JP3399559B2 - 2-phenyl heterocyclic compound - Google Patents

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a 2-phenylazole derivative or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing them, and their medical use.

[0002]

BACKGROUND OF THE INVENTION Gout is a basic disease of hyperuricemia, which causes acute arthritis, gouty nodules, uroliths, renal interstitium and vascular lesions caused by urate deposition. The main symptom is peculiar to human beings, and it is a disease that commonly occurs in adult males.

For the treatment of gout, colchicine and a non-steroidal anti-inflammatory drug are used for the onset of acute arthritis, and after the remission of the attack, ameliorating therapy for hyperuricemia is performed. The therapeutic agents for hyperuricemia are roughly classified into uric acid excretion enhancers and uric acid synthesis inhibitors, and can be appropriately selected depending on the mode and degree of the disease. Examples of the former include probenecid and benzbromarone. On the other hand, as the latter, allopurinol, which is a structural isomer of hypoxanthine, has been used for a long time.
This allopurinol is xanthine oxidase (XO
It inhibits D), suppresses the production of uric acid from hypoxanthine and xanthine, and lowers the uric acid level in blood. This type of enzyme inhibitor has been extensively studied centering on xanthine derivatives, but at present, there is no drug that is satisfactory in terms of efficacy and safety, and only allopurinol is currently used for treatment. Further, JP-A-57-85379,
JP-A-59-95272 describes that isothiazole and pyrazole derivatives inhibit xanthine oxidase and lower serum uric acid levels in mammals, but they are not currently clinically applied as pharmaceuticals.

On the other hand, European Patent No. 419944 (1
991) describes 2- (3-cyano, or 3-nitrophenyl) oxazole-4,5-dicarboxylic acid, and also Journal of Chemical Society Perkin Trans.
I, 1975, p. 1326, 1-isopropoxy-2-
(3-Nitrophenyl) imidazole-4,5-dicarboxylic acid is described. However, the structures of these compounds are completely different from the 2-phenylazole derivative of the present invention in the presence or absence of the carboxyl group at the 4-position. In addition, the XOD inhibitory action of these compounds,
There is no mention of the uric acid-lowering effect and no suggestion of the compound of the present invention.

By the way, a 2-phenylthiazole derivative (WO92 / 09279) is known as a compound having an XOD inhibitory action and a uric acid lowering action, whereas the 2-phenylazole derivative of the present invention has a mother nucleus thereof. The heterocycles in are completely different.

In view of the above-mentioned conventional techniques, the inventors of the present invention have reached the present invention as a result of extensive studies to provide a compound having a novel mother nucleus and having an XOD inhibitory action and the like.

[0007]

That is, the present invention provides the following formula (I):

[0008]

[Chemical 2]

[In the formula, A represents an oxygen atom or NR (wherein R represents a hydrogen atom or a C _1-4 alkyl group). R ¹ represents a nitro group or a cyano group, R ² represents a hydrogen atom; an unsubstituted or substituted phenylthio group; a hydroxy group; an unsubstituted or substituted C _1-6 alkoxy group; or NR′R ″ (here And R ′ and R ″ represent an unsubstituted or substituted C _1-6 alkyl group, or R ′ and R ″ together with the nitrogen atom to which they are bonded are a 5- to 7-membered heterocyclic ring. Is an atomic group forming a group) or R ¹ represents a hydrogen atom and R ² represents CO.
It represents a group represented by R ³ (wherein R ³ is an unsubstituted or substituted aryl group). X represents a hydroxy group or an unsubstituted or substituted C _1-6 alkoxy group, and Y represents a hydrogen atom or a C _1-4 alkyl group. ]
2-phenylazole derivative or a pharmaceutically acceptable salt thereof, a pharmaceutical composition comprising the 2-phenylazole derivative or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, and gout or hyperuric acid A pharmaceutical preparation comprising a 2-phenylazole derivative or a pharmaceutically acceptable salt thereof in an amount effective for treating blood.

