RU2029770C1 - Process for preparing macrolidic compounds - Google Patents

Abstract

FIELD: in agriculture, more specifically as nematodic agents for treating animals and humans affected with endoparasites and/or fungal infection and also as a pesticide. SUBSTANCE: the product includes macrolidic compounds of the formula I wherein R¹ is isopropyl; R²= OR⁵; R³ is H, OR⁵= OC(O)R⁶, OR⁶= C₁-C₄ is alkyl unsubstituted or substituted by phenoxy or C₃-C₅-cycloalkyl or OR⁷ wherein R⁷= C₁-C₄ alkyl unsubstituted or substituted by C₃-C₅-cycloalkyl; or C₃-C₅- alkenyl; OR⁴ is OH. OC(O)R^4a wherein is R^4a-C₁-C₄-alkyl. Reagent 1: a compound of the formula I wherein R² and OR⁴ one or both are OH. Reagent 2: a compound of the formula: R⁶-C(O)OH or R^4a-C(OH), or R⁷Y wherein Y= Cl, Br or J. Compound of the formula I reduce the number of helminths by more than 80% at an application rate of 10 mg/kg. The structure of compounds of the formula I: EFFECT: improved properties of the macrolidic compounds.

Description

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

(Ia) Итак, как описано в данном описании, выявлена дополнительная группа соединений, обладающих антибиотической активностью, которые можно получить посредством химической модификации антибиотика S541 или путем выделения их из культуры микроорганизмов рода Streptomyces.It is known to obtain antibiotics S541, which can be isolated from fermentation products of the species Streptomyces. S541 antibiotics are a group of related compounds having an incomplete form (I)

(Ia) So, as described in this description, an additional group of compounds with antibiotic activity is identified, which can be obtained by chemical modification of the antibiotic S541 or by isolating them from a culture of microorganisms of the genus Streptomyces.

 The novel compounds of the invention possess antibiotic activity and / or are used as intermediates in the preparation of other active compounds and / or in the isolation or purification of S541 antibiotic compounds.

 The compounds of the present invention are substituted hydroxyl analogues of S 541 antibiotics that have a hydroxyl or substituted hydroxyl group at position 5.

(I) где R¹ - изопропил;
R² - группа OR₅;
R³ представляет собой атом водорода; OR⁵-группа является -OCOR⁶-группой, где R⁶ - C₁-C₄-алкил, необязательно замещенный феноксигруппой или фенилом, или С₃-С₅-циклоалкил,
или OR⁷, где R⁷ - C₁-C₄-алкил, необязательно замещенный С₃-С₅-циклоалкилом, или С₃-С₅-алкенил;
OR⁴ является ОН или -OCOR^4a-группой.Thus, in one embodiment of the present invention, there are provided, in particular, compounds of the formula

(I) where R ¹ is isopropyl;
R ² is an OR ₅ group;
R ³ represents a hydrogen atom; The OR ⁵ group is an —OCOR ⁶ group, where R ⁶ is C ₁ -C ₄ alkyl optionally substituted with phenoxy or phenyl, or C ₃ -C ₅ cycloalkyl,
or OR ⁷ where R ⁷ is C ₁ -C ₄ alkyl optionally substituted with C ₃ -C ₅ cycloalkyl or C ₃ -C ₅ alkenyl;
OR ⁴ is OH or —OCOR ^4a group.

Particularly important active compounds of the invention are compounds of formula (II) in which:
R ¹ is an isopropyl group; R ² is a propionoxy group; R ³ is a hydrogen atom and OR ⁴ represents a hydroxyl group;
R ¹ is an isopropyl group; R ² is an ethoxy group, R ³ is a hydrogen atom, and —OR ⁴ is a hydroxyl group; and
R ¹ is an isopropyl group; R ² is n-propoxy; R ³ is a hydrogen atom and OR ⁴ is a hydroxyl group.

R ¹ is a methyl group; R ² is an acetoxy group, R ³ is a hydrogen atom, and OR ^{4 is a} hydroxyl group.

R ¹ is an ethyl group; R ² represents an acetoxy group; R ³ is a hydrogen atom and OR ⁴ is a hydroxyl group.

R ¹ is an ethyl group; R ^{2 is} acetoxy; R ^{3 is} a hydrogen atom and OR ⁴ represents a hydroxyl group.

R ¹ is an isopropyl group; R ² is an acetoxy group; R ³ is a hydrogen atom and OR ⁴ is a hydroxyl group.

As indicated previously, the compounds of the invention can be used as antibiotics and / or as intermediates for the preparation of other active compounds and / or in the isolation and purification of antibiotic compounds. S541. In the case when the proposed compounds have to be used as intermediates, R ² and / or -OR ⁴ can be protected by hydroxyl groups. It is clear that such a group should have a minimum number of additional functional groups in order to avoid additional reaction chains and should be such as to make it possible to selectively recover from it a hydroxyl group.

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

 Ectoparasites and endoparasites infect humans and a number of animals, and especially are widespread among farm animals: pigs, sheep, cattle, goats and poultry, horses and domestic animals, such as dogs and cats. A livestock parasitic infection leading to anemia, malnutrition and weight loss is the leading cause of economic loss worldwide.

 Representative endoparasites infecting these animals and / or humans include Ancylostoma, Ascaridia Ascaris, Aspicularis, Brugia, Bunostomum, Capillari, Chabertia, Coopenia, Dictyocaulus, Pirofilaria Dracunculus, Enterobius, Haemonchus, Heterakis, Neemosp, Loem, Mat Neligomoroides, Nippo-strongylus, Oestophagostonum, Onchocerea, Ostertagia, Oxyuris, Parascanis, Strongylus, Strongyloides, Syphacia, Toxascuris, Toxocara, Trichonema, Trichostrongylus, Trichinella, Trichuris, Unriaaria and.

 Examples of ectoparasites infecting animals and / or humans are arthropod entoparasites, such as stinging insects: carrion flies, fleas, lice, ticks, sucking insects, tick mites and other two-winged insect pests.

 Examples of this kind of entoparasites infecting animals and / or humans include: Ambylomma, Boophilus, Chorioptes, Culliphore, Demodex, Demallenia, Dermatobia, Gastrophilus, Haematobia, Haema topinus, Haemophysalis, Hyalomma, Hyperderma, Iathodes, Linod Lucitia, Melopagus, Oestrus, Otobius, Otodectes, Psorergates, Psoroptes, Rhipicephal Sarcoptes, Stomoxys and Tabanus.

 It was found that the proposed compounds are effective both in vitro and in vivo against a wide range of endoparasites and ectoparasites. In particular, it has been found that the compounds of the present invention are active against nematodes such as Haemonchus contortus, Ostertagicira meineta, Irichostrongylus colubiformis, Dictyeaulus viviparis, Ceoperia oncophera, Ostertagia ostertagi, Nematospiroides dibius and Nippisoptera brazil sp. Thus, the proposed compounds are used in the treatment of animals and people with endoparasitic and / or ectoparasitic infections.

 Species of parasites vary according to the host (the animal and the dominant location of the infection. Therefore, for example, the causative agents of Haemonchus contortus, Ostertagia circunicineta and Trichostrongylus colubiformis usually affect the sheep and are mainly localized in the stomach and small intestine, while Dictyocaulus viviparis and Ostertagia ostertagi usually affect cattle and are located mainly in the lungs, intestines, or stomach.

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

 In addition, the claimed compounds have uses as antifungal agents, for example, against Candida strains, for example Candida alleicans and Candida glabrata, and against yeast, such as Saccharomyces carlsbergensis.

 The compounds of the present invention, in addition, are used in the control of insect pests, ticks and nematodes and in agriculture, horticulture, forestry, health care and food storage. They can successfully treat pests of the soil and crops, including cereals (e.g. wheat, barley, maize, rice), vegetables (e.g. soy), fruits (e.g. apples, grapes, and citrus fruits), along with root crops (e.g. sugar beets, potatoes). Typical examples of such pests are fruit mites and aphids, for example, Aphis fabae, Aulacorthum circum flexum, Myrus persicae, Nephotettix cineticeps, nilpawata lugens, Panonychus ulmi, Phorodon humuli, Phyltocoptréeides urt genus, Trieurodecoides, рода genus triodecoides , Heteroder Meloidogyne and Panagrellus scaly, for example Heliothi Plutella and Spodoptera calender weevil, such as Anthonomus grandis and Sitophlus granarius, mealworms, for example Tribolium castaheu, flies, for example Musca domestica, Richter ants; narrow-winged moths; Pear psylla; thrips tobacco; cockroaches, e.g. Blatella germanica and Periplaneta americana, mosquitoes, e.g. Aedes aegypti.

 In accordance with the present invention, the proposed compounds of formula (II), as described above, which can be used as antibiotics. In particular, they can be used in the treatment of animals and people affected by endoparasitic, ectoparasitic and / or fungal infections, and as pesticides for controlling insect pests, ticks and nematodes, in agriculture, horticulture or forestry. They can be used, moreover, usually as pesticides in other circumstances, for example, in storage facilities, buildings or other public places or places of localization of agricultural pests. Essentially, the proposed compounds can be applied either to the host (animal or human, or to cultivated plants or other vegetation), or to the pests themselves or their location.

