Derivatives of erythromycin, methods for their preparation and pharmaceutical composition based on them

 

(57) Abstract:

The invention relates to new derivatives of erythromycin General formula I, where Z, R1, R2specified in paragraph 1 of the claims. New erythromycin derivatives have antibacterial action. In particular, they are active against gram-positive and grammatically bacteria. Describes the methods for their preparation and pharmaceutical composition based formula I. 4 C. and 8 C.p. f-crystals, 2 PL.

The present invention relates to new derivatives of erythromycin, method for their production and pharmaceutical compositions based on them.

The object of the present invention are compounds of General formula (I):

< / BR>
in which, or R1and R2have identical or different meanings and represent a hydrogen atom or a hydrocarbon radical containing up to 24 carbon atoms, saturated or unsaturated, possibly including one or more heteroatoms and which may have one or more functional groups,

or R1and R2form together with the nitrogen atom to which they are bound, a heterocycle, including possibly one or more heteroatoms, selected from among al the ' have identical or different meanings and represent a hydrogen atom or a hydrocarbon radical, containing up to 23 carbon atoms, saturated or unsaturated, possibly including one or more heteroatoms, which may have one or more functional groups,

Z represents a hydrogen atom or a residue of carboxylic acids containing up to 18 carbon atoms,

the wavy line in position 10 indicates that methyl may be configured as a P or presents a mixture of R and S configuration,

as well as salts of accession with the acid compounds of formula (I).

Among the salts of joining with acids can be called salts formed with acetic acid, propionic acid, triperoxonane acid, maleic acid, tartaric acid, methanesulfonate, benzosulfimide, p-toluensulfonate and, in particular, stearic acid, adelantarnos acid or laurylsulphate.

Hydrocarbon radical, which may be represented by the substituents R1or R2or R1' and R2'can include one or more heteroatoms selected among nitrogen, oxygen and sulfur and may contain one or more groups selected from the group formed by hydroxyl radicals, halogen atoms, groups of NO2, groups CN and N-alkyl, N-alkenyl or N-quinil containing up to 12 carbon atoms, possibly substituted by one or more halogen atoms, a radical where Raand Rbhave identical or different meanings and represent a hydrogen atom or alkyl containing up to 12 carbon atoms; the radical where R3represents alkyl containing up to 12 carbon atoms, or aryl or heteroaryl, possibly substituted; aryl, o-aryl or s-aryl carboxylic or heterocyclic aryl, o-aryl or s-aryl, containing 5 or 6 chains containing one or more heteroatoms, possibly substituted by one or more substituents named above.

Hydrocarbon radical, which is represented by the substituents R1or R2or R1' and R2'may be an alkyl, alkenyl, quinil, aralkyl, aralkyl or aralkyl. When substituents are alkyl, alkenyl or quinil, then preferably they are methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert.butyl, decyl or dodecyl, vinyl, allyl, ethinyl, PROPYNYL, propargyl, cyclobutyl, cyclopentyl or cyclohexyl.

Aryl can be represented by a phenyl or naphthyl.

Aryl can imidazolyl, thiadiazolyl, pyrazolyl or seperatly, pyridyl, pyrimidyl, pyridazinyl, or pyrazinyl or indolyl, benzofuranyl, benzothiazol or chinoline. These arily can contain one or more of the above groups.

When R1and R2form together with the nitrogen atom to which they are bound, a heterocycle, preferably it is about pyrrolyl, pyrrolidinyl, pyridine, pyrazinyl, pyrimidyl, piperidinyl, piperazinil, hinkleville, oxazolyl, isoxazolyl, morpholinyl, indolyl, imidazolyl, benzimidazolyl, triazolyl, thiazolyl, azetidine, aziridine.

More specifically the object of the present invention are the compounds of formula (I) in which Z represents a hydrogen atom, the compounds of formula (I) in which R1represents a hydrogen atom, the compounds of formula (I) in which R1and R2represent each a hydrogen atom.

Among the preferred compounds according to the present invention include compounds of formula (I) in which R1' represents a hydrogen atom, and compounds for which R1and R2together form a radical: = CH(CH2)nAr1where Ar1is a>has, as a preferable value, or another value selected from the preferred values described above for aryl and heteroaryl. Possible substituents Ar1are those referred to above as functional groups.

Among the preferred compounds according to the present invention include compounds of formula (I) in which R1and R2form together a radical:

,

where "p" and "q" are the same or different values and represent an integer having a value from 0 to 6, A and B have identical or different meanings and represent a hydrogen atom or halogen or alkyl containing up to 8 carbon atoms, with the double bond may have a configuration E or Z or a mixture thereof, or A and B form a triple bond with the carbon atoms to which they are linked, and Ar2represents aryl or heteroaryl mono - or polycyclic, possibly substituted.

Among these compounds it is possible to emphasize the connection, in the formula which "p" and "q" are set to 0, and those for which A and B represent a hydrogen atom.

Among the preferred compounds according to the invention can be identified which r" is an integer, having a value in the interval from 0 to 6, and Ar3represents aryl or heteroaryl, possibly substituted, and more specifically, those compounds of the formula where Ar3is a 4 - chinoline, possibly mono - or politeley one and/or the other of quinoline 2 cycles, for example, those compounds in which Ar3represents an unsubstituted 4-chinoline, 4-chinoline, substituted methoxy group, or thiazolyl, substituted pyridinyl.

More specifically, the object of protection are the compounds of formula (I) in which r is an integer from 1 to 4.

Among the preferred compounds according to the present invention are those compounds which are described below in the experimental part of the description, and more specifically, those compounds that have the following names:

-11,12-dideoxy-3-de-((2, 6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-abovecaptionskip)-oxy)-6-O-methyl-3-oxo-12,11-(oxy - carbonyl-(2-(3-(4-chinoline)-propyl)-hydrazono))- erythromycin,

-11,12-dideoxy-3-de-((2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-abovecaptioned)-oxy)-6-O-methyl-3-oxo - 12,11-(oxy-carbonyl-(2-(3-(7-methoxy-4-chinoline)-propyl)- hydrazono))-erythromycin,

-11,12-dideoxy-3-de-(Il-4-thiazolyl)-propyl)- hydrazono))-erythromycin.

Compounds of General formula (I) have very good antibiotic activity on gram-positive bacteria, such as staphylococci, pneumococci.

Thus, the compounds according to the invention can be used as drugs in the treatment of microbial infections, namely staphylococcal infections, such as staphylococcal septicemia, staphylococcal lesions on the face and skin, piodermitov, septic or suppurating wounds, boils, carbuncles, phlegmon, erysipelatous diseases and acne; such staphylococcal diseases, as usual acute tonsillitis or Poligraphia tonsillitis, pneumonia, pulmonary suppuration; such streptococcal diseases such as acute tonsillitis, otitis, sinusitis, scarlet fever, pneumococcal such diseases as pneumonia, bronchitis, brucellosis, diphtheria, gonococcal disease.

The compounds claimed in the present invention are also active against infections caused by these microbes, as Haemophilus influenzae, Rickettsies, Mycoplasma pneumoniae, Chlamydia, Legionella spp., Ureaplasma, Toxoplasma, or microbes of the genus Mycobacterium.

In addition, the object of protection are also in the quality of medicines, especially medicines-antibiotics, connect the Eski suitable acids.

