JP2003342265A - Triazolidine derivative and its pharmaceutical use - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a triazolidine derivative having chymase and tryptase inhibiting activities. <P>SOLUTION: The triazolidine derivative is a compound expressed by formula (I) (A is carbonyl or sulfonyl; R<SP>1</SP>is naphthyl; R<SP>2</SP>is H, a (substituted)lower alkyl or BR<SP>4</SP>(B is carbonyl or sulfonyl; and R<SP>4</SP>is an aryl); and R<SP>3</SP>is a (substituted)aryl) or its pharmecochemically permissible salt. <P>COPYRIGHT: (C)2004,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a triazolidine derivative or a pharmaceutically acceptable salt thereof, and a medicine containing these. These compounds have a chymase or / and tryptase inhibitory activity, and are useful for the prevention and treatment of various diseases involving chymase and tryptase.

[0002]

Chymase is one of the neutral serine proteases (about 30 kD), but it is an enzyme that converts angiotensin I into angiotensin II in tissues [J. Biol. Chem., 265, 22348. Page (1990)]
Therefore, it is considered to be involved in the development of heart and circulatory diseases caused by angiotensin II. In addition, chymase has effects such as activation of collagenase to active collagenase, limited degradation of extracellular matrix, thrombin, and IgG, and promotion of histamine release from mast cells, so that it is involved in allergies or inflammatory diseases. It is thought that Furthermore, chymase itself is known to cause an itching sensation [Acta Dermatovener 52, 125,
(1972)], and chymase may also be involved in the wound healing process, possibly abnormal fibrosis [Arc
h Dermatol Res 290, 553, (1998)]. Regarding chymase in ocular tissues, its function is not yet fully understood, but it is considered to be involved in the regulation of ocular circulation (ocular blood flow, aqueous humor circulation) and ciliary muscle. From the above-mentioned wide-ranging actions of chymase in vivo, inhibitors of such enzymes are expected to be useful as prophylactic and therapeutic agents for various diseases.

Hitherto, as chymase inhibitors, imidazolidine derivatives (WO 9604248) and acetamide derivatives have been used.
(WO 9809949), triazine sulfone derivative
-245384), thiazolidine derivative (JP 2000-95770, JP
2000-103785), quinazoline derivative (WO 9711941), phenol ester derivative (JP-A-10-87567), thiazine derivative (EP 0713876), heterocyclic amide compound (WO 9
633974, WO 9818794), peptide compounds [Proc. Na
tl. Acad. Sci. USA, Vol. 92, p. 6738 (1995)], hydantoin derivatives (JP-A-9-31061) and the like are known. However, these compounds have not yet been put to practical use.

Tryptase belongs to the same serine protease family as chymase, and was isolated and purified from human lung as a protease having trypsin-like substrate specificity [J.
Biol. Chem. 259, 11046, (1984)]. Tryptase is mainly present in mast cells, in addition to lymphocytes and bronchial mucosal secretory cells, and is characterized by being sufficiently maintained in plasma and extracellular space even after being released extracellularly. To do. In mast cells, the majority of tryptase is stored in secretory granules, and when the cell is activated, tryptase contains other enzymes (peroxidase, chymase, etc.) and chemical mediators (eg histamine, leukotrienes, prostaglandins). Released by degranulation with [N. Engl. J. Med. 316
Vol. 1622 (1987)].

Tryptase is involved in the etiology of various diseases. For example, tryptase is said to be one of the causes of asthma because it increases the contractility of airway smooth muscle by inactivating a vasoactive intestinal peptide that has a bronchodilator effect (J. Pharmacol. Exp. Ther. 244, 133 (1988
Year)〕. Tryptase has also been shown to promote fibroblast division, with interstitial pneumonia, pulmonary fibrosis, liver fibrosis,
It is said to be related to cirrhosis and pterygium [J. Cli
n. Invest. 88, 493 (1991), Nikkei, 101, 862.
Page (1997)]. In addition, tryptase activates prostromelysin, which leads to activation of collagenase, which initiates the destruction of cartilage and periodontal connective tissue.Triptase also causes arthritis and periodontal disease. It may also be involved in various tissue inflammations and remodeling. Tryptase is PAR-2 (Protease-activated receptor
-2) is activated, it acts on inflammatory cells such as mast cells and PAR-2 of primary sensory nerves to induce inflammation [NATURE MEDI
CINE. Vol. 6, No. 2, p. 151 (2000)], and also hyperalgesia [Neuro Report. Volume 12, Issue 4, 715 (2001))
It is also known to cause. Furthermore, tryptase is involved in neurogenic inflammation by cleaving calcitonin gene-related peptide [Am. J. Respir. Cell
Mol. Biol. Volume 4, p. 387 (1991)]. Tryptase inactivates the procoagulant function of high molecular weight kininogen and promotes coagulopathy by cleaving fibrinogen [J. Immunol., 135, 2762 (1985)]. Viruses having outer membrane glycoproteins such as influenza and Sendai virus are decomposed by tryptase and fused with the target cell membrane to penetrate into the cells [J. of Virology. Dec. 7211 (1992)]. Other such viruses include parainfluenza virus and RS
Virus, measles virus and mumps virus. From the above-mentioned wide-ranging actions of tryptase in vivo, inhibitors of such enzymes are expected to be useful as prophylactic and therapeutic agents for various diseases.

