Derivatives teicoplanin and the method of obtaining derivatives teicoplanin
(57) Abstract:Usage: as an antimicrobial agent. The inventive product WITH63amide derivatives 34-de(acetylglucosaminyl)-34-desoximetasone f-ly I, where a IS N-(C9-C12)aliphatic acyl-Beta-D-2-deoxy-aminopropanoic, where9-C12aliphatic acyl is (Z)-4-decanoyl, 8-methylnonanoic, decanoyl, 8-methyldecyl, 9-methyldecyl, 6-methyloctanoic, nonanoyl, 10-methylundecanal and dodecanoyl, is hydrogen, Y - di - or polyamine f-crystals of 2-NR-/(CH2)mNR1/X/(CH2)kNR2/n-(CH2)p-NR3R4where R is hydrogen, R1and R2- independently from each other hydrogen or C1-C4alkyl, R3and R4- independently from each other hydrogen or C1-C4alkyl, possibly substituted by a group NH2or is HE, or R3and R4together with the adjacent nitrogen atom - pyrrolidine, piperidine, oxazolidine, thiazolidine, isoxazolidine, isotretoin, morpholine, piperazine, thiomorpholine, hexahydroazepin, hexahydro-1.5-diazepin or hexahydro-1,4-diazepin, m, k, and p is 2, 3 or 4, n and h is 0, 1 or 2, X is a single bond or, if n is 1, taken together with the adjacent group NR1glad the corresponding activated complex ester with amine 2. The structure of compounds 1, 2 and radical 3 (see the description of the C-CI). 2 S. and 4 C.p. f-crystals, 4 PL. This invention is concerned WITH63amide derivatives 34 de(acetylglucosaminyl)-34-desoximetasone formula:
< / BR>in which a represents a N-/(C9-C12)-aliphatic acyl/-beta-D-2-deoxy-2-aminopropanoic; means hydrogen or a protective group of the amine function; M is an alpha-D-mannopyranosyl; Y represents a di - or poliaminov group of the formula:
where R is hydrogen or a linear or branched alkyl with 1-8 carbon atoms; R1is hydrogen or a linear or branched alkyl with 1-8 carbon atoms; R2is hydrogen or a linear or branched alkyl with 1-8 carbon atoms; R3and R4each independently of one another are hydrogen, linear or branched alkyl with 1-8 carbon atoms, optionally bearing NH2-, OH - or S, Deputy, or taken together with the adjacent nitrogen atom form a 5-7 membered saturated heterocyclic ring which may contain another GE the Il-(C1-C4)-alkyl, m, k and p are each independently from each other represent an integer from 2 to 8; n and h each independently from each other represents an integer from zero to four; X is an ordinary relation, or, if n is equal to the unit, taken together with the adjacent group NR1can be a divalent radical of the formula:
< / BR>where r and s each independently from each other represents an integer from 1 to 6, provided that their sum is an integer from 3 to 8,
and their acid additive salts.According to a preferred implementation of this invention aliphatic acyl radicals containing 9-12 carbon atoms and is denoted by A, are preferably fully saturated radicals or have one unsaturated bond. Most preferred are the following radicals: (Z)-4-decanoyl, 8-methylnonanoic, decanoyl, 8-methyldecyl, 9-methyldecyl, 6-methyloctanoic, nonanoyl, 10-methyldecyl and dodecanoyl.The symbols R, R1and R2preferably represented by hydrogen or a linear or branched alkilany radical with 1-4 carbon atoms.The symbols R3and R4each nesamani, optional with NH2- HE - or H-Deputy, or R3and R4taken together with the adjacent nitrogen atom, form a 5-7-membered saturated heterocyclic ring which may contain another heteroatom, selected from among-S-, -O - or-NR5- while following preferred heterocyclic rings: pyrrolidine, piperidine, oxazolidine, thiazolidine, isoxazolidine, isothiazolin, morpholine, piperazine, thiomorpholine, hexahydroazepin, hexahydro-1.5-diazepin, hexahydro-1,4-diazepin; R5preferably is hydrogen or alkyl with 1-4 carbon atoms.The symbols m, k and p preferably represent integers from 2 to 6, most preferably from 2 to 4.The symbols n and h preferably represent 0, 1 or 2, most preferably zero or one.X preferably represents an ordinary link or, if n is equal to the unit, taken together with the adjacent group NR1represents a bivalent radical of the formula:
< / BR>where r and s are both equal to 2 or equal to one unit, and the other is two or three.According to the General definition given above, representative examples of the group:
-NCH3(CH2)3NHCH3; ; ;
< / BR>< / BR>< / BR>< / BR>< / BR>Compounds according to the invention has an antimicrobial activity, particularly against gram-positive bacteria, including group a streptococci and some coagulational staphylococci.Different FROM63amide derivatives teicoplanin complex, the individual components and the aglycone and their pseudoglioma described in the publication of a European patent application N 218099 and in the publication of the application for international patent N 088/06600.Compounds according to the invention is obtained by amidation of the corresponding derivatives of the carboxylic acids). These source materials are specially described in the publication of a European patent application N 290922 or can be obtained by the way described here.The above-mentioned raw materials are produced either from complex teicoplanin AND2(as a result of operations fermentation), or of its five main components (US patent N 4542018; A. Borghi et al. S. Antibiot, Vol. 37, 615-620, 1984; S. S. Barna et al. S. Am. Chem. Soc. 1984, 106, 4895-4902) removing acetylglucosaminyl residue in position 34.As is well known in this field, the above-mentioned five main components of the complex teicoplanin AND2characterized by the fact that part of the molecule aliphatic acyl beta-D-2-deoxy-2-aminopropionitrile residue is an aliphatic acyl with 10-11 carbon atoms, namely:
