WO2017170970A1 - Composition for controlling microsporidia in fishes and method for controlling microsporidia in fishes using same - Google Patents

Abstract

A composition for controlling microsporidia in fishes is prepared by using, as an active ingredient, at least one kind of compound selected from the group consisting of a compound represented by general formula (I) [wherein R², R⁴, R⁵, R⁶ and R⁷ independently represent a specific substitute], a pharmaceutically acceptable salt thereof, and a compound capable of forming a compound represented by general formula (I) when metabolized in a fish body. Provided is a method for controlling microsporidia in fishes, said method comprising using the aforesaid composition for controlling microsporidia in fishes so as to exert excellent effects of preventing microsporidia infection in fish muscles or organs, and/or inhibiting the proliferation of microsporidia in fish muscles or organs, and/or exterminating microsporidia from fish bodies, and having high safety.

Description

Composition for controlling microspores of seafood and method for controlling microspores of seafood using the same

The present invention relates to a composition for controlling microspores of seafood and a method for controlling microspores of seafood using the same.

Microsporidia are a group of unicellular eukaryotes that parasitize the cells of various animals such as insects, crustaceans, seafood, and mammals, and many of them are pathogenic to these animals. As microsporeworms that are pathogenic to seafood,
(1) Amberjack, Hamachi encephalomyelitis-causing microsporidia,
(2) Heterosporis anguillarum, which causes downy mildew in cultured eels
(3) Glugea plecoglossi, etc. that cause Ayu gurugeosis
(4) Microsporidium takedai causing rainbow trout in Takeda microsporidia,
(5) Microsporidium seriolae that causes downy mildew
(6) Enterocytozoon hepatopenaei, which is microsporidia in cultured shrimp, is known.

Buko becosis is an infectious disease of mojaco (brass fry) caused by the microsporidia Microsporidium seriolae, which is currently confirmed in Japan and Taiwan. When Mojaco is infected with Microsporidium seriolae, a cheese mass cyst (spore sac) that can be seen with the naked eye is formed in the muscle. After the formation of the cysts, the fish body becomes uneven as the surrounding muscle tissue melts. Beco's disease generally disappears with age, but part of it remains in the muscle at the time of shipment, which can greatly reduce the commercial value. For this reason, farmers have suffered significant economic losses. In recent years, even in cultured amberjack, although the types of microsporidia that cause it are different, the occurrence of downy mildew has become a problem and the damage is on the rise.

If downy mildew is found in cultured yellowtail after shipment, it will not only cause complaints from consumers and discount requests from graders from distributors, but in the worst case it will result in suspension of transactions. Farmers can be severely hit. Furthermore, if the fish weight exceeds 4 kg, it is difficult to determine whether or not the child suffers from downy mildew from the appearance. Therefore, there is no defense method at the time of shipment.

More than 25 years have passed since Beko's downy mildew was reported, but there are no effective treatments, no therapeutic drugs or vaccines that are effective against downy mildew such as yellowtail, and no control method has been established. Currently. For this reason, it is a realistic measure to stop infection mildly by breeding management. Beko disease infection is concentrated in Mojaco at a specific time (May-August), and yellowtail has been considered to cause little infection since then. Therefore, the only realistic response is to despise the appearance of irregularities on the body surface at the time of vaccination (May to June). However, as for the sputum at the time of vaccination, an economic loss is incurred due to a decrease in yield because the living body is disposed of. In addition, there are no scientifically validated data on the post-mortem results, so questions remain about the effects.

Experimentally, it has been reported that when seawater filtered with sand was used as breeding water, there was no occurrence of downy mildew, but considering the scale and management ability, Virtually impossible.

Another reason for the late establishment of prevention and treatment methods for downy mildew is that the detailed life cycle of downy mildew is unknown. In addition, as a factor that has become a bottleneck in the development of therapeutic drugs, a method for culturing microsporeworms, which are the causative microorganisms, has not been established. It is mentioned that it does not exist. Furthermore, even if microsporeworms obtained from infected fish are directly inoculated into other fish, infection is not established, and therefore, efficient infection experiments in the laboratory cannot be performed. As described above, it is not possible to conduct a test for basic data for control measures for downy mildew.

Benzimidazole drugs are examples of drugs that have a high therapeutic effect on microsporidia in terrestrial animals including humans. For example, in an antibacterial activity test in a culture test, it has been reported that high antibacterial activity is observed for benzimidazole drugs or fumagillin against some microsporidia. In particular, albendazole (see the following formula) has been reported to exhibit high antibacterial activity against many microsporeworms (see Non-Patent Documents 3 to 7).

In addition, benzimidazole-containing drugs including albendazole have become the first choice for encephalistosis in rabbits caused by human microsporidia and microsporidia as the causative agent (see Non-Patent Document 8). ).

On the other hand, as for the report on microsporidian countermeasures in fish, fumagillin, which is an antibiotic against amoeba, is used for Ayu gulgeosis (causative pathogen is a kind of microsporidia belonging to the subfamily of Apansporoblast. Glugea plecoglossi (see Non-Patent Document 1) and eel beko disease (causal pathogen is Heterosporis anguillarum: see Non-Patent Document 2), a high therapeutic effect was observed. Has been reported.

It has been reported that, as a result of a medicinal bath with a benzimidazole-type substance, the decay of pathogenic parasites was observed under a microscope. However, only changes in the protozoa morphology under the microscope after drug sensitization have been confirmed. In addition, glugea anomala is a microsporidia with a pathology that is clearly different from the genus Microsporidium genus, which is susceptible to the action of drugs by a chemical bath and produces cysts in muscles, mainly because it makes cysts on the surface of fish. Non-patent document 9).

Benzimidazole drugs are approved in many countries as animal husbandry and human medicines for parasitic diseases. In Japan as well, as human body drugs, echinococcus control agent, escazole (main component: albendazole), as livestock medicine, facinex (main component: triclabendazole), roundworm, roundworm, whipworm Marine bantel (main component: fenbendazole (see the formula below) for trough puffer's aphids (heterobotulosis) as an insecticide, flumoxal (main component: fulbendazole), Maypol (main component: fenbendazole), and a marine product )) Is commercially available.

However, fumagillin is not approved as a human body medicine or animal husbandry because of its low safety against animals. As for benzimidazole derivatives, only changes in the protozoa morphology under a microscope after drug sensitization to the spiderfish gulgea disease have been confirmed. In addition, glugea anomala is a microsporidia with a pathological condition that is distinctly different from the genus Microsporidium, which is susceptible to the action of drugs in the bath because it makes cysts mainly on the body surface of fish, and forms cysts in the muscles. For this reason, it is not an exaggeration to say that there is no information on the control effect against the genus Microspodium, which is the most important from the viewpoint of productivity for aquaculture business.

