9a-n-[n'-(phenylsulfonyl)carbamoyl]-derivatives of 9-deoxo-9-dihydro-9a-aza-9a-homoerythromycin a and 5-desosaminyl-9-deoxo-9-dihydro-9a-aza-9a-homoerythronolide a, method for their preparing and pharmaceutical composition based on thereof

FIELD: organic chemistry, antibiotics, pharmacy.

SUBSTANCE: invention relates to 9a-N-[N'-(phenylsulfonyl)carbamoyl]-derivatives of 9-deoxo-9-dihydro-9a-aza-9a-homoerythromycin A and 5-O-desosaminyl-9-deoxo-9-dihydro-9a-aza-9a-homoerythronolide A that are new semisynthetic macrolide antibiotics relating to class of azalides showing antibacterial effect and describing by the general formula (1):

wherein R1 means hydrogen atom (H), (C1-C4)-alkyl or halogen atom; R means H or cladinosyl radical, and to their pharmaceutically acceptable salts. Also, invention relates to a method for their preparing and a pharmaceutical composition based on thereof.

EFFECT: improved preparing method, valuable medicinal properties of derivatives.

16 cl, 2 tbl, 14 ex

 

The invention relates to 9a-N-[N'-(phenylsulfonyl)carbarnoyl]derivatives of 9-desoxo-9-dihydro-9a-Aza-9a-homoerythromycin a and 5-O-desosamine-9 desoxo-9-dihydro-9a-Aza-9a-homoerythromycin And new semi-synthetic macrolide antibiotic belonging to the class of azalides with antibacterial action described by the General formula 1,

where R denotes H or ladiesjenny radical and R1denotes H, C1-C4alkyl or halogen, to their pharmaceutically acceptable salts accession inorganic or organic acids, to the way they are received, to a method for producing pharmaceutical compositions, as well as the application of pharmaceutical compositions for the treatment of bacterial infections.

Erythromycin a is a macrolide antibiotic whose structure is characterized by the presence of 14-membered macrolactones ring with the carbonyl group in position C-9.

He was investigated McGuire in 1952 [Antibiot. Chemother.,2(1952) 281], and for more than 40 years he was considered safe and active antimicrobial agent in the treatment of diseases caused by gram-positive and some gram-negative microorganisms. However, in the acidic environment it is easily converted to anhydroerythromycin And inactive C-6/C-12 metabolite with spirochaetales structure [P. Kurath et al.,Experientia 27(1971) 362]. It is known that spiritlessly aliceooa rings erythromycin And successfully inhibits the chemical transformation of the C-9 ketone or hydroxyl groups at positions C-6 and/or C-12. In the result of oxymorphine C-9 ketone [S.et al., Tetrahedron Lett.,1967: 1945] and subsequent modification received 9(E)-oxime with a 9-[O-(2-methoxyethoxy)methyloxime]erythromycin a (ROXITHROMYCIN) [G. S. Ambrieres, FR patent 2,473,525, 1981], or 9(S)-erythromycylamine [R. S. Egan et al., J. Org. Chem.,39(1974) 2492]. or is it more complicated oxazinones derived 9 desoxo-11-{imino[2-(2-methoxyethoxide)oxy]9,8S}erythromycin a (DIRITHROMYCIN) [P. Lugar et al., J. Crist. Mol. Struct.,9(1979) 329] have synthesized new semi-synthetic macrolides, the main characteristics of which in addition to higher resistance in acid environments provide a better pharmacokinetic and long biological half-time of existence compared to the original antibiotic erythromycin A. the third way of modifying the C-9 ketone is used Beckmann rearrangement 9(E)-oximo and restoring the received simple aminoether [G. Kobrehel et al., US patent 4,328,334, 1982] 11-Aza-10-desoxo-10-dihydroartemisinin And (9 desoxo-9-dihydro-9a-Aza-9a-homoerythromycin A) by increasing the 14-membered katolickiego ring with getting 15-membered Galaktionova rings. In the reductive N-methylation 9a-amino group in accordance with the method of the Eschweiler-Clarke (Eschweiler-Clark) [G.Kobrehel et al., BE patent 892,397, 1982] or the preliminary protection of the amino group by conversion to the corresponding N-oxides and subsequent alkylation and recovery [G.M.Bright, US patent 4,474,768, 1984] was synthesized N-methyl-11-Aza-10-desoxo-10-dihydroartemisinin And (9 desoxo-9-dihydro-9a-methyl-9a-Aza-9a-homoerythromycin AND AZITHROMYCIN) is a prototype azalide antibiotics, which in addition to having broad spectrum antimicrobial activity, including gram-negative bacteria and intracellular microorganisms are also different and specific mechanism of transport to the place of application, long biological half-time of existence and quick treatment times. In the patent EP 0316128 (G.M.Bright) describes the new 9a-allyl and 9a-propargyl derivative 9 desoxo-9-dihydro-9a-Aza-9a-homoerythromycin And, in patent US 4492688 (1985, G.M.Bright) described the synthesis and antibacterial activity of cyclic ethers. Then G.Kobrehel et al., J.Antibiot., 46 (1993) 1239-1245 described the synthesis and action spectrum of new 9a,11-cyclic carbamates 9 desoxo-9-dihydro-9a-Aza-11-deoxy-9a-homoerythromycin and their O-methyl derivatives.

By reacting 9-desoxo-9-dihydro-9a-Aza-9a-homoerythromycin And from ISOC what Anat or isothioscyanates respectively G.Kobrehel,HR patent 931480, 1993) were obtained 9a-N-(N'-carbamoyl) and 9a-N-(N'-thiocarbamoyl) derivatives of 9-desoxo-9-dihydro-9a-Aza-9a-homoerythromycin And with some antibacterial activity.

It was discovered, and this constitutes the subject-matter of the present invention, that the compounds described by General formula 1, new semi-synthetic macrolide antibiotic belonging to the class of azalides, and their pharmaceutically acceptable salts accession inorganic or organic acids can be obtained by reacting 9-desoxo-9a-Aza-9a-homoerythromycin or 5-O-desosamine-9 desoxo-9-dihydro-9a-Aza-9a-homoerythromycin And described General formula 2, with phenylsulfonylacetate, and, if necessary, by interacting obtained 9a-N-[N'-(phenylsulfonyl)carbarnoyl]derivatives of 9-desoxo-9-dihydro-9a-Aza-9a-homoerythromycin a and 5-O-desosamine-9 desoxo-9-dihydro-9a-Aza-9a-homoerythromycin And with inorganic or organic acids.

