JP2002179572A - Allergic eye disease treatment - Google Patents

Abstract

(57) [Summary] [Problem] To provide a therapeutic agent for allergic eye disease. SOLUTION: The following general formula (I): [In the above formula, R ₁ represents a C ₁ -C ₈ alkyl group which may have a substituent, R ₂ represents a C ₁ -C ₄ alkyl group, R ₃ represents a hydrogen atom, a substituent C ₁ to which may have
Represents an alkyl group of C ₅ such as, R ₄ is a hydrogen atom, an alkyl group such as a good C ₁ -C ₆ may have a substituent, R ₅ and R ₆ each independently represent a hydrogen atom or a substituent Represents a C _{1 to} C ₅ alkyl group which may have 6-phenyltetrahydro-1,3-oxazine-2 represented by the formula:
-A therapeutic agent for allergic eye diseases containing an -one derivative.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel remedy for allergic eye diseases which is effective for treating allergic conjunctivitis, spring catarrh, spring keratoconjunctivitis and the like. More specifically, a 6-phenyltetrahydro-1,3-oxazin-2-one derivative having phosphodiesterase (PDE) IV (hereinafter sometimes abbreviated as “PDE IV”) inhibitory activity, an optical isomer thereof, Alternatively, the present invention relates to a remedy for allergic eye diseases containing a pharmacologically acceptable salt thereof, or a hydrate or solvate thereof.

[0002]

2. Description of the Related Art Allergic conjunctivitis develops when antigens such as pollen and house dust bind to mast cells on the conjunctiva via antibodies (IgE). Mast cells activated by antigens release conjugation of the conjunctiva, increase vascular permeability, and migrate leukocytes (eosinophils and neutrophils) by releasing chemical mediators such as histamine. Can lead to tissue damage (Abelson, MB et al. Surv Ophthalm
ol 38, p.115-132, 1993).

[0003] In the treatment of this allergic conjunctivitis, antihistamines which suppress the action of released histamine, sodium cromoglycate which suppresses the release of chemical mediators such as histamine, corticosteroids and the like have been used. However, antihistamines and sodium cromoglycate cannot be expected to inhibit the activity of migrating neutrophils and eosinophils, and corticosteroids may cause side effects such as glaucoma, cataract and infection. Therefore, there are restrictions on use (Friedlaender MH Ann Aller
gy Asthma & Immunol. 75, p.212-222, 1995). Under these circumstances, development of a nonsteroidal remedy for allergic conjunctivitis having a clear anti-inflammatory effect has been desired.

[0004]

In recent years, the activity of inflammatory cells, such as neutrophils, eosinophils, and mast cells, has been increased by the use of a second intracellular messenger, cyclic Adenosin Monophos.
phate (cAMP) has been shown to be regulated (Bourne HR et al, Science, 184, p.19-28, 1
974). From this, it is considered that a drug that increases the intracellular cAMP concentration suppresses inflammation, and research is being actively conducted at present. Phosphodiesterase (PDE) IV
Inhibitors are one of them, and cAMP is relatively high in inflammatory cells.
Inhibits the activation of inflammatory cells by increasing the intracellular cAMP concentration by inhibiting PDE IV, a degrading enzyme,
It is expected to exhibit anti-inflammatory effects (Torphy,
TJ et al, Drug News Perspect, 6, p.203-214, 199
3, Torphy TJ and Undem BJ Thorax 46, p.512-5
23, 1991).

Many PDE IV inhibitors have been developed for allergic diseases such as asthma, atopic dermatitis and rheumatism. Some compounds have been reported using allergic conjunctivitis models. (Revel, L.
et al, Eur J Pharmacol. 229, p. 45-53, 1992, Newsho
lme, SJ and Schwartz, L. Inflammation 17, p.25-
31, 1993). The present inventors have proposed a 6-phenyltetrahydro-1,3-oxazine-2 having a PDE IV inhibitory action.
The inventors have found that -one derivatives improve allergic eye diseases, and have completed the present invention. That is, the gist of the present invention is represented by the following general formula (I)

[0006]

Embedded image

[In the above formula, R ₁ is a C ₁ -C ₈ alkyl group which may have a substituent; a C ₃ -C ₇ cycloalkyl group which may have a substituent; A heterocyclic group containing at least one heteroatom selected from an oxygen atom, a nitrogen atom and a sulfur atom; or an indanyl group, wherein R ₂ is a C ₁ -C ₄ Represents an alkyl group, R ₃ is a hydrogen atom; C ₁ to C 5 which may have a substituent;
C ₅ alkyl group; C ₃ -C optionally having substituent (s)
₇ cycloalkyl group; aryl group optionally having substituent (s); optionally having one or more hetero atoms selected from oxygen atom, nitrogen atom and sulfur atom aromatic heterocyclic group; represents or an acyl group, R ₄
Is a hydrogen atom; a C ₁ -C ₆ alkyl group which may have a substituent; an aryl group which may have a substituent; or an oxygen atom or a nitrogen atom which may have a substituent. And an aromatic heterocyclic group containing one or more heteroatoms selected from sulfur atoms and R ₅ and R ₆ are each independently a hydrogen atom; C ₁ which may have a substituent alkyl group -C _5; optionally substituted aryl group; a cycloalkyl group optionally C ₃ -C ₇ may have a substituent may have a or a substituent, oxygen Represents an aromatic heterocyclic group containing one or more heteroatoms selected from atoms, nitrogen atoms and sulfur atoms. A 6-phenyltetrahydro-1,3-oxazin-2-one derivative represented by the formula (I), an optical isomer thereof, a pharmacologically acceptable salt thereof, or a hydrate or solvate thereof: And particularly preferably a therapeutic agent for allergic conjunctivitis, which comprises the compound of the formula (1).

[0008]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described below in detail.
The therapeutic agent for allergic eye disease of the present invention comprises 6-phenyltetrahydro-1,3- represented by the general formula (I).
An oxazin-2-one derivative, an optical isomer thereof or a pharmacologically acceptable salt thereof, or a hydrate or solvate thereof is contained.

