JP2006328018A - Therapeutic agent for disease in ophthalmic field, containing propionic acid derivative or its pharmaceutically permissible salt - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a medicine having excellent prevention and/or treatment effect on diseases in an ophthalmic field, especially on inflammatory diseases and low toxicity. <P>SOLUTION: The medicine for preventing and/or treating diseases in an ophthalmic field, preferably inflammatory diseases comprises a propionic acid derivative represented by formula (1) [R<SP>1</SP>is a 1-12C alkyl group, a phenyl group, a 1-naphthyl group or the like; (R<SP>3</SP>)<SB>b</SB>is 0-4 substituent groups such as a halogen atom or the like; R<SP>4</SP>is a lower alkyl group; R<SP>5</SP>is a hydrogen atom or a lower alkyl group; n is an integer of 2-4; X is -NH- or -O-] or its pharmaceutically permissible salt. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to a preventive and / or therapeutic agent for diseases in the ophthalmic field containing a propionic acid derivative or a pharmacologically acceptable salt thereof.

  As diseases in the ophthalmic field, inflammatory diseases that occur in the conjunctiva, cornea, uvea, etc. are known. Conjunctivitis, which is inflammation at the conjunctival site, is mainly symptom of hyperemia and eyes, but it may become severe in some cases. In addition, conjunctivitis-causing bacteria are strongly infectious and may be transmitted, so it is desired to treat them quickly and in a short period of time. Corneal inflammation, which is inflammation at the corneal site, can be severely painful, and when the corneal disorder progresses, turbidity may remain and visual acuity may decrease. Uveitis, which is inflammation at the uveal site, has many unexplained causes and needs to be treated patiently for a long time. When inflammation occurs in these sites, tissue destruction by the inflammatory reaction proceeds, and in the worst case, it can lead to blindness. In view of preventing blindness, prevention and / or treatment of inflammatory diseases is considered important.

  Causes of these inflammatory diseases include injury caused by wearing contact lenses, contamination of foreign matter in the eye, or trauma such as bruise of the eye. In these inflammatory sites, inflammatory cytokines such as Tumor Necrosis Factor (Non-patent Document 1), Interleukin-1, 2, 6 (Non-patent Document 2), Nitric Oxide (Non-patent Document 3), matrix metalloproteinase-9 (Non-patent Document 2) Mediators such as Patent Literature 4) increase and angiogenesis may occur (Non-Patent Literature 5).

  Since these inflammations are generally caused by viruses and bacteria, instillations such as antibiotics and steroid drugs (adrenocortical hormone drugs) are being used as treatments. However, since no effective antiviral drugs have yet been provided for viral infections, many rely solely on restoring the patient's immunity. Steroids also (1) increase intraocular pressure, (2) slow healing in the case of corneal wounds, (3) worsening ocular infections, (4) worsening viral diseases, and (5) There are also problems such as induction of mycosis. For this reason, it cannot be said that the conventional treatment means are satisfactory, and there is a demand for provision of a superior medicine.

On the other hand, International Publication WO 2003/070692 pamphlet discloses a propionic acid derivative. According to the disclosure of the publication, the propionic acid derivatives, particularly the compounds shown in Examples 2, 56, 57, and 66, have a strong blood glucose lowering action and a strong neutral fat lowering action. It is shown. However, the above publication suggests that the propion derivative is useful for the prevention and / or treatment of diseases in the ophthalmic field, and particularly effective for the prevention and / or treatment of inflammatory diseases in the ophthalmic field. It is not taught.
J. Endocrinol., 169, pp.453-459, 2001, Nature, 391, pp.82-86, 1998, J. Ocul. Pharmacol. Ther., 19, pp. 579-587, 2003, Am. J. Pathol., 153, pp.17-23, 1998, Ocul. Immunol. Inflamm., 9, pp. 9-24, 2001, International Publication WO 2003/070692 Pamphlet

  An object of the present invention is to provide a medicament useful for the prevention and / or treatment of diseases in the ophthalmic field, particularly inflammatory diseases in the ophthalmic field.

  As a result of intensive studies to solve the above-mentioned problems, the present inventor has found that a compound represented by the following general formula (1) is useful for prevention and / or treatment of diseases of ophthalmic tissues. The present invention has been completed based on the above findings.

［式中、Ｒ¹は、ハロゲン原子、低級アルコキシ基、及び１個以上のハロゲン原子で置換されていてもよいフェニル基からなる群より選ばれる１個以上の置換基で置換されていてもよいＣ_1-12アルキル基を示すか、又は下記式（１−１）

{式中、（Ｒ⁶）_aはハロゲン原子、低級アルキル基、低級アルコキシ基、低級アルキルチオ基、ニトロ基、低級アルコキシカルボニル基、シアノ基、トリフルオロメチル基、トリフルオロメトキシ基、及びフェニルオキシ基からなる群より選ばれるａ個（ａは０から５の整数）の互いに異なっていてもよい置換基を示す。}で表わされる基を示すか、又は１−ナフチル基、２−ナフチル基、５−インダニル基、５，６，７，８−テトラヒドロナフタレン−２−イル基、アリル基、３−ブテニル基、及び２−プロピニル基からなる群より選ばれるいずれかの置換基を示し、
Ｒ²は、低級アルコキシ基、アリールオキシ基、アラルキルオキシ基、低級アルキルチオ基、アリールチオ基、アラルキルチオ基、及びフェニル基からなる群より選ばれる１個以上の置換基で置換されていてもよいＣ_2-12のアルキル基（ただし、Ｒ²は、窒素原子と結合するＲ²中のメチレン基を除き、さらに１個以上のハロゲン原子で置換されていてもよい。）を示し、
（Ｒ³）_bはハロゲン原子、低級アルキル基、及び低級アルコキシ基からなる群より選ばれるｂ個（ｂは０から４の整数）の互いに異なっていてもよい置換基を示し、
Ｒ⁴は低級アルキル基を示し、
Ｒ⁵は水素原子又は低級アルキル基を示し、
ｎは２から４の整数を示し、及び
Ｘは−ＮＨ−又は−Ｏ−を示す。］
で表される化合物又は薬理学的に許容されるその塩を有効成分として含む、眼科領域における疾病の予防及び／又は治療のための医薬。 That is, the following medicine is provided by the present invention.
[1] The following general formula (1)

[Wherein R ¹ may be substituted with one or more substituents selected from the group consisting of a halogen atom, a lower alkoxy group, and a phenyl group optionally substituted with one or more halogen atoms. A C _1-12 alkyl group or the following formula (1-1)

{Wherein (R ⁶ ) _a represents a halogen atom, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, a nitro group, a lower alkoxycarbonyl group, a cyano group, a trifluoromethyl group, a trifluoromethoxy group, and a phenyloxy group. The a substituents (a is an integer of 0 to 5) selected from the group consisting of may be different from each other. }, Or a 1-naphthyl group, a 2-naphthyl group, a 5-indanyl group, a 5,6,7,8-tetrahydronaphthalen-2-yl group, an allyl group, a 3-butenyl group, and Any one substituent selected from the group consisting of 2-propynyl groups,
R ² may be substituted with one or more substituents selected from the group consisting of a lower alkoxy group, an aryloxy group, an aralkyloxy group, a lower alkylthio group, an arylthio group, an aralkylthio group, and a phenyl group. _2-12 alkyl group (wherein, R ^2, except for the methylene group in R ² which binds to the nitrogen atom, may be further substituted with one or more halogen atoms.) indicates,
(R ³ ) _b represents _b substituents (b is an integer of 0 to 4), which may be different from each other, selected from the group consisting of a halogen atom, a lower alkyl group, and a lower alkoxy group,
R ⁴ represents a lower alkyl group,
R ⁵ represents a hydrogen atom or a lower alkyl group,
n represents an integer of 2 to 4, and X represents —NH— or —O—. ]
Or a pharmacologically acceptable salt thereof as an active ingredient for the prevention and / or treatment of diseases in the ophthalmic field.

[2] R ¹ is a halogen atom, optionally substituted with one or more substituents selected from the group consisting of lower alkoxy groups and one or more phenyl group which may be substituted by a halogen atom, C ₁ The medicament according to [1] above, which is a _-12 alkyl group.
[3] The medicament according to [2], wherein R ² is a C _2-12 alkyl group which may be substituted with one or more substituents selected from the group consisting of a lower alkoxy group and a lower alkylthio group.
[4] The medicament according to [3], wherein b is 0.
[5] The medicament according to [4], wherein R ⁴ is a methyl group, an ethyl group, or an isopropyl group.
[6] The medicament according to [5], wherein R ⁵ is a hydrogen atom or an ethyl group.
[7] The medicament according to [6], wherein n is 2 or 3.
[8] The medicament according to [7], wherein X is —O—.

[9] R ² is a C _2-12 alkyl group which may be substituted with one or more substituents selected from the group consisting of a lower alkoxy group, an aryloxy group, an aralkyloxy group, and a phenyl group (provided that , R ² may be substituted with one or more halogen atoms, excluding the methylene group in R ² bonded to the nitrogen atom.), B is 0, R ⁴ is an ethyl group The pharmaceutical according to [8], wherein R ₅ is a hydrogen atom or an ethyl group, n is 2, and X is —O—.
[10] R ¹ is the formula (1-1), and (R ⁶ ) _a is a (a is an integer of 0 to 5) fluorine atoms, and R ² is a normal pentyl group or a normal hexyl group. Any one alkyl group selected from the group consisting of normal heptyl group, and normal octyl group, b is 0, R ⁴ is an ethyl group, R ⁵ is hydrogen or an ethyl group, and n is And the drug according to [9], wherein X is —NH—.
[11] R ¹ is methyl group, ethyl group, benzyl group, allyl group, propyl group, p-tolyl group, 4-bromophenyl group, 4-fluorophenyl group, 2-methoxyethyl group, isopropyl group, 2-propynyl A substituent selected from the group consisting of a group, 2-naphthyl group, isobutyl group, 2,2-dimethylpropyl group, and 3-butenyl group, R ² is a heptyl group, b is 0, R ⁴ Is a ethyl group, R ₅ is a hydrogen atom or an ethyl group, n is 2, and X is —O—.