More specifically, the present invention relates as medicines, such as antibiotics, to the compounds of examples 5 or 11, 12 and 13 and their pharmaceutically suitable salts.

In addition, the security object of the present invention are pharmaceutical compositions containing as active ingredient at least one drug that is listed above.

These compositions can be introduced orally, rectally, parenterally or locally by topical application to the skin and mucous membranes, but it is preferable to oral administration of these compositions.

The composition can be a liquid or solid substances and to have the pharmaceutical forms commonly used in the treatment of a person, such as simple or dragevent tablets, gelatin capsules, granules, suppositories, injectable preparations, ointments, creams, gels; these compositions obtained in accordance with the usual methods of getting them. Current or active substances may be present in such pharmaceutical compositions in a mixture with commonly used excipients, such as talc, gum Arabic, lactose, starch, magnesium stearate, cocoa butter, voglibose, various wetting agents, dispersants or emulsifiers, preservatives.

These compositions can also be in the form of powders intended for dilution prior to use in the appropriate excipients, such as sterile pyrogen-free water.

Enter the dose varies depending on the disease, curable patient, the route of administration of the medicinal product and the selected connection. The dose may be, for example, from 50 to 300 mg per day with the introduction of oral adult compound from example 5.

In addition, the object of protection of the present invention is a method of obtaining compounds of formula (I), characterized in that the compound of formula (II):

< / BR>
where Z has the same meaning as above, is subjected to impact or hydrazine NH2NH2obtaining the compounds of formula (IA):

< / BR>
which is optionally exposed to aldehyde R2'CHO or a ketone R1'--R2'where R1' and R2' have the meanings indicated above, to obtain the compounds of formula (IB):

< / BR>
where R1' and R2' save the values specified above, which is optionally subjected to the action in anaut values, above, i.e. the compounds of formula (I) in which R1represents hydrogen, and R2represents a radical CHR1'- R2'then, if desired, the compound of formula (IC) is exposed to an agent capable of replacing the hydrogen atom of the NH group to the group R1the value of which is given above, except for the value of the hydrogen, and then, if desired, the compound obtained is subjected to the action of acid to salt and/or action agent esterification of the OH group located at the 2'position.

The compounds of formula (II) used as starting compounds the method claimed in the present invention, described and claimed in European patent application EP 0596802.

In accordance with a preferred embodiment of the invention

- the process is conducted with an excess of hydrazine at a temperature above ambient temperature, for example at a temperature of from 40 to 80oC, in a solvent such as acetonitrile, dioxane, dimethylformamide, tetrahydrofuran, dimethoxyethane or dimethylsulfoxide (in the presence or in the absence of base),

- interaction with the aldehyde or ketone is carried out in a similar, temperaturechange catalyst, as palladium, platinum, and in the presence or in the absence of such acids as hydrochloric acid or acetic acid,

the etherification is in the 2' position is carried out in accordance with the classical methods,

the salt formation is carried out using acids in accordance with the classical methods.

In addition, the object of protection is the embodiment of the above method, characterized in that the compound of formula (II):

< / BR>
where Z has the values listed above, is exposed to the compound of the formula NH2OTHER2obtaining the compounds of formula (I'A):

< / BR>
which, if you will, is treated with an agent capable of replacing the hydrogen atom of the NH group in the radical R1above, except for the value of hydrogen, to obtain the compounds of formula (I'B)

< / BR>
which, if you will, is exposed to agent, providing for the esterification of the OH group in position 2', or the effects of the acid with the formation of the salt, while the preferred conditions for temperature and pressure similar to the above.

The following examples illustrate the present invention.

EXAMPLE 1: 11,12-dideoxy-3-de-((2,6-dideoxy-3-C-methyl-3-O-methyl-al (S).

In 5 ml of methyl cyanide and 0.5 ml of water is suspended 353 mg of 2'-acetate-11-deoxy-10,11-didehydro-3-de(2,6-dideoxy-3-C - methyl-3-O-methyl-alpha-L-abovecaptionskip)-oxy)-12-O- (1H-imidazol-1-yl)-carbonyl)-6-O-methyl-3-oxo-erythromycin,

obtained by the method specified in the application for the European patent EP 0596802, and 0,097 ml of hydrazine hydrate is added. The reaction mass is heated at a temperature of 60oC for 3 hours. Then the reaction mixture was poured into water, extracted with ethyl acetate, washed, dried. Carry out the chromatography of the reaction mixture on silica, using as eluant mixture of isopropyl ether, triethylamine and methanol (90/10/10). Obtain 101 mg of the target product (product a), Rf=0,45, and 106 mg of the corresponding product 10 (S) (product B).

PRODUCT A see at the end of the description.

EXAMPLE 2: 11,12-dideoxy-3-de(2,6-dideoxy-3-C-methyl-3-O - methyl-alpha-L-abovecaptionskip)-oxy)-6-O-methyl-3-oxo-12,11 - (oxycarbonyl-(2-(3-phenylpropylamine)-hydrazono))-erythromycin.

Dissolved in 2 ml of tetrahydrofuran at a molecular sieve (4 ) 285 mg of product A obtained in example 1 and 156 mg of 3-phenylpropionaldehyde. Add 100 m molecular sieve (4 ) and heated at a temperature of 60oC for 24 hours. Filtrate mixture of ethyl acetate, triethylamine (96-4). Collect the fraction rf=0.41 and obtain 330 mg of the desired product, rf=0,3.

Analysis

% calculated: C 64,58; H compared to 8.26; N 5,65;

% found: C 64,3; H 8,3; N 5,5.

NMR CDCl3- ppm

3.04 FROM - H10(q)

4,46 - H11(d, J=3 Hz)

OF 5.05 - H13(dd)

3,85 - H2(q)

2,38 - NMe (s)

2,79 - 6 OMe (s)

of 7.96 - N = CH (t)

2,86 - CH2-F

7,2, 7,35 - H aromatic

2,61 - NH=CH-CH2(m)

EXAMPLE 3: 11,12-dideoxy-3-de-((2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-abovecaptionskip)-oxy)-6-O-methyl-3-hydroxy - 12,11-(oxycarbonyl-(2-(3-phenylpropyl)-hydrazono))-erythromycin.

Added 23 mg of cyanoborohydride sodium (NaBH3CN) in a solution containing 1.5 ml of methanol, 88 mg of the compound obtained in example 2, and 50 μl of acetic acid. Carry out the concentration, the treatment with ethyl acetate, the addition of water, then with 2N-aqueous solution of sodium hydroxide to provide a pH of 8. This is followed by decanting, washing with a saturated solution of sodium chloride and drying. The resulting product is subjected to chromatography on silica (eluant: simple isopropyl ether-methanol - triethylamine 90-10-10). Collect the fraction rf=0,33. The resulting mixture is treated with a mixture of simple ether-pentane and filtered. P IS R> % found: C 64,2; H 8,3; N 5,6.

NMR CDCl3- ppm

3,74 - H10(s)

5,03 - H13(dd)

3,86 - H2(q)

2,27 - N(CH3)2(s)

2,64 - 6 OMe (s)

2,72 - CH2-F

7,13-7,28 - H aromatic

5,35 - H of NH (t)

EXAMPLE 4: 11,12-dideoxy-3-de-((2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-abovecaptionskip)-oxy)-6-O-methyl-3-oxo-12,11-(oxycarbonyl-(2-(3-(4-chinoline)-2(E)- (propenylidene)-hydrazono))-erythromycin.