[0009] In the compound of the formula (I), R ₁ is a C ₁ -C ₈ linear or branched alkyl group (methyl,
Ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl,
1,1-dimethylpropyl, n-hexyl, 1-methylpentyl, 1,1-dimethylbutyl, 2-ethylbutyl, n-heptyl, n-octyl and the like, and these are substituents (halogen atom; hydroxyl group; Nitro group; cyano group; amino group; carboxyl group; aryl group such as phenyl, tolyl, and naphthyl; aromatic heterocyclic group such as pyridyl, thiazolyl, thienyl, furyl, and quinolyl; cyclo such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Alkyl group; haloalkyl group; carbamoyl group; alkoxy group; alkylcarbonyl group, etc.).

Specific examples of the C ₁ -C ₈ alkyl group having a substituent include, for example, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 1-methylcyclopropylmethyl, 1-phenylcyclopropylmethyl, Benzyl, phenethyl, 4-
Fluorophenethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, 2- (1-naphthyl) ethyl, 2- (2-pyridyl) ethyl, 2- (4-
Methyl-5-thiazolyl) ethyl, 2- (benzyloxy) ethyl, 2- (phenethyloxy) ethyl, 2-
(Methoxy) ethyl, 3- (methoxy) propyl, 4-
(Methoxy) butyl, 2- (ethoxy) ethyl, 3-
(Ethoxy) propyl, 2- (butoxy) ethyl, 2-
(Cyclopropylmethyloxy) ethyl, 2- (cyclopentyloxy) ethyl, 2- (4-methyl-1-piperazinyl) ethyl, 3- (4-benzyl-1-piperazinyl) propyl and the like.

Examples of R ₁ include C ₃ -C ₇ cycloalkyl groups (cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.), which are substituted (alkyl group; halogen atom; hydroxyl group; Nitro group; cyano group; amino group; carboxyl group;
Aryl groups such as phenyl, tolyl, and naphthyl; aromatic heterocyclic groups such as pyridyl, thiazolyl, thienyl, furyl, and quinolyl; cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; haloalkyl groups; carbamoyl groups; An alkylcarbonyl group). C having a substituent
The cycloalkyl group of ₃ -C _7, for example, 4-phenylcyclohexyl, 1-methylcyclopentyl, 3-methylcyclopentyl, and the like.

Examples of R ₁ include a heterocyclic group (pyridyl, thiazolyl, furyl, thienyl, tetrahydrofuryl, piperidinyl, etc.), which are substituted (alkyl group; halogen atom; hydroxyl group; nitro group; cyano group). An amino group; a carboxyl group; an aryl group such as phenyl, tolyl, and naphthyl; an aromatic heterocyclic group such as pyridyl, thiazolyl, thienyl, furyl, and quinolyl;
Arylalkyl groups such as phenethyl and 1-naphthylmethyl; pyridylalkyl groups; cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; haloalkyl groups; carbamoyl groups; alkoxy groups; Often, examples of the substituted heterocyclic group include 1-benzyl-
4-piperidyl, 2-nitropyridyl, 3-tetrahydrofuryl and the like. Further, R ₁ is an indanyl group.

R ₁ is preferably a C ₁ -C ₆ alkyl group, a C ₁ -C ₅ alkyl group having a phenyl group or a cycloalkyl group as a substituent, a C ₄ -C ₆ cycloalkyl group or an indanyl group. And more preferably a cyclopentyl group, a cyclopropylmethyl group, a 2-methylpropyl group, or a 2-indanyl group. As R ₂ of the compound of the general formula (I), a C _{1 to} C ₄ linear or branched alkyl group (methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl)
Butyl, etc.), preferably methyl or ethyl, more preferably methyl.

The R of the compound of formula (I)₃As
Is a hydrogen atom, C₁~ C₅Linear or branched alkyl group
(Methyl, ethyl, n-propyl, isopropyl, n-
Butyl, sec-butyl, t-butyl, n-pentyl
Etc.). This C₁~ C ₅Linear or branched chain
The alkyl group may have a substituent, and the substituent
May have a halogen atom as a substituent.
Reel group (phenyl, tolyl, naphthyl, etc.); halogen
Oxygen atom, nitrogen which may have an atom as a substituent
One or more hetero atoms selected from atoms and sulfur atoms
Aromatic heterocyclic groups containing a group (pyridyl, thiazolyl,
Furyl, thienyl, indolyl, etc.); or alkoxyca
And a rubonyl group.

Specific examples of the C ₁ -C ₅ alkyl group having a substituent of R ₃ include, for example, ethoxycarbonylmethyl, benzyl, 4-bromobenzyl, phenethyl,
Phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, pyridylmethyl, furylmethyl, thiazolylmethyl, 2-quinolylmethyl, 1-naphthylmethyl, 2
-Indolylmethyl and the like. Further, as R ₃ , a C _{3 to} C ₇ cycloalkyl group (cyclopropyl,
Cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like), which may have a substituent. Further, as R ₃ , an aryl group (phenyl, tolyl, naphthyl, and the like) can be mentioned, and these may have a substituent. R ₃ represents an oxygen atom,
An aromatic heterocyclic group containing one or more hetero atoms selected from a nitrogen atom and a sulfur atom (pyridyl, thiazolyl, furyl, thienyl, quinolyl, etc.), which have a substituent; Is also good. Examples of R ₃ include acyl groups (formyl, acetyl, propionyl, benzoyl, 2-naphthoyl, 3-furoyl, 2-thenoyl, nicotinoyl, isonicotinoyl, and the like).

R ₃ is preferably a hydrogen atom, C _1-
An aromatic heterocyclic group containing at least one hetero atom selected from C ₃ alkyl groups, aryl groups, oxygen atoms, nitrogen atoms and sulfur atoms, or oxygen, nitrogen and sulfur atoms as substituents And a C ₁ -C ₂ alkyl group having an aromatic heterocyclic group containing at least one hetero atom selected from the group consisting of: hydrogen atom, methyl, ethyl, benzyl and 2-pyridylmethyl Or 4-pyridylmethyl.