Known tryptase inhibitors include leupeptin and antipain derived from natural products and some benzamidine derivatives [Biol. Ch.
em. Hoppe-Seyler, 369, 617 (1988)]. Other than that, aminohexanoyl derivative (JP 2000-302675),
Polyfluoroalkylated tripeptide derivative (Japanese Patent Application Laid-Open No. 05-
112598), peptide derivatives (Table 08-507768), secretory leukocyte protease inhibitors (Table 10-505833), leech-derived polypeptides (Table 09-500532), guanidino derivatives (Table 97/037969) , Antileukoprotease (re-listed
95/025539) and related peptides (Re-Table 97/003694) and the like are known. However, these compounds have not yet been put to practical use.

[0007]

The object of the present invention is to provide a novel triazolidine derivative having excellent chymase and tryptase inhibitory activity.

[0008]

Means for Solving the Problems As a result of intensive studies by the present inventors, a triazolidine derivative having excellent chymase and tryptase inhibitory activity was created, and further research was conducted to complete the present invention.

That is, the present invention provides (1) general formula (I)

[Chemical 2] [In the formula, A represents a carbonyl group or a sulfonyl group,
R ¹ represents a naphthyl group, R ² represents a hydrogen atom or an optionally substituted lower alkyl group, or —BR ⁴ , (B is a carbonyl group or a sulfonyl group, and R ⁴ is an aryl group).
And R ³ represents an optionally substituted aryl group. ]
A compound represented by or a pharmaceutically acceptable salt thereof, (2) a compound or a pharmaceutically acceptable salt thereof (1), wherein R ³ is a phenyl group, and (3) A and B are A compound having a carbonyl group (1) or a pharmaceutically acceptable salt thereof, (4) a compound or a pharmaceutically acceptable salt thereof according to any of (1) to (3) A drug, a chymase and / or tryptase inhibitor containing the compound according to any one of (5) (1) to (3) or a pharmaceutically acceptable salt thereof, (6)
The drug according to (4), which is a prophylactic or therapeutic agent for a disease involving chymase and / or tryptase, (7) the disease involving chymase is reticulochoroidal disease, glaucoma, myopia or asthenopia (6) The drug according to (8), wherein the disease involving tryptase is blood coagulation disorder, skin disease, interstitial pneumonia, pulmonary fibrosis, liver fibrosis, cirrhosis, pterygium, periodontal disease or viral disease (6) Described medicine, (9)
The drug according to (6), wherein the disease involving chymase and tryptase is an allergic, inflammatory or cardiovascular disease, and the compound according to any one of (10) (1) to (3) or a pharmaceutical preparation thereof. Composition containing a pharmaceutically acceptable salt together with a pharmaceutically acceptable carrier.

[0010]

BEST MODE FOR CARRYING OUT THE INVENTION In the compound of the general formula (I) of the present invention, the naphthyl group represented by R ¹ may be either a 1-naphthyl group or a 2-naphthyl group, preferably a 1-naphthyl group. The lower alkyl group of the optionally substituted lower alkyl group represented by R ² is preferably a linear or branched alkyl group having 1 to 5 carbon atoms, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, Butyl group, sec-
Examples thereof include a butyl group, a tert-butyl group, a pentyl group, an isopentyl group, a neopentyl group and a tert-pentyl group, with a methyl group and an ethyl group being particularly preferred.
Examples of the substituent include a carboxy group, a hydroxy group, a pyridyl group (2-, 3- or 4-pyridyl group), an amino group, a phenyl group and the like, and preferably a carboxy group, a hydroxy group, a pyridyl group (particularly 3 -And 4-pyridyl groups). This carboxy group is an alcohol having 1 to 4 carbon atoms (methyl alcohol, ethyl alcohol, propyl alcohol, isopropyl alcohol, butyl alcohol, isobutyl alcohol, tert-butyl alcohol)
May be esterified with or with an amine having 1 to 4 carbon atoms (methylamine, ethylamine, propylamine, isopropylamine, butylamine, isobutylamine, tert-butylamine), especially esterified with tert-butyl alcohol. A tert-butoxycarbonyl group is preferred. Further, the hydroxy group has 1 to 5 carbon atoms.
Alkyl group (methyl group, ethyl group, propyl group, isopropyl group, butyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group and tert-pentyl group), or silyl group (for example, Trimethylsilyl group, triethylsilyl group, tert-butyldimethylsilyl group, etc.) or having 1 carbon atom
~ 5 carboxylic acids (formic acid, acetic acid, propionic acid, butyric acid,
Isobutyric acid, valeric acid, isovaleric acid, pivalic acid) may form an ester. Examples of the aryl group of R ⁴ in which R ² is BR ⁴ include a phenyl group, a 1-naphthyl group, a 2-naphthyl group, and the like. Examples of the aryl group of the optionally substituted aryl group represented by R ³ include a phenyl group and a naphthyl group, and a phenyl group is preferable. As a substituent, a lower alkyl group having 1 to 3 carbon atoms
(Methyl group, ethyl group, propyl group, isopropyl group) or alkoxy group (methoxy group, ethoxy group, propoxy group, isopropoxy group), halogen atom (chlorine, bromine,
(Fluorine, iodine, etc.), nitro group, hydroxy group and the like. The carbonyl group or sulfonyl group represented by A and B is more preferably a carbonyl group. Among the compounds represented by the general formula (I) of the present invention, in particular, phenyl in which A is a carbonyl group, R ¹ is a 1-naphthyl group, R ² is a benzoyl group, and R ³ may be substituted. Compounds that are groups are preferred.