(Z)-4-decanoyl, 8-methylnonanoic, decanoyl, 8-methyldecyl or 9-methyldecyl.Therefore, the obtained substance used as starting material for producing compounds according to the invention, can be either individual compounds or mixtures of one or more compounds. As mentioned starting materials for producing compounds according to the invention can be used in both the above forms, then the singing of the compounds of the above formula I. These mixtures of compounds are also part of the invention and can be used as such for biological purposes and applications or can be allocated in the form of its individual components are known and described in the field methods of separation. Examples of separation methods suitable for the purposes of receiving the individual components of the final mixture of products derived amide teicoplanin are examples in the publication in the European patent N 218099 and publications describe the application of international patent N WO 88/06600.Other raw materials for producing compounds according to the invention can be obtained by use of the publication in the European patent N 290922 to compounds teicoplanin, such as the compounds described as the connection (identified as RS-4 in the documents referred to below), the connection (identified as RS-3 in the documents mentioned below) in the publication of the description of the application to the European patent N 306645, and those connections, which is identified as RS-1 and RS-2 in the report of M. Canola and collaborators at the 17th International Symposium on chromatography, Vienna, 25-30 September 1988 (A. Barghi et al. The Journal of Antibiotics, Vol. 42, N 3,ETA-D-2-deoxy-2-aminopropionitrile remainder are respectively: nonanoyl, 6-methyloctanoic, 10-methylundecanal and dodecanoyl.The amidation processes described in the two above-mentioned publication of applications at the European patent N 218099 and international patent WO N 88/06600 and can also be used to obtain the compounds according to the present invention. These processes include condensation of the above-mentioned carboxylic acid compounds with an excess of an appropriate amine of formula II:
where R, R1, R2, R3, R4, X, m, n, h, k, and p are as defined above meanings, in an inert organic solvent in the presence of a condensing means, selected among alkyl with 1-4 carbon atoms, phenyl or heterocyclic of phosphorazidate at temperatures from 0oWith up to 20oC. If the amine reactant contains other features that are not inert under the chosen reaction conditions, these functions are adequately protected by known perse protective groups.According to a preferred implementation of the present invention the compounds of formula I in which Y is a di - or polyaminopropyl, as defined above, is produced by interaction of actie preferably protected, with the appropriate amine of formula II.The amino group at the N15may be protected by known methods in this field, such, for example, which are described in reference books like T. W. Greene. Protective Groupps in Organic Synthesis, Sohn Wiley and Sons, New York, 1981 and M. Mc. Omil. Protecting Groups in Organic Chemistry. Plenum Press, New York, 1973.These protecting groups must be stable to the reaction conditions of the process, must not adversely affect the reaction, amidation and should be easily otseplyaet and removed from the reaction medium at the end of the reaction without changing the newly formed amide bond.Representative examples of N-protective groups, which can be favorably used in the method according to the invention for protection of the primary AMINOPHENYL when N15the original connection teicoplanin and, if eligible, NR3R4-part of the molecule of amine reagent of formula II, are forming a carbamate reagents characterized by the following oxycarbonyl groups: 1,1-dimethylphenylcarbinol, tert-butyloxycarbonyl, vinyloxycarbonyl, aryloxyalkyl, cinnamoylcocaine, benzyloxycarbonyl, para-nitrobenzenesulfonyl, 3,4-dimethoxy-6-nitrobenzisoxazole, 2,4-dichlorobenzoylacetonitrile, diphenylethylenediamine, N-benzyloxycarbonyl, 2,2,2-trichlorocyanuric, 2,2,2-trichloro-tert-butoxycarbonyl and the like. Other suitable N-protective agents are aldehydes or ketones or their derivatives, which are capable of forming Schiff bases with be protected amino group.Preferred examples of reagents that form a Schiff base, are benzaldehyde and particularly preferred 2-oxybenzaldehyde (salicylic aldehyde). Traditional remedy when the amine reactant of formula II is set to R, other than hydrogen, and contains the primary aminophenol (i.e., R3and R4both represent hydrogen), is in some cases the formation of a derivative of benzylidene, which can be obtained by the interaction of the amine with benzaldehyde in a lower alcohol, such as ethanol, preferably at room temperature. After the reaction of the selected source connection teicoplanin finished, benzylidene protective group can be removed known in the field methods, i.e., by catalytic hydrogenation, using for example palladium on coal as a catalyst.However, in all slree can be modified by catalytic hydrogenation. A typical sequence of catalytic hydrogenation aminoamide derivative of the formula I in which a represents a group of the above values, acyl part of which is (Z)-decanoyl (or its containing mixture) is at least partly in the fact that decanolide compound is converted into the corresponding decanolide connection. Therefore, if the removal of the protective group is carried out by catalytic hydrogenation and the original connection 34 de(acetylglucosaminyl)-34-deoxy-teicoplanin is (or contains) a derivative component 1 complex teicoplanin AND2(acyl part of which is (Z)-4-decanoyl), then the final amide product in most cases does not have a corresponding derivative, but rather a proportionally large number of derived component 3, acyl residue which is decanoyl.If you wish to obtain a final compound containing component 1 amide derivative of the complex teicoplanin AND2then N-protective group should be selected among the groups that can be removed under conditions that do not use the hydrogenation of acyl portion or hydrolysis parts sugar molecules, teicoplanin substrata groups, such as 2,2,2-trichloro-tert-butoxycarbonyl, which can be removed by methods described H. Eckert et al. in Angew. hem. Int. Ed. Engl. 17, N 5, 361-362 (1978).For