 The claimed compounds can be used for administration in any convenient form when used in veterinary medicine or practical medicine. Thus, the present invention contains within its scope pharmaceutical compositions containing a compound according to the claimed invention, suitable for use in veterinary medicine or therapy. Such compositions may be presented when used in their traditional form using one or more suitable carriers or excipients. The proposed compositions contain compositions in a form particularly suitable for parenteral (including the introduction into the mammary gland), oral, rectal, topical application in the form of an implant, for use in ocular, ear or genitourinary system diseases, suitable methods and agents for preparing the composition Compounds of the present invention suitable for use in veterinary medicine or therapy are known methods for antibiotic compounds S541.

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

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

 The claimed compounds can be formulated in any convenient form suitable for agriculture or horticulture. Thus, the present invention includes, within its scope, compositions containing a compound intended for use in agriculture or horticulture. Such formulations include dry or liquid forms, for example dusts, including pulverulent substrates or concentrates, powders, including soluble or wettable powders, granules, including micro granules and dispersible granules, tablets, fluids, emulsions, such as diluted emulsions or emulsifiable concentrates, impregnating formulations, for example, root and seed impregnation formulations, seed dressers, seed granules, oil concentrates, oil solutions, injections, e.g. barrel injections, solutions or sprayings, smoke and fog.

 Suitable methods and agents for formulating the compounds of the invention for use in horticulture or agriculture turn off those disclosed in the well-known patent for antibiotics S541.

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

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

 When used in veterinary medicine or in horticulture and agriculture, and when the proposed compounds are products formed by fermentation, it is desirable to use the entire fermentation broth as a source of active compounds. In addition, it may be suitable to use a dehydrated broth (containing mycelium) or a mycelium separated from the broth and pasteurized, or more preferably dried. If desired, the specified broth or mycelium can be formulated in the composition, as described above, including traditional inert carriers, excipients or diluents.

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

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

Compounds of formula I are prepared by reacting a compound of formula I, wherein one or both of the radicals R ² and OR ⁴ are a hydroxyl group, with a hydroxyl-substituted reagent of the formula
R ⁶ COOH or R ^4a COOH, (II) where R ⁶ and R ^4a have the above meanings, or a reactive derivative thereof, or a compound of the formula
R ⁷ Y, (III) where R ⁷ has the above meanings;
Y is an atom of chlorine, bromine or iodine.

The acylation reaction may be carried out in an aqueous or non-aqueous reaction medium, preferably at a temperature ranging from -20 to +100 ^C, e.g. from -10 to +50 ^o C.

 Formylation can be carried out using an activated derivative of formic acid, for example, N-formylimidazole or formic acid anhydride under standard reaction conditions.

The sulfonyl group can be introduced using a reactive sulfonic acid derivative R ⁸ O ₃ H such as a sulfonyl halide, for example R ⁸ SO ₂ Cl chloride or sulfonic anhydride. Sulfurylation is preferably carried out in the presence of a suitable acidic binder, as described above.

The esterification can be carried out using a reagent of the formula R ⁷ Y (where R ⁷ has the above meanings and Y represents a leaving group, such as a chlorine, bromine or iodine atom, or a hydrocarbonylsulfonyloxy group, such as methylsulfonyloxy or tolylsulfonyloxy, or a haloalkanoyloxy group, for example dichloroacetoxy) . The reaction may be accompanied by the formation of magnesium alcoholate using a Grignard reagent such as halogenated methyl magnesium, such as iodomethyl magnesium or halogenated trialkylsilylmethyl magnesium, such as chlorotrimethylsilyl methyl magnesium, followed by treatment with R ⁷ Y.

 If desired, the reaction can be carried out in the presence of a silver salt, for example silver oxide, silver perchlorate, silver carbonate or silver salicylate, or mixtures thereof, the system being particularly suitable when the esterification is carried out in the presence of haloalkyl (iodomethyl).

 The esterification can suitably be carried out in a solvent such as an ether, for example diethyl ether.

 The formation of acetals can be carried out by reaction with a cyclic or acyclic simple vinyl ether. This method is particularly suitable for preparing tetrahydropyranyl ethers using dihydropyran or 1-alkoxyalkyl ethers as a reagent, such as 1-ethoxyalkyl ether using a vinyl ether as a reagent. This reaction is preferably carried out in the presence of a strongly acidic catalyst, for example a mineral acid, such as sulfuric acid, or an organic sulfonic acid, such as p-toluenesulfonic acid, in a non-hydroxyl, anhydrous solvent.

 Anhydrous solvents that can be used in the above reactions include ketones (e.g. acetone), amides (e.g. N, N-dimethylformamide, N, N-dimethylacetamide or hexamethylphosphoranide, ethers (e.g. cyclic ethers such as tetrahydrofuran or dioxane and acyclic ethers, for example dimethoxyethane or diethyl ether), nitriles (e.g. acetonitrile), hydrocarbons such as halogenated hydrocarbons (e.g. methylene chloride) and esters, such as ethyl acetate, as well as mixtures of two or b Lee said solvents.

 The introduction of a vinyl group can be carried out by reaction with a silyl halide (for example, chloride), preferably in the presence of a base, such as imidazole triethylamine or pyridine, using a solvent, for example dimethylformamide.

 In many cases, for example, when the 5.23-dihydroxy compound of formula (III) is used as the target material, a mixture of 5-monosubstituted and 5.23-disubstituted derivatives is formed. However, they can be separated using conventional methods, for example, chromatography (silica gel chromatography or preparative thin layer chromatography).

S541 antibiotic intermediates of formula (III), wherein OR ⁵ is a hydroxyl group and OR ⁴ is a hydroxyl or methoxy group, can also be prepared using fermentation and isolation methods, for example, as described in the known patent. Other intermediates of formula (III) can be prepared from these compounds using the methods described above to prepare compounds of formula (II).

The present invention is further presented by the following preparations and examples. All temperatures are given at 0 ^o C.

 The compounds are indicated with reference to the source "Factors", which are the compounds of the formula listed below (see table).

(V)
Факторы А, В, С, D, E, F можно получить уже известным способом.

(V)
Factors A, B, C, D, E, F can be obtained in a known manner.

 PRI me R 1. 5-Phenoxyacetoxy- and 5.23-diphenoxyacetoxy-factor A.

Factor A (2.0g) in dichloromethane solution (25 ml) and pyridine (0.35 mol) at 0 ° ^C was treated with a solution of phenoxyacetyl chloride (0.5 ml) in dichloromethane. After 18 h at 3 ° C., ^the resulting solution was treated with pyridine (1.0 ml) and phenoxyacetyl chloride (1.0 ml) in dichloromethane (5 ml). The solution is thoroughly mixed at a temperature of 0-5 ^about C for 30 minutes, before pouring into ice water. Ether (100 ml) was added to the solution and the mixture was stirred for 20 minutes. The aqueous layer was extracted with ether. The ether layer was combined, washed successively with water and brine, dried and evaporated. The residue was purified by chromatography on a silica column with a mixture of dichloromethane with acetone (40: 1) to give the title compounds as a mixture (1.8 g of monoacyl: diacyl = 6: 1), which was separated by reverse phase high performance liquid chromatography, receiving 5-phenoxyacetoxy factor A, δ (CDCl ₃ ) contains 6.8-7.4 (m; 5H) and 4.6 (s; 2H) m / z includes 746, 728, 710, 594 and 576, and 5 , 23-diphenoxyacetoxy factor A, δ (CDCl ₃ ) contains 6.8-7.4 (m, 10H), 4.60 (s, 2H) and 4.70 (s, 2H).

 PRI me R 2. 5-Phenoxyacetoxy-23- (4-methylphenoxythiocarbonyloxy) -factor A.

5-Fenoksiatsetoksi Factor A (747 mg) in dichloromethane (10 mL) at ⁰ C under nitrogen was treated with pyridine (0.81 mL), followed by 4-metilfenilhlortioformiatom (0.75 g) in dichloromethane (2 ml). The resulting dark solution was stirred vigorously for 15 min at ⁰ C and then for a further 22 hours without cooling. The resulting mixture was poured into cold water and brine (brine) and extracted with ether. The combined ether layers were washed with water and brine, dried and evaporated. The residue is purified by chromatography on a column of silica and preparative reverse phase liquid chromatography to obtain the title compound (430 ml), δ (CDCl ₃ ) contains: 3.34 (m, 1H), 3.58 (m, 1H), 3, 97 (d, 10, 1H), 4.72 (s, 2H), 5.4 (m, 1H), 5.59 (d 6, 1H), and 6.9 to 7.4 (m, 9H) , m / z includes 728, 616, 576, 466, 464, 448, 354, 297, 247, 219 and 151.

 PRI me R 3. 5-tert-Butyldimethylsilyloxyacetoxy factor A.

Factor A (2.144 g) in anhydrous ether (25 ml) and pyridine (2.5 ml) at ⁰ ° C under nitrogen was treated with the dropwise addition of tert-butildimetilsililoksiatsetilhlorida (1.2 g) in ether (10 ml) . The resulting mixture was stirred for 50 min at ⁰ ° C before dropwise again treat the acid chloride (1.10 g) in ether (10 ml). The resulting mixture was stirred vigorously at ⁰ ° C for 60 min and poured into cold water and ether. The aqueous layer was washed with ether. The combined organic layers were washed with water and brine, dried and evaporated. The resulting residue was purified by chromatography on silica using a mixture of dichloromethane with acetone (25: 1) as an eluate to obtain the title compound, δ (CDCl ₃ ) includes: 0.09 (s, 6H), 0.78 (d 6, 3H), 0.90 (s, 9H), 0.93 (d 6, 3H), 0.97 (d 6, 3H), 1.83 (d 6, 3H), 1.51 (s, 3H) 1.59 (s, 3H), 1.74 (s, 3H), 3.32 (m, 1H), 3.52 (d 10, 1H), 3.64 (m, 1H), 3.74 (d 10, 1H), 3.82 (m, 1H), 4.32 (s, 2H), and 5.57 (d 5, 1H); m / s contains 784, 766, 748, 595, 577, 484, 466, 354, 314, 297, 265, 247, 237, 219 and 151.

