R3or R4different and are H or CH3,

Y is O or NH;

Z - CH3or CH(CH3)CH(OH)SON(CH3)CH(OH) C2H5,

or>and R4characterize two epimeria form compounds of General formula (I), which differ only in the configuration of the chiral center at carbon C-8. Although the stereochemistry at C-8 is not installed, the compounds in which R3represents CH3assigned (R)-configuration on the basis of the proximity of the chemical shift of these compounds and source 6,9-aminoether with C-8(R)-configuration.

The present invention also relates to a method of preparing compounds I and to new intermediate products for preparing compounds of General formula (I). The structure of the intermediate product represented by the General formula (II).

< / BR>
in which X Is O or NOR7where R7- H, acyl or arylsulfonyl;

R3or R4different and denote H or CH3;

R5and R6the same or different and denote H or acyl;

Y is O or NH;

Z - CH3CH(C2H5)SON(CH3)CH(OR8)CH(CH3) OTHER9or CH(CH3)CH(OR10)SON(CH3)CH(OR11) C2H5where R8- H or acyl, R9- H, acyl or arylsulfonyl and R10and R11the same and represent H or acyl.

The invention also relates to the pharmaceutically suitable salts formed n the developments of General formula (I) and (II) the right ("East") portion of the molecule, including both sugars, structurally identical to the corresponding C-1/C-9 fragment macrolactones cycle 6,9-aminoether erythromycin A or 9 desoxo-6,9-9a-Aza-9a-homoerythromycin A, whereas "Western" - the left part represents the C-1 methyl ether or unsubstituted or substituted C-10/c-15 fragment of the original aminoether with end unsubstituted or substituted primary group or represents the same piece back associated with atom C-1, giving, instead of C-1 lactone, new, not yet described C-1 amines.

New 9a-azalide fragments of General formula I

< / BR>
in which R1and R2- H or CH3;

R3and R4different and denote H or CH3;

Y is O or NH;

Z - CH3or CH(CH3)CH(OH)SON(CH3)CH(OH)C2H5,

and their pharmaceutically applicable salts of organic or inorganic acids obtained by the method in which the source 6,9-iminoethyl erythromycin A of the formula (III)

< / BR>
put

A) the action of acid in the conditions of hydrolysis aminogroup, and then optionally N - and/or O-acylation anhydride or acid chloride of the acid, and then, if necessary, solvolysis, or

B) the action of hydroxylamine-hydrochloride in the presence of the appropriate reorgani the appropriate inorganic or organic acids under the conditions of hydrolysis of hydroxyisopropyl and then, if you want N - and/or O-acylation, and then the solvolysis, as described in A), or, if you want,

B2) N - and/or O-acylation with anhydrides or acid chlorides of the acids, and then, if necessary, solvolysis, or, if necessary

B3) the appropriate organic or inorganic bases in terms of intramolecular acylation of amine and then, if necessary, N - and/or O-acylation with anhydrides or acid chlorides of the acids and then, if necessary, solvolysis, thus obtaining compounds of General formula (II)

< / BR>
in which X Is O or NOR7where R7- H, acyl or arylsulfonyl;

R3and R4different and represent H or CH3;

R5and R6the same or different and represent H or acyl;

Y is O or NH;

Z - CH3CH(C2H5)SON(CH3)CH(OR8)CH(CH3) OTHER9or CH(CH3CH(OR10)SON(CH3)CH (OR11C2H5where R8- H or acyl, R9- H, acyl or arylsulfonyl, R10and R11the same or are H or acyl,

and their pharmaceutically suitable salts of organic or inorganic acids, which, if necessary, subjected to catalytic recovery, and then, if necessary, reset the rmula (I), where R1- R4, Y, Z represent the above groups. Obtaining new compounds of General formula (I) and (II) can be represented by the schemes of reactions 1 and 2.

Compounds of General formula (II) in which X and Y are the same and represent O, R3- CH3, R4- H, R5and R6the same and represent H, Z is CH(C2H5(A)SON(CH3)CH(IR8)CH(CH3) OTHER9where R8and R9identical and denote H (Scheme 1, 2a), get method A) by the action of acid, preferably glacial acetic, 6.9-iminoethyl erythromycin A of the formula (III) under the conditions of hydrolysis at room temperature for 3 days, while C-9/9a-N bond is cleaved, or inorganic or organic acids under the conditions of hydrolysis of hydroxyisopropyl on the compound of General formula (II) obtained by the method (B), in which X - HOR7where R7- H, R3- CH3, R4- H, R5and R6the same and represent H, Y Is O and Z is CH(CH2H5)SON(CH3)CH(OR8)CH(CH3) OTHER9where R8and R9the same and represent h

Preferably the hydrolysis of hydroxyisopropyl carried out in a mixture of methanol-HCl at room temperature for 10 days. Received subsequent process of evaporation of the combined organic extracts at pH 8.3 and accordingly, if necessary, subjected to N - and/or O-acylation with anhydrides or acid chlorides of the acids.

The reaction of acylation of the resulting lactose anhydride acid is conducted in a conventional manner (Jones et al., J. Med. Chem. 1971, 5:631; Banaszek et al. Rocy et al. Rocy Chem., 1969, 43: 763), receive appropriate tetraalkyl derivatives. So, for example, by acylation with acetic anhydride in a solvent, inert under the reaction conditions, preferably in pyridine, at room temperature for 7 days obtained 2', 4" 11-O,10-N leads to compounds, which the General formula (II) in which X and Y are the same and represent O, R3- CH3and R4- H, R5and R6the same and represent COCH3Z - CH(C2H5)SON(CH3)CH(OR8)CH(CH3) OTHER9where R8and R9the same and represent CHOCH3(Compound 2b). When standing 2', 4", 11-O, 10-N leads to compounds, which in methanol at room temperature for 3 days is the solvolysis of ester group at the 2'-position and is formed 4", 11-O, 10-N-triacetate General formula (II) in which R5- H, and X, Y, Z, R3, R4, R6, R8and R9the same as in the above-mentioned leads to compounds, which (compound 2C). The acylation with the acid chloride of the acid, premudrova ether, at 0-5oC for 3 h, you get a 10-N-bromobenzylamine General formula (II), where X and Y are the same and represent O, R3- CH3, R4- H, R5and R6the same and represent H, Z is CH(C2H5)SON-(CH3)CH(OR8)CH(CH3) WHR9where R8- H, and R9- 4-bromobenzoyl (compound 2d).

The reaction 6,9-aminoether erythromycin A of the formula (III) with hydroxylamine-hydrochloride carried out according to method B) in a solvent inert under the reaction conditions, in the presence of organic and inorganic bases in one or two stages at 25-70oC. When conducting the reaction in one stage, there is a decomposition of C-9/9a-N bond in the formation of the oxime group transformation of at C-9 and the primary amino group atom C-10, forming a compound of General formula (II) in which X denotes a NOR7where R7- H, Y IS O, R3CH3and R4- H, R5and R6the same and represent H, and Z is CH(C2H5)SON(CH3CH(OR8)CH(CH3) OTHER9where R8and R9the same and represent H, isolated as the sole product (Scheme 1.3 a). The reaction is carried out in the presence of 1.1 to 30 molar excess of hydroxylamine-hydrochloride, preferred 5,2-molar excess. aptara acid can be used inorganic bases, such as the carbonates or bicarbonates of alkali metals, preferably sodium carbonate or potassium hydroxide, or organic bases, such as pyridine, and at the same time is a solvent inert under the reaction conditions. The selection is carried out in the usual extraction with organic solvents, often chlorinated hydrocarbons, predominantly methylene chloride at pH 10. If the reaction is carried out in two stages, i.e. at the first stage 6,9-iminoethyl erythrozyten A formula (III) is subjected to at least a 1.3 molar excess of the above-mentioned inorganic or organic base in a solvent inert under the reaction conditions, mainly in alcohol C1-C4, preferably in methanol, boiling the reaction mixture until the disappearance of aminoether (TLC), then the resulting mixture of products is highlighted by extraction, mainly chlorinated hydrocarbons, preferably methylene chloride at a pH of 8, then in the second stage, the crude product is reacted with hydroxylamine-hydrochloride in the presence of inorganic or organic bases, as described above, this reaction is not clear. The resulting mixture of products stands out stepwise extraction of organic the EC at pH 10 the mixture of the two products, one of which is identical to the compound (3a), and the other - his C-8(S) enantiomer of General formula (II), in which the X - NOR7where R7- H, Y IS O, R3Is H and R4- CH3, R5and R6the same and represent H, and Z is CH(C2H5)CHO(CH3)CH(OR8)CH(CH3) OTHER9where R8and R9the same and represent H (scheme 2,3 b). The process of evaporation of the combined organic extracts at pH 8, in addition to the compounds (3a) and (3b) obtained two isomeric oxime S-8 of General formula (II), in which the X - NOR7where R7- H, Y IS O, R3and R4different and represent H or CH3, R5and R6the same and represent H, and Z is CH3(scheme 2, 7a and 7b), as a result of simultaneous cleavage of communication C-9/9a-N and macrocyclic lactone C-1 in the formation of C-1 of ethoxylate. The compounds (7a) and (7b) are distinguished by chromatography on a column of silica gel, as eluent using CHCl3:CH3OH:NH4OH conc. (6: 1: 0.1) and will satcam, if necessary, subjected to catalytic recovery.

