KR20050095317A - Novel 1, 2, 4-triazole compounds - Google Patents

Abstract

Novel 1, 2, 4-triazole compound (TRIAZOLE CONPOUNDS) useful as a gout treatment drug for hyperuricemia and hyperuricemia.

Description

Novel 1, 2, 4-triazole compound and its manufacturing method {NOVEL 1, 2, 4-TRIAZOLE COMPOUNDS}

The present invention may have a novel alkyl group in the 1st, 2nd or 4th position, and 1, 2, 4-trier having an aromatic ring in 3rd and 5th position. It relates to a sol compound (TRIAZOLE COMPOUNDS), its hydrate or salts thereof, and a method for producing the same, and a hyperuricemia and gout treatment drug using them as an active ingredient. .

The number of people with hyperuricemia in Japan is 1.25 million, but asymptomatic hyperuricemia is estimated to be millions of people.

For the current gout caused by hyperuricemia and hyperuricemia, it is recommended that the gout attack is foreseen (preliminary stage), the gout attack and the seizure settled. Improvements and treatments for each drug are being made.

In other words, during the cold season, with the adjustment of the daily living environment, prevention by colchicines, and during seizures, non-steroidal or steroidal anti-inflammatory drugs Therapeutic treatment is mainly performed. After seizure decay, the lifestyle improvement guidance is provided. If it is judged that the improvement is not sufficient, it is urinary acid excretion lowering or urinary acid production. Urine acid excretion such as probenecid and benzbromarone, inhibition of reuptake of uric acid such as sulfinpyrazone, acidic urine using citrate Treatment with drugs that show an inhibitory action of the production of uric acid, such as alloprinol, which is an antioxidative agent of diacid oxidase.

When colchicines are taken 2 to 3 hours before the seizure, 90% of the seizures are prevented by suppression of chemotaxis or phagocytosis, such as neutrophils. Because it is a drug with various side effects, its use is limited to a minimum, and it is difficult to take it at the time of a seizure.

Therefore, the treatment by medicine is the center. The only drug that can be used for uric acid antihyperplasia is allopriinol, and this metabolite, oxypurinol, has a cumulative effect. At the same time, it can cause stones.

In addition, side effects such as rash, renal dysfunction, and hepatitis have been reported, and therefore, this drug was not easy to prescribe.

It has a dexterifying effect of xanthine oxidase which can be used for urinary acid antihyperproliferation and is effective for gout caused by hyperuricemia and hyperuricemia, and it is a journal of medicinal chemistry (J). , 1975, Vol. 18, No. 9, pp895 to 900, JP 49-46622, and JP 50-24315 disclose several 1,2,4-triazole compounds having several 1,3,5 or 3,5 substitutions.

Gout caused by hyperuricemia and hyperuricemia has tended to spread to young people in Japan due to changes in living environment, and it is impossible to overcome this disease only by guiding lifestyle improvement. However, the current situation is that the therapeutic drugs for these diseases are difficult to develop and slow in the development of compounds that have improved their effectiveness.

An object of the present invention is a gout treatment drug having high antioxidative activity of xanthine oxidase and having urinary acid hyperlipidemia and hyperuricemia. To provide useful 1, 2, 4-triazole compounds (TRIAZOLE CONPOUNDS).

When explaining the present invention, the first invention of the present invention is represented by the following general formula (1)

Formula 2

1, 2, 4-triazole compound, a hydrate thereof, or a salt thereof having an aromatic ring substituted at positions 3 and 5 which may have a substituted alkyl group at positions 1,2 or 4; .

The second invention of the present invention is an invention relating to a method for producing a compound represented by the general formula (1), wherein R ₃ is hydrogen, iminoether and aromatic of the corresponding aromatic nitrile. ) Is characterized in that by reacting carboxylic acid hydrazide (hydrogen).

The third invention of the present invention is represented by the general formula (1), wherein the group R ₃ is a pivaloyloxy substituted lower alkyl group in the method for producing a compound, A halo lower alkyl ester of pivalic acid is reacted with a compound in which the group R ₃ in the compound represented by the general formula (1) is hydrogen.

The fourth invention of the present invention relates to a medicament comprising the compound represented by the general formula (1), a hydrate thereof, or a salt thereof as an active ingredient.

The inventors of the present invention, for the creation of a compound having a chisidine oxidase detoxification effect effective for gout caused by hyperuricemia and hyperuricemia of the urinary acid hyperlipidemia which is currently listed only one ingredient (Commercial available), the basic substance The study was continued by setting 1 as 2, 4-triazole compound.

As a result, each said invention was completed.

Hereinafter, the present invention will be described in detail.

First, each group in the said General formula (1) is demonstrated.

In the above formula, R ₂ is a non-substituted pyridyl group or a substituent cyano group, lower alkyl, halogen, lower Substituted pyridyl groups having an alkoxy group or a lower alkylthio group are shown.

R ₁ is a non-substituted or substituted pyridyl group which may have a halogen, cyano group, or phenyl group as a substituent, or an equivalent pyridine-N-oxide group of those pyridyl groups. Alternatively, in addition to the substituted pentyl group having a cyano group or nitro group as the substituent, or the cyano group or the nitro group, as a substituent, a substituted or unsubstituted lower alkoxy group, N-lower alkyl substituted piperage N-lowerer alkyl-piperazino group, a lower alkyldio group, a phenylthio group, or a substituted wastenyl group having a lower alkylamino group is shown.

Provided that when R ₂ is an unsubstituted pyridyl group or a lower alkyl substituted pyridyl group, R ₁ is an unsubstituted pyridyl group, a lower alkyl substituted pyridyl group, or a pyridine N-oxide group corresponding to those pyridyl groups. It is not a (pyridine-N-oxide group).

R ₃ represents hydrogen or a pivaloyloxy group substituted lower alkyl group, and all of one nitrogen of a 1, 2, 4-triazole ring represented by General Formula (1) Is joining in.

In the compounds produced in the present invention, when the substituents at the 3rd and 5th positions are both pyriaine rings, at least one of them is preferably substituted with a cyano group or a halogen, and when one side is a phenyl group. Although the used ring may be substituted with a substituted or unsubstituted lower alkoxy group, a thioether, a substituted piperazino group, a substituted amino group or the like, it is essential that at least one of a cyano group and a nitro group is substituted.

Based on this combination, the compound of the present invention exhibited high detoxifying activity that was not achieved by the known compounds in the xanthine oxidase detoxification test in vivo. The present invention has been completed.

