JPH111479A - Isoxazole derivative having amide bond and chymase inhibitor and suppresant for angiotensin ii production containing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To produce the subject new compound, comprising amide bonds and useful as a chymase inhibitor or a suppressant for the angiotensin II production. SOLUTION: This compound is represented by the formula (A and B are each an aromatic hydrocarbon and substitutable with a halogen, an alkyl, OH, an alkoxy, etc.; X is H, a halogen or an alky) [except 5-methyl-3-(2- chlorophenyl)-4(3-chloro-4-fluorobenzoyl)hydrazinocarbonyl-isoxazole], e.g. 5- methyl-3-(2-chloro-6-fluorophenyl)-4-(2-(2,4-dimethylbenzoyl)-1hydrazi nocarbonyl)- isoxazole. The compound represented by formula is obtained by reacting a benzoic acid ester with hydrazine, providing a benzoic acid hydrazide and then reacting the resultant compound with isoxazolecarbonylchloride having an aromatic hydrocarbon group at the 3-position. The compound is effective in prevent and treating dermatoses, inflammatory reactions, hypertension, cardiac insufficiency, arteriosclerosis, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a novel isoxazole derivative having an amide bond, and a chymase inhibitor and an angiotensin II production inhibitor containing these as an active ingredient.

[0002]

2. Description of the Related Art Angiotensin II (hereinafter abbreviated as Ang II) has an extremely strong vascular smooth muscle cell contractile activity. Such a strong biological activity of AngII causes hypertension and heart failure, and is an inhibitor of angiotensin converting enzyme (hereinafter abbreviated as ACE), an enzyme that produces AngII, ie, A
CE inhibitors have been widely used and effective in treating hypertension and heart failure. AngII is also a factor that promotes the proliferation of vascular endothelial cells and vascular smooth muscle cells and causes arteriosclerosis.

[0003] Regarding the AngII production pathway, only ACE has conventionally been considered as an enzyme having an activity of converting angiotensin I (hereinafter abbreviated as AngI) to AngII. However, recently, besides ACE, chymase, an enzyme having an activity of converting AngI to AngII, has been found. Chymase is a serine protease belonging to the chymotrypsin family,
It is known that the function differs depending on the animal species (Scie
nce 271: 502-505 1996). Human, monkey, dog, and hamster chymase has the activity of converting AngI to AngII, but rat and mouse chymase cannot convert AngI to AngII.

[0004] As described above, in humans, a new AngII production pathway independent of ACE and independent of chymase exists independently. 80% of AngII produced in human heart and vasculature
It has been reported that this is due to chymase, not ACE (J. Biol. Chem. 265: 22348-22357).
1990). Chymase is also involved in the activation of collagenase in addition to AngII (J. Biol. Chem. 269).
18134-18140, 1994).

[0005] If there is a drug capable of specifically inhibiting chymase, the production of AngII independent of ACE can be suppressed.
It can be expected to be effective in the prevention and treatment of all diseases caused by gII (heart and cardiovascular diseases).

In particular, since human chymase is abundant in the heart, the production of AngII in the heart is to a large extent,
It is thought to be dependent on chymase. AngII in the heart
Problems of the effects include arteriosclerosis described above, intravascular restenosis due to intimal thickening after percutaneous coronary angioplasty (hereinafter abbreviated as PTCA), proliferation of cardiomyocytes and stromal cells and extracellular Ventricular remodeling due to matrix production. Chymase inhibitors can be expected to be effective in preventing and treating these. However, no clinically applicable drug capable of specifically inhibiting chymase has been established.

[0007] Patent WO9325 relating to inhibition of chymase
574 (Applicant PFIZER INC.), WO9604248 (Applicant SUNTORY LT
D), JP 312354/94 (applicant WAKAMOTOLTD), and WO9633974 (applicant THE GREEN CROSS CORP.). The compounds of PFIZERINC. Are peptidic.

[0008] The compound of SUNTORY LTD may be an irreversible inhibitor (suicide substrate) of chymase based on its chemical structure. As described above, the inhibitory effect of the compound of WAKAMOTO LTD is examined using rat chymase having properties that are clearly different from human chymase, and the inhibitory effect on human chymase is unknown. For the compound of THE GREEN CROSS CORP.,
A chymase inhibitor obtained by partially modifying or converting the structure of a human leukocyte elastase inhibitor, which is completely different from the structure of the present invention. To date, no clinically applicable human chymase inhibitor has been established.