Oximes (3a) and (3b) with the terminal amino group, if necessary, allroots N - and/or O-atom anhydrides or acid anhydrides as described in method A, and then, if neobk-O, 10-N-tetracetic 9 (E)-acetoxy General formula (II), in which the X - NOR7where the - COOH3, R3- CH3and R4-H, R5and R6the same and represent COCH3Y is O, and Z is CH(C2H5)SON(CH3)CH(OR8)CH (CH3)OTHER9where R8and R9the same and represent COCH3(compound 3c), which, if necessary, is subjected to solvolysis, preferably, methanolysis, giving a compound of General formula (II) in which X is other7where R7represents H, R3- CH3and R4and R5the same and represent H, R6- COCH3, Y is O and Z is CH(C2H5)SON(CH3)CH(OR8)CH(CH3) OTHER9where R8and R9the same and represent COCH3(compound 3d). Reaction of compounds (3a) and (3b) with anhydrides of the acids in a solvent, inert under the reaction conditions, in the presence of inorganic or organic bases when 0-25oC get mono - and disubstituted acyl derivatives, which, if necessary, allocate chromatography on a column of silica gel, using as eluent system CH2Cl2CH3OH (85:15). Mostly the reaction of the compound (3a) with mozillateam in the presence of NaHCO3in R4- R6the same and represent H, Y Is O, and Z is CH(C2H5)SON(CH3)CH(OR8)CH(CH3) OTHER9group, where R8- H, and R9- tosyl (compound 3e) or in which the X - NOR7where H, R3- CH3and R4- R6the same and represent H, Y Is O, and Z is CH(C2H5)SON(CH3)CH(OR8)CH (CH3)OTHER9group, where R8- H, and R9- tosyl (Compound 3f).

If required, the compounds (3a) and (3b) are exposed bases in terms of intramolecular acylation of an amine, and then, if necessary, catalyst recovery. The reaction is intramolecular acylation of the above primary amines proceeds at room temperature in the presence of inorganic and organic bases, preferably such as ammonium hydroxide, sodium hydroxide, sodium hydroxide or triethylamine, thus there is an intramolecular migration of alloctype at C-1 from oxygen to the terminal amino group, leading to the inversion of the C-10/C-15 left (Western) portion of the molecule and formation of C-1 amide of General formula (II), in which the X - NOR7where R7- H, R3and R4different and represent H or CH3, R5and R6the same and represent H, Y is NH, and Z Is the Dreams and represent H (Scheme 2, 4 a and 4b) which, if required, subjected to N - and/or O-acylation with anhydrides or acid chlorides acid, or catalytic recovery.

The reaction of N and/or O-acylation of compounds (4a) and (4b) anhydrides of the acids according to the method (A) gives 2', 4"-O-diacyl-1N-(2,4 - O-diacyl)-9(E)-acyloxy. So, for example, by acylation of the compound (4a) with acetic anhydride in pyridine at room temperature for 10 days the compound obtained of General formula (II), in which the means NOR7where R7- COCH3, R3-CH3and R4- H, R5and R6the same and represent COCH3, Y is NH and Z is CH(CH3)CH(OR10)SON(CH3)CH(OR11) C2H5where R10and R11identical and denote COCH3(compound 4c). If required, the compound (4c) is offered to solvolysis, preferably, methanolysis, then diallylamine of oxyethira in position 2' or 2' and 9', giving compounds of General formula (II), in which the X - NOR7where R7- H, R3- CH3, R4- H, R5- H, R6- COCH3, Y is NH and Z is CH(CH3)CH(OR10)SON(CH3)CH(OR11) C2H5where R10and R11the same and represent COCH3(compound 4d), or X - NOR7where R7- H(OR11) C2H5the group, in which R10and R11the same and represent COCH3(compound 4 e).

Similarly casilinum derivative (3a) and (3f) are obtained monosubstituted acyl derivatives by reaction with anhydrides of the acids. Mainly by the reaction of (4a) with mozillateam in acetone in the presence with NaHCO3at room temperature for 12 h derived the General formula (II), in which the X - NOR7where R7-tosyl, R3- CH3, R4- R6-H, Y IS NH, Z IS CH(CH3)CH(OR10)SON(CH3)CH(OR11) C2H5group, in which R10and R11identical and denote H (compound 4f). Catalytic reduction of the above-mentioned Asimov (4a, 4b, 7a and 7b) proceeds in a solvent inert under the reaction conditions in the presence of noble metals or their oxides as catalysts at room temperature under hydrogen pressure, 5105-7106PA from 10 hours to 3 days. Mainly the recovery is carried out in glacial acetic acid using the oxides of platinum (IV) as a catalyst, for 10 h under hydrogen pressure 7106PA, after which the product is allocated a conventional manual extraction (pH 5.5, 9.0 and 10.5) chlorinated uglevodorodnye amines of General formula (I), in which R1and R2the same and represent H, R3- CH3, R4- H or R3- H, and R4- CH3Y is O or NH, and Z is CH3or CH(CH3)CH(OH)SON(CH3)CH(OH)C2H5(Scheme 2, 5a, 5b, 8a, 8b), if required, subjected to reductive N-alkylation. Mainly reductive methylation takes place with 1-4 equivalents of formaldehyde (37%) in the presence of the same or double the amount of formic acid (98-100%) in a solvent inert under the reaction conditions, such as kaleidotrope, preferably chloroform, at boiling for 2-20 h, which depends on the amount taken aldehyde or acid. The resulting product is allocated a conventional manual extraction (pH 5.0 and 9.5) and, if required, purified column chromatography on silica gel using as eluent system CHCl3:CH3OH: conc. NH4OH(6:1:0,1), thus receive dimethylaminopropane General formula (I) in which R1and R2identical and denote CH3, R3- CH3and R4- H or R3- H, and R4- CH3Y is O or NH, and Z is CH3or CH(CH3)CH(OH)SON(CH3)CH(OH)C2H5(Scheme 2, 6a; 6b, 9a and 9b).

Pharmaceutically acceptable salt, coteries at least equimolar amounts of the corresponding inorganic and organic acids, such as itestosterone, sulfuric, phosphoric, acetic, propionic, triperoxonane, maleic, citric, succinic, Atlanterra acid, methanesulfonate, benzosulfimide, p-toluensulfonate, laurilsulfate, etc. in a solvent, inert under the reaction conditions. Salts are distinguished by filtration, and, if they are soluble in a solvent, inert under the reaction conditions, planting other solvent or by evaporation mainly by the process of lyophilization.

When carrying out the reaction in accordance with the above disclosure is a 15-membered azlactone ring 6,9-aminoether erythromycin A, you get samopromzvolny with different reactive functional terminal groups, which makes possible the synthesis of a number of new macrolides or azalides with modified macrocyclic aglycone. In connection with the inversion of the left (Western) side of the molecule (4,5 and 6) 2,3,4-trihydroxy-1,3-dimethylgermylene group is a C-10/C-15 fragment 6,9-aminoether erythromycin A, for simplicity in the description of spectroscopic data stored denote the carbon atoms that existed prior to inversion. These designations are presented in schemes 1 and 2. Latimer 1. 9 Desoxo-6-deoxy-6,9-epoxy-8(R)-methyl-10-amino - 9,10-securitiesin A9(E)-oxime (13a).

Method A.

To a solution of 6,9-aminoether erythromycin A (1) (36,0 g 0,049 mol) in CH3OH abs. (750 ml) is added NH2OHHCl (18 g, 0,259 mol) and Na2CO3(6.8 g, 0,0642 mol) and the reaction mixture is stirred at the boil for 3 hours, the Suspension is evaporated in vacuum and the solid residue was added 240 ml of H2O and 240 ml of CH2Cl2(pH 6.8), pH adjusted to 10 by addition of 20% NaOH and the aqueous layer was extracted several times CH2Cl2. After drying over K2CO3the combined organic extracts evaporated to dryness and the product is dried in a high vacuum (6 hours, 40oC) receive 34.3 g (91%) of pure chromatographic (TLC) substances (3a).

IR(CHCl3) cm-1: 3425, 2970, 1720, 1690, 1580, 1455, 1380, 1300, 1260, 1165, 1050.

