New cetazolin and method of production thereof

 

The invention relates to compounds represented by the General formula (I)where A represents NH group, and thus C=O-group or A - C=O-group and thus NH-group, R1HE band, L-clavesilla group of the formula (II)or together with R2is a ketone; R2is hydrogen or together with R1represents a ketone; R3is hydrogen or C1-C4-alcoolica group, and pharmaceutically acceptable salts of the accession of organic and inorganic acids. Also claimed is a method of obtaining compounds of General formula (I). The technical result - the new compounds of erythromycin And related antibiotics class macrolides. 2 C. and 10 C.p. f-crystals, 4 PL.

The technical field of the international patent classification (IPC) a 61 K 31/70, C 07 H 17/08.

The present invention relates to new compounds of erythromycin And related antibiotics class macrolides. Specifically, it relates to a new 15-membered ketazolam class 6-O-methyl-8A-Aza-8A-Homo - and 6-O-methyl-9a-Aza-9a-homoerythromycin And to intermediate products and methods for their preparation, to their pharmaceutically acceptable salts accession of organic and is, which is characterized by a 14-membered Laktionova ring, with the C-9 ketone and two sugars, L-cladinose and D-desosamine that glycoside associated with position C-3 and C-5 with aglionby part of the molecule (McGuire: Antibiot. Chemother., 1952, 2: 281). For more than 40 years erythromycin was considered safe and active antimicrobial agent for the treatment of respiratory and genital infections caused by gram-positive bacteria, such as Legionella, Mycoplasma, chlamydia and Helicobacter. Observed changes in bioavailability after oral administration, gastric intolerance to many patients and the loss of activity in an acidic environment are the main disadvantages of therapeutic use of erythromycin A. Spiritlessly aliceooa rings successfully inhibited by a chemical transformation of the C-9 ketone or hydroxyl groups at positions C-6 and/or C-12. Thus, for example, aksamitowana C-9 ketone erythromycin hydrochloride And hydroxylamine, rearrangement of Beckman received 9(E)-oxime and restoration of the thus obtained 6,9-aminoether (6-deoxy-9-deoxo-9a-Aza-9a-homoerythromycin And 6.9-cyclic aminoether), get 9 deoxo-9a-Aza-9a-homoerythromycin And the first semi-synthetic macrolide with 15-membered azlactone ring (Kobrehel G. et al., U.S. patent 43283345/1982). Javalera-Clark (Eschweiler-Clark) was synthesized 9-deoxo-9a-methyl-9a-Aza-9a-homoerythromycin A (AZITHROMYCIN), the prototype of a new class isaligned of antibioticos (Kobrehel G. et al., BE 892375, 7/1982). In addition to a wide spectrum of antimicrobial activity that includes gram-negative bacteria, azithromycin was also characterized by a long biological half-life, specific transfer mechanism to the application site and a short period of therapeutic action. Azithromycin is able to penetrate and accumulate in phagocytic human cells, resulting in improved activity against intracellular pathogens of the genus Legionella, Chlamydia and Helicobacter.

Furthermore, it is known that C-6/C-12 spiritlessly erythromycin And is also inhibited by O-methylation of the C-6 hydroxyl group aliceooa ring (Watanabe Y. et al., U.S. patent 4331803 5/1982). The interaction of eritromicina And benzotrichloride with subsequent methylation of the obtained 2'-Oh, 3'-N-bis(benzyloxycarbonyl)derivative, removing the protective groups and 3'-N-methylation is formed 6-O-methylerythromycin A (CLARITHROMYCIN) (S. Morimoto et al., J. Antibiotics, 1984, 37, 187). Compared with erythromycin And clarithromycin is considered to be more stable in an acidic environment and shows increased activity in vitro against gram-positive bacteria (Kirst N.A. et al., Antimicrobial Agents and Chemother, namely ketolides characterized by 3-geography instead of neutral sugar L-cladinose, the latter is well-known due to its instability even in the slightly acidic environment (Agouridas S. et al., EP 596802 A1, 5/1994, Le Martret O., FR 2697524 A1/ 5/94). Ketolide show significantly improved activity in vitro compared with MLS (macrolide, lincosamide and streptogramin) induced by resistant microorganisms (Jamjian S. , Antimicrob. Agents Chemother., 1997, 41, 485).

European patent A-0507595 reveals 8A-Aza-8A-homoerythromycin the lactam, which differ from the compounds of the present invention in that they do not have metoxygroup in position 6, which significantly alter the chemical and biological properties of the molecule.

Given the known and established facts of the prior art, the latter is not discussed 15-membered getoutline class 6-O-methyl-8A-Aza-8A-Homo - and 6-O-methyl-9a-Aza-9a-homoerythromycin and their pharmaceutically acceptable salts accession of organic and inorganic acids, methods and intermediate products for their obtain, as well as methods of obtaining pharmaceutical drugs and their use.

The object of the present invention includes the rearrangement of Beckman 9(E) and 9(Z)oxime 6-O-methylerythromycin And Zamin, oxidation of 3-hydroxyl group and the removal of protective groups, and get a new, not previously described 15-membered getoutline from class 6-O-methyl-8A-Aza-8A-Homo - and 6-O-methyl-9a-Aza-9a-homoerythromycin A.

Technical solution the New 15-membered getoutline from class 6-O-methyl-8A-Aza-8A-Homo - and 6-O-methyl-9a-Aza-9a-homoerythromycin And the General formula (I)where a represents NH group, and thus represents the C=O group or
A represents C=O-group, and thus represents an NH-group,
R1is IT group, L-ladiesenjoy group of the formula (II)

or together with R2is a ketone,
R2represents hydrogen or together with R1represents a ketone,
R3represents hydrogen or C1-C4alkanoyloxy group,
and their pharmaceutically acceptable salts accession inorganic or organic acids obtained as follows.

