A method of obtaining a macrolide compounds

 

(57) Abstract:

Usage: in agriculture, in particular as nematode funds for the treatment of animals and people affected by endoparasites, and/or fungal infection, and also as a pesticide. The inventive product is a macrolide compounds F.-ly (I), where R1is isopropyl; R2= OR5; R3= N, OR5= OC(O)R6, OR6= C1-C4not - or substituted phenyl or fenoxaprop alkyl or C3-C5-cycloalkyl, or7where R7= C1-C4-alkyl, non - or substituted C3-C5-cycloalkyl, or C3-C5alkenyl; OR4HE, OC(O)R4awhere R4a-C1-C4-alkyl. Reagent 1: compound of formula I, where R2and OR4- one or both are HE. Reagent 2: compound of the formula: R6- C(O)HE or R4a- C(O)HE, or R7Y, where Y = Cl, Br, J. the compounds of formula I reduce the number of worms more than 80% at a dose of 10 mg/kg of the structure of the compounds of formula I.

The invention relates to a method of obtaining new macrolide compounds of formula I.

Known to produce antibiotics S541, which can be distinguished from the products of fermentation of Streptomyces species. Antibio in this description, identified an additional group of compounds with antibiotic activity, which can be obtained through chemical modification of antibiotics S541 or by selecting them from the culture of microorganisms of the genus Streptomyces.

The new compounds of the invention possess antibiotic activity and/or are used as intermediate products in the production of other active compounds and/or selecting or clearing the compounds of antibiotics S541.

Compounds of the present invention are substituted hydroxyl analogues of the antibiotic S 541, which have a hydroxyl or substituted hydroxyl group in position 5.

Thus, in one embodiment, the present invention proposes, in particular, the compounds of formula

(I) where R1is isopropyl;

R2group OR5;

R3represents a hydrogen atom; OR5group is-OCOR6group, where R6- C1-C4-alkyl, optionally substituted by fenoxaprop or phenyl, or C3-C5-cycloalkyl,

or or7where R7- C1-C4-alkyl, optionally substituted C3-C5-cycloalkyl or3-
R1is ISO-propyl group; R2- propionoxy; R3- the hydrogen atom and OR4represents a hydroxyl group;

R1is ISO-propyl group; R2is ethoxypropane, R3represents a hydrogen atom and-OR4is a hydroxyl group; and

R1is ISO-propyl group; R2- n-propoxyphene; R3- the hydrogen atom and OR4- hydroxyl group.

R1is a methyl group; R2- acetoxygroup, R3- the hydrogen atom and OR4hydroxyl group.

R1is an ethyl group; R2is acetoxy; R3- the hydrogen atom and OR4- hydroxyl group.

R1is an ethyl group; R2acetoxygroup; R3a hydrogen atom and OR4represents a hydroxyl group.

R1is ISO-propyl group; R2- acetoxygroup; R3- the hydrogen atom and OR4- hydroxyl group.

As mentioned previously, the compounds of the invention can be used as antibiotics and/or as intermediate compounds for other act is soedineniya have to use as intermediates, R2and/or4can be protected hydroxyl groups. It is clear that such a group must have a minimum number of additional functional groups to avoid further reaction of the circuit should be such that it became possible to selectively restore from it a hydroxyl group.

The proposed compounds have antibiotic activity, such as anthelmintic activity, for example against nematodes, and in particular, anti-endoparasites and anti-ectoparasitic activity.

Ectoparasites and endoparasites infect humans and a variety of animal and, especially, have a wide distribution among farm animals: pigs, sheep, cattle, goats and poultry, horses and domestic animals, such as dogs and cats. Parasitic infection of livestock, leading to anemia, malnutrition and weight loss, is a major cause of economic losses worldwide.

Representatives of endoparasites infecting these animals and/or people are Ancylostoma, Ascaridia Ascaris, Aspicularis, Brugia, Bunostomum, Capillari, Chabertia, Coopenia, Dictyocaulus, Pirofilaria Dracunculus, Enterobius, At, Heterakis, loa, Necator, Nematodirus, Ne - matospiroides, Neligomoroides, Nria and Wuchareria.

Examples of parasites that infect animals and/or people are arthropods entoparasite, such as stinging insects: Madalina fly, fleas, lice, ticks, sucking insects, Academie mites and other dockrillia insect pests.

Examples of this kind of endoparasites infected animals and/or humans include: Ambylomma, Boophilus, Chorioptes, Culliphore, Demodex, Demallenia, Der - matobia, Gastrophilus, Haematobia, Haema - topinus, Haemophysalis, Hyalomma, Hyper - derma, Ixodes, Linognathus, Lucitia, Melopha - gus, Oestrus, Otobius, Otodectes, Psorerga - tes, Psoroptes, Rhipicephal Sarcoptes, Sto - moxys and Tabanus.

Found that the proposed compounds have been effective both in vitro and in vivo against a wide range of endoparasites and ectoparasites. In particular, it is found that the compounds of the present invention are active against nematodes, such as At the contortus, Ostertagicira meineta, Irichostrongylus colubiformis, Dictyeaulus viviparis, Ceoperia oncophera, Ostertagia ostertagi, Nematospiroides dibius and Nippostrongulus braziliensis and parasitic mites, such as Sarcoptes sp and Psoroptes sp. Thus, the proposed compounds find use in the treatment of animals and people with endoparasites and/or ectoparasitic infections.

Parasites vary in accordance with the host (animal and dominant site of infection. Therefore, for example, I in the stomach and the small intestine, while Dictyocaulus viviparis, Cooperia oncophora and Ostertagia ostertagi usually infect cattle and localized mainly in the lungs, the intestines or the stomach.

The antibiotic activity of the proposed compounds can be demonstrated, for example, by their activity in vitro against free living of nematodes, for example Caenorhabioditis elegans.

In addition, the claimed compounds have use as anti-fungal substances, for example against Candida species such as Candida alleicans and Candida glabrata, and yeasts, such as Saccharomyces carlsbergensis.

Compounds of the present invention may also have application in pest control-insects, mites and nematodes in agriculture, horticulture, forestry, health care and storage products. They can successfully handle pests, soil and agricultural crops, including cereals (e.g. wheat, barley, maize, rice), vegetables (e.g., soy), fruits (such as apples, grapes, and citrus), along with root crops (e.g. sugar beet, potatoes). Typical examples of such pests are fruit mites and aphids such as Aphis fabae, Aulacorthum circum flexum, Myrus persicae, Nephotettix cineticeps, nilpawata lugens, Panonychus ulmi, Phorodon humuli, Phyltocloidogyne and Panagrellus scaly, for example Heliothi Plutella and Spodoptera weevil of calandrino, such as Anthonomus grandis and Sitophlus granarius, worms flour, such as Tribolium castaheu, flies, for example Musca domestica, ants Richter; moth-minelayers number; Pear psylla; thrips tobacco; such relic species, such as Blatella germanica and Periplaneta americana, mosquito, for example Aedes aegypti.

In accordance with the present invention, the compounds of formula (II), as mentioned above, which can be used as antibiotics. In particular, they can be used in the treatment of animals and people affected endoparasites, ectoparasitic and/or fungal infections, and as pesticides for pest control-insects, mites and nematodes, agriculture, horticulture or forestry. They can be used, in addition, usually as pesticides in other circumstances, for example in warehouses, buildings or other public places or places of localization of pests. Basically proposed connection can be applied either to the host (animal or person, or to cultivated plants or other vegetation), or to the pests or their location.

The claimed compounds can be primenennoe the invention includes within its scope pharmaceutical compositions containing the compound according to the claimed invention, suitable for use in veterinary medicine or therapy. Such compositions may be presented for use in the traditional manner using one or more suitable carriers or excipients. The proposed compositions are compositions in the form, especially suitable for parenteral (including the introduction inside the breast), oral, rectal, topical application in the form of an implant, for use in eye, ear, or diseases of the genitourinary system, suitable methods and agents for the preparation of the compounds of the present invention, suitable for use in veterinary medicine or therapy, are known methods for compounds of antibiotics S541.

The claimed compounds can be used in combination with other pharmaceutically active ingredients.

The total daily dose of the proposed compounds used in veterinary medicine and therapy will be correspond - ingly in the range of 1-2000 mg/kg body weight, preferably 50-1000 mg/kg and above dose can be taken in fractional doses, for example of 1-4 times a day.

The claimed compounds can be Liu is within its scope compositions containing compound that is intended for use in agriculture or horticulture. Such formulations include dry or liquid form, such as dusty, including pulverulent substrates or concentrates, powders, including soluble or wettable powders, granules, including microspheres and dispersible granules, tablets, liquid substances, emulsions, such as diluted emulsion or emulsifiable concentrates, impregnating compositions, for example compositions for impregnation roots and seeds, seed treaters, seed, pellets, oil concentrates, oil solutions, injections, for example injection into the barrel, solutions or sprays, fumes and mists.

Suitable methods and agents for the preparation of the formulation of the proposed compounds for use in gardening or farming off those disclosed in the known patent for antibiotics S541.

When the formulation, the concentration of the active substance is usually from 0.01 to 99 wt.% and more preferably from 0.01 to 40 wt.%.

Industrial (commercial) products are usually prepared in the form of concentrated compositions that, when used diluted to the desired concentration, for example from 0.001 to 0.0001 wt.%.

The antibiotic compounds of the invention can be introduced and used in combination with other active ingredients.

In particular, the proposed connection of the antibiotic can be used together with compounds of antibiotics S541 or other antibiotikum of the present invention. This may occur, for example, when the crude products of fermentation interact according to the method of the present invention without prior or subsequent separation, this may be preferred, for example, when using the compounds in agriculture, where it is important to ensure (save) low cost of production.

The compounds of formula I pouillenay group, with hydroxyzinesee reagent of the formula

R6COOH or R4aCOOH, (II) where R6and R4ahave the above significance, or its reactive derivative, or a compound of the formula

R7Y, (III) where R7have the above meanings;

Y is a chlorine atom, bromine or iodine.

The acylation reaction can be carried out in aqueous or anhydrous reaction medium, preferably at a temperature in the range from -20 to +100aboutWith, for example, from -10 to +50aboutC.

