JP2500849B2 - Triazolyl-substituted tertiary amino compound or salt thereof - Google Patents

Description

TECHNICAL FIELD The present invention relates to a novel triazolyl-substituted tertiary amino compound having aromatase inhibitory activity, which is useful as a medicine.

BACKGROUND ART The production of estrogen in vivo is known to involve oxygen aromatase at the final stage of its biosynthetic pathway. Aromatase uses androgen as a substrate,
A ring of steroid is aromatized to produce estrogen, and by inhibiting this enzyme activity, it becomes possible to prevent and treat various diseases in which estrogen is involved as an aggravating factor.

Based on this idea, several aromatase inhibitor compounds have been proposed so far. Typical of these are the imidazolyl- or triazolyl- or pyridyl-substituted memory compounds described in EP-A-236,940 and EP-A-293,978.

However, the compounds of the present invention are structurally clearly different from these compounds in that they have a triazolyl-substituted tertiary amino group. The compound having a triazolyl-substituted tertiary amino group has never been synthesized so far, and in particular, direct alkylation of the terminal amino group of the triazolyl group, particularly allylation, is an effective synthetic method. Was not known.

The present invention, in addition to the structural differences from these compounds, provides an optimal synthetic method for novel triazolyl-substituted tertiary amino compounds, and these compounds have excellent aromatase inhibitory activity. It was found that it was completed.

DISCLOSURE OF THE INVENTION The triazolyl-substituted tertiary amino compound of the present invention is represented by the following general formula.

(The groups in the formulas have the following meanings.

A: single bond, lower alkylene group or carbonyl group B: lower alkyl group, optionally substituted aryl group,
Hetero atom consisting of oxygen atom, sulfur atom or nitrogen atom 1
An optionally substituted 5- or 6-membered heterocyclic group having 3 to 3 or an optionally substituted bicyclic fused heterocyclic group in which the heterocycle is condensed with a benzene ring D ring: optionally substituted An optionally substituted 5- or 6-membered heterocyclic group having 1 to 3 heteroatoms consisting of an aryl group, an oxygen atom, a sulfur atom or a nitrogen atom, or an optionally substituted 5- or 6-membered heterocyclic ring thereof condensed with a benzene ring Two-ring condensed heterocyclic group. The same applies hereinafter) E ring: 4H-1,2,4-triazole ring, 1H-1,2,4-triazole ring, or 1H-1,2,3-triazole ring. The same applies to the following) The compound of the present invention will be described in more detail below. Unless otherwise specified in the definition of the general formulas herein, the term “lower” means a straight or branched carbon chain having 1 to 6 carbon atoms.

Therefore, as the "lower alkyl group", specifically,
For example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-
Butyl group, pentyl (amyl group), isopentyl group, neopentyl group, tert-pentyl group, 1-methylbutyl group, 2
-Methylbutyl group, 1,2-dimethylpropyl group, hexyl group, isohexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group Group, 2,2-dimethylbutyl group, 1,3
-Dimethylbutyl group, 2,3-dimethylbutyl group, 3,3-dimethylbutyl group, 1-ethylbutyl group, 2-ethylbutyl group,
1,1,2-trimethylpropyl group, 1,2,2-trimethylpropyl group, 1-ethyl-1-methylpropyl group, 1-ethyl-
A 2-methylpropyl group and the like are preferable, and a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group and the like are preferable.

The "lower alkylene group" is a linear or branched carbon chain having 1 to 6 carbon atoms, and specifically, for example, methylene group, ethylene group, propylene group, tetramethylene group, 2-methyltrimethylene group. 1,1-Ethylethylene group, pentamethylene group, 1,2-diethylethylene group and the like are preferable, and methylene group and ethylene group are preferable.

Further, the "aryl group" which means the B or D ring includes a phenyl group, a naphthyl group, an anthracenyl group, a phenanthrenyl group and the like, and "has 1 to 3 hetero atoms consisting of oxygen atom, sulfur atom and nitrogen atom" Examples of the "5- or 6-membered heteroacid group" include furyl group, thienyl group, thiazolyl group, thiadiazolyl group, oxazolyl group, imidazolyl group, triazolyl group, pyrrolyl group, pyridyl group, pyrimidinyl group, pyrazinyl group and the like. Also,
The “bicyclic condensed heterocyclic group in which the heterocyclic group is condensed with a benzene ring” is, for example, a heterocyclic group composed of benzothiazole, benzoxazole, quinoline, isoquinoline, benzotriazole and benzofurazan.

The above "aryl group", "5 or 6 having 1 to 3 heteroatoms consisting of an oxygen atom, a sulfur atom or a nitrogen atom"
"Membered heterocyclic group" and "bicyclic condensed heterocyclic group in which the heterocycle is condensed with a benzene ring" are 1 to plural, preferably 1
It can have 2 to 2 substituents.

Examples of such a substituent include a halogen atom,
Cyano group, nitro group, trifluoromethyl group, hydroxy group, amino group, mono- or di-lower alkylamino group, lower alkyl group, lower alkoxy group, carboxy group, lower alkoxycarbonyl group, lower alkanoyl group, lower alkanoyloxy Group, lower alkanoylamino group, aroyl group, aroyloxy group, carbamoyl group, mono- or di-lower alkylaminocarbonyl group, sulfonic acid group, lower alkylsulfonyl group, sulfamoyl group, mono- or di-lower alkylsulfamoyl group And the like, preferably a halogen atom, a cyano group, a nitro group, a trifluoromethyl group, a hydroxy group,
It is an amino group, a lower alkyl group, a lower alkoxy group, a carboxy group, a lower alkoxycarbonyl group, or a lower alkanoylamino group, and more preferably a halogen atom, a cyano group or a nitro group.

Here, the "halogen atom" is a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom, and the "lower alkoxy group" is a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, s
ec-Butoxy group, tert-butoxy group, pentyloxy (amyloxy) group, isopentyloxy group, tert-pentyloxy group, neopentyloxy group, 2-methylbutoxy group, 1,2-dimethylpropoxy group, 1-ethyl A propoxy group, a hexyloxy group and the like are preferable, and a methoxy group and an ethoxy group are preferable.

Further, as the "lower alkoxycarbonyl group", a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, a butoxycarbonyl group, a tert-butoxycarbonyl group, a pentyloxycarbonyl group and the like, and a "lower alkanoyl (oxy) group" Is an acetyl (oxy) group, a propionyl (oxy) group, a butyryl (oxy) group, a valeryl (oxy) group, an isovaleryl (oxy) group, etc. , Butylamino group, valerylamino group, isovalerylamino group and the like.

As the "aroyl group" or "aroyloxy group",
Benzoyl (oxy) group, 1-naphthylcarbonyl (oxy) group, 2-naphthylcarbonyl (oxy) group, thienoyl (oxy) group, pyrroloyl (oxy) group, 2,3- or 4-pyridylcarbonyl (oxy) group, etc. Is mentioned.

Examples of the "lower alkyl group" in the "mono- or di-lower alkylaminocarbonyl group" or "mono- or di-lower alkylsulfamoyl group" include the above-mentioned lower alkyl groups. Typical groups are methylaminocarbonyl group, dimethylaminocarbonyl group, diethylaminocarbonyl group, propylaminocarbonyl group, methylsulfamoyl group, dimethylsulfamoyl group, diethylaminosulfamoyl group and the like.

Further, as "lower alkylsulfonyl group", methylsulfonyl group, ethylsulfonyl group, propylsulfonyl group, isopropylsulfonyl group, butylsulfonyl group, isobutylsulfonyl group, sec-butylsulfonyl group, tert-butylsulfonyl group, pentylsulfonyl group, A hexyl sulfonyl group etc. can be mentioned.

The compound of the present invention can easily form a salt with an inorganic acid or an organic acid, and these salts also have an aromatase inhibitory action like the free base. Suitable salts include
Examples thereof include inorganic acid salts such as hydrochloride, hydrobromide, sulfate, nitrate and phosphate, and organic acid salts such as oxalate, fumarate and tartrate.

Further, depending on the kind of the substituent, a salt with a pharmaceutically acceptable alkali metal or alkaline earth metal (for example, sodium, potassium, magnesium or calcium salt), or a salt with an organic amine such as ammonia or triethylamine is also formed. can do.

The compound of the present invention may have an asymmetric carbon atom depending on the kind of the substituent, and the compound of the present invention includes all isomers such as optical isomers and diastereomers based on these.

In addition, although various hydrates, solvates, tautomers and the like exist depending on the case, the compounds of the present invention include all compounds such as isolated compounds of these compounds and mixtures thereof.

The compound of the present invention can be produced by applying various synthetic methods by utilizing the characteristics based on the basic skeleton or the kind of the substituent. The typical manufacturing methods are shown below.

(In the formula, X represents a halogen atom, an arylsulfonyloxy group, a lower alkylsulfonyloxy group, or the like.
The same applies hereinafter) From N-aminotriazole (II) to target compound (I)
As described above, the method for manufacturing the can be performed by two routes. The reaction at each step adopted in these routes is alkylation or acylation of an amino group, and any reaction can be similarly performed.

That is, in the above reaction, the corresponding amount of the raw material compound is
For example, dimethylformamide, dimethylsulfoxide,
In a solvent inert to this reaction, such as tetrahydrofuran, dimethoxyethane, acetone, methyl ethyl ketone,
Contact in the presence of base. As the base, for example,
Sodium hydride, sodium amide, n-butyllithium, potassium t-butoxide, sodium, sodium methoxide, sodium ethoxide, sodium hydroxide, potassium hydroxide can be used. This reaction can be easily performed at room temperature.

In this case, the arylsulfonyloxy group is, for example, a phenylsulfonyloxy group, a benzylsulfonyloxy group or the like, and the lower alkylsulfonyloxy group is a lower alkyl group such as a methylsulfonyloxy group, an ethylsulfonyloxy group or a propylsulfonyloxy group. Mention may be made of substituted sulfonyloxy groups.

(In the formula, A ¹ means a lower alkylene group having one less methylene group than A. The same applies to the following.) This production method corresponds to the reaction between N-aminotriazole (II) and an aldehyde compound (VII). The Schiff's base (IX) is prepared, then this is reduced to lead to the compound (XI), and then alkylation or acylation is carried out in the same manner as in the first production method to obtain the target compound (Ia). The Schiff base formation reaction can be carried out in an alcohol such as methanol or ethanol or a solvent such as benzene or toluene by an azeotropic dehydration reaction under an acid catalyst. Also,
The reduction is carried out by a conventional method using, for example, sodium borohydride, lithium borohydride, sodium cyanoborohydride and the like. Examples of the reaction solvent include alcohols such as methanol and ethanol, organic solvents such as acetic acid, water, and mixed solvents thereof. In this reduction reaction, the Schiff base may not be isolated, and a reducing agent may be added to the reaction solution containing the Schiff base to carry out the reaction.

(In the formula, R ¹ is a protecting group for an amino group, Y is a halogen atom, and B ¹
And D ¹ is an aryl group substituted with a nitro group, a 5- or 6-membered heterocyclic group, or a bicyclic condensed heterocyclic group in which the heterocyclic group is condensed with a benzene ring, and B ² is substituted with an amino group. An aryl group, a 5- or 6-membered heterocyclic group, or a bicyclic condensed heterocyclic group in which the heterocyclic group is condensed with a benzene ring, B ³ is an aryl group substituted with a halogen atom, 5-
It also means a 6-membered heterocyclic group, or a bicyclic condensed heterocyclic group in which the heterocyclic group is condensed with a benzene ring. The same applies hereinafter) This production method is a method for obtaining the compound of the present invention substituted with a halogen atom represented by the general formula (Ib) or (Ic).

That is, the compound represented by the general formula (XIII) or (XVI) is reduced to an amino compound represented by the general formula (XIV) or (XVII), which is then subjected to a Sandmeier reaction to introduce a halogen atom and then protected. It can be obtained by removing the group to give a compound represented by the general formula (XV) or (XVIII), and reacting it with the compound (V) or (III).

The reduction of the compound represented by the general formula (XIII) is carried out by a conventional method such as chemical reduction or catalytic reduction.

Suitable reducing agents used in the chemical reduction are metals such as tin, zinc and iron, and catalytic reductions include platinum catalysts such as platinum and platinum oxide, palladium catalysts such as palladium black and palladium oxide, Raney nickel and the like. A conventional method using a nickel catalyst or the like is used.

Solvents in this case include methanol, ethanol,
Conventional solvents such as propanol and ethyl acetate are used. The nitrogen atom of the compound represented by formula (XIII) or (XVI) is protected by a conventional acyl protecting group such as acetyl group and benzoyl group. The introduction of this protecting group is performed by adding acetic anhydride, acetyl chloride, benzoyl chloride, etc. to sodium acetate,
It can be carried out by reacting in the presence of a base such as pyridine, picoline, lutidine, trimethylamine, triethylamine and the like. In this case, the solvent may be dichloromethane, dichloroethane, chloroform, benzene, toluene or the like, or may be solventless.

Then, the compound (XIV) or (XVII) thus obtained
Can be converted to compound (XV) or (XVIII) by performing a Sandmeyer reaction, introducing a halogen atom, and then removing the protecting group. The Sandmeyer reaction can be carried out by conventional methods using cuprous chloride, cuprous bromide, cuprous iodide and hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and the like. In this case, the solvent is water, acetone, dioxane, tetrahydrofuran or the like. Removal of the protecting group is carried out by acid hydrolysis with dilute hydrochloric acid, dilute sulfuric acid or the like. For the reaction of the compound (XV) thus obtained with the compound (V) or (III), the methods described in the first and second production methods are adopted.

