9-o-joksimovi erythromycin derivatives and pharmaceutical composition based on them

 

(57) Abstract:

Describes the new 9-O-Joksimovi derivatives of erythromycin And the General formula (I), where A, R1, R2, M, n, m and r have the meanings specified in paragraph 1 of the formula, and pharmaceutical compositions containing them as active ingredients. The compounds of formula (I) are suitable for the treatment of infectious diseases. 2 S. and 3 C.p. f-crystals, 3 PL.

The invention relates to derivatives of erythromycin A, has antibiotic activity, suitable for the treatment of infectious diseases, in particular, the invention relates to derivatives of 9-[O-(aminoalkyl)oxime]of erythromycin A, has antibiotic activity against gram-positive and gram-negative microorganisms.

Erythromycin A [The Merck Index, XI ed., N 3626] is a well-known, naturally occurring macrolide, which possess antibiotic activity and which has the following structure

< / BR>
In addition to activity against some microorganisms that are not related to bacteria, such as Rickettsia and Mycoplasma, erythromycin A has antibacterial activity mainly against gram-positive micro the structure to some gram-negative microorganisms, such as, for example, Haemophilus influenzae, Neisseria gonorrhoeae and Bordetella pertussis.

In addition to well-known activity in relation to the above prokaryotes on recent literature data erythromycin A and other antibiotics from the class of macrolides have activity against eukaryotic parasites [R. A. Lartey and others, Advances in Pharmacology, 28, 307-343 (1994)].

With respect to erythromycin A, as well as in relation to other antibacterial drugs, some strains of bacteria observed the phenomenon of resistance. In particular, this phenomenon was observed during prolonged use of erythromycin A in the treatment of infections caused by staphylococci [A. Kucers and N McK. Bennett, The use of antibiotics, A comprehensive Review with Clinical Emphasis, William Heinemann Medical, IV ed., (1987) 851-882].

Interest to antibiotics from the class of macrolides due to the possibility of their application in clinical therapy and veterinary medicine in the treatment of some infectious diseases, such as, for example, infectious diseases of the respiratory tract, gastrointestinal tract, urogenital tract and external organs, such as skin, eyes and ears.

Due to their low stability in the acidic environment of erythromycin A irreversibly transformed, for example, in the gastro-to the fuck bioavailability of the active substance [H. A. Kirst, Annual Reports in Medical Chemistry, 25, 119-128 (1989)].

To overcome the above drawbacks of the study focused on compounds that keeping a good antibiotic properties of erythromycin A, is characterized by a higher stability towards acids and better pharmacokinetic properties, such as, for example, a higher bioavailability in oral introduction, the concentration in the blood, the ability to penetrate tissues and half-life.

As an example in this field of technology can lead to carbamates and carbonates of erythromycin A or 9-O-oxime erythromycin A, is described in the application for the European patent 0216169 and 0284203 (both in the name of Beecham Group PLC), and compounds described in European application 0033255 (firm Roussel-Uclaf).

In European application 0033255, in particular, described 9-O-Joksimovi derivatives of erythromycin A formula

R-A-O-N=Ery,

where Ery stands for the remainder of erythromycin A, which Akimova group (-N= Ery) replaces the carbonyl group at position 9 (O = Ery); And denotes a straight or branched alkyl group with 1-6 carbon atoms; R denotes, in particular, optionally substituted by alkoxygroup with 1-6 carbon atoms or a group [-N(R1

Compounds described in the application for the European patent 0033255, such as, for example, 9-[O-[(2-methoxyethoxy)methyl]oxime] of erythromycin A, is known under the international non-proprietary name roxithromycin [The Merck Index, XI ed. N 8253], 9-[O-[(2-dimethylamino)ethyl]oxime]of erythromycin A 9-[O-[(2-diethylamino)ethyl]oxime]of erythromycin A, have a spectrum of activity in vitro comparable to that of erythromycin A, but have a higher stability towards acids and better pharmacokinetic properties. These compounds, therefore, exhibit antibiotic activity against gram-positive microorganisms such as Staphylococcus, Streptococcus and pneumococcus, and against some gram-negative microorganisms, such as, for example, Haemophilus influenzae and Haemophilus pertussis.

According to the present invention were found connection, which is 9-O-Joksimovi derivatives of erythromycin A, in particular compounds representing derivatives of 9-[O-(aminoalkyl)oxime] of erythromycin A, is partially covered by the volume, but not shown in the example in European application 0033255, which have a broader spectrum of antibacterial activity against the grampa pharmacokinetic properties, such as, for example, the high duration and the greater half-life in the elimination in the tissues compared to the compounds described in the aforementioned European application.

Thus, the object of the present invention are the compounds of formula

< / BR>
where A denotes a phenyl group or a heterocycle with 5 or 6 members containing one or more heteroatoms selected from nitrogen, oxygen and sulfur, optionally substituted by 1-3 identical or different groups selected from straight or branched (C1-C4)alkyl or alkoxygroup, (C1-C2)alkylenedioxy, (C1-C4)alkylsulfonyl groups, phenyl, phenoxy-, hydroxy-, carboxy-, nitro, halogen and triptorelin group;

R1and R2have identical or different meanings and represent a hydrogen atom or straight or branched (C1-C4)alkyl group;

n = 1 or 2;

m = 1 - 8;

r = 2 - 6;

M denotes a group of the formula

< / BR>
where R3denotes a hydrogen atom or methyl group; and their pharmaceutically acceptable salts.

The oximes of the formula (I) can have a Z - or E-configuration.

Thus, PR is positive last.

The compounds of formula (I) possess antibiotic activity and are characterized by high stability towards acids and good pharmacokinetic properties, allowing their use in therapy of a human or in veterinary medicine for the treatment of certain infectious diseases, such as, for example, diseases of the Central nervous system, upper and lower respiratory tract, gastrointestinal tract, urinary tract, bone tissue and external organs, such as skin, eyes and ears.

In the present description, unless otherwise specified, the term (C1-C4)alkyl group understand straight or branched (C1-C4)alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl; the term (C1-C4)alkoxygroup understand straight or branched (C1-C4)alkoxygroup, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy; under the notion of a (C1-C2)alkylenedioxy understand methylendioxy or Ethylenedioxy.

The concept of a heterocycle with 5 or 6 members containing one or more heteroatoms selected from nitrogen, oxygen, and the wound and thiophene.

The preferred compounds are the compounds of formula (I) in which A denotes a phenyl group or a heterocycle selected from pyridine and furan, optionally substituted by 1-3 groups selected from hydroxy, methoxy, methylenedioxy, h-butoxy-proxygroup, phenyl, methylsulfonyl, nitro, halogen and trifloromethyl; R1and R2have the same values and denote a hydrogen atom or methyl group; R3denotes a hydrogen atom.

Even more preferred compounds are the compounds of formula (I) in which A denotes a phenyl group optionally substituted by a group selected from fenoxaprop, nitro and trifloromethyl; R1and R2have the same values and denote a hydrogen atom or methyl group; n = 1; m = 6; r = 2; R is a hydrogen atom.

Pharmaceutically acceptable salts of compounds of formula (I) are salts of organic or inorganic acids, such as, for example, hydrochloric, Hydrobromic, uudistoodetena, nitric, sulfuric, phosphoric, acetic, tartaric, citric, benzoic, succinic, and glutaric acid.

Specific examples of preferred compounds of formula (I) are:

(E)-9-[O-the SIM]erythromycin A;

(E)-9-[O-[6-[6-(phenylethylamine)hexylamino]hexyl]oxime]of erythromycin A;

(E)-9-[O-[6-[3-(phenylethylamine)propylamino]hexyl]oxime]of erythromycin A;

(E)-9-[O-[6-[5-(phenylethylamine)pentylamine]hexyl]oxime]of erythromycin A;

(E)-9-[O-[2-[8-(phenylethylamine)octylamine]ethyl]oxime]of erythromycin A;

(E)-9-[O-[2-[5-(phenylethylamine)pentylamine]ethyl]oxime]of erythromycin A;

(E)-9-[O-[5-[6-(phenylethylamine)hexylamino]pentyl]oxime]of erythromycin A;

(E)-9-[O-[3-[6-(phenylethylamine)hexylamino]propyl]oxime]of erythromycin A;

(E)-9-[O-[3-[4-(phenylethylamine)butylamino]propyl]oxime]of erythromycin A;

(E)-9-[O-[2-[N-methyl-6-(N'-methyl-N'-phenylethylamine)hexylamino] ethyl] oxime]of erythromycin A;

(E)-9-[O-[2-[6-[(biphenyl-4-yl)methylamino] hexylamino]ethyl]oxime]of erythromycin A;

(E)-9-[-[2-[6-[(3-phenoxyphenyl)methylamino] hexylamino]ethyl]oxime]of erythromycin A;

(E)-9-[-[2-[6-[(4-phenoxyphenyl)methylamino] hexylamino]ethyl]oxime]of erythromycin A;

(E)-9-[-[2-[6-(2- pyrimethamine)hexylamino] ethyl]oxime]of erythromycin A;

(E)-9-[O-[2-[6-(3-pyridylmethylamine)hexylamino] ethyl]oxime]of erythromycin A;

(E)-9-[-[2-[6-[(4-methoxyphenyl)methylamino]hexylamino]ethyl] oxime]of erythromycin A;

(E)-9-[O-[2-[6-[(4-n-butoxyphenyl)methylamino] hexylamino] aicina A;

(E)-9-[-[2-[6-[(4-methylsulfinylphenyl)methylamino] hexylamino] ethyl]oxime]of erythromycin A;

(E)-9-[-[2-[6-[(4-forfinal)methylamino]hexylamino]ethyl]oxime]of erythromycin A;