The present invention has been made in view of the above circumstances, and prevents the infection of sea urchin muscles or organs by microsporidia and / or suppresses the growth of microspores in seafood muscles or organs. And / or a composition for controlling microspores of seafood that is highly effective in controlling microsporeworms from the body of seafood and is excellent in safety, and control of microsporeworms of seafood using the same The purpose is to provide a method that can be effectively used in industry.

A first aspect of the present invention that meets the above-described object is represented by the following general formula (I), prevents infection of microspores to muscles or organs of seafood and / or muscles or organs of seafood A compound having an activity of inhibiting the growth of microsporeworms and / or controlling microsporeworms from the body of fish and shellfish, its pharmaceutically acceptable salt, and metabolism in the body of fish and shellfish An object of the present invention is to provide a composition for controlling microspores of fish and shellfish containing one or more selected from the group consisting of compounds that produce a compound represented by formula (I) as an active ingredient. It is.

In the general formula (I),
R ² represents an amino group, a functional group represented by the formula —NH—COOR ⁸ , a functional group represented by the formula —N═CHR ⁹ , a functional group represented by the formula —N═CR ¹⁰ (R ¹¹ ), A functional group selected from the group consisting of a 2-thiazolyl group and an alkylthio group,
R ⁴ , R ⁶ and R ⁷ are each independently a hydrogen atom, halogen atom, nitro group, sulfonic acid group, carboxyl group, cyano group, acyl group, alkyl group, cycloalkyl group, alkoxyl group, aryl group, From heteroaryl group, aryloxy group, heteroaryloxy group, substituted acyl group, substituted alkyl group, substituted cycloalkyl group, substituted alkoxyl group, substituted aryl group, substituted heteroaryl group, substituted aryloxy group, substituted heteroaryloxy group An atom or functional group selected from the group consisting of
R ⁵ represents a hydrogen atom, an amino group, a functional group represented by the formula —NH—COOR ¹² , an alkoxyl group, an alkylthio group, an arylthio group, an alkyl sulfoxide group (an alkylsulfinyl group), an aryl sulfoxide group (an arylsulfinyl group), Acyl group, substituted alkoxyl group, substituted alkylthio group, substituted alkyl sulfoxide group (substituted alkylsulfinyl group), substituted aryl sulfoxide group (substituted arylsulfinyl group), substituted acyl group, halogen group, aryloxy group, substituted aryloxy group and R An atom or a functional group selected from the group consisting of ¹³ —CO—NH— (R ¹³ is an alkyl group);
R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² are each independently an alkyl group, cycloalkyl group, alkoxyl group, aryl group, heteroaryl group, substituted acyl group, substituted alkyl group, substituted cycloalkyl group , A substituted alkoxyl group, a substituted aryl group, or a substituted heteroaryl group.

The second aspect of the present invention is represented by the above general formula (I), prevents infection of microsporeworms to the muscles or organs of seafood and / or microscopically in the muscles or organs of seafood. A compound having an activity of inhibiting the growth of spores and / or eliminating microsporeworms from the body of fish and shellfish, a pharmaceutically acceptable salt thereof, and metabolism in the body of fish and shellfish, the above general formula (I) By providing a method for controlling microsporeworms in fish and shellfish, comprising the step of administering to the fish and shellfish a composition comprising one or more selected from the group consisting of compounds that produce the compound represented by It solves the problem.

In the composition for controlling microsporeworms of seafood according to the first aspect of the present invention and the method for controlling microsporeworms of seafood according to the second aspect of the present invention, the composition is represented by the general formula (I). Is a compound represented by the following formulas (1) to (7) and (10), and the compound that produces the compound represented by the general formula (I) is represented by the following formula (8): ) And any of the compounds represented by (9).

In the composition for controlling microsporeworms of seafood according to the first aspect of the present invention and the method for controlling microsporeworms of seafood according to the second aspect of the present invention, the seafood is, for example, perch It may be a fish belonging to (Perciformes) or the flounder (Pleuronectiformes).

In the composition for controlling microspores of fish and shellfish according to the first aspect of the present invention and the method for controlling microsporeworms of seafood according to the second aspect of the present invention, the fish and shellfish are periwinkle. (Scombridae) Tuna genus (Thunnus), Persimmonidae (Carangidae) Buri (Seriola), Persimmonidae (Sparidae) Red sea bream (Chrysophrys), Lepidoptera (Paralichthyidae) Flatfish (Paralichthys) or flounder It may be a fish belonging to the genus Pleuronectidae (Verasper).

In the composition for controlling microspores of fish and shellfish according to the first aspect of the present invention and the method for controlling microspores of seafood according to the second aspect of the present invention, the microsporeworm is, for example, Microsporidium. It may be a microsporeworm belonging to the genus.

In the composition for controlling microspores of seafood according to the first aspect of the present invention and the method for controlling microspores of seafood according to the second aspect of the present invention, the microsporeworm is Microsporidium seriolae. There may be.

In the composition for controlling microspores of fish and shellfish according to the first aspect of the present invention, the composition may be, for example, an oral administration agent, a feed for fish farming, an injection, or a bath powder. Good.

In the present invention, “control of microsporeworms” means prevention of infection of microsporeworms, prevention of growth of microsporeworms that have entered (infected) the body of seafood, extermination and other muscles of A seafood Or it refers to the prevention of microspore invasion into organs and the management of the population (including extermination and killing).

In the method for controlling microsporeworms of seafood according to the second aspect of the present invention, the administration to the seafood may be oral administration. In this case, the first of the present invention is an oral preparation. The composition for controlling microspores of fish and shellfish according to the embodiment is applied once or a plurality of times at intervals of 1 day or more and 180 days or less so that the dose of the active ingredient is 0.1 mg / kg or more and 100 mg / kg or less. The composition for controlling microsporeworms of fish and shellfish according to the first aspect of the present invention, which is an oral preparation, may be effective for preventing the infection of fish and shellfish by oral administration. The microsporeworms of fish and shellfish may be controlled by oral administration once or multiple times at intervals of 6 hours or more and 180 days or less so that the dose of the component is 20 mg / kg or more and 400 mg / kg or less. .