R _{4 in} the compound of formula (I) is a hydrogen atom, a C ₁ -C ₆ linear or branched alkyl group (methyl, ethyl, propyl, isopropyl, butyl,
sec-butyl, t-butyl, pentyl, hexyl, etc.)
And these may have a substituent. Examples of R ₄ include an optionally substituted aryl group (phenyl, tolyl, naphthyl, 4-methylphenyl, 4-chlorophenyl, and the like). Further, as R ₄ , an aromatic heterocyclic group containing at least one hetero atom selected from an oxygen atom, a nitrogen atom and a sulfur atom (pyridyl, thiazolyl, thienyl, furyl and the like) can be mentioned. It may have a substituent. R ₄ is preferably a hydrogen atom, methyl, ethyl, phenyl or pyridyl, more preferably a hydrogen atom or a methyl group.

R ₅ and R ₆ of the compound of the general formula (I)
As each independently represent a hydrogen atom, a straight-chain or branched-chain alkyl groups (methyl C ₁ -C _6, ethyl, propyl,
Isopropyl, butyl, sec-butyl, t-butyl,
Pentyl, hexyl, etc.), an aryl group (phenyl, naphthyl, etc.), or an aromatic heterocyclic group containing at least one heteroatom selected from oxygen, nitrogen, and sulfur (pyridyl, thiazolyl, thienyl) , Frills, etc.). Further, the C ₁ -C ₆ alkyl groups of R ₅ and R ₆ each independently represent a substituent (halogen atom; hydroxyl group; cyano group; amino group; carboxyl group; cycloalkyl group; haloalkyl group; carbamoyl group; alkoxy group) An alkylcarbonyl group; an aryl group such as phenyl, tolyl, naphthyl, 4-methylphenyl, and 4-chlorophenyl; an aromatic heterocyclic group such as pyridyl, thiazolyl, thienyl, and furyl).

Further, the aryl group and the aromatic heterocyclic group represented by R ₅ and R ₆ are each independently a substituent (halogen atom;
A hydroxyl group; a cyano group; an amino group; a carboxyl group; an alkyl group; a cycloalkyl group; a haloalkyl group; a carbamoyl group; an alkoxy group; R ₅ and R ₆ are preferably a hydrogen atom, a methyl group, or a phenyl group, and more preferably a hydrogen atom or a methyl group.

As specific examples of the compound represented by the general formula (I), 6- (3,4-dimethoxyphenyl) -3,
4,5,6-tetrahydro-2H-1,3-oxazin-2-one, 6- (3,4-dimethoxyphenyl)-
3-methyl-3,4,5,6-tetrahydro-2H-
1,3-oxazin-2-one, 3-benzyl-6-
(3,4-dimethoxyphenyl) -3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one;
6- (3,4-dimethoxyphenyl) -6-methyl-
3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one, 6- (3,4-dimethoxyphenyl)
-6- (2-thiazolyl) -3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one, 6-
(3-butoxy-4-methoxyphenyl) -3,4
5,6-tetrahydro-2H-1,3-oxazine-2
-One, 6- (3-cyclopropylmethyloxy-4
-Methoxyphenyl) -3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one, 6- (3-
Cyclopentyloxy-4-methoxyphenyl) -3,
4,5,6-tetrahydro-2H-1,3-oxazin-2-one, 6- (3-cyclopentyloxy-4-
Methoxyphenyl) -6-methyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one;
6- (3-cyclopentyloxy-4-methoxyphenyl) -6-phenyl-3,4,5,6-tetrahydro-
2H-1,3-oxazin-2-one,

6- (3-cyclopentyloxy-4-methoxyphenyl) -3-methyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one;
-(4-bromobenzyl) -6- (3-cyclopentyloxy-4-methoxyphenyl) -3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one, 6
-(3-cyclopentyloxy-4-methoxyphenyl) -3- (2-quinolylmethyl) -3,4,5,6-
Tetrahydro-2H-1,3-oxazin-2-one,
6- (3-cyclopentyloxy-4-methoxyphenyl) -3- (1-naphthylmethyl) -3,4,5,6
-Tetrahydro-2H-1,3-oxazin-2-one, 6- (3-cyclopentyloxy-4-methoxyphenyl) -3- (4-pyridylmethyl) -3,4,
5,6-tetrahydro-2H-1,3-oxazine-2
-One, 6- (3-cyclopentyloxy-4-methoxyphenyl) -3- (2-naphthylmethyl) -3,
4,5,6-tetrahydro-2H-1,3-oxazin-2-one, 6- (3-cyclopentyloxy-4-
Methoxyphenyl) -3- (2-pyridylmethyl) -2
H-1,3-oxazin-2-one, 3-butyl-6
-(3-cyclopentyloxy-4-methoxyphenyl) -3,4,5,6-tetrahydro-2H-1,3-
Oxazin-2-one, 3-benzoyl-6- (3-cyclopentyloxy-4-methoxyphenyl) -3,
4,5,6-tetrahydro-2H-1,3-oxazin-2-one, 6- (3-cyclopentyloxy-4-
Methoxyphenyl) -3- (ethoxycarbonylmethyl) -3,4,5,6-tetrahydro-2H-1,3-
Oxazin-2-one,

6- (3-cyclopentyloxy-4-methoxyphenyl) -3- (3-pyridylmethyl) -3,
4,5,6-tetrahydro-2H-1,3-oxazin-2-one, 6- (3-cyclopentyloxy-4-
Methoxyphenyl) -3,6-dimethyl-3,4,5
6-tetrahydro-2H-1,3-oxazin-2-one, 6- (3-cyclopentyloxy-4-methoxyphenyl) -6-methyl-3- (4-pyridylmethyl)
-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one, 6- (3-cyclopentyloxy-4-methoxyphenyl) -6-ethyl-3,4,5
6-tetrahydro-2H-1,3-oxazin-2-one, 6- (3-cyclopentyloxy-4-methoxyphenyl) -3-ethyl-3,4,5,6-tetrahydro-2H-1,3- Oxazin-2-one, 6- (3
-Cyclopentyloxy-4-methoxyphenyl) -6
-(2-thienyl) -3,4,5,6-tetrahydro-
2H-1,3-oxazin-2-one, 6-butyl-
6- (3-cyclopentyloxy-4-methoxyphenyl) -3,4,5,6-tetrahydro-2H-1,3-
Oxazin-2-one, 6- (3-cyclopentyloxy-4-methoxyphenyl) -6- (2-thiazolyl) -3,4,5,6-tetrahydro-2H-1,3-
Oxazin-2-one, 6- (3-cyclopentyloxy-4-methoxyphenyl) -3- [2- (1-piperidyl) ethyl] -3,4,5,6-tetrahydro-2
H-1,3-oxazin-2-one, 6- (3-cyclopentyloxy-4-methoxyphenyl) -3- [2
-(4-morpholino) ethyl] -3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one;