Although the following heterogeneity (A) (B) (C) exists in the 1, 2, 4-triazole type compound which this invention makes a basic skeleton, all these are 1, 2, 4- in this invention. It was described as triazole and represented by General formula (1).

Heterogeneity (A)

Formula 3

Duality (B)

Formula 4

Duality (C)

Formula 5

The process for the preparation of the compounds of the present invention is based on the reaction of an iminoether of an aromatic nitrile with an aromatic carboxylic acid hydrazide.

That is, the equivalent (相當) Formula (2): the formula for the hydrazide as represented by R ₂ CONHNH _2, or equivalent (: R _1, a nitrile represented by the CN imino ether with the general formula (3) 4): an iminoether of nitrile represented by R ₂ CN, and a hydrazide represented by general formula (5): R ₁ CONHNH ₂ .

As iminoether, the reaction with an alcohol under basic conditions or with an alcohol under acidic conditions or under acidic conditions may be carried out with an aromatic nitrile such as sodium methoxide and sodium ethoxide. Iminoethers (esters of imino acids) prepared by reacting with alcohols such as methanol and ethanol may be used. Salts prepared under acidic conditions can be separated, and iminoethers prepared under basic conditions can be separated either from free compounds or from salts. .

As a solvent which can be used by the manufacturing method of the compound of this invention, aqueous solvents, such as methanol and ethanol, are mentioned, but metanole is suitable. In addition, the reaction temperature proceeds even at room temperature, but heating is preferable because of the degree of rate and dehydration reaction, and when the methanol is used as a solvent, a temperature near the boiling point (about 65 ° C.) is preferable. In the manufacturing example, heating reflux was employed. Although reaction time changes also with the balance with temperature, it can employ | adopt as long as it is a range which suppresses side reaction and formation of a decomposition product.

In addition, in this invention, when introducing a pivaloyloxy substituted lower alkyl group, reaction is good by well-known dehydrohalogenation reaction, It is a well-known dehydrohalogenation agent, such as an organic base and an alkali chemicals. It is preferable to react in coexistence, and reaction fully advances also in room temperature.

The reaction may be carried out in a solvent, and examples of the solvent include dimethylformamide (hereinafter abbreviated as DMF).

Example.

Compounds of the present invention, preparation methods, test methods for effectiveness and results thereof will be described in more detail by the following examples. However, the said Example is not expressed in order to limit this invention.

Also, in the examples below, Dimethyl sulfoxide abbreviates this as DMSO.

Example 1

3- (4-Isobutoxy-3-nitrophenyl-5- (2-methyl (metyl) -4-pyridyl) -1, 2, 4-triazole .

1) Preparation of 4-isobotokishi-3-nitrobenzonitrild.

Dissolve 19.5 g of 4-chloro-3-nitrobenzonitrile in 200 ml of DMF, further add 16.0 g of 2-methyl-1-propanol, 30 g of potassium carbonate and 7.1 g of potassium iodide, The mixture is heated and stirred at 80 ° C. for 24 hours.

Water was added to the reaction solution, followed by extraction with ethyl acetate. The ethyl acetate layer is washed with saturated brine and dried over magnesium sulfate. After filtration of magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was coated on a silica gel column chromatography, and extracted with Hexane-ethyl acetate (10: 1). Elution was carried out to obtain 5.9 g of the target substance as light yellow crystals.

¹ H-NMR (CDC1 ₃ ) δ ppm: 1.07 (6H, d, J = 6.76 Hz), 2. 11-2. 25 (1H, m), 3.94 (2H, d, J = 6.43 Hz), 7.15 (1H, d, J = 8.91 Hz), 7.81 (1H, dd, J = 8.91, 2.15 Hz), 8.14 (1H, d, J = 2.15 Hz)

2) 1.54 g of the crystal obtained in 1) was dissolved in 50 ml of methanol, 757 mg of sodium methoxide was added, and the mixture was stirred at room temperature under an argon atmosphere for 3 hours.

Then, 1.06 g of 2-methyl isonicotinic acid hydrazide was added, and it heated and refluxed for 16 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, water was added to the residue, the mixture was extracted with ethyl acetate, dried over magnesium sulfate, magnesium sulfate was filtered off, and the solvent was distilled off under reduced pressure.

Chloroform was added to the obtained residue, and the solid precipitated by stirring was filtered at room temperature for 1 hour. After washing with chloroform, the resultant was dried with a vacuum pump to obtain a colorless powder. 1.50 g of the target product was obtained.

¹ H-NMR (DMSO-d ₆ ) δ ppm: 1.01 (6H, d, J = 6.60 Hz), 1.99-2.15 (1H, m), 2.57 (3H, S), 4.03 (2H, d, J = 6.43 Hz ), 7.56 (1H, d, J = 8.91 Hz), 7.80 (1H, d, J = 5.11 Hz), 7.88 (1H, s), 8.31 (1H, dd, J = 8.91, 1.98 Hz), 8.54 (1H , d, J = 1.98 Hz, 8.60 (1H, d, J = 5.11 Hz), 14.86 (1H, s)

Example 2.

3- (3-Cyano-4-isobutoxyphenyl-5- (4-pyridyl-1,2,4, -triazole

1) Preparation of 4-isobutyoxy-3-cyanobenzonitrile.

25.2 g of 4-nitrobenzonitrile were dissolved in 300 ml of DMSO, 20.0 g of potassium cyanide was added, and the mixture was heated and stirred at 100 ° C for 1 hour.

After cooling the reaction liquid at room temperature, 81.6 g of 1-bromo-2-methylpropane and 11.76 g of potassium carbonate were further added, and the mixture was heated and stirred at 80 ° C. for 8 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate, the ethyl acetate layer was washed with brine, dried over magnesium sulfate, and magnesium sulfate was filtered off, and then the solution was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with ethyl acetate (3: 1) to give 21.75 g of a pale yellow powder.

¹ H-NMR (CDC 1 ₃ ) δ ppm: 1.09 (6H, d, J = 6.76 Hz), 2.13-2.28 (1H, m), 3.91 (2H, d, J = 6.43 Hz), 7.04 (1, d, J = 8.74 Hz), 7.77-7.86 (2H, m)

2) Preparation of the target product.