In the 2-phenylazole derivative represented by the above formula (I) of the present invention, A is an oxygen atom or NR.
(Here, R represents a hydrogen atom or a C _1-4 alkyl group. Examples of the C _1-4 alkyl group include a methyl group, an ethyl group, a propyl group, and an isopropyl group.

R ¹ and R ² represent groups represented by the following combinations. First, R ¹ represents a nitro group or a cyano group, R ² is a hydrogen atom; an unsubstituted or substituted phenylthio group; a hydroxy group; an unsubstituted or substituted C
_1-6 alkoxy groups; or NR'R "(where R ',
R ″ represents an unsubstituted or substituted C _1-6 alkyl group, or R ′ and R ″ together with the nitrogen atom to which they are attached form an atom having a 5- to 7-membered heterocycle. Represents a group).

Examples of the C _1-6 alkoxy group include methoxy group, ethoxy group, propyloxy group, butyloxy group, isopropyloxy group, 2,2-dimethylpropyloxy group, pentyloxy group, isopentyloxy group. , Neopentyloxy group and hexyloxy group.

Examples of the C _1-6 alkyl group include a methyl group, an ethyl group, a propyl group, an isopropyl group and a butyl group.

Examples of the 5- to 7-membered heterocyclic ring formed by R'and R "together with the nitrogen atom to which they are bound include a pyrrolidinyl group, a piperidinyl group, a homopiperidinyl group and a morpholino group.

[0015] As here substituent when the phenylthio group of R ^2, an alkoxy group of C _1-6, alkyl groups C _1-6 substituted the substituent in the chain moiety or cyclic moiety, C _Any of _1-2 alkyl group, halogenated alkyl group, alkyloxy group, hydroxyl group, mono- or di-substituted alkylamino group, amino group, nitro group, halogen atom (for example, fluorine atom, chlorine atom, bromine atom, iodine atom) It is. Of these, a halogen atom, a methyl group, an ethyl group and the like are preferable.

Preferred specific examples of R ² are hydrogen atom, phenylthio group, 4-chlorophenylthio group, hydroxy group, methoxy group, ethoxy group, propyloxy group, butyloxy group, isopropyloxy group and 2,2-
Examples thereof include a dimethylpropyloxy group, a hexyloxy group, a dimethylamino group, a diethylamino group, a pyrrolidinyl group, a piperidinyl group and a morpholino group.

Next, R ¹ represents a hydrogen atom, and R ² represents COR.
³ represents a group represented by ³ (wherein R ³ is an unsubstituted or substituted aryl group). Examples of the aryl group include a phenyl group, a thienyl group, a pyridyl group, and a furyl group.

When the aryl group is substituted, the substituent is any of methyl group, ethyl group, fluoro group, chloro group, methoxy group and N, N-dimethylamino group.

Preferable specific examples of R ² include benzoyl group, 4-methylbenzoyl group, 4-chlorobenzoyl group, 4-fluorobenzoyl group, 4-methoxybenzoyl group, 4-N, N-dimethylamino group. Etc.

[0020] While X in the above formula (I) represents a hydroxy group or an unsubstituted or substituted alkoxy group C _1-6, the definition of such unsubstituted or substituted alkoxy group C _1-6, it Including the case where
It is the same as the definition for R ² . Specific preferred examples of X in the present invention include a hydroxy group, a methoxy group, an ethoxy group, a propyloxy group, and an isopropyloxy group.

Y represents a hydrogen atom or a C _1-6 alkyl group, and the definition of such a C _1-6 alkyl group is the same as the definition in R above. Specific preferred examples of Y in the present invention include a hydrogen atom and a methyl group.

In the present invention, when X is a hydroxy group, it forms a carboxyl group together with a carbonyl group to form a pharmaceutically acceptable salt with a non-toxic cation such as sodium and potassium as described below. can do.

