JPS5933288A - 5-oxo derivative of milbemycin d - Google Patents

Abstract

NEW MATERIAL:A compound of formula I (-A- and -B- are double bond or epoxy group). EXAMPLE:5-Oxo derivative of milbemycin D. USE:An acaricide and anthelmintic agent, having improved acaricidal activity and antiparasitic activity, and effective particularly against nematodes infecting domestic animals, etc. PROCESS:A compound of formula II (milbemycin D) is reacted in the presence of an oxidizing agent, e.g. chromic acid anhydride, an inert solvent, e.g. dichloromethane, at -10-+50 deg.C, preferably 0 deg.C- room temperature, for usually 1- 30hr.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to 5-oxo derivatives of the antibiotic milbemycin D.

Strain B-41-146 belonging to the genus Streptomyces (National Institute of Microbiology, Agency of Industrial Science and Technology, No. 1438)
It has been deposited as No. Milbemycin D (B-41D), which has acaricidal and anthelmintic activity, was obtained from the culture of
has been isolated (Japanese Unexamined Patent Publication No. 56-32481)
.

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.

In formula C, -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.

(I[O) (111)) The first step is the step of producing a compound (■a) in which A- and -B- are double bonds in compound 411, and the 5 of milbemycin D (I) This is achieved by oxidizing the hydroxyl group at the position.

The reaction is carried out by contacting compound (1) with an oxidizing agent in an inert bath. 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, and N such as dimethylformamide and dimethylacetamide. .

Mention may be made of N-dialkyl fatty acid amides, with dichloromethane and dimethylformamide being preferred. Oxidizing agents used in this reaction include chromic anhydride such as chromic anhydride/pyridine (Collins' reagent), pyridinium dichromate, and pyridinium chlorochromate. can do. The time required for the reaction is usually 1 to 30 hours.

The second step is to convert compound (■b) in which -A- is an epoxy group and -B- is a double bond in compound (II) to M
In the manufacturing process, organic peroxide or t! is added to compound (Ila) in an inert solvent. This is accomplished by reacting per-Q&hydrogen. Examples of the organic peroxides used include performic acid, peracetic acid, trifluoroperacetic acid, peroxylic acid,
Metachloroperbenzoic acid or monoperphthalic acid may be used, including 90% hydrogen peroxide or SO thioperoxide, preferably metachloroperbenzoic acid. In addition, when the amount of organic peroxide or hydrogen peroxide is 1 to 1.5 times I, the compound (Ilb) is selectively obtained, and when it is 2 to 3 times 1 it, a further oxidized compound is obtained. [(nd): -A- and - in compound beating
A compound in which each B- is an epoxy group] is selectively used.

I can stay. The reaction temperature is -20 DEG to 50 DEG C., preferably under water cooling, and the reaction time is usually 1 to 20 hours.

The third step is to produce a compound (■) in which -A- is a double bond and -B- is an epoxy group. This is achieved by reacting the compound (■a) with an alkyl hydroperoxide in the presence of a metal complex of group vB or group V. Examples of the alkyl hydroperoxides used include methyl-, ethyl-1n-propyl-1n
-butyl- or t-butyl-hydroperoxide, preferably t-butyl hydroperoxide. Examples of the catalyst include vanadium acetylacetonate, molybdenum dioxide acetylacetonate, and molybdenum hexacarbonyl, with vanadium acetylacetonate being preferred.

It is carried out in ethers such as oxane, but preferably benzene is used. The reaction temperature is 0°C to 100°C,
The reaction is preferably carried out at room temperature, and the reaction time is from 1 to 5 hours.

The 4th a step and the 4th b step are performed using a compound (in ID, -
Compounds in which A- and -B- are epoxy groups (II(1)
This is the process of manufacturing.

In Step 4a, the compound (
This is achieved by processing Ill)).

Step 4b is achieved by treating compound (10) under the same reaction conditions as in step 2 (using 1 to 1.5 equivalents of oxidizing agent).

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,
Thoroughly wash the insoluble matter with a water-immiscible organic solvent to remove the insoluble matter.
After separation, water is added to the reaction mixture and extracted with a water-immiscible organic solvent. 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.

Compound (II) of the present invention is a compound of the two-spotted spider mite (Tetranychuθ) that parasitizes fruit trees, vegetables, and flower petals, adults and eggs of apple spider mite, citrus spider mite (Panonychus), rust mite, etc., Ixodidae (xodidaa) that parasitizes animals, Dermanys
side) and Arcoptidae (5arcoptidae)
It has excellent acaricidal activity against θ), etc.

Saranihijihax' (0estrus), Kinbae (
Lu-cilia), cow fly (Hypoderma
), Gautrophilus, etc., and ectoparasites of animals and birds such as chisels and lice; sanitary pests such as cockroaches and houseplants; other agricultural and horticultural pests such as aphids and lepidopteran larvae. It is also active against root-knot nematodes (Mθloidogyne) in the soil.
, Phil g17 phuθ), etc.

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, poultry and pets such as pigs, sheep, goats, cows, horses, dogs, cats and chickens.

Genus Haemonchus.

Trichostrongylus sp.
lus).

Ostθrtagia.

Genus Nematodirus.

Cooperia genus (○oopθria).

Genus Ascaris.

Bunostomum genus.

Oesophagostomum (Oesophagostomum)
um).

Ohabertia j Trichuris spp.

Genus Strongylus.

Trichonema genus.

Genus Dictyocaulus.

Genus Cabillaria (Oapillaria).

Genus Heterakis.

Genus Toxocara.

Genus Ascaridia.

Genus Oxyuris.

Genus Ankylostoma.

Genus Lancinaria (Uncinaria).

Toxacaris and Parasaaris.

Certain species of the genera Nematodeilus, Cooperia, and Esophagostomum attack the intestinal tract, while those of the genera Monchus and Ostiltagia inhabit the stomach, and parasites of the Dictyokaurus species are found in the lungs. However, it also shows activity against these.

Parasites of the Filariaceae and Setariidae families are also found in, and active in, other tissues and organs of the body, such as the heart and blood vessels, subcutaneous tissue, and lymphatic tissue.

It is also useful against parasites that infect humans; the most common parasites of the human gastrointestinal tract are Ankylost-7,
@ (Ancylostoma).

Necator K) A (Necator).

Ascaris genus.

Strongyloides
.

Genus Trichinella.

Capillaria PA (Oapillaria).

'Triahuria' $% Yo0
: Enterobius genus.

Other medically important diatoms found in the blood or other tissues and organs outside the gastrointestinal tract include the genus Wuchereria of the family Filariaceae, the genus Brucia (B
rugia), Oncho/L/ka f74 (Oncho
ce -rea) and parasites of the genus Loa and the genus Dra -cunculus of the family Draounaulidae, the genus Strongyloides and in a special extraintestinal parasitic state of intrabiliary parasites. It also shows activity against the genus Trivinella.

When the compound (ID) is used as an anthelmintic in animals and humans, it can be administered orally as a liquid beverage. The beverage is usually prepared with a suspending agent such as bentonite and a wetting agent or other excipient. as a solution, suspension or dispersion in a non-toxic solvent or water. Beverages generally also contain an antifoaming agent. Beverage formulations generally contain the active compound in an amount of about 0.01 to 0.05 g, preferably 0.05 g. Contains 01-01 wound 1.

When oral administration in a dry, solid dosage form is desired, capsules, pills, or tablets containing the desired amount of active compound are usually employed. These forms of use are
Diluent, filler, etc. made by finely pulverizing the active ingredients.
disintegrants and/or binders, such as starch, lactose,
It is produced by homogeneously mixing it with Merck, stearinated magnesium A, vegetable rubber, etc.

Such 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 desired anti-parasitic effect, the final feed usually contains between 0,000 and 002 hours of active compound.

Also, those dissolved or dispersed in a liquid carrier excipient,
It can be administered to animals parenterally by injection into the proventriculus, intramuscularly, intratracheally or subcutaneously. For parenteral administration, the active compound is preferably mixed with a suitable +IR oil such as peanut oil, cottonseed oil. Such formulations generally contain from 0.05 to 50.7 i% of active compound.

They may also be administered topically by mixing with a suitable carrier such as dimetersulfoquine or a hydrocarbon solvent. This formulation is applied directly to the external surfaces of the animal by spray or direct application.

The optimum use of the active compound for best results will depend on the species of animal being treated and the type and extent of the parasitic infection, but will generally be about 0.001 to 1001 nq/kg of animal, preferably 0.5 ~50.0In
9 by oral administration.

Such use/destruction may occur at one time or in divided use cases.
It is given over a relatively short period of time, such as 5 days.

Furthermore, the compound (n) of the present invention has excellent acaricidal activity,
It is also useful as an intermediate for compounds having anthelmintic activity.

Next, the present invention will be specifically explained with reference to Examples and Reference Examples.

Example 1 A solution dissolved in methylene silicate is added dropwise. The mixture was further stirred for 1 hour while cooling with water. 700m/n-hexane to the reaction solution
was added, filtered using Celite, and concentrated, and the residue was subjected to Kanom chromatography using 100 r silica gel with n-hexane:ethyl acetate (90:10) to obtain the title compound 1.5y. .

Infrared absorption scale) A/, I/””” ”max
: Zuno 7z 2 3470.

1735.1680 Nuclear magnetic resonance spectrum (ODO4) δ:3
ppm Mass spectrum (1), 554 (M+)θ Example 2 5-oxo derivative of milbemycin D (1111n9)
m-chloroperbenzoic acid (52 mg) was added to a 2 ml solution of chloroform and reacted at room temperature overnight.

After the reaction was completed, ether was added to the reaction mixture, washed with water, dried, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (developing agent: n-hexane to
Purification with n-hexane/ethyl acetate-T/3) yielded 60η of the target compound.

nujO4-1 Infrared absorption spectrum ν cln :34701aX 1735.1680 Nuclear magnetic resonance spectrum (o:oaz3) δppm '1
, 23 (θ, 3H, l4-CH,)+j, 90 (b
r, s, 3H, 4-0H3).

3.08 (br, iH, 25-H).

3.47CB, IH, 1-OH).

3.56 (m, IH, 2-H).

3.85 (B, IH, 6-H).

4.7 s (br, s, 2H, 26-0H2)
.

5.2-6.0 (m, 4H).

6.62 (m, IH, 3'-H) Mass spectrum (m//): 570 (M+).

θ 209.181 Example 3 5-oxo visitant of milbemycin D (111my)
m-chloroperbenzoin (MC1nmy) was added to a solution of 6y in chloroform (5ml), and the mixture was reacted at room temperature for 5 hours.

After the reaction was completed, ether was added to the reaction mixture, and the mixture was washed with a saturated sodium bicarbonate aqueous bath solution and water. After drying, the bath agent was distilled off under pressure.

The resulting residual bath was subjected to silica gel column chromatography (
Developer: n-hexane-n-hexane/ethyl acetate-T
/3) to obtain 78 m9 of the target compound.

nujol -1 Infrared absorption spectrum νmaxcnl ;34T5゜1
740. 1680 Nuclear magnetic resonance spectrum (CDCl2) δppm '1
．． 27 (8, 3H, 14-0H5).

1.90 (br, s, 3H, 4-0H3).

3.08 (m, IH, 25-H).

3.5y(a, 1a, J, s, oHz, s-H)j3,
To(m, tH+2-H)s -1 457(d, I H, J-12H+z, 2 B
'H) e5.16(dd, 117.J-9,0,
15Hz, 1O-H).

6, gg (aa, IH, J-10, 15) 1z, 11-
H) j6, yt (m, l, 3-H) Mass spectrum (m/'): 58B (M-t).

568.550.20i9 Patent α (Hachi Sankyo Co., Ltd.) Agent: Patent attorney Shoji Kashi 1-2-58 Hiromachi, Tokyo Parts Ward Gosankyo Co., Ltd. Biological Research Institute

Claims (1)

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