(E)-9-[-[2-[6-[(2-triptoreline)methylamino] hexylamino]ethyl]oxime] of erythromycin A;

(E)-9-[-[2-[6-[(3-triptoreline)methylamino] hexylamino]ethyl]oxime] of erythromycin A;

(E)-9-[-[2-[6-[(4-triptoreline)methylamino] hexylamino]ethyl]oxime] of erythromycin A;

(E)-9-[-[2-[6-[(2-hydroxyphenyl)methylamino]hexylamino]ethyl]oxime]of erythromycin A;

(E)-9-[O-[2-[6-[(3-hydroxyphenyl)methylamino]hexylamino]ethyl]oxime]of erythromycin A;

(E)-9-[-[2-[6-[(4-hydroxyphenyl)methylamino]hexylamino]ethyl]oxime]of erythromycin A;

(E)-9-[-[2-[6-[(3,5-dichloro-2-hydroxyphenyl)methylamino]hexylamino]ethyl] oxime]of erythromycin A;

(E)-9-[-[2-[6-[(2-nitrophenyl)methylamino] hexylamino]ethyl]oxime]of erythromycin A;

(E)-9-[-[2-[6-[(3-nitrophenyl)methylamino] hexylamino]ethyl]oxime]of erythromycin A;

(E)-9-[-[2-[6-[(4-nitrophenyl)methylamino] hexylamino]ethyl]oxime]of erythromycin A;

(E)-9-[O-[2-[6-[(4-hydroxy-3-nitrophenyl)methylamino] hexylamino] ethyl] oxime]of erythromycin A;

(E)-9-[-[2-[6-[(3-hydroxy-4-nitrophenyl)methylamino] hexylamino] ethyl] oxime]of erythromycin A;

(E)-9-[O-[is the compounds of formula (I), which is the subject of the present invention may be implemented in accordance with the following method of synthesis. The method comprises, first, a condensation reaction between the corresponding acid of the formula

< / BR>
R1and m have the above significance, with an acyl chloride of the formula

A-(CH2)n-1-COCl (III)

where A and n have the above values.

The condensation reaction is carried out in accordance with standard methods in an inert solvent and in the presence of a base, such as, for example, a hydroxide of an alkali metal, to obtain the compounds of the formula

< / BR>
where A, R1n and m have the above values.

Thus obtained N-acylaminoacyl formula (IV) is further subjected to condensation in accordance with standard methods with the amino esters of the formula

< / BR>
where R2and r have the above values, a R4denotes a methyl or ethyl group, to obtain compounds of the formula

< / BR>
where A, R1, R2, R4n, m and r have the above values.

In accordance with the standard methods of compounds of formula (VI) then restore, for example, using sodium borohydride in the presence of acids, the pirates of the formula

< / BR>
where A, R1, R2n, m and r have the above values.

The aminoalcohols of the formula (VII) is then converted into the corresponding sulfonylurea derivatives of the formula (VIII), for example, using methanesulfonanilide or para-toluensulfonate, and then condense with 9-O-oxime erythromycin A or 9-O-oxime 6-O-methylerythromycin A, both compounds may be represented by the formula (IX), with compounds of formula (I)

< / BR>
where A, R1, R2, M, n, m and r have the above values, a R5represents mesyl or tonilou group.

The reaction between the compounds of formula (VIII) and oximes of the formula (IX) is carried out in an inert organic solvent, such as, for example, tetrahydrofuran, ethyl ether or 1,2-dimethoxyethane, in the presence of potassium tert-butylate and 18-crown-6-ether as a complexing agent.

To a person skilled in the art it is obvious that, if the reaction sulfonylamine carried out using compounds of the formula (VII), in which one or both of the substituent R1and R2represent a hydrogen atom, it may be necessary to protect the atom or the nitrogen atoms before the reaction of sulfonylureas the Sims formula (IX) carry out the same as described above, and the subsequent removal of the protective groups is carried out according to accepted methods, which enables to obtain the compounds of formula (I), in which one or both of the substituent R1and R2represent a hydrogen atom. More protection of the amines described in the literature, for example, see T. W. Greene and P. G. M. Wuts, Protective groups in organic synthesis, John Wiley & Sons, Inc., 2nd ed., (1991), 309-405.

Compounds of formula (II), (III) and (V) are known or can easily be obtained in accordance with known methods.

The oximes of the formula (IX) are known compounds and can be obtained in accordance with standard methods, including, for example, the interaction of erythromycin A or 6-O-methylerythromycin a with hydroxylamine hydrochloride.

Esters of formula (VI) may not necessarily be obtained in accordance with an alternative method of synthesis, including, first, condensation of the corresponding amino acids of the formula (II) with aminoethanol formula (V) obtaining compounds of the formula

< / BR>
where R1, R2, R4, m and r have the above values.

Specialist in the art it is obvious that before carrying out the condensation reaction of meditite the amino group of the amino acid of formula (II) similarly, as it was described for the reaction of sulfonylurea.

Subsequent condensation of the compounds of formula (X) with the compound of the formula (III) is carried out in accordance with standard methods, and optional removal of the protective group then allows to obtain the compounds of formula (VI).

Obtaining compounds of formula (I) in which at least one of the two substituents R1and R2denotes a group selected from ethyl, n-propyl, n-butyl and isobutyl, can be carried out in accordance with an alternative method of synthesis described below.

This method comprises, first, the acylation of an atom or atoms of nitrogen aminoalcohols of the formula (VII), where one or both of the substituent R1and R2represent a hydrogen atom.

For example, when using the compounds of formula (VII), in which each substituent R1and R2represent a hydrogen atom, in accordance with standard methods in the presence of suitable acylchlorides (R COCl) can be obtained the compounds of formula

< / BR>
where A, n, m and r have the above values, a R' denotes a straight or branched (C1-C3)alkyl group.

The recovery of the compounds of formula (XI), carried out in sosanya above values, a R1and R2denote ethyl, n-propyl, n-butyl or isobutyl, of which, after conversion into the corresponding sulfonylurea derivatives and condensation with oximes of the formula (IX) in the same way as described above, it is possible to obtain the compounds of formula

< / BR>
where A, M, n, m and r have the above values, a R1and R2denote ethyl, n-propyl, n-butyl or isobutyl.

Below is described the synthesis process, an alternative to that described previously, to obtain compounds of formula (I), which is the subject of the present invention.

This process involves, first, the oxidation of the corresponding N-protected amerosport, such as, for example, N-benzyloxycarbonylamino formula (XIII) in the presence of sodium hypochlorite and free radical 2,2,6,6-tetramethylpiperidinyloxy (TEMPO) in an inert organic solvent to obtain compounds of the formula (XIV)

< / BR>
where m has the abovementioned meanings and Z represents a protective group.

Examples of inert organic solvents suitable for the oxidation reaction are, for example, methylene chloride, chloroform, cerysemilay carbon, 1,2-dichloroethane, ethyl acetate, benzene and toluene.

Amineral the received intermediate product, for example, in the presence of sodium borohydride, allows to obtain the aminoalcohols of the formula (XVI)

< / BR>
where Z, m and r have the above values.

Subsequent protection of the nitrogen of the amino group of compounds of formula (XVI), and thus the transformation into the corresponding sulfonylurea derivatives, condensation with oximes of the formula (IX) and removing the protective group of the nitrogen atoms in the same way as described above, allow to obtain the compounds of formula

< / BR>
where M, m and r have the above values.

Intermediate oximes of the formula (XVII), condensed with an appropriate aldehyde of formula (XVIII) and recovered, for example, by catalytic hydrogenation, allow to obtain the compounds of formula (I)

< / BR>
where A, M, M and r have the above values.

Compounds of formula (XIII), (XV) and (XVIII) are known or can easily be obtained in accordance with known methods.

The compounds of formula (I), in which one or both of the substituent R1and R2represent a hydrogen atom, obtained in accordance with one of the methods described above, may not necessarily be alkylated on the atom or the nitrogen atoms of diminishment in accordance with standard methods, including, S="ptx2">

In this way receive the compounds of formula (I) in which R1and R2have identical or different meanings and represent a straight or branched (C1-C4)alkyl group.

Obtaining compounds of formula (I) having the Z - or E-configuration, is carried out according to one of the schemes of synthesis described above, using the oxime of formula (IX) in the desired configuration [J. C. Cas and others, The Journal of Antibiotics, 44, 313-330, (1991)].

It was found that the compounds of formula (I) exhibit antibacterial activity against some gram-positive and gram-negative microorganisms and are suitable for use in clinical therapy and in veterinary medicine in the treatment of some infectious diseases, such as, for example, diseases of the Central nervous system, upper and lower respiratory tract, gastrointestinal tract, urinary tract, bone tissue and external organs, such as skin, eyes and ears.

In addition, these compounds have activity against some clinical interest of gram-positive microorganisms resistant to erythromycin A or more generally to antibiotics from the class of macrolides, characterized by the presence of the to gram-positive microorganisms, such as Streptococcus pyogenes, Streptococcus pneumoniae, Enterococcus faecalis and Staphylococcus aureus, and gram-negative microorganisms, such as Escherichia coli and Klebsiella pneumoniae were evaluated using in vitro experiments, suitable for estimating the minimum concentration of antibiotic that allows you to inhibit bacterial growth (MIC) (example 23). As standards were used roxithromycin and clarithromycin [The Merck Index, XI ed., N 8253 and N 2340, respectively].

It was found that the antibacterial activity of compounds of the formula (I) in relation to gram-positive microorganisms almost comparable to that of roxithromycin and clarithromycin, i.e., two macrolides, characterized in experiments in vitro high antibacterial activity (table 1).