the person skilled in the art it is clear that the final choice of a specific protective group depends on the characteristics of specific amide derivative, which wish to receive. Indeed, this amide function end connection must be stable under the conditions of removal of the protective(s) group (s).As the conditions for the removal of various protective groups known to the person skilled in the art can choose a suitable protective group.In some cases, when the amine of formula II contains two primary amino groups (i.e. R, R3and R4all represent hydrogen), it may be convenient to obtain a mixture of the reaction products obtained from the formation of amide bond with each of two primary amine functions and divide it by conventional methods such as evaporation column chromatography, reverse-phase column chromatography or preparative high performance liquid chromatography.Getting "activated esters" are described in General terms by L. Fisera and M Fizeram in "Reagentnyj esters, which can be usually used in the method according to the invention, reagents are described by R. Saerom and co-authors in Helv. Chim. Acta, 1955, 38, 69-70, and include , BrCH2COOC2H5, BrCH(COOC2H5)2, ClCH2COCH3, , ClCH2CH2N(C2H5)2. The preferred reagent of this type is chloroacetonitrile. In this case, chloroacetonitrile or dimethylformamide can be used as a preferred solvent. Generally inert organic solvents useful for the formation of "activated esters" are those organic aprotic solvents, which do not impact negatively on the course of the reaction and is capable of at least partially dissolving the original connection carboxylic acid.Examples of the aforementioned inert organic solvents are organic amides, simple alkalemia esters, sulfoxidov and aromatic compounds. Preferred examples of inert organic solvents are dimethylformamide, dimethoxyethane, hexamethylphosphoramide, dimethyl sulfoxide, benzene, toluene, and mixtures thereof.More preferably a solvent selected from acetonitrile, dimethylsulfoxide does not affect the course of the reaction, such as sodium carbonate or potassium or bicarbonate, trialkylamine, i.e. triethylamine. It is used in 2-6-molar with respect to the original carboxymaltose connection teicoplanin and it is preferable to use it in about a three-fold molar excess. The preferred base is triethylamine.The reagent, forming an "activated ester" is used in large excess with respect to the original carboxymaltose material teicoplanin. It generally is used in 5-35-fold molar ratio and preferably its use in the 20-30-fold molar excess. The reaction temperature is in the range of 10-60oC and preferably between 15oC and 30oC. usually, the reaction time depends on other specific parameters of the reaction and may be generally from 3 to 48 hoursIn this case, the duration of the reaction may be accompanied by high-performance liquid chromatography or thin-layer chromatography, to determine when the reaction is finished and begin the process of separating the desired intermediate compounds. Intermediate "activated ester" can be used directly in the same reactio the diluents, and it is used as such without further purification in the next stage of the reaction. However, if you wish, it can be purified column chromatography, such as evaporative chromatography or reverse-phase column chromatography.Received "activated ester", as an intermediate connection, then interacts with a molar excess of amine derivative of formula II:
OTHER-/(CH2)mNR1/n-X-(CH2)kNR2/h-(CH2)p-NR3R4< / BR>in the presence of an organic polar solvent and the temperature range from 5 to 60oWith, preferably 10-30oC.The organic polar solvent may be in this case proton polar or aprotic solvent.Preferred examples of the organic proton polar solvents are lower-(C2-C4)-alkanols, such as ethanol, n-propanol, isopropanol, n-butanol and the like, or mixtures thereof, preferably used in the dry form.Preferred examples of the organic polar aprotic solvents are N, N-dimethylformamide, hexamethylphosphoramide or mixtures thereof, 1,3-dimethyl-3,4,5,6-one ether" and the selected amine can be carried out at a temperature between 5oWith the 60oWith, but the preferred temperature range in General between 10 and 30oS, and most preferably in the range of 20-25oSecond, whereas the preferred molar ratio between the "activated complex ester and an amine of the formula II, as defined above, is from 1:5 to 1:30 and more preferably from 1:10 to 1:20. The course of the reaction can be controlled as usual thin-layer chromatography or high performance liquid chromatography.Received from the amidation reaction of amide derivative isolated from the reaction solution by conventional methods, for example, by evaporating the solvent or by adding a precipitant. Remove aminosidine group usually carried out on the crude product, isolated from the amidation reaction.Examples of ways to remove the mentioned protective groups in derivatives teicoplanin described, for example, in the publication of International patent application N WO 88/06600.If you use the process of catalytic hydrogenation, the reaction is carried out usually in the presence of dilute aqueous strong acid, preferably a mineral acid, in an organic solvent, miscible with the above-mentioned diluted with water, a strong acid. FILA formula I, or the corresponding free base. Similar processes adhere to when aminosidine group is a group which can be removed by treatment with diluted mineral acids (i.e., Schiff base or C1-C4-alkoxycarbonyl group) in conditions that do not cause splitting of sugar molecules (i.e., low temperature, short reaction time).To highlight an acid additive salt reaction solution obtained after removal of aminosidine group, usually lead to a pH value of 6 and 7 by addition of an aqueous base, i.e., aqueous sodium hydroxide, and after evaporation of the solvent under reduced pressure, the obtained solid is isolated in the form of additive salts with a strong