HK1067132B - 1,2,4-triazole compound - Google Patents

Description

1,2, 4-triazoles

Technical Field

The present invention relates to novel 1,2, 4-triazole compounds which may have a substituted alkyl group at the 1,2 or 4 position and an aromatic ring at the 5 position, hydrates thereof, salts thereof, and processes for producing the same, and drugs for treating hyperuricemia and gout, which contain these compounds as active ingredients.

Background

The total number of hyperuricemia patients in China is said to be 125 thousands of people, but the number of asymptomatic hyperuricemia patients is estimated to be as many as millions of people, and the disease becomes a common disease in China gradually.

Currently, for hyperuricemia and gout caused by hyperuricemia, corresponding living environment adjustment and various drug treatments are respectively carried out according to a pre-induced gout attack period (pre-induced period), a gout attack period and a gout remission period. That is, the daily living environment is adjusted during the pre-sensing period and the prevention is carried out with colchicine as an auxiliary measure, the treatment is carried out mainly on the treatment with drugs such as steroidal and non-steroidal anti-inflammatory drugs during the attack period, the improvement of living habits is guided after the release of the attack, the treatment is carried out with drugs having uric acid excretion action such as probenecid and coumarone, having uric acid reabsorption inhibition action such as phensulidone, having acidic urine improvement action such as citrate, and having uric acid production inhibition action such as xanthine oxidase inhibitor allopurinol after the low uric acid excretion or high uric acid production is confirmed when the improvement is incomplete. If colchicine is taken 2-3 hours before the onset of disease, it can inhibit chemotaxis and phagocytosis of neutrophil, etc., thereby preventing 90% of the onset of disease. However, this drug has various side effects, and it is difficult to take the drug with minimal restrictions and at a good onset.

Although mainly used for drug therapy, the drugs for uric acid overproduction only contain allopurinol, and allopurinol, which is a metabolite thereof, is easily accumulated in the body to form calculi. Moreover, it has been reported that the drug causes side effects such as eruption, renal dysfunction, and hepatitis, and therefore, the drug is not easily prescribed.

In Journal of Medicinal Chemistry 1975, Vol.18, No.9, pp895 to 900 Japanese patent publication No. 49-46622 and Japanese patent publication No. 50-24315, several 1, 3, 5-or 3, 5-substituted 1,2, 4-triazole compounds are disclosed as compounds having xanthine oxidase inhibitory activity and being effective for hyperuricemia and gout caused by hyperuricemia, which are useful for hyperuricemia.

Hyperuricemia and gout caused by the hyperuricemia have increasingly high incidence in young people in China due to the change of living environment and the like, and the disease cannot be overcome only by requiring people to change living habits. However, the development of a therapeutic drug for such a disease is very slow, and it is difficult to develop a compound that improves the therapeutic effectiveness, and there is no great progress.

The purpose of the present invention is to provide a novel 1,2, 4-triazole compound which has a high xanthine oxidase activity-inhibiting effect and is a drug capable of effectively treating hyperuricemia with uric acid production-accelerating type and gout caused by hyperuricemia.

Disclosure of the invention

The present invention is briefly described as follows. The invention of claim 1 relates to a 1,2, 4-triazole compound represented by the following general formula (1), hydrate thereof, or salt thereof:

the 1,2 or 4 position may have a substituted alkyl group and the 5 position may have a substituted aromatic ring.

The invention according to claim 2 is the compound represented by the general formula (1) above, R₃A process for the preparation of a compound which is hydrogen, characterized in that an imino ether of a corresponding aromatic nitrile is reacted with an aromatic carboxylic acid hydrazide.

The invention according to claim 3 is the group R represented by the above general formula (1)₃Is a new pentaneA process for producing a compound having a lower alkyl group substituted with an acyloxy group, characterized in that R in the compound represented by the general formula (1)₃Reacting a compound having a hydrogen group with a halogenated lower alkyl ester of pivalic acid.

The invention of claim 4 relates to a pharmaceutical agent containing the compound represented by the general formula (1), a hydrate thereof, or a salt thereof as an active ingredient.

The present inventors have conducted studies on a 1,2, 4-triazole compound as a basic structure in order to develop a compound having a xanthine oxidase inhibitory activity and being capable of effectively treating hyperuricemia with uric acid production and gout caused by hyperuricemia, which are currently marketed as only one compound. Finally, the above inventions have been completed.

Best Mode for Carrying Out The Invention

The present invention will be described in detail below.

First, each group in the above general formula (1) is explained.