It was found also that, with respect to gram-negative microorganisms, in particular in relation to the enterobacteria, such as Escherichia coli and Klebsiella pneumoniae, the compounds of formula (I) are significantly more active compared to both compounds used as standards (table 2).

In this connection it is interesting to note that the compounds of formula (I), which is the subject of the present invention, was more active than roxithromycin described in the above m derived, such as, for example, 9-[O-[(2-dimethylamino)ethyl]oxime]of erythromycin A [J. C. Cas and others, The Journal of Antibiotics, 44, 313-330, (1991)].

In addition, it was found that the compounds of formula (I) are active in in vivo studies (table 3). Antibacterial activity of the compounds of formula (I) in experiments in vivo, expressed as average protects dose PD50(mg/kg) was evaluated using an experimental pulmonary infection induced in mice with Streptococcus pyogenes (example 23).

When analyzing data about activity detected in in vivo studies, it is apparent that the compounds of formula (I) are prolonged action and a long half-life in the elimination of the tissue. Indeed, after intraperitoneal administration mouse compounds of formula (I) is rapidly and widely distributed throughout the body, and levels in tissues were higher than in plasma. These results are particularly apparent in the analysis of the values PD50for compounds of formula (I) entered for 24 hours before or 1 hour after infection. Indeed, these values were almost unchanged after the introduction of 24 hours before or 1 hour after infection.

In the case of experimental pulmonary infection, calling the concentration of compounds of formula (I), introduced intraperitoneally, were preserved in the field of light within 24-48 hours after injection. In contrast, roxithromycin and clarithromycin, i.e., used as reference compounds being introduced for 24 hours before infection, was inactive. Therefore, the compounds of formula (I) also have selective activity against light and can be used successfully to treat infections of the respiratory tract.

In addition to the above activity against bacterial pathogens of compounds of formula (I), which is the subject of the present invention are active against eukaryotic pathogens, in particular, they have a pronounced activity in relation to the simplest, such as Plasmodium falciparum, which is a well-known causative agent of malaria. Therefore, the compounds of formula (I) can also be successfully used for the treatment of malaria.

Along with the fact that they are characterized by a broad spectrum antibiotic activity against gram-positive and gram-negative microorganisms and simple, good stability towards acids and good pharmacokinetic properties, acute toxicnaanette in the application, they can be successfully used in human therapy and veterinary medicine.

The compounds of formula (I) preferably should be used in an appropriate pharmaceutical form suitable for oral, parenteral administration in the form of a suppository or for local use. Thus, the object of the present invention are pharmaceutical compositions containing a therapeutically effective amount of one or more compounds of the formula (I) in a mixture with a pharmaceutically acceptable carrier. These pharmaceutical forms include tablets, capsules, syrups, injectable solutions, ready to use or receive before use by dilution of freeze-dried forms, suppositories, solutions, creams, ointments and eye lotions. For veterinary purposes in addition to the above compositions can be manufactured solid or liquid concentrates to be diluted in food or water to drink.

In accordance with the type of composition in addition to therapeutically effective amounts of one or more compounds of the formula (I), these compositions should contain solid or liquid excipients or diluents for pharmaceutical or veterinary purposes and not the marijuana agents, aggregation agents, sizing agents, contributing to the disintegration, corrigentov and dyes.

For treatment of specific infections compound of formula (I) may be combined with an effective amount of another active ingredient.

An effective amount of the compounds of formula (I) may vary depending on various factors such as the seriousness and the phase of the disease, organ or system, susceptible to disease characteristics host species, the sensitivity of the bacterial species causing the infection, and the selected route of administration. therapeutic dose is usually from 0.5 to 100 mg/kg of body weight per day and can be applied in a single dose or multiple daily doses.

Below the invention is illustrated in the examples, not limiting its scope.

The structure of compounds of formula (I) and intermediates of synthesis when receiving confirmed with1H-NMR or16C-NMR spectroscopy. The values for significant signals the most important intermediates and compounds of formula (I) below in the description.

Example 1

Obtain N-benzoyl-6-aminocaproic acid

A solution of benzoyl chloride (0,18 mol) of the acid of 0.15 mol) in ethyl ether (150 ml) and water (200 ml), containing sodium hydroxide (0,15 mol), and stirred at a temperature of from 0 to 5oC. Upon completion of addition compounds of the temperature of the reaction mixture was brought to room temperature and was stirred for another 4 hours. After separation of the phases the aqueous phase was washed with ethyl ether (200 ml) and acidified with concentrated hydrochloric acid using reactive paper of the Congo. After extraction with ethyl acetate (CH ml) the combined organic phases are washed with saturated aqueous sodium chloride (200 ml), dried over sodium sulfate and evaporated under reduced pressure. In this way received N-benzoyl-6-aminocaproic acid, which was directly used in the subsequent reactions.

A similar technique has received the following connections:

N-benzoyl-3-aminopropanoic acid; N-benzoylglycine; N-benzoyl-8-aminooctanoic acid; N-benzoyl-4-aminobutanoic acid; N-phenylacetyl-6-aminocaproic acid; N-phenylacetylene; N-benzoyl-N-isopropyl-4-aminobutanoic acid; N-benzoyl-N-isopropyl-6-aminocaproic acid.

Example 2

Obtaining the ethyl ester of N-[6-(benzoylamine)hexanoyl]glycine

The solution dicyclohexylcarbodiimide (112 mmol) in anhydrous tetrahydro is obtained according to example 1, the hydrochloride of the ethyl ester of glycine (112 mmol), triethylamine (112 mmol) and anhydrous 1-hydroxybenzotriazole (112 mmol) in tetrahydrofuran (330 ml) and was stirred at a temperature of 0oC. Next, the temperature of the reaction mixture was brought to room temperature and was stirred for 16 hours. The result obtained precipitate, which was removed by filtration, and the thus obtained filtrate was evaporated under reduced pressure. The residue was combined with ethyl acetate (300 ml) and then washed with a solution of 5% hydrochloric acid (g ml), a saturated solution of sodium chloride (100 ml), a solution of 5% sodium bicarbonate (g ml) and finally saturated sodium chloride solution (100 ml). The organic phase was dried over sodium sulfate and evaporated to dryness under reduced pressure, thus obtaining the ethyl ester of N-[6-(benzoylamine)hexanoyl]glycine, which was directly used in the subsequent reactions.

A similar technique has received the following connections:

ethyl ester of N-1(benzoylamine)acetyl] glycine; ethyl ester of N-[6-(phenylacetylamino)hexanoyl]glycine; ethyl ester of N-[(phenylacetylamino)acetyl] glycine; ethyl-6-[6-(benzoylamine)hexanamine] hexanoate; methyl ester of N-[5-(benzoylamine)Penta is of CIN; methyl-5-[6-(benzoylamine)hexanamine] pentanoate; methyl-6-[(benzoylamine)acetylamino] hexanoic; methyl-3-[6-(benzoylamine)hexanamine]propionate; ethyl-6-[N-isopropyl(phenylacetylamino)acetylamino]hexanoic; methyl-6-[4-(benzoylamine)butanamine] hexanoate; methyl-4-[N-isopropyl-4-(N'-isopropyl-N'-benzoylamine)butanamine]butanoate.

Example 3

Obtaining the ethyl ester of N-(6-aminohexanoic)glycine

a) To a solution of sodium hydroxide (33,54 g; 0,831 mol) in water (840 ml) and methanol (400 ml) was added 6-aminocaproic acid (100 g; 0,762 mol) was gradually added a solution of di-tert-BUTYLCARBAMATE (168 g; 0,762 mol) in methanol (140 ml). The reaction mixture was stirred at room temperature for 4 hours. Once this was added solid di-tert-BUTYLCARBAMATE (17.5 g; 0,08 mol) and the reaction mixture was stirred for 16 hours. Then the reaction mixture was washed with hexane (h ml), acidified with a solution of potassium bisulfate to pH 1.5 and were extracted with ethyl acetate (CH ml). The combined organic phases were dried over sodium sulfate and was evaporated to dryness, thus obtaining 6-(tert-butoxycarbonylamino)Caproic acid (163 g) in the form of butter.

b) Analogously to the method described in example 2 6-(Trets the Fira glycine (118 g; 0,845 mol), thus obtaining the ethyl ester of N-[6-(tert-butoxycarbonylamino)hexanoyl]glycine (285 g) as a crude product, which was directly used in the subsequent reaction, tPL76-77oC (isopropyl ether).

C) a Solution of 6N. hydrochloric acid (150 ml) in ethyl acetate (150 ml) was added to a solution of ethyl ester of N-[6-(tert-butoxycarbonylamino)hexanoyl]glycine (285 g) in ethyl acetate (500 ml) and stirred at room temperature. After 24 hours, the formed precipitate, which was filtered, washed with ethyl acetate and ethyl ether, and dried in a thermostat (50oC) under vacuum. In this way received ethyl ester of N-(6-aminohexanoic)glycine (93 g) as a crude product, which was directly used in the subsequent reactions. TLC (methylene chloride:methanol:ammonia = 10:2:1) Rf=0,2.

Example 4

Obtaining the ethyl ester of N-[6-[(4-perbenzoic)amino]hexanoyl]glycine

A solution of 4-tormentilla (47.4 mmole) in methylene chloride (30 ml) was gradually added to the suspension containing the ethyl ester of N-(6-aminohexanoic)glycine (39,5 mmole), obtained according to example 3, and triethylamine (87 mmol) in methylene chloride (150 ml) and stirred at 0oC. the Temperature of the obtained toderici for 1 hour under these conditions, the reaction mixture was washed with a solution of 5% hydrochloric acid (g ml) and a saturated solution of sodium chloride (g ml). The separated organic phase was dried over sodium sulfate and evaporated to dryness under vacuum. In this way received ethyl ester of N-[6-[(4-perbenzoic)amino]hexanoyl]glycine in the form of the crude product, which was directly used in the subsequent reactions, tPL121-122oC (ethyl acetate); TLC (ethyl acetate) Rf=0,3.

