JPS5936681A - Epoxy derivative of milbemycin d - Google Patents

Abstract

NEW MATERIAL:A compound shown by the formula I (-A- is double bond, or epoxy) shown by the formula I . EXAMPLE:A 8,9-14,15-diepoxy 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 cookroaches, etc. Having improved vermicidal activity as a vermicide for domestic animals and man. PROCESS:A compound shown by the formula II is reacted with an organic peroxide (e.g., metachloroperbenzoic acid, performic acid, etc.) or hydrogen peroxide in a solvent such as chloroform, benzene, etc. at -20-50 deg.C for 1-10hr to give a compound shown by the formula I . The amount of the organic peroxide or hydrogen peroxide is 2.5-3 equivalents when A is double bond, and 5-6 equivalents when A is epoxy. The reaction is carried out optionally in the presence of optical active tartaric acid, to give a corresponding optical active epoxy derivative.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to epoxy 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 (D-41D), which has acaricidal activity and anthelmintic activity, was obtained from the culture of
was isolated and tailed (Japanese Unexamined Patent Publication No. 32481/1993).

n Milbemycin T) (I) As a result of intensive studies on the synthesis of derivatives of Milbemycin D by chemical means, the present inventors discovered and invented a compound that has leopard, insecticidal, anthelmintic, etc. Y
completed.

(In the formula, -A- represents a double bond or an epoxy group.)

The compound (IIJ) according to the present invention is manufactured by reacting the compound (IIJ'a' with an organic peroxide or hydrogen peroxide).

Perbenzoic acid or monoperphthalic acid is used, and 9
0% hydrogen peroxide or 80% alkali hydrogen peroxide is used. Preferred is metachloroperbenzoic acid. or,
It is important to use an appropriate amount of organic peroxide or hydrogen peroxide, and a compound (lla) in which -Am is a double bond
25 to 3 equivalents are used in the production of 1, and 5 to 6 equivalents are preferably used in the production of compounds (Its) in which -A- is an epoxy group.

In addition, depending on the packaging, a corresponding optically active epoxy substance can be obtained by performing the reaction in the presence of optically active tartaric acid.

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, etc.
It is carried out in ethers such as ether, tetrahydrofuran, dioxane, but preferably halogenated hydrocarbons are used. The reaction is preferably carried out at about 120-50'C1 at room temperature, and the reaction time is usually 1 hour to 101 degrees Celsius.

In addition, the 5β-hydroxy form of compound (Ila) can be converted to 5-oxo-8 of milbemycin D, which can be easily converted to 14, by treatment with compound (1) chromic acid-pyridine and then tri-functional metachloroperbenzoic acid. , 9-14,15-diepoxy derivative (1) with a reducing agent.

Furthermore, although the hydroxyl group at the 5-position of compound (1) obtained by culturing is in the β-coordination, the starting compound in which it is in the α-coordination is produced as shown in the following reaction formula.

Alkane of formula (1) 5β-alkane Organic acid tetra-5β-hydroxy sulfosulfosulfonyloxy alkyl ammo 5α-acyl Formula (]
The first step is to produce a 5β-alkanesulfonyloxy derivative, in which the 5β-hydroxy compound of formula (1) and This is achieved by a reaction formula with alkanesulfonyl chloride.

The second step 8 is a step for producing a 5α-acyloxy derivative, which can be accomplished by reacting a 5β-arakanesulfonyloxy derivative with an organic tetraalkylammonium salt in an inert solvent.

Examples of the organic acid tetraalkylammonium salts used include, for example, tetraethelammonium formate or monoacetate or tetrabutylammonium formate or monoacetate, preferably tetraethel (or butyl) ammonium formate. It is. The reaction temperature is room temperature to the reflux temperature of the solvent, preferably Kenne temperature, and the time required for the reaction is 10 to 50 hours.