In the method for controlling microsporeworms of seafood according to the second aspect of the present invention, the composition for controlling microsporeworms of seafood according to the first aspect of the present invention, which is an oral agent, is used as an active ingredient thereof. Even if the dose is 20 mg / kg or more and 400 mg / kg or less, it is administered orally several times at intervals of 3 days or more and 180 days or less to control the microsporidia of seafood and prevent reinfection. Good. In this case, oral administration may be performed at intervals of 5 days or more and 21 days or less, and the plurality of oral administrations may be defined as one cycle, and the cycle may be repeated at intervals of 3 days or more and 180 days or less.

In the method for controlling microspores of seafood according to the second aspect of the present invention, the administration to the seafood may be intramuscular injection or intraperitoneal injection.

In the method for controlling microspores of fish and shellfish according to the second aspect of the present invention, the administration to the fish and shellfish may be immersion in a medicine bath, and in this case, it is a medicine bath. Immersion in fish and shellfish in a medicinal bath solution containing the composition for controlling microspores of fish and shellfish according to the first aspect of the present invention in an amount such that the concentration of the active ingredient is 1 to 1000 ppm. Administration may be performed.

According to the present invention, it is possible to prevent infection of microsporeworms in muscles or organs of seafood and / or suppress the growth of microsporeworms in muscles or organs of seafood, and / or the body of seafood. The present invention provides a composition for controlling microspores of seafood that is highly effective in controlling microsporeworms and is excellent in safety, and a method for controlling microspores of seafood using the same.

Subsequently, an embodiment of the present invention will be described to provide an understanding of the present invention.

[First Embodiment]
Composition for controlling microspores of seafood according to the first embodiment of the present invention (hereinafter sometimes referred to as “composition for controlling microspores of seafood” or simply “composition”) .) Is represented by the following general formula (I), and prevents the infection of fish and muscles or organs with microsporeworms and / or the growth of microspores in fish and shellfish muscles or organs: It is represented by the following general formula (I) by a compound having an activity of inhibiting and / or eliminating microsporeworms from the body of fish and shellfish, a pharmaceutically acceptable salt thereof, and metabolism in the body of fish and shellfish One or more selected from the group consisting of compounds that produce compounds (prodrugs) are included as active ingredients.

In the general formula (I),
R ² represents an amino group, a functional group represented by the formula —NH—COOR ⁸ , a functional group represented by the formula —N═CHR ⁹ , a functional group represented by the formula —N═CR ¹⁰ (R ¹¹ ), A functional group selected from the group consisting of a 2-thiazolyl group and an alkylthio group,
R ⁴ , R ⁶ and R ⁷ are each independently a hydrogen atom, halogen atom, nitro group, sulfonic acid group, carboxyl group, cyano group, acyl group, alkyl group, cycloalkyl group, alkoxyl group, aryl group, From heteroaryl group, aryloxy group, heteroaryloxy group, substituted acyl group, substituted alkyl group, substituted cycloalkyl group, substituted alkoxyl group, substituted aryl group, substituted heteroaryl group, substituted aryloxy group, substituted heteroaryloxy group An atom or functional group selected from the group consisting of
R ⁵ represents a hydrogen atom, an amino group, a functional group represented by the formula —NH—COOR ¹² , an alkoxyl group, an alkylthio group, an arylthio group, an alkyl sulfoxide group (an alkylsulfinyl group), an aryl sulfoxide group (an arylsulfinyl group), Acyl group, substituted alkoxyl group, substituted alkylthio group, substituted alkyl sulfoxide group (substituted alkylsulfinyl group), substituted aryl sulfoxide group (substituted arylsulfinyl group), substituted acyl group, halogen group, aryloxy group, substituted aryloxy group and R An atom or a functional group selected from the group consisting of ¹³ —CO—NH— (R ¹³ is an alkyl group);
R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² are each independently an alkyl group, cycloalkyl group, alkoxyl group, aryl group, heteroaryl group, substituted acyl group, substituted alkyl group, substituted cycloalkyl group , A substituted alkoxyl group, a substituted aryl group, or a substituted heteroaryl group.
The substituted or unsubstituted alkyl group in the general formula (I) is preferably an alkyl group having 1 to 6 carbon atoms, preferably 1 to 3 carbon atoms.
Included in the above general formula (I) are a substituted or unsubstituted alkylthio group, a substituted or unsubstituted acyl group, a substituted or unsubstituted alkoxyl group, and a substituted or unsubstituted alkyl sulfoxide group (alkylsulfinyl group). The alkyl groups are each independently an alkyl group having 1 to 6 carbon atoms, preferably 1 to 3 carbon atoms.
The substituted or unsubstituted cycloalkyl group is preferably a cycloalkyl having 3 to 7 carbon atoms.
The substituted or unsubstituted aryl group in the above general formula is preferably a phenyl group.
As the aryl group of the substituted or unsubstituted aryloxy group, substituted or unsubstituted acyl group, substituted or unsubstituted arylthio group, substituted or unsubstituted aryl sulfoxide group (arylsulfanyl group) in the above general formula (I), A phenyl group is preferred.
A halogen atom can be mentioned as a substituent of an aryl group.
Examples of the substituted phenyl group include a 4-fluorophenyl group and a 2,3-dichlorophenyl group.
Examples of the acyl group having a substituted or unsubstituted aryl group include a phenylcarbonyl group and a 4-fluorophenylcarbonyl group.
An example of a substituted aryloxy group is a 2,3-dichlorophenyloxy group.
Examples of the alkylthio group include a methylsulfanyl group, an ethylsulfanyl group, and a propylsulfanyl group.
Examples of the arylthio group include a phenylthio group.
Examples of the alkyl sulfoxide group (alkylsulfinyl group) include a methylsulfinyl group, an ethylsulfinyl group, and a propylsulfinyl group.
Examples of the aryl sulfoxide group (arylsulfinyl group) include a phenylsulfinyl group.

Benzimidazole is a compound composed of a complex ring of benzene and imidazole (benzimidazole ring) as shown in the general formula (I), and this skeleton is strong against tubulin in nematode and microsporidia cells. By binding, it is thought to exert an anthelmintic action by inhibiting the polymerization action of intracellular microtubules. Moreover, the difference in antibacterial activity is recognized by the difference in the functional group of a side chain (reference literature: E.Lacey. Mode of action of benzimidazoles. Parasitology Today 1990, 6, p112-115.).