When the ambient temperature is stirred for 5 hours 125 mg of compound A obtained in example 1, 73 mg of 4-chinainternational, the receipt of which is described below, and 40 μl of acetic acid. Under reduced pressure to remove the methanol, after which the residue is treated with a mixture of methylene chloride-water. Using a concentrated solution of hydroxide ammonium establish a pH of 9. Then perform decanting, drying on magnesium sulfate, filtration and evaporation dry. Obtain 211 mg of product, which is subjected to chromatography on silica, using as eluant a mixture of methylene chloride-methanol (92-8). Product c rf =0.4 to thicken in a mixture of ethyl acetate: pentane (1-1). Then the obtained product is squeezed and washed in at least a mixture of ethyl acetate: pentane, dried in susheela 4-genolyptus.

Dissolved in 80 ml of methylene chloride of 3.9 g of 4-chinainternational. The solution is cooled to a temperature of 10oC 5oC, then for 1 hour 30 minutes are added, keeping the temperature at a level of 10oC, of 8.3 g of 3- (triphenylphosphine)-propenal (C6H5)3P= C-CHO. The reaction mixture is left up until its temperature returns to a value of 20oC, and then continue stirring for 24 hours. Then again cooled to a temperature of 10oC, was added 0.4 g (C6H5)3P=C-CHO. Stirred for 3 hours at ambient temperature. Evaporate the methylene chloride and receive a product that is subjected to chromatography on silica, using as eluant a mixture of ethyl acetate-cyclohexane (4 - 6). Allocate 2,12 g of the target product. TPL90oC.

EXAMPLE 5: 11,12-dideoxy-3-de-((2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L - abovecaptionskip)-oxy)-6-O-methyl-3-oxo-12,11-(oxycarbonyl-(2-(3-(4-chinoline)-2-propyl)-hydrazono))-erythromycin.

Dissolved in 10 ml of ethyl acetate of 0.38 g of the compound obtained in example 4, and 38 mg of platinum oxide. Hydronaut with vigorous stirring for 24 hours. The resulting product is filtered, washed in ethyl whom μl of acetic acid and 90 mg of sodium borohydride. Stirred for 3 hours at ambient temperature. Distilled methanol, and the residue is treated with a mixture of methylene chloride-water. Using 28% aqueous solution of hydroxide of ammonium establish a pH of 8-9. Then the reaction mass is decanted, washed with water, dried, filtered and evaporated to dryness. Gain of 0.37 g of product, which is subjected to chromatography on silica, using as eluant a mixture of ethyl acetate-triethylamine 96-4. Obtain 127 mg of the compound (rf = 0.25 in), which is drained, washed and dried. Receive 90 mg of the target product. TPL= 189oC.

NMR CDCl3ppm 300 MHz

1,34 (s)-1,48 (s): 6 and 12 CH3; 2,30 (s): N(CH3)2; 2,65 (s): 6-OCH3; 3,06 (dq): H43,19 (q): H10; 3,74 (s): H11; 5,50 (t variable): NH-CH2; 7,30 (d): H3the quinoline; 7,53-to 7.68 (dt): H6-H7the quinoline; 8,10 (m): H5-H8the quinoline; 8,79 (d): H2the quinoline.

EXAMPLE 6: 11,12 - dideoxy-3-de-((2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L - abovecaptionskip)-oxy)-6-O-methyl-3-oxo-12,11- (oxycarbonyl-(2-(3-(1H-benzimidazole-1-yl)-propyl)- hydrazono))-erythromycin.

Carry out stirring for 18 hours at ambient temperature solution of 300 mg of the product obtained in example 1, 168 mg of 3-imidazo the Yeni in the reaction mixture is added 40 mg of cyanoborohydride sodium and carry out stirring for 5 hours, and then added 120 mg of cyanoborohydride sodium and 200 μl of acetic acid. Stirring is continued for 48 hours, then add a mixture of methylene chloride and water, using 32% aqueous solution of hydroxide of ammonium establish a pH of 8-9, and then the organic phase is separated, dried and evaporated dry. Obtain 0.6 g of residue, which was subjected to chromatography on silica (allanton is ethyl acetate-methanol-triethylamine 92-6-2); the resulting product is condensed in a mixture of simple ether-pentane: 1-5. Obtain 143 mg of the target of the crude product, which was dissolved in 1 ml ethyl acetate, filtered and crystallized by addition of 3 ml of pentane. After drying obtain 85 mg of the target product (TPL= 197oC).

Analysis of C41H63N5O10785,98

% calculated: C 62,65; H 8,08; N 8,91;

% found: C 62,5; H 8,1; N 8,8.

NMR CDCl3ppm

3,18: H10; 3,69 (s): H11; 0,84 (t): 15 CH3; 3,86 (q): H2; 2,45: N-(CH3)2; 2,60 (s): 6 OCH3; 5,56 (t): NH; 2,65-2,81: NH-CH2-; 4,50: ; 7,26-8,02: 5H of the benzimidazole.

For EXAMPLE 6: Preparation of 3-imidazolidinone.

STAGE A: 2-[2-(3-imidazolyl)-ethyl]-1,3-dioxolane.

To a solution of 1.2 g of benzimidazole in 15 ml of dimethylformamide PR is after the gassing, added, allowing the temperature to rise to 35oC, 1.2 ml of 2-(2-bromacil)-1,3-dioxolane. Carry out stirring for two hours, then add water, saturated sodium chloride, then extracted with simple ether, dried, filtered and evaporated under reduced pressure. Receive 2 g of residue, which was subjected to chromatography on silica, using as eluant methylene chloride-methanol (95-5). Thus obtained 1.6 g of the target product.

NMR CDCl3:

2,25 and 4.35: group CH2ethyl; 3,85-4,00 group CH2dioxolane; 4,87: CH dioxolane; 7,29 - 7,46 - 7,81: 4H benzimidazole; 7,92: H in position 2 of the imidazole.

STAGE B: 3-imidazolidinyl.

Carry out stirring for 5 hours at reflux a solution of 1.6 g of the product obtained at stage A, 1.45 g of paratoluenesulfonyl in 60 ml of methanol. Using potassium carbonate establish a pH of 8, the methanol is removed under reduced pressure, extraction carried out with methylene chloride, washed with water, dried and evaporated to dryness under reduced pressure. Obtain 1.45 g of the intermediate dimethoxyethane, which is stirred at a temperature of 40oC for 18 hours in the presence of 70 ml of acetone and 34 ml of 2 N-Noah hydrochloric oxide of ammonium, carry out the extraction with methylene chloride, washing with water, drying and evaporation to dryness under reduced pressure. Obtain 1.13 g of the product, which is subjected to chromatography on silica, using as eluant methylene chloride-methanol 95-5. Get coefficient was 0.796 g of the target product.

NMR CDCl3250 MHz

of 3.07 (t) to 4.52 (t): group CH2ethyl; 7,25-7,50: aromatic; 9,79 (s): CH aldehyde.

EXAMPLE 7: 11,12-dideoxy-3-de-((2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L - abovecaptionskip)-oxy)-6-O-methyl-3-oxo-12,11- (oxycarbonyl-(2-(3-(2-phenyl-5-thiazolyl)-propyl)-hydrazono))-erythromycin.