For the hydrolysis reaction of the 5α-acyloxy visiting conductor to the 5α-hydroxy compound, alcohols such as methyl alcohol, ethyl alcohol, furoyl alcohol, or butyl alcohol, or water-soluble ethers such as tetrahydrofuran or dioxane, and water are used. Examples of the base used include hydroxides, carbonates or bicarbonates of alkali metals such as sodium or potassium, with bicarbonates of alkali metals being particularly preferred.

After the completion of each of the above reactions, the target product of each reaction is recovered from the reaction mixture according to a conventional method. For example, it can be obtained by pouring the reaction mixture into ice water, extracting with a water-immiscible organic solvent, drying, and then distilling off the organic solvent. Purification can also be carried out by recrystallization or column chromatography according to ζ et al.

The compound of the present invention (IIJ is a two-spotted spider mite (Tetranychus) that parasitizes fruit trees, vegetables, and flower petals, adults and eggs of apple spider mites, orange spider mites (Panonychus), and rust mites; Dermanidae (Derman)
yeslde) and Sarcoptidae (Sarcoptidae)
It has excellent acaricidal activity against insects such as 1daθ).

Historically, sheep flies (Ostrus) and silver flies (Lu
−c i ], j IL ), bull fly (FIypod
Orn+a), horse fly (Ga117rophj 1+
+θ), etc., and animals such as chisels, lice, etc.
M fjl (Iy 11.t !IJ; Kokif')
It is active against various sanitary pests such as aphids and lepidopteran larvae.

Furthermore, root-knot nematodes (Mel-oldogyn) in the soil
e), it is also active against bed mites (Phizoglyphtis), etc.

Furthermore, the compounds of the present invention (DJ) have immediate parasitic activity as anthelmintics in animals and humans.

It is especially effective against the following nematodes that infect domestic animals such as pigs, sheep, goats, cows, horses, dogs, cats, and chickens, poultry, and vets.

Haemonchus 1116 (onch++a for lIa, o
).

Trichoserongy
lu, s).

Ostilter gear pg (OsL; areagia)
e Nematodilus (Nema, todirue).

Cooperia genus (0oopθrja).

Genus Ascarie.

Bunstomum).

Genus Oesophagoetom
um).

Chabertia genus.

Genus Trichuris.

Genus Strongylus *Genus Trichonema.

Dictyocaurus (us)
.

Genus Cabillaria (Oapillaria).

Genus Heterakis.

Toxocara - Ascaridia.

Genus Oxyuris * Genus Ancylostoma.

Uncinaria + Toxascaris and Parascaris.

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

Parasites of the Flaridae family (Flaridae, 1 dae) are found in the heart and other tissues and organs in the body, such as blood vessels, subcutaneous and lymphatic tissue, and cause infection in these. also shows activity.

It is also useful against parasites that infect humans; the most common parasite of the human gastrointestinal tract is Ancyloatoma.

Necator Kaede * Ascaris 714 (Ascaris).

strongyloides)
.

;・Genus Triahinella.

Gearpilaria J @ (Oa, pil, 1aria).

Trichuris @ (Trichurl, s) and Enterobius genus (EnterObl, us).

Other medically important parasites found in the blood or other tissues and organs outside the gastrointestinal tract include Wuchereria of the family Filariaceae, genus Brucia (B
rugia), Onchocerca J16 (Onchoce
-rca) parasites of the genus Loa and the genus Dra-cunculus of the family Dracunculidae, the genus Strongyloites in a special extraintestinal parasitic state of intrabiliary parasites It also shows activity against the genus Trivinella.

The compound (IJY) for use as an anthelmintic in animals and humans 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. The non-toxic solvent may be a solution, suspension or dispersion in ice water. Generally the beverage will also contain an antifoaming agent. The beverage formulation will generally contain about 0.01 to 0.5 iiL of active compound, preferably is 0.0
Contains 1 to 01 weights.

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. The usage of these devices is as follows:
The active ingredient is mixed homogeneously with suitable (11) finely divided diluents, fillers, disintegrants and/or binders such as starch, lactose, Merck, magnesium stearate, physical gums, etc. In particular, 1 is manufactured.

