JP2002097133A - Antimalaria agent and nematicidal agent containing triazene compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an antimalaria agent useful as a medicine, and a nematicidal agent useful as an agrochemical or an animal drug, and further to provide a compound having antimalaria activities and nematicidal activities. SOLUTION: The antimalaria agent and the nematicidal agent contains a compound represented by formula (1) [wherein, ring A is a benzene ring or a pyridine ring; R1 and R2 are each independently hydrogen, a halogen, hydroxy, a lower alkyl which may have a substituent or the like, or form a cyclic group which may have a substituent, with an N atom bonded thereto; X1, X2, X3 and X4 are each independently hydrogen, a halogen, hydroxy, a lower alkyl which may have a substituent or the like], or a salt or solvate thereof. The new compound represented by formula (1), or the salt or solvate thereof is also provided.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to an antimalarial agent useful as a medicament, a nematicide useful as an agricultural or veterinary drug, and a compound having antimalarial activity and nematicidal activity.

[0002]

BACKGROUND OF THE INVENTION Malaria is a malaria parasite (Plasmodium).
Genus) and is transmitted by Anopheles mosquitoes. There are four types of human malaria: P. vivax, P. malariae, and P. falciparum.
And P. ovale are pathogens. Among them, P. falciparum is particularly prone to serious complications and high mortality. Symptoms of malaria are mainly fever, splenomegaly, and anemia, and in addition, hepatoma, gastrointestinal disorders, and brain disorders.

As a remedy for malaria, quinine has been used for a long time, and chloroquine, quinacrine and the like have also been used. Other compounds known to have antimalarial activity include the structural formula:

[0004]

Embedded image There is isometamidium having
This compound is known to have an inhibitory activity on histamine N-methyltransferase and diamine oxidase which have an important effect on antimalarial activity [Bio
chem.Pharmacol. (1984), 33 (9), 1547-53, DS Duc
h et al.]. Also, the structural formula:

[0005]

Embedded image Is also known to have 125 times the antimalarial activity of chloroquine [Z. Trop
enmed. Parasitol. (1971), 22 (3), 243-9, Heischkei
l, R. et al.]. Although several antimalarial drugs are known, malaria epidemics have recently become a global problem due to the emergence of antimalarial drug resistant strains, an increase in overseas travelers, and global warming. Therefore, new antimalarial drugs are eagerly desired. In addition, nematode is a taxonomic
Construct a nematoda. About 10 species of nematodes
It is said to be 100,000, among which there are parasitic nematodes that infest animals and plants, predatory nematodes that prey on small organisms, and self-active nematodes that depend on organic matter and microorganisms in the soil and water to live.
Plant parasitic nematodes that infest crops generally grow parasitically on the root surface or in tissues of the crop, causing nematode disease. The main nematode disease includes root rot nematode disease of potato, Chinese cabbage, strawberry, etc., clubroot nematode disease of mulberry, tomato, etc., rice heart nematode and chrysanthemum leaf nematode. Nematicides are agents used for controlling these nematodes. The nematicide disperses into the soil after soil treatment and needs to come into contact with the nematodes that live there, so that highly volatile fumigating drugs such as DD, DCIP, chlorpicrin, bromide Methyl and the like have been used for a long time.

[0006] Since nematicides need to reach nematodes living in soil, highly volatile soil fumigants that migrate through the soil by self-diffusion are often used. However, soil fumigants also have an adverse effect on cultivated crops and must be used several days to several weeks before planting to remove residual gases if necessary. In addition, a special treatment tool is required, and the amount of soil moisture affects the diffusivity, so that the treatment time is greatly restricted by the weather. Generally, it has a strong irritating odor, so that there are some problems such as a need for protective equipment for workers. The recently emerging non-fumigating nematicides
Since it does not have self-diffusion like a fumigant, it needs to be sufficiently stirred and mixed with soil in advance, and it cannot be said that it can be used easily. In addition, the degree of mixing affects the effectiveness, and a sufficient control effect cannot be obtained in many cases. In view of such circumstances, development of a nematicide that is highly effective and can be easily used has been demanded.

[0007]

SUMMARY OF THE INVENTION In view of the above circumstances, an object of the present invention is to provide a novel antimalarial agent and a nematicide.

[0008]

Means for Solving the Problems The present inventors have conducted intensive studies to find novel antimalarial agents and nematicides, and as a result, specific benzene and pyridine derivatives having an amidino group have antimalarial activity. And found that they have nematicidal activity, and completed the present invention. That is, the present invention provides a compound of the formula (I):

Formula (I):

Embedded image [Wherein, ring A is a benzene ring or a pyridine ring,
R ¹ and R ² are each independently hydrogen, halogen, hydroxy, lower alkyl optionally having substituent (s), lower alkenyl optionally having substituent (s), It may be a good acyl, phenyl or cyano which may have a substituent, or may form a cyclic group which may have a substituent together with a bonding N atom. , X ¹ , X ² , X ³ and X ⁴ are each independently hydrogen, halogen, hydroxy, lower alkyl optionally having substituent (s), lower alkenyl optionally having substituent (s), Lower alkoxy optionally having a group,
Lower alkenyloxy optionally having substituent (s), lower alkynyloxy optionally having substituent (s), carboxy, lower alkoxycarbonyl optionally having substituent (s), optionally having substituent (s) Acyl, an optionally substituted acyloxy, an optionally substituted amino, nitro, cyano or tri (lower alkyl) silyl], a salt thereof, or a solvate thereof. An antimalarial agent containing X ¹ ,
X ² , X ³ and X ⁴ are not all amidinos) and nematicides. The present invention also provides novel benzene and pyridine derivatives among the compounds of formula (I). The present invention also provides a method for treating and / or preventing malaria and a method for controlling nematodes, which comprise administering a compound of the formula (I). Furthermore, there is provided the use of a compound of formula (I) for the manufacture of a medicament for treating and / or preventing malaria and an animal drug or pesticide for controlling nematodes.

[0010]

BEST MODE FOR CARRYING OUT THE INVENTION The lower alkyl in the formula (I) of the present invention includes linear or branched alkyl having 1 to 6 carbon atoms, and includes methyl, ethyl, n-propyl, isopropyl and n-alkyl. Butyl, isobutyl, sec-butyl, te
Examples are rt-butyl, n-pentyl, isopentyl, neopentyl, hexyl, isohexyl and the like. Preferably, it is a C1-C3 alkyl.

The lower alkenyl includes straight or branched alkenyl having 2 to 6 carbon atoms, and includes vinyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl. , Hexenyl, isohexenyl, hexadienyl and the like. Preferably, it is an alkenyl having 2 to 3 carbon atoms.

Acyl includes lower alkylcarbonyl having 1 to 6 carbons, lower alkenylcarbonyl having 2 to 6 carbons and arylcarbonyl having 6 to 10 carbons,
Examples include formyl, a carbonyl group having a lower alkyl group, a carbonyl group having a lower alkenyl group, benzoyl, and naphthylcarbonyl.

When R ¹ and R ² are combined with the N atom to which they are bonded to form a cyclic group which may have a substituent, the cyclic group is one or more nitrogen atoms and Includes aromatic heterocyclic groups and saturated heterocyclic groups having 3 to 6 carbon atoms and which may further contain an oxygen atom and a sulfur atom, and include pyrrolyl, imidazolyl, oxazolyl, thiazolyl, and pyridyl. , Pyridazinyl, pyrimidinyl, pyrazinyl, azetidinyl, pyrrolidinyl, piperidinyl,
Examples include piperazinyl, hexahydroazepinyl, morpholino and thiomorpholino.

The lower alkoxy includes alkoxy having 1 to 6 carbon atoms, preferably 1 to 3 carbon atoms, and includes, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-
Butoxy, isobutoxy, sec-butoxy, tert
-Butoxy, n-pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, isohexyloxy and the like.

[0015] Lower alkenyloxy is defined as having 2 to 2 carbon atoms.
6, preferably 2-3 alkenyloxy,
Examples include vinyloxy, n-propenyloxy, n-butenyloxy, isobutenyloxy, sec-butenyloxy, n-pentenyloxy, isopentenyloxy, butadienyloxy, pentadienyloxy, hexadienyloxy and the like.

Lower alkynyloxy is a compound having 2 to 2 carbon atoms.
6, preferably 2-3 alkynyloxy,
For example, ethynyloxy, n-propynyloxy, n-
Butynyloxy, n-pentynyloxy, isopentynyloxy and the like.

The lower alkoxycarbonyl includes a carboxylic acid group esterified with the above lower alkyl group, and includes methoxycarbonyl, ethoxycarbonyl, n-propyloxycarbonyl, isopropyloxycarbonyl, n-butoxycarbonyl and isobutoxycarbonyl. , Sec-butoxycarbonyl, tert-butoxycarbonyl, n-pentyloxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbonyl, hexyloxycarbonyl, isohexyloxycarbonyl and the like. Preferably, they are methoxycarbonyl and tert-butoxycarbonyl.

The term "acyloxy" includes an oxy group substituted with the aforementioned acyl group, and includes formyloxy, acetyloxy, propionyloxy, butyryloxy, valeryloxy, acryloyloxy, benzoyloxy, and naphthylcarbonyloxy groups. Halogen refers to bromine, chlorine, fluorine or iodine. The term “tri (lower alkyl) silyl” includes a silyl group substituted with the above-mentioned three lower alkyl groups, and includes tri (methyl) silyl.
Silyl is particularly preferred.

