JPH1036259A - Preventive and therapeutic agent for cataract - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject medicine capable of preventing and treating cataract, comprising a furanone derivative. SOLUTION: This medicine comprises a furanone derivative of the formula (R1 to R3 are each H, hydroxyl, amino, a halogen, mercapto, carboxyl, carbamoyl, an alkyl, an alkenyl, an aryl, etc.; R4 is H, amino, a halogen, carboxyl, an alkyl, an aryl, an aralkyl, etc.) or its salt as an active ingredient. 2.5-Dimethyl-4-pivaloyloxy-3H(2H)-furanone is preferable as the compound of the formula. A dose is 0.01-1,000mg/time/day/adult in the case of injection. In the case of an internal medicine, the medicine is administered several times per adult daily and a dose is 0.1-1,000mg/time. In the case of an eye drop, one to two drops of 0.01-10% solution are applied once to five times a day drop. Senile cataract based on oxidation disorder can be prevented and treated by instillation or administration.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to an agent for preventing or treating cataract, and more particularly to an agent for preventing or treating cataract comprising a furanone derivative having 3 (2H) -furanone as a skeleton or a salt thereof.

[0002]

2. Description of the Related Art Currently, pirenoxine eye drops, reduced glutathione eye drops,
Salivary gland hormone tablets, thiopronin tablets, vitamins (eg, vitamin C, vitamin E, etc.), aldose reductase (AR) activity inhibitors (eg, tolrestat,
(Epalrestat, etc.) is used in actual clinical practice (Kumakura, Seiji: Chemical Economics, November 1993, 7).
8-83). However, these do not have a sufficient therapeutic effect. Therefore, for diabetic cataract, various drugs that inhibit AR activity are under development.
It has also been proposed. One of them is a composition containing a furanone derivative having a 2 (5H) -furanone skeleton as an active ingredient (JP-A-59-16884 and JP-A-60-1).
No. 78879, JP-A-61-267566,
Japanese Patent Publication No. 8-13739) has a sufficient therapeutic effect on diabetic cataract but cannot exert a preventive or therapeutic effect on senile cataract caused by oxidative disorders and the like. . Further, currently known cataract remedies exhibit their therapeutic effects by oral, intravenous, or intraperitoneal administration, but hardly appear by instillation.

[0003]

An object of the present invention is to provide a preventive or therapeutic agent for cataract that can exert a sufficient preventive or therapeutic effect not only by taking it but also by eye drops against cataract caused by oxidative disorders and the like. To provide.

[0004]

Means for Solving the Problems The present inventors have conducted intensive studies to achieve the above object. As a result, a furanone derivative having a 3 (2H) -furanone skeleton or a salt thereof hardly inhibits AR activity. It has been found that, for cataracts caused by oxidative disorders or the like, sufficient preventive or therapeutic effects can be exerted not only by taking the drug but also by eye drops. The present invention has been completed based on the findings.

That is, the present invention provides the following formula:

Embedded image (Wherein, R ₁ , R ₂ , and R ₃ may be the same or different, and include a hydrogen atom, a hydroxyl group, an amino group, a halogen atom, a mercapto group, a carboxyl group, a carbamoyl group,
An alkyl group, an alkenyl group, an alkynyl group, an aryl group, an aralkyl group, an alkoxyl group, an alkenyloxy group, an alkynyloxy group, an aryloxy group, an acyloxy group, or an alkoxycarbonyl group, and R ₄ represents a hydrogen atom, an amino group, or a halogen atom. , Mercapto group, carboxyl group, alkyl group, alkenyl group, alkynyl group,
It represents an aryl group, an aralkyl group, an alkoxyl group, an acyloxy group, an alkenyloxy group, an alkynyloxy group, an aryloxy group, or an alkoxycarbonyl group. ) Is a prophylactic or therapeutic agent for cataract comprising the furanone derivative or a salt thereof. In the above formula 1, R ₁ , R ₂ , and R ₃ may be the same or different and include a hydrogen atom, a hydroxyl group, a carboxyl group,
Alkyl group, an alkenyl group, an aryl group, an aralkyl group, with an alkoxycarbonyl group, R ₄ is a hydrogen atom, a carboxyl group, an alkoxyl group, an acyloxy group wherein the cataract or furanone derivative or a salt thereof with an alkoxycarbonyl group, Is a prophylactic or therapeutic agent. In the above formula 1, R ₁ , R ₂ and R ₃ may be the same or different and each represents a hydrogen atom, a hydroxyl group or an alkyl group, and R ₄ represents an acyloxy group, an alkoxyl group or an alkoxycarbonyl group. And / or a salt thereof for preventing or treating cataract. Further, the above-mentioned furanone derivative or a salt thereof is 2,5-dimethyl-4-pivaloyloxy-3
(2H) -furanone, 2 (or 5) -ethyl-5 (or 2) -methyl-4-pivaloyloxy-3 (2H) -furanone, 4-acetoxy-2 (or 5) -ethyl-5
(Or 2) -methyl-3 (2H) -furanone, 2,5-
Dimethyl-4-isopropyloxy-3 (2H) -furanone, 4-tert-butoxy-2,5-dimethyl-3
(2H) -furanone, 2,5-dimethyl-4- (2-methyl-2-butoxy) -3 (2H) -furanone, 2,5
-Dimethyl-4- (3-methyl-3-pentyloxy)
-3 (2H) -furanone, 2,5-dimethyl-4- (1
-Methyl-1-cyclopentyloxy) -3 (2H)-
Furanone, 2,5-dimethyl-4- (1-methyl-1-
Cyclohexyloxy) -3 (2H) -furanone or a salt thereof, which is an agent for preventing or treating cataract described above. Further, the above-mentioned furanone derivative is an alkali metal salt, an alkaline earth metal salt, an ammonium salt or an amine salt, which is a preventive or therapeutic agent for cataract.

Hereinafter, the present invention will be described in detail. In the formula (1), the alkyl group may have any of a linear, branched, or cyclic structure, and has 1 or more carbon atoms,
Preferably, they are groups of 1 to 6. Specifically, a methyl group,
Ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-amyl, tert-amyl, n-hexyl, cyclohexyl and the like are exemplified. You.