Stage 1.:
The first stage of the invention includes oxymorphine C-9 ketone 6-O-methylerythromycin And (clarithromycin) of the formula (III)

in the corresponding oxime. The conversion of the ketone to an oxime is a well known reaction the organic base in a suitable proton and an aprotic solvent. Hydroxylamine hydrochloride is used in 1-15-equimolar excess, preferably 10-equimolar excess, relative to clarithromycin. As suitable bases are hydroxides, carbonates, bicarbonates and acetates of alkali metals, whereas as solvents used C1-C3the alcohols. The preferred base is sodium carbonate or sodium acetate, and the preferred solvent is methanol. Usually, the reaction is carried out at a temperature of from 0 to 80oC, preferably at 65oWith over 2 hours to several days, but basically it runs from 8 to 20 hours. The processing is carried out in the usual way, for example by evaporation of the solvent in vacuo, add a mixture of water and an organic solvent followed by extraction in an alkaline medium, preferably at pH 8.0 to 10.0. As solvents for extraction of the product are methylene chloride, chloroform, ethyl acetate, diethyl ether and toluene, is preferably chloroform. The product distinguish the separation of the organic layer and evaporation of the solvent, giving a mixture of 6-O-methylerythromycin And 9(E) and 9(Z)-oxime of formula (IV)

in with the of images, using the system methylene chloride - methanol - ammonium hydrochloride 90:9:1.5 a, which gives a chromatographically homogeneous 6-O-methylerythromycin And 9(E)-oxime with Rf 0,446 formula (IVa)

and chromatographically homogeneous 6-O-methylerythromycin A 9(Z)-oxime with Rf 0,355 formula (IVb)

Stage 2
The conversion of 6-O-methylerythromycin And 9(E)-oxime of the formula (IVa), 6-O-methyl-9a-9-Aza-9a-homoerythromycin And the General formula (I)

where a represents the group NH, and is a C=O group, R1is L-ladiesenjoy group of the formula (II)

R2and R3the same and represent hydrogen,
by using rearrangement reaction of Beckman (see "Comprehensive Organic Chemistry", I. O. Sutherland (Ed)., Pergamon Press, New York, 1979, vol. 2, 398-400 and 967-968). In General, the rearrangement of Beckman ketoxime gives carboxamide or, in the case of cyclic systems, the lactam. The mechanism of the rearrangement includes mainly the transformation of eximguaranty more easily removed from the group, which in the second reaction stage is cleaved with the simultaneous migration of the carbon atom in contraposition with respect to the deleted gruppi, giving the corresponding amide.

The rearrangement reaction of Beckman takes place in conditions of acidic, neutral and alkaline environment. Conventional acid reagent, catalyzes the rearrangement include concentrated sulfuric acid, polyphosphoric acid, thionyl chloride, pentachloride phosphorus, sulfur dioxide and formic acid. Due to the sensitivity of the macrolide molecule in the acidic environment and in particular due to the ease of removal of neutral sugar L-cladinose, these reagents are not suitable for the rearrangement of the oxime of formula (IV)6-O-9a-Aza-9a-homoerythromycin And the General formula (I), where a, b, R1, R2and R3have the above values. Preferably rearrangement of Beckman of oxime (IVa) is performed by the initial O-sulfating of eximguaranty alkylhalogenide, arylsulfonate or arylsulfonamides. Intermediate oxysulphate allocate or, usually, rearrangement to the desired product is carried out in situ. In General, the sulfonation and the rearrangement is conducted in the presence of organic or inorganic bases.

Preferred reagents for sulfating that catalyzes the rearrangement of the oxime (IV) include methysulfonylmethane and para-toluensulfonate acid. The reaction is carried out in the presence of inorganic bases, such as sodium bicarbonate or potassium carbonate or in the presence of organic bases, such as pyridine, 4-dimethylaminopyridine, triethylamine and N,N-Diisopropylamine. Suitable solvents include water mixture such as a mixture of acetone-water and a mixture of dioxane-water, and organic solvents such as methylene chloride, chloroform, ethyl acetate, diethyl ether, tetrahydrofuran, toluene, acetonitrile and pyridine. In General, the reaction is carried out using 1-3 equimolar excess sulphurouses agent and with the same or greater equimolar amount of a base at a temperature of from -20 to 50oC. the Pyridine is often used as a solvent and at the same time as the base. Preferably rearrangement of Beckman of oxime (IVa) is carried out in a mixture of acetonitrile-water with a double equimolar excess para-toluensulfonate and sodium bicarbonate. If necessary, the product was then purified using chromatography on a column of silica gel using the solvent system methylene chloride - methanol - ammonium hydroxide 90:9:1.5, the receiving chromatographically homogeneous 6-O-methyl-9a-Aza-9a-homoerythromycin A.

Rearrangement of Beckman 6 a group C= O, and represents the group NH, R1is an L-ladiesenjoy group of the formula (II) and R2and R3the same and represent hydrogen, is carried out in the same manner as 9(E)-oxime (IV).

Stage 3.

6-O-Methyl-9a-Aza-9a-homoerythromycin or 6-O-methyl-8A-Aza-8A-homoerythromycin And stage 2 of General formula (I), where a, b, R1, R2and R3have the above meanings, is subjected, if possible, the impact of strong acids, preferably of 0.25 to 1.5 N. hydrochloric acid at room temperature for 10-30 hours, getting the 3-O-descladinose-3-auxiproizvodnykh 6-O-methyl-9a-Aza-9a-homoerythromycin or 6-O-8A-Aza-8A-homoerythromycin And the General formula (I), where a is an NH-group, and represents the C=O group, or a represents C=O-group, and is a NH group, R1is IT group, and R2and R3the same and represent hydrogen.

Stage 4.

3-O-Descladinose-3-hydroxy-6-O-9a-Aza-9a-homoerythromycin or 6-O-methyl-8A-Aza-8A-homoerythromycin And stage 3 of the General formula (I), where a, b, R1, R2and R3have the above meanings, is subjected, if possible, the reaction of selective acylation of the hydroxyl group at the 2'-position desolina of acetic anhydride, in the presence of inorganic or organic bases in an inert organic solvent at a temperature of from 0 to 30oC receives 2'-O-acetate 3-descladinose-3-hydroxy-6-O-methyl-9a-Aza-9a-homoerythromycin a or 2'-acetate 3-descladinose-3-hydroxy-6-O-methyl-8A-Aza-8A-homoerythromycin And the General formula (I), where a is an NH-group, and represents the C=O group, or a represents C=O group, and represents an NH group, R1HE is a-group, R2represents hydrogen and R3represents acetyl. As suitable bases are sodium bicarbonate, sodium carbonate, potassium carbonate, triethylamine, pyridine, tributylamine, preferably sodium bicarbonate. As a suitable inert solvent is methylene chloride, dichloroethane, acetone, pyridine, ethyl acetate, tetrahydrofuran, preferably methylene chloride.