To 0.08 g of a methanol solution of 0.50 g of the powder obtained in 1) was added 0.08 g of sodium methotoxide (methoxide) and stirred overnight at room temperature. Isonicotinic acid hydrazide was added to the reaction solution and heated to reflux overnight. The precipitate was filtered off and recrystallized from methanol to give 0.14 g of a colorless powder that is the title compound.

¹ H-NMR (DMSO-d ₆ ) δ ppm: 1.03 (6H, d, J = 6.77 Hz), 2.03-2.15 (1H, m), 4.01 (2H, d, J = 6.43 Hz), 7.45 (1H, d , J = 8.74 Hz), 7.99 (2H, dd, J = 4.45, 1.65 Hz), 8.29-8.34 (2H, m), 8.73 (2H, dd, J = 4.45, 1.65 Hz)

The following compounds were prepared in the same manner as in Example 1 or 2 below.

Example 3.

3- [3-cyano-4-{(2-methoxy) ethoxymethyl (ethoxymethy) oxyphenyl (oxypheny) -5- (2-methyl-4-pyridyl-1, 2, 4-triazole

Light Brown Powder

¹ H-NMR (DMSO-d ₆ ) δ ppm: 2.57 (3H, s), 3.22 (3H, s), 3.47-3.51 (2H, m), 3.80-3.83 (2H, m), 5.52 (2H, s) , 7.53 (1H, d, J = 9.08 Hz), 7.79 (1H, d, J = 4.95 Hz), 7.88 (1H, s), 8.30-8.35 (2H, m), 8.60 (1H, d, J = 4.95 Hz)

Example 4.

3- [4- (4-methyl-1-piperazino-3-nitrophenyl] -5- (2-methyl-4-pyridyl) -1, 2, 4-triazole

 Yellow powder

¹ H-NMR (CDC 1 ₃ ) δ ppm: 2.39 (3H, s), 2.62-2.66 (7H, m), 3.19-3.23 (4H, m), 7.20 (1H, d, J = 8.74 Hz), 7.81 ( 1H, d, J = 5.11 Hz), 7.91 (1H, s), 8.15 (1H, dd, J = 8.74, 1.98 Hz), 8.48 (1H, d, J = 1.98 Hz), 8.63 (1H, d, J = 5.11 Hz)

Example 5.

3- (4-Isobutylamino-3-nitropheny-5- (2-methyl-4-pyridyl) -1, 2, 4-triazole

 Orange powder

¹ H-NMR (DMSO-d ₆ ) δ ppm: 0.98 (6H, d, J = 6.59 Hz), 1.94-2.04 (1H, m), 2.56 (1H, s), 3.17-3.32 (2H, m), 7.28 (1H, d, J = 9.40 Hz), 7.77-7.87 (2H, m), 8.17 (1H, dd, J = 9.40, 1.98 Hz), 8.43-8.58 (2H, m), 8.81 (1H, d, J = 1.98 Hz)

Example 6.

5- (2-methyl-4-pyridyl) -3- (3-nitro-4- wastenidyldiopenyl (phenylthiopheny) -1,2,4-triazole

Yellow powder

¹ H-NMR (DMSO-d ₆ ) δ ppm: 2.56 (3H, s), 7.03 (1H, d, J = 8.58Hz), 7.57 ~ 7.87 (7H, m), 8.20 (1H, dd, J = 8.58Hz ), 8.61 (1H, d, J = 5.12 Hz), 8.88 (1H, s), 15.04 (1H, s)

Example 7.

3- (4-Isobutylthio-3-nitrophenyl) -5- (2-methyl-4-pyridyl) -1, 2,4-triazole

Yellow powder

¹ H-NMR (DMSO-d ₆ ) δ ppm: 1.07 (6H, d, J = 6.60 Hz), 1.91-1.96 (1H, m), 2.57 (3H, s), 3.03 (2H, d, J = 6.76 Hz ), 7.80 to 7.89 (3H, m), 8.33 (1H, dd, J = 8.41, 1.98 Hz), 8.61 (1H, d, J = 5.12 Hz), 8.84 (1H, d, J = 1.98 Hz)

Example 8.

5- (2-methyl-4-pyridyl) -3- (3-nitro-4-pentylthiomethyl oxyphenyl oxyphenyl) -1, 2, 4-triazole

Pale yellow powder

¹ H-NMR (DMSO-d ₆ ) δ ppm: 2.57 (3H, s), 5.95 (2H, s), 7.27-7.51 (5H, m), 7.71-7.88 (3H, m), 8.33 (1H, dd, J = 8.91, 2.15 Hz), 8.53-8.61 (2H, m), 14.92 (1H, s)

Example 9.

5- (2-methyl-4-pyridyl) -3- (4-methylthiomethyloxy-3-nitrofenyl) -1, 2, 4-triazole

Yellow powder

¹ H-NMR (DMSO-d ₆ ) δ ppm: 2.22 (3H, s), 2.57 (3H, s), 5.58 (2H, s), 7.65-7.89 (3H, m), 8.31 (1H, dd, J = 8.41, 1.65 Hz), 8.54-8.61 (2H, m), 14.94 (1H, s)

Example 10.

3- (4-benzyloxymethyloxy-3-nitrofenyl) -5- (2-methyl-4-pyridyl) -1, 2,4-triazole

Pale yellow powder

¹ H-NMR (CDC 1 ₃ ) δ ppm: 2.68 (3H, s), 4.79 (2H, s), 5.48 (2H, s), 7.30 ~ 7.38 (5H, m), 7.52 (1H, d, J = 8.90 Hz), 7.79 (1H, d, J = 5.44 Hz), 7.90 (1H, s), 8.24 (1H, dd, J = 8.90, 2.14 Hz), 8.57 (1H, d, J = 2.14 Hz), 8.66 ( 1H, d, J = 5.44 Hz)

Example 11.

5- (2-methyl-4-pyridyl) -3- [3-nitro-4- (2-tetrahydropyranylmethyl oxypheny] -1, 2, 4-triazole

Pale yellow powder

¹ H-NMR (DMSO-d ₆ ) δ ppm: 1.35-1.81 (6H, m), 2.57 (3H, s), 3.43-4.26 (4H, m), 7.58 (1H, d, J = 8.91 Hz), 7.80 (1H, d, J = 4.621 Hz), 7.88 (1H, s), 8.30 (1H, dd, J = 8.91, 1.82), 8.53 (1H, d, J = 1.82 Hz), 8.60 (1H, d, J = 4.62 Hz)

Example 12.