The above-mentioned compound represented by the general formula (I) can be produced, for example, by the following production method or in accordance with it. i) When R ² is hydrogen

[Chemical 3] [Wherein R ¹ , R ³ and A in the above reaction formula are as described above,
X is a halogen atom (chlorine, bromine, fluorine, iodine, etc.)
Indicates. ] 4-position substituted triazolidine-3 represented by the general formula (II),
By reacting 5-dione or a salt thereof with an acid halide derivative represented by the general formula (III) and performing ordinary purification such as recrystallization or column chromatography, a compound represented by the general formula (I) can be obtained. Compounds of general formula (I ′) in which R ² is hydrogen can be prepared.

Such a reaction can be carried out in a reaction solvent in the presence or absence of an inorganic and organic base. Examples of the reaction solvent that can be used in this reaction include dichloromethane, chloroform, N, N-dimethylformamide (DMF), benzene, toluene, ethylbenzene, cyclohexane, hexane, heptane, diethyl ether, tetrahydrofuran and the like. A common solvent that does not have a bad influence, a mixed solvent thereof or the like can be mentioned, and DMF or tetrahydrofuran is preferable. The inorganic base used in this reaction is an alkali metal hydride such as sodium hydride, an alkali metal carbonate such as potassium carbonate, an alkali metal hydrogen carbonate such as sodium hydrogen carbonate, and the organic base is triethylamine,
Trialkylamines such as diisopropylethylamine,
Pyridine, lutidine, picoline, 4-dimethylaminopyridine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,5-diazabicyclo [4.
3.0] Non-5-ene (DBN) and the like, but sodium hydride or potassium carbonate is preferable. The base is 0 to 1 mol of 4-substituted triazolidine-3,5-dione represented by the general formula (II) or a salt thereof.
It is preferably used in the range of 2.0 molar ratio. The reaction temperature is usually in the range of cooling to warming, preferably in the range of -10 ° C to 30 ° C.

Ii) when R ² is an optionally substituted alkyl group or BR ⁴

[Chemical 4] (In the above reaction formula, R ⁵ represents an optionally substituted lower alkyl group, and A, B, R ¹ , R ³ , R ⁴ , and X are as described above.) Represented by the general formula (I ′) 1,4-disubstituted triazolidine-3,5-dione or a salt thereof, and a compound represented by the general formula (IV)
The alkyl halide derivative represented by or the acid halide derivative represented by the general formula (V) is used in a range of 0.5 to 2.0 molar ratio, preferably 0.9 to 1.2 molar ratio, and other reaction conditions are By carrying out the reaction under the same conditions as in the above i) and carrying out ordinary purification, R ^{2 in the} compound represented by the general formula (I) is represented by R ⁵ (I ″) or BR ⁴ (I It is possible to produce compounds of the formula "''). As shown in the reaction formula below, the general formula (I ″)
Alternatively, the compound represented by the formula (I ″ ′) is obtained by reacting the compound represented by the general formula (II) with the compounds represented by the general formulas (IV) and (V) by the same method as in the above i). ,
Synthesis by reacting the obtained 1,4-di-substituted triazolidine-3,5-dione represented by the general formulas (VI) and (VI ′) with the acid halide derivative represented by the general formula (III) You can also

[Chemical 5] (Each symbol in the above formulas is as described above.) Furthermore, when the acid halide derivative represented by the general formula (V) is the same as the compound represented by the general formula (III), it is represented by the general formula (II). 1 to 3 mol of the compound represented by the general formula (III), preferably 2 to 2.2.
When the reaction is carried out by adding in a molar ratio, the compound of the general formula (I ′ ″) can be easily obtained by a one-step reaction. In addition, when the substituent is chemically protected in each step of the synthesis, the deprotection reaction is appropriately performed. For example, tert-
When a compound represented by the general formula (I ″) is obtained using a substituted alkyl acid halide having a protecting group such as butyl bromoacetate and 2-bromoethoxy-tert-butyldimethylsilane, The protective group can be removed by dissolving the compound in a commonly used organic solvent and stirring in the presence of an acid. The commonly used organic solvent includes, for example, a conventional solvent which does not adversely influence the reaction such as tetrahydrofuran, dichloromethane, ethyl acetate and the like, or a mixed solvent thereof, but is preferably dichloromethane. Examples of the acid include hydrochloric acid, trifluoroacetic acid, p-toluenesulfonic acid, and the like, but trifluoroacetic acid is preferable. The reaction temperature is not particularly limited, but is usually under cooling, room temperature or warming, and preferably under ice-cooling to room temperature.

