WO2001094326A1

WO2001094326A1 - Novel thiazolidinedione derivatives and use thereof as drugs

Info

Publication number: WO2001094326A1
Application number: PCT/JP2001/004469
Authority: WO
Inventors: Yusuke Sakai; Jun Inoue
Original assignee: Senju Pharmaceutical Co., Ltd.
Priority date: 2000-06-07
Filing date: 2001-05-28
Publication date: 2001-12-13
Also published as: AU2001258854A1

Abstract

Novel compounds of the general formula (|) or pharmaceutically acceptable salts thereof exhibit chymase-inhibitory activity and are usable as preventive and therapeutic drugs for allergic and inflammatory diseases, glaucoma, and so on. (In the formula (|), A is carbonyl or sulfonyl; R1 is hydrogen or a benzene ring; R2 is an optionally substituted benzene ring; and R3 is an aromatic hydrocarbon group.)

Description

Description New thiazolidinediene derivatives and their pharmaceutical applications

The present invention relates to novel thiazolidinediene derivatives and pharmaceutical uses thereof. These derivatives have chymase inhibitory activity and are useful for the prevention and treatment of various diseases involving chymase. Background art

Chymase is one of the neutral serine proteases (about 30 kD), but it is an enzyme that converts angiotensin I to angiotensin 11 in tissues ["Biol. Chem. , 265, 22348 (1990)], it is considered to be involved in the development of heart and circulatory system diseases caused by Anji Taishin 11. In addition, chymase has been shown to activate collagen from collagenase to active collagenase, limit the degradation of extracellular matrix, trombin and IG, and promote the release of histamine from mast cells. Biochem. 103, 820 (1988)], chymase is considered to be involved in allergic or inflammatory diseases. Furthermore, although the function of chimase in ocular tissues has not yet been fully elucidated, it is involved in regulation of ocular inflammation and allergy, ocular circulation (eye blood flow, aqueous humor circulation) and ciliary muscle. it seems to do. From the above-mentioned widespread action of chymase in vivo, inhibitors of such enzymes are expected to be useful as preventive and therapeutic agents for various diseases. As chymase inhibitors, conventionally, imidazolidine derivatives (W09604248), acetate amide derivatives (W09809949), triazine sulfone derivatives (JP-A-10-245384), and hydantoin derivatives (JP-A-9-31061) ), Quinazoline derivatives (W09711941), phenol ester derivatives (JP-A-10-87567), thiazine derivatives (EP 0713876), heterocyclic amide compounds (W09633974, WI9818794), peptide compounds (Proc. Natl. Acad ScI. USA, Vol. 92, p. 6738, (1995)], but these compounds have not yet been put to practical use. In recent years, compounds having a thiazolidine skeleton and having a chimase inhibitory activity have been disclosed (JP-A-2000-95770, WO 00/06594), but these compounds have not been put into practical use. In addition, some compounds having an aldose reductase inhibitory activity have been reported for diphenylthiazolidinediene derivatives (Chem. Pharm. Bull. 30, 3601-3616 (1982)). Is not reported at all.

Under such a state of the art, the present inventors have conducted research for the purpose of developing a novel thiazolidinediene derivative having a chymase inhibitory action.

An object of the present invention is to provide a novel thiazolidinedione derivative having an excellent chimase inhibitory action. It is another object of the present invention to provide a method for preventing and treating diseases associated with chimase. Disclosure of the invention

The present inventors have conducted intensive studies to achieve the above object, and as a result, have created a novel thiazolidinedione derivative having an excellent chymase inhibitory action, and have further studied to complete the present invention.

That is, the present invention

1. General formula (I)

(I)

[Wherein A represents a carbonyl group or a sulfonyl group, R ¹ represents a hydrogen or a benzene ring, R ² represents an optionally substituted benzene ring, and R ³ represents an aromatic hydrocarbon group. A thiazolidinedione derivative represented by the formula or a pharmaceutically acceptable salt thereof,

2. In the general formula (I), A represents a carbonyl group, and R ¹ represents hydrogen. A zolidinedione derivative or a pharmaceutically acceptable salt thereof,

3. The thiazolidinediene derivative according to the above 1, wherein in the general formula (I), R ¹ and R ² are both a benzene ring.

