JPH0491024A - Anthelminthic, insecticide and antiprotozoal - Google Patents

Abstract

PURPOSE:To provide an anthelminthic, insecticide or antiprotozoal useful against parasites (oxyurids and protozoas), exvivo parasites, insects and mites living on men, animals and plants by compounding an antibiotic IKD-8344 substance as an active ingredient. CONSTITUTION:An antibiotic IKD-8344 substance of the formula which is a substance produced by Actinomyces bacteria called the genus Alkalomyes, is low toxic and has an antitumor activity and is employed as an active ingredient to prepare the anthelminthic, insecticide or antiprotozoal which can be safely employed in an effective amount because of exhibiting excellent anthelminthic, insecticidal and antiprotozoal activities and of being low toxic for men and animals.

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to anthelmintic agents, insecticides, and antiprotozoal agents characterized by containing the antibiotic IKD-8344 substance as an active ingredient. More specifically, the present invention provides anthelmintic agents, insecticides, and antiprotozoa having utility against parasites (sphenoid and protozoan), ectoparasites, insects, and mites that infect humans, animals, and plants. It is a drug.

[Conventional technology]

Many compounds are known to have anthelmintic and insecticidal effects, but
Examples of microorganism-produced substances having anthelmintic and insecticidal activities, such as the antibiotic IKD-8344 of the present invention, include destomycin, hygromycin, avermectin, and milbemycin.

[Problem to be solved by the invention]

In general, parasitic diseases are caused by parasites, i.e., single-celled protozoa (
It is caused by parasitic infection of an animal host by a protozoan or multicellular butterfly.

Parasitic diseases are said to have decreased markedly in Japan due to improvements in environmental sanitation, but from a global perspective, they are widespread, especially in developing countries, and cause considerable damage.

Recently, parasitic diseases have begun to show a new increasing trend in Japan, including infections introduced by long-term and short-term travelers to these foreign countries and infections caused by the so-called gourmet boom (eating and drinking of raw animals and fish meat).

Parasitic diseases are also a common and serious economic problem in domestic animals such as pigs, horses, cattle, sheep, goats, dogs, cats and poultry. In other words, parasitic infections can cause infected animals to suffer from anemia, malnutrition, wasting, weight loss, and severe damage to the intestinal wall and other tissues and organs, contributing to reduced feed efficiency and productivity. This results in large economic losses.

Therefore, it is always important to provide new anthelmintic agents, insecticides, or antiprotozoal agents.

[Measures to solve problems]

The present invention solves the problems of the previous stage, and the antibiotic IK
The present invention provides an anthelmintic, an insecticide, and an antiprotozoal agent containing the D-8344 substance (hereinafter abbreviated as "R8344 substance").

The present inventors previously discovered 8344 substances produced by actinomycetes, which we named the genus Alcalomyces (Japanese Patent Application Laid-Open No.
009382).

Substance 8344 has low toxicity and excellent antitumor activity, and has the following structural formula.

Hi " CH.

This time, 8,344 new substances have been added as internal and external anthelmintics, insecticides, and antiprotozoans against parasites (screwworms and protozoa), ectoparasites, insects, and mites that parasitize humans, animals, and plants. The present inventors have discovered that the present invention has useful properties as a method, and have completed the present invention.

Animals to which the 8344 substance is applied as anthelmintic, insecticide, and antiprotozoal agent include pigs, horses, cows, sheep, goats, rabbits,
Examples include livestock, poultry, pets, and laboratory animals such as chickens, ducks, turkeys, dogs, cats, small birds, monkeys, 20-day rats, black rats, and guinea pigs.

Among the parasites of these animals, nematodes belonging to the class Scrophida are
Causes serious infections in various animals.

The types of boat fishing are Ascaris, Toxocara, and Toxascari.
s), Para, 5 caris, Chicken caedia (Para, 5 caris), Chicken caecum (Heterakis).
), Oxyuris, Strong
yIoicles), native land (Trichuris)
, Capillaria, Tri
chinella), Strongylus.

