JPH0250913B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to 5-lower alkylcarbamoyloxy and 5-lower alkylsulfonyloxy derivatives of antibiotic B-41. B-41 group antibiotics are derived from a culture of B-41-146 strain belonging to the genus Streptomyces (deposited with the Hui Institute of Biotechnology, Agency of Industrial Science and Technology as Microtechnology Research Institute Bacteria No. 1438). A compound having the structural formula () was isolated.

[Table] Among the B-41 group antibiotics mentioned above, A ₃ , A ₄ , C ₁ and C ₂ are described in JP-A-50-29742. In addition, B-41D is described in Japanese Patent Application No. 107550-1982, and B-41F is described in Japanese Patent Application No. 153141-1983, together with their respective physical properties. The B-41 group antibiotics mentioned above are the B-41-146 strain (the mycological properties are described in JP-A No. 50-29742), which have been used to culture Streptomyces bacteria. under aerobic conditions in a medium containing
After culturing at about 28°C for 5 to 15 days, the resulting culture was separated with a supernatant such as diatomaceous earth, and the resulting cake was extracted with methanol and then n-hexane to obtain an oily substance. It is obtained by fractionation using silica gel column chromatography. The present invention provides a novel B having the following structural formula () obtained by chemical means from the compound of the above formula ().
-41 5-lower alkylcarbamoyloxy and 5-lower alkanesulfonyloxy derivatives. (In the formula, R ₁ represents an isopropyl group. _{R 2} represents a methyl group. _{R 3} represents a lower alkylcarbamoyl group or a lower alkanesulfonyl group.) As the lower alkylcarbamoyl group for R ₃ ,
Examples include methylcarbamoyl, ethylcarbamoyl and isopropylcarbamoyl, and examples of lower alkanesulfonyl groups include methanesulfonyl and ethanesulfonyl. -OR ₃ at the 5th position in the formula and is α, β
Two stereoisomers of coordination exist and the present invention encompasses those stereoisomers. The compounds of formula () have acaricidal and anthelmintic activity. Further, a compound in which R ₃ is methylcarbamoyl or methanesulfonyl is preferable, and a compound in which the substituent -OR ₃ at the 5th position is β-coordinated is preferable. To produce the 5-lower alkylcarbamoyloxy derivative of B-41, the compound of formula () is reacted with a lower alkyl isocyanate. The reaction can be carried out in the presence or absence of a solvent,
As a solvent, solvents without active hydrogen, such as aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as methylene chloride and chloroform; ethers such as ether, tetrahydrofuran, and dioxane; DMSO,
Polar solvents such as dimethylformamide are used, and aromatic hydrocarbons are particularly preferred. This reaction is also possible in the absence of a base, but
The reaction proceeds more smoothly in the presence of a base. Examples of the base used include tertiary organic amines,
Triethylamine is preferred, and the amount added is generally 1/10 to 1/5 of the isocyanate.
It is. The reaction proceeds at a temperature of 0 to 100°C, preferably room temperature to 80°C, and the reaction time depends on the reaction temperature, but is usually 1 to 24 hours. Further, in order to produce the 5-lower alkanesulfonyloxy derivative of B-41, the compound of formula () is reacted with lower alkanesulfonyl chloride.
The reaction can be carried out in the presence or absence of a solvent, and as the solvent, for example, the solvents shown in the above-mentioned production of the 5-lower alkylcarbamoyloxy derivative are used, and aromatic hydrocarbons or tetrahydrofuran are particularly preferred. However, it is preferable to carry out the reaction under anhydrous conditions. This reaction is carried out in the presence of a base, and the bases used include, for example, pyridine, triethylamine, DBU,
Mention may be made of tertiary organic amines such as DBN, preferably triethylamine. Reaction temperature is -30~50
It can be carried out at 0°C, but preferably from 0°C to