The 2-aryl azole derivative represented by the above formula (I) is shown in Journal of Chemical Society (J. Chem. Soc) 1953 edition, page 93,
It can be synthesized by the method of Cornforth et al.

Specifically, first, a substituted benzoic acid,
Reaction with 2-chloroacyl acetic acid ester or 2-chloroformyl acetic acid ester gives (2-arylcarbonyloxy) acyl acetic acid ester or (2-arylcarbonyloxy) formyl acetic acid ester. Then, the reaction product is heated in acetic acid in the presence of ammonium acetate to obtain a mixture of 2-aryl-5-oxazolecarboxylic acid ester and 2-aryl-5-imidazolecarboxylic acid ester. Both compounds are separated from the obtained mixture by an appropriate method to obtain the 2-phenylazole derivative of the present invention represented by the above formula (I). Further, if necessary, an imidazole derivative is reacted with an alkyl halide under an organic or inorganic base condition to obtain a 1-alkyl-2-aryl-5-imidazolecarboxylic acid ester in the case where A is NR in the present invention. You can also The 2-phenylazole derivative of the present invention thus obtained can be derivatized into a carboxylic acid by hydrolysis, if necessary.

The 2-phenylazolecarboxylic acid derivative thus obtained is optionally converted into a salt with a pharmaceutically acceptable non-toxic cation. Examples of this kind of cation include alkali metal cations such as Na and K, Mg and C.
In addition to the alkaline earth metal cations such as a, metal cations such as Al and Zn that are commonly used, or organic bases such as ammonia, triethylamine, pyridine and the like can be mentioned. Further, the compound represented by the above formula (I) is
When it has an amino group in the molecule, it can be converted into a corresponding acid addition salt. Examples of the acid include mineral acids such as hydrochloric acid, sulfuric acid and nitric acid, and pharmaceutically acceptable organic groups such as acetic acid, benzoic acid, fumaric acid, maleic acid, methanesulfonic acid and toluenesulfonic acid.

Further, the compound obtained in the present invention can be made into a pharmaceutical composition by a known method using, for example, a pharmaceutically acceptable carrier of an appropriate excipient. Then, this pharmaceutical composition is used to provide an oral preparation such as a soft capsule, a hard capsule, a tablet, a granule, a powder, a suspension, a liquid, and a syrup, an injection, a suppository, or an external preparation. Such excipients include vegetable oils (eg corn oil, cottonseed oil, coconut oil, almond oil, peanut oil, olive oil, etc.), oily esters such as medium-chain fatty acid glyceride oil, mineral oil, tricaprylin, glycerin esters such as triacetin, Alcohols such as ethanol, physiological saline,
Propylene glycol, polyethylene glycol, petrolatum, animal fats and oils, cellulose derivatives (crystalline cellulose,
(Hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), polyvinylpyrrolidone, dextrin, lactose, mannitol, sorbitol, starch and the like.

The dose of the active ingredient is usually 1 to 500 mg.
/ Day / person, preferably 10 to 300 mg / day / person, and it is preferable to formulate so as to satisfy such conditions.

[0028]

EXAMPLES The present invention will now be described in detail with reference to examples. Note that ¹ HNMR of hydrogen of a carboxyl group may not be observed.

Example 1 2- (4-isopropoxy-3-nitrophenyl) -4
-Methyl-5-oxazolecarboxylic acid 4-isopropoxy-3-nitrobenzoic acid ( 1 ) (1.
0 g, 4.4 mmol) and ethyl 2-chloroacetoacetate (740 mg, 4.6 mmol) in DMF (10 ml).
Sodium hydride (60%, 180 mg, 4.
6 mmol) was added, and the mixture was heated to 50 ° C. and stirred for 2 hours.

After cooling, the mixture was washed with water, extracted with ethyl acetate, dried over magnesium sulfate and concentrated. The obtained residue was purified by silica gel chromatography (hexane: ethyl acetate = 2: 1) to obtain 1.08 g of ethyl 2- (4-isopropoxy-3-nitrobenzoyloxy) acetoacetate (3 0.1 mmol, yield 69%).