3- (1-acetyl-3-methyl-2-indolylmethyl) -6- (3-cyclopentyloxy-
4-methoxyphenyl) -3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one, 6- (3
-Cyclopentyloxy-4-methoxyphenyl) -3
-(2-furylmethyl) -3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one, 6- (3
-Cyclopentyloxy-4-methoxyphenyl) -6
-(3-pyridyl) -3,4,5,6-tetrahydro-
2H-1,3-oxazin-2-one, 6- (3-cyclopentyloxy-4-methoxyphenyl) -3-
(2-pyrazinylmethyl) -3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one, 6-
(3-cyclopentyloxy-4-methoxyphenyl)
-3- (2-thienylmethyl) -3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one, 6
-(3-cyclopentyloxy-4-methoxyphenyl) -6- (2-pyridyl) -3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one, 6-
(4-methoxy-3-phenethyloxyphenyl)-
3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one, 6- (4-methoxy-3-phenethyloxyphenyl) -3-methyl-3,4,5,6-tetrahydro- 2H-1,3-oxazin-2-one,
6- [4-methoxy-3- (5-phenylpentyloxy) phenyl] -6-methyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one, 6-
(4-methoxy-3-phenethyloxyphenyl) -6
-Methyl-3,4,5,6-tetrahydro-2H-1,
3-oxazin-2-one,

3,6-dimethyl-6- [4-methoxy-
3- (5-phenylpentyloxy) phenyl] -3,
4,5,6-tetrahydro-2H-1,3-oxazin-2-one, 3,6-dimethyl-6- (4-methoxy-3-phenethyloxyphenyl) -3,4,5,6-
Tetrahydro-2H-1,3-oxazin-2-one,
6- [3- (2-Indanyloxy) -4-methoxyphenyl] -3,4,5,6-tetrahydro-2H-1,
3-oxazin-2-one, 6- [3- (2-indanyloxy) -4-methoxyphenyl] -3-methyl-
3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one, 6- [3- (2-indanyloxy) -4-methoxyphenyl] -6-methyl-3,4,
5,6-tetrahydro-2H-1,3-oxazine-2
-One, 6- [4-methoxy-3- (5-phenylpentyloxy) phenyl] -3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one, 6-
[4-methoxy-3- (5-phenylpentyloxy)
Phenyl] -3-methyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one, 3,6-
Dimethyl-6- [3- (2-indanyloxy) -4-
Methoxyphenyl] -3,4,5,6-tetrahydro-
2H-1,3-oxazin-2-one, 6- (3-cyclopropylmethyloxy-4-methoxyphenyl)-
3-methyl-3,4,5,6-tetrahydro-2H-
1,3-oxazin-2-one, 6- (3-cyclopropylmethyloxy-4-methoxyphenyl) -6-methyl-3,4,5,6-tetrahydro-2H-1,3-
Oxazin-2-one,

6- (3-cyclopropylmethyloxy-
4-methoxyphenyl) -3,6-dimethyl-3,4,
5,6-tetrahydro-2H-1,3-oxazine-2
-One, 6- (3-butoxy-4-methoxyphenyl) -6-methyl-3,4,5,6-tetrahydro-2
H-1,3-oxazin-2-one, 6- (3-butoxy-4-methoxyphenyl) -3-methyl-3,4,
5,6-tetrahydro-2H-1,3-oxazine-2
-One, 6- (3-butoxy-4-methoxyphenyl) -3,6-dimethyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one, 6- [4
-Methoxy-3- [2- (2-pyridyl) ethoxy] phenyl] -3,4,5,6-tetrahydro-2H-1,
3-oxazin-2-one, 6- [4-methoxy-3
-[(1-phenylcyclopropyl) methyloxy] phenyl] -3,4,5,6-tetrahydro-2H-1,
3-oxazin-2-one, 6- [4-methoxy-3
-[(1-phenylcyclopropyl) methyloxy] phenyl] -3-methyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one, 6- [3-
(10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5-yloxy) -4-methoxyphenyl] -3,4,5,6-tetrahydro-2H-1,3-
Oxazin-2-one, 6- [3- (10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5
-Yloxy) -4-methoxyphenyl] -3-methyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one, 6- [3- [3- (4-benzyl-1) -Piperazinyl) propoxy] -4-methoxyphenyl] -3,4,5,6-tetrahydro-2H-1,3
-Oxazin-2-one,

6- (3-cyclobutylmethyloxy-4)
-Methoxyphenyl) -3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one, 6- (3-
Cyclobutylmethyloxy-4-methoxyphenyl)-
3-methyl-3,4,5,6-tetrahydro-2H-
1,3-oxazin-2-one, 6- [4-methoxy-3-[(1-methylcyclopropyl) methyloxy]
Phenyl] -3,4,5,6-tetrahydro-2H-
1,3-oxazin-2-one, 6- [4-methoxy-3-[(1-methylcyclopropyl) methyloxy]
Phenyl] -3-methyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one, 6- [4-
Methoxy-3- (2-methylpropoxy) phenyl]-
3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one, 6- [4-methoxy-3- (2-methylpropoxy) phenyl] -3-methyl-3,4,
5,6-tetrahydro-2H-1,3-oxazine-2
-One, 6- [4-methoxy-3- [2- (1-naphthyl) ethoxy] phenyl] -3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one, 6-
[4-methoxy-3- [2- (1-naphthyl) ethoxy] phenyl] -3-methyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one, 6-
[3- (2-ethylbutoxy) -4-methoxyphenyl] -3,4,5,6-tetrahydro-2H-1,3-
Oxazin-2-one, 6- [3- (2-ethylbutoxy) -4-methoxyphenyl] -3-methyl-3,
4,5,6-tetrahydro-2H-1,3-oxazin-2-one,