In accordance with known and established prior art 9a-N-[N'-(phenylsulfonyl)carbarnoyl]derivatives of 9-desoxo-9-dihydro-9a-Aza-9a-homoerythromycin a and 5-O-desosamine-9 desoxo-9-dihydro-9a-Aza-9a-homoerythromycin and their pharmaceutically acceptable salts of addition of inorganic or organic acids, the method and the receipt and methods of preparation and use as pharmaceutical compositions hitherto described were not.

It was found that the new 9a-N-[N'-(phenylsulfonyl)carbarnoyl]derivatives of 9-desoxo-9-dihydro-9a-Aza-9a-homoerythromycin a and 5-O-desosamine-9 desoxo-9-dihydro-9a-Aza-9a-homoerythromycin And described General formula1,

where R and R1have the above meanings, and their pharmaceutically acceptable salts of addition of inorganic or organic acids can be obtained by reacting 9-desoxo-9-dihydro-9a-Aza-9a-homoerythromycin or 5-O-desosamine-9 desoxo-9-dihydro-9a-Aza-9a-homoerythromycin And described General formula2where R represents H or ladiesjenny radical

with phenylsulfonylacetate described General formula3,

where R1has the above values, in toluene, xylene or some other aprotic solvent at a temperature in the range from 0 to 110°during the time required for complete conversion of the parent compound2, preferably in the range from 0.5 to 10 hours.

Pharmaceutically acceptable salts of addition, which are also the object of the present invention, is produced by the interaction of 9a-N-[N'-(phenylsulfonyl)carbarnoyl]derivatives of 9-desoxo-9-dihydro-9a-Aza-9a-homoerythromycin a and 5-O-des is seminal-9 desoxo-9-dihydro-9a-Aza-9a-homoerythromycin And, the described General formula2at least with equimolar amounts of the corresponding inorganic or organic acid, such as hydrochloric, uudistoodetena, sulfuric, phosphoric, acetic, triperoxonane, propionic, benzoic, benzolsulfonat, methansulfonate, laurylsulfate, stearic, palmitic, amber, Atlanterra, lactic, oxalic acid, salicylic acid and similar acid, in an inert solvent. Salt additions allocate by evaporation of the solvent or, alternatively, by filtering after spontaneous deposition, or by deposition of adding a non-polar co-solvent.

To 9a-N-[N'-(phenylsulfonyl)carbarnoyl]derivatives of 9-desoxo-9-dihydro-9a-Aza-9a-homoerythromycin a and 5-O - desosamine-9 desoxo-9-dihydro-9a-Aza-9a-homoerythromycin And described General formula 1 and their pharmaceutically acceptable salts of addition of inorganic or organic acids possess in vitro antibacterial activity. The minimum inhibiting concentration (MIC, μg/ml) was determined by the method of dilution on the microplate in accordance with the recommendations of the National Committee for Clinical Laboratory Standards (NCCLS, M7-A2). So, for example, the minimum inhibitory concentration in the case of Streptococcus pneumoniae ATCC 6305 for compounds of examples 1 and 4 is equal to 2 μg/ml, and for the compounds of examples 2 and 3 is equal to 1 is kg/ml Therefore, they can be used for disinfection, surgical instruments and people, as well as drugs in the treatment of infectious diseases in animals, particularly in mammals, or humans that are caused by a wide range of gram-positive bacteria, microorganisms or mainly pathogenic microorganisms, which have sensitivity to compounds described by formula 1.

Thus, the present invention relates to pharmaceutical compositions containing at least one compound of General formula 1 or its pharmaceutically acceptable salt of the added acid, organic or inorganic, as well as pharmaceutically acceptable carriers such as excipients or diluents. For this purpose the above compounds or their pharmaceutically acceptable salts of the acids can be used in normal oral doses in the range from 0.2 mg/kg of body weight per day to about 250 mg/kg/day, most often 5-50 mg/kg/day, or parenterally in the form of a subcutaneous or intramuscular injection. The media can be "acceptable" in light of its compatibility with other components of the drug and do not have undesirable effects on the recipient.

Obtaining pharmaceutical compositions according to the invention may include mixing, regulirovanie, tableting or dissolution of the components. Chemical media can be in solid or liquid form. Solid carriers can be lactose, sucrose, talc, gelatin, agar, pectin, magnesium stearate, fatty acids, without restrictions. Liquid carriers can be syrups, oils, such as olive, sunflower or soybean, water or saline solution, without restrictions. In addition, the media may also contain a component for slow release of the active component, such as glyceryl the monostearate or glyceryl distearate. Can be obtained from various forms of pharmaceutical compositions. If you are using solid media, such forms include tablets, pills in the form of capsules, hard gelatin capsules, powders or granules, without limitation, which can be administered orally. The amount of solid carrier may vary, but typically ranges from 25 mg to 1 g If you use a carrier liquid, the drug may be in the form of a syrup, emulsion, soft gelatin capsule or sterile solution for injection or non-aqueous liquid suspensions injected locally or systemically, such as orally, parenterally, subcutaneously, mucosa, buccal, intranasal, intrarectal and intrawaginalno. "Parenteral" means intravenous, intramuscular or subcutaneous route of administration.

The phrase is pharmaceutically acceptable", as used here in relation to the compositions according to the invention, refers to molecular structures and other elements such compositions that are physiologically satisfactory and usually do not give negative reactions when introducing a mammal (e.g. human). In particular, as used here, the term "pharmaceutically acceptable" means a substance for use in mammals, and more specifically, to the people that are allowed by the regulatory Agency of the Federal or a state government or listed in the U.S. Pharmacopoeia or other generally known pharmacopoeias.

The term "pharmaceutically acceptable"as used in the pharmaceutical compositions according to the invention refers to a diluent, excipient, or solvent, which is introduced active connection. Such pharmaceutical carriers can be sterile liquids, such as water, saline solutions, aqueous dextrose, aqueous solutions of glycerin and oils, including those derived from oil, or have an organic, vegetable or synthetic nature, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. However, because macrolides are vysokochastotnymi, aqueous solutions are preferred. Fit farmacevticheskie media described E.W.Martin in "Remington''s Pharmaceutical Sciences", 18thEdition. Particularly preferred in accordance with the present invention are media that are appropriate for immediate release, i.e. the release of the majority of all the active ingredients within a short period of time, such as 60 minutes or less, and allow rapid absorption of the drug.

"Therapeutically effective amount" refers to an amount of compound that, when administered to a mammal for treatment of a condition, illness or condition, is sufficient for the implementation of such treatment.

The method of obtaining the compounds according to the present invention is further illustrated in the following examples, which in no way limit the scope of the invention. "Therapeutically effective amount" will depend on the structure of the compound, the disease severity and the age, weight, physical condition and responsiveness of the mammal being treated.

