Macrolide compound, the composition having antibiotic activity, veterinary composition, insecticidenematicides composition and method for killing insects and/or mites, nematodes

 

(57) Abstract:

Described compounds characterized by formula (I) contained in the description text. These compounds can be used as antibiotics for humans and animals and for the destruction of pests. 5 C. and 7 C.p. f-crystals, 2 tab.

The invention relates to new compounds antibiotics, to the processes of obtaining these compounds, and to pharmaceutical compositions containing these compounds.

In the patent description N 2166436 (UK) described receiving antibiotics S 541, which may be separated from the fermentation products of new Streptomyces sp.

The authors of the present invention discovered another group of compounds characterized antibiotic activity, which can be obtained by chemical modification of antibiotics S 541.

In accordance with one aspect, the present invention particularly relates to compounds characterized by formula I

< / BR>
and their salts,

where R1is a methyl-, ethyl - or isopropylate,

R2the atom of hydrogen, C3-8is an alkyl group or a C3-8-Alchemilla group,

OR3the hydroxyl group is, hence, adaptation.

The term "alkyl" or "Alchemilla" referring to a group or part of a group in the compounds characterized by formula I, means that this group is a linear or branched.

In those cases where R2in the compounds characterized by formula I, represents a C1-8alkyl group, for example, it may be methyl group, ethyl group norms-through group, isopropyl group, standards-butilkoi group, isobutylene group or tert-butilkoi group, and preferably it is a methyl group.

In those cases where R2represents a C3-8alkenylphenol group, it may, for example, be an allyl group.

In cases where a group OR3in the compounds characterized by formula (I) is substituted with hydroxyl group, it can represent acyloxy-group, i.e. a group characterized by the formula-OCOR4, OCO2R4or OCSOR4(where R4represents an aliphatic, analiticheskoy or aromatic group, such as, for example, an alkyl group, Alchemilla group, Alchemilla group, cycloalkyl group, kalkilya group or aryl group), and the AK was listed for R4), a group characterized by the formula-OSO2R6(where R6represents a C1-4alkyl group or a C6-10aryl group), a cyclic or acyclic acetaldoxime, a group characterized by the formula OCO(CH2)pCO2R7(where R7represents a hydrogen atom or group as described above for R4and p is 0, 1 or 2) or a group characterized by the formula OCONR8R9(where R8and R9can each independently from each other be a hydrogen atom or a C1-4alkyl group, i.e., for example, methyl group).

In those cases where R4and R5represent alkyl groups, they may be, for example, C1-8alkyl groups, i.e., methyl group, ethyl group norms-through group, isopropyl group, standards-butilkoi group, isobutylene group, tert-butilkoi group or standards-heptylene group and the alkyl groups may also be substituted. In those cases where R4is a substituted alkyl group, this group may be substituted, for example, one or more, for example, two or three halogen atoms (for example, atoms chlorite, silyloxy group. In those cases, code R5represents a substituted alkyl group, this group may be substituted with cycloalkyl group, such as for example, cyclopropyl group.

In those cases where R4and R5are alkenylphenol or alkenylphenol groups, they can be, for example, C2-8alkenylphenol group, such as, for example, allyl group, or a C2-8Alchemilla group.

In those cases where R4or R5are cycloalkyl group, they may constitute, for example, C3-11cycloalkyl groups, such as C3-7cycloalkyl group, i.e. for example, cyclopentyl group.

In those cases where R4and R5are kalkilya groups, they preferably contain from 1 to 6 carbon atoms in the alkyl fragment and the aryl group or the aryl group may represent a carbocyclic group or heterocyclic group, preferably containing from 4 to 15 carbon atoms, i.e., for example, phenyl groups. Examples of such groups are the Hairdryer-C1-6alkyl groups, i.e., for example, benzyl group.

In those cases where R4and R5predstavitelno contain from 4 to 15 carbon atoms and may for example, be a phenyl group.

In those cases where R4contains silyloxy Deputy, the silyl group may include three groups, which may be the same or different and selected from the group comprising alkyl, alkenylphenol, alkoxy cycloalkyl, Uralkaliy, aryl or aryloxy group. Such groups may be the same as described above for R4especially the methyl tert-butilkoi or phenyl groups. Typical examples of such silyloxy groups are trimethylsilyloxy group and tert-butyldimethylsilyloxy group.

In those cases, when-OR3is a group characterized by the formula-OSO2R6it may, for example, to represent methylsulfonylamino-group or pair-toluensulfonate group.

In cases where OR3represents a cyclic acetyloxy group, this group may have, for example, from 5 to 7 ring members and may constitute, for example, tetrahydropyranyloxy group.

In cases where OR3is a group characterized by the formula OCO(CH2)nCO2R7t>H2CO2R7awhere R7arepresents a hydrogen atom or a C1-4alkyl group, i.e., for example, methyl group, or ethyl group.

Salt, which can be obtained by using the compounds characterized by formula I containing an acid group, are salts with bases, i.e., for example, alkali metal salts, i.e., such as salts of sodium or potassium.

In the compounds characterized by formula I, R1preferably should be an ISO-propyl group.

Group OR3preferably represents methoxy, carbonyloxy group or in particular acetoxy group, methoxy group or hydroxy group. In General, compounds characterized by formula I, in which OR3represents a hydroxy group are preferred. Important compounds obtained in accordance with the present invention are those compounds characterized by formula (I) in which R1represents an ISO-propyl group, R2represents a methyl group and OR3represents a hydroxy group, an acetoxy group or methoxycarbonylamino group.

As mentioned previously, coedine, which is the subject of the present invention can also be used as intermediates in obtaining other active compounds. In cases where compounds are the subject of this invention are used as intermediates, OR3the group may be a protected hydroxyl group, and the invention especially relates to such protected compounds. It must be emphasized that such a group must possess minimum of additional functionality to avoid further reaction centres, and should be such that it is possible to make it selective regenerative hydroxyl group. Examples of protected hydroxyl groups are well known groups, which are described, for example, in the book "Protective Groups in Organic Chimistry" by Theodora W. Greene (Wilty-Interscience, New York, 1981) and "Protective Groups in Organic Chemistry" by J. F. W. McOmie (Plenum Press. London, 1973).

Examples OR3protected hydroxyl groups are phenoxyacetate group, soliloquizes-group (i.e., for example, trimethylsilylacetamide group and tert-butyldimethylsilyloxy-group), silyloxy groups, such as, for example, trimethylsilyloxy-Asia such groups, you will mainly find use as intermediates. Other groups, such as acetoxy groups, can serve as a protected hydroxyl groups, but may also be present in the target active compounds.

Compounds that are the subject of the present invention, are characterized by antibiotic activity, i.e., for example, de-worming (antihelminthic) activity, for example, against nematodes, especially these compounds are characterized by antiindependence and anticlimactically activity.

Ectoparasites and endoparasites affect people and many different animals, in particular they affect farm animals such as pigs, sheep, cattle, and poultry (such as chickens and turkeys), horses, rabbits, birds and domestic animals such as dogs, cats, Guinea pigs, hamsters, etc. Parasitic infection in living organisms leads to anemia and weight loss, which is an important cause of economic losses worldwide.

Examples of species of endoparasites, affecting such animals and/or people are Ancylostoma, Ascaridia, Ascaris, Aspicularis, Brugia, Bunostomum, Capillaria, Chabertia, Cooperia, Cyathostomes, Dictyocaulus, Dirofilaria, Dracunculus, Enterobiuaris, Probstmayria. Strongylus, Strongyloides, Syphacia, Thelazia, Toxascaris, Toxocara, Trichomema, Trichostrongylus, Trichinella, Trichuris, Triodontophorus, Uncinaria and Wuchereria.

Examples of parasites that infect animals and/or people are Arthropoda ectoparasites, such as stinging, biting insects, meat flies, fleas, lice, blood-sucking insects, mites and other dockrillia insects.

Examples of parasites that infect animals and/or people are Ambylomma, Anopheles, Boophious, Chorioptes, Culexpipiens, Culliphore, Demodex, Damalinia. Dermatobea, Haematobia, Haematopinus, Haematophysalis, Hyaloma, Hypoderma, Ixodes, Linognathus, Lucilia, Melophagus, Oestrus, Otobius, Otodectes, Psorergates, Psoroptes, Rhipicephalus, Sacroptes, Solenopotes, Stomoxys and Tabanus.

Compounds that are the subject of the present invention, as installed, are effective as when used in vitro and in vivo against a wide range of endoparasites and ectoparasites. The antibiotic activity of the compounds which are the subject of the present invention may be, for example, shown in the form of their activity to free-living nematodes such as Caemorhabditis elegans and Nematospiroides dubius.

Important active compound which is the subject of the present invention, is a compound characterized by the formula (I) in which R1before the methoxy group.

Another important active compound which is the subject of the present invention, is a compound characterized by the formula I, in which R1represents an ethyl group, R2represents a methyl group and OR3represents a hydroxyl group.

Particularly important active compound which is the subject of the present invention, is a compound characterized by the formula (I) in which R1represents an ISO-propyl group, R2represents a methyl group and OR3represents a hydroxyl group.

Compound characterized by the formula (I) in which R1represents an isopropyl group, R2represents a methyl group and OR3represents a hydroxyl group, is an active compound against a wide range of endoparasites and ectoparasites. For example, it was found that the connection specified above, is active in the application of in vivo against parasitic of nematodes, such as Ascaris, Cooperia curticei, Cooperia oncophora, Cyathostomes, Dictyocaulus viviparus, Dirofilaria immitis, Jastophilus, Hacmonchus, Conforfus, Nematodirus battus, Nematodirus helvefianus, Nematodirus spathiger, Nematospiroides dubius, Nippostronontophorus and Uncinaria stenocephala, and against parasitic larvae, caterpillars, scabby ticks, fleas, lice, such as Amblyomma hebraeum, Anopheles stevensi, Boophilus dicolararfus, Boophilus microplus, Choriopfes ovis, Culexpipiens molesfus, Datalinia bovis Dermafobia, Hatmafopinus, Hypoderma, Linognafhus vifuli, Lucilia sericafa, Psoropfes ovis, Phipicephalus appendiculafus u Sarccopfes.

Compounds that are the subject of the present invention can also be used as insecticides, acaricides and nematicides for the destruction of insects in agriculture, in forestry, plantations of fruit trees, as well as in public areas and warehouses. Insects living in the kidney or on crops, including cereals (e.g. wheat, barley, maize and rice), cotton, tobacco, vegetables, such as, for example, soybeans, fruits, such as apples and citrus, and tuberous plants, such as sugar beet and potatoes, can be successfully destroyed with the help of the compounds that are the subject of the present invention. Typical examples of such insects are different kinds of fruit mites and aphids such as Aphis fabae, Aulacorthum circumflexum, Myzus persicae, Nephotettix cineticeps, Nilparvata lugens, Panonychus ulmi, Pherodon humuli, Phyllocoptruta oleivora, Tetranychus urticae and insect species Trialeuroides; nematodes, such as the species randis and Sitophilus granarius; flour beetles, such as Triboluim castaneum, flies, such as Musca domestica, ants, termites, such as Pear Psylla; Tripstabaci; cockroaches, such as Blatella germanica and Periplaneta americana, as well as mosquitoes, such as Aedes aegypti.

In particular, as identified by the applicants of the present invention, the compound which is the subject of the present invention and characterized by the formula (I) in which R1represents an ISO-propyl group, R2represents a methyl group and OR3represents a hydroxyl group, is active against Tetranychus urticae, on the leaves, French beans, against Myzus persicae, are on leaves of Chinese cabbage, against Heliothis virescens, on the leaves of the cotton against Nilaparvata lugens, on the shoots of rice, against Musa domestica, in plastic boxes, in which is placed a solution of sugar and cotton yarn, against Blattella germanica, placed in plastic boxes with pieces of food, against Spodoptera exique found on leaves of cotton, and against Melodogynt incognita.

