JPH0952802A - Anthelmintic - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain an anthelmintic which is effective against nematodes parasitic to human and animals, particularly against eggs and larvae of tapeworm, and can persistently maintain its anthelmintic effect for a long time even when it is applied to sand pits or flow pathways because it is slightly soluble in a variety of solvents and thermally stable. SOLUTION: A quaternary ammonium salt ion having the anthelmintic action is intercalated to a laminar phosphate salt or a clay mineral. The laminar phosphate salt is, for example, a crystalline laminar phosphate salt of the general formula: M(HPO4 )2 .XH2 O (M is Zr, Ti or Ce; X=0-2), aluminum tripolyphosphate of the chemical formula: AlH2 P3 O10 .2H2 O, while the clay mineral is, for example, montmorillonite or bentonite.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an anthelmintic agent effective against nematodes parasitic on humans and animals, particularly eggs and larvae of helminths, and more specifically, it has high heat stability and is effective against various solvents. And poorly soluble anthelmintic agent.

[0002]

2. Description of the Related Art Although the spread of flush toilets has significantly reduced parasitic diseases such as helminths that parasitize humans, the present situation is that the developing world still suffers from parasitic diseases. is there. In recent years, in Japan, sandboxes such as schools and parks in urban areas have become toilets for dogs and cats nearby,
It has been a problem that animal-derived parasites, which originally do not parasitize humans, enter the human body temporarily and sometimes over a fairly long period of time via animals. Since these parasites orally invade humans at the stage of eggs or larvae, a method of disinfecting eggs and larvae by spraying a fungicide in a sandbox has been conventionally adopted.

[0003]

However, in the case of spraying a bactericide to a sandbox or the like, it is necessary to spray a bactericide emulsion having a high concentration of 3% or more. Therefore, it is frequently used in a park where many people come and go. I can't. In addition, even if it was sprayed, there was a concern that it would affect the environment because it would be washed out by rain.

Therefore, the present invention does not need to be sprayed in the form of a high-concentration emulsion and does not flow out due to rain, so that it can be applied for a long time even when applied to an open space such as a sandbox or even a running water channel. The object of the present invention is to provide a new and improved anthelmintic agent capable of maintaining the anthelmintic effect.

[0005]

That is, the anthelmintic agent of the present invention is characterized in that a quaternary ammonium ion having anthelmintic action is intercalated into a layered phosphate or a clay mineral.

[0006] The present inventors
By intercalating a quaternary ammonium ion, which has an antibacterial action against mold, with layered phosphate and aluminum tripolyphosphate, it is possible to obtain a stable antibacterial phosphate against heat and various solvents. Patent applications have already been filed (Japanese Patent Laid-Open Nos. 5-124806 and 5-124
186208).

In the present invention, it was found that a layered clay mineral having a cation exchange ability can also be used as a support for intercalating quaternary ammonium ions.

Although quaternary ammonium ions such as alkylbenzyldimethylammonium ion and alkylpyridinium ion are known to have anthelmintic action against worms, which are members of invertebrates, they have anthelmintic effect. There are few actual examples showing the degree, and quaternary ammonium ion alone having such anthelmintic action dissolves in water easily, so even if it is sprayed in an open space such as a sandbox or running channel, it will take a long time. The anthelmintic effect could not be sustained. However, by exchanging these quaternary ammonium ions having anthelmintic action with some or all of the ion-exchangeable ions of the support as used in the present invention to intercalate into the support, heat is removed. The stability is also increased, and it is hardly soluble in various solvents such as water and alcohol. Further, the results of the test revealed that the quaternary ammonium ion intercalated in the support has a higher anthelmintic effect than the quaternary ammonium ion alone. The reason for this has not been clarified yet, but it was an unexpected effect.

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION The quaternary ammonium ion having anthelmintic action used in the present invention is one cation in which four carbon atoms are directly bonded to a nitrogen atom, and examples thereof include alkyltrimethylammonium ion, Alkyldimethylethylammonium ion, dialkyldimethylammonium ion, trialkylmethylammonium ion, alkyldimethylbenzylammonium ion, alkylpyridinium ion, alkylquinolium ion, alkylamidopropyldimethylbenzylammonium ion, benzyldimethyl p- (1, 1, 3 Examples include 3,3-tetramethylbutylphenoxy) ethylammonium ion. These are usually supplied by quaternary ammonium salts such as chloride, bromide, iodide.
Not only one kind of these quaternary ammonium ions but also several kinds thereof may be supported on the support.