 PRI me R 4. 5-tert-Butyldimethylsilyloxy factor A.

Factor A (250 mg) and imidazole (163 mg) in dry dimethylformamide (10 ml) are treated with tert-butyldimethylsilyl chloride (197 mg). The resulting solution was thoroughly stirred for 2 hours and poured into cold water. The mixture was carefully extracted with ether, and the combined ether extracts were dried and evaporated. The residue was purified by chromatography on silica using a mixture of dichloromethane with acetone (10: 1) as an eluate to give the title compound (235 mg), δ (CDCl ₃ ) contains: 0.13 (s, 6H), 0.80 (d 6, 3), 0.92 (s, 9H), 0.96 (d 6, 3H), 1.00 (d 6, 3H), 1.03 (d, 6, 3H), 1.53 (s , 3H), 1.60 (s, 3H), 1.80 (s, 3H), 3.37 (m, 1H), 3.56 (d 10, 1H), 3.64 (m, 1H), 3.75 (d 10, 1H) and 4.43 (d 5, 1H); m / s contains 726, 708, 691, 651, 633, 466, 448, 354, 314, 297, 265, 247, 219 and 151.

 PRI me R 5. 5-Acetoxy and 5.23-diacetoxy-factor A.

Factor A (3.0 g) in pyridine (20 ml) at -5 ^{° C} is treated with an acid anhydride (8 ml) and the resulting solution left at 3 ° ^for 20 hr. To the solution was added benzene (100 ml) and the resulting the mixture is concentrated in vacuo. The residual oil is chromatographed on silica using a mixture of dichloromethane with acetone (40: 1) as an eluate to give Factor A 5-acetate (2.06 g) containing 5.23-diacetate (10%). The resulting compounds were separated by reverse phase preparative liquid chromatography to give 5-acetoxy factor (79% yield). λ _max (Et OH) 244.5 nm (E ', 4.62); δ (CDCl ₃ ): contains 2.14 (s, 3H); m / z contains 654, 594 and 576 and 5.23-diacetoxy factor A (6.5% yield); δ (CDCl ₃ ) contains 2.01 (s, 3H) and 2.13 (s, 3H); m / s contains 696 and 636.

 PRI me R 6. 5.23-Diacetoxy-factor A.

A solution of factor A (600 mg) in dry pyridine (1.0 ml) was treated with an excess of acid anhydride (0.50 ml) and several crystals of 4-N, N-dimethylaminopyridine. After 24 hours at room temperature, the solution was poured into ether and then the organic phase was washed alternately with 2N. hydrochloric acid, saturated sodium bicarbonate solution and, finally, brine. Evaporation of the dried organic layer provides gum, which is purified by chromatography through a Merch Kieselgel 60 column with silica (45 g) measuring 230-400 mesh. Elution of the column with a mixture of dichloromethane with ether (9: 1) gave the title compound as a colorless foam (560 mg), [α] _D ²⁶ + 169 ^° (s, 0.48, CHCl ₃ ).

The compound of example 7 was obtained in a similar manner:
PRI me R 7. 5.23-Diacetoxy-factor C.

T. pl. ^About 211-213, [α] _D ²² + 200 ^o (c, 0,40, CHCl _3); λ _max ^EtOH 238.5 (30, 400) and 245 nm (ε _max 32, 500); ν _max 3440 (OH) and 1718 cm ^-1 (acetoxy and ester); δ (CDCl ₃ ) contains 4.90 (m, 1H), 4.04 (d.6 Hz, 1H), 3.96 (d, 10 Hz, 1H), 3.58 (m, 1H), 3, 32 (m, 1H), 2.14 (s, 3H), 1.75 (s, 3H), 1.67 (d 6 Hz, 3H), 1.60 (s, 3H), 1.52 (s , 3H), 0.99 (d, 6 Hz, 3H), and 0.71 (d, 7 Hz, 3H), m / z = 668 (M ⁺ ), from factor C (312 mg).

 The reaction mixture was poured into ethyl rather than ether and finally crystallized by trituration with diisopropyl ether.

 PRI me R 8. 23-Acetoxy factor A.

To a stirred and cooled ^(0-5 °) solution of the compound of Example 6 (530 mg) in methanol (10 ml) was added dropwise an aqueous solution (1 ml) of sodium hydroxide (30 mg). After 1.3 hours, the mixture was poured into ethyl acetate and the organic phase, then washed with 2N in turn. hydrochloric acid; water and finally brine. Evaporation of the dried organic phase gives a yellow gum which is introduced into dichloromethane into a Merch Kieselgel 60 chromatography column, with silica (50 g), particle size 230-400 mesh, added to the same solvent. Elution with a mixture of dichloromethane with ether (9: 1) gave the title compound, which was obtained as an almost colorless solid by evaporation of a solution of n-pentane. The specified substance (330 mg) has [α] _D ²³ + 166 ^o (s, 0.64, CHCl ₃ ), λ _max ^EtOH 239 (26,500) and 245 nm (ε _max 29,300); ν _max (CHBr ₃ ) 3540, 3460 (OH) and 1712 cm ^-1 (ester); δ (CDCl ₃ ) contains 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) 1.85 (s, 3H), 1.59 (s, 3H), 1.51 (s, 3H), 1.03 (6 Hz, 3H), 0.98 (d, 6 Hz, 3H), 0.94 (d, 6 Hz, 3H), and 0.69 (d, 7 Hz, 3H); m / s = 654 (M ⁺ ).

The compound of example 9 was obtained in a similar way:
PRI me R 9. 23-Acetoxy factor C.

[α] _D ²³ + 139 ^o (c 0.52, CH ₂ Cl ₂ ): λ _max ^EtOH 244.5 nm (ε _max 29,400); ν _max (CHBr ₃ ) 3550, 3480 (OH); 1716 (ester and acetate) and 1255 cm ^-1 (acetate); δ (CDCl ₃ ) contains 4.91 (d, 3 Hz, 1H), 2.03 (s, 3H), and 1.64 (d, 7 Hz, 3H) and 1.60 (s, 3H), m / s = 626 (M ⁺ ).

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

 PRI me R 10. 5-Acetoxy-23-methylsulfonyloxy factor A.

A solution of 5-acetoxy factor A (3.46 g) in pyridine (30 ml) was cooled in an ice bath and treated with methanesulfonium anhydride (2.2). After 30 minutes, the mixture was warmed to ambient temperature and after another 60 minutes, it was partitioned between ethyl acetate and 2N. hydrochloric acid. The organic phase is separated and washed successively with 2 N. hydrochloric acid, saturated aqueous sodium bicarbonate solution and finally saturated brine. The organic solution was dried (Na ₂ SO ₄₎ and the solvent evaporated to yield a foam which was chromatographed through a column on silica (Merck Art) 9385) added to a mixture of hexane (boiling range ^60-80) with acetyl acetate (3: 1) and elute in the same solvent. The appropriate fractions of the main component were combined and the solvent was evaporated to give the title compound as a foam (2.08 g).

[α] _D ²² + 154 ^o (c = 0.56; CHCl ₃ ), λ _max ^CHCl3 247 nm (ε 29070); ν _max (CHBr ₃ ) 3550, 3470 (OH) and 1735, 1715 (ester :); δ (CDCl ₃ ) contains 4.90 (m, 1H), 3.05 (s, 3H), and 2.16 (s, 3H).

 PRI me R 11. 23-Tosyloxy factor B.

Factor B (250 mg), tosyl anhydride (204 mg) and several crystals of 4-N, N-dimethylamine pyridine were stirred in dry pyridine (0.5 ml) for 24 hours. The mixture was poured into ether and the organic phase was washed successively with 2M hydrochloric acid acid, saturated aqueous sodium bicarbonate, and finally, brine. Evaporation of the dried (Na ₂ SO ₄ ) ether layer gives a crude product, into which dichloromethane is introduced into a silica gel chromatography column (50 g of Merck Kieselgel 60, 203-400 mesh), included in the same solvent. Mixtures of dichloromethane with ether (9: 1) of the main component, which are additionally purified by preparative high performance liquid chromatography, are also eluted. The title compound was obtained as a resin [α] _D ²³ + 173 ^° (0.84, CHCl ₃ ); λ _max (Et 235 (30,000) and 244.5 nm (ε _max. 30,800); ν _max. 1708 cm ^-1 (ether); δ (CDCl ₃ ) contains 7.82 (d, 10 Hz, 2H), 7.29 (d, 10 Hz, 2H), 4.83 (q, 3 Hz, 1H), 3.50 (s, 3H) and 2.43 (s, 3H); m / s = 1752 (M ⁺ ).

 PRI me R 12. 5-Acetoxy-23-n-butoxy factor A.