Stage 5.

3-Descladinose-3-hydroxy-6-O-methyl-9a-Aza-9a-homoerythromycin And 2'-O-acetate or 3-O-descladinose-3-hydroxy-6-O-methyl-8A-Aza-8A-homoerythromycin And 2'-acetate stage 4 of the General formula (I), where a, b, R1, R2and R3have the above meanings, is subjected, if possible, the oxidation of the hydroxyl group on C-3 poliaminopolicarboxilic in the presence of dimethyl sulfoxide and trifurcation pyridinium as a catalyst, in an inert organic solvent, preferably methylene chloride, at a temperature of from 10oWith up to room temperature, getting the 3-descladinose-3-oxo-6-O-methyl-9a-Aza-9a-homoerythromycin And 2'-O-acetate or 3-descladinose-3-oxo-6-O-methyl-8A-Aza-8A-homoerythromycin And 2'-acetate of General formula (I), where a is an NH-group, and represents the C=O group, or a represents a C=O group, and is a NH group, R1and R2together represent a ketone and R3represents an acetyl group.

Stage 6.

3-Descladinose-3-oxo-6-O-methyl-9a-Aza-9a-homoerythromycin And 2'-O-acetate or 3-descladinose-3-oxo-6-O-methyl-8A-Aza-8A-homoerythromycin And 2'-acetate stage 5 of General formula (I), where a, b, R1, R2and R3have the above values, then subjected to solvolysis in the lower alcohols, preferably methanol, at a temperature of solvent from room temperature to the boiling temperature under reflux, getting the 3-descladinose-3-oxo-6-O-methyl-9a-Aza-9a-homoerythromycin or 3-descladinose-3-oxo-6-O-methyl-8A-Aza-8A-homoerythromycin And the General formula (I), where a is an NH-group, and represents the C=O group, or a represents C=O group, the Wallpaper hydrogen.

Pharmaceutically acceptable salts of accession, which are also the subject of the present invention is produced by interaction of the new compounds of the class of 6-O-methyl-8A-Aza-8A-homoerythromycin and 6-O-9a-Aza-9a-homoerythromycin And the General formula (I), where a, b, R1, R2and R3have the above meanings, with at least equimolar amounts of the corresponding inorganic or organic acid, such as hydrochloric, uudistoodetena, sulfuric, phosphoric, acetic, propionic, triperoxonane, maleic, citric, stearic, succinic, Atlanterra, methansulfonate, benzolsulfonat, para-toluensulfonate and laurylsulphate acid, in a solvent inert to the reaction. Salt accession allocate filtering, if they are insoluble in a solvent inert to the reaction, deposition using herstories or by evaporation of the solvent, mainly by way lyophilization.

Antibacterial activity in vitro of new compounds of General formula (I), where a, b, R1, R2and R3have the above meanings, or their pharmaceutically acceptable salts joining with inorganic or organic acids opredelyayuschii Protocol NCCLS (The National Commitee for Clinical Laboratory Standards, Document M7-F2, vol. 10, No 8, 1990, and Document M110F2, vol. 10, 15, 1991). The laboratory process is performed using the control strain of Staphyloccocus aureus ATTC 29213 (The American Type Culture Collection) in accordance with the Protocol NCCLS Document M7-F2, Table 3, M100-S4).

Antibacterial activity in vitro, with a set of test microorganisms for the 6-O-methyl-8A-Aza-8A-homoerythromycin As in example 3 in comparison with azithromycin, erythromycin and clarithromycin are presented in table. 1.

Compounds of the present invention differ from the compounds described in the above documents of the prior art in that they have methoxy (och3-group in position 6 instead of the hydroxy (OH) groups. The substitution group HE group co3in position 6 significantly alter the chemical and biological properties of the molecule. Comparing, for example, the biological activity of 6-O-methyl-8A-lactam of the present invention with 6-hydroxy-8A-lactam, you can see that the introduction of co3instead HE's in position 6 increases biological activity against gram-negative bacteria.

Thus, when comparing the table. 1 of this application with the data presented in table. 1, compound 5, Wilkening et al., Bioorg. Med. Chem. Lett. (1993), 3(6): 1287-1292, and EP-595 clear that the distinction between antimicrobial AK is thew on this application can be summarized as follows (table. 1A).

Also when comparing erythromycin with clarithromycin: Sasaki et al., J. Antibiot. (1988), 41 (7): 908-915,, and U.S. patent 4680386, Marimoto et al. (PL. 2, the compound (I).

In addition, HE and co3groups have different impacts on physico-chemical properties (e.g., electronegativity, conductivity, ability to form conformations and hydrogen bonding stability in the acidic environment, and so on )
The authors of the present invention has been 3-ketopropane 6-methoxy-8-lactam, with good activity against inducible resistant strains. This, in particular, by, for example, the following values of MIC (mg/l) for S. aureus ATCC 27660 (iMLS):
Azithromycin - 8
6-Methoxy-8A-lactam - >128
6-O-Methyl-8A-lactam - >128
3-Ketopropane 6-O-methyl-8A-lactam - 1
This is also confirmed in vivo activity.

The importance of 3-metafunction for activity against inducible resistant strains is confirmed by the data presented for other ketolides (see Agouridas et al., J. Med. Chem. (1998), 41: 4080-4100).

It should also be noted that in the case of 6-hydroxysultaine get a 3-ketopropane (ketolide) is impossible because of the formation of inactive 3,6-policealna derived or cyclic ethers (newly formed O-methyl derivative, presented in Kobrehel et al., WO 99/20639.

Introduction metoxygroup was not chemically obvious. From the literature it is known that the substitution at position 6 is not a direct replacement because of the presence of other hydroxyl groups in the molecule, which can also be methylated. It depends on the reaction conditions, as well as the conformation aliceooa ring, the position of which must be methylated (see Watanabe et al. , (1993), J. Antibiot., 46(4): 647-660, and Wadel et al., (1998), Bioorg. Med. Chem. Lett., 8: 1321-1326).