acid, which was added during surgery to remove the protection. Such product may be further purified by conventional methods, i.e., column chromatography, precipitation from solutions by adding the precipitating, preparative high performance liquid chromatography and the like. An acid additive salt can be converted into the corresponding free base of formula I suspendirovanie or by dissolving the acid additive salt in an aqueous solvent to the product emit, for example, extraction with an organic solvent or converted into another acid additive salt by adding an acid selected and processed as described above.Sometimes after the above procedure may be necessary to expose the selected product is the usual process for desalting.For example, there can be used conventional chromatography on dextranomer resins with adjustable pore sizes (such as Sephadex LH 20) or the silane treated silica gel. After leaching of undesirable salts in an aqueous solution of the desired product elute through a linear gradient or stepwise gradient of a mixture of water with polar or aprotic organic solvent such as a mixture of acetonitrile-water or acetonitrile-water-acetic acid containing acetonitrile from 50 to 100% and then allocate the evaporation of solvent or by lyophilization.If the compound of formula I obtained in free base form, it can be converted to the corresponding acid additive salt suspendirovanie or dissolution of the form of the free base in an aqueous solvent and adding a slight molar excess of the selected acid. The resulting solution which cases the final selection of salt by precipitation by adding precipitator, miscible with water.When the final salt is insoluble in the organic solvent, whereas the form of the free base is soluble, it can be isolated by filtration from the organic solution mesolevel form after adding a stoichiometric amount or a slight molar excess of the selected acid.Representative and suitable acid additive salts of compounds of formula I include salts formed by standard reaction with both organic and inorganic acids, such as, for example, hydrochloric, Hydrobromic, sulfuric, phosphoric, acetic, triperoxonane, trichloroacetic, succinic, citric, ascorbic, lactic, maleic, fumaric, palmitic, cholic, palm, mucus, camphoric, glutaric, glycolic, phthalic, tartaric, lauric, stearic, salicylic, methansulfonate, benzolsulfonat, sorbic, picric, benzoic, cinnamic and like acids.The preferred additive salts of the compounds according to the invention are the pharmaceutically acceptable acid additive salt.The term "pharmaceutically acceptable acid additive salt" POM drugs compatible with pharmaceutical practice.Examples of acids suitable for "pharmaceutically acceptable acid additive salts" include those listed above acid.Characteristic of the compounds according to the invention, which further distinguishes them from the corresponding starting compound is an amide bond configuration 51, 52-th position, which is a CIS-configuration, whereas the same relationship in the original teicoplanin carboxylic acid is "TRANS". This means that the conformation of the core teicoplanin new compounds significantly changed in comparison with the conformation of the source materials.Compounds according to the invention in the form of free bases and their acid additive salts which are useful as antimicrobial agents, mainly active against gram-positive bacteria. More specifically, they are useful in the treatment of infections caused by Streptococcus group a (i.e., Streptococcus pyogenes). And indeed, at the present time they are the most active antibiotics teicoplanin against microorganisms of the genus. They are also more active than teicoplanin against coagulase-negative staphylococci (i.e., Streptococcus hemolyticus and Streptococcus epidermidis, especially against Staphy standard tests cultivation of agar in microtitre. Isocentrically nutrient liquid medium (oxoid, Oxoid) and broth Todd-Hewitt (difco, Difco) was used for cultivation of staphylococci and streptococci, respectively. Broth cultures were diluted so that the final sowing culture contained 104viable units per milliliter. Minimum inhibitory concentration was taken as the lowest concentration which shows no visible growth after 18-24 h incubation at 37oC.The results of antimicrobial testing of individual compounds of formula I are summarized in table. 1.The active compounds according to the invention against Streptococcus pyogenes in some cases higher than the activity of teicoplanin and the most active compounds according to the publication of a European patent application N 290922, the publication of a European patent application N 218099 and publication of the application for international patent N WO 88/06600, minimum concentration (micrograms/ml) against the same microorganisms were never drops below 0.06.Of the most useful applications of biological activity of compounds according to the invention of particular interest is their selective activity against Streptococcus pyogenes, which is evident by comparing snakey concentration against other tested microorganisms presented in table. 1 above, especially against Staphylococcus aureus.Activity against some clinical cultures of microorganisms Streptococcus pyogenes compounds 3, 5 and 32 are presented in table. 