 Silver carbonate (lg) was added to a solution of 5-acetoxy factor A (325 mg) in dry ether, followed by the administration of iodobutane (0.5 ml) and silver perchlorate (550 mg). The resulting mixture was stirred at room temperature for 20 hours when sollydin (0.5 ml) was added. After stirring for another 20 minutes, the mixture was filtered and the filtrate was washed alternately with 2N. hydrochloric acid, saturated aqueous sodium bicarbonate and water. The dried organic phase is evaporated almost to dryness and the oil is purified by chromatography on a Merck Kieselgel 60 column with a pore size of 230-400 mesh. Elution from the column with a mixture of hexane and ethyl acetate (3: 1) gave the title compound as a colorless foam (276 mg).

[α] _D ²² + 160 ^o (s, 0.94, CHCl ₃ ); λ _max (EtOH) 245 nm.

 PRI me R 13. Factor A-23-hemioxalate.

Factor A (70% purification ha) and calcium carbonate (1.5 g) was stirred with dichloromethane (20 ml) at 21 ^{° C} and to the resulting suspension was added an excess oxalyl once; (1.0 ml). After 4-5 minutes, the mixture was treated with water (15 ml) and after another 5 minutes with 2 M hydrochloric acid (10 ml) and ethyl acetate (70 ml). The organic phase is separated, washed with water and brine, and then treated with decolorizing charcoal. After 5-10 minutes, the organic solution formed is filtered through phase-separation paper and the filtrate is stripped from the solvent. The residue in ether (50 ml) was purified by filtration through Hyflo and, removing the solvent, a pale yellow foam was obtained. Trituration of the specified foam with diisopropyl ether (7 ml) afforded the title compound as a crystalline solid (750 mg) after washing the solid with diisopropyl ether and n-pentane.

ν _max (CHBr ₃ ) 3360-3600 (OH), 1805 (acid monomer) and 1720 cm ^-1 (acid dimer and esters): δ (CDCl ₃ ) contains 4.30 (d, 5 Hz, 1H) and 5.14 (m, 1H).

 PRI me R 14. Factor A.

A solution of 23-gemioksalat Factor A (500 mg) in dichloromethane (30 ml) was stirred vigorously with an aqueous solution of sodium hydroxide (1.54 g in 30 ml H ₂ O) for 2 hours at 21 ^C. The organic phase was collected and the aqueous the phase is washed with a small amount of dichloromethane. The organic phases are combined, washed with 2M HCl, then dried (Na ₂ SO ₄ ) and stripped from solvent to give the title compound (430 mg) as a foam. The specified compound was demonstrated as factor A when comparing the production of high performance liquid chromatography with a similar sample of factor A.

 PRI me R 15. Factor A, 5-hemisuccinate.

A solution of Factor A (306 mg) and succinic anhydride (60 mg) in dry pyridine (0.5 ml) was stirred at ²² ° C for 24 hours. The mixture was diluted with ether and the organic phase was washed with 2N hydrochloric acid and brine. By evaporating the dried ether layer, a foamed substance is obtained, from which the title compound is isolated by reverse phase high performance liquid chromatography. The resulting product in ether precipitates as a white amorphous solid (86 mg) with the addition of additional p-pentane.

[α] _D ²² + 125 ^o (s, 0.44, CHCl ₃ ), λ _max ^EtOH 245 nm, (ε _max. 30,700), ν _max. (CHBr ₃ ) 3490 (OH), 3,300-2,200 (CO ₂ H). 1730 (acid carbonyl) and 1710 cm ^-1 (complex alcohol); (CDCl ₃ ) contains 2.74 (4H), m / z = 712 (M ⁺ ).

 PRI me R 16. 5-Acetoxy-23-ethyloxyalkyloxy factor A.

A solution of 5-acetoxy factor A (320 mg) and excess ethyl oxalyl chloride (0.5 ml) in dry dichloromethane (6 ml) were mixed in the presence of calcium carbonate (300 mg) for 1 h. The resulting mixture, diluted with ether, was poured into saturated sodium bicarbonate and then before pouring into ethyl acetate, stirred for 20 minutes Evaporation of the dried (Na ₂ SO ₄ ) organic phase makes a resin (325 mg), which is introduced into dichloromethane into a chromatographic column from Merck Kiezelgel 60, with silica (25 g) with a particle size of 70-230 mesh added to the same solvent. Elution from the column with dichloromethane and then with a mixture of dichloromethane with ether (95: 5) gave the title compound (265 mg) as a white foam, [α] _D ²³ + 157 ^o (c 0.41, CHCl), λ _max ^EtOH 245 nm (ε _max. 32,800); ν _max (CHBr ₃ ) 3530, 3480 (OH), 1760 and 1735 cm ^-1 (esters); δ (CDCl ₃ ): 5.4-5.6 (m, 2H), 5.05 (m, 1H), 4.32 (q, 7 Hz, 2H); 2.13 (s, 3H); and 1.35 (m, 7 Hz, 3H).

 PRI me R 17. 23-Methyloxalyloxy factor A.

A solution of 5-acetoxy-23-etiloksaliloksi Factor A (50 mg) in methanol (1 ml) containing concentrated sulfuric acid (0.01 ml) is kept at 21 ^{° C} for 17 hours. The mixture was then poured into ethyl acetate and the organic phase acts as a neutral product. The indicated product was purified by chromatography through a Mersk Kieselgel-60 column on silica (15 g) with a particle size of 70-230 mesh, using initially dichloromethane and then a mixture of dichloromethane with ether (9: 1) as eluting solvents. The title compound was obtained as a colorless resin (25 mg), [α] _D ²³ + 147 ^° (x, 0.28, CHCl ₃ ), λ _max. ^EtOH 245 nm (ε _max. 26,000); ν _max (CHBr ₃₎ 3550, 3480 (0H), 1763, 1737 and 1710 cm ^- 1 (esters); δ (CDCl ₃ ), 4.29 (t, 7 Hz, 1H), 5.09 (m, 1H), and 3.88 (s, 3H).

 PRI me R 18. 5-Acetoxy-23-cyclopropylcarbonyloxy factor A.

A solution of 5-acetoxy factor A (140 mg) and pyridine (1 ml) was treated with cyclopropenocarboxylic acid chloride (0.08 ml). After 3 hours, the reaction mixture was partitioned between ethyl acetate and 2N. of hydrochloric acid. The organic phase is separated and washed sequentially with 2 N. hydrochloric acid and saturated aqueous sodium bicarbonate. The organic solution was dried (Na ₂ SO ₄ ) and the solvent was evaporated to give an oil, which was chromatographed on a Merck Ar 9385 silica column; 80 ml) was introduced into a mixture of hexane (boiling range ^60-80 with ethyl acetate (3: 1)., And eluted with the same solvent appropriate fractions major component were combined and the solvent evaporated to give the title compound as a foam (70 mg).

[α] _D ²² + 143 ^o (c = 0.54; CHCl ₃ ); λ _max ^CHCl3 250.2 (ε = 20310); ν _max (CHBr ₃ ) 3550, 3470, (OH) and 1733, 1712 (ester); δ (CDCl ₃ ): 2.16 (s, 3H), 3.33 (m, 1H), 3.88 (d, J 10 Hz, 1H), 5.01 (m, 1H) and 5.5- 5.6 (m, 2H). The compounds of example 19 are obtained in a similar manner.

 PRI me R 19. 5-Acetoxy-23-cyclopentylcarbonyloxy factor A.

5-Acetoxy factor A (0.28 g) and cyclopentylcarbonyl chloride (0.2 ml) give the title compound as a foam (0.17 g), [α] _D ²² + 149 ^° (c = 0.475; CHCl ₃ ); λ _max. ^CHCl3 ); 250.2 nm (ε = 19900); ν _max (CHBr ₃ ) 3480 (OH).

 PRI me R 20. 23-Cyclopropylcarbonyloxy factor A.

A mixed solution of 5-acetoxy-23-cyclopropylcarbonyloxy factor A (230 mg) in methanol (15 ml) was cooled in an ice bath and treated with a 3% aqueous sodium hydroxide solution (0.5 ml). After 5 hours, during which the reaction mixture was warmed to room temperature, the solution was partitioned between ethyl acetate and 2 N. hydrochloric acid. The organic phase is separated, washed with 2 N. hydrochloric acid (x 2), dried (Na ₂ SO ₄ ) and the solvent is evaporated. The residue was chromatographed on (Merck Art 9385; 150 ml) silica column, introduced into a mixture of hexane (boiling range 60-80 ° ^C) ethyl acetate and eluted with the same solvent. The appropriate fractions of the main component are combined and the solvent is evaporated to yield the title ester as a foamed substance 170 mg), [α] _D ²² + 146 ^° (c = 0.46; CHCl ₃ ); λ _max 250.2 nm (ε = 20090); ν _max (CHBr ₃ ) 3550, 3480 (OH) and 1709 (ester); δ (CHCl ₃ ): 3.26 (m, 1H), 3.88 (d, 10 Hz, 1H), 4.29 (m, J 7 Hz, 1H) and 5.01 (m, 1H).

The compounds of example 21 are obtained in a similar manner:
PRI me R 21. 23-Cyclopentylcarbonyloxy factor A.

Cleavage of the protective group of 5-acetoxy-23-cyclopentylcarbonyloxy factor A (0.25 g) afforded the title ester as a foam (0.215 g). [α] _D ²⁰ + 141 ^o (c = 0.63; CHCl ₃ ); λ _max ^CHCl3 250.2 nm (ε = 19990); ν _max (CHBr ₃ ) 3550, 3480 (OH) and 1710 (ester); δ (CDCl ₃ ): 2.74 (q, J Hz, 1H), 3.26 (m, 1H), 3.91 (d, J 10 Hz, 1H), 4.30 (m, J Hz, 1H ), 4.95 (m, 1H).