In the above structural formula, R₂Represents unsubstituted pyridyl or substituted pyridyl with cyano, lower alkyl, halogen, lower alkoxy, lower alkylthio as substituent. R₁Represents unsubstituted or substituted pyridyl which may have halogen, cyano or phenyl as a substituent, or pyridine N-oxyl corresponding to these pyridyl, or substituted phenyl which may have cyano or nitro as a substituent, or substituted phenyl which may have, in addition to the cyano or nitro, substituted or unsubstituted lower alkoxy, N-lower alkyl-substituted piperazinyl, lower alkylthio, phenylthio or lower alkylamino as a substituent. However, if R is₂When it is unsubstituted pyridyl or lower alkyl substituted pyridyl, then R₁Is not unsubstituted pyridyl, lower alkyl substituted pyridyl or the corresponding pyridyl N-oxy groups of these pyridyl groups. R₃Represents hydrogen, pivaloyloxy-substituted lower alkylWhich is bonded to any one of the nitrogens on the 1,2, 4-triazole rings represented by the general formula (1).

In the compounds of the present invention, if the substituents at the 3-position and the 5-position are both pyridine rings, at least one of them is preferably substituted by cyano or halogen, and if one of them is a benzene ring, the benzene ring may be substituted by substituted or unsubstituted lower alkoxy, thioether, substituted piperazinyl, substituted amino, or the like, but at least it is necessary to be substituted by cyano or nitro.

The present invention has been completed based on the finding that the compound of the present invention has a high inhibitory activity in vivo xanthine oxidase inhibition experiments, which has not been achieved by the known compounds.

The 1,2, 4-triazole compound as the basic skeleton of the present invention includes several isomers (a), (B), and (C), which are collectively referred to as 1,2, 4-triazole in the present invention and represented by the general formula (1).

Isomer (A)

Isomer (B)

Isomer (C)

The process for the preparation of the compounds of the invention is essentially a reaction of the imino ether of the corresponding aromatic nitrile and the aromatic carboxylic acid hydrazide.

That is, it is characterized by the corresponding general formula (2): r₁Imino ethers of nitriles represented by CN and compounds represented by the general formula (3): r₂CONHNH₂The hydrazide represented by (a) or a compound represented by the corresponding general formula (4): r₂Imino ethers of nitriles represented by CN and compounds represented by the general formula (3): r₁CONHNH₂The hydrazide shown was reacted.

The imino ether to be used may be an imino ether (an ester of an imidic acid) obtained by reacting an aromatic nitrile with an alcohol under basic conditions, for example, with sodium methoxide or sodium ethoxide, or an aromatic nitrile with an alcohol such as methanol or ethanol under acidic conditions. Salts produced under acidic conditions can be isolated, and imino ethers produced under basic conditions can also be isolated as monomers or salts.

Examples of the solvent usable in the method for producing the compound of the present invention include water-soluble solvents such as methanol and ethanol, but methanol is suitable. In addition, the reaction can be carried out at room temperature, but the reaction is preferably carried out by heating in consideration of the reaction rate and the dehydration reaction in the reaction, and a temperature close to the boiling point (about 65 ℃ C.) is preferable when methanol is used as the solvent. The compound preparation of the present invention is conducted under reflux. The reaction time and temperature are dependent on each other, but may be in a range in which the side reactions and the formation of decomposition products are suppressed.

In the present invention, when a pivaloyloxy group-substituted lower alkyl group is introduced, the reaction may be carried out by a conventional dehydrohalogenation reaction, and preferably, the reaction is carried out in the presence of a dehydrohalogenation agent such as a conventional organic base or an alkaline agent, and the reaction may be carried out sufficiently at room temperature. The reaction may be carried out in a solvent, and dimethylformamide (hereinafter abbreviated as DMF) may be mentioned as a solvent.

Examples

The compounds, the preparation method, the experimental method of effectiveness and the results of the present invention are specifically described below by examples. However, the invention is not limited to the embodiments disclosed.

In the following examples, dimethylsulfoxide is abbreviated as DMSO.

Example 1

3- (4-isobutoxy-3-nitrophenyl) -5- (2-methyl-4-pyridine

Base of

) -1, 2, 4-triazole

1) Preparation of 4-isobutoxy-3-nitrobenzonitrile

19.5g of 4-chloro-3-nitrobenzonitrile was dissolved in 200ml of DMF, and 16.0g of 2-methyl-1-propanol, 30g of potassium carbonate and 7.1g of potassium iodide were added thereto, followed by stirring at 80 ℃ for 24 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with saturated brine and was dried over magnesium sulfate. After magnesium sulfate was filtered off, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography and eluted with hexane-ethyl acetate (10: 1) to give the objective product as pale yellow crystals 5.9 g.