Trioclontophorus), Hairy nematode (Tri
chonema), pig kidney (Stephanurus)
, Oesophagostomum, Chabertia, Syn
amus), hookworm (Ancylostoma, IJn)
cinaria, NecatorXBunost.

mum), Trichostrongylu
s), Cooper ia, Nematodirus, H
aemonchus), Ostertag stomach worm (stomach worm)
rtagia), Lungworm (Dictyocau) us.

Metastrongylus), Dir.
ofilaria), Parafila
ar+a), Setaria, Onchocerca, Habrone
ma.

Arduenna, Acuaria). Also,
As a tapeworm, Diphyllobothr
ium), Anoplocepha spp.
ra), Moniezia (T, 1oniezia), Dipylidium, Taenia solium and Taenia, Dithyridium
, the genus Raillietina, and the chinococcus, and the trematodes include Schistosoma, Paramphistomum, and Fasci flukes.
ola) and various other parasites are known.

Substance 8344 is also useful against parasites that infect humans. Common parasites that infect the human gastrointestinal tract include ``caris'' and hookworm.
lostomaSNecator), Strongyloides nematodes (Stro
ngyloides), Trichinella
a), Capillaria, local (T.
richuris), Enterobius
, Anisakis, and Capillaria. Medically important parasites that parasitize the vascular system or other tissues and organs other than the gastrointestinal tract include parasites of the Filaridae family, such as Wuchereria and Brugi.
a), Onchocerca, Loa, Dracuncula
s) and the extraintestinal parasitic stages of the intestinal parasites Strongyloides and Trichinella, as well as the subcutaneous parasitic gnathostomes.
ma). In addition, Dirofilaria and Toxocar, which can be transmitted from animals to humans.
a) is known.

In addition, tapeworms include Diphyllobothrium, Diphyllobothrium, Taenia solium, Taenia solium, and Taenia solium.
ococcus), Taenic cyst ((1'ysticerc)
us), small tapeworms, but trematodes include schistosomes (
Schistosoma), liver fluke (fl'1onor
chis), lung fluke (Paragonimus), liver fluke (Fasciola), etc.

The protozoa that cause parasitic diseases include malaria parasites (
Plasmodium), leash? -'-A (Le
i-shmania), trypanoso-7 (Trypan
osoma), Entamoeba histolytica (Entamoeba),
Flagellates (Giardia), Trichomonas (Tric)
homonas), Toxoplasma gondii (Tox.

plasma), Cryptosporidium (Crypt
ospor idium), coccidium (εime
ria), Pneumocystis
s) etc.

Examples of ectoparasites that infect animals, humans are arthropod ectoparasites such as biting insects, blood-sucking insects, fleas, lice, house flies, spider mites, ticks and other migratory dipteran larvae.

Household pests include cockroaches, cloth moths, bonito bugs, and houseflies.

In addition, pests of stored grains, such as rice beetles, rice beetles, and pests of agricultural crops, such as barley beetles,
Included are aphids, migratory Orthoptera, such as grasshoppers, and the larvae of insects that live in plant tissues. Further examples include plant parasites such as soil nematodes and root-knot nematodes.

The 8344 substance can be administered in any conventional manner for the treatment or prevention of parasitic diseases as an animal or human medicine. The administration method can be either oral or parenteral, and when administered orally, soft/hard capsules or tablets, pills, powders, granules, fine granules, powders, syrups, enteric coated agents, As a suspension, paste, and
It can be administered by incorporating it into liquid drinks or feed for animals. For parenteral administration, injections, drops, fixatives, emulsions, suspensions, drops (e.g. eye drops,
It can be administered in a dosage form that maintains mucosal or transdermal absorption, such as as a nasal spray), ointment, cream, liquid, lotion, spray, aerosol, poultice, or tape. It can also be administered as a mammary gland preparation and pour-on for livestock.