Compounds that are the subject of the present invention can also be used as fungicides, for example, against stamov species of Candida sp. such as Candida and Candida ablicans glabra is inane, characterized by formula (I) as described above, which can be used as antibiotics. In particular, these compounds can be used for the treatment or processing of animals and people infected with endoparasites, ectoparasites and/or mold infections, and can also be used in agriculture, forestry, plantations, as pesticides to kill insects, as well as acaricides and nematicides. These compounds can also be used in General as a pesticide to kill insects and in other cases, such as in warehouses, buildings and other public places or habitats insects. In General, these compounds can be applied directly to the body of the habitat of these parasites (i.e. animal or human body, or plants, or vegetables) or the compounds can be applied to habitat or directly on the insects themselves.

Compounds that are the subject of the invention may be prepared for use in any convenient way for use in veterinary medicine or medicine, and thus the present invention relates also to what I use in veterinary and human medicine. Such compositions can be prepared for use in the usual manner using one or more suitable carriers or diluents. Compositions of the subject invention include such forms, which are especially prepared for parenteral input, including input into the mammary gland, as well as compositions designed for oral, rectal, topical, vnutrikoronarnogo implanted, ophthalmic applications, applied through the nose or genito-urinary application.

Compounds that are the subject of the invention may be prepared for use in veterinary medicine or medicine by injection, they can be prepared in the form of a unit dose, in ampoules or other containers containing a single dose, or in containers containing multi-dose, if necessary, to such compositions may be added as preservatives. Compositions intended for injection, can be prepared in the form of suspensions, solutions or emulsions in aqueous media, or using media that does not contain water, they may contain agents that promote the formation of compositions, i.e., such as suspendida, stabilizing, em is prepared in the form of a sterile powder for subsequent introduction into a suitable carrier, such as, for example, sterile water, not containing pyrogens. This preparation is made before applying.

To the oil media include polyhydric alcohols and their esters, such as complex glycerol esters, fatty acid series, vegetable oils, such as peanut oil, cotton seeds or fractionated coconut oil, mineral oil, such as, for example, liquid paraffin, isopropyl myristate and etiloleat, and other similar compounds. Other media containing materials, such as glycerol formal, propylene glycol, polyethylene glycols, ethanol or glycoluril, can also be used. Conventional nonionic, cationic or anionic surface-active agents may be used either alone, or in combination with each other in the preparation of the composition.

Compositions intended for veterinary use, can also be prepared in the form of injections to enter into the mammary gland as providing a slow release of active component (for long exposure), and based on, quickly produce the active ingredient. These compositions can imagine with humaydi or suspendisse agent, such as, for example, soft or hard paraffins, beeswax, 12-hydroxy stearin, hydrogenated, Kastoria oil, stearates of aluminum or glyceryl the monostearate. Conventional nonionic, cationic or anionic surfactants can be used either one by one or in combination with each other in the preparation of such compositions.

Compounds that are the subject of the present invention can also be applied to veterinary or medical appointment in a form suitable for oral administration, i.e. in the form of solutions, syrups, emulsions or suspensions or in the form of a dry powder for subsequent mixing with water or other suitable media and before use, optionally with the addition of coloring or flavoring agent. Solid compositions such as tablets, capsules, pellets, beads, pastes, powders, granules or pre-mixed form may also be used. Solid and liquid compositions intended for oral use can be obtained in accordance with methods well known to specialists in this field. Such compositions may also contain one or more farmatsevticheskii suitable carriers, designed for use in solid ready-made forms are linking agents, i.e., such as, for example, pre-gelatinizing maize starch, polyvinylpyrrolidone or oksipropilmetiltselljuloza, fillers such as, for example, lactose, microcrystalline cellulose or calcium phosphate, lubricants, such as magnesium stearate, talc or silica, disintegrant, such as, for example, potato starch or sodium, glycolate starch, or moisturizing agents, such as, for example, the sulphate of lauryl sodium. Tablets can be coated using methods well known to specialists in this field.

Examples of pharmaceutically suitable additives for use in the preparation of liquid ready-made forms are suspendresume agents, such as, for example, sorbitol syrup, methyl cellulose or hydrogenated edible fats, emulsifying agents, such as, for example, lecithin or acacia, anhydrous media, such as, for example, almond oil, oily esters or ethyl alcohol; and preservatives, such as, for example, methyl - or popilar-oxybenzoates or sorbic acid, also in such forms that can be included stabilizing the ENES in accordance with the methods well-known specialists in this field. Examples of pharmaceutically acceptable suitable additives intended for use when applying a paste-like compositions are suspendresume or gelling agents, such as, for example, distearate aluminum or hydrogenated castor oil; dispersing agents, such as, for example, Polysorbate, anhydrous media, such as, for example, peanut oil, oily esters, glycols or macrogol; stabilizing and solubilizing agents. Compounds that are the subject of the present invention can also be applied in veterinary purposes by introducing them into the daily diet as in solid and liquid food, i.e. as part of the daily dose of food or drinking water.

Compounds that are the subject of the present invention may also be administered orally for veterinary purposes in the form of a liquid dose of medication, such as solution, suspension or dispersion of the active ingredient together with a pharmaceutically suitable carrier or excipient.

Compounds that are the subject of the present invention can also, for example, be prepared in the form of suppositories, i.e., the dosage, the content is such purposes, or in the form of a pessary, i.e., for example, contains the materials used for the manufacture of ordinary pessary.

Compounds that are the subject of the present invention can be used for topical application in veterinary or medical purposes in the form of ointments, creams, lotions, shampoos, powders, aerosols, compositions for makanya or drops, such as eye drops or nasal drops. Ointments or creams can be, for example, prepared using an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Ointment for ophthalmic use may be made under sterile technique using a sterile components. Compositions intended for application by irrigation of the surface can be prepared for veterinary purposes with the use of organic solvents or in the form of aqueous suspension may contain agents which accelerate the process of adsorption through the skin, these compositions can also contain agents that provide the solubilization, stabilization or preservation, or in some way improve the storage characteristics and/or ease of use.

Lotions can be prepared viceroyship agents, dispersing agents, suspendida agents, thickening agents, or coloring agents.

Powders can be prepared using any suitable powder base. Drops can be obtained by using aqueous or anhydrous base and also contain one or more dispersing agents, stabilizing agents, solubilizing agents or suspendida agents. They may also contain a preservative.

For application by inhalation the compounds that are the subject of the present invention can be used for veterinary or medical purposes in the form of an aerosol stream or in the form of a spray or stream.

The total daily dosage of the compounds that are the subject of the present invention and used in veterinary and medical purposes, should be in the range from one to 2000 mg/kg body weight, preferably in the range of from 5 to 800 µg/kg of body weight, and this dose may be divided into individual doses taken, for example, from 1 to 4 times a day. It should be emphasized that dosage will depend on the age and condition of the patient, the body being treated, the input method of the preparation and the form of the deposits, for example, by comparing the activities of this compound and of a known agent of antibiotic.

Compounds that are the subject of the present invention can be used in any normal way when agricultural or horticultural use, and thus the invention includes all those compositions containing compounds that are suitable for use in agriculture and in the processing of gardens, plantations. Such forms include anhydrous or liquid compositions, for example, dusty, bases containing dusty or concentrates, powders, including soluble or irrigated powders; granules, including microspheres and dispersible granules; fluid composition; emulsions, such as, for example, a diluted emulsion or emulsifiable concentrates, spray solutions, such as, for example, solutions for processing roots and seeds; solutions for watering seeds; oil concentrates, solutions, oil; injection, such as, for example, injections for watering stems; compositions for spraying, fumigation and treatment mist.

In General, these preparations will include a connection associated with a suitable carrier or diluent. Such but the use of the compounds or by dispersing it in there, where it should be applied, or by creating a prepare which can be received and processed in dispergirovannoyj composition. These arrangements are well known to specialists in this field and can be obtained using conventional methods, such as, for example, mixing and/or grinding the active ingredient or ingredients together with a carrier or diluent, such as, for example, a solid carrier, solvent or surface active agent.

Suitable solid carriers for use in finished form, such as, for example, dusty, granules or powders, can be a material selected from the group comprising, for example, natural mineral fillers, such as diatomaceous earth, talc, kaolinite, montmorillonite, profilit or attapulgite. Highly dispersed silicic acid or highly dispersed absorbent polymers can, if necessary, be added to the composition. Granular media having adsorption ability, which can be used may be a porous material such as, for example, pumice, crushed brick, thick or bentonite, or non-porous materials, take and which may be organic or inorganic nature, are dolomite and crushed remains of plants.

Suitable solvents for use as carriers or diluents are aromatic hydrocarbons, aliphatic hydrocarbons, alcohols and glycols or their ethers, esters, ketones, amides, acids, strong polar base, if necessary epoxydecane vegetable oil and water.

Conventional nonionic, cationic or anionic surface-active agents, such as, for example, ethoxylated alkyl phenols and alcohols, salts of alkali metals or alkaline-earth metal, alkyl benzene sulfonic acids, lignosulfonic acids or sulfosuccinic acids or sulfonates polymeric phenols, which have good emulsifying, dispersing and/or wetting properties, may also be used either in pure form or in combination in the above compositions.

Stabilizers, agents, caking; agents that prevent foaming, agents, viscosity regulators, fillers and adhesives, photostabilization and fertilizers, food stimulants and other active substances may be, if necessary, introduced in compose insecticides, acaricides and nematicides.

In these preparations the concentration of active material in General should be in the range from 0.01 to 99 wt. more preferably in the range of from 0.01 to 40 wt.

Industrial products in General are produced in the form of concentrated compositions, which should be diluted in their application, for example, 0.001 and 0.0001 wt.

The number of used connections is dependent on a number of factors that must be considered, these include the type of insect and the degree of contamination. However, in the General case, the flow rate in the range from 10 g/ha to 10 kg/ha is suitable, preferably applied in an amount of 10 g/kg to 1 kg/ha to destroy mites and insects, in an amount of 50 g/ha to 10 kg/ha for the destruction of nematodes.

Compounds that are the subject of the present invention, can be introduced or applied in combination with other active ingredients. In particular compounds which are the subject of the present invention, can be introduced or applied in combination with other known anthelminthic drugs. By combining the compounds of the subject invention, with other protivogelmintnye able to successfully fight. Can be realized the possibility of successful struggle against parasitic infections, against which certain drugs are ineffective or have only partial activity.

Compounds that are the subject of the invention may be obtained using methods that will be described later. In accordance with some of these methods seems to be necessary to protect the hydroxyl group in 5-position in the source material before you can implement the described reaction. In such cases, then it may be necessary to ensure the removal of the protection of this hydroxyl group with the purpose of carrying out the reaction, designed to obtain the target compound, which is the subject of the invention. The usual ways to protect and unprotect can be used for these purposes, these methods, such as described in the above-mentioned book, greens and Mac-AMI.

In accordance with one aspect of the present invention, the applicant has developed a method (A) obtain the compounds characterized by formula (I), which involves the reaction between a compound characterized by the formula (II):

< / BR>
where R1and OR3there is as mentioned above,

and the connection is above), and if necessary, followed by removing protection for compounds characterized by formula (I), in which OR3represents a protected hydroxyl group, and, if necessary, followed by the formation of salt.

The reaction oxymorphine can be carried out in aqueous or anhydrous reaction medium, typically at temperatures in the range from -20 to +100oC, for example from -10 to +50oC. it Seems convenient to use a reagent characterized by the formula H2NOR2in salt form, for example attached acid salt such as hydrochloride. In those cases, when such a salt is used, the reaction can be carried out in the presence of an agent that binds acid.

Solvents that can be used are water and miscible with water, solvents such as alcohols, e.g. methanol or ethanol, amides, such as N,N-dimethylformamide, N,N-dimethylacetamide or hexamethylphosphoramide, ethers, such as simple cyclic ethers, i.e., tetrahydrofuran or dioxane, and allowee ethers, such as dimethoxyethane or simple diethyl ether, NITRILES, such as acetonitrile, sulfones, such as, for example, sulfolan, the s, such as ethyl acetate, and also mixtures composed of two or more such solvents.

