JPH0363551B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to 5-oxo derivatives of the antibiotic milbemycin D. From a culture of the B-41-146 strain belonging to the genus Streptomyces (deposited with the Institute of Microbial Technology, Agency of Industrial Science and Technology as FAIKEN Article No. 1072),
Milbemycin D (B-41D), which has acaricidal and anthelmintic activity, has been isolated (Japanese Patent Application Laid-Open No. 1989-1999).
Publication No. 32481). The present inventors conducted intensive studies on the synthesis of derivatives of milbemycin D by chemical means, and as a result, they discovered a compound having excellent acaricidal activity, anthelmintic activity, etc., and completed the invention. The novel compound of the present invention has the general formula (In the formula, -A- and -B- are the same or different and represent a double bond or an epoxy group.) The compound () according to the present invention is produced by the method shown below. The first step is to produce compound (a) in which -A- and -B- are double bonds, and is achieved by oxidizing the hydroxyl group at the 5-position of milbemycin D (). Ru. The reaction is carried out by contacting the compound () with an oxidizing agent in an inert solvent. The inert solvent used in the reaction is not particularly limited as long as it does not participate in the reaction, but examples include halogenated hydrocarbons such as dichloromethane, dichloroethane, and chloroform; N such as dimethylformamide and dimethylacetamide; , N-dialkyl fatty acid amides,
Dichloromethane and dimethylformamide are preferred. Examples of the oxidizing agent used in this reaction include complexes of chromic anhydride and organic bases such as chromic anhydride/pyridine (Collins' reagent), pyridinium dichromate, and pyridinium chlorochromate; - Pyridine is preferred. The reaction can be carried out at -10°C to 50°C, preferably 0°C to room temperature. The time required for the reaction is usually 1 to 30 hours. The second step is to produce a compound (b) in which -A- is an epoxy group and -B- is a double bond, in which compound (a) is added with organic peroxide in an inert solvent. This is accomplished by reacting hydrogen peroxide or hydrogen peroxide. Organic peroxides used are, for example, performic acid, peracetic acid, trifluoroperacetic acid, perbenzoic acid, metachloroperbenzoic acid or monoperphthalic acid;
Mention may be made of hydrogen peroxide or 90% hydrogen peroxide-alkali, preferably metachloroperbenzoic acid. In addition, when the amount of organic peroxide or hydrogen peroxide is 1 to 1.5 equivalents, compound (b)
is selectively obtained, and in the case of 2 to 3 equivalents, a further oxidized compound [(d): compound in which -A- and -B- are both epoxy groups] is selectively obtained. can get. The reaction is carried out in an inert solvent such as aromatic hydrocarbons such as benzene, toluene, xylene, halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, ethers such as ether, tetrahydrofuran, dioxane, etc. However, halogenated hydrocarbons are preferably used. The reaction temperature is -20 to 50°C, preferably under ice cooling, and the reaction time is usually 1 hour to 20°C.
It's time. The third step is a step of producing a compound (c) in which -A- is a double bond and -B- is an epoxy group in the compound (), and the third step is to prepare a compound (c) in which -A- is a double bond and -B- is an epoxy group. This is achieved by reacting compound (a) with an alkyl hydroperoxide in the presence of a Group B metal complex.
The alkyl hydroperoxides used are, for example, methyl, ethyl, n-propyl, n-
-butyl- or t-butyl-hydroperoxide, preferably t-butyl hydroperoxide. Also, as a catalyst,
For example, vanadium acetylacetonate, molybdenum trioxide acetylacetonate or molybdenum hexacarbonyl can be mentioned, and vanadium acetylacetonate is preferred. The reaction is carried out in an inert solvent, for example aromatic hydrocarbons such as benzene, toluene, xylene, halogenated hydrocarbons such as methylene chloride, chloroform, ethers, ethers, tetrahydrofuran, dioxane, etc. Benzene is preferably used. The reaction temperature is between 0°C and
The reaction is carried out at 100° C., preferably at room temperature, and the reaction time is 1 to 5 hours. The 4th step and the 4th step are steps for producing a compound (d) in which -A- and -B- are epoxy groups in the compound (). Step 4a is the second step (adding oxidizing agent from 1 to 1.5
Use equivalent amount. ) or by treating compound (b) under the same reaction conditions as in the third step. Step 4b is the second step (adding an oxidizing agent of 1 to 1.5
Use equivalent amount. ) under similar reaction conditions to the compound (
This is achieved by processing c). The target compound for each step is collected from the reaction mixture according to a conventional method. For example, if there are insoluble substances in the reaction mixture, wash the insoluble substances thoroughly with a water-immiscible organic solvent, separate the insoluble substances, add water to the reaction mixture, and extract with a water-immiscible organic solvent. do. It can be obtained by washing the extract with water, drying, and then distilling off the solvent. Furthermore, if necessary, the obtained compound can be purified by recrystallization or column chromatography. The compound () of the present invention is applicable to adults and eggs of two-spotted spider mites (Tetranychus) that parasitize fruit trees, vegetables, and flower petals, apple spider mites, citrus spider mites (Panonychus), and rust mites, and insects of Ixodidacidae (Ixodidac) and Acarinae (Dermanysside) that parasitize animals.