In the alkyl group, a part of a hydrogen atom bonded to a carbon atom is, for example, a hydroxyl group, an amino group, a mercapto group, a nitro group, a sulfonic acid group, a halogen atom, a carboxyl group, a carbamoyl group, an aryl group. ,
It may be substituted with an aralkyl group, an aralkoxy group, an alkoxyl group, an acyloxy group, an alkoxycarbonyl group, or the like.

The alkenyl group and the alkynyl group may have any of a linear, branched, or cyclic structure, and are a group having 2 or more carbon atoms, preferably 1 to 6 carbon atoms. Specific examples of the alkenyl group include a vinyl group and an allyl group. Specific examples of the alkynyl group include an ethynyl group and a propynyl group. Further, as in the case of the alkyl group, the alkenyl group and the alkynyl group each have a part of the hydrogen atoms bonded to the carbon atoms substituted with the same groups as the substituents exemplified in the case of the alkyl group. Is also good.

The alkoxycarbonyl group has an alkyl moiety of 1 or more carbon atoms, preferably 1 to 6 carbon atoms, and the alkyl moiety may have a linear, branched or cyclic structure. Specific examples include a methoxycarbonyl group and an ethoxycarbonyl group. Further, as in the case of the above alkyl group, the alkyl portion of the alkoxycarbonyl group may be substituted with a group similar to the substituent exemplified in the case where a part of the hydrogen atom bonded to the carbon atom is the alkyl group. Good.

The alkoxyl group has an alkyl moiety of 1 or more carbon atoms, preferably 2 to 22 carbon atoms, and the alkyl moiety may have a linear, branched or cyclic structure. Specifically, methoxy group, ethoxy group, n-
Propoxy group, isopropoxy group, isobutoxy group, s
Examples thereof include an ec-butoxy group, a tert-butoxy group, an n-pentoxy group, and an n-hexoxy group. Further, as in the case of the alkyl group, the alkyl portion of the alkoxyl group may be substituted with a group similar to the substituent exemplified in the case where a part of the hydrogen atom bonded to the carbon atom is the alkyl group. . Among these groups, particularly preferred are a methoxy group and an ethoxy group.

The alkenyloxy group and the alkynyloxy group have a alkenyl portion and an alkynyl portion of 2 or more carbon atoms, preferably 2 to 22 carbon atoms, respectively. , Or a ring-shaped structure. Specific examples of the alkenyloxy group include a vinyloxy group and an allyloxy group. Specific examples of the alkynyloxy group include an ethynyloxy group and a propynyloxy group. In the same manner as in the case of the alkyl group, the alkyl portion of the alkenyloxy group and the alkynyloxy group is substituted with the same group as the substituent exemplified when a part of the hydrogen atoms bonded to the carbon atoms is the alkyl group. It may be.

As the aryloxy group, specifically,
Phenoxy and the like are exemplified. Further, as in the case of the above-mentioned alkyl group, the aryl portion of the aryloxy group may have a part of the hydrogen atoms bonded to carbon atoms substituted with the same group as the substituent exemplified in the case of the alkyl group. Good.

An acyloxy group has a hydrocarbon moiety
It is a saturated or unsaturated aliphatic hydrocarbon group or an aryl group. When the hydrocarbon moiety is a saturated or unsaturated aliphatic hydrocarbon group, the number of carbon atoms is 1 or more, preferably 2 to 22, and may be any of linear, branched or cyclic structures. Examples of the acyloxy group include acetooxy, pivaloyloxy, propionyloxy, butyryloxy, isobutyryloxy, valeryloxy, isovaleryloxy, and n-
Hexanoyloxy group, n-hexanoyloxy group, n
-Heptanoyloxy group, n-octanoyloxy group,
n-nonanoyloxy group, n-decanoyloxy group, n
-Undecanoyloxy group, n-dodecanoyloxy group, n-tridecanoyloxy group, n-tetradecanoyloxy group, n-pentadecanoyloxy group, palmitoyloxy group, n-heptadecanoyloxy group, Stearoyloxy group, oleoyloxy group, linoleoyloxy group, n-nonadecanoyloxy group, n-eicosanoyloxy group, n-heneicosanoyloxy group, n-
Docosanoyloxy group, 4,7,10,13,16,1
9-docosahexaenoyloxy group, n-tricosanoyloxy group, n-tetracosanoyloxy group, n-pentacosanoyloxy group, β-aminopropionyloxy group, γ-aminobutyryloxy group, β- Examples thereof include an aminoisobutyryloxy group, a δ-aminovaleryloxy group, a γ-aminoisovaleryloxy group, and an ε-amino-n-hexanoyloxy group.

As in the case of the above-mentioned alkyl group,
In the hydrocarbon portion of the acyloxy group, part of the hydrogen atoms bonded to the carbon atoms may be substituted with the same substituents as those exemplified when the alkyl group is an alkyl group. Specifically, a β-aminopropionyloxy group, a γ-aminobutyryloxy group,
β-aminoisobutyryloxy group, δ-aminovaleryloxy group, γ-aminoisovaleryloxy group, ε-amino-n-hexanoyloxy group, β-mercapto-α-
Examples thereof include an aminopropionyloxy group. Among the acyloxy groups, particularly preferred are an acetooxy group and a pivaloyloxy group.

Examples of the aryl group include a phenyl group. Further, as in the case of the above-mentioned alkyl group, the aryl group may have a part of the hydrogen atoms bonded to the carbon atoms substituted with the same substituents as those exemplified in the case of the alkyl group.

In the aralkyl group and the aralkoxy group, the alkylene portion is a group having 1 or more carbon atoms, preferably 1 to 6 carbon atoms.
Any of a branched structure and a cyclic structure may be used. As the aralkyl group, specifically, a 3-phenylpropyl group,
A 4- (4'-nitrophenyl) -butyl group is exemplified. Specific examples of the aralkoxy group include a 2-phenylethoxy group and a 6- (3 ′, 4′-dichlorophenyl) -hexoxy group. Further, as in the case of the alkyl group, the alkylene portion of each of the aralkyl group and the aralkoxy group is substituted with the same group as the substituent exemplified in the case where a part of the hydrogen atom bonded to the carbon atom is an alkyl group. May be. Further, the aryl portion of each of the aralkyl group and the aralkoxy group may be substituted with a group similar to the substituent exemplified when a part of the hydrogen atom bonded to the carbon atom is an alkyl group.