Other Production Methods 1) When the compound of the present invention has an amino group as a substituent, it can be obtained by reducing the compound of the present invention having a corresponding nitro group. This reaction is a conversion reaction between substituents, and the reduction reaction in this case employs the reduction reaction in the third production method.

2) When the compound of the present invention has a lower alkanoylamino group as a substituent, it can be obtained by a method of reacting the compound of the present invention having a corresponding amino group with acetic anhydride or the like according to a conventional method.

3) Furthermore, in the case where the substituent B or D of the compound of the present invention has a benzotriazole ring, a compound having an amino group (or a mono-substituted amino group) and a nitro group as adjacent substituents of a phenyl group Reduce the nitro group,
It can be obtained by once converting it to an amino group, then reacting it with sodium nitrite, potassium nitrite, etc. and subjecting it to a ring closure reaction.

The compound of the present invention thus produced can be isolated and purified by known methods such as extraction, precipitation fractionation chromatography, fractional crystallization, recrystallization and the like.
Further, the salt of the compound of the present invention can be converted into a desired salt by subjecting it to an ordinary salt-forming reaction.

INDUSTRIAL APPLICABILITY The compound of the present invention has an action of inhibiting the activity of the aromatase, an aromatizing enzyme involved in the production of estrogen from androgen in vivo. Therefore, the compound of the present invention is effective in treating various diseases in which estrogen is associated with an aggravating factor,
Breast cancer, mastopathy, endometriosis, benign prostatic hyperplasia,
It is useful as a preventive and therapeutic drug for uterine fibroids, endometrial cancer, etc.

[Pharmacia26(6) 558 (1990); Clinical Endocr
inology,32 623 (1990); J. Steroid Biochem. Molec. Bio
l.,37(3) 335 (1990); Br.J.Cancer60 5 (1989); En
docrinology,126(6) 3263 (1990); The Journal of
Pharmacology and Experimental Therapeutics244
(2) (1988); Endocrinol. Japan,37(5) 719 (199
0); Steroids50 1 (1987)].

[Experimental Method] The pharmacological action of the compound of the present invention was measured by the following method.

(1) In vitro inhibitory activity of aromatase activity a) Inhibitory activity of aromatase derived from rat ovary It was measured according to the method described in Journal of Biological Chemistry (J. Biol. Chem.) 249 , 5364 (1974). The IC ₅₀ values for aromatase inhibition test compound in microsomes Rat Ovarian [1,2- ³
[H] Androstenedione was determined by inhibition of ³ H ₂ O liberated.

b) Human placenta-derived aromatase inhibitory activity It was measured according to the method described in Endocrine Research., 16 (2). 253 (1990).

³ H ₂ O inhibitory activity of the compounds released from [1,2- ³ H] androstenedione in human placenta microsomes
It was obtained by suppressing.

(2) In vivo inhibitory activity of aromatase activity Immature female Wistar rats weighing 60 g were subcutaneously injected with 100 IU / rat of mare serum gonadotropin (PMSG). 72 hours later, an aqueous test compound solution dissolved in 0.5 ml of 20% polyethylene glycol in water was orally administered. The control group received only 20% polyethylene glycol. Three hours following drug or placebo administration, rats were killed by decapitation and ovaries were harvested and ovarian estradiol levels were measured by RIA.

(3) Antitumor activity The antitumor activity against breast cancer was measured in dimethylbenzanthracene (DMBA) -induced animal tumors of female Sprague-Dawlay rats.

(4) Inhibitory activity of aldosterone production in vitro and in vivo a) Inhibitory activity of aldosterone production in vitro It was measured according to the method described in J. Vet. Pharmacol. Therap., 11 345 (1988).

The inhibitory activity of the test compound was determined using rat adrenal primary culture cells.
It was determined by suppression of aldosterone produced by stimulation with ACTH. Aldosterone was measured by RIA.

b) Aldosterone production in vivo inhibitory activity It was measured according to the method described in J. Steroid Biochem, 34 567 (1989).

The inhibitory activity of the test compound was determined by suppressing blood aldosterone, which is increased by stimulating the rat with ACTH. Aldosterone was measured by RIA.

(5) Cortisol production in vitro inhibitory activity It was measured according to the method described in Endocrinology., 114 (2) 486 (1984).

The inhibitory activity of the test compound was found in AC of rabbit adrenal primary culture cells.
It was determined by suppression of cortisol produced by stimulation with TH. Cortisol was measured by RIA.

[Experimental Results] The results for the compounds of the present invention are shown below.

1. Aromatase in v in human placenta-derived microsomes
Itro inhibitory activity The IC ₅₀ value of aromatase in vitro inhibitory activity in human placenta-derived microsomes was determined by the above experimental method (1) b), and the results are shown in the following table.

Control compound; European Published Patent No. 236,940 Example 20
Compound of b). Similarly, as is apparent from these results, the compound of the present invention exhibited a significantly stronger aromatase in vitro inhibitory activity in human placenta-derived microsomes than the control compound.

2. Selective selection of aromatase in vitro inhibitory activity and aldosterone in vitro inhibitory activity in rat IC ₅₀ of aromatase in vitro inhibitory activity in rat
Value, IC of aldosterone in vitro inhibitory activity in rats
₅₀ values were measured according to (1) a) and (4) a) above,
Their selectivity was calculated and shown in the table below. The selectivity refers to the ratio of the IC ₅₀ value of rat aldosterone in vitro inhibitory activity to the IC ₅₀ value of rat aromatase in vitro inhibitory activity.

As is clear from these results, the compound of the present invention exhibited a predominantly stronger aromatase in vitro inhibitory activity in rats than the symmetrical compound. The in vitro inhibitory activity of aldosterone was almost the same.

Therefore, the selectivity (B / A) between the aromatase in vitro inhibitory activity and the aldosterone in vitro inhibitory activity was determined in Example 15
6100 times for the compound of 1 and 1700 for the symmetrical compound
It was double. This indicates that the compound of the present invention has very little effect on the aldosterone synthesis system and is a more selective aromatase inhibitor.

It is generally known that inhibition of aldosterone biosynthesis, which is known as mineralocorticoid, may lead to side effects such as loss of potassium in the body and abnormal electrolytes, resulting in decreased blood pressure due to fluid loss and orthostatic hypotension. Has been. Therefore, since the compound of the present invention is an aromatase inhibitor with high enzyme selectivity, it is expected to be a highly safe compound with less side effects on aldosterone in vitro inhibition and fewer side effects.

3. In vivo inhibitory activity of aldosterone in rat The in vivo inhibitory activity of aromatase in rat was measured by the above experimental method (4) b). When the control compound was administered to each of 5 rats at 10 mg / kg, the production of aldosterone was significantly inhibited compared with the control group, and the inhibition rate was 37%.
%Met.

On the other hand, when the compounds of Examples 10, 12 and 15 of the present invention were administered to 5 rats at a dose of 10 times each of 100 mg / kg, aldosterone inhibition was not caused at all.
The significance test was performed by one-way analysis of variance. This indicates that the compound of the present invention is a highly safe compound with fewer side effects even in in vivo tests.

4. Cortisol in vitro inhibitory activity in rabbits Cortisol in microsomes derived from rabbit adrenal gland
The IC ₅₀ value of the in vitro inhibitory activity was determined by the above experimental method (5), and the results are shown in the table below.

As is clear from the table, the compound of the present invention is predominantly weaker in cortisol in vitro inhibitory activity in rabbits than the control compound.

It is generally known that inhibiting the biosynthesis of cortisol known as glucocorticoid may cause side effects such as hypoglycemia, dysfunction of nervous system, increased stress, and increased inflammation. Therefore, since the compound of the present invention has weak cortisol inhibitory activity, it is expected to have fewer side effects than the control compound.

5. In vivo inhibitory activity of aromatase activity In the measurement of in vivo inhibitory activity of rat aromatase activity carried out by the above-mentioned experimental method (2), the minimum effective dose of the compound of the present invention was 0.001 mg / kg.

6. Antitumor activity In the above experimental method (3), the compound of the present invention was added daily about
Oral administration of 0.1 to 1.0 mg / kg suppressed or regressed tumor swelling.

7. Metabolism When the compound of Example 15 is orally administered to rats at 3 mg / kg, the maximum plasma unchanged drug concentration (Cmax) is 2.88 μg / ml.
The elimination half-life (T1 / 2) was 11 hours. From these results, the compound of the present invention is a compound that is excellent in oral absorption, has a long-lasting action, and has a favorable floro profile as a drug.

To use the compound represented by the general formula (I), a non-toxic salt thereof, or a hydrate thereof for the above purpose, it is usually administered orally or parenterally. The dose varies depending on the age, body weight, symptoms, therapeutic effect, administration method, treatment time, etc., but is usually 0.1 mg to 100 mg per adult per day, preferably 1 mg to
Orally administered in the range of 10 mg once to several times a day, or parenterally in the range of 0.1 mg to 100 mg per adult per day, once to several times a day, or 1
It is continuously administered intravenously within the range of 1 hour to 24 hours a day. Since the dose varies depending on various conditions, a dose smaller than the above dose range may be sufficient.

The solid composition for oral administration according to the present invention includes:
Tablets, powders, granules, etc. are used. In such solid compositions, one or more active substances are
At least one inert diluent such as lactose, mannitol, glucose, hydroxypropyl cellulose,
Microcrystalline cellulose, starch, polyvinylpyrrolidone,
Mixed with magnesium aluminometasilicate. According to a conventional method, the composition may be an additive other than an inert diluent, for example, a lubricant such as magnesium stearate, a disintegrating agent such as calcium fibrin glycolate, a stabilizer such as lactose, glutamic acid or asparagine. It may contain a solubilizing agent such as an acid. If necessary, tablets or pills may be coated with a film of a gastric or enteric substance such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like, and commonly used inert diluents such as purified water. , Including ethanol. In addition to the inert diluent, this composition may contain an auxiliary agent such as a wetting agent and a suspending agent, a sweetening agent, a flavoring agent, an aromatic agent and a preservative.

Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions and emulsions. Examples of the aqueous solution and suspension include distilled water for injection and physiological saline. Examples of non-water-soluble solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and polysorbate 80. Such compositions may further include preservatives, wetting agents, emulsifiers, dispersants, stabilizers (eg lactose), solubilizers (eg
Adjuvants such as glutamic acid, aspartic acid) may be included. These are sterilized by, for example, filtration through a bacteria-retaining filter, blending of a bactericide, or irradiation. They can also be used by preparing a sterile solid composition and dissolving it in sterile water or a sterile solvent for injection before use.

BEST MODE FOR CARRYING OUT THE INVENTION Next, the present invention will be described more specifically with reference to Examples. The production method of the raw material compounds used in the examples will be described as a reference example.

Reference example 1 4-amino-1,2,4-triazole 8.4 g, p-cyanobenzaldehyde 13.1 g and p-toluenesulfonic acid 1
80 ml of benzene was added to 1.9 g of water, and the mixture was heated under reflux for 4 hours under azeotropic dehydration. After cooling, the precipitated crystals are collected by filtration,
[(4-Cyanobenzylidene) amino] -4H-1,2,4-
Triazole was obtained quantitatively.

Mass spectrum (m / z): 198 (M ⁺ +1) Reference example 2 To a suspension of 1.2 g of sodium hydride in dimethyl sulfoxide, 2.52 g of 4-amino-1,2,4-triazole was added little by little at room temperature. After stirring at room temperature for 3 hours, 1.21 g of 4-fluorobenzonitrile was added all at once, and the stirring was continued for another hour. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate.
The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained crystals were washed with ethyl acetate, 4-
1.0 g of [(4-cyanophenyl) amino] -4H-1,2,4-triazole was obtained.

Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 6.57 (2H, d, J = 9Hz), 7.69 (2H, d, J = 9H1), 8.83 (2
H, s) Mass spectrum (m / z): 185 (M ⁺ ) Reference Example 3 In the same manner as in Reference Example 2, the following compound was obtained.

4-[(4-nitrophenyl) amino] -4H-1,2,4
-Triazole raw material compound: 4-amino-1,2,4-triazole and 4-fluoronitrobenzene nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 6.53-6.70 (2H, m), 8.08-8.31 ( 2H, m), 8.88 (2H,
s), 10.52 (1H, s) Mass Spec (m / z): 205 (M ⁺ ) Reference Example 4 In the same manner as in Reference Example 2, the following compound was obtained.

1-[(4-cyanophenyl) amino] -1H-1,2,4
- triazole starting compounds: 1-amino-1,2,4-triazole and 4-fluorobenzonitrile Nuclear Magnetic Resonance Spectrum (DMSO-d _6, TMS internal standard δ: 6.59 (2H, d, J = 9Hz), 7.70 ( 2H, d, J = 9Hz), 8.18 (1
H, s), 8.82 (1H, s), 10,51 (1H, brs) Mass spectrum (m / z): 185 (M ⁺ ) Reference example 5-1 The following compounds were prepared in the same manner as in Reference example 2. Obtained.