Carry out stirring for 4 hours at an ambient temperature of 200 mg of the product obtained in example 1, 139 mg of 3-(2-phenyl-5-thiazolyl)-propanal (the receipt of which is described below), 180 ml of acetic acid and 7 ml of methanol, then add 60 mg of cyanoborohydride sodium. The reaction mixture is stirred for 18 hours at ambient temperature, then evaporated dry under reduced pressure, the residue is absorbed by the mixture of water-ethyl acetate, set to pH 9 with an aqueous solution of hydroxide of ammonium. Conduct extraction with ethyl acetate, then the t chromatography on silica, using as eluant ethyl acetate, and then ethyl acetate - triethylamine (96/4).

Obtain 170 mg of product, which is crystallized in a mixture of ethyl acetate: pentane 1/5. Thus receive 80 mg of the target product.

Analysis of C43H64N4O10S 829,07

% calculated: C of 62.3; H 7,78; N 6,76; S A 3.87,

% found: C 62,0; H 7,8; N 6,8; S 4,0,

NMR CDCl3300 MHz

3,17 (m): H10; 1,07 (d): 14 CH3; 1,48: 15 CH3; a 3.87 (q): H2; and 2.26 (s): N-(CH3)2; 3,53 (m): 2'OH; 2,67 (s): 6-OCH3; 5,43 (t): NH; 2,86 (m) 1,95 (m)- 3,03 (m): group CH2propyl; 7,55 (s): H thiazole; 7,39 (m) 3H and 7,89 (m) 2H: aromatic compounds; 1,19 (d): H8.

For EXAMPLE 7: Preparation of 2-phenyl-5-diazopropane. STAGE A: 2-phenyl-5-keratocytes.

To a suspension of 78 g thiobenzamide in 200 ml of benzene was added a solution of formyl-beta-chloracetate in 240 ml of benzene. The reaction mass is heated under reflux for 3 hours 30 minutes, removing the formed water. Then the reaction mass is then cooled and slowly added 320 ml of 20% aqueous potassium carbonate solution and 220 ml of water, then extracted with simple ether, washed, dried and distil under reduced pressure and get the 75.5 g of the target product.

STAGE B: 2-phenyl-5-thiazol g of potassium hydroxide in the form of tablets, dissolved in 410 ml of ethanol, carry out the heating of the reaction mixture for 15 minutes, then cooled and drained salt of potassium, washed in a simple ether and dried under reduced pressure. Get to 53.5 g of the intermediate potassium salt, which is dissolved in 1.2 liters of water, acidified to pH 1 solution of concentrated hydrochloric acid after filtration, obtain 29 g of the target product (TPL=192oC), 24.5 g of the product will recrystallized in 750 ml of toluene. Get 20 g of the target product, TPL= 195oC.

Analysis of C10H7NO2S 205,2

% calculated: C 58,52; H 3,43; N 6,82; S 15,6;

% found: C 58,5; H 3,7; N 6,8; S 15,2.

STAGE C: 2-phenyl-5-thiazolecarboxamide.

To a solution of 4.77 g of the acid obtained in Stage b In 160 ml of methanol was added 2.5 ml of acetylchloride and carry out heating at reflux for 18 hours. When reduced pressure is brought state of the reaction mass to dry, then treated with ethyl acetate, filtered, concentrated to a reduced volume and press the resulting crystals. The mother liquor is washed with sodium hydroxide, extracted with ethyl acetate, washed with water and evaporated to dryness, connect 2 crystallized fraction and get 4,54 which begins:

To a suspension of 1.45 g of hydride lithium aluminium in 65 ml of tetrahydrofuran, cooled to 10oC, was added over 20 minutes, maintaining the temperature of 10oC, a solution of 4.5 g of the product obtained in stage C in 35 ml of tetrahydrofuran; carry out stirring for 45 minutes at a temperature of 10oC, then for 2 hours at ambient temperature. After that, add tetrahydrofuran containing first 10, then 50% of water, keeping the temperature below 20oC, then add 15 ml of double potassium-sodium tartrate salt, then filtered, washed, dried dried under reduced pressure; the resulting residue is thickened in hexane, squeezed and dried at a temperature of 40oC under reduced pressure to obtain 3.6 g of product. TPL= 82oC.

Oxidation:

Carry out stirring for 2 hours 30 minutes at ambient temperature 3.57 g of the product obtained above, with 143 ml of toluene and 17.9 g of manganese dioxide. The reaction mixture is filtered and dried to dryness under reduced pressure. The residue is treated in hexane, squeezed and dried at a temperature of 40oC under reduced pressure, you get to 3.09 g of the target product. TPL= 94oCPL=104oC).

NMR CDCl3(250 MHz)

8,04 (s): H triazole; of 6.49 (dd, J= 7,5) and 7.69 (d, J = 15,5): H propene; 9,67 (J = 7,5): CHO; 7,50 (m) 3H and 7,97 (m) 2H: aromatic compounds.

STAGE F: 3-(2-phenyl-5-thiazolyl)-propanol.

To a suspension of 475 mg of sodium borohydride in 50 ml of ethanol is added portions of 900 mg of the aldehyde obtained in stage E, described above, then stirred for 20 minutes at ambient temperature, then remove the excess sodium borohydride by adding acetone. Carry out evaporation dry under reduced pressure, and then treat the residue with ethyl acetate, washed with brine, and dried under reduced pressure brought to dryness, thus obtain 960 mg of the product used, as it is at the next stage.

STAGE G: 2-finechina 9 hours a solution of 960 mg of the product, obtained in stage F, 10 ml of methanol in the presence of 150 mg of palladium on coal. After filtration is evaporated dry under reduced pressure and the residue is subjected to chromatography on silica (eluant: ethyl acetate-cyclohexane (4-6). Receive 759 mg of the target product.

NMR CDCl3200 MHz

of 1.52 (m): OH; 3,74 (m) -1,97 (m) of 2.92 (dt): group CH2; 7,40 - of 7.90 (m): 5H, aromatic; 7,53 (t, J = 1): H thiazole.

Stage H: 2-phenyl-5-diazopropane.

To the solution was cooled to 10oC, 584 mg of the product obtained in the previous phase, 800 µl of dimethyl sulfoxide and 1.15 ml of triethylamine and 8 ml of methylene chloride was added, maintaining the temperature of 10oC, 1.27 g of the complex sulfuroxidizing. The reaction mass is stirred for 1 hour and 15 minutes at a temperature of 10oC, then bring the reaction mass to ambient temperature, followed by extraction with methylene chloride, washing with water, drying and evaporation dry under reduced pressure, the result 806 mg of product, which is subjected to chromatography on silica (eluant: ethyl acetate-cyclohexane 3-7), you get 450 mg of the target product.

NMR CDCl3200 MHz

2,88 - 3,20 (t): group CH2prop-methyl-3-O-methyl-alpha-L-abovecaptionskip)-oxy)-6-O-methyl-3-oxo-12,11- (oxycarbonyl-(2-(3-(4-phenyl-1H-imidazol-1-yl)-propyl)-hydrazono))-erythromycin.