 PRI me R 22. 23-Cyclopropylcarbonyloxy-5-methoxycarbonyloxy factor A.

A solution of 23-cyclopropylcarbonyloxy factor A (0.1 g) in dry dichloromethane (15 ml) was cooled in an ice bath and treated with pyridine (0.2 ml), followed by treatment with a 1M solution of methyl chloroformate 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. The residue is chromatographed in a column of silica (Merck Art 9385; 100 ml) was included in hexane (60-80 ° ^C) and ethyl acetate (3: 1) and eluted with the same solvent. The appropriate fractions of the main component were combined, and the solvent was evaporated to give the title compound as a foam (0.106 g).

[α] _D ²⁰ + 149 ^o (c = 0.63; CHCl ₃ ) λ _max ^CHCl3 250.2 nm; ν _max (CHBr ₃ ) 3470 (OH), 1745 λ _max (carbonate), 1710 (ester), 998 (C-O); δ (CDCl ₃ ) contains (s, 1H), 5.01 (m, 1H), 3.88 (d, J 10 Hz), 353 (s, 3H); 0.67 (d, J Hz, 3H).

 PRI me R 23. Factor A, 5-acetate, 23-isobutyrate.

A solution of Factor A, 5-acetate (131mg), isobutyryl chloride (0.05 ml), pyridine (0.1 ml) and 4-dimethylaminopyridine (25 mg) in dry dichloromethane (10 ml) was stirred at ²⁰ ° C for 16 h. The solution was diluted with dichloromethane (30 ml), washed with 2 N. hydrochloric acid and dried with magnesium sulfate) and evaporated to dryness. The residue was purified by chromatography on Kieselgel 60 (15). Elution from the column with a mixture of light oil with ethyl acetate (4: 1) gave the title compound (5.7 mg) as a colorless foam product.

[α] _D ²⁰ + 159 ^o (c 0.61, CHCl ₃ ) λ _max. (EtOH) 2.44 nm (ε = 30.400); ν _max (CHBr ₃ ) 3480 (OH), and 1713 cm ^-1 (ester), δ (CDCl ₃ ) contains 5.5-5.6 (m, 2H), 4.95 (m, 1H), 3.93 (d, 10 Hz), 2.55 (septite, J Hz, 1H), 2.17 (s, 3H), 1.20 (d, J 7 Hz, 6H) and 0.70 (d, J 7 Hz) , 3H).

 PRI me R 24. Factor A, 5-23-di-n-butyrate.

A solution of Factor A (306 mg), n-butyric anhydride (0.33 mg) and 4-dimethylaminopyridine (244 mg) in pyridine (5 ml) was stirred at ²⁰ ° C for 18 hours 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 brine (25 ml), and dried (magnesium sulfate) and evaporated to dryness. The residue was purified by chromatography on Kieselgel 60 (40 g). Elution from the column with a mixture of light oil and ethyl acetate (5: 1) gave the title compound (200 mg) as a colorless foam.

[α] _D ²⁰ + 144 ^o (s, 1.13, CDCl ₃ ), ν _max (EtOH), 245 nm (ε = 31800), ν _max . (CHBr ₃ ) 1720 cm ^-1 (ester), δ (CDCl ₃ ) contains 5.5-5.6 (m, 2H), 4.94 (m, 1H), 3.92 (d, J 10 Hz , 1H), 2.39 (m, J 7 Hz, 2H), and 0.70 (d, J 7 Hz, 3H), m / s = 752 (M ⁺ ).

The compounds of examples 25-27 receive in a similar manner:
PRI me R 25. Factor A, 5-acetate, 23-pivaloate (70 mg).

[α] _D ²⁰ + 159 ^o (c 0.69, CHCl ₃ ), λ _max. (EtOH) 244 nm (ε = 29.900), ν _max (CHBr ₃ ) 3470 (OH) and 1730 and 1710 cm ^-1 (ester), δ (CDCl ₃ ) contains 5.5-5.6 (n, 2H ), 4.95 (m, 1H), 3.91 (d, J 10 Hz, 1H), 2.16 (s, 3H, 1.22 (s, 9H), and 0.68 (d, J 7 Hz, 3H) from factor A, 5-acetate (131 mg) and pivaloyl chloride (0.06 ml).

 PRI me R 26. Factor A, 5-acetate, 23-benzoate (180 mg).

[α] _D ²⁰ + 153 ^o (c 0.59, CHCl ₃ ), λ _max . (EtOH) 236 nm (ε = 36,200), ν _max . (CHBr ₃ ) 3460 (OH) and 1730 and 1707 cm ^-1 (ester), δ (CDCl ₃ ) contains 8.21 (d, J 7 Hz, 2H), 7.56 (m, J 7 Hz, 1H ), 7.44 (m, J 7 Hz), 5.5-5.6 (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 benzoic anhydride (339 mg).

 PRI me R 27. Factor A, 5.23-dibenzoate (370 mg) and 5-benzoate (200 mg).

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

[α] _D ²⁰ + 86 ^o (c 0.65, CHCl ₃ ), λ _max . (EtOH) 2.36 nm (ε 46.200), ν _max . (CHBr ₃ ) 3480 (OH), 1710 (esters), and 1602 and 1585 cm ^-1 (phenyl), δ (CDCl ₃ ): 8.2-8.0 (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 0.76 (d, J 7 Hz, 3H).

Subsequent fractions give the named benzoate [α] _D ²⁰ + 80 ^o (s, 0.61, CHCl ₃ ); λ _max (EtOH) 2.37 nm (ε 39,200), ν _max . (CHBr ₃ ) 3500 (OH), 1712 (esters), and 1601 and 1585 cm ^-1 (phenyl), δ (CDCl ₃ ): 8.09 (l, 1H).

 PRI me R 28. Factor A, 5-chloroacetate.

A solution of Factor A (123 mg) and pyridine (0.1 ml) in dry dichloromethane (5 ml) was stirred at ⁰ ° C and chloroacetyl chloride administered (0.3 ml of a 1M solution in dichloromethane. The resulting solution was stirred at ⁰ ° C temperature for 15 minutes and then more chloroacetyl chloride (0.1 ml of a 1M solution) is added and stirring is continued for an additional 15 minutes, the Solution is diluted with dichloromethane (50 ml), then washed with 2 N. hydrochloric acid (2 x 20 ml), and saturated bicarbonate sodium (20 ml) and dried (magnesium sulfate) and evaporated to dryness. The residue (140 mg) is purified romatografiey column of Kieselgel-60 (15 g) Elution of the column with a mixture of light petroleum and ethyl acetate (4: 1). to give the title compound (90 mg) as a colorless foamy substance.

[α] _D ²⁰ + 143 ^o (s, 1.11, CDCl ₃ ), λ _max. (EtOH) 245.5 nm (ε 30,400); ν _max (CHBr ₃ ) 3500 (OH), 1760 (chloroacetate) and 1710 cm ^-1 (ester), δ (CDCl ₃ ): 5.5-5.6 (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 / s = 688 (M ⁺ , 35 Cl).

 The compounds of examples 29, 39 and 44 are obtained in a similar manner.

 PRI me R 29. Factor A, 5-bromoacetate (447 mg).

[α] _D ²⁰ + 132 ^° (c 0.77, CHCl ₃ ); λ _max (EtOH) 245.5 nm (ε 31500), ν _max (CHBr ₃ ) 3495 (OH), 1730 (bromoacetate) and 1712 cm ^-1 (ester), δ (CDCl ₃ ) includes 5.5-5.6 (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 bromoacetic acid bromide anhydride (0.13 ml).

 PRI me R 30. Factor A, 5.23-dichloroacetate.

A mixture of Factor A, 5-chloroacetate (365 mg), chloroacetyl chloride (0.21 ml) and calcium carbonate (265 mg) was stirred at ²⁰ for 48 hours in dry dichloromethane (15 ml). The resulting suspension was diluted with dichloromethane (50 ml), then washed with 2 N. hydrochloric acid and saturated sodium bicarbonate, dried (magnesium sulfate) and evaporated to dryness. The residue was purified by Kieselgel 60 column chromatography (30 g). Elution of the column with petroleum ether: ethyl acetate (4: 1) gave the title compound (167 mg) as a colorless foam, [α] _D ²⁰ + 151 ^° (c 1.17, CHCl ₃ ), λ _max. (EtOH) 245.5 nm (ε 29400), ν _max . (CHBr ₃ ) 3470 (OH) and 1725 cm ^-1 (esters), δ (CDCl ₃ ) includes 5.5-5.6 (m, 2H), 5.00 (m, 1H), 4.17 ( s, 2H), 4.10 (d, J 15 Hz, 1H), 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 were prepared in a similar manner.

 PRI me R 31. Factor A, 23-methoxyacetate (92 mg).

[α] _D ²⁰ + 157 ^° (c 0.75; CHCl ₃ ); λ _max (EtOH) 244 nm (32300); ν _max (CHBr ₃ ) 3560 and 3480 (OH), 1740 (methoxy acetate) and 1712 cm ^-1 (ester), δ (CDCl ₃ ) includes 5.01 (m, 1H), 4.28 (t, J 7 Hz, 1H), 4.01 (s, 2H), 3.89 (d, J 10 Hz, 1H), 3.46 (s, 3H) and 0.71 (d, J 7 Hz, 3H), from factor A (184 mg) and methoxyacetyl chloride (0.3 ml).