In those cases, when using a water medium for the reaction, the reaction medium can usually be bateriafina using the appropriate acid, base or buffer solution to a value of pH equal to from 2 to 9 pH units.

Suitable acids include mineral acids such as hydrochloric acid or sulfuric acid, and carboxylic acid, such as for example, acetic acid. Suitable bases are carbonates and bicarbonates of alkali metals such as sodium bicarbonate, hydroxide, such as, for example, sodium hydroxide, and carboxylates of alkali metals, such as, for example, sodium acetate. Suitable buffer solution is a solution consisting of sodium acetate and acetic acid.

The compounds characterized by formula II are either known compounds, which are listed in the patent description UK N 2176182, or can be obtained from known compounds described in this text, using standard procedures.

In accordance with another aspect of the present invention applicants n the o a C1-8alkyl group or a C3-8alkenylphenol group, OR3represents a substituted hydroxyl group. This method consists in the reaction between a compound characterized by the formula (I), in which OR3represents a hydroxyl group, and a reagent, the function of which is the conversion of the hydroxyl group in the substituted hydroxyl group, followed if necessary by the formation of salt.

Acylation, formirovanie, sulfonation, esterification, solirovanie or the reaction of formation of the acetal can be conducted using conventional methods, as will be indicated below.

For example, the acylation reaction may be carried out using Alliluyeva agent, such as, for example, acid characterized by the formula R4COOH, or a reactive derivative of this acid, such as, for example, acid halide, i.e., such as, for example, acid chloride; anhydride or activated ester, or a reactive derivative of carboxylic acid having the formula R4OCOOH, or thiocarbonic acid having the formula R4OCSOH.

In the acylation reactions using halide acids and anhydrides, can if is such as for example, the tertiary amine (i.e., for example, triethylamine, dimethylaniline or pyridine), inorganic bases (such as, for example, calcium carbonate or sodium bicarbonate), and cyclic radicals, such as lower oxide 1,2-alkylene (i.e., for example ethylene oxide or propylene oxide), in which the halide, hydrogen bonding, is released in the reaction of acylation.

The acylation reaction using an acid, usually should be carried out in the presence of a condensing agent such as carbodiimide, such as, for example, N, N'-dicyclohexylcarbodiimide or N-ethyl-N' -dimethylaminopropylamine; carbonyl compounds such as carbonyldiimidazole, or salts isoxazol such as, for example, perchlorate, N-ethyl-5-phenylisoxazole.

The activated ester can be conveniently obtained by using, for example, 1-oxibendazole in the presence of a condensing agent as described above. Alternative activated ester can be obtained in advance.

The acylation reaction can be carried out in water or in an anhydrous reaction medium, typically at temperatures in the range from -20 to +100, i.e., for example, from -10 to +50oC.

The reaction formiliar, N-formyl an imidazole or an anhydride of formic-acetic acid, under normal reaction conditions.

The reaction sulfonylurea can be carried out using a reactive derivative of sulfonic acids, characterized by the formula R6SO3H, such as, for example, sulfanilamide, i.e., for example, chloride R6SO2Cl, or sulfonovy anhydride. The reaction sulfonylamine preferably conducted in the presence of a suitable agent that binds acid, as indicated above.

The esterification reaction can be carried out using a reagent characterized by the formula R5Y ( where R5there are as above and Y is a chip off the group, such as chlorine, bromine or iodine, or hydrocarboncontaminated group, such as methylsulfonate or telesurveillance, or haloalkoxy group, such as dichloroacetate). This reaction can be carried out by formation of a magnesium alcoholate with the use of the Grignard reagent, such as, for example, halide Metalmania, such as iodide Metalmania, or using a halide trialkylamine, such as, for example, chloride trimethylsilylmethylamine followed by treatment with a reagent, Imami as the oxide of silver, the silver perchlorate, silver carbonate, silver salicylate and mixtures thereof, and this system may be particularly suitable in those cases where the process of esterification is carried out using the halide of the alkyl, i.e., for example, methyl iodide.

The esterification reaction can be conveniently carried out in a solvent such as simple ether, i.e., for example, diethyl simple ether.

The formation of the acetal can be carried out by reaction with a cyclic or acyclic simple vinyl ether. This method is particularly suitable for simple tetrahydropyranyloxy esters using as reagent dihydropyran or 1-alkoxyalkyl ethers, such as 1-adaxially simple ether, using as reagent simple alkylvinyl ether. This reaction should be carried out in the presence of a strong acid catalyst such as mineral acids, such as sulfuric acid or in the presence of organic sulfonic acids, such as, for example, paratoluenesulfonyl, digitoxigenin, containing no water solvent.

Solvents that can be used to hold above the reaction is of ethylphosphonate), ethers (i.e., for example, cyclic ethers, such as tetrahydrofuran or dioxane, and acyclic ethers, such as dimethoxyethane or diethyl simple ether), NITRILES (e.g. acetonitrile), hydrocarbons such as, for example, halogenated hydrocarbons (e.g. methylene chloride), and esters, such as, for example, ethyl acetate, and also mixtures composed of two or more such solvents.

The reaction sililirovanie can be carried out by reacting with halide Silla (i.e., for example, chloride), preferably in the presence of a base, such as, for example, triethylamine imidazole or pyridine, using a solvent such as dimethylformamide.

The reaction carbamylcholine, allowing to obtain a compound characterized by the formula (I), in which OR3is a group characterized by the formula OCONR8R9may be carried out by reacting with suitable allermuir (i.e. carbamoylethyl) agent. Suitable carbamoyloximes agents that can be used to obtain compounds in which one of R8and R9represents a hydrogen atom, and the other predstavljaet a C1-4alkyl group). The reaction carbamylcholine should, as appropriate, be carried out in the presence of a solvent or mixture of solvents selected from the group comprising hydrocarbons (for example, aromatic hydrocarbons such as benzene or toluene), halogenated hydrocarbons (such as dichloromethane), amides (such as, for example, formamide or dimethylformamide), esters (such as ethyl acetate), ethers (e.g., such as cyclic ethers, i.e., tetrahydrofuran or dioxane), ketones (such as acetone), the sulfoxidov (i.e., for example, such as dimethyl sulfoxide or mixtures of these solvents. This reaction can be conducted at temperatures in the range from -80oC to the temperature of the boiling point of the reaction mixture, for example to 100oC, preferably in the range from -20 to +30oC.

Reaction carbamylcholine can contribute to the presence of a base, such as, for example, tertiary organic base, for example, three-/lower alkyl/amine, e.g. triethylamine.

Other suitable carbamoylethyl agent is cyanic acid, which can usually be done at the place, aprimarily, such as, for example, a strong organic acid, such as triperoxonane acid. Cyanic acid effectively corresponds to the isocyanate compounds mentioned above, in which R10represents hydrogen and thereby contributes to the transformation of compounds characterized by formula (II), directly in their carbamoylated analogs (compounds characterized by formula (I), in which OR3is a group OCONH2).

Alternative carbamylcholine can be carried out by reaction with phosgene or carbonyl diimidazol followed by reaction with ammonia or suitable substituted amine, optionally in aqueous or anhydrous reaction medium.

The formation of compounds characterized by formula (I), in which OR3is a group characterized by the formula OCO/CH2/nCO2R7can be achieved by acylation of the corresponding 5-oxycoedone using acid characterized by the formula HO2C/CH2/nCO2R7or its reactive derivative, in accordance with the procedure for acylation of the above.

In accordance with another aspect of the present izobreteny the>represents a C1-8alkyl group or a C3-8alkenylphenol group, which consists of the reaction between a compound characterized by the formula (I) in which R2represents a hydrogen atom, OR3represents a substituted hydroxyl group, and etherification agent R2Y (where R2represents a C1-8alkyl or alkyl group or a C3-8-alkenylphenol group and Y is as described above); if necessary, removing protection for compounds characterized by formula (I), in which OR3represents a protected hydroxyl group, and further optionally salt formation.

The esterification reaction can be carried out, for example, by formation of a magnesium alcoholate with the use of the Grignard reagent, such as a halide Metalmania, i.e., for example, iodide Metalmania, followed by treatment with a reagent R2Y. Alternative this reaction can be carried out in the presence of silver salts, such as, for example, silver oxide, silver perchlorate, silver carbonate or silver salicylate or mixtures thereof, or in the presence of a base, such as, for example, potassium carbonate or sodium hydride. The reaction Emmy simple ether, tetrahydrofuran or dioxane, or in amide, such as, for example, dimethylformamide or hexamethylphosphoric triamide, or a mixture of such solvents at ambient temperature. Under these conditions, the configuration of oximino group was almost unchanged after carrying out the esterification reaction.

In accordance with another aspect of the present invention, the applicant proposes another way (L) to obtain the compounds characterized by formula (I), in which OR3represents a hydroxyl group, which is to restore the compounds characterized by formula (III)

< / BR>
with further education, if necessary salts.

The reduction may be effected using a reducing agent which is capable of stereoselective reduction of 5-keto group. Suitable regenerating agents include borohydrides, such as borohydride alkali metals (for example, borohydride sodium and lithium alkoxyamine hydrides, such as lithium tributoxy aluminum hydride.

The reaction using borohydride reducing agent takes place in the presence of a solvent, such as alkanol, P>C, i.e. for example at 0oC. the Reaction involving the use of lithium alkoxyamine hydride, in the presence of a solvent, such as, for example, a simple ester, i.e., for example, tetrahydrofuran or dioxane, and can be conducted at temperatures ranging from -78 to 0oC.

Intermediate compounds characterized by formula (III) can be obtained from 5,23-diketone, characterized by formula (IV)

< / BR>
by treating one equivalent amount of reagent H2NOR2(where R2there are as mentioned earlier) using the reaction conditions of oxymorphine mentioned previously, to obtain compounds characterized by formula (I).

The compounds characterized by formula (IV) can be obtained by oxidation of compounds characterized by formula (V)

< / BR>
This reaction can be carried out using an oxidizing agent, designed for converting the secondary hydroxyl group, resulting connection is characterized by the formula (VI).

Suitable oxidizing agents include quinones in the presence of water, i.e., for example, 2,3-sodium dichloro-5,6-dicyano-1,4-benzoquinone or 2,3,5,6-tetrachloro-1,4-Benjamine, oxidizing agents, predpochtitelno in the presence of a catalyst transfer phase; oxidizing agent containing a 4-valent manganese, i.e., for example, manganese dioxide in dichloromethane; N-glowczewski, i.e., for example, N-chlorosuccinimide or N-bromosuccinimide; diallylsulfide, i.e., for example, dimethyl sulfoxide, in the presence of an activating agent such as, for example, N,N-dicyclohexylcarbodiimide or acyl halide, such as, for example, oxalicacid, or a complex containing pyridine and sulfur trioxide.

The reaction can be conducted efficiently in a suitable solvent, which may be selected from the group comprising a ketone, such as acetone; a simple ether, such as diethyl simple ether, dioxane or tetrahydrofuran; a hydrocarbon, such as hexane; halogenated hydrocarbons, such as chloroform or methylene chloride; or an ester, such as ethyl acetate, or a substituted amide such as dimethylformamide. Combinations of such solvents either in pure form or with water can also be used. The choice of solvent will depend on the type of oxidizing agent used in the reaction conversion.

This reaction can be conducted at temperatures in the range from -80oC to +50oC.

Soy is(founded September 10, 1984 in Permanent Fund cultures of the National Fund of industrial and marine bacteria, research station, Torry, Aberdeen, United Kingdom) or its mutant with the isolation of compounds from the thus obtained fermentation broth.

The organism Streptomyces thermoarchaensis can be grown using conventional methods, i.e., in the presence capable of assimilation of carbon sources, nitrogen and mineral salts. Able to assimilate sources of carbon, nitrogen and minerals can be represented as either simple or complex nutrients, such as described in patent description UK N 2166436. A suitable medium containing specified substances described in preparation No. 1, presented below.