3-ethyl-6- [3- (2-indanyloxy) -4-methoxyphenyl] -3,4,5,6-
Tetrahydro-2H-1,3-oxazin-2-one,
6- [4-methoxy-3- [2- (4-methyl-5-
Thiazolyl) ethoxy] phenyl] -3,4,5,6-
Tetrahydro-2H-1,3-oxazin-2-one,
6- [4-methoxy-3- [2- (4-methyl-5-thiazolyl) ethoxy] phenyl] -3-methyl-3,
4,5,6-tetrahydro-2H-1,3-oxazin-2-one, 6- [3- [2- (4-fluorophenyl) ethoxy] -4-methoxyphenyl] -3,4
5,6-tetrahydro-2H-1,3-oxazine-2
-One, 6- [3- [2- (4-fluorophenyl)
Ethoxy] -4-methoxyphenyl] -3-methyl-
3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one, 6- (3-cyclopentylmethyloxy-4-methoxyphenyl) -3,4,5,6-tetrahydro-2H-1 , 3-oxazin-2-one, 6
-(3-cyclopentylmethyloxy-4-methoxyphenyl) -3-methyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one, 6- [4-
Methoxy-3- (cis-4-phenylcyclohexyloxy) phenyl] -3,4,5,6-tetrahydro-
2H-1,3-oxazin-2-one, 6- [4-methoxy-3- (trans-4-phenylcyclohexyloxy) phenyl] -3,4,5,6-tetrahydro-2H-1,3-oxazine -2-one, 6- [4-
Methoxy-3- (trans-4-phenylcyclohexyloxy) phenyl] -3-methyl-3,4,5,6
-Tetrahydro-2H-1,3-oxazin-2-one,

6- [4-methoxy-3- (1-methylcyclopentyloxy) phenyl] -3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one;
6- [4-methoxy-3- (2-methylpropoxy) phenyl] -6-methyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one, 3,6-dimethyl- 6- [4-methoxy-3- (2-methylpropoxy) phenyl] -3,4,5,6-tetrahydro-2
H-1,3-oxazin-2-one, 6- [3- (2
-Benzyloxyethoxy) -4-methoxyphenyl]
-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one, 6- [3- (2-benzyloxyethoxy) -4-methoxyphenyl] -3-methyl-
3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one, 6- (3-cyclopentyloxy-
4-methoxyphenyl) -5,5-dimethyl-3,4,
5,6-tetrahydro-2H-1,3-oxazine-2
-One, 6- (3-cyclopentyloxy-4-methoxyphenyl) -3,5,5-trimethyl-3,4,
5,6-tetrahydro-2H-1,3-oxazine-2
-One, 5,5-dimethyl-6- [3- (2-indanyloxy) -4-methoxyphenyl] -3,4,5.
6-tetrahydro-2H-1,3-oxazin-2-one, 6- [3- (2-indanyloxy) -4-methoxyphenyl] -3,5,5-trimethyl-3,4,
5,6-tetrahydro-2H-1,3-oxazine-2
-One, 6- [3- (1-benzyl-4-piperidyloxy) -4-methoxyphenyl] -3,4,5,6-
Tetrahydro-2H-1,3-oxazin-2-one,

6- [3- [2- (cyclopropylmethyloxy) ethoxy] -4-methoxyphenyl] -3,
4,5,6-tetrahydro-2H-1,3-oxazin-2-one, (5RS, 6SR) -6- (3-cyclopentyloxy-4-methoxyphenyl) -5-phenyl-3,4,5, 6-tetrahydro-2H-1,3-oxazin-2-one, (5RS, 6RS) -6- (3
-Cyclopentyloxy-4-methoxyphenyl) -5
-Phenyl-3,4,5,6-tetrahydro-2H-
1,3-oxazin-2-one, 6- [3- (3-tetrahydrofuryloxy) -4-methoxyphenyl]-
3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one, (-)-6- [3- (2-indanyloxy) -4-methoxyphenyl] -6-methyl-3 ,
4,5,6-tetrahydro-2H-1,3-oxazin-2-one, (+)-6- [3- (2-indanyloxy) -4-methoxyphenyl] -6-methyl-3,4 ,
5,6-tetrahydro-2H-1,3-oxazine-2
-On and the like.

The 6-phenyltetrahydro-1,3-oxazin-2-one derivative represented by the general formula (I) is produced by the method described in WO98 / 04534. Further, the 6-phenyltetrahydro-1,3-oxazin-2-one derivative represented by the general formula (I) has an asymmetric carbon atom and may have an optical isomer. These optically pure compounds can be obtained by resolving the racemate produced by the method described in the above-mentioned publication into two types of optically active compounds using high performance liquid chromatography (HPLC). Further, by recrystallizing the obtained optically active substance with various solvents as needed, an optically active substance with higher purity can be obtained. These optical isomers are also included in the contents of the therapeutic agent for allergic eye diseases in the present invention.

The compounds of the above formula (I) and salts of the optical isomers thereof are also included in the contents of the therapeutic agent for allergic eye diseases in the present invention. As such salts, pharmacologically acceptable salts are preferable, for example, inorganic salts such as hydrochloride, hydrobromide, hydroiodide and phosphate, and oxalate and maleate , Fumarate, lactate, malate, citrate, tartrate, benzoate, methanesulfonate, p-toluenesulfonate and the like. Further, the components of the therapeutic agent for allergic eye disease according to the present invention include a compound of the above general formula (I),
Hydrates or solvates of the optical isomers or salts thereof are also included. Examples of the solvent for the solvate include methanol, ethanol, isopropanol, butanol, acetone, ethyl acetate, chloroform and the like.