It has excellent acaricidal activity against Sarcoptidae and other members of the Sarcoptidae family. Furthermore, the sheep fly (Oestrus) and the golden fly (Lu-
cilia), Hypoderma, Gautrophilus, and other ectoparasites of animals and birds such as chisels and lice; sanitary pests such as cockroaches and house flies; and various other agricultural and horticultural pests such as aphids and lepidopteran larvae. It is active against. Furthermore, it is also active against root-knot nematodes (Meloidogyne), mites (Phizoglyphus), etc. in the soil. Furthermore, the compounds of the present invention () have excellent parasiticidal activity as anthelmintics for animals and humans. It is particularly effective against the following nematodes that infect livestock such as pigs, sheep, goats, cows, horses, dogs, cats, and chickens, poultry, and pets. Haemonchus, Trichostrongylus, Ostertagia, Nematodirus, CooPeuria, Ascaris, Bunostomum, Ethophagostomum Oesophagostomum, Chabertia, Trichuris, Strongylus, Trichonema, Dictyocaulus, Capillaria, Heterakis , Toxocara, Ascaridia, Oxyuris, Ancylostoma, Uncinaria, Toxascaris and Parascaris. Certain members of the genera Nematodeilus, Cooperia and Esophagostomum attack the intestinal tract, while those of the genera Haemonchus and Ostertagia inhabit the stomach, and parasites of the genus Deictyokaurus are found in the lungs. However, it also shows activity against these. Parasites of the Filariidae and Setariidae families are also found in and active in other tissues and organs in the body, such as the heart and blood vessels, subcutaneous and lymphatic tissues. It is also useful against parasites that infect humans; the most common parasites of the human gastrointestinal tract include Ancylostoma, Necator, Ascaris, and Strongyloides. The genera Strongyloides, Trichinella, Capillaria, Trichuris, and Enterobius. Other medically important diatoms found in the blood or other tissues and organs outside the gastrointestinal tract; members of the family Filariaceae such as Wuchereria, Brugia, Onchocerca;
and Dracunculus (Loa) and Dracunculidae (Dracunculidae).
cunculus), as well as in the special extraintestinal parasitic state of intestinal parasites of the spp. Strongyloides and Trivinella. When the compound () is used as an anthelmintic in animals and humans, it can be administered orally as a liquid drink. Beverages are usually solutions, suspensions or dispersions in a suitable non-toxic solvent or water with suspending and wetting agents such as bentonite or other excipients. Beverages generally also contain antifoaming agents. Beverage formulations generally contain active compounds of approx.
It contains 0.01-0.5% by weight, preferably 0.01-0.1% by weight. When oral administration in a dry, solid unit dosage form is desired, capsules, pills, or tablets containing the desired amount of active compound are commonly employed.
These use forms involve homogeneously admixing the active ingredient with suitable finely divided diluents, fillers, disintegrants and/or binders such as starch, lactose, talc, magnesium stearate, vegetable gums, etc. Manufactured by Such unit use formulations can vary widely with respect to weight and content of anthelmintic agent depending on the type of host animal being treated, the degree of infection and the type of parasite and the weight of the host. When administered via animal feed, it is homogeneously dispersed in the feed, used as a top dressing, or used in the form of pellets. To achieve the normally desired antiparasitic effect, the active compound in the final feed should be between 0.0001 and 0.02
Contains %. Furthermore, a solution dissolved or dispersed in a liquid carrier excipient can be administered parenterally to animals by injection into the forestomach, intramuscularly, intratracheally, or subcutaneously. For parenteral administration, the active compound is preferably mixed with a suitable vegetable oil, such as peanut oil, cottonseed oil. Such formulations generally contain 0.05 of the active compound.
Contains ~50% by weight. They may also be administered topically by mixing with a suitable carrier such as dimethyl sulfoxide or a hydrocarbon solvent. The formulation is applied directly to the external surface of the animal by spray or direct injection. The optimum amount of active compound to be used to obtain the best results will depend on the type of animal being treated and the type and severity of the parasitic infection, but will generally be about 0.01 to 100 mg/kg of animal body weight, preferably 0.5 mg/kg of animal body weight. Obtained by oral administration of ~50.0 mg. Such dosages may be given at once or in divided dosages over a relatively short period of time, such as from 1 to 5 days. Furthermore, the compound () of the present invention is useful as an intermediate for compounds having excellent acaricidal activity, anthelmintic activity, etc. Next, the present invention will be specifically explained with reference to Examples and Reference Examples. Example 1 5-oxo derivative of milbemycin D (a) 2.78 g of milbemycin D was dissolved in 50 ml of methylene chloride under ice cooling into a chromic anhydride pyridine complex prepared from 5.0 g of chromic anhydride; 8.0 g of pyridine and 115 ml of methylene chloride. Drop the solution. The mixture was further stirred for 1 hour under ice cooling. Add 700 ml of n-hexane to the reaction solution, filter it through Celite, concentrate the solution,
The residue was subjected to column chromatography using 100 g of silica gel with n-hexane:ethyl acetate (90:10) to obtain 1.5 g of the title compound. Infrared absorption spectrum, ν ^nujol _nax cm ^-1 : 3470, 1735,
1680 Nuclear magnetic resonance spectrum (CDCl ₃ ) δ _ppn : 6.5 (s, 1H,