It is at room temperature. Reaction time is about 20 minutes to 2 hours. Note that the starting compound of formula () may or may not be isolated, and other fractions of B-41, such as B-41 in which R ₃ is a methyl group, as disclosed in JP-A No. 50-29742, -41 B ₂ , B ₃ , A ₁ and A ₅ etc. may be included. In addition, in the method of the present invention, only the hydroxy group at the 5-position is reacted,
Substituents at other positions remain unchanged. In addition, the hydroxyl group at the 5th position of the B-41 group antibiotic obtained by culture is β-coordinated, but the raw material compound (), which is α-coordinated, is produced as shown in the following reaction formula. Ru. 5β-Hydroxy compound of formula () Alkanesulfonyl chloride 5β ――――――――――――――――――→ ―Alkanesulfonyloxy derivative Organic acid tetraalkylammonium salt ―――――――――― ――――――――――――――→ 5α-acyloxy derivative Hydrolysis――――――→ 5α-hydroxy derivative of formula () In the above reaction, as the organic acid tetraalkylammonium salt, for example, Tetraethylammonium formate or -acetate, tetrabutylammonium formate or -acetate are used, preferably tetraethyl (or butyl) ammonium formate. The reaction is carried out in an inert solvent or a polar solvent, and the reaction temperature is between room temperature and the reflux temperature of the solvent, preferably room temperature. The hydrolysis reaction from 5α-acyloxy derivatives to 5α-hydroxy compounds is carried out using methyl alcohol,
The process is carried out in a water-containing solvent consisting of alcohols such as ethyl alcohol, propyl alcohol, and butyl alcohol, water-soluble ethers such as tetrahydrofuran and dioxane, and water, and the base used is an alkali metal hydroxide, carbonate or Bicarbonates, especially bicarbonates, are preferably used. Examples of manufacturing the compound of formula () of the present invention are shown below. Example 1 5β-Methylcarbamoyloxy derivative of B-41D To a solution of 278 mg of B-41D in 3 ml of benzene, 57 mg of methyl isocyanate and 1 drop of triethylamine were added, and after standing overnight at room temperature, 1 ml of dimethylformamide, 57 mg of methyl isocyanate, and 1 drop of triethylamine were added. was added and left overnight at room temperature.
The reaction solution was further heated at 80°C for 7 hours, then cooled, ether was added, washed with water, dried over anhydrous sodium sulfate, the solvent was distilled off, and silica gel column chromatography (developing agent, n-hexane→n ―
Purification was performed using hexane:ethyl acetate=85:15) to obtain 139 mg of the desired product. Molecular weight: 613 IR (Nujol mull): 3350, 1730, 1710, 1540 cm ^-1 NMR (CDCl ₃ , δppm, 100MHz): 2.79 (-NH-CH ₃ , d, J = 5.0Hz), 3.95 (7-
OH, s), 4.59 (26-CH ₂ , br.s), 4.01 (6-
CH, d, J=6.0Hz), 4.80(-NH-, br.d,
Example 2 5β-methanesulfonyloxy derivative of B-41D 556 mg of B-41D and 300 mg of triethylamine were dissolved in 10 ml of anhydrous tetrahydrofuran, and a solution of 286 mg of methanesulfonyl chloride dissolved in 2 ml of anhydrous tetrahydrofuran was stirred under ice cooling. Made and dripped. After the dropwise addition was completed, the mixture was stirred for 30 minutes under ice cooling, and further stirred for 20 minutes at room temperature. Add 100ml of benzene to the reaction solution.
After washing twice with water and drying with anhydrous sodium sulfate, the solvent was distilled off to obtain the desired product as an amorphous powder.
Obtained 755 mg. Molecular weight: 634.8 IR (Nujol mull): 3500, 1745, 1725, 1180 cm ^-1 NMR (CDCl ₃ , 100MHz, δppm): 1.51 (14-CH ₃ , s), 1.85 (4-CH ₃ , br.s),
3.10 (-SO ₂ CH ₃ , s), 4.07 (6-H, d, J=
6.0Hz), 4.65 (26-CH ₂ ,s) Example 3 5α-methanesulfonyloxy derivative of B-41D 1.906 g of 5α-hydroxy derivative of B-41D and 0.97 g of triethylamine were added to anhydrous tetrahydrofuran.
A solution of 0.926 g of methanesulfonyl chloride dissolved in 5 ml of anhydrous tetrahydrofuran was slowly added dropwise to the solution under ice-cooling and stirring. Example 2 below
The mixture was treated in the same manner as above to obtain 2.3 g of the desired product as an amorphous powder. Molecular weight: 634.8 IR (Nujol mull): 3500, 1730, 1720, 1180 cm ^-1 NMR (CDCl ₃ , 100MHz, δppm): 1.51 (14-CH ₃ , s), 1.91 (4-CH ₃ , br.s),