In addition, among the compounds represented by the above formula (1), R ₁ , R ₂ and R ₃ are each a hydrogen atom,
A hydroxyl group, an alkyl group, an alkenyl group, an aryl group, an aralkyl group, or an alkoxycarbonyl group;
Furanone derivatives in which R4 is an alkoxyl group or an acyloxy group are preferred. Among these compounds, in particular, a furanone derivative in which R ₁ , R ₂ , and R ₃ are a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and R ₄ is an alkoxyl group or an acyloxy group, Particularly preferred. Further, a furanone derivative in which the hydrocarbon part of the alkoxyl group or the acyloxy group is a saturated or unsaturated aliphatic hydrocarbon group and the number of carbon atoms of which is 1 to 22 is particularly preferable.

The active ingredient of the pharmaceutical composition for preventing or treating cataract according to the present invention is 3 (2) represented by the above formula (1).
H) -furanone derivatives, which include known compounds and novel substances synthesized for the first time by the present inventors. The derivatives thereof are as follows when they are separated by each group of R ₄ in the formula (1). In addition, in Formula 1, when R ₄ is an alkoxyl group, the furanone derivative is a 4-alkoxy-3
(2H) -furanone derivatives and, when it is an acyloxy group, are generically referred to as 4-acyloxy-3 (2H) -furanone derivatives.

1) R ₄ = hydrogen blatenone (R ₁ = phenyl group, R ₂ = R ₃ = methyl group, R ₄ = hydrogen atom), 2,2
-Dimethyl-3 (2H) -furanone (2,2-dim
tyl-3 (2H) -furanone) (R ₁ = R ₄ =
Hydrogen atom, R ₂ = R ₃ = methyl group), (E) -5- (prop-1-enyl) -3 (2H) -furanone {(E) -5
-(Prop-1-enyl) -3 (2H) -fura
none @ R ₁ = prop-1-enyl (prop-
1-enyl) group, R ₂ = R ₃ = methyl group, R ₄ = hydrogen atom｝, 5-vinyl-3 (2H) -furanone (5-vin
yl-3 (2H) -furanone) (R ₁ = vinyl group, R ₂ = R ₃ = methyl group, R ₄ = hydrogen atom), 2,5-
Dimethyl-3 (2H) -furanone ｛2,5-dimet
hyl-3 (2H) -furanone {(R ₁ = R ₂ =
Methyl group, R ₃ = R ₄ = hydrogen atom) and the like. Further, 5-amino-2-alkyl-2-methyl-3 (2
H) -furanone (R ₁ = amino group, R ₂ = methyl group or ethyl group, R ₃ = methyl group, R ₄ = hydrogen atom) and the like (Khim. Geterotsik).
l. Soedin. , No. 9, 1286-1287
1988).

The above derivative can be synthesized by a known method, for example, by the method of Smith et al. (AB Smi).
th III et al. : J. Am. Chem. S
oc. 103, 1501, 1981;
No. 9-20671). For example, 2,5-dimethyl-
In the case of 3 (2H) -furanone, 5-acetyltetrahydro-2- obtained by aldol condensation of diacetyl
It can be prepared by starting from the diacetyl dimer of hydroxy-2,5-dimethyl-3-oxofuran and removing acetic acid by acid hydrolysis.

2) R ₄ = phenyl group 2-methoxy-2,4-diphenyl-3 (2H) -furanone {2-methyoxy-2,4-diphenyl
-3 (2H) -furanone {(R ₁ = hydrogen atom,
R ₂ = methoxy, R ₃ = phenyl, R ₄ = phenyl, or R ₁ = hydrogen, R ₂ = phenyl, R ₃ = methoxy, R ₄ = phenyl｝, 2-hydroxy-2,
4-diphenyl-3 (2H) -furanone {2-hydr
oxy-2,4-diphenyl-3 (2H) -fu
ranone｝ (R ₁ = hydrogen atom, R ₂ = hydroxyl group,
R ₃ = phenyl, R ₄ = phenyl, or R ₁ = hydrogen, R ₂ = phenyl, R ₃ = methoxy, R ₄ = phenyl. 2-hydroxy-
2,4-Diphenyl-3 (2H) -furanone is commercially available (sold by Tokyo Kasei Co., Ltd.) and can be easily obtained.

3) R ₄ = carboxyl group 4-carboxy-2,5-dimethyl-3 (2H) -furanone (R ₁ = methyl group, R ₂ = methyl group, R ₃ = hydrogen atom, R ₄ = carboxyl group Or R ₁ = methyl group, R ₂
= Hydrogen atom, R ₃ = methyl, R ₄ = carboxyl group) and the like (JP-49-82656 JP).

4) R ₄ = alkoxycarbonyl group 4-ethoxycarbonyl-2,5-dimethyl-3 (2
H) -furanone (R ₁ = methyl group, R ₂ = methyl group, R ₃
= Hydrogen atom, R ₄ = ethoxycarbonyl group, or R ₁ =
Methyl group, R ₂ = hydrogen atom, R ₃ = methyl group, R ₄ = ethoxycarbonyl group), 4-ethoxycarbonyl-2-n
-Hexyl-5-methyl-3 (2H) -furanone (R ₁
= Methyl group, R ₂ = n-hexyl, R ₃ = hydrogen atom, R ₄
= Ethoxycarbonyl group, or R ₁ = methyl group, R ₂ =
Hydrogen atom, R ₃ = n-hexyl, R ₄ = ethoxycarbonyl group), 4-ethoxycarbonyl-2-methyl-5-n
-Propyl-3 (2H) -furanone (R ₁ = n-propyl, R ₂ = methyl group, R ₃ = hydrogen atom, R ₄ = ethoxycarbonyl group, or R ₁ = n-propyl, R ₂ = hydrogen atom, R ₃ = methyl group, R ₄ = ethoxycarbonyl group) and the like (JP-A-49-82656).