1H NMR (300 MHZ, CDCl3) : 4.98 (H-1"), 4.78 (H-13), 4.45 (H-1'), 4.60 (H-3), 3.90 (H-5), 3.49 (H-11), 3.28 (3"-OCH3), 3.05 (H-10), 2.92 (H-8), 2.84 (H-2), 2.28 /3'N(CH3)2/, 2.08 (H-7a), 1.88 (H-7b), 1.87 (H-14a), 1.82 (H-4), 1.51 (H-14b), 0.87 (H-15).

13C NMR (75 MHZ, CDCl3) : : 175.5 (C-1), 161.1 (C-9), 103.1 (C-1'), 95.0 (C-1'), 88.5 (C-6), 81.9 (C-5), 78.1 (C-13), 76.7 (C-3), 73.5 (C-12), 72.5 (C-11), 48.7 (3"-OCH3), 46.7 (C-10), 43.4 (C-2), 39.8/3'N(CH3)2/, AND 39.7 (C-4), 31.9 (C-8), 21.3 (C-14), 10.6 (C-15).

is troizina A (1) (36,0 g, 0,049 mol) in pyridine (100 ml) was added NH2OHHCl (18 g, 0,259 mol) and the mixture is stirred for 3 h at room temperature. To the reaction solution add H2O (400 ml) and CH2Cl2(140 ml) and produce the product speed ekstraktsiei at pH 7.0 and 10.0. After evaporation of the organic extracts at pH of 10.0 allocate 25,0 g (66.4%) of product, identical physico-chemical properties of the product obtained according to method A.

Example 2. 2', 4" 11-0, 10-N-Tetraacetyl-9 desoxo-6-deoxy-6,9-epoxy-8(R)-methyl-10-amino-9,10-securitiesin A 9(E)-acetoxy (3c).

To a solution of (3a) (1.0 g, 0.0013 mol) in pyridine (40 ml) is added 4 ml of acetic anhydride and left to stand, the reaction mixture for 7 days at room temperature. After completion of the acylation (TLC) is poured into a mixture of ice water (200 ml) and was extracted with CHCl3at pH 9.0. The combined organic extracts evaporated under vacuum, thus obtain 1.3 g of crude product, from which the resultant deposition rates from a mixture of ether-petroleum ether to obtain 1.13 g of chromatographic (TCS) of the pure product (3c).

1H NMR (300 MHz, CDCl3) : 6.15 (CONH), 4.97 (H-13), 4.81 (H-2'), 4.78 (H-1"), 4.69 (H-4"), 4.67 (H-11), 4.48 (H-10), 4.59 (H-1'), 4.11 (H-3), 3.79 (H-5), 3.30 (H-3"-OCH3), 3.14 (H-8), 2.75 (H-2), 2.27 /3'N(CH2)2/, 2.16, 2.13, 2.05, and 1.96 (COCH

The solution pentaacetate (3c) (0.5 g, 0.0005 mol) in methanol (20 ml) was allowed to stand for 3 days at room temperature. The reaction mixture was evaporated in vacuum and the resulting crude product was then purified by chromatography on a column of silica gel, using as eluent system CHCl3:CH3OH:NH4OH conc. (90: 9: 1,5). Get 0.250 g 4", 11-0,10-N-triacetate (3b) having the following physico-chemical characteristics:

1H NMR (300 MHz, CDCl3) : 6.31 (CONH), 4.95 (H-13) 4.85(H-1"), 4.67 (H-4"), 4.65 (H-11), 4.49 (H-10), 4.49 (H-1'), 4.21 (H-3), 3.79 (H-5), 3.29 (H-3"-OCH3), 3.28 (H-2'), 3.02 (H-8), 2.78 (H-2), 2.30 /3'N (CH3)2/, 2.17, 2.13 I1.96 (COCH3), 2.07 (H-7a), 2.02 (H-4), 1.85 (H-14a), 1.49 (H-14b), 0.88 (H-15).

C NMR (75 MHz, CDCl3) : 175.0 (C-1), 172.0, 170.7, and 169.3 (COCH3), 162.1 (C-9), 103.5 (C-1'), 95.5 (C-1'), 89.6 (C-6), 81.2 (C-5), 78.3 (C-11), 78.1 (C-3), 76.8 (C-13), 74.9 (C-12), 49.3 (3"-OCH3), 45.0 (C-10), 42.5 (C-2), 40.1/3'N(CH3)2)/, 39.5 (C-7), 38.4 (C-4), 32.7 (C-8), 23.1, 20.6 20.6 (COCH3), 21.9 (C-14), 10.7 (C-15).

Example 4. 9-0,10-N-Detail-9 desoxo-6-deoxy-6,9-epoxy-8(P)-methyl-10 - amino-9,10-securitiesin A 9(E)-oxime (3e) 10-N-tosyl-9-deoxy-6 - deoxy-6,9-epoxy-8(R)-methyl-10-amino-9, 10-securitiesin A 9(E)-oxime (3f).

To a suspension of compound (3a) (2.0 g, 0,026 mol) from example 1 in 70 ml of acetone, cooled to 0 to 5oC, was added simultaneously a solution of the e 30 minutes The suspension is stirred for another 3 h at room temperature, and then the acetone is evaporated in vacuo and the aqueous residue extracted with CHCl3at pH 5.0. After drying, the K2CO3and evaporation CHCl3obtain 2.58 g of a mixture of compounds (3e) and (3f). Chromatography of the crude product (1.8 g) on a column of silica gel (eluent CH2Cl2: CH3OH, 85:15) get 0,250 g of pure (TLC, CHCl3:CH3OH, 7:3) compound (3e) with Rf0.63 and 1.1 g of compound (3e) with Rf0.43.

The compound (3e):

IR (CHCl3) cm-1: 3460, 2975, 2940, 1730, 1660, 1600, 1455, 1370, 1190, 1180, 1160, 1090, 1050, 1000, 975, 855, 815, 665.

1H NMR (300 MHz, CDCl3) : 7.80 (p-Ph), 7.30 (p-Ph), 4.81 (H-13), 4.78 (H-1"), 4.48 (H-1'), 4.26 (H-3), 3.96 (H-5"), 3.76 (H-5), 3,68 (H-5'), 3.60 (H-11), 3.50 (H-10), 3.41 (H-2'), 3.23 (3"-OCH3), 3.09 (H-8), 3.03 (H-4"), 2.94 (H-2), 2.54 /3'N(CH3)2/, 2.43 (p-Ph-CH3), 2.41 (p-Ph-CH3), 2.24 (H-7a), 2.09 (H-7b), 1.91 (H-4), 1.83 (H-4'a), 1.68 (H-14a), 1.52 (H-2"b), 1.41 (H-14b), 1.49 (6-CH3), 0.89 (H-15).

The compound (3f):

1H NMR (300 MHz, CDCl3) : 7.43 (p-Ph), 7.14 (SO2NH), 4.91 (H-13), 4.78 (H-1"), 4.60 (H-1'), 4.36 (H-3), 4.00 (H-5"), 3.82 (H-5), 3.73 (H-10), 3.68 (H-5'), 3.64 (H-11), 3.15 (H-2'), 3.28 (3"-OCH3), 3.08 (H-8), 3.00 (H-4"), 2.79 (H-2), 2.39 (p-Ph-CH3), 2.24 (H-2"a), 1.73 (H-14a), 1.52 (6-CH3), 0.85 (H-15).

Example 5. 6-Deoxy-6,9-epoxy-8(R)-methyl-10-amino-9,10-securitiesin And (2a).

Method A.

3at pH 5.5, 6.5 and 8.3. After drying, the K2CO3the combined organic extracts at pH 8.3 evaporated to dryness and the final product is dried in a high vacuum (6 h, 40oC) gain of 8.2 g (80%) chromatographic (TLC) of the pure product (2a)

IR (CHCl3) cm-1: 1740 (C-1 lactone) and 1710 (C-9, lactone)

1H NMR (300 MHz, CDCl3) : 4.77 (H-1"), 5.00 (H-13), 4.39 (H-1'), 4.18 (H-3), 3.74 (H-5), 3.35 (H-11), 3.29 (H-3"-OCH3), 3.16 (H-10), 2.76 (H-8), 2.72 (H-2), 2.29 /3'N(CH3)2/, 2.22 (H-7a), 2.10 (H-7b), 2.00 (H-4), 1.85 (H-14a), 1.55 (H-14b) 0,88 (H-15).

13C NMR (75 MHZ, CDCl3) : 179.6 (C-1), 176.1 (C-9), 103.9 (C-1'), 95.7 (C-1"), 86.1 (C-6), 81.2 (C-5), 78.8 (C-13), 77.9 (C-3), 75.7 (C-11), 74.5 (C-12), 49.5 (3"-OCH3), 47.9 (C-10), 43.2 (C-2), 40.4/3' N(CH3)2/, 39.7 (C-4), 38.0 (C-7,), 34.1 (C-8), 22.2 (C-14, 11.6 (C-15).

ES-MS (M+) 748.