4. A drug containing the thiazolidinedione derivative or the pharmaceutically acceptable salt thereof according to the above 1 to 3,

5. A chymase inhibitor comprising the thiazolidinediene derivative or the pharmaceutically acceptable salt thereof according to the above 1 to 3,

6. The medicament according to the above 4, which is a prophylactic or therapeutic agent for a disease associated with chymase.

7. The medicament according to the above 6, wherein the disease associated with chymase is a circulatory disease.

8. The medicament according to the above 6, wherein the disease associated with chymase is an allergic or inflammatory disease.

9. The disease according to the above 6, wherein the disease involving chymase is retinochoroidal disease or glaucoma.

10. The chymase inhibitor according to the above 5, which is a ciliary muscle contraction and relaxation regulator,

. 1 1 Osamu chymase mediated diseases administering the 1-3 thiazolidinedione derivative or a pharmaceutically acceptable salt thereof according to a patient chymase suffering a disease involving ^care:, Neyobi

12. Use of the thiazolidinedione derivative or the pharmaceutically acceptable salt thereof according to any one of the above-mentioned to 3, for producing a preventive or therapeutic drug for a chimase-related disease,

About.

In the novel thiazolidinedione derivative of the present invention represented by the general formula (I), the substituent which may be substituted on the benzene ring represented by is halogen (chlorine, bromine, fluorine, etc.), hydroxyl group, carboxyl group, Examples thereof include an alkyl group which may have a group, an alkoxy group which may have a substituent, and an aromatic ring group which may have a substituent.

Examples of the alkyl group which may be substituted on the benzene ring include a linear or branched alkyl group having 1 to 9 carbon atoms, such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group and an isobutyl group. Tert-butyl, pentyl, isopentyl, tert-pentyl, 1-methylpentyl, 2-methylpentyl, A hexyl group, a octyl group, a nonyl group, etc., preferably an alkyl group having 1 to 6 carbon atoms, for example, a methyl group, an ethyl group, a propyl group, an isobutyl group, a tert-butyl group, a pentyl group, an isopentyl group, tert-pentyl, hexyl, 1-methylpentyl, 2-methylpentyl and the like. Examples of the substituent which the alkyl group may have include an aryl group such as a phenyl group and a naphthyl group, and a phenyl group is preferable. These aryl groups may further have a substituent such as halogen (chlorine, bromine, fluorine, etc.). Examples of the alkoxy group which may be substituted on the benzene ring include a linear or branched alkoxy group having 1 to 10 carbon atoms, such as a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, and a methoxy group. , Isobutoxy group, tert-butoxy group, pentyl group, isopentyl group, tert-pentyl group, hexyl group, 1-methylpentyl group, 2-methylpentyloxy group, Examples include a butyloxy group, an octyloxy group, a nonyloxy group, and a decyloxy group, and preferred are alkoxy groups having 1 to 6 carbon atoms, such as a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group. Butoxy, isobutoxy, tertbutoxy, pentyloxy, isopentyl, tert-pentyl Hexyl old alkoxy group, I - methylpentyl old alkoxy group, 2 - methylpentyl old alkoxy group. Examples of the substituent which the alkoxy group may have include an aryl group such as a phenyl group and a naphthyl group, and a phenyl group is preferable. These aryl groups may further have a substituent such as halogen (chlorine, bromine, fluorine, etc.).

Examples of the aromatic ring group which may be substituted on the benzene ring include an aryl group, for example, a phenyl group, a naphthyl group, an indenyl group, an azulenyl group, a phenyl phenyl group, a phenanthrenyl group, and an anthryl group. No. Preferred is a phenyl group. These aromatic ring groups may be further substituted with a halogen (eg, chlorine, bromine, fluorine, etc.), a hydroxyl group, an alkyl group, an alkoxy group, or the like.

These substituents which may be substituted on the benzene ring may be substituted at any of 2-, 3- and 4-positions. Further, it may have two or more same or different substituents, and the two or more substituents may be 2, 3-, 2, 4, 1, 2, 5-, 2, 6-, 3,4-, 3,5-disubstituted, 2,3,4-mono, 2,4,6-, 2,3,5-trisubstituted, 2,3,4,5-tetrasubstituted Or 2, 3, 4, 5, 6-pentasubstituted form. Preferably, a 3,4-disubstituted product is used. Specifically, for example, a 3-ethoxy-14-pentyloxyphenyl group and the like can be mentioned.