20 hours carry out the mixing 125 mg of the product obtained in example 1, 80 mg of 3-(4-phenyl-1H - imidazol-1-yl)-propanal (the receipt of which is below) and 2 ml of methanol. Then added 54 mg of cyanoborohydride sodium. After the reaction mass is concentrated under reduced pressure, then treated with 20 ml of ethyl acetate, washed with in sodium hydroxide, then with water saturated with sodium chloride, then dried, evaporated dry under reduced pressure and perform chromatography of the residue on silica (eluent; chloroform-methanol-hydroxide ammonia 95/5/0,5), the crude product is absorbed by the mixture of simple ether-ethyl acetate, filtered, evaporated to dryness and obtain 85 mg of the target product.

Analysis of C43H65N5O10812,02

% calculated: C 63,6; H 8,07; N 8,62.

% found: C and 63.4; H 8,2; N 8,3.

NMR CDCl3400 MHz

3,70 (s): H in position 11; to 4.98 (dd): H13; 3,86 (q): H in position 2; and 2.26 (s): N-(CH3)2; 2,63: 6-OCH3; 5,54 (t): NH; 4,27 and 1,97: group CH2propyl; and 7.3 (d) - EUR 7.57 (d): 2H imidazole; 7,2-7,35-7,8: aromatic compounds.

For EXAMPLE 8: Preparation of 3-(4-phenyl-1H-imidazol-1-yl)-propanal.

STAGE A: 3-(4-phenyl-1H-imidazol-1-yl)-ethyl-1,3-dioxol the t as initial substances 1.44 g of 4-phenylimidazole and 1,17 ml bromatological, after chromatography carried out on silica obtain 1.8 g of the target product.

NMR CDCl3< / BR>
2,19 (d,t) and 4.13 (t): CH2propyl; 3,8-4,05: group CH2dioxolane; 4,88 (t): H oxolan; 7.23 percent and 7,53: group CH imidazole; 7.23 percent-7,37 to 7.75: aromatic compounds.

STAGE B: 3-(4-phenyl-1H-imidazol-1-yl)-propanal.

For 20 hours, heated at a temperature of 60oC 1,77 g of the product obtained in stage A above, 35 ml of acetone and 30 ml of 2N-Noah hydrochloric acid. The acetone is then removed under reduced pressure, and the solution is neutralized by adding sodium bicarbonate, followed by extraction with ethyl acetate, drying, evaporation dry under reduced pressure. The residue is subjected to chromatography on silica (eluant: ethyl acetate-methanol 97-3). Get 900 mg of the target product.

NMR CDCl3250 MHz

9,81 (s): CHO; 7,10 - 7,76: H of the imidazole and aromatic; 3,01 (t) and the 4.29 (t): H propyl.

EXAMPLE 9: 11,12-dideoxy-3-de-((2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-abovecaptionskip)-oxy)-6-O-methyl-12,11-(oxycarbonyl-(2-(3-(3-phenyl-1,2,4-oxadiazol-5-yl)-propyl)-hydrazono)-erythromycin.

Operate in conditions similar to those specified in example 6, but on the basis of 125 mg is about described below). After chromatography on silica (eluant: simple isopropyl ether-triethylamine-methanol 90-10-10) and crystallization in a simple mixture of isopropyl ether-methanol to obtain 107 mg of the target product.

Analysis of C42H63N5O11814,00

% calculated: C 61,97; H 7,8; N 8,6.

% found: C of 61.7; H 7,9; N 8,5.

NMR CDCl3300 MHz

3,74 (s): H11; to 5.03 (dd): H13; a 3.87 (q): H2; 2,27 (s): 6-OCH3; 2,27 (s): N-(CH3)2; 5,49 (t): NH; 3,17 (m) and 2,11 (m): various groups CH2; 7,47 - 8,08: aromatic compounds.

For EXAMPLE 9: Preparation of 3-(3-phenyl-1,2,4 - oxadiazol-5-yl)-propanal.

STAGE A: 3-(3-phenyl-1,2,4-oxadiazol-5-yl)-propanol.

For 1 hour at ambient temperature stirred 2M solution of 2.5 ml of the complex hydride of boron-metilsulfate in tetrahydrofuran, 920 mg of 3-(3-phenyl-1,2,4 - oxadiazol-5-yl)-propanolol acid (obtained according to R. M. SRIRASTAVA et all. , J. Heterocycl. Chem., 21, 1193 (1984) and 20 ml of tetrahydrofuran. Within 5 minutes, add 10 ml of methanol. When reduced pressure is evaporated to dryness and the residue chromatographic on silica (eluant: ethyl acetate-hexane 6-4). Obtain 485 mg of the target product.

NMR CDCl3250 MHz

2,07 (s-5-yl)-propanal.

To the solution was cooled to 10oC, 460 mg of the product obtained at stage A, 680 μl of dimethyl sulfoxide and 970 μl of triethylamine in 5 ml of methylene chloride was added, keeping the temperature at a level of 10oC, 1.07 g of the complex pyridinesulfonamide, the reaction mass to leave until she acquires the ambient temperature, then add 15 ml of methylene chloride, washed with water, dried, evaporated to dryness under reduced pressure and perform chromatography on silica (eluant: ethyl acetate-hexane 4-6), thus obtain 365 mg of the target product.

NMR CDCl3< / BR>
3,13 (m) - 3,26 (m): group CH2; 7,49 - 8,05: aromatic compounds.

EXAMPLE 10: 11,12-dideoxy-3-de-((2,6 - dideoxy-3-C-methyl-3-O-methyl-alpha-L-abovecaptionskip)-oxy)-6-O-methyl-3-oxo-12,11-(oxycarbonyl-(2-(3-(2-chlorophenyl)- propyl)-hydrazono)-erythromycin.

Operate in conditions similar to those specified in example 6, but originate from 125 mg of the product obtained in example 1, using 67 mg of 2-chlorpheniramine (the receipt of which is given below). After chromatography on silica (eluant: simple isopropyl ether-triethylamine-methanol 90-10-10) obtain 48 mg of the target product.

Analysis of C40H62tx2">

NMR CDCl3400 MHz

to 3.73 (s): H in position 11; 5,13 (dd): H in position 13; a 3.87 (q): H in position 2; and 2.26 (s): N-(CH3)2; 2,64 (s): 6-OCH3; are 5.36 (t): NH; 1,83 (m) - 2,70 (m) - 2,79 (m): group CH2; 7,05 - 7,2: aromatic compounds.

For EXAMPLE 10: Preparation of 3-(2-chlorophenyl)-propanal.

STAGE A: 3-(2-chlorophenyl)-methylpropanoate.

In for 1 hour in an inert atmosphere mix 4.35 g metalorganics acid, 430 mg of palladium on coal and 70 ml of methanol. The reaction mass is then stirred for 3 hours in hydrogen atmosphere. Then filtered and evaporated to dryness under reduced pressure, and the residue is subjected to chromatography on silica (eluant: ethyl acetate-hexane 2-8) obtain 3.1 g of the target product.

NMR CDCl3250 MHz

2,6 (t) - 2.8 (t): group CH2; 3,6 (s): OCH3; 7,05-7,37: aromatic compounds.

STAGE B: 3-(2-chlorophenyl)-propanol.