In the formula (I), “lower alkyl optionally having substituent (s)”, “lower alkenyl optionally having substituent (s)”, “acyl optionally having substituent (s)”, "Phenyl optionally having substituent (s)", "cyclic group optionally having substituent (s)", lower alkoxy optionally having substituent (s), "optionally having substituent (s)""Good lower alkenyloxy", "optionally substituted lower alkynyloxy", "optionally substituted lower alkoxycarbonyl", "optionally substituted acyloxy" and " Substituents in "amino which may have a substituent (s)" include lower alkyl, lower alkenyl, halogen, aryl (where aryl is
Phenyl and naphthyl, etc.), aryl lower alkyl, hydroxy, lower alkoxy, lower alkenyloxy, acyl, amino, lower alkylamino, imino, acyloxy, carboxy and lower alkoxycarbonyl and the like. Preferably it is lower alkyl, halogen, aryl, hydroxy, lower alkoxy, acyl or carboxy.

As the active ingredient of the antimalarial agent, X¹,
X^Two, X^ThreeAnd X^FourAre not amidino
Compound (I) or a salt thereof or a solvate thereof
Is used, of which R¹And R^TwoAre each independently
Hydrogen, lower alkyl optionally having substituent (s) or
Lower alkenyl which may have a substituent, or
Or has a substituent together with the bonding N atom.
Compounds of formula (I) which form an optionally cyclic group are preferred.
R¹And R^TwoAre each independently a lower alkyl,
Benzyl or benzyl, or
Together with the N atom,
Pyrrolidinyl, piperidinyl, hexahydroaze
Formulas that form pinyl, piperazinyl or morpholino
The compound of (I) is more preferred. Also, X¹, X^Two, X^Three
And X^FourAre each independently hydrogen, halogen, halogen
Lower alkyl and lower alkoxy which may be substituted with
Formula (I), which is silo, nitro or trimethylsilyl
Compound, X¹Is -N = N-NR¹R^TwoIn the para position of
A halogen or a low optionally substituted halogen
A lower alkyl, X ^Two, X^ThreeAnd X^FourAre all hydrogen
A compound of formula (I)¹And R^TwoAre both lower alkyl
Or together with the attached N atom
Pyrrolidinyl or each optionally having a substituent
Forms piperidinyl and X¹, X^Two, X ^ThreeAnd X^FourIs each
Each independently substituted with hydrogen, halogen or halogen
Also preferred are compounds of formula (I) which are optionally lower alkyl.
New

The active ingredients of the nematicide include X ¹ , X ² ,
Compounds of the formula (I), including those in which X ³ and X ⁴ are both amidino, or a salt thereof, or a solvate thereof are used, wherein ring A is a pyridine ring and R ¹
And R ² is lower alkyl which may have a substituent or phenyl which may have a substituent, or R ² has a substituent together with a bonding N atom. X ¹ , X ² , X ³
And X ⁴ is preferably a compound of formula (I) wherein each is independently hydrogen, lower alkyl optionally having substituent (s) or lower alkoxy optionally having substituent (s).

The present invention relates to a compound of the formula (I)
Is a benzene ring, and R ¹ and R ² are
Together with the atom forms pyrrolidinyl, piperidinyl, hexahydroazepinyl, piperazinyl or morpholino which may each have a substituent, and X ¹ is
-N = an optionally substituted lower alkyl bonded to the para position of N-NR ¹ R ² , wherein X ² , X ³ and X ⁴ are all hydrogen. In the formula (I), R ¹ and R ² together with the bonded N atom form piperidinyl, and X ¹ is methyl bonded to the para position of -N = N-NR ¹ R ^2. )) Are preferred. The present invention also provides a novel compound of the formula (I) wherein X ¹ is tri (lower alkyl) silyl,
In particular, X ¹ is trimethylsilyl, X ² , X ³ and X ⁴
Are all hydrogens.

The present invention also provides that the ring A is a pyridine ring,
X ¹ is a halogen substituted at the para position of —N ＝ N—NR ¹ R ² , hydroxy, halogenated lower alkyl, halogenated lower alkoxy, lower alkoxycarbonyl or acyloxy; and X ^{2 to} X ⁴ are all hydrogen. , R ¹ and R ² are each independently a lower alkyl optionally having a substituent, or a pyrrolidinyl optionally having a substituent together with a bonding N atom , Piperidinyl, hexahydroazepinyl, piperazinyl or morpholino (provided that R
X ¹ is not chloro when ¹ is substituted lower alkyl). Also provided are compounds of formula (I). Further, ring A is a pyridine ring, X ^{1 to} X ⁴ are all hydrogen, —N ＝ N—NR ¹ R ² is bonded to the 2-position of the pyridine ring,
R ¹ and R ² are each independently lower alkyl, or together with the attached N atom, pyrrolidinyl, hexahydroazepinyl, piperazinyl or morpholino which may have a substituent. A compound of the formula (I) which may be formed, wherein ring A is a pyridine ring, X ^{1 to} X ⁴ are all hydrogen, and -N = N-NR ¹ R ²
Is bonded to the 3-position of the pyridine ring, and R ¹ and R ² are taken together with the bonded N atoms to form an optionally substituted hexahydroazepinyl, piperazinyl or morpholino , Formula (I) are also provided.

Among the compounds represented by formula (I) of the present invention, particularly preferred compounds are 3,3-dimethyl-1- (m
-Trimethylsilylphenyl) -triazene, 3,3-
Dimethyl-1- (p-trimethylsilylphenyl) -triazene, 3,3-dimethyl-1- (p-trifluoromethylphenyl) -triazene, 1- (p-chlorophenyl) -3,3-dimethyltriazene, 3, 3-dimethyl-1- (2,4,6-trimethylphenyl) -triazene, 1-pyrrolidinylazo-4-trifluoromethylbenzene, 1-piperidinylazo-4-trifluoromethylbenzene, 1-hexamethyleneiminylazo-2 ,
6-dimethylbenzene, 3,3-dimethyl-1-pyridin-3-yl-triazene, 3-hexamethyleneiminylazopyridine, 3-pyrrolidinylazopyridine, 3-
Piperidinylazopyridine, 3,3-dimethyl-1-
(O-trimethylsilylphenyl) -triazene, 1-
Pyrrolidinylazo-2,6-dimethylbenzene, 1-pyrrolidinylazo-2,4,6-trimethylbenzene, 3
-Methyl-3-phenyl-1-pyridin-3-yl-triazene 3-morpholinoazopyridine, 3-methyl-3
-Butyl-1-pyridin-3-yl-triazene, 3,
3-diethyl-1-pyridin-3-yl-triazene,
1-piperidinylazo-4-methylbenzene 1-piperidinylazo-4-pyridine 2-methoxy-5-pyrrolidinylazopyridine 2-methoxy-5-piperidinylazopyridine.

The compounds of the formula (I) can also be used in the form of salts or solvates. Salts of the compounds of formula (I) include salts with inorganic or organic acids, or with inorganic or organic bases, and are not particularly limited as long as they are pharmaceutically acceptable. For example, salts with alkali metals such as sodium and potassium or alkaline earth metals such as calcium and magnesium; salts with organic bases such as ammonium, trimethylamine, triethylamine, and pyridine salts; for example, acetic acid, oxalic acid, maleic acid, and tartaric acid , Methanesulfonic acid, benzenesulfonic acid, formic acid,
Salts with organic acids such as toluenesulfonic acid and trifluoroacetic acid; and salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid. The solvate is not particularly limited as long as it is a pharmaceutically acceptable solvate, and includes, for example, a hydrate and the like. The solvent molecule may be coordinated.

Further, when the compounds of formula (I) contain one or more asymmetric carbon atoms, they may exist in racemic and optically active forms, and may be present in the compounds of formula (I) of the present invention. Includes all these isomers and mixtures thereof.

The compounds of the formula (I) can be prepared from suitable phenyl-substituted anilines or aminopyridines and suitable primary or secondary alkylamines or cycloaliphatic amines. For example, one equivalent of a phenyl-substituted aniline or aminopyridine and an appropriate amount of water are mixed, and while stirring at 0 ° C. to room temperature, an acid such as concentrated H ₂ SO ₄ or concentrated HCl (3 to 5 equivalents).
And added NaNO _2, etc. Nitrate (1.5 eq) in portions, stirred for several minutes to several hours. In another container, a primary or secondary alkylamine or an alicyclic amine (1-1.
5 equivalents) and an inorganic salt (5 to 10 equivalents) such as K ₂ CO ₃ , Na ₂ CO ₃ , NaOH, and KOH, and the aqueous solution is added thereto with stirring at 0 ° C. to room temperature. After stirring for several minutes to several hours,
Extract with a suitable organic solvent, wash with water, dry and concentrate under reduced pressure. If necessary, the compound of formula (I) can be obtained by purification with an organic solvent such as hexane or column chromatography. Further, the compound of the formula (I) may be obtained by combining methods known in the art.

The compound of the formula (I) of the present invention has an antimalarial activity and is useful as an active ingredient of an antimalarial agent, as shown in the following examples. When used as an antimalarial agent, the compound of formula (I) or a salt or solvate thereof is formulated and used as a usual preparation for oral or parenteral administration. As an oral administration preparation, for example,
Various dosage forms, such as solid preparations such as tablets, capsules, granules and powders, and liquid preparations such as syrups, solutions and suspensions, may be mentioned. In the case of parenteral administration, it can be used as a solution or suspension for injection such as intravenous injection, intramuscular injection and subcutaneous injection. In addition, preparations for transdermal administration such as ointments and parenteral preparations such as suppositories can be made. Preferably, it is a preparation for oral administration.