The therapeutic agent for allergic eye diseases of the present invention comprises 6-phenyltetrahydro- represented by the above general formula (I).
A 1,3-oxazin-2-one derivative, an optical isomer thereof or a pharmacologically acceptable salt thereof, or a hydrate or solvate thereof, alone or mixed with a pharmaceutically acceptable carrier, It can be manufactured by preparing an appropriate dosage unit form. Its composition is determined by the solubility, chemical properties, route of administration, dosing regimen, etc., of the compound.
Examples of dosage forms include ophthalmic solutions, ophthalmic ointments, and the like for topical administration, and tablets, granules, and
Powders, capsules, solutions, injections and the like can be mentioned. In particular, the therapeutic agent for allergic eye diseases of the present invention is preferably used in the form of eye drops.

The remedy for allergic eye diseases of the present invention comprises 6-phenyltetrahydro- represented by the above general formula (I).
A 1,3-oxazin-2-one derivative, an optical isomer thereof, or a pharmacologically acceptable salt thereof, or a hydrate or solvate thereof, and a pharmaceutically acceptable carrier. And manufactured by methods known to those skilled in the art.
Furthermore, if desired or necessary, suitable binders, lubricants, disintegrants, preservatives, buffers, thickeners, solubilizers, chelating agents, stabilizers, pH adjusters, tonicity agents, etc. Various additives commonly used in the preparation of various formulations may be added.

For example, in the case of oral preparations, excipients such as lactose, glucose, corn starch, sucrose, sorbitol, erythritol, disintegrants such as calcium carboxymethylcellulose and hydroxypropylcellulose;
Calcium stearate, magnesium stearate,
Use lubricants such as talc, polyethylene glycol and hardened oil, wetting agents such as hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, polyvinyl alcohol, gelatin, gum arabic, and other surfactants and flavoring agents as required Thus, a desired dosage form can be prepared.

In the case of a parenteral preparation, a solubilizing agent (polyvinylpyrrolidone, polyvinylpyrrolidone, etc.)
Polyoxyethylene hydrogenated castor oil, polyethylene glycol, polysorbate 80, polyoxyethylene monostearate, etc.), preservatives (chlorobutanol, sodium dehydroacetate, benzalkonium chloride, cetylpyridinium chloride, phenethyl alcohol, paraoxybenzoates, Bezethonium chloride, etc.), buffers (borate buffer, phosphate buffer, carbonate buffer, acetate buffer,
Citrate buffer, etc.), stabilizers (sodium edetate,
PH adjusters (sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate, acetic acid, citric acid, phosphoric acid, etc.), tonicity agents (sodium chloride, potassium chloride, glycerin, polyvalent) Alcohol, sorbitol, mannitol, glucose, etc.), soothing agents and the like. In the case of eye ointments, commonly used bases (white petrolatum for ophthalmology, plastibase, propet, etc.) can be used, and examples of additives include liquid paraffin.

The compound of the formula (I) used in the present invention is usually 0.01 to 3.0 w /
v%, and in the case of eye ointments, it is usually 0.1%.
Used at a concentration of 01 to 10.0 w / v%. When used as a preparation for systemic administration, the dosage is oral administration, generally 0.01 to 1000 mg / day, preferably 0.01 to 100 mg / day. It is more preferable to increase or decrease as appropriate depending on the age, disease state, symptom, presence or absence of simultaneous administration and the like.

The dosage and administration of the therapeutic agent for allergic eye diseases of the present invention varies depending on age, medical condition, symptoms and the like. In the case of eye drops, it is usually 1 to 6 times a day and 1 to 2 drops at a time. To be instilled. In the case of eye ointment, an appropriate amount is usually applied to the conjunctival sac once or twice a day. In the case of oral administration, it is taken once or several times a day. In the case of an injection, it is administered once or several times a day.

[0038]

The present invention will be described more specifically with reference to examples and test examples below, but the present invention is not limited to these examples and test examples.

Reference Example 1 Method for Producing Optical Isomers Racemic (±) -6- [3- (2-indanyloxy) produced by the method described in WO 98/04534
-4-methoxyphenyl] -6-methyl-3,4,5
After dissolving 70 g of 6-tetrahydro-2H-1,3-oxazin-2-one in 7.0 L of denatured ethanol, about 3.0 g of a sample solution was injected into the column, and HPLC was performed under the following conditions. Column: CHIRALPAK AS (10 cm φ x 50 cm) Solvent: denatured ethanol Flow rate: 100 mL / min The fractions of the first peak and the second peak were concentrated under reduced pressure, and ethanol and n-hexane were added to the obtained oily residue. Thereafter, the mixture was again concentrated under reduced pressure to obtain a powdery optically active substance. By repeating the above operation, (±) −body 7
0 g, two kinds of optically active substances, (-)-isomer 31.5 g,
29.6 g of the (+)-isomer was obtained. The structure was confirmed by comparison with ¹ H-NMR of the racemic body before optical resolution.

(-)-Form: retention time 50 to 62 minutes, column temperature 40 ° C. [α] ²⁰ _D 68 ° (c = 1.00, MeOH) ¹ H-NMR (CDCl ₃ ) δ (ppm): 1.68 (3H) , s),
2.14 (1H, ddd, J = 14.0, 10.6, 5.6 Hz), 2.30 (1H, d
dd, J = 14.0, 3.9, 3.9 Hz), 3.06 (1H, ddd, J = 10.6, 1
0.6, 4.8 Hz), 3.20 (1H, dd, J = 16.7, 3.9 Hz), 3.2
2 (1H, dd, J = 16.7, 3.9 Hz), 3.25-3.30 (1H, m),
3.36 (1H, dd, J = 16.7, 6.6 Hz), 3.37 (1H, dd, J = 1
6.7, 6.6 Hz), 3.81 (3H, s), 5.21 (1H, dddd, J = 6.
6, 6.6,3.9, 3.9Hz), 6.13 (1H, broad), 6.86 (1H,
d, J = 8.3Hz), 6.90 (1H, dd, J = 8.3, 2.2Hz), 6.95
(1H, d, J = 2.2Hz), 7.15-7.19 (2H, m), 7.21-7.23
(2H, m) (+)-form: retention time 69-88 minutes, column temperature 40 ° C. [α] ²⁰ _D + 68 ° (c = 1.00, MeOH)