[0009]

SUMMARY OF THE INVENTION An object of the present invention is to selectively inhibit human chymase to effectively inhibit skin diseases and inflammatory reactions, as well as diseases such as hypertension, heart failure and arteriosclerosis caused by angiotensin II. Another object of the present invention is to provide a novel isoxazole derivative which can be prevented and treated, and a medicament containing the same as an active ingredient.

[0010]

Means for Solving the Problems The present inventors have prepared recombinant human chymase using human chymase cDNA cloned from human heart, and synthesized and developed using the enzyme activity as an index to obtain the formula (I). It has been found that the isoxazole derivative containing an amide bond shown in 1) has a chymase-selective inhibitory action. Recombinant chymase can be equally substituted for native chymase extracted and prepared from the heart, for example, by URATA et al. (J. Biol.
Chem. 268, 24318-24322, 1993) and MURAKAMI et al. (J. Biol. Chem. 270, 2218-2223, 1995). The present invention provides the following general formula (1):

[0011]

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(Wherein A and B represent the same or different aromatic hydrocarbon groups. These aromatic hydrocarbon groups include halogen atoms, alkyl groups, hydroxyl groups, alkoxy groups, phenoxy groups, nitro groups, cyano groups, X represents any one of hydrogen, halogen, and an alkyl group.) An isoxazole derivative having an amide bond [provided that 5-methyl-3 -(2-chlorophenyl) -4- (3-chloro-4-fluorobenzoyl) -hydrazinocarbonyl-isoxazole]. The present invention also provides a medicament containing the isoxazole derivative represented by the general formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.

[0013] Examples of the medicament include a chymase inhibitor and an inhibitor of angiotensin II production enhancement. In the compounds A and B of the compound of the general formula (1) of the present invention, examples of suitable aromatic hydrocarbon groups include a phenyl group. The hydrogen atom of the aromatic hydrocarbon group is a halogen atom such as chlorine and fluorine, an alkyl group having 1 to 3 carbon atoms such as a methyl group, a hydroxyl group, an alkoxy group having 1 to 3 carbon atoms such as a methoxy group, a phenoxy group, a nitro group. Group, a cyano group, or the like. A and B may be the same or different. X is preferably a halogen such as hydrogen, chlorine or fluorine, and the alkyl group preferably has 1 to 3 carbon atoms, and more preferably is a methyl group.

The preferred compound as the active ingredient of the medicament of the present invention is 5-methyl-3- (2-chlorophenyl) -4- (3-
(Chloro-4-fluorobenzoyl) -hydrazinocarbonyl-
Examples include isoxazole, 5-methyl-3- (2-chloro-6-fluorophenyl) -4- (4-methoxybenzoyl) -hydrazinocarbonyl-isoxazole, and the like.

The isoxazole derivative having an amide bond of the present invention can be produced by chemical synthesis.
Hereinafter, the production method for the compound of the general formula (1) of the present invention will be described.

As a reaction route, benzoic acid ester having a substituent is reacted with hydrazine to obtain benzoic acid hydrazide, which is reacted with isoxazolecarbonyl chloride having an aromatic hydrocarbon group at the 3-position. An isoxazole derivative having an amide bond of the general formula (1) is obtained.

The reaction conditions in each step are as follows: solvents such as chloroform, dichloromethane, N, N-dimethylformamide, dimethyl sulfoxide, pyridine, dioxane, tetrahydrofuran, diethyl ether, ethyl acetate, hexane, acetonitrile, methanol, benzene, ethanol, Preferably, acetic acid or acetone is used. The reaction temperature can be appropriately selected depending on the selected solvent and other conditions.

In each reaction step, functional groups not directly involved in the reaction (eg, hydroxy, sulfonyl, sulfinyl, mercapto, amino, etc.) can be protected by generally known means. Protecting groups used for protecting the functional groups not directly involved in the reaction include
Protecting groups commonly used in organic chemistry, such as "Protective groupes in organic synthesis" [Gre
en, John Wiley & Sons, Inc. (1981)].

For the produced compound of the present invention, after a series of reactions, generally known separation and purification means can be used. For example, extraction, distribution, reprecipitation,
The compound of the present invention can be obtained in a purer form by recrystallization, column chromatography, distillation, sublimation and the like.