The active ingredient of the control composition is a benzimidazole derivative, and the benzimidazole derivative containing a basic functional group such as an amino group or an acidic functional group such as a carboxylic acid group or a sulfonic acid group as a substituent. Pharmaceutically acceptable salts and compounds that produce benzimidazole derivatives or pharmaceutically acceptable salts thereof by metabolism in the body of fish and shellfish (not necessarily containing a benzimidazole ring). . The active ingredient may be one of these, or a mixture containing any two or more of them in any proportion.

Specific examples of pharmaceutically acceptable salts include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, ammonium salt, acetate salt, propionate salt, butyrate salt, Organic acid salts such as lactate, tartrate, citrate, succinate, fumarate and maleate, inorganic acid salts such as hydrochloride, nitrate, sulfate, hydrogensulfate, carbonate, bicarbonate Is mentioned.

Preferable examples of the prodrug of the compound represented by the general formula (I), a pharmaceutically acceptable salt thereof, and a compound that generates the compound represented by the general formula (I) include the following formula (1) ) To (10).
The compound of the formula (8) is an albendazole prodrug, and the compound of the formula (9) is a fenbendazole prodrug.

Of these, fenbendazole represented by formula (1), albendazole represented by formula (3), flubendazole represented by formula (6), and formula (10) are particularly preferable. Triclabendazole.

The target seafood is not particularly limited. For example, fish belonging to the order Perciformes or Pleuronectiformes, and particularly belonging to the genus Scombridae, Thunnus, bluefin tuna, southern bluefin tuna , Bigeye, yellowfin, etc., Periphyceae (Carangidae) belonging to the genus Seriola, Amberjack, Hiramasa, Persimmonidae (Sparidae), Red sea bream (Chrysophrys), Red sea bream, Flatfish, Paralechthyidae ) Flatfish belonging to the genus Paralichthys, Hoshigarei belonging to the genus Pleuronectidae and Verasper.

Although the target microsporidia is not particularly limited, for example, it belongs to the genus Microsporidium, and in particular, Microsporidium seriolae, which is a causative agent of yellowtail rot.

The composition for controlling microspores of seafood may take any form suitable for administration to seafood, and specific examples include oral preparations, injections, and bath preparations. . These compositions may contain components other than at least one active ingredient selected from any pharmaceutically acceptable carrier, solvent, excipient, spreading agent and other additives. Known or conventionally used carriers, solvents, excipients, spreading agents and other additives can be used.
As described above, it comprises a compound represented by general formula (I) and a pharmaceutically acceptable salt thereof, and a compound that generates a compound represented by general formula (I) by metabolism in the body of fish and shellfish. At least one selected from the group can be used as an active ingredient of the composition for controlling microsporeworms. Therefore, from the group consisting of a compound represented by the general formula (I) and a pharmaceutically acceptable salt thereof, and a compound that produces a compound represented by the general formula (I) by metabolism in the body of fish and shellfish. At least one selected can be used as an active ingredient in the production of a composition for controlling microsporeworms. In the production of the composition for controlling microsporidia, at least one active ingredient selected from any of the above-mentioned pharmaceutically acceptable carriers, solvents, excipients, spreading agents and other additives. These ingredients may be blended. Therefore, this invention includes the usage method in manufacture of the composition for microspore insect control of such an active ingredient.

[Second Embodiment]
The method for controlling microspores of fish and shellfish according to the second embodiment of the present invention (hereinafter sometimes referred to as “control method of microspores of fish and shellfish” or simply “control method”). Represented by the above general formula (I), preventing the infection of seafood muscles or organs with microsporeworms and / or suppressing the growth of microspores in seafood muscles or organs, and / or Or from a compound that has the activity of controlling microsporidia from the body of fish and shellfish, a pharmaceutically acceptable salt thereof, and a compound that generates the compound represented by the general formula (I) by metabolism in the body of fish and shellfish A step of administering one or more selected from the group to seafood. In addition, about the matter which overlaps with description of the composition for controlling the microsporeworm of the seafood concerning the 1st Embodiment of this invention, description is abbreviate | omitted.

As for the administration method to the seafood of the composition for controlling the microspores of the seafood that can be used in the method for controlling the microspores of the seafood, any administration method is particularly applicable as long as it can be applied to the seafood. Can be used without limitation. Specific examples of the administration method include oral administration, injection (intramuscular injection, intraperitoneal injection), and immersion administration in a drug bath.

In the case of oral administration, administration in any form suitable for oral administration is possible, but it is convenient and preferable to ingest with feed in the form of inclusion in feed during feeding. The dose, administration interval, and administration period are appropriately adjusted according to the target seafood, the type of microsporeworm to be controlled, and the purpose of administration (for example, prevention (infection prevention), extermination, etc.). For the prevention of microsporeworms, for the control of microsporeworms of seafood at a single time or at intervals of 1 day or more and 180 days or less so that the dose of the active ingredient is 0.1 mg / kg or more and 100 mg / kg or less. The composition is administered orally multiple times. By administering the composition for controlling microspores of fish and shellfish at such doses and intervals, the effect of preventing microspore infections is maintained for at least about 4 weeks after the end of the administration.

In the case of control of microsporidia, it is orally administered once or multiple times at intervals of 6 hours or more and 180 days or less so that the dose of the active ingredient is 20 mg / kg or more and 400 mg / kg or less. In the case of multiple administrations, the dose for each administration may be changed, and the administration interval may not be constant.

In the case of controlling microsporidia and preventing reinfection, the dose of the active ingredient is 20 mg / kg or more and 400 mg / kg or less, preferably 3 days or more and 180 days or less, more preferably 5 days or more and 21 days or less, The composition for controlling microspores of seafood may be orally administered multiple times. When the composition for controlling microspores of fish and shellfish is administered at such doses and intervals, the composition for controlling microspores of fish and shellfish per time increases, but between each time of administration In addition, it is expected that fish and shellfish will acquire immunity to microsporidia and the reinfection prevention effect of microsporidia will last for a long period of time, and the total dose of the composition for controlling microspores of seafood Can be reduced. In this case, the plurality of oral administrations described above may be one cycle, and this administration cycle may be repeated at intervals of 3 days or more and 180 days or less.

In the case of immersion administration in a chemical bath, the concentration of the active ingredient in the chemical bath solution is, for example, 0.1 to 1000 ppm. The most preferable concentration and time are 10 mg / kg and 2 hours, but since the effect and toxicity differ depending on the water temperature, it is necessary to adjust while observing the state of the fish. Administration may be single or multiple. The concentration of the active ingredient in the chemical bath, the soaking time for each time, and the administration interval are appropriately adjusted according to the drug metabolism status of the target fish. In addition, the administration interval may be constant as in the case of oral administration, or may be changed every time.