Additional antibacterial activity of some compounds is evident from the above table. 2.

The cytotoxicity of the compounds of the present invention is shown in the table. 3, from which it is evident that none of the compound is not toxic.

Cytotoxicity was determined in four cell lines:
TNR-1, COS-7 and HepG and CHO.

50,000 cells per well were incubated for 20 hours (37oC; 5% CO2) with the test compounds. Compounds were tested at 10 different concentrations (limits of concentration of 62.5 ng/ml to 64 μg/ml). Used DMEM, supplemented with 5% fetal bovine serum. The cytotoxic effect was determined spectrophotometrically (490 nm) using MTT as a substrate. In light of the above, the known analogues connection.

Example 1
Obtain 6-O-methylerythromycin And 9(E) and 9(Z)-oxime
Method And
6-O-Methylerythromycin A (2.0 g, of 0.003 mol) in methanol (100 ml) is heated to the boiling temperature under reflux, add hydroxylamine hydrochloride (2.0 g, 0.03 mol) and sodium carbonate (0.2 g, 0.002 mol) and heated to boiling under reflux with stirring for 3 hours. Then re-add the same amount of hydroxylamine hydrochloride and sodium carbonate and heated to boiling under reflux for 6 hours. The methanol is evaporated under reduced pressure and then add water (200 ml) and chloroform (100 ml), pH adjusted to 9.8, the layers separated and the aqueous layer was extracted twice more with chloroform. The combined organic extracts are dried over potassium carbonate, filtered and evaporated under reduced pressure, obtaining 2.0 g of the mixture mentioned in the title products. Using chromatography on a column of silica gel using methylene chloride - methanol - conc. hydrochloride ammonia, 90:9:1.5 to receive 0,63 g of chromatographically homogeneous 6-O-methylerythromycin And 9(E)-oxime with Rf 0,446 and 0.61 g of chromatographically homogeneous 6-O-methylerythromycin And 9(Z)-oxime with Rf 0,355.

9(E)-Oxime:
Rf 0,418, atilas the

1H NMR (300 MHz, CDCl3): 5,11 (H-13), 4,95 (H-1"), 4,45 (H-1'), A 4.03 (H-5"), Of 3.77 (H-8), 3,76 (H-3), 3,75 (H-11), 3,66(H-5), 3,48(N-5'), 3,33 (3"-och3), 3,24 (H-2'), 3,10 (6-och3),3,03 (H-4"), 2,89 (N-2), 2.57 M (H-10), 2,45 (H-3'), 2,37 (H-2"), 2,31 [3'-N(CH3)2], 1,93 (H-4), 1,93 (H-14a), 1,68 (N-4 a), 1,58 (H-2"b), 1,53 (H-7a), 1,48 (6-CH3), 1,46 (H-14b), 1,31 (5"-CH3), 1,25 (3"-CH3), 1,23 (5'-CH3), 1,20 (2-CH3), 1,13 (10-CH3), 1,13 (12-CH3), 1,08 (4-CH3), and 1.00 (8-CH3), 0,86 (15-CH3).

13With NMR (75 MHz, Dl3): 175,5 (S-1), 169,2 (C-9), 102,5 (C-1'), OR 95.7 (C-1"), AN 80.2 (C-5), IS 78.4 (C-6), 78,0 (P-3) 77,8 (C-4"), WITH A 76.5 (C-13), OF 73.8 (C-12), TO 72.4 (C-3"), A 71.1 (C-2'), 70,0 (C-11), of 68.2 (C-5'), To 65.2 (C-5"), 64,9 (C-3'), 50,8 (6-och3), 49,1(3"-och3), a 44.7 (C-2), 40,1 [3'-N(CH3)2], of 38.7 (C-4), 37,0 (C-7), 34,6 (C-2"), And 32.3 (C-10), 29,4 (-4'), 24,9 (6-8), 21,1 (5'-CH3), 21,0 (3"-CH3), to 20.8 (C-14) and 19.6 (6-CH3), and 18.3 (5"-CH3), 18,2 (8-CH3), 15,7 (12-CH3) and 15.6 (2-CH3), 14,6 (10-CH3), 10,2 (15-CH3), 8,8 (4-CH3).

9(Z)-Oxime:
Rf 0,300, ethyl acetate-n-hexane-diethylamin, 100:100:20.

IR (KBR), cm-1: 3433, 2973, 2939, 2832, 1733, 1638, 1459, 1379, 1348, 1286, 1169, 1114, 1054, 1011, 958, 892, 755.

1H NMR (300 MHz, Dl3): 5,07 (H-13), Is 4.93 (H-1"), 4,43 (H-1'), A 4.03 (H-5"), 3,98 (H-11), Of 3.77 (H-3), 3,62 (H-5), 3,48 (N-5'), 3,33 (3"-och3), 3,21 (N-2'), 3,09 (6-�67 (N-4 a), 1,59 (H-2"b), 1,58 (H-7a), 1,47 (H-7b), 1,38 (6-CH3), 1,32 (10-CH3), 1,31 (5"-CH3), 1,25 (3"-CH3), 1,24 (5'-CH3), 1,19 (2-CH3), 1,14 (12-CH3), 1,07 (4-CH3), 1,06 (8-CH3), 0,84 (15-CH3).

13With NMR (75 MHz, Dl3): 176,0 (S-1), 167,4 (C-9), 102,7 (C-1'), 96,0 (C-1"), 80,4 (C-5), TO 78.7 (C-6), WAS 78.5 (C-3), 77,8 (C-4"), OF 76.9 (C-13), TO 74.7 (C-12), TO 72.6 (C-3"), TO 70.9 (C-2'), 70,3 (C-11), to 68.4 (C-5'), 65,5 (C-5"), Was 65.3 (C-3'), 50,0 (6-och3), 49,3 (3"-och3), 45,0 (C-2), 41,0 [3' -N(CH3)2], for 38.9 (C-4), 37,0 (C-7), Of 35.6 (C-8), To 34.7 (C-2"), To 34.1 (C-10), 28,9 (-4'), 21,3 (3"-CH3) and 21.2 (5'-CH3), a 21.1 (C-14), 19,7 (6-CH3) and 19.6 (8-CH3), and 18.5 (5"-CH3), and 16.4 (12-CH3), 15,7 (2-CH3) and 10.7 (10-CH3), 10,4 (15-CH3), 9,8 (15-CH3).