 PRI me R 32. Factor A, 23-phenoxyacetate (112 mg).

[α] _D ²⁰ + 129 ^o (c 0.75, CHCl ₃ ), λ _max. (EtOH) 244 nm (ε 25,900), ν _max. (CHBr ₃ ) 3550 and 3470 (OH), and 1745 and 1708 cm ^-1 (esters), δ (CDCl ₃ ) includes 7.30 (t, J 8 Hz, 2H), 7.00 (t, 8 Hz) , 1H), 6.94 (d, J 8 Hz, 2H), 5.02 (m, 1H), 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) from factor A (184 mg) and phenoxyacetyl chloride (0 3 ml).

 PRI me R 33. Factor A, 5.23-di- (2,2,2-trichloroethyl) carbonate (362 mg).

[α] _D ²⁰ + 110 ^° (c 0.94, CHCl ₃ ); λ _max (EtOH) 244 nm (ε 28000); ν _max (CHBr ₃ ) 3550 and 3460 (OH), 1750 (carbonate), and 1710 cm ^-1 (ester), δ (CDCl ₃ ) includes 5.60 (s, 1H), 4.89 and 4.75 (ABg , J 12 Hz, 2H), 4.85 (m, 1H), 4.81 and 4.71 (ABg, J 14 Hz, 2H), and 0.79 (d, J 7 Hz, 3H), from the factor A (306 mg) and 2,2,2-trichloroethyl chloroformate (0.14 ml).

 PRI me 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) was stirred at a temperature of about 20 ^about and add 1M sodium hydroxide (0.5 ml). The resulting solution was stirred for 30 minutes, then another 1M sodium hydroxide (1 ml) was added and stirring was continued for 1 hour. The solution was diluted with ethyl acetate (50 ml), washed with 2 N. hydrochloric acid, dried (magnesium sulfate) and evaporated to dryness. The residue was chromatographed on a Kieselgel 60 column (15 g). Elution of the column with a mixture of petroleum ether: ethyl acetate (2: 1) gave the title compound (80 mg) as a colorless foam, [α] _D ²⁰ + 142 ^o (s, 0.92, CHCl ₃ ), λ _max. (EtOH) 245 nm (ε 29200), ν _max. (CHBr ₃ ) 3560 and 3500 (OH), 1745 (carbonate) and 1710 cm ^-1 (ester), δ (CDCl ₃ ) includes 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).

 PRI me R 35. Factor A, 5-acetate, 23- (2,2,2-trichloroethane) carbonate (385 mg).

[α] _D ²⁰ + 140 ^o (s, 1.07, CHCl ₃ ) λ _max . (EtOH) 245.5 nm, (ε 29200); ν _max (CHBr ₃ ) 3300-3620 (OH), 1738 (carbonate), and 1720 cm ^-1 (ester), δ (CDCl ₃ ) includes 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-trichloroethyl chloroformate (2 ml of a 1M solution in dichloromethane).

 PRI me R 36. Factor A, 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 ²⁰ for 18 hours and then poured into a mixture of ethyl acetate and 2N. hydrochloric acid (50 ml of each component). The organic phase is washed with 2 N. hydrochloric acid, saturated sodium bicarbonate (25 ml) and brine (25 ml), dried (magnesium sulfate) and evaporated to dryness. The residue was purified by chromatography on a Kieselgel 60 column (40 g). Elution of the column with petroleum ether: ethyl acetate (5: 1) gave the title compound (200 mg) as a colorless foam.

[α] _D ²⁰ + 144 ^o (c 1.13, CHCl ₃ ) λ _max. (EtOH) 245 nm (ε 31800), ν _max . (CHBr ₃ ) 1720 cm ^-1 (esters), δ (CDCl ₃ ) includes 5.5-5.6 (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 / s = 752 (M ⁺ ).

 PRI me R 37. Factor A, 23-n-butyrate.

A solution of Factor A, 5,23-di-n-butyrate (160 mg) in methanol (10 ml) was stirred at ⁰ and was added 1M sodium hydroxide (10.25 ml). The resulting solution was stirred for 90 minutes at ^0-5, then added another 0.25 ml of 1M sodium hydroxide and stirring was continued for 4 hours. The solution was poured into a mixture of ethyl acetate (50 ml) and 2N. hydrochloric acid (25 ml), the organic phase is washed with water, brine, dried (magnesium sulfate) and evaporated to dryness. The residue was purified by Kieselgel 60 column chromatography (20 g). Elution of the column with petroleum ether: ethyl acetate (2: 1) gave the title compound (68 mg) as a colorless foam. [α] _D 20 + 164 ^° (c 1.03, CHCl ₃ ); λ _max (EtOH) 244.5 nm (E 29600); ν _max (CHBr ₃ ) 3550 and 3470 (OH), and 1710 cm ^-1 (esters); δ (CDCl ₃ ), includes 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), 0.94 (t, J 7 Hz, 3H) and 0.69 (d, J 7 Hz, 3H), m / s = 682 (M ⁺ ).

The compound of example 38 is obtained in a similar manner:
PRI me R 38. Factor A, 23-methyl carbonate (155 mg).

[α] _D ²⁰ + 169 ^o (s, 0.81, CHCl ₃ ), λ _max . (EtOH) 245 nm (E 26600); ν _max (CHBr ₃ ) 3300-3610 (OH), 1735 (carbonate), and 1710 cm ^-1 (ester), δ (CDCl ₃ ) includes 5.40 (s, 1H), 4.28 (m, 1H), 3.94 (d, J 10 Hz, 1H), 3.77 (s, 3H), and 0.76 (d, J 7 Hz, 3H); m / s = 670 (M ⁺ ), from factor A, 5-acetate, 23- (2,2,2-trichloroethyl) carbonate (300 mg).

 PRI me R 39. 23-Deoxy-factor A, 5-methyl carbonate (57 mg).

[α] _D ²⁰ + 152 ^o (s, 0.6, CHCl ₃ ), λ _max. (EtOH) 244.5 nm (E 28200); ν _max (CHBr ₃₎ 3530 and 3460 (OH), 1740 (carbonate) and 1707 cm ^- 1 (ester); δ (CDCl ₃ ) includes 5.55 (s, 1H), 3.82 (s, 3H), 3.42 (d, J 10 Hz, 1H) and 0.69 (d, J 4 Hz, 3H), from 23-deoxy-factor A (90 mg) and methyl chloroformate (0.3 ml of a 1M solution in dichloromethane).

 PRI me R 40. Factor A, 23-chloroacetate (193 mg).

[α] _D ²⁰ + 162 ^o (s, 1.04, CHCl ₃ ), λ _max. (EtOH) 245 nm (ε 28900); ν _max (CHBr ₃ ) 3320-3620 (OH), 1748 (chloroacetate), and 1710 cm ^-1 (ester); δ (CDCl ₃ ) includes 5.42 (s, 1H), 4.28 (m, 1H), 4.09 and 4.01 (ABg, J 15 Hz, 2H), 3.91 (d, J 10 Hz , 1H) and 0.73 (d, J 7 Hz, 3H), m / z = 688 (M ⁺ , 35Cl) from factor A (306 mg) and chloroacetic acid chloride (0.2 ml).

 PRI me R 41. Factor A, 5.23-dipropionate (387 mg).

[α] _D ²⁰ + 157 ^o (s, 0.96, CHCl ₃ ), λ _max. (EtOH) 244.5 nm (ε 30200); ν _max (CHBr ₃ ) 3500 (OH) and 1720 cm ^-1 (esters); δ (CDCl ₃ ) includes 5.52 (s, 1H), 3.93 (, J 10 Hz, 1H), 2.43 (g, J 7 Hz, 2H), 2.32 (d, J 7 Hz, 2H), 1.18 (t, J 7 Hz, 3H), 1.16 (t, 7 Hz, 3H) and 0.70 (d, J 7 Hz, 3H), m / s = 7.24 (M ⁺ ), from factor A (613 mg) and propionic anhydride (0.5 ml).

 PRI me R 42. Factor A, 23-propionate (155 mg).

[α] _D ²⁰ + 168 ^° (s, 1.03, CHCl ₃ ); λ _max (EtOH) 244.5 (ε 30600); ν _max (CHBr ₃ ) 3550 and 3480 (OH), and 1710 cm ^-1 (ester); δ (CDCl ₃ ) includes 5.39 (s, 1H), 4.27 (m, 1H), 3.91 (d, J 10 Hz, 1H), 2.31 (d, J 7 Hz, 2H0, 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), similar manner for the compound of example 37.

 PRI me R 43. Factor A, 5-methyl carbonate, 23-ketone (830 mg).

[α] _D ²⁰ + 132 ^° (c 0.82, CHCl ₃ ); λ _max (EtOH) 245 nm (ε 29800), IR and NMR spectra are similar to those of the compound described in Example 34, from factor 4, 23-ketone (916 mg) and methyl chloroformate (0.23 ml).

 PRI me R 44. Factor A, 5-benzyl carbonate, 23-ketone (57 mg).