¹H-NMR(CDCl₃)δppm：1.07(6H，d，J＝6.76Hz)，2.11～2.25(1H，m)，3.94(2H，d，J＝6.43Hz)，7.15(1H，d，J＝8.91Hz)，7.81(1H，dd，J＝8.91，2.15Hz)，8.14(1H，d，J＝2.15Hz)

2) 1.54g of the crystal obtained in 1) was dissolved in 50ml of methanol, and 757mg of sodium methoxide was added thereto, followed by stirring at room temperature for 3 hours under argon atmosphere. Then, 1.06g of 2-methylisonicotazine was added thereto, and the mixture was refluxed for 16 hours. After the reaction, the solvent was distilled off under reduced pressure, water was added to the residue, extraction was performed with ethyl acetate, drying was performed with magnesium sulfate, and then magnesium sulfate was filtered off, and the solvent was distilled off under reduced pressure. Chloroform was added to the obtained residue, and the mixture was stirred at room temperature for 1 hour, and the precipitated solid was filtered off, washed with chloroform, and dried by a vacuum pump to obtain 1.50g of the objective compound as a colorless powder.

¹H-NMR(DMSO-d₆)δppm：1.01(6H d，J＝6.60Hz，1.99～2.15(1H，m)，2.57(3H，s)，4.03(2H，d，J＝6.43Hz)，7.56(1H，d，J＝8.91Hz)，7.80(1H，d，J＝5.11Hz)，7.88(1H，s)，8.31(1H，dd，J＝8.91，1.98Hz)，8.54(1H，d，J＝1.98Hz)，8.60(1H，d，J＝5.11Hz)，14.86(1H，s)

Example 2

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

1) Preparation of 4-isobutoxy-3-cyanobenzonitrile

25.2g of 4-nitro-benzonitrile are dissolved in 300ml of DMSO, 20.0g of potassium cyanide are added, and the mixture is stirred at 100 ℃ for 1 hour. After the reaction mixture was cooled to room temperature, 81.6g of 1-bromo-2-methylpropane and 11.76g of potassium carbonate were added thereto, and the mixture was heated and stirred at 80 ℃ for 8 hours. The reaction mixture was extracted with ethyl acetate after adding water, and the ethyl acetate layer was washed with saturated brine, dried over magnesium sulfate, filtered off magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with hexane-ethyl acetate (3: 1) to give 21.75g of a pale yellow powder.

¹H-NMR(CDCl₃)δppm：1.09(6H d，J＝6.76Hz，2.13～2.28(1H，m)，3.91(2H，d，J＝6.43Hz)，7.04(1H，d，J＝8.74Hz)，7.77～7.86(2H，m)

2) Preparation of the target Compound

To 10ml of a methanol solution of 0.50g of the powder obtained in 1) was added 0.08g (catalytic amount) of sodium methoxide, and the mixture was stirred at room temperature overnight. Isoniazid was added to the reaction solution and heated under reflux overnight. The precipitated product was collected by filtration and recrystallized from methanol to obtain 0.14g of the titled compound as a colorless powder.

¹H-NMR(DMSO-d₆)δppm：1.03(6H d，J＝6.77Hz，2.03～2.15(1H，m)，4.01(2H，d，J＝6.43Hz)，7.45(1H，d，J＝8.74Hz)，7.99(2H，dd，J＝4.45，1.65Hz)，8.29～8.34(2H，m)，8.73(2H，dd，J＝4.45，1.65Hz)

The following compounds were prepared by the same procedures as in example 1 or 2.

Example 3

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

Light brown powder

¹H-NMR(DMSO-d₆)δppm：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＝9.08Hz，7.79(1H，d，J＝4.95Hz)，7.88(1H，s)，8.30～8.35(2H，m)，8.60(1H，d，J＝4.95Hz)

Example 4

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

Yellow powder

¹H-NMR(CDCl₃)δppm：2.39(3H，s)，2.62～2.66(7H，m)，3.19～3.23(4H，m)，7.20(1H d，J＝8.74Hz)，7.81(1H d，J＝5.11Hz)，7.91(1H，s)，8.15(1H，dd，J＝8.74，1.98Hz)，8.48(1H，d，J＝1.98Hz)，8.63(1H，d，J＝5.11Hz)

Example 5

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

Orange powder

¹H-NMR(DMSO-d₆)δppm：0.98(6H d，J＝6.59Hz，1.94～2.04(1H，m)，2.56(1H，s)，3.17～3.32(2H，m)，7.28(1H，d，J＝9.40Hz)，7.77～7.87(2H，m)，8.17(1H，dd，J＝9.40，1.98Hz)，8.43～8.58(2H，m)，8.81(1H，d，J＝1.98Hz)

