WO2006064825A1

WO2006064825A1 - Therapeutic agent for dry eye

Info

Publication number: WO2006064825A1
Application number: PCT/JP2005/022913
Authority: WO
Inventors: Masatsugu Nakamura; Shin-Ichiro Hirai; Keiichi Shibagaki
Original assignee: Santen Pharmaceutical Co., Ltd.
Priority date: 2004-12-14
Filing date: 2005-12-14
Publication date: 2006-06-22

Abstract

A novel use of a compound represented by the general formula (1) or a salt thereof. The compound represented by the general formula (1) or salt thereof produces an excellent alleviating effect in a corneal disorder healing effect test using a dry eye model. It is useful as a therapeutic agent for dry eye or diseases accompanying dry eye. Symbol A is lower alkylene or lower alkenylene; ring X is a nonaromatic ring or nitrogenous aromatic heterocycle; R1 is hydrogen or lower alkyl and R2 is hydroxy, provided that R1 may be fused to R2 to form a lactone ring; R3 is hydrogen or lower alkyl; R4 is optionally substituted lower alkyl, cycloalkyl, optionally substituted aryl, hydroxy or an ester thereof, lower alkoxy, carboxy or an amide thereof, or lower alkylamino or an amide thereof; and m is an integer of 0-4, provided that when m is 2 or larger, then the R4's may be the same or different.

Description

Specification

Dry eye treatment

Technical field

[0001] The present invention relates to a therapeutic agent for dry eye comprising a statin compound as an active ingredient.

Background art

The cornea is a transparent avascular tissue having a diameter of about 1 cm and a thickness of about 1 mm, and the conjunctiva is a mucous membrane covering the surface of the eyeball behind the cornea edge and the back of the eyelid. It is known that when the cornea and conjunctiva are damaged, visual function is seriously affected. Corneal and conjunctival damage associated with dry eye adversely affects the normal reconstruction of the corneal epithelium and conjunctival epithelium, and as a result, the structure and function of the corneal stroma and corneal endothelium can be impaired. In recent years, with the development of cell biology, factors involved in cell division, migration, adhesion, extension and differentiation have been elucidated, and these factors play an important role in repairing keratoconjunctival disorders. (Non-patent document 1, Non-patent document 2).

[0003] On the other hand, statin compounds are known to suppress the biosynthesis of blood cholesterol and are widely used as therapeutic agents for hyperlipidemia and the like. Patent Document 1 describes that statins such as atorvastatin, lovastatin, pravastatin, flupastatin, cerivastatin, and simpastatin are useful as immunomodulators, immune inhibitors, and anti-inflammatory agents. Patent Document 2 describes that statin compounds such as cerivastatin, atorvastatin, sympastatin, and pravastatin are useful as therapeutic agents for TNF_a related diseases such as inflammatory diseases and cardiovascular diseases.

[0004] However, there are no reports on the pharmacological effects of statin compounds on keratoconjunctival diseases such as dry eye.

Patent Document 1: Japanese Translation of Special Publication 2004-512278

Patent Document 2: Japanese Patent Laid-Open No. 2001-294526

Non-Patent Document 1: Eyesight, 46, 738-743 (1992)

Non-Patent Document 2: Ophthalmic Surgery, 5, 719-727 (1992)

Disclosure of the invention Problems to be solved by the invention

[0005] It is an interesting task to search for new medicinal uses of statin compounds.

Means for solving the problem

[0006] The inventors of the present invention conducted intensive research in order to search for new pharmaceutical uses of statin compounds. In a corneal disorder healing efficacy test using a rat dry eye model, (+)-(IS, 3R, 7S, 8S, 8aR) -3, 7 Dimethinole 1, 2, 3, 7, 8, 8a Hexahydro 8-

[2— [(2R, 4R) — 4 Hydroxy-6-oxotetrahydro-1 2H Pyran-2-yl] ethyl] 1 Naphthyl 2, 2 Dimethylbutanoate (Sympastatin), (+)-(3R , 5R) —3, 5 Dihydroxy— 7— [(IS, 2S, 6S, 8S, 8aR) — 1, 2, 6, 7, 8, 8a Hexahydro_6_hydroxy_2_methyl_8 _ [( 23) _2_methylbutyryloxy] _1_ naphthyl] heptanoic acid (pravastatin), (+) _ (1S, 3R, 7S, 8S, 8aR) _3, Ί— Dimethinole _1, 2, 3, 7, 8, 8a— Hexahydro 8_ [2 _ [(2R, 4R) _4—Hydroxy-6-oxotetrahydro _ 2H _pyran _ 2 _yl] ethyl] _ 1 _Naphthyl (2S) _ 2 —Methylbutanoate (lovastatin) , (±) _ (3R *, 5S *, 6E) -3,5-Dihydroxy-7- [3- (4-Fluorophenyl) _1_ (1-methylethyl)-1H indole-2-yl] _6_heptene Acid (flupastatin), (+)-(3R, 5S, 6E) _3, 5-di Droxy 1-7- [2, 6 Diisopropyl 1 4- (4 Funelorelophenyl) 1 5- (Methoxymethyl) 3-pyridyl] -6-heptenoic acid (cerivastatin), (1) One (3R, 5R) -3, 5—Dihydroxyl 7— [2— (4 Fluorophenyl) 5— (1—Methylethyl) 3 Phenyl—4—Phenylaminocarbonyl 1H—pyrrole 1-yl] heptanoic acid (atorbus Tachin), (+) (3R, 5S, 6E) — 7— [2 Cyclopropyl 4- (4-fluorophenyl) quinoline 3-yl] —3,5-Dihydroxy-1-6-heptenoic acid (Pitapastatin) , Itapastatin), (+) — (3R, 5S, 6E) -3, 5-dihydroxy mono 7— [4- (4-fluorophenyl) 6-isopropylinole 2— [N-methylsulfonyl (N-methylsulfonyl) Amino] pyrimidine-5-yl] -6-heptenoic acid (rospastatin) or its salt It has been found that it exhibits an excellent corneal disorder improving effect and has led to the present invention.

That is, the present invention provides: [1] A therapeutic agent for dry eye or a disease associated with dry eye, comprising a compound represented by the following general formula (1) or a salt thereof as an active ingredient,

[Chemical 1]

(In the formula, A represents a lower alkylene group or a lower alkenylene group;

Ring X represents a non-aromatic ring or a nitrogen-containing aromatic heterocycle;

R ¹ represents a hydrogen atom or a lower alkyl group;

R ² represents a hydroxy group;

R ¹ and R ² may be condensed to form a rataton ring;

R ³ represents a hydrogen atom or a lower alkyl group;

R ⁴ is an optionally substituted lower alkyl group, cycloalkyl group, optionally substituted aryl group, hydroxy group or ester thereof, lower alkoxy group, carboxyl group or amide thereof, or lower alkyl An amino group or an amide thereof; m represents an integer of 0 to 4, and when m is 2 or more, each R ⁴ may be the same or different. )

[2] —The general formula (1) is

[Chemical 2]

Before [1], or a therapeutic agent for a disease associated with dry eye,

[3] —In the general formulas (1) to (3),

Ring X is

[Chemical 3]

Indicates;

R ⁵ and R ⁶ are the same or different and each represents a hydrogen atom, a hydroxy group, a lower alkoxy group or a lower alkyl group;

R ⁷ represents a hydroxy group or an ester thereof;

R ⁸ and R ¹¹ are the same or different and each represents a hydrogen atom, a lower alkyl group or an aryl group which may have a substituent;

R ⁹ and R ^1Q are the same or different and each represents an optionally substituted aryl group, carboxy group or amide thereof;