Example 1

9 Desoxo-9-dihydro-9a-N-[N'-(4-chlorobenzenesulfonyl)carbarnoyl]-9a-Aza-9a-homoerythromycin And

9 Desoxo-9-dihydro-9a-utahamerican And (3,38 g, 0,0046 mol) was dissolved in toluene (40 ml) and at a temperature of from 0 to 5°added 4-chlorobenzalmalononitrile (about 1.0 g, 0,0046 mol). After stirring the reaction mixture for one hour at the same temperature is ur the resulting crystals of the crude product was sucked out. Isolation of pure 9-desoxo-9-dihydro-9a-N-[N'-(4-chlorobenzenesulfonyl)carbarnoyl]-9a-Aza-9a-homoerythromycin And carried out by chromatography on a column of silica gel in the solvent system methylene chloride: methanol:ammonia = 90:9:1.5 to

IR (KBr)/cm-1: 1728, 1579, 1556, 1126, 1013.

1H NMR (500 MHz, DMSO)/δ: to 4.46 (1H, H-1'), 4,91 (1H, H-1"), 3,93 (1H, H-3), OF 3.46 (1H, H-5), TO 3.34 (3H, 3"-och3), only 2.91 (1H, H-4"), 2,50 (6N, 3'-N' (CH3)2), and 2.26 (1H, H-2"b), of 1.52 (1H, H-2"a), 1.27mm (1H, H-8), of 1.23 (3H, 10-CH3), to 1.14 (3H, 3"-CH3), is 0.96 (3H, 4-CH3), OF 0.82 (3H, H-5).

13With NMR (500 MHz, DMSO/δ): 177,1 (s-1), 154, 6mmof 101.4 (C-1'), The 95.8 (C-1"), to 82.6 (C-5), for 77.2 (C-3), 48,7 (3"-och3), a 44.7 (C-2), Of 25.7 (C-8), 20,9 (8-CH3), and 12.2 (10-CH3)and 10.7 (C-15).

MC (ES+) m/z (%): 952,5.

Example 2

9 Desoxo-9-dihydro-9a-N-[N'-(p-toluensulfonyl)carbarnoyl]-9a-Aza-9a-homoerythromycin And

Similar to the method described in example 1, 9-desoxo-9-dihydro-9a-utahamerican And (3.88 g, 0,0051 mol) was dissolved in toluene (40 ml) and at a temperature of from 0 to 5°C was added dropwise n-toluensulfonate (1.04 g, 0,0053 mol). After stirring the reaction mixture for one hour at the same temperature, the resulting crystals of the crude product was sucked out. Isolation of pure 9-desoxo-9-dihydro-9a-N-[N'-(4-chlorobenzenesulfonyl)carbarnoyl]-9a-Aza-9a-homoerythromycin And carried out by chromatography on a column of silicagel in the solvent system methylene chloride:methanol = 1:1.

IR (KBr)/cm-1: 1731, 1644, 1556, 1126, 1013.

1H NMR (500 MHz, pyridine)/δ: by 8.22, 8,15, 7,18 (phenyl), 5,70of 5.40 (1H, H-13), lower than the 5.37 (1H, H-1"), free 5.01 (1H, H-1'), to 4.81 (1H, H-3), of 4.54 (1H, H-5"), 4,11 (1H, H-5), a 4.03 (1H, H-5'), to 3.67 (1H, H-2'), 3,47 (1H, 3"-och3), of 3.32 (1H, H-10), 3,24 (1H, H-4"), of 3.13 (1H, H-2), 2,42 (1H, 3'-N(CH3)2), to 2.18 (3H, R-CH3), a 1.96 (1H, 7a), at 1.91 (1H, H-8), is 1.82 (1H, H-7b)and 1.51 (3H, 4-CH3), of 1.52 (1H, 5"-CH3), OF 0.93 (3H, H-15).

13With NMR (500 MHz, pyridine/δ): 179,0 (C-1), 142,7to 130.1, 127,9, 126,9 (phenyl), to 103.8 (C-1'), the 95.8 (C-1'), 84,7 (C-5), 79,2 (C-4"), 79,0 (C-3), 78,0 (C-13), 75,4 (C-6), at 73.7 (C-12), to 72.6 (C-11), and 71.4 (C-2')and 68.4 (C-5'), with 66.5 (C-5"), 58,3 (C-10), 50,0 (3"-och3), a 46.5 (C-2), 43,7 (C-7), While 27.8 (C-8), and 19.3 (5"-CH3), 15,7 (2-CH3), and 14.3 (12-CH3), and 11.8 (C-15), 10,3 (4-CH3).

MC (EI+) m/z (%): 932,5.

Example 3

9 Desoxo-9-dihydro-9a-N-[N'-(o-toluensulfonyl)carbarnoyl]-9a-Aza-9a-homoerythromycin And

Similar to the method described in example 1, 9-desoxo-9-dihydro-9a-utahamerican And (of 3.73 g, 0,0051 mol) was dissolved in toluene (40 ml) and at a temperature of from 0 to 5°was added dropwise o-toluensulfonate (1.0 g, 0,0051 mol). After stirring the reaction mixture for one hour at the same temperature, the resulting crystals of the crude product was sucked out. Isolation of pure 9-desoxo-9-dihydro-9a-N-[N'-(o-toluensulfonyl)carbarnoyl]-9a-Aza-9a-homoerythromycin And carried out by chromatography on a column of forces is by Kagel in the solvent system methylene chloride:methanol:ammonia = 90:9:1,5.

IR (KBr)/cm-1: 1727, 1633, 1556, 1126, 1013.

1H NMR (500 MHz, DMSO)/δ: to 7.77, 7,25, 7,14 (phenyl), of 4.90 (1H, H-1'), IS 4.85 (1H, H-13), OF 4.44 (1H, H-1'), TO 4.01 (1H, H-5"), 3,47 (1H, H-5), 3,47 (1H, H-5), OF 3.69 (1H, H-5'), OF 3.25 (3H, 3"-och3), to 3.00 (1H, H-2'), ONLY 2.91 (1H, H-4"), IS 2.37 (3H, 3'-N(CH3)2), and 2.27 (1H, H-2"), of 1.95 (1H, H-4), OF 1.52 (1H, H-2"b), 1,25 (1H, H-8), of 1.17 (3H, 5"-CH3), of 1.09 (3H, 5'-CH3), is 0.96 (3H, 4-CH3), OF 0.82 (3H, H-15).

13With NMR (500 MHz, DMSO/δ): 178,0 (s-1), 102,7 (C-1'), Is 95.2 (C-1"), Or 83.2 (C-5), Of 78.2 (C-4"), 78,0 (C-3), To 75.8 (C-13), For 74.4 (C-6), At 73.7 (C-12), 73,5 (C-3"), 71,0 (C-2'), Is 67.7 (C-5'), 65,8 (C-5"), 65,5 (-3'), 51,6 (3"-och3), of 45.7 (C-2), Or 42.8 (C-4), 40,1 (3'-N(CH3)2), of 35.4 (C-2"), Of 30.9 (C-4'), and 25.8 (C-8), and 18.3 (5"-CH3)and 15.6 (12-CH3), 11,9 (C-15), 10,0 (4-CH3).