These formulations can be prepared using any suitable carrier known to those skilled in the art,
It can be produced using excipients, solvents, bases and the like.
Excipients include, for example, binders (eg, corn starch, polyvinylpyrrolidone), fillers (eg, lactose, microcrystalline cellulose), disintegrants (eg, sodium starch glycolate), lubricants (eg, stearin) Magnesium acid, talc) and the like are used. Tablets may be coated as appropriate. In the case of liquid preparations such as syrups, solutions and suspensions, for example, suspending agents (eg, methyl cellulose), emulsifiers (eg, lecithin), preservatives and the like are used. Injectable preparations may be in the form of solutions, suspensions or oily or aqueous emulsions, which may contain preservatives, stabilizers or dispersants.

The dose of the compound (I) varies depending on the administration form, the condition of the patient, age, weight, sex, or concomitant drug (if any), and ultimately depends on the judgment of a physician. But 0.05 kg / kg body weight per day
-100 mg, preferably 0.1-10 mg, is orally administered. In the case of parenteral administration, 0.1 mg / kg body weight / day.
Administer 0001-10 mg, preferably 0.01-10 mg. This may be administered in 1 to 3 divided doses.

The compounds of formula (I) of the present invention are also useful as agricultural and animal nematicides. Examples of applicable nematodes include plant parasitic nematodes, insect-preferring and insect parasitic nematodes, animal parasitic nematodes, soil nematodes, and the like. For example, Arenaria root-knot nematode, Ishuku nematode, Strawberry nematode, Rice singares nematode insecticide paddy, Rice cyst nematode, Imogusaresenchu, Ogatahari nematode, Kaichu, Kikuhareenchu, Kitanegusa nematode, Kuki nematode, Walnut nematode , Wheat root nematode, sweet potato root nematode,
Potato cyst nematode, scutella nematode, nematode, soybean cyst nematode, tsubu nematode, sugar beet cyst nematode, pygmy nematode, nagahari nematode, namikuki nematode, foxglove nematode, foxglove nematode, foxglove nematode, foxglove Pin nematodes, bentgrass nematodes, pine wood nematodes,
Citrus nematodes, southern nematode nematodes, wheat cyst nematodes, yumihari nematodes, nematodes and nematodes.

The plants to which the nematocide of the present invention is applied include various cultivated plants such as sugar beet, pineapple, soybean,
Peanut, onion, potato, radish, carrot, cucumber, mulberry, fig, strawberry, apple, tea, green onion, tobacco, chisha, pepper, chrysanthemum, etc., as well as trees (eg, pine, palm), grass, etc. No. Examples of animals to which the nematocide of the present invention is applied include humans and domestic animals (eg, cows, sheep, pigs, goats, chickens, turkeys, horses, rabbits, etc.) and pet animals (eg, dogs, cats, parakeets, etc.) Such as mammals, birds, amphibians, reptiles, or fish.

The nematicide of the present invention contains at least the compound represented by the formula (I) in an amount of 0.1 to 95% by weight, preferably 2 to 80% by weight. These nematicides,
It can be used alone or diluted. The method of use and the concentration of use vary depending on the purpose of use, the target plant or animal, the period of use, the type of soil, etc., but in general,
It is as follows. For example, as a tablet formulation, 10 to 50 kg per 10a is mixed into the soil from the surface up to a depth of about 20 cm. The nematocide of the present invention is 1 per 10a.
0 g to 100 kg, preferably 100 g to 20 kg are used. When the treatment area is large, there is a method of mixing with a tractor or mixing with irrigation water and penetrating into soil. In general, the formulations comprise at least one compound of formula (I) in an amount of 0.1-95% by weight, preferably
Contains 2 to 80% by weight. These preparations can be used alone or diluted. The use concentration depends on the purpose of use,
Depends on the time of use, but generally about 1-5,000pp
m, preferably in the range of about 100 to 5,000 ppm. About 10 g to 5 kg of the compound of formula (I)
/ Ha, preferably about 100 g to 1,000 g
/ Use in hectares.

When the present nematicide is used, it can be mixed with various carriers according to the use scene and used, for example, as granules, wettable powders, emulsions or suspensions.
Embodiments as described above include at least one compound of the present invention and suitable solid or liquid carriers, and, if desired,
Auxiliaries suitable for improving the dispersibility and other properties of the active substance (eg surfactants, spreading agents, dispersants, stabilizers, emulsifiers, suspending agents, penetrants, wetting agents, etc.) Together with the usual method. Examples of solid carriers or diluents include botanicals (eg,
Grain flour, tobacco stem flour, soy flour, walnut flour, vegetable flour, canna refuse, bran, bark flour, fibrous flour, vegetable extraction residue), fibrous substances (eg, paper, cardboard, rags), artificial Plastic powders, clays (eg, kaolin, diatomaceous earth, bentonite, clay, clay), talc and inorganic substances (pyroxene, sericite, pumice, sulfur powder, activated carbon), chemical fertilizers (eg, ammonium sulfate, ammonium phosphate, ammonium nitrate) Urea, ammonium chloride) and the like. Examples of the liquid carrier and diluent include water, alcohols (eg, methanol, ethanol), ketones (eg, acetone,
Methyl ethyl ketone), ethers (eg, diethyl ether, dioxane, cellosolve, tetrahydrofuran), aromatic hydrocarbons (eg, benzene, toluene,
Xylene, methylnaphthalene), aliphatic hydrocarbon (for example, gasoline, kerosene, kerosene), ester, nitrile, acid amide (for example, N, N-dimethylformamide, N, N-dimethylacetamide), halogenated hydrocarbon (Eg, dichloroethane, carbon tetrachloride), solvent naphtha, cyclohexane, and the like.

Examples of the surfactant include alkyl sulfate, alkyl sulfonate, alkylaryl sulfonate, polyethylene glycol ether, polyhydric alcohol esters and the like. Examples of spreading or dispersing agents include casein, gelatin, starch, carboxymethyl cellulose, acacia, alginic acid, lignin,
Bentonite, molasses, polyvinyl alcohol, pine oil, agar and the like. As a stabilizer, PAP
(Isopropyl phosphate mixture), tricresyl phosphate (TCP), tall oil, epoxy oil, surfactants, fatty acids and esters thereof. In addition to the above components, the formulations of the present invention can be used in admixture with other fungicides, insecticides, acaricides, or fertilizers. Further, the nematicide of the present invention can be used in a mixture with an insecticide, a bactericide, a fertilizer, a soil treatment agent (improving agent) and the like.

Hereinafter, the present invention will be described in detail with reference to examples. However, these are merely examples, and the present invention is not limited thereto.

【Example】

Production Examples In the following examples, the melting points were measured by a micro-melting point analyzer MP-S3 of Yanagimoto Seisakusho, and are all uncorrected. Infrared absorption spectrum (IR) was measured using Shimadzu IR-435 and expressed as νcm ⁻¹ . Proton nuclear magnetic resonance spectrum
( ¹ H-NMR) and carbon nuclear magnetic resonance spectrum ( ¹³
C-NMR) was measured using JEOL JNM-GSX270, and tetramethylsilane (TMS) was used as an internal standard. High-resolution mass spectra (HRMS) were measured using JEOL JMS-HX100 at an ionization voltage of 70 eV. Yanagimoto Seisakusho MT-3 type was used for elemental analysis. Specific rotation is JASCO DIP-3
A type 70 polarimeter was used. Thin layer chromatography (TLC)
The precoat Silica gel 60 F254 manufactured by Merck was used for detection, and the detection was confirmed by irradiation with ultraviolet light, heating after penetration of a phosphomolybdic acid reagent solution, or heating after penetration of a ninhydrin reagent solution. Silica gel column chromatography is used as a filler, Merica Silica gel60 (230-
400 mesh ASTM) and followed the method of Still.

Example 1 3,3-dimethyl-1- (m-
Trimethylsilylphenyl) -triazene (Compound 56)
Synthesis of 1) Under a nitrogen atmosphere, 1- (m-bromophenyl) -3,3-
Dimethyl triazene (3.7512 g, 16.4 mmol
l) and THF (16 mL) were cooled to -84 ° C and stirred.
While stirring, 10 mL of n-BuLi / n-hexane (1.
72M, 17.2 mmol), and 5 minutes later
Chlorotrimethylsilane (2.1 mL, 16.6 mmol
l) was added dropwise. Add water to this and add diethyl ether
Extracted three times. Wash the organic layer with brine and dry with anhydrous sodium sulfate.
After drying with thorium, the mixture was concentrated under reduced pressure. Flash this
Separation by column chromatography (50 times weight Si
O _TwoHex: AcOEt = 19: 1, 100 times weight S
iO_TwoHex: AcOEt = 50: 1), compound of the title
The product was obtained in a yield of 3.0403 g (13.7 mmol) and a yield of 6
Obtained at 3%. TLC Rf 0.41 (solvent; Hex: AcOEt = 9: 1) VPC tR (min) 7.04 (state; OV-1 1% 2m 100-230 ℃ 10 ℃ /
Minutes)¹ H NMR (270MHz; solvent CDCl_Three) δ: 7.43 (m, 4H), 3.34
(s, 6H), 0.28 (s, 9H),¹³C NMR (67MHz; solvent CDCl_Three)
δ: 150.13, 141.09, 130.42, 128.27, 126.00, 120.33,
 39.09, -1.08, IR (cm^-1) (State; neat) 2900 (m), 1570 (w), 1440
(s), 1380 (s), 1300 (s), 1240 (s), 1070 (s), 820
(s), 740 (s)