1-[(4-nitrophenyl) amino] -1H-1,2,4
- triazole starting compound: with 1-amino-1,2,4-triazole 4-fluoronitrobenzene Nuclear Magnetic Resonance Spectrum (DMSO-d _6, TMS internal standard δ: 6.59 (2H, d, J = 9Hz), 8.16 (2H , d, J ＝ 9Hz), 8.20 (1
H, s), 8.85 (1H, s), 10.80 (1H, s), mass spectrum (m / z): 205 (M ⁺ ) Reference example 5-2 4-[(4-cyanobenzylidene) amino] -4H-1,2,4-triazole obtained in Reference Example 1 9.85 g of methanol 10
2.28 g of sodium borohydride was added little by little to the 0 ml suspension solution under ice cooling. After stirring at the same temperature for 1 hour, the solvent was evaporated under reduced pressure, water was added to the obtained residue, sodium chloride was added, salting out was performed, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was subjected to silica gel column chromatography. The crystals obtained from the chloroform-methanol (15: 1) eluate were washed with chloroform to obtain 4.2 g of 4-[(4-cyanobenzyl) amino] -4H-1,2,4-triazole.

Physicochemical properties Mass spectrum (m / z): 199 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 4.31 (2H, d, J = 4Hz), 7.29 (1H, t, J = 4Hz), 7.51 (2
H, d, J = 9Hz), 7.82 (2H, d, J = 9Hz), 8.48 (2H, s) Example 1 3.74 g of 4- [N- (4-bromobenzyl) -N- (4-nitrophenyl) amino] -4H-1,2,4-triazole
A catalytic amount of Raney nickel was added to 50 ml of an ethanol solution containing and the mixture was stirred at room temperature in the presence of hydrogen gas for about 2 hours. After the catalyst was removed by filtration, the obtained filtrate was evaporated under reduced pressure, the residue was purified by silica gel column chromatography, and 4- [N- (4-
Aminophenyl) -N- (4-bromobenzyl) amino] -4H-1,2,4-triazole (1.1 g) was obtained.

Mass spectrum (m / z): 344 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 4.71 (2H, s), 4.98 (2H, br), 6.52 (2H, d, J = 9Hz),
6.85 (2H, d, J = 9Hz), 7.26 (2H, d, J = 9Hz), 7.48 (2H,
d, J = 9Hz), 8.73 (2H, s) Example 2 Sodium hydride 65 mg N, N-dimethylformamide 5
0.3 g of 4-[(4-dianophenyl) amino] -4H-1,2,4-triazole obtained in Reference Example 2 was added little by little to room temperature at room temperature. After all the additions were completed, the reaction solution was stirred at 50 ° C for 30 minutes and then cooled. N, N-dimethylformamide solution of 0.20 g of 4-fluorobenzonitrile under ice cooling
5 ml was added dropwise. After the dropping, the mixture was stirred at 100 ° C for 5 hours, and the solvent was distilled off under reduced pressure. Water was added to the obtained residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The residue was purified by silica gel column chromatography, chloroform-
Crude crystals were obtained from the elution part of methanol (100: 1).

Recrystallization from ethyl acetate gave 0.28 g of 4- [bis (4-cyanophenyl) amino] -4H-1,2,4-triazole.

Elemental analysis value (as C ₁₆ H ₁₀ N ₆ ) C (%) H (%) N (%) Theoretical value 67.13 3.52 29.35 Experimental value 66.92 3.62 29.23 Mass spectrometry value (m / z): 286 (M ⁺ ) Nuclear magnetic Resonance spectrum (CDCl ₃ , TMS internal standard) δ: 7.04 (4H, d, J = 9Hz), 7.69 (4H, d, J = 9Hz), 8.44 (2
H, s) In the same manner as in Example 2, the following compound of Example 3 was obtained.

Example 3 4- [N- (4-cyanophenyl) -N- (4-nitrophenyl) amino] -4H-1,2,4-triazole Raw material compound: 4-[(4-cyanophenyl) amino] -4H-1 , 2,4-
Triazole and 4-fluoronitrobenzene Elemental analysis: (as C ₁₅ H ₁₀ N ₆ O ₂ ) C (%) H (%) N (%) Theoretical 58.82 3.29 27.44 Experimental 58.79 3.46 27.37 Mass spec (m / z) ): 307 (M ⁺ +1) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 6.98−7.16 (4H, m), 7.72 (2H, d, J = 9Hz), 8.26 (2
H, d, J = 9 Hz), 8.46 (2H, s) In the same manner as in Example 2, the compound of Example 4 below was obtained.

Example 4 4- [N- (4-cyanophenyl) -N-methylamino] -4H-1,2,4-triazole Raw material compound: 4-[(4-cyanophenyl) amino] -4H-1,2,4-
Triazole and methyl iodide Elemental analysis value: (as C ₁₀ H ₉ N ₅ ) C (%) H (%) N (%) Theoretical value 60.29 4.55 35.15 Experimental value 60.24 4.66 35.12 Mass analysis value (m / z): 199 (M ⁺ ) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 3.56 (3H, s), 6.60 (2H, d, J = 9Hz), 7.60 (2H, d, J =
9 Hz), 8.41 (2H, s) In the same manner as in Example 2, the following compound of Example 5 was obtained.

Example 5 4- [N- (4-cyanophenyl) -N-propylamino] -4H-1,2,4-triazole Raw material compound: 4-[(4-cyanophenyl) amino] -4H-1,2,4-
Triazole and propyl iodide Elemental analysis value: (as C ₁₂ H ₁₃ N ₅ ) C (%) H (%) N (%) Theoretical value 63.42 5.77 30.82 Experimental value 63.41 5.82 30.77 Mass spectrometry value (m / z): 227 (M ⁺ ), 198 Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.03 (3H, t, J = 7Hz), 1.45-1.76 (2H, m), 3.67 (2
H, dd, J = 7Hz, J = 7Hz), 6.54 (2H, d, J = 9Hz), 7.56 (2H,
d, J = 9 Hz), 8.33 (2H, s) In the same manner as in Example 2, the compound of the following Example 6 was obtained.

Example 6 4-Cyano-N- (4-cyanophenyl) -N- (4H
-1,2,4-triazol-4-yl) benzamide Raw material compound: 4-[(4-cyanophenyl) amino] -4H-1,2,4-
Triazole and 4-cyanobenzoyl chloride Elemental analysis value (as C ₁₇ H ₁₀ N ₆ O) C (%) H (%) N (%) Theoretical value 64.96 3.21 26.74 Experimental value 64.81 3.35 26.72 Mass analysis value (m / z) : 314 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO−d ₆ , TMS internal standard) δ: 7.61 (2H, d, J = 9Hz), 7.77−7.99 (6H, m), 9.13 (2
H, s) In the same manner as in Example 2, the following compound of Example 7 was obtained.

Example 7 4- [N- (4-cyanophenyl) -N- (2,4-dinitrophenyl) amino] -4H-1,2,4-triazole Raw material compound: 4-[(4-cyanophenyl) amino] -4H -1,2,4-
Triazole and 2,4-dinitrofluorobenzene Elementary analysis (C ₁₄ H ₉ N ₇ as _{O 6) C (%) H} (%) N (%) Theoretical values 45.29 2.44 26.41 Found 45.25 2.55 26.40 Mass spectrometry value (m / z): 371 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 6.82 (2H, d, J = 9Hz), 7.95 (1H, d, J = 9Hz), 8.20 (2
H, d, J = 9Hz), 8.71 (1H, q, J = 9Hz), 8.95 (1H, d, J = 3H
z), 9.21 (2H, s) In the same manner as in Example 2, the following compound of Example 8 was obtained.

Example 8 4- [bis (4-nitrophenyl) amino] -4H-1,
2,4-triazole Raw material compound: 4-[(4-nitrophenyl) amino] -4H-1,2,4-
Triazole and 4-fluoronitrobenzene Elemental analysis value (as C ₁₄ H ₁₀ N ₆ O ₄ ) C (%) H (%) N (%) Theoretical value 51.54 3.09 25.76 Experimental value 51.59 3.14 25.80 Mass spectrometry value (m / z) : 326 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO−d ₆ , TMS internal standard) δ: 7.24 (4H, d, J = 9Hz), 8.30 (4H, d, J = 9Hz), 9.28 (2
H, s) Example 9 i) In Example 2, the same reaction was performed using 4-fluoro-2-methylaminonitrobenzene instead of 4-fluorobenzonitrile, and 4- [N- (4-cyanophenyl) -N-[(3 -Methylamino-4-nitro)
(Phenyl) amino] -4H, 1,2,4-triazole was obtained.

Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 3.16 (3H, s), 7.23 (2H, d, J = 8Hz), 7.75 (2H, d, J =
9Hz), 7.80 (2H, s), 8.13 (2H, d, J = 9Hz), 8.87 (2H,
s) Mass spectrum (m / z): 335 (M ⁺ ) ii) 4- [N- (4-cyanophenyl) -N-[(3-methylamino-4-nitro) phenyl obtained in i) above. ] Amino] -4H-1,2,4-triazole (1.8 g) was mixed with 30 ml of methanol and 1 g of Raney nickel and subjected to catalytic reduction reaction in a hydrogen atmosphere under normal pressure. Raney nickel is removed and the solvent is distilled off under reduced pressure to obtain the desired 4-[[N- (4-
Amino-3-methylamino) phenyl] -N- (4-cyanophenyl) amino] -4H-1,2,4-triazole was quantitatively obtained. This product was dissolved in 30 ml of 6N hydrochloric acid, and 2 ml of an aqueous solution of 0.37 g of sodium nitrite was added dropwise at 5 ° C or lower.
After dropping, the mixture was stirred at 5 ° C for 30 minutes and then made alkaline with aqueous sodium hydroxide solution. Extracted with ethyl acetate,
The organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography, ethyl acetate-methanol (100:
1) Crude crystals were obtained from the elution part. Recrystallized from ethyl acetate to give 6- [N- (4-cyanophenyl) -N- (4H-1,2,
4-triazol-4-yl) amino] -1-methyl-1
0.17 g of H-benzotriazole was obtained.

Nuclear magnetic resonance spectrum (CDCl ₃ + DMSO−d ₆ , TMS internal standard) δ: 2.81 (3H, s), 6.75 (2H, d, J = 9Hz), 7.36 (1H, dd, J
= 9Hz, J = 2Hz), 7.59 (1H, d, J = 2Hz), 7.63 (1H, d, J = 9
Hz), 8.11 (2H, d, J = 9Hz), 8.73 (2H, s) Mass spec (m / z): 316 (M ⁺ ), 220 Example 10 In 20 ml of a 2-butanone suspension solution containing 0.37 g of 4-[(4-nitrophenyl) amino] -4H-1,2,4-triazole obtained in Reference Example 3, 0.83 g, p of anhydrous potassium carbonate was added at room temperature.
-Nitrobenzyl bromide 1.30 and a catalytic amount of sodium iodide were sequentially added, and the mixture was heated under reflux for about 2 hours. After cooling, the solvent was distilled off under reduced pressure, an appropriate amount of purified water was added to the resulting residue, and the mixture was extracted several times with ethyl acetate. The ethyl acetate layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain crude crystals from the chloroform-methanol (100: 1) eluate. The obtained crude crystals were recrystallized from ethanol to give 4- [N- (4-nitrobenzyl) -N- (4
0.28 g of -nitrophenyl) amino] -4H-1,2,4-triazole was obtained.

Elemental analysis value (as C ₁₅ H ₁₂ N ₆ O ₄ ) C (%) H (%) N (%) Theoretical value 52.94 3.55 24.70 Experimental value 52.94 3.62 25.02 Mass spectrometry value (m / z): 340 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 5.33 (2H, s), 6.77 (2H, d, J = 9Hz), 7.66 (2H, d, J =
9Hz), 8.20 (4H, d, J = 9Hz), 8.93 (2H, s) In the same manner as in Example 10, the compound of the following Example 11 was obtained.

Example 11 4- [N- (4-cyanobenzyl) -N- (4-cyanophenyl) amino] -4H-1,2,4-triazole Raw material compound: 4-[(4-cyanophenyl) amino]- 4H-1,2,4-
Triazole and 4-cyanobenzyl bromide Mass spectrum (m / z): 300 (M ⁺ ) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 4.98 (2H, s), 6.64 (2H, d, J = 9Hz), 7.26-7.74 (6
H, m), 8.20 (2H, s) Example 12 4- [N- (4-nitrophenyl) amino] -4, -1,
2,4-triazole 0.63 g, 4-bromobenzyl bromide 0.
82 g and 0.62 g of anhydrous potassium carbonate, 8 ml of acetonitrile
Was added and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, water was added to the obtained residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography, and chloroform-methanol (10
0: 1) Crude crystals were obtained from the elution part. The crude crystals were recrystallized from acetone to give 4- [N- (4-bromobenzyl) -N- (4
-Nitrophenyl) amino] -4H-1,2,4-triazole 0.71 g was obtained. Melting point 241 ° C Elemental analysis value (as C ₁₅ H ₁₂ BrN ₅ O ₂ ) C (%) H (%) N (%) Br (%) Theoretical value 48.15 3.23 18.72 21.35 Experimental value 48.21 3.17 18.97 21.50 Mass spectrum value (m / z): 374 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 5.12 (2H, 2H, s), 6.79 (2H, d, J = 9Hz), 7.29 (2H, d, J =
9Hz), 7.54 (2H, d, J = 9Hz), 8.19 (2H, d, J = 9Hz), 8.84
(2H, s) In the same manner as in Example 10, the compound of the following Example 13 was obtained.

