JPS5920284A - 5-ether derivative of milbemycin d and its salt - Google Patents

Abstract

NEW MATERIAL:A compound shown by the formula I {R is lower alkoxyalkyl, CH2COX[X is lower alkyl, OH, or group shown by the formula II(Y is H, or lower alkyl), group shown by the formula III, etc.]} and its salt. EXAMPLE:5beta-(1-Ethoxyethoxy) derivative of milbemycin D. USE:An acaricide. An insecticide. Showing improved acaricidal activity against Tetranychus, Ixodidae, Dermanysside, living in fruit trees, vegetables, or petals and improved insecticidal activity against noxious insects such as flies, lice, cockroaches, etc. and nematodes, etc. PROCESS:A compound shown by the formula IV is reacted with a compound shown by the formula V(R1 is H, methyl, ethyl, or n-propyl; R2 is lower alkyl) in an inert solvent in the presence of an acid catalyst (e.g., salt of hydrochloric acid or p-toluenesulfonic acid and pyridine) at room temperature for 1-10hr, to give a compound shown by the formula I .

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to 5-ether derivatives of the antibiotic milbemycin D and salts thereof.

B-41-146 strain belonging to the genus Streptomyces
(The 14th microbiological research institute at the Institute of Microbial Technology, Agency of Industrial Science and Technology)
It has been deposited as No. 38. ) has acaricidal and anthelmintic activity.

Milbemycin D (B-41D) has been isolated (
JP-A-56-32481).

0H Milbemycin D (I) As a result of extensive research into the synthesis of derivatives of Milbemycin D by chemical means, the present inventors discovered a compound with excellent acaricidal and anthelmintic activity, and completed the invention.

The novel compound of the present invention has the general formula [wherein R is a 1-lower alkoxyalkyl group, -0H200X group]
X is a lower alkyl group, hydroxyl group, lower alkoxy group, -0c group (Y represents a hydrogen atom or a lower alkyl group),
Amino group, mono- or di-lower alkylamino group, -N
H-Q' l (Y indicates the same meaning as above.) or Boki group (Y indicates the same meaning as above!)
shows. ], -0H2ON group, -OH2-Q''M (Y has the same meaning as above), shows the same meaning as in the book, ).].

In the above formula, the alkyl group of the 1-lower alkoxyalkyl group can be an ethyl, n-propyl, n-butyl or n-pentyl group, preferably an ethyl group.

The lower alkyl group of x, y, z and mono- or di-lower alkylamino group is methyl, ethyl, n-propyl,
It can be n-butyl or inbutyl, preferably methyl or ethyl.

The 1-alkoxyalkyl group and the lower alkyl group of X may be methoxy, ethoxy, n-propoxy, n-butoxy, imbutoxy or 1-butoxy, preferably methyl or ethyl.

The low gauze alkanesulfonyl group of 2 is methanesulfonyl, ethanesulfonyl, n-propanesulfonyl group,
Preferably it is a methanesulfonyl group.

Further, in the compound (T1), the compound in which R is 10H2000H can be in the form of a salt, and such salts include m-class inorganic metals such as lithium, sodium, potassium, or magnesium, or ammonium, Ammonium salts of cyclohexynyl ammonium, diisopropylammonium or triethylammonium can be used, but sodium or potassium salts are preferred.

In compound (n), R is preferably a blind methoxyethyl group, a 1-ethoxyethyl group, a 2-oxopropyl group,
Carboxymethyl group, sodeoxycarbonylmethyl group,
Botaoxycarbonylmethyl group, methoxycarbonylmethyl group, ethoxycarbonylmethyl group, phenoxycarbonylmethyl group, P-)lyloxycarbonylmethyl group, carbamoylmethyl group, N-methylcarbamoylmethyl &, N-ethylcarbamoylmethyl group, N- Phenylcarbamoylmethyl group, phenacyl group, P-methylphenacyl group, m-methylphenacyl group, cyanmethyl group,
Benzyl group, P-methylbenzyl group, O-methylbenzyl group, tetrahydrofuran-2-,! Titrahydropyran-2-glu group, 6-medoxymethyltetrahydrobyran-2-yol group, 6-methanesulfonyloxymethyltetrahydrobyran-2-table group, 6-benzenesulfonyloyoxymethyltetrahydro biran-2-#l group or 6-(
P-) luenesulfonyloxymethyl) tet, ato. Pi, y-2-A ya group, ah, y, hardware can be mentioned.