Specific examples of the compound of the present invention are shown below. (1) 1- (naphthalene-1-carbonyl) -4-phenyl-
1,2,4-triazolidine-3,5-dione (2) 1,2-bis (naphthalene-1-carbonyl) -4-phenyl-1,2,4-triazolidine-3,5-dione (3) 1 -(Naphthalene-2-sulfonyl) -4-phenyl-1,2,4-triazolidine-3,5-dione (4) 1,2-bis (naphthalene-2-sulfonyl) -4
-Phenyl-1,2,4-triazolidine-3,5-dione (5) [2- (naphthalene-2-sulfonyl) -3,5-dioxo-4-phenyl-1,2,4-triazolidine-1- Iyl] acetic acid tert-butyl ester (6) [2- (naphthalene-1-carbonyl) -3,5-dioxo-4-phenyl-1,2,4-triazolidin-1-yl]
Acetic acid tert-butyl ester (7) [2- (naphthalene-1-carbonyl) -3,5-dioxo-4-phenyl-1,2,4-triazolidin-1-yl]
Acetic acid (8) [2- (naphthalene-2-sulfonyl) -3,5-dioxo-4-phenyl-1,2,4-triazoridin-1-yl] acetic acid (9) 1- (naphthalene-2-carbonyl) -4-phenyl-
1,2,4-triazolidine-3,5-dione (10) 1- (naphthalene-1-carbonyl) -4-phenyl-
2-pyridin-4-ylmethyl-1,2,4-triazolidine-
3,5-dione (11) 1- (naphthalene-1-carbonyl) -4-phenyl-
2-pyridin-3-ylmethyl-1,2,4-triazolidine-
3,5-dione (12) 1- (phenylcarbonyl) -2- (naphthalene-1-
Carbonyl) -4-phenyl-1,2,4-triazolidine-
3,5-dione (13) 1- (2-hydroxyethyl) -2- (naphthalene-1)
-Carbonyl) -4-phenyl-1,2,4-triazolidine-
3,5-dione The pharmaceutically acceptable salt of the compound represented by the general formula (I) of the present invention includes, for example, alkali metal salts such as sodium salt and potassium salt, alkali salts such as calcium salt and magnesium salt. Salts with inorganic acids such as earth metal salts, hydrochlorides, hydrobromides, sulfates, nitrates, phosphates and salts with organic acids such as acetates, citrates, toluenesulfonates But is not limited to these. further,
The present invention also includes various solvates and crystalline polymorphs of the compound represented by the formula (I), and prodrugs thereof. The compound represented by the general formula (I) of the present invention and a pharmaceutically acceptable salt thereof (hereinafter, sometimes referred to as the compound of the present invention) are novel compounds which have not been described in the literature, and as shown in the test examples below. Since it has excellent chymase and / or tryptase activity, it is useful as a drug as a chymase and / or tryptase inhibitor by combining them as an active ingredient and, if necessary, a carrier described below.

Since the compounds of the present invention have chymase and tryptase inhibitory activity, they are warm-blooded animals (for example, monkeys,
It is useful for the prevention / treatment of diseases involving chymase and tryptase in mammals such as dogs, cats, rabbits, guinea pigs, rats, humans, and birds such as chickens, pigeons, and turkeys. For example, by chymase and tryptase inhibitory action, systemic and local inflammatory and allergic diseases (systemic pancreatitis, ulcerative colitis, digestive tract inflammation such as Crohn's disease, nephritis, hepatitis, bronchopulmonary inflammation, atopy, arthritis, rheumatism, etc. , Locally as a preventive / therapeutic agent for keratoconjunctivitis, iridocyclitis, uveitis, orbital inflammation, spring catarrh, allergic rhinitis, etc., and also for cardiovascular diseases (hypertension, arteriosclerosis, myocardial infarction, As a prophylactic / therapeutic agent for restenosis after angiopathies such as cardiac hypertrophy and heart failure) and percutaneous transluminal coronary angioplasty, diabetic and non-diabetic nephropathy, and peripheral circulatory disorders. It can be used as a prophylactic / therapeutic agent for itch and irritability. Ocular circulation disorder due to chymase inhibitory effect (retinochoroidal disease; retinitis pigmentosa, macular degeneration, ischemic optic neuropathy, retinal arterial vein occlusion, diabetic retinopathy, choroidal disease secondary to retinal lesions), glaucoma and surgery It can be used as a preventive / therapeutic agent for the subsequent tissue adhesion, etc., and also for improving myopia and asthenopia because it has a relaxing effect on ciliary muscle tone. In addition, due to tryptase inhibitory activity, blood coagulation disorders such as thrombophlebitis and general intravascular coagulation,
In addition to skin diseases such as psoriasis and scleroderma and viral diseases, it can be used as a prophylactic / therapeutic agent for diseases such as interstitial pneumonia, pulmonary fibrosis, cirrhosis, periodontal disease, and pterygium.

For the above-mentioned prevention / treatment, the compound of the present invention is appropriately applied orally or parenterally. Examples of the form of the preparation for application include solid preparations such as tablets, granules, powders, capsules and ointments, and liquid preparations such as injections, eye drops and nasal drops. Both formulations
It can be appropriately prepared by a known method. These formulations include commonly used excipients (starch, glucose,
Fructose, sucrose, mannitol, calcium phosphate, etc.), binders (starch, gum arabic, gelatin solution, sodium alginate, carmellose solution, etc.), disintegrants (starch, calcium carbonate, crystalline cellulose, etc.), lubricants (calcium stearate, stearin) Magnesium acid, talc, etc.), absorption promoters (thioglycolic acid, capric acid, caprylic acid, etc.), buffers (boric acid, borax, sodium acetate, citrate buffer, phosphate buffer, etc.), surfactants (Sodium lauryl sulfate, polysorbate 80, polyoxyethylene hydrogenated castor oil, etc.), solubilizer (sodium lauryl sulfate, sodium benzoate, ethylenediamine, potassium iodide, etc.), preservative (benzalkonium chloride, parabens, chlorobutanol) Etc.), emulsifier (gum arabic, tiger Agent, gelatin, polyvinylpyrrolidone, etc.), isotonicity agent (sodium chloride, glycerin, mannitol, etc.), suspending agent (hydroxypropylmethylcellulose, etc.), stabilizer (sodium edetate, sodium pyrosulfite, etc.), pH adjustment Agents (hydrochloric acid, citric acid, sodium hydroxide, etc.) and the like may be appropriately used.