This compound (1.0 g, 2.8 mmol)
And ammonium acetate (1.3 g), acetic acid (6.0 ml)
The mixture was heated at 105 ° C. for 2 hours. After cooling, the mixture was washed with water, extracted with ethyl acetate, dried over magnesium sulfate and concentrated. The obtained residue was separated and purified by silica gel chromatography, and ethyl 2- (4-isopropoxy-3-nitrophenyl) -4-methyl-5-oxazolecarboxylate ( 2 ) (200 mg, 0.6 mmol, 21%). )
And ethyl 2- (4-isopropoxy-3-nitrophenyl) -4-methyl-5-imidazolecarboxylate ( 3 ) (510 mg, 1.5 mmol, 54%) was obtained.

2 (120 mg, 0.3
6 mmol) was heated to 80 ° C. in a mixed solvent of ethanol (3 ml) and 2N aqueous sodium hydroxide solution (2 ml), and stirred for 1 hour. After cooling, the mixture was neutralized with an aqueous hydrochloric acid solution, the precipitated crystals were filtered, dried, and recrystallized from a methanol-ethanol system to give the desired title compound (99 mg,
0.33 mmol) was obtained (yield 90%). mp226-229 ° C. ¹ H-NMR (DMSO-d ₆ ) δ 1.36 (d, J = 6 Hz, 6 H), 2.45 (s, 3)
H), 4.94 (m, J = 6 Hz, 1H), 7.55
(D, J = 9 Hz, 1H), 8.19 (dd, J = 2H
z, 9 Hz, 1 H), 8.37 (d, J = 2 Hz, 1
H)

Example 2 2- (4-isopropoxy-3-nitrophenyl)-
1,4-Dimethyl-5-imidazolecarboxylic acid 3 obtained in Example 1 (500 mg, 1.5 mmol)
And methyl iodide (240 mg, 1.65 mmol) and potassium carbonate (250 mg, 1.8 mmol) 5 m
The 1DMF suspension was stirred at room temperature for 2 hours. After washing with water, the mixture was extracted with ethyl acetate, dried over magnesium sulfate and concentrated. The obtained residue was separated and purified by silica gel chromatography to give ethyl 2- (4-isopropoxy-3-nitrophenyl) -1,4-dimethyl-5-imidazolecarboxylate (240 mg, 0.69 mmol). (Yield 46%).

This compound (240 mg, 0.69 mmo
l) was heated to 80 ° C. in a mixed solvent of ethanol (4 ml) and 2N aqueous sodium hydroxide solution (4 ml) and stirred for 1 hour. After cooling, the mixture was neutralized with an aqueous hydrochloric acid solution, the precipitated crystals were filtered, dried, and recrystallized from a methanol-chloroform system to obtain the desired title compound (yield 90.
%). mp207-215 ° C. ¹ H-NMR (DMSO-d ₆ ) δ 1.34 (d, J = 6 Hz, 6 H), 2.41 (s, 3)
H), 3.84 (s, 3H), 4.92 (m, J = 6H
z, 1H), 7.49 (d, J = 9Hz, 1H), 7.
89 (dd, J = 2 Hz, 9 Hz, 1 H), 8.09
(D, J = 2Hz, 1H)

Example 3 4-Methyl-2- (3-nitro-4-pyrrolidinylphene
Nyl) -5 -oxazolecarboxylic acid The title compound was obtained using 3-nitro-4-pyrrolidinylbenzoic acid instead of 1 used in Example 1 (yield 2
6%). mp233-237 ° C. ¹ H-NMR (DMSO-d ₆ ) δ 1.96 (sbr, 4H), 2.43 (s, 3H),
3.27 (sbr, 4H), 7.19 (d, J = 9H
z, 1H), 7.99 (dd, J = 2,9 Hz, 1
H), 8.27 (d, J = 2Hz, 1H)