R ¹² represents a hydrogen atom or a lower alkyl group; R represents a hydrogen atom or a lower alkyl group;

R ¹⁴ represents a hydrogen atom or a lower alkyl group which may have a substituent;

R ¹⁵ represents an aryl group which may have a substituent;

R ¹⁶ and R ¹⁸ are the same or different and each represents a hydrogen atom, a lower alkyl group or an aryl group which may have a substituent;

R ¹⁷ represents a lower alkylamino group or an amide thereof;

R ¹⁹ represents a hydrogen atom or a lower alkyl group;

R ^2Q represents an aryl group which may have a substituent;

R ²¹ represents an aryl group which may have a substituent;

R ²² represents a cycloalkyl group before [1] or [2], or dry eye or a therapeutic agent for a disease associated with dry eye,

[4] 3, 7-Dimethinole _1, 2, 3, 7, 8, 8a—Hexahydro _8_ [2— [4-Hydroxy-6-oxotetrahydro 2H pyran-1-yl] ethyl] 1 naphthyl 2, 2 -Dimetholebutanoate, 3, 5 Dihydroxy-7— [1, 2, 6, 7, 8, 8a Hexahydro-6-hydroxy 2-methyl-8- [2-methylbutyryloxy] 1 naphthyl] heptanoic acid 3, 7 Dimethinole 1, 2, 3, 7, 8, 8a Hexahydro 8— [2- [4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl] ethyl] 1 naphthyl 2-methylbutanoate, 3, 5-dihydroxy 1—7- [3- (4-Fluorophenyl) -1- 1- (1-methylethyl) -1H-indole-2-yl] -6 heptenoic acid, 3, 5 dihydroxy 7-7 [2, 6-diisopropyl mono 4— (4-Fluorophenyl) -5- (methoxymethyl) 3-pyridinole] — 6 Heptenoic acid, 3, 5 Dihydroxy 1 7- [2— (4 Fluorophenyl) 1 5 — (1-Methylethyl) -3-Pheninole _ 4 _Pheninoreaminocanoleboninole 1H—Pyrroinole 1_yl] heptanoic acid , 7_ [2-Cyclopropinole _4_ (4-Fluorophenyl) quinoline _3—yl] _3, 5-Dihydroxy mono-6_heptenoic acid, 3, 5-Dihydroxy mono 7_ [4_ (4-fluorophenyl) -6-isopropyl 2— [N _Methyl _ (N _Methylsulfonyl) amino] pyrimidine _5_yl] _6_Before heptenoic acid [1] to [3] any force 4 accompanying dry eye or dry eye Therapeutic agent for diseases,

[5] —The compound represented by the general formula (1) is (+)-(lS, 3R, 7S, 8S, 8aR) —3, 7-dimethyl. Tinole 1, 2, 3, 7, 8, 8a Hexahydro 8— [2— [(2R, 4R) — 4-Hydroxy-6-oxotetrahydro 2H-pyran-1-yl] ethyl]] 1-naphthyl 2, 2-Dimethylenobutanoate, (+) (3R, 5R) — 3, 5 Dihydroxy-7— [(IS, 2S, 6S, 8S, 8aR) _l, 2, 6, 7, 8, 8a—Hexahydro _6-hydroxy _2—Metinore _8_ [(2S) _ 2—Metinolebutyrinole xy naphthinole] heptanoic acid, (+)-(lS, 3R, 7S, 8S, 8aR) _3, 7—Dimethinole _1, 2, 3, 7, 8,8a-Hexahydro _8_ [2— [(2R, 4R) -4-hydroxy-6-oxotetrahydro-1 2H-pyran-1-2-yl] ethyl]] 1-naphthyl (2S) _2-methylbuta Noate, (±) _ (3R *, 5S *, 6E) _3, 5-Dihydroxy-7- [3- (4-Fluorophenyl) _1_ (1-Methylethyl) — 1H-indole-2 —yl] — 6-heptenoic acid, (+) — (3R, 5S, 6E) -3, 5-dihydroxy mono 7— [2, 6 —Diisopropinole _4_ (4-Fluorophenyl) _5_ (Methoxymethyl) _3_pyridyl] _6_Heptenoic acid, (_) _ (3R, 5R) _3, 5-Dihydroxy mono 7_ [2_ ( 4-Fluorophenyl) 5— (1-Methylethyl) 3-phenyl 4-ruylaminocarbonyl — 1H-pyrrole 1-yl] heptanoic acid, (+) (3R, 5S, 6E) — 7— [2 Cyclov. Mouth pills 4— (4-Fluorophenyl) quinoline 3-yl] — 3,5, dihydroxy-6-heptenoic acid, (+) — (3R, 5S, 6E) — 3,5-dihydroxy-7— [ 4— (4 fluorophenyl) 6-isopropylinole 2— [N-methyl- (N-methylsulfonyl) amino] pyrimidine-5-yl] 6-heptenoic acid, [1] to [3] Any one of the above-mentioned dry eye or a therapeutic agent for diseases associated with dry eye,

[6] —Salt power of compounds represented by general formula (1) S, (+)-(3R, 5R) — 3, 5—dihydroxy-7— [(IS, 2S, 6S, 8S, 8aR) − 1, 2, 6, 7, 8, 8a Hexahydro-6-hydroxy-2-methyl _8 _ [(2S) _2_methylbutyryloxy] _ 1 _naphthyl] heptanoic acid monosodium salt, (±) _ (3R * , 5S *, 6E) _3, 5-Dihydroxy _7_ [3_ (4-Funole olofynyl) _ 1 _ (1-Methylethyl)-1H-indole _2_yl] _6_Heptenoic acid monosodium salt, (+) — (3R, 5S, 6E) _3, 5-Dihydroxy mono 7- [2, 6-diisopropyl- 4_ (4-fluorophenyl) _5_ (methoxymethyl) _3_pyridyl] _6 — heptenoic acid monosodium salt, (_) _ (3R, 5R) _3, 5-Dihydroxy-7_ [2_ (4_Fluorophenyl) _5_ (1-Methylethyl) _3_Phenenole 1_Pheninoreamino Carbonyl 1H—pyrrole 1 yl] heptanoic acid calcium salt (2: 1), (+) (3 R, 5S, 6E) — 7— [2 cyclopropyl 1 4- (4 fluorophenyl) quinoline 1 3—Ninole] — 3, 5 Dihydroxy 1-6 heptenoic acid calcium salt (2: 1), (+) — (3R, 5S, 6E) _ 3, 5—Dihydroxy 1 7— [4— (4-Fluorophenyl) ) 1-6-Isopropynol 2- [N-methyl-1- (N-methylsulfonyl) amino] pyrimidine 1 5 _yl] -6 _Heptenoic acid calcium salt (2: 1) before [1]-[ 3], slip force 4, the therapeutic agent for diseases associated with dry eye or dry eye according to 4,

[7] Before the disease associated with dry eye is corneal ulcer, punctate superficial keratopathy, corneal epithelial defect or conjunctival epithelial defect [1] to [6], with dry eye or dry eye according to 1 Disease treatments, and

[8] The agent for treating diseases associated with dry eye or dry eye according to any one of [1] to [7], wherein the dosage form is an eye drop or an eye ointment.

[0011] Hereinafter, each group, ring, and atom defined in this specification will be described in detail.

The “lower alkylene group” refers to a linear or branched alkylene group having 1 to 8 carbon atoms. For example, methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, otatamethylene, methylmethylene, ethylmethylene group and the like can be mentioned.

The “lower alkenylene group” refers to a linear or branched alkenylene group having 2 to 8 carbon atoms. For example, a group containing one or two double bonds in ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, otatamethylene, methylmethylene, propylene, 2-methyltrimethylene and the like.