Cultivation of the organism Streptomyces in General should be carried out at a temperature in the range from 20 to 50oC and preferably in the range of from 25 to 40oC it is necessary to make the aeration and mixing, for example by shaking or stirring. The environment can be initially subjected to insulinopenia using a small number sporulirovannyh suspension of microorganisms, but to avoid a delay in growth, vegetative inoculum of the organism can be prepared by insulinopenia nebrasa, can be placed in a fermentation medium or, preferably, at one or several stages of sowing, on which further growth takes place before the transfer into the main fermentation medium. Fermentation in General should be conducted at pH values in the range from 2.5 to 8.5 pH units.

Fermentation can be carried out within 2 to 10 days, for example 5 days.

The compounds characterized by formula (V) can be separated from the thus obtained of the whole fermentation broth by conventional methods of separation and division. This can be used a variety of methods of fractionation, such as, for example, adsorption chromatography, precipitation, fractional crystallization and extraction solvent, which may be combined in various ways. By solvent extraction and chromatography, it was found that are the most suitable method of separation and separation of compounds. Suitable method of obtaining the compounds characterized by formula (V) using these procedures, specified in the Preparation of N 1, described below.

In accordance with another aspect of the present invention applicants propose method (S) on which the SCP, and that is that is removes the protection from the corresponding compounds characterized by formula (I), in which OR3represents a protected hydroxyl group, as described above.

So, for example, acyl group such as acetyl group may be removed by basic hydrolysis, i.e., for example, using sodium hydroxide or potassium hydroxide in an aqueous solution of alcohol; or using acid hydrolysis, for example using concentrated sulfuric acid in methanol. Acetylene groups, such as tetrahydropyranyl may be removed, for example, by acid hydrolysis, i.e., using acid, such as acetic or triperoxonane acid, or a dilute mineral acid. Silyl group can be removed using fluoride ions (for example, from tetraalkylammonium, such as Tetra-standards-butylaniline), hydrogen fluoride in aqueous acetonitrile or acid, such as para-toluene acid (for example, in methanol). Arylmethyl group can be removed by treatment with Lewis acid (e.g. boron TRIFLUORIDE/apiret) in the presence of a thiol, such as, for example, ethanthiol, premie formula (I), can be obtained using conventional methods, for example, by treatment with acid, base, or by conversion of one salt into another by ion exchange.

The invention is further illustrated by, but is not limited to specified further preparations and examples, in which temperatures are listed in oC, "L" means liter and EtOH means ethanol.

In the following preparations and examples, the compounds are named as derivatives of known factors, factors a, b, C and D. the Factor And is a compound characterized by the formula (VI) in which R1represents isopropyl, and R3hydrogen; the factor is a compound characterized by the formula (VI) in which R1represents methyl and R3methyl; the factor is a compound characterized by the formula (VI) in which R1represents methyl and R3hydrogen; factor D is a compound characterized by the formula (VI) in which R1represents ethyl and R3the hydrogen.

< / BR>
Preparation 1-5-keto factor A.

Spores of Streptomyces thermoarchaensis NCIB 12015 were inoculated on the beveled ohar made of the following components (g/l-1
Agar No. 3 (Oxoid L 13) 15

Distilled water Up to 1 liter

The pH value of 5.4 pH units

and were insulinopenia at a temperature of 28oC for 10 days.

Ripe culture on the sloped agar was then covered with 6 ml of 10% aqueous solution of glycerol solution and then protected with a sterile tool to loosen the spores and mycelium. Aliquot share of volume of 0.4 ml of the resulting suspension of spores were transferred to sterile polypropylene tubes, which were then brew (sealed) and kept in an atmosphere of vapor of liquid nitrogen until then, until the need arose to use them.

Two Erlenmeyer flask with a capacity of 250 ml containing 50 ml of the seeded medium were prepared as follows, g/l-1:

D-glucose 15,0

Glycerin 15

Peptone soybean 15

Sodium chloride 3,0

Calcium carbonate 1,0

Distilled water To 1 liter

The value of pH of the medium was initially 6.7 pH units, which then had to 7.0 pH units with an aqueous solution of sodium hydroxide before the treatment in the autoclave. The value of pH of the medium after treatment in the autoclave was equal to 7.3 pH units. Each of the flasks Podvis incubation at a temperature of 28oC for 3 days in a shaker rotating at a speed of 250 rpm (with a diameter of orbital rotation 50 mm).

The contents of both flasks were used for insulinopenia fermentation capacity (volume 70 l), containing 40 l of the same medium, with the addition of polypropylene 2000 (0,06 about. /about.). Polypropylene 2000 was added as needed during the process of fermentation to control foaming. The fermentation process was carried out at a temperature of 28oC under stirring and aeration sufficient to maintain dissolved oxygen level above 30% of saturation. After 24 h of fermentation, a portion of the broth with a capacity of 9 l was loaded into the fermenter with a volume of 700 l, containing 450 l environment, obtained in the following way, g/l-1:

D-glucose 2,8

Malt dextrin (MDE) 27,8

Arcasoy-50 (Avka oy 50) 13,9

Molasses (molasses) 1,7

K2HPO40,14

CACO31,39

Silicone-525 (Dow Carning) 0,06 about./about.

Before sterilization, the value of pH was brought to 6.5 pH units.

The fermentation process was carried out at a temperature of 28oC under stirring and aeration. Protivovspenivayushchie drug polypropylene 2000 was added in soarnol acid until while there was no maturation culture. Fermentation with maturation culture occurred after 5 days.

The broth in the amount of 450 l was subjected to clarification in a centrifuge of the type "Westphalia CA and a residual material is formed at the top of the sedimentation was replaced by water in a volume of 20 L. the Extracted cellular material in the amount of 25.5 g) was subjected to stirring for 1 h in the mixer type "Silverson, model I with a sufficient amount of ethanol to produce in the resulting material, the total volume of 75 liters of the Obtained suspension was subjected to filtration, and the solid residue was re-extracted with methanol in the amount of 35 liters and filtered. The combined filtrate in the amount of 87 l was diluted with water in an amount of 40 l and was then extracted with petroleum ether in a quantity of 30 l, having a temperature of 60-80oC. After 30 min, the phases were separated in a centrifuge of the type "Westphalia MEM and lower methanol phase was subjected to repeated extraction with petroleum ether in a quantity of 30 l, having a temperature of 60-80oC, after adding water in the amount of 40 HP After separation, the lower phase was re-subjected to extraction with petroleum ether in a quantity of 30 l, with the temperature is at spas transmittance through the film-type evaporators company "Powder 8.8-12V-27 (the vapor pressure of 0.1 Bar, the temperature of the vapor 20oC, the temperature of the vapor 127oC). Concentrate in volume 9 l were subjected to drying using sodium sulfate in the amount of 2 kg and was then subjected to concentration under reduced pressure at a temperature of 40oC using a rotary film evaporators.

The oily residue 130 g were dissolved in chloroform to obtain material in the volume of 190 ml, which was then passed through a column of type "Merck-7734" filled with silica-60 (200 x 4 cm), placed in chloroform. The column was subjected to washing with chloroform (500 ml) and then elution was carried out with a mixture consisting of chloroform and ethyl acetate (3:1), and fractions with an equal volume of 40 ml was collected after selection of the preceding volume equal to 1400 ml.

Fractions N 32-46 was subjected to mixing and evaporation from the obtained oil in the amount of 21.2 G. of Fraction N 47-93 were mixed and evaporated from the obtained oil in the amount of 20.1 g, which were dissolved in a mixture of chloroform and ethyl acetate (ratio 3:1) to volume of 50 ml of This mixture was then introduced into a column of type "Merck 7734" filled dioxide crelnm an equal volume of 40 ml was collected after the previous sampling fractions in the amount of 1,400 ml. Fractions N 22-36 were combined and subjected to evaporation to obtain oil in the amount of 3.1 g, which was then added to the oil obtained from fractions 32-46 of the first column. The combined oils were dissolved in boiling methanol (4 ml) and then added to hot propan-2-Olu in 20 ml and then subjected to crystallization.

The mother liquor after crystallization was subjected to evaporation to obtain the oil, which was dissolved in an equal volume of methylene chloride, and the resulting mixture was loaded into the column (30 x 2.2 cm) type Merck Kieselgel 60" (sieve N 70-230 by the ASTM, art. N 7734) containing methylene chloride. The layer was rinsed with methylene chloride in a quantity equal to the volume of the layer, and then subjected to elution with a mixture consisting of chloroform and ethyl acetate in a ratio of 3:1, in an amount equal to two volumes of the layer. Evaporation of the eluate was possible to obtain the oil, which was subjected to dissolution in methanol and then subjected to preparative liquid chromatographicaliy with high resolution at the "Spherisorb S5ODS-2" (250 mm x 20 mm Phase Sep. Ltd.). Portions of the sample volume of 5 ml was dispensed by the pump into the column for 1 min and the column was exposed to E. the Filing, ml/min

0,00 0,00

Type

1,00 0,00

1,10 30,00

39,90 30,00

40,00 35,00

75,00 35,00

The material that was blueraven from the column preparative liquid chromatograph high resolution, were subjected to examination by means of UV spectroscopy at a wavelength of 238 nm.

As the result of evaporation of the combined fractions from the peak elution occurred 33.4 minutes, there was obtained the connection specified in the header, 34 mg of solid material.

E. I. Mass spectrometry revealed a molecular ion at 610 and gave the characteristic fragments at 592, 574, 556, 422, and 241 259.

Example No. 1. 23/E/-Methoxyimino Factor A.

/a/ 5,23-diketo Factor A.

Ice solution obtained from concentrated sulfuric acid in the amount of 1.2 ml of sodium dichromate in an amount of 120 mg in water, 2 ml) was added over 15 min to a cooled with ice to a solution of 5-keto Factor A (200 mg) and acid sulfate tetrabutylamonium in the amount of 15 mg in ethyl acetate in a quantity of 4 ml) under vigorous stirring. After one hour the mixture had been diluted with ethyl acetate and the organic phase p and the obtained resin was purified by chromatography was carried out on Merck Kieselgel 60", sieve N 230-400 mesh in the amount of 100 ml In the elution with 10% solution of ethyl acetate in dichloromethane was received on the connection specified in the header, in the form of a pale yellow foam, in the amount of 86 mg; (CDCl3) included 6,57 (multiplet, 1H), 2,50 (singlet, 2H), 1,89 (multiplet, 3H).

// 5-keto, 23/E/-methoxyimino Factor A.

In accordance with this example 5,23-diketo Factor And the number of 475 mg, hydrochloride methoxylamine in the amount of 69 mg of anhydrous sodium acetate in the amount of 175 mg were dissolved in methanol. After 1.5 h of incubation at room temperature the solution was aged for 16 hours at a temperature of -18oC, was diluted ethyl acetate and were carefully rinsed odnomomentnoe hydrochloric acid, water and brine. The dried organic phase was subjected to chromatographicaliy using Merck Kieselgel 60, 230-400 mesh sieve N in the amount of 120 ml In the elution of the column with the mixture of hexane and ethyl acetate in the ratio of 4:1 was received on the connection specified in the header, in the form of a yellow foam in the number 255 mg.

()2D1+80o(1,20, CHCl3),max(EtOH) 241 nm ( 27,500), nmax(CHBr3), 3530, 3460 (OH), 1708 (C=O), 1676 (C=C, ,00 (doublet 6, 3H), 0,96 (doublet 6, 3H), 0,92 (doublet 6, 3H).

/s/ 23/E/-methoxyimino Factor A.

/1/ Borohydride sodium in the amount of 6.5 mg was added to a cooled with ice to a solution of 5-keto, 23/E/-methoxyimino Factor And /83 mg/ isopropanol /20 mg/. The resulting mixture of yellow color was subjected to stirring for 35 min in an ice bath, then was diluted with ethyl acetate and were carefully rinsed odnomomentnoe hydrochloric acid, water and brine. The dried organic phase was then evaporated and the resulting yellow resin was subjected to purification by chromatography was carried out through Merck Kieselgel 60, 230-400 mesh sieve N (60 ml). Elution of the content of the column was carried out by a mixture of hexane and ethyl acetate in the ratio 2:1, allowing for the connection specified in the header, in the form of a yellow foam in the amount of 58 mg.