In the general formula (I), the aromatic hydrocarbon group represented by R ³ is preferably a group having 6 to 18 carbon atoms, for example, a phenyl group, a naphthyl group, an anthryl group, a phenanthrenyl group, Examples thereof include a naphthacenyl group and a triphenylenyl group, preferably a naphthyl group, and more preferably a 1-naphthyl group or a 2-naphthyl group.

The compound of the present invention includes, for example, 5- (3-ethoxy-4-pentyloxyphenyl) -1,3- (2-naphthyl) -1,1,3-thiazolidine-2,4-dione, 5- (3 —Ethoxy 1 4-pentyl xyphenyl) 1 3— (1—Naphthoyl) 1,1,3-thiazolidine—2,4-dione, 5— (3-ethoxy—4_pentyl xy phenyl) 1-3 benzoyl—1,3 _Thiazolidine-1 2,4-diene, 5,5-diphenyl-3- (2-naphthyl) _1,3-Thiazolidine-2,4 dione, 5,5-diphenyl-3- (1 Naphthyl) _ 1,3-thiazolidin -2,4 diene, 5,5-diphenyl-3-(2-naphthylsulfonyl) -1,1,3-thiazolidine-1,2,4-diethylene and , 5,5-diphenyl-3- (1-naphthylsulfonyl) -1-1,3-thiazolidine- 1,2,4-dione Etc. can be mentioned, et al. Are.

The compound represented by the general formula (I) of the present invention can be produced, for example, by the following production method or according to the method. Expression

X- A- R

[In the formula (II), X represents an octagen atom (chlorine, bromine, fluorine, etc.), and A and R ³ have the same meanings as in the description of the formula (I). The acid octalide derivative represented by

(Ml)

[In the formula (III), R ′ and R ² are the same as those in the formula (I). By reacting with a 5-substituted 1,3-thiazolidine-2,4-dione derivative or a salt thereof, and subjecting the compound to a general formula by recrystallization or column chromatography.

The compound represented by (I) can be produced. Such a reaction can be carried out in a reaction solvent, in an organic solvent and in the presence / absence of an organic base. Examples of the reaction solvent that can be used in this reaction include anhydrous methylene chloride, chloroform, N, N-dimethylformamide, benzene, toluene, ethylbenzene, cyclohexane, hexane, heptane, getyl ether, terephthalic acid Conventional solvents that do not adversely affect the reaction, such as trihydrofuran (hereinafter sometimes referred to as THF), or a mixed solvent thereof may be used. Preferred is THF or a mixed solvent of THF and N, N-dimethylformamide.

Inorganic bases that can be used in this reaction include alkali metal hydrides such as sodium hydride, alkali metal carbonates such as potassium carbonate, and alkali metal bicarbonates such as sodium hydrogen carbonate. Organic bases that can be used in this reaction include trialkylamines such as triethylamine and diisopropylethylamine, pyridine, lutidine, picoline, 4-dimethylaminopyridine and the like. Particularly preferred base used is sodium hydride. Such inorganic and organic bases are preferably used in a ratio of 0.5 to 1.5 mol per 1 mol of the thiazolidinediene derivative represented by the formula (III). The reaction temperature is usually in a range from under cooling to under heating, and preferably in a range from −10 ° C. to 30 ° C.

Examples of the pharmaceutically acceptable salt of the compound represented by the general formula (I) thus obtained include, for example, alkali metal salts such as sodium salt and potassium salt, and calcium salts. Alkaline earth metal salts such as sodium salt, magnesium salt, etc., salts with inorganic acids such as hydrochloride, hydrobromide, sulfate, nitrate, phosphate, and acetate, citrate, toluene sulfone Examples thereof include salts with organic acids such as acid salts, but are not limited thereto.

Furthermore, the present invention includes various solvates and polymorphs of the compound represented by the general formula (I), and prodrugs thereof.