Example 2 3,3-dimethyl-1- (p-
Trimethylsilylphenyl) -triazene (Compound 60)
Synthesis of 4) Under a nitrogen atmosphere, 1- (p-bromophenyl) -3,3-
Dimethyl triazene (3.6575 g, 16.0 mmo
l) and THF (16 mL) are cooled to -84 ° C and n-BuLi / n-hexane (10 mL,
1.72 M, 17.2 mmol) were added dropwise and 5 minutes later chlorotrimethylsilane (2.1 mL, 16.6 m).
mol) was added dropwise. Water was added thereto, extracted three times with diethyl ether, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. This was separated by flash column chromatography (50 times weight SiO ₂ ,
CHCl ₃ : Hex: = 1: 4) to give 2.6812 g (12.1 mmol) of the title compound in a yield of 76%. TLC Rf 0.5 (solvent; Hex: CHCl ₃ = 3: 1) VPC tR (min) 7.88 (state; OV-1 1% 2m 100-230 ℃ 10 ℃ /
Min) ¹ H NMR (270 MHz; solvent CDCl ₃ ) δ: 7.44 (AA'BB ', 4H),
3.34 (br s, 6H), 0.26 (s, 9H), ¹³ C NMR (67 MHz; solvent CDCl ₃ ) δ: 151.39, 136.93, 13
3.95, 119.86, 41.29, 37.36, -1.00, IR (cm ^-1 ) (State; neat) 2950 (s), 1590 (s), 1450
(s), 1410 (s), 1380 (s), 1320 (s), 1250 (s), 1070
(s), 820 (s), 750 (s)

Example 3 3,3-dimethyl-1- (p-
Trifluoromethylphenyl) -triazene (compound 1
120) Synthesis of p-trifluoromethylaniline (2.5730 g, 1
6.0 mmol) and H ₂ O (30 mL) to 0 ° C., and with stirring, concentrated HCl (5.3 mL, 64.5 m).
mol) and NaNO ₂ (1.1991 g, 17.4 g)
mmol) and stirred for 45 minutes. In a separate container, dimethylamine (6.5 mL, 57.7 mmol), K ₂ C
O ₃ (8.4 g, 60.8 mmol) and H ₂ O (53
mL), the temperature was adjusted to 0 ° C, and the above aqueous solution was added with stirring, followed by stirring for 30 minutes. This with diethyl ether
Extracted once, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Recrystallization from hexane gave the title compound. Further, the filtrate was separated by flash column chromatography (50-fold weight SiO ₂ , Hex:
AcOEt = 14: 1), yield of the title compound 3.19.
03 g, 92% yield. TLC Rf 0.31 (solvent; Hex: AcOEt = 9: 1) VPC tR (min) 4.63 (state; OV-1 1% 2m 100-230 ℃ 10 ℃ /
Min) ¹ H NMR (270 MHz; solvent CDCl ₃ ) δ: 3.38 (brd, 6H), 7.
53 (m, 4H), ¹³ C NMR (67 MHz; solvent CDCl ₃ ) δ: 153.54, 126.83 (q),
126.06, 126.00, 124.52 (q), 120.53, 43.24, 35.78, IR (cm ^-1 ) (State; KBr) 2900 (w), 1650 (m), 1480
(m), 1380 (m), 1320 (s), 1160 (s), 1090 (s), 1060
(s), 840 (m)

Example 4 1- (p-chlorophenyl)-
Synthesis of 3,3-dimethyltriazene (compound 862) p-chloroaniline (2.0540 g, 16.1 mmol)
l) and H ₂ O (30 mL) were brought to 0 ° C., concentrated HCl (5.6 mL, 68.2 mmol) and NaNO ₂ (1.1362 g, 16.5 mmol) were added with stirring, and the mixture was stirred for 45 minutes. In a separate container, dimethylamine (7.0 mL, 62.1 mmol), K ₂ CO ₃ (8.5
g, 61.5 mmol) and H ₂ O (53 mL).
Stirred for minutes. This is extracted three times with diethyl ether,
The extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Recrystallization from n-hexane gave the title compound. The filtrate was separated by flash column chromatography (50-fold weight SiO ₂ , Hex: AcOE).
(t = 4: 1) to give quantitatively (yield 3.0517 g) the title compound. TLC Rf 0.16 (solvent; Hex: AcOEt = 9: 1) VPC tR (min) 6.4 (state; OV-1 1% 2m 100-230 ℃ 10 ℃ /
Min) ¹ H NMR (270 MHz; solvent CDCl ₃ ) δ: 3.33 (br s, 6H), 7.
27, 7.35 (AA'BB ', 4H), ¹³ C NMR (67 MHz; solvent CDCl ₃ )
δ: 42.14, 121.65, 128.81, 130.42, 149.48IR (cm ^-1 )
(State; KBr) 2850 (m), 1645 (m), 1425 (s), 1300
(s), 1190 (m), 1050 (br m), 810 (m) Low-resolution MS (%) 183 (M +, 25), 139 (43), 111
(100), 75 (23), High-resolution MS (M + 183) Calculated for C ₈ H ₁₀ ClN ₃ 183.0563, found 183.0552 mp. (℃) 56

Example 5 3,3-dimethyl-1- (2,3
4,6-trimethylphenyl) -triazene (compound 3
657) Synthesis of 2,4,6-trimethylaniline (2.1986 g, 1
6.3 mmol) and H ₂ O (30 mL) to 0 ° C. and with stirring, concentrated HCl (5.3 mL, 64.5 m).
mol) and NaNO ₂ (1.2194 g, 17.7)
mmol) and stirred for 45 minutes. In a separate container, dimethylamine (6.8 mL, 60.3 mmol), K ₂ C
O ₃ (8.5 g, 61.5 mmol) and H ₂ O (50
mL), the temperature was adjusted to 0 ° C., and the above aqueous solution was added with stirring, followed by stirring for 30 minutes. This with diethyl ether
Extracted once, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. This was separated by flash column chromatography (50 times weight SiO ₂ , Hex:
AcOEt: Et ₃ N = 190: 10: 1), 2.8279 g (14.78 mmol) of the title compound was obtained in a yield of 90.7%. TLC Rf 0.45 (solvent; Hex: AcOEt = 9: 1) VPC tR (min) 6.04 (state; OV-1 1% 2m 100-230 ℃ 10 ℃ /
Min) ¹ H NMR (270 MHz; solvent CDCl ₃ ) δ: 6.83 (s, 2H), 3.29
(s, 6H), 2.25 (s, 3H), 2.14 (s, 6H), ¹³ C NMR (67 MHz; solvent CDCl ₃ ) δ: 146.39, 133.90, 12
9.84, 129.06, 38.89, 20.79, 18.40, IR (cm ^-1 ) (state; neat) 2800 (s), 1590 (w), 1480
(s), 1410 (s), 1310 (s), 1200 (m), 1080 (s), 850
(m)

Example 6 1-Pyrrolidinylazo-4-to
Synthesis of trifluoromethylbenzene (Compound 1159) 4-aminobenzotrifluoride (0.25 mL,
1.99 mmol) in H _TwoO (4 mL) and add to 0 ° C
Chilled. Add HCl (0.64mL) dropwise
Was. Further NaNO_Two(150.5 mg, 2.19 mm
ol) was added in portions and stirred at 0 ° C. for 30 minutes. another
Pyrrolidine (0.18 mL, 2.16 mmol) was added to the reaction vessel.
l) and K_TwoCO_Three(1.14 g, 8.25 mmol) in H
_TwoDissolve in O (7 mL) and stir at 0 ° C.
, The above-mentioned hydrochloric acid solution was added little by little. Stir for 30 minutes
After, Et_TwoExtract with O (x3) and wash the organic layer with saturated NaC
1 aqueous solution, Na_TwoSO_FourAnd concentrated.
This is separated by flash column chromatography.
(100 times weight SiO_TwoHex: AcOEt = 9:
1), 0.3842 g (79%) of yellow crystals were obtained. Mp 104-107 ℃ IR (cm^-1) (State; Nujol) 2850 (S), 1600 (m), 1470 (w), 1
300 (m), 1090 (w), 1060 (w), 830 (m)¹ H NMR (270 MHz; solvent CDCl_Three) δ: 7.56 (d, 2H, J = 9),
7.48 (d, 2H, J = 9), 3.93 (br s, 2H), 3.70 (br s, 2
H), 2.05 (s, 4H)

Example 7 1-piperidinylazo-4-to
Synthesis of trifluoromethylbenzene (Compound 1160) 4-aminobenzotrifluoride (0.25 mL,
1.99 mmol) in H _TwoO (4 mL) and add to 0 ° C
Chilled. Add HCl (0.64mL) dropwise
Was. Further NaNO_Two(151.4 mg, 2.19 mm
ol) was added in portions and stirred at 0 ° C. for 30 minutes. another
Piperidine (0.22 mL, 2.22 mmol) was added to the reaction vessel.
l) and K_TwoCO_Three(1.14 g, 8.25 mmol) in H
_TwoDissolve in O (7 mL) and stir at 0 ° C.
, The above-mentioned hydrochloric acid solution was added little by little. Stir for 30 minutes
After, Et_TwoExtract with O (x3) and wash the organic layer with saturated NaC
1 aqueous solution, Na_TwoSO_FourAnd concentrated.
This is separated by flash column chromatography.
(100 times weight SiO_TwoHex: AcOEt = 9:
1), 0.2386 g (47%) of a brown oily substance was obtained. IR (cm^-1) (State; neat) 2900 (S), 2850 (S), 1650 (s), 14
00 (w), 1260 (w), 1220 (w), 1060 (w), 950 (m), 920 (w)¹ H NMR (270 MHz; solvent CDCl_Three) δ: 7.58 (d, 2H, J = 9),
7.49 (d, 2H, J = 9), 3.83 (s, 4H), 1.72 (s, 6H)