A similar technique has received the following connection:

ethyl ester of N-[6-(2-prolamine)hexanoyl] glycine, tPL104-106oC (acetonitrile/isopropyl ether); TLC (methylene chloride:methanol = 95:5) Rf=0,3.

Example 5

Obtaining the ethyl ester of N-[6-[(4-methoxybenzoyl)amino]hexanoyl]glycine

Analogously to example 2 using 4-methoxybenzoic acid (33 mmole) and ethyl ester of N-(6-aminohexanoic)glycine (39,5 mmole), obtained according to example 3 was obtained ethyl ester of N-[6-[(4-methoxybenzoyl)amino] hexanoyl] glycine in the form of the crude product, which was directly used in the subsequent reactions, tPL106-107oC. TLC (methylene chloride:methanol = 90:10) Rf=0,46.

A similar technique has received the following connections:

ethyl ester of N-[6-[(3,4-methylenedioxybenzyl)amino]hexanoyl]glycine, TLC (methylene chloride:methanol = 90:10) Rf= 0,39; e methanol = 96:4) Rf=0,31; ethyl ester of N-[6-[(3-trifloromethyl)amino] hexanoyl] glycine, tPL102-104oC; TLC (methylene chloride:methanol = 95:5) Rf= 0,38.

Example 6

Getting 2-[6-(phenylethylamine)hexylamino]ethanol

Sulfuric acid (6 A.D.) in ethyl ether (40,9 ml, 700 mmol) obtained by the mixture of 96% sulfuric acid (33 ml) and ethyl ether (100 ml) was gradually added to the suspension containing the ethyl ester of N-[6-(benzoylamine)hexanoyl] glycine (46,8 mmole), obtained according to example 2, and borohydride sodium (700 mmol) in anhydrous tetrahydrofuran (200 ml), and stirred at a temperature of from 15oC to 20oC. the Reaction mixture is brought to boiling point for 24 hours and then was cooled to 0oC. Then, with stirring, was added methanol (150 ml). The solvent is evaporated under reduced pressure and the residue was combined with a solution of 6 n sodium hydroxide (200 ml), maintaining the resulting mixture at boiling point for 24 hours. Then the reaction mixture was cooled to room temperature, was extracted with tetrahydrofuran (g ml) and the organic phase was evaporated to dryness, combined with ethyl acetate and dried over sodium sulfate. By acidification with ethereal hydrochloric acid solution received osado the crude product was directly used in the subsequent reactions.

A similar technique has received the following connections:

2-[2-(phenylethylamine)ethylamino]ethanol; 2-[6-(2-phenylethylamine)hexylamino] ethanol; 6-[6-(phenylethylamine)hexylamino]hexanol; 2-[5-(phenylethylamine)pentylamine] ethanol; 2-[8-(phenylethylamine)octylamine]ethanol; 5-[6-(phenylethylamine)hexylamino]pentanol; 6-[3-(phenylethylamine)propylamino] hexanol; 3-[6-(phenylethylamine)hexylamino] propanol; 3-[4-(phenylethylamine)butylamino]propanol; 6-[2-(phenylethylamine)ethylamino]hexanol; 6-[N-isopropyl-4-(phenylethylamine)butylamino]hexanol; 2-[6-[(4-forfinal)methylamino]hexylamino] ethanol; 2-[6-[(4-methoxyphenyl)methylamino] hexylamino]ethanol; 2-[6-[(3,4-methylenedioxyphenyl)methylamino] hexylamino] ethanol; 2-[6-[(3-triptoreline)methylamino] hexylamino] ethanol; 2-[6-[(4-methylsulfinylphenyl)methylamino] hexylamino] ethanol; 4-[N-isopropyl-4-(N'-isopropyl-N'-phenylethylamine)butylamino]butanol.

Example 7

Obtain 6-[N-acetyl-6-(N'-acetyl-N-phenylethylamine)hexylamino]vexillata

The triethylamine (1,95 ml; 14 mmol) and the solution acetylchloride (of 0.62 ml; 8,69 mmole) in methylene chloride (5 ml) was gradually added to the suspension containing 6-[6-(phenylethylamine)hexylamino]hexanol (1 g, 2.6 mmole), obtained according to example 6, the tour of the reaction mixture was brought to room temperature and stirred for 16 hours. Then the reaction mixture was washed with a solution of 10% hydrochloric acid (10 ml) and a saturated solution of sodium chloride. After separation of the phases the organic phase was dried over sodium sulfate and evaporated to dryness under vacuum, thus obtaining 6-[N-acetyl-6-(N'-acetyl-N'-phenylethylamine) hexylamino]exilerated (1.18 g) in the form of oil, which was directly used in the subsequent reactions.

A similar technique was obtained the following compound: 2-[N-acetyl-6-[N'-acetyl-N'-(2-phenylethyl)amino]hexylamino] acetate.

Example 8

Obtain 6-[N-ethyl-6-(N'-ethyl-N'-phenylethylamine)hexylamino]hexanol

Analogously to example 6 from 6-[N-acetyl-6-(N'-acetyl-N'- phenylethylamine)hexylamino]vexillata obtained according to example 7, was obtained 6-[N-ethyl-6-(N'-ethyl-N'-phenylethylamine)hexylamino]hexanol.

A similar technique was obtained the following compound: 2-[N-ethyl-6-[N'-ethyl-N'-(2-phenylethyl)amino]hexylamino]ethanol.

Example 9

Getting 2-[N-benzyloxycarbonyl-6-(N'-benzyloxycarbonyl-N'- phenylethylamine)hexylamino]ethanol

A solution of 1 n sodium hydroxide (44,5 ml) and a toluene solution of 50% benzylchloride (44,5 mmole) in ethyl acetate (33 ml) slowly and odnoo according to example 6, in a solution of 1 n sodium hydroxide (37.1 ml) and ethyl acetate (40 ml), and stirred at a temperature of 0oC. Upon completion of the additions the temperature of the reaction mixture was brought to room temperature and was stirred for 24 hours. After separation of the phases the aqueous phase was washed with ethyl acetate (CH ml). The combined organic phases were washed with a saturated solution of sodium chloride (50 ml), dried over sodium sulfate and evaporated to dryness under vacuum. The way it was obtained 2-[N-benzyloxycarbonyl-6-(N'-benzyloxycarbonyl-N'-phenylethylamine)hexylamino] ethanol in the form of oil, which was directly used in the subsequent reactions. TLC (ethyl acetate:hexane = 50:50) Rf=0,20.

A similar technique has received the following connections:

2-[N-benzyloxycarbonyl-2-(N'-benzyloxycarbonyl-N'-phenylethylamine) ethylamino]ethanol, TLC (ethyl acetate:hexane = 60:40) Rf=0,25;

6-[N-benzyloxycarbonyl-6-(N'-benzyloxycarbonyl-N'-phenylethylamine)hexylamino]hexanol, TLC (ethyl acetate:hexane = 50:50) Rf=0,27;

6-[N-benzyloxycarbonyl-5-(N'-benzyloxycarbonyl-N'-phenylethylamine) pentylamine]hexanol;

2-[N-benzyloxycarbonyl-5-(N'-benzyloxycarbonyl-N'-phenylethylamine) pentylamine]ethanol;

2-[N-benzyloxycarbonyl-8-(N'-benzyloxycarbonyl-N'-fenile]pentanol;

6-[N-benzyloxycarbonyl-3-(N'-benzyloxycarbonyl-N'-phenylethylamine) propylamino]hexanol;

3-[N-benzyloxycarbonyl-6-(N'-benzyloxycarbonyl-N'-phenylethylamine) hexylamino]propanol;

3-[N-benzyloxycarbonyl-4-(N'- benzyloxycarbonyl-N'-phenylethylamine) butylamino]propanol;

6-[N-isopropyl-2-[N'-benzyloxycarbonyl-N'-(2-phenylethyl)amino]ethylamino] hexanol, TLC (methylene chloride:methanol:ammonia = 95:5:0.5) with Rf=0,33;

6-[N-benzyloxycarbonyl-4-(N'-isopropyl-N'-phenylethylamine)butylamino] hexanol, TLC (methylene chloride:methanol:ammonia = 95:5:0.5) with Rf=0,42;

2-[N-benzyloxycarbonyl-6-[N'-benzyloxycarbonyl-N'-[(4-forfinal)methyl] amino]hexylamino]ethanol, TLC (ethyl acetate:hexane = 60:40) Rf=0,35;

2-[N-benzyloxycarbonyl-6-[N'-benzyloxycarbonyl-N'-[(4-methoxyphenyl) methyl]amino]hexylamino]ethanol, TLC (ethyl acetate:hexane = 50:50) Rf=0,2;

2-[N-benzyloxycarbonyl-6-[N'-benzyloxycarbonyl-N'- [(3,4-methylenedioxyphenyl)methyl] amino] hexylamino] ethanol, TLC (ethyl acetate:hexane = 60:40) Rf=0,26;

2-[N-benzyloxycarbonyl-6-[N'-benzyloxycarbonyl-N'- [(3-triptoreline)methyl] amino] hexylamino] ethanol, TLC (ethyl acetate:hexane = 50:50) Rf= 0,25;

2-[N-benzyloxycarbonyl-6-[N'-benzyloxycarbonyl-N'-[(4 - methylsulfinylphenyl)methyl] amino] hexylamino]etano the carbonyl-N'-phenylethylamine) hexylamino]ethylmethanesulfonate

The solution methanesulfonanilide (3,16 mmole) in methylene chloride (5 ml) was gradually added to a solution of 2-[N-benzyloxycarbonyl-6-(N'-benzyloxycarbonyl-N'- phenylethylamine)hexylamino]ethanol (2.6 mmole), obtained according to example 9, in methylene chloride (15 ml) containing triethylamine (of 0.44 ml; and 3.16 mmole), and stirred at a temperature of 0oC. the Reaction mixture, the temperature was brought to room temperature and was stirred for 5 hours, was added to a solution of 5% hydrochloric acid (20 ml). After phase separation the organic phase is washed with 5% hydrochloric acid (10 ml) and saturated sodium chloride solution (3x10 ml). Then the organic phase was dried over sodium sulfate and was evaporated to dryness, thus obtaining 2-[N-benzyloxycarbonyl-6-(N'-benzyloxycarbonyl-N'-phenylethylamine)hexylamino]ethylmethanesulfonate, which was directly used in the reaction shown in the following example.