Formirovanie can be performed using an activated derivative of formic acid, for example, N-formylindole or anhydride of formic acid under standard reaction conditions.

Introduction sulfonyloxy can be accomplished by using a reactive derivative of sulfonic acids R8O3H such as sulfanilamide, for example chloride R8SO2Cl or sulfonic anhydride. Sulfonylurea preferably in the presence of a suitable acid-binding agent, as indicated above.

The etherification can be carried out using a reagent of formula R7Y (where R7have the above meanings and Y is departing is iloxi or tailcall - phenyloxy, or haloalkoxy, for example, dichloracetate). The reaction may be accompanied by formation of a magnesium alcoholate with the use of the Grignard reagent, such as kaleidotile, for example idetermine or helodrilus - silymarine, for example chlorotrimethylsilane followed by treatment with a reagent R7Y

If desired, the reaction may be conducted in the presence of silver salts such as silver oxide, silver perchlorate, silver carbonate or silver salicylate, or their mixtures, and this system may be particularly suitable when the etherification is carried out in the presence of haloalkyl (yodmetilat).

The etherification can be respectively carried out in a solvent such as simple ether, for example diethyl simple ether.

The formation of acetals can be performed by reaction with a cyclic or acyclic simple vinyl ether. This method is particularly suitable for receiving tetrahydropyranyl ethers using as reagent dihydropyran, or 1-alkoxyalkyl ethers, such as 1-ethoxyaniline simple ether, using as reagent simple vinyl ether. The specified R is Oh as sulfuric acid, or organic sulfonic acids, such as p-toluensulfonate, digitoxigenin, anhydrous solvent.

Anhydrous solvents that can be used in the above reaction include ketones (e.g. acetone), amides (e.g. N,N-dimethylformamide, N, N-dimethylacetamide or hexamethylphosphoramide, ethers (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 golozhabernyi hydrocarbons (e.g. methylene chloride) and esters such as ethyl acetate, and also mixtures of two or more of these solvents.

The introduction of cyanide can be accomplished by interaction with similaroriginal (e.g., chloride), mainly in the presence of a base, such as imidazolidinyl or pyridine solvent, such as dimethylformamide.

In many cases, for example, when 5,23-dihydroxytoluene formula (III) used as a target material formed of a mixture of 5-and one-deputizing 5,23-disubstituted derivatives. However, they can be separated using aromaterapia).

Intermediate compounds of antibiotics S541 formula (III), where OR5is a hydroxyl group OR4represents hydroxyl or metaxylene group, can also be obtained using the methods of fermentation and separation, for example, as described in the patent. Other intermediate compounds of formula (III) can be obtained from these compounds by using the above-described methods for producing compounds of the formula (II).

The present invention further represented by the following preparations and examples. All temperatures are given at 0aboutC.

Connections marked with reference to the source of the "Factors" that represent the following compounds of the formula (see table).

(V)

The factors a, b, C, D, E, F can be obtained in a known manner.

P R I m e R 1. 5-Phenoxyacetate - 5,23-diphenoxyethane factor A.

Factor A (2.0 g) in a solution of dichloromethane (25 ml) and pyridine (0.35 mol) at 0aboutWith process solution phenoxyacetamide (0.5 ml) in dichloromethane. After 18 hours at a temperature of 3aboutWith the resulting solution was treated with pyridine (1.0 ml) and phenoxyacetamide (1.0 ml) in dichloromethane (5 ml). The solution carefully paramesh is in the solution and the mixture is stirred for 20 minutes The aqueous layer was extracted with simple ether. Ether layers are combined sequentially washed with water and saline solution, dried and evaporated. The residue is purified by chromatography on a column of silica with a mixture of dichloromethane with acetone (40:1) c output of the above mentioned compounds in the form of a mixture of 1.8 g monoacyl:diacyl = 6:1), which is shared by preparative high-performance liquid chromatogra - via reverse phase, receiving 5-phenoxyacetate factor And, (CDCl3contains of 6.8 to 7.4 (m, 5H) and 4.6 (s; 2H) m/z 746 includes, 728, 710, 594 and 576, and 5,23-diphenoxyethane factor And, (CDCl3contains of 6.8 to 7.4 (m, 10H), 4,60 (s, 2H) and 4,70 (s, 2H).

P R I m m e R 2. 5-Phenoxyacetate-23-(4-methylphenoxyacetic) factor A.

5-Phenoxyacetate factor And (747 mg) in dichloromethane (10 ml) at 0aboutC in nitrogen atmosphere is treated with pyridine (0,81 ml) and then 4-methylphenylethylamine (0.75 g) in dichloromethane (2 ml). The obtained dark solution was thoroughly stirred for 15 min at 0aboutWith and then for a further 22 h without cooling. The resulting mixture was poured into cold water and salt solution (brine) and extracted with simple ether. Joined layers of simple ether washed with water and saline solution, dried and evaporated. The remainder zoé obtaining these compounds (430 ml), (CDCl3contains: 3,34 (m, 1H), to 3.58 (m, 1H), 3,97 (d, 10, 1H), 4.72 in (s, 2H), 5,4 (m, 1H), 5,59 (d 6, 1H), 6.9 to 7.4 (m, N), m/z includes 728, 616, 576, 466, 464, 448, 354, 297, 247, 219 and 151.

P R I m e R 3. 5-tert-Butyldimethylsilyloxy factor A.

Factor A (2,144 g) in anhydrous simple ether (25 ml) and pyridine (2.5 ml) at 0aboutC in nitrogen atmosphere is treated with the addition of one drop of tert-butyldimethylchlorosilane (1.2 g) in a simple ether (10 ml). The resulting mixture was stirred for 50 min at 0aboutWith before handling drop again the acid chloride (1.10 g) in a simple ether (10 ml). The resulting mixture was thoroughly mixed at a temperature of 0aboutC for 60 min and poured into cold water and simple ether. The aqueous layer was washed with simple ether. United organic layers washed with water and saline solution, dried and evaporated. The resulting residue is purified by chromatography on silica, using a mixture of dichloromethane with acetone (25:1) as an eluate to obtain these compounds, (CDCl3includes: 0,09 (C, 6N), 0,78 (d 6, 3H), of 0.90 (s, N), 0,93 (d 6, 3H), 0,97 (d 6, 3H) and 1.83 (d 6, 3H) and 1.51 (s, 3H), of 1.59 (s, 3H), of 1.74 (s, 3H), of 3.32 (m, 1H), 3,52 (l 10, 1H), to 3.64 (m, 1H), 3,74 (l 10, 1H), is 3.82 (m, 1H), 4,32 (s, 2H), and to 5.57 (d 5, 1H); m/z contains 784, 766, 748, 595, 577, 484, 450 mg) and imidazole (163 mg) in dry dimethylformamide (10 ml) is treated with tert-butyldimethylsilyloxy (197 mg). The resulting solution was thoroughly stirred for 2 h and poured into cold water. This mixture is thoroughly extracted with simple ether, and joined the ether extracts dried and evaporated. The residue is purified by chromatography on silica, using a mixture of dichloromethane with acetone (10:1) as an eluate to obtain the above compound (235 mg), (CDCl3contains: 0,13 (c, 6H), 0,80 (d 6, 3), to 0.92 (s, N), is 0.96 (d 6, 3H), 1.00 m (d 6, 3H), of 1.03 (d, 6, 3H), of 1.53 (s, 3H), 1,60 (s, 3H), of 1.80 (s, 3H), 3,37 (m, 1H), 3,56 (l 10, 1H), to 3.64 (m, 1H), 3.75 to (d 10, 1H) and 4,43 (d 5, 1H); m/z contains 726, 708, 691, 651, 633, 466, 448, 354, 314, 297, 265, 247, 219 and 151.

P R I m e R 5. 5-Acetoxy and 5,23-diacetoxy factor A.

Factor A (3.0 g) in pyridine (20 ml) at a temperature of -5aboutTo treat acid anhydride (8 ml) and the resulting solution was left for 3aboutWith over 20 hours To the solution was added benzene (100 ml) and the resulting mixture was concentrated in vacuum. The residual oil chromatographic on silica, using as the eluate mixture with dichloromethane-acetone (40:1) to give 5-acetate factor And from 2.06 g) containing 5,23-diacetate (10%). The compounds obtained is separated by preparative liquid chromatography reverse phase with obtaining 5-acetoxy factor (79% yield).max(Et OH) 244,5 nm (E', 4,62); (CDCl(s, 3H), and 2.13 (s, 3H); m/z contains 696 and 636.

P R I m e R 6. 5,23-Diacetoxy factor A.

A solution of factor A (600 mg) in dry pyridine (1.0 ml) is treated with excess amount of acid anhydride (0,50 ml) and a few crystals of 4-N,N-dimethylaminopyridine. After 24 h at room temperature the solution is poured out in a simple ether and then the organic phase is washed with 2 N. hydrochloric acid, saturated sodium bicarbonate solution and finally with brine. Evaporation of the dried organic layer provides a gum which is purified by chromatography through a column of Merch Kieselgel 60 silica (45 g) of size 230-400 mesh mesh. Elution of the column with a mixture of dichloromethane and ether (9:1) gave the titled compound as a colourless foam (560 mg), []D26+ 169o(c, 0,48, CHCl3).

The compound of example 7 were obtained in a similar way:

P R I m e R 7. 5,23-Diacetoxy factor C.

So pl. 211-213about, []D22+ 200o(c, 0,40, CHCl3);maxEtOH238,5 (30, 400) and 245 nm (max32, 500); max3440 (OH) and 1718 cm-1(acetoxy and ester); (CDCl3contains the 4.90 (m, 1H), 4.04 the (D. 6 Hz, 1H), 3.96 points (d, 10 Hz, 1H), to 3.58 (m, 1H), 3,32 (m, 1H), and 2.14 (s, 3H), of 1.75 (s, 3H), 1,67 (d 6 Hz, 3H), 1,60 (s, 3H), of 1.52 (s, ethyl, and not in a simple ether and zakluchenii crystallized on poroshkovaya diisopropyl ether.

P R I m e R 8. 23-Acetoxy factor A.