As a result of crystallization from hexane there was obtained the connection specified in the header, having a melting point equal to 203oC.

()2D1+133o(1,12, CDCl3), (EtOH) 244 nm ( 26,200), d (CDCl3) included 4,29 (triplet 7, 1H), 3,84 (singlet, 3H), 3,29 (doublet 15, 1H).

(II) a Solution of 5-keto, 23/E/-mitoko temperature -78oWith the solution of the hydride lithium Tris-tert-butoxy aluminum in the amount of 261 mg of anhydrous tetrahydrofuran in an amount of 3 ml After 0,75 h of incubation at a temperature of -78oC the resulting solution was diluted with ethyl acetate in a quantity of 30 ml and then were carefully rinsed with 0.5 normal hydrochloric acid and water. The dried organic phase was subjected to evaporation and intermediate raw was subjected to purification by chromatography was carried out on Merck Kieselgel 60, 230-400 mesh sieve N, 40 ml of Elution was carried out 25% ethyl acetate in hexane to obtain the result of the connection specified in the header, in the form of a white foam +128o(0.95, and CHCl3), (CDCl3including 4,29 (triplet 7, 1H), 3,84 (singlet, 3H), 3,29 (doublet 15, 1H).

Example 2. 23/E/-methoxyimino Factor A, 5-acetate.

In accordance with this example, anhydrous sodium acetate solution in the amount of 2.8 g in water (15 ml) was added to a solution of 25-keto Factor A, 5-acetate (3.13 g, example 18 the patent description UK N 2176182) in methanol and then added hydrochloride methoxyamine in the number 3,01, the thus Obtained solution was subjected to stirring for 1.5 h at a temperature of 20oC, was diluted with ethyl acetate phase was evaporated until almost dry condition, and the whitish foam was subjected to purification by chromatography was carried out on Merck Kieselgel 60, 230-400 mesh sieve N, 600 ml of Elution of the column was carried out by a mixture of hexane and ethyl acetate in the ratio of 4:1, allowing for the connection specified in the header as a colourless foam, in the amount 2,14,

+128o(with 1.35, CHCl3),max(EtOH) 244 nm (max27,250),max(CHBr3) 3460, 3480 (OH), 1733 (acetate), 1715 (C=O), 995 (C-O), (CDCl3) consisted of 5.5 to 5.6 (multiplet, 2H), 3,84 (singlet, 3H), 3,29 (doublet 15, N), 2,16 (singlet, 3H).

Example 3. 23/E/-oxyimino Factor A, 5-acetate.

Response 25-keto Factor A, 5-acetate hydrochloride hydroxylamine was carried out in accordance with methods similar to those described in example 1. Intermediate crude was subjected to purification by chromatography was carried out on Merck Kieselgel 60, 230-400 mesh sieve N. The process of elution was carried out with a mixture consisting of ethyl acetate and acetonitrile in the ratio of 4:1, which results in the connection specified in the header, in the form of a colorless foam.

+132o(1,01, CHCl3), max(EtOH) 244 nm (max27800),max(CHBr3) 3565, 3470 OH 1732 (acetate), 1712 (C=O), 993 (C-O), (CDCl3including 8.12 (singlet, 1H), 5,5-5,6 the creative product, obtained in accordance with example 2, the number of 1.88 g of methanol were cooled in an ice bath and then were added odnopolyarnogo aqueous solution of sodium hydroxide in the amount of 5.6 ml, and thus obtained solution was subjected to stirring in an ice bath for 1.5 hours the resulting solution was diluted with ethyl acetate and were carefully rinsed with 0.5 normal hydrochloric acid, water and brine. The dried organic phase was evaporated and the resulting foam was purified by chromatography was carried out on Merck Kieselgel 60, 230-400 mesh sieve N in 400 ml. In the elution content column a mixture of hexane and ethyl acetate in the ratio of 2:1 was obtained a colorless foam in the number of 1,429, After crystallization from hexane there was obtained the connection specified header, in pure form, having a melting point 203oC.

+132o(1,21, CHCl3),max(EtOH) 244 nm (max29200),max(CHBr3) 3540 (OH), 1708 (C=O), 992 (C-O)), (CDCl3) included 4,29 (triplet 7: 1H), 3,84 (singlet: 3H), 3,29 (doublet 15:1H).

Example 5. 23 /E/-oxyimino Factor A.

As a result of hydrolysis of the product obtained in example 3, in sootvetstvuyuschei 60", sieve N 230-400 mesh, 400 ml After elution of a mixture of hexane and ethyl acetate in the ratio of 1: 1 was obtained the connection specified in the header, in the form of a colorless foam.

()2D1+140o(from 1.24, CHCl3),max(EtOH) 244 nm (max26700),max(CHBr3) 3565, 3490 (OH), 1710 (C= O) 994 (C-O), (CDCl3) included 8,11 (singlet: 1H), 4,29 (triplet 7:1H), 3,41 (doublet 15:1H).

Example 6. 23/E/-amoxiillin Factor A.

A solution of anhydrous sodium acetate in the amount of 140 mg in water in an amount of 3 ml was added to a solution of 23-keto Factor in the amount of 200 mg (obtained as described in example 23 the patent description UK N 2176182) and hydrochloride amoxilina in the amount of 126 mg) in methanol (20 ml After 2 h of incubation at a temperature of 20oC the resulting solution was diluted with simple ether (40 ml) and washed with water. The dried organic phase was evaporated, and the resultant product, which is a whitish foam that was purified by chromatography was carried out on Merck Kieselgel 60, 230-400 mesh sieve N, 90 ml. In the elution content column using a mixture of ethyl acetate and hexane in a ratio of 1:2, SUB>D1+125o(from 1.00, CHCl3),max(EtOH) 244 nm (max28200),max(CHBr3) 35400, 34800 (OH), 1705 (C=O), 990 (C-O), (CDCl3) included 3,40 (triplet 7: 1H), 4,10 (quintet 7:2N), and 3.31 (doublet 15:1H), 1,21 (triplet 7: 3H).

Compounds 7, 8 and 9 were obtained similarly from the 23-keto Factor a and the corresponding suitable alkoxyamine.

Example 7. 23/E/-aliakseyeu Factor A.

()2D1+124o(1,17, CHCl3),max(EtOH) 244 nm (max28400),max(CHBr3) 35500, 34900 (OH), 1708 (C=O), 990 (C-O), (CDCl3included 5,98 (multiplet, 1H), 5,28 (double doublet 17,2; 1H), 5,15 (double doublet 9,2; 1H), 4,5-4,7 (multiplet; 2H), 4,29 (triplet 7, 1H), 3,36 (doublet 14, 1H), compound was obtained from hydrochloride allylacetamide.

Example 8. 23/E/-isopropylamino Factor A.

()2D1+116o(0,97, CHCl3),max(EtOH) 244 nm (max u25000),max(CHBr3) 3550, 3490 (OH), 1708 (C=O), 992 (C-O), (CDCH3included 4,2-4,4 (multiplet, 2H), 3,30 (doublet 14, 1H), 1,21 (doublet 7, 3H), 1,20 (doublet 7, 3H), this compound was obtained from hydrochloride isopropylaniline.

Example 9. 23/E/-standards-butachimie Factor A.

+115o(1,10, CHCl3),max(EtOH) 244 nm (maxBet 6, 1H), and 3.31 (doublet 14, 1H), 0,9-1,1 (multiplet, 15 NM), the compound was obtained from hydrochloride of the standards. butoxyaniline.

Example 10. 23/E/-methoxyimino Factor A, 5-acetate.

/I/ In accordance with this example was produced by adding 3 M iodide solution Metalmania simple ether in the amount of 0.16 ml to a stirred solution of the product obtained in example No. 3 in the amount of 120 mg of anhydrous hexamethylphosphoric triamide in an amount of 5 ml in a nitrogen atmosphere. Next were added iodomethane in the amount of 0.09 ml, after one hour the mixture had been diluted with ethyl acetate in a quantity of 30 ml and Then were carefully rinsed 2 N. hydrochloric acid and water. The dried organic phase was subjected to evaporation and the resulting resin was subjected to purification by chromatographytandem on Merck Kieselgel 60, 230-400 mesh sieve N, in the amount of 80 ml In the elution content of the column was obtained the compound indicated in the heading, for elution was used a mixture of hexane and ethyl acetate in the ratio of 2:1, the product was a white foam.

+123o(1.25, CHCl3),max(EtOH) 245 nm (max30,300); spectrum of nuclear magnetic resonance was described in example 2.

Example 11. 23/E/-methoxyimino Factor A, 5-methylcarbamate.

Methyl isocyanate in the amount of 0.13 ml, 125 mg and triethylamine (2 drops) was added to a solution of 23/E/-methoxyimino Factor in the amount of 350 ml of anhydrous dimethylformamide in the amount of 0.75 ml. Flask with the thus obtained mixture was tightly closed and heated for 5.5 hours at a temperature of 80oC and under stirring. Thus obtained mixture was poured in water in an amount of 150 ml and then was extracted with dichloromethane in the amount of 75 ml The obtained extract was dried with magnesium sulfate and were concentrated to produce in the resulting yellow foam, which was subjected to purification on a chromatographic column filled with silica gel under medium pressure ( 125 g, Merck Kieselgel 60, 230-400 mesh sieve N). In the elution of a mixture of hexane and ethyl acetate in a ratio of 1:1 was received on the connection specified in the header, in the form of a white foam in number 206 mg.

()2D2+99o(0,55, CH2Cl2), max(EtOH) 244,4 nm ( 28710), nmax(CHBr3) 3530 (OH), 3455 (NH), 1720 (ester), 1720 + 1510 (carbamate) and 993 cm-1(C-O), (CDCl3includes 1,78 (singlet, 3H), 2,86 (doublet, 5 Hz, 3H), 3,29 (doublet 14 Hz, 1H), 3,83 (singlet, 3H), 4,80 (quintet, 5 Hz, 1H) and 5,50 (multiplet, 2H).

Example 12. 2/E/-methoxyimino Factor A, 5-methylcarbonate.

To a solution of 23/E/-methoxyimino Factor in the amount of 150 mg in dichloromethane in the amount of 15 ml and pyridine (0.3 ml) under stirring at a temperature of 0oC was carried out adding methylchloroform (0.7 ml, 1.0 M solution in dichloromethane). Thus obtained reaction mixture was subjected to stirring at a temperature of 0 to 3oC for 20 min, and then add the as 50 ml The organic phase was dried by magnesium sulfate, and the solvent was removed with the formation of foam, which was subjected to purification by chromatography was carried out at an average pressure on a column filled with silica (40 g, Merck Kieselgel 60, 230-400 mesh sieve N). In the elution of a mixture of dichloromethane and ethyl acetate in the ratio of 30: 1, white received the connection specified in the header, in the form of a white foam in number 127 mg.

+ 145o(C=0,41, CH2Cl2),max(EtOH) 244,4 nm ( 3121), d (CHBr3) 3460 + 3540 (OH), 1342 (carbonate) 1710 (ester) and 992 (cm-1) (C-O), d (CDCl3includes 1,82 (singlet, 3H) 329 (doublet 14 Hz, 1H), 3,82 (singlet, 3H), 3,83 (singlet, 3H), 5,2-5,4 (multiplet, 3H), 5.56mm (singlet, 1H).

Example 13. 23/E/-methoxyimino Factor D, 5-acetate.