Method B.

A solution of (3a) (2.0 g, 0,0026 mol) in methanol (30 ml), acidified with 1 N. HCl to 3 and leave to stand for 10 days at room temperature. Bring the pH of the reaction mixture to 7.0 with 10% NaOH, and evaporated methanol in vacuo, the aqueous residue was added CHCl3then extracted at pH 5.5, 6.5 and 8.3. Dried K2CO3the combined extracts at pH 8.3 evaporated to dryness; receive the product (2a) 6. 2', 4",11-0,11-N-Tetraacetyl-6-deoxy-6,9-epoxy-8(R)- methyl-10-amino-9,10-securitiesin A (2b).

To a solution of (2a) (3.4 g, 0.0045 mol) in pyridine (45 ml) is added 12 ml of acetic anhydride and leave to stand for 7 days at room temperature. Upon completion of the acylation (TLC), the reaction mixture was poured on ice (200 ml) and extracted with CHCl3at pH 9. The combined organic extracts washed with saturated solution of NaHCO3and water, dried with K2CO3and evaporated in vacuum. The resulting crude product is dried in a high vacuum (6 h, 40oC) obtain 4.10 g (98%) of chromatographically pure product (2b).

IR (CHCl3) cm-1: 1740 (C-1, lactone), 1720 (C-6, lactone), 1720 and 1240 (C= O, ester), 1655 (C=O, amide).

1H-NMR (300 MHz, CDCl3) : 6.35 (CONH), 4.99 (H-13), 4.79 (H-1"), 4.79 (H-2'), 4.68 (H-11), 4.62 (H-1'), 4.44 (H-10), 4.14 (H-3), 3.76 (H-5), 3.32 (H-3" -OCH3), 2.74 (H-8), 2.65 (H-2), 2.28/3'N(CH3)2/, 2.10, 2.06, 2.03, and 1.92 (COCH3), 2.08 (H-7a), 1.96 (H-7b), 1.90 (H-4), 1.81 (H-14a), 1.60 (H-14,), 0.86 (H-15).

13C NMR (75 MHz, CDCl3) : 179.3 (C-1), 174.7 (C-9), 171.9 170.5, 169.9 and 169.2 (COCH3).

ES-MS (M+) 916.

Example 7. 4",11-0,10-N-Triacetyl-6-deoxy-6,9-epoxy-8(R)-methyl-10-amino-9,10 - securitiesin A (2c).

Solution (2b) (1.5 g, 0,0016 mol) in methanol (40 ml) was allowed to stand for 3 days in to the B>2Cl2(50 ml), add 100 ml of water (pH 6.6) and bring the pH of the reaction mixture to 9 with 20% aqueous NaOH solution. Separate the organic layer and water and twice extracted with CH2Cl2. After drying the combined organic extracts K2CO3and evaporation of the solvent in vacuo obtain 1.35 g of crude product which is purified by chromatography on a column with SiO2(CHCl2:CH3OH:NH4OH conc., 6:1:0,1). Obtained chromatographically pure (TLC) triacetate (2c) with the following physicochemical characteristics:

1H NMR (300 MHz, CDCl3) : 6,39 (CONH), 4.99 (H-13), 4.79 (H-1"), 4.68 (H-4"), 4.66 (H-11), 4.48 (H-1'), 4.46 (H-10), 4.21 (H-3), 3.76 (H-5), 3.30 (3"-OCH3), 3.23 (H-2'), 2.75 (H-8), 2.70 (H-2), 2.29 /3'N(CH3)2/, 2.26 (H-7a), 2.16, 2.12 and 1.96 (COCH3), 2.02 (H-7b), 1.94 (H-4), 1.83 (H-14a), 1.56 (H-14b), 0.86 (H-15).

13C NMR (75 MHz, CDCl3) : 179.2 (C-1), 174.7 (C-9), 171.7, 170.3 and 169.0 (COCH3), 102.9 (C-1'), 94.9 (C-1'), 85.6 (C-6), 80.5 (C-5), 78.3 (C-3), 78.2 (C-11), 76.7 (C-13), 74.7 (C-12), 49.2 (3"-OCH3), 45.1 (C-10), 42.4 (C-2), 40.0 /3'N(CH3)2/, 39.3 (C-4), 37.3 (C-7), 33.9 (C-8), 21.9 (C-14), 21.1, 20.9 20.6 (COCH3), 10.7 (C-15).

Example 8. 10-N-(4-Bromobenzoyl)-6-deoxy-6,9-epoxy-8(R)-methyl - 10-amino-9,10-securitiesin A (2d).

To a solution of 10 g (0,013 mol) (2a) in ether (60 ml) for 1 h and added dropwise at 0-5oC solution of 4-Bambi the same temperature, the solvent is evaporated under vacuum, then add CHCl3(70 ml) and water (50 ml) to the resulting solid residue and extracted at pH 8.5. The reaction mixture was evaporated in vacuum and purified by chromatography on a column of silica gel (eluent CH2Cl2:CH3OH:NH4OH conc., 90:9: 1,5). Get chromatographically pure (TLC) 4-bromobenzoate (2d) with the following physicochemical characteristics:

IR (CHCl3) cm-1: 1740 (C-1, lactone), 1710 (C-9, lactone), 1640 and 1500 (C-10, amide), 1580 (Ph).

1H NMR (300 MHz, CDCl3) : 7.60 (Ph), 7.05 (CONH), 4.91 (H-13), 4.70 (H-1"), 4.35 (H-1'), 4.37 (H-10), 4.21 (H-3), 3.70 (H-5), 3.67 (H-11), 3.27 (3"-OCH3), 3.15 (H-2'), 2.91 (H-4"), 2.73 (H-8), 2.71 (H-2), 2.26 /3'N(CH3)2/, 2.21 (H-7a), 2.10 (H-7b), 1.94 (H-4), 1.86 (H-14a), 1.57 (H-14b), 0.89 (H-15).

13C NMR (75 MHz, CDCl3) : 179.6 (C-1), 176.7 (C-9), 165.4 (CONH), 133.8, 131.6, 128.9 and 125.8 (Ph), 104.0 (C-1'), 86.4 (C-6), 81.7 (C-5), 79.9 (C-3), 75.6 (C-13), 73.4 (C-11), 74.6 (C-12), 49.4 (3"-OCH3), 47.3 (C-10), 43.2 (C-2), 40.0 /3'N(CH3)2/, 40.0 (C-4), 37.8 (C-7), 34.2 (C-8), 22.5 (C-14), 11.2 (C-15).

ES-MS (M+) 931.

Example 9. 1-N-(2,3,4-Trihydroxy-1,3-dimethyl-hexyl)-amido - 10,11,12,13,14,15-hexanor-9 desoxo-6-deoxy-6,9-epoxy-8(R)-methyl - 9,10-securitiesin A 9 (E) oxime (4a).

The compound (3a) (31 g, 0,041 mol of example 1 dissolved in CH2Cl2:CH3OH (1: 1.80m), add to Aut overnight and then evaporated in vacuum and the resulting solid residue is suspended in CH2CH2, filtered and the filtrate evaporated to dryness, to obtain 29.5 g (95%) of chromatographically pure product (4a) (TLC - CHCl3:CH3OH:NH4OH conc., 6:1: 0,1).

IR (CHCl3) cm-1: 3420, 2980, 1690, 1650, 1530, 1455, 1380, 1260, 1175, 1050.

1H NMR (300 MHz, CDCl3) : 7.53 (CONH), 4.93 (H-1"), 4.45 (H-1'), 4.20 (H-3), 4.11 (H-10), 3.79 (H-11), 3.66 (H-5), 3.39 (3"-OCH3), 3.22 (H-13), 3.04 (H-8), 2.53 (H-2), 2.29 /3'N(CH3)2/, 2.10 (H-7a), 1.97 (H-4), 1.79 (H-7b), 1.59 (H-14a), 1.33 (H-14b), 1.04 (H-15).

13C NMR (75 MHz, CDCl3) : 174.4 (C-1), 162.0 (C-9), 105.6 (C-1'), 96.2 (C-1'), 90.3 (C-6), 86.3 (C-5), 83.0 (C-13), 79.8 (C-3), 75.1 (C-11), 74.9 (C-12), 49.3 (3"-OCH3), 48.6 (C-10), 42.8 (C-2), 41.0 (C-7), 39.8 /3'N(CH3)2/, 38.6 (C-4), 32.9 (C-8), 24.8 (C-14), 11.5 (C-15).

FAB (MH+) 764.4

Example 10. 1-N-(2,3,4-Trihydroxy-1,3-dimethylpentyl)-amido - 10,11,12,13,14,15-hexanor-9 desoxo-6-deoxy-6,9-epoxy-8(R)-methyl - 9,10-securitiesin A 9(E) oxime (4a) and 1-N-(2,3,4-trihydroxy-2,3 - dimethylpentyl)-amido-10,11,12,13,14,15-hexanor-9 desoxo-6-deoxy - 6,9-epoxy-8(S)-methyl-9,10-securitiesin A 9(E) the oxime (4b).