Such dosage regimens can be varied widely with respect to the dosage and content of the anthelmintic depending on the type of host animal being treated, the type of infection and the weight of the host.

When administered via animal feed, it is either homogeneously dispersed in the feed or used in the form of pellets in the field feeder as a top dressing. In order to achieve the desired anti-parasitic effect, the final feed contains 0,0001 to 0.02 of the active compound.

In addition, glue dispersed in a liquid phase excipient,
It can be administered to animals parenterally by intravenous, intramuscular, intratracheal or subcutaneous injection. 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 to 50 weight Ji of the active (12) compound.

It 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 spraying 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 extent of the parasitic infection, but will generally be about 0.9 m/9 m of animal body weight.
．． 01-100#9, suitable K11-ff0.5-50.
It can be obtained by orally administering 0~.

Such usage t may range from 1 to 1 at a time or in divided usage amounts.
It is given over a relatively short period of time, such as 5 days.

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

Example 1 8.11-14.15-jepoxy derivative of milbemycin D 5-oxo-8,9-14°15- of milbemycin D
Methanol (2 ml) of jepoxy derivative (132~)
Sodium borohydride (8,59) was added to the solution # and allowed to react at room temperature for 1 hour. After the reaction is complete, add ether to the reaction mixture, then add dilute hydrochloric acid, water, and saturated carbonated water in sequence)
After washing with an aqueous solution of aluminum and water, and drying, the solvent was distilled off under reduced pressure.

Purification was performed by silica gel column chromatography (developing agent: n-hexane/ethyl acetate-3/2 to 2/3), and recrystallization was performed using a mixed solvent of isopropanol/chloroform-3/1 to obtain the target compound Y72- Obtained.

Melting point 233-238℃ Infrared g&yield spectrum, νnuj0''cm':
ax 3470.3400. 1740. 1165 nuclear magnetic resonance spectrum (0DOj, )δ: 1.26(s,
3H, 14-0H5), 1-87 (br, s.

3H,4-OH,), 2.10(ti, IH; J=
9.0H2e-OH), 3.10(s, IH,-O
H), 3.50 ((1゜IH* J"9-5Hz-
9H)-a, 5a(a, IH; J-11Hz, 26
H), 4.47(d-tab, T==11H2,2[
1-H), 4.06 (a, IH; J=5.5H2゜9-H), 5.11 (dd,, IH; J=9
．． 5. 15H2゜1O-H), 5゜3B (m,
I H, 3-'H), s, s 6 (dd.

IH; J=9.0. 15Hz, 11H) Mass spectrum (m/e): saa (M), 209
81 Example 2 Derivative of 3.4-8.9-14.15-triepoxymilbemycin b of Milbemycin D Milbemycin D (
m-chloroperbenzoic acid (244rny) was added to a chloroform (10 mA) solution of 224
After reacting for an hour, m-chloroperbenzoic acid (244
1119) was added and reacted at room temperature for 3 hours. After the reaction was completed, ethyl acetate was added to the reaction mixture, and the mixture was washed with a saturated aqueous solution of hydrogen carbonate and water, dried, and then the solvent was distilled off under reduced pressure. Residue silica gel column chromatography (Developing agent: n-hexane/ethyl acetate-2/1
~3/7] to obtain the target compound 22B m9.

Melting point: 204-210°C nujol -1.

Infrared absorption spectrum, νrnaXcFn.

3m25.　1740. 1170 Nuclear mountain resonance spectrum (ODCl,) δ.

1.26 (s, an, 14 0H5), 1.50
(θ, 3H.

40H3)-2-32(d, IH; J=:10.
5H2, 5-0H), 2.83 (s, IH, 7-0H)
, 3.00 (s.