Example 13 4- [N- (4-methylbenzene) -N- (4-nitrophenyl) amino] -4H-1,2,4-triazole Raw material compound: 4-[(4-Nitrophenyl) amino] -4H-1 , 2,4-
Triazole and 4-methylbenzyl bromide Elemental analysis value (as C ₁₆ H ₁₅ N ₅ O ₂ ) C (%) H (%) N (%) Theoretical value 62.13 4.89 22.64 Experimental value 61.87 5.00 22.43 Mass spectrometry value (m / z ): 309 (M ⁺ ) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 2.34 (3H, s), 4.90 (2H, s), 6.68 (2H, d, J = 6Hz),
7.08 (2H, d, J = 8Hz), 7.16 (2H, d, J = 8Hz), 8.10 (2H,
s), 8.19 (2H, d, J = 6Hz) In the same manner as in Example 10, the following compound of Example 14 was obtained.

Example 14 4- [N- (4-methoxybenzyl) -N- (4-nitrophenyl) amino] -4H-1,2,4-triazole Raw material compound: 4-[(4-nitrophenyl) amino] -4H-1 , 2,4-
Triazole and p-methoxybenzyl chloride Elemental analysis value (as C ₁₆ H ₁₅ N ₅ O ₃ ) C (%) H (%) N (%) Theoretical value 59.07 4.65 21.53 Experimental value 59.05 4.61 21.50 Mass spectrometric value (m / z ): 325 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO−d ₆ , TMS internal standard) δ: 3.73 (3H, s), 5.04 (2H, s), 6.76−6.92 (4H, m), 7.
22 (2H, d, J = 9Hz), 8.19 (2H, d, J = 9HZ), 8.75 (2H, s) Example 15 4- [N- (4-cyanophenyl) amino] -4H-1,
2,4-triazole 3.15 g, 4-bromobenzyl bromide 4.
Acetonitrile 40 ml to 25 g and anhydrous potassium carbonate 3.52 g
Was added and the mixture was stirred at room temperature for 2 hours. The solvent is distilled off under reduced pressure,
Water was added to the residue and extracted with chloroform. The chloroform layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography, and crude crystals were obtained from the chloroform-methanol (100: 1) eluate. Recrystallized from crude crystalline ethanol, 4
There were obtained 3.92 g of-[N- (4-bromobenzyl) -N- (4-cyanophenyl) amino] -4H-1,2,4-triazole.

Melting point 203 ° C Elemental analysis value (as C ₁₆ H ₁₂ BrN ₅ ) C (%) H (%) N (%) Br (%) Theoretical value 54.26 3.41 19.77 22.56 Experimental value 53.96 3.48 19.72 22.65 Mass spectrometry value (m / z) ): 354 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 5.06 (2H, s), 6.75 (2H, d, J = 9Hz), 7.27 (2H, d, J =
9Hz), 7.53 (2H, d, J = 9Hz), 7.75 (2H, d, J = 9Hz), 8.81
(2H, s) In the same manner as in Example 10, the compound of the following Example 16 was obtained.

Example 16 4- [N- (4-nitrophenyl) -N- (4-thiazolylmethyl) amino] -4H-1,2,4-triazole Raw material compound: 4-[(4-nitrophenyl)] amino-4H-1, 2,4-
Triazole and 4- (chloromethyl) thiazole Elemental analysis value (as C ₁₂ H ₁₀ N ₆ O ₂ S) C (%) H (%) N (%) S (%) Theoretical value 47.68 3.33 27.80 10.61 Experimental value 47.51 3.45 27.75 10.45 Mass spectrum (m / z): 302 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 5.28 (2H, s), 6.77 (2H, d, J = 9Hz), 7.77 (1H, br
s), 8.17 (2H, d, J = 9Hz), 8.80 (2H, s), 9.12 (1H, br
s) In the same manner as in Example 10, the following compound of Example 17 was obtained.

Example 17 4- [N- (4-fluorobenzyl) -N- (4-nitrophenyl) amino] -4H-1,2,4-triazole Raw material compound: 4-[(4-nitrophenyl] amino-4H-1, 2,4-triazole and p-fluorobenzyl bromide Elemental analysis value (as C ₁₅ H ₁₂ FN ₅ O ₂ ) C (%) H (%) N (%) F (%) Theoretical value 57.51 3.86 22.35 6.06 Experimental value 57.44 3.98 22.37 5.85 Mass spectrum (m / z): 313 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 5.12 (2H, s), 6.81 (2H, d, J = 9Hz) , 7.05-7.46 (4
H, m), 8.20 (2H, d, J = 9Hz), 8.81 (2H, s) In the same manner as in Example 10, the compound of the following Example 18 was obtained.

Example 18 4- [N- (4-chlorobenzyl) -N- (4-nitrophenyl) amino] -4H-1,2,4-triazole Raw material compound: 4-[(4-nitrophenyl) amino] -4H-1 , 2,4-
Triazole and p-chlorobenzyl chloride Elemental analysis value (as C ₁₅ H ₁₂ ClN ₅ O ₂ ) C (%) H (%) N (%) Cl (%) Theoretical value 54.64 3.67 21.24 10.75 Experimental value 54.59 3.85 21.13 10.72 Mass Analysis value (m / z): 392 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 5.14 (2H, s), 6.79 (2H, d, J = 9Hz), 7.36 (2H) , d, J ＝
9Hz), 7.40 (2H, d, J = 9Hz), 8.20 (2H, d, J = 9Hz), 8.84
(2H, s) In the same manner as in Example 10, the compound of the following Example 19 was obtained.

Example 19 4- [N- (4-iodobenzyl) -N- (4-nitrophenyl) amino] -4H-1,2,4-triazole Raw material compound: 4-[(4-Nitrophenyl) amino] -4H-1 , 2,4-
Triazole and p-iodobenzyl chloride Elemental analysis value (as C ₁₅ H ₁₂ IN ₅ O ₅ ) C (%) H (%) N (%) I (%) Theoretical value 42.77 2.87 16.63 30.13 Experimental value 42.68 3.01 16.46 30.26 Mass Analysis value (m / z): 422 (M ⁺ +1) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 5.10 (2H, s), 6.78 (2H, d, J = 9Hz), 7.14 ( 2H, d, J ＝
9Hz), 7.70 (2H, d, J = 9Hz), 8.19 (2H, d, J = 9Hz), 8.84
(2H, s) In the same manner as in Example 10, the following compound of Example 20 was obtained.

Example 20 2-[[N- (4-nitrophenyl) -N- (4H-1,
2,4-Triazol-4-yl) amino] methyl] quinoline Raw material compound: 4-[(4-nitrophenyl) amino] -4H-1,2,4-
Triazole and 2- (chloromethyl) quinoline Elementary analysis value (C ₁₈ H ₁₄ N as _{6 O 2) C (%)} H (%) N (%) Theoretical values 62.42 4.07 24.26 Found 62.42 4.22 24.30 Mass spectrometry value (m / z): 347 (M ⁺ +1) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 5.52 (2H, s), 6.70 (2H, d, J = 8Hz), 7.61 (1H, t, J =
6Hz), 7.67 (1H, d, J = 7Hz), 7.76 (1H, t, J = 6Hz), 7.98
-8.03 (2H, m), 8.42 (1H, d, J = 7Hz), 9.08 (2H, s) In the same manner as in Example 10, the following compound of Example 21 was obtained.

Example 21 4- [N- (4-nitrophenyl) -N- (4-pyridylmethyl) amino] -4H-1,2,4-triazole Raw material compound: 4-[(4-nitrophenyl) amino] -4H-1 , 2,4-
Triazole and 4-picolyl chloride Elemental analysis value (as C ₁₄ H ₁₂ N ₆ O ₂ ) C (%) H (%) N (%) Theoretical value 56.75 4.08 28.36 Experimental value 56.67 4.23 28.36 Mass spectrometry value (m / z ): 297 (M ⁺ +1) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 5.23 (2H, s), 6.72 (2H, d, J = 9Hz), 7.40 (2H, d, J =
6Hz), 8.19 (2H, d, J = 9Hz), 8.55 (2H, d, J = 6Hz), 8.97
(2H, s) In the same manner as in Example 10, the compound of the following Example 22 was obtained.

Example 22 4- [N- (4-cyanophenyl) -N- (4-nitrobenzyl) amino] -4H-1,2,4-triazole Raw material compound: 4-[(4-cyanophenyl) amino] -4H-1 , 2,4-
Triazole and 4-nitrobenzyl bromide Elemental analysis value (as C ₁₆ H ₁₂ N ₆ O ₂ ) C (%) H (%) N (%) Theoretical value 60.00 3.78 26.24 Experimental value 59.75 3.71 26.28 Mass spectrometry value (m / z ): 320 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 5.27 (2H, s), 6.74 (2H, d, J = 9Hz), 7.65 (2H, d, J =
9Hz), 7.77 (2H, d, J = 9Hz), 8.20 (2H, d, J = 9Hz), 8.90
(2H, s) In the same manner as in Example 10, the compound of the following Example 23 was obtained.

Example 23 4- [N- (4-cyanobenzyl) -N- (4-nitrophenyl) amino] -4H-1,2,4-triazole Raw material compound: 4-[(4-nitrophenyl) amino] -4H-1 , 2,4-
Triazole and 4-cyanobenzyl bromide Elemental analysis value (as C ₁₆ H ₁₂ N ₆ O ₂ ) C (%) H (%) N (%) Theoretical value 60.00 3.78 26.24 Experimental value 59.94 3.98 26.21 Mass spectrometry value (m / z ): 320 (M ⁺ , EI) Nuclear magnetic resonance spectrum (DMSO−d ₆ , TMS internal standard) δ: 5.27 (2H, s), 6.76 (2H, d, J = 9Hz), 7.57 (2H, d, J) =
9Hz), 7.84 (2H, d, J = 9Hz), 8.20 (2H, d, J = 9Hz), 8.91
(2H, s) In the same manner as in Example 10, the compound of the following Example 24 was obtained.

Example 24 4- [N- (4-nitrophenyl) -N- [4- (trifluoromethyl) benzyl] amino] -4H-1,2,4-
Triazole raw material compound: 4-[(4-nitrophenyl) amino] -4H-1,2,4-
Triazole and 4- (trifluoromethyl) benzyl bromide Elemental analysis value (as C ₁₆ H ₁₂ F ₃ N ₅ O ₂ ) C (%) H (%) N (%) F (%) Theoretical value 52.90 3.33 19.28 15.69 Experiment Value 52.88 3.36 19.38 15.60 Mass spectrum (m / z): 363 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 5.27 (2H, s), 6.78 (2H, d, J = 7Hz), 7.59 (2H, d, J =
8Hz), 7.72 (2H, d, J = 8Hz), 8.21 (2H, d, J = 7Hz), 8.91
(2H, s) In the same manner as in Example 10, the following compound of Example 25 was obtained.

Example 25 1- [N- (4-nitrobenzyl) -N- (4-nitrophenyl) amino] -1H-1,2,4-triazole Raw material compound: 1-[(4-nitrophenyl) amino] -1H-1 , 2,4-
Triazole and p-nitrobenzyl bromide Elemental analysis value (as C ₁₅ H ₁₂ N ₆ O ₄ ) C (%) H (%) N (%) Theoretical value 52.94 3.55 24.70 Experimental value 52.66 3.74 24.62 Mass spectrometry value (m / z) ): 340 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO−d ₆ , TMS internal standard) δ: 5.33 (2H, s), 6.75 (2H, d, J = 9Hz), 7.72 (2H, d, J =
9 Hz), 8.10-8.27 (5H, m), 8.84 (1H, s) In the same manner as in Example 10, the following compound of Example 26 was obtained.

Example 26 1- [N- (4- (bromobenzyl) -N- (4-nitrophenyl) amino] -1H-1,2,4-triazole Raw material compound: 1-[(4-nitrophenyl) amino] -1H- 1,2,4-
Triazole and p-bromobenzyl bromide Elemental analysis value (as C ₁₅ H ₁₂ BrN ₅ O ₂ ) C (%) H (%) N (%) Br (%) Theoretical value 48.15 3.23 18.72 21.35 Experimental value 48.00 3.31 18.72 21.42 Mass Analysis value (m / z): 374 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 5.10 (2H, s), 6.76 (2H, d, J = 9Hz), 7.23 (2H) , d, J ＝
9Hz), 7.54 (2H, d, J = 9Hz), 8.17 (2H, d, J = 9Hz), 8.20
(1H, s), 8.72 (1H, s) In the same manner as in Example 10, the compound of the following Example 27 was obtained.

Example 27 1- [N- (4-cyanophenyl) -N- (4-nitrobenzyl) amino] -1H-1,2,4-triazole Raw material compound: 1-[(4-cyanophenyl) amino] -1H-1 , 2,4-
Triazole and p-nitrobenzyl bromide Elemental analysis value (as C ₁₆ H ₁₂ N ₆ O ₂ ) C (%) H (%) N (%) Theoretical value 60.00 3.78 26.24 Experimental value 60.02 3.91 26.21 Mass spectrometry value (m / z) ): 320 (M ⁺ ) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 5.04 (2H, s), 6.67 (2H, d, J ＝ 9Hz), 7.54 (2H, d, J ＝
9Hz), 7.58 (2H, d, J = 9Hz), 7.96 (1H, s), 8.05 (1H,
s), 8.21 (2H, d, J = 9Hz) In the same manner as in Example 2, the compound of the following Example 28 was obtained.