Example 8 1-Hexamethyleneiminylur
Synthesis of zo-2,6-dimethylbenzene (Compound 3655)
4-aminobenzotrifluoride (0.25 mL,
1.99 mmol) in H _TwoO (4 mL) and add to 0 ° C
Chilled. Add HCl (0.64mL) dropwise
Was. Further NaNO_Two(151.1 mg, 2.19 mm
ol) was added in portions and stirred at 0 ° C. for 30 minutes. another
Hexamethyleneimine (0.25 mL, 2.
22 mmol) and K_TwoCO_Three(1.14 g, 8.25 mm
ol) to H _TwoDissolve in O (7 mL) and stir at 0 ° C
Then, the above-mentioned hydrochloric acid solution was gradually added thereto. 30 minutes
After stirring for a while, Et_TwoExtract with O (× 3) and saturate the organic layer
Wash with aqueous NaCl aqueous solution_TwoSO_FourAnd dry
Shrunk. This is used for flash column chromatography
And separate (100 times weight SiO 2_Two, Hex: AcOEt
= 39: 1), pale yellow crystals (0.3992 g, 74%)
I got Mp 46 ℃ IR (cm^-1) (State; Nujol) 2850 (S), 1600 (s), 1300 (m), 1
100 (m), 1060 (w), 900 (w), 840 (m)¹ H NMR (270 MHz; solvent CDCl_Three) δ: 7.51 (d, 4H, J = 8),
4.00 (t, 2H, J = 11), 3.82 (t, 2H, J = 11), 1.76-1.9
4 (m, 4H), 1.65 (t, 4H, J = 7)

Example 9 Synthesis of 3,3-dimethyl-1-pyridin-3-yl-triazene (compound 3994) 3-aminopyridine (477.7 mg, 5.08 mmol)
The l) was dissolved in H ₂ O (10mL) was cooled to 0 ° C., H ₂
SO ₄ (1.1 mL, 20.2 mmol) was added dropwise. Next, NaNO ₂ (417.7 mg, 6.05 mmol)
l) was added in portions and stirred at 0 ° C. for 30 minutes. Further, a dimethylamine solution (40%, 0.68 mL, 6.03
mmol) and NaOH (1.6165 g, 40.4 mm)
ol), and the mixture was stirred at 0 ° C. for 30 minutes and gradually heated to room temperature. NaCl and Et ₂ O were added and extracted with Et ₂ O (×
3), the organic layer is washed with a saturated aqueous solution of NaCl, and Na ₂ S
Dried over O ₄ and concentrated. This was separated by flash column chromatography (100-fold weight SiO ₂ ,
Hex: AcOEt = 3: 1), brown oil 0.58
g (76%). ¹ H NMR (270 MHz; solvent C ₆ D ₆ ) δ: 9.22 (dd, 1H, J = 2.8,
0.8), 8.44 (dd, 1H, J = 4.9, 1.5), 7.71 (ddd, 1H,
J = 7.5, 2.8, 1.5), 6.83 (ddd, 1H, J = 7.5, 4.9,
0.8), 2.75 (br.s, 3H), 2.66 (br.s, 3H)

Example 10 Synthesis of 3-hexamethyleneiminylazopyridine (compound 4014) 3-aminopyridine (477.0 mg, 5.07 mmol)
The l) was dissolved in H ₂ O (10mL) was cooled to 0 ° C., H ₂
SO ₄ (1.1 mL, 20.2 mmol) was added dropwise. Next, NaNO ₂ (421.3 mg, 6.11 mmol)
l) was added in portions and stirred at 0 ° C. for 30 minutes. Furthermore, hexamethylene imine (0.68 mL, 6.03 mmol)
l) and NaOH (1.6418 g, 41.0 mmol)
Was added, and the mixture was stirred at 0 ° C. for 30 minutes, and gradually heated to room temperature. NaCl and Et ₂ O were added and extracted with Et ₂ O (×
3), the organic layer is washed with a saturated aqueous solution of NaCl, and Na ₂ S
Dried over O ₄ and concentrated. This was separated by flash column chromatography (100-fold weight SiO ₂ ,
Hex: AcOEt = 2: 1), orange crystal 0.8629
g (83%). ¹ H NMR (270MHz; solvent _{C 6 D 6) δ: 9.28} (dd, 1H, J = 2.0,
0.8), 8.46 (dd, 1H, J = 5.0, 2.0), 7.77 (ddd, 1H,
J = 7.5, 2.0, 2.0), 6.86 (ddd, 1H, J = 7.5, 5.0, 0.
8), 3.46-3.59 (m, 4H), 1.24-1.41 (m, 4H), 1.05-1.22
(m, 4H)

Example 11 Synthesis of 3-pyrrolidinylazopyridine (compound 4012) 3-aminopyridine (477.0 mg, 5.08 mmol)
The l) was dissolved in H ₂ O (10mL) was cooled to 0 ° C., H ₂
SO ₄ (1.1 mL, 20.2 mmol) was added dropwise. Next, NaNO ₂ (416.2 mg, 6.03 mmol)
l) was added in portions and stirred at 0 ° C. for 30 minutes. Further, pyrrolidine (0.63 mL, 6.09 mmol) and Na
OH (1.6780 g, 42.0 mmol) was added and 3
The mixture was stirred at 0 ° C. for 0 minutes and gradually warmed to room temperature. NaCl
And Et ₂ O, extract with Et ₂ O (× 3), wash the organic layer with saturated aqueous NaCl, dry over Na ₂ SO ₄ ,
Concentrated. This was separated by flash column chromatography (100-fold weight SiO ₂ , Hex: AcOE).
t = 3: 1), milky white crystals (0.6906 g, 77%)
I got IR (cm ^-1 ) (State; nujor) 2850 (s), 1560 (m), 1400 (w), 1
310 (w), 1210 (w ), 1090 (w), 810 (m), 710 (m) 1 H NMR (270MHz; solvent _{C 6 D 6) δ: 9.30} (d, 1H, J = 2.5),
8.46 (dd, 1H, J = 5.0, 1.5), 7.80 (ddd, 1H, J = 8.0
, 2.5, 1.5), 6.85 (ddd, 1H, J = 8.0, 4.5, 1.0),
3.34 (t, 4H, J = 6.5), 1.03-1.30 (m, 4H) MS (EI,%) 176 (M +, 13), 106 (28), 78 (100), 51 (27),
41 (11) HRMS (M + , 178) calcd 176.1062 for C ₉ H ₁₂ N _4,
Found 176.1059

Example 12 Synthesis of 3-piperidinylazopyridine (compound 4013) 3-aminopyridine (472.1 mg, 5.02 mmol)
The l) was dissolved in H ₂ O (10mL) was cooled to 0 ° C., H ₂
SO ₄ (1.1 mL, 20.2 mmol) was added dropwise. Next, NaNO ₂ (418.3 mg, 6.06 mmol)
l) was added in portions and stirred at 0 ° C. for 30 minutes. Further piperidine (0.60 mL, 6.07 mmol) and Na
OH (1.6222 g, 40.6 mmol) was added and 3
The mixture was stirred at 0 ° C. for 0 minutes and gradually warmed to room temperature. NaCl
And Et ₂ O were added and extracted with Et ₂ O (× 3), the organic layer was washed with saturated aqueous NaCl, dried over Na ₂ SO ₄ and concentrated. This was separated by flash column chromatography (100-fold weight SiO ₂ , Hex: AcOEt).
= 3: 1), brown oil (0.4940 g, 52%)
I got IR (cm ^-1 ) (state; neat) 3400 (s), 2900 (s), 2850 (s), 18
60 (w), 1730 (w), 1570 (m), 1410 (w), 1350 (w), 1290
(w), 1250 (w), 1170 (m), 1090 (m), 990 (m), 800 (m), 700
(w), 610 (w) ¹ H NMR (270 MHz; solvent C ₆ D ₆ ) δ: 9.26 (d, 1 H, J = 2.5),
8.46 (dd, 1H, J = 5.0, 1.5), 7.75 (ddd, 1H, J = 8.0
, 2.5, 1.5), 6.83 (ddd, 1H, J = 8.0, 5.0, 0.5),
3.44 (br s, 4H), 1.05-1.23 (m, 6H) MS (EI,%) 190 (M +, 10), 106 (27), 78 (100), 51 (22),
42 (11) HRMS (M + , 178) calcd 190.1218 for C ₁₀ H ₁₄ N _4,
Observed 190.1218

Example 13 3,3-dimethyl-1- (o
-Trimethylsilylphenyl) -triazene (compound 3
700) Synthesis under a nitrogen atmosphere, 1- (o-bromophenyl) -3,3-
Dimethyltriazene (3.68 g, 16.1 mmol)
And THF (16.0 mL) were cooled to -84 ° C, and n-BuLi / n-hexane (10.0 m
L, 1.72 M, 17.2 mmol) was added dropwise, and 5 minutes later, 2.08 mL of TMS-Cl (16.4 mmol) was added.
l) was added dropwise. Water was added thereto, extracted three times with diethyl ether, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. This was separated by flash column chromatography (50-fold weight SiO ₂ , only hexane), yielding 1.7759 g of the title compound (8.
03 mmol) in a yield of 50%. TLC Rf 0.61 (solvent; Hex: AcOEt = 9: 1) VPC tR (min) 7.11 (state; OV-1 1% 2m 100-230 ℃ 10 ℃ /
Min) TLC Rf 0 (solvent; Hex: AcOEt = 9: 1) VPC tR (min) 3.15 (state; OV-1 1% 2m 100-230 ℃ 10 ℃ /
Min) ¹ H NMR (270 MHz; solvent CDCl ₃ ) δ: 7.30 (m, 4H), 3.35
(br s, 6H), 0.31 (s, 9H), ¹³ C NMR (67 MHz; solvent CDCl ₃ ) δ: 155.59, 134.38, 12
9.90, 124.82, 115.46, 41.26, 39.39, -0.22 IR (cm ^-1 ) (State; neat) 2900 (s), 1580 (m), 1460
(s), 1400 (s), 1320 (s), 1250 (s), 1060 (s), 830 (s), 7
50 (s)