In formulating the 8344 substance, pharmaceutically acceptable solubilizing agents, suspending agents, emulsifying agents, dispersing agents, surfactants, binders, thickening agents, fillers, excipients, lubricants, disintegrant,
Wetting agents, adjuvants and others may be used as appropriate to suit the preparation of solid, semi-solid, liquid, etc. formulations. Additionally, stabilizers, colorants and fragrances may be used. The active ingredient is contained in the formulation in sufficient quantity to treat or prevent the disease.

When using 8344 substance as a medicine for animals or humans, the optimal amount of 8344 substance to be used depends on whether the treatment is for treatment or prevention, the type of infected animal, the type and degree of infection, the dosage form, etc. , in the range of about 0.001 to 50 mg/kg body weight per day for oral administration,
The upper limit is preferably about 25 mg/kg body weight, and in the case of parenteral administration, the upper limit is about 5 mg/kg body weight, preferably about 1 mg/kg body weight,
It can be administered once or in divided doses for about 1 to 5 days.

For horticultural or agricultural purposes, such as ectoparasiticides, insecticides, and agricultural pest treatments, 8344 substances can be used in sprays, powders, pellets, emulsions, and the like according to standard industrial or agricultural methods. shall be applied as similar. It can also be formulated by mixing with other insecticides, acaricides, and nematicides.

In the formulation, the concentration of the 8344 substance is generally 0.01
It is about 99% by weight, preferably about 0.01 to 10% by weight. Commercial products are generally provided, for example, as concentrated compositions that are diluted to the appropriate concentration for use.

[Acute Toxicity of Substance 8344] No deaths were observed when BDF was administered intraperitoneally to mice at a single dose of 5 mg/kg or once a day for 5 days.

In addition, 25 mg/d was administered orally to male mice.
No toxicity or mortality was observed after a single administration of 1 kg.

The following formulation examples and test examples are provided merely for the purpose of illustrating the present invention and are not intended to limit its scope.

Formulation example 1 (tablet) [A] 8344 substances 2.00 g milk
Sugar 17.94 g Hydroxypropyl cellulose 0.06 g Magnesium stearate 0.20 g [B] Cellulose acetate phthalate 0.60 g [A]
Take the ingredients, mix them well, press them directly, or knead them well, then form them into granules through the screen of an extrusion type granulator, and after sufficient drying, press them to make tablets 10
0 pieces were prepared.

Furthermore, if necessary, the molded tablets were well dissolved [B]
Enteric-coated tablets are prepared by coating the base material.

Formulation example 2 (capsule) [A] 8344 substances 2.00 g milk
Sugar 10.46 g Hydroxypropyl cellulose 0.04 g [B] Cellulose acetate phthalate 1.00 g After taking the ingredients in [C] above and mixing them well, form them into granules according to a conventional method, and dry them thoroughly. The mixture was sieved to obtain granules suitable for capsules, and the granules were filled into capsules to prepare 100 capsules.

Further, if necessary, the granules are coated with the dissolved base [B] while floating and flowing to form enteric-coated granules, which are then filled into capsules to obtain enteric-coated capsules.

Formulation example 3 (injection) 83471 substance benzyl alcohol polysorbate 80 propylene glycol Distilled water for injection 0,50 g 2,00 g 10,00 g 50,00 g Appropriate total amount 100 ml Substance 8344, benzyl alcohol, polysorbate 80 and propylene glycol and add distilled water for injection to bring the total volume to 100 mf.

Manufactured aseptically and dispensed aseptically.

Formulation example 4 (intramammary injection for livestock) 8344 substances 0.10 g Peanut oil 1.82 g White honey wax
0.12 g polysorbate 8
0 0.06 gThe components other than substance 8344 are heated and stirred at 160°C, and after cooling, substance 8344 is added and dispersed.