5) R ₄ = alkoxyl group The following derivatives can be mentioned, and these are novel substances synthesized for the first time by the present inventors (Japanese Patent Application No. Hei 7 (1994) -207).
-264527): 2-ethyl-4-methoxy-5-methyl-3 (2H) -furanone (R ₁ = methyl group, R ₂ = ethyl group, R ₃ = hydrogen, R ₄ = methoxy group), 5-ethyl −
4-methoxy-2-methyl-3 (2H) -furanone (R
₁ = ethyl group, R ₂ = methyl group, R ₃ = hydrogen, R ₄ = methoxy group), 4-ethoxy-2-ethyl-5-methyl-3
(2H) -furanone (R ₁ = methyl group, R ₂ = ethyl group,
R ₃ = hydrogen, R ₄ = ethoxy group), 4-ethoxy-5-ethyl-2-methyl-3 (2H) -furanone (R ₁ = ethyl group, R ₂ = methyl group, R ₃ = hydrogen, R ₄ = Ethoxy group), 2-ethyl-5-methyl-4-propoxy-3
(2H) -furanone (R ₁ = methyl group, R ₂ = ethyl group,
R ₃ = hydrogen, R ₄ = propoxy group), 5-ethyl-2-methyl-4-propoxy-3 (2H) -furanone (R ₁ =
Ethyl group, R ₂ = methyl group, R ₃ = hydrogen, R ₄ = propoxy group), 2-ethyl-4-isopropoxy-5-methyl-3 (2H) -furanone (R ₁ = methyl group, R ₂ = Ethyl group, R ₃ = hydrogen, R ₄ = isopropoxy group), 5-ethyl-4-isopropoxy-2-methyl-3 (2H) -furanone (R ₁ = ethyl group, R ₂ = methyl group, R ₃ = Hydrogen, R ₄
= Isopropoxy group), 4-butoxy-2-ethyl-5
-Methyl-3 (2H) -furanone (R ₁ = methyl group, R ₂
= Ethyl group, R ₃ = hydrogen, R ₄ = butoxy group), 4-butoxy-5-ethyl-2-methyl-3 (2H) -furanone (R ₁ = ethyl group, R ₂ = methyl group, R ₃ = Hydrogen, R ₄ = butoxy group), 2-ethyl-4-isobutoxy-5-methyl-3 (2H) -furanone (R ₁ = methyl group, R ₂ = ethyl group, R ₃ = hydrogen, R ₄ = isobutoxy group ), 5-ethyl-4-isobutoxy-2-methyl-3 (2H) -furanone (R ₁ = ethyl group, R ₂ = methyl group, R ₃ = hydrogen, R ₄ =
Isobutoxy group), 4-sec-butoxy-2-ethyl-5-methyl-3 (2H) -furanone (R ₁ = methyl group, R ₂ = ethyl group, R ₃ = hydrogen, R ₄ = sec-butoxy group) 4-sec-butoxy-5-ethyl-2-methyl-3 (2H) -furanone (R ₁ = ethyl group, R ₂ = methyl group, R ₃ = hydrogen, R ₄ = sec-butoxy group), 4- t
ert-butoxy-2-ethyl-5-methyl-3 (2
H) -furanone (R ₁ = methyl group, R ₂ = ethyl group, R ₃
= Hydrogen, R ₄ = tert-butoxy group), 4-tert
-Butoxy-5-ethyl-2-methyl-3 (2H) -furanone (R ₁ = ethyl group, R ₂ = methyl group, R ₃ = hydrogen,
R ₄ = tert-butoxy group), 2-ethyl-5-methyl-4-n-pentoxy-3 (2H) -furanone (R ₁
= Methyl group, R ₂ = ethyl group, R ₃ = hydrogen, R ₄ = n-pentoxy group), 5-ethyl-2-methyl-4-n-pentoxy-3 (2H) -furanone (R ₁ = ethyl group , R ₂ =
Methyl group, R ₃ = hydrogen, R ₄ = n-pentoxy group), 2-
Ethyl-4-n-hexoxy-5-methyl-3 (2H)
-Furanone (R ₁ = methyl group, R ₂ = ethyl group, R ₃ = hydrogen, R ₄ = n-hexoxy group), 5-ethyl-4-n-
Hexoxy-2-methyl-3 (2H) -furanone (R ₁
= Ethyl group, R ₂ = methyl group, R ₃ = hydrogen, R ₄ = n-hexoxy group), 2,5-dimethyl-2-ethyl-4-methoxy-3 (2H) -furanone (R ₁ = methyl group) , R ₂ =
Ethyl group, R ₃ = methyl group, R ₄ = methoxy group), 2,2
-Dimethyl-5-ethyl-4-methoxy-3 (2H)-
Furanone (R ₁ = ethyl group, R ₂ = methyl group, R ₃ = methyl group, R ₄ = methoxy group), 2,2-diethyl-4-ethoxy-5-methyl-3 (2H) -furanone (R ₁ = Methyl group, R ₂ = ethyl group, R ₃ = ethyl group, R ₄ = ethoxy group), 2,5-diethyl-4-ethoxy-2-methyl-3 (2H) -furanone (R ₁ = ethyl group, R ₂ = methyl group, R ₃ = ethyl group, R ₄ = ethoxy group), 2-ethyl-
5-methyl-4-propoxy-2-propyl-3 (2