[0014] "Non-aromatic ring" means a monocyclic or bicyclic non-cyclic ring having 6 to 10 carbon atoms, and may contain:! To 2 double bonds in the ring. An aromatic hydrocarbon ring is shown. For example, cyclohexane, decahydronaphthalene, cyclohexene, cyclohexane 1,3-gen, cyclohexa-1,4-gen, 1, 2, 3, 4, 4a, 5, 6, 8a—octahydronaphthalene, 1, 2, 3, 7, 8, 8a—hexahydronaphthalene ring, etc., and preferably 1, 2, 3, 7, 8, 8a—hexahydronaphthalene ring Can be mentioned.

[0015] "Nitrogen-containing aromatic heterocycle" means:! ~ A single 4 to 9 carbon atom having 2 nitrogen atoms A cyclic or bicyclic aromatic heterocycle is shown. Examples include pyrrole, pyrazole, imidazole, pyridine, pyridazine, pyrimidine, pyrazine, quinoline, isoquinoline, phthalazine, cinnoline, quinazoline, quinoxaline, indole, isoindole, indazole, benzoimidazole ring, preferably pyrrole, Examples include pyridine, quinoline and indole rings.

[0016] The "lower alkyl group" refers to a straight or branched alkyl group having from 6 to 6 carbon atoms. Examples thereof include methinole, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, se c-butinole, tert-butinole, n_pentinole, isopentinole, neopentinole, n_hexinole, isohexenole group and the like.

[0017] The substituent of the "lower alkyl group optionally having substituent (s)" represents one or two groups selected from a hydroxy group and a lower alkoxy group.

[0018] The "cycloalkyl group" refers to a cycloalkyl having 3 to 8 carbon atoms. For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl group and the like can be mentioned.

[0019] The "lower alkoxy group" refers to straight-chain or branched alkoxy having 1 to 6 carbon atoms. For example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, n-pentyloxy, n xyloxy groups and the like are shown.

[0020] The "aryl group" refers to a monocyclic or bicyclic aromatic hydrocarbon having 6 to 10 carbon atoms. For example, a phenyl, a naphthyl group, etc. are mentioned,

The substituent of “optionally substituted aryl group” is 1 or 2 groups selected from a halogen atom and an alkyl group.

“Halogen atom” refers to a fluorine, chlorine, bromine or iodine atom.

[0022] "Ester of hydroxy group" refers to an ester composed of a hydroxy group and an aliphatic carboxylic acid. Here, the aliphatic carboxylic acid refers to a straight-chain or branched monocarboxylic acid having 1 to 7 carbon atoms. Specific examples thereof include formic acid, acetic acid, propionic acid, butyric acid, valeric acid, 2-methylbutane. Examples include acid and 2,2_dimethylbutanoic acid.

[0023] In particular, an ester composed of a hydroxy group and 2-methylbutanoic acid, and a hydroxy group and 2,

An ester consisting of 2-dimethylbutanoic acid is preferred. The “carboxy group amide” refers to an amide having a carboxy group and ammonia, a primary or secondary amine, and the like. Here, the amine may be a lower alkylamine or an arylamine, and specific examples of the lower alkylamine include methylamine, ethylamine, ethylmethylamine, dimethylamine, jetylamine, dihexylamine and the like, and specific examples of the arylamine are ananiline, naphthylamine. Etc.

[0025] The "lower anolenoquinamino group" refers to a mono- or dialkylamino group in which a hydrogen atom of an amino group is substituted 1 or 2 with the lower alkyl group.

[0026] Specific examples of the monoalkylamino group include methinoreamino, ethenoreamino, and ethylmethylamino. Specific examples of the dialkylamino group include dimethylenoamino, dimethylamino-containing dihexylamino, and the like.

[0027] The "amide of a lower alkylamino group" refers to a sulfonic acid amide composed of a lower alkylamino group and an aliphatic sulfonic acid. Here, the aliphatic sulfonic acid refers to a linear or branched monosulfonic acid having from 6 to 6 carbon atoms. Specific examples include methanesulfonic acid, ethanesulfonic acid, hexanesulfonic acid, 2-butanesulfonic acid and the like.

[0028] "Lataton ring" refers to a 6-membered δ-latathon ring.

[0029] The "salt" in the present compound is not particularly limited as long as it is a pharmaceutically acceptable salt. With respect to an inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, etc. Salt, acetic acid, fumaric acid, maleic acid, succinic acid, citrate, tartaric acid, adipic acid, darconic acid, darcoheptic acid, glucuronic acid, terephthalic acid, methanesulfonic acid, lactic acid, hippuric acid, 1, 2 —Ethane disulfonic acid, isethionic acid, ratatobionic acid, oleic acid, pamoic acid, polygalatathuronic acid, stearic acid, tannic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, ρ-tonoleenesulfonic acid, lauryl sulfate, methyl sulfate , Salts with organic acids such as naphthalene sulfonic acid and sulfosalicylic acid, quaternary ammonium salts with methyl bromide, methyl iodide, bromine ion, chlorine ion Salts with halogen ions such as lithium and iodine ions, salts with alkali metals such as lithium, sodium and potassium, salts with alkaline earth metals such as calcium and magnesium, metal salts with iron and zinc, and ammonia Salt, triethylenediamine, 2-aminoamino norole, 2,2-iminobis (ethanol), 1-deoxy _ 1- (methylamino) 1 2-D- sorbitol, 2-aminomino 2 _ (hydroxymethyl) _ 1 , 3_propanediol, professional power In, N, N salts with organic amines such as bis (phenylmethyl) -1,2-ethanediamine.

[0030] When the present compound and its "salt" exist as crystals, polymorphs of the crystals are also included in the scope of the present invention.

[0031] When geometric isomers or optical isomers are present in the present compound, these isomers are also included in the scope of the present invention.

[0032] The present compound may be in the form of a hydrate or a solvate.

[0033] Furthermore, when proton tautomerism exists in the present compound, those tautomers are also included in the present invention.

This compound is described in, for example, patent publications such as JP-T-2004-512278, JP-A-2001-294526, JP-B-2-46031, JP-A-1-279866, and JP-A-2004-115500. And may be pharmaceutically acceptable salts of these compounds.

[0035] Preferable specific examples of the present compound include, for example, (+)-one (IS, 3R, 7S, 8S, 8aR) — 3, 7 Dimethinole 1, 2, 3, 7, 8, 8a Hexahydro 8— [2 — [(2R, 4R) — 4-hydroxy-6-oxotetrahydro-1 2H pyran-1-yl] ethyl] 1 naphthyl 2, 2-dimethylbutanoate (sympastatin), (+) — (3R, 5R) — 3, 5-Dihydroxy 1 7 — [(IS, 2S, 6S, 8S, 8aR) -1, 2, 6, 7, 8, 8a Hexahydro 1-6 Hydroxy 1 2-Methyl-8— [(2S) — 2-Methylbutyryloxy] 1 naphthyl] heptanoic acid (Pura / statin), (+) (IS, 3R, 7S, 8S, 8aR) -3, 7 Dimethinore 1, 2, 3, 7, 8,, 8a Hexahydro-I 8— [2— [(2R, 4R) —4 Hydroxy-6-xotetrahydro-1 2H-pyran _2_yl] ethyl naphthyl (2S) _2-methylbutanoate (lovastatin), (± ) _ (3R *, 5S *, 6E) _3, 5—Dihydroxy 1 7_ [3_ (4—Full Olof ヱ nyl) _ 1 _ —methylethyl)-iH—indole _ 2_yl] _6_heptenoic acid (flupastatin), (+) _ (3R, 5S, 6E) _3, 5-dihydroxy _ 7 _ [2 , 6-Diisopropinole 4- (4-Fluorophenyl) -5- (methoxymethyl) -1-3-pyridyl] -6-heptenoic acid (cerivastatin), (_) _ (3R, 5R) -3, 5— Dihydroxy 1 7_ [2— (4—Funoleolofeninore) 1 5_ (1—Methinoreethinore) _3_Hueninore 1_Fueninoreamino force Nore Bonyl- 1H—pyrrolone 1-yl] heptanoic acid (atorvastatin), (+)-(3R, 5S, 6E) —7— [2 cyclopropinole 4— (4 funoleolofeninore) quinoline 1— Inole] — 3, 5-Dihydroxy-6-heptenoic acid (pitapastatin, itapastatin), (+)-(3R, 5S, 6E) _ 3, 5-Dihydroxy mono 7_ [4_ (4_ fluorophenyl) _ 6 _ Isopropinole-2- [N-methyl_ (N_methylsulfonyl) amino] pyrimidine-5_yl] _6_heptenoic acid (rospastatin), mepastatin, compactin and pharmaceutically acceptable salts of these compounds Can be mentioned.