(±) -form ¹ H-NMR (CDCl ₃ ) δ (pp
m): 1.66 (3H, s), 2.11 (1H, ddd, J = 13.9, 10.3, 5.4H)
z), 2.27 (1H, ddd, J = 13.9, 4.2, 4.2Hz), 3.00-3.0
7 (1H, m), 3.20 (1H, dd, J = 16.6, 3.7Hz), 3.22 (1
H, dd, J = 16.6, 3.7Hz), 3.22-3.29 (1H, m), 3.36
(2H, dd, J = 16.6,6.6Hz), 3.80 (3H, s), 5.21 (1H,
dddd, J = 6.6, 6.6, 3.7, 3.7Hz), 6.13 (1H, broa
d), 6.86 (1H, d, J = 8.3Hz), 6.90 (1H, dd, J = 8.3,
2.2Hz), 6.95 (1H, d, J = 2.2Hz), 7.14-7.18 (2H,
m), 7.19-7.23 (2H, m)

Example 1 Production of Eye Drops 0.3 g of methylcellulose and a trace amount of benzalkonium chloride solution in sterile purified water, 0.2 g of sodium dihydrogen phosphate,
After adding an appropriate amount of sodium hydroxide and dissolving, dust removal and sterilization filtration were performed. Dust-free and sterile 6- (3-cyclopentyloxy-4-methoxyphenyl) -6-methyl-
0.5 g of 3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one was suspended, and sterilized purified water was added to make a total volume of 100 mL. The obtained suspension was filled in a fixed volume into a washed, dried, and sterilized eye drop container, and a nozzle and a cap were provided to produce an eye drop.

<Example 2> Preparation of ophthalmic ointment 6- (3-cyclopentyloxy-4-methoxyphenyl) -6-methyl-3,4,5,6-tetrahydro-2
Take 0.5 g of H-1,3-oxazin-2-one, 10.0 g of purified lanolin, 80.0 g of ophthalmic white petrolatum and 0.5 g of liquid paraffin, prepare them according to the ophthalmic ointment manufacturing method, and further prepare ophthalmic white petrolatum. To prepare 100 g of an eye ointment.

<Test Example 1> Improvement effect on allergic conjunctivitis model Wistar rats (CLEA Japan) were used for the experiment. Egg albumin (OA, Sigma) 10
The mice were sensitized by suspending 0 μg and 10 mg of aluminum hydroxide (Alum, manufactured by PIERCE) in 1 mL of physiological saline and intraperitoneally administering the suspension. Allergic conjunctivitis was induced in rats 3 weeks after the sensitization day using saline at 30 mg /
It was induced by instilling 10 μL of OA prepared to a concentration of mL. The drug was suspended in a physiological saline solution at a concentration of 1.0% (w / v) and instilled 10 minutes before inducing conjunctivitis with OA (diphenhydramine was added as a positive control at 0.1%).
(Suspended in physiological saline at a concentration of 3% (w / v) and instilled 10 minutes before conjunctivitis is induced with OA). The effect of the drug is
The number of gestures (Itch-Scratch response: considered to be an index of itch) observed in the hind limb for 20 minutes after instillation of OA was measured, and the inhibition rate of itch was determined by the following formula. Control group: physiological saline was instilled 10 minutes before conjunctivitis was induced with OA in rats sensitized in advance. Untreated group: saline was instilled into unsensitized rats.

Calculation formula:

(Equation 1)

Table 1 shows that, as test substances, 6- (3-cyclopentyloxy-4-methoxyphenyl) -6-methyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one ( Compound 1), 6- [3- (2-Indanyloxy) -4-methoxyphenyl] -6-methyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one (Compound 2), 6- [3- (2-Indanyloxy) -4-methoxyphenyl] -3-methyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one (compound 3 ), 6- (3-cyclopropylmethyloxy-4-methoxyphenyl) -6-methyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one (compound 4), (- ) -6- [3-
(2-Indanyloxy) -4-methoxyphenyl]-
6-methyl-3,4,5,6-tetrahydro-2H-
1,3-oxazin-2-one (compound 5), (+)-6
-[3- (2-Indanyloxy) -4-methoxyphenyl] -6-methyl-3,4,5,6-tetrahydro-
The results when 2H-1,3-oxazin-2-one (compound 6) was used are shown.

[0047]

[Table 1]

As a result, 1.0% of the above compounds 1 to 6
The eye drops showed an inhibitory effect on the Itch-Scratch response equal to or higher than that of diphenhydramine as the positive control drug, and it was considered that edema and eye itching expressed in an allergic conjunctivitis model were suppressed. No edema was observed in the untreated group in which physiological saline was instilled, and the Itch-Scratch Response was observed once in 4 out of 4 cases. This is considered to be caused by physical stimulation by eye drops. In the control group in which OA was instilled, all cases showed mild to moderate edema and Itch-Scratch
A response was observed, suggesting that acute allergic conjunctivitis was induced.

[0049]

EFFECT OF THE INVENTION The therapeutic agent for allergic eye diseases of the present invention comprises:
Action different from existing allergic eye disease therapeutics (PD
A compound having an E IV inhibitory effect exerts a favorable ameliorating effect on allergic conjunctivitis, and is therefore extremely useful as a new type of therapeutic agent for allergic eye diseases.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) C07D 265/04 C07D 265/04 265/10 265/10 // C07M 7:00 C07M 7:00 (72) Inventor Shinji Ina 1-3346 Kitabukuro-cho, Saitama-shi, Saitama F-term in Omiya Research Laboratories, Niken Chemical Co., Ltd. 4C056 AA02 AB01 AC02 AD01 AE02 AF04 DA03 DA05 DB04 DC01 4C076 AA12 BB24 CC03 CC10 4C086 AA01 AA02 BC72 MA01 MA04 MA17 NA14 ZA33 ZB13

Claims (6)