Example 11

Obtaining (E)-9-[O-[2-[N-benzyloxycarbonyl-6-(N'-benzyloxycarbonyl-N'-phenylethylamine) hexylamino]ethyl]oxime]of erythromycin A

(E)-9-O-oxime erythromycin A (627 mg; 0,84 mmole), 18-crown-6-ether (220 mg; 0,84 mmole) and a solution of 2-[N-benzyloxycarbonyl-6-(N'-benzyloxycarbonyl-N'- phenylethylamine)hexylamino]Atil the data to a suspension of potassium tert-butylate (103 mg; to 0.92 mmole) in anhydrous tetrahydrofuran (5 ml) and kept at room temperature and under stirring in nitrogen atmosphere. The reaction mixture was stirred at room temperature for 20 hours and then was evaporated under reduced pressure. The residue was combined with ethyl acetate (10 ml) and the resulting mixture was washed with a saturated solution of sodium chloride (10 ml). The aqueous phase was extracted with ethyl acetate (2x10 ml) and the combined organic phases were dried over sodium sulfate and evaporated to dryness. The way it was obtained (E)-9-[O-[2-[N-benzyloxycarbonyl-6-(N'benzyloxycarbonyl-N'- phenylethylamine)hexylamino] ethyl]oxime] of erythromycin A and was used directly in subsequent reactions. TLC (methylene chloride:methanol:ammonia = 90:9:1) Rf=0,58; MS (C. I. ) (M+N)+= 1250;1H-NMR (200 MHz, CDCl3): (part./million) 7,38-7,10 (m, 15 NM, (aromatic compounds); 5,18-5,10 (m, 4H, ); 3,30 (s, 3H, OCH3); and 2.26 (s, 6N, 2NCH3); 0,81 (t, 3H ).

A similar technique has received the following connections:

(E)-9-[O-[2-[N-benzyloxycarbonyl-2-(N'-benzyloxycarbonyl-N'- phenylethylamine)ethylamino]ethyl]oxime]of erythromycin A, TLC (methylene chloride:methanol:ammonia = 90:10:1) Rf=0,5;1H-NMR (200 MHz, CDCl3): (part./million) 7,11-6,97 (m, 15 NM, aromatic soy is biloxicasino-N'- phenylethylamine)hexylamino] hexyl] oxime]of erythromycin A, TLC (methylene chloride:methanol: ammonia = 90:10:1) Rf=0,6;1H-NMR (200 MHz, CDCl3): (part./million) 7,27-of 6.96 (m, 15 NM, aromatics); of 5.05 to 4.92 (m, 4H, ); 3,17 (s, 3H, OCH3); to 2.13 (s, 6N, 2NCH3); 0,70 (t, 3H, );

(E)-9-[O-[6-[N-benzyloxycarbonyl-3-(N'-benzyloxycarbonyl-N'- phenylethylamine)propylamino] hexyl] oxime]of erythromycin A, TLC (methylene chloride:methanol: ammonia = 90: 10:1) Rf=0,65; MS (C. I.) (M+N)+= 1194;1H-NMR (200 MHz, CDCl3): (part./million) 7,39-7,01 (m, 15 NM, aromatics); 5,17-5,02 (m, 4H, ); 3,30 (s, 3H, OCH3); and 2.27 (s, 6H, 2NCH3); of 0.82 (t, 3H, );

(E)-9-[O-[6-[N-benzyloxycarbonyl-5-(N'-benzyloxycarbonyl-N'- phenylethylamine)pentylamine]hexyl]oxime]of erythromycin A;

(E)-9-[O-[2-[N-benzyloxycarbonyl-8-(N'-benzyloxycarbonyl-N'- phenylethylamine)octylamine]ethyl]oxime]of erythromycin A;

(E)-9-[O-[2-[N-benzyloxycarbonyl-5-(N'-benzyloxycarbonyl-N'- phenylethylamine)pentylamine]ethyl]oxime]of erythromycin A;

(E)-9-[O-[5-[N-benzyloxycarbonyl-6-(N'-benzyloxycarbonyl-N'- phenylethylamine)hexylamino]pentyl]oxime]of erythromycin A;

(E)-9-[O-[3-[N-benzyloxycarbonyl-6-(N'-benzyloxycarbonyl-N'- phenylethylamine)hexylamino]propyl]oxime]of erythromycin A;

(E)-9-[O-[3-[N-benzyloxycarbonyl-4-(N'-benzyloxycarbonyl-N'- phenylethylamine)butylamino]propyl]okexil]oxime]of erythromycin A, tPL74-76oC; MS (C. I.) (M+N)+= 1172;1H-NMR (200 MHz, CDCl3): (part./million) 7,38-7,03 (m, 10H, aromatics); 5,13-to 5.03 (m, 2H, ); 3,29 (s, 3H, OCH3); to 2.25 (s, 6N, 2NCH3);

(E)-9-[O-[6-[N-ethyl-6-(N'-ethyl-N'-phenylethylamine)hexylamino] hexyl] oxime] of erythromycin A (compound 1), tPL80-82oC (acetonitrile); MS (C. I.) (M+N)+= 1094;13C-NMR (50 MHz, CDCl3): (part./million) 175,20; 171,35; 140,06; 128,86; 128,07; 126,62; 102,96; 96,27; 53,54;

(E)-9-[O-[2-[N-ethyl-6-[N'-ethyl-N'-(2-phenylethyl)amino] hexylamino] ethyl] oxime]of erythromycin A (compound 2), TLC (chloroform:hexane:triethylamine = 45: 45: 10) Rf= 0,2; MS (C. I.) (M+N)+= 1052;1H-NMR (200 MHz, CDCl3): frequently. /million) 7,26? 7.04 baby mortality (m, 5H, aromatics); up 3.22 (s, 3H, OCH3); 2,20 (s, 6N, 2NCH3); of 0.79 (t, 3H, );

(E)-9-[O-[6-[N-benzyloxycarbonyl-4-(N'-isopropyl-N'- phenylethylamine)butylamino] hexyl] oxime] of erythromycin A, tPL75-77oC;1H-NMR (200 MHz, CDCl3): (part./million) 7,47 for 7.12 (m, 10H, aromatics); 5,18 is equal to 4.97 (m, 4H, );3,30 (s, 3H, OCH3); to 2.25 (s, 6N, 2NCH3); of 0.82 (t, 3H, );

(E)-9-[O-[2-[N-benzyloxycarbonyl-6-[N'-benzyloxycarbonyl-N'- [(4-forfinal)methyl]amino]hexylamino]ethyl]oxime]of erythromycin A, TLC (methylene chloride: methanol:ammonia = 90:10:1) Rf= 0,62;1H-NMR (200 MHz, CDCl3): frequently. /million) 7,38-to 6.88 (m, oxycarbonyl-6-[N'-benzyloxycarbonyl-N'-[(4 - methoxyphenyl)methyl]amino]hexylamino]ethyl]oxime]of erythromycin A, TLC (methylene chloride:methanol:ammonia = 45:45:10) Rf=0,3;1H-NMR (200 MHz, CDCl3): frequently. /million) 7,40-of 7.23 (m, 10H, ); 7,20 to 6.75 (m, 4H, ); 5,52-5,17 (m, 4H, ); of 3.77 (s, 3H, ); 3,29 (s, 3H, OCH3); to 2.25 (s, 6H, 2NCH3); of 0.82 (t, 3H );

(E)-9-[O-[2-[N-benzyloxycarbonyl-6-[N'-benzyloxycarbonyl-N'- [(3,4-methylenedioxyphenyl)methyl] amino] hexylamino] ethyl]oxime]of erythromycin A, TLC (methylene chloride: methanol:ammonia = 95:5:0.5) with Rf=0,31;1H-NMR (200 MHz, CDCl3): (part./million) 7,38-7,22 (m, 10H, ); 6,78-6,55 (m, 3H, aromatics); 5,90 (s, 2H, OCH2O); 5,15-5,02 (m, 4H, ); 3,29 (s, 3H, OCH3); and 2.26 (s, 6N, 2NCH3); of 0.82 (t, 3H, );

(E)-9-[O-[2-[N-benzyloxycarbonyl-6-[N'-benzyloxycarbonyl-[(3 - triptoreline)methyl]amino]hexylamino]ethyl]oxime]of erythromycin A, TLC (methylene chloride:methanol:ammonia = 90:10:1) Rf=0,65;1H-NMR (200 MHz, CDCl3): frequently. /million) 7,54-to 7.15 (m, 14H, aromatics); 5,20-to 5.03 (m, 4H, ); 3,30 (s, 3H, OCH3); and 2.26 (s, 6N, 2NCH3); of 0.82 (t, 3H );

(E)-9-[O-[2-[N-benzyloxycarbonyl-6-[N'-benzyloxycarbonyl-N'- [(4-methylsulfinylphenyl)methyl] amino] hexylamino] ethyl] oxime]of erythromycin A, TLC (methylene chloride:methanol:ammonia = 95:5:0.5) with Rf=0,5;1H-NMR (200 MHz, CDCl3): frequently. /mn) of 7.90-7,79 (m, 4H, ); of 7.48-to 7.15 (m, 10H ); 5,19-to 5.03 (m, 4H, ); 3,30 (s, 3H, OCH3); to 3.02 (s, 3H, CH3SO2); and 2.27 (s, 6N, 2NCH3); of 0.82 (t, 3H, );

(E)-9-[O-[4-[N-isopropyl-4-(is Xan); MC (C. I.) (M+N)+= 1066;1H-NMR (200 MHz, CDCl3): (part./million) 7,37-7,10 (m, 5H, aromatics); 3,50 (s, 2H, ); 3,30 (s, 3H, OCH3); and 2.26 (s, 6H, 2NCH3); of 0.82 (t, 3H, ).