[0036] These compounds can be produced and used according to the above-mentioned patent publications. Moreover, what is marketed can also be used.

In the present invention, the disease associated with dry eye is not particularly limited as long as it is a disease associated with dry eye, such as corneal ulcer, punctate superficial keratopathy, corneal epithelial defect, conjunctival epithelial defect and the like.

[0038] The therapeutic agent for dry eye or a disease associated with dry eye according to the present invention can be administered either orally or parenterally.

[0039] Examples of the dosage form include eye drops, eye ointments, injections, tablets, capsules, granules, powders and the like, and eye drops are particularly preferable. These can be formulated using widely used techniques. For example, eye drops include isotonic agents such as sodium chloride and concentrated glycerin, buffering agents such as sodium phosphate and sodium acetate, polyoxyethylene sorbitan monolate, polyoxyl stearate 40, polyoxyethylene hardened castor A surfactant such as oil, a stabilizer such as sodium quenate and sodium edetate, and a preservative such as benzalkonium chloride and paraben can be used as necessary. If the pH is within the range allowed for ophthalmic preparations, the range of 4-8 is preferred.

[0040] An eye ointment can be prepared using a widely used base such as white petrolatum or liquid paraffin. Oral preparations such as tablets, capsules, granules, powders, etc. include bulking agents such as lactose, crystalline cellulose, starch, vegetable oil, lubricants such as magnesium stearate and talc, hydroxypropylcellulose, polybulurpyrrolidone, etc. 1J, carboxymethyl cellulose Calcium, low-substituted hydroxypropyl methylcellulose and other disintegrants, hydroxypropylmethylcellulose, macrogol, silicone resin, etc. A film agent such as a latin film can be added as necessary to prepare the film.

[0041] The present invention also relates to a method for treating dry eye or a disease associated with dry eye, comprising administering an effective amount of the compound represented by the general formula (1) or a salt thereof to a patient.

[0042] The dose of the active ingredient can be appropriately selected depending on the symptom, age, dosage form, etc. In the case of eye drops, 0.0001-10% (wZv), preferably 0.001-3% (w / v) Do it one to several times. In addition, for oral preparations, usually 0.1 to 5000 mg per day, preferably 1 to 1000 mg should be administered once or divided into several doses.

The invention's effect

[0043] As described later, a curative effect test for corneal injury was performed. (+)-(IS, 3R, 7S, 8S, 8aR) -3, 7 Dimethinore 1, 2, 3, 7, 8, 8a Hexahydro-I 8— [2— [(2R, 4R) — 4-Hydroxy-6-oxotetrahydro 2H-pyran-2-yl] ethyl] 1—Naftinole 2, 2 dimethylbutanoate, (+) (3R, 5R) — 3, 5 Dihydroxy mono 7— [(IS, 2S, 6S, 8S, 8aR) -1, 2, 6, 7, 8, 8a Hexahydro mono 6 hydroxy mono 2-methyl-8— [(2S) — 2 —Methylbutyryloxy] 1 naphthyl] heptanoic acid mono sodium salt, (+) (IS, 3R, 7S, 8S, 8aR) -3, 7 Dimethinole 1, 2, 3, 7, 8, 8 a-Hexahydro 1—8- [2 — [(2R, 4R) —4-Hydroxy-1 6-oxotetrahydro-1 2H-pyran _ 2 _yl] ethyl] -1 naphthyl (2S) -2-methylbutanoate, ( Sat) Ichi (3R *, 5S *, 6E) _3, 5-Dihydroxy I 7— [3— (4-Fluorophe Nyl) 1 1— (1—methylethyl) — 1H—indole _2_yl] _6_ heptenoic acid monosodium salt, (+) — (3R, 5S, 6E) _3, 5—dihydroxy 1 7— [2, 6 —Diisopropyl mono 4— (4-Fluorophenyl) _5_ (methoxymethyl) _3_pyridyl] _6_ heptenoic acid monosodium salt, (_) _ (3R, 5R) _3, 5-dihydroxy mono 7_ [2_ (4— Fluorophenyl) — 5— (1-methylethyl) 1 3-phenyl 1 4-phenylaminocarbonyl 1 H-pyrrole_1_yl] heptanoic acid calcium salt (2: 1), (+) _ (3R , 5S, 6E) _7_ [2 —Cyclopropyl 1- 4- (4-fluorophenyl) quinoline 1-yl] —3,5-dihydroxy-6-heptenoic acid calcium salt (2: 1), (+) — (3R, 5S, 6E) — 3, 5 Dihydroxyl 7- [4— (4 Fluorophenyl) 6-Isopropynole 2 — [N-Methylolone ) Amino] pyrimidine 5 yl] 6 heptenoic acid calcium salt (2: Statin compounds such as 1) exert an excellent improvement effect in a dry eye model, and are therefore useful as a therapeutic agent for dry eye or a disease associated with dry eye.

BEST MODE FOR CARRYING OUT THE INVENTION

[0044] The results of the pharmacological test and formulation examples are shown below, but these are for better understanding of the present invention and do not limit the scope of the present invention.

[0045] [Pharmacological test]