In accordance with this example a solution containing 22-keto Factor D, 5-acetate (251 mg, obtained in example 119 patent description UK N 2176182), sodium acetate in the amount of 350 mg hydrochloride methoxyamine ( 250 mg) in methanol ( 40 ml) was maintained at a temperature of 20oC for 24 h, then concentrated to a volume of approximately 10 ml was diluted with ethyl acetate in a quantity of 50 ml and then were carefully rinsed with 0.5 N. chloride color which was purified by chromatography was carried out on Merck Kieselgel 60, 230-400 mesh sieve N, 120 ml. result of elution of the column with hexane was received on the connection specified in the header, in the form of a pale yellow foam in the amount of 144 mg.

lmax(EtOH) 244 nm ( 26,400), nmax(CHBr3) (cm-1) 3500 (OH), 1742 (OAc), 1710 (C=O), (CDCl3) included 5,54 (multiplet, 2H), 4.92 in (multiplet, 1H), 3,84 (singlet, 3H), 3,32 (multiplet, 1H), 3,30 (doublet 14, 1H), 2,17 (singlet, 3H), 1.91 a (doublet 14, 1H), 1,76 (singlet, 3H), 1,63 (singlet, 3H) and 1.51 (singlet, 3H), 1,01 (triplet 7, 3H), 0,99 (doublet 6, 3H), 0,92 (doublet 6, 3H).

Example 14. 23/E/-methoxyimino Factor D.

In accordance with this example, the solution containing the product specified in example 13, in the amount of 140 mg and odnokorennye solution of sodium hydroxide ( 0.6 ml) in methanol (8 ml) was subjected to stirring in an ice bath for 1.5 hours the resulting solution was diluted with ethyl acetate and were carefully rinsed odnomomentnoe hydrochloric acid and water. The dried organic phase was evaporated from the obtained yellow foam, which was purified by chromatography was carried out on Merck Kieselgel-60, 230-400 mesh sieve N (50 ml). In the elution content column with a mixture that consists of hexane in the amount of 105 mg.

+ 96o(1.38, CHCl3),max(EtOH) 244 nm ( 26700), nmax(CHBr3) (cm-1) 3550, 3500 (OH), 1710 (C=O), (CDCl3) included 4,93 (multiplet, 1H), 4,30 (triplet 6, 1H) 3,95 (doublet 6, 1H), 3,84 (singlet, 3H), 3,30 (doublet 14, 1H), 3.27 to (multiplet, 1H), 1,88 (singlet, 3H), 1,64 (singlet, 3H), 1,52 (singlet, 3H), 1,01 (triplet 7, 3H), 1.00 m (doublet 6, 3H), 0,92 (doublet 6, 3H).

Example 15. 23/E/-methoxyimino Factor Century.

A solution containing 23-keto factor a (1 g) obtained in example 19 the patent description UK N 2176182, sodium acetate in 400 mg and hydrochloride methoxyamine in the amount of 400 g, was subjected to stirring at a temperature of 20oC for 20 h and then concentrated to a volume approximately equal to 10 ml, and then diluted with ethyl acetate and washed with water. The organic phase was thoroughly washed with 0.5 N. hydrochloric acid and water, and the dried organic phase was subjected to evaporation. The obtained intermediate crude was subjected to purification by chromatography was carried out on Merck Kieselgel 60, 230-400 mesh sieve N (200 ml). In the elution content column with a mixture consisting of ethyl acetate and dichloromethane in the ratio of 1: 9 was obtained the connection specified in the header, in the form of a white foam in kolichestvo3) (cm-1) 3540, 3460 (OH), 1708 (C=O), (CDCl3) included 5,46 (quintet 6, 1H), 4,03 (doublet 5, 1H), 3,97 (doublet 5, 1H), 3,83 (singlet, 3H), 3,50 (singlet, 3H), 3,32 (multiplet, 1H), 3,29 (doublet 14, 1H), 1,82 (singlet, 3H), 1,68 (doublet 6, 3H), 1.00 m (doublet 6, 3H), 0,92 (doublet 6, 3H).

Example 16. 23 /E/-methoxyimino Factor C.

In accordance with this example, anhydrous sodium acetate in an amount of 0.54 g of the hydrochloride methoxyamine in the number of 0.58 g) was added to a solution of 23-keto Factor (the number of 1.97 g, obtained in accordance with example 12 of the patent description UK N 2176182) in methanol in the amount of 300 ml containing water in an amount of 5 ml of thus Obtained mixture was subjected to stirring for 30 min at room temperature. Ethyl acetate ( 30 ml) and 0.5 M hydrochloric acid ( 30 ml) was added to the mixture and the resulting aqueous layer was re-extracted with ethyl acetate in 15 ml. of Mixed organic layers were washed in turn with 0.5 M hydrochloric acid, 5% saturated aqueous sodium bicarbonate and 10% saturated aqueous sodium chloride, and then was subjected to concentration under vacuum obtaining in the foam is yellow. This product was subjected to PTS then elution was carried out with dichloromethane, containing a small amount of ethyl acetate (10%) to obtain the compound indicated in the title, in the amount of 1.0 g

+ 64o(1,0, CH3OH), 1H nuclear magnetic resonance (CDCl3) included the following signals: 4,95 (multiplet, 1H), 4,29 (triplet, 1H, 7 Hz), 3.96 points (doublet, 1H, 7 Hz), 3,85 (singlet, 3H [=NOCH3]), 3,66 (doublet, 1H, 10 Hz) and 1.51 (singlet, 3H), 1,42 (triplet, 1H, 12 Hz), infrared spectrum (CHBr3) 3620-3340 cm-1(-OH), 1711 cm-1(C=O).

The following examples relate to compositions prepared in accordance with the present invention. The term "active ingredient" as used hereinafter, refers to compounds that are the subject of this invention and may constitute, for example, the connection specified in example 4.

Reusable dose for parenteral injection

Example 1 (wt. /about.).

The active ingredient 2,0

Benzyl alcohol 1,0

Polysorbate 80 10

Formal glycerol 50

Water for injection To 100.0

The range of 0.1 to 6.0 wt./about.

In accordance with this example was produced by dissolving the active ingredient in Polysorbate 80 and formal glycerol. Next were added benzyl alcohol and the MCA is given using conventional methods, for example, sterile filtration or by heating in an autoclave, followed by packaging in a sterile environment.

Example 2 ( wt./vol.).

The active ingredient 4,0

Benzyl alcohol 2,0

The triacetate of glyceryl 30,0

Propylene glycol To 100.0

The range of 0.1 to 7.5 wt./about.

In accordance with this example is the dissolution of the active ingredient in benzyl alcohol and the triacetate of glyceryl. Next is adding propylene glycol to the desired volume. Sterilization of the obtained product is manufactured using conventional pharmaceutical methods, for example by sterile filtration, followed by packaging in a sterile environment.

Example 3 (wt./vol.).

The active ingredient 2,0

Ethanol 36,0

Nonionic surfactant, such as, for example, Synperonic PEL44 10,0

Propylene glycol 1000

The range of 0.1 to 7.5 wt./about.

In accordance with this example, the active ingredient is dissolved in ethanol and the surface-active substance and the mixture is brought to the desired volume by adding propylene glycol. Sterilization of the resulting product is carried out in accordance with conventional pharmaceutical methods, e.g. the).

The active ingredient 2,0

Nonionic surfactant Synperonic PE F68x- 2,0

Benzyl alcohol 1,0

Miglyol 840xx16,0

Water for injection To 100.0

The range of 0.1 to 3.0 wt./about.

Note: (x) the product manufactured by the I. C. I.

xx) the product produced by the company Dynamit Nobel.

In accordance with this example is the dissolution of the active ingredient in Myglyol 840. Is the dissolution of nonionic surfactants and benzyl alcohol in most of the water. Is the preparation of the emulsion by adding oil solution to aqueous solution and simultaneously homogenization is carried out using conventional methods. The volume of the mixture is brought to the desired and is Packed in sterile conditions.

Aerosol spray ( wt./vol.):

The active ingredient of 0.1

Trichloroethane 29,9

Trichlorofluoromethane 35,0

DICHLORODIFLUOROMETHANE 35,0

The range of 0.01-2.0 wt./wt.

In accordance with this example is made by mixing the active ingredient with dichloromethane, and the resulting mixture is introduced into the aerosol container. Is blowing the upper part of the cylinder gaseous propellant dkim a propellant under pressure through the valve. The installation of the pressure head and the cover.

Tablets.

Method for the production of wet granulation.

The active ingredient 250.0 mg

Magnesium stearate 4.5 mg

Maize starch 22,5 mg

Glycolate starch sodium 9.0 mg

Sulphate of Laurila of 4.5 mg sodium

Microcrystalline cellulose for coating tablets weighing Up to 450 mg

In accordance with this example is added to a sufficient quantity of a 10% starch paste to the active ingredient with obtaining the result desired wet mass suitable for granulation. Retrieves the granules and drying using a dryer fluidized bed or tray dryer, and further sieving through a sieve, add the remaining ingredients and tableting.

If necessary, the tablets may be film-coated by using oksipropilmetiltselljulozy or other similar film-forming material using a solvent system of water or anhydrous basis. The plasticizer or a suitable dye can be introduced into the solution forming a film coating.

Veterinary tablets for the treatment of small home>/BR>Magnesium stearate 7.5 mg

Microcrystalline cellulose for coating tablets, weighing About 75 mg

In accordance with this example is made by mixing the active ingredient with magnesium stearate and microcrystalline cellulose. Next is the compaction of the mix and reduce its lumps by passing through the rotary granulator to produce in the resulting free flowing granules and subsequent processing of these granules into tablets. Tablets may be film-coated, if necessary, as indicated above.

Injections for entry into the mammary gland of animals (mg/dose):

The active ingredient 150 mg

Polysorbate 60 3.0 mass. /Mac.

White beeswax to 6.0 wt./wt. up to 3 g up to 3 or 15 grams

Peanut butter 91,0 wt. /Mac.

The range of 0.05 to 1.0,

In accordance with this example were heated peanut oil, white beeswax and Polysorbate 60 to a temperature of 160oC under stirring. Thus obtained mixture was maintained at a temperature of 160oC for 2 h and then cooled to room temperature under stirring. Next were added to the sterile environment of the active ingredient to the carrier, proizvoditel by passing through a colloid mill. Then the product was introduced into a sterile syringes made of plastic.

Large veterinary pills with slow release of active component (wt. /wt.):

The active ingredient 0,35

Colloidal silicon dioxide 2,0

(the required quantity to volume)

Microcrystalline cellulose To 100.0

The range of 0.25-2 g

In accordance with this example, the active ingredient was mixed with colloidal silicon dioxide and microcrystalline cellulose by using a suitable aliquot of the technology of mixing in order to provide the necessary distribution of the active ingredient throughout the volume of the filler. Next is the entry of the pharmaceutical composition in a device that provides a slow release of active ingredient, which provides sustained release of the active ingredient or pulsed release of active ingredient.

Veterinary remedy for oral irrigation ( wt. /about.):

The active ingredient 0,35

Polysorbate 85 5,0

Benzyl alcohol 3,0

Propylene glycol 3,0

Buffer phosphate To the value of godortnopants of 6.0 to 6.5 pH units

Water Up to 100% of the full volume of

The range of 0.01-2.0 wt. /about.

vom alcohol and propylene glycol. Next were adding water and, if necessary, the pH value was brought to 6.0-6.5 pH units by adding phosphate buffer and then adding water to the desired volume. The resulting composition was loaded into a container for oral administration to animals.

Veterinary paste for oral administration ( wt./wt.)

The active ingredient 4,0

Saccharin sodium 2,5

Polysorbate 85 3,0

Distearate aluminum 5,0

Fractionated coconut oil To 100.0

The range of 1-20 wt. /Mac.

In accordance with this example was produced dispersion distearate aluminum in fractionated coconut oil and Polysorbate 85 by heating. Next, the resulting mixture was cooled to room temperature and produced a dispersion of saccharin sodium in the oil medium, and then dispersing the active ingredient in the thus obtained basis. The finished material was rasfasovyvaetsya in plastic syringes.

Granules are intended for reception with food, veterinary ( wt. /wt.):

The active ingredient 2,5

The calcium sulfate hemihydrate To 100.0

The range of 0.05-5 wt./wt.