Example 12

Obtaining (E)-9-[O-[2-[6-(phenylethylamine)hexylamino]ethyl]oxime] of erythromycin A (compound 4)

To a solution of (E)-9-[O-[2-[N-benzyloxycarbonyl-6-(N'-benzyloxycarbonyl - N'-phenylethylamine)hexylamino]ethyl]oxime]of erythromycin A (5.9 mmole), obtained according to example 11, in ethanol (150 ml) was added 10% palladium on coal (750 mg). Thus obtained mixture was placed in hydrogenator Parra, loaded with hydrogen (1 bar), and stirred at room temperature. After 7 hours the catalyst was filtered and the alcohol solution was evaporated to dryness. This way, after purification by chromatography on silica gel (eluent methylene chloride: methanol: ammonia = 90:10:1) was obtained (E)-9-[O-[2-[6-(phenylethylamine)hexylamino] ethyl]oxime] of erythromycin A. MS (C. I.) (M+N)+= 982;13C-NMR (50 MHz, CDCl3): (part./million) 140,48; 128,39; 128,11; 126,88.

A similar technique has received the following connections:

(E)-9-[O-[2-[2-(phenylethylamine)ethylamino] ethyl] oxime] of erythromycin A (compound 5),13C-NMR (50 MHz, CDCl3): (part./million) 176,51; 172,36; 140,96; 129,08; 128,95; 127,6 H)+= 1038;13C-NMR (50 MHz, CDCl3): frequently. /million) 175,24; 171,31; 140,33; 128,37; 128,13; 126,89; 102,92; 96,27; 54,01;

(E) 9-[O-[6-[3-(phenylethylamine)propylamino]hexyl]oxime] of erythromycin A (compound 7), MS (C. I.) (M+N)+= 995;13C-NMR (50 MHz, CDCl3): frequently. /million) 175,15; 171,37; 140,41; 128,38; 128,09; 126,89; 102,92; 96,27; 54,04;

(E)-9-[O-[6-[5-(phenylethylamine)pentylamine]hexyl]oxime] of erythromycin A (compound 8),1H-NMR (200 MHz, CDCl3): (part./million) 7,35-to 7.15 (m, 5H, aromatics); of 3.75 (s, 2H, CH2Ph); of 2.25 (s, 6N, 2NCH3); 0,81 (t, 3H, );

(E)-9-[O-[2-[8-(phenylethylamine)octylamine] ethyl] oxime] of erythromycin A (compound 9),1H-NMR (200 MHz, CDCl3): (part./million)

7,40-to 7.15 (m, 5H, aromatics); of 3.75 (s, 2H ), 3,29 (s, 3H, OCH2); to 2.25 (s, 6H, 2NHC3); of 0.82 (t, 3H, );

(E)-9-[O-[2-[5-(phenylethylamine)pentylamine] ethyl] oxime] of erythromycin A (compound 10),13C-NMR (50 MHz, CDCl3): (part./million) 174,96; 172,00; 140,31; 128,39; 128,14; 126,93; 103,16; 96,20; 53,98;

(E)-9-[O-[5-[6-(phenylethylamine)hexylamino]pentyl]oxime] of erythromycin A (compound 11),13C-NMR (50 MHz, CDCl3): (part./million) 175,24; 171,24; 140,41; 128,38; 128,13; 126,88; 102,97; 96,28; 54,06;

(E)-9-[O-[3-[6-(phenylethylamine)hexylamino]propyl]oxime] of erythromycin A (compound 12),13C-NMR (50 MHz, CDCl3): (part./million) 175,23; 171,46; 140,45; 128,39; 128,13; 126,-NMR (50 MHz, CDCl3): (part./million) 175,22; 171,45; 140,35; 128,39; 128,13; 126,90; 102,98; 96,26; 53,94;

(E)-9-[O-[6-[N-isopropyl-2-(2-phenylethylamine)ethylamino] hexyl] oxime] of erythromycin A (compound 14), tPL93-95oC; MS (C. I.) (M+N)+= 1038;13C-NMR (50 MHz, CDCl3): frequently. /million) 174,92; 170,96; 139,71; 128,42; 128,10; 125,79; 102,62; 95,94; 50,93;

(E)-9-[O-[6-[4-(N-isopropylacrylamide)butylamino] hexyl] oxime] of erythromycin A (compound 15), tPL78-80oC; MS (C. I.) (M+N)+= 1052;13C-NMR (50 MHz, CDCl3): frequent. /million) 175,47; 171,30; 140,95; 128,61; 128,02; 126,70; 116,87; 102,94; 53,94;

(E)-9-[O-[2-[6-[(4-forfinal)methylamino] hexylamino] ethyl] oxime] of erythromycin A (compound 16), MS (C. I.) (M+N)+= 999,5;13C-NMR (50 MHz, CDCl3): (part./million) 161,88; 136,06; 129,65; 115,14;

(E)-9-[O-[2-[6-[(4-methoxyphenyl)methylamino]hexylamino]ethyl]oxime] of erythromycin A (compound 17), MS (C. I. ) (M+N)+= 1011;13C-NMR (50 MHz, CDCl3): (part./million) 158,57; 132,58; 129,31; 113,76;

(E)-9-[O-[2-[6-[(3,4-methylenedioxyphenyl)methylamino] hexylamino] ethyl] oxime] of erythromycin A (compound 18), MS (C. I.) (M+N)+= 1025;13C-NMR (50 MHz, CDCl3): (part./million) 147,65; 146,44; 134,39; 121,18; 108,66; 108,06;

(E)-9-[O-[2-[6-[(3-triptoreline)methylamino] hexylamino]ethyl]oxime] of erythromycin A (compound 19), MS (C. I.) (M+N)+= 1050;13C-NMR (50 MHz, CDCl+= 1059;13C-NMR (50 MHz, CDCl3): (part./million) 147,23; 138,97; 128,79; 127,49.

Example 13

Obtaining N-benzyloxycarbonyl-6-aminohexanoic

Benzylchloride (50% in toluene; 84,8 ml; 0,256 mol) in ethyl acetate (171 ml) and a solution of 1 n sodium hydroxide (256 ml) gradually and simultaneously added to a mixture of 6-aminohexanoic (25 g; of 0.21 mol) in ethyl acetate (250 ml) and water (200 ml) and stirred at 0oC. the Temperature of the reaction mixture (pH 9) was brought to room temperature and was stirred for 5 hours. After separation of the phases the aqueous phase was washed with ethyl acetate (200 ml). 3 Quiroga combined organic phases were washed with a saturated solution of sodium chloride (150 ml), dried over sodium sulfate and evaporated to dryness. The residue was combined with ethyl ether (300 ml) and the precipitate was filtered and dried under vacuum at 50oC, thus obtaining the N-benzyloxycarbonyl-6-aminohexyl (44,5 g), tPL80-82oC.

Example 14

Obtaining N-benzyloxycarbonyl-6-aminohexyl

A solution of potassium bromide (1.89 g; 16 mmol) in water (31 ml) was added to a solution of N-benzyloxycarbonyl-6-aminohexanoate (40 g; strength of 0.159 mol), obtained according to example 13, in methylene chloride (600 ml) containing a free radical tapeno was added a solution of sodium hypochlorite (215 ml), obtained by mixing 7% sodium hypochlorite solution (240 ml) with sodium bicarbonate (4,22 g) and 5% hydrochloric acid (5 ml), and stirred at 10oC. after the addition was finished, and after phase separation the organic phase is washed with methylene chloride (CH ml), dried over sodium sulfate and evaporated to dryness. In this way received N-benzyloxycarbonyl-6-aminohexyl (39,45 g) as oil. TLC (ethyl acetate: hexane = 1:1) Rf=0,41.

Example 15

Getting 2-[6-(benzyloxycarbonylamino)hexylamino]ethanol

A mixture containing N-benzyloxycarbonyl-6-aminohexyl (35 g; of 0.14 mol) and 2-aminoethanol (51,3 g; 0,84 mol) in ethanol (250 ml) in the presence of molecular sieves (3 ) was stirred at room temperature for 2 hours. 3 Quiroga, the reaction mixture was filtered through celite and the resulting solution was added borohydride sodium (6,33 g; has 0.168 mol). After stirring for 4 hours at room temperature, the reaction solvent is evaporated under vacuum and the residue was combined with water (500 ml) and ethyl acetate (500 ml). After separation of the phases the aqueous phase was additionally extracted with ethyl acetate (200 ml). The combined organic phases were washed with a saturated solution of sodium chloride (250 ml), dried over sulfate nalatac:methanol:ammonia = 10:2:1) Rf=0,4.