Curative efficacy test for corneal disorders

Using male SD rats, a dry eye model was prepared according to the method of Fujihara et al. (Invest. Ophthalmol. Vis. Sci 42 (1): 96-100 (2001)). After the dry eye model was prepared, corneal damage was scored according to the method of Murakami et al. (New Ophthalmology 21 (1): 87-90 (2004)), and the improvement rate of corneal damage after instillation of each statin compound was determined. Asked. As a statin compound, (+) — (IS, 3R, 7S, 8S, 8aR) -3, 7 Dimethinole 1, 2, 3, 7, 8, 8a Hexahydro 1-8— [2— [(2R, 4R ) — 4 Hydroxy-6-oxotetrahydro-1 2H Pyran-2-ylol] ethyl] — 1-Naphthyl 2, 2-dimethylbutanoate (hereinafter referred to as “Compound A”), (+) — (3R, 5R) -3, 5 Dihydroxy— 7— [(IS, 2S, 6S, 8S, 8aR) — 1, 2, 6, 7, 8, 8a—Hexahydro _6-hydroxy-1-2_methyl _8 _ [( 2S) _2 Methylbutyryloxy] _1_naphthyl] heptanoic acid monosodium salt (hereinafter referred to as “compound B”), (+)-(lS, 3R, 7S, 8S, 8aR) _3, 7-Dimethylolate _1, 2, 3, 7, 8, 8a—Hexahydr Mouth 8— [2— [(2R, 4R) — 4 Hydroxy 6 oxotetrahydro 1 2H Pyran 1 2 yl] ethyl]-1 _Naphthyl (2S ) _ 2—Methylbutanoate (hereinafter referred to as “Compound C”), (±) _ (3R *, 5S *, 6 E) _3,5-Dihydroxy mono 7_ [3_ (4-fluorophenyl) 1 _ (1-methylethyl) -1H-indole _2_yl] _ 6 _heptenoic acid monosodium salt (hereinafter “I complex”) D +), (+)-(3R, 5S, 6E) _3, 5-dihydroxy-7- [2,6-diisopropinole _4_ (4 fluorophenyl) _5_ (methoxymethyl) 1 3-pyridyl] — 6-Heptenoic acid monosodium salt (hereinafter referred to as “Compound E”), (1) One (3R, 5R) -3, 5 Dihydroxy one 7— [2— (4 Fluorophenyl) one 5— (1 —Methylethyl) 3—Phenol, 4-Phenylaminocarbolu, 1H—Pyrrole, 1—yl] Putanoic acid calcium salt (2: 1) (hereinafter referred to as “Compound F”), (+)-(3R, 5S, 6E) -7 — [2 Cyclopropinole 4— (4 Funoleolofeninore) Quinoline 1 3 Inole 3, 5 Dihydroxy 6 Heptenoic acid calcium salt (2: 1) (hereinafter referred to as “Compound G”), (+) ( 3 R, 5S, 6E) — 3, 5—Dihydroxy mono 7— [4— (4-Fluorophenyl) 6—isopropyl _ 2 _ [N _methyl _ (N _methylsulfonyl) amino] pyrimidine—5 _ 6] Calcium salt of heptenoic acid (2: 1) (hereinafter referred to as “Compound H”) was used.

[0046] (Experimental method)

Male SD rats were administered and nembutal for general anesthesia. Subsequently, the extraorbital lacrimal gland was removed, and corneal damage was induced over 2 months.

Next, the test compound (compounds A to H) was instilled (instillation amount: 5 μL / time) as follows.

[0048] Compound: Eye drops:

A physiological phosphate buffer solution (PBS solution) of Compound A (0.02%) was instilled into both eyes 6 times a day for 14 days (4 eyes per group, 8 eyes).

[0049] Compound B ophthalmic group:

Compound Β (0 · 002%) in PBS was instilled into both eyelids 6 times a day for 14 days (4 animals per group, 8 eyes)

) ₀

[0050] Compound C ophthalmic group:

Compound C (0.02%) in PBS was instilled into both eyelids 6 times a day for 14 days (4 animals per group, 8 eyes)

[0051] Compound D ophthalmic group:

Compound D (0.02%) in PBS was applied to both eyes 6 times a day for 14 days (4 eyes per group, 8 eyes)

[0052] Compound E ophthalmic group:

Compound E (0.02%) in PBS was instilled into both eyelids 6 times a day for 14 days (4 animals per group, 8 eyes)

[0053] Compound F ophthalmic group:

Compound F (0.02%) in PBS was instilled into both eyelids 6 times a day for 14 days (4 animals per group, 8 eyes)

[0054] Compound G ophthalmic group: Compound G (0.002%) in PBS was applied to both eyelids 6 times a day for 14 days (4 animals per group, 8 eyes) ₀

[0055] Compound H ophthalmic group:

Compound H (0.02%) in PBS was instilled into both eyelids 6 times a day for 14 days (4 animals per group, 8 eyes)

[0056] In the control group, PBS solution was applied to both eyes 6 times a day for 14 days (4 eyes per group, 8 eyes).

[0057] Fourteen days after the start of instillation, the damaged part of the cornea was stained with fluorescein. The degree of staining with fluorescein in each of the upper, middle and lower parts of the cornea was scored according to the following criteria, and the average value of the total score in each of the above-mentioned parts was calculated.

[0058] Further, for normal eyes, the average of the total score in each of the above parts was determined. (Judgment criteria)

0: Not dyed.

[0059] 1: Dyeing is sparse and each dot-like dyeing part is separated.

[0060] 2: Dyeing is moderate, and part of the dotted dye portions are adjacent.

[0061] 3: Densely dyed, and each dot-like dyed part is adjacent

(Result)

Based on the following formula, using the average score of the control group (PBS solution) as the standard (improvement rate: 0%), the improvement rate of the Compound A ophthalmic group and the Compound B ophthalmic group, the Compound C ophthalmic group to the Compound F ophthalmic solution The improvement rate of the group and the improvement rate of the compound G eye drop group and the compound H eye drop group were calculated, respectively. These are shown in Tables:! The average score is the average of 8 eyes.

[0062] Improvement rate (%) = {(control)-(this compound)} / disorder degree X 100

Disability = (control)-(normal eye)

[table 1] Group composition Average score Improvement rate (%) Normal eye 2.7

Control group 5.4

Compound A (0.02%) ophthalmic group 4. 9 1 8.5 Compound B (0.02%) ophthalmic group 4. 1 48. 1

Group composition Average score Improvement rate (%) Normal eye 3.1

Control group 4. 9

Compound C (0.02%) ophthalmic group 3. 8 6 1.1 Compound D (0.02%) ophthalmic group 3.5 5 77.8 Compound E (0.02%) ophthalmic group 3. 9 5 5. 6 Compound F (0. 02%) ophthalmic group 3. 8 6 1. 1

Group composition Average score Improvement rate (%) Normal eye 2.3

Control group 5.1

Compound G (0.02%) ophthalmic group 3. 9 42.9 Compound H (0.02%) ophthalmic group 3. 3 64. 3

[0063] (Discussion)

As apparent from the results of the pharmacological tests using the rats, compounds A to H significantly improved corneal damage.

[0064] [Formulation example]

The typical formulation example using compound AH is shown below. [0065] Formulation Example 1 (eye drops)

In 100ml

Compound A lOOmg Sodium chloride 900mg Sterile purified water

By changing the amount of compound A added, the concentration was adjusted to 0.003% (, 0.03% (w / v), 0.05% (w / v), 0.3% (w / v), 1% Eye drops can be prepared.

[0066] Formulation Example 2 (eye drops)

In 100ml

Compound B lOmg Sodium chloride 800mg Disodium hydrogen phosphate lOOmg Sodium dihydrogen phosphate

Sterile purified water

By changing the amount of compound B added, the concentration becomes 0.001% (, 0.1% (w / v), 0.3% (w / v), 1.0% (w / v), 3. 0% (Yes.

[0067] Formulation Example 3 (eye drops)

In 100ml

Compound C lOOmg Sodium chloride 900mg Sterilized purified water Appropriate amount By changing the amount of Compound C added, the concentration becomes 0.003% (, 0.03% (w / v), 0.05% (w / v), 0. 3% (w / v), 1% eye drops can be prepared, and each compound D eye drop can be prepared instead of compound C.

[0068] Formulation Example 4 (eye ointment) in lOOg

Compound B 0.3g

Liquid paraffin 10. Og

White petrolatum

By changing the amount of Compound B added, an ointment with a concentration of 1% (WZW) or 3% (wZw) can be prepared.

Formulation Example 5 (eye ointment)

in lOOg

Compound E 0.3g

Liquid paraffin 10.0 g

White petrolatum

By changing the amount of Compound E added, an ointment with a concentration of 1% (w / w) or 3% (w / w) can be prepared. Each eye ointment can be prepared by using Compound C, Compound D, and Compounds F to H instead of Compound E.