To a stirred and cooled (0-5about) to a solution of compound of example 6 (530 mg) in methanol (10 ml) was injected dropwise an aqueous solution (1 ml) of sodium hydroxide (30 mg). After 1.3 h the mixture was poured into ethyl acetate and the organic phase is then washed successively 2 N. hydrochloric acid; water and at the end of the salt solution. Evaporation of the dried organic phase gives a yellow resin, which in dichloromethane is introduced into a chromatographic column Merch Kieselgel 60, with the addition in the same solvent - silica (50 g), particle size 230-400 mesh mesh. Elution with a mixture of dichloromethane with simple ether (9: 1) gave the titled compound, which is obtained as an almost colorless solid by evaporation of a solution of n-pentane. Specified substance (330 mg) is []D23+ 166o(c, 0,64, HCl3),maxEtOH239 (26,500) and 245 nm (max29,300);max(CHBr3) 3540, 3460 (OH) and 1712 cm-1(of ester); (CDCl3contains 4,89 (m, 1H), 4,27 (m, 6 Hz, 1H); 3,93 (d, 6 Hz, 1H), 3,91 (d, 10 Hz, 1H), 3,55 (m, 1H), 3,25 (m, 1H), 2,01 (s, 3H), of 1.85 (s, 3H), of 1.59 (s, 3H) and 1.51 (s, 3H), of 1.03 (6 Hz, 3H), and 0.98 (d, 6 Hz, 3H), of 0.94 (d, 6 Hz, 3H) and 0.69 (on the toxi-factor With.

[]D23+ 139o(c 0,52, CH2Cl2):maxEtOH244,5 nm (max29,400);max(CHBr3) 3550, 3480 (OH); 1716 (ester and acetate) and 1255 cm-1(acetate); (CDCl3contains 4,91 (d, 3 Hz, 1H), 2,03 (s, 3H), and of 1.64 (d, 7 Hz, 3H) and 1.60 (s, 3H), m/z = 626 (M+).

From the compound of example 7 as a white amorphous solid.

P R I m e R 10. 5-Acetoxy-23-methylsulfonylamino factor A.

A solution of 5-acetoxy factor A (of 3.46 g) in pyridine (30 ml) cooled in an ice bath and treated methanesulfonyl anhydride (2,2). After 30 min the mixture was warmed up to ambient temperature and after another 60 min divided between ethyl acetate and 2 N. hydrochloric acid. The organic phase is separated and washed sequentially 2 N. hydrochloric acid, saturated aqueous sodium bicarbonate and finally with a saturated salt solution. The organic solution is dried (Na2SO4) and the solvent is evaporated to yield that chromatographic through the column on silica (Merck Art 9385), added to a mixture of hexane (boiling within 60-80aboutwith acetylacetone (3: 1), and elute in the same solvent. The appropriate fraction of the main component are combined and the solvent of viparita/SUB>),maxCHCl3247 nm ( 29070);max(CHBr3) 3550, 3470 (OH) and 1735, 1715 (ester:); (DCl3contains the 4.90 (m, 1H), 3,05 (s, 3H), and 2.16 (s, 3H).

P R I m e R 11. 23 Tosyloxy factor Century.

The factor In (250 mg), tailby anhydride (204 mg) and a few crystals of 4-N, N-dimethylaminopyridine stirred in dry pyridine (0.5 ml) for 24 hours the Mixture is poured into a simple ether and the organic phase is washed successively 2M hydrochloric acid, saturated aqueous sodium bicarbonate and finally with brine. Evaporation of the dried (Na2SO4) the ether layer gives the crude product in dichloromethane is introduced into a chromatographic column on silica gel (50 g, Merck Kieselgel 60, 203-400 mesh. ) included in the same solvent. Exercise and elution with a simple mixture of dichloromethane-ether (9:1) main component, which is further purified preparative high performance liquid chromatography. The named compound are obtained in the form of resin []D23+ 173o(0,84, HCl3);max(Et 235 (30,000) and 244,5 nm (max30,800);max1708 cm-1(ether); (CDCl3contains of 7.82 (d, 10 Hz, 2H), 7,29 (d, 10 Hz, 2H), a 4.83 (K, 3 Hz, 1H), 3,50 (s, 3H) and 2.43 (s, 3H); m/z = 1752 (M+).

P R I m e R 12. 5-Acetoxy simple ether, followed by the introduction of idbutton (0.5 ml) and silver perchlorate (550 mg). The resulting mixture was stirred at room temperature for 20 h, when injected Solliden (0.5 ml). After stirring for another 20 min, the mixture is filtered and the filtrate washed successively with 2 N. hydrochloric acid, saturated aqueous sodium bicarbonate solution and water. The dried organic phase is evaporated almost to dryness and the oil purified by chromatography on a column of Merck Kieselgel 60 c the pore size 230-400 mesh mesh. Elution from the column with a mixture of hexane with ethyl acetate (3:1) to give the named compound as a colourless foam (276 mg).

[]D22+ 160o(c 0,94, HCl3);max. (EtOH) 245 nm.

P R I m e p 13. Factor a-23-hemiacetal.

Factor A (ha 70% clearance) and calcium carbonate (1.5 g) was stirred with dichloromethane (20 ml) at a temperature of 21aboutWith and to the resulting suspension is added in excess once oxalicacid; (1.0 ml). After 4-5 min, this mixture is treated with water (15 ml) and after 5 min of 2 M hydrochloric acid (10 ml) and ethyl acetate (70 ml). The organic phase is separated, washed with water and salt solution and then treated with decolorizing charcoal. After 5-10 min educated organic solution is filtered through patristically paper and the filtrate was stripped and the get a pale yellow foam. Poroshkovaya specified foamed material diisopropyl ether (7 ml) to give the named compound as crystalline solid (750 mg) after washing the solids diisopropyl ether and n-pentane.

max(CHBr3) 3360-3600 (OH), 1805 (acidic monomer) and 1720 cm-1(acid dimer and esters): (DCl3contains 4,30 (d, 5 Hz, 1H) and 5,14 (m, 1H).

P R I m e R 14. Factor A.

A solution of 23-hemoccult factor A (500 mg) in dichloromethane (30 ml) was vigorously stirred with an aqueous solution of sodium hydroxide (1.54 g in 30 ml of N2On) for 2 h at 21aboutC. the Organic phase is collected, the aqueous phase is washed with a small amount of dichloromethane. The organic phases are combined, washed with 2M HCl, then dried (Na2SO4) and was stripped of solvent to obtain the above compound (430 mg) as a foam substance. The specified connection is demonstrated in the quality factor And the comparison of high-performance liquid chromatography with a similar pattern of factor A.

P R I m e R 15. Factor A, 5-hemisuccinate.

A solution of factor A (306 mg) and actinophage anhydride (60 mg) in dry pyridine (0.5 ml) is stirred what Laney acid and brine. Upon evaporation of the dried ether layer receive foamed substance, from which emit by preparative high performance liquid chromatography reverse phase named connection. Received the product in ether precipitates as a white amorphous solid (86 mg) with the introduction of additional n-pentane.

[]D22+ 125o(c, 0,44, CHCl3),maxEtOH245 nm (max30,700),max(CHBr3) 3490 (OH), 3,300-2,200 (CO2H). 1730 (acid carbonyl), and 1710 cm-1(hard alcohol); (CDCl3contains is 2.74 ( 4H), m/z = 712 (M+).

P R I m e R 16. 5-Acetoxy-23-ethoxysilane factor A.

A solution of 5-acetoxy factor A (320 mg) and excess ETHYLACETYLENE (0.5 ml) in dry dichloromethane (6 ml) are mixed in the presence of calcium carbonate (300 mg) for 1 h Formed mixture, diluted simple ether, poured into saturated sodium bicarbonate and then before pouring in ethyl acetate, stirred for 20 minutes Evaporation of the dried (Na2SO4) the organic phase makes the resin (325 mg), which in dichloromethane is introduced into the chromatographic column from Merck Kiezelgel 60, and silicon dioxide (25 g) with a particle size 70-230 mesh, added to advanoe compound (265 mg) as a white foam substance, []D23+ 157o(c 0,41, CHCl),maxEtOH245 nm (max32,800);max(CHBr3) 3530, 3480 (OH), 1760 and 1735 cm-1(esters); (CDCl3): of 5.4 to 5.6 (m, 2H), of 5.05 (m, 1H), 4,32 (K, 7 Hz, 2H); 2.13 and (s, 3H), and 1.35 (m, 7 Hz, 3H).

P R I m e R 17. 23 Metalocalypse factor A.

A solution of 5-acetoxy-23-ethoxysilane factor A (50 mg) in methanol (1 ml) containing concentrated sulfuric acid (0.01 ml) maintained at 21aboutC for 17 h and Then the mixture was poured into ethyl acetate and the organic phase acts as a neutral product. The specified product is purified by chromatography through a column of Megs Kieselgel-60 on the silicon dioxide (15 g) with a particle size 70-230 mesh, using as an eluting solvent initially dichloromethane and then a mixture of dichloromethane and ether (9: 1). The named compound is obtained as a colourless resin (25 mg), []D23+ 147o(x, 0,28, HCl3),maxEtOH245 nm (max26,000);max(CHBr3) 3550, 3480 (0H), 1763, 1737 and 1710 cm-1 (esters); (CDCl3), the 4.29 (t, 7 Hz, 1H), 5,09 (m, 1H), 3,88 (s, 3H).

P R I m e R 18. 5-Acetoxy-23-cyclopropanecarboxylate factor A.

A solution of 5-acetoxy factor A (140 mg) and pyridine (1 ml) is treated glareolidae acid. The organic phase is separated and washed sequentially with 2 N. hydrochloric acid and saturated aqueous sodium bicarbonate. The organic solution is dried (Na2SO4) and the solvent evaporated to obtain an oil, which chromatographic column of silica Merck Ar 9385; 80 ml), entered into a mixture of hexane (boiling within 60-80aboutwith ethyl acetate (3:1) and aliremove the same solvent. The appropriate fraction of the main component are combined and the solvent is evaporated to obtain these compounds in the form of a foamed substance (70 mg).