As the layered phosphate serving as a quaternary ammonium ion carrier, a crystalline layered phosphate of a tetravalent metal such as zirconium phosphate, titanium phosphate or cerium phosphate may be used alone or in combination of two or more kinds. Can be mixed and used.
The crystalline layered phosphate of a tetravalent metal has the general formula M (HPO ₄ ).
₂ · XH ₂ O (wherein M is Zr, Ti or Ce, and X = 0 to 2), and a monohydrate α-form,
The gamma form of dihydrate and the like are generally well known. These are solid acids that are sparingly soluble in water and have cation exchange ability. The protons of the hydrogen phosphate group (HPO ₄ ²⁻ ) are responsible for the ion exchange capacity, and the theoretical ion exchange capacity is 6.64 meq / g for α-type zirconium phosphate and 7.76 for α-type titanium phosphate.
meq / g, γ-type zirconium phosphate is 6.27 meq
/ G, γ-type titanium phosphate is 7.25 meq / g.

The reaction in which the quaternary ammonium ion intercalates with the crystalline layered phosphate is considered to be an ion exchange reaction with the proton of the hydrogen phosphate group. That is,
A part or all of the protons that can be ion-exchanged by the ion-exchange method may be replaced with quaternary ammonium ions, and the reaction can be carried out at ordinary temperature to high temperature by a general batch method or column method. After the intercalation, the solid phase is separated by filtration, washed with water to remove unreacted quaternary ammonium ions, and then dried to intercalate the quaternary ammonium ions between the layers of the crystalline layered phosphate. Further, the anthelmintic agent of the present invention can be obtained.

The layered phosphate has a chemical formula of AlH ₂ P.
Aluminum tripolyphosphate (hereinafter abbreviated as AlP) represented by ₃ O ₁₀ · 2H ₂ O can also be used. The ion exchange capacity is carried by the protons of the hydrogen tripolyphosphate group (H ₂ P ₃ O ₁₀ ^{3 −} ), and the theoretical ion exchange capacity is 6.29 m.
eq / g. This AlP has a layered structure in which unit crystal layers are stacked on each other. The bond between the crystal layers is relatively weak, and the quaternary ammonium ion can be intercalated between the layers without breaking the layered structure.

To intercalate quaternary ammonium ions in AlP, AlP is brought into contact with an aqueous solution containing quaternary ammonium ions and ammonia or amine for ion exchange. This ion exchange reaction is considered as the following equation.

AlH ₂ P ₃ O ₁₀ + nR-NH ₂ → AlH _2-n (R-NH ₃ ) _n P ₃ O ₁₀ (1) AlH _2-n (R-NH ₃ ) _n P ₃ O ₁₀ + nR [R ′] ⁺ → AlH _2−n [R ′] _n P ₃ O ₁₀ + nR-NH ₃ ⁺ (2).

Here, R-NH ₂ is an alkylamine,
[R '] ⁺ represents a quaternary ammonium ion. First, according to the formula (1), the amine is bound (protonated) to the proton in AlP, and then according to the formula (2), the quaternary ammonium ion is exchanged with the alkylammonium ion and carried. Thus, the reaction proceeds in two steps, and it is considered that the amine acts catalytically. The same can be considered when ammonia is used instead of amine.

After intercalating quaternary ammonium ions in AlP as described above, the solid phase is separated and washed to remove excess quaternary ammonium ions and ammonia or amine, and then dried. To obtain the anthelmintic agent of the present invention.

As the amine, aliphatic amines such as methylamine, ethylamine, propylamine, butylamine, monoethanolamine and allylamine, cyclic amines such as cyclobutylamine, aniline and pyridine, and aromatic amines can be used.

Clay minerals can also be used as a support for the quaternary ammonium ions. Examples of the clay minerals include crystalline hydrous silicates belonging to the smectite genus, which are natural products or synthetic products having a high cation exchange capacity used as swelling agents for organic bentonites, and more specifically, montmorillonite and bentonite. The cation exchange capacity of montmorillonite is 0.8 to 1.5 meq / g, and quaternary ammonium ions can be intercalated between the layers without breaking the layered structure like AlP. In order to intercalate the quaternary ammonium ion in the clay mineral, a method similar to the above-mentioned method for intercalating the quaternary ammonium ion in the crystalline layered phosphate may be adopted.

[0019]

EXAMPLES Next, the present invention will be described in detail with reference to Examples, but the following Examples are described merely for the purpose of illustration.
The present invention is not limited by these examples.