Example 4 1,4-Dimethyl-2- (3-nitro-4-pyrrolidini)
Butylphenyl) -5 to 1 instead of using imidazole carboxylic acid Example 1 using 3-nitro-4-pyrrolidinyl acid instead of 2- (3-nitro-4-pyrrolidinylmethyl phenyl 3) - Ethyl 4-methyl-5-imidazolecarboxylate is obtained, further from Example 2
According to the above procedure, the title compound was obtained (total yield: 7%). mp192-196 ° C. ¹ H-NMR (DMSO-d ₆ ) δ 1.99 (sbr, 4H), 2.56 (s, 3H),
3.27 (sbr, 4H), 3.93 (s, 3H),
7.25 (d, J = 9 Hz, 1H), 7.81 (dd,
J = 2Hz, 9Hz, 1H), 8.19 (d, J = 2H
z, 1H)

Example 5 2- (4-isobutoxy-3-nitrophenyl) -4-
Methyl-5-oxazolecarboxylic acid 4-isobutoxy-3-instead of 1 used in Example 1
The title compound was obtained using nitrobenzoic acid (yield 1
5%). mp202-210 ° C ¹ H-NMR (DMSO-d ₆ ) δ 1.05 (d, J = 6 Hz, 6 H), 2.12 (m, J
= 6 Hz, 1H), 2.49 (s, 3H), 4.08
(D, J = 6 Hz, 2H), 7.57 (d, J = 9H
z, 1H), 8.26 (dd, J = 2Hz, 9Hz, 1
H), 8.46 (d, J = 2Hz, 1H)

Example 6 2- (4- (4-chlorophenylthio) -3-nitrophenyl
Instead of one used in Eniru) -4-methyl-5-imidazole-carboxylic acid Example 1 4- (using 4-chlorophenylthio) -3-nitrobenzoic acid in place of 3 2- (4- ( Ethyl 4-chlorophenylthio) -3-nitrophenyl) -4-methyl-5-imidazolecarboxylate was obtained, and the title compound was obtained by hydrolysis in a mixed solvent of ethanol and sodium hydroxide (total). Yield 8%). mp204 to 209 ° C. ¹ H-NMR (DMSO-d ₆ ) δ 2.50 (s, 3H), 7.02 (d, J = 9 Hz, 1)
H), 7.67-7.69 (m, 4H), 8.21 (d
d, J = 2 Hz, 9 Hz, 1 H), 8.95 (d, J =
2Hz, 1H)

Example 7 2- (4- (4-chlorophenylthio) -3-nitrophenyl
Phenyl) -1,4-dimethyl-5-imidazolecarbo
Instead of one used in phosphate Example 1 using 4- (4-chlorophenylthio) -3-nitrobenzoic acid instead of 2- (4- (4-chlorophenylthio 3) 3-nitrophenyl ) Ethyl 4-methyl-5-imidazolecarboxylate was obtained, and the title compound was further obtained according to Example 2 (total yield 5%). mp215-227 ° C. ¹ H-NMR (DMSO-d ₆ ) δ 2.40 (s, 3H), 3.87 (s, 3H), 6.9.
7 (d, J = 9 Hz, 1H), 7.62 (d, J = 9H
z, 2H), 7.68 (d, J = 9Hz, 2H), 7.
86 (dd, J = 2 Hz, 9 Hz, 1 H), 8.49
(D, J = 2Hz, 1H)

[Example 8] 2- (4-benzoylphenyl) -4-methyl-5-o
Xazole carboxylic acid The title compound was obtained by substituting 4-benzoylbenzoic acid for 1 used in Example 1 (total yield 21%). mp 243 to 244 ° C. ¹ H-NMR (DMSO-d ₆ ) δ 2.49 (s, 3H), 7.58 (t, J = 7.5H.
z, 2H), 7.70 (t, J = 7.5Hz, 1H),
7.78 (d, J = 7.5 Hz, 2H), 7.90
(D, J = 8.5 Hz, 2H), 8.19 (d, J =
8.5Hz, 2H)