【formula】), 3.80(s, 1H,

【formula】), 4.71 (m, 2H,

[Formula]) Mass spectrum (m/e): 554 (M ⁺ ) Example 2 5-oxo-14,15-epoxy derivative of milbemycin D (b) 5-oxo derivative of milbemycin D (111 mg)
m-chloroperbenzoic acid (52 mg) was added to a chloroform (2 ml) solution of the mixture, and the mixture was reacted at room temperature overnight. After the reaction is complete, add ether to the reaction mixture,
After washing with water and drying, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing agent: n-hexane to n-hexane/ethyl acetate = 7/3) to obtain 60 mg of the target compound. Infrared absorption spectrum ν ^nujol _nax cm ^-1 : 3470, 1735, 1680 Nuclear magnetic resonance spectrum (CDCl ₃ ) δ _ppn : 1.23 (s, 3H, 14-CH ₃ ), 1.90 (br.s, 3H, 4-CH ₃ ), 3.08 (br, 1H, 25-H), 3.47 (s, 1H, 7-OH), 3.56 (m, 1H, 2-H), 3.85 (s, 1H, 6-H), 4.76 (br , s, 2H, 26-CH ₂ ), 5.2-6.0 (m, 4H), 6.62 (m, 1H, 3-H) Mass spectrum (m/e): 570 (M ⁺ ), 209, 181 Example 3 Milbemycin D 5-oxo-(8,9-14,
15)-Diepoxy derivative (d) 5-oxo derivative of milbemycin D (111 mg)
m-chloroperbenzoic acid (122 mg) was added to a chloroform (5 ml) solution of the mixture, and the mixture was reacted at room temperature for 5 hours. After the reaction is complete, add ether to the reaction mixture,
Wash with saturated aqueous sodium bicarbonate solution and water,
After drying, the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (developing agent:
n-hexane ~ n-hexane/ethyl acetate = 7/
Purification was performed in step 3) to obtain 78 mg of the target compound. Infrared absorption spectrum ν ^nujol _nax cm ^-1 : 3475, 1740, 1680 Nuclear magnetic resonance spectrum (CDCl ₃ ) δ _ppn : 1.27 (s, 3H, 14-CH ₃ ), 1.90 (br.s, 3H, 4-CH ₃ ), 3.08 (m, 1H, 25-H), 3.57 (d, 1H, J=9.0Hz, 9-H), 3.70 (m, 1H, 2-H), 3.89 (s, 1H, 6-H ), 4.07 (d, 1H, J=12Hz,

【formula】), 4.57 (d, 1H, J=12Hz,

[Formula]), 5.16 (dd, 1H, J=9.0, 15Hz, 10-H), 6.00 (dd, 1H, J=10, 15Hz, 11-H), 6.71 (m, 1H, 3-H) Mass Spectrum (m/e): 586 (M ⁺ ), 568, 550, 209

Claims (1)

[Claims] 1 formula (In the formula, -A- and -B- are the same or different and represent a double bond or an epoxy group.) A 5-oxo derivative of milbemycin D.