[] D22+ 143o(c = 0,54; CHCl3);maxCHCl250,2 ( = 20310);max(CHBr3) 3550, 3470, (OH) and 1733, 1712 (ester); (CDCl3): 2,16 (c, 3H), of 3.33 (m, 1H), 3,88 (d, J 10 Hz, 1H), free 5.01 (m, 1H) and 5.5 to 5.6 (m, 2H). The compound of example 19 receive a similar way.

P R I m e R 19. 5-Acetoxy-23-cyclopentanecarboxylate factor A.

5-Acetoxy factor A (0.28 g) and cyclopentanecarbonitrile (0.2 ml) to give the titled compound in the form of a foamed substance (0.17 g), []D22+ 149o(c = value (0.475); Hl3);max.CHCl); 250,2 nm ( =19900);max(CHBr3) 3480 (OH).

P R I m e R 20. 23 Cyclopropanecarboxylate the ml) cooled in an ice bath and treated with 3% aqueous solution of sodium hydroxide (0.5 ml). After 5 h, during which time the reaction mixture was warmed to room temperature, the solution was separated between ethyl acetate and 2 N. hydrochloric acid. The organic phase is separated, washed with 2 N. hydrochloric acid (×2), dried (Na2SO4) and the solvent evaporated. The remainder chromatographic on a column of silica (Merck Art 9385; 150 ml), entered into a mixture of hexane (boiling within 60-80about(C) with ethyl acetate and aliremove the same solvent. The appropriate fraction of the main component are combined and the solvent evaporated to yield the named of ester in the form of a foamed substance 170 mg), []D22+ 146o(c = 0,46; HCl3);max250,2 nm (= 20090); max(CHBr3) 3550, 3480 (OH) and 1709 (ether complex); (CHCl3): 3,26 (m, 1H), 3,88 (d, 10 Hz, 1H), 4,29 (m, J 7 Hz, 1H) and free 5.01 (m, 1H).

The compound of example 21 receive a similar way:

P R I m e R 21. 23 Cyclopentanecarboxylate factor A.

Cleavage of the protective group 5-acetoxy-23-cyclopentanecarboxylate factor A (0.25 g) to give the titled ester in the form of a foamed substance (0,215 g). []D20+ 141o(c = 0,63; HCl3);max.CHCl3250,2 nm ( = 19990);max(CHBr3) 3550, 3480 (OH) and 1710 (ester); (CDCl3):-5-methoxycarbonylamino factor A.

A solution of 23 cyclopropanecarboxylate factor A (0.1 g) in dry dichloromethane (15 ml) cooled in an ice bath and treated with pyridine (0.2 ml) followed by treatment of the 1M solution of methylchloroform in dichloromethane (0.3 ml). After 20 min the solution was diluted with dichloromethane and washed with 2 N. hydrochloric acid, then dried with sodium sulfate and the solvent is evaporated. Sediment chromatographic column of silica (Merck Art 9385; 100 ml), included in the mixture of hexane (60-80about(C) with ethyl acetate (3:1) and elyuirovaniya the same solvent. The appropriate fraction of the main component are combined and the solvent is evaporated to yield the named compound in the form of a foamed substance (0,106 g).

[]D20+ 149o(c = 0,63; CHCl3)maxCHCl3250,2 nm;max(CHBr3) 3470 (OH), 1745max(carbonate), 1710 (ester), 998 (C-O); (CDCl3contains (s, 1H), free 5.01 (m, 1H), 3,88 (d, J 10 Hz), 353 (s, 3H); 0,67 (d, J Hz, 3H).

P R I m e R 23. Factor A, 5-acetate, 23-isobutyrate.

A solution of factor A, 5-acetate (131 mg), isobutyramide (0.05 ml), pyridine (0.1 ml) and 4-dimethylaminopyridine (25 mg) in dry dichloromethane (10 ml) was stirred at 20aboutC for 16 hours the Solution was diluted with dichloromethane (30 ml), prom is on Kieselgel 60 (15). Elution from the column with a mixture of light oil with ethyl acetate (4:1) to give the titled compound (5.7 mg) as a colourless foam product.

[]D20+ 159o(c 0,61, CHCl3) max(EtOH) 2,44 nm ( = 30,400);max. (CHBr3) 3480 (OH), 1713 cm-1(ester), (CDCl3contains a 5.5 to 5.6 (m, 2H), 4.95 points (m, 1H), 3,93 (d, 10 Hz), 2,55 (septet, J Hz, 1H), 2,17 (s, 3H), 1,20 (d, J 7 Hz, 6N) and 0.70 (d, J 7 Hz, 3H).

P R I m e R 24. Factor And, 5-23-di-n-butyrate.

A solution of factor A (306 mg), n-buterbaugh anhydride (0.33 mg) and 4-dimethylaminopyridine (244 mg) in pyridine (5 ml) was stirred at 20aboutC for 18 h, and then poured into a mixture of ethyl acetate and 2 N. hydrochloric acid (50 ml each). The organic phase is washed with 2 N. hydrochloric acid, saturated sodium bicarbonate (25 ml) and saline (25 ml), and dried (magnesium sulfate) and evaporated to dryness. The residue is purified by chromatography on Kieselgel 60 (40 g). Elution from the column with a mixture of light oil with ethyl acetate (5: 1) to give the titled compound (200 mg) as a colourless foam substance.

[]D20+ 144o(c, 1,13, CDCl3), max(EtOH), 245 nm ( = 31800),max. (CHBr3) 1720 cm-1(ester), (CDCl3contains a 5.5 to 5.6 (m, 2H), 4,94 (m, 1H), 3,92 (d, J the s ' method:

P R I m e R 25. Factor A, 5-acetate, 23-pivaloate (70 mg).

[]D20+ 159o(c 0,69, CHCl3),max(EtOH) 244 nm ( = 29,900), max(CHBr3) 3470 (OH) and 1730 and 1710 cm-1(ester), (CDCl3contains 5,5-5,6 (n, 2N), of 4.95 (m, 1H), 3,91 (d, J 10 Hz, 1H), 2,16 (s, 3H, 1,22 (s, N), and 0.68 (d, J 7 Hz, 3H), from factor A, 5-acetate (131 mg) and pivaloate (0.06 ml).

P R I m e R 26. Factor A, 5-acetate, 23-benzoate (180 mg).

[]D20+ 153o(c 0,59, CHCl3),max. (EtOH) 236 nm ( = 36,200),max. (CHBr3) 3460 (OH) and 1730 and 1707 cm-1(ester), (CDCl3contains 8,21 (d, J 7 Hz, 2H), 7,56 (m, J 7 Hz, 1H), 7,44 (m, J 7 Hz), and 5.5 to 5.6 (m, 2H), 4,07 (d, J 10 Hz, 1H), 2,17 (s, 3H) and 0.75 (d, J 7 Hz, 3H), from factor A, 5-acetate (327 ml) and the anhydride of benzoic acid (339 mg).

P R I m e R 27. Factor And, 5,23-dibenzoate (370 mg) and 5-benzoate (200 mg).

Of factor A (613 mg) and benzoyl chloride (0.35 ml); the initial fractions give the named dibenzoate.

[]D20+ 86o(c 0,65, CHCl3),max. (EtOH) at 2.36 nm ( 46,200),max. (CHBr3) 3480 (OH), 1710 (ester), and 1602, and 1585 cm-1(phenyl), (CDCl3): of 8.2 to 8.0 (m, 4H), 7,7-7.5 (m, 2H), 7,46 (m, J 7 Hz, 4H), 5,61 (s, 1H, 4,07 (d, J 10 Hz, 1H) and from 0.76 (d, J 7 Hz, 3H).

Subsequent fractions give the named benzoate []D1601 and 1585 cm-1(phenyl), (CDCl3): 8,09 (l, 1H).

P R I m e R 28. Factor A, 5-CHLOROACETATE.

A solution of factor A (123 mg) and pyridine (0.1 ml) in dry dichloromethane (5 ml) is stirred at a temperature of 0aboutWith and enter chlorocatechol (0.3 ml of 1M solution in dichloromethane. The resulting solution was stirred at 0aboutWith temperature for 15 min and then add chlorocatechol (0.1 ml, 1M solution) and continue stirring additionally for 15 minutes the Solution was diluted with dichloromethane (50 ml), then washed 2 N. hydrochloric acid (2 x 20 ml), and saturated sodium bicarbonate (20 ml), and dried (magnesium sulfate), and evaporated to dryness. The residue (140 mg) is purified by chromatography in a column of Kieselgel-60 (15 g). Elution from the column with a mixture of light oil with ethyl acetate (4:1) gives the titled compound (90 mg) as a colourless foam substance.

[]D20+ 143o(c, 1,11, CDCl3), max(EtOH) 245,5 nm ( 30,400);max(CHBr3) 3500 (OH), 1760 (CHLOROACETATE) and 1710 cm-1(ester), (CDCl3): of 5.5 to 5.6 (m, 2H), 4,18 (s, 2H), sa, 3,81 (m, 1H), 3,74 (d, J 10 Hz, 1H) and 0.80 (d, 7 Hz, 3H); m/z = 688 (M+, 35 Cl).

The compounds of examples 29, 39 and 44 receive a similar way.

P R I m e R 29. Factor A, 5-bromoacetate (447 mg)95 (OH), 1730 (bromoacetate) and 1712 cm-1(ester), (CDCl3includes a 5.5 to 5.6 (m, 2H), 3,97 (d, J 12 Hz, 1H), 3,90 (d, J 12 Hz, 1H), 3,81 (m, 1H), 3,75 (d, J 10 Hz, 1H) and 0.81 (d, J 7 Hz, 3H), from factor A (613 g) and bromohydrin bromoxynil acid (0,13 ml).

P R I m e R 30. Factor And, 5,23-dichloracetate.