2.Compounds according to the invention show much lower activity against bacteria other groups of steptococcus other than group a and coagulase-negative staphylococci, and therefore can be considered as antibiotics, showing a very narrow and selective range of activity, are particularly useful for specific targets in the fight against streptococcal infections with low probability of selection of resistant strains of another kind.Streptococcal infection is usually responsible for severe pathological complications such as rheumatic fever, nephritis, endocarditis, erysipelas and the like.Receiving antibiotics with a very specific narrow spectrum of activity is regarded as an important need for the development of chemotherapy. Cm. W. Brumfitt et al. Postgraduate Medical Journal, Vol. 64, (1988), N 753, S. 552-558.In view of the above-described antimicrobial activity of the compounds according to the present invention can be applied as the active ingredient about the infectious diseases, caused by pathogenic bacteria, which are sensitive to the above-mentioned active ingredient.For these purposes, these compounds can be applied as such or in the form of mixtures in any proportion.Compounds according to the present invention can be administered orally, locally or parenterally, of which, however, parenteral administration is preferred. Depending on the route of administration, these compounds can be prepared in various dosage forms. Preparations for oral administration may be in the form of capsules, tablets, liquid solutions or suspensions. As is well known in this field, capsules and tablets may contain in addition to the active ingredient conventional excipients, such as diluents, e.g. lactose, calcium phosphate, sorbitol and the like, lubricants, i.e., magnesium stearate, talc, polyethylene glycol, binders, i.e., polyvinylpyrrolidone, gelatin, sorbitol, tragakant, Arabian gum, aromatic agents and acceptable dispersing and wetting means. Liquid preparations usually in the form of aqueous or oil solutions or suspensions may also contain conventional additives, such as suspendresume funds. For local application which deposits on the skin, the mucous membranes of the nose and throat or bronchial tissues and may have a corresponding form of creams, ointments, liquids for dispersion and inhalation, cakes, lubricants for the throat. For the treatment of eyes or ears dosage form can be presented in liquid or semi-liquid and cooked in a hydrophobic or hydrophilic basis in the form of ointments, creams, lotions, lubricants or powders.For rectal injection of the compounds according to the invention is used in the form of suppositories, mixed with traditional media, such as, for example, cocoa butter, beeswax, spermaceti or glycols and their derivatives.Compositions for injection may have such forms of drugs, as suspensions, solutions or emulsions in oily or aqueous carriers can contain a forming tool such as suspendida, stabilizing and/or dispersing the funds.Alternative active ingredient may be in powder form for dilution at the time of application in a suitable carrier, such as sterile water.The number of active compound for administration depends on various factors such as the size and condition of the subject treated of the subject, the route and castrichini dose, enclosed in the interval from 0.3 to 30 mg of active ingredient per kg of body weight, preferably divided into 2-4 a day. Particularly desirable compositions prepared in the form of dosage units containing from 20 to 600 kg of active ingredient per unit.Examples
The overall process
In the following examples, the starting material can be complex 34 de(acetylglucosaminyl)-34-desoximetasone AND2(i.e., the mixture of compounds obtained from complex teicoplanin AND2the method described in the publication of a European patent application N 290922, its individual component or a mixture of two or more of the above components).A typical complex mixture mainly consists of five components corresponding to the formula I, in which part of the molecule aliphatic acyl beta-D-2-deoxy-2-aminopropionitrile radical represented by the symbol A, are respectively: (Z)-4-decanoyl (°C1), 8-methylnonanoic (°C2), decanoyl (°C3), 8-methyldienolone (°C4) and 9-methyldienolone (°C5). B is hydrogen, M is alpha-D-mannopyranosyl and Y means IT. This mixture is determined by the acronym TGAC1-5. If the source materu>, GAC2, GAC3, GAC4or GAC5depending on the specific residue of aliphatic acyl mentioned above aminopropionitrile radical. If you use a mixture of one or more components, then it is determined in the same system as that for the complex. For example, the acronym GAC2-5while component 1 is missing. This mixture is currently produced by the method described in the publication of a European patent application N 290922, which used the catalytic hydrogenation, which saturates the double bond of the component 1, transforming it into the component 3. The acronym GAC2,3determines the mixture of components 2 and 3, and the acronym GAC4,5indicates the mixture of components 4 and 5.The final products the following table. 3 are identified with reference to formula I with an indication for a character And a specific aliphatic acyl substituent β-D-2-deoxy-2-aminopropionitrile radical (A/AC) by the use of traditional determinants AU1AC2AC3AC4and AU5as explained above. If the mixture of two or more components, it is shown by the same conditional descriptors, which are described above.Analysis of vysokoaffinnye sample 20 microlitres type Rheodyme, model 7125 and detector ultraviolet radiation at 254 nanometers.Column: pre-column (1.9 cm) Hibar Lichro Cart 25-4 (Merck), pre-filled with Lichrosorb RP-8 (20-30 μm) followed by column Hibart RT 250-4 (Merck) with gasket Lichrosorb BR-8 (10 μm). Eluent: A) 0.2% aqueous HCOONH4;) CH3CN. Flow rate: 2 ml/min Injection: 20 microlitres. Elution: linear gradient from 20 to 60% eluent In eluent And within 30 minutes Time delay of some exemplary compounds are shown in table 3 b.Acid-base titration. The products were dissolved in methylcellosolve and water in the ratio 4:1 by volume, then in the same solvent mixture was added an excess of 0.01 M hydrochloric acid and the resulting solution was titrated to 0.01 N. sodium hydroxide. The equivalent weight of some exemplary compounds are shown in table 3.Spectrum of nuclear magnetic resonance in nuclei of hydrogen at 500 MHz recorded in the temperature range from 20 to 30oWith spectrometer brouckère AM 500 in dimethyl sulfoxide D6with tetramethylsilane was as an internal standard (Delta equal to 0.00 million