Example 6

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

Yellow powder

¹H-NMR(DMSO-d₆)δppm：2.56(3H，s)，7.03(1H，d，J＝8.58Hz)，7.57～7.87(7H，m)，8.20(1H，d，J＝8.58Hz)，8.61(1H，d，J＝5.12Hz)，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

¹H-NMR(DMSO-d₆)δppm：1.07(6H d，J＝6.60Hz，1.91～1.96(1H，m)，2.57(3H，s)，3.03(2H，d，J＝6.76Hz)，7.80～7.89(3H，m)，8.33(1H，dd，J＝8.41，1.98Hz)，8.61(1H，d，J＝5.12Hz)，8.84(1H，d，J＝1.98Hz)

Example 8

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

Light yellow powder

¹H-NMR(DMSO-d₆)δppm：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＝8.91，2.15Hz)，8.53～8.61(2H，m)，14.92(1H，s)

Example 9

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

Yellow powder

¹H-NMR(DMSO-d₆)δppm：2.22(3H，s)，2.57(3H，s)，5.58(2H，s)，7.65～7.89(3H，m)，8.31(1H，dd，J＝8.41，1.65Hz)，8.54～8.61(2H，m)，14.94(1H，s)

Example 10

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

Light yellow powder

¹H-NMR(DMSO-d₆)δppm：2.68(3H，s)，4.79(2H，s)，5.48(2H，s)，7.30～7.38(5H，m)，7.52(1H，d，J＝8.90Hz)，7.79(1H，d，J＝5.44Hz)，7.90(1H，s)，8.24(1H，dd，J＝8.90，2.14Hz)，8.57(1H，d，J＝2.14Hz)，8.66(1H，d，J＝5.44Hz)

Example 11

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

Light yellow powder

¹H-NMR(DMSO-d₆)δppm：1.35～1.81(6H，m)，2.57(3H，s)，3.43～4.26(4H，m)，7.58(1H，d，J＝8.91Hz)，7.80(1H，d，J＝4.62Hz)，7.88(1H，s)，8.30(1H，dd，J＝8.91，1.82Hz)，8.53(1H，d，J＝1.82Hz)，8.60(1H，d，J＝4.62Hz)

Example 12

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

1) Preparation of methyl isonicotinate N-oxide

To 13.9g of isonicotinic acid N-oxide was added 209ml of dichloromethane, to which was further added 29.7g of 1-ethoxycarbonyl-2-ethoxy-1, 2-dihydroquinoline, and the mixture was stirred at room temperature for 1 hour under an argon atmosphere. To the reaction mixture was added 32.1g of methanol, and the mixture was stirred at room temperature for 17 hours, and then the solvent was distilled off under reduced pressure, and then the residue was subjected to silica gel column chromatography and eluted with chloroform-acetone (3: 1) to give 11.1g of white crystals.

¹H-NMR(CDCl₃)δppm：3.95(3H，s)，7.88(2H，d，J＝7.25Hz)，8.22(2H，J＝7.25Hz)

2) Preparation of methyl 2-cyanoisonicotinate

11.1g of the crystal obtained in the above-mentioned step 1) was dissolved in 170ml of acetonitrile, 14.6g of triethylamine and 21.5g of trimethylsilonitrile were added to the solution, the mixture was refluxed under argon atmosphere for 16 hours, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography and eluted with chloroform-acetone (95: 5) to give 8.44g of a pale yellow crystal.

3)¹H-NMR(CDCl₃) δ ppm: preparation of 4.01(3H, s), 8.08(1H, d, J ═ 5.45Hz), 8.24(1H, s), 8.90(1H, d, J ═ 5.45Hz) 2-cyanoisonicotinyl hydrazide

To 8.44g of the crystals obtained in 2) were added 85ml of methanol and 1.84g of hydrazine, and the mixture was stirred at room temperature for 2 hours under an argon atmosphere. The solvent was removed by distillation under the reduced pressure, and chloroform was added to the residue, followed by stirring at room temperature for 1 hour. The precipitated crystals were collected by filtration, washed with chloroform and then dried by a vacuum pump to obtain 4.15g of pale yellow crystals.

¹H-NMR(DMSO-d₆)δppm：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 Compound

2.67g of 4-cyanopyridine was dissolved in 40ml of methanol, and 0.83g of sodium methoxide was further added thereto, followed by stirring at room temperature for 1 hour. Then, 4.15g of the crystals obtained in 3) was added thereto, and the mixture was refluxed for 37 hours. After completion of the reaction, the precipitated solid was filtered off, washed with methanol, and dried by a vacuum pump to obtain 3.66g of the objective compound as a yellow powder.

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

Example 13

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

A white powdery material was obtained in the same manner as in example 1.