Claims

The scope of the claims

Dry eye or a therapeutic agent for a disease associated with dry eye, which contains a compound represented by the following general formula (1) or a salt thereof as an active ingredient.

[Chemical 1]

R ¹ represents a hydrogen atom or a lower alkyl group;

R ² represents a hydroxy group;

R ¹ and R ² may be condensed to form a rataton ring;

R ³ represents a hydrogen atom or a lower alkyl group;

General formula (1) is

[Chemical 2]

The dry eye according to claim 1, or a therapeutic agent for a disease associated with dry eye _c.

In general formulas (1) to (3),

Ring X is

[Chemical 3]

(6;

Indicates;

R ⁷ represents a hydroxy group or an ester thereof;

R ¹⁵ represents an aryl group which may have a substituent;

R ¹⁷ represents a lower alkylamino group or an amide thereof;

R ¹⁹ represents a hydrogen atom or a lower alkyl group;

R ^2Q represents an aryl group which may have a substituent;

R ²¹ represents an aryl group which may have a substituent;

3. The therapeutic agent for dry eye or a disease associated with dry eye according to claim 1, wherein R ²² represents a cycloalkyl group.

The compound represented by the general formula (1) is 3, 7-dimethyl 1, 2, 3, 7, 8, 8a-hexahydro — 8— [2— [4-hydroxy-6-oxotetrahydro 2H pyran 2yl] ethyl] 1 naphthyl 2, 2 dimethylbutanoate, 3, 5 dihydroxy-7— [1, 2, 6, 7, 8, 8a hexahydro-6 hydroxy-2-methyl-8— [2-methylbutyryl Xy] 1 naphthinole] heptanoic acid, 3, 7 dimethinole 1, 2, 3, 7, 8, 8a hexahydro-8 — [2— [4-hydroxy-6-oxotetrahydro 2H pyran-1-yl] ethyl] -1 —Naphtyl 2-methylbutanoate 3,5 dihydroxy 1 7- [3— (4 fluorophenyl) -1 (1-methylethyl) —1H-indole-2-yl] 6-heptenoic acid 3,5 dihydroxy 1 7— [2, 6 Diisopropinoleate 4— (4 Funoleolophenyleno) 1 5- (Methoxymethyl) -3 Pi Zyl] -6 Heptenoic acid, 3, 5 Dihydroxy-7— [2— (4 —Fluorophenyl) _ 5_ (1—Methylethyl) _ 3 _Pheninoleol 4_Pheninoreamino force Rubonyl 1H-pyrrole _ 1 _i L] heptanoic acid, 7_ [2-cyclopropinole _4_ (4-fluorophenyl) quinoline 3-yl] —3,5-dihydroxy-1-6-heptenoic acid, 3,5-dihydroxy-1-7— [4— (4— 1) 6-Isopropinole 2)-[N-methyl_ (N_methylsulfonyl) amino] pyrimidine-5_yl] _6_heptenoic acid 1. A therapeutic agent for dry eye or disease associated with dry eye according to 1. The compound represented by the general formula (1) is (+) _ (1S, 3R, 7S, 8S, 8aR) — 3, 7-dimethyl — 1, 2, 3, 7, 8, 8a Hexahydro 1-8— [2— [(2R, 4R) —4 Hydroxy 1 year old xotetrahydro 2H-pyran 2-yl] ethyl] 1 Naphthyl 2, 2— Dimethylbutanoate, (+) (3R, 5R) -3, 5 Dihydroxy mono 7— [(IS, 2S, 6S, 8S, 8aR) — 1, 2, 6, 7, 8, 8a—Hexahydro mono 6— Hydroxy 1-methinole 1 8- [(2S) -2 2-Methylenobutyrinore xy naphthinole] heptanoic acid, (+)-(lS, 3R, 7S, 8S, 8aR) _3, 7-Dimethinore _1, 2, 3, 7, 8, 8a—Hexahydro _8_ [2 _ [(2R, 4R) _4_ Hydroxy 1-oxotetrahydro 1 2H-pyran 1 2-ynole] ethinore]-1 _Naphthinore (2S) _ 2 -Methylbuta Noate, (±) _ (3R *, 5S *, 6E) _3, 5-dihydroxy-7_ [

3— (4-Fluorophenyl) — 1_ (1-Methylethyl) — 1H—Indole _ 2 _yl] _6_Heptenoic acid, (+) _ (3R, 5S, 6E) _3, 5-Dihydroxy _7_ [2 , 6-Diisopropinole _4_ (4-Fluorophenyl) _5_ (Methoxymethyl) _3_Pyridyl] _6_ Heptenoic acid, (_) _ (3R, 5R) _3, 5-Dihydroxy mono 7_ [2_ (4_Fluorophenyl) — 5 (1—Methylethyl) —3—Phenilolu 4—Phenylaminocarbolulu 1H—Pyrrole— 1—yl] heptanoic acid, (+) (3R, 5S, 6E) — 7— [2 Cyclo Propyl—

4— (4-Fluorophenole) quinoline 3-yl] —3, 5-dihydroxy 6-heptenoic acid, (+) — (3R, 5S, 6E) 3, 5-dihydroxy-7— [4— (4 Fluorophenyl) — 6 Isopropyl 2— [N Methylsulfonyl] amino] Pyrimidine

The therapeutic agent for diseases associated with dry eye or dry eye according to any one of claims 1 to 3, which is 5-yl] 6-heptenoic acid.

The salt of the compound represented by the general formula (1) is (+) — (3R, 5R) —3, 5-dihydroxy-7— [(IS, 2S, 6S, 8S, 8aR) -1, 2, 6 , 7, 8, 8a Hexahydro-1 6 Hydroxyl 1-Methanole 8-[(2S) -2-Methylbutyryloxy]-1 _naphthyl] heptanoic acid monosodium salt, (±) _ (3R *, 5S * , 6E) _3, 5—Dihydroxy mono 7_ [3_ (4_fluorophenyl) _1_ (1-methylethyl) — 1H—indole _2_yl] _6_ monosodium heptenoate, (+) — (3R, 5S, 6E) _3,5-Dihydroxy mono 7- [2,6-Diisopropinole 4- (4-Fluorophenyl) -5- (methoxymethyl) -1-3-pyridyl] -6-heptenoic acid monosodium salt, (_ ) _ (3R, 5R) _3, 5—Dihydroxy 1 7_ [2_ (4_ Funoleolofeninore) 1 5_ (1—Methinoreethinore) _3_Fuenore 1 4_Pheninoreamino force Bonyl-1H-pyrrole-1-yl] heptanoic acid calcium salt (2: 1), (+) — (3R, 5S, 6E) —7— [2-cyclopropynole 4— (4-fluorophenyl) Quinoline 3-yl] —3,5-Dihydroxy-6-heptenoic acid calcium salt (2: 1), (+) — (3R, 5S, 6E) —3, 5-Dihydroxy-7- [4— ( 4—Fluorophenyl) 1-6-isopropylinol 2— [N-methyl _ (N _methylsulfonyl) amino] pyrimidine—5 _yl] _ 6 _heptenoic acid calcium salt (2: 1) Any one of -3, The dry eye of 1 or the therapeutic agent of the disease accompanying dry eye.

[7] The disease associated with dry eye is corneal ulcer, punctate superficial keratopathy, corneal epithelial defect or conjunctival epithelial defect. Therapeutic agent.

[8] The therapeutic agent for dry eye or a disease associated with dry eye according to any one of claims 1 to 7, wherein the dosage form is an eye drop or an eye ointment.

[9] A method for treating dry eye or a disease associated with dry eye, comprising administering an effective amount of a compound represented by the following general formula (1) or a salt thereof to a patient.