parts). Table 3 presents some significant chemical shifts (Delta (million share) for some p what about a single component or a mixture of two or more separate components) and 0.36 ml (about 2.6 mmol) of triethylamine in 20 ml of dimethylformamide was stirred at room temperature for 30 min, adding meanwhile, 0.4 ml (about 2.8 mmol) of the benzyl ether of Harborview acid. Then further added 0.4 ml (about 3.3 mmol) of triethylamine and 4 ml (65 mmol) of chloroacetonitrile, and stirring continued at room temperature for 20 hours the Reaction mixture was poured into 300 ml of ethyl acetate, precipitated precipitated solid substance was collected by filtration, washed with 100 ml of ethyl ether and after drying in vacuum at room temperature for half a day was obtained 4.3 g of the crude cyanomethylene ether N15-carbobenzoxy-G.b) To a stirred solution of product obtained above in 30 ml of dimethylformamide was added 35 mmol of a suitable reactive amine, and the resulting solution was left overnight under stirring at room temperature. Then add 25 ml of absolute ethanol followed by the addition of 250 ml of ethyl acetate. Precipitated precipitated solid substance was collected by filtration, washed with 100 ml of ethyl ether, dried in vacuum at room temperature for 4 h, and was obtained 4.1 g of crude N15-carbobenzoxy formula I, which
C) was dissolved in 350 ml of methanol in 0.01 N. hydrochloric acid in the ratio of 7:3 by volume. The resulting solution Dov is lady coal soaking in 120 ml of hydrogen gas for 2 hours the Catalyst was filtered, and the pH of the clear filtrate was set to 6.5 using 1 N. sodium hydroxide. After adding 300 ml of n-butanol and 15 g silanizing silica gel (0.06 to 0.2 mm, Merck) and the solvents evaporated at 40oC under reduced pressure. The solid residue suspended in 200 ml of water and the resulting suspension was loaded into the upper part of the column with the same the silane treated silica gel in water (400 g). Column showed a linear gradient from 10 to 80% acetonitrile in 0.1 G. of acetic acid for 20 h at a flow rate of 250 ml/h, collecting 25 ml fractions, which were checked by high-performance liquid chromatography. The fractions containing pure compound mentioned in the title of the example were combined, and the pH of the resulting solution was set to 8.5 with 1 N. sodium hydroxide and then concentrated at 40oWith under reduced pressure to a small volume (about 50 ml). Separated solid substance was collected by centrifugation, washed with 10 ml of water, then 250 ml of ethyl ether. After drying at room temperature in vacuum for half a day received the compound of formula I in free base form.To obtain soedinitelny complex G1-5or G1or a mixture of two or more components containing this part, from 2,2,2-trichloro-n-butoxyaniline by the above procedure and the first part of the operation) replace the contacts obtained WITH63-amide-N15-protected amine with zinc in acetic acid according to the method described, Eckert and co-authors in Angew. Chem. Int. Ed. Engl. 17, N 15, 361-362 (1978). Purification was performed in the same manner as described in the second part of the operation).Using suitable reagents GAC and amine of the formula:
in the above-described conditions, obtained compounds are shown in table. 3.Notes to the table. 3 (legend)
(*) AU1means (Z)-4-decanoyl)
(**) M stands for alpha-d-mannopyranosyl
(1) and (2): two products simultaneously obtained in the interaction of two different amino groups separated in the process of reverse-phase column chromatography.(3): the product obtained by carrying out graphy, which showed a very close time delay (min), as verified by high-performance liquid chromatography (instead of collecting all fractions containing the reaction product of the formula (I).(4): the product obtained by conducting the same process as when the connection is 3, but the allocation and accumulation of only those fractions by reversed-phase chromatography, which showed very close values of delay time (min) when tested by high performance liquid chromatography (instead of the accumulation of all fractions containing the reaction products of the formula (I).(5): the product obtained by carrying out the same process to obtain compound 3, but the allocation and accumulation of only those fractions by reversed-phase chromatography, which showed very close values of time delay (min), determined by high performance liquid chromatography (instead of the accumulation of all fractions containing the products of formula (I).(6): the product obtained by the process for obtaining compounds 4, but the allocation and accumulation of only those fractions by reversed-phase chromatography, which show very close values of delay time (min) when testing high-performance liquid XP is e values of the NMR spectrum of the hydrogen nuclei of some representative compounds registered in dimethyl sulfoxide-d6with tetramethylsilane was as an internal standard (Delta 0,00 million shares).Connection 1
2,17 (NCH3): 3,15, 2,32 (CH2polyominoes aliphatic chain); 2,02, 1,45, 1,13, 0,82 (chain aliphatic acyl); 4,32-6,09 (peptide group SN); 6,32-8,62 (aromatic protons and the peptide group NH).Connection 2
3,23, 2,95, 1,58 (CH2-polianinova aliphatic chain); 2,04, 1,45, 1,15, 0,84 (chain aliphatic acyl); 3,42 (mannose); 4,36-6,13 (peptidic CH's); to 6.43-8,56 (aromatic protons and peptidic NH's).Connection 3
3,31, 2,93, 2,11, 1,58 (polianinova aliphatic chain of CH2): 2,04, 1,45, 1,15, 0,82 (chain aliphatic acyl); 4,35-5,75 (peptidic CH's); 6.42 per-8,42 (aromatic protons and peptidic NH's).Connection 4
3,31, 2,93, 2,22, 1,58 (CH2-polianinova aliphatic chain); 2,04, 1,45, 1,15, 0,82 (aliphatic acyl chain); 4,35-5,75 (peptidic CH's); 6.42 per-8,42 (aromatic protons and peptidic NH's).Connection 5
3,29, 2,93, 2,64, 2,08, 1,71, 1,22 (CH2-polianinova aliphatic chain); 2,03, 1,43, 1,18, 0,84 (aliphatic acyl chain); 4,32-6,04 (peptidic CH's); 6,28-8,62 (aromatic and peptide NH).The connection 32