¹H-NMR(DMSO-d₆)δppm：1.01(6H，d，J＝6.60Hz)，2.00～2.12(1H，m)，4.04(2H，d，J＝6.43Hz)，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＝6.10Hz)，14.92(1H，s)

Example 14

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

354mg of the powdery substance obtained in example 1 was dissolved in 3ml of DMF, and 181mg of pivaloyloxymethyl chloride and 276mg of potassium carbonate were added to stir at room temperature for 18 hours. Ethyl acetate was added to the reaction solution, followed by washing with water, drying over magnesium sulfate, filtering off magnesium sulfate, and distilling off the solvent under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with chloroform-acetone (95: 5) to give 358mg of the objective compound as a white powder.

¹H-NMR(CDCl₃)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)，6.13～6.19(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 example 1,2 or 12.

Example 15

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

Greenish crystal

¹H-NMR(DMSO-d₆) δ ppm: 1.34(3H, t, J ═ 7.29Hz), 1.70(2H, m), 1.75(2H, m), 7.60(1H, d, J ═ 8.91Hz), 8.00 (each 2H, d, J ═ 5.94Hz), 8.29(1H, dd, J ═ 8.91, 2.16Hz), 8.50(1H, d, J ═ 2.16Hz), 8.74 (each 2H, d, J ═ 5.94Hz)

Example 16

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

Pale yellow crystals

¹H-NMR(DMSO-d₆) δ ppm: 1.34(3H, d, J ═ 5.94Hz), 1.36(3H, d, J ═ 5.94Hz), 4.94(1H, m), 7.60(1H, d, J ═ 8.91Hz), 8.00 (each 2H, d, J ═ 5.94Hz), 8.29(1H, dd, J ═ 8.91, 2.16Hz), 8.50(1H, d, J ═ 2.16Hz), 8.74 (each 2H, d, J ═ 5.94Hz)

Example 17

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

Brown crystals

¹H-NMR(DMSO-d₆)δppm：0.97(3H，d，J＝6.48Hz)，1.01(3H，d，J＝6.48Hz)，2.08(1H，m)，4.04(2H，d，J＝6.48Hz)，7.58(1H，d，J＝9.18Hz)，8.01～8.05(2H，m)，8.31(1H，dd，J＝9.18，2.16Hz)，8.56～8.58(2H，m)

Example 18

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

Light yellow powder

¹H-NMR(DMSO-d₆)δppm：1.01(6H，d，J＝6.76Hz)，2.08(1H，m)，4.02(2H，d，J＝6.43Hz)，7.54(2H，m)，8.03(1H，t，J＝7.67Hz)，8.19(1H，d，J＝7.92Hz)，8.31(1H，d，J＝8.91Hz)，8.50(1H，s)，8.74(1H，d，J＝4.62Hz)，14.93(1H，brs)

Example 19

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

Off-white powder

¹H-NMR(DMSO-d₆)δppm：1.01(6H，d，J＝6.60Hz)，2.08(1H，m)，4.03(2H，d，J＝6.27Hz)，7.57(2H，m)，8.32(1H，dd，J＝1.98，8.91Hz)，8.41(1H，d，J＝8.08Hz)，8.54(1H，d，J＝1.98Hz)，8.68(1H，d，J＝3.79Hz)，9.25(1H，d，J＝2.15Hz)

Example 20

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

White powder

¹H-NMR(DMSO-d₆)δppm：1.04(6H，d，J＝6.76Hz)，2.11(1H，m)，2.57(3H，s)，4.01(2H，d，J＝6.60Hz)，7.45(1H，d，J＝8.58Hz)，7.79(1H，d，J＝5.11Hz)，7.88(1H，s)，8.30(1H，d，J＝8.74Hz)，8.33(1H，s)，8.59(1H，d，J＝5.11Hz)

Example 21

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

Yellow-white powder

¹H-NMR(DMSO-d₆)δppm：2.57(3H，s)，4.02(3H，s)，7.58(1H，d，J＝9.07Hz)，7.80(1H，d，J＝5.11Hz)，7.88(1H，s)，8.34(1H，dd，J＝2.31，8.91Hz)，8.55(1H，d，J＝2.31Hz)，8.60(1H，d，J＝5.11Hz)

Example 22

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

Light brown crystal

¹H-NMR(DMSO-d₆)δppm：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＝8.60Hz)，7.79(1H，d，J＝5.11Hz)，7.88(1H，s)，8.31(1H，d，J＝9.07Hz)，8.33(1H，s)，8.59(1H，d，J＝5.11Hz)