5- (2-cyano-4-pyridyl) -3- (4-pyridyl) -1, 2, 4-triazole

1) Preparation of isonicotinic acid methyl N-oxide.

13.9 g of isonicotinic acid methyl N-oxide is added to 209 ml of chlorinated methylene, where 1-ethoxycarbonyl-2-ethoxy-1, 2-dihydrogrine is added. 29.7 g of norin (dihydroquinoline) were added, and it stirred at room temperature for 1 hour in argon atmosphere. 32.1 g of methanol was added to the reaction solution, the mixture was stirred at room temperature for 17 hours, the solvent was distilled off under reduced pressure, and the residue was applied to silica gel karum chromatodo, and eluted with chloroform-acetone (3: 1). Thus, 11.1 g of white crystals were obtained.

¹ H-NMR (CDC-1 ₃ ) δ ppm: 3.95 (3H, s), 7.88 (2H, d, J = 7.25 Hz), 8.22 (2H, J = 7.25 Hz)

2) Preparation of 2-cyanoisonicotinate methyl.

11.1 g of the crystal obtained in 1) was dissolved in 170 ml of acetonitrile. 14.6 g of triethylamine and 21.5 g of trimethylsilylnitrile were added, and the mixture was heated to reflux under an argon atmosphere for 16 hours, and the solvent was distilled off under reduced pressure. It was coated with water and eluted with chloroform-acetone (95: 5) to obtain 8.44 g of pale yellow crystals.

¹ H-NMR (CDC-1 ₃ ) δ ppm: 4.01 (3H, s), 8.08 (1H, d, J = 5.45Hz), 8.24 (1H, s), 8.90 (1H, d, J = 5.45Hz)

3) Preparation of 2-cyano isnicotinic acid hydrazide

8.44 g of the crystal obtained in 2) was added to 85 ml of methanol, 1.84 g of hydrazine was added thereto, and the mixture was stirred at room temperature for 2 hours under argon atmosphere. After distilling off the solvent under reduced pressure, chlorofoam was added to the residue, followed by stirring at room temperature for 1 hour. Precipitated crystals were filtered off, and then washed with chromopol, and dried with a vacuum pump to obtain 4.15 g of pale yellow crystals.

¹ H-NMR (DMSO-d ₆ ) δ ppm: 4.72 (2H, s), 8.05 (1H, d, J = 5.12Hz), 8.31 (1H, s), 8.90 (1H, d, J = 5.12Hz), 10.23 (1H, s)

4) Preparation of the target object

Dissolve 2.67 g of 4-cyanopyridine in 40 ml of methanol, add 0.83 g of sodium methoxide, stir at room temperature for 1 hour, then add 4.15 g of crystals obtained in 3), and reflux at 37 hours. It was. After the completion of the reaction, the precipitated solid was filtered, washed with methanol and dried with a vacuum pump to obtain 3.66 g of the target substance as a yellow powder.

¹ H-NMR (DMSO-d ₆ ) δ ppm: 8.01 (2H, dd, J = 4.54, 1.57 Hz), 8.31 (1H, dd, J = 5.11, 1.65 Hz), 8.53 (1H, dd, J = 1.65, 0.50 Hz), 8.80 (2H, dd, J = 4.54, 1.57 Hz), 8.93 (1H, dd, J = 5.11, 0.50 Hz)

Example 13.

3- (4-isobutoxy-3-nitrofenyl) -5- (4-pyridyl) -1, 2, 4-triazole

In the same manner as in Example 1, white powder was obtained.

¹ H-NMR (DMSO-d ₆ ) δ ppm: 1.01 (6H, d, J = 6.60 Hz), 2.00-2.12 (1H, m), 4.04 (2H, d, J = 6.43 Hz), 7.57 (1H, d , J = 9.07Hz), 8.00 (2H, d, J = 6.10Hz), 8.31 (1H, dd, J = 6.10, 1.98Hz), 8.55 (1H, d, J = 1.98Hz), 8.74 (2H, d , J = 6.10 Hz), 14.92 (1H, s)

Example 14.

3- (4-isobutoxy-3-nitrophenyl) -5- (2-methyl-4-pyridyl) -N-pivaloyloxymethyl-1, 2, 4-triazole

354 mg of the powder obtained in Example 1 was dissolved in 3 ml of DMF, 181 mg of pivaloyloxymethyl chloride and 276 mg of potassium carbonate were added, followed by stirring at room temperature for 18 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed with water, dried over magnesium sulfate, filtered with magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was applied to silica gel karum chromat and eluted with chloroforme-acetone (95: 5) to give 358 mg of the target substance as a white powder.

¹ H-NMR (CDC-1 ₃ ) δppm: 1.06 ~ 1.11 (6H, m), 1.26 ~ 1.27 (9H, m), 2.11 ~ 2.29 (1H, m), 2.64 ~ 2.68 (3H, m), 3.91 ~ 3.98 (2H, m), 6.13-6.91 (2H, m), 7.12-7.26 (2H, m), 7.49-7.59 (2H, m), 7.82-8.05 (3H, m), 8.27-8.37 (2H, m ), 8.60-8.72 (3H, m)

The following compounds were obtained in the same manner as in Examples 1, 2 or 12 below.

Example 15.

3- (4-Butoxy-3-nitrophenyl) -5- (4-pyridyl) -1, 2, 4-triazole

Light green crystals

¹ H-NMR (DMSO-d ₆ ) δ ppm: 1.34 (3H, t, J = 7.29 Hz), 1.70 (2H, m), 1.75 (2H, m), 7.60 (1H, d, J = 8.91 Hz), 8.00 (2H, d, J = 5.94 Hz each), 8.29 (1H, dd, J = 8.91, 2.16 Hz), 8.50 (1H, d, J = 2.16 Hz), 8.74 (2H each, d, J = 5.94 Hz )

Example 16.

5- (4-isopropoxy-3-nitrofenyl) -3- (4-pyridyl) -1, 2, 4-triazole

Pale yellow crystals

¹ H-NMR (DMSO-d ₆ ) δ ppm: 1.34 (3H, d, J = 5.94 Hz), 1.36 (3H, d, J = 5.94 Hz), 4.94 (1H, m), 7.60 (1H, d, J = 8.91 Hz), 8.00 (2H, d, J = 5.94 Hz), 8.29 (1H, dd, J = 8.91, 2.16 Hz), 8.50 (1H, d, J = 2.16 Hz), 8.74 (2H, d each) , J = 5.94 Hz)

Example 17.