When the compound of the present invention is used, for example, as a prophylactic / therapeutic agent for cardiovascular disease, the dose is selected according to the kind of target disease, the kind of compound used, the age of the patient,
For example, in the case of an oral preparation, the compound of the present invention is administered to an adult patient several times a day in a single dose of 1 mg to 100 mg, more preferably 5 mg, although it varies depending on the body weight, symptoms and dosage form thereof.
It is advisable to administer mg to 25 mg. In the case of an intravenous injection, it is preferable to administer 0.1 mg to 25 mg, more preferably 0.5 mg to 5 mg to the same patient once a day. Furthermore, when administered locally to a patient with a local inflammatory disease, the compound of the present invention is contained in an amount of 0.01 w / v% to 2.0 w / v%, preferably 0.05 w / v% to 0.5 w / v%. Eye drops, nasal drops or ointment, 1 to several drops at a time or appropriate amount, 1
It is advisable to apply eye drops, nose drops or apply about 1 to 8 times a day.

The compound of the present invention may be used in 2
It is also possible to use a combination of two or more species as appropriate. Also,
The compound of the present invention, unless contrary to the object of the present invention, the chymase and tryptase inhibitory component not included in the present invention, another component having the same drug efficacy as the present invention, and other drug components are used in appropriate combination. You can also

[0019]

EXAMPLES The present invention will be described in more detail with reference to the following examples and test examples, but the present invention is not limited thereto. The nuclear magnetic resonance spectra (NMR) of the compounds described in Examples are Varian Gemini 2000.
It was measured using. Example 1 1- (naphthalene-1-carbonyl) -4-phenyl-1,2,4
-Triazolidine-3,5-dione (Compound 1) 4-phenylurazole 1.77 g was dissolved in tetrahydrofuran (10 mL), and sodium hydride (60%, oily) (420 mg) was added at 0 ° C under ice cooling. It was After stirring for 30 minutes, 1-naphthoyl chloride (1990
mg) was added and the mixture was stirred at room temperature for 2.5 hours. After carefully adding water, ethyl acetate (200 mL) was added for partitioning. The obtained organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off. Further silica gel chromatography (hexane: ethyl acetate =
Purification by 1: 1) gave white crystals. Further recrystallized from isopropyl ether (IPE) to give the title compound 114
0 mg was obtained as white crystals. ¹ H-NMR (CDCl ₃ ) δ7.33-7.44 (5H, m), 7.51-7.62 (3H,
m), 7.81 (1H, d, J = 7.0 Hz), 7.91 (1H, dd, J = 6.
9, 2.3 Hz), 8.05 (1H, d, J = 8.1 Hz), 8.10 (1H, d,
J = 7.5 Hz).

Example 2 1,2-bis (naphthalene-1-carbonyl) -4-phenyl-
1,2,4-triazolidine-3,5-dione (Compound 2) The same procedure as in Example 1 was carried out except using 1980 mg of 1-naphthoyl chloride to obtain 900 mg of the title compound as white crystals. ¹ H-NMR (CDCl ₃ ) δ 7.30-7.39 (5H, m), 7.56-7.71 (3H,
m), 7.95 (2H, d, J = 8.1 Hz), 8.13 (2H, d, J = 8.4
Hz), 8.26 (2H, dd, J = 8.3, 1.2 Hz), 8.65 (2H, dd,
J = 8.5, 0.9 Hz).

(Example 3) 1- (naphthalene-2-sulfonyl) -4-phenyl-1,2,
4-Triazolidine-3,5-dione (Compound 3) The same operation as in Example 1 was carried out except that 2-naphthalenesulfonyl chloride (2260 mg) was used instead of 1-naphthoyl chloride, to give 2540 mg of the title compound as white crystals. Obtained. ¹ H-NMR (CDCl ₃ + CD ₃ OD) δ 7.08-7.14 (2H, m), 7.30-
7.38 (3H, m), 7.65-7.78 (2H, m), 7.95-8.09 (4H, m),
8.65 (1H, s).

Example 4 1,2-Bis (naphthalene-2-sulfonyl) -4-phenyl
-1,2,4-Triazolidine-3,5-dione (Compound 4) The title compound 190 was prepared in the same manner as in Example 3 except that 4250 mg of 2-naphthalenesulfonyl chloride was used.
mg was obtained as white crystals. ¹ H-NMR (CDCl ₃ ) δ6.41 (2H, dd, J = 8.0, 0.7 Hz),
7.10-7.23 (3H, m), 7.65-7.77 (4H, m), 7.95-8.04 (8
H, m), 8.66 (2H, s).