The compound of the present invention represented by the general formula (I) or a pharmaceutically acceptable salt thereof (hereinafter may be abbreviated as the compound of the present invention) has chymase inhibitory activity, so Diseases involving chymase in blood animals (eg monkeys, dogs, cats, cats, guinea pigs, rats), eg heart and cardiovascular diseases (restenosis after vascular injury due to percutaneous transluminal coronary angioplasty, hypertension) Prevention and treatment of diseases, arteriosclerosis, myocardial infarction, cardiac hypertrophy, cardiac insufficiency, diabetic and non-diabetic renal disorders, peripheral circulatory disorders, etc. , Macular degeneration, ischemic optic neuropathy, iridocyclitis, retinal artery occlusion, retinal vein occlusion, diabetic retinopathy, retinal disease Choroidal disease secondary to alteration, and glaucoma) , It is also used as a regulator of ciliary muscle contraction and relaxation to improve myopia and asthenopia, etc. It is also used for the whole body (e.g., gastrointestinal tract inflammation such as nephritis, hepatitis, pneumonia, and inflammation, atopy, arthritis, rheumatism) and ocular localization. (Keratoconjunctivitis, uveitis, orbital inflammation, spring catarrh, etc.) It can be appropriately used orally or parenterally as a preventive or therapeutic agent for inflammatory or allergic diseases.

Examples of the form of the preparation of the compound of the present invention include solid preparations such as tablets, granules, powders, capsules and ointments and liquid preparations such as injections and eye drops. Any of the preparations can be appropriately prepared by a known method. These preparations contain commonly used excipients (starch, pudose, fructose, sucrose, calcium phosphate, etc.), binders (starch, acacia, gelatin solution, sodium alginate, carmellose solution, etc.), disintegrants (starch, Calcium carbonate, crystalline cellulose, etc.), Lubricants (stearic acid, magnesium stearate, talc, etc.), Absorption promoters (thin glycolic acid, acetic acid, prillic acid, etc.), Buffering agents (boric acid, boric acid) Sand, sodium acetate, citrate buffer, phosphate buffer, etc.), surfactants (sodium lauryl sulfate, polysorbate 80, poly Oxyethylene hydrogenated castor oil, etc.), solubilizers (sodium lauryl sulfate, sodium benzoate, ethylenediamine, potassium iodide, etc.), preservatives (benzalcodium chloride, parabens, chlorobutanol, etc.), emulsifiers (gum arabic) , Tragacanth, gelatin, polyvinylpyrrolidone, etc.), tonicity agents (sodium chloride, glycerin, mannitol, etc.), stabilizers (sodium edetate, sodium pyrosulfite, etc.),

PH adjusters (hydrochloric acid, citric acid, sodium hydroxide, etc.) may be used as appropriate. When the compound of the present invention is used as a prophylactic or therapeutic agent for cardiovascular or cardiovascular diseases, the dosage depends on the type of disease to be treated, the type of compound used, the age, weight, symptom of the patient and the dosage form thereof. For example, in the case of oral administration, it is better to administer to an adult patient several times a day, about 1 mg to 100 mg per dose. In the case of injections, it is recommended to administer about 0.1 mg to 3 Omg to adult patients once a day. Further, when used as a topical ophthalmic dosage form for ocular circulatory disorders, the compound of the present invention may be used in an amount of about 0.01 w / v% to 1.1 w / v.

%, Preferably about 0.05 w / v% to 0.5 w / v%, one to several drops at a time, about 1 to 8 times a day. Even if the disease is local to the eye, it may be administered systemically for the purpose of efficiently reaching the compound to the inner eye such as the retina.

The compound of the present invention may be used alone or in an appropriate combination of two or more of the compounds of the present invention, if necessary.

The compound of the present invention may be used in an appropriate combination of a chymase-inhibiting component not included in the present invention, another component having the same medicinal properties as the present invention, and other medicinal components, as long as the object of the present invention is not contradicted. it can. BEST MODE FOR CARRYING OUT THE INVENTION

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.

5,5-diphenyl-1,3-thiazolidine-1,4-diamine is synthesized according to the method of Sohda et al. (Chem. Pharm. Bui I. 30 (10), 3601-3616 (1982)). did. In the physical properties of the compound described in the examples, the nuclear magnetic resonance spectrum (NMR) is It was measured using Gemini 2000. Example 1

5- (3-Ethoxy 4-pentyl xyphenyl) 3- (2-Naphthyl) 1-1,3-Thiazolidine 1-2,4-

5- (3-Ethoxy 4-pentyl xyphenyl) _ 1,3 _thiazolidine 1,2,4-diphenyl 2.0 dissolved in 1 ~ 1 (15 mL), ice; 0 ° C At room temperature, 0.31 g of sodium hydride (60%, oil) was added. After stirring for 30 minutes, 1.41 g of 2-naphthoyl chloride was added at 0 ° C, and the mixture was stirred at room temperature for 2.5 hours. After careful addition of water, 20 OmL of ethyl acetate was added and partitioned. The obtained organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off. Further purification was performed by silica gel chromatography (hexane: ethyl acetate = 5: 1) to obtain 0.88 g of the title compound (compound 1) as a pale yellow powder.