H) -furanone (R ₁ = methyl group, R ₂ = ethyl group, R ₃
= Propyl group, R ₄ = propoxy group), 5-ethyl-2
-Methyl-4-propoxy-2-propyl-3 (2H)
-Furanone (R ₁ = ethyl group, R ₂ = methyl group, R ₃ = propyl group, R ₄ = propoxy group), 2-ethyl-4-isopropoxy-2-isopropyl-5-methyl-3 (2
H) -furanone (R ₁ = methyl group, R ₂ = ethyl group, R ₃
= Isopropyl group, R ₄ = isopropoxy group), 5-ethyl-4-isopropoxy-2-isopropyl-2-methyl-3 (2H) -furanone (R ₁ = ethyl group, R ₂ = methyl group, R ₃ = Isopropyl group, R ₄ = isopropoxy group), 4-n-butoxy-2-n-butyl-2-ethyl-5-methyl-3 (2H) -furanone (R ₁ = methyl group, R ₂ = ethyl group) , R ₃ = n-butyl group, R ₄ = n-butoxy group), 2-ethyl-4-isobutoxy-2-isobutyl-5-methyl-3 (2H) -furanone (R ₁ = methyl group, R ₂ = Ethyl group, R ₃ = isobutyl group, R ₄ = isobutoxy group), 5-ethyl-4-isobutoxy-2-
Isobutyl-2-methyl-3 (2H) -furanone (R ₁
= Ethyl group, R ₂ = methyl group, R ₃ = isobutyl group, R ₄
= Isobutoxy group), 4-sec-butoxy-2-se
c-butyl-2-ethyl-5-methyl-3 (2H) -furanone (R ₁ = methyl group, R ₂ = ethyl group, R ₃ = sec
-Butyl group, R ₄ = sec-butoxy group), 4-sec
-Butoxy-2-sec-butyl-5-ethyl-2-methyl-3 (2H) -furanone (R ₁ = ethyl group, R ₂ = methyl group, R ₃ = sec-butyl group, R ₄ = sec-butoxy Group), 4-tert-butoxy-2-tert-butyl-2-ethyl-5-methyl-3 (2H) -furanone (R ₁ = methyl group, R ₂ = ethyl group, R ₃ = tert-butyl group, R ₄ = sec-butoxy group), 4-tert-
Butoxy-2-tert-butyl-5-ethyl-2-methyl-3 (2H) -furanone (R ₁ = ethyl group, R ₂ = methyl group, R ₃ = tert-butyl group, R ₄ = sec-butoxy group ), 2-ethyl-5-methyl-4-n-pentoxy-2-n-pentyl-3 (2H) -furanone (R ₁ =
Methyl group, R ₂ = ethyl group, R ₃ = n-pentyl group, R ₄
= N-pentyl group), 5-ethyl-2-methyl-4-n
-Pentoxy-2-n-pentyl-3 (2H) -furanone (R ₁ = ethyl group, R ₂ = methyl group, R ₃ = n-pentyl group, R ₄ = n-pentoxy group), 2-ethyl-4 -Isopentoxy-2-isopentyl-5-methyl-3 (2
H) -furanone (R ₁ = methyl group, R ₂ = ethyl group, R ₃
= Isopentyl group, R ₄ = isopentoxy), 5-ethyl-4-isopentoxy-2-isopentyl-2-methyl -3 (2H) - furanone (R ₁ = ethyl, R ₂ = methyl, R ₃ = isopentyl Group, R ₄ = isopentoxy group), 2-ethyl-4-n-hexoxy-2-n-hexyl-5-methyl-3 (2H) -furanone (R ₁ = methyl group, R ₂ = ethyl group, R ₃ = N-hexyl group, R ₄ = n
-Hexoxy group), 5-ethyl-4-n-hexoxy-
2-n-hexyl-2-methyl-3 (2H) -furanone (R ₁ = ethyl group, R ₂ = methyl group, R ₃ = n-hexyl group, R ₄ = n-hexoxy group) and the like. Also, 2,5-dimethyl-4-isopropyloxy-3
(2H) -furanone (R ₁ = methyl group, R ₂ = methyl group,
R ₃ = hydrogen atom, R ₄ = isopropyloxy group), 4-t
ert-butoxy-2,5-dimethyl-3 (2H) -furanone (R ₁ = methyl group, R ₂ = methyl group, R ₃ = hydrogen atom, R ₄ = tert-butyloxy group), 2,5-dimethyl- 4- (2-methyl-2-butoxy) -3 (2H)
-Furanone (R ₁ = methyl group, R ₂ = methyl group, R ₃ = hydrogen atom, R ₄ = 2-methyl-2-butyloxy group),
2,5-dimethyl-4- (3-methyl-3-pentyloxy) -3 (2H) -furanone (R ₁ = methyl group, R ₂ =
Methyl group, R ₃ = hydrogen atom, R ₄ = 3-methyl-3-pentyloxy group), 2,5-dimethyl-4- (1-methyl-1-cyclopentyloxy) -3 (2H) -furanone (R ₁ = methyl group, R ₂ = methyl group, R ₃ = hydrogen atom, R ₄
= 1-methyl-1-cyclopentyloxy group), 2,5
-Dimethyl-4- (1-methyl-1-cyclohexyloxy) -3 (2H) -furanone (R ₁ = methyl group, R ₂ =
Methyl group, R ₃ = hydrogen atom, R ₄ = 1-methyl-1-cyclohexyloxy group) and the like.