In the case of intramuscular and intraperitoneal injection, the concentration of the active ingredient in the injection solution is, for example, 1 mg to 300 mg / kg. Administration may be single or multiple. The most preferred concentration is 10 to 100 mg / kg, and the concentration of active ingredient and the administration interval may be constant as in the case of oral administration, or may be changed each time. Moreover, in order to maintain the blood concentration continuously for a long period of time, it is desirable to use it together with cacao oil or an adjuvant.

Next, examples carried out for confirming the effects of the present invention will be described.
Example 1 Bacterial Disease Prevention Test 1-1. Mojaco's Boko Disease Prevention Test Using Fenbendazole The prevention test was conducted according to the following procedure.
・ Test cage 5m × 5m × 5m
・ Number of test fish 1000 (starting weight 12g)
・ Administration method Oral administration (feeding with spreading agent)
Test period 6 weeks Drug use Fenbendazole (compound represented by the above formula (1))
・ Dose 20mg / kg Bw (20mg per kg fish weight)
・ Dose interval 6 times / week

Sampling inspection was performed according to the following procedure.
Six weeks after the start of administration, each test group (control group (test was conducted under the same conditions as described above except that the feed fed did not contain fenbendazole), fenbendazole group) ) 10 mojakos were taken out from each of them and dropped into 3 pieces, and it was visually inspected for microsporeworm cysts (becocysts) in one body. If becocyst was observed, it was determined as positive and counted. The number of becocysts confirmed with the naked eye was confirmed, and the average number of infections per fish was determined.

Table 1 shows the inspection results.

Regarding the number of infections, the number of positives in the control group was 8 out of 10, whereas the number of positives in the fenbendazole group was 6 out of 10 animals, and no significant difference was observed. On the other hand, the average number of becocysts per fish is 8.0 ± 5.20 for the control group, while it is 3.5 ± 3.83 for the fenbendazole group. Significant differences were observed within 5%.

1-2. Mojaco's downy mildew prevention test using flubendazole The prevention test was conducted according to the following procedure.
・ Test cage 5m × 5m × 5m
・ Number of test fish 1000 (starting weight 12g)
・ Administration method Oral administration (feeding with spreading agent)
Test period 4 weeks Drug used Flubendazole (compound represented by the above formula (6))
・ Dose 20mg / kg Bw (20mg per kg fish weight)
・ Dose interval 6 times / week ・ Sampling test procedure: 1-1. the same as

Table 2 shows the inspection results.

Regarding the number of infections, 7 out of 10 were positive in the control group, while 5 out of 10 were positive in the fulbendazole group. As a result, no significant difference was observed. On the other hand, the average per becocyst was 3.9 ± 2.9 for the control group and 1.0 ± 1.1 for the fulbendazole group. As a result, a significant difference was recognized within 5% between the control group and the fulbendazole group.

1-3. Prevention test using albendazole (1)
The prevention test was conducted according to the following procedure.
・ Test cage 5m × 5m × 5m
・ Number of test fish 1000 (starting weight 7g)
・ Administration method Oral administration (feeding with spreading agent)
Test period 2 months Drug Albendazole (compound represented by the above formula (3))
・ Dose 20mg / kg Bw (20mg per kg fish weight)
・ Dose interval 6 times / week

Sampling inspection was performed according to the following procedure.
Every 2 weeks from the start of administration, 20 mojaco (100 fish in the 8th week after the start of administration) are picked up from each test group, dropped into 3 pieces, and microsporeworm cysts (becocysts) are observed on one side Inspect visually. If becocyst is found, it is determined as positive and counted. The number of becocysts confirmed with the naked eye is confirmed, and the average number of infections per animal is determined.

Table 3 shows the inspection results.

Regarding the number of infections, 38 out of 160 positives were found in the control group, whereas no positive was found in the albendazole group with respect to the number of 160 conducted. As a result, in this test, a surprisingly high preventive effect was observed that the occurrence of downy mildew in the cultured fish was zero.

Table 4 shows the changes in the weight of Mojaco subjected to the test.

From the results of this test, a significant increase in body weight was observed in the albendazole group compared to the control group. This is probably because Beko's disease did not occur, and it grew smoothly without being stressed. In addition, in the albendazole group during the administration period, neither an increase in the number of deaths from the control group nor a decrease in food consumption was observed. This result also suggests that albendazole does not have a detrimental effect on the growth of Mojaco.

1-4. Prevention test using albendazole (2)
The above 1-3. Except that the dose of albendazole was reduced to 5, 10 mg / kg Bw. Albendazole administration and sampling test were performed according to the same procedure. In the 10 mg / kg administration group, the occurrence of becocysts was confirmed (positive) in 100 Mojaco fish 8 weeks after the start of administration. When the dose of albendazole was decreased to 5 mg / kg Bw, the occurrence of becocysts was confirmed in 3 out of 100 Mojaco 8 weeks after the start of administration. When the dose of albendazole is 5 mg / kg Bw, the occurrence of becocysts cannot be completely suppressed, but the occurrence of becocysts is significantly suppressed as compared with the control group.

1-5. Prevention test using albendazole (3)
1-3. In the same manner as above, the administration of albendazole was continued for 16 weeks, and sampling tests were performed at 2 weeks, 4 weeks, 6 weeks, 8 weeks, 12 weeks and 16 weeks after the start of the administration. . Sampling test was performed by the same procedure 4 weeks after the end of the administration of albendazole (20 weeks after the start of administration).

The results of the sampling test are shown in Table 5, and the results of counting the infection rate over the entire administration period of 16 weeks are shown in Table 6, respectively.

In the albendazole group, no becocyst was observed in all the fish sampled during the albendazole administration period. As a result, it was suggested that if the administration of albendazole is continued, beco's disease can be prevented almost completely. Even in Mojaco, which was sampled and tested 4 weeks after the end of administration, no becocyst was observed. From this result, it was confirmed that the effect of preventing the infection with microsporidia by albendazole lasted for at least 4 weeks even after the administration was completed.