'H-related R (DMS0-d ₆ ) 50.88 (3H, t, J = 6.7 Hz), 1.27-1.40 (7H, m), 1.66-1.73 (2H, m), 3.97 (2H, t, J = 6.6 Hz), 4.03-4.11 (2H, m), 6.07 (1H, s), 7.02 (1H, d, J = 8.2 Hz), 7.11 (1H, d, J = 8.2 Hz), 7.19 (1H, d, J = 1.8 Hz), 7.67-7.80 (2H, m), 7.98-8.18 (4H, m), 8.81 (1H, s).

^{, 3 C-NMR (D S0} -d 6) <5 13,9, 14.7, 21.8, 27.7, 28.3, 53.8, 64.2, 68.4, 113. 7, 114.1, 121.6, 124.5, 126.2, 127.6, 127.8, 127.9, Example 2 129.3, 129.9, 130.2, 131.9, 133.9, 136.1, 148.5, 149.1, 167.2, 169.1, 172.1.

5- (3-ethoxy) 4-pentyl xyphenyl) -3- (1-naphthyl) — 1,3-thiazolidine 1-2,4-di

The same operation as in Example 1 was carried out except that 1-naphthoyl chloride was used instead of 2-naphthoyl chloride, to give the title compound (compound 2) as white crystals (yield 61).

%).

'Η-Oki R (DMS0-d ₆ ) (50.87 (3H, t, J = 6.1 Hz), 1.10-1.35 (7H, m), 1.69 (2H, m), 3.93-4.11 (4H, m), 5.99 (1H, s), 6.98-7.14 (3H, m), 7.64-7.80 (3H, m), 8.12 (1H, d, J = 7.9 Hz), 8.35 (2H, d, J = 7.5 Hz), 8.65 (1H, d, J = 8.4 Hz).

^{, 3} C-NMR (DMSO-d ₆ ) δ 13.9, 14.7, 21.9, 27.7, 28.4, 53.4, 64,2, 68.4, 113.7, 114.1, 121.6, 124.2, 125.1, 126.3, 127.2, 127.4, 129.2, Example 3 129.5, 130.3, 132.9, 133.5, 136.2, 148.5, 149.1, 166.6, 169.1, 171.9.

5— (3-ethoxy—4-pentyl xyphenyl) — 3-benzoyl—1,3-thiazolidine-1,2,4-diene

The same operation as in Example 1 was carried out except that benzoyl chloride was used instead of 2-naphthoyl chloride, to give the title compound (compound 3) as white crystals (yield 9%).

'H-Country R (DMS0-d ₆ ) (50.88 (3H, t, J = 7.1 Hz), 1.29-1.41 (7H, m), 1.70 (2H, t, J = 6.9 Hz), 3.96 (2H, t , J = 6.7 Hz), 4.01-4.09 (2H, m), 6.04 (1H, s), 6.98-7.07 (2H, m), 7.13 (1H, d, J = 2.0 Hz), 7.62 (2H, td, J = 7,1, 1.7 Hz), 7.82 (1H, tt, J = 6.8, 1.2 Hz), 8.05 (2H, dt, J = 6.6, 1.3 Hz).

' ³ C-Oki R (DMS0-d ₆ ) δ 13.9, 14.7, 21.8, 27.7, 28.3, 53.7, 64.2, 68.4, 113.7, 114.1, 121.5, 126.2, 129.5, 130.5, 130.7, 136.0, 148.5, 149.1 , 167.2, 169.1, 171.9.

5, 5-diphen-2-l 3- (2-naphthyl) — 1, 3-thiazolidine

Dissolve 2.0 _§ of 5,5-diphenyl-3-thiazolidine-2,4-dione in 1 ^ F (15 mL) and add sodium hydride (60%, oil at 0 ° C under ice-cooling). 0.36 g was added. After stirring for 30 minutes, 1.70 g of 2-naphthoyl chloride was added at 0 ° C, and the mixture was stirred at room temperature for 2.5 hours. After careful addition of water, ethyl acetate 2 O OmL was added and partitioned. The obtained organic layer was washed with saturated saline, dried using anhydrous magnesium sulfate, and then the solvent was distilled off. After recrystallization from a mixed solvent of hexane, isopropyl ether and isopropyl alcohol, recrystallization gave the title compound (compound 4) was obtained as white crystals (yield 86%).