When the thus-defined compound of the present invention having a structure defined in the present invention is used, for example, as a chymase inhibitor, the compound having the structure of the present invention or a pharmaceutically acceptable compound thereof is used as an active ingredient. It is preferable to formulate the salt with a solid or liquid pharmaceutical carrier or diluent, that is, with excipients and stabilizers. In the formulation, the ratio of the active ingredient to the carrier component is 1 to
It can vary between 90% by weight. The dosage form and administration form of the preparation can be used in the form of granules, fine granules, powders, tablets, capsules, pills or liquids.

Further, it can be administered orally as it is, or can be administered as an injection by intravenous administration, intramuscular administration or subcutaneous administration. When used as an injection, the compound that defines the structure of the present invention can be prepared as an injection powder.

Organic or inorganic, also solid or liquid, pharmaceutically acceptable carriers or diluents suitable for oral, enteral or parenteral administration may be used to prepare chymase inhibitors whose structure is defined in the present invention. Can be used. Water, gelatin, lactose, starch, magnesium stearate,
Talc, animal and vegetable oils, benzyl alcohol, gums, polyalkylene glycols, petroleum resins, coconut oil, lanolin and other carriers used in medicine are all used as carriers or diluents for chymase inhibitors that define the structure in the present invention. be able to. In addition, a stabilizer, a wetting agent or an emulsifier can be added, or a salt can be used as an auxiliary agent as an osmotic pressure adjusting agent or a pH adjusting agent.

Further, the chymase inhibitor having a structure defined in the present invention may be used, in addition to the above-mentioned active ingredient, in treating other diseases, if necessary, other pharmaceutically active ingredients, for example, other kinds of chymase inhibitors. Components can also be included.

When the composition is in the form of granules, fine granules, powders, tablets or capsules, it is preferable to contain 5-80% by weight of the active ingredient. In the case of a liquid preparation, it is preferable to contain the active ingredient in a ratio of 1 to 30% by weight. Furthermore, among parenteral administration preparations, when used as an injection, it is preferable to contain the active ingredient in a proportion of 1 to 10% by weight.

In the case of oral administration, it is preferable to administer 100 to 1000 mg of the above-mentioned active ingredient per day to an adult. However, the dosage can also be increased or decreased as appropriate according to the patient's age, symptoms, and the like. The above-mentioned chymase inhibitor of the present invention can be administered once a day, but can also be administered at appropriate intervals in two or three divided doses.

Further, when used as an injection, the above-mentioned active ingredient may be used in an amount of 1 to several hundred m per adult per dose.
g is preferred. In addition, the administration can be carried out by step administration by injection or continuous administration by infusion or the like. When the compound of the present invention is used for extracorporeal circulation, it can be used in the form of the above-mentioned injection. The dose also depends on the dose of the above-mentioned injection.

[0027]

DESCRIPTION OF THE PREFERRED EMBODIMENTS Hereinafter, the present invention will be described specifically with reference to examples, but the scope of the present invention is not limited to these examples.

Example 1 Synthesis of 5-methyl-3- (2-chloro-6-fluorophenyl) -4- (2- (2,4-dimethylbenzoyl) -1-hydrazinocarbonyl) -isoxazole 2, 4-dimethylbenzoic acid methyl ester (1.98 g, 12.1 mm
ol) was dissolved in isopropanol (40 ml), saturated hydrazine (0.5 g, 1.3 eq) was added, and the mixture was refluxed for 3 days. After evaporating the solvent, the residue was azeotroped with toluene three times, and further washed with ether to obtain a white powder of 2,4-dimethylbenzoic acid hydrazide (1.55 g, 78%). This 2,4-dimethylbenzoic acid hydrazide (216 mg, 1.2 mmol) was dissolved in pyridine (2 ml), and 5-methyl-3- (2-chloro-6-fluorophenyl) -4-isoxazolecarbonyl chloride ( 0.3 g, 1.1 mmo
l) was added and the mixture was stirred at room temperature for 3 hours. After evaporating the solvent, the residue was dissolved in ethyl acetate, and washed successively three times with 6N hydrochloric acid, 5% aqueous sodium hydrogen carbonate solution and saturated saline. After drying over sodium sulfate, ethyl acetate was distilled off to obtain crude crystals. This was recrystallized from ether to give white crystals of the title compound (0.30 g, 68%).