The way In
6-O-Methylerythromycin And (10.8 g, 0.014 mol) in methanol (800 ml) is heated at boiling temperature under reflux, then, to the reaction solution was added hydroxylamine hydrochloride (27,0 g, 0,388 mol) and anhydrous sodium acetate (15.0 g, 0,183 mol) in four portions over 10 hours and then heated to boiling under reflux with stirring for a further 8 hours. The methanol is evaporated under reduced pressure, add water (1500 ml) and methylene chloride (200 ml) and extracted with gradient extraction at pH 5.0 and 9.8. United organia 9.5 g of the mixture mentioned in the title products. Using chromatography on a column of silica gel using methylene chloride - methanol - conc. hydrochloride ammonia, 90:9:1.5 to receive a chromatographically homogeneous 6-O-methylerythromycin And 9(E)-oxime and 6-O-methylerythromycin And 9(Z)-oxime with physico-chemical constants identical to those obtained in method A.

Example 2
Rearrangement of Beckman 6-O-methylerythromycin And 9(E)-oxime
6-O-Methylerythromycin And 9(E)-oxime from example 1 (4.0 g, of 0.005 mol) is dissolved in acetone (130 ml) and the solution cooled to 0-5oC. Sequentially dropwise over 1 hour with stirring solutions of para-toluensulfonate (2.6 g, 0.01 mol) in acetone (40 ml) and sodium bicarbonate (0,830 g, 0.01 mol) in water (130 ml). The reaction mixture was stirred at room temperature for 8 hours, the acetone is evaporated under reduced pressure and added dropwise an aqueous solution of chloroform (40 ml), then extracted with gradient extraction at pH 5.0 and 9.0. The combined organic extracts at pH of 9.0 is evaporated, obtaining 2.8 g of 6-O-methyl-9a-Aza-9a-homoerythromycin A.

Rf 0,218, ethyl acetate-n-hexane-diethylamin, 100:100:20.

IR (KBR), cm-1: 3449, 2974, 2939, 2834, 1734, 1706, 1659, 1534, 1459, 1379, 1274, 1169, 1111, 1053, 1011, 958.

1H NMR (300 MHz, Dl3ub>), 3,32 (6-och3), 3,22 (H-11), 3,20 (H-2'), 3.04 From (H-4"), 2,83 (N-2), 2,43 (H-3'), 2,38 (H-2"), 2,30 [3'-N(CH3)2], 2,22 (H-8), 2,07 (H-7a), 1,87 (H-4), 1,87 (H-14a), 1,67 (N-4 a), 1,57 (H-2"b), of 1.57 (H-14b), 1,36 (6-CH3), 1,33 (H-7b), 1,32 (5"-CH3), 1,25 (3"-CH3), 1,24 (H-4'b), 1,23 (5'-CH3), 1,23 (2-CH3), 1,18 (12-CH3), 1,16 (10-CH3), 1,09 (8-CH3), 1,02 (4-CH3), 0,89 (15-CH3).

13With NMR (75 MHz, Dl3): 179,5 (S-1), 177,3 (C-9), 102,5 (C-1'), 94,9 (C-1"), WAS 79.1 (C-6), WAS 78.5 (C-5), WITH 77.7 (C-4"), WITH 77.7 (C-13), 75,9 (P-3) 73,9 (C-12), TO 72.5 (C-3"), TO 72.6 (C-11), TO 70.7 (C-2'), of 68.2 (C-5'), 65,3 (C-5"), a total of 65.1 (C-3'), 51,0 (6-och3), 49,1 (3"-och3), 45,1 (C-10), 44.5cm (C-2), A 41.3 (C-4), 40,0 [3'-N(CH3)2], 39,6 (C-7), Of 35.4 (C-8), 34,4 (C-2"), 28,8 (-4'), 21,1 (5'-CH3), 21,0 (3"-CH3), and 20.3 (C-14), 20,2 (6-CH3), 19,1 (8-CH3), 18,1 (5"-CH3), 15,9 (12-CH3), 14,6 (2-CH3), and 13.4 (10-CH3) and 10.7 (15-CH3), 8,7 (4-CH3).

Example 3
Rearrangement of Beckman 6-O-methylerythromycin And 9(Z)-oxime
6-O-Methylerythromycin And 9(Z)-oxime from example 1 (1.4 g, 0.002 mol) is dissolved in acetone (50 ml) and the solution cooled to 0-5oC. There is added dropwise over 1 hour under stirring successively added a solution of a para-toluensulfonate (1.84 g, 0.014 mol) in acetone (56 ml) and sodium bicarbonate (1,16 g, 0.014 mol) in water (180 ml). The reaction to shift the keys to aqueous solution of chloroform (70 ml), then extracted gradient extraction at pH 5.0 and 9.0. The combined organic extracts at pH of 9.0 is evaporated, getting to 0.80 g of product, which, if possible, purified using chromatography on a column of silica gel using methylene chloride - methanol - conc. the ammonium hydroxide 90: 9: 1/5, getting 6-O-methyl-8A-Aza-8A-homoerythromycin And having the following physical-chemical constants:
Rf 0,152, ethyl acetate-n-hexane-diethylamin, 100:100:20.

IR (KBR), cm-1: 3442, 2974, 2938, 2833, 1736, 1648, 1535, 1459, 1379, 1284, 1169, 1110, 1055, 1013, 960, 902.

1H NMR (300 MHz, CDCl3): 5,78 (8a-CONH), 5,02 (H-1"), 4,96 (H-13), TO 4.41 (H-1'), 4,19 (H-8), WAS 4.02 (H-5"), 3,96 (H-3), 3,69 (H-5), 3,51 (H-11), 3,47 (N-5'), 3,32 (3"-och3), 3,18 (H-2'), and 3.16 (6-och3), to 3.02 (H-4"), 2,68 (N-2), 2,44 (H-3'), 2,35 (H-2"), 2,29 [3'-N(CH3)2], 2,22 (H-10), 1,92 (H-4), 1,91 (H-14a), 1,68 (H-7a), 1,64 (N-4 a), and 1.56 (H-2'b), 1,53 (H-7b), 1,47 (H-14b), 1,39 (6-CH3), 1,29 (5"-CH3), 1,24 (3"-CH3), 1,23 (5'-CH3), 1,20 (2-CH3), 1,18 (10-CH3), 1,13 (12-CH3), 1,13 (8-CH3), 1,07 (4-CH3), 0,88 (15-CH3).