[12] (R) -3- (4- {2- [3- (2,4-difluorophenyl) -1-heptylureido] ethoxy} phenyl) -2-ethoxypropionic acid, (R) -3- ( 4- {2- [3- (2,4-difluorophenyl) -1-heptylureido] ethoxy} phenyl) -2-ethoxypropionic acid ethyl ester, (S) -3- (4- {2- [3- (2,4-difluorophenyl) -1-heptylureido] ethoxy} phenyl) -2-ethoxypropionic acid, (S) -3- (4- {2- [3- (2,4-difluorophenyl) -1 -Heptylureido] ethoxy} phenyl) -2-ethoxypropionic acid ethyl ester, 3- (4- {2- [3- (2,4-difluorophenyl) -1-heptylureido] ethoxy} phenyl) -2 -Ethoxypropionic acid and a compound selected from the group consisting of 3- (4- {2- [3- (2,4-difluorophenyl) -1-heptylureido] ethoxy} phenyl) -2-ethoxypropionic acid ethyl ester Or the pharmaceutical for the prevention and / or treatment of the disease in ophthalmology field which contains the salt accept | permitted pharmacologically as an active ingredient.

[13] 2-Ethoxy-3- (4- {2- [heptyl (isopropyloxycarbonyl) amino] ethoxy} phenyl) propionic acid, 2-ethoxy-3- (4- {2- [heptyl (isopropyloxycarbonyl) Amino] ethoxy} phenyl) propionic acid ethyl ester, (R) -2-ethoxy-3- (4- {2- [heptyl (isopropyloxycarbonyl) amino] ethoxy} phenyl) propionic acid, (R) -2-ethoxy -3- (4- {2- [Heptyl (isopropyloxycarbonyl) amino] ethoxy} phenyl) propionic acid ethyl ester, (S) -2-ethoxy-3- (4- {2- [heptyl (isopropyloxycarbonyl) Amino] ethoxy} phenyl) propionic acid, and (S) -2-ethoxy-3- (4) -A compound selected from the group consisting of {2- [heptyl (isopropyloxycarbonyl) amino] ethoxy} phenyl) propionic acid ethyl ester or a pharmacologically acceptable salt thereof as an active ingredient, A medicine for prevention and / or treatment.

[14] 3- (4- {2- [benzyloxycarbonyl (heptyl) amino] ethoxy} phenyl) -2-ethoxypropionic acid, 3- (4- {2- [benzyloxycarbonyl (heptyl) amino] ethoxy} Phenyl) -2-ethoxypropionic acid ethyl ester, (R) -3- (4- {2- [benzyloxycarbonyl (heptyl) amino] ethoxy} phenyl) -2-ethoxypropionic acid, (R) -3- ( 4- {2- [benzyloxycarbonyl (heptyl) amino] ethoxy} phenyl) -2-ethoxypropionic acid ethyl ester, (S) -3- (4- {2- [benzyloxycarbonyl (heptyl) amino] ethoxy} Phenyl) -2-ethoxypropionic acid, and (S) -3- (4- {2- [benzyloxycarbonyl] (Heptyl) amino] ethoxy} phenyl) -2-ethoxypropionic acid ethyl ester or a pharmacologically acceptable salt thereof as an active ingredient, the prevention of disease and / or Medicine for treatment.

[15] (R) -2-ethoxy-3- {4- [2- (N-heptyl-N-methoxycarbonylamino) ethoxy] phenyl} propionic acid, (R) -2-ethoxy-3- {4- [2- (N-heptyl-N-methoxycarbonylamino) ethoxy] phenyl} propionic acid ethyl ester, (S) -2-ethoxy-3- {4- [2- (N-heptyl-N-methoxycarbonylamino) Ethoxy] phenyl} propionic acid, (S) -2-ethoxy-3- {4- [2- (N-heptyl-N-methoxycarbonylamino) ethoxy] phenyl} propionic acid ethyl ester, 2-ethoxy-3- { 4- [2- (N-heptyl-N-methoxycarbonylamino) ethoxy] phenyl} propionic acid, 2-ethoxy-3- {4- [2- (N-heptyl- -Methoxycarbonylamino) ethoxy] phenyl} propionic acid ethyl ester or a pharmacologically acceptable salt thereof as an active ingredient, for the prevention and / or treatment of diseases in the ophthalmic field Medicine.
[16] The medicament according to any one of [1] to [15], wherein the disease in the ophthalmic field is a disease caused by inflammation and / or a disease accompanied by inflammation.
[17] Any one of the above [1] to [15], wherein the disease in the ophthalmic region is a disease selected from the group consisting of diseases caused by an increase in inflammatory cytokines and / or inflammatory mediators, and diseases caused by angiogenesis The medicine according to one.

From another point of view, according to the present invention, [16] the compound represented by the above general formula (1) or pharmacologically acceptable for the manufacture of the medicament according to any one of [1] to [15] And [17] a method for the prevention and / or treatment of diseases in the ophthalmic field, preferably diseases caused by inflammation and / or diseases associated with inflammation in the ophthalmic field, There is provided a method comprising the step of administering an effective amount of a compound represented by the above general formula (1) or a pharmacologically acceptable salt thereof to mammals including humans.

  The medicament of the present invention has excellent efficacy in the prevention and / or treatment of diseases in the ophthalmic field of mammals including humans, particularly diseases caused by inflammation and / or diseases accompanied by inflammation. Moreover, since the toxicity of the medicament of the present invention is remarkably low, the above prevention and / or treatment can be performed safely.

  The medicament of the present invention can be used as a medicament for the prevention and / or treatment of diseases in the ophthalmic field. In this specification, the term “prevention and / or treatment” should be interpreted in the broadest sense including prevention of the onset of diseases in the ophthalmic field, reduction or improvement of symptoms of diseases, or understanding of symptoms. In any sense, it should not be interpreted in a limited way. Examples of diseases in the ophthalmic field preferably include inflammatory diseases of ophthalmic tissues. More specifically, both diseases caused by inflammation of ophthalmic tissues and diseases accompanied by inflammation are considered to be the subject of application of the medicament of the present invention. can do. Particularly preferred applications include diseases caused by an increase in inflammatory cytokines and / or inflammatory mediators in ophthalmic tissues, diseases caused by angiogenesis, and the like.

Examples of inflammatory diseases of ophthalmic tissues include conjunctivitis, which is inflammation of the conjunctival region, keratitis and corneal herpes, which are inflammation of the corneal region, and uveitis, which is inflammation of the uveal region (iris, ciliary body, choroid). , Lacrimal inflammation in which the nasolacrimal duct is clogged and inflammation occurs in the lacrimal sac, blepharitis that is inflammation of the eyelid, optic neuritis, scleritis and the like.
Diseases resulting from ophthalmic tissue inflammation include macular degeneration of the retina due to neovascularization, stye that is purulent inflammation, granuloma of chronic inflammation, and glaucoma and cataract associated with uveitis, etc. Is mentioned.
Diseases associated with ophthalmic tissue inflammation include retinal artery occlusion with clogged artery, retinal vein occlusion with clogged vein, central chorioretinopathy with clogged network, subconjunctival hemorrhage, and fundus Bleeding and so on.

  More specifically, as an application target of the medicament of the present invention, inflammation occurring in the conjunctiva, cornea, or uvea (iris, ciliary body, choroid) and the like can be mentioned as a suitable example. Examples of conjunctival inflammation include epidemic keratoconjunctivitis, acute hemorrhagic conjunctivitis, and bacterial conjunctivitis. Examples of corneal inflammation include bacterial keratitis, corneal mycosis, corneal herpes, scleritis, and the like. Examples of uveitis inflammation include uveitis. Among these inflammatory diseases, for example, epidemic keratoconjunctivitis, acute hemorrhagic conjunctivitis, bacterial conjunctivitis, bacterial keratitis, corneal mycosis, corneal herpes, scleritis, uveitis, etc. The preferred application subjects of the medicine are epidemic keratoconjunctivitis, acute hemorrhagic conjunctivitis, bacterial conjunctivitis, bacterial keratitis, and uveitis, which are further preferred application subjects of the medicine of the present invention. Of these, epidemic keratoconjunctivitis, bacterial conjunctivitis, and bacterial keratitis are particularly preferred applications of the medicament of the present invention.

  The medicament of the present invention is also useful for the prevention and / or treatment of lacrimal cystitis, blepharitis, stye, granuloma, optic neuritis, scleritis and the like. Further, the medicament of the present invention is glaucoma, cataract, diabetic retinopathy, central chorioretinopathy, subconjunctival hemorrhage, fundus hemorrhage, spring catarrh, pterygium, subconjunctival hemorrhage, eyelid droop, eyelid spasm, corneal ulcer, cone Cornea, retinal tear, retinal detachment, retinal artery occlusion, retinal vein occlusion, retinitis pigmentosa, lateral degeneration, flying mosquito disease, myopia, hyperopia, astigmatism, presbyopia, strabismus, fatigued eyes, dry eye, leprosy, etc. It is also useful for prevention and / or treatment.

  Tumor Necrosis Factor (J. Endocrinol., 169, pp.453-459, 2001) and Interleukin-1, -2, and -6, (Nature, 391, pp.82-86) , 1998) and Nitric Oxide (J. Ocul. Pharmacol. Ther, 19, pp. 579-587, 2003), matrix metalloproteinase-9 (Am. J. Pathol., 153) , pp.17-23, 1998), Prostaglandin (J. Immunol., 172, pp.5790-5798, 2004), nuclear factor kappa-B (J. Endocrinol., 169, pp.453-459, 2001), Nuclear factor of activated T lymphocyte (J. Biol. Chem., 275, pp.4541-4544, 2000) is known. Increases in these inflammatory cytokines and mediators induce increased vascular permeability and angiogenesis at the inflammatory site (Ocul. Immunol. Inflamm., 9, pp.9-24, 2001).

Examples of the compound that can be used as the active ingredient of the medicament of the present invention include compounds represented by the above general formula (1). In the compound represented by the general formula (1), the carbon atom substituted by the oxygen atom to which R ⁴ is bonded is an asymmetric carbon. The configuration of this asymmetric carbon is not particularly limited and may be either S configuration or R configuration, and the compound of the present invention may be any mixture or racemic of an optically active pair in a pure form based on this asymmetric carbon. It may be a body. The compound of the present invention may further have one or two or more asymmetric carbons depending on the type of substituent, but the configuration thereof is not particularly limited like the above-mentioned specific asymmetric carbon, Arbitrary steric arrangement may be sufficient. Stereoisomers such as optically active forms or diastereoisomers in pure form based on one or more asymmetric carbons, any mixture of stereoisomers, racemates, etc. are all included in the scope of the present invention. .