To a solution of 1.85 g of the product obtained at stage A, in 20 ml of tetrahydrofuran is added at a temperature of 0oC 30 ml hydride diisobutylaluminum in the form of a 1 M aqueous solution in tetrahydrofuran. The reaction mixture is left up until it acquires the ambient temperature, and stirred for 2 hours filtered and evaporated dry under reduced pressure. The residue is subjected to chromatography on silica (eluant: ethyl acetate-hexane 2-8), receive 1 g of the target product.

STAGE C: 3-(2-chlorophenyl)-propanal.

Follow the same process specified at the stage section B

"Cooking. .." for example 9, but come from 1 g of the product obtained in stage B above, using 2.5 ml of triethylamine, to 1.75 ml of dimethyl sulfoxide and 2.8 g of complex pyridine-sulfurdioxide. After chromatography on silica using as eluant ethyl acetate-hexane (1 - 9) obtain 425 mg (43%) of the target product.

NMR CDCl3250 MHz.

2,79 (m) and 2.94 (m): group CH2; 7,05-7,25: aromatic compounds; 9,82 (t): CHO.

EXAMPLE 11: 11,12-dideoxy-3-de-((2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-abovecaptionskip)-oxy)-6-O-methyl-3-oxo-12,11- (oxycarbonyl-(2-(3-(4-chinoline)-2-propyl)-hydrazono))-erythromycin.

STAGE A: 11,12-dideoxy-3-de-((2,6-dideoxy-3-C - methyl-3-O-methyl-alpha-L-abovecaptionskip)-oxy)-6-O-methyl-3-oxo-12,11-(oxycarbonyl-(hydrazono)-erythromycin, isomer 10 (R) and isomer 10 (S), respectively.

In 176 ml of methyl cyanide dissolved 17,65 g 2'-acetate-11-deoxy-10,11-didehydro-3-de-(2, 6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-abovecaptionskip)-is anhydrate. Heated 10 minutes at a temperature of 85oC, the solvent is distilled off under reduced pressure and a temperature of approximately 40oC, extracted with methylene chloride, washed with water, dried, the solvent is evaporated, the residue absorb methanol, press the precipitation and dried at a temperature of 50oC under reduced pressure, get 6,04 g of the product. Concentrate to dryness fallopian water, perform chromatography on silica (eluant: simple isopropyl ether-methanol-triethylamine 80-10-10) and get 0,83 g of isomer A (rf = 0,4) and 2.65 g of isomer B (rf = 0,2).

STAGE B: 11,12-dideoxy-3-de-((2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-abovecaptionskip)-oxy)-6-O-methyl-3-oxo-12,11-(oxocarbon-(2-(3-(4- chinoline)-2-propyl)-hydrazono))-erythromycin.

In 130 ml of methanol is suspended 13 g of the product obtained at stage A, and of 4.66 g of 4-jinlinprovince obtained as follows. Add 4.8 ml of acetic acid and stirred for 20 hours at ambient temperature. Then add 5.3g of cyanoborohydride sodium, and then continue stirring for 4 hours. Remove methanol under reduced pressure, extracted with ethyl acetate, washed with aqueous N-s ' solution of hydrate of sodium oxide, and then with water; wt - triethylamine 97:3) and obtain 12.7 g of product with a rf =0.15 in. After the new chromatography on silica (eluant: methylene chloride - methanol 95-5, then 85-15) and crystallization in simple isopropyl ether to obtain pure product, TPL= 183oC, analysis data which is identical to the data analysis of the product from example 5.

For EXAMPLE 11: Preparation of 4-jinlinprovince.

STAGE A: 2-(4-chinainternational)-1,3-dioxolane.

In 40 ml of tetrahydrofuran is suspended 3,15 g of 4-chinainternational and 8.6 g of [1,3- (dioxolan-2-yl)-methyl]-triphenylphosphonium, cool it to a temperature of -30oC, then add 2.5 g of tert.the butyl potassium and stirred for 1 hour. The reaction mass leave until then, until it acquires the ambient temperature, then stirred for 3 hours, poured into a mixture of water/ice, extracted with methylene chloride, washed with water, dried, the solvent is evaporated under reduced pressure, the residue is absorbed by simple mixture of ethyl ether-pentane 3-7, stirred for 2 hours, filtered and the solvent is evaporated filtrate, get 3,99 g of the desired product.

STAGE B: 2-[2-(4-chinoline)-ethyl]-1,3-dioxolane.

In 40 ml of methanol was dissolved 4.3 g of the product obtained at stage A, add 0.2 t in methanol, the solvent is evaporated and the gain of 4.2 g of the target product, used as it is at a later stage.

STAGE C: 4-jinlinprovince.

of 4.2 g of the product obtained at stage B, is dissolved in 70 ml of acetone, then add 70 ml of 2 N-Noah hydrochloric acid. The reaction mixture is heated for 6 hours at a temperature of 40oC, remove the acetone under reduced pressure, extracted with ethyl acetate, washed with water, then with an aqueous solution of hydroxide of ammonium bring the pH of the aqueous phase to a value of 9. Extracted with ethyl acetate, the combined organic phase dried and the solvent evaporated. After chromatography on silica (eluant: ethyl acetate-cyclohexane 6-4) gain of 1.36 g of the target product.

EXAMPLE 12: 11,12-dideoxy-3-de-((2,6-dideoxy-3-C - methyl-3-O-methyl-alpha-L-abovecaptionskip)-oxy)-6-O-methyl-3-oxo-12,11-(oxycarbonyl-2-(3-(7-methoxy-4-chinoline)-propyl) -hydrazono))-erythromycin.

Dissolved in 2 ml of methanol 299 mg of 7-methoxy-4-jinlinprovince, the receipt of which is listed below, and 313,9 mg of product A obtained in example 1 and 120 μl of acetic acid. Stirred for 2 hours and 15 minutes at ambient temperature, then add 62,84 mg cyanoborohydride ethyl acetate, washed in 15 ml of N-aqueous hydroxide of sodium, then water, dried, the solvent is evaporated under reduced pressure and receive 549 mg of product, which is purified by chromatography on silica (eluant: simple isopropyl ether-methanol-triethylamine 80-10-10, then chloroform-methanol-hydroxide ammonium 96-4-0,4). Get 37,2 mg of the target product,

rf=0,2.

Analysis

% calculated: C 63,84; H 8,04; N 6,77;

% found: C to 63.8; H 8,1; N 6,6.

NMR CDCl3300 MHz

3,74 (s): H11; 3,17 (m): NH-CH2; 3,95 (s): OCH3quinoline; 7,16-7,41 (d) - 8,00 (d) - 8,70 (d): H quinoline; a 3.87 (q): H2; 2,65 (s): 6-OCH3; 2,65 (m): H8; 0,82 (t): CH3-CH2.

For EXAMPLE 12: Preparation of 7-methoxy-4 - jinlinprovince.

STAGE A: 2-[(7-methoxy-4-chinoline)-ethynyl]-1,3-dioxolane.

Work as described in preparation example 11, step A, but using as starting compound 787 mg of 7 - methoxy-4-chinainternational. Get 2,61 g of product, which is subjected to chromatography on silica (eluant: chloroform-ethyl acetate 7-3). Receive 931 mg of the target product.

STAGE B: 2-[2-(7-methoxy-4-chinoline)-ethyl]-1,3-dioxolane.

Work as described in preparation example 11, the OIA C: 2-(7-methoxy-4-quinoline)-propanal.