The 4-alkoxy-3 (2H) -furanone derivative has, for example, the following formula:

Embedded image (Wherein R ₁ , R ₂ , and R ₃ have the same meanings as described above) to a 4-hydroxy-3 (2H) -furanone derivative represented by the following formula in the presence of a reactive alkali metal compound:

Embedded image (Wherein, A represents an alkyl group, an alkenyl group, an alkynyl group, an aryl group or an aralkyl group, and X represents a halogen atom). Further, a 4-hydroxy-3 (2H) -furanone derivative represented by the above formula 3 is
Propylene, isobutylene, 2-methyl-1- Butene, 2-ethyl-1-butene, 1-methyl-1-cyclopentene, 1
It can also be produced by reacting with an alkene such as -methyl-1-cyclohexene. Further, it can be manufactured by other methods.

At this time, 4-
In the hydroxy-3 (2H) -furanone derivative, R ₁
And when R ₃ is different from each other and R ₂ is a hydrogen atom, it exhibits tautomerism represented by the following formula (6), and each tautomer, that is, formula (4) and (5) Are present in equilibrium.

Embedded image

4-hydroxy-3 (2H)-of the formula (2)
Examples of the furanone derivative include various tautomers, for example, 2 (or 5) -ethyl-4-hydroxy-5 (or 2)
-Methyl-3 (2H) -furanone, 4-hydroxy-5
(Or 2) -methyl-2 (or 5) -n-propyl-3
(2H) -furanone, 4-hydroxy-2 (or 5)-
Isopropyl-5 (or 2) -methyl-3 (2H) -furanone, 2 (or 5) -n-butyl-4-hydroxy-
5 (or 2) -methyl-3 (2H) -furanone, 4-hydroxy-2 (or 5) -isobutyl-5 (or 2)-
Methyl-3 (2H) -furanone, 5 (or 2) -ethyl-4-hydroxy-2 (or 5) -n-propyl-3
(2H) -furanone, 5 (or 2) -ethyl-4-hydroxy-2 (or 5) -isobutyl-3 (2H) -furanone, and 2,5-dimethyl-4-hydroxy-3
(2H) -furanone, 2,5-diethyl-4-hydroxy-3 (2H) -furanone, 4-hydroxy-3 (2
H) -furanone, 4-hydroxy-2,2,5-trimethyl-3 (2H) -furanone, 2,5-diethyl-4-
And hydroxy-2-methyl-3 (2H) -furanone. Furthermore, 2- (1-hydroxyethyl)-
2,5-dimethyl-4-hydroxy-3 (2H) furanone, 2- (1-hydroxybenzyl) -2,5-dimethyl-4-hydroxy-3 (2H) furanone, 2- (1-
(Hydroxy-2-phenylethyl) -2,5-dimethyl-4-hydroxy-3 (2H) furanone.

The 4-hydroxy-3 (2H)-
Examples of the alkyl halide of the formula (3) to be reacted with the furanone derivative include methyl iodide, methyl bromide, ethyl iodide, ethyl bromide, propyl iodide, propyl bromide,
Propyl chloride, isopropyl iodide, isopropyl bromide, isopropyl chloride, butyl iodide, butyl bromide, butyl chloride, isobutyl iodide, isobutyl bromide, isobutyl chloride, sec-butyl iodide, sec-butyl bromide, sec chloride -Butyl, tert-butyl iodide, tert-butyl bromide, tert-butyl chloride, amyl iodide, amyl bromide, amyl chloride, isoamyl iodide, isoamyl bromide, isoamyl chloride, hexyl iodide, hexyl bromide, Hexyl chloride and the like can be mentioned.

In the formula (2), 4-hydroxy-3 (2
The H) -furanone derivative can be synthesized by a known synthesis method. For example, as a general method, a compound represented by the formula (7) is used as a raw material, and after ozone (O ₃ ) oxidation, reductive treatment ｛triphenylphosphine (triphenylphosphine) is used.
shine (φ ₃ P) treatment} to give a compound of the formula (8), which is further cyclized with oxalic acid {(COOH) ₂ }, and via an intermediate represented by the formula (8-2), 2) 4-hydroxy-3 (2H) -furanone derivative (JP-A-49-82656, U.S. Pat. No. 3,576,014, U.S. Pat. No. 37,283)
No. 97).

[0030]

Embedded image (R ₁ , R ₂ and R ₃ have the same meaning as described above.)

In the formula (2), one of R ₂ and R ₃ is a hydrogen atom and the other is an alkyl group, an alkenyl group,
When substituted with an alkynyl group and a carboxyl group, an amino acid group, a hydroxyl group, or a mercapto group,
For example, they are synthesized as follows (US Pat. No. 3,576,014, US Pat. No. 3,728,392).
No. 7).

A) When substituted with a carboxyl group: Using a propargyl alcohol derivative represented by the following formula (10) as a starting material, reacting with a Grignard reagent represented by the following formula (11), Reaction with the compound represented by the following formula (12) gives an intermediate of the following formula (13). Further, as shown in the following equation (18), ozone (O ₃ )
After the oxidation, reductive treatment is performed using triphenylphosphine (tri)
phenylphosphine: φ ₃ P) treatment, and further cyclization with oxalic acid {(COOH) ₂ } to obtain a mixture of the isomers (14) and (15), which are hydrolyzed and deprotected After the reaction, the target substance (16), (1
7) can be obtained.

Embedded image (Wherein, R ₁ has the same meaning as described above.)

Embedded image (Where Et is an ethyl group, Mg is a magnesium atom, B
r represents a bromo atom. )

Embedded image (In the formula, Et represents an ethyl group, and Z represents an alkylene group.)

Embedded image (In the formula, R ₁ and Z have the same meanings as described above.)

B) When substituted with an amino group: Instead of the compound of the formula (11), the compound of the formula (19) is used in the same manner as in the above-mentioned formula (18), using the compound of the formula (18)
Or (21) can be obtained.

Embedded image (In the formula, Z has the same meaning as described above, and Boc represents a tert-butoxycarbonyl group.)

Embedded image (In the formula, Et and Z show the same meaning as described above.)

C) When substituted with a hydroxyl group: The target substance (23) or (24) can be obtained using the compound of the formula (22) in the same manner as in the case of the amino group.

Embedded image (In the formula, Z has the same meaning as described above, and Ac represents an acetyl group.)

Embedded image (In the formula, R ₁ and Z have the same meanings as described above.)

C) When substituted with a mercapto group:
In the same manner as in the case of the amino group, the target substance (26) or (27) can be obtained using the compound of the formula (25).

Embedded image (In the formula, S represents a sulfur atom, and Ac and Z have the same meaning as described above.)

Embedded image (In the formula, R ₁ and Z have the same meanings as described above.)

Also, 4-hydroxy-2-ethyl-5-
In the case of methyl-3 (2H) -furanone, acetoacetic acid t
-Butyl ester was reacted with sodium (dispersion) followed by bromoethylacetyl bromide and -40.
C. to -50.degree. C. to give the intermediate 4-t-butoxycarbonyl-2 (or 5) -ethyl-5 (or 2)-
Methyl-3 (2H) -furanone is produced, and then can be synthesized by a deprotection reaction (Recuil).
Travaux Chimiques des Pa
ys-Bas, 92, 731 (1973)).

Also, 4-hydroxy-5-methyl-3
In the case of (2H) -furanone, it can be synthesized in eight steps using D-xylitol as a raw material (J. Org.
Chem. 48, 5126, 1983).

The reaction is mainly carried out on the mother nucleus 3 (2H) -furanone.
Alkyl substitution of the hydrogen atom of the hydroxyl group at position
When a tautomer mixture of the above formulas (4) and (6) is used as the 4-hydroxy-3 (2H) -furanone derivative of the above formula 2, 4 corresponding to each tautomer is used. Alkyl-substituted hydrogen atom of the hydroxyl group at the 2-position, that is, the following formula:

Embedded image (R ₁ ′, R ₂ ′, R ₃ ′ and A have the same meaning as described above.)

Embedded image (R ₁ ′, R ₂ ′, R ₃ ′, and A have the same meanings as described above). When a hydrogen atom is present at the 2-position, the reaction may be accompanied by an alkyl substitution reaction. In this case, the reaction product is a derivative of the following formula (30) with respect to the derivative of the formula (28), The derivative of the formula (29) is a derivative of the following formula (31).

Embedded image

Embedded image

The reaction is carried out in the presence of a reactive alkali metal compound, especially an alkali metal hydride such as potassium hydride or sodium hydride. In addition, various other reactions such as a reaction between a corresponding alkoxide and a dialkyl sulfate or an alkyl aromatic sulfonic acid ester, a dehydration reaction between the corresponding alcohols, and a methylation reaction of the corresponding alcohols with diazomethane can be used.

The reaction is preferably carried out by dissolving a starting material, a 4-hydroxy-3 (2H) -furanone derivative of the formula (2), preferably in a solvent, adding a reactive alkali metal compound, and adding an alkyl halide to the solution. Is added as it is or after dissolving it in a suitable solvent. At this time, if desired, the reaction can be promoted by heating to a temperature up to the boiling point of the solvent.

The solvent is not particularly limited as long as it is inert to the reaction.
Aromatic hydrocarbons such as tetrahydrofuran, benzene, toluene, xylene, halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, amides such as dimethylformamide and diethylacetamide, and etherification such as dimethylsulfoxide An organic solvent commonly used in the reaction is used. When a basic catalyst such as pyridine or dimethylaniline is used, these can be used also as a solvent.

The 4-alkoxy-3 (2H) -furanone derivative as a target substance is separated and purified from the reaction mixture thus obtained by distillation, solvent extraction, fractional crystallization column chromatography, liquid chromatography, etc. Can be carried out using a commonly used method.

The 4-alkoxy-3 (2H) -furanone derivative of the present invention thus obtained can be identified by a mass spectrum, an infrared absorption spectrum, and a nuclear magnetic resonance spectrum.

5) R ₄ = acyloxy group, alkenyloxy group, alkynyloxy group, or aryloxy group In the present invention, in formula (1), one of R ₂ and R ₃ is a hydrogen atom and the other is a hydrogen atom. Furanone derivatives substituted with groups other than hydrogen atoms (each is a stereoisomer) can be mentioned as preferred. Thus, for convenience, the hydrogen atom is omitted and the general formula is represented by the following formula:

Embedded image (Wherein, R ₁ and R ₄ have the same meanings as described above, and R represents a hydrogen atom, a hydroxyl group, an amino group, a halogen atom, a mercapto group, a carboxyl group, a carbamoyl group, an alkyl group, an alkenyl group, an alkynyl group, Represents an aryl group, an aralkyl group, an alkoxyl group, an alkenyloxy group, an alkynyloxy group, an aryloxy group, an acyloxy group, or an alkoxycarbonyl group, and an alkyl group, an alkenyl group, an alkynyl group, an aryl group, or an aralkyl group. The hydrocarbon part of the group, alkoxyl group, alkenyloxy group, alkynyloxy group, aryloxy group, acyloxy group, or alkoxycarbonyl group may be linear, branched or cyclic. Some are hydrogen, hydroxyl, amino, Gen atom, a mercapto group, a carboxyl group, a carbamoyl group, an alkyl group, an alkenyl group,
It may be substituted with an alkynyl group, an aryl group, an aralkyl group, an alkoxyl group, an alkenyloxy group, an alkynyloxy group, an aryloxy group, an acyloxy group, or an alkoxycarbonyl group. Further, R1, R4, R
May be the same or different. ). Among these, as particularly preferred derivatives,
A 4-acyloxy-3 (2H) -furanone derivative can be mentioned. An example is described below.

Examples of known substances include, for example, 4-acetoxy-2-ethyl-5-methyl-3 (2H) -furanone (R ₁ = methyl group, R = ethyl group, R ₄ = acetoxy). it can.