Example 28 1- [bis (4-nitrophenyl) amino] -1H-1,
2,4-triazole Raw material compound: 1-[(4-nitrophenyl) amino] -1H-1,2,4-
Triazole and p-nitrofluorobenzene Elemental analysis value (as C ₁₄ H ₁₀ N ₆ O ₄ ) C (%) H (%) N (%) Theoretical value 51.54 3.09 25.76 Experimental value 51.39 3.43 25.36 Mass spectrometry value (m / z) ): 326 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO−d ₆ , TMS internal standard) δ: 7.22 (4H, d, J = 9Hz), 8.28 (4H, d, J = 9Hz), 8.37 (1
H, s), 9.24 (1H, s) Reference example 6 4-[(4-nitrophenyl) amino] -4H-1,2,4
-To 15 ml of a pyridine solution containing 0.62 g of triazole, 2.8 ml of acetic anhydride was added at room temperature and stirred for about 2 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, an appropriate amount of aqueous sodium hydrogen carbonate solution was added to the obtained residue, and the mixture was extracted several times with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography, and 4- [N-acetyl-N- was obtained from the eluate of chloroform-methanol (100: 1).
0.52-g of (4-nitrophenyl) amino] -4H-1,2,4-triazole was obtained.

Mass spectrum (m / z): 247 (M ⁺ ) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 2.13 (3H, s), 7.49 (2H, d, J = 9Hz), 8.28 (2H, d, J ＝
9Hz), 8.52 (2H, s) Reference example 7 An appropriate amount of 10% palladium-carbon was added to 15 ml of a methanol solution containing 0.38 g of 4- [N-acetyl-N- (4-nitrophenyl) amino] -4H-1,2,4-triazole in the presence of hydrogen gas. The catalytic reduction was carried out at room temperature for about 40 minutes. After the reaction was completed, the catalyst was filtered off and the resulting filtrate was distilled off under reduced pressure. The residue was purified by silica gel chromatography, and chloroform-methanol (50: 1) eluted with 4-
[N-acetyl-N- (4-aminophenyl) amino]
0.33 g of -4H-1,2,4-triazole was obtained.

Mass spectrum (m / z): 217 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 1.97 (3H, s), 5.53 (2H, br), 6.58 (2H, d, J = 9Hz),
7.35 (2H, d, J = 9Hz), 8.88 (2H, s) Reference example 8 After cooling 1 ml of a 47% hydrobromic acid solution containing 0.32 g of 4- [N-acetyl-N- (4-aminophenyl) amino] -4H-1,2,4-triazole to 0 to 5 ° C, 1 ml of an aqueous solution containing 0.1 g of sodium nitrate was gradually added dropwise, and the mixture was stirred at the same temperature for about 20 minutes. Next, cuprous bromide that had been prepared in advance 0.
This was poured into a cooled aqueous solution containing 55 g and 1% of 47% hydrobromic acid and stirred at room temperature for about 20 hours. The reaction solution was extracted several times with an aqueous solution of sodium hydrogen carbonate with neutralized ethyl acetate, and the obtained ethyl acetate layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the obtained crude crystals were washed with ether to obtain 4- [N-acetyl-N- (bromophenyl) amino] -4H-1,2,4-triazole (0.29 g).

Mass spectrum (m / z): 281 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 2.00 (3H, s), 7.74 (4H, m), 9.06 (2H, s) Reference example 9 5 ml of 4N hydrochloric acid was added to 0.22 g of 4- [N-acetyl-N- (4-bromophenyl) amino] -4H-1,2,4-triazole, and the mixture was heated at 90 ° C for about 40 minutes. After allowing to cool, the solution was neutralized with an aqueous sodium hydrogen carbonate solution and extracted several times with ethyl acetate. The obtained ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
0.18 g of 4- (4-bromophenyl) amino) -4H-1,2,4-triazole was obtained from the elution part of methanol (50: 1).

Mass spectrum (m / z): 239 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 6.45 (2H, d, J = 9Hz) 7.41 (2H, d, J = 9Hz) , 8.77 (2
H, s), 9.62 (1H, s) Reference example 10 26.70 g of potassium tert-butoxide was dissolved in 100 ml of anhydrous dimethylsulfoxide, then 4-amino-4H-1,
20.00 g of 2,4-triazole was added and stirred at room temperature for 2 hours. The solution is then treated with 5-fluorobenzofurazan 11.0
A solution of 0 g of 50 ml of anhydrous dimethyl sulfoxide was added dropwise over 20 minutes, and the mixture was further stirred for 15 minutes. The reaction solution was added to 500 ml of water and ice.
In addition to 500 g, washed with 200 ml of ethyl acetate and then adjusted to pH with 1N hydrochloric acid
Crystals precipitated at 7.0. The crystals were collected by filtration, extracted from the mother liquor with ethyl acetate, the organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained crude crystals were recrystallized from ethanol and combined with the crystals collected by filtration earlier to give 5-[(4H-1,2,4-triazol-4-yl) amino] benzofurazan. 12.49 g was obtained.

Mass spectrum (m / z): 202 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 6.09 (1H, dd, J = 2Hz, 1Hz), 7.29 (1H, dd, J) = 10Hz, 2H
z), 8.17 (1H, dd, J = 10Hz, 1Hz), 8.89 (2H, s), 10,46
(1H, brs) Reference example 11 6.67 g of potassium tert-butoxide was dissolved in 36 ml of anhydrous dimethylsulfoxide, then 4-amino-4H-1,2,
4-Triazole (5.00 g) was added, and the mixture was stirred at room temperature for 15 minutes. Then, a solution of 3.23 g of 2-fluorobenzonitrile in 9 ml of anhydrous dimethyl sulfoxide was added dropwise to this solution over 10 minutes, and the mixture was further stirred for 15 minutes. The reaction solution was added to 90 ml of water and 90 g of ice and adjusted to pH 5.7 with 1N hydrochloric acid. The precipitated crystals are collected by filtration,
Dried to 4- (2-cyanophenyl) amino] -4H-1,
2.64 g of 2,4-triazole was obtained.

Mass spectrum (m / z): 185 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 6.22 (1H, d, J = 8Hz), 7.05 (1H, m), 7.54 ( 1H, m),
7.74 (1H, dd, J = 8Hz, 1Hz), 8.81 (2H, s), 10.14 (1H,
s) Example 29 Sodium hydride 0.12g N, N-dimethylformamide
0.56 g of 4-[(4-cyanophenyl) amino] -4H-1,2,4-triazole was added little by little to the 6 ml suspension solution at room temperature. After all the additions, the reaction was stirred at 50 ° C for 30 minutes and then cooled. While cooling, 0.42 g of 5-fluorobenzofurazan was added, and the mixture was subsequently stirred at 100 ° C for 1 hour. The solvent was evaporated under reduced pressure, water was added to the obtained residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The residue was purified by silica gel column chromatography, and crude crystals were obtained from the chloroform-methanol (200: 1) eluate. Recrystallized from ethyl acetate to give 5- [N- (4-cyanophenyl) -N
0.17 g of-(4H-1,2,4-triazol-4-yl) amino] benzofurazan was obtained.

Elemental analysis value (as C ₁₅ H ₉ N ₇ O) C (%) H (%) N (%) Theoretical value 59.40 2.99 32.33 Experimental value 59.43 3.01 32.38 Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 7.06 −7.27 (4H, m), 7.74 (2H, d, J = 9Hz), 7.93 (1
H, d, J = 9 Hz), 8.49 (2H, s) In the same manner as in Example 29, the following compound of Example 30 was obtained.

Example 30 4- [N- (4-nitrophenyl) -N- (5-nitropyridin-2-yl) amino] -4H-1,2,4-triazole Raw material compound: 4-[(4-Nitrophenyl) amino] −4H-1,2,4−
Triazole and 2-bromo-5-nitropyridine Elementary analysis (C ₁₃ H ₉ N ₇ as _{O 4) C (%) H} (%) N (%) Theoretical values 47.71 2.77 29.96 Found 47.46 2.90 30.04 Mass spectrometry value ( m / z): 327 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 6.77 (1H, d, J = 9Hz), 7.74 (2H, d, J = 9Hz), 8.38 ( 2
H, d, J = 9Hz), 8.53 (1H, d, J = 9Hz), 9.13 (1H, s), 9.25
(2H, s) Example 31 4-[(4-cyanophenyl) amino] -4H-1,2,4
-Triazole 500 mg, 4-fluorobenzyl bromide 0.4
To 2 ml and potassium carbonate 746 mg, add 40 ml of acetonitrile,
The mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, water was added to the obtained residue, and the mixture was extracted with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The residue was subjected to silica gel column chromatography, and crude crystals were obtained from the eluate of chloroform-methanol (100: 2). The crude crystals were recrystallized from ethyl acetate to give 4-
314 mg of [N- (4-cyanophenyl) -N- (4-fluorobenzyl) amino] -4H-1,2,4-triazole was obtained.

Elemental analysis value (as C ₁₆ H ₁₂ N ₅ F) C (%) H (%) N (%) F (%) Theoretical value 65.52 4.12 23.88 6.48 Experimental value 65.53 4.16 23.93 6.43 Mass analysis value (m / z): 293 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 5.05 (2H, s), 6.77 (2H, d, J = 9Hz), 7.04-7.44 (4
H, m), 7.76 (2H, d, J = 9Hz), 8.78 (2H, s) In the same manner as in Example 31, the compound of the following Example 32 was obtained.

Example 32 4- [N- (4-chlorobenzyl) -N- (4-cyanophenyl) amino] -4H-1,2,4-triazole Raw material compound: 4-[(4-cyanophenyl) amino] -4H-1 , 2,4-
Triazole and 4-chlorobenzyl bromide Elemental analysis value (as C ₁₆ H ₁₂ N ₅ Cl) C (%) H (%) N (%) Cl (%) Theoretical value 62.04 3.90 22.61 11.45 Experimental value 61.97 4.10 22.59 11.26 Mass spectrometry Value (m / z): 309 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 5.07 (2H, s), 6.75 (2H, d, J = 9Hz), 7.37 (4H, s),
7.76 (2H, d, J = 9Hz), 8.80 (2H, s) In the same manner as in Example 31, the compound of the following Example 33 was obtained.

Example 33 4- [N- (4-cyanophenyl) -N- (4-iodobenzyl) amino] -4H-1,2,4-triazole Raw material compound: 4-[(4-cyanophenyl) amino] -4H-1 , 2,4-
Triazole and 4-iodobenzyl chloride Elemental analysis value (as C ₁₆ H ₁₂ N ₅ I) C (%) H (%) N (%) I (%) Theoretical value 47.90 3.01 17.46 31.63 Experimental value 47.76 3.05 17.46 31.51 Mass spectrometry Value (m / z): 401 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 5.03 (2H, s), 6.74 (2H, d, J = 9Hz), 7.13 (2H, d, J ＝
8Hz), 7.68 (2H, d, J = 8Hz), 7.76 (2H, d, J = 9Hz), 8.81
(2H, s) In the same manner as in Example 31, the compound of the following Example 34 was obtained.

Example 34 4- [N- (4-cyanophenyl) -N-[(4-trifluoromethyl) benzyl] amino] -4H-1,2,4-
Triazole raw material compound: 4-[(4-cyanophenyl) amino] -4H-1,2,4-
Triazole and 4- (trifluoromethyl) benzyl bromide Elemental analysis value (as C ₁₇ H ₁₂ N ₅ F ₃ ) C (%) H (%) N (%) F (%) Theoretical value 59.48 3.52 20.40 16.60 Experimental value 59.40 3.59 20.41 16.48 Mass spectrum (m / z): 343 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 5.20 (2H, s), 6.75 (2H, d, J = 9Hz) , 7.58 (2H, d, J ＝
8Hz), 7.71 (2H, d, J = 8Hz), 7.77 (2H, d, J = 9Hz), 8.88
(2H, s) In the same manner as in Example 31, the compound of the following Example 35 was obtained.

Example 35 4- [N-[(5-chlorothiophen-2-yl) methyl] -N- (4-nitrophenyl) amino] -4H-1,
2,4-triazole Raw material compound: 4-[(4-nitrophenyl) amino] -4H-1,2,4-
Triazole and 2-chloro-2- (chloromethyl) thiophene Elemental analysis value (as C ₁₃ H ₁₀ N ₅ ClO ₂ S) C (%) H (%) N (%) Cl (%) S
(%) Theoretical value 46.50 3.00 20.86 10.56
9.55 Experimental value 46.30 3.02 20.77 10.69
9.48 Mass spectrum (m / z): 335 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 5.30 (2H, s), 6.74-7.02 (4H, m), 8.20 (2H) , d, J = 1
0 Hz), 8.81 (2H, s) In the same manner as in Example 31, the compound of the following Example 36 was obtained.

Example 36 4- [N- (4-nitrophenyl) -N- (thienylmethyl) amino] -4H-1,2,4-triazole Raw material compound: 4-[(4-nitrophenyl) amino] -4H-1,2 , 4-
Triazole and 2- (chloromethyl) thiophene Elemental analysis value (as C ₁₃ H ₁₁ N ₅ O ₂ S) C (%) H (%) N (%) S (%) Theoretical value 51.82 3.68 23.24 10.64 Experimental value 51.94 3.72 23.10 10.60 Mass spectrum (m / z): 301 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 5.35 (2H, s), 6.80-7.02 (4H, m), 7.54 ( 1H, d, J ＝ 5
Hz), 8.20 (2H, d, J = 10Hz), 8.74 (2H, s) In the same manner as in Example 31, the compound of the following Example 37 was obtained.