MC (EI+) m/z (%): 932,8.

Example 4

9 Desoxo-9-dihydro-9a-N-[N'-(benzazolyl)carbarnoyl]-9a-Aza-9a-homoerythromycin And

Similar to the method described in example 1, 9-desoxo-9-dihydro-9a-utahamerican And (4,01 g, 0,0055 mol) was dissolved in toluene (40 ml) and at a temperature of from 0 to 5°was added dropwise benzosulfonazole (1.0 g, 0,0055 mol). After stirring the reaction mixture for one hour at the same temperature, the resulting crystals of the crude product was sucked out. Isolation of pure 9-desoxo-9-dihydro-9a-N-[N'-(benzazolyl)carbarnoyl]-9a-Aza-9a-homoerythromycin And carried out by chromatography on a column of silica gel in the solvent system methylene chloride:methanol:and the MIAK = 90:9:1,5.

IR (KBr)/cm-1: 1719, 1638, 1551, 1126, 1011.

1H NMR (500 MHz, DMSO)/δ: 7,84, 7,71, 7,54, 7,36 (phenyl), of 4.77 (1H, H-1"), OF 4.44 (1H, H-1'), TO 4.01 (1H, H-5"), 3,21 (3H, 3"-och3), 2,90 (1H, H-4"), 2,49 (3H, 3'N(CH3)2), and 2.26 (1H, H-2"a)to 1.76 (1H, H-14a)and 1.51 (1H, H-2"b), 1,32 (1H, H-14b), of 1.16 (3H, 5"-CH3), TO 0.78 (3H, H-15).

13With NMR (500 MHz, DMSO/δ): 159,0 (9a-N-CO-NH), 128,8, 127,7, 126,3 (phenyl), 77,4 (C-4"), Against 72.7 (C-3"), 65,0 (-5"), 49,0 (3"-och3), 39,4 (3'-N(CH3)2), and 35.1 (C-2"), 18,7 (5"-CH3)and 11.1 (C-15), and 9.5 (4-CH3).

MC (ES+) m/z (%): 918,8.

Example 5

9 Desoxo-9-dihydro-9a-N-[N'-(2-chlorobenzenesulfonyl)carbarnoyl]-9a-AAA-9a-homoerythromycin And

Similar to the method described in example 1, 9-desoxo-9-dihydro-9a-utahamerican And (3,38 g, 0,0046 mol) was dissolved in toluene (40 ml) and at a temperature of from 0 to 5°was added dropwise 2-chlorobenzalmalononitrile (1.0 g, 0,0046 mol). After stirring the reaction mixture for one hour at the same temperature, the resulting crystals of the crude product was sucked out. Isolation of pure 9-desoxo-9-dihydro-9a-N-[N'-(2-chlorobenzenesulfonyl)carbarnoyl]-9a-Aza-9a-homoerythromycin And carried out by chromatography on a column of silica gel, first in the solvent system methylene chloride:methanol = 7:3, and then in the solvent system methylene chloride:methanol:ammonia = 90:9:1,5.

IR (KBr)/cm-1: 1728, 1579, 1126, 1012.

1H NMR (500 MHz, DMSO)/δ: 7,71 (phenyl), 5,08 1H, H-13), 4,80 (1H, H-1"), OF 4.49 (1H, H-1'), IS 4.15 (1H, H-3'), A 4.03 (1H, H-5"), OF 3.43 (1H, H-5), UP 3.22 (3H, 3"-och3), only 2.91 (1H, H-4"), WAS 2.76 (1H, H-2), OF 2.50 (3H, 3'-N(CH3)2), 2,39 (1H, H-2"a)to 1.14 (3H, 3"-CH3), to 0.88 (3H, H-15)TO 0.85 (3H, 12-CH3).

13With NMR (500 MHz, DMSO/δ): 102,0 (C-1'), 97,0 (C-1"), 85,6, (C-5), Was 78.5 (C-4"), To 68.0 (C-3'), 65,8 (C-5"), 45,2 (C-2), 40,5 (3'-N(CH3)2), 45,9 (3"-och3), 35,6 (-2"), 21,2 (3"-CH3), 18,7 (5"-CH3), and 14.3 (12-CH3), and 10.8 (C-15).

MC (EI+) m/z (%): 952,9.

Example 6

9 Desoxo-9-dihydro-9a-N-[N'-(4-permentantly)carbarnoyl]-9a-Aza-9a-homoerythromycin And

Similar to the method described in example 1, 9-desoxo-9-dihydro-9a-utahamerican And (1,46 g, 0.002 mol) was dissolved in toluene (20 ml) and at a temperature of from 0 to 5°C was added dropwise a suspension of 4-forbindelsesfanebladet (0.4 g, 0.002 mol) in toluene. After stirring the reaction mixture for one hour at the same temperature, the resulting crystals of the crude product was sucked out. Isolation of pure 9-desoxo-9-dihydro-9a-N-[N'-(4-permentantly)carbarnoyl]-9a-Aza-9a-homoerythromycin And carried out by chromatography on a column of silica gel in the solvent system methylene chloride:methanol = 7:3.

IR (KBr)/cm-1: 1727, 1638, 1593, 1552, 1126, 1013.

1H NMR (500 MHz, DMSO)/δ: 7,74, 7,71, 7,16 (phenyl), 4,78 (1H, H-1"), OF 4.45 (1H, H-1'), TO 4.01 (1H, H-5"), 3,21 (3H, 3"-och3), only 2.91 (1H, H-4"), OF 2.51 (3H, 3'-N(CH3)2), 2,27 1H, H-2"), of 1.52 (1H, H-2"b), of 1.17 (3H, 5"-CH3), to 1.14 (3H, 3"-CH3), were 0.94 (3H, H-15), 0,81 (3H, 4-CH3).

13With NMR (500 MHz, DMSO/δ): 177,2 (C-1), 160,6 (9a-NCO), to 101.1 (C-1'), the 95.8 (C-1'), 84,1 (C-5), for 77.2 (C-4"), accounting for 72.2 (C-3"), 64,8 (-5"), 39,9 (3'-N(CH3)2), 49,1 (3"-och3), 44,3 (C-2), To 34.8 (C-2"), and 29.9 (C-4'), 22,9 (5'-CH3), and 18.5 (5"-CH3), 10,0 (C-15), and 9.5 (4-CH3).

MC (ES+) m/z (%): 936,3.