Work as described in preparation example 11, step C, but using 845 mg of the product obtained in stage B. Obtain 310 mg of the desired product, rf = 0.15 in.

EXAMPLE 13: 11,12-dideoxy-3-de-((2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-abovecaptionskip)-oxy)-6-O-methyl-3-oxo-12,11-(oxycarbonyl-2-(3-(2-(3-pyridinyl-4-thiazolyl)-propyl)- hydrazono))-erythromycin.

The process of obtaining the above-mentioned compound is similar to that specified in example 12, but as the original product use taken in 3.7 g of methanol 158 mg of 2-(3 - pyridinyl)-4-diazopropane, 370 mg of compound A obtained in example 1, and 70 μl of acetic acid, and then after stirring for 4 hours at an ambient temperature of 75 mg cyanoborohydride sodium. After stirring the reaction medium for 16 hours at ambient temperature again added 16 mg of aldehyde and 20 mg a reducing reagent, and then continue stirring for another 3 hours. Then add water, ethyl acetate, alkalinized reaction mass to pH 9 using hydroxide of ammonia, the organic phase is washed with water, dried and the solvent is evaporated under reduced pressure. After chromatography on silica (eluant: a simple isop): H5the thiazole; 7,37 (dd) - 8,24 (ddd) - to 8.62 (dd) - 9,13 (dd): pyridine; 3,86 (q): H2; 2,65 (s): 6-OCH3; 2,66 (m): H8; 0,85 (t): CH3-CH2.

For EXAMPLE 13: Preparation of 2-(3-pyridinyl)-4 - diazopropane.

STAGE A: [[2-(3-pyridinyl)-4-thiazolyl]ethynyl] -1,3-dioxolane.

Work as in preparation example 11, step A, but using as starting substances 2.6 g of 2-(3 - pyridinyl)-4-thiazolecarboxamide. After chromatography carried out on silica (eluant: ethyl acetate-hexane 2-1) obtain 4.8 g of the desired product (rf = 0.35 in), using the form as it is at a later stage.

STAGE B: 2-[2-((3-pyridinyl)-4-thiazolyl)-ethyl]-1,3-dioxolane.

Work as described in preparation example 11, step B, but using as starting substances 4.8 g of the product obtained in stage A. After chromatography of the residue is carried out on silica (eluant: ethyl acetate-cyclohexane 2-1) obtain 1.4 g of the target product.

STAGE C: 2-(3-pyridinyl)-4-triazolylmethyl.

Work as described in preparation example 11, step C, but using as starting substances 1.2 g of the product obtained at stage C. After chromatography carried out on doukasen in the previous examples, using as the starting material the compound according to example 1 and the appropriate aldehyde enjoy these products.

EXAMPLE 14: 11,12-dideoxy-3-de-((2,6-dideoxy-3-C - methyl-3-O-methyl-alpha-L-abovecaptionskip)-oxy)-6-O-methyl-3-oxo-12,11-(oxycarbonyl-2-(3-(1H-imidazol-1-yl)-propyl)- hydrazono))-erythromycin.

NMR CDCl3300 MHz

0,83 (t): CH3-CH2: 1,08 (d) - 1,17 (d) a 1.25 (d) and 1.3 (d) and 1.35 (d): group CH3-CH; 1,3 (s) to 1.47 (s): 6 and 12 Me; 2,12 (m): CH2-CH2-CH2; 2,27 (s): N(Me)2; 2,45 (m): H3'; 2,59 (s): 6-OMe; 3,05 (m): H4; 2,6-3,2: H2', H10: H8and CH2NH; 3,53 (m): H5'; 3,72 (s): H11; 3,85 (q): H2; 4,27: H1' and H5; 4,63 (m): CH2-N; 4,99 (dd): H13; 5,46 (t): NH-CH2; 7,10-of 7.64-7,66-7,97: aromatic compounds.

EXAMPLE 15: 11,12-dideoxy-3-de-((2,6 - dideoxy-3-C-methyl-3-O-methyl-alpha-L-abovecaptionskip)-oxy)- 6-O-methyl-3-oxo-12,11-(oxycarbonyl-2-(3-(3H-imidazo-(4,5-b) -pyridine-3-yl)-propyl)-hydrazono))-erythromycin.

NMR CDCl3300 MHz

0,85 (t): CH3-CH2; 1,09 - 1,19 (d) a 1.25 (d) to 1.31 (d) to 1.34 (d): group CH3CH; of 1.33 1.48: 6 and 12 Me; 1.57 and a 1.96: CH2in position 14, 1.66, and 1,87: CH2in position 7; 2.05 and 2,18: CH2-CH2-CH2; and 2.26 (s): N(CH3)2; 2,44 (m): H3'; 2,6 (s): 6-OCH3' and H5; 4,42 - 4,70: CH2-N; equal to 4.97 (dd): H13; 5,56 (t): NH; by 8.22 (dd)- 8,05 (d) 8,28 (s) -8,38 (d): aromatic compounds.

EXAMPLE 16: 11,12-dideoxy-3-de-((2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-abovecaptionskip)-oxy)-6-O-methyl-3-oxo-12, 11-(oxycarbonyl-2-(3-(1,1'-biphenyl-4-yl)-propyl)- hydrazono))-erythromycin.

NMR CDCl3300 MHz

0,87 (t): CH3-CH2; 1,08 (d) of 1.18 (d) of 1.23 (d) 1,32 (d) 1,38 (d): CH3-CH; 1,34 (s), 1.48 (s): 6 and 12 Me; and 2.26 (s): N(CH3)2; 2,44 (m): H3'; 2,65 (s): 6-OCH3; 2,65 (m): H8; 2,77 (m): CH2-Ar; 2,85 (t): CH2NH; 3,07 (m): H4; 3,18 (m): H2'H10; 3,25 (m): H5', 3,76 (s): H11; a 3.87 (q): H2; 4,27: H1' and H5; 5,04 (dd): H13; lower than the 5.37 (t): NH-CH2; 7,25-7,6: aromatic compounds.

EXAMPLE 17: 11,12-dideoxy-3-de-((2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-abovecaptionskip)-oxy)-6-O-methyl-3-oxo-12,11- (oxycarbonyl-2-(3-(2-phenyl-4-thiazolyl)-propyl)-hydrazono)) -erythromycin.

NMR CDCl3300 MHz

0,86 (t): CH3-CH2; 1,07 (d) - 1,19 (d) 1,24 (d) to 1.31 (d) and 1.35 (d): group CH3-CH; 1,32 (s) to 1.48 (s): 6-CH3and 12-CH3; and 2.26 (s): N(CH3)2; 2,65 (s): 6-OCH3; 2,45 (m): H3'; 2,65 (m): H8; 2,8-3,25 (m): H4H10H2', CH2- Ar and CH2N; 3,53 (m): H5'; 3,76 (m): H11; 3,86 (q): H2; 4,27 (d): H

0,87 (t): CH3-CH2; of 1.33 and 1.47: 6 and 12 Me; 2,17 (m): CH2-CH2-CH2; and 2.26 (s): N(CH3)2; 2,67 (s): 6-OCH3; 2,67 (s): H8; 3,76 (s): H11; 3,85 (q): H2; of 5.06 (dd): H13; 5,39 (t): NH-CH2; 7,49-7,94: aromatic compounds.