Example 14 1-Pyrrolidinylazo-2,
Synthesis of 6-dimethylbenzene (compound 3653) 2,6-xylidine (1.939 g, 16.1 mmol)
1) and H ₂ O (30.0 mL) were brought to 0 ° C., concentrated HCl (5.3 mL, 64.5 mmol) and NaNO ₂ (1.20 g, 17.3 mmol) were added with stirring, and the mixture was stirred for 45 minutes. . Pyrrolidine (4.2) in another container
0 g, 59.1 mmol), K ₂ CO ₃ (8.50 g, 6
1.5 mmol) and H ₂ O (53.0 mL), take the temperature to 0 ° C., add the above aqueous solution with stirring, and add
Stirred for minutes. This is extracted three times with diethyl ether,
The extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. This was separated by flash column chromatography (50-fold weight SiO ₂ , Hex: AcOE).
t: Et ₃ N = 1000: 25: 2), and the title compound was obtained in a yield of 2.73 g (13.4 mmol) and a yield of 83%. TLC Rf 0.21 (solvent; Hex: AcOEt = 39: 1) VPC tR (min) 8.23 (state; OV-1 1% 2m 100-230 ℃ 10 ℃ /
Min) ¹ H NMR (270 MHz; solvent CDCl ₃ ) δ: 6.96 (m, 3H), 3.75
(t, 4H), 2.19 (s, 6H), 2.01 (m, 4H), ¹³ C NMR (67 MHz; solvent CDCl ₃ ) δ: 149.14, 129.99, 12
8.28, 124.42, 48.29,23.81, 18.44, IR (cm ^-1 ) (State; neat) 2950 (m), 1580 (w), 1420
(s), 1320 (s), 1200 (m), 1150 (m), 1090 (m), 1020
(w), 760 (m)

Example 15 1-Pyrrolidinylazo-2,
Synthesis of 4,6-trimethylbenzene (Compound 3696) 2,4,6-trimethylaniline (2.17 g, 16.
1 mmol) and H _TwoO (30 mL) to 0 ° C.
With stirring, concentrated HCl (5.3 mL, 64.5 mmol
l) and NaNO_Two(1.19 g, 17.3 mmo
l) was added and stirred for 45 minutes. Pyrrolidine in another container
(4.20 g, 59.1 mmol), K_TwoCO_Three(8.5
0 g, 61.5 mmol) and H_TwoO (53.0m
L) to 0 ° C and add the above aqueous solution while stirring.
And stirred for 30 minutes. This three times with diethyl ether
Extract, wash with brine and dry over anhydrous sodium sulfate
Then, the mixture was concentrated under reduced pressure. This is flash column chromatog
Separate by luffy (50 times weight SiO_Two, Hex: A
cOEt: Et_ThreeN = 1000: 25: 2), conversion of title
The compound was obtained in a yield of 2.69 g (12.4 mmol) and a yield of 77.
%. TLC Rf 0.22 (solvent; Hex: AcOEt = 39: 1) VPC tR (min) 9.46 (state; OV-1 1% 2m 100-230 ℃ 10 ℃ /
Minutes)¹ H NMR (270MHz; solvent CDCl_Three) δ: 6.81 (s, 2H), 3.72
(t, 4H), 2.23 (s, 3H), 2.16 (s, 6H), 1.97 (m, 4H),¹³ C NMR (67MHz; solvent CDCl_Three) δ: 146.62, 133.54, 12
9.67, 128.89, 48.20, 23.71, 20.66, 18.37, IR (cm^-1) (State; neat) 2900 (s), 1600 (w), 1430
(s), 1300 (s), 1200 (s), 1140 (m), 1020 (w), 840
(m)

Example 16 3-Methyl-3-phenyl-
1-pyridin-3-yl-triazene (Compound 399
Synthesis of 9) 3-aminopyridine (473.5 mg, 5.03 mmol)
The l) was dissolved in H ₂ O (10mL) was cooled to 0 ° C., H ₂
SO ₄ (1.1 mL, 20.2 mmol) was added dropwise. Next, NaNO ₂ (422.1 mg, 6.11 mmol)
l) was added in portions and stirred at 0 ° C. for 30 minutes. Further, N-methylaniline (0.66 mL, 6.09 mmol)
1) and NaOH (1.8223 g, 45.5 mmol)
Was added, and the mixture was stirred at 0 ° C. for 30 minutes, and gradually heated to room temperature. NaCl and Et ₂ O were added and extracted with Et ₂ O (×
3), the organic layer is washed with a saturated aqueous solution of NaCl, and Na ₂ S
Dried over O ₄ and concentrated. This was separated by flash column chromatography (100-fold weight SiO ₂ ,
Hex: AcOEt = 3: 1), brown oil 0.88
21 g (83%) were obtained. IR (cm ^-1 ) (State; neat) 2950 (m), 1590 (s), 1420 (m), 139
0 (m), 1310 (s), 1200 (m), 1180 (m), 1090 (s), 1020 (w),
980 (w), 800 (w), 740 (w), 680 (w) ¹ H NMR (270 MHz; solvent CDCl ₃ ) δ: 8.83 (dd, 1 H, J = 2.5
, 0.5), 8.46 (dd, 1H, J = 4.5, 2.5), 7.86 (ddd, 1H
, J = 8.0, 2.5, 2.0), 7.37-7.49 (m, 4H), 7.31 (ddd
, 1H, J = 8.0, 4.5, 1.0), 7.17 (tt, 1H, J = 14.0
, 3.0), 3.69 (s, 3H) MS (EI,%) 212 (M +, 5), 106 (35), 78 (100), 77 (25), 5
1 (44), 39 (6 ) HRMS (M +, 212) calcd 212.1062 for C ₁₂ H ₁₂ N _4,
Found 212.1062

Example 17 Synthesis of 3-morpholinoazopyridine (compound 4015) 3-aminopyridine (472.2 mg, 5.02 mmol)
The l) was dissolved in H ₂ O (10mL) was cooled to 0 ° C., H ₂
SO ₄ (1.1 mL, 20.2 mmol) was added dropwise. Next, NaNO ₂ (415.0 mg, 6.01 mmol)
l) was added in portions and stirred at 0 ° C. for 30 minutes. Further, morpholine (0.53 mL, 6.08 mmol) and Na
OH (1.7634 g, 44.1 mmol) was added and 3
The mixture was stirred at 0 ° C. for 0 minutes and gradually warmed to room temperature. NaCl
And Et ₂ O were added and extracted with Et ₂ O (× 3), the organic layer was washed with saturated aqueous NaCl, dried over Na ₂ SO ₄ and concentrated. This was separated by flash column chromatography (100-fold weight SiO ₂ , Hex: AcOEt).
= 3: 1), yielding 0.7153 g (74%) of brown crystals. IR (cm ^-1 ) (State; nujor) 3400 (m), 2850 (m), 1570 (m), 1
410 (s), 1350 (s), 1290 (w), 1150 (s), 1100 (s), 1010
(s), 930 (w), 890 (w), 850 (w), 800 (m), 690 (m), 590
^{(w) 1 H NMR (270MHz} ; solvent C6D6) δ: 9.20 (dd, 1H, J = 2.5,
0.5), 8.46 (dd, 1H, J = 5.0, 1.5), 7.68 (ddd, 1H,
J = 8.0, 2.0, 1.5), 6.82 (ddd, 1H, J = 8.0, 4.5,
1.0), 3.23-3.36 (m, 8H) MS (EI,%) 192 (M +, 9), 106 (22), 78 (100), 51 (30), 4
3 (5) HRMS (M +, 192) Calculated for C ₉ H ₁₂ N ₄ O 192.1012,
Found 192.1029

Example 18 3-Methyl-3-benzyl-
1-pyridin-3-yl-triazene (Compound 400
Synthesis of 0) 3-aminopyridine (471.9 mg, 5.01 mmol)
The l) was dissolved in H ₂ O (10mL) was cooled to 0 ° C., H ₂
SO ₄ (1.1 mL, 20.2 mmol) was added dropwise. Next, NaNO ₂ (419.3 mg, 6.08 mmol)
l) was added in portions and stirred at 0 ° C. for 30 minutes. Further, N-methylbenzylamine (0.80 mL, 6.21 m
mol) and NaOH (1.7527 g, 43.8 mmol)
l) was added, and the mixture was stirred at 0 ° C. for 30 minutes, and gradually heated to room temperature. NaCl and Et ₂ O were added and extracted with Et ₂ O (×
3), the organic layer is washed with a saturated aqueous solution of NaCl, and Na ₂ S
Dried over O ₄ and concentrated. This was separated by flash column chromatography (100-fold weight SiO ₂ ,
Hex: AcOEt = 3: 1), yellow oil 0.87
36 g (77%) were obtained. IR (cm ^-1 ) (State; neat) 3350 (s), 3000 (m), 2900 (m), 15
70 (m), 1420 (m), 1320 (m), 1160 (w), 1060 (w), 910 (w),
800 (w), 700 (w) ¹ H NMR (270 MHz; solvent CDCl ₃ ) δ: 8.73 (d, 1H, J = 2.0),
8.39 (dd, 1H, J = 5.0, 1.5), 7.77 (ddd, 1H, J = 8.0
, 2.0, 1.5), 7.30-7.40 (m, 2H), 7.23-7.30 (m, 4
H), 4.97 (s, 2H), 3.15 (br s, 3H) MS (EI,%) 226 (M +, 6), 149 (4), 120 (27), 106 (21), 9
7 (8), 78 (100 ), 69 (12), 51 (23), 43 (23) HRMS (M +, 226) calcd 226.1219 for C ₁₃ H ₁₄ N _4,
Observed 226.1204