NMR: ¹ H (270 MHz: CDCl3: 27) C 2.3
0, s, 6H; 2.78, s, 3H; 7.12-7.28, m, 2H; 7.31-7.56,
m, 4H; 8.64, br-s, 1H; 9.29, br-s, 1H MS: [M + H] ⁺ calculated 402.10 found 402

Example 2 Synthesis of 5-methyl-3- (2-chloro-6-fluorophenyl) -4- (2,3-dimethylbenzoyl) -hydrazinocarbonyl-isoxazole By the same method as in Example 1. Then, white crystals (0.32 g, 73%) of the title compound were obtained from 2,3-dimethylbenzoic acid hydrazide (216 mg, 1.3 mmol).

NMR: ¹ H (270 MHz: CDCl3: 27) C 2.6
7, s, 6H; 2.75, s, 3H; 7.03-7.29, m, 4H; 7.38-7.56,
m, 2H; 8.33, br-s, 1H; 8.62, br-s, 1H MS: [M + H] ⁺ calculated 402.10 found 402

Example 3 Synthesis of 5-methyl-3- (2-chloro-6-fluorophenyl) -4- (4-fluorobenzoyl) -hydrazinocarbonyl-isoxazole By a method similar to that of Example 1, 4 -Fluorobenzoic acid hydrazide (161 mg, 1.0 mmol) gave white crystals of the title compound (0.35 g, 86%). MS: [M + H] ⁺ 392.06 found 392.

Example 4 5-methyl-3- (2-chloro-6-
Synthesis of fluorophenyl) -4- (3-fluorobenzoyl) -hydrazinocarbonyl-isoxazole By the same method as in Example 1, white crystals of the title compound were obtained from m-fluorobenzoic acid hydrazide (203 mg, 1.3 mmol). (0.22 g, 51%). MS: [M + H] ⁺ calculated 392.06 found 392

Example 5 Synthesis of 5 -methyl-3- (2-chloro-6-fluorophenyl) -4- (2-fluorobenzoyl) -hydrazinocarbonyl-isoxazole By the same method as in Example 1, o -Fluorobenzoic acid hydrazide (203 mg, 1.mmol) gave white crystals of the title compound (0.20 g, 47%). MS: [M + H] ⁺ calculated 392.06 found 392

Example 6 Synthesis of 5-methyl-3- (2-chloro-6-fluorophenyl) -4- (4-methylbenzoyl) -hydrazinocarbonyl-isoxazole By a method similar to that of Example 1, 4 White crystals of the title compound from 1-methylbenzoic acid hydrazide (157 mg, 1.0 mmol)
(0.37 g, 91%). MS: [M + H] ⁺ 388.08 found 388

Example 7 Synthesis of 5-methyl-3- (2-chloro-6-fluorophenyl) -4- (3-methylbenzoyl) -hydrazinocarbonyl-isoxazole In the same manner as in Example 1, 3 White crystals of the title compound from 1-methylbenzoic acid hydrazide (157 mg, 1.0 mmol)
(0.24 g, 59%). MS: [M + H] ⁺ 388.08 found 388

Example 8 Synthesis of 5-methyl-3- (2-chloro-6-fluorophenyl) -4- (2-methylbenzoyl) -hydrazinocarbonyl-isoxazole By the same method as in Example 1, 2 White crystals of the title compound from 1-methylbenzoic acid hydrazide (157 mg, 1.0 mmol)
(0.21 g, 52%). MS: [M + H] ⁺ 388.08 found 388

Example 9 Synthesis of 5-methyl-3- (2-chloro-6-fluorophenyl) -4- (3,4-dimethylbenzoyl) -hydrazinocarbonyl-isoxazole By the same method as in Example 1. Then, white crystals (0.31 g, 71%) of the title compound were obtained from 3,4-dimethylbenzoic acid hydrazide (216 mg, 1.3 mmol). MS: [M + H] ⁺ calculated value 402.10 actual value 402

Example 10 Synthesis of 5-methyl-3- (2-chloro-6-fluorophenyl) -4- (2,5-dimethylbenzoyl) -hydrazinocarbonyl-isoxazole By the same method as in Example 1. White crystals (0.15 g, 35%) of the title compound were obtained from 2,5-dimethylbenzoic acid hydrazide (216 mg, 1.3 mmol). MS: [M + H] ⁺ calculated value 402.10 actual value 402