Example 7

5-O-Desosamine-9 desoxo-9-dihydro-9a-N-[N'-(p-toluensulfonyl)carbarnoyl]-9a-AAA-9a-homoerythromycin And

5-O-Desosamine-9 desoxo-9-dihydro-9a-Aza-9a-homoerythromycin A (1.0 g, 0,00173 mol) was dissolved in toluene (25 ml) and at a temperature in the range from 0 to 5°C was added dropwise n-toluensulfonate (about 0,34 mg, 0,00173 mol). After stirring the reaction mixture for one hour at the same temperature, the resulting crystals of the crude product was sucked out. Isolation of pure 5-O-desosamine-9 desoxo-9-dihydro-9a-N-[N'-(p-toluensulfonyl)carbarnoyl]-9a-Aza-9a-homoerythromycin And carried out by chromatography on a column of silica gel in the solvent system methylene chloride:methanol:ammonia = 90:9:1,5.

IR (KBr)/cm-1: 1726, 1171, 1129, 1075.

MC(ES+) m/z (%): 774,9.

Example 8

5-O-Desosamine-9 desoxo-9-dihydro-9a-N-[N'-(4-chlorobenzenesulfonyl)carbarnoyl]-9a-Aza-9a-homoerythromycin And

Similar to the method described in example 1, 5-O-desosamine-9 desoxo-9-dihydro-9a-Aza-9a-Homeric valid And (2,54 g, 0,0046 mol) was dissolved in toluene (50 ml) and at a temperature in the range from 0 to 5°was added dropwise 4-chlorobenzalmalononitrile (1.0 g, 0,00459 mol). After stirring the reaction mixture for one hour at the same temperature, the resulting crystals of the crude product was sucked out. The allocation of 5-O-desosamine-9 desoxo-9-dihydro-9a-N-[N'-(4-chlorobenzenesulfonyl)carbarnoyl]-9a-Aza-9a-homoerythromycin And carried out by chromatography on a column of silica gel in the solvent system methylene chloride: methanol = 7:3.

IR (KBr)/cm-1: 1725, 1171, 1133, 1078.

MC (EI+) m/z (%): 784,7.

Example 9

5-O-Desosamine-9 desoxo-9-dihydro-9a-N-[N'-(4-permentantly)carbarnoyl]-9a-Aza-9a-homoerythromycin And

Similar to the method described in example 1, 5-O-desosamine-9 desoxo-9-dihydro-9a-Aza-9a-homoerythromycin A (1.0 g, 0,00173 mol) was dissolved in toluene (25 ml) and at a temperature in the range from 0 to 5°was added dropwise 4-forbindelsesfanebladet (0.36 g, 0,00173 mol). After stirring the reaction mixture for one hour at the same temperature, the resulting crystals of the crude product was sucked out. Isolation of pure 5-O-desosamine-9 desoxo-9-dihydro-9a-N-[N'-(4-permentantly)carbarnoyl]-9a-Aza-9a-homoerythromycin And carried out by chromatography on a column of silica gel in the solvent system methylene chloride:methanol = 7:3.

<> IR (KBr)/cm-1: 1727, 1174, 1129, 1076.

MC (EI+) m/z (%): 778,8.

Example 10

5-O-Desosamine-9 desoxo-9-dihydro-9a-N-[N'-(benzazolyl)carbarnoyl]-9a-Aza-9a-homoerythromycin And

Similar to the method described in example 1, 5-O-desosamine-9 desoxo-9-dihydro-9a-Aza-9a-homoerythromycin And (3,055 g, 0,0055 mol) was dissolved in toluene (25 ml) and at a temperature in the range from 0 to 5°was added dropwise benzosulfonazole (1.0 g, 0,0055 mol). After stirring the reaction mixture for one hour at the same temperature, the resulting crystals of the crude product was sucked out. Isolation of pure 5-O-desosamine-9 desoxo-9-dihydro-9a-N-[N'-(benzazolyl)carbarnoyl]-9a-Aza-9a-homoerythromycin And carried out by chromatography on a column of silica gel in the solvent system methylene chloride:methanol = 7:3.

IR (KBr)/cm-1: 1728, 1176, 1128, 1077.

MC (ES+) m/z (%): 760,7.

Example 11

5-O-Desosamine-9 desoxo-9-dihydro-9a-N-[N'-(o-toluensulfonyl)carbarnoyl]-9a-Aza-9a-homoerythromycin And

Similar to the method described in example 1, 5-O-desosamine-9 desoxo-9-dihydro-9a-Aza-9a-homoerythromycin And (2,84 g, 0,0051 mol) was dissolved in toluene (40 ml) and at a temperature in the range from 0 to 5°was added dropwise o-toluensulfonate (1.0 g, 0,0046 mol). After stirring the reaction mixture for one hour at the same temperature obrazovanie the crystals of the crude product was sucked out. Isolation of pure 5-O-desosamine-9 desoxo-9-dihydro-9a-N-[N'-(o-toluensulfonyl)carbarnoyl]-9a-Aza-9a-homoerythromycin And carried out by chromatography on a column of silica gel in the solvent system methylene chloride:methanol = 7:3.

IR (KBr)/cm-1: 1728, 1173, 1129, 1075.

MC (EI+) m/z (%): 774,7.

Example 12

5-O-Desosamine-9 desoxo-9-dihydro-9a-N-[N'-(2-chlorobenzenesulfonyl)carbarnoyl]-9a-Aza-9a-homoerythromycin And

Similar to the method described in example 1, 5-O-desosamine-9 desoxo-9-dihydro-9a-Aza-9a-homoerythromycin And (2.65 g, 0,00459 mol) was dissolved in toluene (50 ml) and at a temperature in the range from 0 to 5°C was added dropwise a suspension of 2-chlorobenzalmalononitrile (1.0 g, 0,00459 mol) in toluene. After stirring the reaction mixture for one hour at the same temperature, the resulting crystals of the crude product was sucked out. Isolation of pure 5-O-desosamine-9 desoxo-9-dihydro-9a-N-[N'-(2-chlorobenzenesulfonyl)carbarnoyl]-9a-Aza-9a-homoerythromycin And carried out by chromatography on a column of silica gel in the solvent system methylene chloride:methanol = 7:3.

IR (KBr)/cm-1: 1728, 1170, 1125, 1071.

MC (ES+) m/z (%): 794,1.