The mixture of factor A, 5-chloracetate (365 mg), acid chloride Chloroacetic acid (0,21 ml) and calcium carbonate (265 mg) in dry dichloromethane (15 ml) was stirred at 20aboutwithin 48 hours, the resulting suspension was diluted with dichloromethane (50 ml), then washed 2 N. hydrochloric acid and saturated sodium bicarbonate, dried (magnesium sulfate) and evaporated to dryness. The residue is purified by chromatography on a column of Kieselgel 60 (30 g). Elution of the column with a mixture of petroleum ether: ethyl acetate (4:1) gives the titled compound (167 mg) as a colorless foam, []D20+ 151o(c 1,17, CHCl3),max(EtOH) 245,5 nm ( 29400), max. (CHBr3) 3470 (OH) and 1725 cm-1(esters), (CDCl3includes a 5.5 to 5.6 (m, 2H), 5,00 (m, 1H), 4,17 (s, 2H), 4,10 (d, J 15 Hz, 1H), was 4.02 (d, J 15 Hz, 1H), 3,92 (d, J 10 Hz, 1H), 0,73 (d, J 7 Hz, 3H), m/z = 764 (M+, 35Cl). The compounds of examples 31, 32 and 40 receive a similar way.

P R I m e R 31. Factor A, 23-methoxyacetate (92 mg).

[]Dcitat) and 1712 cm-1(ester), (CDCl3includes free 5.01 (m, 1H), 4,28 (t, J 7 Hz, 1H), 4,01 (s, 2H), 3,89 (d, J 10 Hz, 1H), 3.46 in (s, 3H) and 0.71 (d, J 7 Hz, 3H), from factor A (184 mg) and methoxyacetanilide (0.3 ml).

P R I m e R 32. Factor A, 23-phenoxyacetate (112 mg).

[]D20+ 129o(c 0,75, CHCl3), max(EtOH) 244 nm ( 25,900),max(CHBr3) 3550 and 3470 (OH), 1745 and 1708 cm-1(esters), (CDCl3includes 7,30 (t, J 8 Hz, 2H), 7,00 (t, 8 Hz, 1H), 6,94 (d, J 8 Hz, 2H), 5,02 (m, 1H), and 4.68 (d, J 16 Hz, 1H), 4,58 (d, J 16 Hz, 1H), 4,30 (d, J 7 Hz, 1H), 3,92 (d, 10 Hz, 1H) and 0.67 (d, J 7 Hz, H) of factor A (184 mg) and phenoxyacetamide (0.3 ml).

P R I m e R 33. Factor And, 5,23-di-(2,2,2-trichloroethyl)carbonate (362 mg).

[]D20+ 110o(c 0,94, CHCl3);max. (EtOH) 244 nm ( 28000);max. (CHBr3) 3550 and 3460 (OH), 1750 (carbonate), and 1710 cm-1(ester), (CDCl3includes ceiling of 5.60 (s, 1H), 4,89 and 4,75 (ABg, J 12 Hz, 2H), around 4.85 (m, 1H), 4,81 and 4,71 (ABg, J 14 Hz, 2H), and 0.79 (d, J 7 Hz, 3H), from factor A (306 mg) and 2,2,2-trichlorethylphosphate (0,14 ml).

P R I m e R 34. Factor A, 23-(2,2,2-trichloroethyl)carbonate.

A solution of factor A, 5,23-di-(2,2,2-trichloroethyl)carbonate (200 mg) in dioxane (10 ml) is stirred at a temperature of approximately 20aboutand added 1M sodium hydroxide (0.5 ml). Get Rast is Uchenie 1 h The solution is diluted with ethyl acetate (50 ml), washed with 2 N. hydrochloric acid, dried (magnesium sulfate) and evaporated to dryness. The remainder chromatographic on a column of Kieselgel 60 (15 g). Elution of the column with a mixture of petroleum ether: ethyl acetate (2:1) gives the titled compound (80 mg) as a colorless foam, []D20+ 142o(c 0,92, CHCl3),max(EtOH) 245 nm ( 29200),max(CHBr3) and 3560 3500 (OH), 1745 (carbonate) and 1710 cm-1(ester), (CDCl3) consists of 5.40 (s, 1H), 4,80, and 4,70 (ABg, J 14 Hz, 2H), 4,28 (m, 1H) and 0.79 (d, J 7 Hz, 3H).

P R I m e R 35. Factor A, 5-acetate, 23-(2,2,2-trichloroethane)carbonate (385 mg).

[]D20+ 140o(c 1.07, and CHCl3)max. (EtOH) 245,5 nm, ( 29200);max. (CHBr3) 3300-3620 (OH), 1738 (carbonate), and 1720 cm-1(ester), (CDCl3) consists of 5.53 (s, 1H), 4,81 and 4,70 (ABg, J 14 Hz, 2H), 4,84 (m, 1H), 3,98 (d, J 10 Hz, 1H), 2,16 (s, 3H) and 0.79 (d, J 7 Hz, 3H), from factor A, 5-acetate (393 mg) and 2,2,2-trihloretilamina (2 ml of 1M solution in dichloromethane).

P R I m e R 36. Factor And, 5,23-di-n-butyrate.

A solution of factor A (306 mg), n-butyric anhydride (0.33 ml) and 4-dimethylaminopyridine (244 mg) in pyridine (5 ml) was stirred at 20aboutfor 18 h and then poured into a mixture of ethyl acetate and 2 N. of chlorestol Ishenim sodium bicarbonate (25 ml) and brine (25 ml), dried (magnesium sulfate) and evaporated to dryness. The residue is purified by chromatography on a column of ieselgel 60 (40 g). Elution of the column with a mixture of petroleum ether: ethyl acetate (5:1) gives the titled compound (200 mg) as a colorless foam.

[]D20+ 144o(c 1,13, CHCl3)max(EtOH) 245 nm ( 31800),max. (CHBr3) 1720 cm-1(esters), (CDCl3includes a 5.5 to 5.6 (m, 2H), 4,94 (m, 1H), 3,92 (d, J 10 Hz, 1H), 2,39 (t, J 7 Hz, 2H), 2,28 (t, J 7 Hz, 2H) and 0.70 (d, J 7 Hz, 3H), m/z = 752 (M+).

P R I m e R 37. Factor A, 23-n-butyrate.

A solution of factor A, 5,23-di-n-butyrate (160 mg) in methanol (10 ml) stirred at 0aboutand added 1M sodium hydroxide (of 10.25 ml). The resulting solution is stirred for 90 minutes at a temperature of 0-5aboutthen add another 0.25 ml of 1M sodium hydroxide solution and stirring is continued for 4 hours the Solution is poured into a mixture of ethyl acetate (50 ml) and 2 N. chlorostoma - burly acid (25 ml), the organic phase is washed with water, brine, dried (magnesium sulfate) and evaporated to dryness. The residue is purified by chromatography on a column of Kieselgel 60 (20 g). Elution of the column with a mixture of petroleum ether: ethyl acetate (2: 1) gives the titled compound (68 mg) as a colorless foam. []D20 + 164o3
), includes is 4.93 (m, 1H), 4,28 (t, J 7 Hz, 1H), 3,91 (d, J 10 Hz, 1H), 2,28 (t, J 7 Hz, 2H), 1,65 (m, 2H), were 0.94 (t, J 7 Hz, 3H) and 0.69 (d, J 7 Hz, 3H), m/z = 682 (M+).

The compound of example 38 receive a similar way:

P R I m e R 38. Factor A, 23-methylcarbonate (155 mg).

[]D20+ 169o(c, 0,81, CHCl3), max. (EtOH) 245 nm (E 26600);max(CHBr3) 3300-3610 (OH), 1735 (carbonate), and 1710 cm-1(ester), (CDCl3) consists of 5.40 (s, 1H), 4,28 (m, 1H), 3,94 (d, J 10 Hz, 1H), of 3.77 (s, 3H), and from 0.76 (d, J 7 Hz, 3H); m/z = 670 (M+), from factor A, 5-acetate, 23-(2,2,2-trichloroethyl)carbonate (300 mg).

P R I m e R 39. 23-Deoxy-factor And 5-methylcarbonate (57 mg).

[]D20+ 152o(c, 0,6, CHCl3),max(EtOH) 244,5 nm (E 28200);max(CHBr3) 3530 and 3460 (OH), 1740 (carbonate) and 1707 cm-1 (ester); (CDCl3) consists of 5.55 (s, 1H), 3,82 (s, 3H), 3,42 (d, J 10 Hz, 1H), and 0.69 (d, J 4 Hz, 3H), of 23-deoxy-factor A (90 mg) and methylchloroform (0.3 ml of 1M solution in dichloromethane).

P R I m e R 40. Factor A, 23-CHLOROACETATE (193 mg).

[]D20+ 162o(c, 1,04, CHCl3),max(EtOH) 245 nm ( 28900);max. (CHBr3) 3320-3620 (OH), 1748 (CHLOROACETATE), and 1710 cm-1(ester); (CDCl3includes 5,42 (s, 1H), 4,28 (m, 1H), 4.09 to and 4,01 (ABg, J 15 Hz, the (0.2 ml).

P R I m e R 41. Factor And, 5,23-dipropionate (387 mg).

[]D20+ 157o(c, 0,96, CHCl3),max(EtOH) 244,5 nm ( 30200);max. (CHBr3) 3500 (OH) and 1720 cm-1(esters); (CDCl3includes 5,52 (s, 1H), 3,93 ( , J 10 Hz, 1H), 2,43 (g, J 7 Hz, 2H), 2,32 (d, J 7 Hz, 2H), of 1.18 (t, J 7 Hz, 3H), of 1.16 (t, 7 Hz, 3H) and 0.70 (d, J 7 Hz, 3H), m/z = 7,24 (M+), from factor A (613 mg) and propionic anhydride (0.5 ml).

P R I m e R 42. Factor A, 23-propionate (155 mg).

[]D20+ 168o(c 1,03, CHCl3);max. (EtOH) 244,5 ( 30600); max(CHBr3) 3550 and 3480 (OH) and 1710 cm-1(ester); (CDCl3) consists of 5.39 (s, 1H), 4,27 (m, 1H), 3,91 (d, J 10 Hz, 1H), 2,31 (d, J 7 Hz, N, to 1.14 (t, J 7 Hz, 3H) and 0.69 (d, 7 Hz, 3H), m/z = 668 (M+), from factor A, 5,23-dipropionate (327 mg), in a similar manner to compounds of example 37.

P R I m e R 43. Factor A, 5-methylcarbonate, 23-ketone (830 mg).