Example 16

Getting 2-[N-benzyloxycarbonyl-6-(benzyloxycarbonylamino) hexylamino]ethanol

Analogously to example 9 using 2-[6-(benzyloxycarbonylamino) hexylamino] ethanol (38,3 g; 0,13 mol), obtained according to example 15 was obtained 2-[N-benzyloxycarbonyl-6- (benzyloxycarbonylamino)hexylamino] ethanol in the form of oil. TLC (ethyl acetate:hexane = 65:35) Rf=0.45 in.

Example 17

Getting 2-[N-benzyloxycarbonyl-6-(benzyloxycarbonylamino) hexylamino]ethylmethanesulfonate

Analogously to example 10 using 2-[N-benzyloxycarbonyl-6- (benzyloxycarbonylamino)hexylamino]ethanol (20 g; 47,8 mmole), obtained according to example 16 was obtained 2-[N-benzyloxycarbonyl-6- (benzyloxycarbonylamino)hexylamino] ethylmethanesulfonate (24,35 g) which was used directly in subsequent reactions.

Example 18

Obtaining (E)-9-[O-[2-[N-benzyloxycarbonyl-6-(benzyloxycarbonylamino) hexylamino]ethyl]oxime]of erythromycin A

Analogously to example 11 using 2-[N-benzyloxycarbonyl-6- (benzyloxycarbonylamino)hexylamino] ethylmethanesulfonate (24,25 g; 47,8 mmole), obtained according to example 17, after chromatography on silica gel (eluent methylene chloride: methanol:ammonia = 95: (36,1 g). TLC (methylene chloride:methanol:ammonia = 85:15:1,5) Rf= 0,5;1H-NMR (200 MHz, CDCl3): (part./million) 7,39-7,22 (m, 10H, aromatics); 5,14-of 5.05 (m, 4H, 2); 3,29 (s, 3H, OCH3); to 2.25 (s, 6H, 2NCH2); to 0.80 (t, 3H, ).

Example 19

Obtaining (E)-9-[O-[2-(6-aminobenzoylamino)ethyl]oxime]of erythromycin A

Analogously to example 12 using (E)-9-[O-[2-[N - benzyloxycarbonyl-6-(benzyloxycarbonylamino)hexylamino] ethyl] oxime] of erythromycin A, obtained according to example 18, after chromatography on silica gel (eluent methylene chloride: methanol: ammonia = 85:15:1.5) was obtained (E)-9-[O-[2-(6-aminobenzoylamino)ethyl] oxime] of erythromycin A. TLC (methylene chloride:methanol:ammonia = 85: 15: 1,5) Rf=0,2;13C-NMR (50 MHz, CDCl3): (part./million) 175,18; 171,26; 102,96; 96,28.

Example 20

Obtaining (E)-9-[O-[2-[6-[(2-triptoreline)methylamino] hexylamino] ethyl]oxime] of erythromycin A (compound 21)

To a solution of (E)-9-[O-[2-(6-aminobenzoylamino)ethyl]oxime]of erythromycin A (2 g; 2,24 mmole), obtained according to example 19, in ethanol (50 ml) was added 2-triftormetilfosfinov (0.4 g) and molecular sieves (4.5 g; 3 ) and stirred at room temperature. After 2 hours 30 molecular sieve was filtered and the resulting solution was added 10% palladium on coal (0.2 g). Reaccelerate the catalyst was filtered and the solvent evaporated. The residue was purified by chromatography on silica gel (eluent methylene chloride:methanol:ammonia = 95:5:0.5), and thus obtaining (E)-9-[O-[2-[6-[(2-triptoreline)methylamino] hexylamino]ethyl]oxime]of erythromycin A (2 g). MS (C. I.) (M+N)+1050;13C-NMR (50 MHz, CDCl3): frequent./million) 139,14; 131,88; 130,38; 127,58; 126,81; 125,82.

A similar technique has received the following connections:

(E)-9-[-[2-[6-(3-pyridylmethylamine)hexylamino]ethyl]oxime] of erythromycin A (compound 22), MS (C. I.) (M+N)+= 982;13C-NMR (50 MHz, CDCl3): frequently. /million) 149,66; 148,39; 135,81; 123,40;

(E)-9-[O-[2-[6-[(4-triptoreline)methylamino]hexylamino]ethyl] oxime] of erythromycin A (compound 23), MS (C. I.) (M+N)+= 1050; 13C-NMR (50 MHz, CDCl3): (part./million) 144,73; 128,23; 125,25; 124,26;

(E)-9-[-[2-[6-[(2-hydroxyphenyl)methylamino]hexylamino]ethyl]oxime] of erythromycin A (compound 24), MS (C. I. ) (M+N)+= 997;13C-NMR (50 MHz, CDCl3): (part./million) 158,37; 128,60; 128,19; 122,54; 118,88; 116,32;

(E)-9-[O-[2-[6-[(3-hydroxyphenyl)methylamino] hexylamino] ethyl] oxime] of erythromycin A (compound 25), MS (C. I.) (M+N)+= 997;13C-NMR (50 MHz, CDCl (part./million) 157,28; 140,46; 129,56; 119,70; 115,55; 114,89;

(E)-9-[O-[2-[6-[(4-n-butoxyphenyl)methylamino] hexylamino] ethyl] oxime] of erythromycin A (compound 26), MS (C. I.) (M+N)+] ethyl] oxime] of erythromycin A (compound 27), MS (C. I.) (M+N)+= 1073;13C-NMR (50 MHz, CDCl (part./million) 157,32; 157,28; 142,69; 129,72; 129,64; 123,16; 122,91; 118,84; 118,52; 117,29;

(E)-9-[O-[2-[6-[(4-hydroxyphenyl)methylamino] hexylamino] ethyl] oxime] of erythromycin A (compound 28), MS (C. I.) (M+N)+= 997;13C-NMR (50 MHz, CDCl (part./million) 156,49; 130,00; 128,87; 115,88;

(E)-9-[O-[2-[6-[(4-phenoxyphenyl)methylamino] hexylamino] ethyl] oxime] of erythromycin A (compound 29), MS (C. I.) (M+N)+= 1073;13C-NMR (50 MHz, CDCl (part./million) 157,43; 156,05; 135,43; 129,69; 129,49; 123,07; 118,92; 118,72; 118,67;

(E) -9-[O-[2-[6-[(biphenyl-4-yl)methylamino] hexylamino] ethyl] oxime] of erythromycin A (compound 30), MS (C. I.) (M+N)+= 1057;13C-NMR (50 MHz, CDCl (part./million) 140,94; 139,86; 139,40; 128,74; 128,58; 127,13; 127,03;

(E)-9-[O-[2-[6-(2-pyrimethamine)hexylamino]ethyl]oxime] of erythromycin A (compound 31), MS (C. I.) (M+N)+= 971;13C-NMR (50 MHz, CDCl (part./million) 153,92; 141,73; 110,08; 106,81.

Example 21

Obtaining (E)-9-[O-[2-[6-[(3,5-dichloro-2-hydroxyphenyl)methylamino] hexylamino]ethyl]oxime]of eritromicina A (compound 32)

Molecular sieves (6 g; 3 ) and 3,5-dichloro-2-hydroxybenzaldehyde (0,535 g, 2.8 mmole) was added to a solution of (E)-9-[O-[2-(6-aminobenzoylamino) ethyl] oxime]of erythromycin A (2.5 g; 2.8 mmole), obtained according to example 19, in anhydrous ethanol (100 ml). The reaction mixture was stirred and added borohydride sodium (0,106 g; 2,89 mmole). After stirring for 3 hours the solvent is evaporated under reduced pressure and the residue was purified by chromatography on silica gel (eluent methylene chloride: methanol: ammonia = 85:15:1,5), thus obtaining (E)-9-[-[2-[6-[(3,5-dichloro-2-hydroxyphenyl)methylamino]hexylamino]ethyl] oxime]of erythromycin A (2.2 g). MS (C. I.) (M+N)+= 1066;13C-NMR (50 MHz, CDCl frequent./million) 153,43; 128,43; 126,42; 124,41; 122,91; 121,61.

A similar technique has received the following connections:

(E)-9-[-[2-[6-[(2-nitrophenyl)methylamino]hexylamino]ethyl]oxime] of erythromycin A (compound 33), MS (C. I.) (M+N)+= 1027;13C-NMR (50 MHz, CDCl (part./million) 149,14; 135,79; 133,13; 131,26; 127,87; 124,70;

(E)-9-[O-[2-[6-[(3-nitrophenyl)methylamino]hexylamino]ethyl]oxime] of erythromycin A (compound 34), MS (C. I.) (M+N)+= 1027;13C-NMR (50 MHz, CDCl (part./million) 148,37; 142,87; 134,17; 129,22; 122,81; 121,96;

(E)-9-[O-[2-[6-[(4-nitrophenyl)methylamino]hexylamino]ethyl]oxime] of erythromycin A (compound 35), MS (C. I.) (M+N)+= 1027;13C-NMR (50 MHz, CDCl (part./million) 148,41; 147,00; 128,59; 123,60;

(E)-9-[O-[2-[6-[(4-hydroxy-3-nitrophenyl)methylamino] hexylamino] ethyl] oxime] of erythromycin A (compound 36), MS (C. I.) (M+N)+= 1043;13C-NMR (50 MHz, CDCl (part./million) 157,29; 137,40; 134,05; 128,01; 125,23; 121,70;

(E)-9-[O-[2-[6-[(3-hydroxy-4-nitrophenyl)DCl (part./million) 155,50; 151,98; 132,51; 125,13; 119,67; 118,59.