Example 37 4- [N- (4-Bromophenyl) -N- (4-cyanobenzyl) amino] -4H-1,2,4-triazole Raw material compound: 4-[(4-Bromophenyl) amino] -4H-1 , 2,4-
Triazole and α-bromo-p-tolunitrile Elemental analysis value (as C ₁₆ H ₁₂ N ₅ Br) C (%) H (%) N (%) Br (%) Theoretical value 54.26 3.41 19.77 22.56 Experimental value 54.17 3.55 19.70 22.43 Mass spectrum (m / z): 354 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 5.07 (2H, s), 6.66 (2H, d, J = 10Hz), 7.45- 7.90 (6
H, m), 8.84 (2H, s) In the same manner as in Example 31, the compound of the following Example 38 was obtained.

Example 38 4- [N- (4-bromophenyl) -N- (4-nitrobenzyl) amino] -4H-1,2,4-triazole Raw material compound: 4-[(4-bromophenyl) amino] -4H-1 , 2,4-
Triazole and 4-nitrobenzyl bromide Elemental analysis value (as C ₁₅ H ₁₂ N ₅ O ₂ Br) C (%) H (%) N (%) Br (%) Theoretical value 48.15 3.23 18.72 21.35 Experimental value 48.08 3.39 18.66 21.19 Mass spectrum (m / z): 374 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 5.13 (2H, s), 6.68 (2H, d, J = 9Hz), 7.51 ( 2H, d, J ＝
9Hz), 7.65 (2H, d, J = 9Hz), 8.19 (2H, d, J = 9Hz), 8.88
(2H, s) In the same manner as in Example 31, the compound of the following Example 39 was obtained.

Example 39 4- [N-benzyl-N- (4-cyanophenyl) amino] -4H-1,2,4-triazole Raw material compound: 4-[(4-cyanophenyl) amino] -4H-1,2,4-
Triazole and benzyl bromide Elemental analysis value (as C ₁₆ H ₁₃ N ₅ ) C (%) H (%) N (%) Theoretical value 69.80 4.76 25.44 Experimental value 69.66 4.84 25.43 Mass spec (m / z): 275 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 5.07 (2H, s), 6.76 (2H, d, J = 9Hz), 7.32 (5H, s),
7.76 (2H, d, J = 9Hz), 8.80 (2H, s) In the same manner as in Example 31, the compound of the following Example 40 was obtained.

Example 40 4- [N-benzyl-N- (4-nitrophenyl) amino] -4H-1,2,4-triazole Raw material compound: 4-[(4-Nitrobenzyl) amino] -4H-1,2,4-
Triazole and benzyl bromide Elemental analysis value (as C ₁₅ H ₁₃ N ₅ O ₂ ) C (%) H (%) N (%) Theoretical value 61.01 4.44 23.72 Experimental value 60.68 4.49 23.67 Mass spectrometry value (m / z): 295 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 5.13 (2H, s), 6.79 (2H, d, J = 9Hz), 7.33 (5H, s),
8.20 (2H, d, J = 9Hz), 8.83 (2H, s) In the same manner as in Example 31, the compound of the following Example 41 was obtained.

Example 41 5-[[N- (4-cyanophenyl) -N- (4H-1,
2,4-triazol-4-yl) amino] methyl] benzofurazan raw material compound: 4-[(4-cyanophenyl) amino] -4H-1,2,4-
Triazole and 5-bromomethylbenzofurazan Elemental analysis value (as C ₁₆ H ₁₁ N ₇ O) C (%) H (%) N (%) Theoretical value 60.56 3.49 30.90 Experimental value 60.56 3.41 31.05 Mass spectrometry value (m / z): 317 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 5.27 (2H, s), 6.75 (2H, d, J = 9Hz), 7.61 (1H, d, J =
9Hz), 7.78 (2H, d, J = 9Hz), 8.02 (1H, s), 8.08 (1H, d,
J = 9 Hz), 8.99 (2H, s) In the same manner as in Example 31, the compound of the following Example 42 was obtained.

Example 42 5-[[N- (4-nitrophenyl) -N '-(4H-
1,2,4-triazol-4-yl) amino] methyl] benzofurazan raw material compound: 4-[(4-nitrophenyl) amino] -4H-1,2,4-
Triazole and 5-bromomethylbenzofurazan Elemental analysis value (as C ₁₅ H ₁₁ N ₇ O ₃ ) C (%) H (%) N (%) Theoretical value 53.41 3.29 29.07 Experimental value 53.27 3.38 29.08 Mass spectrometry value (m / z): 337 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 5.33 (2H, s), 6.78 (2H, d, J = 7Hz), 7.61 (1H, d, J =
9Hz), 8.04 (1H, s), 8.09 (1H, d, J = 9Hz), 8.21 (2H, d,
J = 7 Hz), 9.03 (2H, s) In the same manner as in Example 31, the compound of the following Example 43 was obtained.

Example 43 4- [N- (4-cyanophenyl) -N- (3,4-dichlorobenzyl) amino] -4H-1,2,4-triazole Raw material compound: 4-[(4-cyanophenyl) amino] -4H -1,2,4-
Triazole and 3,4-dichlorobenzyl chloride Elemental analysis value (as C ₁₆ H ₁₁ Cl ₂ N ₅ ) C (%) H (%) N (%) Cl (%) Theoretical value 55.83 3.22 20.35 20.60 Experimental value 55.98 3.27 20.48 20.46 Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 5.09 (2H, s), 6.74 (2H, d, J = 9Hz), 7.31 (2H, dd, J)
= 9Hz, J = 2Hz), 7.60 (1H, d, J = 9Hz), 7.63 (1H, d, J = 2)
Hz), 7.77 (2H, d, J = 9Hz), 8.86 (2H, s) In the same manner as in Example 31, the compound of the following Example 44 was obtained.

Example 44 4- [N- (4-cyanophenyl) -N- [1- (4
-Nitrophenyl) ethyl] amino] -4H-1,2,4-triazole Raw material compound: 4-[(4-cyanophenyl) amino] -4H-1,2,4-
Triazole and 4- (1-iodoethyl) nitrobenzene Elemental analysis value (as C ₁₇ H ₁₄ N ₆ O ₂ ) C (%) H (%) N (%) Theoretical value 61.07 4.22 25.14 Experimental value 60.92 4.27 25.11 Mass spectrometry value ( m / z): 334 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 1.48 (3H, d, J = 7Hz), 5.88 (1H, d, J = 7Hz), 6.66 ( 2
H, d, J = 9Hz), 7.68 (2H, d, J = 9Hz), 7.74 (2H, d, J = 9H)
z), 8.20 (2H, d, J = 9Hz), 8.77 (2H, s) In the same manner as in Example 31, the compounds of the following Examples were obtained.

Example 45 4-[[N- (4-cyanophenyl) -N- [2-
(4-Nitrophenyl) ethyl] amino] -4H-1,2,4
-Triazole raw material compound: 4-[(4-cyanophenyl) amino] -4H-1,2,4-
Triazole and 4-nitrophenethyl bromide Elementary analysis (C ₁₇ H ₁₄ N ₆ as _{O 2) C (%) H} (%) N (%) Theoretical values 61.07 4.22 25.14 Found 61.01 4.26 25.14 Mass spectrometry value (m / z ): 334 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO−d ₆ , TMS internal standard) δ: 2.99 (2H, t, J = 7Hz), 4.18 (2H, t, J = 7Hz), 6.26 (2
H, d, J = 9Hz), 7.61 (2H, d, J = 9Hz), 7.72 (2H, d, J = 9H)
z), 8.17 (2H, d, J = 9Hz), 8.88 (2H, s) In the same manner as in Example 31, the compound of the following Example 46 was obtained.

Example 46 4- [N- (2-bromobenzyl) -N- (4-cyanophenyl) amino] -4H-1,2,4-triazole Raw material compound: 4-[(4-cyanophenyl) amino] -4H-1 , 2,4-
Triazole and 2-bromobenzyl bromide Elemental analysis value (as C ₁₆ H ₁₂ BrN ₅ ) C (%) H (%) N (%) Br (%) Theoretical value 54.26 3.41 19.77 22.56 Experimental value 54.10 3.32 19.85 22.72 Mass spectrometry value (M / z): 353 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO−d ₆ , TMS internal standard) δ: 5.14 (2H, s), 6.75 (2H, d, J = 9Hz), 7.27−7.36 (3
H, m), 7.65 (1H, d, J = 7Hz), 7.78 (2H, d, J = 9Hz), 8.80
(2H, s) In the same manner as in Example 31, the following compound of Example 47 was obtained.

Example 47 4- [N- (3-Bromobenzyl) -N- (4-cyanophenyl) amino] -4H-1,2,4-triazole Raw material compound: 4-[(cyanophenyl) amino] -4H-1,2 , 4-Triazole and 3-bromobenzyl bromide Elemental analysis value (as C ₁₆ H ₁₂ BrN ₅ ) C (%) H (%) N (%) Br (%) Theoretical value 54.26 3.41 19.77 22.56 Experimental value 54.16 3.29 19.89 22.59 Mass spectrum (m / z): 353 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 5.09 (2H, s), 6.75 (2H, d, J = 9Hz), 7.27- 7.34 (2
H, m), 7.50 (1H, d, J = 7Hz), 7.56 (1H, s), 7.77 (2H, d,
J = 9 Hz), 8.86 (2H, s) In the same manner as in Example 31, the compound of the following Example 48 was obtained.

Example 48 5- [N- (4-nitrobenzyl) -N- (4H-1,2,
4-triazol-4-yl) amino] benzofurazan raw material compound: 5-[(4H-1,2,4-triazol-4-yl) amino] benzofurazan and 4-nitrobenzyl bromide Elemental analysis value (C ₁₅ H ₁₁ N ₇ O ₃ ) C (%) H (%) N (%) Theoretical value 53.41 3.29 29.07 Experimental value 53.13 3.28 29.10 Mass spectrum (m / z): 337 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 5.29 (2H, s), 7.04 (1H, dd, J = 10Hz, 2Hz), 7.5 (1H,
d, J = 2Hz), 7.69 (2H, d, J = 9Hz), 8.05 (1H, d, J = 10H)
z), 8.21 (2H, d, J = 9Hz), 8.92 (2H, s) In the same manner as in Example 31, the compound of the following Example 49 was obtained.

Example 49 5- [N- (4-bromobenzyl) -N- (4H-1,2,
4-triazol-4-yl) amino] benzofurazan raw material compound: 5-[(4H-1,2,4-triazol-4-yl) amino] benzofurazan and 4-bromobenzyl bromide Elemental analysis value (C ₁₅ H ₁₁ BrN ₆ O) C (%) H (%) N (%) Br (%) Theoretical value 48.54 2.99 22.64 21.53 Experimental value 48.36 3.03 22.71 21.67 Mass spectrum (m / z): 370 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 5.07 (2H, s), 7.02 (1H, dd, J = 10Hz, 2Hz), 7.18 (1
H, d, J = 2Hz), 7.31 (2H, d, J = 8Hz), 7.54 (2H, d, J = 8H)
z), 8.03 (1H, d, J = 10 Hz), 8.83 (2H, s) In the same manner as in Example 31, the compound of the following Example 50 was obtained.

Example 50 4- [N- (4-Bromobenzyl) -N- (2-cyanophenyl) amino] -4H-1,2,4-triazole Raw material compound: 4-[(2-cyanophenyl) amino] -4H-1 , 2,4-
Triazole and 4-bromobenzyl bromide Elemental analysis value (as C ₁₆ H ₁₂ N ₅ Br) C (%) H (%) N (%) Br (%) Theoretical value 54.26 3.41 19.77 22.56 Experimental value 54.19 3.41 19.90 22.42 Mass spectrometry Value (m / z): 335 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 4.92 (2H, s), 7.37 (2H, d, J = 9Hz), 7.40-7.53 ( 2
H, m), 7.54 (2H, d, J = 9Hz), 7.75-7.79 (1H, m), 7.89
(1H, d, J = 8Hz), 8.86 (2H, s) In the same manner as in Example 31, the compound of the following Example 51 was obtained.

Example 51 4-[[N- (4-bromonaphthalen-1-yl) methyl] -N- (4-nitrophenyl) amino] -4H-1,
2,4-triazole Raw material compound: 4-[(4-nitrophenyl) amino] -4H-1,2,4-
Triazole and α, 4-dibromo-1-methylnaphthalene Elemental analysis value (as C ₁₉ H ₁₄ N ₅ BrO ₂ ) C (%) H (%) N (%) Br (%) Theoretical value 53.79 3.33 16.51 18.83 Experimental value 53.77 3.38 16.46 18.87 Mass spectrum (m / z): 425 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 5.61 (2H, s), 6.90 (2H, d, J = 9Hz ), 7.35 (1H, d, J ＝
8Hz), 7.68-7.83 (3H, m), 8.09-8.29 (4H, m), 8.64
(2H, s) In the same manner as in Example 31, the compound of the following Example 52 was obtained.