6,9-Iminoethyl erythromycin A(1) (30 g, 0,041 mol) is dissolved in CH3OH (600 ml), add Na2CO3(5.6 g, 0,053 mol) and the reaction mixture is stirred at the boil until the disappearance of the original aminoether (8 hours). The resulting suspension is evaporated in vacuum, primove extracts dried K2CO3and evaporated; obtain 28 g of a solid residue, which was dissolved in CH3OH (600 ml), the solution was added NH2OH. HCl (14 g) and Na2CO3(5.1 g) and stirred for 3 h at boiling. The reaction mixture is evaporated to dryness, add CH2Cl2(150 ml) and H2O (300 ml) (pH 6.6) and extracted at pH 8 and 10. The combined organic extracts at pH 10 dried K2CO3and evaporated. Obtain 15.6 g of the solid residue, which is dissolved in a mixture of CH3OH-CH2Cl2(1 : 1,40 ml) and NH4OH conc. (170 ml) and stirred for 12 h at room temperature. The reaction mixture is evaporated to dryness and the resulting mixture of products is divided column chromatography on silica gel. From 2.2 g of crude product is obtained (eluent CHCl3: CH3OH : NH4OH conc., 6 : 1 : 0,1) 1.08 g of chromatographically pure product (4a) (Rf0.38), the physico-chemical characteristics as described in example 9, and 0.80 g of substance (4b) (Rf0.26) with the following physicochemical characteristics:

The compound (4b):

IR (CHCl3) cm-1: 3340, 2975, 1685, 1650, 1530, 1450, 1380, 1280, 1240, 1160, 1040.

1H NMR (300 MHz, CDCl3) : 7.30 (CONH), 4.88 (H-1"), 4.35 (H-1'), 4.23 (H-3), 4.15 (H-10), 3.82 (H-11), 3.60 (H-5), 3.29 (3"-OCH3), 3.26 (H-13), 3.14 (H-8), 2.78 (H-7a), 2.52 (H-2), 2.29 /3'N(CH33), 47.4 (C-10), 42.7 (C-2), 42.0 (C-7), 39.4 /3'N(CH3)2/, 38.7 (C-4), 33.8 (C-8), 24.1 (C-14), 11.0 (C-15).

FAB (MH+) 764.5.

Example 11. 2',4"-O-Diacetyl-1-N-(2,4-O-diacetyl-3 - hydroxy-1,3-dimethylpentyl)-amido-10,11,12,13,14,15-hexanor-9 desoxo-6-deoxy-6,9-epoxy-8(R)-methyl-9,10-securitiesin A 9(E) acetoxy (4c).

To a solution of the substance (4a) (1.0 g, 0,0013 mol) from example 9 in pyrimidine (40 ml) is added 4 ml of acetic anhydride and the reaction mixture is allowed to stand for 10 days at room temperature, then pour in a mixture of water (200 ml) with ice (pH 4.8), alkalinized with 20% NaOH, and then extracted with CHCl3at a pH of 9.0. The combined organic extracts dried (K2CO3and evaporated in vacuum. Obtain 1.25 g (98%) of pentaacetate (4c) with the following physical-chemical constants:

1H NMR (300 MHz, CDCl3) : 6.61 (CONH), 4.94 (H-13), 4.82 (H-1"), 4.80 (H-2'), 4.69 (H-4"), 4.58 (H-1'), 4.58 (H-10), 4.55 (H-11), 4.04 (H-3), 3.79 (H-5), 3.32 (3"-OCH3), 3.13 (H-8), 2.59 (H-2), 2.27 /3'N(CH3)2/, 2.15, 2.12, 2.12, 2.06, and 2.01 (COCH3), 2.07 (H-7a), 2.03 (H-4), 2.03 (H-7b), 1.82 (H-14a), 1.55 (H-14b), 0.90 (H-15).

13C NMR (75 MHz, CDCl3) : 173.4 (C-1), 171.8, 170.6, 170.2, and 169.8, and 168, 8mm (COCH3)), 167.2 (C-9), 100.6 (C-1'), 95.5 (C-1'), 91.7 (C-6), 79.8 (C-3), 79.6 (C-5), 78.6 (C-11), 75.7 (C-13), 74.7 (C-12), 49.3 (3"-OCH3), 45.1 (C-10), 42.6 12. 4"-O-Acetyl-1-N-(2,4-O-diacetyl-3 - hydroxy-1,3-dimethylpentyl)-amido-10,11,12,13,14,15-hexanor-9 desoxo-6-deoxy-6,9-epoxy-8(R)-methyl-9,10-securitiesin A 9(E) acetoxy (4d) and 4"-O-acetyl-1-N-(2,4-O-diacetyl-3 - hydroxy-1,3-dimethylpentyl)-amido-10,11,12,13,14,15-hexanor-9 desoxo-6-deoxy-6,9-epoxy-8(P)-methyl-9,10-securitiesin A 9(E) oxime (4e).

A solution of 0.5 g (0.0005 mol) of the substance (4c) from example 11 in methanol (20 ml) is stirred 3 days at room temperature. The solvent is evaporated in vacuum and the resulting mixture was purified column chromatography on silica gel (eluent CHCl3: CH3OH : NH4OH conc., 6:1:0,1). After evaporation of chromatographically pure fractions with Rf0.47 and Rf0.34 received 0.213 g leads to compounds, which (4d) and 0.151 g triacetate (4e) with the following physicochemical characteristics:

The compound (4d):

1H NMR (300 MHz, CDCl3) : 7.38 (CONH), 4.94 (H-13), 4.83 (H-1"), 4.66 (H-4"), 4.62 (H-11), 4.55 (H-10), 4.44 (H-1'), 4.10 (H-3), 3.80 (H-5), 3.32 (3"-OCH3), 3.35 (H-2'), 3.18 (H-8), 2.76 (H-2), 2.30 /3'N(CH3)2/, 2.07 (H-7a), 2.13, 2.10, 2.09, and 2.03 (COCH3), 1.90 (H-7b), 1.96 (H-4), 1.84 (H-14a), 1.53 (H-14b), 0.90 (H-15).

13C NMR (75 MHz, CDCl3) : 174.4 (C-1), 171.1, 170.7, 170.4 and 168.4 (COCH3), 167.2 (C-9), 105.2 (C-1'), 96.9 (C-1'), 92.9 (C-6), 84.5 (C-5), 81.3 (C-3), 78.5 (C-11), 75.9 (C-13), 75.0 (C-12), 49.4 (3"-OCH3), 44.6 (C-10), 41.1 (C-2), 40.1 /3'N(CH3)2/,Cl3) : 7.24 (CONH), 4.88 (H-13), 4.81 (H-1"), 4.68 (H-4"), 4.62 (H-11), 4.50 (H-10), 4.45 (H-1'), 4.07 (H-3), 3.75 (H-5), 3.34 (3"-OCH3), 3.26 (H-2'), 2.98 (H-8), 2.56 (H-2), 2.30 /3'N(CH3)2/, 2.09 (H-7a), 2.14, 2.09 and 2.03 (COCH3), 1.92 (H-7b), 1.89 (H-4), 1.83 (H-14a), 1.51 (H-14b), 0.89 (H-15).

13C NMR (75 MHz, CDCl3) : 174.6 (C-1), 171.1, 170.8, 170.8 (COCH3), 162.5 (C-9), 104.2 (C-1'), 96.4 (C-1'), 90.4 (C-6), 83.9 (C-5), 79.6 (C-3), 78.7 (C-11), 76.1 (C-13), 75.1 (C-12), 49.5 (3"-OCH3), 44.7 (C-10), 43.7 (C-2), 40.1 /3'N(CH3)2/, 40.4 (C-7), 39.3 (C-4), 32.5 (C-8), 21.8 (C-14), 20.7, 20.7 and 20.6 (COCH3), 10.7 (C-15).

Example 13. 1-N-(2, 3, 4 Trihydroxy-1,3-dimethylpentyl)-amido-10, 11, 12, 13, 14, 15 -hexanor-9 desoxo-6-deoxy-6,9-epoxy-8 (R)-methyl-9, 10-securitiesin A 9 (E) tosyloxy (4f).