Formulation Example 5 (Oral liquid medicine for livestock) 8344 substances 0.50 g Benzyl alcohol 2. OOg Polysorbate 80 5.00 g Propylene Glycol 30. OOg water
Appropriate amount Total amount 100d Dissolve substance 8344 in benzyl alcohol, polysorbate 80 and propylene glycol, and add water to make the total amount 100ml. If necessary, add phosphate buffer to adjust p++ to near neutrality.

Formulation Example 6 (Pour-on for livestock) 8344 substances 1.00 g dimethyl sulfoxide 10.00 g methyl isobutyl ketone 30. OOg Propylene glycol appropriate amount total amount 100- Dissolve the 8344 substance in dimethyl sulfoxide and methyl isobutyl ketone and add propylene glycol to make the total amount 100-. Add pigment if necessary.

Test Example 1 In vitro antiparasitic (insecticidal) test 1
) Trichinella 5piralis
(Thai 5train) and T, pseudo
Mature larva of P. ospiralis.

2) Test method Substance 8344 dissolved in DMSO was added to M199 medium (
(containing 20% tallow serum and kanamycin), aliquoted into 3 wells each of a 96-well flat-bottomed microplate, put several tens of the above larvae in each, and immediately incubate at 37°C at 15°C.
% CO2.

The controls were M199 alone and the content of % D used for dissolution.
By M199 including MSO.

Also, Mebendazol, a known antiparasitic substance
e was also investigated using a method similar to the above and compared with this substance.

3) Judgment Criteria After the start of culture, the viability or deadness of the worms was observed orally, and the mortality rate and ED. The value was calculated.

4) Test results ■8344 substance: Trichinella 5pir
alis and T, pseudosp+ral+s Mortality rate % (3rd day of culture) ■Mebendazole: Trichinella
5piral + s mortality rate% (3.5 days of culture) It is difficult to determine whether all individuals in a certain test group are completely alive or dead, so for convenience of calculation, 100%
% was 99% and 0% was 1%.

The antiparasitic (insecticidal) effect of Substance 8344 appears to be relatively immediate, and the overall trend becomes clear by the third day of culture. In the high concentration range, the activity of the insects was affected a little more than half a day after exposure, with some individuals tending to stay still in a coiled state, and an increasing number of insects becoming inactive after oral administration.

The EDso value is T, 1 for 5piralis
．． 65μs/mj2, T, pseudospiral
For is, it was calculated to be 2.18 μg/ml.

On the other hand, Mebendazole was used as a comparative drug.
is quite slow-acting, and the obvious antiparasitic effect is observed in culture 4
It was recognized after ~5 days. Its action also rarely caused the living body to stay still in a coiled state.

Test Example 2 In Shi 1 O Anti-parasitic (Anthelmintic) Test l) Test Main Trichinella 5piralis (Thai
5train) mature larva.

2) Test method ddy 7 mice (SPF female) are infected with 400 T.5 piralis larvae/head, and 3 and 155 days after infection Intestinal parasitic phase: In addition to adults, newborn larvae and larvae in the muscle transition stage CM 83/14 substance at 5 mg/kg of body weight at 2 months (muscle parasitic phase, mature larva)
C. Orally administered in physiological saline PQ. Approximately one month after administration, the mice were anesthetized, and all larvae were collected from all skeletal muscles by artificial digestion, and the anthelmintic effect was determined by comparing the degree of infection and the number of survivors.

Test results Because of its low toxicity, can be done.

When used safely in effective doses, substance 8344 has excellent anti-parasitic properties (
showed anthelmintic) activity. The trichinella used in the experiment is a common prison parasite that infects animals such as pigs, rats, and dogs, as well as humans, and the 8344 substance showed insecticidal and anthelmintic activity. A wide range of applications are possible.

〔Effect of the invention〕

Claims (3)

[Claims] (1) An anthelmintic agent characterized by containing the antibiotic IKD-8344 substance as an active ingredient. (2) An insecticide characterized by containing the antibiotic IKD-8344 substance as an active ingredient. (3) An antiprotozoal agent containing the antibiotic IKD-8344 substance as an active ingredient.