Example 23

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

Light yellow powder

¹H-NMR(DMSO-d₆)δppm：7.81(1H，d，J＝5.61Hz)，7.90(1H，s)，8.31(1H，dd，J＝0.99，5.11Hz)，8.54(1H，s)，8.66(1H，d，H＝5.11Hz)，8.92(1H，d，H＝5.11Hz)

Example 24

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

White powder

¹H-NMR(DMSO-d₆)δppm：2.57(3H，s)，3.78(3H，s)，5.29(2H，s)，7.00(2H，d，J＝8.74Hz)，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，5.11Hz)

Example 25

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

White powder

¹H-NMR(DMSO-d₆)δppm：0.97(6H，d，J＝6.60Hz)，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＝4.78Hz)，14.80(1H，brs)

Example 26

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

Brown powder

¹H-NMR(DMSO-d₆)δppm：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＝5.28Hz)，

Example 27

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

Light brown powder

¹H-NMR(DMSO-d₆)δppm：7.80(1H，d，J＝5.28Hz)，7.89(1H，s)，8.02(1H，d，J＝5.11Hz)，8.05(1H，s)，8.59(1H，d，J＝5.11Hz)，8.64(1H，d，J＝5.11Hz)

Example 28

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

Light brown crystal

¹H-NMR(DMSO-d₆)δppm：2.57(3H，s)，3.76(3H，s)，5.12(2H，d，J＝1.81Hz)，7.52(1H，d，J＝8.41Hz)，7.79(1H，d，J＝5.61Hz)，7.88(1H，s)，8.36(1H，d，J＝8.25Hz)，8.37(1H，s)，8.60(1H，d，J＝5.11Hz)

Example 29

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

White powder

¹H-NMR(DMSO-d₆)δppm：2.79(3H，s)，3.59～3.72(8H，m)，3.85(2H，m)，4.40(2H，m)，7.53(1H，d，J＝8.91Hz)，8.31(1H，d，J＝5.28Hz)，8.38(1H，dd，J＝1.98，8.91Hz)，8.43(2H，brs)，8.83(1H，d，J＝6.10Hz)

Example 30

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

Yellow powder

¹H-NMR(DMSO-d₆)δppm：1.06(6H，d，J＝6.60Hz)，1.08(6H，d，J＝5.61Hz)，1.99(1H，m)，2.19(1H，m)，3.14(2H，d，J＝6.76Hz)，3.94(2H，d，J＝6.43Hz)，7.17(1H，d，J＝8.91Hz)，7.60(1H，d，J＝4.45Hz)，7.85(1H，s)，8.22(1H，dd，J＝1.98，8.74Hz)，8.53(1H，s)，8.54(1H，d，J＝5.11Hz)

Example 31

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

White powder

¹H-NMR(DMSO-d₆)δppm：2.65(3H，s)，3.51(3H，s)，3.87(2H，t，J＝4.70Hz)，4.33(2H，t，J＝4.62Hz)，7.16(1H，d，J＝8.58Hz)，7.82(1H， brs)，7.91(1H，s)，8.28(1H，dd，J＝2.15，8.58Hz)，8.31(1H，s)，8.56(1H，d，J＝5.28Hz)

Example 32

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

White powder

¹H-NMR(DMSO-d₆)δppm：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＝8.91Hz)，7.78(1H，d，J＝5.28Hz)，7.89(1H，s)，8.19(1H，dd，J＝2.31，8.74Hz)，8.26(1H，d，J＝2.14Hz)，8.63(1H，d，J＝5.11Hz)

Example 33

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

White powder

¹H-NMR(DMSO-d₆)δppm：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＝8.91Hz)，8.33(1H，d，J＝6.02Hz)，8.39(1H，d，J＝8.91Hz)，8.44(2H，s)，8.84(1H，d，J＝6.02Hz)

Example 34

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

Yellow crystals

¹H-NMR(DMSO-d₆)δppm：1.01(6H，d，J＝6.76Hz)，2.08(1H，m)，3.92(3H，s)，4.03(2H，d，J＝6.43Hz)，7.40(1H，s)，7.55(1H，d，J＝8.74Hz)，7.61(1H，d，J＝5.77Hz)，8.30(1H，dd，J＝2.15，8.75Hz)，8.32(1H，d，J＝5.11Hz)，8.53(1H，d，J＝1.98Hz)，14.88(1H，brs)

Example 35

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

Yellow powder

¹H-NMR(DMSO-d₆)δppm：8.01(2H，dd，J＝1.98，5.36Hz)，8.29(1H，dd，J＝1.65，5.11Hz)，8.40(2H，dd，J＝1.98，5.36Hz)，8.52(1H，d，J＝1.65Hz)，8.92(1H，dd，J＝1.65，5.11Hz)