  The type of physiologically acceptable salt of the compound of the general formula (1) is not particularly limited, and may be either an acid addition salt or a base addition salt, and may take the form of an intramolecular counter ion. . Examples of acid addition salts include hydrochloride, hydrobromide, sulfate, hydrogen sulfate, dihydrogen phosphate, citrate, maleate, tartrate, fumarate, gluconate, methane Examples include sulfonates and addition salts with optically active acids such as camphorsulfonic acid, mandelic acid, substituted mandelic acid. The base addition salt may be formed, for example, when one or more acidic groups such as carboxylic acid and phenolic hydroxyl group are present. For example, a metal salt such as sodium salt or potassium salt, or ammonium A salt etc. can be illustrated. Needless to say, the type of salt is not limited to these and can be appropriately selected by those skilled in the art.

  In this specification, “lower” means about 1 to 10 carbon atoms, preferably about 1 to 8 carbon atoms, more preferably about 1 to 6 carbon atoms, and particularly preferably 1 to 5 carbon atoms. About one. As the halogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, or the like can be used. The alkyl group may be linear, branched, cyclic, or a combination thereof. The same applies to the alkyl moiety in other substituents having an alkyl group as a partial structure (for example, an alkoxy group or an alkylthio group). Examples of the aryl group include monocyclic or polycyclic aromatic hydrocarbons, and more specifically, a phenyl group or a naphthyl group. You may have an atom (for example, an oxygen atom, a nitrogen atom, or a sulfur atom). Further, in this specification, when it is said that “may be substituted” for a certain functional group, one or more substituents may be present at any position on the functional group. This means that the number of substituents and the substitution position are not particularly limited. When two or more substituents are present, they may be the same or different.

In General Formula (1), R ¹ is preferably a C _1-12 alkyl group, a group represented by Formula (1-1), or a 5-indanyl group. As R ¹ , for example, it may be substituted with one or more substituents selected from the group consisting of a halogen atom, a lower alkoxy group, and a phenyl group optionally substituted with one or more halogen atoms. A C _1-12 alkyl group is mentioned. Examples of the halogen atom substituted on the C _1-12 alkyl group include fluorine, chlorine, bromine, or iodine. Of these, fluorine and chlorine are preferable, and fluorine is particularly preferable.

The lower alkoxy group is a group in which lower alkyl is bonded to an oxygen atom, and examples of the lower alkyl include straight-chain or branched saturated hydrocarbon groups having 1 to 5 carbon atoms. As the lower alkoxy group substituted on the C _1-12 alkyl group, for example, a methoxy group, an ethoxy group, and a propoxy group are preferable, and a methoxy group is particularly preferable.
When the above C _1-12 alkyl group is substituted with a phenyl group which may be substituted with one or more halogen atoms, the phenyl group may be substituted with a halogen atom or unsubstituted. Also good. An unsubstituted phenyl group is preferred, and a substituted phenyl group is also suitable. When substituted with a halogen atom, the type of the halogen atom is any one of fluorine, chlorine, bromine, and iodine. A preferred halogen atom is a fluorine or chlorine atom, more preferably a fluorine atom. The number of halogen atoms is 1 to 5, preferably 1, 2, or 3, more preferably 1 or 2. Substitution positions of the halogen atom include 2-position, 3-position, 4-position, 5-position, or 6-position when the carbon atom with a bond on the phenyl group is defined as the 1-position. Preferred examples include When the number of halogen atoms is 1, it is 2-position, 3-position or 4-position, more preferably 3-position or 4-position. A preferable example in the case where the number of halogen atoms is 2 or more is a case where one of the halogen atoms is in the 2nd, 3rd, or 4th position, and more preferably in the 3rd or 4th position. .

In the C _1-12 alkyl group which may be substituted with one or more substituents shown above, examples of the C _1-12 alkyl group include saturated hydrocarbons having 1 to 12 carbon atoms. The saturated hydrocarbon skeleton may contain one or more branched chains and / or cyclic structures. For example, preferred examples include methyl group, ethyl group, propyl group, butyl group, isopropyl group, isobutyl group, 1-methylpropyl group, t-butyl group, 3-methylbutyl group, 2,2-dimethylpropyl group, cyclopentyl. A group, a cyclohexyl group, a cycloheptyl group, or a cyclohexylmethyl group. Of these, particularly preferred alkyl groups are methyl, ethyl, propyl, butyl, isopropyl, isobutyl, t-butyl, 1-methylpropyl, 2,2-dimethylpropyl, cyclopentyl, or It is a cyclohexyl group. The C _1-12 alkyl group may be substituted or unsubstituted. When substituted with one or more substituents, the types of substituents described above can be used, and the number of substituents is, for example, 1 to 20 when substituted with a halogen atom. , Preferably 1 to 5, more preferably 1 to 3. When the substituent is a lower alkoxy group and a phenyl group which may be substituted with one or more halogen atoms, the number of substituents is preferably one. In addition, with respect to the substitution position of the substituent, when each carbon atom of the alkyl group is at the 1st, 2nd, 3rd,... More preferably, it is 2-position or 3-position.

More specifically, C may be substituted with one or more substituents selected from the group consisting of a halogen atom, a lower alkoxy group, and a phenyl group optionally substituted with one or more halogen atoms. _{The 1-12} alkyl group is preferably a methyl group, an ethyl group, a propyl group, a butyl group, an isopropyl group, an isobutyl group, a 1-methylpropyl group, a t-butyl group, a 3-methylbutyl group, or 2,2-dimethylpropyl. A group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, or a cyclohexylmethyl group. In addition, 2,2,2-trifluoroethyl group, 2,2-difluoropropyl group, 2,2-difluorobutyl group, 2-methoxyethyl group, 2-ethoxyethyl group, 3-methoxypropyl group, 3-ethoxy Propyl group, benzyl group, 2-phenylethyl group, 4-fluorobenzyl group, 4-chlorobenzyl group, 4-bromobenzyl group, 2,4-difluorobenzyl group, 3,5-difluorobenzyl group, 2- (4 -Fluorophenyl) ethyl group, 2- (4-chlorophenyl) ethyl group, 2- (4-bromophenyl) ethyl group, 2- (2,4-difluorophenyl) ethyl group, or 2- (3,5-difluoro A phenyl) ethyl group is preferred. Furthermore, a methyl group, an ethyl group, a propyl group, a butyl group, an isopropyl group, an isobutyl group, a t-butyl group, a 1-methylpropyl group, a 2,2-dimethylpropyl group, a cyclopentyl group, or a cyclohexyl group is particularly preferable. -Methoxyethyl group, benzyl group, 2-phenylethyl group, or 2,2,2-trifluoroethyl group are also particularly preferred examples.

The R ^1, for example, it is also preferred that the above-mentioned formula (1-1). In formula (1-1), (R ⁶ ) _a is a halogen atom, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, a nitro group, a lower alkoxycarbonyl group, a cyano group, a trifluoromethyl group, a trifluoromethoxy group, And a substituents (a is an integer of 0 to 5) selected from the group consisting of phenyloxy groups and may be different from each other. Examples of the halogen atom include fluorine, chlorine, bromine, or iodine. Fluorine, chlorine, or bromine is preferable, and fluorine or chlorine is particularly preferable. As the lower alkyl group, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a 2-methylpropyl group, or a t-butyl group is preferable, and a methyl group or an isopropyl group is particularly preferable. As the lower alkoxy group, for example, a methoxy group, an ethoxy group, or a propoxy group is preferable, and a methoxy group is particularly preferable. The lower alkylthio group is a group in which a lower alkyl is bonded to a sulfur atom, and examples of the lower alkyl include a linear or branched saturated hydrocarbon group having 1 to 5 carbon atoms. As the lower alkylthio group, for example, a methylthio group, an ethylthio group, or a propylthio group is preferable, and a methylthio group is particularly preferable. The lower alkoxycarbonyl group is a group in which a lower alkyl is bonded to an ester bond (—O (C═O) —). The lower alkyl is a linear or branched chain having 1 to 5 carbon atoms. Examples include saturated hydrocarbon groups (in the lower alkoxycarbonyl group, the bond out of the oxygen atom out of the two bonds of the ester bond is bonded to the lower alkyl). As the lower alkoxycarbonyl group, for example, a methoxycarbonyl group, an ethoxycarbonyl group, or a propoxycarbonyl group is preferable, and a methoxycarbonyl group is particularly preferable.

R ⁶ is a group selected from a lower alkyl group, a lower alkoxy group, a lower alkylthio group, or a lower alkoxycarbonyl group, and when there are a plurality of R ⁶ groups, the lower alkyl parts of the two substituents are combined together. An annular structure may be formed. Examples of formula (1-1) showing such a structure include a 3,4- (methylenedioxy) phenyl group. Examples of the number a of substituents include integers from 0 to 5. When a is 0, it means that R ⁶ is not present, and thus R ¹ is a phenyl group. When a is 1, it means that there is one substituent represented by R ⁶ . When a is an integer of 2 to 5, it means that there are a plurality of substituents represented by R ⁶ , and the substituents in that case may be the same or different. Preferred examples of a are 0, 1, 2, or 3. Particularly preferred is 0, 1, or 2. Examples of the substitution position of the substituent include 2-position, 3-position, 4-position, 5-position, and 6-position when the carbon atom having a bond to X is located at position 1, and when a is 1. Is preferably 3-position or 4-position, and when a is 2 or more, a plurality of substitution positions including 3-position or 4-position is preferable, and a plurality of substitution positions including 4-position is particularly preferable.