In compound (n), R is more preferably a 1-methoxyethyl group, a 1-ethoxyethyl group, a carboxymethyl group, an deoxycarbonylmethyl group, a methoxycarbonylmethyl group, an ethoxycarbonylmethyl group, a carbamoylmethyl group, or a phenacyl group. group, tetrahydrofuran-2-
f-x group, tetrahydrobilane-2-! Examples include compounds which are a 6-methanesulfonyloxymethyltetrahydrobilain-2-yl, f, or 8-(P-toluenesulfonyloxymethyl)tetrahydrobilain-2-yl group.

In compound (Il), particularly preferred is a compound in which R is a 1-ethoxyethyl group or a methoxycarbonylmethyl group.

Compound (II) is produced according to the following method.

In compound (II), R is 1-lower alkoxy and 2 has the same meaning as defined above. ) is a compound (J
[a) In an inert solvent under an acid catalyst, compound (r) and the general formula % (% formula %) (wherein R1 is a hydrogen atom, a methyl group, an ethyl group, or
It represents a propyl group, and R2 represents a lower alkyl group. ), a compound having the general formula (wherein n has the same meaning as above), or a compound having the general formula (wherein 2 has the same meaning as above). It can be produced by reaction.

Acid catalysts used include, for example, inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, acidic acids such as trifluoroacetic acid, menthanesulfonic acid, benzenesulfone II, p-toluenesulfonic acid or p-toluenesulfonic acid. Examples include acid salts such as salts of P-toluenesulfonic acid and pyridine, but salts of P-toluenesulfonic acid and pyridine are preferred.

The inert solvent used is not particularly limited as long as it does not participate in the reaction, but preferably ethers, ethers such as tetrahydrofuran, or halogenated hydrocarbons such as methylene chloride and chloroform can be used.

The reaction temperature is usually around room temperature, and the time required for the reaction is usually 1 to 10 hours.

In compound (■), R is 10) 1200X, group [
Xl represents a lower alkyl group, a hydroxyl group, a lower alkoxy group, and has the same meaning as described above. ) is the compound (IIb)
is the compound (1) in the presence of oxidation in an inert solvent and the general formula % () (wherein, Xt has the same meaning as sister, Q
represents a halogen atom such as chlorine, bromine, or iodine. ), a compound having the general formula %() (wherein, Q has the same meaning as defined above) or a compound having the general formula %() (wherein, Y and Q have the same meaning as defined above) ) is produced by reacting with a compound having the same meaning as

1. The solvent to be used is not particularly limited as long as it does not participate in the reaction, but preferably nitriles such as acetonitrile, amides such as dimethylformamide, dimethylacetamide, hexamethylphosphorotriamide, or dimethyl sulfoxide. These are sulfoxides such as.

The reaction temperature is usually around room temperature), and the time required for the reaction is 3
Hours to + (10 hours).

In addition, the compound (I[O) in which R is 10H2000H,
A compound in which R is 10H2000Bu according to a conventional method,
It can also be prepared separately by treatment with an acid such as trifluoroacetic acid, p-)luenesulfonic acid.

Compound (n) has O-'(, Rka0H200X2 groups CX
2 is an amine group, a mono- or di-lower alkylamino group, or -NH-G (Y has the same meaning as described above).

) is shown. ] The compound (IId) having
(IIQ) is converted into a reactive derivative such as an acid halide and reacted with ammonia, mono- or di-lower alkylamine or NH2-σ (Y has the same meaning as above). .

The process for producing acid halide is to prepare the sodium or potassium salt of compound (nc) or compound (■0), thionyl chloride, oxalyl chloride, or phosphorous tribromide in an inert solvent such as benzene, toluene, ether, or tetrahydrofuran. This is achieved by reacting with a halogenating agent such as at room temperature for 1 to 10 hours.

The process of producing compound (■d) includes benzene, toluene, ether, tetrahydrofuran, methylene chloride,
In an inert solvent such as chloroform, the above acid halide and ammonia, mono- or di-lower alkylamine or NH2-cy'' (Y has the same meaning as above).
This can be achieved by reacting them at 0° C. to 50° C. for 1 hour to 10 hours.