Example 36

3- (2-cyano-4-pyridinyl) -5- [ 3-cyano-4- { (2-methoxyethoxy) ethoxy } phenyl-1, 2, 4-triazole

Light yellow powder

¹H-NMR(DMSO-d₆)δppm：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＝7.24Hz)，8.24～8.28(3H，m)，8.45(1H，s)，8.81(1H，d，J＝5.28Hz)，

Example 37

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

Pale yellow crystals

¹H-NMR(DMSO-d₆)δppm：8.02(1H，d，J＝5.11Hz)，8.08(1H，s)，8.31(1H，dd，J＝1.65，5.11Hz)，8.55(1H，s)，8.63(2H，d，J＝5.11Hz)，8.94(1H，d，J＝5.11Hz)

Example 38

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

Light yellow powder

¹H-NMR(DMSO-d₆)δppm：7.55(3H，m)，7.98(1H，d，J＝4.95Hz)，8.17(2H，m)，8.35(1H，d，J＝4.95Hz)，8.58(2H，m)，8.88(2H，d，J＝4.95Hz)，8.93(1H，d，J＝4.95Hz)

Example 39

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

1) Preparation of N2-tert-butoxycarbonylisoniazid-1-oxide

To 39.0g of isonicotinic acid N-oxide was added 585ml of methylene chloride, followed by addition of 34.0g of triethylamine, and the mixture was cooled to-15 ℃ under an argon atmosphere. To this reaction solution, a solution of ethyl chlorocarbonate (33.5 g) in 117ml of methylene chloride was added dropwise, followed by stirring at-5 to-10 ℃ for 1 hour. Then, a solution of 44.4g of tert-butyl carbazate and 117ml of methylene chloride was added dropwise thereto, and the mixture was stirred while slowly raising the temperature to room temperature. After 15 hours, the precipitated crystals were collected by filtration, washed with methylene chloride, and dried by a vacuum pump to obtain 49.7g of white crystals.

¹H-NMR(DMSO-d₆)δppm：1.42(9H，s)，7.82(2H，d，J＝7.09Hz)，8.33(2H，d，J＝7.09Hz)，9.02(1H，s)，10.44(1H，s)

Preparation of 2-cyanoisoniazid 11/2 p-toluenesulfonate

To 30.4g of the crystal obtained in the above-mentioned step 1), 228ml of dioxane was added, and 13.1g of trimethylsilonitrile and 38.8g of N, N-dimethylcarbamoyl chloride were added, followed by stirring at 60 ℃ for 5 hours under argon atmosphere. The solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate, washed with a 1.5M aqueous sodium carbonate solution and saturated brine in this order, and then dried over magnesium sulfate. After magnesium sulfate was filtered off, the solvent was distilled off under reduced pressure, and ethyl acetate and 68.5g of p-toluenesulfonic acid monohydrate were added to the residue, followed by stirring at room temperature for 22 hours. The precipitated crystals were collected by filtration, washed with ethyl acetate and dried by vacuum pump to obtain 40.3g of white crystals 2).

¹H-NMR(DMSO-d₆)δppm：2.28(4.5H，s)，7.12(3H，dd，J＝7.92，0.66Hz)，7.48(3H，dd，J＝7.92，0.66Hz)，8.10(1H，dd，J＝5.11，1.81Hz)8.39(1H，dd，J＝1.81，0.33Hz)，8.99(1H，dd，J＝5.11，0.33Hz)

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

9.98g of 4-cyanopyridine was dissolved in 250ml of methanol, and 7.77g of sodium methoxide was added thereto, followed by stirring at room temperature for 1 hour. Then, 40.3g of the crystals obtained in 2) were added thereto, and the mixture was refluxed for 24 hours. After completion of the reaction, the precipitated crystals were collected by filtration, washed with methanol, and dried by a vacuum pump to obtain 16.3g of yellow crystals.

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

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

To 3.0g of the crystals obtained in the above step 3), 45ml of ethanol and 15ml of 1-methyl-2-pyrrolidone were added, and the mixture was stirred at 80 ℃ for 19 hours. The crystals were filtered off, washed with a mixture of ethanol and 1-methyl-2-pyrrolidone (3: 1) in this order and ethanol, and then dried by a vacuum pump to obtain 2.71g of yellow crystals.

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

5ml of ethanol and 30ml of water were added to 2.48g of the crystal obtained in the above step 4), and 3.8g of p-toluenesulfonic acid monohydrate was further added, followed by stirring at room temperature for 5 hours. The precipitated crystals were collected by filtration, washed with a mixture of ethanol and water (1: 6), water and ethanol in this order, and then dried by a vacuum pump to obtain 3.5g of white crystals.