In accordance with this example made the CSOs granulation. Drying of the pellets was carried out by drying in a fluidized bed or by using a tray dryer. The obtained granules were loaded into a suitable container.

Veterinary composition for irrigation ( wt./vol.):

The active ingredient 2,0

Dimethyl sulfoxide 10,0

A mixture of 30.0

Propylene glycol (and pigment) To 100

The range from 0.1 to 30%

In accordance with this example was produced by dissolving the active ingredient in dimethyl sulfoxide and the mixture, was then produced by adding a pigment and propylene glycol in an amount necessary up to a specified amount. The resulting composition was poured into containers intended for watering.

Emulsifiable concentrate:

The active ingredient 50 g

Anionic emulsifier (this, catnapper, phenyl sulfonate CA L X) 40 g

Nonionic emulsifier (such as, for example, Synperonic NP-13x) - 60 grams

Aromatic solvent (such as, for example, Solvesso 100) To 1 litre

x) the Product produced by the company ICI.

In accordance with this example was produced by mixing all ingredients until then, until they complete dissolution.

Granules:

/a/ Active ingredient 50 g

EXT ).

// Active ingredient 50 g

Synperonic NP-13*40 g

Granules of gypsum (sieve N 20-60) up to 1 kg * Manufacturer - the company ICI.

In accordance with this example was produced by dissolving all the ingredients in a volatile solvent, such as, for example, methylene chloride, and then the pellets were subjected to Galloway in the mixer and then dried to remove solvent.

Pesticidal activity of the compounds that are the subject of the present invention, was determined by checking on various insects and their habitats in accordance with the following General methodology:

the product was used in the form of a liquid preparation. Preparations were obtained by dissolving the product in acetone. The solutions were then subjected to dilution with water containing 0.1 or 0.01 wt. moisturizing agent, until such time as the liquid preparation was not characterized by a given concentration of the product.

The test procedure adopted in the case of most insects, included the maintenance of a certain number of insects in the environment, which is typically a habitat, or by processing environment obtained by cooking (residual test), or by what prigotovleniem (contact test). In the case of Meliodogyne incognita solution was applied to the soil in which were planted tomatoes, which then was amazed worms, and was determined by the decrease in the number of outgrowths on the roots compared to the control plants.

Using these procedures, a compound characterized by the formula (I) in which R1represents isopropyl, R2represents methyl and R3represents hydrogen, as was found to be effective at concentrations equal to 100 wt.h. per million or less.

The effectiveness of the compounds prepared in accordance with the invention was tested on mice infected with worms Nematospiroides dibius. Mice female CR/H (18-22 g) were introduced 100 L 3 larvae worms Nematospiroides dibius and left to the full development of the infection (usually three weeks). Then the mice were injected inside the connection in accordance with the invention in a quantity equal to one 3/4 levels of doses of powdered drugs. Compounds were injected in a solution of propylene glycol. After that, mice were left for at least 3 days (usually 5 days), then mice with developed in them the infection killed and removed the small intestine. A remote part of the intestine is cut with scissors with blunt ends to found the society of Baerman. The migration time was 5 h, and during this period of migratory worms maintained at a temperature of 37oC. After 5 h of nylon mesh, through which migrated worms, examined under a magnifying glass (x2). Estimate the number of worms, caught by the net, and migrated worms, having a total content of worms in each mouse, which was compared with the control mice.

Thus, it was found that the dose of 2 mg/kg of the compounds in accordance with the invention significantly reduced the content of worms in mice subjected to treatment. For example, each connection examples 2, 4, 6, 7, 8, 11, 12 and 15 gave a decrease in the average percentage of worms in mice treated compared with control mice, more than 85%

Factor (A) 23 /E/ methoxyamino.

Assessment connection Factor And to control Trichostrongylus colubriformis (kidney worms) in rodents (gerbils).

In these tests rodents male age five weeks infected larvae kidney worms 400-600 T columbriformis larvae of sheep origin, causing infection on day O. On the seventh day of rodents were weighed and started their treatment. Rodents killed on the eleventh day and calculated kolichestvennyh treatment, with infected control animals not treated, it was used the following formula for the average value of three measurements:

Efficiency (average control animals) (the average of the treated animals) / mean control 100.

The drug was dissolved in polyethylene glycol and dimethyl sulfoxide (PEG DMSO) (1: 2 vol./about.) in sufficient quantity to treat the animal, which was introduced from 0,0313 to 0,1250 mg of the drug per 1 kg of weight of the animal.

The data obtained are presented in table. 1.

Insecticidal activity.

All concentrations shown here are for the active ingredient. Test solutions are prepared by dissolving the active ingredient in 35-s ' solution of acetone in water at a concentration of 1 g/l and then diluted with water on demand.

Tetranychus urtical (P. resistant strain), spotted spider mite.

Chose legumes Sieva lima with the main leaves grown on the length of 7-8 cm, they were reduced to one plant per pot. From the sheet, taken from the main colony, cut off a small piece and placed on each sheet of the test plants. Did it in about 2 h prior to processing plants to pests moga about 100 mites per leaf. During the processing of a piece of sheet, which is used to transfer the ticks were removed and thrown away. Plants infected ticks, dipped in the test solution for 3 with under stirring and placed in a hood to dry. The plants were kept for 2 days prior to the experiment on the elimination of pests using the first sheet. Another sheet was kept on the plant for an additional 5 days before began to observe the destruction of eggs and/or new larvae.

Empoasca abrupta, adult potato locusts.

Sheet legumes Sieva lima length of about 5 cm was loaded onto 3 in the test solution with stirring and placed in a hood to dry. The sheet was placed in a Petri dish 100 x 10 mm, containing filtered paper on the bottom for moisture. In each Cup was added approximately 10 kobyluck adult and processing was continued for 3 days before counting the number of killed kobyluck.

Heliothis virescens tobacco Bud caterpillars.

Cotyledons of cotton dipped in the test solution and was dried in the hood. After drying, each of the cotyledons were cut into four different parts, and ten parts were placed separately in plastic medical Cup volume one caterpillar and closed cardboard cover. Treatment was maintained for 3 days before counting the number of caterpillars destroyed and then assessed the reduction of impaired nutrition ( see tab.2).

The screening, held at the plant parasite nematode root knot.

Purpose:

The purpose of this test is to detect nematocides of activity of new substances. This test is a test of toxicity by direct contact, when living nematodes are immersed in water, the drug substance.2 Materials and methods:

1. Culture of plant parasite nematodes root knot (Maloidogyne ineagnins).

Modified hydroponic system nematode culture (Phytopathology, V. 82, p. 512-515, 1992), which provides fast production and reproduction svezhevypechennyj infective juvenile nematodes root knot, was developed in 1995 in the Department of identification of insecticides and improved tests. This hydroponic system is easy to install and maintain. In addition, it provides a sufficient number of infective juvenile nematodes, located on the 2nd stage of development (J2) daily, and for a long period of time.

2. Test method

VI is of plant nematodes.

The subjects of the substance was dissolved in acetone and the pipette was introduced (25 ál) to each well Microtiterwells plate with 96 wells. Processed mikrotechnologie plate was placed under a ventilated hood to ensure evaporation of acetone for 2 hours Infectious nematodes root knot (stage 2, 25-50 worms) in 50 μl of water was introduced by pipette into each treated well and in more control. After the introduction of nematodes in wells containing various compounds, the plates were covered with lids to prevent evaporation and kept at 25oC.

The effect observed under preparative microscope after 24 and 48 h after treatment. Directly in front of observations knock on the plate, in order to stimulate the movement of worms. Activity was assessed by semi-quantitative method based on chemical effects on the motility of larvae J2. Were selected by the following criteria: 9 the lack of mobility, 7 markedly decreased mobility in approximately 95% of the worms, 5 - slightly decreased mobility, 0 normal mobility as the control worms. Easily noted other factors, indicating the activity, such as mortality, rigid paralysis, reduce curl, Ana ivermectin, moxidectin and levamisole.

1. Macrolide compounds of the formula I

< / BR>
or its salt,

where R1methyl, ethyl or isopropyl;

R2hydrogen, C1C8-alkyl or C3- C8alkenyl, the group NOR2is S-configuration, OR3is hydroxy, OR4, OCOR4, OCOOR4or OCONR8R9, R4C1C6-alkyl, R8and R9independently means hydrogen or C1C4-alkyl.

2. Connection on p. 1, where OR3methoxycarbonylamino, acetoxygroup, a methoxy group or a hydroxyl group.

3. Connection on p. 1, where OR3hydroxyl group.

4. The compound according to any one of paragraphs.1 3, where R1the isopropyl group.

5. The compound according to any one of paragraphs.1 to 4, where R2methyl group.

6. Connection on p. 1, where R1ISO-propyl group, R2is a methyl group and OR3the hydroxy-group, acetoxygroup or methoxycarbonylamino.

7. Connection on p. 1, where R1ISO-propyl group, R2is a methyl group and OR3hydroxyl group.

8. Connection on p. 1, where R1methyl group, R2is a methyl group and OR3is 2">

9. The composition having antibiotic activity containing the active ingredient and pharmaceutically acceptable carrier, wherein the active ingredient is used at least one of the compounds of formula I on p. 1, taken in an effective amount.

10. Veterinary composition comprising activetestsuite substance and pharmaceutically acceptable additives, wherein the domain activitiesthese substances it contains a connection on p. 1 of the claims in an effective amount.

11. Insecticidenematicides composition comprising the active substance and the target additives, characterized in that the active substance it contains a compound of the formula I

< / BR>
where R1methyl, ethyl, isopropyl, R2lower alkyl, OR3hydroxyl group, in an effective amount.

12. Method of destroying insects and/or mites, nematodes by treating them or the plants on which they live, active substance, characterized in that the active substance use compounds of formula I, where R1methyl, ethyl, isopropyl, R2lower alkyl, OR3- hidroxizina group, in effective amounts, the

 

Same patents:

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The invention relates to certain 13-alkyl-23-imino - 13-halogen-23-imino-LL-F28249-compounds and to their use for combating endo - and ectoparasitic infections and infestations in warm-blooded animals

The invention relates to new 2-imidazolin-2-yl)thieno - foroperational compounds, to intermediates used to obtain these compounds, and the way of dealing with these compounds with unwanted annual and perennial plants, namely 6-(2-imidazolin-2-yl)thieno - and furo[2,3-b] and 5-(2-imidazolin-2-yl)thieno - and furo[3,2-b]the pyridine compounds and the corresponding 2,3-dihydrothieno and 2,3-dihydropyrimidine with structural formulas (Ia) and (Ib):

< / BR>
whererepresents a single or double bond; R1represents a C1-C4alkyl; R2represents a C1-C4alkyl or C3-C6cycloalkyl; R1and R2together with the carbon atom to which they are joined, can form WITH3-C6cycloalkyl, optionally substituted stands; And represents СООR3CHO, CH2OH, COCH2HE, CONHCH2CH2OH, CONHOH or