[]D20+ 132o(c 0,82, CHCl3);max(EtOH) 245 nm ( 29800), IR - and NMR-spectra are similar to those that have a connection to that described in example 34, from factor 4, 23-ketone (916 mg) and methylchloroform (0,23 ml).

P R I m e R 44. Factor A, 5-benzylcarbamoyl, 23-ketone (57 mg).

[]D20+ 99o(c 0,4, CHCl3);max. (EtOH) 245,5 nm ( 29600);

P R I m e R 45. 5-Acetoxy-23-n-butoxy factor A.

Silver carbonate (1 g) was added to a solution of 5-acetoacetate And (325 mg) in dry ether with subsequent igbotako (0.5 ml) and silver perchlorate (550 mg). The mixture is stirred at room temperature for 20 h, after which add kallidin (0.5 ml). After stirring for a further 20 min the mixture is filtered and the filtrate washed sequentially 2 N. hydrochloric acid, saturated aqueous sodium bicarbonate and water. The dried organic phase is evaporated almost to dryness and the oil purified by chromatography on a column of Merck Kieselgel 60 c size 230-400 mesh mesh (100 ml). Elution of the column with a mixture of hexane:ethyl acetate (3:1) allows to obtain the titled compound as a colorless foam (276 mg, 78%). []D20+ 160o(c 0,94, CHCl3),max(EtOH) 245 nm (max28300); (CDCl3includes and 3.16 (m, 1H), 3.43 points (m, 1H) and 3.59 (m, 1H).

P R I m e R 46. 5-Acetoxy-23-cyclopropylmethoxy factor A.

[]D21+ 174o(c 1,74, CHCl3),max(t0) 244 nm (E 28360), max(CHBr3) 3470 (OH), 1732, 1710 (the word is), of 2.16 (s, 3H), 0,76 (d, J 7, 3H), of 0.44 (m, 2H), 0,22 (m, 2H), 5-acetoxy factor a and bromelicola, similarly to compounds of example 12.

P R I m e R 47. 5-tert-butyldimethylsiloxy-23-methoxy-factor A.

The solution idetermine simple ether 30,35 ml (3M solution) was added at room temperature under nitrogen to a magnetically stirred solution of 5-butyldimethylsilyloxy factor A (239 mg dry hexamethylphosphorotriamide (18 ml) with rapid evolution of gas. After 30 minutes add logmean (0.4 ml), the mixture was stirred for 5 h, diluted simple ether (100 ml) and washing copiously with water. The ether solution is then washed with brine (50 ml) and dried organic phase is evaporated. The resulting foam (280 mg) purified by chromatography on a column of Merck Kieselgel 60 c size 230-400 mesh mesh (80 ml). Elution with a mixture of hexane:ethyl acetate (5:1) allows to obtain the titled compound as a colorless foam (46%), []D21+ 142o(c 1,13, CHCl3), max(EtOH) 244 nm (max27900);max. (CHBr3) 3460 (OH), 1708 (wide; ester) and 995 cm-1(C-O); (CDCl3includes was 4.42 (m, 1H), 3,92 (l 10, 1H), 3,3-3,4 (m, 2H), 3,32 (s, 3H), of 0.92 (s, N IN), 0.75 (D 7, 3H) 0,12 (C, 6N).

The compound of example 48 receive similar Obo(c 1,16, CHCl3),max(EtOH) 244 nm (max29950);max(ADHD3) 3460 (OH), 1705 (ester) and 995 cm-1(C-O); (CDCl3) consists of 4.44 (m, 1H), 3.96 points (l, 10, 1H), of 3.56 (m, 1H), of 3.45 (m, 1H), 3,14 (m, 1H), 0,93 (s, N in), 0.75 (d 7, 3H), 0,13 (C, 6N) of 5-tert-butyldimethylsilyloxy-factor and 1-jumprope.

P R I m e R 49. 5-Acetoxy factor D (923 mg).

[] D21+ 143,9o(s, 0,9, CHCl3);max(EtOH) 239 (28700) and 245 nm; (max31000);max. (CHBr3) 3490 (OH), 1730 and 1710 (ester); (CDCl3) 0,81 (d, 7 Hz, 3H), 0,99 (d, 7 Hz, 3H), and 1.00 (t, 7 Hz, 3H); 1,53 (s, 3H), of 1.59 (s, 3H), of 1.75 (s, 3H), of 2.16 (s, 3H), of 3.32 (m, 1H), 3,65 (m, 1H), Android 4.04 (d, 6 Hz, 1H) and of 5.53 (m, 2H), m/z = 640 (M+), factor D (2.5 g) and acetic anhydride (0,47 ml), in a similar manner to the corresponding compounds of example 5.

P R I m e R 50. 5,23-Diacetoxy factor D (286 mg).

So pl. 147-149about(diamond of pentane in a simple ether []D21+ 152,6o(c 0,9, CHCl3),max(EtOH) 232,5 (21500) 238 (26600), and 244,5 nm (max28300),max(CHBr3) 1720-1(ester), (CDCl3) to 0.72 (d, 6 Hz, 3H), 0,99 (d, 6 Hz, 3H), 1,01 (t, 7 Hz, 3H), of 1.53 (s, 3H), 1,60 (s, 3H), of 1.75 (s, 3H), 2,02 (s, 3H), of 2.15 (s, 3H), and 3.31 (m, 1H), Android 4.04 (d, 6 Hz, 1H), 4,91 (m, 1H) and 5.5 to 5.6 (m, 2H), m/z = 682 (M+), factor D (439 mg) and acetic anhydride (0.25 m is []D21+ 150o(c 0.5, CHCl3);max.(EtOH) 238 (29200) and 244,5 nm; (max15600);max. (CHBr3) 3300, 3590 (OH) and 1710 cm-1(ester); (CDCl3) to 0.72 (d, J 7 Hz, 3H), 0,99 (d, J 7 Hz, 3H), 1,01 (t, J 7 Hz, 3H), of 1.53 (s, 3H), and 1.6 (s, 3H), of 1.86 (s, 3H), 3,26 (m, 1H), 3,95 (s, J 6 Hz, 1H), 4.26 deaths (t, J 6 Hz, 1H), and to 4.01 (m, 1H), m/z = 640 (M+), and/ 5,23-diacetoxy factor D (207 mg), and similarly for compounds of example 8.

P R I m e R 52. Factor A, 23-phenyl acetate (240 mg).

[]D20+ 140 (c, 0,92, CHCl3);max. (CHBr3) 3550 and 3470 (OH) and 1730 cm-1(esters); (DCl3includes to 7.32 (s, 5H), 5,0 (m, 1H), 4,29 (t, J 7 Hz, 1H), 3,83 (d, J 10 Hz, 1H), 3,62 (s, 2H) and 0.54 (d, J 7 Hz, 3H) receive in a manner analogous to compound of example 32 from factor A (306 mg) and phenylacetylene (0.33 ml).

P R I m e R 53. 23 Ethoxy factor A.

A solution of 5-acetoxy-23-ethoxy factor A (306 mg) in methanol (18 ml) cooled in an ice bath, then enter 1 N. aqueous sodium hydroxide solution (1 ml) and the resulting solution was light yellow color is stirred in an ice bath for 1.25 hours the Solution was diluted with ethyl acetate (80 ml), then successively washed with 1 N. hydrochloric acid, water and salt solution. The dried organic phase is evaporated and poluchenno ml). Elution of the column, 15% ethyl acetate in dichloromethane gives the named compound as a colourless foam (623 mg) []D21+ 178 (c, 1,13, CHCl3); max. (EtOH) 244 nm (max29400); (CDCl3includes the 4.29 (t, 7, 1H), 5,65 (m, 1H), 3,47 (m, 1H), 3,26 (m, 2H) and 1.15 (t, 7, 3H).

Connection examples 54-57 obtained in the same way.

P R I m e R 54. 23-n-butoxy factor A (61%) was obtained as a colorless foam.

[]D21+ 161 (c, 1,47, CHCl3);max(EtOH) 244 nm ( 33100); (DCl3includes 4,30 (t, 7, 1H), 3,60 (m, 1H), 3.43 points (m, 1H), 3,17 (m, 1H) 5-acetoxy-23-n-butoxy factor A.

P R I m e R 55. 23-n-Propoxy-factor (83%) was obtained as a colorless foam.

[]D21+ 165o(c 1,01, CHCl3),max(EtOH) at 2.45 nm ( 30,970), (CDCl3includes the 4.29 (t, 7; H), 3,55 (m, 1H), 3,13 (m, 1H), from 5-acetoxy-23-n-propoxy-factor A.

P R I m e R 56. 23-Methoxy-factor (66%) was obtained as a colorless foam []D21+ 175o(c 101, CHCl3);max(EtOH) 244 nm ( 19,10); (DCl3includes the 4.29 (t, J 7; 1H), 3,40 (m, 1H), 3.33 and (s, 3H) 5-acetoxy-23-methoxy-factor A.

P R I m e R 57. 23 Cyclopentyloxy factor A (75%) was obtained as a colorless foam.

[]D21+ 160o(c 1,65, CHCl3),the C acetoxy-23-cyclopentyloxy factor A.

P R I m e R 58. (a) 5-acetoxy-23-allyloxy factor A.

The silver salicylate (872 mg) are added to a solution of 5-acetoxy factor A (207 mg) and alreadyd (1.0 ml) in a dry simple ether (25 ml) and the resulting mixture was stirred at room temperature for 4 days, and then filtered. The filtrate is evaporated to obtain a yellow oil, which was purified by chromatography on a column of Merck Keiselgel 60, 230-400 mesh mesh. Elution with a mixture of dichloromethane with ethyl acetate (19:1) to give the named compound as a colourless foam (105 mg).

[]D21+ 152o(c and 1.00, CHCl3);max(EtOH) 245 nm ( 22000); (CDcl3) consists of 3.54 (m, 1H), 4,14 (m, 1H).

Similarly receive the following connections:

(b) 5-Acetoxy-23-n-propyloxy factor And is obtained from 5-acetoxy factor a and n-propyliodide. When cleaning by chromatography on a column of Merck Keiselgel 60 with a particle size of silica 230-400 mesh mesh. and elution with a mixture of hexane with ethyl acetate (3: 1) get the named compound as a colourless foam.