[Chemical 4]

R ¹ represents a hydrogen atom or a lower alkyl group;

R ² represents a hydroxy group;

R ¹ and R ² may be condensed to form a rataton ring;

R ³ represents a hydrogen atom or a lower alkyl group; R ⁴ is an optionally substituted lower alkyl group, cycloalkyl group, optionally substituted aryl group, hydroxy group or ester thereof, lower alkoxy group, carboxyl group or amide thereof, or lower alkyl An amino group or an amide thereof; m represents an integer of 0 to 4, and when m is 2 or more, each R ⁴ may be the same or different. )

General formula (1) is

[Chemical 5]

The method for treating dry eye or a disease associated with dry eye according to claim 9.

In general formulas (1) to (3),

Ring X is

[Chemical 6]

Indicates;

R ⁵ and R ⁶ are the same or different and each represents a hydrogen atom, a hydroxy group, a lower alkoxy group or Represents a lower alkyl group;

R ⁷ represents a hydroxy group or an ester thereof;

R ¹² represents a hydrogen atom or a lower alkyl group;

R ¹³ represents a hydrogen atom or a lower alkyl group;

R ¹⁵ represents an aryl group which may have a substituent;

R ¹⁷ represents a lower alkylamino group or an amide thereof;

R ¹⁹ represents a hydrogen atom or a lower alkyl group;

R ² ° represents an aryl group which may have a substituent;

R ²¹ represents an aryl group which may have a substituent;

11. The method for treating a disease associated with dry eye or dry eye according to claim 9, wherein R ²² represents a cycloalkyl group.

The compound represented by the general formula (1) is 3, 7-dimethyl-1, 2, 3, 7, 8, 8a-hexahydro — 8— [2— [4-hydroxy-6-oxotetrahydro 2H Yl] ethyl] 1 naphthyl 2, 2 dimethylbutanoate, 3, 5 dihydroxy-7— [1, 2, 6, 7, 8, 8a—hexahydro _ 6—hydroxy mono 2_methyl _ 8_ [2— Methylbutyryloxy] _ 1 _Naphthinole] heptanoic acid, 3, 7-Dimethylolone 1, 2, 3, 7, 8, 8a-Hexahydro 1 8 — [2— [4-Hydroxy 1 6-oxotetrahydro 1 2H—Pyran-2-ylole] ethyl]-1 —Naphthyl _ 2—Methylbutanoate, 3, 5-Dihydroxy 1 7_ [3— (4-Fluorophenyl) _ 1 _ (1-Methylethyl) — 1H—Indole _ 2_yl] _ 6 _heptenoic acid, 3, 5-dihydroxy _ 7_ [2, 6-diisopropinoleol 4_ (4-funoleololophenol) 1 _ (methoxymethyl) ) _ 3 _pyridyl] _ 6 _heptenoic acid, 3,5-dihydroxy _ 7_ [2— (4 —Fluorophenyl) 5— (1-Methylethyl) 3—Phenol, 4-Phenylamino force Rubonyl 1H—Pyrrol-1-yl] heptanoic acid, 7— [2-Cyclopropynole 4— (4 —Fluorophenol) ) Quinoline 3-yl] -3,5-dihydroxy-6-heptenoic acid 3,5-dihydroxy-1-7- [4- (4-funoleolopheninole) 1-6-isopropinole 2- The method for treating dry eye or a disease associated with dry eye according to claim 1, which is —methyl_ (N_methylsulfonyl) amino] pyrimidine-5_yl] _6_heptenoic acid.

The compound represented by the general formula (1) is (+) _ (1S, 3R, 7S, 8S, 8aR) — 3, 7-dimethyl —1, 2, 3, 7, 8, 8a—hexahydro [2 _ [(2R, 4R) _4—Hydroxy _6—aged xotetrahydro _ 2H _pyran _ 2 _il] ethyl] _ 1 _naphthyl 2, 2-dimethylbutanoate, (+) _ (3R, 5R)- 3,5-Dihydroxy 1 7_ [(IS, 2S, 6S, 8S, 8aR) — 1, 2, 6, 7, 8, 8a-Hexahydro 1-Hydroxy 1 2-Methinore 8— [(2S) — 2—Methylenobutyrinole xoxynaphthinole] heptanoic acid, (+)-(lS, 3R, 7S, 8S, 8aR) —3, 7 Dimethinore 1, 2, 3, 7, 8, 8a Hexahydro 1— [2 — [(2R, 4R) — 4—Hydroxy-6-oxotetrahydro 2H pyran-2-yl] ethyl]-1—naphthyl (2S) —2-methylbutanoate, (±) (3R *, 5S *, 6E) — 3, 5 Dihydroxy 1 7— [3— (4 Fluorophenyl) -1 (1-methylethyl) -1H-indole 2 yl] —6 Heptenoic acid, (+) (3R, 5S, 6E) — 3, 5 Dihydroxy mono 7— [2, 6 Diisopropyl mono 4-— (4-Fluorophenyl) 5- (methoxymethyl) 3— Pyridyl] -6-heptenoic acid, (1) One (3R, 5R) -3, 5-Dihydroxy-7— [2— (4-Fluorophenyl) — 5 (1-Methylethyl) —3—Phenol —Phenylaminocarbolulu 1H—Pyrrole— 1—yl] heptanoic acid, (+) (3R, 5S, 6E) — 7— [2 Cyclopropyl— 4- (4-fluorophenyl) quinoline 1— Yl] —3,5-Dihydroxy-1-6-heptenoic acid, (+) _ (3R, 5S, 6E) _3, 5-Dihydroxy-7_ [4_ (4_fluorophenyl) — 6-isopropyl-2- [N— 2. The method for treating dry eye or a disease associated with dry eye according to claim 1, which is methyl 1 (N-methylsulfonyl) amino] pyrimidine 1 5 _yl] _ 6 _heptenoic acid.

The salt of the compound represented by the general formula (1) is (+) _ (3R, 5R) _3, 5-dihydroxy-7_ [(IS, 2S, 6S, 8S, 8aR) -1, 2, 6, 7 , 8, 8a-Hexahydro _6-hydroxy-1 2_ Methinole 8— [(2S) — 2-Methylbutyryloxy] 1 naphthyl] heptanoic acid monosodium salt, (±) — (3R *, 5S *, 6E) — 3, 5-dihydroxy mono 7— [3— ( 4-fluorophenyl) -1 (1-methylethyl) -1H-indole-2-yl] 6 heptenoic acid monosodium salt, (+)-(3R, 5S, 6E) _3, 5-dihydroxy mono 7- [2, 6 —Diisopropinole 4- (4-Fluorophenyl) -5- (methoxymethyl) -1-3-pyridyl] -6-heptenoic acid monosodium salt, (_) _ (3R, 5R) _3, 5-dihydroxy mono 7_ [2_ (4_ Funoreolofeninore) 1 5_ (1-Methinoreethinole) _3_Pheninole 1 4_Phenenoleamino strength Norbonyl-1H-Pyrrol_1_1-yl] heptanoic acid calcium salt (2: 1), (+ )-(3R, 5S, 6E) —7— [2-Cyclopropinole 4- (4-Fluorophenyl) quinoline 3-yl] —3, 5-Di Droxy-6-heptenoic acid calcium salt (2: 1), (+) — (3R, 5S, 6E) —3, 5-Dihydroxy 1 7— [4— (4-Fluorophenyl) 1 6-isopropinole 1 — [N-methyl _ (N _methylsulfonyl) amino] pyrimidine—5 _yl] _ 6 _Heptenoic acid calcium salt (2: 1) Treatment method.