Example 5 [2- (naphthalene-2-sulfonyl) -3,5-dioxo-4]
-Phenyl-1,2,4-triazolidin-1-yl] acetic acid te
rt-Butyl ester (Compound 5) 1- (naphthalene-2-sulfonyl) -4-phenyl-1,
2,4-Triazolidine-3,5-dione (1000 mg)
Was dissolved in DMF (2 mL), tert-butyl bromoacetate (530 mg) was added, and potassium carbonate (3
90 mg) was added. The reaction solution was stirred overnight at room temperature.
After carefully adding water, ethyl acetate (200 mL) was added for extraction. The obtained organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off. Further purification by silica gel chromatography (hexane: ethyl acetate = 1: 1) gave white crystals. Further IP
Recrystallization from E gave 220 mg of the title compound as white crystals. ¹ H-NMR (CDCl ₃ ) δ 1.50 (9H, s), 4.69 (2H, s), 6.95-
6.98 (2H, m), 7.29-7.31 (3H, m), 7.68 (1H, t, J =
7.6 Hz), 7.75 (1H, t, J = 7.2 Hz), 7.93-8.07 (4H,
m), 8.60 (1H, s).

(Example 6) [2- (naphthalene-1-carbonyl) -3,5-dioxo-4-
Phenyl-1,2,4-triazolidin-1-yl] acetic acid ter
t-Butyl ester (Compound 6) 1- (naphthalene-2-sulfonyl) -4-phenyl-1,2,
Example 5 except that 1- (naphthalene-1-carbonyl) -4-phenyl-1,2,4-triazolidine-3,5-dione (500 mg) was used in place of 4-triazolidine-3,5-dione. The same reaction was performed, and after completion of the reaction, a white solid precipitated when water was carefully added was collected by filtration. The obtained white solid was recrystallized using IPE to give the title compound (610 mg) as white crystals. ¹ H-NMR (CDCl ₃ ) δ1.54 (9H, s), 4.82 (2H, s), 7.32-
7.47 (5H, m), 7.48-7.60 (3H, m), 7.80 (1H, dd, J =
7.1, 0.9 Hz), 7.90 (1H, dd, J = 6.7, 2.5 Hz), 8.0
4 (1H, d, J = 8.2 Hz), 8.23 (1H, dd, J = 5.8, 1.5
Hz),

Example 7 [2- (naphthalene-1-carbonyl) -3,5-dioxo-4-phenyl-1,2,4-triazolidin-1-yl] acetic acid (Compound 7) [2- ( Naphthalene-1-carbonyl) -3,5-dioxo-4-
Phenyl-1,2,4-triazolidin-1-yl] acetic acid ter
t-Butyl ester (600 mg) was dissolved in 20% trifluoroacetic acid / dichloromethane solution (2 mL), and the mixture was stirred at room temperature overnight. After adding a 1N hydrochloric acid aqueous solution, the mixture was extracted three times with chloroform (50 mL). The obtained organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off. Further, recrystallization was performed using IPE to obtain 310 mg of the title compound as white crystals. ¹ H-NMR (CDCl ₃ ) δ 4.89 (2H, s), 7.32-7.44 (4H, m),
7.49-7.62 (4H, m), 7.84-7.92 (2H, m), 8.04 (1H, d,
J = 8.2 Hz), 8.27 (1H, dd, J = 8.6, 1.1 Hz).

Example 8 [2- (naphthalene-2-sulfonyl) -3,5-dioxo-4]
-Phenyl-1,2,4-triazolidin-1-yl] acetic acid (Compound 8) [2- (naphthalene-1-carbonyl) -3,5-dioxo-4--
Phenyl-1,2,4-triazolidin-1-yl] acetic acid ter
Instead of using t-butyl ester, [2- (naphthalene-1
-Carbonyl) -3,5-dioxo-4-phenyl-1,2,4-
Triazolidin-1-yl] acetic acid tert-butyl ester (200 mg) was used for the same procedure as in Example 7 to obtain 150 mg of the title compound as a brown solid. ¹ H-NMR (CDCl ₃ ) δ 4.86 (2H, s), 6.91 (1H, d, J =
4.6 Hz), 6.94 (1H, d, J = 2.1 Hz), 7.28-7.31 (3H,
m), 7.68 (1H, t, J = 3.7 Hz), 7.75 (1H, t, J = 2.
6 Hz), 7.94-8.07 (4H, m), 8.62 (1H, s).

Example 9 1- (naphthalene-2-carbonyl) -4-phenyl-1,2,4
-Triazolidine-3,5-dione (Compound 9) 4-phenylurazole (2.00 g) was dissolved in tetrahydrofuran (10 mL), and sodium hydride (60%, oily) (490 mg) was added at 0 ° C under ice cooling. It was After stirring for 30 minutes, 2-naphthoyl chloride (2260) was added at 0 ° C.
mg) was added and the mixture was stirred at room temperature for 2.5 hours. After carefully adding water to the reaction solution, ethyl acetate (200 mL) was added for partitioning. The yellow solid precipitated at that time was collected by filtration. The obtained yellow solid was recrystallized from isopropyl alcohol and IPE to give the title compound (1750 mg). ¹ H-NMR (CDCl ₃ + CD ₃ OD) δ7.26-7.56 (7H, m), 7.70 (1
H, dd, J = 8.5, 1.5 Hz), 7.78-7.84 (3H, m), 8.22
(1H, s).

Example 10 1- (Naphthalene-1-carbonyl) -4-phenyl-2-pyridin-4-ylmethyl-1,2,4-triazolidine-3,5-
Dione (Compound 10) The reaction was performed in the same manner as in Example 5 except that 4-picolyl chloride (54 mg) was used instead of tert-butyl bromoacetate, and after the completion of the reaction, white was precipitated when water was carefully added. The solid was collected by filtration. The obtained white solid was recrystallized using IPE to obtain 102 mg of the title compound as white crystals. ¹ H-NMR (CDCl ₃ ) δ5.33 (2H, s), 7.31-7.55 (12H, m),
7.86-7.92 (1H, m), 8.01 (1H, d, J = 8.1 Hz), 8.72
(2H, brs).