Examples of pharmaceutical compositions

Example: the Drug in pill form

9a-N-[N'-(phenylsulfonyl)carbarnoyl]derived 9 desoxo-9-dihydro-9a-Aza-9a-homoerythromycin a and 5-O-desosamine-9 desoxo-9-is hydro-9a-Aza-9a-homoerythromycin And, such as 9-desoxo-9-dihydro-9a-N-[N'-(4-chlorobenzenesulfonyl)carbarnoyl]-9a-Aza-9a-homoerythromycin a (example 1), 9 desoxo-9-dihydro-9a-N-[N'-(p-toluensulfonyl)carbarnoyl]-9a-Aza-9a-homoerythromycin A (example 2), 9 desoxo-9-dihydro-9a-N-[N'-(o-toluensulfonyl)-carbarnoyl]9a-Aza-9a-homoerythromycin And (example 3) or 9 desoxo-9-dihydro-9a-N-[N'-(benzazolyl)carbarnoyl]-9a-Aza-9a-homoerythromycin And (example 4) granularit together with starch, microcrystalline cellulose and sodium croscarmellose conventional methods of granulation. The dried pellets are homogenized using stearate and tabletirujut using conventional machines for the manufacture of tablets. Core tablets are covered with a coating based on hydroxypropylmethylcellulose (receiver array). The composition of the tablets weighing 150, 200, 250, 300, 500 and 600 mg are presented in table 1.

Table 1
The composition of the drug/dosage:150 mg200 mg250 mg300 mg350 mg600 mg
Example 1158210263316526632
Starch162025305060
Microcrystalline of all the vine 85115140170280340
Sodium croscarmellose579101821
Magnesium stearate2345910
The hypromellose (receiver array)81114162732

Example: the Drug in pill form

Water, co-solvent (glycerol, polyethylene glycol), preservatives (methyl and propyl paraben), stabilizer and gelling polymer homogenize the usual way of obtaining the aqueous phase. To this aqueous phase add connection 1 and it is dispersed or dissolved. The oil component (such as liquid paraffin, and cetyl alcohol) is ground with the addition of emulsifier and, after cooling, mixed with a previously prepared aqueous phase. Final homogenization is carried out at reduced pressure. In the last phase can be added flavoring, i.e. homogeneous gel, and may not necessarily have a specific pH. Typical preparation containing the compound 1 obtained in this way are presented in table 2.

Table 2
ComponentDose (mg/d)Function
Example 4100the active ingredient
Glycerin100,00the co-solvent
Isopropanol400,00the co-solvent
PEG60,00the co-solvent
Carbomer15,00gelling polymer
Citric acidqsthe pH regulator
Polysorbate 4010,00emulsifier
Methylparaben0,70preservative
Propylparaben0,30preservative

cont. table 2
Disodium-EDTA0,5stabilizer
Liquid paraffin25,00the oil component
Cetyl alcohol25,00the oil component
Flavorqs
Waterto 1 g

1. 9a-N-[N'-(Phenylsulfonyl the l)carbarnoyl]derivatives of 9-desoxo-9-dihydro-9a-Aza-9a-homoerythromycin a and 5-O-desosamine-9 desoxo-9-dihydro-9a-Aza-9a-homoerythromycin And the General formula 1

where R1denotes H, C1-C4alkyl or halogen and R represents H or ladiesjenny radical

and their pharmaceutically acceptable salts accession inorganic or organic acids.

2. The compound according to claim 1, where R1denotes H and R denotes ladiesjenny radical.

3. The compound according to claim 1, where R1denotes CH3in p-position and R denotes ladiesjenny radical.

4. The compound according to claim 1, where R1denotes CH3in the on-position and R denotes ladiesjenny radical.

5. The compound according to claim 1, where R1denotes Cl in p-position and R denotes ladiesjenny radical.

6. The compound according to claim 1, where R1denotes Cl in o-position and R denotes ladiesjenny radical.

7. The compound according to claim 1, where R1denotes F in p-position and R denotes ladiesjenny radical.

8. The compound according to claim 1, where R1and R denote N.

9. The compound according to claim 1, where R1denotes CH3in p-position and R denotes N.

10. The compound according to claim 1, where R1denotes CH3in the on-position and R denotes N.

11. The compound according to claim 1, where R1denotes Cl in p-position and R denotes N.

12. The compound according to claim 1, where R1denotes Cl in o-position and R denotes N.

13. The compound according to claim 1, where R1denotes F and R N.

14. The way to obtain 9a-N-[N'-(phenylsulfonyl)carbarnoyl]derivatives of 9-desoxo-9-dihydro-9a-Aza-9a-homoerythromycin a and 5-O-desosamine-9 desoxo-9-dihydro-9a-Aza-9a-homoerythromycin And the General formula 1, where R1denotes H, C1-C4alkyl or halogen and R represents H or ladiesjenny radical, characterized in that 9 desoxo-9-dihydro-9a-Aza-9a-homoerythromycin or 5-O-desosamine-9 desoxo-9-dihydro-9a-Aza-9a-homoerythromycin And General formula 2

subjected to interaction with phenylsulfonylacetate General formula 3

where R1matter specified in claim 1,

in toluene, xylene or some other aprotic solvents at temperatures from 0 to 110°C.

15. Pharmaceutical composition having antibacterial activity, containing a pharmaceutically acceptable carrier and an antibacterial effective amount of a compound according to claim 1.

16. The compound according to any one of claims 1 to 13 to obtain pharmaceutical compositions for treatment of bacterial infections.



 

Same patents:

FIELD: organic chemistry, antibiotics, pharmacy.

SUBSTANCE: invention describes crystalline forms A, C and D of erythromycin derivative of the formula (VII): . Crystalline forms are prepared by recrystallization of crude fumarate crystal from an alcoholic solvent (form A) and, additionally, from ethyl acetate (form C) or, additionally, from an aqueous ethyl acetate (form D). Also, invention relates to methods for preparing intermediate compounds. Prepared crystalline forms possess the better quality, in particular, high stability that is important in preparing pharmaceutical preparations.

EFFECT: improved preparing methods.

16 cl, 8 dwg, 13 ex

FIELD: organic chemistry, antibiotics, pharmacy.

SUBSTANCE: invention describes crystalline forms A, C and D of erythromycin derivative of the formula (VII): . Crystalline forms are prepared by recrystallization of crude fumarate crystal from an alcoholic solvent (form A) and, additionally, from ethyl acetate (form C) or, additionally, from an aqueous ethyl acetate (form D). Also, invention relates to methods for preparing intermediate compounds. Prepared crystalline forms possess the better quality, in particular, high stability that is important in preparing pharmaceutical preparations.

EFFECT: improved preparing methods.

16 cl, 8 dwg, 13 ex

FIELD: organic chemistry, antibiotics, chemical technology.

SUBSTANCE: invention relates to a novel crystalline form E of erythromycin derivative fumarate salt represented by the formula (I)

and to a method for its preparing. Indicated crystalline form E shows strong roentgen diffraction peaks at diffraction angles (2θ) 5.6° and 10.4° that was established by roentgen diffractometry with Cu-Kα-radiation. Also, invention proposes crystalline form D of erythromycin derivative fumarate salt represented by the formula (I) showing average particles size 90 mcm or above and/or the content of residual solvent 1500 ppm or less. Method for preparing indicated crystalline form D involve suspending indicated crystalline form E in mixture ethyl acetate and water in the ratio = (99:1)-(97:3) at temperature from -20°C to 20°C. Invention provides reducing the content of residual solvent and elimination of difficulties in making tablets.