Ή-N R (CDCh) δ 7.41-7.50 (6Η, m), 7.52-7.58 (5H, m), 7.65 (1H, ddd, J

= 8.1, 6.9, 1.2 Hz), 7.70 (1H, d, J = 8.5 Hz), 7.83-7.91 (3H, m), 8.12 (1 H, s).

5,5-diphenyl-3- (1-naphthyl) 1-1,3-thiazolidine-2,4

Dissolve 0.2 g of potassium salt of 5,5-diphenyl-1,3-thiazolidine_2,4-diamine in THF (5 mL) and add 0.15 g of 1-naphthoyl chloride at room temperature. The mixture was stirred at room temperature for 12 hours. After evaporating the solvent under reduced pressure, the residue was dissolved in ethyl acetate 1 O OmL. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The product was further purified by silica gel chromatography (hexane: ethyl acetate = 4: 1) to give the title compound (compound 5) as white crystals (44% yield). Ή-NMR (CDCh) d 7.37-7.51 (11H, m), 7.57-7.71 (3H, m),

7.92 (1H, d, J = 8.5 Hz), 8.11 (1H, d, J = 8.2 Hz), 8.80 (1H, d, J = 9.0 Hz).

5,5-diphenyl-3- (2-naphthylsulfonyl) 1-1,3-thiazolidin-2,4-dione

Dissolve 0.2 g of 5,5-diphenyl-1,3-thiazolidine_2,4-dione in THF (1 OmL) and add sodium hydride (60%, oil) at 0 ° C under ice-cooling. 0.036 g was added. After stirring for 30 minutes, 0.2 g of 2-naphthylsulfonyl chloride was added at 0 ° C, and the mixture was stirred at room temperature for 2.5 hours. After the solvent was distilled off, 1 O OmL of ethyl acetate was added, and the mixture was washed with saturated saline and dried with anhydrous magnesium sulfate. After evaporating the solvent, the residue was recrystallized from ethyl acetate to give the title compound (compound 6) as white crystals (yield 59%). R-CD R (CDC) 57.24-7.35 (10H, m), 7.67 (1H, ddd, J = 6.9, 5.5, 1.4 Hz), 7.74 (1H, td, J = 8.0, 1.4 Hz), 7.94-8.02 Example 7 (3H, m), 8.05 (1H, dd, J = 8.8, 1.8 Hz), 8.73 (1H, d, J = 1.2 Hz).

5,5-diphenyl-3- (1-naphthylsulfonyl) 1-1,3-thiazolidin-2,4

The title compound (Compound 7) was obtained as white crystals (yield 16%) „'H-, except that 1-naphthylsulfonyl chloride was used instead of 2-naphthylsulfonyl chloride. Seki R (CDCL) δ 7.13-7.31 (10H, m), 7.50-7.65 (3H, m), 7.96 (1H, d, J = 7.9 Hz), 8.19 (1H, d, J = 8.1 Hz), 8.54- 8.58 (2H, m). Test Example 1. Chymase inhibitory activity

Chymase inhibitory activity was measured according to the method of Kato et al. (J. Biochem., 103, 820 (1988)). That is, 2.5 ^ L of the test substance dissolved in dimethyl sulfoxide (hereinafter referred to as DMSO) was added to a solution prepared with HEPES buffer so that the enzyme activity of recombinant human chymase (JP-A-10-87567) was 2.3 Units. L, and incubated at 30 ° C for 5 minutes, and added 125 L of 0.6 mM Suc-AIa-AIa-Pro-Phe-MCA (manufactured by Peptide Research Laboratories) / Tris buffer as a substrate. The reaction solution was used. The reaction solution was set in a multiwell plate reader CYT0FLU0R Series 4000 (manufactured by Perceptive Biosystems), and the change in fluorescence intensity was measured over time at 30 ° C for 30 minutes (excitation wavelength 360 nm, detection wavelength 450 nm),

Control was performed using DMS02.5ALL containing no test substance, and treated and measured in the same manner. Planck added HEP ESS buffer instead of chymase solution, treated similarly, and measured.