Example 11 1- (Naphthalene-1-carbonyl) -4-phenyl-2-pyridin-3-ylmethyl-1,2,4-triazolidine-3,5-
Dione (Compound 11) Treated in the same manner as in Example 10 except that 4-picolyl chloride (54 mg) was used instead of 4-picolyl chloride, to give 71 mg of the title compound as white crystals. ¹ H-NMR (CDCl ₃ ) δ 5.36 (2H, s), 7.32-7.44 (8H, m),
7.47-7.55 (2H, m), 7.75 (1H, dt, J = 7.9, 1.8 H
z), 7.85-7.91 (1H, m), 7.97-7.99 (1H, m), 8.01 (1H,
d, J = 7.0 Hz), 8.71 (2H, brs).

Example 12 1- (Phenylcarbonyl) -2- (naphthalene-1-carbonyl) -4-phenyl-1,2,4-triazolidine-3,5-dione (Compound 12) 1- (phenyl Carbonyl) -2-4-phenyl-1,2,4-triazolidine-3,5-dione (200 mg) was added to DMF.
Dissolved in (1 mL) and 1-naphthoyl chloride (140
mg) was added, and potassium carbonate (103 mg) was further added. The reaction solution was stirred overnight at room temperature. Ethyl acetate (100 mL) was added to the reaction solution, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was recrystallized from hexane and IPE to give 71 mg of the title compound as white crystals. ¹ H-NMR (CDCl ₃ ) δ 4.54 (2H, t, J = 4.4 Hz), 4.63 (2
H, t, J = 4.4 Hz), 7.33-7.43 (4H, m), 7.48-7.63 (4
H, m), 7.86-7.95 (2H, m), 8.05 (1H, d, J = 7.5 H
z), 8.20 (1H, d, J = 7.3 Hz).

Example 13 1- (2-Hydroxyethyl) -2- (naphthalene-1-carbonyl) -4-phenyl-1,2,4-triazolidine-3,5-dione (Compound 13) 1- (Naphthalene-1-carbonyl) -4-phenyl-1,2,4-
Triazolidine-3,5-dione (100 mg) in DMF
Dissolve in (1 mL), 2-bromoethoxy-tert-butyldimethylsilane (75 mg) and potassium carbonate (43 m
g) was added. The reaction solution was stirred at room temperature for 3 hours and then post-treated in the same manner as in Example 12 to give 1- [2- (tert-butyldimethylsilanyloxy) -ethyl] -2- (naphthalene-1-carbonyl)-. 4-Phenyl-1,2,4-triazolidine-3,5-dione (80 mg) was obtained as white crystals. The obtained crystals are 20% trifluoroacetic acid / dichloromethane solution (2
mL) and stirred at room temperature overnight. Water and ethyl acetate (100 mL) were added and partitioned, and the obtained organic layer was washed with saturated brine. The extract was dried over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel chromatography (hexane: ethyl acetate = 1: 1) to obtain 27 mg of the title compound as a brown solid. ¹ H-NMR (CDCl ₃ ) δ 4.54 (2H, t, J = 4.4 Hz), 4.63 (2
H, t, J = 4.4 Hz), 7.33-7.43 (4H, m), 7.48-7.63 (4
H, m), 7.86-7.95 (2H, m), 8.05 (1H, d, J = 7.5 H
z), 8.20 (1H, d, J = 7.3 Hz).

Test Example 1 Chymase Inhibitory Activity (Test Method) The chymase inhibitory activity was determined by the method of Kato et al.
iochem., 103, 820 (1988)). That is, a test substance (2.5 μL) dissolved in dimethyl sulfoxide (DMSO) was prepared with 50 mM Tris-HCl buffer (pH 8.0) so that the enzyme activity of the recombinant human chymase (JP-A-10-87567) was 2.3 μUnit. After adding 62.5 μL of the solution and incubating at 30 ° C for 5 minutes, 0.6 mM Suc-Ala-Ala-Pro-Phe-MCA as a substrate
(Peptide Laboratories) / Tris buffer (125 μL) was added to prepare a reaction solution. This reaction solution was set in a multi-well plate reader CYTOFLUOR Series 4000 (manufactured by Applied Biosystems), and changes in fluorescence intensity were measured over time at 30 ° C. for 30 minutes (excitation wavelength 360 n
m, detection wavelength 450 nm).

The control is DM containing no test substance.
Using 2.5 μL of SO, the same treatment and measurement were performed. The blank was 50 mM instead of the chymase solution (pH 8.
0) Tris-hydrochloric acid buffer was added and treated in the same manner, and the measurement was carried out.
The chymase inhibition rate (%) was determined from the change in fluorescence intensity, the slope of the approximate straight line of the test substance (S), the slope of the approximate straight line of the control (C), the slope of the approximate straight line of the blank of the test drug (Bs), and the control. The slope (Bc) of the blank approximation line was calculated and calculated from the following formula. Inhibition rate (%) = [1- (S-Bs) / (C-Bc)] × 1
00 (Test result) The chymase inhibitory activity of the compound of the present invention (8 concentrations) was measured by the above-mentioned method, and 50% inhibitory concentration (I
C ₅₀ ) was calculated, and the results are shown in Table 1.