Example 9 2- (4-benzoylphenyl) -4-methyl-5-i
Ethyl Midazole Carboxylate (4) 4-Benzoylbenzoic acid was used in place of 1 used in Example 1 and the title compound was obtained in place of 3 (total yield 15%). mp157-164 ° C. ¹ H-NMR (DMSO-d ₆ ) δ 1.35 (t, J = 7 Hz, 3 H), 2.67 (s, 3)
H), 4.35 (q, J = 7 Hz, 2H), 7.46
(T, J = 7 Hz, 2H), 7.59 (t, J = 7H
z, 1H), 7.72 (d, J = 7Hz, 2H), 7.
78 (d, J = 8 Hz, 2H), 8.34 (d, J = 8)
Hz, 2H)

Example 10 2- (4-benzoylphenyl) -1,4-dimethyl-
5-Imidazolecarboxylic acid The title compound was obtained according to Example 2 from 4 obtained in Example 9 (total yield 10%). mp 238 to 240 ° C. ¹ H-NMR (DMSO-d ₆ ) δ 2.45 (s, 3H), 3.90 (s, 3H), 7.5.
7 (t, J = 7.5 Hz, 2H), 7.69 (t, J =
7.5 Hz, 1 H), 7.79 (d, J = 7.5 Hz,
2H), 7.89 (s, 4H)

Example 11 2- (3-Cyano-4-hydroxyphenyl) -4-me
Ethyl tyl-5-oxazolecarboxylate (6) 4-hydroxybenzoic acid was used in place of 1 used in Example 1, 2- (4-hydroxyphenyl) -4-methyl-5-oxazole was used in place of 3. Ethyl carboxylate was obtained, and this compound (560 mg, 2.3 mm
hexamethylenetetramine (1.2 g, 8.
6 mmol) and trifluoroacetic acid (4 ml) were added, and 8
Heated at 5 ° C. for 30 hours. After cooling, it is washed with water, extracted with ethyl acetate, dried over magnesium sulfate, and purified by column chromatography to give 2- (3-formyl-4-).
Ethyl hydroxyphenyl) -4-methyl-5-oxazolecarboxylate was obtained (450 mg, 1.64 m).
mol, 72%). Furthermore, this compound (450 mg),
Hydroxylamine hydrochloride (130 mg, 1.9 mmo
l), sodium formate (180 mg, 2.6 mmol)
Was heated at 120 ° C. under reflux for 4 hours. After cooling, water was added and the resulting crystals were filtered, dried and recrystallized from methanol to obtain the title compound ( 6 ) (300 mg, 1.1 mmol, 69%). mp 214-217 ° C. ¹ H-NMR (DMSO-d ₆ ) δ 1.34 (t, J = 7 Hz, 3 H), 2.44 (s, 3)
H), 4.33 (q, J = 7 Hz, 2H), 7.18
(D, J = 9 Hz, 1H), 8.10 (dd, J = 2H
z, 1H), 8.14 (d, J = 2Hz, 1H)

Example 12 2- (3-Cyano-4-isobutoxyphenyl) -4-
Ethyl methyl-5- oxazolecarboxylate (7) 6 obtained in Example 11 (100 mg, 0.36 mmo
l), potassium carbonate (190 mg, 1.4 mmol),
DM of isobutyl bromide (200 mg, 1.4 mmol)
The F (1 ml) suspension was heated to 70 ° C. and stirred for 17 hours. After cooling, it was washed with water, extracted with ethyl acetate, dried over magnesium sulfate, and purified by column chromatography to obtain the title compound ( 7 ) (88 mg, 0.2).
7 mmol, 74%) mp 140-141 ° C. ¹ H-NMR (CDCl ₃ ) δ 1.09 (d, J = 7 Hz, 6 H), 1.42 (t, J
= 7 Hz, 3 H), 2.21 (m, J = 7 Hz, 1
H), 2.53 (s, 3H), 3.91 (d, J = 7H
z, 2H), 4.41 (q, J = 7Hz, 2H), 7.
04 (d, J = 9 Hz, 1H), 8.25 (dd, J =
2Hz, 9Hz, 1H), 8.33 (d, J = 2Hz,
1H)