  More specifically, the formula (1-1) includes phenyl group, 2,4-difluorophenyl group, 3,4-difluorophenyl group, 2-fluorophenyl group, 3-fluorophenyl group, 4-fluorophenyl. Group, 4-bromophenyl group, 2-chlorophenyl group, 4-chlorophenyl group, 2,4-dichlorophenyl group, 4-nitrophenyl group, 4-isopropylphenyl group, 4-phenyloxyphenyl group, 2-methylphenyl group, 3-methylphenyl group, 4-methylphenyl group, 2,4,5-trimethylphenyl group, 2,4,6-trimethylphenyl group, 2-trifluoromethylphenyl group, 3-trifluoromethylphenyl group, 4- Trifluoromethylphenyl group, 2-trifluoromethoxyphenyl group, 4-trifluoromethoxyphenyl group, 3 Cyanophenyl group, 4-cyanophenyl group, 2-methoxyphenyl group, 3-methoxyphenyl group, 4-methoxyphenyl group, 4-methyl-3-nitrophenyl group, 2-methoxy-5-methylphenyl group, or 3 , 4- (methylenedioxy) phenyl group is preferred, phenyl group, 2,4-difluorophenyl group, 3,4-difluorophenyl group, 2-fluorophenyl group, 3-fluorophenyl group, 4-fluorophenyl group, 4-bromophenyl group, 2-chlorophenyl group, 4-chlorophenyl group, 2,4-dichlorophenyl group, 4-nitrophenyl group, 4-isopropylphenyl group, 4-phenyloxyphenyl group, 2-methylphenyl group, 3- Methylphenyl group, 4-methylphenyl group, 2,4,5-trimethylphenyl group, 2,4,6 Trimethylphenyl group, 2-trifluoromethylphenyl group, 3-trifluoromethylphenyl group, 4-trifluoromethylphenyl group, 2-trifluoromethoxyphenyl group, 4-trifluoromethoxyphenyl group, 2-methoxyphenyl group, Particularly preferred examples include 3-methoxyphenyl group, 4-methoxyphenyl group, 4-methyl-3-nitrophenyl group, 2-methoxy-5-methylphenyl group, or 3,4- (methylenedioxy) phenyl group. It is done. Phenyl group, 2,4-difluorophenyl group, 3,4-difluorophenyl group, 2-fluorophenyl group, 3-fluorophenyl group, 4-fluorophenyl group, 4-bromophenyl group, 2-chlorophenyl group, 4- A most preferred example is a chlorophenyl group, a 2,4-dichlorophenyl group, a 4-isopropylphenyl group, or a 3,4- (methylenedioxy) phenyl group.

R ¹ is, for example, 1-naphthyl group, 2-naphthyl group, 5-indanyl group, 5,6,7,8-tetrahydronaphthalen-2-yl group, allyl group, 3-butenyl group, and 2-propynyl group. It is also preferably any substituent selected from the group consisting of: a 5-indanyl group, a 3-butenyl group, or a 2-propynyl group. More specifically, as R ¹ , for example, methyl group, ethyl group, propyl group, butyl group, isopropyl group, isobutyl group, 1-methylpropyl group, t-butyl group, 3-methylbutyl group, 2,2- Dimethylpropyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclohexylmethyl group, 2,2,2-trifluoroethyl group, 2,2-difluoropropyl group, 2,2-difluorobutyl group, 2-methoxyethyl group 2-ethoxyethyl group, 3-methoxypropyl group, 3-ethoxypropyl group, benzyl group, 2-phenylethyl group, 4-fluorobenzyl group, 4-chlorobenzyl group, 4-bromobenzyl group, 2,4- Difluorobenzyl group, 3,5-difluorobenzyl group, 2- (4-fluorophenyl) ethyl group, 2- (4- Rophenyl) ethyl group, 2- (4-bromophenyl) ethyl group, 2- (2,4-difluorophenyl) ethyl group, 2- (3,5-difluorophenyl) ethyl group, phenyl group, 2,4-difluoro Phenyl group, 3,4-difluorophenyl group, 2-fluorophenyl group, 3-fluorophenyl group, 4-fluorophenyl group, 4-bromophenyl group, 2-chlorophenyl group, 4-chlorophenyl group, 2,4-dichlorophenyl Group, 4-nitrophenyl group, 4-isopropylphenyl group, 4-phenyloxyphenyl group, 2-methylphenyl group, 3-methylphenyl group, 4-methylphenyl group, 2,4,5-trimethylphenyl group, 2 , 4,6-trimethylphenyl group, 2-trifluoromethylphenyl group, 3-trifluoromethylphenyl group, 4-trifluoromethylphenyl group, 2-trifluoromethoxyphenyl group, 4-trifluoromethoxyphenyl group, 3-cyanophenyl group, 4-cyanophenyl group, 2-methoxyphenyl group, 3-methoxyphenyl group, 4- Methoxyphenyl group, 4-methyl-3-nitrophenyl group, 2-methoxy-5-methylphenyl group, 3,4- (methylenedioxy) phenyl group, 1-naphthyl group, 2-naphthyl group, 5-indanyl group 5,6,7,8-tetrahydronaphthalen-2-yl group, allyl group, 3-butenyl group, or 2-propynyl group are preferred, methyl group, ethyl group, propyl group, butyl group, isopropyl group, isobutyl group T-butyl group, 1-methylpropyl group, 2,2-dimethylpropyl group, cyclopentyl group, cyclohexyl group, 2 Methoxyethyl group, benzyl group, 2-phenylethyl group, 2,2,2-trifluoroethyl group, phenyl group, 2,4-difluorophenyl group, 3,4-difluorophenyl group, 2-fluorophenyl group, 3 -Fluorophenyl group, 4-fluorophenyl group, 4-bromophenyl group, 2-chlorophenyl group, 4-chlorophenyl group, 2,4-dichlorophenyl group, 4-nitrophenyl group, 4-isopropylphenyl group, 4-phenyloxy Phenyl group, 2-methylphenyl group, 3-methylphenyl group, 4-methylphenyl group, 2,4,5-trimethylphenyl group, 2,4,6-trimethylphenyl group, 2-trifluoromethylphenyl group, 3 -Trifluoromethylphenyl group, 4-trifluoromethylphenyl group, 2-trifluoromethoxy Enyl group, 4-trifluoromethoxyphenyl group, 2-methoxyphenyl group, 3-methoxyphenyl group, 4-methoxyphenyl group, 4-methyl-3-nitrophenyl group, 2-methoxy-5-methylphenyl group, 3 , 4- (methylenedioxy) phenyl group, 1-naphthyl group, 2-naphthyl group, 5-indanyl group, 5,6,7,8-tetrahydronaphthalen-2-yl group, allyl group, 3-butenyl group, Or 2-propynyl group is mentioned as a particularly preferable example. Methyl group, ethyl group, propyl group, butyl group, isopropyl group, isobutyl group, benzyl group, 2,2,2-trifluoroethyl group, phenyl group, 2,4-difluorophenyl group, 3,4-difluorophenyl group 2-fluorophenyl group, 3-fluorophenyl group, 4-fluorophenyl group, 4-bromophenyl group, 2-chlorophenyl group, 4-chlorophenyl group, 2,4-dichlorophenyl group, 4-isopropylphenyl group, 3, A 4- (methylenedioxy) phenyl group, a 5-indanyl group, a 3-butenyl group, or a 2-propynyl group is most preferred.

The R ^2, a lower alkoxy group, an aryloxy group, an aralkyloxy group, a lower alkylthio group, an arylthio group, aralkylthio group, and optionally substituted with a substituent selected from the group consisting of phenyl C _{2- 12} alkyl groups (wherein R ² may be further substituted with one or more halogen atoms, excluding the methylene group in R ² bonded to the nitrogen atom).
_{Examples of the} C _2-12 alkyl group represented by R ² include a saturated hydrocarbon group having 2 to 12 carbon atoms, which may contain a linear, branched, or cyclic structure. However, the carbon atom in the C _2-12 alkyl group adjacent to the nitrogen atom does not participate in the branched chain structure and the ring structure, and becomes methylene carbon (—CH ₂ —). Specific examples of the C _2-12 alkyl group include, for example, ethyl group, propyl group, butyl group, pentyl group, hexyl group, heptyl group, octyl group, nonyl group, decyl group, undecyl group, dodecyl group, 2 -Methylpropyl group, 3-methylbutyl group, 4-methylpropyl group, 2-ethylbutyl group, 2,2-dimethylbutyl group, 2-propylpentyl group, cyclopropylmethyl group, cyclobutylmethyl group, cyclopentylmethyl group, cyclohexyl A methyl group, 2-cyclopentylethyl group, 3-cyclohexylpropyl group, or 4-cyclohexylbutyl group can be mentioned. Of these, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, 3-methylbutyl, 4-methylpentyl, 2,2-dimethylbutyl, 2-cyclopentyl An ethyl group, a 3-cyclohexylpropyl group, or a 4-cyclohexylbutyl group is preferable, and an ethyl group, a propyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group, a 4-methylpentyl group, a 2,2-dimethylbutyl group, A more preferred example is a 3-cyclohexylpropyl group or a 4-cyclohexylbutyl group.

When R ² is substituted, preferred examples include ethyl, propyl, butyl, pentyl, or 2-methylpropyl. Particularly preferred is an ethyl group or a propyl group. When R ² is not substituted, butyl, pentyl, hexyl, heptyl, octyl, nonyl, 3-methylbutyl, 4-methylpentyl, 2,2-dimethylbutyl, 2- A cyclopentylethyl group, a 3-cyclohexylpropyl group, or a 4-cyclohexylbutyl group is preferable, and a pentyl group, a hexyl group, a heptyl group, an octyl group, a 4-methylpentyl group, a 2,2-dimethylbutyl group, and a 3-cyclohexylpropyl group. Or a 4-cyclohexylbutyl group is a more preferred example.

The C _2-12 alkyl group may be substituted with the above substituent. Among the above substituents, the lower alkoxy group is preferably, for example, a methoxy group, an ethoxy group, a propoxy group, a butoxy group, or a pentyloxy group, and particularly preferably an ethoxy group, a propoxy group, or a butoxy group. In addition, examples of the aryloxy group as the substituent include a group in which an aromatic ring (aryl ring) is bonded to an oxygen atom, and the ring constituent elements include heteroelements in addition to carbon and hydrogen. It may contain some nitrogen, sulfur or oxygen. The aryl ring may be monocyclic or polycyclic. Examples of the aryloxy group include phenoxy group, 3-pyridyloxy group, 4-pyridyloxy group, 2-thienyloxy group, 3-thienyloxy group, 2-furyloxy group, and 3-furyloxy group. A phenoxy group, a 2-thienyloxy group, a 3-thienyloxy group, a 2-furyloxy group, or a 3-furyloxy group is preferable, and a phenoxy group is particularly preferable.