Furthermore, the hydroxyl group at the 5-position of compound (I) obtained by culturing is β-coordinated, whereas the starting compound (I) is α-coordinated.
) is produced as shown in the following reaction formula.

Alkane of formula (■) 5β-alkane Organic acid tetra-5β-hydroxy sulfonyl sulfonyloxy alkylammo-5α-acyl Formula (I
The first step in ) is a step for producing a 5ρ-alkanesulfonyloxy derivative, which is 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 -acetate or tetrabutylammonium formate or baracetate, 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 temperature at which the solvent passes, preferably room temperature.

The third step is a step of producing a 5α-human tetraxy derivative,
5α-acyloxy derivatives in aqueous solvents of water and water-soluble ethers such as methyl alcohol, ethyl alcohol, flobyl alcohol, methyl alcohol, tetrahydrone, and dioxane, alkali metal hydroxides, and carbonic acid. This is achieved by reaction with a base such as a salt or bicarbonate (preferably bicarbonate).

After completion of the above reactions, the target compound of each 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, 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 method or large scale chromatography.

The compound (II) of the present invention can be used to infect fruit trees, vegetables, and flower petals, including two-spotted spider mites (Tetranychus), apple spider mites, and orange spider mites (Panonychus).
and adult insects and eggs of rust mites, parasitizing animals such as Ixodidae (Ixodidaa), Dermanidae (Dermanidae), etc.
ysside) and Sarcoptidae (Sarcopt.
It has excellent acaricidal activity against insects such as A. idae).

Furthermore, sheep fly (Oestrug), golden fly (Lu
-ci'1ia), Hypoderma,
It is active against ectoparasites of animals and birds such as Gautrophilus, chisels, and lice; sanitary pests such as cockroaches and house flies; and various agricultural and horticultural pests such as aphids and lepidopteran larvae. Furthermore, root-knot nematodes (Mo2O3(l101(lo), root-knot nematodes (Mo2O3(lo),
Phizoglyphug) etc.

Furthermore, the compound (II) of the present invention has excellent parasiticide activity as an anthelmintic for animals and humans. Especially pigs,
Effective against the following nematodes that infect livestock, poultry and pets such as sheep, goats, cattle, horses, dogs, cats and chickens.

Genus Haemonchus.

Trichostrongylus sp.
lus).

Ostertagia and Nematodirus.

Cooperia genus (coop@ria).

Genus Ascaria.

Genus Bunoatomum.

Oesophag Ostom
um).

Genus Chabertia.

The genus Triohuri.

Strongylus genus (8strongylus).

Trichonema genus.

Genus Diotyoaaulus
).

Genus Capillaria.

-＼Genus Heterakis.

Toxocara, Ascariteia genus (Asoaridia).

Genus Oxyuris.

Genus Ankylostoma.

Genus Lancinaria (Uncinaria).

Toxascarie and Parascarig.

Certain species of the genera Nematodeilus, Cooperia and Eso7 Agostomum attack the intestinal tract, while those of the genera Hemonchus and Ostiltagia inhabit the stomach, and parasites of the Dictyokaurus species are found in the lungs. Instantly, these K also show activity.

Parasites of the family Filariidae and 5etarila are also found in, and active in, other tissues and organs of the body, such as the heart and blood vessels, subcutaneous and lymphatic tissues.

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

Genus Neoator.

Genus Ascaris.

8strongyloides
.

Triohinella genus.

Cabillaria genus (Oapil'1 arra).

The genus Trichuris and the genus Enterobius.

Other medically important parasites found in the blood or other tissues and organs outside the gastrointestinal tract include the family Filariaceae, Wuhereria, Br.
ugia), Onachocerca (Onahooerca)
) and the genus Loa and the family Serpentidae (D
racunculidae) of the genus Dracunculus (D
It is also active against the genus Strongyloides and Trivinella in the special extraintestinal parasitic state of intestinal parasites.

When compound (n) 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 about 0.01-0.5% by weight of active compound, preferably 0.01-0.
．． 1 Contains a weight factor.