1-6. Prevention test using albendazole (4)
A prophylaxis test was conducted using two different methods of administration of albendazole at different doses and intervals. The prevention test was conducted according to the following procedure.
・ Test cage 5m × 5m × 5m
・ Number of test fish 1000 (starting weight 7g)
・ Administration method Oral administration (feeding with spreading agent)
Test period: 6 months Drugs used Albendazole (compound represented by the above formula (3))
・ Dose Test Section 1: 20 mg / kg Bw (20 mg per kg of fish body weight)
Test plot 2: 40 mg / kg Bw (40 mg / kg fish weight)
・ Dosing interval Test group 1: 6 times / week (administration over 16 weeks)
Study group 2: Twice / 2 weeks (administration over 16 weeks)

Sampling inspection is as described in 1-5. The same procedure was followed. The results of the sampling test are shown in Table 7 below.

The dose and administration interval of albendazole per time are as described in 1-1. In the same test group 1, the prevention of becopathic infection did not continue until 8 weeks after the end of the administration of albendazole, and the occurrence of becocysts was confirmed. In the test group 2, the end of the administration of albendazole It was confirmed that the occurrence of becocysts was greatly suppressed even after the lapse of 8 weeks (24 weeks after the start of administration). The becocysts confirmed in Test Zone 2 are old and hardened and are not considered to have newly occurred after the administration of albendazole. From these results, it was suggested that the resistance to reinfection of Beco's disease was acquired in Test Group 2 by administering albendazole by a different administration method from Test Group 1.

1-7. Prevention test using albendazole (5)
Using amberjack instead of Mojaco, a prophylaxis test for downy mildew by administration of albendazole was conducted. The prevention test was conducted according to the following procedure.
・ Test cage 5m × 5m × 5m
・ Number of test fish 1000 (starting weight 50g)
・ Administration method Oral administration (feeding with spreading agent)
Test period 8 weeks Drug Albendazole (compound represented by the above formula (3))
・ Dose 40mg / kg Bw (40mg / kg fish weight)
・ Dose interval 6 times / week ・ Sampling test procedure: 1-1. the same as

The results of the sampling inspection are shown in Table 8 below.

Also for amberjack, it was confirmed that the administration of albendazole significantly suppressed the occurrence of becocysts.

1-8. Prevention test using albendazole (6)
A prophylactic test for amberjack downy mildew was conducted using triclabendazole. The prevention test was conducted according to the following procedure.
・ Test cage 5m × 5m × 5m
・ Number of test animals 1000 (starting weight 50g)
・ Administration method Oral administration (feeding with spreading agent)
-Test period 8 weeks-Drugs used Triclabendazole (compound represented by the above formula (10))
・ Dose 40mg / kg Bw (40mg / kg fish weight)
・ Dose interval 6 times / week ・ Sampling test procedure: 1-1. the same as

The results of the sampling inspection are shown in Table 9 below.

It was confirmed that administration of triclabendazole significantly suppressed the generation of becocysts.

1-9. Prevention test using albendazole (7)
Some microsporeworms of humans and animals have an effect of benzimidazole drugs, and benzimidazole drugs are used as first-line drugs for these microsporeworms. As a mechanism of action, it acts on glutamic acid (E) at the 198th codon of β-tubulin to inhibit protein production. The 198th microsporeworm that does not have the effect of benzimidazole is other than glutamic acid. Therefore, in theory, the microsporeworm β-tubulin gene which is a pathogen of seafood shows a high homology with the microsporeworm β-tubulin gene sensitive to benzimidazole drugs, Furthermore, it can be presumed that a benzimidazole drug is highly likely to be a microsporeworm control drug for those whose codon 198 is glutamic acid. Therefore, the β-tubulin gene was isolated from microsporidia that were infectious to various fish and shellfish, amplified by PCR, sequencing and amino acid sequence confirmation. The results are shown in Table 10 below. The amino acid sequence of β-tubulin of human and rabbit microsporidia is Franzen C, Salzberger B Analysis of the beta-tubulin gene from Vittaforma corneae suggests benzimidazole resistance. Antimicrob Agents Chemother. 2008 Feb; 52 (2): 790 Quoted from -3.

The amino acid sequence of β-tubulin from rabbit-derived microsporidia that is sensitive to benzimidazole drugs is highly homologous to the amino acid sequence of β-tubulin from yellowtail, amberjack, bluefin tuna, red sea bream, and flounder It was. Furthermore, the microsporeworm β-tubulin gene codon 198 derived from these fish was all glutamic acid (E). From the above test results, it was suggested that the microspores derived from red sea bream, hoshigarei and bluefin tuna may be sensitive to benzimidazole.

Example 2: Treatment test 2-1. Therapeutic test of downy mildew-infected mojaco using albendazole The therapeutic test was performed according to the following procedure.
・ Test cage 5m × 5m × 5m
・ Number of test fish: 100 (tests were conducted by selecting fish that were clearly infected with downy mildew by visual inspection at the time of vaccination)
・ Administration method Oral administration (feeding with spreading agent)
Test period 2 months Drug Albendazole (compound represented by the above formula (3))
・ Dose 50mg / kg Bw (50mg / kg fish weight)
・ Dose interval 6 times / week

Examination method Mojaco with irregularities on the surface of the body and visual confirmation that Beko was infected by visual inspection at the time of vaccination was selected and randomly divided into a control group and a test group. Taken on the 0th, 10th, and 21st days after the start of administration, the mochaco was taken down to 3 sheets, tested for becocysts in one body, and positive if the becopathic cysts were observed with the naked eye Aggregated.

Treatment test results The results are shown in Table 11.

1) Percentage of infection with becosis cysts After selecting those with becosis cysts from the appearance and conducting a dosing test, the results of counting the number of positive with becocysts are shown below. There was no difference in the infection rate up to the 10th day of dosing, but the results after 21 days of dosing were positive in 28 of 63 (44.4%) in the test group. In contrast, in the control group, it was 54 out of 82 (65.85%). As a result, a significant difference was recognized at a risk rate of less than 1%.

Claims (27)

1. Represented by the following general formula (I), preventing the infection of the microspores in the muscles or organs of seafood and / or suppressing the growth of microspores in the muscles or organs of seafood; and Compounds having activity to control microsporidia from the body of seafood, pharmaceutically acceptable salts thereof, and compounds that produce a compound represented by the following general formula (I) by metabolism in the body of seafood A composition for controlling microsporidia of fish and shellfish containing one or more selected from the group consisting of as active ingredients.
   