R3hydrogen, C1-C12alkyl, which can be broken od is alkoxy, halogen, hydroxyl, C3-C6cycloalkyl, benzyloxy, fullam, phenyl, furfuryl, galopera, lower alkylphenyl, lower alkoxyphenyl, nitrophenyl, carboxyla, lower alkoxycarbonyl, cyano, C1-C4alkylthio or three (lower) alkylammonium; C3-C6alkenyl, optionally substituted by one of the following groups:1-C3alkoxy, phenyl, halogen or two WITH1-C3alkoxygroup or two halogen groups; C3-C6cyclooctyl, optionally substituted by one or two1-C3alkyl groups; C3-C10quinil, optionally substituted by phenyl, halogen or CH2IT; or the cation of an alkali metal or alkaline-earth metal (CA, BA) manganese, copper, iron, ammonium, or organic ammonium; RWITHand RDrepresent N or CH3; Represents N; COR4or SO2R5provided that when a represents a COR4or SO2R5and is a СOOR3the radical R3cannot be hydrogen or a salt-forming cation; R4represents a C1-C11alkyl, chloromethyl or phenyl, optionally substituted A5 alkyl or phenyl, optionally substituted one metalno, chloro - or nitro-group; W represents 0 or S; X represents 0, S or whenis a single bond, the group S 0; Y and Y', Z and Z' represent hydrogen, halogen, C1-C6alkyl, C1-C4hydroxy (lower) alkyl, C1-C6alkoxy, C1-C6acyloxy, benzoyloxy, optionally substituted by one or two1-C4alkyl, C1-C4alkoxygroup or halogen; C1-C4alkylthio, phenoxy,1-C4haloalkyl,1-C4haloalkoxy, nitro, cyano, C1-C4alkylamino,1-C4dialkylamino,1-C4alkylsulfonyl or phenyl, optionally substituted by one or more1-C4the alkyl, C1-C4alkoxy, halogen, or any combination of these two groups, where Y and Z are the same provided that Y and Z represent hydrogen, halogen, alkyl or alkoxy, and when Y and Y' or Z and Z' are the same group they are hydrogen or alkyl; and taken together, Y and Z form a ring in which YZ has the structural formula -(CH2)n- where n являе/www.fips.ru/fullimg/rupat2/19962/004.dwl/2058313-8t.gif" ALIGN="ABSMIDDLE">-=where L, M, Q, and R7each represent hydrogen, halogen, nitro, C1-C4lower alkyl, C1-C4lower alkoxy, methoxy, phenyl, phenoxy, provided that only one of the radicals L, M, Q or R7may have a value different from hydrogen, halogen, C1-C4the alkyl or C1-C4alkoxy; or a pyridine-N-oxides, when W represents oxygen or sulfur and a is COOR3; and when R1and R2not the same, the optical isomers of these compounds, except for the case when R3represents a salt-forming cation, their salts kislotoustoichivam

The invention relates to a pesticide composition on the basis of new chemical compounds having pesticidal activity, and is used for pest control

The invention relates to new ways of combating nematodes

FIELD: agriculture.

SUBSTANCE: invention describes a method for feeding potato and tomato with 6-benzylaminopurine an aqueous solution taken in the concentration 10-4 M and growing pants up to preparing harvest according to technology accepted for the culture crop. Invention proposes 3-fold treatment of plants for vegetation: at the lateral branching phase, at onset of forming economically value organs and immediately after the growth termination. Method provides the effective enhancing the productivity of the most important vegetable crops - tomato and potato.

EFFECT: improved enhancing method.

6 tbl, 4 ex

FIELD: organic chemistry, chemical technology, herbicides.

SUBSTANCE: invention describes a method for preparing compounds of the formula (I):

wherein each R1, R2, R3 means independently of one another (C-C6)-alkyl; R can represent also pyridyl; R4 and R5 in common with nitrogen atoms to which they are joined form unsaturated 5-8-membered heterocyclic ring that can be broken by oxygen atom; G means hydrogen atom. Method involves interaction of compound of the formula (II):

wherein R1, R2 and R3 have above given values; R6 is a group RR9N-; R7 is a group R10R11N-; each among R8, R, R10 and R11 means independently of one another hydrogen atom or (C1-C6)-alkyl in inert organic solvent being optionally with the presence of a base with compound of the formula (IV) ,

(IVa)

or (IVb) ,

wherein R4 and R have above given values; H x Hal means hydrogen halide. The prepared compound of the formula (I) wherein G represents ammonium cation is converted to the corresponding compound of the formula (I) by treatment with Brensted's acid wherein G represents hydrogen atom. Also, invention describes compound of the formula (II) wherein R1, R2, R3, R6 and R7 have above indicated values.

EFFECT: improved preparing method.

9 cl, 12 ex

FIELD: organic chemistry, herbicides, agriculture.

SUBSTANCE: invention describes a synergistic composition of herbicides comprising components (A) and (B) wherein (A) represents herbicide taken among the group of the formula (I):

wherein R1 means (C1-C4)-alkyl; R2 means (C1-C4)-alkyl; R3 means hydrogen atom; X and Y mean (C1-C4)-alkoxy-group; (B) represents one or two herbicides taken among the group of compounds or their acceptable forms: alachlor, metolachlor, acetochlor, dimetenamide, atrazine, cyanasin, metribusin, fluthiamide, nicosulfuron, rimsulfuron, primisulfuron, pendimetalin, sulcotrion, dicamba, mesotrion, isoxachlortol, metosulam, anilofos, fenoxaprop-ethyl, setoxydim, diclofop-methyl, MCPA, bromoxynil, pyridat, clopyralid, iodosulfuron-methyl, ethoxysulfuron, amidosulfuron, gluphosinat-amminium, isopropylammonium-glyphosate, imasetapir wherein components (A) and (B) are taken in the effective doses. Also, invention describes a method for control of weeds by using above indicated herbicide composition. Invention provides the development of the synergistic herbicide composition eliciting high activity.

EFFECT: improved method for control, valuable properties of composition.

6 cl, 26 tbl, 3 ex

FIELD: agriculture, plant science, plant protection.

SUBSTANCE: the suggested herbicidal composition of selective action contains, except generally accepted additional substances for the composition, a mixture as an active substance including a) herbicidally efficient quantity of compound of formula (I) , where R1 and R3 each independently means ethyl, ethynyl, C1- or C2alkoxy; R4 and R5 forms together the group Z2-CR14(R15)-CR16(R17)-O-CR18(R19)-CR20(R21)-(Z2); R14, R15, R16, R17, R18, R19, R20 and R21 means hydrogen; G means hydrogen, -C(X1)-R30, -C(X2)-X3-R31; X1, X2, X3 means oxygen; R30, R31 each independently means C1-C10alkyl, or salts or diastereoisomer of compound of formula (I), and b) efficient quantity of antidote of formula IIa to prevent harmful action of herbicide, where R22 means hydrogen, alkaline-earth metal or ethyl, or of formula IIb , where R23 means hydrogen, alkaline-earth metal or ethyl, and method for selective control for weed plants and grasses in cultivated plants. Thus, the antidote decreases the damage of cultivated plants induced by herbicide of formula (I).

EFFECT: higher efficiency of plant protection.

3 cl, 4 ex, 4 tbl

FIELD: organic chemistry, agriculture, herbicide composition.

SUBSTANCE: invention relates to herbicide composition, containing conventional inert additives and mixture of a) herbicidically effective amount of substance satisfying the formula I [in formula R1 and R3 are the same or different C1-C4-alkyl; R4 and R5 together form groups of formulae: -C-R6(R7)-O-C-R8(R9)-C-R10(R11)-C-R12(R13)-(Z1), -C-R14(R15)-C-R16(R17)-O-C-R18(R19)-C-R20(R21)-(Z2), or -C-R22(R23)-C-R24(R25)-C-R26(R27)-O-C-R28(R29)-(Z3), wherein each R6-R29 is hydrogen; G is hydrogen or -C(X2)-X3-R31; X2 and X3 independently are oxygen; R31 is C1-C10-alkyl]; b) herbicidic synergic amount of at least one herbicide selected from group containing sulfonylureas, phenoxyacetic acids, as well as florsulam, tralcoxidim, klodinafol-propargil, phenoxaprop-P-ethyl, trifluramine, pendimethaline, picolinafen, etc. Composition also may contain safety effective amount of protective agent, such as chloquintocet-mexyl and additive (e.g., mineral oil or C8-C22-fat acid alkyl esters) in amount of 0-2 mass %. Also disclosed is method for selective controlling of weeds and grassy plants in cultural plants by treatment of cultural plants, seeds or seedlings thereof, or vegetation area thereof with claimed composition.

EFFECT: effective composition and method for weed controlling.

5 cl, 11 tbl, 7 ex

FIELD: organic chemistry, veterinary science.

SUBSTANCE: invention relates to a method for control over exto- and endoparasites taken among group including acariform mites, parasitoformous mites and nematodes parasitizing in animals, productive cattle and domestic animals. Method involves applying veterinary preparation comprising 1-[4-chloro-3-(3-chloro-5-trifluoromethyl-2-pyridyloxy)phenyl]-3-(2,6-difluoro)urea and compound of the formula (i):

wherein R1 means one of radicals:

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

EFFECT: valuable properties of compounds.

7 cl, 3 tbl, 8 ex

FIELD: organic chemistry, agriculture.

SUBSTANCE: invention relates to selective herbicidal compositions, containing customary auxiliary substances, as well as: a) herbicidal effective amount of compound of formula I or agriculture acceptable salt thereof wherein R are independently C1-C6-alkyl, C1-C6-haloalkyl, C1-C4-alcoxy-C1-C4-alkyl, or C1-C4-alcoxy-C1-C4-alcoxy-C1-C4-alkyl; m = 2; Q is group of formula wherein R23 is hydroxyl and Y is C1-C4-alkylen bridge; and b) synergetically effective amount of one or more herbicides; and methods for controlling of undesired plants in tame cultures using the said composition. Also disclosed is composition containing customary auxiliary substances, as well as herbicidal and synergetically effective amount of 4-hydroxy-3-(2-methyl-6-trifluoromethylpyridine-3-carbonyl)bicyclo[3.2.1]octo-3-ene-2-one of formula 2.2 and herbicidal antagonistically effective amount of antidote of formula 3.1. Compositions based on 4-hydroxy-3-(2-methyl-6-trifluoromethylpyridine-3-carbonyl)bicyclo[3.2.1]octo-3-ene-2-one and herbicidal antagonistically effective amount of antidote, as well as methods for controlling of weeds and cereal grasses in tame cultures also are described.

EFFECT: compositions useful in effective controlling of many weeds both in pre-spring and post-spring phases.

5 cl, 63 tbl, 12 ex

FIELD: organic chemistry, agriculture.

SUBSTANCE: invention relates to herbicidal composition containing synergetically effective amounts of (A) and (B) components, wherein (A) has formula II (R1 is C1-C6-alkyl, substituted with halogen; R2, R3 and R4 are hydrogen; R5 is rest of formula -B1-Y1, wherein B1 is direct bond and Y1 is acyclic C1-C6-hydrocarbon or cyclic C3-C6-hydrocarbon; F is -CH2-CH2-, -CH2-CH2-CH2- and CH2-O-; X are independently halogen or C1-C4-alkoxy; n = 0-2; and (B) represents one or more herbicides, selected from group containing isoprothuron, flufenacet, anylophos, ethoxysulphuron, mecoprop-(P), ioxinyl, florazulam, pendimethalin, MV 100, etc. Also disclosed is method for weed controlling using abovementioned composition.

EFFECT: composition with improved herbicidal action.

12 cl, 23 ex, 23 tbl

FIELD: agriculture, in particular method for controlling of specific insect pests.

SUBSTANCE: invention relates to method for controlling of lepidopterous, homopterous, hemipterans, coleopterous, and physopods by contacting of said pests or environment thereof with effective amount of compound of formula I SSS1, N-oxide or agriculturally acceptable salt thereof being effective against abovementioned insects, wherein A and B are independently O or S; R1, R2 represent H, C1-C6-alkyl; R3 represents H, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkinyl, or C3-C6-cycloalkyl; R4 represents H, C1-C6-alkyl, C2-C6-alkinyl, C1-C6-haloalkyl, CN, halogen, C1-C4-alkoxy, C1-C4-haloalkoxy, NO2;. R5 represents H, C1-C6-alkyl, C1-C6-haloalkyl, C1-C4-hydroxyalkyl, CO2R11R12, halogen or C1-C4-alkoxy; R6 represents H, C1-C6-alkyl, C1-C6-haloalkyl; R7 represents H, C1-C6-alkyl, C2-C6-alkenyl, C1-C6-haloalkyl, phenyl ring, benzyl ring, or 5-6-membered heteroaromatic rind, naphthyl ring system, or 8-10-membered condensed heterodicyclic system. Also claimed are compound of formula I and benzoxazine derivative of formula 10 .

EFFECT: compounds effective against agriculture spineless depredators.

22 cl, 13 tbl, 1 dwg, 24 ex

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