EFFECT: improved preparing methods.

14 cl, 1 tbl, 5 dwg, 6 ex

FIELD: organic chemistry, chemical technology, antibiotics.

SUBSTANCE: derivative of 9-deoxo-9a-aza-9a-homoerythromycin A of the formula (3) wherein R4 represents hydroxyl protecting group is prepared by protection of 2'-hydroxy-group of compound of the formula (5) to form compound of the formula (4)

and by oxidation of C-4''-hydroxy-group of compound of the formula (4) that is carried out by addition of dimethylsulfoxide to solution containing compound of the formula (4) and a solvent followed by cooling the mixture up to about -70°C, activation of dimethylsulfoxide in situ and defoaming the reaction mixture. Compound of the formula (4) is converted to the oxidation stage directly without its isolation. Also, invention proposes additive salt of trifluoroacetic acid of compound of the formula (3) and a method for its preparing by treatment of compound of the formula (3) with trifluoroacetic acid. Invention provides increasing yield and improving purity of the end product.

EFFECT: improved preparing method.

11 cl, 6 ex

FIELD: antibiotics, chemical technology.

SUBSTANCE: crystallization of azithromycin dihydrate is carried out by alkalization of an aqueous-organic azithromycin salt with the ratio water/solvent = from 1:1 to 3;1 and up to pH value 8-10. Methanol, ethanol, isopropanol, acetonitrile or dioxane can be used as a solvent. Method provides enhancing stability and homogeneity of the end crystalline product.

EFFECT: improved crystallizing method.

1 dwg, 3 ex

FIELD: antibiotics, chemical technology.

SUBSTANCE: azithromycin is prepared by the methylation reaction of 11-aza-10-deoxo-10-dihydroerythromycin in boiling in chlorinated hydrocarbon medium, in the presence of formic acid taken in the amount from 0.1 to 0.2 weight part per one weight part of 11-aza-10-deoxo-10-dihydroerythromycin. Paraform is used as a methylating agent taken in the amount from 0.05 to 0.2 weight part per one part of 11-aza-10-deoxo-10-dihydroerythromycin. Invention provides increasing yield and improved quality of the end product.

EFFECT: improved preparing method.

2 cl, 3 ex

FIELD: antibiotics, chemical technology.

SUBSTANCE: invention relates to a method for preparing erythromycin oxime in homogenous conditions by oximylation of erythromycin A with hydroxylamine hydrochloride in dry methanol using triethylamine as a base. Method provides enhancing yield and quality of product.

EFFECT: improved method for preparing.

3 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to new compounds - pluraflavines of the formula (I): wherein R1 represents sugar group of the formula: ; R2 represents -COOH or -CH2-O-(R7)m wherein R7 represents sugar group of the formula: ; R3 is taken among the groups: and , and to all its stereochemical forms and mixtures of indicated forms in any ratio, and to their physiologically acceptable salts; R5 means hydrogen atom; R4 and R6 represent in common group -X2 with a double bond wherein X2 means oxygen atom (O); R8 and R10 represent in common group -X2 with a double bond wherein X2 means oxygen atom (O), and m = n = 1, and to all its stereochemical forms and mixtures of indicated forms in any ratio and to its physiologically acceptable salts. Invention relates to a method for preparing these compounds from culture of microorganism actinomycetes HAG 003959, DSM 12931 by fermentation, to the strain Actinomycetales HAG 003959, DSM 12931 used for preparing compounds of the formula (I) and to pharmaceutical composition inhibiting transcriptase activity and eliciting cytotoxic effect based on above said compounds. Compounds of the formula (I) are used as medicinal agents, for example, as antitumor agents.

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

19 cl, 3 tbl, 12 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to new acid-additive nitrate salts of compounds taken among salbutamol, cetirizine, loratidine, terfenadine, emedastine, ketotifen, nedocromil, ambroxol, dextrometorphan, dextrorphan, isoniazide, erythromycin and pyrazinamide. Indicated salts can be used for treatment of pathology of respiratory system and elicit an anti-allergic, anti-asthmatic effect and can be used in ophthalmology also. Indicated salts have less adverse effect on cardiovascular and/or gastroenteric systems as compared with their non-salt analogues. Also, invention proposes pharmaceutical compositions for preparing medicinal agents for treatment of pathology of respiratory system and comprising above indicated salts or nitrate salts of metronidazol or aciclovir.

EFFECT: improved and valuable properties of compounds.

6 cl, 5 tbl, 19 ex

FIELD: organic chemistry, pharmaceutical industry.

SUBSTANCE: invention relates to clathrate of azithromycin hydrate with 1,2-propyleneglycol of formula I , wherein m =1-2 and n = 0.20-0.40. Method for production of target compound includes azithromycin dissolution in acetone followed by addition of 1,2-propyleneglycol and water in solution, formed crystal filtering, washing with water and drying. Also disclosed is pharmaceutical composition for microbial infection treatment based on clathrate of formula I.

EFFECT: azithromycin with reduced hygroscopicity and increased storage stability.

7 cl, 7 dwg, 2 tbl, 4 ex

FIELD: medicine.

SUBSTANCE: method involves covering lesion focus with cell containing dialysis solution composed of Dimexid, antibiotic, 0.1% potassium furagin and 25% glucose solution taken in 1:4:3:2 proportion. The cell is fixed on teeth with ligature. Cell wall adjacent to gingiva is covered with semipermeable Cuprofan membrane and the opposite wall with latex rubber. Dialysis is carried out 20 min long twice a day.

EFFECT: enhanced effectiveness of treatment; retained natural protection factors; reduced edema and inflammation manifestations.

Modified chitosan // 2269542

FIELD: organic chemistry of natural compounds, chemical technology, medicine.

SUBSTANCE: invention relates to the group of chitosan-containing compounds. Invention relates to synthesis of modified chitosan of the following structure: wherein n = 150-1400. The modified chitosan possesses the bactericidal activity, in particular, antituberculosis activity.

EFFECT: valuable medicinal properties of modified chitosan.

1 tbl, 1 dwg, 3 ex

FIELD: medicine.

SUBSTANCE: the present innovation deals with technique of revaccination in adults against diphtheria and tetanus under conditions of Far North. For this purpose one should form a group of people vaccinated more than 10 years ago to vaccinate them in February. The method leads to increased efficiency of vaccination due to decreased duration of vaccination period.

EFFECT: higher efficiency of revaccination.