EXAMPLE 19: 11,12-dideoxy-3-de-((2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-abovecaptionskip)-oxy)-6-O-methyl-3-oxo-12,11-(oxycarbonyl-2-(3-(4- (4-chlorophenyl-1H-imidazol-1-yl)propyl)-hydrazono))-erythromycin.

EXAMPLE 20: 11,12-dideoxy-3-de-((2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-abovecaptionskip)-oxy)-6-O-methyl-3-oxo-12,11-(oxycarbonyl-2-(3-(6-methoxy-4 - chinoline)-propyl)-hydrazono))-erythromycin.

Acting similarly indicated in example 12, to obtain the target product.

NMR CDCl3300 MHz

3,74 (s): H11; 5,52 (tl): NH-CH2; 3,98 (s): OCH3quinoline; 7,25 - 7,35 (d) - 7,99 (d) - 8,65 (d): H quinoline; a 3.87 (q): H2; 2,64 (s): 6-OCH3; 2,64 (m): H8; 5,02 (dd): H13.

Acting similarly to the above, obtain the compounds of formula (I), where the radical is a radical

< / BR>
THE EXAMPLE OF THE PHARMACEUTICAL COMPOSITION

Prepare tablets containing:

The product obtained in example 5 - 150 mg

Excipient (sufficient for) 1 g

Op is S

The method of dilution in liquid medium.

Prepare a series of tubes, in which are placed the same amount of sterile nutrient medium. Injected into each tube increasing the number of tested compound, then each tube absement strain of bacteria.

After incubation for twenty-four hours in a thermostat at 37oC growth inhibition assessed with x-ray, which allows to determine the minimum inhibiting concentration (MIC) expressed in micrograms/cm3.

The following results were obtained when using the product from example 5 (after 24 hours):

Gram-positive strains of bacteria

Staphylococcus aureus 011UC4 - 0.02

Staphylococcus aureus 011G0251 - 0,08

Staphylococcus epidermidis 012GO11I - 0.04

Streptococcus pyogenes Group A 02A1UC1 - 0.02

Streptococcus agalactiae Group B 02B1HT1 - 0.02

Streptococcus faecalis Group D 02D2UC1 - 0.02

Streptococcus faecium Group D 02D3HT1 - 0.02

Streptococcus sp Group G 02G0GR5 - 0.02

Streptococcus mitis 02mitCB1 - 0.02

Streptococcus agalactiae Group b 02B1SJ1 - 0.02

Streptococcus pneumoniae 032UC1 - 0.02

Streptococcus pneumoniae 030SJ5 - 0.02

Moreover, the compound obtained in example 5 showed interesting activity against grammaticalising strains of bacteria: Yunosti against gram-positive and grammaticalising strains of bacteria.

Acting similarly to the above, the following results were obtained when using the compounds of examples 12 and 13 (after 24 hours) (see table).

1. Derivatives of erythromycin a General formula I

< / BR>
in which Z denotes a hydrogen atom;

R1means a hydrogen atom;

R2means a radical- (CH2)rAr3where "r" denotes an integer from 0 to 6, Ar3means a phenyl radical, unsubstituted or substituted by a halogen atom, chinoline, unsubstituted or substituted o-alkyl containing up to 6 carbon atoms, biphenyl, imidazolyl, unsubstituted or substituted phenyl or guaifenisen, benzimidazolyl, thiazolyl, substituted phenyl or pyridium, 1,2,4-oxadiazole or 1,2,4-thiadiazolyl, substituted phenyl, or imidazo-(4,5-C)-pyridinylmethyl,

or R1and R2form together a radical =CH(CH2)nAr1where Ar1means phenyl or hyalinization, n is an integer from 0 to 8,

the wavy line in position 10 indicates that methyl can have the R configuration or S, or presents a mixture of R and S configuration, as well as their additive salts with acids.

2. The compound of formula I under item 1, in which Ar3is a 4-hee who fight unsubstituted 4-chinoline.

4. The compound of formula I under item 1, in which Ar3is a substituted group, methoxy 4-chinoline.

5. The compound of formula I under item 1, in which Ar3represents thiazolyl, replaced by pyridium.

6. The compound of formula I according to any one of paragraphs.1 to 5, where "r" is an integer from 1 to 4.

7. The compound of formula I on p. 1, selected from the following compounds: 11,12-dideoxy-3-de-((2,6-dideoxy-3-C-methyl-3-0-methyl-alpha-L-abovecaptionskip)-oxy)-6-0-methyl-3-oxo-12,11-(oxycarbonyl-(2-(3-4-chinoline)-2-propyl)-hydrazono))-erythromycin; 11,12-dideoxy-3-de((2,6-dideoxy-3-C-methyl-3-0-methyl-alpha-L-abovecaptionskip)-oxy)-6-0-methyl-3-oxo-12,11-(oxycarbonyl-2-(3-(methoxy-4-chinoline)-propyl)-hydrazono))-erythromycin; 11,12-dideoxy-3-de-((2,6-dideoxy-3-C-methyl-3-0-methyl-alpha-L-abovecaptionskip)-oxy)-6-0-methyl-3-oxo-12,11-(oxycarbonyl-2-(3-(2-(3-pyridinyl-4-thiazolyl)-propyl)-hydrazono))-erythromycin.

8. The compounds of formula I according to any one of paragraphs.1 - 7, as well as their salts connection with pharmaceutically acceptable acids with antibiotic activity.

9. Connection on p. 7, as well as their salts connection with pharmaceutically acceptable acids with antibiotic artistshouse substance and excipient, characterized in that the active substance it contains at least one connection on p. 8 or 9.

11. The method of obtaining compounds of formula I on p. 1, characterized in that the compound of formula II

< / BR>
where Z means a hydrogen atom, is subjected to the influence of hydrazine NH2NH2obtaining the compounds of formula IA

< / BR>
which is subjected to the action of aldehyde R'1-CO-R'2where R'1means a hydrogen atom, and R'2means a hydrocarbon radical -(CH2)r'Ar3where r' is an integer from 0 to 5, or a radical -(CH2)n'Ar1where n' is an integer from 0 to 7, and Ar3and Ar1have the values listed in paragraph 1, with the formation of the compounds of formula IB< / BR>
< / BR>
where R'1and R'2have the meanings indicated above, which is optionally exposed to a recovery agent to obtain compounds of formula Ic< / BR>
< / BR>
in which R'1= a hydrogen atom and R'2means a radical -(CH2)r'Ar3then, if desired, subjecting the resulting compound to the action of acid to salt.

12. Method of producing compounds of the formula I, characterized in that the connection form is 2
where R2has the meaning specified in paragraph 1, and the resulting product, if desired, is subjected to the action of acid to salt.

 

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The invention relates to chemical-pharmaceutical industry, namely to antiviral drugs exhibiting in-vitro high activity against human immunodeficiency virus, against herpes virus and cytomegalovirus

FIELD: medicine.

SUBSTANCE: method involves carrying out hernia removal in intralaminar way. Posterior longitudinal ligament defect is covered with Tacho-Comb plate after having done disk cavity curettage. Subcutaneous fat fragment on feeding pedicle is brought to dorsal surface of radix and dural sac.

EFFECT: enhanced effectiveness of treatment; reduced risk of traumatic complications.

1 dwg

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