Substance (4a) (0.5 g 0.0007 mol) from example 9 are suspended in acetone ( 10 ml) and cooled to 0 to 5oC. To the reaction mixture simultaneously dropwise with stirring was added a solution of tosylchloramide (0,486 g, 0.00286 mol) in acetone (10 ml) and NaHCO3(0.425 g, 0.0051 mol) in water (25 ml) for 30 minutes the Reaction solution is stirred for further 12 h at room temperature, evaporated acetone in vacuo, the aqueous residue was added CHCl3(30 ml) and extracted with a step at pH 5 and 8. The process of evaporation of the combined organic extracts at pH 5 is selected 0.320 g of crude product (4f). Chromatography on a column of silica gel (SUP>H NMR (300 MHz, CDCl3) :/ 7.80 (CON (H), 7.62 (Ph), 3.21 (H-13), 4.96 (H-1"), 4.41 (H-1'), 4.17 (H-3), 4.11 (H-10), 3.79 (H-11), 3.58 (H-5), 3.39(H-2'), 3.25 (3"OCH3), 3,10(H-8), 2,94 (H-4") 2.55 (H-2), 2.29/3'N (CH3)2/, 2.08(H-7a), 1,86 (H-4), 1.64 (H-7b), 1.56 (H-14a), 1.43 (H-14b), 1.05 (H-15).

Example 14. 1-N-(2,3,4-Trihydroxy-1,3-dimethylpentyl)-amido-10,11,12,13,14,15-hexanor-9 desoxo-9-dihydro-9a-amino-8 (R)-methyl-9a-homoerythromycin A (5a).

The crude product (4a) (6.0 g, 0.008 mol) from example 9 was dissolved in glacial acetic acid (60 ml), add PtO2(2.0 g, 83% Pt) and hydronaut at a pressure of H27106PA under stirring for 10 hours Filtered the resulting suspension, the filtrate evaporated, add H2O (100 ml) and CHCl2(60 ml) and extracted with a step at pH 5.5, 9.0 and 10.5. The combined chloroform extracts at pH 10.5 evaporated in vacuum and receive a 4.3 g (73%) of chromatographically pure (TLC) product (5a) with the following physicochemical characteristics:

IR(CHCl3)cm-1:3400, 2975, 1650, 1535, 1450, 1375, 1165, 1040.

1H NMR (300 MHz, CDCl3) : 7.52 (CONH), 4.94 (H-1"), 4.37 (H-1'), 4.26(H-3), 4.17 (H-10), 3.76 (H-11), 3.41 (H-5), 3.28 (3"-OCH3), 3.17 (H-13), 2.62 (H-9a), 2.52 (H-2), 2.27 /3'H(CH3)2/ 2.20(H-7a), 2.01(H-4), 1.85 (H-8), 1.55 (H-14a), 1.34 (H-7b), 1.34 (H-14b), 1.05 (H-15).

13C NMR (75 MHz, CDCl3) : 174.1 (C-1), 106.7 (C-1'), 96.0 (C-1'), 92.3 (C-5), 83.8 (C-13), 79.7 (C-3), 75.1 (C-1CLASS="ptx2">

FAB(NH+)752.3.

Example 15. 1-N-(2,3,4-Trihydroxy-1,3-dimethylpentyl)-amido-10,11,12,13-14,15-hexanor-9 desoxo-9-dihydro-9a-amino-8(S)-methyl-9a-homoerythromycin A (5b).

The compound (4b) (0.71 g, 0,009 mol) is dissolved in glacial acetic acid (30 ml), add PtO2(0.350 g, 83% Pt) and hydronaut under stirring and the pressure of the H27106PA for 10 hours, the Reaction mixture is filtered, the filtrate evaporated to a thick oil and the product emit speed extraction at pH 5.5, 9.0 and 10.5, as described in example 14, the result after evaporation of the combined organic extracts at pH 10.5 allocated 0.260 g (38%) of chromatographically pure (TLC) product (5b)/

1H NMR (300 MHz, CDCl3) : 7.63 (CONH), 4.93 (H-1"), 4.40 (H-1'), 4.23 (H-3), 4.19(H-10) 3,75 (H-11), 3.53 (H-5), 3.29 (3"-OCH3), 3.18 (H-13), 2.72 (H-9a), 2.57 m (H-9b), 2.52 (H-2), 2.27/3' N(CH3)2/, 1.93 (H-4), 1.78 (H-8), 1.57 (H-14a), 1.47 (H-7a), 1.36 (H-14b), 1.23 (H-7b), 1.04 (H-15).

13C NMR (75 MHz, CDCl3) : 174.3 (C-1), 107.2 (C-1'), 97.0 (C-1'), 92.3 (C-5), 83.8 (C-13), 80.7 (C-3), 75.7 (C-12), 75.2 (C-11), 75.2 (C-6), 49.6 (3"-OCH3), 49.2 (C-9), 49.2 (C-10), 43.7 (C-7), 42.1 (C-2), 39.8/3' N(CH3)2/, 37.8 (C-4), 31.3 (C-8), 25.0 (C-14), 11.7 (C-15).

Example 16. 1-N-(2,3,4-Trihydroxy-1,3-dimethylpentyl)-amido-10,11,12-13,14,15 - hexanor-9 desoxo-9-dihydro-9a-dimethylamino-8(R)-methyl-9a-homoerythromycin A (6a).

To R is(98-100%) and 0.232 ml of 0.003 mol) of formaldehyde (36%), the pH of the reaction mixture is adjusted to 5.0 (2% NaOH solution) and stirred at the boil for 9 hours After addition of H2O (100 ml) the product emit speed extraction at pH 5.0 and 9.5 and the combined organic extracts at pH 9.5 evaporated in vacuum. Chromatography on a column of silica gel (eluent CHCl3:CH3OH:NH4OH conc., 6:1:0,1)allocated 0.63 g of TLC pure product (6A).

(CHCl3)cm-1: 3400, 2970, 1650, 1530, 1450, 1375, 1165, 1040.

1H-NMR (300 MHz, CDCl3) : 7.26 (CONH), 4.91 (H-1"), 4.37 (H-1'), 4.27 (H-3), 4.18 (H-10), 3.77 (H-11), 3.41 (H-5), 3.29 (3"-OCH3), 3.18 (H-13), 2.57 (H-2), 2.52 (H-9a), 2.30/3'N(CH3)2/, 2.27/9a N(CH3)2/, 2.20 (H-9b), 2.16 (H-4), 2.01 (H-8), 1.56 (H-14a), 1.50 (H-7a), 1.37 (H-14b), 1.15 (H-7b), 1.04 (H-15).

13C NMR (75 MHz, CDCl3) : 174.7 (C-1), 106.1 (C-1'), 95.4 (C-1'), 90.5 (C-5), 83.3 (C-13), 79.8 (C-3), 7.48 (C-12), 74.6 (C-11), 73.7 (C-6), 68.2 (C-9), 49.2 (3"-OCH3), 48.6 (C-10), 45.3/9a N(CH3)2/44.2 (C-7), 41.7 (C-2), 39.6/3'N(CH3)2/, 37.3 (C-4), 26.4 (C-8), 24.9 (C-14), 11.5 (C-15).

FAB (MH+)780.6.

Example 17. 1-N-(2,3,4-Trihydroxy-1,3-dimethylpentyl)-amido-10,11,12-13,14,15 - hexanor-9 desoxo-9-dihydro-9a-dimethylamino-8(S)-methyl-9a - homoerythromycin A (6b).

To a solution of the compound (5b) (0.3 g, of 0.0004 mol) from example 15 in CHCl3(50 ml) is added 0.12 ml (0.0032 mol) of formic acid (98-100%) and 0.13 ml (0.0016 mol) of the product is carried out as described in example 16. Obtained after chromatography on a column with SiO2(eluent CHCl3:CH3OH:NH4OH conc., 6:1:0,1) 0,150 g TCX - pure product (6b).

1H NMR (300 MHz, CDCl3) : 7.58 (CONH), 4.95 (H-1"), 4.41 (H-1'), 4.25 (H-3), 4.18 (H-10), 3.76 (H-11), 3.43 (H-5), 3.28 (3"-OCH3), 3.17 (H-13), 2.51 (H-2), 2.27/3'N(CH3)2/, 2.23/9a-N(CH3)2/, 2.06 (H-9b), 2.19(H-4), 1.97 (H-8), 1.57(H-14a), 1.47 (H-7a), 1.37 (H-14b), 1.16 (H-7b), 1.05 (H-15).

13C NMR (75 MHz, CDCl3) : 173.5 (C-1), 106.0 (C-1), 95.3 (C-1'), 91.9 (C-5), 83.2 (C-13), 79.0 (C-3), 74.4 (C-12), 74.1 (C-11), 74.2 (C-6), 67.5 (C-9), 48.6 (3"-OCH3), 48.4 (C-10), 44.9/9-N(CH3)2/, 43.1 (C-7), 40.8 (C-2), 38.9/3'N(CH3)2, 36.7 (C-4), 25.8 (C-8), 23.9(C-14), 10.4 (C-15).

Example 18. 9 Desoxo-6-deoxy-6,9-epoxy-8 (R)-methyl-10,11,12,13,14,15-hexanor-erythromycin A 9 (E) oxime (7a) and 9 desoxo-6-deoxy-6,9-epoxy-8(S)-methyl-10,11,12,13,14,15 - hexanor-erythromycin a 9(E) oxime (7b).