5- (2-chloro-4-pyridyl) -3- (isobutoxy-3-nitrofenyl) -1, 2, 4-triazole

Brown crystals

¹ H-NMR (DMSO-d ₆ ) δ ppm: 0.97 (3H, d, J = 6.48Hz), 1.01 (3H, d, J = 6.48Hz), 2.08 (1H, m), 4.04 (2H, d, J = 6.48 Hz), 7.58 (1H, d, J = 9.18 Hz), 8.01-8.05 (2H, m), 8.31 (1H, dd, J = 9.18, 2.16 Hz), 8.56-8.58 (2H, m),

Example 18.

3- (2-pyridyl) -5- (3-nitro-4-isobutoxyphenyl) -1, 2, 4-triazole

Pale yellow powder

¹ H-NMR (DMSO-d ₆ ) δ ppm: 1.01 (6H, d, J = 6.76 Hz), 2.08 (1H, m), 4.02 (2H, d, J = 6.43 Hz), 7.54 (2H, m), 8.03 (1H, t, J = 7.67 Hz), 8.19 (1H, d, J = 7.92 Hz), 8.31 (1H, d, J = 8.91 Hz), 8.50 (1H, s), 8.74 (1H, d, J = 4.62 Hz), 14.93 (1 H, brs)

Example 19.

3- (3-pyridyl) -5- (3-nitro-4-isobutoxyphenyl) -1, 2, 4-triazole

Off-white powder

¹ H-NMR (DMSO-d ₆ ) δ ppm: 1.01 (6H, d, J = 6.60 Hz), 2.08 (1H, m), 4.03 (2H, d, J = 6.27 Hz), 7.57 (2H, m), 8.32 (1H, dd, J = 1.98, 8.91 Hz), 8.41 (1H, d, J = 8.08 Hz), 8.54 (1H, d, J = 1.98 Hz), 8.68 (1H, d, J = 3.79 Hz), 9.25 (1H, doublet, J = 2.15 Hz)

Example 20.

3- (2-methyl-4-pyridyl) -5- (3-cyano-4-isobutoxyphenyl) -1, 2, 4-triazole

White Powder

¹ H-NMR (DMSO-d ₆ ) δ ppm: 1.04 (6H, d, J = 6.76 Hz), 2.11 (1H, m), 2.57 (3H, s), 4.01 (2H, d, J = 6.60 Hz), 7.45 (1H, d, J = 8.58 Hz), 7.79 (1H, d, J = 5.11 Hz), 7.88 (1H, s), 8.30 (1H, d, J = 8.74 Hz), 8.33 (1H, s), 8.59 (1H, d, J = 5.11 Hz)

Example 21.

3- (2-methyl-4-pyridyl) -5- (3-nitro-4-methoxyphenyl) -1, 2, 4-triazole

Yellowish white powder

¹ H-NMR (DMSO-d ₆ ) δ ppm: 2.57 (3H, s), 4.02 (3H, s), 7.58 (1H, d, J = 9.07 Hz), 7.80 (1H, d, J = 5.11 Hz), 7.88 (1H, s), 8.34 (1H, dd, J = 2.31, 8.91 Hz), 8.55 (1H, d, J = 2.31 Hz), 8.60 (1H, d, J = 5.11 Hz)

Example 22.

3- (2-methyl-4-pyridyl) -5- (3-cyano-4-cyclopropylmethoxyphenyl-1, 2, 4-triazole

Light brown crystals

¹ H-NMR (DMSO-d ₆ ) δ ppm: 0.42 (2H, m), 0.65 (2H, m), 1.31 (1H, m), 2.57 (3H, s), 4.10 (2H, d, J = 7.09Hz ), 7.44 (1H, d, J = 8.60 Hz), 7.79 (1H, d, J = 5.11 Hz), 7.88 (1H, s), 8.31 (1H, d, J = 9.07 Hz), 8.33 (1H, s ), 8.59 (1H, d, J = 5.11 Hz)

Example 23.

3- (2-cyano-4-pyridyl) -5- (2-methyl-4-pyridyl) -1, 2, 4-triazole

Pale yellow powder

¹ H-NMR (DMSO-d ₆ ) δ ppm: 7.81 (1H, d, J = 5.61 Hz), 7.90 (1H, s), 8.31 (1H, dd, J = 0.99, 5.11 Hz), 8.54 (1H, s ), 8.66 (1H, d, J = 5.11 Hz), 8.92 (1H, d, H = 5.11 Hz)

Example 24.

3- (2-methyl-4-pyridyl) -5- [3-cyano-4- (4-methoxybenzyloxy) phenyl] -1, 2, 4-triazole

White powder

¹ H-NMR (DMSO-d ₆ ) δ ppm: 2.57 (3H, s), 3.78 (3H, s), 5.29 (2H, s), 7.00 (2H, d, J = 8.74 Hz), 7.46 (2H, d , J = 8.74Hz), 7.57 (1H, d, J = 8.74Hz), 7.79 (1H, d, J = 4.78Hz), 7.88 (1H, s), 8.33 (1H, dd, J = 2.15, 8.74Hz ), 8.34 (1H, s), 8.59 (1H, d, 5.11 Hz)

Example 25.

3- (2-methyl-4-pyridyl) -5- (3-cyano-4-isopentyloxyphenyl-1, 2, 4-triazole

White powder

¹ H-NMR (DMSO-d ₆ ) δ ppm: 0.97 (6H, d, J = 6.60 Hz), 1.70 (2H, m), 1.84 (1H, m), 2.57 (3H, s), 4.26 (2H, t , J = 6.52Hz), 7.48 (1H, d, J = 8.58Hz), 7.79 (1H, d, J = 4.78Hz), 7.88 (1H, s), 8.32 (1H, dd, J = 2.31, 8.58Hz ), 8.33 (1H, s), 8.59 (1H, d, J = 4.78 Hz), 14.80 (1H, brs)

Example 26.

3- (2-methyl-4-pyridyl) -5- (3-cyano-4-methoxyphenyl) -1, 2, 4-triazole

Brown powder

¹ H-NMR (DMSO-d ₆ ) δ ppm: 2.57 (3H, s), 4.01 (3H, s), 7.47 (1H, d, J = 5.77Hz), 7.88 (1H, s), 8.35 (2H, m ), 8.59 (1H, d, J = 5.28 Hz)

Example 27.