  Among the above substituents, the aralkyloxy group is a group in which aralkyl is bonded to an oxygen atom, and the aralkyl has a structure in which one or more aryl rings are substituted on a lower alkyl group. Examples of the aralkyloxy group include benzyloxy group, 2-phenylethyloxy group, 1-phenylethyloxy group, 3-phenylpropyloxy group, and 2- (4-pyridyl) ethyloxy group, and preferably benzyl An oxy group, 2-phenylethyloxy group, or 3-phenylpropyloxy group is mentioned, More preferably, a benzyloxy group or 2-phenylethyloxy group is mentioned. As the lower alkylthio group, for example, a methylthio group, an ethylthio group, a propylthio group, a butylthio group, or a pentylthio group is preferable, and an ethylthio group, a propylthio group, and a butylthio group are particularly preferable. The arylthio group is a group in which an aryl ring is bonded to a sulfur atom. For example, a phenylthio group or a 4-pyridylthio group is preferable, and a phenylthio group is particularly preferable. The aralkylthio group is a group in which aralkyl is bonded to a sulfur atom. For example, a benzylthio group, a 2-phenylethylthio group, a 1-phenylethylthio group, a 3-phenylpropylthio group, or 2- (4-pyridyl) ethylthio group. Group, preferably benzylthio group, 2-phenylethylthio group or 3-phenylpropylthio group, more preferably benzylthio group and 2-phenylethylthio group.

When the C _2-12 alkyl group is substituted with the above-described substituent, the number of substituents is not particularly limited as long as it is less than the number that can be substituted, but is usually 1 to 4, and 1 or Two are preferable, and one is particularly preferable. In addition, the substitution positions of these substituents are as follows when the C _2-12 alkyl group is in the 1st, 2nd,..., Nth position in order from the carbon atom bonded to the nitrogen atom (here And the n-position is the position of the carbon atom farthest from the bond, and therefore the 2-position for the ethyl group and the 3-position for the propyl group), and the substitution position is preferably between the 2-position and the n-position. And particularly preferably n-position or (n-1) -position.
R ² may be further substituted with one or more halogen atoms, except for the methylene group in R ² bonded to the nitrogen atom. Examples of the halogen atom include fluorine, chlorine, bromine, or iodine, preferably fluorine, chlorine, or bromine, more preferably fluorine or chlorine. The number of halogen atoms is not particularly limited as long as it can be substituted, but is usually 1 to 15. Preferably 1 to 10, more preferably 1 to 5 are exemplified. The substitution position of the halogen atom is not particularly limited, may be substituted at any position of the alkyl moiety of R ^2, or can be substituted at any position of the substituents on R ^2, there in both May be.

More specifically, as R ² , ethyl group, propyl group, butyl group, pentyl group, hexyl group, heptyl group, octyl group, nonyl group, decyl group, undecyl group, dodecyl group, 2-methylpropyl group, 3-methylbutyl group, 4-methylpropyl group, 2-ethylbutyl group, 2,2-dimethylbutyl group, 2-propylpentyl group, cyclopropylmethyl group, cyclobutylmethyl group, cyclopentylmethyl group, cyclohexylmethyl group, 2- Examples include a cyclopentylethyl group, a 3-cyclohexylpropyl group, or a 4-cyclohexylbutyl group. 2-methoxyethyl group, 2-ethoxyethyl group, 2-propoxyethyl group, 2-butoxyethyl group, 2-pentyloxyethyl group, 3-methoxypropyl group, 3-ethoxypropyl group, 3-propoxypropyl group, 3 -Butoxypropyl group, 3-pentyloxypropyl group, 2-methylthioethyl group, 2-ethylthioethyl group, 2-propylthioethyl group, 2-butylthioethyl group, 2-pentylthioethyl group, 3-methylthiopropyl Group, 3-ethylthiopropyl group, 3-propylthiopropyl group, 3-butylthiopropyl group, 3-pentylthiopropyl group, 2-phenoxyethyl group, 3-phenoxypropyl group, 4-phenoxybutyl group, 5- Phenoxypentyl group, 2-benzyloxyethyl group, 3-benzyloxypropyl group, 4- Benzyloxybutyl group, 5-benzyloxypentyl group, 2- (2-phenylethoxy) ethyl group, 3- (2-phenylethoxy) propyl group, 4- (2-phenylethoxy) butyl group, 5- (2 -Phenylethoxy) pentyl group, 2- (3-phenylpropyloxy) ethyl group, 3- (3-phenylpropyloxy) propyl group, 4- (3-phenylpropyloxy) butyl group, 5- (3-phenylpropyl) Oxy) pentyl group, 2-phenylthioethyl group, 3-phenylthiopropyl group, 4-phenylthiobutyl group, 5-phenylthiopentyl group, 2-benzylthioethyl group, 3-benzylthiopropyl group, 4-benzyl Thiobutyl group, 5-benzylthiopentyl group, 2- (2-phenylethylthio) ethyl group, 3- (2-phenylethyl) Ruthio) propyl group, 4- (2-phenylethylthio) butyl group, 5- (2-phenylethylthio) pentyl group, 2- (3-phenylpropylthio) ethyl group, 3- (3-phenylpropylthio) propyl group 4- (3-phenylpropylthio) butyl group, 5- (3-phenylpropylthio) pentyl group, 2-phenylethyl group, 3-phenylpropyl group, 4-phenylbutyl group, or 5-phenylpentyl group. It is done.

  Furthermore, 7,7,7-trifluoroheptyl group, 6,6-difluoroheptyl group, 5,5-difluoroheptyl group, 4,4-difluoroheptyl group, 3,3-difluoroheptyl group, 6,6,6 -Trifluorohexyl group, 5,5-difluorohexyl group, 4,4-difluorohexyl group, 3,3-difluorohexyl group, 5,5,5-trifluoropentyl group, 4,4-difluoropentyl group, 3 , 3-difluoropentyl group, 6,6,7,7,7-pentafluoroheptyl group, 5,5,6,6-tetrafluoroheptyl group, 4,4,5,5-tetrafluoroheptyl group, 5, 5,6,6,7,7,7-heptafluoroheptyl group, 4,4,5,5,6,6-hexafluoroheptyl group, 4,4,5,5,6,6,7,7, 7-Nonafluo Heptyl group, 3,3,4,4,5,5,6,6,7,7,7-undecafluoroheptyl group, 2,2,3,3,4,4,5,5,6,6 , 7,7,7-tridecafluoroheptyl group, 5,5,6,6,6-pentafluorohexyl group, 4,4,5,5-tetrafluorohexyl group, 3,3,4,4-tetra Fluorohexyl group, 4,4,5,5,6,6,6-heptafluorohexyl group, 3,3,4,4,5,5-hexafluorohexyl group, 3,3,4,4,5 5,6,6,6-nonafluorohexyl group, 2,2,3,3,4,4,5,5,6,6,6-undecafluorohexyl group, 4,4,5,5,5 -Pentafluoropentyl group, 3,3,4,4-tetrafluoropentyl group, 3,3,4,4,5,5,5-heptafluoropen Group, 2,2,3,3,4,4,5,5,5-nonafluoropentyl group, 2- (3,3,3-trifluoropropoxy) ethyl group, 2- (2,2-difluoro (Propoxy) ethyl group, 2- (1,1-difluoropropoxy) ethyl group, 2- (1,1,2,2,3,3,3-heptafluoropropoxy) ethyl group, 2- (4,4,4 -Trifluorobutoxy) ethyl group, 2- (3,3-difluorobutoxy) ethyl group, 2- (2,2-difluorobutoxy) ethyl group, 2- (1,1-difluorobutoxy) ethyl group, 2- ( 1,1,2,2,3,3,4,4,4-nonafluorobutoxy) ethyl group, 2- (5,5,5-trifluoropentyloxy) ethyl group, 2- (4,4-difluoro Pentyloxy) ethyl group, 2- (3,3-difluoro Pentyloxy) ethyl group, 2- (2,2-difluoropentyloxy) ethyl group, 2- (1,1-difluoropentyloxy) ethyl group, 2- (1,1,2,2,3,3,4) , 4,5,5,5-undecafluoropentyloxy) ethyl group, 3- (2,2,2-trifluoroethoxy) propyl group, 3- (1,1-difluoroethoxy) propyl group, 3- ( 1,1,2,2,2-pentafluoroethoxy) propyl group, 3- (3,3,3-trifluoropropoxy) propyl group, 3- (2,2-difluoropropoxy) propyl group, 3- (1 , 1-difluoropropoxy) propyl group, 3- (1,1,2,2,3,3,3-heptafluoropropoxy) propyl group, 2- (4-fluorophenoxy) ethyl group, 2- (3,5 -Difluoroph Noxy) ethyl group, 2- (4-chlorophenoxy) ethyl group, 2- (3,5-dichlorophenoxy) ethyl group, 3- (4-fluorophenoxy) propyl group, 3- (3,5-difluorophenoxy) Propyl group, 3- (4-chlorophenoxy) propyl group, 3- (3,5-dichlorophenoxy) propyl group, 4- (4-fluorophenoxy) butyl group, 4- (3,5-difluorophenoxy) butyl group 4- (4-chlorophenoxy) butyl group, 4- (3,5-dichlorophenoxy) butyl group, 2- (4-fluorobenzyloxy) ethyl group, 2- (3,5-difluorobenzyloxy) ethyl group 2- (4-chlorobenzyloxy) ethyl group, 2- (3,5-dichlorobenzyloxy) ethyl group, 3- (4-fluorobenzyloxy) propyl Pill group, 3- (3,5-difluorobenzyloxy) propyl group, 3- (4-chlorobenzyloxy) propyl group, 3- (3,5-dichlorobenzyloxy) propyl group, 4- (4-fluorobenzyl) Oxy) butyl group, 4- (3,5-difluorobenzyloxy) butyl group, 4- (4-chlorobenzyloxy) butyl group, 4- (3,5-dichlorobenzyloxy) butyl group, 2- [2- (4-fluorophenyl) ethoxy] ethyl group, 2- [2- (3,5-difluorophenyl) ethoxy] ethyl group, 2- [2- (4-chlorophenyl) ethoxy] ethyl group, 2- [2- ( 3,5-dichlorophenyl) ethoxy] ethyl group, 2- [2- (4-fluorophenyl) ethoxy] propyl group, 2- [2- (3,5-difluorophenyl) ethoxy ] Propyl group, 2- [2- (4-chlorophenyl) ethoxy] propyl group, 2- [2- (3,5-dichlorophenyl) ethoxy] propyl group, 2- (3,3,3-trifluoropropylthio) Ethyl group, 2- (2,2-difluoropropylthio) ethyl group, 2- (1,1-difluoropropylthio) ethyl group, 2- (1,1,2,2,3,3,3-heptafluoro Propylthio) ethyl group, 2- (4,4,4-trifluorobutylthio) ethyl group, 2- (3,3-difluorobutylthio) ethyl group, 2- (2,2-difluorobutylthio) ethyl group 2- (1,1-difluorobutylthio) ethyl group, 2- (1,1,2,2,3,3,4,4,4-nonafluorobutylthio) ethyl group, 2- (5,5 , 5-Trifluoropentylthio) ethyl 2- (4,4-difluoropentylthio) ethyl group, 2- (3,3-difluoropentylthio) ethyl group, 2- (2,2-difluoropentylthio) ethyl group, 2- (1,1- Difluoropentylthio) ethyl group, 2- (1,1,2,2,3,3,4,4,5,5,5-undecafluoropentylthio) ethyl group, 3- (2,2,2- Trifluoroethylthio) propyl group, 3- (1,1-difluoroethylthio) propyl group, 3- (1,1,2,2,2-pentafluoroethylthio) propyl group, 3- (3,3,3) 3-trifluoropropylthio) propyl group, 3- (2,2-difluoropropylthio) propyl group, 3- (1,1-difluoropropylthio) propyl group, 3- (1,1,2,2,3) , 3,3-Heptafluoropropylthio ) Propyl group, 2- (4-fluorophenylthio) ethyl group, 2- (3,5-difluorophenylthio) ethyl group, 2- (4-chlorophenylthio) ethyl group, 2- (3,5-dichlorophenylthio) ) Ethyl group, 3- (4-fluorophenylthio) propyl group, 3- (3,5-difluorophenylthio) propyl group, 3- (4-chlorophenylthio) propyl group, 3- (3,5-dichlorophenylthio) ) Propyl group, 4- (4-fluorophenylthio) butyl group, 4- (3,5-difluorophenylthio) butyl group, 4- (4-chlorophenylthio) butyl group, 4- (3,5-dichlorophenylthio) ) Butyl group, 2- (4-fluorobenzylthio) ethyl group, 2- (3,5-difluorobenzylthio) ethyl group, 2- (4-chlorobenzylthio) ) Ethyl group, 2- (3,5-dichlorobenzylthio) ethyl group, 3- (4-fluorobenzylthio) propyl group, 3- (3,5-difluorobenzylthio) propyl group, 3- (4-chloro) Benzylthio) propyl group, 3- (3,5-dichlorobenzylthio) propyl group, 4- (4-fluorobenzylthio) butyl group, 4- (3,5-difluorobenzylthio) butyl group, 4- (4 -Chlorobenzylthio) butyl group, 4- (3,5-dichlorobenzylthio) butyl group, 2- [2- (4-fluorophenyl) ethylthio] ethyl group, 2- [2- (3,5-difluorophenyl) ) Ethylthio] ethyl group, 2- [2- (4-chlorophenyl) ethylthio] ethyl group, 2- [2- (3,5-dichlorophenyl) ethylthio] ethyl group, 2- [2- (4- Fluorophenyl) ethylthio] propyl group, 2- [2- (3,5-difluorophenyl) ethylthio] propyl group, 2- [2- (4-chlorophenyl) ethylthio] propyl group, 2- [2- (3,5- Dichlorophenyl) ethylthio] propyl group, 3- (4-fluorophenyl) propyl group, 3- (3,5-difluorophenyl) propyl group, 3- (4-chlorophenyl) propyl group, 3- (3,5-dichlorophenyl) Propyl group, 4- (4-fluorophenyl) butyl group, 4- (3,5-difluorophenyl) butyl group, 4- (4-chlorophenyl) butyl group, 4- (3,5-dichlorophenyl) butyl group, 5 -(4-fluorophenyl) pentyl group, 5- (3,5-difluorophenyl) pentyl group, 5- (4-chlorophenyl) pe It can be methyl group, or a 5- well as (3,5-dichlorophenyl) pentyl group mentioned as an example.