3,33, 2,82 (CH2-N, polyamine); 1,65 (CH2-the (aromatic protons and peptidic NH's). 1. Derivatives teicoplanin General formula I
< / BR>where A N[(C9WITH12)-aliphatic acyl] - beta-D-2-deoxy-2-aminopropanoic, where C9WITH12- aliphatic acyl is (Z)-4-decanoyl, 8-methylnonanoic, decanoyl, 8-methyldecyl, 9-methyldienolone, 6-methyloctanoic, nonanoyl, 10-methylbutanoyl and dodecanol;
In hydrogen or a protective group for amino group;
Y di - or polyamine of the formula
NR [(CH2)mNR1]nX - [(CH2)kNR2]n(CH2)pNR3R4< / BR>where R is hydrogen, R1and R2each independently from each other hydrogen or C1WITH4-alkyl;
R3and R4each independently from each other hydrogen or C1WITH4-alkyl, optionally substituted by a group NH2or is HE, or R3and R4together with the adjacent nitrogen atom, pyrrolidine, piperidine, oxazolidine, thiazolidine, isoxazolidine, isothiazolin, hexahydro-1.5-diazepin, or hexahydro-1,4-diazepin;
m, k and p 2, 3, 4;
n and h 0,1 or 2;
X is a single bond, or when n is 1, taken together with the adjacent group NR1represents a radical of the formula
< / BR>or their additive salts with pharmaceutically acceptable to the12)-aliphatic acyl] - beta-D-2-deoxyadenosylcobalamin, where C9WITH12-aliphatic acyl is (Z)-4-decanol, nonanol, decanol, 8-methyldecyl, 9-methyldecyl, 6-methyloctanoic, nonanoyl, 10-metrodetroit and dodecanol;
B is hydrogen or a protective group for amino group;
Y di - or polyamine of the formula
NR [(CH2)mNR1]nX - [(CH2)kNR2]h(CH2)pNR3R4< / BR>where R is hydrogen;
R1and R2each independently from each other hydrogen or C1WITH4-alkyl;
R3and R4each independently from each other hydrogen or C1WITH4-alkyl, optionally substituted by a group NH2or HE, or R3and R4together with the adjacent nitrogen atom, pyrrolidine, piperidine, oxazolidine, thiazolidine, isoxazolidine, isothiazolin, hexahydro-1.5-diazepin, or hexahydro-1,4-diazepin;
m, k and p 2, 3, 4.n and h 0,1 or 2.X is a single bond, or when n is 1, taken together with the adjacent group NR1represents a radical of the formula
< / BR>or their additive salts with pharmaceutically acceptable acids, characterized in that carry out the transformation of the carboxylic PY N15the amino group, followed by the interaction of the specified activated complex ester with a molar excess of amine of the formula
OTHER-[(CH2)mNR1]n- X-[(CH2)kNR2]h-(CH2)p- NR3R4< / BR>where R, R1, R2, R3, R4, X, m, n, h, k and p have the above meanings, in the presence of an organic polar solvent in the temperature range 5 60oWith and, if necessary, remove protection N15-amino group.3. The method according to p. 1, wherein the activated ester is cyanomethylene complex ether and its molar ratio to amine is in the range 1:10 to 1:20.4. The method according to p. 2, characterized in that the complex cinematology ether is produced by interaction of the original carboxylic acid, preferably protected on the N-aminophenol, approximately 20-30-fold molar excess of chloroacetonitrile in the presence of an inert organic solvent and the base, which is inert to the reaction, when 15 30oC.5. The method according to p. 1, wherein the process is carried out in an inert organic solvent in the presence of a condensing agent selected from among (C1-C4)-alkyl, Fe what aliphatic acyl radical of the molecule, represented by the symbol A, is10-C11aliphatic acyl radical, selected from among (Z)-4-decanoyl, 8-methylnonanoic, decanoyl, 8-methyldecyl, 9-methyldecyl,
In hydrogen or a protective group aminophenol;
R is methyl;
R3and R4each independently from each other hydrogen, linear or branched alil1WITH4possibly substituted NH2group, IT group, or R3and R4taken together with the adjacent nitrogen atom, pyrrolidine, morpholine or piperazine;
m, k and p 2, 3, 4;
n and h is 0 or 1;
X is a single bond or, if n 1, then, taken together with the adjacent group NR1represents a radical of the formula
< / BR>or additive salts with pharmaceutically acceptable acids.
FIELD: organic chemistry, chemical technology, antibiotics.
SUBSTANCE: invention relates to a method for preparing fumarate salt of compound of the formula (II) wherein R1 represents hydrogen atom or lower alkyl group; R2 represents lower alkyl group. Method involves interaction of compound of the formula (I) wherein R1 represents hydrogen atom or lower alkyl group with chloroformate. Then all carbamate groups are removed followed by alkylation of nitrogen atom at 3'-position of desosamine ring to obtain compound of the formula (II) and conversion of this compound to fumarate salt. Interaction of compound of the formula (I) with chloroformate is carried out in the presence of cyclic ether or carboxylic acid ester. Carbamate groups are removed in the presence of sodium hydrocarbonate. Crystallization and re-crystallization of compound of the formula (II) fumarate salt is carried out from alcohol-containing solvent, in particular, from isopropyl alcohol. Method provides increasing yield and enhancing purity of the end product.
EFFECT: improved preparing and purifying method.
28 cl, 11 ex
FIELD: production of macrolide road-spectrum antibiotic tylosine.
SUBSTANCE: claimed method includes tylosine deposition from organic tylosine base concentrate with organic solvent (hexane). Deposition is carried out by addition of organic tylosine base concentrate to hexane at velocity of 3-5 ml/min per 50 ml of concentrate.
EFFECT: method for production of tylosine base in granulated form with homogeneous composition.
2 cl, 6 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: 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.
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, 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
SUBSTANCE: invention relates to azithromycin as a stable monohydrate comprising from 4.0% to 6.5% of water and to a method for its preparing. Invention provides preparing the stable form of azithromycin monohydrate.
EFFECT: improved preparing method.