The chymase inhibition rate (%) was calculated from the change in fluorescence intensity based on 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 Planck of the test substance (Bs), and the control. The slope (Be) of the Planck approximate straight line was calculated from the following equation.

Inhibition rate (%) = [1 _ (S—Bs) / (C—Bc)] X 100 For the compound of the present invention, 50% inhibition concentration (IC _5D ) was calculated from the chymase inhibitory activity determined by this method. The results are shown in Table 1. This result indicates that the compound represented by the general formula (I) of the present invention has chymase inhibitory activity.

〔table 1〕

Formulation Example 1 Tablet

Compound 1 b 0 mg

Lactose 80 mg

Starch 17 mg

Magnesium stearate 3 mg

Microcrystalline cellulose 10 mg

Tablets were formed by a conventional method using the above ingredients as a material for one tablet. The tablets may be coated with a sugar coating and a film (eg, technical cellulose). Formulation Example 2 Capsules

Compound 2 75 mg

Mannit 7 5 mg

Starch 17 mg

Calcium stearate 3 mg The above components were uniformly mixed as a material for one capsule, granulated by a conventional method, and filled into hard capsules. The granules to be filled may be coated with a sugar coating and a film (eg, ethyl cellulose, etc.) if necessary. Formulation Example 3 aqueous suspension ophthalmic solution

Compound 4 0.5 g

Hydroxypropyl methylcellulose 0.1 g

0.9 g of sodium chloride

Sodium dihydrogen phosphate 'dihydrate 0.1

Benzalkonium chloride 0.005 g

0.1 N NaOH proper amount (PH 7,2)

Purified water 1 O OmL

After heating and dispersing hydroxypropyl methylcellulose in about 8 OmL of purified water, the mixture was cooled to room temperature and dissolved. Sodium chloride, sodium dihydrogen phosphate dihydrate and benzalkonium chloride were added to this solution to dissolve it, and 0.1 N sodium hydroxide was added to adjust the pH to 7.2. Compound 4 was added to this solution, and the mixture was uniformly suspended with a homogenizer. Purified water was added to adjust the total volume to 1 O OmL to prepare an aqueous suspension ophthalmic solution. Industrial applicability

The compound of the present invention represented by the general formula (I) or a pharmaceutically acceptable salt thereof has excellent chymase inhibitory activity, and therefore has various chymase-related diseases such as systemic and local ocular circulatory system. It is useful as a prophylactic / therapeutic agent for diseases, inflammatory and allergic diseases, and as a regulator of ciliary muscle contraction tone.

Claims

General formula (I)

(I)

[In the formula (1), A represents a carbonyl group or a sulfonyl group, fT represents a hydrogen or benzene ring, R ² represents an optionally substituted benzene ring, and R ³ represents an aromatic hydrocarbon. Represents a group. ] The thiazolidinedione derivative represented by these, or its pharmaceutically acceptable salt.

2. — The thiazolidinedione derivative or the pharmaceutically acceptable salt thereof according to claim ¹ , wherein in the general formula (I), A is a carbonyl group, and R ¹ is hydrogen.

3. The thiazolidinediene derivative according to claim 1, wherein in formula (I), R ′ and R ² are both a benzene ring.

4. A medicament comprising the thiazolidinediene derivative according to claims 1 to 3 or a pharmaceutically acceptable salt thereof.

5. A chymase inhibitor comprising the thiazolidinedione derivative according to claims 1 to 3 or a pharmaceutically acceptable salt thereof.

6. The medicament according to claim 4, which is a prophylactic or therapeutic agent for a disease associated with chimase.

7. The medicament according to claim 6, wherein the disease associated with chimase is a circulatory disease.

8. The medicament according to claim 6, wherein the disease associated with chymase is an allergic or inflammatory disease.

9. Claim 6 wherein the disease involving chymase is retinochoroidal disease or glaucoma. The medicament according to claim.

10. The chymase inhibitor according to claim 5, which is a regulator of ciliary muscle contraction and relaxation.

11. A method for treating a chymase-related disease, which comprises administering the thiazolidinediene derivative or the pharmaceutically acceptable salt thereof according to claims 1 to 3 to a patient suffering from a disease involving chymase.

12. Use of the thiazolidinedione derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3 for producing a prophylactic or therapeutic drug for chymase-related diseases.