3- (2-chloro-4-pyridyl) -5- (2-methyl-4-pyridyl) -1, 2, 4-triazole

Light brown powder

¹ H-NMR (DMSO-d ₆ ) δ ppm: 7.80 (1H, d, J = 5.28 Hz), 7.89 (1H, s), 8.02 (1H, d, J = 5.11 Hz), 8.05 (1H, s), 8.59 (1H, d, J = 5.11 Hz), 8.64 (1H, d, J = 5.11 Hz)

Example 28.

3- (2-methyl-4-pyridyl) -5- (3-cyano-4-propalyloxyphenyl) -1, 2, 4-triazole

Light brown crystals

¹ H-NMR (DMSO-d ₆ ) δ ppm: 2.57 (3H, s), 3.76 (1H, s), 5.12 (2H, d, J = 1.81 Hz), 7.52 (1H, d, J = 8.41 Hz), 7.79 (1H, d, J = 5.61 Hz), 7.88 (1H, s), 8.36 (1H, d, J = 8.25 Hz), 8.37 (1H, s), 8.60 (1H, d, J = 5.11 Hz)

Example 29.

3- (2-methyl-4-pyridyl) -5- [3-cyano-4-{(<2-chloroepoxy> epoxy) epoxy} phenyl] 1, 2, 4-triazole

White powder

¹ H-NMR (DMSO-d ₆ ) δ ppm: 2.79 (3H, s), 3.59-3.72 (8H, m), 3.85 (2H, m), 4.40 (2H, m), 7.53 (1H, d, J = 8.91 Hz), 8.31 (1H, d, J = 5.28 Hz), 8.38 (1H, dd, J = 1.98, 8.91 Hz), 8.43 (2H, brs), 8.83 (1H, d, J = 6.10 Hz)

Example 30.

3- (2-isobutylthio-4-pyridyl) -5- (3-nitro-4-isobutoxyphenyl) -1, 2, 4-triazole

Yellow powder

¹ H-NMR (CDC-1 ₃ ) δ ppm: 1.06 (6H, d, J = 6.60 Hz), 1.08 (6H, d, J = 5.61 Hz), 1.99 (1H, m), 2.19 (1H, m), 3.14 (2H, d, J = 6.76 Hz), 3.94 (2H, d, J = 6.43 Hz), 7.17 (1H, d, J = 8.91 Hz), 7.60 (1H, d, J = 4.45 Hz), 7.85 ( 1H, s), 8.22 (1H, dd, J = 1.98, 8.74 Hz), 8.53 (1H, s), 8.54 (1H, d, J = 5.11 Hz)

Example 31.

3- (2-methyl-4-pyridyl) -5- (3-cyano-4-methoxyethoxyphenyl-1, 2, 4-triazole

White powder

¹ H-NMR (CDC-1 ₃ ) δ ppm: 2.65 (3H, s), 3.51 (3H, s), 3.87 (2H, t, J = 4.70 Hz), 4.33 (2H, t, J = 4.62 Hz), 7.16 (1H, d, J = 8.58 Hz), 7.82 (1H, brs), 7.91 (1H, s), 8.28 (1H, dd, J = 2.15, 8.58 Hz), 8.31 (1H, s), 8.56 (1H , d, J = 5.28 Hz)

Example 32.

3- (2-methyl-4-pyridyl) -5- [3-cyano-4-{(2-methoxyethoxy) ethoxy} pentyl] -1, 2, 4-triazole

White powder

¹ H-NMR (CDC-1 ₃ ) δ ppm: 2.66 (3H, s), 3.42 (3H, s), 3.66 (2H, m), 3.84 (2H, m), 3.96 (2H, m), 4.25 (2H , m), 7.01 (1H, d, J = 8.91 Hz), 7.78 (1H, d, J = 5.28 Hz), 7.89 (1H, s), 8.19 (1H, dd, J = 2.31, 8.74 Hz), 8.26 (1H, d, J = 2.14 Hz), 8.63 (1H, d, J = 5.11 Hz)

Example 33.

3- (2-methyl-4-pyridyl) -5- [3-cyano-4-{(<2-methoxyethoxy> ethoxy) ethoxy} pentyl] -1, 2, 4-triazole

White powder

¹ H-NMR (DMSO-d ₆ ) δ ppm: 2.81 (3H, s), 3.23 (3H, s), 3.43 (2H, m), 3.51-3.57 (4H, m), 3.65 (2H, m), 3.84 (2H, m), 4.39 (2H, m), 7.53 (1H, d, J = 8.91 Hz), 8.33 (1H, d, J = 6.02 Hz), 8.39 (1H, d, J = 8.91 Hz), 8.44 (2H, s), 8.84 (1H, d, J = 6.02 Hz)

Example 34.

3- (2-methoxy-4-pyridyl) -5- (3-nitro-4-isobutoxyphenyl) -1, 2, 4-triazole

Yellow crystals

¹ H-NMR (DMSO-d ₆ ) δ ppm: 1.01 (6H, d, J = 6.76 Hz), 2.08 (1H, m), 3.92 (3H, s), 4.03 (2H, d, J = 6.43 Hz), 7.40 (1H, s), 7.55 (1H, d, J = 8.74 Hz), 7.61 (1H, d, J = 5.77 Hz), 8.30 (1H, dd, J = 2.15, 8.75 Hz), 8.32 (1H, d , J = 5.11 Hz), 8.53 (1H, d, J = 1.98 Hz), 14.88 (1H, brs)

Example 35.

3- (2-cyano-4-pyridyl) -5- (1-oxy-4-pyridyl) -1, 2, 4-triazole

Yellow powder

¹ H-NMR (DMSO-d ₆ ) δ ppm: 8.01 (2H, dd, J = 1.98, 5.36 Hz), 8.29 (1H, dd, J = 1.65, 5.11 Hz), 8.40 (2H, dd, J = 1.98, 5.36 Hz), 8.52 (1H, d, J = 1.65 Hz), 8.92 (1H, dd, J = 1.65, 5.11 Hz)

Example 36.

3- (2-cyano-4-pyridyl) -5- [3-cyano-4-{(2-methoxyethoxy) ethoxy} pentyl] -1, 2, 4-triazole

Pale yellow powder

¹ H-NMR (CDC 1 ₃ ) δ ppm: 3.41 (3H, s), 3.60 (2H, m), 3.79 (2H, m), 3.97 (2H, m), 4.35 (2H, m), 7.18 (1H, d, J = 7.24 Hz), 8.24 to 8.28 (3H, m), 8.45 (1H, s), 8.81 (1H, d, J = 5.28 Hz)

Example 37.