Example 1 [Alkylbenzyldimethylammonium ion / AlP] An alkylbenzyldimethylammonium ion (alkyl group: C ₃ H _{17 to} C ₁₈ H ₃₇ ) as a quaternary ammonium ion having anthelmintic action is a carrier. AlP was used as the layered phosphate, respectively. 1 g of AlP
% Alkylbenzyldimethylammonium chloride (benzalkonium chloride) and 0.5% n-butylamine were added to 500 ml of an aqueous solution and stirred at room temperature for about 5 hours for ion exchange. Next, the solid phase was separated by filtration, washed with water and dried to obtain anthelmintic agent sample 1. The content of alkylbenzyldimethylammonium ion was 8.4% by weight.

Example 2 Sample 1 of Example 1 was held at 150 ° C. for 2 hours to obtain anthelmintic agent sample 2.

Example 3 5 g of the sample 1 of Example 1 was immersed in 10 liters of tap water for 24 hours, filtered, and dried to obtain an insect repellent sample 3.

Example 4 5 g of the sample 1 of Example 1 was immersed in 10 liters of ethyl alcohol for 24 hours, filtered and dried to obtain an insect repellent sample 4.

Example 5 5 g of the sample 1 of Example 1 was immersed in 10 liters of acetone for 24 hours, filtered, and dried to obtain anthelmintic sample 5.

Example 6 [Alkylbenzyldimethylammonium ion / α-zirconium phosphate] Example 1 except that α-zirconium phosphate was used as the layered phosphate and ultrasonic dispersion was adopted instead of stirring. In the same manner as described above, anthelmintic sample 6 was obtained. The content of alkylbenzyldimethylammonium ion is 9.
It was 3% by weight.

Example 7 [Cetylpyridinium ion / A
1P] Anthelmintic agent sample 7 was obtained in the same manner as in Example 1 except that cetylpyridinium ion was supplied as the quaternary ammonium ion by cetylpyridinium chloride and the mixture was stirred at 80 ° C. for 1 hour. The content of cetylpyridinium ion was 10.1% by weight.

Example 8 [Cetylpyridinium ion / γ
-Titanium phosphate] Anthelmintic acid sample 8 was prepared in the same manner as in Example 1 except that cetylpyridinium ions were supplied as quaternary ammonium ions by cetylpyridinium chloride and γ-titanium phosphate was used as the layered phosphate. Got The content of cetylpyridinium ions was 30.3% by weight.

Example 9 [Trioctylmethylammonium ion / AlP] An anthelmintic sample was prepared in the same manner as in Example 1 except that trioctylmethylammonium ion was supplied as the quaternary ammonium ion by trioctylmethylammonium chloride. Got 9. The content of trioctylmethylammonium ion was 8.2% by weight.

Example 10 Sample 9 of Example 9 was held at 150 ° C. for 2 hours to obtain anthelmintic agent sample 10.

Example 11 5 g of the sample 9 of Example 9 was immersed in 10 liters of tap water for 24 hours, filtered and dried to obtain an anthelmintic sample.
11 was set.

Example 12 5 g of the sample 9 of Example 9 was immersed in 10 liters of ethyl alcohol for 24 hours, filtered and dried to obtain an anthelmintic sample 12.

Example 13 5 g of the sample 9 of Example 9 was immersed in 10 liters of acetone for 24 hours, filtered and dried to obtain an anthelmintic sample 13.

Example 14 [Cetylpyridinium ion / montmorillonite] The same as Example 1 except that cetylpyridinium ion was supplied as cetylpyridinium chloride as the quaternary ammonium ion and montmorillonite was used as the clay mineral of the support. Go and sample 14
I got The content of cetylpyridinium ions was 8.4% by weight.

Example 15 [Alkylbenzyldimethylammonium ion / γ-titanium phosphate] The procedure of Example 8 was repeated except that alkylbenzyldimethylammonium ion was supplied as the quaternary ammonium ion by alkylbenzyldimethylammonium chloride. Anthelmintic sample 15 was obtained. The content of alkylbenzyldimethylammonium ion is 10.4
% By weight.

Comparative Example 1 [Alkyl benzyl dimethyl ammonium chloride simple substance] Alkyl benzyl dimethyl ammonium chloride (benzalkonium chloride) which is a quaternary ammonium ion.
The simple substance was Sample 16.