[]D21+ 160o(c 0,75, CHCl3);max(EtOH) 245 nm (, 27600); (CDCl3) consists of 3.33 (s, 3H), 3,39 (m, 1H).

(C) 5-Acetoxy-23-methoxy-factor And is obtained from 5-acetoxy factor a and methyliodide. Named soy is (EtOH) 245 nm, (, 27600), (CDCl3includes 3,33 (C, H) and 3.59 (m, 1H).

P R I m e R 59. 5-Acetoxy-23-ethoxy factor And is obtained from 5-acetoxy factor a and ethyliodide. A named connection comes in the form of a colorless foam.

[]D21+ 1,670 (c 1,02, CHCl3);max(EtOH) 245 nm (, 28070), (CDCl3includes of 3.25 (m, 1H), 3.46 in (m, 1H), 3,64 (3M, 1H), obtained in a manner analogous to compound of example 12.

Test compounds (1) is the main test nematocidal activity. According to the applicant, all compounds described in the examples, are active in this test, however, at the present time, the applicant cannot confirm this experimentally. Tests (2) and (3) are more specific; connection examples 6, 8, 18, 20, 21, 23, 32, 37, 42, 46, 52-55, 58A, 58b, 59 are active in these tests.

Based on this comparison, it can be expected that other connection pending applications have these advantages.

It should be noted that the compounds (avermectins and milbemycin) belong to other types of connections. In particular, they have another Deputy (simple alkyl group) in the 25-position, compared with the unsubstituted group of the compounds of the present invention, the deposits of this application can not be formed by standard modifications of the compounds of the prototypes.

In addition, it should be noted that the compounds of prototypes are unsubstituted or have IT simple group in 23-position, and are only found in the nature of the substituents (HE or methoxy in the 5-position. In these prototypes do not have any indication that these groups can be modified as suggested in this application.

1. Activity against Caenorhabditis elegans.

Compounds of the present invention were investigated for their activity against free-living nematodes Caenorhabditis elegans. Solutions or suspensions of the compounds were prepared in methanol, and serial dilution was done (400 µg/ml and below) in 20% propylene glycol. Each 10 μl of the obtained solution was mixed with 20 μl of an aqueous solution containing 100-200 Caenorhabditis elegans larvae, and the resulting solution was kept for 20 h at room temperature.

In the above test, the compounds described in the examples, mainly through 20 h had destroys - paralyzing effect on the >98% of larvae at a concentration of <10 μg/ml.

2. Activity against Nematospiroides dubius.

Determined the effectiveness of the compounds of the present compounds against Nematospiroides dubius, which were infected mice. Female mice CF/H is probatively by only a single oral administration of the compounds of the present invention in one of the 3/4. Compounds were introduced in the form of a solution in propylene glycol. Then the mice were left for at least 3 days, usually 5 days for ripening infection, after which the mice were scored and removed the small intestine. Cut part of the small intestine were digested, blunt scissors to highlight the mucosa of the small intestine. Mature larvae were collected using a modified apparatus Baarnmann. The migration time was 5 hours, and during this period the migration of the larvae were maintained the temperature of the 37aboutC. After 5 h the nylon gauze, through which migrated nematodes, explored through 2 x magnifying glass. Then counted the number of nematodes detained Marley, and passed through cheesecloth, thereby obtaining the total number of nematodes for each mouse, and the results were compared with the control.

Thus, using this procedure have found that when using doses of compounds of the present invention 10 mg/kg is possible to achieve a significant reduction in the number of nematodes in treated mice. For example, the compounds of examples 6, 8, 18, 20, 21, 23, 32, 37, 42, 46, 52-55, 58A, 58B and 59 showed the percentage reduction in the number of nematodes in treated mice, compared to control more than 80%.

3. Active is 00 ug/kg) compound of example 53, administered intravenously or subcutaneously, was achieved by the complete destruction of Cooperia oncophera in calves infected with the helminth.

(C) the compound of example 53 is absolutely effective when orally administered at a dose of 200 µg/kg in horses infected Parascoris.

(d) Compound of example 53 is as effective as Ivermectin, destruction of both larval and adult Osteitagia ciraimcineta, Trichostrongylus axei, At contortus, Nematodirus spathiger, Cooperia curticei, Trichostrongylus vitrinus, oral dose injection of 200 µg/kg

(e) Compound of example 53 has an absolute efficiency in the treatment of dogs infected Those by oral dose of 150 mcg/kg specified connection.

(f) Compound of example 53, introduced subcutaneously pigs infected with the recommended dose rate, the dose of 800 mg/kg showed the efficiency of >98%.

A method of OBTAINING a MACROLIDE COMPOUNDS of General formula I

< / BR>
where R1is isopropyl;

R3is hydrogen,

R2group OR5where OR5is - OCOR6group, where R6- C1- C4-alkyl, optionally substituted by fenoxaprop or phenyl, or C3C5-cycloalkyl or OR7where R7- C1- C4-alkyl, what if - OCOR4agroup, where R4a- C1- C4-alkyl,

characterized in that carry out the reaction of the corresponding compounds of formula I where one or both of the radicals R2and OR4are a hydroxyl group, with hydroxyzinesee reagent of General formula II

R6COOH or R4aCOOH,

or its reactive derivative, or a compound of General formula III:

R7Y

where R6, R7and R4andhave the specified values;

Y is chlorine, bromine or iodine.

Priority signs:

30.04.85 when R1is isopropyl, R2- OR5, R3- H, where OR5- OCOR6group, where R6- C1- C4-alkyl, optionally substituted by fenoxaprop or phenyl, or C3- C5-cycloalkyl, OR4is a hydroxyl group or - OCOCR4andgroup, where R4a- C1- C4-alkyl;

12.03.86 when R1is isopropyl, R2- OR5, R3- H, where OR5- OCOR6group, where R6- C1- C4-alkyl, optionally substituted by fenoxaprop or phenyl, or C1- C5-cycloalkyl or OR7group, where R7- C1- C4the alkyl, optional the or - OCOR4andgroup, where R4a- C1- C4-alkyl.

 

Same patents:

The invention relates to methods of producing a range of new macrolide compounds that are chemically related to some well-known classes of macrolides, including milbemycin and avermectins

The invention relates to a method of obtaining new compounds with antibiotic

The invention relates to 7-examinerlawrence heterocyclic Amida - analogues of prostaglandins, which are receptor antagonists AND thromboxane a2(THA2or combined receptor antagonists AND thromboxane a2(thromboxane synthetase inhibitors, and are used, for example, in the treatment of thrombotic disease and/or vascular spasm: have a long duration of action

The invention relates to medicine, namely to Virology

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of borrelidin of the general formula (I)

wherein R represents the group of the general formulae -COOR1, -CONR2R3, -CONR4CONR2R5 or -CH2OR6 wherein R1 represents (C2-C6)-alkyl group, (C1-C6)-alkyl group substituted with hydroxyl group or 5-8-membered saturated nitrogen-containing heterocyclic group (it can comprise oxygen atom in addition to nitrogen atom) or 5-6-membered nitrogen-containing aromatic heterocyclic group or (C3-C6)-cycloalkyl group; R2 and R3 are similar or different and represent independently hydrogen atom or (C1-C6)-alkyl group that can be substituted optionally with hydroxyl, (C2-C5)-alkoxycarbonyl or 5-8-membered saturated nitrogen-containing heterocyclic group (it can comprises oxygen atom in addition to nitrogen atom) or 5-6-membered aromatic homocyclic group or aromatic heterocyclic group comprising oxygen and/or nitrogen atom, 5-6-membered cycloalkyl or heteroaryl group; R4 and R5 are similar or different and represent independently hydrogen atom or (C3-C6)-cycloalkyl group; R6 represents hydrogen atom; also, invention relates to tautomers, solvates of these compounds, their mixtures and acid-additive salts. Also, invention relates to pharmaceutical compositions comprising compounds of the general formula (I) as an active component. Angiogenesis inhibitors of the present invention inhibit formation of new vessels in tissues of live organisms and can be used for prophylaxis and inhibition of the angiogenesis process arising in the tumor proliferation, and for prophylaxis of formation of tumor metastasis. Invention provides preparing new derivatives of borrelidin eliciting the value physiological effect.

EFFECT: valuable medicinal properties of compounds.

8 cl, 15 ex

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to new taxanes of the general formula (I)

wherein R2 means benzoyloxy-group; R7 means hydroxyl (OH); R9 means keto-group; R10 means R10aCOO-; R10 means (C2-C6)-alkyl, (C2-C6)-alkenyl, (C3-C6)-cycloalkyl or 5-6-membered heteroaromatic group wherein heteroatom represents oxygen atom (O), sulfur atom (S) or nitrogen atom (N); R14 means hydrogen atom (H); X3 means (C2-C6)-alkyl, (C2-C6)-alkenyl, (C3-C6)-cycloalkyl, phenyl substituted possibly with nitro-group (-NO2), 5-6-membered heteroaromatic group wherein heteroatom represents O, S or N; X5 means -COX10, -COOX10; X10 means (C2-C6)-alkyl, (C2-C6)-alkenyl, (C3-C6)-cycloalkyl, phenyl or 5-6-membered heteroaromatic group wherein heteroatom represents O, S, N; Ac means acetyl. Compounds of the formula (I) elicit antitumor activity.

EFFECT: valuable medicinal properties of compounds.

68 cl, 1 tbl, 6 ex

FIELD: organic chemistry of natural compounds, medicine.

SUBSTANCE: invention relates to new taxanes with carbonate substitute at C7 of the general formula (I) given in the invention description wherein R2 means benzoyloxy group; R7 means -COO; R9 means -CO; R10 means -OH; R14 means hydrogen atom (H); X3 means (C1-C6)-alkyl, (C2-C6)-alkenyl, (C3-C6)-cycloalkyl or 5-membered heteroaromatic group wherein heteroatom is represented by oxygen (O) or sulfur (S) atom; X5 means -COX10, -COOX10 wherein X10 means (C1-C6)-alkyl, (C2-C6)-alkenyl, phenyl or 5-membered heteroaromatic group wherein heteroatom is represented by oxygen (O) or sulfur (S) atom, and Ac means acetyl. Proposed compounds possess an anti-tumor activity.