  Among these, hexyl group, heptyl group, octyl group, nonyl group, 3-methylbutyl group, 4-methylpentyl group, 2,2-dimethylbutyl group, 2-cyclopentylethyl group, 3-cyclohexylpropyl group, 4-cyclohexyl Butyl group, 2-propoxyethyl group, 2-pentyloxyethyl group, 2-benzyloxyethyl group, 3-benzyloxypropyl group, 2-phenylthioethyl group, 3-phenylthiopropyl group, 3-phenylpropyl group 4-phenylbutyl group, 7,7,7-trifluoroheptyl group, 2- (4-chlorophenoxy) ethyl group, or 2- (3,5-dichlorophenoxy) ethyl group is preferable, and hexyl group, Heptyl group, octyl group, nonyl group, 3-methylbutyl group, 4-methylpentyl group, 2,2-dimethyl Butyl group, 2-cyclopentylethyl group, 3-cyclohexylpropyl group, 4-cyclohexylbutyl group, 2-propoxyethyl group, 2-pentyloxyethyl group, 2-benzyloxyethyl group, 3-benzyloxypropyl group, 2 -Phenylthioethyl group, 3-phenylthiopropyl group, 3-phenylpropyl group, or 4-phenylbutyl group are particularly preferable, hexyl group, heptyl group, octyl group, 2-butoxyethyl group, 2-propoxyethyl group, A 2-butoxyethyl group or a 2-pentyloxyethyl group is most preferred.

(R ³ ) _b includes b (b is an integer of 0 to 4) substituents that may be different from each other, selected from the group consisting of a halogen atom, a lower alkyl group, and a lower alkoxy group. The halogen atom is selected from fluorine, chlorine, bromine, or iodine. Of these, fluorine or chlorine is preferable, and fluorine is more preferable. Examples of the lower alkyl group include linear or branched saturated hydrocarbon groups having 1 to 5 carbon atoms. Among them, a methyl group or an ethyl group is preferable, and a methyl group is more preferable. Examples of the lower alkoxy group include linear or branched alkoxy groups having 1 to 5 carbon atoms, preferably a methoxy group or an ethoxy group, and more preferably a methoxy group. As a kind of substituent, a halogen atom or a lower alkoxy group is preferable among a halogen atom, a lower alkyl group, or a lower alkoxy group, and a lower alkoxy group is more preferable. The number of substituents (integer b) is 0, 1, 2, 3, or 4, with 0 or 1 being preferred, and 0 being particularly preferred. When b is 0, it means that R ³ does not exist. In the case where b is 1 or more, the position of the substituent R ³ is such that, among the carbon atoms on the benzene ring to which R ³ is bonded, the carbon to which the methylene carbon is bonded is the first position, and the carbon to which the oxygen atom is bonded is the fourth position. 2nd, 3rd, 5th, or 6th is preferred, and the 2nd or 3rd is preferred, and the 3rd is more preferred. More specifically, (R ³ ) _b is preferably one methoxy group bonded to the 3-position, and it is also preferable that b is 0 (that is, when no substituent is present).

R ⁴ represents a lower alkyl group. Examples of the lower alkyl group include linear or branched alkyl groups having 1 to 5 carbon atoms, preferably a methyl group, an ethyl group, or an isopropyl group, and more preferably an ethyl group or an isopropyl group.
R ⁵ represents a hydrogen atom or a lower alkyl group. Examples of the lower alkyl group include linear or branched alkyl groups having 1 to 5 carbon atoms, preferably a methyl group, an ethyl group, or an isopropyl group, and more preferably an ethyl group. R ⁵ is most preferably an ethyl group or a hydrogen atom.
n is an integer of 2 to 4. n is preferably 2 or 3.
X represents —NH— or —O—. X may be —NH—, but is preferably —O—.

Preferred compounds in general formula (1) are as follows.
<1> R ¹ is a halogen atom, optionally substituted with one or more substituents selected from the group consisting of lower alkoxy groups and one or more phenyl group which may be substituted by a halogen atom, C ₁ A compound represented by general formula (1) which is a _-12 alkyl group.
<2> R ² is represented by the general formula (1), which is a C _2-12 alkyl group which may be substituted with one or more substituents selected from the group consisting of a lower alkoxy group and a lower alkylthio group. Compound or the compound according to <1> above.
<3> A compound represented by the general formula (1) in which b is 0, or a compound according to the above <1> or <2>.
<4> A compound represented by the general formula (1) wherein R ⁴ is a methyl group, an ethyl group, or an isopropyl group, or a compound according to any one of the above <1> to <3>.
<5> The compound represented by the general formula (1) in which R ⁵ is a hydrogen atom or an ethyl group, or the compound according to any one of the above <1> to <4>.
<6> A compound represented by the general formula (1) wherein n is 2 or 3, or a compound according to any one of the above <1> to <5>.

<7> A compound represented by the general formula (1) wherein X is —O—, or a compound according to any one of the above <1> to <6>.
<8> R ² is a lower alkoxy group, an aryloxy group, aralkyloxy group, and one or more substituents optionally substituted good C _2-12 optionally alkyl group selected from the group consisting of phenyl group (provided that , R ² may be substituted with one or more halogen atoms, excluding the methylene group in R ² bonded to the nitrogen atom.), B is 0, R ⁴ is an ethyl group The compound according to <7>, wherein R ₅ is a hydrogen atom or an ethyl group, n is 2, and X is —O—.
<9> R ¹ is the formula (1-1), and (R ⁶ ) _a is a (a is an integer of 0 to 5) fluorine atoms, and R ² is a normal pentyl group or a normal hexyl group. Any one alkyl group selected from the group consisting of normal heptyl group, and normal octyl group, b is 0, R ⁴ is an ethyl group, R ⁵ is hydrogen or an ethyl group, and n is 2. The compound according to <8>, wherein X is —NH—.
<10> R ¹ is methyl group, ethyl group, benzyl group, allyl group, propyl group, p-tolyl group, 4-bromophenyl group, 4-fluorophenyl group, 2-methoxyethyl group, isopropyl group, 2-propynyl A substituent selected from the group consisting of a group, 2-naphthyl group, isobutyl group, 2,2-dimethylpropyl group, and 3-butenyl group, R ² is a heptyl group, b is 0, R ⁴ <9> The compound according to <9>, wherein is an ethyl group, R ₅ is a hydrogen atom or an ethyl group, n is 2, and X is —O—.