The combined chloroform extracts at pH 8 from example 10 dried K2CO3and evaporated in vacuum. Obtain 8.0 g of a mixture of (7a) and (7b). Column chromatography on SiO2(eluent CHCl3:CH3OH: NH4OH conc., 6:1:0,1) of 2.0 g of crude product is obtained 0,530 g of substance (7a) and (Rf0.44) and 0,880 g of substance (7b) (Rf0.39), which are identified by spectroscopic methods as C-8 stereoisomers.

The compound (7a):

IR (CHCl), 4.11 (H-3), 3,84 (H-5). 3.67 (1-OCH3), 3.29 (3"-OCH3), 3.26 (H-2') 3.03 (H-8), 3.01 (H-4"), 2.84 (H-2), 2.09 (H-7a), 2.33/3' N(CH3)2/, 1.97 (H-4), 2.01 (H-7b).

13C NMR (75 MHz, CDCl3) : 176.1(C-1), 161.8 (C-9), 103.8 (C-1'), THE 95.8 (C-1'), 89.7 (C-6), 81.0 (C-5), 79.8 (C-3), 51.8 (1-OCH3), 49.4 (3"-OCH3). 39.9 (C-7), 41.7 (C-2), 40.4/3' N(CH3)2/, 37.8 (C-4), 33.0 (C-8).

FAB (MH+) 619.4:

The compound (7b):

IR (CDCl3) cm-1: 3360, 2890, 2940, 1730, 1690, 1650, 1455, 1380, 1245, 1165, 1040

1H NMR (300 MHz, CDCl3) : 4.61 (H-1"), 4.43 (H-1'), 4.09 (H-3), 3.71 (H-5), 3.68 (1-OCH3), 3.28 (3"-OCH3), 3.17 (H-8), 2.89 (H-7a), 2.74 (H-2), 2.33 /3'N (CH3)2/, 2.16 (H-4), 1.47 (H-7b)

13C NMR (75 MHz, CDCl3) : 176.0 (C-1), 162.9 (C-9), 102.7 (C-1'), 95.1 (C-1'), 90.4 (C-6), 80.1 (C-5), 79.0 (C-3), 51.6 (1-OCH3), 49.2 (3"-OCH3), 42.5 (C-7), 41.0 (C-2), 40.3/3' N(CH3)2, 38.1 (C-4), 34.5 (C-8).

Example 19. 9 Desoxo-9-dihydro-9a-amino-8 (R)-methyl-10,11,12,13,14,15-hexanor-9a-homoerythromycin A (8a).

Substance (7a) (0.90 g, 0.0015 mol) is dissolved in glacial acetic acid (30 ml), add PtO2(0.30 g, 83% Pt) and hydronaut adding H26106PA under stirring for 15 hours, the Reaction mixture is filtered, the filtrate is evaporated to the consistency of thick oil and the product emit speed extraction at pH 5.5, 9.0 and 10.5, as described in example 14; after evaporation of the z, CDCl3) : 4.64 (H-1"), 4.40 (H-1'), 4.14 (H-3), 3.67 (1-OCH3), 3.54 (H-5), 3.29 (H-3"OCH3), 2.85 (H-2), 2.74 (H-9a), 2.50 (H-9b), 2.30/3'N(CH3)2/, 2.10 (H-4), 1.84 (H-8), 1.44 (H-7a), 1.22 (H-7b).

13C NMR (75 MHz, CDCl3) : 176.4 (C-1), 104.4 (C-1'), 96.0 (C-1'), 85.9 (C-5), 80.3 (C-3), 73.8 (C-6), 51.5 (1-OCH3), 49.2 (3"-OCH3), 49.1 (C-9), 42.9 (C-7), 41.2 (C-2), 40.2/3'N(CH3)2, 37.3 (C-4), 31.1 (C-8).

Example 20. 9 Desoxo-9-dihydro-9a-amino-8(S)-methyl-10,11,12,13,14,15-hexanor - 9a-homoerythromycin A (8b),

Substance (7b) (0.70 g, 0.0011 mol) is dissolved in glacial acetic acid (25 ml), add PtO2(0.23 g, 83% Pt) and hydronaut 15 h with stirring and the pressure of the H26106PA. The reaction mixture is filtered, the filtrate evaporated in vacuum to the consistency of a viscous oil and the product emit speed extraction at pH 5.5, 9.0 and 10.5, as described in example 14; after evaporation of the combined organic extracts at pH 10.5 get 0.350 g (52.4%) of pure (TLC) of the above product (8b).

IR: (CHCl3) cm-1: 3400, 2975, 2940, 1735, 1580, 1455, 1375, 1260, 1170, 1050, 1000

1H NMR (300 MHz, CDCl3) : 4.64 (H-1"), 4.37 (H-1'), 4.15 (H-3), 4.04 (H-5"), 3.67 (1-OCH3, 3.60 (H-5'), 3.51 (H-5), 3.37 (H-2'), 3.28 (H-3" OCH3), 2.98 (H-4"), 2.75 (H-2), 2.68 (H-9a), 2.56 (H-9b(, 2.54 (H-3'), 2.31/3'-N(CH3)2/, 1.93 (H-4), 1.79 (H-8), 1.70 (H-4'a), 1.47 (H-2").

Example 21. 9 Desoxo-9-dihydro-9a-time) from example 19 in CHCl3(50 ml) was added 0.05 ml (0.0013 mol) of formic acid (98-100%) and 0.052 ml (0.0007 mol) of formaldehyde (36%); pH of the reaction mixture was adjusted to 5.2 (2% NaOH solution and then stirred at the boil for 2.5 hours the Selection of the product were carried out as described in example 16. Get 0.280 g (89.0%) of pure (TLC) product (9a).

IR (CHCl3) cm-1: 3450, 2975, 2940, 1735, 1465, 1375, 1260, 1200, 1165, 1000

1H NMR (300 MHz, CDCl3) : 4.641 (H-1"), 4.43 (H-1'), 4.13 (H-3), 4.06 (H-5"), 3.65 (1-OCH3), 3.64 (H-5), 3.53 (H-5'), 3.30 (H-3"-OCH3), 3.27 (H-2'), 2.97 (H-2), 2.53 (H-3'), 2.29/3'N(CH3)2/, 2.28 (H-2'a), 2.24/9a-N(CH3)2/, 2.10 (H-4), 1.96 (H-8), 1.67 (H-7a).

Example 22. 9 Desoxo-9-dihydro-9a-dimethylamino-8-(S)-methyl-10,11,12,13,14,15-hexanor - 9a-homoerythromycin A (9b).

To a solution of the substance (8b) (0.6 g, 0.001 mol) from example 19 in CHCl3(50 ml) is added 0.1 ml (0.0026 mol) of formic acid (98-100%) and 0.104 ml (0.0014 mol) of formaldehyde (36%). the pH of the reaction mixture was adjusted to 5.2 (2% NaOH solution and then stirred at the boil for 2.5 hours Produce the product as described in example 16, get 0.550 g (87.7%) of pure (TLC) product (9b).

1. 9a-Azalide fragments macrolide antibiotic class of azalides General formula (I)

< / BR>
in which R1and R2the same and represent H and CH3;

R3and R4)CH(OH)C2H5,

or their pharmaceutically acceptable salts of inorganic or organic acids.

2. Connection on p. 1, in which R1, R2and R4the same and represent H, R3- CH3, Y is NH and Z is CH(CH3)CH(OH)SON(CH3)CH(OH)C2H5.

3. Connection on p. 1, in which R1, R2and R3the same and represent H; R4- CH3, Y is NH and Z is CH(CH3)CH(OH)SON(CH3)CH(OH)C2H5.

4. Connection on p. 1, in which R1- R3identical and denote CH3, R4- H, Y is NH and Z is CH(CH3)CH(OH)SON(CH3)CH(OH)C2H5.

5. Connection on p. 1, in which R1, R2and R4identical and denote CH3, R3- H, Y is NH and Z is CH(CH3)CH(OH)SON(CH3)CH(OH)C2H5.

6. Connection on p. 1, in which R1, R2and R4the same and represent H, R3- CH3, Y 0, and Z is CH3.

7. Connection on p. 1, in which R1- R3the same and represent H; Z and R4- CH3and Y is 0.

8. Connection on p. 1, in which R1- R3the same and represent CH3, R4- H, Y - 0, Z - CH3.

9. Connection on p. 1, to the"ptx2">

10. The compound of General formula (II)

< / BR>
in which the X - NOR7where R7- H, acyl or arylsulfonyl;

R3and R4different and denote H or CH3;

R5and R6the same or different and represent H or acyl;

Y represents-O-, where Z is CH3CH(C2H5)SON(CH3)CH(OR8)CH(CH3)OTHER9or Y = -NH-, where Z is CH(CH3)CH(OR10)SON(CH3)CH(OR11)C2H5where R8- H or acyl, R9- H, acyl or arylsulfonyl, R10and R11the same and represent H or acyl,

or their pharmaceutically acceptable salts of inorganic or organic acids.