13With NMR (75 MHz, Dl3): 177,0 (S-1), 174,3 (C-9), TO 102.9 (C-1'), 95,1 (C-1"), TO 80.1 (C-5), OF 78.6 (C-6), UP 77.9 (C-4"), FOR 77.2 (C-3), TO 76.7 (C-13), 74,0 (C-12), TO 72.6 (C-3"), OF 70.4 (C-2'), 70,1 (C-11), of 68.7 (C-5'), And 65.4 (C-3'), To 65.2 (C-5"), 51,5 (6-och3), 49,1 (3"-och3), 45,4 ), 21,1 (5'-CH3), 21,1 (3"-CH3), 17,9 (5"-CH3), 15,8 (8-CH3), 14,8 (2-CH3), 10,8 (15-CH3), and 9.2 (10-CH3), and 9.1 (4-CH3).

Example 4
3-Descladinose-3-hydroxy-6-O-methyl-9a-Aza-9a-homoerythromycin And
The substance from example 2 (1.5 g, 0.002 mol) is dissolved in a 0.25 N. hydrochloric acid (40 ml) and left for 24 hours at room temperature. To the reaction mixture are added methylene chloride (30 ml) (pH 1.8) and then the pH of the mixture was adjusted to 9.0 with concentrated ammonia, the layers separated and the aqueous layer was extracted twice with methylene chloride (30 ml). The combined organic extracts are washed with 10% aqueous sodium hydrogen carbonate solution and water and then evaporated, obtaining 1.3 g of crude product, which, if possible, purified using chromatography on a column of silica gel using methylene chloride - methanol - conc. hydrochloride ammonia 90:9:1,5. Of 0.9 g of crude product emit 0.65 g chromatographically homogeneous 3-descladinose-3-hydroxy-6-O-methyl-9a-Aza-9a-homoerythromycin And having the following physical-chemical constants:
Rf 0,152, ethyl acetate-n-hexane-diethylamin, 100:100:20.

IR (KBr), cm-1: 3438, 2973, 2939, 2879, 2788, 1702, 1658, 1535, 1458, 1373, 1329, 1270, 1173, 1112, 1050, 985, 958, 937.

1H NMR (300 MHz, Dl3): 7,16 (9a-CONH),ub>3)2], 2,05 (H-4), 1,92 (H-14a), 1,84 (H-7a), 1,68 (N-4 a), 1,57 (H-14b), 1,43 (H-7b), 1,38 (6-CH3), 1,33 (2-CH3), 1,26 (5'-CH3), 1,26 (H-4'b), 1,20 (10-CH3), 1,12 (12-CH3), 1,11 (8-CH3), 1,01 (4-CH3), 0,91 (15-CH3).

13With NMR (75 MHz, CDCl3): 179,3 (s-1), 176,9 (C-9), Of 106.4 (C-1'), At 88.1 (C-5), 79,1 (C-6), To 78.7 (C-13), 78,0 (C-3), Of 73.8 (C-12), 73,9 (C-11), To 70.2 (C-2'), Was 69.7 (C-5'), And 65.4 (C-3'), a 49.9 (6-och3), to 45.6 (C-10) And 43.9 (C-2) And 40.8 (C-7), And 39.9 [3'-N(CH3)2] , with 35.6 (C-4), Is 32.8 (C-7), 27,8 (-4'), 20,9 (5'-CH3), 20,5 (C-14), and 18.3 (6-CH3), 17,4 (8-CH3), 15,8 (12-CH3), 15,9 (2-CH3), 14,8 (10-CH3) and 10.7 (15-CH3), 7,5 (4-CH3).

Example 5
3-Descladinose-3-hydroxy-6-O-methyl-8A-Aza-8A-homoerythromycin And
Of substances (1.5 g, 0.002 mol) from example 3 receive in accordance with the method described in example 4, 1.2 g of crude product, which, if possible, purified using chromatography on a column of silica gel using methylene chloride - methanol - conc. the ammonium hydroxide 90:9:1.5, the receiving chromatographically homogeneous 3-descladinose-3-hydroxy-6-O-methyl-8A-Aza-8A-homoerythromycin And having the following physical-chemical constants:
Rf of € 0.195, chloroform - methanol - conc. the ammonium hydroxide, 6:1:0,1.

IR (KBR), cm-1: 3438, 2974, 2939, 2788, 1733, 1648, 1535, 1458, 1378, 1263, 1165, 1113, 1075, 1050, 985, 958, 934 (N-2), 3,54(H-5'), 3,47 (H-11), 3,25 (H-2'), 2,11 (H-4), 3,12 (6-och3), 2,48 (H-3'), 2,38 (H-10), 2,25 [3'-N(CH3)2] , 1,94 (H-14a), 2,11 (H-7a), 1,66 (N-4 a) and 1.51 (H-7b), 1,50 (H-14b), 1,31 (2-CH3), 1,39 (6-CH3), 1,12 (4-CH3), 1,26 (5'-CH3), 1,26 (H-4'b), 1,20 (10-CH3), 1,25 (8-CH3), 1,13 (12-CH3), 0,88 (15-CH3).

13With NMR (75 MHz, Dl3): 176,0 (s-1), Of 174.4 (C-9), 106,1 (C-1'), 89,6 (C-5), For 77.3 (C-6), To 75.8 (C-13), To 78.3 (C-3), Of 74.3 (C-12), Is 70.3 (C-11), To 69.9 (C-2'), 69,4 (C-5'), 64,9 (C-3'), 49,7 (6-och3), 42,1 (C-10), While 43.8 (C-2), And 41.7 (C-7), And 39.9 [3'-N(CH3)2] , 35,2 (C-4), 42,4 (C-8), 27,4 (-4'), 22,3 (5'-CH3), to 20.9 (C-14) to 20.4 (6-CH3), 20,5 (8-CH3), 15,7 (12-CH3), and 15.2 (2-CH3), and 9.5 (10-CH3), 10,1 (15-CH3), 7,50 (4-CH3).