Comparative Example 2 Sample 17 was prepared by holding Sample 16 of Comparative Example 1 at 150 ° C. for 2 hours.

COMPARATIVE EXAMPLE 3 Sample 18 of Comparative Example 1 was taken in an amount of 5 g, immersed in 10 liters of tap water for 24 hours, filtered and dried.

Comparative Example 4 [Cetylpyridinium chloride simple substance] Sample 19 was a single substance of cetylpyridinium chloride, which is a quaternary ammonium ion.

Comparative Example 5 Sample 20 was prepared by holding Sample 19 of Comparative Example 4 at 150 ° C. for 2 hours.

Comparative Example 6 5 g of the sample 19 of the comparative example 4 was immersed in 10 liters of tap water for 24 hours, filtered and dried to obtain a sample 21.

Test 1 : Egg-killing effect of dog wormworm eggs The ovum-killing effect of dog beetle worm eggs of Samples 1 to 21 obtained in Examples 1 to 15 and Comparative Examples 1 to 6 was tested. As the dog wormworm eggs used in the test, 100% single-cell stage eggs that parasitize the dog's uterus were collected and placed in an aqueous solution whose sample concentration was adjusted to 25 mg / ml for each sample.
The egg-killing effect was examined by the growth condition after leaving it for a day. During the development process, single-cell stage eggs become larval-encapsulated eggs through morula premature eggs, mulberry late-stage eggs, and bryophyte-stage eggs. The ineffective anthelmintic agent becomes almost 100% larva-containing eggs after 10 days. With some kinds of anthelmintic agents, even the larva-embedded eggs develop, but the larva may be dead in the egg. Therefore, after confirming that the larva-embedded eggs are 100%, the eggshell is broken and the larvae are alive or dead. It confirmed and investigated the extermination effect. For the extermination effect, the number of unfertilized eggs is subtracted from the total number of eggs collected to calculate the number of fertilized eggs. The number of larva-embedded eggs that had developed was examined, and the number obtained by dividing the number by the number of fertilized eggs was expressed as a percentage to give the degree of development. The results are shown in Table 1.

Test 2 : Insecticidal effect of Larvae of canine larvae Samples 1 to 21 obtained in Examples 1 to 15 and Comparative Examples 1 to 6 were tested for their larvicidal efficacy. As the larvae of the canine helminth used in the test, those obtained by collecting 100% single-cell stage eggs parasitizing the uterus of dogs and growing the larvae were used. The larvae were put into an aqueous solution whose sample concentration was adjusted to 10 mg / ml for each sample, and the extermination effect was examined by the growth status after standing for 1 day at 37 ° C, and the number of dead insects was divided by the number of collected insects. The numerical value was expressed as a percentage and used as the growth rate. Table 2 shows the results.

[0043] .

[0044] .

As can be seen from Tables 1 and 2, sample 1
It can be seen that the insect repellents of Examples 15 to 15 of the present invention show good ovicidal and insecticidal effects, and are stable to heat and to various solvents such as water, alcohol and acetone.

Of particular note is the fourth, which has anthelmintic activity.
It is shown that both the ovicidal effect and the insecticidal effect are improved by intercalating the primary ammonium salt with the carrier having the cation exchange ability, as compared with the simple ammonium salt alone (Sample 16 and Sample 19).

[0047]

As described above, the anthelmintic agent of the present invention is vulnerable to heat by itself and intercalates a quaternary ammonium ion having an anthelmintic action, which is easily dissolved in various solvents, on a predetermined support. By making it harder, the thermal stability is improved and it becomes insoluble in various solvents. As a result, by applying it to open spaces such as sandboxes and drainage channels such as drainage gutters, the anthelmintic effect can be maintained for a long time, effectively preventing the spread of parasites to humans and animals. You can

Claims (3)

[Claims] 1. An anthelmintic agent characterized by intercalating a quaternary ammonium ion having an anthelmintic action with a layered phosphate or a clay mineral. 2. The layered phosphate is of the general formula M (HPO
₄ ) ₂ · XH ₂ O (wherein M is Zr, Ti or Ce, and X = 0 to 2) and a crystalline layered phosphate and a chemical formula AlH ₂ P ₃ O ₁₀ · 2H ₂ O The anthelmintic agent according to claim 1, which is selected from the group consisting of aluminum tripolyphosphate represented by: 3. The anthelmintic agent according to claim 1, wherein the clay mineral is selected from the group consisting of crystalline hydrous silicates belonging to the genus Smectite of natural products or synthetic products.