   

   In the general formula (I),
   R ² represents an amino group, a functional group represented by the formula —NH—COOR ⁸ , a functional group represented by the formula —N═CHR ⁹ , a functional group represented by the formula —N═CR ¹⁰ (R ¹¹ ), A functional group selected from the group consisting of a 2-thiazolyl group and an alkylthio group,
   R ⁴ , R ⁶ and R ⁷ are each independently a hydrogen atom, halogen atom, nitro group, sulfonic acid group, carboxyl group, cyano group, acyl group, alkyl group, cycloalkyl group, alkoxyl group, aryl group, From heteroaryl group, aryloxy group, heteroaryloxy group, substituted acyl group, substituted alkyl group, substituted cycloalkyl group, substituted alkoxyl group, substituted aryl group, substituted heteroaryl group, substituted aryloxy group, substituted heteroaryloxy group An atom or functional group selected from the group consisting of
   R ⁵ represents a hydrogen atom, an amino group, a functional group represented by the formula —NH—COOR ¹² , an alkoxyl group, an alkylthio group, an arylthio group, an alkyl sulfoxide group, an aryl sulfoxide group, an acyl group, a substituted alkoxyl group, or a substituted alkylthio group. An atom selected from the group consisting of a substituted alkyl sulfoxide group, a substituted aryl sulfoxide group, a substituted acyl group, a halogen group, an aryloxy group, a substituted aryloxy group and R ¹³ —CO—NH— (wherein R ¹³ is an alkyl group), Functional group,
   R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² are each independently an alkyl group, cycloalkyl group, alkoxyl group, aryl group, heteroaryl group, substituted acyl group, substituted alkyl group, substituted cycloalkyl group , A substituted alkoxyl group, a substituted aryl group, or a substituted heteroaryl group.
2. The compound represented by the general formula (I) is any one of the compounds represented by the following formulas (1) to (7) and (10), and the compound represented by the general formula (I): The composition for controlling microsporeworms of seafood according to claim 1, wherein the compound to be produced is any one of the compounds represented by the following formulas (8) and (9).
   

   
3. 3. The composition for controlling microspores of fish and shellfish according to claim 1 or 2, wherein the fish and shellfish are fish belonging to the order of Perciformes or Pleuronectiformes.
4. The seafood includes Persian Scombridae (Thunnus), Persian Carridae (Seriola), Persian (Sparidae), Chrysophrys, Paralichthyidae (Paralichthyidae) 4. The composition for controlling microspores of fish and shellfish according to claim 3, which is a fish belonging to the genus Paralichthys or the genus Pleuronectidae or Verasper.
5. The composition for controlling microspores of seafood according to any one of claims 1 to 4, wherein the microspores are microsporidia belonging to the genus Microsporidium.
6. 6. The composition for controlling microspores of seafood according to claim 5, wherein the microsporeworm is Microsporidium seriolae.
7. The composition for controlling microspores of fish and shellfish according to any one of claims 1 to 6, which is an oral administration agent.
8. The composition for controlling seafood microsporeworms according to any one of claims 1 to 6, which is a feed for fish farming.
9. The composition for controlling microspores of seafood according to any one of claims 1 to 6, which is an injection.
10. The composition for controlling microspores of fish and shellfish according to any one of claims 1 to 6, which is a bath salt.
11. Represented by the following general formula (I), preventing the infection of the microspores in the muscles or organs of seafood and / or suppressing the growth of microspores in the muscles or organs of seafood; and / Or a compound having an activity to control microsporidia from the body of fish and shellfish, a pharmaceutically acceptable salt thereof, and a compound that generates the compound represented by the general formula (I) by metabolism in the body of fish and shellfish A method for controlling microsporeworms of fish and shellfish, comprising a step of administering to the fish and shellfish a composition comprising one or more selected from the group consisting of as active ingredients.
    

    

    In the general formula (I),
    R ² represents an amino group, a functional group represented by the formula —NH—COOR ⁸ , a functional group represented by the formula —N═CHR ⁹ , a functional group represented by the formula —N═CR ¹⁰ (R ¹¹ ), A functional group selected from the group consisting of a 2-thiazolyl group and an alkylthio group,
    R ⁴ , R ⁶ and R ⁷ are each independently a hydrogen atom, halogen atom, nitro group, sulfonic acid group, carboxyl group, cyano group, acyl group, alkyl group, cycloalkyl group, alkoxyl group, aryl group, From heteroaryl group, aryloxy group, heteroaryloxy group, substituted acyl group, substituted alkyl group, substituted cycloalkyl group, substituted alkoxyl group, substituted aryl group, substituted heteroaryl group, substituted aryloxy group, substituted heteroaryloxy group An atom or functional group selected from the group consisting of
    R ⁵ represents a hydrogen atom, an amino group, a functional group represented by the formula —NH—COOR ¹² , an alkoxyl group, an alkylthio group, an arylthio group, an alkyl sulfoxide group, an aryl sulfoxide group, an acyl group, a substituted alkoxyl group, or a substituted alkylthio group. An atom selected from the group consisting of a substituted alkyl sulfoxide group, a substituted aryl sulfoxide group, a substituted acyl group, a halogen group, an aryloxy group, a substituted aryloxy group and R ¹³ —CO—NH— (wherein R ¹³ is an alkyl group), Functional group,
    R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² are each independently an alkyl group, cycloalkyl group, alkoxyl group, aryl group, heteroaryl group, substituted acyl group, substituted alkyl group, substituted cycloalkyl group , A substituted alkoxyl group, a substituted aryl group, or a substituted heteroaryl group.
12. The compound represented by the general formula (I) is any one of the compounds represented by the following formulas (1) to (7) and (10), and the compound represented by the general formula (I): The method for controlling microsporeworms of fish and shellfish according to claim 11, wherein the compound to be produced is one of the compounds represented by the following formulas (8) and (9).
    

