JP2002105067A - 2-phenylthiazone derivative and medicine composition comprising the same as active ingredient - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new high-quality xathine oxidase inhibitor. SOLUTION: This 2-phenylthiazole derivative is represented by formula (1) (R is a hydrogen atom, an isobutyl group substituted with a hydroxy group or a n-propyl group substituted with a carboxy group). This therapeutic agent for gout, hyperuricemia or diseases following ischemia-reperfusion disorder of the organ comprises the 2-phenylthiazole derivative represented by formula (1) or its pharmaceutically acceptable salt as an active ingredient.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD OF THE INVENTION

The present invention relates to a pharmaceutical composition for treating gout, hyperuricemia, and diseases associated with ischemia-reperfusion injury of organs, which comprises a novel 2-phenylthiazole derivative or a pharmaceutically acceptable salt thereof as an active ingredient. About things.

[0002]

[Prior art]

Gout is a disease whose underlying condition is hyperuricemia, and whose main symptoms are acute arthritis due to precipitation of urate, gouty nodules, urolithiasis, interstitial kidney, and vascular lesions. Therapeutic agents include uric acid excretion enhancers and uric acid synthesis inhibitors,
In the latter, allopurinol has been used for a long time. Allopurinol is an inhibitor of xanthine oxidase which catalyzes the production of hypoxanthine and uric acid from xanthine, and is known to suppress uric acid production and lower uric acid level in blood. Recently, it has been discovered that a 2-arylthiazole derivative has a strong xanthine oxidase inhibitory activity, and it has been disclosed that it is effective against gout and hyperuricemia (WO92 / 09279). .

On the other hand, in various organs such as the heart, a large amount of active oxygen is generated during ischemia-reperfusion, and it is becoming clear that this is one of the factors that induce various diseases. . During this ischemia-reperfusion, xanthine oxidase converted from xanthine dehydrogenase metabolizes xanthine and hypoxanthine to uric acid using oxygen as an electron acceptor. At this time, a large amount of active oxygen (oxygen anion radical) is generated as a by-product, which causes tissue damage and contributes to ischemia-reperfusion injury. Heretofore, it has been known that xanthine oxidase inhibitors such as allopurinol and the above-mentioned 2-arylthiazole derivatives have a suppressing effect on organ damage due to ischemia-reperfusion as a substance that suppresses the generation of active oxygen. (WO96 / 32111).

[0004]

[Problems to be solved by the invention]

An object of the present invention is to provide a novel and highly active xanthine oxidase inhibitor.

[0005]

[Means for Solving the Problems]

The present inventors have conducted intensive studies for the above purpose, and as a result, have found that a 2-phenylthiazole derivative represented by the following formula (1) has a strong xanthine oxidase inhibitory activity, and completed the present invention. That is, the present invention is a 2-phenylthiazole derivative represented by the following formula (1).

[0006]

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(Wherein, R represents a hydrogen atom, an isobutyl group substituted with a hydroxyl group, or a normal propyl group substituted with a carboxy group.) The present invention is represented by the above formula (1). A pharmaceutical composition comprising a 2-phenylthiazole derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

[0008] The present invention further comprises a 2-phenylthiazole derivative represented by the above formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
It is a therapeutic agent for gout, hyperuricemia, or diseases associated with ischemia-reperfusion injury of organs.

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION

Preferred examples of the 2-phenylthiazole derivative represented by the formula (1) include (R) -2- (3-cyano-4- (3-hydroxy-2).
-Methylpropyloxy) phenyl) -4-methyl-5-thiazolecarboxylic acid (A-1) (S) -2- (3-cyano-4- (3-hydroxy-2)
-Methylpropyloxy) phenyl) -4-methyl-5-thiazolecarboxylic acid (A-2) 2- (3-cyano-4- (2-hydroxy-2-methylpropyloxy) phenyl) -4-methyl- 5-thiazolecarboxylic acid (B) 2- (3-cyano-4-hydroxyphenyl) -4-methyl-5-thiazolecarboxylate (C) 2- (3-cyano-4- (2-carboxypropyloxy) phenyl ) -4-Methyl-5-thiazolecarboxylic acid (D) and the like.

The compound represented by the formula (1) is synthesized by a method shown in the following scheme. The common intermediate in the scheme is synthesized according to the method described in JP-A-10-45733.

[0011]

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The compound represented by the formula (1) may form a salt with a pharmaceutically acceptable cation. The cation used here is N
Metal ions such as a, Ca, and K; and organic bases such as ammonia, triethylamine, and pyridine.

Further, the compound represented by the formula (1) can be prepared by a known method using an appropriate excipient, etc., into an oral preparation such as a soft capsule, a hard capsule, a tablet and a syrup, and an injection. Or as an external preparation.

Examples of such excipients include vegetable oils (eg, corn oil, cottonseed oil, coconut oil, almond oil, peanut oil, etc.), oily esters such as medium-chain fatty acid glycerides, mineral oils, petrolatum, animal oils and fats, and cellulose derivatives (crystals). Cellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose), polyvinylpyrrolidone, dextrin, lactose, mannitol, sorbitol, starch and the like.

The dose of the active ingredient is usually 0.1-300 mg / kg / kg.
The dose is usually about 1-3 times / day.

[0016]

【Example】

All of the compounds described below are described in International Publication WO92 / 0.
9279 and Japanese Patent Application Laid-Open No. 10-45733.