Example 22 to Obtain (E)-9-[O-[2-[N-methyl-6-(N'-methyl-N'-phenylethylamine)hexylamino] ethyl]oxime]of erythromycin A (compound 38)

Aqueous 37% formaldehyde solution (2 ml; to 26.6 mmole) and 10% palladium on coal (0,82 g) were added in sequence to a solution of (E)-9-[O-[2-[6-(phenylethylamine)hexylamino]ethyl]oxime]of erythromycin A (2 g; 2 mmole), obtained according to example 12, in a mixture of ethanol:water = 1:1 (20 ml) and stirred at room temperature. The reaction mixture was placed in hydrogenator Parra, loaded with hydrogen (1 bar). After 2 hours the reaction mixture was filtered to remove the catalyst and the resulting solution was evaporated to dryness. The resulting residue was purified by chromatography on silica gel (eluent methylene chloride:methanol:ammonia = 90:10:1) to give (E)-9-[O-[2-[N-methyl-6-(N'-methyl-N'-phenylethylamine)hexylamino] ethyl] oxime] of erythromycin A (1.8 g). MS (C. I.) (M+N)+= 1009; 13C-NMR (50 MHz, CDCl3(part./million) 139,20; 129,04; 128,17; 126,86.

A similar technique has received the following connection:

(E)-9-[O-[2-[N-methyl-6-[N'-methyl-N'-(4-triptoreline)methylamino] hexylamino] ethyl] oxime] of erythromycin A (compound 39), MC (C. I.) (M+N)+= 1078;13C-NMR (50 MHz, CDCl3): (part.) - Rev. I activity in vitro

Determination of the minimum inhibiting concentrations (MIC) against gram-positive and gram-negative bacteria was carried out by microbiological method serial twofold gradual dilution liquid environment [National Committee for Clinical Laboratory Standards, 1990; Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; Approved standard M7-A2, NCCLS, Villanova, Pa] by using as a medium for the cultivation broth Mueller-Hinton (EOM). In the case of "demanding" bacteria (Streptococcus pneumoniae and Streptococcus pyogenes) in medium was added 5% horse serum. As reference compounds from the class of macrolides used roxithromycin and clarithromycin [The Merck Index, XI ed., N 8253 and N 2340, respectively].

MICK, expressed in (mg/ml) was determined after incubation of the microplate at 37oC for 18 hours, when evaluating the lowest concentration of antibiotic that has the ability to inhibit the growth of bacteria.

b) Antibacterial activity in vivo

Therapeutic effectiveness, expressed as the average protects dose (PD50) of the studied compounds of formula (I), evaluated at the sample induced by experimental infection of the lungs, called the mouse Streptococcus pyogenes C 203. Used mice-Albany food and water at will. A suspension of S. pyogenes C 203 (corresponding to approximately 108UFC) in tryptose broth (0.05 ml) was administered intranasally each mouse shot with a mixture of ethyl ether and chloroform. The investigated compounds were administered intraperitoneally as a single dose in 0.2% suspension of Twin 24 hours before or 1 hour after infection. The observation of the death of the mice was carried out over a period of time up to 10 days after infection.

Definition PD50expressed as (mg/kg), was performed by the method of probit analysis.

Data on antibacterial activity in vitro against gram-positive microorganisms (table 1) and gram-negative microorganisms (table 2) and antibacterial activity in in vivo studies (table 3) some characteristic compounds of formula (I) below.

Are given in table. 1, the data clearly indicate that the compounds of formula (I), which is the subject of the present invention possess antibacterial activity against gram-positive microorganisms, almost comparable to that of roxithromycin and clarithromycin.

Antibacterial activity of the compounds of formula (I) in relation to gramotritsatelnyh connections.

The compounds of formula (I) has been active in experiments in vivo, and their activity profiles indicate that these compounds have a significantly higher duration of action and half-life with the elimination of tissue than any of the compounds of the standards.

1. 9-O-Joksimovi derivatives of erythromycin And General formula I

< / BR>
where a denotes a phenyl group optionally substituted by 1 to 3 identical or different groups selected from straight or branched (C1-C4)alkoxygroup, (C1-C2)alkylenedioxy, (C1-C4)alkylsulfonyl groups, phenyl, phenoxy-, hydroxy-, nitro, halogen and triptorelin group, or pyridyl, or furyl;

R1and R2the same or different, is a hydrogen atom or a straight or branched (C1-C4)alkyl group;

n = 1 or 2;

m = 1 - 8, integer;

r = 2 - 6 integer;

M is a group of the formula

< / BR>
where R3is a hydrogen atom,

and their pharmaceutically acceptable salts.

2. Connection under item 1, with the E-configuration.

3. Connection on p. 1, where a is pyridyl, furyl or phenyl group, optionally substituted by 1 to 3 groups, fibrinogen and triptorelin group; R1and R2the same or different, is a hydrogen atom or a methyl group.

4. Connection on p. 1, where a denotes a phenyl group optionally substituted by a group selected from phenoxy, nitro and trifloromethyl; R1and R2the same and represent a hydrogen atom or methyl group; n = 1; m = 6; r = 2;

5. Pharmaceutical composition having antibiotic activity and containing a therapeutically effective amount of a derivative of erythromycin And in a mixture with a pharmaceutically acceptable carrier, characterized in that as a derivative of erythromycin A. it contains a 9-O-akimovoi derivative of erythromycin And General formula I on p. 1.

 

Same patents:
The invention relates to a method for producing a drug that belongs to the macrolide group of antibiotics designed to treat a number of infectious diseases in animals

The invention relates to new derivatives of erythromycin, method of production thereof, to pharmaceutical compositions based on them and to intermediate compounds

The invention relates to new derivatives of erythromycin General formula I, where Z, R1, R2specified in paragraph 1 of the claims
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The invention relates to new compounds of the class of cetomacrogol and semisolids, potential intermediates in obtaining new macrolide and asamenew antibiotics, as well as the way they are received and intermediate compounds for their production

The invention relates to new derivatives of erythromycin formula Iwhere Z, X and Y are hydrogen; R is lower alkyl substituted by phenyl, which in turn may be substituted by one or more radicals selected from the group consisting of halogen, lower alkyl, hydroxyl, trifloromethyl, lower alkoxy, phenyl, phenoxy, with the possibility of substitution of the latter by one or more halogen; lower alkyl, substituted hydroxy, amino, halogen, phenoxy, cyclohexyl, (C8-C12)-alkylamino or triphenyl(lower)alkoxygroup; unsubstituted WITH8-C12alkyl, 3, 7, 11-trimethyl-2, 6, 10 - dodecadienal radical or (C3-6)-alkenyl, substituted phenyl, biphenyl or phenoxyphenyl; in all possible stereoisomeric forms

The invention relates to new derivatives of erythromycin, method of production thereof, to pharmaceutical compositions based on them and to intermediate compounds
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FIELD: medicine, pulmonology.

SUBSTANCE: one should apply lycopid to study initial level of mature T-cells (CD3+) in % and solve following discriminant equation: D = 0.840 · (CD3+), and at D value being above 29.24 one should predict positive curative effect as a result of lycopid application, and at D value being below 29.24 on should predict no positive curative effect.

EFFECT: higher efficiency of lycopid-including therapy.

2 ex

FIELD: chemical engineering; pharmaceutical engineering.

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4 cl, 25 dwg

FIELD: pharmaceutical industry.

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EFFECT: reduced treatment time, lowered recurrence of diseases, lack of adverse effects, and lowered cost.

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SUBSTANCE: invention relates to an antibacterial preparation azithromycin. The stable pharmaceutical suspension of azithromycin comprises the therapeutically effective dose of azithromycin and special additives - sorbitol, sodium benzoate, aromatic principles, glycerol, glutamic acid, methylcellulose, polyvinylpyrrolidone and propylene glycol. Also, invention proposes a method for preparing the stable suspension of azithromycin that involves addition of mixture of azithromycin with glutamic acid as solution in glycerol or as dry form to an aqueous solution of methylcellulose containing propylene glycol and glycerol or propylene glycol and successively dissolved sodium benzoate, polyvinylpyrolidone and sorbitol followed by dilution with water up to the azithromycin concentration that is necessary for using. Invention provides creature of new stable suspension that is resistant for 1 year, not less, and useful for treatment of children being among them suffering with diabetes mellitus.

EFFECT: improved method for preparing, valuable medicinal properties of suspension.

4 cl, 4 tbl, 1 dwg, 4 ex

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EFFECT: improved method for preparing, valuable medicinal properties of compounds and composition.

19 cl, 3 tbl, 12 ex

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wherein R1 means one of radicals:

or ; R2 means -CH(CH3)-CH3, -CH(CH3)-C2H5, -C(CH3)=CH-CH(CH3)2 or cyclohexyl; R3 means hydrogen atom or hydroxy-group if a bond between atoms 22 and 23 represents a double bond, or it means hydrogen atom or group =N-O-CH3 if an ordinary bond presents between atoms 22 and 23; R4 means HO-, and the preparation can be in free form or in physiologically acceptable form. Invention provides preparing preparations with good tolerance and rapid effect and persistence with respect to different helminth-associated diseases, parasitiformous and acariformous mites being without adverse effect on normal behavior of animals.

EFFECT: valuable properties of compounds.

7 cl, 3 tbl, 8 ex

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EFFECT: improved treatment method, enhanced effectiveness of agent and treatment.

2 cl, 1 ex

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EFFECT: higher efficiency of therapy and prophylaxis.

2 cl, 4 ex, 4 tbl

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EFFECT: higher efficiency of therapy.

2 ex, 2 tbl

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