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

4) Preparation of the target Compound

To 3.36g of the crystals obtained in 5) were added 17ml of ethanol and 17ml of water, and the mixture was stirred at room temperature for 30 minutes. Further, sodium hydrogencarbonate solution (a solution of sodium hydrogencarbonate 0.74g and water 17 ml) was added and the mixture was stirred at room temperature for 2 hours. After the crystals were collected by filtration, they were washed with water and ethanol in this order and dried by a vacuum pump to obtain 1.89g of the objective compound as pale yellow crystals.

Examples of the experiments

Method for measuring effect of reducing serum uric acid in vivo

Male Wistar rats (1 group, 4 rats) of 7 weeks old were selected, and a suspension of the test substance in a 0.5% aqueous solution of Methyl Cellulose (MC) was forcibly administered orally through a gastric catheter at a dose of 0.3mg/5ml/kg [ 1mg/5ml/kg of Compound 44 of Journal of Medicinal Chemistry (1975) of example 17 and the comparative example ]. Blood was collected from the orbital vein 6 hours after administration of the test substance, and the blood was left at room temperature for 1 hour, centrifuged at 2000 Xg for 10 minutes, and serum was collected. The uric acid value in serum is measured by using a uric acid measuring kit (Wako pure chemical industries, Ltd., phosphotungstic acid method), and the serum uric acid reduction rate is calculated by the following calculation formula.

Equation 1

Serum uric acid reduction rate (%)

(1-mean serum uric acid value of test substance administered group/mean serum uric acid value of MC administered group). times.100

TABLE 1

Reduction rate of serum uric acid

Example 166.5%

Example 262.3%

Example 340.0%

Example 443.9%

Example 539.9%

Example 640.6%

Example 742.7%

Example 832.5%

Example 935.7%

Example 1041.6%

Example 1141.6%

Example 1251.1%

Example 1346.8%

Example 1443.0%

Example 1541.2%

Example 1636.1%

TABLE 2

Reduction rate of serum uric acid

Example 1740.6%

Example 2067.5%

Example 2152.9%

Example 2232.6%

Example 2341.1%

Example 2438.3%

Example 2547.2%

Example 2637.9%

Example 2732.9%

Example 2835.3%

Example 2940.7%

Example 3136.5%

Example 3252.0%

Example 3344.7%

Example 3546.8%

Example 3733.6%

Comparative example of Activity

Example 3 Compound of Japanese examined patent publication No. 49-46622-11.1%

26.1% of the compound of Ex.2 of Japanese patent publication No. Sho 50-24315

Example 1 of Japanese patent publication Sho-50-24315 Compound-0.4%

Journal of pharmaceutical chemistry (Journal of

Medicinal Chemistry)(Vol.18，

Compounds 44-7.7% of NO.9, 1975)

Industrial applicability

According to the present invention, a 1,2, 4-triazole compound having a high xanthine oxidase inhibitory activity and being effective in treating hyperuricemia with uric acid production-type and gout caused by hyperuricemia can be obtained by selecting a compound represented by the general formula (1).

Claims (10)

1. 3- (4-isobutoxy-3-nitrophenyl) -5- (2-methyl-4-pyridyl) -1, 2, 4-triazole, or a salt thereof.
2. 3- (3-cyano-4-isobutoxyphenyl) -5- (4-pyridyl) -1, 2, 4-triazole or a salt thereof.
3. 3.5- (2-cyano-4-pyridyl) -3- (4-pyridyl) -1, 2, 4-triazole or a salt thereof.
4. 3- (2-methyl-4-pyridyl) -5- (3-cyano-4-isobutoxyphenyl) -1, 2, 4-triazole or a salt thereof.
5. 3- (2-methyl-4-pyridyl) -5- (3-nitro-4-methoxyphenyl) -1, 2, 4-triazole or a salt thereof.
6. 3- (2-methyl-4-pyridyl) -5- [ 3-cyano-4- { (2-methoxyethoxy) ethoxy } phenyl ] -1, 2, 4-triazole or a salt thereof.
7. 7. A pharmaceutical comprising the 1,2, 4-triazole compound or salt thereof according to any one of claims 1 to 6 as an active ingredient.
8. 8. Use of the 1,2, 4-triazole compound or a salt thereof according to any one of claims 1 to 6 for the preparation of a medicament for inhibiting xanthine oxidase.
9. 9. Use of the 1,2, 4-triazole compound or a salt thereof according to any one of claims 1 to 6 for the preparation of a therapeutic agent for gout.
10. 10. Use of the 1,2, 4-triazole compound or a salt thereof according to any one of claims 1 to 6 for producing a therapeutic agent for hyperuricemia.