<11> (R) -3- (4- {2- [3- (2,4-difluorophenyl) -1-heptylureido] ethoxy} phenyl) -2-ethoxypropionic acid, (R) -3- ( 4- {2- [3- (2,4-difluorophenyl) -1-heptylureido] ethoxy} phenyl) -2-ethoxypropionic acid ethyl ester, (S) -3- (4- {2- [3- (2,4-difluorophenyl) -1-heptylureido] ethoxy} phenyl) -2-ethoxypropionic acid, (S) -3- (4- {2- [3- (2,4-difluorophenyl) -1 -Heptylureido] ethoxy} phenyl) -2-ethoxypropionic acid ethyl ester, 3- (4- {2- [3- (2,4-difluorophenyl) -1-heptylureido] ethoxy} phenyl) -2 -Ethoxypropionic acid and a compound selected from the group consisting of 3- (4- {2- [3- (2,4-difluorophenyl) -1-heptylureido] ethoxy} phenyl) -2-ethoxypropionic acid ethyl ester .

<12> 2-ethoxy-3- (4- {2- [heptyl (isopropyloxycarbonyl) amino] ethoxy} phenyl) propionic acid, 2-ethoxy-3- (4- {2- [heptyl (isopropyloxycarbonyl) Amino] ethoxy} phenyl) propionic acid ethyl ester, (R) -2-ethoxy-3- (4- {2- [heptyl (isopropyloxycarbonyl) amino] ethoxy} phenyl) propionic acid, (R) -2-ethoxy -3- (4- {2- [Heptyl (isopropyloxycarbonyl) amino] ethoxy} phenyl) propionic acid ethyl ester, (S) -2-ethoxy-3- (4- {2- [heptyl (isopropyloxycarbonyl) Amino] ethoxy} phenyl) propionic acid, and (S) -2-ethoxy-3- (4) {2- [heptyl (isopropyloxy carbonyl) amino] ethoxy} phenyl) compound selected from the group consisting of propionic acid ethyl ester.
<13> 3- (4- {2- [benzyloxycarbonyl (heptyl) amino] ethoxy} phenyl) -2-ethoxypropionic acid, 3- (4- {2- [benzyloxycarbonyl (heptyl) amino] ethoxy} Phenyl) -2-ethoxypropionic acid ethyl ester, (R) -3- (4- {2- [benzyloxycarbonyl (heptyl) amino] ethoxy} phenyl) -2-ethoxypropionic acid, (R) -3- ( 4- {2- [benzyloxycarbonyl (heptyl) amino] ethoxy} phenyl) -2-ethoxypropionic acid ethyl ester, (S) -3- (4- {2- [benzyloxycarbonyl (heptyl) amino] ethoxy} Phenyl) -2-ethoxypropionic acid, and (S) -3- (4- {2- [benzyloxycarbonyl] Heptyl) amino] ethoxy} phenyl) -2-ethoxy-propionic consisting acid ethyl ester compound selected from the group.

<14> (R) -2-ethoxy-3- {4- [2- (N-heptyl-N-methoxycarbonylamino) ethoxy] phenyl} propionic acid, (R) -2-ethoxy-3- {4- [2- (N-heptyl-N-methoxycarbonylamino) ethoxy] phenyl} propionic acid ethyl ester, (S) -2-ethoxy-3- {4- [2- (N-heptyl-N-methoxycarbonylamino) Ethoxy] phenyl} propionic acid, (S) -2-ethoxy-3- {4- [2- (N-heptyl-N-methoxycarbonylamino) ethoxy] phenyl} propionic acid ethyl ester, 2-ethoxy-3- { 4- [2- (N-heptyl-N-methoxycarbonylamino) ethoxy] phenyl} propionic acid, 2-ethoxy-3- {4- [2- (N-heptyl- N-methoxycarbonylamino) ethoxy] phenyl} propionic acid ethyl ester.

  The compound of the above general formula (1) or a physiologically acceptable salt thereof is described in, for example, International Publication WO 2003/070692, and a person skilled in the art can use the above general formula based on the disclosure of the above publication. Compounds of formula (1) or physiologically acceptable salts thereof can be readily prepared. Examples of particularly preferred compounds represented by the general formula (1) that can be used in the medicament of the present invention include the example compounds disclosed in the above-mentioned International Publication WO 2003/070692. All of the above international disclosures are incorporated herein by reference.

  The medicament of the present invention may be used in combination with one or more medicaments having other pharmacological actions. Examples of drugs that can be used in combination include PPAR modulators, RXR agonists, blood pressure lowering agents, antibiotics, steroids (corticosteroids), non-steroids (such as NSAIDs), antivirals, and antioxidants One or two or more kinds of drugs selected from the group consisting of However, drugs that can be used in combination are not limited to these.

  The preventive and / or therapeutic action of diseases in the ophthalmological field is, for example, a method of examining the variation in production of Nitric Oxide by adding the drug of the present invention to Lacrimal Gland Acinar cells (J. Ocular Pharmacol. Therap., 19, pp.579). -587, 2003), a method of examining changes in the number of neovascularization by administering the pharmaceutical of the present invention to an experimental animal such as a rat that has undergone angiogenesis by attaching Vasucular endothelial growth favtor (VEGF) to the eyeball (Exp Eye Research, 80, pp.435-442, 2005) can be easily evaluated by those skilled in the art.

Since the compound represented by the above general formula (1) which is an active ingredient of the medicament of the present invention is not toxic as disclosed in International Publication WO 2003/070692, the medicament of the present invention is safe. It is useful as a high drug.
It has been suggested that the compound represented by the general formula (1) has Peroxisome proliferator-activated receptor (PPAR) alpha activating action and PPAR gamma activating action (International Publication WO2003 / 070692). Recently, PPAR alpha agonists have been reported to be effective for corneal dry eye, corneal ulcers, keratitis, etc. (JP-A-2005-8570), and PPAR gamma agonists are effective for ophthalmic inflammation and angiogenesis. It has been reported (International Publication WO2000 / 00194 and US Pat. No. 6,316,465). From the above, PPAR alpha activation action and / or PPAR gamma activation action is involved in all or part of the prevention and / or treatment action of diseases in the ophthalmic field by the compound represented by the general formula (1). The possibility is suggested.

  Examples of the medicament containing the compound represented by the general formula (1) of the present invention or a physiologically acceptable salt thereof as an active ingredient include the compound represented by the general formula (1) and the physiologically acceptable salt thereof. In addition, one or two or more substances selected from the group consisting of hydrates or solvates thereof may be used as they are (if two or more substances are used, a mixture thereof may be used. It is preferable to prepare and administer a pharmaceutical composition by adding one or more physiologically acceptable pharmaceutical additives to the above substances. The administration route of the medicament of the present invention is not particularly limited, and can be administered orally or parenterally. The type of physiologically acceptable formulation additive is not particularly limited, and examples thereof include excipients, binders, disintegrants, lubricants, and additives. Examples of the excipient include D-mannitol. Examples of the binder include carboxymethyl cellulose. Examples of the disintegrant include corn starch. Examples of the lubricant include glycerin. Examples of the additive include paraoxybenzoic acid esters. Further, examples of additives include surfactants such as Polyoxyethylenesorbitan monooleate (tween 80) and HC60.

  More specifically, preferred administration routes for administering the medicament of the present invention to mammals including humans include, for example, eye drops, eye ointments, oral, transdermal, intravenous, or intranasal spray. Eye drops or eye ointments are preferred, with eye drops being the most preferred route of administration. 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 monooleate, polyoxyl 40 stearate, and polyoxyethylene hydrogenated castor oil. A surfactant, a stabilizer such as sodium citrate and sodium edetate, and a preservative such as benzalkonium chloride or paraben can be used as necessary. The pH may be in the range acceptable for ophthalmic preparations, but is preferably in the range of 4-9. The eye ointment can be prepared using a widely used base such as white petrolatum or liquid paraffin.

The administration period of the medicament of the present invention is not particularly limited and is generally continued for several weeks to 1 year, but can be further continued depending on the pathological condition, or after recovery of clinical symptoms. Continuous administration is also possible. Furthermore, even if no clinical symptoms are manifested, it can be administered prophylactically at the discretion of the clinician. The dose of the medicament of the present invention is not particularly limited. For example, the eye drop may be instilled 0.0001 to 1% (w / v) once to several times a day. In the oral preparation, 0.01 to 2000 mg of an active ingredient per day for an adult can be administered in one to several divided doses. The administration frequency can be administration at various frequencies such as once a month to every day, and preferably once / week to 3 times / week, or 5 times / week, or every day. The daily dose, administration period, administration frequency, and the like can be appropriately increased or decreased depending on the age, weight, and physical health of the patient, and the disease to be treated and its severity.
The scope of the medicament of the present invention includes, for example, a compound represented by the general formula (1) or a physiologically acceptable salt thereof when a compound or a salt thereof administered as a prodrug is metabolized in vivo. The case of generating is also included.

Although this invention is demonstrated based on an Example, a reference example, a formulation example, and a test example, the scope of the present invention is not limited to the following examples.
Reference example 1
Each compound was converted into Example 2 (3- (4- {2- [3- (2,4-difluorophenyl) -1-heptylureido] ethoxy} phenyl) -2 shown in WO 2003/070692 pamphlet. -Ethoxypropionic acid; hereinafter referred to as “Compound A”), Example 56 (2-ethoxy-3- {4- [2- (N-heptyl-N-methoxycarbonylamino) ethoxy] phenyl} propionic acid; Compound 57 ", Example 57 (3- (4- {2- [benzyloxycarbonyl (heptyl) amino] ethoxy} phenyl) -2-ethoxypropionic acid; hereinafter referred to as" Compound C "), Example 66 (2-ethoxy-3- (4- {2- [heptyl (isopropyloxycarbonyl) amino] ethoxy} phenyl) propionic acid; hereinafter referred to as “Compound D”) And synthesized.