7 ex

FIELD: medicine, obstetrics.

SUBSTANCE: one should conduct antibacterial therapy 3 mo before planned pregnancy consisting of preparations of tetracyclinic group or macrolides in combination with nystatin and metronidasol to continue it since the first day of menstrual cycle and, also, it is necessary to perform correction of vaginal biocenosis, and about 3-4 wk after therapy carried out for 2 next mo before planned pregnancy starting, also, since the first day of menstrual cycle - metabolic therapy; At the onset of pregnancy one should conduct courses for preventing placental deficiency dealing with introduction of preparations that improve uterine-placental circulation, and preparations that improve rheological properties of blood and vitamin-metabolic therapy or the same preparations, and additionally - introduction of macrolides ad viferon rectally in case of activation of chlamydial infection. The present innovation enables to sanitize uterine cavity, improve uterine-placental circulation, restoration of placental tissue structure that, in its turn favors the birth of healthy generation.

EFFECT: higher efficiency of prophylaxis.

1 cl, 9 tbl

FIELD: medicine, pharmacy.

SUBSTANCE: medicinal formulation possessing the bacteristatic effect consists of a core comprising the following components, wt.-%: clarithromycin, 40.0-80.0; polyvinylpyrrolidone, 3.0-10.0; sodium lauryl sulfate, 2.0-5.0; sodium croscarmelose, 4.0-10.0; aerosil, 0.5-2.0; magnesium stearate, 0.5-2.0, and microcrystalline cellulose, 10.0-31.0. Also, the medicinal formulation consists of envelope comprising the following components, wt.-%: hydroxypropylmethylcellulose, 30.0-70.0; polyethylene glycol, 12.0-22.0; titanium dioxide, 11.0-20.0, hydroxypropylcellulose, 2.0-10.0, dye yellow quinoline, 1.0-4.0, and vanillin, 1.0-4.0. Also, invention describes a method for preparing the medicinal formulation by wet granulation followed by tableting and applying the envelope from an aqueous suspension. Prepared tablets show the necessary mechanical strength, insignificant scattering index by mass (± 3.5%) and dissolving 88-91% for 30 min.

EFFECT: improved and valuable properties of medicinal formulation.

3 cl, 2 tbl

FIELD: medicine, gynecology, surgery.

SUBSTANCE: one should introduce 3.5%-chitosan ascorbate gel into fistulous channel that contains metronidasol at the dosage of 2 mg/ml, at the volume up to 20 ml once/2 d till complete fistula's closing. The present innovation enables to activate reparative processes and fistulous epithelization that favors for closing fistulous channel in earlier terms.

EFFECT: higher efficiency of therapy conducted.

2 ex

FIELD: medicine, surgery.

SUBSTANCE: one should apply a polycompositional film onto donor's wounds after autodermoplasty performed. This film contains the following components in weight proportions: chitosan 78.3-89.4; polyvinyl alcohol 9.8-19.8; antibiotic of aminoglycoside group 0.5-2.0; anesthetic 0.1-0.2. It is perforated at tension coefficient being 1:4. The innovation enables to decrease wound's traumatization, improves prophylaxis of suppuration and increases cosmetic effect even at a single application of the film suggested.

EFFECT: higher efficiency of therapy.

2 ex

FIELD: medicine.

SUBSTANCE: the present innovation deals with application of pleuromutilin derivatives, that is valnemulin and thiamulin, for transdermal treatment of bacterial diseases, in particular those induced by Dichelobacter nodosus, Fusobacterium necrophorum, Bacteriodes nodosus and Bacteriodes melamnogenicus, for manufacturing medicinal preparation or as an active ingredient of medicinal preparation of the same indication and corresponding method for transdermal treatment of diseases, for example foot rot. It has been detected the capacity of antibiotics to penetrate skin and enter either plasma or blood at concentrations being efficient against systemic bacterial infections, so, medicinal preparation could be designed in the form of ointment, cream, solution, shampoo, powder and spray.

EFFECT: higher efficiency of application.

9 cl, 1 tbl

FIELD: biotechnology, immunology.

SUBSTANCE: invention proposes preparation that comprises the immunoelectrophoretically pure secretory immunoglobulin A isolated from whey milk and/or colostrum of immunized ungulate animals and pharmaceutically acceptable vehicles. The base preparation (substance) comprises 6-12% of secretory immunoglobulin A at pH 4-8, an anti-complementary activity at least 10 mg of protein, not activating 2 CH50, protects in >70% against corresponding infections (in infection macroorganism in doses ≥10 ID50), shows areactogenic property in intravenous administration, can comprise stabilizing additives in the total concentration 4%, not above. The preparation possesses high purity, low anti-complementary activity, stable in storage, useful for oral, parenteral and topical using and possesses therapeutic activity with respect to microorganisms and viruses against which humans and animals immunization have been carried out. Invention can be used in treatment and prophylaxis of immunodeficiency states, bacterial and viral infections in humans and animals.

EFFECT: valuable medicinal and veterinary properties of preparation.

9 cl, 1 tbl, 10 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to novel heterocyclic compounds comprising 2-aminopyridin-3-sulfonic fragment of the general formula (1) or their pharmaceutically acceptable salts, N-oxides or hydrates possessing properties of antagonists of glutamate-induced calcium ions transport, in particular, neuroprotective effect. Also, invention relates to the focused library for the search of biologically active leader-compounds comprising at least one heterocyclic compound of the general formula (1) and to pharmaceutical composition if form of tablets, capsules or injections placed into pharmaceutically acceptable package containing compounds of invention as an active substance. In compound of the general formula (1) R1 represents hydrogen atom; R2 represents chlorine atom, optionally substituted hydroxyl group, optionally substituted amino-group, optionally substituted azaheterocyclyl; or R1 and R2 in common with nitrogen and sulfur atoms to which they are bound form optionally substituted and optionally condensed with other cycles 1,1-dioxo-4H-pyrido[2,3-e][1,2,4]thiadiazine or optionally substituted and optionally condensed with other cycles 5,5-dioxo-5,6,7,9-tetrahydro-5-thia-1,6,9-triazabenzocyclohepten-8-one. Also, invention discloses methods for preparing different compounds of the general formula (1).

EFFECT: improved preparing methods, valuable medicinal properties of compounds.

10 cl, 4 sch, 4 tbl, 9 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention proposes using xenogenous oligo-and/or polyribonucleotides, namely total RNA and tRNA, as an active component of external anhydrous medicinal agent for a single treatment of skin tumor relapse (for example, basalioma) or infections caused by herpes virus and the corresponding method for treatment. The claimed external anhydrous medicinal agents decline effectively relapses of indicated diseases after a single intake.

EFFECT: enhanced effectiveness and valuable medicinal properties of agents.

5 cl, 2 ex

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