Example 11 Synthesis of 5-methyl-3- (2-chloro-6-fluorophenyl) -4- (3,5-dimethylbenzoyl) -hydrazinocarbonyl-isoxazole By the same method as in Example 1. Then, white crystals (0.23 g, 52%) of the title compound were obtained from 3,5-dimethylbenzoic acid hydrazide (216 mg, 1.3 mmol). MS: [M + H] ⁺ calculated value 402.10 actual value 402

Example 12 Synthesis of 5-methyl-3- (2-chloro-6-fluorophenyl) -4- (4-methoxybenzoyl) -hydrazinocarbonyl-isoxazole By a method similar to that of Example 1, 4 From -methoxybenzoic acid hydrazide (170 mg, 1.0 mmol), white crystals of the title compound (0.31 g, 75%) were obtained. MS: [M + H] ⁺ calc. 404.08 found 404

Example 13 Synthesis of 5-methyl-3- (2-chloro-6-fluorophenyl) -4- (4-hydroxybenzoyl) -hydrazinocarbonyl-isoxazole By a method similar to that of Example 1, 4 -Hydroxybenzoic acid hydrazide (160 mg, 1.0 mmol) gave white crystals of the title compound (0.14 g, 34%). MS: [M + H] ⁺ calculated 390.07 found 390

Example 14 Synthesis of 5-methyl-3- (2-chlorophenyl) -4- (3-chloro-4-fluorobenzoyl) -hydrazinocarbonyl-isoxazole Chloro-4-fluorobenzoic acid hydrazide (226 mg, 1.2 mmol) and 5-methyl-3-
White crystals (0.32 g, 72%) of the title compound were obtained from (2-chlorophenyl) -4-isoxazolecarbonyl chloride (0.28 g, 1.1 mmol).

NMR: ¹ H (270 MHz: CDCl3: 27) C 2.8
0, s, 3H; 7.18, t, J = 9.0Hz, 1H; 7.46-7.70, m, 5H;
7.85, dd, J = 6.8Hz, 4.4Hz, 1H; 8.10, br-d, J = 5.9Hz,
1H; 9.11, br-d, J = 5.90Hz, 1H MS: [M + H] ⁺ calculated 408.03 found 408

Example 15 5-methyl-3-phenyl-4- (4-
Synthesis of methylbenzoyl) -hydrazinocarbonyl-isoxazole By the same method as in Example 1, 4-methylbenzoic acid hydrazide (180 mg, 1.2 mmol) and 5-methyl-3-phenyl-4-isoxazolecarbonyl chloride ( (0.30 g, 1.4 mmol)
Thus, an oil (0.34 g, 86%) of the title compound was obtained. MS: [M + H] ⁺ calculated 336.14 found 336.

Example 16 5-methyl-3-phenyl-4- (3-
Synthesis of methylbenzoyl) -hydrazinocarbonyl-isoxazole By a method similar to that in Example 15, oil of the title compound was obtained from 3-methylbenzoic acid hydrazide (180 mg, 1.2 mmol).
(0.28 g, 71%). MS: [M + H] ⁺ calculated 336.14 found 336.

Example 17 5-methyl-3-phenyl-4- (4-
Synthesis of (methoxybenzoyl) -hydrazinocarbonyl-isoxazole In the same manner as in Example 15, white crystals of the title compound (0.32 g, 76%) were obtained from 4-methoxybenzoic acid hydrazide (200 mg, 1.2 mmol). Was. MS: [M + H] ⁺ calculated 352.13 found 352 The compounds obtained in Examples 1-17 are shown in Table 1.

[0048]

[Table 1]

[0049]

[0050]

Test Example 1 Inhibitory Activity of the Compound of the Present Invention on Human Chymase The inhibitory activity of compound (1) of the present invention on human chymase was measured as follows, and the inhibitory activity was evaluated.

0.4 units of human chymase (enzyme activity of chymase which produces 1 pmol of angiotensin II from angiotensin I per second) was converted to 0.75 mM synthetic substrate succinyl-alanyl-alanyl-prolyl-phenylalanine-p-nitroanilide at 0.75 mM. The reaction was carried out at 37 ° C. in the presence of 0.1 nM to 1 mM of the compound (1) whose structure is defined by the present invention as a substrate. The amount of p-nitroaniline produced was detected spectrophotometrically by increasing the absorbance at 405 nm. The composition of the reaction solution is
It was 250 mM Tris-HCl, 1 M KCl, 0.01% Triton X-100 (pH 8). The compound (1), whose structure is defined in the present invention, is previously dissolved in dimethyl sulfoxide (DMS
The solution dissolved in O) was added to the reaction system at 1/10 volume, and finally the reaction was carried out with 10% DMSO.