3.10 (-SO ₂ CH ₃ , s), 3.94 (6-H, d, J=
1Hz), 4.60 (26-CH ₂ , s) Reference example 25α-hydroxy derivative of B-41D 5β-methanesulfonyloxy derivative of B-41D
4.5g and 2.4g of tetramethylammonium formate
g The mixture was stirred in 130 ml of anhydrous methylene chloride at room temperature for 35 hours. 300 ml of benzene was added to the reaction solution, washed twice with water, dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain 3.8 5α-formyloxy derivative of crude B-41D.
I got g. This was dissolved in 110 ml of methanol, 1.2 g of sodium bicarbonate and 4 ml of water were added, and the mixture was stirred in a 45°C water bath for 6 hours. After cooling, insoluble matter was filtered out, the solvent was distilled off, and the residue was purified by silica gel column chromatography (developing solvent, n-hexane: ethyl acetate = 100:50) to obtain 2.09 g of the target product. . Molecular weight: 556 IR (Nujol mull): 3550, 3380, 1720 cm ^-1 NMR (CDCl ₃ , 100MHz, δppm): 1.50 (14-CH ₃ , s), 1.88 (4-CH ₃ , br.s),
3.78 (6-H, d, J = 1Hz), 4.10 (7-OH,
s), 4.56 (26-CH ₂ -, s) The derivative of formula () of the present invention is a two-spotted spider mite (Tetranychus) that parasitizes fruit trees, vegetables and flowers;
It has excellent acaricidal activity against adults and eggs of apple spider mites, orange spider mites (Panonychus), and rust mites, as well as against animals such as Ixodidac, Darmanysside, and Sarcoptidae. Furthermore, ectoparasites of animals and birds such as sheep flies (Oestrus), golden flies (Lucilia), cow flies (Hypoderma), and horse flies (Gautrophilus), as well as chisels and lice; hygiene pests such as cockroaches and house flies; other aphids, and lepidoptera. It is active against various agricultural and horticultural pests such as larvae. Furthermore, it is also active against root-knot nematodes (Meloidogyne), mites (Phizoglyphus), etc. in the soil. Furthermore, the derivatives of formula () according to the 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, Cooperia, Ascaris, Bunostomum, Esophagostomum 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 tissue. It is also useful against parasites that infect humans, and the most common parasites of the human gastrointestinal tract are Ancylostoma, Necator, Ascaris, and Strongyloides. The genera Strongyloides, Trichinella, Capillaria, Trichuris and Enterobius. Other medically important parasites found in the blood or other tissues and organs outside the gastrointestinal tract; members of the family Filariaceae such as Wuchereria, Brugia, Onchocerca;
and parasites of the genus Loa and the genus Dracunculus of the family Dracunculidae, as well as the spp. Strongyloides and Trichinella in the special extraintestinal parasitic state of intestinal parasites. show. When the derivatives of formula () are used as anthelmintics in animals and humans, they 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 about 0.01-0.5%, preferably 0.01-0.1% by weight of active compound. 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.

[Brief explanation of the drawing]

Figure 1 shows the infrared absorption spectrum of the 5β-methylcarbamoyloxy derivative of B-41D, Figure 2 shows the nuclear magnetic resonance spectrum of the same substance, and Figure 3 shows the 5β-methylcarbamoyloxy derivative of B-41D.
The infrared absorption spectrum of the 5α-methanesulfonyloxy derivative of 41D, Figure 4 shows the nuclear magnetic resonance spectrum of the same substance, Figure 5 shows the infrared absorption spectrum of the 5β-methanesulfonyloxy derivative of B-41D, and Figure 6 shows the infrared absorption spectrum of the 5β-methanesulfonyloxy derivative of B-41D. This shows the nuclear magnetic resonance spectrum of the same substance.

Claims (1)

[Scope of Claims] 1. A 5-lower alkylcarbamoyloxy or 5-lower alkanesulfonyloxy derivative of B-41 having the following structural formula. (In the formula, R ₁ represents an isopropyl group. _{R 2} represents a methyl group. _{R 3} represents a lower alkylcarbamoyl group or a lower alkanesulfonyl group.)