Example 52 1- [N- (4-bromobenzyl) -N- (4-cyanophenyl) amino] -1H-1,2,4-triazole Raw material compound: 1-[(4-cyanophenyl) amino] -1H-1 , 2,4-
Triazole and 4-bromobenzyl bromide Physicochemical properties Elemental analysis value (as C ₁₆ H ₁₂ N ₅ Br) C (%) H (%) N (%) Br (%) Theoretical value 54.26 3.41 19.77 22.56 Experimental value 54.30 3.43 19.84 22.75 Mass spectrum (m / z): 353 (M ⁺ -1) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 4.87 (2H, s), 6.69 (2H, d, J = 9Hz) , 7.14 (2H, d, J ＝
9Hz), 7.47 (2H, d, J = 9Hz), 7.57 (2H, d, J = 9Hz), 7.87
(1H, s), 8.03 (1H, s) Reference example 12 After adding potassium tert-butoxide (3.36 g) to anhydrous dimethyl sulfoxide (15 ml) and stirring at room temperature for 30 minutes, 2.52 g of 4-amino-4H-1,2,4-triazole was added to this solution. After stirring at room temperature for 15 minutes, 1.64 g of 4-fluorobenzotrifluorolide was added, and the mixture was further stirred at room temperature for 30 minutes. Ice water was added to the reaction solution and neutralized with dilute hydrochloric acid. The precipitated crystals were collected by filtration to obtain 4-[(4-trifluoromethylphenyl) amino] -4H-1,2,4-triazole (1.93 g).

Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 6.62 (2H, d, J = 8Hz), 7.60 (2H, d, J = 8Hz), 8.82 (2
H, s), 10.06 (1H, br) Example 53 4-[(4-trifluoromethylphenyl) amino]
0.23 g of -4H-1,2,4-triazole, 0.28 g of 4-bromobenzyl bromide and 0.17 g of anhydrous potassium carbonate were added to 5 ml of acetonitrile, and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off, water was added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography, and crude crystals were obtained from the chloroform eluate. The crude crystals were recrystallized from a mixed solvent of ethyl acetate-ether to give 4- [N- (4-bromobenzyl) -N- (4-
Trifluoromethylphenyl) amino] -4H-1,2,4-
0.22 g of triazole was obtained.

Elemental analysis value (as C ₁₆ H ₁₂ N ₄ BrF ₃ ) C (%) H (%) N (%) Br (%) F
(%) Theoretical value 48.38 3.05 14.11 20.12
14.35 Experimental value 48.46 3.04 14.06 20.36
14.12 Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 4.86 (2H, s), 6.74 (2H, d, J = 9Hz), 7.13 (2H, d, J =
9Hz), 7.49 (2H, d, J = 9Hz), 7.57 (2H, d, J = 9Hz), 8.22
(2H, s) In the same manner as in Example 53, the following compound was obtained.

Example 54 4- [N- (4-cyanophenyl) -N- (4-methoxycarbonylbenzyl) amino] -4H-1,2,4-triazole Raw material compound: 4- [N- (4-cyanophenyl) amino]- 4H-1,2,
4- triazole and 4-bromomethyl-benzoic acid methyl Elemental analysis (C ₁₈ H ₁₅ N ₅ as _{O 2) C (%) H} (%) N (%) Theoretical values 64.86 4.54 21.01 Found 64.77 4.54 21.07 Mass spectrometry value ( m / z): 333 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 3.84 (3H, s), 5.18 (2H, s), 6.74 (2H, d, J = 9Hz) ,
7.49 (2H, d, J = 9Hz), 7.76 (2H, d, J = 9Hz), 7.91 (2H,
d, J = 9Hz), 8.84 (2H, s) Example 55 4- [N- (4-methoxycarbonylbenzyl) -N
-(4-Nitrophenyl) amino] -4H-1,2,4-triazole Raw material compound: 4- [N- (4-nitrophenyl) amino] -4H-1,2,
4- triazole and 4-bromomethyl-benzoic acid methyl Elemental analysis (C ₁₇ H ₁₅ N ₅ as _{O 4) C (%) H} (%) N (%) Theoretical values 57.79 4.28 19.82 Found 57.60 4.26 19.86 Mass spectrometry value ( m / z): 353 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 3.85 (3H, s), 5.25 (2H, s), 6.79 (2H, d, J = 9Hz) ,
7.51 (2H, d, J = 8Hz), 7.93 (2H, d, J = 8Hz), 8.20 (2H,
d, J = 9Hz), 8.88 (2H, s) Example 56 1-methyl-6-[[N- (4-nitrophenyl)-
N- (4H-1,2,4-triazol-4-yl) amino]
Methyl] -1H-benzotriazole Raw material compound: 4-[(4-nitrophenyl) amino] -4H-1,2,4-
Triazole and 6-chloromethyl-1-methyl-1H-benzotriazole Elemental analysis value (as C ₁₆ H ₁₄ N ₈ O ₂ ) C (%) H (%) N (%) Theoretical value 54.85 4.03 31.98 Experimental value 54.83 4.05 32.21 Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 4.28 (3H, s), 5.34 (2H, s), 6.82 (2H, d, J = 9Hz),
7.37 (2H, dd, J = 9Hz, 2Hz), 7.84 (1H, d, J = 2Hz), 8.00
(2H, d, J = 9Hz), 8.21 (2H, d, J = 9Hz), 8.91 (2Hz, s) Example 57 2-methyl-5-[[N- (4-nitrophenyl)-
N- (4H-1,2,4-triazol-4-yl) amino]
Methyl] -2H-benzotriazole Raw material compound: 4-[(4-nitrophenyl) amino] -4H-1,2,4-
Triazole and 5-chloromethyl-2-methyl -2H- benzotriazole Elemental analysis (C ₁₆ H ₁₄ N ₈ as _{O 2) C (%) H} (%) N (%) Theoretical values 54.85 4.03 31.98 Found 54.68 4.02 32.08 Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 4.74 (3H, s), 5.28 (2H, s), 6.84 (2h, d, J = 9Hz),
7.42 (2H, dd, J = 9Hz, 2Hz), 7.84 (1H, d, J = 2Hz), 7.89
(2H, d, J = 9Hz), 8.21 (2H, d, J = 9Hz), 8.84 (2H, s) Example 58 1-methyl-5-[[N- (4-nitrophenyl)-
N- (4H-1,2,4-triazol-4-yl) amino]
Methyl] -1H-benzotriazole Raw material compound: 4-[(4-nitrophenyl) amino] -4H-1,2,4-
Triazole and 5-chloromethyl-1-methyl-1H-benzotriazole Elemental analysis value (as C ₁₆ H ₁₄ N ₈ O ₂ ) C (%) H (%) N (%) Theoretical value 54.85 4.03 31.98 Experimental value 54.77 4.05 32.08 Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 4.30 (3H, s), 5.30 (2H, s), 6.85 (2H, d, J = 9Hz),
7.54 (2H, dd, J = 9Hz, 2Hz), 7.84 (2H, d, J = 9Hz), 7.98
(1H, d, J = 2Hz), 8.21 (2H, d, J = 9Hz), 8.84 (2H, s) Example 59 6-[[N- (4-nitrophenyl) -N- (4H-1,
2,4-Triazol-4-yl) amino] methyl] benzothiazole Raw material compound: 4-[(4-nitrophenyl) amino] -4H-1,2,4-
Triazole and 6- (chloromethyl) benzothiazole Mass spec (m / z): 352 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 5.31 (2H, s), 6.81 (2H , d, J = 9Hz), 7.52 (1H, dd, J
= 9Hz, J = 2Hz), 8.06 (1H, d, J = 9Hz), 8.17 (1H, d, J = 2)
Hz), 8.21 (2H, d, J = 9Hz), 8.89 (2H, s), 9.40 (1H, s) Example 60 4- [N-[(2-bromothiazol-5-yl) methyl] -N- (4-nitrophenyl) amino) -4H-1,
2,4-Triazole raw material compound: 4- (4-nitrophenyl) amino-4H-1,2,4-thiazole and 2-bromo-5- (bromomethyl) thiazole Elemental analysis value (C ₁₂ H ₇ N ₆ O ₂ As BrS) C (%) H (%) N (%) S (%) Br
(%) Theoretical 37.81 2.38 22.05 8.41 2
0.96 experimental value 37.64 2.35 21.96 8.29 2
0.71 Mass spectrum (m / z): 379 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 5.42 (2H, s), 6.83 (2H, d, J = 10Hz), 7.61 (1H, s),
8.21 (2H, d, J = 10Hz), 8.88 (2H, s) Example 61 4- [N-[(2-bromothiazol-5-yl) methyl] -N- (4-cyanophenyl) amino) -4H-1,
2,4-triazole Raw material compound: 4- (4-cyanophenyl) amino-4H-1,2,4-triazole and 2-bromo-5- (bromomethyl) thiazole Elemental analysis value (as C ₁₃ H ₉ N ₆ SBr ) C (%) H (%) N (%) Br (%) S
(%) Theoretical 43.23 2.51 23.27 22.12
8.88 Experimental value 43.08 2.41 23.27 22.27
8.75 Mass spectrum (m / z): 362 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 5.36 (2H, s), 6.79 (2H, d, J = 9Hz), 7.58 (1H, s),
7.79 (2H, d, J = 9Hz), 8.84 (2H, s) Example 62 4- [N- (4-aminophenyl) -N- (4-bromobenzyl) amino] -4H-1,2,4-triazole 0.35 g
0.28 ml of acetic anhydride was added to 10 ml of a pyridine solution containing the mixture at room temperature and stirred for about 20 minutes. After completion of the reaction, the solvent was distilled off under reduced pressure, an appropriate amount of sodium hydrogen carbonate solution was added to the obtained residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography, and 4- [N- (4-acetylaminophenyl) -N- (4
0.33 g of -bromobenzyl) amino] -4H-1,2,4-triazole was obtained.

Elemental analysis value (as C ₁₇ H ₁₆ N ₅ OBr) C (%) H (%) N (%) Theoretical value 52.86 4.18 18.13 Experimental value 52.85 4.22 18.24 Mass spectrometry value (m / z): 387 (M ⁺ +1) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 2.01 (3H, s), 4.86 (2H, s), 6.78 (2H, d, J = 9.0H
z), 7.27 (2H, d, J = 8.6Hz), 7.51 (4H, d, J = 9.0Hz), 8.
75 (2H, s), 9.88 (1H, br) Example 63 To a suspension of 0.04 g of sodium hydride in N, N-dimethylformamide was added 0.23 g of 4-[(4-trifluoromethylphenyl) amino] -4H-1,2,4-triazole little by little at room temperature. . After stirring at room temperature for 30 minutes, 0.15 g of 4-fluoronitrobenzene was added, and the mixture was stirred at 100 ° C for 15 minutes. The solvent was evaporated under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and dried over anhydrous magnesium sulfate, the solvent was distilled off, and the obtained final was ethyl acetate-
Recrystallization from a mixed solvent of ether gave 4- [N- (4-nitrobenzyl) -N- (4-trifluoromethylphenyl) amino] -4H-1,2,4-triazole (280 mg).

Elemental analysis value (as C ₁₅ H ₁₀ N ₅ F ₃ O ₂ ) C (%) H (%) N (%) F (%) Theoretical value 51.58 2.89 20.05 16.32 Experimental value 51.58 2.84 20.11 16.22 Nuclear magnetic resonance spectrum (CDCl) ₃ , TMS internal standard) δ: 6.90 (2H, d, J = 9Hz), 7.24 (2H, d, J = 8Hz), 7.72 (2
H, d, J = 8 Hz), 8.22 (2H, d, J = 9 Hz), 8.47 (2H, s) In the same manner as in Example 53, the following compounds were obtained.