Example 6
3-Descladinose-3-hydroxy-6-O-methyl-9a-Aza-9a-homoerythromycin And 2'-O-acetate
To a solution of 3-descladinose-3-hydroxy-6-O-methyl-9a-Aza-9a-homoerythromycin And (0,750 g, 0,0012 mol) from example 4 in methylene chloride (25 ml) is added sodium bicarbonate (0,440 g, 0,0052 mol) and acetic anhydride (0,128 ml, 0,0013 mol) and stirred for 3 hours at room temperature. To the reaction mixture is added a saturated solution of sodium bicarbonate (30 ml), the layers separated, and the aqueous portion is again shaken out with methylene chloride (2 x 20 ml). The combined organic extracts washed down the agolove product with the following physical-chemical constants:
Rf 0,403, chloroform-methanol-conc. the ammonium hydroxide, 6:1:0,1.

IR (KBR), cm-1: 3455, 2974, 2940, 2880, 2787, 1748, 1702, 1658, 1540, 1459, 1376, 1239, 1173, 1112, 1061, 986, 958, 937, 904.

Example 7
3-Descladinose-3-hydroxy-6-O-methyl-8A-Aza-8A-homoerythromycin And 2'-O-acetate
To a solution of 3-descladinose-3-hydroxy-6-O-methyl-9a-Aza-9a-homoerythromycin And (1.5 g, 0,0024 mol) from example 5 in methylene chloride (40 ml) is added sodium hydrogen carbonate (0.88 g, 0.01 mol) and acetic anhydride (0,250 ml 0,0025 mol) and then in accordance with the method described in example 6, to obtain 1.4 g named in the title compound with the following physico-chemical constants:
Rf 0,423, chloroform-methanol-conc. the ammonium hydroxide, 6:1:0,1.

IR (KBR), cm-1: 3394, 2972, 2939, 2784, 1736, 1649, 1542, 1459, 1376, 1262, 1165, 1085, 1059, 986, 958, 904.

Example 8
3-Descladinose-3-oxo-6-O-methyl-9a-Aza-9a-homoerythromycin And
To a solution of 3-descladinose-3-hydroxy-6-O-methyl-9a-Aza-9a-homoerythromycin And 2'-O-acetate (0,760 g, 0,0012 mol) from example 6 in methylene chloride (15 ml) is added dimethyl sulfoxide (1,27 ml) and N,N-dimethylaminopropylamine (1,335 g to 0.007 mol). The reaction mixture is cooled to 15oAnd then, under stirring, maintaining the same temperature, gradually dropwise within 30 minutes, add a solution of pyridine trifenatate (1,37 g is, stirring is continued for further 3 hours and then the reaction is interrupted by addition of a saturated solution of NaCl (20 ml) and methylene chloride (20 ml). After alkalizing the reaction mixture to a pH of 9.5 with 2 N. NaOH its extracted with CH2CL2organic extracts washed sequentially with saturated solution of NaCl, Panso3and water, then dried over K2CO3. After filtration and evaporation of the methylene chloride under reduced pressure 0.800 to get g of oily residue. The oily residue is subjected to methanolysis (30 ml methanol) for 24 hours at room temperature. The methanol is evaporated under reduced pressure and the obtained residue (0.625 g) purified by low pressure chromatography on a column of silica gel using the solvent system dichloromethane - methanol - conc. the ammonium hydroxide, 90:9:0.5 in. Viparita combined extracts with Rf 0,235 get chromatographically homogeneous named in the title of the product with the following physical-chemical constants:
Rf 0,235, methylene chloride - methanol-conc. the ammonium hydroxide, 90:9:0.5 in.

IR (KBR), cm-1: 3438, 2975, 2939, 2878, 2787, 1744, 1655, 1530, 1458, 1380, 1340, 1304, 1169, 1111, 1075, 1051, 986, 959, 940.

1H NMR (300 MHz, Dl3): 6,63 (9a-CONH), WITH 4.64 (H-13), 4,49 (H-5), TO 4.41 (H-1'), 4,20 (H-10),a), 1.69 in (N-4 a), and 1.63 (H-14b), 1,42 (H-7b), 1,40 (2-CH3), 1,30 (5'-CH3), 1,29 (4-CH3), 1,26 (5-CH3), 1,25 (H-4'b), 1,22 (12-CH3), 1,19 (10-CH3), 1,10 (8-CH3), 0,91 (15-CH3).

13With NMR (75 MHz, CDCl3): 206,8 (C-3), 177,3 (s-1), 173,8 (C-9), 102,6 (C-1'), To 79.3 (C-13), Is 78.4 (C-6), Of 74.4 (C-5), 73,9 (C-12), 73,1 (C-11), 70,0 (C-2'), 69,1 (C-5'), 65,5 (C-3'), 50,1 (6-och3), is 49.0 (C-2) And 46.2 (C-4), 45,3 (C-10), Of 40.3(C-7), 40,0 [3'-N(CH3)2] that 34.6 (C-8), And 28.3 (C-4'), 21,0 (6-CH3), 20,7 (C-14) and 19.6 (5'-CH3), and 18.6 (8-CH3), 15,9 (12-CH3), 14,1 (2-CH3), 13,9 (10-CH3), 13,9 (4-CH3) and 10.7 (15-CH3).

Example 9
3-Descladinose-3-oxo-6-O-methyl-8A-Aza-8A-homoerythromycin And
To a solution of 3-descladinose-3-hydroxy-6-O-methyl-8A-Aza-8A-homoerythromycin And 2'-O-acetate (1.4 g, 0,0022 mol) from example 7 in methylene chloride (30 ml) is added dimethyl sulfoxide (2.5 ml) and N,N-dimethylaminopropylamine (2.7 g, 0.014 mol). The reaction mixture is cooled to 15oWith stirring and maintain this temperature, gradually dropwise within 30 minutes, add a solution of pyridine trifenatate (2.7 g, 0.014 mol) in methylene chloride (10 ml). In accordance with the method described in example 8, to obtain 1.1 g named in the title of the product with the following physical-chemical constants.