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 forms of use are
The active ingredient is combined with suitable finely divided diluents, fillers, disintegrants and/or binders, such as densities. pun, lactose,
Manufactured by homogeneously mixing with talc, 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 either homogeneously dispersed in the feed or used as a top dressing or in the form of pellets. To achieve the desired antiparasitic 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 to animals parenterally by injection into the proventriculus, 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 from 0.05 to 50% by weight of active compound.

It may be administered topically by mixing with a suitable carrier such as Ti, dimethyl sulfoxide or a hydrocarbon solvent. This formulation is applied directly to the external surface of the animal by spraying or direct injection.

The optimal fecal dose of active compound for best results will depend on the type of animal being treated and the type and extent of parasitic infection, but is generally about 0.01 kg/kg of animal body weight.
It is obtained by oral administration of ~100 mg, preferably 0.5-so, omg. Such usage may be extended over a relatively short period of time, such as one to five days, either all at once or in divided usage.

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

Example 1 5β-(1-ethoxyethoxy) derivative of milbemycin D Milbemycin D (278 mg) was added to a solution of ethyl vinyl ether (72+n
g) Topyridinium P-)luenesulfonate (1
2, smg) was added and reacted for 45 minutes 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. /1), and the target product is j00m
I got g.

Infrared absorption spectrum (-1 woman 01 cm-1) 23475
, 1715. 1680 nuclear magnetic resonance spectrum (
ODO13) δ: 1.1B, 1.18 (3H,'t
, J=6.0H2).

1.35 + 1-37 (3H, d, J=
5. (OHz).

3.61 (2H+(1*J=6.0Hz), 4.0
4(” * S) + 4.59 (2Hz br
+ s l) mass hek)/l/ (m/8)
: 628 (M+)+556.428,209,1
81 Example 2 Milbemycin D 5β-(tetrahydropyran-2-
The target compound was obtained from milbemycin D and dihydropyran in the same manner as in Example 1.

Infrared absorption spectrum/l/ (*Lightning Pi0'cm-'
) :3360, 1730. 1710 nuclear magnetic resonance spectrum (0DO1,s) δ: 3.96 (I
H, S), 3.93 (IH, ad, J = 3. (1°6.0H2), 4.03 (IH, da, J = 3.0
, 6.0H2).

4.61 (2H, br, S), 4.71 (1a,
t, y=4, gaz) Mass hexle (m/e): 640 (M+).

556.538, 209.181 Example 3 Milbemycin D and 6- (P-
) The target compound was obtained from luenesulfonyloxymethyl) dihydropyran.

Infrared absorption spectrum (4jo1Cm-+).

3475, 1710. 15115 nuclear magnetic resonance spectrum (0DO715) δppm: 2.40 (S,
3H), 7.30 (IH, d, J=9.0Hz) *
7-75 (1-H+ d* J = 90 Hz
)Mass spectrum Oze): 822 (M+).

556, 538. 209. 181 Example 4 5β-methoxycarbonylmethoxy derivative of milbemycin D Milbemycin D (334 mg) and methyl iodoacetate (eosmg) in acetonitrile (5 ml)
Silver oxide (1.1 eg) was added to the solution and reacted for 3 days at t and g temperatures. After the reaction is complete, remove the insoluble matter with Celite,
The residue obtained by distilling off the solvent under reduced pressure was subjected to silica gel column chromatography [Lover columns (Merck & Co., Ltd.), size B, 2 columns; developing agent: chloroform/ethyl acetate = 90/1
0) to obtain 107 mg of the target compound.
1760. 1740. 1710 nuclear magnetic resonance spectrum (CDal13) δppm: 3.68 (3H,
El), 3.96 (IH, d, J = 5°0 Hz).

4.06 (IH, S), 4.19 (2H, El),
4.58(za,br+1-qsxvec)le(m/e): s2s(M+).

428, 4 10. 209. 181 Patent Applicant: Sankyo Co., Ltd. Representative Patent Attorney Osamu Kashi Dejo Osamu 1-2-58 Hiromachi, Tokyo Parts Industry Ward Sankyo Co., Ltd. Biological Laboratory - 61'

Claims (1)

[Claims] General formula [in the formula, R is a 1-lower alkoxyalkyl group, 10H200X group (! indicates the same meaning as above)], -0H2ON group, 1, CH2- It represents a C3Y group (Y has the same meaning as described above). ] A 5-nee til derivative of milbemycin D and a salt thereof.