IH, 2-1 (), 3.43 C days, IH, 3-
H), 3.47(d, IT(;J=11.5Hz,
9-H), 3.85(a, IH;J"11Hz-
26H), s, 5sca, IH;J"13-0Hz,
6 H), 4.14((1(L, IH; J-6,0-
10, [iHz, 5-H), 4.36(d, IH
;, T=11H2,26H), 6.10(dd, I
H; J=9.5.15H2,1O-H), 196(d,
d, s'IH; J-8-5, 15H2-11-H) Mass spectrum (m/e): 604 (M),
209゜ 81 Example 1 Milbemycin D 5-oxo derivative chromium anhydride ms, o9's pyridine 8, Og and chloride (1
5) Add dropwise a solution of Milbemycin 7.789 dissolved in methylene chloride (50ml 1 VC) into the complex under water cooling. Stir for 1 hour under water cooling.Reaction solution + cn-hexane 7.
After adding 0 Orut and filtering through Celite and concentrating the P solution, the residue was subjected to column chromatography using 100 g of silica gel with n-hegisan° acetic acid ff-1' (90:1 G) to obtain the title compound. Obtain 1.5 g.

nujol -1.

Infrared absorption spectrum, νmaXcm.

3470, 1735. 1680 Nuclear magnetic resonance spectrum (CDC15) δppm 'Mass spectrum (m/e): 554 (M) Reference example 2 5-oxo-14,15-epoxy derivative of milbemycin D 5-oxo derivative of milbemycin D (111 (16) m-chlorobenzoin # (521A9) was added to a solution of (2) in chloroform (21nj), and the mixture was allowed to react overnight at room temperature. 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 purified by silica gel column chromatography (developing agent: n-hexane-n-hexane/ethyl acetate-T/3),
The target compound was obtained.

nLljol　-1゜ Infrared absorption spectrum, νInaXcrn.

3470, 173! l, 1680 nuclear magnetic resonance spectrum (0DO45)δ; 1.23(s, 3H,1
4-0HIs), 1.90(br, s.

3H-40'FTs)-3-08(br-IH-2H
)-3,47(e, IH,7-0H), 3.56(
m, IH, 2H), 3.85(s, IH, 8H
), 4.76 (br, s.

2H-260H2), 6.2-6.0 (m-4H)-
6,62 (m, IH, 3-H) Mass spectrum (m/e): 570 (M),
209° 81 Reference Example 3 Milbemycin D 5-oxo-(8,51-14,I
A chloroform (5M) bath solution of the 5-oxo derivative (111M9) of the S)-jepoxy derivative milbemycin D was added to the solution Km-Rio-perbenzoic acid (122~), and the reaction was allowed to proceed at room temperature for 51 kFF. After the reaction was completed, ether was added to the reaction mixture, washed with a saturated aqueous sodium bicarbonate solution and water, dried, and the solvent was distilled off under reduced pressure.

The resulting residue was subjected to silica gel column chromatography (
Developer: n-hexane-n-hexane/ethyl acetate = 7
/3) to obtain 78 ml of the target compound.

nujol - infrared absorption spectrum, νmaX ml・3475, 1
740. 1680 Nuclear magnetic resonance spectrum (CDO/3) δ: 1.27
(s, 3H, 14-0H5), 1.90 (br,
a.

3H,40H3)-108(m-ITd-25H).

3.57 (6,1'[(; , T'-11,0Hz,
9-H), 31◎(m, IH, 2-H), 3.8
! I(a, IH, 6-H).

, U 4.07((1,1HiJ=12Hz, 26-(3-H
).

4-b7c d-IHiJ"12H2, 260H).

5.16 (drl, IH↓, T=9.0. 15H2,
1G-H).

tt, oocaa, IHiJ=10-15Hz, 11
H).

6.71 (m, IH, 3-H,) Mass spectrum (m/e): 5Hg (M), sea.

550.209 Applicant: Sankyo Co., Ltd. Agent: Patent attorney Shoji Mide (19) Continuation of page 1 0 shots clear person Noritoshi Kitano 1-2-58 Hiromachi, Tokyo Parts Ward Gosankyo Co., Ltd. Biological Research Institute (20)

Claims (1)

[Claims] An epoxy derivative of milbemycin D having the formula (wherein - represents a double bond or an epoxy group).