Example 19 Synthesis of 3,3-diethyl-1-pyridin-3-yl-triazene (Compound 4001) The title compound was obtained in the same manner as in Example 18. IR (cm ^-1 ) (condition; neat) 3640 (w), 3250 (m), 2990 (m), 140
0 (w), 1140 (m ), 910 (s), 790 (w), 700 (w) 1 H NMR (270MHz; solvent _{CDCl 3) δ: 8.52 (dd} , 1H, J = 2.5
, 1.0), 8.31 (dd, 1H, J = 4.5, 1.5), 7.66 (ddd, 1H
, J = 8.0, 2.5, 1.5), 7.32 (ddd, 1H, J = 8.0, 4.5
, 1.0), 3.78 (dd, 4H, J = 7.0, 7.0), 1.23 (t, 6H
, J = 7.0) MS (EI,%) 178 (M +, 10), 106 (22), 78 (100), 72 (6), 5
1 (22), 44 (8 ) HRMS (M +, 178) calcd 178.1219 for C ₉ H ₁₄ N _4,
Found 178.1221

Example 20 1-piperidinylazo-4-
Synthesis of methylbenzene (Compound 171) The title compound was obtained in the same manner as in Example 18. TLC Rf 0.59 (solvent; Hex: AcOEt = 9: 1) VPC tR (min) 9.48 (state; OV-1 1% 2m 100-230 ℃ 10 ℃ /
Min) ¹ H NMR (270 MHz; solvent CDCl ₃ ) δ: 7.33 (AA ', dd, 2H,
J = 8.5, 2Hz), 7.13 (BB ', dd, 2H, J = 8.5, 2Hz), 3.75
(br d, 2H J = 2Hz), 3.73 (br d, 2H J = 5Hz), 2.33 (s,
3H), 1.68 (m, 6H), ¹³ C NMR (67 MHz; solvent CDCl ₃ ) δ: 148.62, 135.32, 12
9.45, 120.39, 48.20, 25.29, 24.48, 21.03 IR (cm ^-1 ) (State; KBr) 2920 (m), 2850 (m), 1510
(m), 1435 (s), 1350 (s), 1260 (m), 1180 (s), 1100
(s), 825 (s), 715 (m), 635 (m), 550 (s), 520 (s) MS (EI,%) 203 (M +, 11.2), 119 (18.4), 91 (100) ,
84 (6), 65 (6), 55 (1.6), 41 (1.6) HRMS (M +, 203) Calculated for C ₁₂ H ₁₇ N ₃ 203.1422,
Measured value 203.1421

The compounds shown in the following Tables 1 to 107 were produced by the same method as that for producing the above compounds.

[0059]

[Table 1]

[0060]

[Table 2]

[0061]

[Table 3]

[0062]

[Table 4]

[0063]

[Table 5]

[0064]

[Table 6]

[0065]

[Table 7]

[0066]

[Table 8]

[0067]

[Table 9]

[0068]

[Table 10]

[0069]

[Table 11]

[0070]

[Table 12]

[0071]

[Table 13]

[0072]

[Table 14]

[0073]

[Table 15]

[0074]

[Table 16]

[0075]

[Table 17]

[0076]

[Table 18]

[0077]

[Table 19]

[0078]

[Table 20]

[0079]

[Table 21]

[0080]

[Table 22]

[0081]

[Table 23]

[0082]

[Table 24]

[0083]

[Table 25]

[0084]

[Table 26]

[0085]

[Table 27]

[0086]

[Table 28]

[0087]

[Table 29]

[0088]

[Table 30]

[0089]

[Table 31]

[0090]

[Table 32]

[0091]

[Table 33]

[0092]

[Table 34]

[0093]

[Table 35]

[0094]

[Table 36]

[0095]

[Table 37]

[0096]

[Table 38]

[0097]

[Table 39]

[0098]

[Table 40]

[0099]

[Table 41]

[0100]

[Table 42]

[0101]

[Table 43]

[0102]

[Table 44]

[0103]

[Table 45]

[0104]

[Table 46]

[0105]

[Table 47]

[0106]

[Table 48]

[0107]

[Table 49]

[0108]

[Table 50]

[0109]

[Table 51]

[0110]

[Table 52]

[0111]

[Table 53]

[0112]

[Table 54]

[0113]

[Table 55]

[0114]

[Table 56]

[0115]

[Table 57]

[0116]

[Table 58]

[0117]

[Table 59]

[0118]

[Table 60]

[0119]

[Table 61]

[0120]

[Table 62]

[0121]

[Table 63]

[0122]

[Table 64]

[0123]

[Table 65]

[0124]

[Table 66]

[0125]

[Table 67]

[0126]

[Table 68]

[0127]

[Table 69]

[0128]

[Table 70]

[0129]

[Table 71]

[0130]

[Table 72]

[0131]

[Table 73]

[0132]

[Table 74]

[0133]

[Table 75]

[0134]

[Table 76]

[0135]

[Table 77]

[0136]

[Table 78]

[0137]

[Table 79]

[0138]

[Table 80]

[0139]

[Table 81]

[0140]

[Table 82]

[0141]

[Table 83]

[0142]

[Table 84]

[0143]

[Table 85]

[0144]

[Table 86]

[0145]

[Table 87]

[0146]

[Table 88]

[0147]

[Table 89]

[0148]

[Table 90]

[0149]

[Table 91]

[0150]

[Table 92]

[0151]

[Table 93]

[0152]

[Table 94]

[0153]

[Table 95]

[0154]

[Table 96]

[0155]

[Table 97]

[0156]

[Table 98]

[0157]

[Table 99]

[0158]

[Table 100]

[0159]

[Table 101]

[0160]

[Table 102]

[0161]

[Table 103]

[0162]

[Table 104]

[0163]

[Table 105]

[0164]

[Table 106]

[0165]

[Table 107]

Example 21 The following compound was produced by a method similar to the above-mentioned method for producing a compound. 1-piperidinylazo-4-pyridine (compound 421
7) IR (cm ^-1 ) (state; neat) ¹ H NMR (270 MHz; solvent C ₆ D ₆ ) δ: 8.67 (dd, 2H, J =
5.0, 1.5), 7.41 (dd, 2H, J = 4.5, 1.5), 3.57
(Br s, 2H), 3.30 (br s, 2H), 1.03-1.20 (m,
6H) MS (EI,%) 190 (M ⁺ , 12), 106 (31), 84 (38), 7
8 (100), 51 (31 ), 42 (16) HRMS (M +, 190) calcd 190.1219 for C ₁₀ H ₁₄ N _4,
Obtained 190.1206 2-methoxy-5-pyrrolidinylazopyridine (compound 4218) Mp 80.0-80.5 ° C ¹ H NMR (270 MHz; solvent C ₆ D ₆ ) δ: 8.82 (d, 1H, J =
2.5), 7.88 (dd, 1H, J = 8.5, 2.5), 6.73 (d, 1
H, J = 9.0), 3.87 (s, 3H), 3.39 (dt, 4H, J =
7.0, 3.5), 1.19-1.29 (m, 4H) MS (EI,%) 206 (M ⁺ , 14), 136 (41), 108 (100),
93 (31), 81 (26 ), 66 (12), 53 (16), 39 (36) HRMS (M +, 206) C 10 H 14 N 4 O calcd for 206.116
7, found 206.1145 2-methoxy-5-piperidinylazopyridine (compound 4219) Mp 49.0-50.0 ° C ¹ H NMR (270 MHz; solvent C ₆ D ₆ ) δ: 8.77 (d, 1H, J =
2.5), 7.85 (dd, 1H, J = 9.0, 0.5), 6.71 (dd,
1H, J = 9.0, 0.5), 3.85 (s, 3H), 3.47 (t, 4H
, J = 5.0), 1.08-1.29 (m, 4H) MS (EI,%) 220 (M ⁺ , 16), 136 (38), 108 (100),
93 (21), 81 (18 ), 66 (7), 53 (10), 39 (23) HRMS (M +, 220) calcd for C ₁₁ H ₁₆ N ₄ O 220.132
4, measured 220.1343

Example 22 Activity of Antimalarial Agent of the Present Invention Test Method Animal: ICR 4.5 week old mouse (Female, CLEA Japan)
Was used as 5 animals per group. Pathogen: Mouse malaria Plasmodium berghei (NK-
65 strains), and the amount of infection was 3.3 as the number of infected red blood cells.
× 10 ⁶ /0.2 ml / mouse was intraperitoneally ingested. The infectious dose was calculated from the erythrocyte count and the erythrocyte infection rate of the protozoa. Test compound: The compound according to the present invention has a dose of 1 body weight.
It was dissolved and prepared in arabic gum or oil (corn oil) at a concentration of 0.1 ml (0.1 ml / 10 gbw) per 0 g, and administered twice subcutaneously 2 hours and 48 hours after infection. Tables 108 and 109 show the survival rate, 50% survival days, and erythrocyte infection rate 14 days after infection.

[0168]

[Table 108]

[0169]

[Table 109] NT: Not tested. As shown in the table, 14 days after infection, 5% arabic gu
The survival rate was 0% in the infected control group to which m was administered, while 4% in the treatment group to which the antimalarial agent of the present invention was administered.
The survival rate was 0% or more. Also, the erythrocyte infection rate was shown to be lower in the treatment group administered with the antimalarial agent of the present invention than in the infection control group.