[α] _D ²⁰ + 99 ^° (c 0.4, CHCl ₃ ); λ _max (EtOH) 245.5 nm (ε 29600); ν _max (CHBr ₃ ) 3600, 3550 and 3480 (OH), 1740 (carbonate) and 1715 cm ^-1 (ester and ketone); δ (CDCl ₃ ) includes 7.5-7.2 (m, 5H), 5.57 (s, 1H), 5.21 (s, 2H), 3.70 (d, J 10 Hz, 1H), 2.49 (s, 2H) and 0.86 (d, J 6 Hz, 3H), from factor A, 23-ketone (92 mg) and benzyl chloroformate (0.05 ml).

 PRI me R 45. 5-Acetoxy-23-n-butoxy factor A.

Silver carbonate (1 g) was added to a solution of 5-acetoxyfactor A (325 mg) in dry ether, followed by iodobutane (0.5 ml) and silver perchlorate (550 mg). The mixture was stirred at room temperature for 20 hours, after which collidine (0.5 ml) was added. After stirring for another 20 minutes, the mixture was filtered and the filtrate was washed sequentially with 2 N. hydrochloric acid, saturated aqueous sodium bicarbonate and water. The dried organic phase was evaporated to almost dryness and the oil was purified by chromatography on a Merck Kieselgel 60 column measuring 230-400 mesh (100 ml). Elution of the column with hexane: ethyl acetate (3: 1) afforded the title compound as a colorless foam (276 mg, 78%). [α] _D ²⁰ + 160 ^o (s, 0.94, CHCl ₃ ), λ _max. (EtOH) 245 nm (ε _max. 28300); δ (CDCl ₃ ) includes 3.16 (m, 1H), 3.43 (m, 1H), 3.59 (m, 1H).

 PRI me R 46. 5-Acetoxy-23-cyclopropylmethoxy factor A.

[α] _D ²¹ + 174 ^o (c 1.74, CHCl ₃ ), λ _max. (Et0H) 244 nm (E 28360), ν _max. (CHBr ₃ ) 3470 (OH), 1732, 1710 (esters) and 998 cm ^-1 (C-O), δ (CDCl ₃ ) includes 5.5-5.6 (m, 2H), 3.96 ( d, J 10, 1H), 3.49 (m, 1H), 3.17 (dv. J 10, 1H), 3.17 (dv. J 10, 1H), 2.16 (s , 3H), 0.76 (d, J 7, 3H), 0.44 (m, 2H), 0.22 (m, 2H), from 5-acetoxy factor A and bromomethylcyclopropane, similarly for the compound of Example 12 .

 PRI me R 47. 5-tert-butyldimethylsiloxy-23-methoxy factor A.

A solution of iodomethylmagnesium in 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 in dry hexamethylphosphoric triamide (18 ml) with vigorous evolution of gas. Iodomethane (30 min) was added. 0.4 ml), the resulting mixture was stirred for 5 hours, diluted with ether (100 ml) and washed with plenty of water. The ether solution was then washed with brine (50 ml) and the dried organic phase was evaporated. The resulting foam (280 mg) was purified by chromatography on column Merck Kieselgel 6 0 with a size of 230-400 mesh (80 ml). Elution with a mixture of hexane: ethyl acetate (5: 1) affords the title compound as a colorless foam (46%), [α] _D ²¹ + 142 ^o (c 1.13, CHCl ₃ ), λ _max. (EtOH) 244 nm (ε _max. 27900); ν _max . (CHBr ₃ ) 3460 (OH), 1708 (broad; ester) and 995 cm ^-1 (С-О); δ ( CDCl ₃ ) includes 4.42 (m, 1H), 3.92 (d 10, 1H), 3.3-3.4 (m, 2H), 3.32 (s, 3H), 0.92 (s 9H); 0.75 (D 7, 3H) 0.12 (s, 6H).

The compound of example 48 receive in the same way:
PRI me R 48. 5-tert-Butyldimethylsilyloxy-23-n-propyloxy factor A.

[α] _D ²¹ + 153 ^o (c 1.16, CHCl ₃ ), λ _max. (EtOH) 244 nm (ε _max. 29950); ν _max (CHBr ₃ ) 3460 (OH), 1705 (ester) and 995 cm ^-1 (C-O); δ (CDCl ₃ ) includes 4.44 (m, 1H), 3.96 (d, 10, 1H), 3.56 (m, 1H), 3.45 (m, 1H), 3.14 (m, 1H), 0.93 (s, 9H), 0.75 (d 7, 3H), 0.13 (s, 6H) from 5-tert-butyldimethylsilyloxy factor A and 1-iodopropane.

 PRI me R 49. 5-Acetoxy factor D (923 mg).

[α] _D ²¹ + 143.9 ^o (s, 0.9, CHCl ₃ ); λ _max (EtOH) 239 (28700) and 245 nm; (ε _max. 31000); ν _max (CHBr ₃ ) 3490 (OH), 1730 and 1710 (ester); δ (CDCl ₃ ) 0.81 (d, 7 Hz, 3H), 0.99 (d, 7 Hz, 3H), 1.00 (t, 7 Hz, 3H); 1.53 (s, 3H), 1.59 (s, 3H), 1.75 (s, 3H), 2.16 (s, 3H), 3.32 (m, 1H), 3.65 (m , 1H), 4.04 (d, 6 Hz, 1H) and 5.53 (m, 2H), m / z = 640 (M ⁺ ), from factor D (2.5 g) and acetic anhydride (0, 47 ml), similarly for the corresponding compound of example 5.

 PRI me R 50. 5.23-Diacetoxy-factor D (286 mg).

T. pl. 147-149 ^o (diamond from pentane in ether [α] _D ²¹ + 152.6 ^o (c 0.9, CHCl ₃ ), λ _max. (EtOH) 232.5 (21500) 238 (26600), and 244 , 5 nm (ε _max. 28300), ν _max. (CHBr ₃ ) 1720 ^-1 (ester), δ (CDCl ₃ ) 0.72 (d, 6 Hz, 3H), 0.99 (d, 6 Hz , 3H), 1.01 (t, 7 Hz, 3H), 1.53 (s, 3H), 1.60 (s, 3H), 1.75 (s, 3H), 2.02 (s, 3H) ), 2.15 (s, 3H), 3.31 (m, 1H), 4.04 (d, 6 Hz, 1H), 4.91 (m, 1H) and 5.5-5.6 (m , 2H), m / z = 682 (M ⁺ ), from factor D (439 mg) and acetic anhydride (0.25 ml), similarly for the compound of example 6.

 PRI me R 51. 23-Acetoxy-factor D (127 mg).

[α] _D ²¹ + 150 ^o (c 0.5, CHCl ₃ ); λ _max (EtOH) 238 (29,200) and 244.5 nm; (ε _max. 15600); ν _max (CHBr ₃ ) 3300, 3590 (OH) and 1710 cm ^-1 (ester); δ (CDCl ₃ ) 0.72 (d, J 7 Hz, 3H), 0.99 (d, J 7 Hz, 3H), 1.01 (t, J 7 Hz, 3H), 1.53 (s, 3H), 1.6 (s, 3H), 1.86 (s, 3H), 3.26 (m, 1H), 3.95 (s, J 6 Hz, 1H), 4.26 (t, J 6 Hz, 1H), and 4.01 (m, 1H), m / z = 640 (M ⁺ ), and / 5.23-diacetoxy factor D (207 mg), similarly for the compound of Example 8.

 PRI me R 52. Factor A, 23-phenylacetate (240 mg).

[α] _D ²⁰ + 140 (s, 0.92, CHCl ₃ ); λ _max (CHBr ₃ ) 3550 and 3470 (OH) and 1730 cm ^-1 (esters); δ (CDCl ₃ ) includes 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) were obtained in a similar manner to the compound of Example 32 from factor A (306 mg) and phenylacetyl chloride (0.33 ml).

 PRI me R 53. 23-Ethoxy factor A.

A solution of 5-acetoxy-23-ethoxy-factor A (306 mg) in methanol (18 ml) was cooled in an ice bath, then 1 N. an aqueous solution of sodium hydroxide (1 ml) and the resulting solution of light yellow color is stirred in an ice bath for 1.25 hours. The solution is diluted with ethyl acetate (80 ml), then washed successively with 1 N. hydrochloric acid, water and brine. The dried organic phase is evaporated and the resulting resin is purified by chromatography on Merck Kieselgel 60 with a silica particle size of 230-400 mesh. (200 ml). Elution from the column with 15% ethyl acetate in dichloromethane afforded the title compound as a colorless foam (623 mg) [α] _D ²¹ + 178 (c, 1.13, CHCl ₃ ); λ _max (EtOH) 244 nm (ε _max. 29400); δ (CDCl ₃ ) includes 4.29 (t, 7, 1H), 5.65 (m, 1H), 3.47 (m, 1H), 3.26 (m, 2H), 1.15 (t, 7, 3H).

 The compounds of examples 54-57 obtained in a similar manner.

 PRI me R 54. 23-n-butoxy factor A (61%) was obtained as a colorless foam.

[α] _D ²¹ + 161 (s, 1.47, CHCl ₃ ); λ _max (EtOH) 244 nm (ε 33100); δ (CDCl ₃ ) includes 4.30 (t, 7, 1H), 3.60 (m, 1H), 3.43 (m, 1H), 3.17 (m, 1H) from 5-acetoxy-23- n-butoxy factor A.

 PRI me R 55. 23-n-Propoxy factor A (83%) was obtained as a colorless foam.

[α] _D ²¹ + 165 ^o (c 1.01, CHCl ₃ ), λ _max. (EtOH) 2.45 nm (ε 30.970), (CDCl ₃ ) includes 4.29 (t, 7; H), 3.55 (m, 1H), 3.13 (m, 1H), from 5-acetoxy -23-n-propoxy factor A.