3- (2-cyano-4-pyridyl) -5- (2-chloro-4-pyridyl) -1, 2, 4-triazole

Pale yellow crystals

¹ H-NMR (DMSO-d ₆ ) δ ppm: 8.02 (1H, d, J = 5.11 Hz), 8.08 (1H, s), 8.31 (1H, dd, J = 1.65, 5.11 Hz), 8.55 (1H, s ), 8.63 (1H, d, J = 5.11 Hz), 8.94 (1H, d, J = 5.11 Hz)

Example 38.

3- (2-cyano-4-pyridyl) -5- (2-pentyl-4-pyridyl) -1, 2, 4-triazole

Pale yellow powder

¹ H-NMR (DMSO-d ₆ ) δ ppm: 7.55 (3H, m), 7.98 (1H, d, J = 4.95 Hz), 8.17 (2H, m), 8.35 (1H, d, J = 4.95 Hz), 8.58 (2H, m), 8.88 (2H, d, J = 4.95 Hz), 8.93 (1H, d, J = 4.95 Hz)

Example 39.

5- (2-cyano-4-pyridyl) -3- (4-pyridyl) -1, 2, 4-triazole

1) Preparation of isonicotinic acid (N2-tert-butoxycarbonyl) hydrazide-1-oxide.

585 ml of methylene chloride was added to 39.0 g of isonicotinic acid N-oxide, and 34.0 g of triethylamine was added thereto, and the mixture was cooled to -15 ° C under an argon atmosphere. To this reaction solution was added dropwise a solution of 117 ml of methylene chloride of 33.5 g of ethyl crorocarbonate, which was stirred at -5 to -10 ° C for 1 hour. Then, a solution of 117 mL of 44.4 g of carbazic acid tert-butyl ester (methylene chloride) was added dropwise, and the mixture was stirred while slowly warming to room temperature.

After 15 hours, the precipitated crystals were filtered, washed with methylene chloride and dried with a vacuum pump to obtain 49.7 g of white crystals.

1 H-NMR (DMSO-d ₆ ) δ ppm: 1.42 (9H, s), 7.82 (2H, d, J = 7.09 Hz), 8.33 (2H, d, J = 7.09 Hz), 9.02 (1H, s), 10.44 (1H, s)

2) Preparation of 2-cyano-isonicotinic acid hydrazide ¹ _1/2 P- tolen seulpo acid (toluenesulfonic acid) salt (salt).

228 ml of dioxane was added to 30.4 g of the crystal obtained in 1), followed by 13.1 g of trimethylsilyl cyanide, and 38.8 g of N, N-dimedyl garbamoyl chloride. In addition, under argon atmosphere. It stirred at 60 degreeC for 5 hours. After distilling off the solvent under reduced pressure, the residue was dissolved in ethyl acetate, washed successively with 1.5 M aqueous sodium carbonate solution and saturated brine, and dried over magnesium sulfate. After filtration of magnesium sulfate, the solvent was distilled off under reduced pressure, ethyl acetate was added to the residue, 68.5 g of P-toluenesulfonic acid monohydrate was added, and the mixture was stirred at room temperature for 24 hours. The precipitated crystals were filtered off, washed with ethyl acetate and dried with a vacuum pump to obtain 40.3 g of white crystals 2).

1 H-NMR (DMSO-d ₆ ) δ ppm: 2.28 (4.5 H, s), 7.12 (3H, dd, J = 7.92 & 0.66 Hz), 7.48 (3H, dd, J = 7.92 & 0.66 Hz Hz), 8.10 (1 H) , dd, J = 5.11 & 1.81 Hz), 8.39 (1H, dd, J = 1.81 & 0.33 Hz), 8.99 (1H, dd, J = 5.11 & 0.33 Hz)

3) Preparation of 5- (2-cyano-4-pyridyl) -3- (4-pyridyl) -1, 2, 4-triazole.

9.98 g of 4-cyanopyridine was dissolved in 250 ml of methol, 7.77 g of sodium methoxide was added, and the mixture was stirred at room temperature for 1 hour. Thereafter, 40.3 g of the crystal obtained in 2) was added, and the mixture was heated to reflux for 24 hours. After the completion of the reaction, the precipitated crystals were filtered out, washed with methanol and dried with a vacuum pump to give a yellow crystal 16.3.

1 H-NMR (DMSO-d6) δ ppm: 8.01 (2H, dd, J = 4.54 & 1.57 Hz), 8.31 (1H, dd, J = 5.11 & 1.65 Hz Hz), 8.53 (1H, dd, J = 1.65 & 0.50 Hz ), 8.80 (2H, dd, J = 4.54 & 1.57 Hz), 8.93 (1H, dd, J = 5.11 & 0.50 Hz)

4) Preparation of 5- (2-cyano-4-pyridyl) -3- (4-pyridyl) -1, 2, 4-triazole.

45 ml of ethanol and 15 ml of 1-methyl-2-pyrrolidone were added to 3.0 g of the crystal obtained in 3), and the mixture was heated and stirred at 80 ° C. for 19 hours. The crystals were filtered, ethanol and 1-methyl-2-pyrrolidone (3: 1) were washed sequentially with a mixed solution and ethanol, and then dried with a vacuum pump to give 2.71 g of yellow crystals.

5) Preparation of 5- (2-cyano-4-pyridyl) -3- (4-pyridyl) -1, 2, 4-triazole P-tolensulfonic acid salt.

5 ml of ethanol and 30 ml of water were added to 2.48 g of the crystal obtained in 4), and then 3.8 g of P-toluenesulfonic acid monohydrate was added and stirred at room temperature for 5 hours. The precipitated crystals were filtered, washed sequentially with a mixture of ethanol and water (1: 6), water and ethanol, and dried with a vacuum pump to obtain 3.5 g of white crystals.

1 H-NMR (DMSO-d6) δ ppm: 2.28 (3H, s), 7.12 (2H, dd, J = 7.75 & 0.50 Hz), 7.48 (2H, dd, J = 7.75 & 0.50 Hz Hz), 8.33 (1H, dd) , J = 5.12 & 1.65 Hz), 8.45 (2H, d, J = 6.11 Hz), 8.57 (1H, dd, J = 1.65 & 0.66 Hz), 8.96-9.02 (3H, m)

6) Preparation of the target product.