Example 13 2- (3-Cyano-4-isobutoxyphenyl) -4-
Methyl-5- oxazolecarboxylic acid 7 obtained in Example 12 (80 mg, 0.23 mmo
l) was added to a mixed solvent of ethanol (1 ml) and 1N sodium hydroxide (0.4 ml), and the mixture was heated at 60 ° C. for 2 hours. The mixture was neutralized with aqueous hydrochloric acid, and the obtained crystals were filtered and dried to give the title compound (56 mg, 0.19 mmo)
1, 82%) mp 207 to 211 ° C. ¹ H-NMR (DMSO-d ₆ ) δ 1.04 (d, J = 7 Hz, 6 H), 2.12 (m, J
= 7 Hz, 1H), 2.44 (s, 3H), 4.01
(D, J = 7 Hz, 2H), 7.40 (d, J = 9H
z, 1H), 8.20-8.25 (m, 2H)

Example 14 2- (3-Cyano-4-hydroxyphenyl) -4-me
Ethyl tyl-5-oxazolecarboxylate 6 obtained in Example 11 (60 mg, 0.22 mmo
l) was added to a mixed solvent of ethanol (1 ml) and 1N sodium hydroxide (1 ml), and the mixture was heated at 50 ° C. for 3 hours. The mixture was neutralized with aqueous hydrochloric acid, and the obtained crystals were filtered and dried to give the title compound (40 mg, 0.17 mmo
1, 75%) mp 270 ° C. to decomp; ¹ H-NMR (DMSO-d ₆ ) δ 2.50 (s, 3H), 7.18 (d, J = 9 Hz, 1)
H), 8.09 (dd, J = 2Hz, 9Hz, 1H),
8.14 (d, J = 2Hz, 1H)

[Pharmacological Test] (1) Preparation of Test Compounds 2 of the present invention obtained in the above Examples as described in Table 1.
The phenylazole derivative was the test compound. After dissolving the test compound in dimethyl sulfoxide, 50m
An aqueous solution having a predetermined concentration was prepared by diluting with M phosphate buffer.

(2) Measuring method Xanthine oxidase (from buttermilk, Sigma
a Chemical Company) 3 ml of a pH 7.4 phosphate buffer solution containing 3 mU of xanthine 45 mmole and test compounds prepared at various concentrations and reacted at 37 ° C., and a Hitachi spectrophotometer U-3
ODat292nm based on uric acid production using 200
Was measured with time to obtain the initial reaction rate.

The inhibition rate was calculated by the following formula.

[0050]

[Equation 1]

The inhibition rate (%) was determined for each of the test compounds prepared in (1), and the IC ₅₀ value for xanthine oxidase (XOD) inhibition was calculated from the obtained rate. The results are summarized in Table 1.

[0052]

[Table 1]

[Formulation Example] A tablet having the following composition was produced.

[0054] The above Example compound, lactose and potato starch are mixed, this is evenly moistened with a 20% solution of polyvinylpyrrolidone in ethanol and passed through a 20 mesh screen,
It was dried at 45 ° C. and passed through 15 mesh again. The granules thus obtained were mixed with magnesium stearate and compressed into tablets.