PRI me R 56. 23-Methoxy factor A (66%) was obtained as a colorless foam [α] _D ²¹ + 175 ^o (c 101, CHCl ₃ ); λ _max (EtOH) 244 nm (19.10); δ (CDCl ₃ ) includes 4.29 (t, J 7; 1H), 3.40 (m, 1H), 3.33 (s, 3H) from 5-acetoxy-23-methoxy factor A.

 PRI me R 57. 23-Cyclopentyloxy factor A (75%) was obtained as a colorless foam.

[α] _D ²¹ + 160 ^o (c 1.65, CHCl ₃ ), λ _max. (EtOH) 244 nm (ε 19.800); δ (CDCl ₃ ) includes 4.29 (t, J 7, 1H), ca 3.96 (invisible m, 1H), 3.95 (d, J 5, 1H), 3.91 (d, J 10, 1H), 0.69 (d, 7, 3H) from acetoxy-23-cyclopentyloxy factor A.

 PRI me R 58. (a) 5-acetoxy-23-allyloxy factor A.

 Silver salicylate (872 mg) was added to a solution of 5-acetoxy factor A (207 mg) and allyl iodide (1.0 ml) in dry ether (25 ml), and the resulting mixture was stirred at room temperature for 4 days, after which filtered. The filtrate was evaporated to give a yellow oil, which was purified by Merck Keiselgel 60 column chromatography, 230-400 mesh. Elution with a mixture of dichloromethane with ethyl acetate (19: 1) will give the title compound as a colorless foam (105 mg).

[α] _D ²¹ + 152 ^° (s, 1.00, CHCl ₃ ); λ _max (EtOH) 245 nm (ε 22000); δ (CDcl ₃ ) includes 3.54 (m, 1H), 4.14 (m, 1H).

The following compounds are prepared in a similar manner:
(b) 5-Acetoxy-23-n-propyloxy factor A is prepared from 5-acetoxy factor A and n-propyl iodide. When purified by chromatography on a Merck Keiselgel 60 column with a silica particle size of 230-400 mesh. and eluting with a mixture of hexane and ethyl acetate (3: 1) gave the title compound as a colorless foam.

[α] _D ²¹ + 160 ^o (c 0.75, CHCl ₃ ); λ _max (EtOH) 245 nm (ε, 27600); δ (CDCl ₃ ) includes 3.33 (s, 3H), 3.39 (m, 1H).

 (c) 5-Acetoxy-23-methoxy-factor A is obtained from 5-acetoxy-factor A and methyl iodide. The title compound is obtained as a colorless foam.

[α] _D ²¹ + 159 ^o (s, 0.98, CHCl ₃ ), λ _max. (EtOH) 245 nm, (ε, 27600), δ (CDCl ₃ ) includes 3.33 (s, H), 3.59 (m, 1H).

 PRI me R 59. 5-Acetoxy-23-ethoxy-factor A is obtained from 5-acetoxy-factor A and ethyl iodide. The title compound leaves as a colorless foam.

[α] _D ²¹ + 1.670 (c 1.02, CHCl ₃ ); λ _max (EtOH) 245 nm, (ε, 28070), δ (CDCl ₃ ) includes 3.25 (m, 1H), 3.46 (m, 1H), 3.64 (3m, 1H), obtained by a method similar to the compounds of example 12.

 The test of compounds (1) is the main test for nematicidal activity. According to the applicant, all compounds considered in the examples are active in this test, however, at present, the applicant cannot confirm this experimentally. Tests (2) and (3) are more specific; the compounds of examples 6, 8, 18, 20, 21, 23, 32, 37, 42, 46, 52-55, 58a, 58b, 59 are active in these trials.

 Based on this comparison, it can be expected that other compounds of the pending application have the indicated advantages.

 It should be noted that the compounds (avermectins and milbemycins) belong to other types of compounds. In particular, they have a different substituent (simple alkyl group) at the 25-position, compared with the unsubstituted group of compounds of the present invention, and this fact may affect the properties of the compounds in an unpredictable way. In addition, 25-substituents of the compounds of this application cannot be formed by standard modifications of the compounds of the prototypes.

 In addition, it should be noted that the prototype compounds are unsubstituted or have a simple OH group at the 23-position, and also have only naturally occurring substituents (OH or methoxy) at the 5-position. In these prototypes there is no indication that these groups can be modified, as is assumed in this application.

 1. Activity against Caenorhabditis elegans.

 The compounds of the present invention were tested for their activity against the free-living nematode Caenorhabditis elegans. Solutions or suspensions of the compounds were prepared in methanol, and serial dilutions were made (400 μg / ml or lower) in 20% propylene glycol. Every 10 μl of the resulting solutions 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 test described above, the compounds described in the examples mainly after 20 hours exerted a killing - paralyzing effect on> 98% of the caterpillars at a concentration of <10 μg / ml.

 2. Activity against Nematospiroides dubius.

The efficacy of the compounds of the present compound against Nematospiroides dubius that infected mice was determined. Female CP / H mice 18-22 g were infected with 100 <3-larvae of N. dubius and the infection was brought to maturity by larvae (usually 3 weeks). Then the mice were treated by only one oral administration of the compound of the present invention in one of 3/4. Compounds were administered as a solution in propylene glycol. Then the mice were left for at least 3 days, usually 5 days, to mature the infection, after which the mice were sacrificed and the small intestine was removed. The excised portion of the small intestine was cleaved with blunt scissors to isolate the mucous membrane of the small intestine. Adult larvae were collected using a modified Baarnmann apparatus. Migration time was 5 hours, and during this period the larvae migrate maintained at 37 ^C. After 5 hours, the nylon gauze, through which migrated nematodes were examined after 2 x - a magnifying glass. Then, the number of nematodes held up by gauze and passed through the gauze was counted, thereby obtaining the total number of nematodes for each mouse, and the results were compared with the control.

 Thus, using this procedure, it was found that by using a dose of the compounds of the present invention of 10 mg / kg, a significant reduction in the number of nematodes in the treated mice can be achieved. For example, the compounds of examples 6, 8, 18, 20, 21, 23, 32, 37, 42, 46, 52-55, 58A, 58B and 59 showed a percentage reduction in the number of nematodes in the treated mice, compared with control more than 80% .

 3. Activity against various ecto- and endoparasites for various animals.

 (a) With only one dose (800 μg / kg) of the compound of Example 53, administered intravenously or subcutaneously, complete destruction of Cooperia oncophera was achieved in calves infected with this helminth.

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

 (d) The compound of Example 53 is as effective as Ivermectin in killing both larvae and adults of Osteitagia ciraimcineta, Trichostrongylus axei, Haemonchus contortus, Nematodirus spathiger, Cooperia curticei, Trichostrongylus vitrinus with an oral dose of 200 μg .

 (f) The compound of Example 53 is absolutely effective in treating dogs infected with Tohosa by oral administration of a dose of 150 μg / kg of said compound.

 (f) The compound of Example 53, administered subcutaneously to pigs infected with Oesophagostomum at a dose of 800 μg / kg, showed an efficacy of> 98%.

Claims (1)

METHOD FOR PRODUCING MACROLIDE COMPOUNDS of general formula I

where R ₁ is isopropyl;
R ₃ is hydrogen,
R ₂ is an OR ₅ group, where OR ₅ is an OCOR ₆ group, where R ₆ is C ₁ -C ₄ alkyl optionally substituted with phenoxy or phenyl, or C ₃ C ₅ cycloalkyl, or OR ₇ , where R ₇ - C ₁ - C ₄ alkyl optionally substituted with C ₃ - C ₅ cycloalkyl or C ₃ - C ₅ alkenyl;
OR ₄ is OH or is OCOR _{4 a} , where R _{4 a} is C ₁ is C ₄ alkyl,
characterized in that the reaction of the corresponding compound of formula I is carried out, where one or both of the radicals R ₂ and OR ₄ are a hydroxyl group, with a hydroxyl-substituted reagent of the general formula II
R ₆ COOH or R _{4 a} COOH,
or a reactive derivative thereof, or a compound of the general formula III:
R ₇ Y
where R ₆ , R ₇ and R _{4 a} have the indicated meanings;
Y is chlorine, bromine or iodine. Priority by signs:
04/30/85 at R ₁ is isopropyl, R ₂ is OR ₅ , R ₃ is H, where OR ₅ is an OCOR ₆ group, where R ₆ is C ₁ is C ₄ alkyl optionally substituted with a phenoxy group or phenyl, or C ₃ - C ₅ -cycloalkyl, OR ₄ is a hydroxyl group, or is an OCOCR _{4 a} group, where R _{4 a} is C ₁ is C ₄ alkyl;
03/12/86 at R ₁ is isopropyl, R ₂ is OR ₅ , R ₃ is H, where OR ₅ is an OCOR ₆ group, where R ₆ is C ₁ is C ₄ alkyl optionally substituted with a phenoxy group or phenyl, or C ₁ - C ₅ -cycloalkyl, or OR ₇ -group, where R ₇ - C ₁ - C ₄ -alkyl, optionally substituted by C ₃ - C ₅ -cycloalkyl or C ₃ - C ₅ alkenyl; OR ₄ is a hydroxyl group or is an OCOR _{4 a} group, where R _{4 a} is C ₁ is C ₄ alkyl.

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