EFFECT: valuable medicinal properties of compounds.

61 cl, 1 tbl, 5 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to lyophilized composition comprising epotilone in the effective amount and mannitol or cyclodextrin. The second variant of the lyophilized composition involves epotilone and hydroxypropyl-beta-cyclodextrin. The preferable content of epotilone in the lyophilized composition is from 0.1% to 1.5%, and cyclodextrin - from 90% to 99% as measured for the total mass of solid components. Epotilone-containing lyophilized compositions can be used fro preparing an anti-tumor medicinal agent useful for parenteral administration and the lyophilized composition can be reduced preferably before administration directly. Epotilone-containing lyophilized compositions show improved indices of epotilone solubility and can retain stability for 24-36 months at temperature from 2°C to 30°C being without change of the solubility index.

EFFECT: improved and valuable properties of composition.

10 cl, 4 tbl, 14 ex

FIELD: organic chemistry, medicine, parasitology, pharmacy.

SUBSTANCE: invention relates to spiro- or dispiro-1,2,4-trioxolane of the general formula (I): wherein R1 and R2 taken in common represent spiroadamantyl, 3,3,5,5-tetramethylspirocyclohexyl, spirocyclododecanyl; R3 and R4 are similar or different and taken among substituted or unsubstituted aromatic or pyridyl group wherein neither among R3 and R4 can't represent hydrogen atom; also, R3 and R4 taken in common can form substituted or unsubstituted alicyclic group that is broken optionally with one oxygen, sulfur or nitrogen atom. Proposed compounds can be easily used for synthesis of nontoxic and active agents used against anti-malaria parasites. Also, invention describes a pharmaceutical composition based on compounds of the formula (I) and a method for treatment of malaria and schistosomiasis.

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

19 cl, 10 tbl, 9 ex

FIELD: medicine, phytotherapy, pharmacy.

SUBSTANCE: invention relates to using Ginkgo biloba extracts comprising 20-30% of flavone glycosides, 2.5-4.5% of mainly gynkgolides A, B, C and J, 2-4% of bilobalide, less 10% of proanthocyanidines and less 10 ppm of compounds of alkylphenol type. Also, the invention relates to using the Ginkgo biloba extract of type Egb 761® for preparing a medicinal agent designated for prophylaxis and treatment of sarcopenia. Proposed extracts reduce age-dependent loss of muscle mass and increase the ratio of a muscle mass to the total body mass.

EFFECT: valuable medicinal properties of extracts.

5 cl, 1 tbl, 2 ex

FIELD: veterinary science, veterinary pharmacology.

SUBSTANCE: the present innovation deals with applying 3-O-acetyl-4"-O-isovaleryl-tylosine or its pharmacologically acceptable acidic-additive salt as an active agent for obtaining the desired veterinary preparation for treating and preventing Lawsonia-induced infections in swine, particularly, in case when this veterinary preparation is being a fodder additive or drinking water additive. It has been, also, suggested to apply veterinary medicinal preparation for treating and preventing Lawsonia-induced infections in swine that contains as active ingredients in the mixture of 3-O-acetyl-4"-O-isovaleryl-tylosine or its pharmacologically acceptable acidic-additive salt and tetracycline, at weight ratio ranged 1:5 up to 1:10 in which, particularly, tetracycline is being either chlorotetracycline or oxytetracycline.

EFFECT: higher efficiency of therapy and prophylaxis.

4 cl, 6 ex, 10 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I): wherein R1 is chosen from group consisting of hydrogen atom (H), halogen atom and oxygen atom (O); R2 is chosen from consisting of H, halogen atom and N=N; R3 is chosen from group consisting of H and halogen atom; R4 is chosen from group consisting of H, halogen atom, amino and N=N; R5 is chosen from group consisting of H, halogen atom, methoxy, methyl and O; or R1 and R2, or R and R5 are joined and form unsaturated carbon ring; R6 is chosen from group consisting of H, (C1-C6)-alkyl, (C2-C6)-alkenyl, 3-phenyl-2-propin-1-yl, benzyl, benzyl substituted with halogen atom, phenyl or methoxy, CH2-cycloalkyl, CH2-2-furan, -(CH2)2SCH3 and -(CH2)2NHBOC; R7 is chosen from group consisting of H, (C1-C6)-alkyl and cycloalkyl; R8 is chosen from group consisting of benzyl and benzyl substituted with OCH2-phenyl; T represents group of the formula or wherein R9 and R10 represent H; or R9 represents H, and R10 are chosen from group consisting of (C1-C6)-alkyl, (C2-C6)-alkenyl, methyl-substituted (C2-C6)-alkenyl, (C2-C6)-alkynyl, cycloalkyl, phenyl substituted with (C1-C6)-alkyl, halogen atom, methoxy, -SCH3 or -N(CH3)2, 1-naphthyl and CH2-CH2-1,3-dioxolane; or R9 and R10 are chosen independently from group consisting of (C1-C6)-alkyl, (C2-C6)-alkenyl, phenyl, phenyl substituted at position 4 with halogen atom, methoxy, -SCH3 or -N(CH3)2 and 1-naphthyl, or its pharmaceutically acceptable salt, hydrate, or its prodrug as carbamate or ester. Also, invention relates to compounds of the formula (Ia) and the formula (Ib) given in the invention description, and to a method for decreasing levels of beta-amyloid, and to their using and to a method for prophylaxis or treatment of Alzheimer's disease, Down's syndrome. Invention provides preparing novel biologically active compounds.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

30 cl, 17 tbl, 278 ex

FIELD: chemistry.

SUBSTANCE: invention refers to compounds of formula (I) as well as to synthesis procedure and application for treatment of various disorders, including inflammatory and autoimmune disorders, and disorders caused by malignant growths or by increased angiogenesis where R1-R11, t, X, Y, Z and n have values specified in the description.

EFFECT: production of macrocyclic compounds used for treatment of various disorders, including inflammatory and autoimmune disorders, and disorders caused by malignant growths or by increased angiogenesis.

41 cl, 2 tbl

FIELD: chemistry.

SUBSTANCE: present invention pertains to new macrocyclic compounds with formula (I): (where R3, R6, R7 and R21 can be identical or different from each other, and each of them assume values given in the description), their salts used in pharmacology and their hydrate. Compounds with formula (I) are capable of inhibiting angiogenesis, particularly VEGF production in hypoxic conditions, and can be used as therapeutic means of treating solid malignant tumours. The invention also relates to medicinal agents based on these compounds, prevention and treatment method and use of these compounds in making preparations for preventing and treating cancerous diseases.

EFFECT: obtaining compounds, capable of inhibiting angiogenesis, particularly VEGF production in hypoxic conditions, which can be used as therapeutic means of treating solid malignant tumours.

35 cl, 3 tbl, 147 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of mycanolide of the formula (I): corresponding to the general subformulae (I)1 and (I)2 wherein L, R1 and R2 have values given in the invention description. Also, invention relates to a medicinal agent and pharmaceutical composition based on compounds of the formula (I), and to using compounds of the formula (I) for preparing a medicinal agent designated for inhibition of activity of DNA polymerases and treatment of diseases arising as result of anomalous cellular proliferation. Invention provides preparing new derivatives of mycanolide possessing the valuable pharmaceutical effect.

EFFECT: valuable medicinal and biochemical properties of derivatives.

12 cl, 2 tbl, 52 ex

FIELD: chemistry.

SUBSTANCE: invention pertains to compounds with general formula (I), which can be used for insect pest control where A represents -C(=Z)-, -O-C(=Z)-, -S-C(=Z)-, NR4-C(=Z)- or a bond; X-Y represents -CH=CH- or -CH2-CH2-; Z represents O; R1 represents alkyl, cyclo-alkyl, alkenyl; R2 and R3 together with A represent =N+=N- or each is independently chosen from a group of different aliphatic, cyclo-aliphatic, aromatic and heterocyclic substitutes.

EFFECT: obtaining new biologically active compounds.

1 cl, 21 ex, 19 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel antitumour compounds of general formula I

, where R1-16 are groups independently selected from hydrogen, protected or unprotected hydroxyl, C1-C24 alkyl, C2-C24 alkenyl, =O and ORa, OCORa; X and Y are C5-C12 alkyl groups which are substituted with one or more C1-C6 alkyl groups, hydroxyl groups and/or tetrahydropyran which can be optionally substituted with an alkyl and/or ORa group; Ra is independently selected from hydrogen and C1-C12 alkyl; and the dotted line denotes a double bond. The invention also relates to a method of producing said compounds, a pharmaceutical composition based on said compounds, having antitumour activity and use of formula I compounds to prepare a medicinal agent for treating cancer.

EFFECT: novel compounds which have cytotoxic activity and can be used to treat cancer are obtained and described.

15 cl, 2 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: avermectin B reacts with succinic anhydride in the medium of an organic solvent, e.g., pyridine or a mixture of dimethyl formamide and pyridine, in the presence of an amine-type catalyst, e.g., triethylamine and dimethylaminopyridine. The process can be carried out at temperature from 15°C to 60°C, preferably at room temperature. 5-O-succinoyl avermectin can be used as an antiparasitic agent in small concentrations compared to existing antiparasitic agents.

EFFECT: high efficiency, which significantly reduces the concentration of the agent used, its cost and widens the range of antiparasitic agents.

6 cl, 1 tbl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel 5-O-derivatives of avermectin of general formula I: where: A=Me or Et, R=OH, OAlk or NR1R2, where: R1, R2=H, Alk, X=-(CH2)n-, where: n-2-12, where: R3, R4, R5, R6=H, Alk, Ph or Ha1; n=1-5; or X is a heterocyclic fragment. The invention also relates to a method of producing said compounds.

EFFECT: obtaining novel compounds which exhibit antiparasitic activity and can be used as antiparasitic agents in medicine, veterinary agriculture, fish industry and other sectors associated with animal breeding as antiparasitic agents.

6 cl, 1 tbl, 27 ex

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