[Claims] 1. A compound represented by the following general formula (I) [In the above formula, R ₁ is a C ₁ -C which may have a substituent.
₈ alkyl groups; C ₃ -C ₇ which may have a substituent
Cycloalkyl group; which may have a substituent, a heterocyclic group containing an oxygen atom, 1 or more heteroatoms selected from among nitrogen atom and a sulfur atom; represents or indanyl group, R ₂ Represents a C _{1 to} C ₄ alkyl group, R ₃ is a hydrogen atom; a C _{1 to} C ₅ alkyl group which may have a substituent; a C _{3 to} C ₇ which may have a substituent. An aryl group which may have a substituent, which contains one or more heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom which may have a substituent An aromatic heterocyclic group; or an acyl group, wherein R ₄ is a hydrogen atom;
A C ₁ -C ₆ alkyl group which may have a substituent; an aryl group which may have a substituent; or an oxygen atom, a nitrogen atom and a sulfur atom which may have a substituent. aromatic containing one or more heteroatoms selected from among a heterocyclic group, R ₅ and R ₆ are each independently a hydrogen atom; which may have a substituent C ₁ -C ₅ alkyl groups; optionally substituted aryl group; a cycloalkyl group optionally C ₃ -C ₇ may have a substituent may have a or a substituent, an oxygen atom, a nitrogen atom And an aromatic heterocyclic group containing one or more hetero atoms selected from sulfur atoms. A 6-phenyltetrahydro-1,3-oxazin-2-one derivative, an optical isomer thereof, or a pharmacologically acceptable salt thereof,
Or a therapeutic agent for allergic eye diseases, comprising a hydrate or a solvate thereof. 2. C ₁ to R _{1 in} which R ₁ may have a substituent.
C ₆ alkyl group, C ₄ -C optionally having substituent (s)
_{6 represents} a cycloalkyl group, an optionally substituted heterocyclic group containing at least one hetero atom selected from an oxygen atom, a nitrogen atom and a sulfur atom, or an indanyl group; ₂ represents a methyl group, R ₃ is a hydrogen atom; C ₁
Alkyl group -C _4; aryl group, aromatic heterocyclic group, or a C ₁ -C ₃ having as the substituent any of the ethoxycarbonyl group alkyl group; an optionally substituted aryl group; oxygen An aromatic heterocyclic group containing at least one heteroatom selected from an atom, a nitrogen atom and a sulfur atom; or an acyl group, wherein R ₄ is a hydrogen atom; C _{1 to} C ₄
An alkyl group; an aryl group which may have a substituent;
Or an aromatic heterocyclic group containing one or more hetero atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, wherein R ₅ and R ₆ are each independently a hydrogen atom; An optionally substituted C ₁ -C ₅ alkyl group; an optionally substituted C ₃ -C ₇ cycloalkyl group; an optionally substituted oxygen atom, nitrogen atom and sulfur atom 6-phenyltetrahydro according to claim 1, which is an aromatic heterocyclic group containing at least one hetero atom selected from the group consisting of: and an aryl group which may have a substituent. Allergic eye disease containing a -1,3-oxazin-2-one derivative, an optical isomer thereof, a pharmacologically acceptable salt thereof, or a hydrate or solvate thereof Therapeutic agent. 3. The method of claim 1, wherein the 6-phenyltetrahydro-1,3-oxazin-2-one derivative is 6- (3-cyclopentyloxy-4-methoxyphenyl) -3-methyl-3,
4,5,6-tetrahydro-2H-1,3-oxazin-2-one, 6- (3-cyclopentyloxy-4-methoxyphenyl) -6-methyl-3,4,5,6-tetrahydro-2H- 1,3-oxazin-2-one, 6-
(3-cyclopentyloxy-4-methoxyphenyl)
-3,6-dimethyl-3,4,5,6-tetrahydro-
2H-1,3-oxazin-2-one, 6- (3-cyclopentyloxy-4-methoxyphenyl) -3-ethyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2- On, 6- (3-cyclopentyloxy-4-methoxyphenyl) -6-ethyl-3,4,5,
6-tetrahydro-2H-1,3-oxazin-2-one, 6- [3- (2-indanyloxy) -4-methoxyphenyl] -3,4,5,6-tetrahydro-2H-
1,3-oxazin-2-one, 6- [3- (2-indanyloxy) -4-methoxyphenyl] -3-methyl-3,4,5,6-tetrahydro-2H-1,3-oxazine -2-one, 6- [3- (2-Indanyloxy) -4-methoxyphenyl] -6-methyl-3,4,
5,6-tetrahydro-2H-1,3-oxazine-2
-One, 3,6-dimethyl-6- [3- (2-indanyloxy) -4-methoxyphenyl] -3,4,5,6
-Tetrahydro-2H-1,3-oxazin-2-one, 6- (3-cyclopropylmethyloxy-4-methoxyphenyl) -6-methyl-3,4,5,6-tetrahydro-2H-1,3 -Oxazin-2-one, 6-
(3-cyclopropylmethyloxy-4-methoxyphenyl) -3-methyl-3,4,5,6-tetrahydro-
2H-1,3-oxazin-2-one, 6- (3-cyclopropylmethyloxy-4-methoxyphenyl)-
3,6-dimethyl-3,4,5,6-tetrahydro-2
H-1,3-oxazin-2-one, 6- (3-cyclopentylmethyloxy-4-methoxyphenyl) -3,
4,5,6-tetrahydro-2H-1,3-oxazin-2-one, 6- (3-cyclopentylmethyloxy-
4-methoxyphenyl) -3-methyl-3,4,5,6
-Tetrahydro-2H-1,3-oxazin-2-one, (-)-6- [3- (2-indanyloxy) -4-
Methoxyphenyl] -6-methyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one or (+)-6- [3- (2-indanyloxy) -4- The therapeutic agent for allergic eye diseases according to claim 1, which is [methoxyphenyl] -6-methyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one. 4. The therapeutic agent for allergic eye disease according to claim 1, wherein the allergic eye disease is allergic conjunctivitis. 5. The method according to claim 1, wherein the dosage form is a topical administration.
The therapeutic agent for an allergic eye disease according to claim 4. 6. The remedy for allergic eye diseases according to claim 5, wherein the dosage form is an eye drop.