2. The method for treating dry eye or a disease associated with dry eye according to claim 1, wherein the disease associated with dry eye is corneal ulcer, punctate superficial keratopathy, corneal epithelial defect or conjunctival epithelial defect. The method for treating dry eye or a disease associated with dry eye according to claim 1, wherein the compound represented by the general formula (1) or a salt thereof is in the form of an eye drop or an eye ointment.

Use of a compound represented by the following general formula (1) or a salt thereof for producing dry eye or a therapeutic agent for a disease associated with dry eye.

[Chemical 7]

R ¹ represents a hydrogen atom or a lower alkyl group;

R ² represents a hydroxy group;

R ¹ and R ² may be condensed to form a rataton ring;

R ³ represents a hydrogen atom or a lower alkyl group;

General formula (1) is

[Chemical 8]

18. Use according to claim 17, wherein

In general formulas (1) to (3),

Ring X is

[Chemical 9]

Indicates;

R ⁷ represents a hydroxy group or an ester thereof;

R ¹² represents a hydrogen atom or a lower alkyl group;

R ¹³ represents a hydrogen atom or a lower alkyl group;

R ¹⁵ represents an aryl group which may have a substituent;

R ¹⁷ represents a lower alkylamino group or an amide thereof;

R ¹⁹ represents a hydrogen atom or a lower alkyl group;

R ^2Q represents an aryl group which may have a substituent;

R ²¹ represents an aryl group which may have a substituent;

R ²² is The use according to claim 17 or claim 18, wherein a cycloalkyl group.

The compound represented by the general formula (1) is 3, 7-dimethyl 1, 2, 3, 7, 8, 8a-hexahydro — 8— [2— [4-Hydroxy-6-oxotetrahydro 2H pyran-1-yl] ethyl] 1 naphthyl 2, 2 dimethylbutanoate, 3, 5 dihydroxy-7— [1, 2, 6, 7, 8, 8a Hexahydro-6-hydroxy-2-methyl-8— [2-methylbutyryloxy] _1_naphthinole] heptanoic acid, 3, 7-dimethylol 1, 2, 3, 7, 7, 8, 8a—Hexahydro 1 — [2— [4—Hydroxy-1 6-oxotetrahydro-1 2H—pyran-1 2-ynole] ethyl]-1 —naphthyl _ 2—methylbutanoate, 3, 5—dihydroxy 1 7_ [3— (4-fluoro Enyl) _1_ (1-methylethyl) — 1H—indole _2_yl] _6_ heptenoic acid, 3, 5-dihydroxy _7_ [2, 6-diisopropinole 4_ (4-funoleolopheninole) 1 5_ ( Methoxymethyl) _3_pyridyl] _6_heptenoic acid, 3,5-dihydroxy _7_ [2— (4 —fluorophenyl) _5_ (1-Methylethyl) _3_Pheninole 4_Phenenoleamino force Rubonyl 1H-pyrrole_1_yl] heptanoic acid, 7_ [2-cyclopropinole _4_ (4-Fluorophenyl) quinoline 3-yl] -3, 5-Dihydroxy-1, 6-heptenoic acid, 3,5 Dihydroxy-1, 7- [4- (4-Funoleolophenol), 6-Isopropynole, 2 -— [N-Methylsulfonyl] amino] pyrimidine The use according to any one of claims 17 to 19 which is 5-yl] 1-heptenoic acid.

The compound represented by the general formula (1) is (+) (lS, 3R, 7S, 8S, 8aR) —3, 7-dimethyl — 1, 2, 3, 7, 8, 8a 2 — [(2R, 4R) —4 Hydroxy 1-6 years old xotetrahydro 2H—pyran 2-yl] ethyl] 1 Naphthyl 2, 2-dimethylbutanoate, (+) (3R, 5R) -3, 5 Dihydroxy mono 7— [(IS, 2S, 6S, 8S, 8aR) — 1, 2, 6, 7, 8, 8a Hexahydro-6-hydroxy-1-2-methyl 8 -— [(2S) -2-methylbutyryloxy] 1 Naphthyl] heptanoic acid, (+) (lS, 3R, 7S, 8S, 8aR) _3, 7-Dimethylolene _1, 2, 3, 7, 8, 8a-Hexahydro _8_ [2 _ [(2R, 4R) _4_ Hydroxy 6-oxotetrahydro-1 2H-pyran-1 2-ynole] ethinole]-1 _naphthinole (2S) _ 2-methylbutanoate, (±) _ (3R *, 5S *, 6E) _3, 5-dihydroxy 7_ [3- (4-Fluorophenyl) — 1_ (1-Methylethyl) — 1H—Indole _ 2 _il] _6_ Ptenoic acid, (+) _ (3R, 5S, 6E) _3, 5-dihydroxy _7_ [2,6-diisopropinole _4_ (4-fluorophenyl) _5_ (methoxymethyl) _3_pyridyl] _6_ heptenoic acid, (_) _ (3R, 5R) _3, 5-dihydroxy-7_ [2_ (4_fluorophenyl No. 1-5 (1-Methylethyl) 3—Phenilolu 4—Phenylaminocarbolulu 1H—Pyrrole—1-yl] heptanoic acid, (+) (3R, 5S, 6E) — 7— [2 Cyclopropyl— 4— (4-Fluorophenole) quinoline 3-yl] —3, 5-Dihydroxy-1-6-heptenoic acid, (+) _ (3R, 5S, 6E) _3, 5-Dihydroxy-7_ [ 20. The power of any one of claims 17 to 19, which is 4_ (4_fluorophenyl) -6-isopropyl-1- [N-methyl-1- (N-methylsulfonyl) amino] pyrimidine-5_yl] _6_heptenoic acid. Use of.

[22] The salt of the compound represented by the general formula (1) is (+) _ (3R, 5R) _3, 5-dihydroxy-7_ [

(IS, 2S, 6S, 8S, 8aR) -1, 2, 6, 7, 8, 8a—Hexahydro _6-hydroxy-1-methylthiolate 8-[(2S) -2-methylbutyryloxy] -1 naphthyl ] Heptanoic acid monosodium salt, (±) _ (3R *, 5S *, 6E) _3, 5-dihydroxy mono 7_ [3_ (4_fluorophenyl) _1_ (1-methylethyl) — 1H-indole _2_yl] _6_Heptenoic acid monosodium salt, (+) — (3R, 5S, 6E) _3, 5—Dihydroxy mono 7— [2, 6—Diisopropyl pill mono 4- (4-Fluorophenyl) -5- (methoxymethyl ) 1 3-Pyridyl] -6-heptenoic acid monosodium salt, (1) 1 (3R, 5R) — 3, 5 Dihydroxy 1 7— [2— (4-Fluorophenyl) 5— (1-Methylethyl) 3 —Phenol, 4-phenylamino force, norbonyl—1H—pyrrole—1—yl] heptanoic acid calcium salt (2: 1), (+) — (3R, 5S, 6E) —7— [2 cyclopropynole 4— (4 Fluorophenyl) quinoline 3-yl] —3,5 dihydroxy-6 heptenoic acid calcium salt (2: 1), (+) — (3R, 5S, 6E) —3,5 dihydroxy 1 7— [4— ( 4-fluorophenyl) 6-isopropyl-2- [N-methyl (N-methylsulfonyl) amino] pyrimidine-5-yl] -6-heptenoic acid calcium salt (2: 1) Use according to any one.

23. The use according to any one of claims 17 to 22, wherein the disease associated with dry eye is corneal ulcer, punctate superficial keratopathy, corneal epithelial defect or conjunctival epithelial defect.

24. The use according to any one of claims 17 to 23, wherein the dosage form is an eye drop or an eye ointment.