11. Connection on p. 10, in which the X - NOR7in which R7- H, R3- CH3, R4- R6the same and represent H, Y Is 0, Z is - CH(C2H5)SON(CH3)CH(OR8)CH(CH3)OTHER9where R8and R9the same and represent h

12. Connection on p. 10, in which the X - NOR7where R7is acetyl, R3- CH3, R4- H, R5and R6the same and represent acetyl, Y is 0 and Z is - CH(C2H5)SON(CH3)CH(OR8)CH(CH3)OTHER9where R8and R9the same and represent acetyl.

14. Connection on p. 10, in which the X - NOR7where R7- tosyl, R3- CH3, R4- R6the same and represent H, Y is 0 and Z is - CH(C2H5)SON(CH3)CH(CH3)OTHER9where R8- H, and R9- tosyl.

15. Connection on p. 10, in which the X - NOR7where R7- H, R3- CH3, R4- R6the same and are H, Y is 0 and Z is - CH(C2H5)SON(CH3)CH(OR8)CH(CH3)OTHER9where R8- H, and R9- tosyl.

16. Connection on p. 10, in which the X - NOR7where R7- H, R3- H, R4- CH3, Y is 0 and Z is CH(C2H5)SON(CH3)CH(OR8)CH(CH3)OTHER9where R8and R9the same and are h

17. Connection on p. 10, in which the X - NOR7where R7- H, R3- CH3, R4- R6the same and represent H, Y is NH and Z is CH(CH3)CH(OR10)SON(CH3)CH(OR11)C2H5where R10and R11the same and are h

18. Connection on p. 10, in which the X - NOR7where R7is acetyl, R3- CH3, R4- H, R52H5where R10and R11the same and represent acetyl.

19. Connection on p. 10, in which the X - NOR7where R7is acetyl, R3- CH3, R4and R5the same and represent acetyl, Y is NH, Z is CH(CH3)CH(OR10)SON(CH3)CH(OR11)C2H5where R10and R11the same and represent acetyl.

20. Connection on p. 10, in which the X - NOR7where R7- H, R3- CH3, R4and R5the same and are H, R6- acetyl, Y is NH and Z is CH(CH3)CH(OR10)SON(CH3)CH(OR11)C2H5where R10and R11the same and represent acetyl.

21. Connection on p. 10, in which the X - NOR7where R7- tosyl, R3- CH3, R4- R6the same and are H, Y is NH and Z is CH(CH3)CH(OR10)SON(CH3)(OR11)C2H5where R10and R11the same and are h

22. Connection on p. 10, in which the X - NOR7where R7- H, R3, R5and R6the same and are H, R4- CH3, Y is NH and Z is CH(CH3)CH(OR10)SON(CH3)CH(OR11)C2H5where R10and R11the same and are h

23. Connection on p. 10, in which the X - NOR7< 24. Connection on p. 10, in which the X - NOR7where R7- H, R3, R5and R6the same and are H, R4- CH3, Y 0, and Z is CH3.

25. The way to obtain 9a-azalide fragments macrolide antibiotic class of azalides General formula (I)

< / BR>
in which R1and R2the same and represent H or CH3;

R3and R4different and represent H or CH3;

Y represents-O-, where Z is CH3or Y = -NH-, where Z is CH(CH3)CH(OH)SON(CH3)CH(OH)C2H5,

or their pharmaceutically acceptable salts with organic or inorganic acids, characterized in that iminoethyl erythromycin A of the formula (III)

< / BR>
put

B) the action of hydroxylaminopurine in the presence of an appropriate organic or inorganic bases in a solvent inert under the reaction conditions, in one stage, getting the connection to the basic formula II

< / BR>
where X is NOR7where R7- H;

R3- CH3;

R4- H;

R5and R6the same and are H;

Y IS-O-;

Z - CH(C2H5)SON(CH3)CH(OR8)CH(CH3)OTHER9where R8and R9the same and are H, or

C) action by southwestem hydrochloride in the second stage in the solvent, inert under the reaction conditions,

the formation of compounds of General formula (II), in which the X - NOR7where R7is hydrogen, R3and R4different and represent H or CH3, R5and R6the same and represent H, Y Is-O - and Z is - CH3or CH(C2H5)SON(CH3)CH(OR8)CH(CH3)OTHER9where R8and R9the same and denotes H, and then the compounds obtained in stage B) and (C) is subjected, if required,

D1) N - and/or O-acylation with acid anhydrides or chlorides in an inert solvent and then, if required, methanolysis or

D2) the action of the corresponding organic or inorganic bases in terms of intramolecular aminoacylation, then, if you want,

D2A) N - and/or O-acylation with acid anhydrides or chlorides in an inert solvent and then, if required, methanolysis,

receiving the compound of General formula II, where X = NOR7where R7- acyl or arylsulfonyl group, R3and R4different and denote H or CH3, R5and R6the same or different and denote H or allgroups, Y Is-O-, where Z is CH3or CH(C2H5)SON(CH3)CH(OR8)CH(CH3)OTHER9or Y is-NH-, where Z is and arylsulfonyl group, R10and R11identical and denote H or allgroups, or

D2B) catalytic recovery in an inert solvent and then, if required, replacement of the N-alkylation with the appropriate regenerating agent, receiving the compound of General formula I, where R1- R4, Y and Z have the specified values.

26. The method according to p. 25, characterized in that the reaction aminoether erythromycin A of the formula (III) with hydroxylaminopurine carried out at 25 - 70oC.

27. The method according to p. 26, characterized in that the applied inorganic and organic bases are carbonates of sodium, potassium or pyridine.

28. The method according to p. 26, characterized in that the solvent is inert under the reaction conditions, are methanol or pyridine.

29. The method according to p. 25, characterized in that the N - and/or O-acylation of compounds of General formula (II)

< / BR>
in which the X - NOR7where R7- H;

R3and R4different and denotes CH3or H;

R5and R6the same and are H;

Y is-O-, where Z is CH(C2H5)SON(CH3)CH(OR8)CH(CH3)OTHER9or Y = -NH-, where Z is CH(CH3)CH(OR10)SON(CH3)CH(OR11)C2H5in which RoC, or 4-bromobenzylcyanide in diethyl ether at 0 - 5oC.

30. The method according to p. 29, characterized in that the compound of General formula (II), in which the X - NOR7where R7is acetyl, R3and R4different and represent CH3or H, R5and R6the same and represent acetyl, Y Is O when Z is CH(C2H5)SON(CH3)CH(OR8)CH(CH3)OTHER9Y is-NH-, where Z is CH(CH3)CH(OR10)SON(CH3)CH(OR11)C2H5where R8- R11the same and represent acetyl, subjected, if required, methanolysis, giving a compound of General formula (II), in which X - NOR7where R7- H or acetyl, R3and R4different and represent CH3or H, R5- H, R6- acetyl, Y Is O when Z is CH(C2H5)SON(CH3)CH(OR8)CH(CH3)OTHER9or Y is-NH-, where Z is CH(CH3)CH(OR10)SON(CH3)CH(OR11)C2H5where R8- R11the same and represent acetyl.

31. The method according to p. 25, characterized in that as the appropriate organic or inorganic bases for the intramolecular acylation of amines using ammonium hydroxide, caustic soda, caustic potash or triethylene the reaction conditions, takes place in the presence of noble metals or their oxides as catalysts at room temperature and at a hydrogen pressure of 5 1057 of 106PA.

33. The method according to p. 32, wherein as the catalyst using platinum oxide (IV).

34. The method according to p. 32, characterized in that the solvent is inert under the reaction conditions, is a glacial acetic acid.

35. The method according to p. 25, characterized in that the reductive N-alkylation of compounds of General formula (II) in which R1and R2the same and are H, R3and R4different and represent CH3or H, Y is-NH-, Z is - CH(CH3)CH(OH)SON(CH3)CH(OH)C2H5or their pharmaceutically acceptable salts with organic and inorganic acids, conduct suitable alkylating agents in the presence of suitable reducing agents in a solvent, inert under the reaction conditions, at boiling point in the compounds of General formula (I) in which R1and R2the same and are CH3, R3and R4different and represent CH3or H, Y is-NH - and Z is - CH(CH3)CH(OH)SON(CH3)CH(OH)C2H5or their pharmaceutically acceptable salts of inorganic or organicheskikh alkylation is aldehyde.

37. The method according to p. 36, characterized in that as a suitable aldehyde using formaldehyde.

38. The method according to p. 35, characterized in that as a suitable reductant use formic acid.

39. The method according to p. 35, characterized in that it as inert under the reaction conditions solvent used chloroform.

 

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