3 cl, 2 tbl, 2 ex
SUBSTANCE: invention concerns macrolide compounds of the formula I , where R is hydrogen or methyl; R1 is hydrogen, N,N-di(C1-C3)alkylamino, N,N-di(C1-C3)alkylamino-N-oxide, N-(C1-C3)alkyl-N-benzylamino, N-(C1-C4)acyl-N-(C1-C3)alkylamino, N-[N,N-dimethylamino-(C1-C4)alkylamino]acetyl-N-(C1-C3)alkylamino or a chain of the formula: , where A is hydrogen, phenyl or thiazolyl; X is O or NR6 where R6 is hydrogen; Y is thiazolyl, pyrinidyl or NR6 where R6 is hydrogen; r is a whole number of 1 to 3; m is a whole number of 1 to 6; n is a whole number of 0 to 2; R2 is hydrogen; or R1 and R2 together form a link; R3 is a hydroxygroup or forms a =N-O-R5 group together with R4, where R5 is hydrogen, alkyl or a chain of the formula -(CH2)r-X-(CH2)m-Y-(CH2)n-A where r, m, n are the whole number as defined above; A is hydrogen, thiazolyl, furanyl or thiophenyl; X is NR6 where R6 is hydrogen; Y is a phenylene group or NR6 where R6 is hydrogen; R4 is hydrogen or forms =N-O-R5 group together with R3, with the same R5 as defined above; and its pharmaceutically acceptable salts, on the condition that R1 is not a dimethylamino group when R3 is a hydroxy group, and both R2 and R4 are hydrogen; R1 is not a dimethylamino group when in the =N-O-R5 substitute in 9 position R5 is hydrogen, linear or branched (C1-C5)alkyl; R1 is not a methylamino group when in the =N-O-R5 substitute in 9 position R5 is hydrogen, linear or branched (C1-C5)alkyl. The invention also concerns a method of obtaining the claimed compounds by elimination of L-cladinose residuum in the 3 position in compounds of the general formula II , where R, R1, R2, R3 and R4 are the same as defined above. Besides, the invention also concerns compounds of the general formula II, where R is hydrogen or methyl; R1 is hydrogen, N,N-di(C1-C3)alkylamino, N,N-di(C1-C3)alkylamino-N-oxide, N-(C1- C3)alkyl-N-benzylamino, N-(C1-C4)acyl-N-(C1-C3)alkylamino, N-[N,N-dimethylamino(C1-C4)alkylamino]acetyl-N-(C1-C3)alkylamino or a chain of the formula: where A is hydrogen, phenyl or thiazolyl; X is O or NR6 where R6 is hydrogen or C1-C3alkoxycarbonyl; Y is thiazolyl, pyrinidyl or NR6 where R6 is hydrogen or C1- C3alkoxycarbonyl; r is a whole number of 1 to 3; m is a whole number of 1 to 6; n is a whole number of 0 to 2; R2 is hydrogen; or R1 forms a link together with R2; R3 is a hydroxy group; R4 is hydrogen; and their pharmaceutically acceptable salts; on the condition that (i) R1 is not N,N-dimethylamino or (ii) R1 is not N,N-dimethylamino-N-oxide when R is hydrogen. The invention also concerns pharmaceutical composition based on the compound of the formula I, exhibiting anti-inflammatory effect.
EFFECT: obtaining of compounds with anti-inflammatory effect.
29 cl, 78 ex
SUBSTANCE: invention concerns avermectin B1 and avermectin B1 monosaccharide derivatives of the general formula I , where n is 0 or 1; A- B is -CH=CH- or -CH2-CH2-; R1 is C1-C8-alkyl, C3-C8-cycloalkyl or C2-C8-alkenyl; R2 is C1-C8-alkyl or C2-C8-alkenyl, optionally substituted by a subsitutde selected out of the group of -OH, - N3, -NO2, C1-C8-alkoxy-, C1-C6-alkoxy-C1-C6-alkoxy, C1-C8-alkylthio, C1-C8-alkylsulfinyl, C1-C8-alkylsulfonyl, -NR4R6, -X- C(=Y)-R4, -X-C(=Y)-Z-R4, or phenyl substituted optionally by halogen; R3 is H or C1-C8-alkyl substituted by halogen; or R2 and R3 together are a 3-7-membered alkylene bridge substituted optionally by C1-C4-alkyl, or form together a -CH2-CH2-O-CH2- or -CH2-CH2-C(=O)-CH2- group; X is -O- or NR5; Y is -O-; Z is -O-; R4 is hydrogen or C1-C8-alkyl substituted optionally by C1-C6-alkoxy; R5 is hydrogen or C1-C8-alkyl; R6 is hydrogen or C1-8-alkyl if the compound is not a avermectin B1a or B1b derivative where n is 1, R3 is H and R2 is -CH2-CH2-OCH3 or -CH2-CH2-O-phenyl; and is not a B1a or B1b derivative where n is 1, and R2 and R3 form together an unsubstituted -CH2-CH2-CH2- group; while their E/Z isomers, mixes of E/Z isomers and/or tautomers, in a free or salt form in each case.
EFFECT: production of insecticide composition and method of cultivated plant pest eradication.
7 cl, 5 tbl, 27 ex
SUBSTANCE: invention concerns (a) new compounds of the formula I: , where M is a macrolipid subunit (macrolipid group) obtained from a macrolipid inclined to accumulation in inflamed cells, S is a steroid subunit (steroid group) obtained from a steroid medicine with anti-inflammatory effect, and L is a linker molecule connecting M and S; (b) their pharmacologically acceptable salts, prodrugs and solvates; (c) methods and mediators for their obtaining; and (d) methods of their application in treatment of human and animal inflammation diseases and conditions. The claimed compounds are inhibiting many cytokines and immune mediators participating in immune reactions that cause inflammation, allergy or alloimmunity, including IL (interleukin)-1, 2, 4, 5, 6, 10, 12, GMCSF (Granulocyte Macrophage Colony Stimulating Factor), ICAM (Intercellular Adhesion Molecule) and TNF (tumour necrosis factor) - α without limitation. At that, antiinflammation steroids have immediate anti-inflammatory effect due to the link to glycocorticosteroid receptor.
EFFECT: application in treatment of human and animal inflammation diseases and conditions.
30 cl, 40 ex, 4 dwg