Continuation of front page (51) Int.Cl. ⁷ identification code FI C07D 401/10 C07D 401/10 405/10 405/10 409/10 409/10 413/10 413/10 (72) Inventor Masahiro Tsuchmoto Tokyo 4-3, Asahigaoka, Tohino City, Tokyo Research Center, Teijin Limited (72) Inventor Yoshio Nagata 4-32, Asahigaoka, Tokyo, Hino City, Tokyo Research Center, Teijin Limited (72) Inventor Komoriya Keiji 4-3 Asahigaoka, Hino City, Tokyo Teijin Limited Tokyo Research Center

Claims (9)

(57) [Claims] 1. The following formula (I): [In the formula, A represents an oxygen atom or NR (wherein R represents a hydrogen atom or a C _1-4 alkyl group). R ¹ represents a nitro group or a cyano group, R ² is a hydrogen atom; an unsubstituted or substituted phenylthio group; a hydroxy group; an unsubstituted or substituted C _1-6 alkoxy group; or N
R'R "(wherein R ', R" represents an unsubstituted or substituted C _1-6 alkyl group, or R'and R "together with the nitrogen atom to which they are bonded are Is a group of atoms that forms a 7-membered heterocyclic ring) or
Alternatively, R ¹ represents a hydrogen atom and R ² represents a group represented by COR ³ (wherein R ³ is an unsubstituted or substituted aryl group). X represents a hydroxy group or an unsubstituted or substituted C _1-6 alkoxy group, and Y represents a hydrogen atom or a C _1-4 alkyl group. R ² is a phenylthio group, a C _1-6 alkoxy group, or NR′R ″
When the C _1-6 alkyl group of R ′ or R ″ is substituted, the substituent is a C _1-2 alkyl group or a halogenated alkyl group as a substituent in the chain portion or the cyclic portion thereof. , An alkyloxy group, a hydroxyl group, a mono- or di-substituted alkylamino group, an amino group, a nitro group, or a halogen atom.When the aryl group of R ³ of COR ³ is substituted, the substituent is methyl. A group, an ethyl group, a fluoro group, a chloro group, a methoxy group, an N, N-dimethylamino group, etc. When the C _1-6 alkoxy group of X is substituted, the substituent is As a substituent in the chain part or the cyclic part, C _1-2
Is an alkyl group, a halogenated alkyl group, an alkyloxy group, a hydroxyl group, a mono- or di-substituted alkylamino group, an amino group, a nitro group, or a halogen atom. ]
The 2-phenylazole derivative represented by or a pharmaceutically acceptable salt thereof. 2. R ¹ is a nitro group or a cyano group,
R ² is a hydrogen atom; unsubstituted or substituted phenylthio group; hydroxy group; unsubstituted or substituted C _1-6
Or an NR'R "(wherein R ', R"
Is a group represented by the formula (6), which together with the nitrogen atom to which they are attached, form a 5- to 7-membered heterocyclic ring.) The 2-phenylazole derivative according to claim 1, or a pharmaceutically acceptable derivative thereof. salt. 3. R ¹ is a nitro group or a cyano group,
R ¹ is an unsubstituted or substituted C _1-6 alkoxy group;
Or a group represented by NR'R "(wherein R'and R" are atoms which, together with the nitrogen atom to which they are bonded, form a 5- to 7-membered heterocyclic ring). 2-phenylazole derivative or a pharmaceutically acceptable salt thereof. 4. R ¹ is a hydrogen atom and R ² is COR.
The 2-phenylazole derivative according to claim 1 or a pharmaceutically acceptable salt thereof, which is ³ (wherein R ³ is an unsubstituted or substituted aryl group). 5. The 2-phenylazole derivative or the pharmaceutically acceptable salt thereof according to claim 4, wherein R ² is COR ³ (wherein R ³ is a phenyl group). 6. The 2-phenylazole derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein A is an oxygen atom. 7. A 2-phenylazole derivative or a pharmaceutically acceptable derivative thereof according to any one of claims 1 to 5, wherein A is NR (wherein R is the same as defined in the above formula (I)). salt. 8. A pharmaceutical composition for gout or hyperuricemia comprising the 2-phenylazole derivative according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 9. A pharmaceutical preparation for gout or hyperuricemia comprising the 2-phenylazole derivative according to claim 1 or a pharmaceutically acceptable salt thereof in an amount effective for the treatment of gout or hyperuricemia.