    
13. 13. The method for controlling microspores of seafood according to claim 11 or 12, wherein the seafood is a fish belonging to the order Perciformes or Pleuronectiformes.
14. The seafood includes Persian Scombridae (Thunnus), Persian Carridae (Seriola), Persian (Sparidae), Chrysophrys, Paralichthyidae (Paralichthyidae) 14. The method for controlling microspores of fish and shellfish according to claim 13, which is a fish belonging to the genus Paralichthys or the genus Pleuronectidae or Verasper.
15. The method for controlling microspores of fish and shellfish according to any one of claims 11 to 14, wherein the microspores are microspores belonging to the genus Microsporidium.
16. The method of controlling a microspore of a seafood according to claim 15, wherein the microsporidia is Microsporidium seriolae.
17. The method for controlling microsporeworms of seafood according to any one of claims 11 to 16, wherein the administration to the seafood is oral administration.
18. The composition for controlling microspores of fish and shellfish according to claim 7 or 8, wherein the dose of the active ingredient is 0.1 mg / kg or more and 100 mg / kg or less at a single time or 1 day or more and 180 days or less. The method for controlling microsporeworms of seafood according to claim 17, wherein the microsporeworm infection of seafood is prevented by oral administration multiple times at intervals.
19. 9. The composition for controlling microspores of seafood according to claim 7 or 8, wherein the dose of the active ingredient is 20 mg / kg or more and 400 mg / kg or less at a single time or at intervals of 6 hours or more and 180 days or less. 18. The method for controlling seafood microsporeworms according to claim 17, wherein the microsporeworms of seafood are controlled by oral administration multiple times.
20. 9. The composition for controlling microspores of seafood according to claim 7 or 8, wherein the active ingredient dose is 20 mg / kg or more and 400 mg / kg or less at an interval of 3 days or more and 180 days or less. The method for controlling microspores of fish and shellfish according to claim 17, wherein the microsporeworms of fish and shellfish are controlled and reinfection is prevented by administration.
21. The method for controlling microspores of fish and shellfish according to claim 20, wherein the composition for controlling microspores of fish and shellfish is orally administered at intervals of 5 days or more and 21 days or less.
22. The method for controlling microspores of fish and shellfish according to claim 20 or 21, wherein the plurality of oral administrations are defined as one cycle, and the cycle is repeated at intervals of 3 days or more and 180 days or less.
23. The method for controlling microsporeworms of seafood according to any one of claims 11 to 16, wherein the administration to the seafood is intramuscular injection or intraperitoneal injection.
24. The method for controlling microsporeworms of fish and shellfish according to any one of claims 11 to 16, wherein the fish and shellfish are administered by immersion in a medicine bath.
25. Claims for immersing administration to seafood in a medicinal bath solution containing the composition for controlling microspores of seafood according to claim 10 in an amount such that the concentration of the active ingredient is 1 to 1000 ppm. Item 25. A method for controlling microspores of seafood according to Item 24.
26. From the group consisting of a compound represented by the following general formula (I) and a pharmaceutically acceptable salt thereof, and a compound that produces a compound represented by the following general formula (I) by metabolism in the body of fish and shellfish Prevention of infection of microsporeworms in one or more selected muscles or organs of seafood and / or suppression of microsporeworm growth in muscles or organs of seafood and / or seafood Use to control microsporidia from the body of moss.
    

    

    In the general formula (I),
    R ² represents an amino group, a functional group represented by the formula —NH—COOR ⁸ , a functional group represented by the formula —N═CHR ⁹ , a functional group represented by the formula —N═CR ¹⁰ (R ¹¹ ), A functional group selected from the group consisting of a 2-thiazolyl group and an alkylthio group,
    R ⁴ , R ⁶ and R ⁷ are each independently a hydrogen atom, halogen atom, nitro group, sulfonic acid group, carboxyl group, cyano group, acyl group, alkyl group, cycloalkyl group, alkoxyl group, aryl group, From heteroaryl group, aryloxy group, heteroaryloxy group, substituted acyl group, substituted alkyl group, substituted cycloalkyl group, substituted alkoxyl group, substituted aryl group, substituted heteroaryl group, substituted aryloxy group, substituted heteroaryloxy group An atom or functional group selected from the group consisting of
    R ⁵ represents a hydrogen atom, an amino group, a functional group represented by the formula —NH—COOR ¹² , an alkoxyl group, an alkylthio group, an arylthio group, an alkyl sulfoxide group, an aryl sulfoxide group, an acyl group, a substituted alkoxyl group, or a substituted alkylthio group. An atom selected from the group consisting of a substituted alkyl sulfoxide group, a substituted aryl sulfoxide group, a substituted acyl group, a halogen group, an aryloxy group, a substituted aryloxy group and R ¹³ —CO—NH— (wherein R ¹³ is an alkyl group), Functional group,
    ^{R 8, R 9, R 10} , R 11, R 12 are each independently an alkyl group, a cycloalkyl group, an alkoxyl group, an aryl group, a heteroaryl group, a substituted acyl group, a substituted alkyl group, a substituted cycloalkyl group , A substituted alkoxyl group, a substituted aryl group, or a substituted heteroaryl group.
27. From the group consisting of a compound represented by the following general formula (I) and a pharmaceutically acceptable salt thereof, and a compound that produces a compound represented by the following general formula (I) by metabolism in the body of fish and shellfish Prevention of infection of microsporeworms in one or more selected muscles or organs of seafood and / or suppression of microsporeworm growth in muscles or organs of seafood and / or seafood Use as an active ingredient in the manufacture of a control composition for controlling microsporidia from the body of mosses.
    

    

    In the general formula (I),
    R ² represents an amino group, a functional group represented by the formula —NH—COOR ⁸ , a functional group represented by the formula —N═CHR ⁹ , a functional group represented by the formula —N═CR ¹⁰ (R ¹¹ ), A functional group selected from the group consisting of a 2-thiazolyl group and an alkylthio group,
    R ⁴ , R ⁶ and R ⁷ are each independently a hydrogen atom, halogen atom, nitro group, sulfonic acid group, carboxyl group, cyano group, acyl group, alkyl group, cycloalkyl group, alkoxyl group, aryl group, From heteroaryl group, aryloxy group, heteroaryloxy group, substituted acyl group, substituted alkyl group, substituted cycloalkyl group, substituted alkoxyl group, substituted aryl group, substituted heteroaryl group, substituted aryloxy group, substituted heteroaryloxy group An atom or functional group selected from the group consisting of
    R ⁵ represents a hydrogen atom, an amino group, a functional group represented by the formula —NH—COOR ¹² , an alkoxyl group, an alkylthio group, an arylthio group, an alkyl sulfoxide group, an aryl sulfoxide group, an acyl group, a substituted alkoxyl group, or a substituted alkylthio group. An atom selected from the group consisting of a substituted alkyl sulfoxide group, a substituted aryl sulfoxide group, a substituted acyl group, a halogen group, an aryloxy group, a substituted aryloxy group and R ¹³ —CO—NH— (wherein R ¹³ is an alkyl group), Functional group,
    R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² are each independently an alkyl group, cycloalkyl group, alkoxyl group, aryl group, heteroaryl group, substituted acyl group, substituted alkyl group, substituted cycloalkyl group , A substituted alkoxyl group, a substituted aryl group, or a substituted heteroaryl group.