[Table 1]

Test Example 2 Tryptase Inhibitory Activity (Test Method) Tryptase inhibitory activity was determined by the method of Muramatsu et al. (Biol. Chem. Hoppe-Seyler, 369, p. 617 (1988).
Year)). That is, 2.5 μL of the test substance dissolved in DMSO was added to human lung tryptase (SIGM
0.1) so that the enzyme activity of A) may be 7.9 μUnit.
After adding 62.5 μL of a solution prepared with M phosphate buffer-1.5 M NaCl (pH 7.1) and incubating at 30 ° C. for 5 minutes, 0.6 mM Boc-Val-Pro-Arg-M was used as a substrate.
CA.HCl (manufactured by BACHEM) /0.1M phosphate buffer (pH
125 μL of 7.1) was added to obtain a reaction solution. Set this reaction solution in a multi-well plate reader and
The change in fluorescence intensity was measured with time at 30 ° C. (excitation wavelength 360 nm, detection wavelength 450 nm).

The control is DM containing no test substance.
Using 2.5 μL of SO, the same treatment and measurement were performed. In the blank, 0.1 M phosphate buffer-1.5 M NaCl (pH 7.1) was added instead of the tryptase solution, and the same treatment was performed. The tryptase inhibition rate (%) was determined from the change in fluorescence intensity, the slope of the approximate straight line of the test substance (S), the slope of the approximate straight line of the control (C), the slope of the approximate straight line of the blank of the test drug (Bs), and the control. The slope (Bc) of the blank approximation line was calculated and calculated from the following formula. Inhibition rate (%) = [1- (S-Bs) / (C-Bc)] × 1
00 (Test result) The tryptase inhibitory activity of the compound of the present invention (8 concentrations) was measured by the above-mentioned method, and 50% inhibitory concentration (I
C ₅₀ ) was calculated, and the results are shown in Table 2.

[Table 2] The results of tests 1 and 2 show that the compound represented by the general formula (I) of the present invention has chymase and tryptase inhibitory activity.

(Formulation Example 1) Tablet Compound 1 50 mg Lactose 80 mg Starch 17 mg Magnesium stearate 3 mg Crystalline cellulose 10 mg
A tablet is formed by a conventional method using the above ingredients as a material for one tablet. The tablets may be coated with sugar coatings and films such as ethyl cellulose.

(Formulation Example 2) Capsule compound 2 75 mg Mannitol 75 mg Starch 17 mg Calcium stearate 3 mg The above ingredients are uniformly mixed as one capsule material,
Granules are formed by a conventional method and filled into hard capsules. The filled granules may be coated with a sugar coating and a film (eg, ethyl cellulose) if necessary.

(Formulation Example 3) Aqueous suspension ophthalmic solution Compound 12 0.5 g Hydroxypropyl methylcellulose 0.1 g Sodium chloride 0.9 g Sodium dihydrogen phosphate dihydrate 0.1 g Benzalkonium chloride 0.005 g 0 1N Sodium hydroxide proper amount (pH 7.2) Purified water 100 mL Totally about 80 mL of purified water is heated and dispersed with hydroxypropylmethylcellulose, and then cooled to room temperature to dissolve. Sodium chloride, sodium dihydrogen phosphate dihydrate and benzalkonium chloride are added to and dissolved in this solution, and 0.1N sodium hydroxide is added to adjust the pH to 7.2. Compound 12 is added to this liquid and uniformly suspended by a homogenizer. Purified water is added and the total amount is 100m
L to prepare an aqueous suspension eye drop.

[0039]

INDUSTRIAL APPLICABILITY Since the compound represented by the general formula (I) of the present invention or a pharmaceutically acceptable salt thereof has excellent chymase and / or tryptase inhibitory activity, various diseases in which chymase and tryptase are involved. Prevention /
It is useful as a therapeutic agent.

Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61P 9/00 A61P 9/00 11/00 11/00 17/00 17/00 27/02 27/02 27/06 27 / 06 27/10 27/10 29/00 29/00 31/12 31/12 37/08 37/08 43/00 111 43/00 111

Claims (10)

[Claims] 1. A compound represented by the general formula (I): [In the formula, A represents a carbonyl group or a sulfonyl group,
R ¹ represents a naphthyl group, R ² represents a hydrogen atom or an optionally substituted lower alkyl group, or —BR ⁴ , (B represents a carbonyl group or a sulfonyl group, R ⁴ represents an aryl group), and R ³ represents a substituted group. Represents an aryl group which may be. ] The compound or its pharmaceutically acceptable salt represented by these. 2. The compound according to claim 1, wherein R ³ is a phenyl group, or a pharmaceutically acceptable salt thereof. 3. A and B are carbonyl groups.
The described compound or a pharmaceutically acceptable salt thereof. 4. A medicine containing the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof. 5. A chymase and / or tryptase inhibitor containing the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof. 6. The pharmaceutical according to claim 4, which is a prophylactic or therapeutic agent for diseases involving chymase and / or tryptase. 7. A disease involving chymase is a retina choroidal disease,
The medicine according to claim 6, which is glaucoma, myopia or eye strain. 8. The disease involving tryptase is blood coagulation disorder, skin disease, interstitial pneumonia, pulmonary fibrosis, liver fibrosis, cirrhosis, pterygium, periodontal disease or viral disease.
The medicine according to. 9. The medicine according to claim 6, wherein the diseases involving chymase and tryptase are allergic, inflammatory or cardiovascular diseases. 10. A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier.