JPS5936682A - Hydroxy derivative of milbemycin d - Google Patents

Abstract

NEW MATERIAL:A compound shown by the formula I (R1 and R2 are hydroxy, or R1 and R2 are linked to form double bond; R3 is H, or lower alkyl). EXAMPLE:A 14,15-dihydroxy derivative of milbemycin D. USE:An acaricide. An insecticide. Showing improved activity against acarids living in fruits, vegetables, etc., outer parasites such as flies, fleas, lice, etc. sanitary noxious insects such as cockroaches, etc. Having improved vermicidal activity as a vermicide for domestic animals and men. PROCESS:A compound shown by the formula II is reacted with an alcohol shown by the formula R3OH in the presence of an acid catalyst (e.g., mineral acid, boron trifluride-ether complex, etc.) in an inert solvent at room temperature for 10hr-15days to give a compound shown by the formula I (in case that R1 and R2 are linked to show double bond). The compound shown by the formula IIis obtained by treating milbemycin D with m-chloroperbenzoic acid.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to hydroxy derivatives of milbemycin D.

Strain B-41-146 belonging to the genus Streptomyces (received at the Institute of Microbiology, Agency of Industrial Science and Technology [1438
It is said to be in season. ), Milbema 1cin D (B-41
D) has been isolated (Japanese Unexamined Patent Application Publication No. 1983-32481).

H. Milbemycin 1) (1) As a result of intensive investigation into the synthesis of derivatives of Milbemycin D by chemical means, the authors discovered a compound with excellent acaricidal and anthelmintic activity, and completed the invention. did.

QM (wherein R4 and R2 represent a hydroxy group, or R1 and R2 together represent a double bond; R3 represents a hydrogen atom or a lower alkyl group).

In the above formula, the lower alkyl group can be a methyl, ethyl, n-propyl, n-butyl or isobutyl group, preferably a methyl or ethyl group.

In compound (n), a preferred compound is a compound in which R1 and R2 together represent a double bond, and R3 represents a hydrogen atom or a methyl group.

Furthermore, in Milbemycin D (I) and Compound (II), the hydroxy group at the 5-position has two stereoisomers, α and β, and the present invention includes these stereoisomers, but preferably is a β-coordinated compound.

The compound having general formula (II) according to the present invention is produced according to the method shown below.

, 0H (Ill) 0)! (1111,) (Tlb’) In the above formula, R3 has the same meaning as defined above.

The raw material compound (IIT) for this method is Milbemycin D (I
) with m-chloroperbenzoic acid.

The first step is to produce a compound (ffa) in which R1 and R2 together represent a double bond in the compound (H), in which compound (m) is mixed in an inert solvent in the presence of an acid catalyst, This is achieved by reacting with water or an alcohol having the formula %( ), where R3 has the same meaning as defined above.

The acid catalyst used in this step includes, for example, mineral acids such as hydrochloric acid, nitric acid, and sulfuric acid, organic acids such as trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, P-)luenesulfonic acid, or boron trifluoride. , boron trifluoride-ether complexes, aluminum chloride, innistinous chloride, but preferably mineral acids in reaction with water and boron trifluoride-ether complexes in reaction with compound (rV). Examples include trifluoride-ether complexes.

The inert solvent is not particularly limited as long as it does not participate in the reaction, but water, aqueous acetone, aqueous tetrahydrofura Z1, aqueous dioxane, or a compound (rv
> is preferably used. The reaction temperature is usually around room temperature, and the 16 hours required for the reaction is 10 hours to 15 days.

The second step is a step of producing a compound (nb) in which R1 and 0''R2 are hydroxy groups in compound (11),
It is rapidly produced by reacting compound (Ua) with osminium tetroxide in an inert solvent followed by treatment with a reducing agent.

The inert solvent used in this step is not particularly limited as long as it does not participate in the reaction, but examples include ether, tetrahydrofuran, nityl compounds such as dioxane, dichloromethane, chlorophore, 1. Examples include halogenated hydrocarbons such as carbon tetrachloride, organic amines such as pyridine and triethylamine, and pyridine is preferred. Furthermore, hydrous pyridine is also suitable for treatment with a reducing agent.

Examples of reducing agents used include sodium sulfite,
Sulfites such as potassium sulfite, hydrogen sulfite) I
Hydrogen, bisulfite such as potassium hydrogen, dimethyl sulfide, dialkyl sulfide such as diethyl sulfide, but preferably sulfur! Salt.

The reaction temperature is usually 0°C to room temperature, and the time required for the reaction is 10 minutes to 2 hours.

Furthermore, in the compound (I), a compound in which R1 and R2 are hydroxy groups and R3 is a hydrogen atom can be used in the second step using the compound (D and 2- to 3#1t osminium tetraoxide). It is also possible to carry out the reaction in the same manner and to conduct the reaction separately.

In addition, the hydroxy group at the 5-position of the compound (r) obtained by culturing has a 6I coordination, but the starting compound (r) has an α-coordination.
) l'j is produced as shown in the following reaction formula.

Alkane of formula (D)
Derivative of 3rd root Derivative at 1 Step ii; 6β-alkanesulfonyloxy derivative jL! Steps up to 1 are achieved by reacting compound (I) with an alkanesulfonyl halide in an inert solvent in the presence of a base according to a conventional method.

The second step is a step for producing a 5α-acyloxy derivative, which is achieved by reacting a 5β-antanesulfonyloxy derivative and an organic tetraalkylammonium salt in an inert solvent.

The organic acid tetraalkylammonium salt used is, for example, tetraethylammonium formate or monoacetate or tetrabutylammonium formate or -acetate, 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 third step is a step of producing a 5α-hydroxy derivative,
The 5α-acyloxy derivative is mixed with an alkali metal hydroxide, carbonate, or heavy alkali metal hydroxide in a water-containing solvent of water and a water-soluble ether such as methyl alcohol, ethyl alcohol, propyl alcohol, phthyl alcohol, tetrahydrofuran, or dioxane. This is achieved by reaction with a base such as a carbonate, preferably a bicarbonate.

The target compound of the above-mentioned reaction completion extraction reaction is collected from the reaction mixture according to a conventional method. For example, it can be obtained by pouring the reaction mixture into ice water, appropriately neutralizing the aqueous solution if it is acidic or basic, extracting with a water-immiscible organic solvent, drying, and then distilling off the solvent from the extract. . Further, if necessary, it can be purified by conventional methods such as recrystallization and column chromatography.

The compound (n) of the present invention can be used for the adults and eggs of two-spotted spider mites (Tetranychuθ) that parasitize fruit trees, vegetables and flower petals, apple spider mites, citrus spider mites (Panonychua), rust mites, etc.
saide ) and Arcoptidae (8 arcopti
It has excellent acaricidal activity against bacteria such as daθ).

In addition, Oestrua x (Oestrua), Kimba z (Lu
-cilia), Hypoderma x
, Gautrophilua, ectoparasites of animals and birds such as flies and lice: cockroaches,
It is active against sanitary pests such as house flies and other garden pests such as aphids and lepidopteran larvae. Furthermore, root-knot nematodes (Meloidogynθ) and mites (Meloidogynθ) in the soil
It is also active against Phizoglyphθ) and the like.

Furthermore, the compounds (TI) of the present invention have excellent parasiticidal activity as anthelmintics for animals and humans. Especially pigs,
Effective against the following nematodes that infect livestock such as sheep, goats, cows, horses, dogs, cats and chickens, poultry and bedding.

Genus Haemonchus.

Trichostrongylus sp.
lus).

Genus Ostertagia.

Genus Nematodirus.

Cooperia genus (Oooperla).

Genus Ascaris (A8 (!ariB).

Bunostomum genus.

Genus Oesophagostmu
m).

Genus Chabertia.

Genus Triohuris.

(11) Eltrongylus.

Triohonema genus.

Dictyocaulus Jf & (Diotyocaulus
).

Genus Cabillaria (Oapillarim).

Genus Heterakis (Hoterakig).

Toxoara 744 (Toxoara).

7th power Lydia g (Aaaaridia).

Genus Oxyuris (oxyuriθ).

Genus Ankyloatoma.

Lancinaria JQ (Unoinaria).

Toxaaris (To, xasaaris) and Parascaria.

Parasites of the genera Nematodeilus, Cooperia, and Esophacostomum attack the intestinal tract; those of the genera Haemonchus and Ostiltargia infest pottery, and parasites of the genus Teutiocaurus are found in the lungs. but,
It also shows activity in these.

Parasites of the family Filariiclae and Setarildae are also found in, and active in, other tissues and organs in the body, such as the heart and blood vessels, (12) subcutaneous and lymphatic tissues. show.

It is also useful against parasites that infect humans,
The most common parasite of the human gastrointestinal tract is Ankylostoma.

Genus Necator.

Genus Ascaris.

Strongyloides
.

Genus Trichinella.

Capillary genus (Oapil'1aria).

These are the genus Triahuris and the genus Knterobius.

Other medically important parasites found in the blood or other tissues and organs outside the gastrointestinal tract include members of the family Filariaceae, Wuθhθrθria, Bru
gia), Onchoerca and Loa and Dra
Dracunculus (Dra- cunoulinae)
It is also active against the genus Strongyloides and Trivinella in the special extraintestinal parasitic state of intestinal parasites.

When the compound (IT) is used as an anthelmintic in animals and humans, it can be administered orally as a liquid beverage. Beverages are commonly 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 to 0.5% active compound, preferably 0.05% by weight.
Contains 1 to 0.1 weight and 1 inch.

When oral administration in a dry, solid unit dosage form is desired, capsules, pills, or tablets containing the desired amount of active compound are usually employed. These usage forms consist of the active ingredient in a suitable finely divided diluent, filler,
Disintegrants and/or binders, such as starch, lactose,
Manufactured by homogeneously mixing with Merck, magnesium stearate, vegetable gum, etc.

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 desired anti-parasitic effect, the final feed usually contains 0.0001-0.02% of active compound.

Also, those dissolved or dispersed in a liquid carrier excipient,
It can be administered parenterally to animals by injection into the proventriculus, intramuscularly, intracranially, or subcutaneously. For parenteral administration, the active compound is preferably mixed with a suitable vegetable oil, such as peanut oil or cotton oil. Such formulations generally contain from 0.05 to 50 parts by weight of active compound.

They may also be administered topically by mixing with a suitable carrier such as dimethyl sulfoxide or a hydrocarbon solvent. This formulation is applied directly (15) to the external surface of the animal by spray or direct application.

The optimal fecal dose of active compound for best results depends on the type of animal being treated and the type and extent of parasitic infection, but is generally about 0.01 per animal body weight IKF.
~100m9, preferably 0.5-500m9, can be obtained by oral administration.

Such usage is 1. at one time or in divided usage.
given over a relatively short period of time, such as ~5 days.

Next, the present invention will be explained in more detail with reference to Examples and Reference Examples.

Example 1 14.15-dihydroxy derivative of milbemycin D 14.15-epoxy derivative of milbemycin D (20
0IR9), acetone (4 ml), water (2 mA), and concentrated sulfuric acid (38 da) were reacted for 12 days at room temperature. After distilling off the solvent from the reaction mixture under reduced pressure, ether was added and saturated carbonic acid was added. It was washed sequentially with an aqueous sodium hydrogen solution, water, and saturated brine, and dried over anhydrous magnesium sulfate (16).The solvent was distilled off under reduced pressure, and the resulting device was subjected to silica gel column chromatography (developing agent: n-hexane/ethyl acetate). = 100/100) to obtain 44 parts of the target compound.

nujol-1 infrared absorption spectrum, ν+nax Cm: 334
10゜1730.1700,1190; Nuclear magnetic resonance spectrum (ODOls) δ: 1-10 (sa 3
H, 14-0HS) +2.2-2.6 (m, 2
H, 14-0HI 5-OH)'-rxx vector (
m/e): 590 (M+), 572 (M-H2O).

5154 (M-21120), 462. 209 Example 2 14-methoxy-15-hydroxy derivative of milbemycin D 14.15-epoxy derivative of milbemycin D (ts
om9), boron trifluoride-ether complex (30''P) and methanol (2 mA) were reacted at a solution temperature for 24 hours. The reaction mixture was poured into a water-cooled aqueous sodium bicarbonate solution and extracted with ether. After washing with water and an aqueous sodium bicarbonate solution, it was dried over anhydrous magnesium sulfate.The solvent was distilled off under reduced pressure and the apparatus was subjected to silica gel column chromatography (developing agent: n-
Purification was carried out using hexane/ethyl acetate (70/130) to obtain 75 μl of the desired compound.

nujol-1 infrared absorption spectrum, ν cm: 348 (Is
ax 1710.1180 Nuclear magnetic resonance spectrum (aDe/3) δ: 1.02('
1B"+ 14-"'3)+313(θ+3H21
5-O0H3) Mass hect” (I mouth/”): 604 (M+), 47
6゜09 Example 3 3.4.14 of Milbema "Sin D. Pyridine (5 mA) of Is-tetrahydroxy derivative Milbemycin D (220+Q)
Sodium sulfite (1, Of), pyridine (1
A mixture of 0 ml) and water (liml) was added dropwise, and the mixture was reacted at room temperature for 10 minutes. After the reaction was completed, the reaction mixture was poured into water-cooled dilute hydrochloric acid and extracted with ether.

The extract was washed successively with water, saturated aqueous sodium bicarbonate solution, water, and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by silica gel column chromatography (developing agent: benzene/ethyl acetate = 20/200) to obtain 81 days of the target compound.

n1jo 1 -1° Infrared absorption spectrum, νmax (Bm, 346
0.

1700, 11115 Nuclear magnetic resonance spectrum (DOO7,) δ: 1.10 (B
, 3H, 114-0h5) 1.40 (El, 3H#
4-0H3) Mass spectrum (m/8): 624 (M+), 606 (
M-H2O) s 5”8 (M-2H20L 2011
Reference example 1 14.15-epoxy derivative of milbemycin D Methylene chloride (ssom9) of milbemycin D (ssom9)
5vrLl) solution, methylene chloride (5ml) of m-chloroperbenzoic acid (19) (0mt) was added under water cooling.
C was added dropwise, and the mixture was reacted for 40 minutes under water cooling. Furthermore, m-chloroperbenzoic acid (o, 1yr) was added, and the mixture was cooled with water for 30 min.
Stir for 7 minutes. The reaction mixture was cooled with ice, poured into a sodium sulfite water bath, and extracted with ethyl acetate. After drying the extract over anhydrous magnesium sulfate, the solvent was distilled off and the residue was purified by silica gel column chromatography (developing agent: n-hexane/ethyl acetate = 2oo7t50) to obtain 455 da of the desired product.

Infrared absorption spectrum, νnuj01 -t・max
Cm, 348L 1735.1730. 1170 Nuclear magnetic resonance spectrum (ona73) δ: 1.23('
e 3H, 14-0Hs L 1.5y(s, 3H
,4-0Hx)e 3J4(d, 111; J
=(i, 4Hz, 6-H).

4.27(tl, 1.↓1: Jz$, 4HI,
5-H), 4.72 (8゜2H, 28-OH2) Patent applicant: Sankyo Co., Ltd. Representative patent attorney Detection: Osamu Sho (20)

Claims (1)

[Scope of Claims] Milbemycin having the formula (wherein R1 and R2 represent a hydroxy group or R1 and R2 together represent a double bond; R5 represents a hydrogen atom or a lower alkyl group) p
Hydroxy derivatives of.