IR (KBR), cm-1//img.russianpatents.com/chr/948.gif">: of 5.89 (9a-CONH), 5,08 (H-13), 4,42 (H-1'), 4,27 (H-5), A 4.03 (H-8), 3,78 (N-2), 3,60 (H-5'), TO 3.58 (H-11), 3,18 (H-2'), 3,05 (H-4), 2.91 in (6-och3), 2,49 (H-3'), 2,39 (H-10), 2,27 [3'-N(CH3)2], 1,96 (H-14a), 2,68 (H-7a), 1,68 (N-4 a), 1,50 (H-14b), 1,41 (2-CH3), 1,32 (6-CH3), 1,30 (4-CH3), 1,25 (5'-CH3), 1,23 (H-4'b), 1,20 (10-CH3), 1,19 (8-CH3), 1,17 (12-CH3), 0,88 (15-CH3).

13With NMR (75 MHz, CDCl3): 206,2 (C-3), 170,0 (C-9), 174,6 (s-1), 103,1 (C-1'), To 78.2 (C-6), Up 77.9 (C-5), Of 77.5 (C-13), 74,1 (C-12), 70,6 (C-11), 70,0 (C-2'), 69,1 (C-5'), 65,5 (C-3'), and 50.5 (6-och3), and 50.4 (C-2), Or 47.6 (C-4), 42,2 (C-10), 42,1 (C-7), to 41.6 (C-8), and 39.9 [3'-N(CH3)2], 28,0 (C-4'), 22,8 (8-CH3) and 21.2 (C-14), 20.8 (the 5'-CH3), 20,1 (6-CH3), 16,1 (12-CH3), 15,4 (2-CH3), 14.4V (4-CH3), and 10.5 (15-CH3), 10,1 (10-CH3).


Claims

1. The connection represented by the General formula (I)

where A represents NH group and at the same time-C= O-group or a represents C= O-group and In-NH-group,
R1HE band, L-clavesilla group of the formula (II)

or together with R2is a ketone;
R2is hydrogen or together with R1- ketone;
R3is hydrogen or C1-C4-alcoolica group,
and it Parliament fact, what is A - NH-group, - C= O group, R1- L-clavesilla group of the formula (II), R2and R3the same is hydrogen.

3. Connection on p. 1, characterized in that A - C= O-group, - NH-group, R1- L-clavesilla group of the formula (II), and R2and R3the same is hydrogen.

4. Connection on p. 1, characterized in that A - NH-group, - C= O group, R1- Oh group, and R2and R3the same is hydrogen.

5. Connection on p. 1, characterized in that A - C= O-group, - NH-group, R1- Oh-group, and R2and R3the same is hydrogen.

6. Connection on p. 1, characterized in that A - NH-group, - C= O group, R1- Oh-group, R2is hydrogen, R3- C1-C4alcoolica group.

7. Connection on p. 6, wherein R3- acetyl group.

8. Connection on p. 1, characterized in that A - C= O-group, - NH-group, R1- Oh-group, R2is hydrogen, and R3- C1-C4alcoolica group.

9. Connection on p. 8, wherein R3- acetyl group.

10. Connection on p. 1, characterized in that A - NH-group, - C= O group, R1and R2together, ketone, and R3- hydrogen.

11. Connection on p. 1, characterized in that A - C= O-groupaverage (I)

and its pharmaceutically acceptable salts joining with organic and inorganic acids,
where A - NH-group and - C= O-group or A - C= O-group and In - NH-group;
R1HE band, L-clavesilla group of the formula (II)

or together with R2- ketone;
R3is hydrogen or together with R1- ketone;
R3is hydrogen or C1-C4alcoolica group,
wherein the 6-O-methylerythromycin And formula (III)

subjected to reaction with hydroxylamine hydrochloride in the presence of appropriate inorganic and organic bases, receiving a mixture of 6-O-methylerythromycin And 9(E) and 9(Z)-oxime of formula (IV)

which, if possible, is subjected to separation on a column of silica gel using methylene chloride - methanol-conc. hydrochloride ammonia 90: 9: 1.5, the receiving chromatographically homogeneous 9(E)-oxime 6-O-methylerythromycin A Rf 0,446 formula (IVa)

and chromatographically homogeneous 6-O-methylerythromycin And 9(Z)-oxime with Rf 0,355 formula (IVb)

and then subjected peregi inorganic bases, preferably sodium bicarbonate, in a solvent or mixture of solvents inert to the reaction, preferably in a mixture of acetone - water, getting in case 9(E)-oxime 6-O-methylerythromycin And formula (IVa) with a compound of General formula (I) where A - NH-group; - C= O-group; R1- L-clavesilla group of the formula (II), and R2and R3the same is hydrogen, or in the case of 9(Z)-oxime 6-O-methylerythromycin A formula (IVb) with a compound of General formula (I), where A is C= O-group, - NH-group, R1- L-clavesilla group, and R2and R3the same is hydrogen, which are then subjected to the action of dilute inorganic acids, preferably of 0.25 n hydrochloric acid at room temperature, obtaining a compound of General formula (I) where A - NH-group and - C= O-group or A - C= O-group and In - NH-group; R1- Oh-group, and R2and R3the same is hydrogen, which is then subjected to reaction selective acylation with anhydrides of carboxylic acids having up to 4 carbon atoms, preferably with acetic anhydride in an inert organic solvent, preferably methylene chloride, receiving the compound of General formula (I) where A - NH-group and - C= O-group or A - C is shown to oxidation with diimide, preferably with N, N-dimethylaminopropyl-ethylcarbodiimide, in the presence of dimethyl sulfoxide and trifurcation pyridinium as a catalyst in an inert organic solvent, preferably methylene chloride, at a temperature of from 10oWith up to room temperature, obtaining a compound of General formula (I) where A - NH group, and at the same time - C= O-group or A - C= O-group, and - NH-group; R1and R2together ketone and R3- acetyl group, which is then subjected to reaction diallylamine position 2' by solvolysis in lower alcohols, preferably methanol, at room temperature, obtaining a compound of General formula (I) where A - NH-group, and - C= O-group or A - C= O-group, and - NH-group; R1and R2together, ketone, and R3- hydrogen, which then, if possible, is subjected to the interaction with inorganic and organic acids, receiving their pharmaceutically acceptable salts accession.

 

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< / BR>
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