Example 64 1- [N- (4-cyanobenzyl) -N- (4-cyanophenyl) amino] -1H-1,2,4-triazole Raw material compound: 1- [N- (4-cyanophenyl) amino] -1H -1,2,
4-triazole and 4-cyanobenzyl bromide Elemental analysis value (as C ₁₇ H ₁₂ N ₆ ) C (%) H (%) N (%) Theoretical value 67.99 4.03 27.98 Experimental value 67.94 4.17 27.99 Mass spectrometry value (m / z ): 300 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 5.18 (2H, s), 6.70 (2H, d, J = 9Hz), 7.61 (2H, d, J =
9Hz), 7.75 (2H, d, J = 9Hz), 7.82 (2H, d, J = 9Hz), 8.19
(1H, s), 8.77 (1H, s) Example 65 1- [N- (4-cyanophenyl) -N- (4-methoxybenzyl) amino] -1H-1,2,4-triazole Raw material compound: 1- [N- (4-cyanophenyl) amino] -1H -1,2,
4- triazole and 4-methoxybenzyl chloride Elementary analysis (C ₁₇ H ₁₅ N ₅ O as) C (%) H (% ) N (%) Theoretical values 66.87 4.95 22.94 Found 66.88 5.09 22.92 Mass spectrometry value (m / z): 305 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO−d ₆ , TMS internal standard) δ: 3.72 (3H, s), 4.93 (2H, s), 6.77 (2H, d, J = 9Hz),
6.85 (2H, d, J = 9Hz), 7.23 (2H, d, J = 9Hz), 7.74 (2H,
d, J = 9Hz), 8.15 (1H, s), 8.53 (1H, s) Example 66 1- [N- (4-chlorobenzyl) -N- (4-cyanophenyl) amino] -1H-1,2,4-triazole Raw material compound: 1- [N- (4-cyanophenyl) amino] -1H -1,2,
4-triazole and 4-chlorobenzyl chloride Elemental analysis value (as C ₁₆ H ₁₂ N ₅ Cl) C (%) H (%) N (%) Cl (%) Theoretical value 62.04 3.90 22.61 11.45 Experimental value 61.85 3.94 22.64 11.53 Mass spectrum (m / z): 309 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 5.05 (2H, s), 6.74 (2H, d, J = 9Hz), 7.38 ( 4H, s),
7.75 (2H, d, J = 9Hz), 8.17 (1H, s), 8.66 (1H, s) Example 67 1- [N- (2-bromobenzyl) -N- (4-cyanophenyl) amino] -1H-1,2,4-triazole Raw material compound: 1- [N- (4-cyanophenyl) amino] -1H -1,2,
4-triazole and 2-bromobenzyl bromide Elemental analysis value (as C ₁₆ H ₁₂ N ₅ Br) C (%) H (%) N (%) Br (%) Theoretical value 54.25 3.41 19.77 22.56 Experimental value 54.05 3.42 19.78 22.66 Mass spectrum (m / z): 353 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 5.10 (2H, s), 6.76 (2H, d, J = 9Hz), 7.24- 7.34 (3
H, m), 7.66 (1H, dd, J = 1Hz, 8Hz), 7.71 (2H, d, J = 9Hz)
8.17 (1H, s), 8.56 (1H, s) Example 68 1- [N- (3-bromobenzyl) -N- (4-cyanophenyl) amino] -1H-1,2,4-triazole Raw material compound: 1- [N- (4-cyanophenyl) amino] -1H -1,2,
4-triazole and 3-bromobenzyl bromide Elemental analysis value (as C ₁₆ H ₁₂ N ₅ Br) C (%) H (%) N (%) Br (%) Theoretical value 54.25 3.41 19.77 22.56 Experimental value 54.08 3.41 19.78 22.64 Mass spectrum (m / z): 353 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 5.07 (2H, s), 6.72 (2H, d, J = 9Hz), 7.29 ( 1H, t, J ＝
8Hz), 7.38 (1H, d, J = 8Hz), 7.49 (1H, d, J = 8Hz), 7.61
(1H, s), 7.75 (2H, d, J = 9Hz), 8.19 (1H, s), 8.74 (1
H, s) Example 69 1- [N-benzyl-N- (4-cyanophenyl) amino] -1H-1,2,4-triazole Raw material compound: 1- [N- (4-cyanophenyl) amino] -1H-1,2,
4-triazole and benzyl bromide Elemental analysis value (as C ₁₆ H ₁₃ N ₅ ) C (%) H (%) N (%) Theoretical value 69.80 4.76 25.44 Experimental value 69.72 4.81 25.41 Mass spec value (m / z): 275 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO−d ₆ , TMS internal standard) δ: 5.03 (2H, s), 6.75 (2H, d, J = 9Hz), 7.28−7.36 (5
H, m), 7.75 (2H, d, J = 9Hz), 8.16 (1H, s), 8.62 (1H,
s) Example 70 1- [N- (4-fluorobenzyl) -N- (4-cyanophenyl) amino] -1H-1,2,4-triazole Raw material compound: 1- [N- (4-cyanophenyl) amino] -1H -1,2,
4-triazole and 4-fluorobenzyl bromide Elemental analysis value (as C ₁₆ H ₁₂ N ₅ F) C (%) H (%) N (%) F (%) Theoretical value 65.52 4.12 23.88 6.48 Experimental value 65.60 4.23 23.83 6.47 Mass spectrum (m / z): 293 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 5.02 (2H, s), 6.76 (2H, d, J = 9Hz), 7.03- 7.47 (4
H, m), 7.75 (2H, d, J = 9Hz), 8.15 (1H, s), 8.60 (1H,
s) Example 71 1- [N- (4-cyanophenyl) -N- (4-iodobenzyl) amino] -1H-1,2,4-triazole Raw material compound: 1- [N- (4-cyanophenyl) amino] -1H -1,2,
4-triazole and 4-iodobenzyl chloride Elemental analysis value (as C ₁₆ H ₁₂ N ₅ I) C (%) H (%) N (%) I (%) Theoretical value 47.90 3.01 17.46 31.63 Experimental value 47.62 3.00 17.50 31.71 Mass spectrum (m / z): 401 (M ⁺ ) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 4.85 (2H, s), 6.69 (2H, d, J = 7Hz), 7.01 (2H, d, J ＝
8Hz), 7.52-7.71 (4H, m), 7.87 (1H, s), 8.02 (1H, s) Example 72 1- [N- (4-cyanophenyl) -N- (4-methylbenzyl) amino] -1H-1,2,4-triazole Raw material compound: 1- [N- (4-cyanophenyl) amino] -1H -1,2,
4-triazole and α-bromo-p-xylene Elemental analysis value (as C ₁₇ H ₁₅ N ₅ ) C (%) H (%) N (%) Theoretical value 70.57 5.23 24.20 Experimental value 70.46 5.28 24.12 Mass spectrometry value (m / z): 289 (M ⁺ ) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 2.32 (3H, s), 4.85 (2H, s), 6.71 (2H, d, J = 7Hz),
7.11 (4H, s), 7.56 (2H, d, J = 7Hz), 7.80 (1H, s), 8.01
(1H, s) Example 73 5-[[N- (4-cyanophenyl) -N- (1H-1,
2,4-triazol-1-yl) amino] methyl] benzofurazan raw material compound: 1- [N- (4-cyanophenyl) amino] -1H-1,2,
4-triazole and 5-bromomethylbenzofurazan Elemental analysis value (as C ₁₆ H ₁₁ N ₇ O) C (%) H (%) N (%) Theoretical value 60.56 3.49 30.90 Experimental value 60.51 3.53 30.88 Mass spec value ( m / z): 317 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO−d ₆ , TMS internal standard) δ: 5.26 (2H, s), 6.75 (2H, d, J = 9Hz), 7.68 (1H, d, J =
9Hz), 7.77 (2H, d, J = 9Hz), 8.03 (1H, s), 8.08 (1H, d,
J = 9 Hz), 8.22 (1H, s), 8.89 (1H, s) Example 74 5-[[N- (4-nitrophenyl) -N- (1H-1,
2,4-triazol-1-yl) amino] methyl] benzofurazan raw material compound: 1- [N- (4-nitrophenyl) amino] -1H-1,2,
4- triazole and 5-bromomethyl-benzo hula disilazane Elemental analysis (C ₁₅ H ₁₁ N ₇ as _{O 3) C (%) H} (%) N (%) Theoretical values 53.41 3.29 29.07 Found 53.29 3.32 29.16 Mass spectrometry value (M / z): 337 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO−d ₆ , TMS internal standard) δ: 5.33 (2H, s), 6.78 (2H, d, J = 9Hz), 7.70 (1H, d , J ＝
9Hz), 8.07 (1H, s), 8.10 (1H, d, J = 9Hz), 8.20 (2H, d,
J = 9 Hz), 8.26 (1H, s), 8.95 (1H, s) Example 75 5- [N- (4-thiazolylmethyl) -N- (4H-1,
2,4-Triazol-4-yl) amino] benzofurazan raw material compound: 5- [N- (4H-1,2,4-triazol-4-yl) amino] benzofurazan and 4-chloromethylthiazole Elemental analysis value (C ₁₀ H ₉ N ₇ OS) C (%) H (%) N (%) S (%) Theoretical value 48.15 3.03 32.76 10.71 Experimental value 48.05 3.05 32.72 10.60 Mass spectrum (m / z): 299 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 5.26 (2H, s), 7.04-7.06 (2H, m), 7.75 (1H, s), 8.
01 (1H, d, J = 9Hz), 8.77 (2H, s), 9.11 (1H, s) Compound 1.0mg Lactose 76.4mg Cornstarch 19.3mg hydroxypropylcellulose 3.0 formulation Additives formed Joko Example 15 oral dosage mg Magnesium stearate 0.3 mg Subtotal 100 mg Coated hydroxypropylmethylcellulose 2910 2.9 mg Polyethylene glycol 6000 0.4 mg Titanium oxide 1.6 mg Talc 0.1 mg Subtotal 5 mg Total 105 mg 1 mg tablet 7 g of the compound of Example 15 and 534.8 g of lactose were mixed in a polyethylene bag. This mixture was mixed and ground with a sample mill (manufactured by Hosokawa Micron). 541.8 g of the mixed pulverized product and 135.1 g of Konstarch were uniformly mixed in a fluidized granulation coating apparatus (manufactured by Okawara Seisakusho). 210 g of a 10% hydroxypropyl cellulose solution was sprayed on this and granulated. After drying, 20
Pass through a mesh sieve and put magnesium stearate on it.
2.1g added, rotary tableting machine (Hata Iron Works) φ6.5mm ×
Each tablet was made into 100 mg tablets using a 7.8R pestle.
In a coating device (manufactured by Freund Sangyo), 20.3 g of hydroxypropylmethylcellulose, 2.8 g of polyethylene glycol 6000, 11.2 g of titanium oxide and talc were applied to the tablets.
Spraying 350g of coating liquid containing 0.7g, 5mg per tablet
The film-coated tablets were coated.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical indication location C07D 249/18 501 C07D 249/18 501 401/12 249 401/12 249 409/12 249 409/12 249 413/12 249 413/12 249 417/12 249 417/12 249 417/14 249 417/14 249 C12N 9/99 C12N 9/99 (72) Inventor Yasuo Isomura Yakushidai, Moriya-cho, Kitasoma-gun, Ibaraki Prefecture 3 Publication No. 4-8 (56) References International Publication 90/14338 (WO, A) European Patent Application Publication 324359 (EP, A) European Patent Application Publication 283245 (EP, A) European Patent Application Publication 236940 (EP, A) European Patent Application Publication 293978 (EP, A)

Claims (8)

(57) [Claims] 1. A triazolyl-substituted tertiary amino compound represented by the following general formula (I) or a salt thereof. (Groups in the formula have the following meanings: A: single bond, lower alkylene group or carbonyl group B: lower alkyl group, optionally substituted aryl group,
Hetero atom consisting of oxygen atom, sulfur atom or nitrogen atom 1
To 3 optionally substituted 5- or 6-membered heterocyclic group, or optionally substituted bicyclic fused heterocyclic group in which the heterocycle is condensed with a benzene ring D ring: optionally substituted An optionally substituted 5- or 6-membered heterocyclic group having 1 to 3 heteroatoms consisting of an aryl group, an oxygen atom, a sulfur atom or a nitrogen atom, or an optionally substituted 5- or 6-membered heterocyclic group condensed with a benzene ring. Two-ring condensed heterocyclic group E ring: 4H-1,2,4-triazole ring, 1H-1,2,4-triazole ring, or 1H-1,2,3-triazole ring where E ring is 1H-1 And 2,2,4-triazole, and when the D ring is a nitro group, a phenyl group which is mono-substituted with a fluorine atom or a chlorine atom, -AB is 2,4-dichlorophenylethylidene or 2, 4-dichlorophenylpyrrolidene The following groups are shown. ) 2. The substituent of the aryl group, heterocyclic group or condensed heterocyclic group represented by B or D ring is halogen atom, cyano group, nitro group, trifluoromethyl group, hydroxy group, amino group, mono- or mono- or Di-lower alkylamino group, lower alkyl group, lower alkoxy group, carboxy group, lower alkoxycarbonyl group, lower alkanoyl group, lower alkanoyloxy group, lower alkanoylamino group, aroyl group, aroyloxy group, carbamoyl group, mono- or di- -A lower alkylaminocarbonyl group, a sulfonic acid group, a lower alkylsulfonyl group, a sulfamoyl group, a mono- or di-lower alkylsulfamoyl group, or a compound thereof according to claim 1. 3. The substituent of the aryl group, heterocyclic group or condensed heterocyclic group represented by the B or D ring is a halogen atom, a cyano group, a nitro group, a trifluoromethyl group, a hydroxy group, an amino group or a lower alkyl group. A lower alkoxy group, a carboxy group, a lower alkoxycarbonyl group, or a lower alkanoylamino group, or a salt thereof. 4. The compound or its salt according to claim 1, wherein the aryl group represented by the B or D ring is a phenyl group substituted with a halogen atom, a cyano group or a nitro group. 5. 4- [N- (4-bromobenzyl) -N-
(4-Cyanophenyl) amino] -4H-1,2,4-triazole or a salt thereof 6. 4- [N- (4-bromobenzyl) -N-
(4-Nitrophenyl) amino] -4H-1,2,4-triazole or salt thereof 7. An aromatase inhibitor comprising a triazolyl-substituted tertiary amino compound represented by the following general formula (I) or a salt thereof as an active ingredient. (Groups in the formula have the following meanings: A: single bond, lower alkylene group or carbonyl group B: lower alkyl group, optionally substituted aryl group,
Hetero atom consisting of oxygen atom, sulfur atom or nitrogen atom 1
To 3 optionally substituted 5- or 6-membered heterocyclic group, or optionally substituted bicyclic fused heterocyclic group in which the heterocycle is condensed with a benzene ring D ring: optionally substituted An optionally substituted 5- or 6-membered heterocyclic group having 1 to 3 heteroatoms consisting of an aryl group, an oxygen atom, a sulfur atom or a nitrogen atom, or an optionally substituted 5- or 6-membered heterocyclic group condensed with a benzene ring. Two-ring condensed heterocyclic group E ring: 4H-1,2,4-triazole ring, 1H-1,2,4-triazole ring, or 1H-1,2,3-triazole ring) 8. Estrogen is involved as an aversive factor,
The pharmaceutical composition according to claim 7, which is a therapeutic agent for breast cancer, mastopathy, endometriosis, uterine fibroids, or endometrial cancer.