Example 23 Self- acting nematode Caenorhabditis e
Evaluation of nematicidal activity using legans Compounds shown in Table 110 below as test compounds, and methyl isothiocyanate (MITC) as a control compound
Was used for Caenorhabditis elegans N2, a stage III larva selected from a population in aseptic subculture (Sayer et., Al, 1963).
And tested its nematicidal activity. The test compound and the control compound were added to DMSO to make a 1% solution. This is Twee
M-9 buffer containing 100 ppm of n20 (Brenner, Genetics, 77, 7
1-94, 1974) to prepare a test solution having a compound concentration of 500 ppm. 3-hole hole slide glass (hole diameter 15
40 μl of M-9 buffer solution was placed in a single hole (mm, depth 1 mm), 10 nematodes were transferred to the well with a transplant needle, and 40 μl of the above-mentioned test solution (500 ppm) was added and gently stirred. The final concentration was 250 ppm or 125 ppm. Put the slide glass in the wet room, about 22
After 24 and 48 hours, the number of surviving insects was determined. In addition,
Repeat 3 for one treatment, final concentration of control is 250p
pm or 125 ppm. The results are shown in Table 110.

[0171]

[Table 110] This result is expressed as a corrected mortality rate obtained by converting the mortality rate of the untreated group to 0%. Each compound at a concentration of 250 ppm
It showed 100% mortality. Compound 39 at a concentration of 125 ppm
99, 4217, 4218 and 4219 showed more than 95% activity.

Example 24 Formulation Example of Pharmaceutical Containing Compound of the Invention (Tablet) Compound (I) 15 parts Starch 15 parts Lactose 15 parts Crystalline cellulose 19 parts Polyvinyl alcohol 3 parts Distilled water 30 parts Calcium stearate 3 parts Calcium stearate The other components were uniformly mixed, crushed and granulated, and dried to obtain granules of an appropriate size. Next, calcium stearate was added and compression molded to obtain tablets.

Example 25 Formulation Example of Pharmaceutical Containing Compound of the Present Invention (Injection) Compound (I) 0.5 part Nonionic surfactant 2.5 parts Physiological saline 97 parts After the above components were heated and mixed, And sterilized to give an injection.

[0174]

According to the present invention, an antimalarial agent and a nematicide containing the compound of the formula (I) having excellent antimalarial activity and nematicidal activity are provided.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 31/4402 A61K 31/4402 31/4409 31/4409 31/4453 31/4453 31/496 31/496 31 / 5377 31/5377 31/55 31/55 A61P 33/00 171 A61P 33/00 171 33/06 33/06 C07C 245/24 C07C 245/24 C07D 213/76 C07D 213/76 // C07D 295/22 295 / 22 Z (72) Inventor Keizo Matsuo 7-11-14 Nishitomigaoka, Nara City, Nara Prefecture (72) Inventor Katsuaki Oba 1405 Gotanda, Oga, Koka-cho, Koka-gun, Shiga Prefecture 4C055 AA01 BA02 BA42 BB02 CA02 CA54 CB17 DA54 DB17 4C086 AA01 AA03 BC05 BC17 BC21 BC31 GA12 MA04 NA14 ZB31 ZB37 ZC61 4C206 AA01 AA02 AA03 HA05 KA01 MA04 MA16 NA14 ZB31 ZB37 4H006 AA01 BC03

Claims (15)

[Claims] 1. A compound of formula (I): [Wherein, ring A is a benzene ring or a pyridine ring, and R ¹ and R ² are each independently hydrogen, halogen, hydroxy, a lower alkyl optionally having a substituent, or a substituent. Optionally substituted lower alkenyl, optionally substituted acyl, optionally substituted phenyl or cyano, or a substituent together with a bonding N atom X ¹ , X ² , X ^3, and X ⁴ may each independently have hydrogen, halogen, hydroxy, or a substituent. Lower alkyl, lower alkenyl optionally having substituent (s), lower alkoxy optionally having substituent (s), lower alkenyloxy optionally having substituent (s), lower optionally having substituent (s) Alkynyloxy, carboxy, with substituents Lower alkoxycarbonyl which may be substituted, acyl which may have a substituent, acyloxy which may have a substituent, amino which may have a substituent, nitro,
An antimalarial agent comprising a compound represented by the formula (I) which is cyano or tri (lower alkyl) silyl (provided that X ¹ , X ² , X ³ and X ⁴ are not all amidino) or a salt thereof or a solvate thereof; . 2. R ¹ and R ² are each independently hydrogen, lower alkyl which may have a substituent or lower alkenyl which may have a substituent, or The antimalarial agent according to claim 1, which forms a cyclic group which may have a substituent together with the existing N atom. 3. R ¹ and R ² are each independently a lower alkyl, phenyl or benzyl, or together with a bonding N atom, each may have a substituent. The antimalarial agent according to claim 1, which forms pyrrolidinyl, piperidinyl, hexahydroazepinyl, piperazinyl or morpholino. 4. The method according to claim ¹ , wherein X ¹ , X ² , X ³ and X ⁴ are each independently hydrogen, halogen, lower alkyl optionally substituted with halogen, lower alkoxy, nitro or trimethylsilyl. 3. The antimalarial agent according to any one of 3. 5. X¹Is -N = N-NR¹R^TwoIn para rank
Bonded, halogen or substituted with halogen
A good lower alkyl, X^Two, X^ThreeAnd X ^FourIs all water
The antimalarial according to any one of claims 1 to 3, which is elementary.
Agent. 6. X ¹ is a group in which R ¹ and R ² are both lower alkyl or form a pyrrolidinyl or piperidinyl each optionally having a substituent together with a bonding N atom; , X ² , X ³ and X ⁴ are each independently hydrogen, halogen or lower alkyl optionally substituted with halogen. 7. Formula (I): [Wherein, ring A is a benzene ring or a pyridine ring, and R ¹ and R ² are each independently hydrogen, halogen, hydroxy, a lower alkyl which may have a substituent or a substituent. Optionally substituted lower alkenyl, optionally substituted acyl, optionally substituted phenyl or cyano, or a substituent together with a bonding N atom X ¹ , X ² , X ^3, and X ⁴ may each independently have hydrogen, halogen, hydroxy, or a substituent. Lower alkyl, lower alkenyl optionally having substituent (s), lower alkoxy optionally having substituent (s), lower alkenyloxy optionally having substituent (s), lower optionally having substituent (s) Alkynyloxy, carboxy, substituent And optionally substituted lower alkoxycarbonyl optionally, acyl which may have a substituent, acyloxy which may have a substituent, amino optionally having substituent, nitro,
A cyanide or a tri (lower alkyl) silyl], a salt thereof, or a solvate thereof. 8. Ring A is a pyridine ring, and R ¹ and R
² is a lower alkyl which may have a substituent or a phenyl which may have a substituent, or may have a substituent together with a bonding N atom. X ¹ , X ² , X ³ and X ⁴ may be each independently hydrogen,
The nematicide according to claim 7, which is a lower alkyl which may have a substituent or a lower alkoxy which may have a substituent. 9. Ring A is a benzene ring, and R ¹ and R ²
Together with the attached N atom form pyrrolidinyl, piperidinyl, hexahydroazepinyl, piperazinyl or morpholino, each of which may have a substituent, and X ¹ is -N = N-NR ^{1 is} an optionally substituted lower alkyl bonded to the para position of R ² , X ² ,
The compound of the formula (I) according to claim 1, wherein X ³ and X ⁴ are all hydrogen, a salt thereof, or a solvate thereof. 10. R ¹ and R ² together with the attached N atom form piperidinyl, wherein X ¹ is -N = N
It is bound methyl para -NR ¹ R ^2, claim 9
Or a salt thereof or a solvate thereof. 11. The compound of the formula (I) according to claim 1, wherein X ¹ is tri (lower alkyl) silyl, a salt thereof, or a solvate thereof. 12. X ¹ is trimethylsilyl, X ² ,
The compound of the formula (I) according to claim 1, wherein X ³ and X ⁴ are all hydrogen, a salt thereof, or a solvate thereof. 13. Ring A is a pyridine ring and X ¹ is —N
= Halogen substituted at the para-position of N-NR ¹ R ² , hydroxy, halogenated lower alkyl, halogenated lower alkoxy, lower alkoxycarbonyl or acyloxy; X ^{2 to} X ⁴ are all hydrogen; R ¹ and R ² is each independently a lower alkyl which may have a substituent, or a pyrrolidinyl, piperidinyl, hexahydrogen which may have a substituent together with a bonding N atom. A compound of formula (I) according to claim 1, which may form azepinyl, piperazinyl or morpholino (provided that when R ¹ is substituted lower alkyl, X ¹ is not chloro), or Salts or solvates thereof. 14. Ring A is a pyridine ring, X ^{1 to} X ⁴ are all hydrogen, and —N ＝ N—NR ¹ R ² is ² of the pyridine ring.
Pyrrolidinyl, hexahydroazepinyl, which may be substituted at each position, wherein R ¹ and R ² are each independently lower alkyl, or each may have a substituent together with the attached N atom. The compound represented by the formula (I) according to claim 1, which may form a piperazinyl or morpholino, a salt thereof, or a solvate thereof. 15. Ring A is a pyridine ring, X ^{1 to} X ⁴ are all hydrogen, and —N ＝ N—NR ¹ R ² is 3
And R ¹ and R ² together with the N atom to which they are attached form hexahydroazepinyl, piperazinyl or morpholino, each of which may optionally have substituents. Or a salt thereof, or a solvate thereof, represented by the formula (I):