Example 1 (R) -2- (3-cyano-4- (3-hydroxy-2)
-Methylpropyloxy ) phenyl) -4-methyl-5-thiazolecarboxylic acid
(A-1) and (S ) -2- (3-cyano-4- (3-hydroxy-2-me)
Chill propyloxy) off Eniru) -4-methyl-5-thiazolecarboxylic acid (A
-2) Synthesis ¹ H-NMR (d ₆ -DMSO, δ ppm) 1.01 (d, J = 6.8 Hz, 3H) 1.95-2.15 (m, 1H) 2.66 (s, 3H) ) 3.47 (d, J = 6.2 Hz, 2H) 4.0-4.25 (m, 2H) 7.35 (d, J = 8.8 Hz, 1H) 8.19 (d, J = 2) 0.4 & 8.8 Hz, 1H) 8.25 (d, J = 2.2 Hz, 1H) IR (KBr, cm ⁻¹ ) 2232, 1692, 1605, 1435, 1300,
1271

Example 2 2- (3-cyano-4- (2-hydroxy-2-methyl)
Propyloxy) a phenyl) -4-methyl-5-thiazolecarboxylic acid (B)
Synthetic ¹ H-NMR (d ₆ -DMSO, δ ppm) 1.27 (s, 6H) 2.66 (s, 3H) 3.97 (s, 2H) 7.36 (d, J = 9.0 Hz, 1H) ) 8.18 (d, J = 2.4 & 8.8 Hz, 1H) 8.24 (d, J = 2.4 Hz, 1H) IR (KBr, cm ⁻¹ ) 3526, 2244, 1680, 1610, 1512,
1381, 1304, 1 289

Example 3 2- (3-cyano-4-hydroxyphenyl) -4-me
Synthesis _{^{1 H-NMR (d 6 -DMSO}} , δppm) chill -5 Chiazoruka carboxylic acid (C) 2.64 (s, 3H ) 7.12 (d, J = 8.8Hz, 1H) 8.06 ( dd, J = 2.4 & 8.8 Hz, 1H) 8.15 (d, J = 2.2 Hz, 1H) IR (KBr, cm ⁻¹ ) 2238, 1688, 1609, 1524, 1428,
1308

Example 4 2- (3-cyano-4- (2-carboxypropyloxy)
) Phenyl) -4- main Synthesis ¹ H-NMR (d ₆ -DMSO chill-5-thiazolecarboxylic acid (D), δppm) 1.23 ( d, J = 7.1Hz, 3H) 2.67 ( s, 3H) 2.8-3.0 (m, 1H) 4.2-4.4 (m, 2H) 7.43 (d, J = 8.9 Hz, 1H) 8.24 (dd, J = 2.3 & 8.8 Hz, 1H) 8.30 (d, J = 2.2 Hz, 1H) IR (KBr, cm ^-1 ) 2232, 1725, 1609, 1512, 1426
1302,1283

Example 5 A tablet having the following composition was prepared. Racemic mixture of compounds A-1 and A-2 50 mg Lactose 230 mg Potato starch 80 mg Polyvinylpyrrolidone 11 mg Magnesium stearate 5 mg Total amount 376 mg The above phenylthiazole derivative, lactose, and potato starch are mixed well, and polyvinyl A 20% ethanol solution of pyrrolidone was evenly infiltrated. Thereafter, the mixture was filtered with 20 mesh, dried at 45 ° C., and further filtered with 15 mesh. The granules thus obtained were mixed with magnesium stearate and compressed into tablets.

Example 6 Xanthine oxidase (XOD) inhibitory activity (Ki value) (1) Preparation of test compound A test compound (compound shown in Table 1; corresponding to the compound number in the description) was dissolved in a 20 mM NaOH aqueous solution. It was dissolved and adjusted to a predetermined concentration. (2) Measurement method Xanthine oxidase 5.9 purified from bovine milk
Xanthine and test compounds prepared at various concentrations in (1) were added to 2.5 mL of 0.1 M phosphate buffer (pH 7.4) containing mUnit, and reacted at 25 ° C. Using a spectrophotometer (Hitachi U-3200), the change in absorbance at 292 nm based on uric acid production was monitored for 1 minute. Uric acid production was calculated from the change in absorbance using the molar difference molecular extinction coefficient (Δε) between xanthine and uric acid at 292 nm, and this was defined as the initial rate of enzyme activity. The calculation of the Ki value was performed by Dixon plot. That is, a xanthine concentration of 5 points and a test compound concentration of 5 points were taken to obtain a total of 2 points.
Five plots were obtained and each plot was created. Table 1 summarizes the results.

[0023]

[Table 1]

[0024]

As shown in Table 1 above, it was found that the compounds of the present invention have high xanthine oxidase inhibitory activity. Therefore, the compound of the present invention or a pharmaceutically acceptable salt thereof can be used for treating gout, hyperuricemia, or a disease associated with ischemia-reperfusion injury of an organ.

 ────────────────────────────────────────────────── ─── Continuing from the front page (72) Inventor Toru Minoshima 2-1 Hinode-cho, Iwakuni-shi, Yamaguchi Prefecture Inside the Iwakuni Research Center, Teijin Limited (72) Inventor Yasuhiro Takano 4-2-2 Asahigaoka, Hino-shi, Tokyo Teijin Tokyo Research Center Co., Ltd. F-term (reference) 4C033 AD16 AD17 AD20 4C086 AA01 AA02 AA03 BC82 MA01 MA04 NA05 ZA36 ZA54 ZA96 ZC20 ZC31

Claims (3)

[Claims] 1. A 2-phenylthiazole derivative represented by the following formula (1). Embedded image (In the formula, R represents a hydrogen atom, an isobutyl group substituted with a hydroxyl group, or a normal propyl group substituted with a carboxy group.) 2. A pharmaceutical composition comprising the 2-phenylthiazole derivative according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. 3. A disease associated with gout, hyperuricemia, or ischemia-reperfusion injury of an organ, which comprises the 2-phenylthiazole derivative or the pharmaceutically acceptable salt thereof according to claim 1 as an active ingredient. Therapeutic agent.