Example 1: Preparation of pellet formulation
Pellets were prepared according to the method of Sarayba et al. (Exp. Eye Res. 80, 435-442, 2005). That is, the polymer was dissolved in ethanol to prepare a pellet. In this, 1 μg of Vascular endothelial growth factor (VEGF) and Compound A (1.4 μg) were dissolved. The content of Compound A can be adjusted by changing the amount of Compound A added. A pellet preparation containing compounds B, C and D was also prepared in the same manner.

Test Example 1: Inhibitory effect on angiogenesis in rat cornea
According to the method of Sarayba et al. (Exp. Eye Res. 80, 435-442, 2005), the inhibitory effect of each compound on angiogenesis in the rat cornea was examined. That is, male rats were divided into a control group, a Vascular endothelial growth factor (VEGF) administration group, and a VEGF + compound administration group. VEGF (1 ug) +/- test compounds (pellets containing compounds AD prepared according to Example 1) were transplanted and the extent of angiogenesis was measured on day 7 of pellet transplantation. The results are shown in Table 1. The inhibition rate was calculated with the amount of neovascularization increased by VEGF as 100% compared to the control. From these results, it was strongly shown that the compounds represented by the general formula (1), particularly the compounds A to D, are useful as anti-inflammatory drugs in the ophthalmic field.

Claims (18)

The following general formula (1)

[Wherein R ¹ may be substituted with one or more substituents selected from the group consisting of a halogen atom, a lower alkoxy group, and a phenyl group optionally substituted with one or more halogen atoms. A C _1-12 alkyl group or the following formula (1-1)

{Wherein (R ⁶ ) _a represents a halogen atom, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, a nitro group, a lower alkoxycarbonyl group, a cyano group, a trifluoromethyl group, a trifluoromethoxy group, and a phenyloxy group. The a substituents (a is an integer of 0 to 5) selected from the group consisting of may be different from each other. }, Or 1-naphthyl group, 2-naphthyl group, 5-indanyl group, 5,6,7,8-tetrahydronaphthalen-2-yl group, allyl group, 3-butenyl group, and 2-propynyl group Any one of the substituents selected from the group consisting of:
R ² may be substituted with one or more substituents selected from the group consisting of a lower alkoxy group, an aryloxy group, an aralkyloxy group, a lower alkylthio group, an arylthio group, an aralkylthio group, and a phenyl group. _2-12 alkyl group (wherein, R ^2, except for the methylene group in R ² which binds to the nitrogen atom, may be further substituted with one or more halogen atoms.) indicates,
(R ³ ) _b represents _b substituents (b is an integer of 0 to 4), which may be different from each other, selected from the group consisting of a halogen atom, a lower alkyl group, and a lower alkoxy group,
R ⁴ represents a lower alkyl group,
R ⁵ represents a hydrogen atom or a lower alkyl group,
n represents an integer of 2 to 4,
X represents —NH— or —O—. ]
Or a pharmacologically acceptable salt thereof as an active ingredient for the prevention and / or treatment of diseases in the ophthalmic field. R ¹ is a C _1-12 alkyl optionally substituted with one or more substituents selected from the group consisting of a halogen atom, a lower alkoxy group, and a phenyl group optionally substituted with one or more halogen atoms. The medicament according to claim 1, which is a group. The medicament according to claim 2, wherein R ² is a C _2-12 alkyl group which may be substituted with one or more substituents selected from the group consisting of a lower alkoxy group and a lower alkylthio group. The medicine according to claim 3, wherein b is 0. The pharmaceutical according to claim 4, wherein R ⁴ is a methyl group, an ethyl group, or an isopropyl group. The pharmaceutical according to claim 5, wherein R ⁵ is a hydrogen atom or an ethyl group. The medicament according to claim 6, wherein n is 2 or 3. The medicament according to claim 7, wherein X is -O-. R ² is a C _2-12 alkyl group optionally substituted by one or more substituents selected from the group consisting of a lower alkoxy group, an aryloxy group, an aralkyloxy group, and a phenyl group (provided that R ² May be substituted with one or more halogen atoms except for the methylene group in R ² bonded to the nitrogen atom.), B is 0, R ⁴ is an ethyl group, R The medicament according to claim 8, wherein ₅ is a hydrogen atom or an ethyl group, n is 2, and X is -O-. R ¹ is a group represented by the formula (1-1), and (R ⁶ ) _a is a (a is an integer of 0 to 5) fluorine atoms, and R ² is a normal pentyl group or a normal hexyl group. Any one alkyl group selected from the group consisting of normal heptyl group, and normal octyl group, b is 0, R ⁴ is an ethyl group, R ⁵ is hydrogen or an ethyl group, and n is The medicament according to claim 9, wherein X is 2 and X is —NH—. R ¹ is methyl group, ethyl group, benzyl group, allyl group, propyl group, p-tolyl group, 4-bromophenyl group, 4-fluorophenyl group, 2-methoxyethyl group, isopropyl group, 2-propynyl group, 2 A substituent selected from the group consisting of a naphthyl group, an isobutyl group, a 2,2-dimethylpropyl group, and a 3-butenyl group, R ² is a heptyl group, b is 0, and R ⁴ is an ethyl group The medicament according to claim 10, wherein R ₅ is a hydrogen atom or an ethyl group, n is 2, and X is -O-. (R) -3- (4- {2- [3- (2,4-difluorophenyl) -1-heptylureido] ethoxy} phenyl) -2-ethoxypropionic acid, (R) -3- (4- { 2- [3- (2,4-difluorophenyl) -1-heptylureido] ethoxy} phenyl) -2-ethoxypropionic acid ethyl ester, (S) -3- (4- {2- [3- (2, 4-difluorophenyl) -1-heptylureido] ethoxy} phenyl) -2-ethoxypropionic acid, (S) -3- (4- {2- [3- (2,4-difluorophenyl) -1-heptylureido ] Ethoxy} phenyl) -2-ethoxypropionic acid ethyl ester, 3- (4- {2- [3- (2,4-difluorophenyl) -1-heptylureido] ethoxy} phenyl) -2-ethoxy A compound selected from the group consisting of cypropionic acid and 3- (4- {2- [3- (2,4-difluorophenyl) -1-heptylureido] ethoxy} phenyl) -2-ethoxypropionic acid ethyl ester; A medicament for the prevention and / or treatment of diseases in ophthalmic tissues comprising a pharmacologically acceptable salt thereof as an active ingredient. 2-Ethoxy-3- (4- {2- [heptyl (isopropyloxycarbonyl) amino] ethoxy} phenyl) propionic acid, 2-ethoxy-3- (4- {2- [heptyl (isopropyloxycarbonyl) amino] ethoxy } Phenyl) propionic acid ethyl ester, (R) -2-ethoxy-3- (4- {2- [heptyl (isopropyloxycarbonyl) amino] ethoxy} phenyl) propionic acid, (R) -2-ethoxy-3- (4- {2- [Heptyl (isopropyloxycarbonyl) amino] ethoxy} phenyl) propionic acid ethyl ester, (S) -2-ethoxy-3- (4- {2- [heptyl (isopropyloxycarbonyl) amino] ethoxy } Phenyl) propionic acid, and (S) -2-ethoxy-3- (4- {2- [Heptyl (isopropyloxycarbonyl) amino] ethoxy} phenyl) propionic acid ethyl ester, a compound selected from the group consisting of ethyl ester or a pharmacologically acceptable salt thereof as an active ingredient for prevention and / or treatment of diseases in the ophthalmic field For medicine. 3- (4- {2- [benzyloxycarbonyl (heptyl) amino] ethoxy} phenyl) -2-ethoxypropionic acid, 3- (4- {2- [benzyloxycarbonyl (heptyl) amino] ethoxy} phenyl)- 2-Ethoxypropionic acid ethyl ester, (R) -3- (4- {2- [benzyloxycarbonyl (heptyl) amino] ethoxy} phenyl) -2-ethoxypropionic acid, (R) -3- (4- { 2- [Benzyloxycarbonyl (heptyl) amino] ethoxy} phenyl) -2-ethoxypropionic acid ethyl ester, (S) -3- (4- {2- [benzyloxycarbonyl (heptyl) amino] ethoxy} phenyl)- 2-ethoxypropionic acid, and (S) -3- (4- {2- [benzyloxycarbonyl (heptyl For the prevention and / or treatment of diseases in the ophthalmic field containing a compound selected from the group consisting of (l) amino] ethoxy} phenyl) -2-ethoxypropionic acid ethyl ester or a pharmacologically acceptable salt thereof as an active ingredient Medicines. (R) -2-ethoxy-3- {4- [2- (N-heptyl-N-methoxycarbonylamino) ethoxy] phenyl} propionic acid, (R) -2-ethoxy-3- {4- [2- (N-Heptyl-N-methoxycarbonylamino) ethoxy] phenyl} propionic acid ethyl ester, (S) -2-ethoxy-3- {4- [2- (N-heptyl-N-methoxycarbonylamino) ethoxy] phenyl } Propionic acid, (S) -2-ethoxy-3- {4- [2- (N-heptyl-N-methoxycarbonylamino) ethoxy] phenyl} propionic acid ethyl ester, 2-ethoxy-3- {4- [ 2- (N-heptyl-N-methoxycarbonylamino) ethoxy] phenyl} propionic acid, 2-ethoxy-3- {4- [2- (N-heptyl-N-meth) A drug for the prevention and / or treatment of diseases in the ophthalmic field, comprising as an active ingredient a compound selected from the group consisting of xyloxyamino) ethoxy] phenyl} propionic acid ethyl ester or a pharmacologically acceptable salt thereof. The medicine according to any one of claims 1 to 15, wherein the disease in the ophthalmic field is an inflammatory disease. The medicament according to claim 16, wherein the inflammatory disease is a disease caused by inflammation and / or a disease accompanied by inflammation. The medicine according to any one of claims 1 to 15, wherein the disease in the ophthalmic field is a disease caused by an increase in inflammatory cytokines and / or inflammatory mediators and / or a disease caused by angiogenesis.