17 ml of ethanol and 17 ml of water were added to 3.36 g of the crystal obtained in 5), followed by stirring at room temperature for 30 minutes. Thereafter, a sodium bicarbonate solution (a solution of 17 ml of 0.74 g of sodium bicarbonate water) was added and stirred at room temperature for 2 hours.

The crystals were filtered, washed sequentially with water and ethanol, and then dried with a vacuum pump to obtain 1.89 g of a pale yellow crystal.

Test example.

A method of measuring serum uric acid lowering effect in a living body.

In a male wistar rat (4 group 1), 7 weeks old, the test substance suspended in 0.5% methylcellulose (MC) aqueous solution was dosed 0.3 mg / 5 mL / kg [1 mg / 5 mL / kg of Compound 44 of Medical Chemistry (1975) of Example 17 and the Control Example] was forced orally administered using a feed tube. (Iii).

Six hours after the administration of the test substance, blood was collected from the orbital vein, and the blood was left at room temperature for 1 hour and centrifuged at 2000 × g for 10 minutes to collect serum.採取). Serum uric acid value was measured by a kit for measuring uric acid (Hwagwang Pure Chemical Co., Ltd., phosphotungstic acid method), and the rate of decrease of serum uric acid was calculated by the following equation.

Number 1.

Serum uric acid lowering rate (%)

= (Mean serum uric acid level of the 1-subject administered group / mean serum uric acid level of the MC administration group) × 100

Table 1.

Serum uric acid lowering rate

Example 1 66.5%

Example 2 62.3%

Example 3 40.0%

Example 4 43.9%

Example 5 39.9%

Example 6 40.6%

Example 7 42.7%

Example 8 32.5%

Example 9 35.7%

Example 10 41.6%

Example 11 41.6%

Example 12 51.1%

Example 13 46.8%

Example 14 43.0%

Example 15 41.2%

Example 16 36.1%

Example 17 40.6%

Example 20 67.5%

Example 21 52.9%

Example 22 32.6%

Example 23 41.1%

Example 24 38.3%

Example 25 47.2%

Example 26 37.9%

Example 27 32.9%

Example 28 35.3%

Example 29 40.7%

Example 31 36.5%

Example 32 52.0%

Example 33 44.7%

Example 35 46.8%

Example 37 33.6%

Active control example

Compound 3 of compound No. 49-46622 -11.1%

Example 2 Compound 26.1%

Compound 1 of compound No. 50-24315, -0.4%

Compound 44 -7.7% of Journal of Medical Chemistry (Vol. 18, No. 9, 1975).

According to the present invention, by selecting the compound represented by the general formula (1), xanthine oxidase detoxification activity is increased, and hyperuricemia of uric acid-producing hyperplasia is high. Iv) and 1, 2, 4-triazole compounds (TRIAZOLE CONPOUNDS) useful as gout treatments for hyperuricemia.

Claims (9)

General formula (1) below. Formula 2. (One) [In the above formula, R ₂ is an unsubstituted pyridyl group or a cyano group as a substituent. A substituted pyridyl group having a lower alkyl group, a halogen, a lower alkoxy group or a lower alkylthio group is represented. . R ₁ may have a halogen, a cyano group, or a phenyl group as a substituent. An unsubstituted or substituted pyridyl group or a pyridine-N-oxide group corresponding to those pyridyl groups or a cyano group as a substituent Substituted or unsubstituted as a substituent in addition to a substituted phenyl group having a cyano group or a nitro group, or a cyano group or a nitro group. Lower alkoxy groups, N-lowerer alkyl-piperazino groups, lower alkylthio groups, phenylthio groups, or Substituted phenyl group having a lower alkylamino group, provided that R ₁ is a phenyl group substituted with only one cyano group, or one nitro group is not a closed-group (phenyl group) substituted only (nitro group). In addition, R ₂ is a non- If the ring pyridyl group (pyridyl group) or lower alkyl-substituted pyridyl group (pyridyl group), R ₁ is a pyridyl group (pyridyl group), or a lower (低級) alkyl substituted pyridyl group (pyridyl group) unsubstituted (非置換) Or not the corresponding pyridine-N-oxide of those pyridyl groups, R ₃ is hydrogen or a pivaloyloxy substituted lower alkyl group Which is bound to one nitrogen of the 1,2,4-triazole ring represented by the general formula (1). It is a triazole compound (TRIAZOLE CONPOUNDS), its hydrate, or its salt, The novel 1, 2, 4-triazole type compound characterized by the above-mentioned. A compound, a hydrate thereof, or a salt thereof is a cyano group or a nitro group according to claim 1, wherein the group R ₁ is a substituent. a novel 1, 2, 4-triazole type, characterized in that it is a substituted phenyl group having a nitro group and a substituted or unsubstituted lower alkoxy group. compound. A compound, a hydrate thereof, or a salt thereof, wherein the group R ₂ is a cyano group or a lower group as a substituent. Iii) A novel 1, 2, 4-triazole compound characterized in that it is a substituted pyridyl group having a lower alkyl group. The compound according to any one of claims 1 to 3, wherein the compound according to any one of claims, a hydrate thereof, or a salt thereof is used as an active ingredient of a medicine. Novel 1, 2, 4-triazole compound characterized by the above-mentioned. 5. The novel 1, 2 and 4-triazole compound according to claim 4, wherein the active ingredient of the drug is a drug for the purpose of deximating xanthine oxidase. The novel 1, 2, 4-triazole-based compound according to claim 4, wherein the active ingredient of the medicine is a medicine which is a gout treatment medicine. The novel 1, 2, 4-triazole-based compound according to claim 4, wherein the active ingredient of medicine is medicine, which is a treatment for hyperuricemia. General formula (1) In the method for producing a compound in which the group R ₃ is hydrogen, an iminoether of an aromatic nitrile and an aromatic carboxylic acid hydra A method for producing a novel 1, 2, 4-triazole-based compound, characterized by reacting with a hydrogen. The method for producing a compound according to claim 8, wherein the group R ₃ is a pivaloyloxy substituted lower alkyl group. To react a halo lower alkyl ester of pivalic acid with a compound in which the group R ₃ in the compound represented by the general formula (1) is hydrogen. Method for producing a novel 1, 2, 4-triazole compound characterized in that.