The activity of human chymase was not suppressed even in 10% DMSO. As a positive control, a similar experiment was performed as a control experiment even in a reaction system containing 10% DMSO without containing the compound (1) of the present invention, and the reaction system containing the compound (1) of the present invention for chymase activity was used. Was compared with the chymase activity, and the concentration of the compound of the present invention (1) when the chymase activity was reduced to 50% was determined, and the IC50 value (unit: M) was determined.

The inhibitory activity of the compound (1) of the present invention on human chymase is shown in Table 2 in terms of IC50 value (unit: M). In all cases, the IC50 values were 1 mM or less, and inhibited human chymase activity. On the other hand, the compound (1) of the present invention for chymotrypsin
The IC50 values of all were> 1 mM. Therefore, the compound (1) of the present invention has an activity of specifically inhibiting chymase.

[0055]

[Table 2]

Test Example 2 Toxicity test The toxicity of the isoxazole derivative having an amide bond of the present invention was tested by the following method. To a 6-week-old male SD rat, the test substance was suspended in a 0.5% CMC-Na solution and orally administered at a dose of 100 mg / kg once a day for 2 weeks. The body weight was measured before administration and on each day during administration. A predetermined amount of blood was collected the day after the end of the administration period, a blood test was performed, and a test of the collected urine was performed. In addition, necropsy examined the organs for mutations.

In the case where the compound of Example 14 was administered, no death was observed during the administration period, and no obvious abnormality was observed in weight change, blood test, urinalysis, necropsy and the like. These test results suggest that the isoxazole derivative having an amide bond of the present invention has low toxicity.

Formulation Example A tablet containing the compound of Example 14 as an active ingredient was produced according to the following formulation. Compound of Example 14 100 mg Magnesium stearate 30 mg Hydroxypropyl methylcellulose 2 mg Polyethylene glycol 0.5 mg Lactose Remainder (total weight per tablet 200 mg)

[0059]

INDUSTRIAL APPLICABILITY According to the present invention, an isoxazole derivative compound having an amide bond and a drug containing the same as an active ingredient exhibit a chymase-selective inhibitory action and can be used for the prevention and treatment of various diseases caused by Ang II. Very effective as a medicine.

 ──────────────────────────────────────────────────の Continuing from the front page (72) Inventor Riko Muramatsu 3-35-1 Ida, Nakahara-ku, Kawasaki-shi, Kanagawa Prefecture New Nippon Steel Corporation Technology Development Division (72) Inventor Atsushi Katada Ida, Nakahara-ku, Kawasaki-shi, Kanagawa Prefecture 3-35-1 New Nippon Steel Corporation Technology Development Division

Claims (5)

[Claims] 1. The following general formula (1): (Wherein A and B represent the same or different aromatic hydrocarbon groups. The aromatic hydrocarbon groups are selected from halogen atoms, alkyl groups, hydroxyl groups, alkoxy groups, phenoxy groups, nitro groups, and cyano groups. X may be substituted with 1 to 3 groups; X represents any one of hydrogen, halogen, and an alkyl group.) An isoxazole derivative having an amide bond [provided that 5-methyl-3- ( 2-chlorophenyl) -4- (3-chloro-4-fluorobenzoyl) -hydrazinocarbonyl-isoxazole]. 2. The following general formula (1): (Wherein A and B represent the same or different aromatic hydrocarbon groups. The aromatic hydrocarbon groups are selected from halogen atoms, alkyl groups, hydroxyl groups, alkoxy groups, phenoxy groups, nitro groups, and cyano groups. X represents any one of hydrogen, halogen, and an alkyl group), or an isoxazole derivative having an amide bond represented by the formula (I) or a pharmaceutically acceptable salt thereof. Pharmaceutical containing as an active ingredient. 3. The medicament according to claim 2, which is a chymase inhibitor. 4. The method according to claim 2, wherein the drug is angiotensin.
II A drug that inhibits the increase in production. 5. A pharmaceutical composition comprising the medicine according to claim 2 and a pharmaceutically acceptable carrier.