The following example is a novel substance synthesized for the first time by the present inventors (Japanese Patent Application No. 7-264526). 2-ethyl-5-methyl-4-propionyloxy-3 (2
H) -furanone (R ₁ = methyl group, R = ethyl group, R ₄ =
Propionyloxy group), 5-ethyl-2-methyl-4
-Propionyloxy-3 (2H) -furanone (R ₁ =
Ethyl group, R = methyl group, R ₄ = propionyloxy group), 4-butyryloxy-2-ethyl-5-methyl-
3 (2H) -furanone (R ₁ = methyl group, R = ethyl group, R ₄ = butyryloxy group), 4-butyryloxy-
5-ethyl-2-methyl-3 (2H) -furanone (R ₁
= Ethyl radical, R = methyl radical, R ₄ = butyryloxy), 2-ethyl-4-isobutyryl-5- methyl -3 (2H) - furanone (R ₁ = methyl radical, R = ethyl radical, R ₄ = isobutyryloxy group), 5-ethyl-4
-Isobutyryloxy-2-methyl-3 (2H) -furanone (R ₁ = ethyl group, R = methyl group, R ₄ = isobutyryloxy group), 2-ethyl-5-methyl-4-valeryloxy- 3 (2H) -furanone (R ₁ = methyl group, R =
Ethyl group, R ₄ = valeryloxy group), 5-ethyl-2
-Methyl-4-valeryloxy-3 (2H) -furanone (R ₁ = ethyl group, R = methyl group, R ₄ = valeryloxy group), 2-ethyl-4-isovaleryloxy-5-methyl-3 (2H ) -Furanone (R ₁ = methyl group, R = ethyl group, R ₄ = isovaleryloxy group), 5-ethyl-4
-Isovaleryloxy-2-methyl-3 (2H) -furanone (R ₁ = ethyl group, R = methyl group, R ₄ = isovaleryloxy group), 2-ethyl-4-n-hexanoyloxy- 5-methyl-3 (2H) -furanone (R ₁ = methyl group, R = ethyl group, R ₄ = n-hexanoyloxy group), 5-ethyl-4-n-hexanoyloxy-2-
Methyl-3 (2H) -furanone (R ₁ = ethyl group, R =
Methyl group, R ₄ = n-hexanoyloxy group), 2-ethyl-4-n-heptanoyloxy-5-methyl-3
(2H) -furanone (R ₁ = methyl group, R = ethyl group,
R ₄ = n-heptanoyloxy group), 5-ethyl-4-
n-heptanoyloxy-2-methyl-3 (2H) -furanone (R ₁ = ethyl group, R = methyl group, R ₄ = n-heptanoyloxy group), 2-ethyl-5-methyl-4-n
-Octanoyloxy-3 (2H) -furanone (R ₁ =
Methyl group, R = ethyl group, R ₄ = n-octanoyloxy group), 5-ethyl-2-methyl-4-n-octanoyloxy-3 (2H) -furanone (R ₁ = ethyl group, R ₁
= Methyl group, R ₄ = n-octanoyloxy group), 2-
Ethyl-5-methyl-4-n-nonanoyloxy-3
(2H) -furanone (R ₁ = methyl group, R = ethyl group,
R ₄ = n-nonanoyloxy group), 5-ethyl-2-methyl-4-n-nonanoyloxy-3 (2H) -furanone (R ₁ = ethyl group, R = methyl group, R ₄ = n-nonanoyloxy group), 4-n-decanoyloxy-2-ethyl-5-methyl-3 (2H) -furanone (R ₁ = methyl group, R = ethyl group, R ₄ = n-decanoyloxy group),
4-n-decanoyloxy-5-ethyl-2-methyl-
3 (2H) -furanone (R ₁ = ethyl group, R = methyl group, R ₄ = n-decanoyloxy group), 2-ethyl-5
-Methyl-4-n-undecanoyloxy-3 (2H)
-Furanone (R ₁ = methyl group, R = ethyl group, R ₄ = n-
Undecanoyloxy group), 5-ethyl-2-methyl-
4-n-undecanoyloxy-3 (2H) -furanone (R ₁ = ethyl group, R = methyl group, R ₄ = n-undecanoyloxy group), 4-n-dodecanoyloxy-2-ethyl -5-methyl-3 (2H) -furanone (R ₁ = methyl group, R = ethyl group, R ₄ = n-dodecanoyloxy group), 4-n-dodecanoyloxy-5-ethyl-2-
Methyl-3 (2H) -furanone (R ₁ = ethyl group, R =
Methyl group, R ₄ = n-dodecanoyloxy group), 2-ethyl-5-methyl-4-n-tridecanoyloxy-3
(2H) -furanone (R ₁ = methyl group, R = ethyl group,
R ₄ = n-tridecanoyloxy group), 5-ethyl-2
-Methyl-4-n-tridecanoyloxy-3 (2H)
-Furanone (R ₁ = ethyl group, R = methyl group, R ₄ = n-
Tridecanoyloxy group), 2-ethyl-5-methyl-
4-n-tetradecanoyloxy-3 (2H) -furanone (R ₁ = methyl group, R = ethyl group, R ₄ = n-tetradecanoyloxy group), 5-ethyl-2-methyl-4-n
-Tetradecanoyloxy-3 (2H) -furanone (R
₁ = ethyl group, R = methyl group, R ₄ = n-tetradecanoyloxy group), 2-ethyl-5-methyl-4-n-pentadecanoyloxy-3 (2H) -furanone (R ₁ = methyl Group, R = ethyl group, R ₄ = n-pentadecanoyloxy group), 5-ethyl-2-methyl-4-n-pentadecanoyloxy-3 (2H) -furanone (R ₁ = ethyl group, R = Methyl group, R ₄ = n-pentadecanoyloxy group), 2-ethyl-5-methyl-4-palmitoyloxy-3 (2H) -furanone (R ₁ = methyl group, R = ethyl group, R ₄ = Palmitoyloxy group), 5-ethyl-
2-methyl-4-palmitoyloxy-3 (2H) -furanone (R ₁ = ethyl group, R = methyl group, R ₄ = palmitoyloxy group), 2-ethyl-4-n-heptadecanoyloxy-5 Methyl-3 (2H) -furanone (R ₁ =
Methyl group, R = ethyl group, R ₄ = n-heptadecanoyloxy group), 5-ethyl-4-n-heptadecanoyloxy-2-methyl-3 (2H) -furanone (R ₁ = ethyl group, R = methyl group, R ₄ = n-heptadecanoyloxy group), 2-ethyl-5-methyl-4-stearoyloxy-3 (2H) -furanone (R ₁ = methyl group, R = ethyl group, R ₄ = Stearoyloxy group), 5-ethyl-
2-methyl-4-stearoyloxy-3 (2H) -furanone (R ₁ = ethyl group, R = methyl group, R ₄ = stearoyloxy group), 2-ethyl-5-methyl-4-oleoyloxy-3 (2H) -furanone (R ₁ = methyl group,
R = ethyl group, R ₄ = oleoyloxy group), 5-ethyl-2-methyl-4-oleoyloxy-3 (2H)-
Furanone (R ₁ = ethyl group, R = methyl group, R ₄ = oleoyloxy group), 2-ethyl-4-linoleoyloxy-5-methyl-3 (2H) -furanone (R ₁ = methyl group, R = ethyl group, R ₄ = linoleoyloxy group), 5
-Ethyl-4-linoleoyloxy-2-methyl-3
(2H) -furanone (R ₁ = ethyl group, R = methyl group,
R ₄ = linoleoyloxy group), 2-ethyl-4-linolenoyloxy-5-methyl-3 (2H) -furanone (R ₁ = methyl group, R = ethyl group, R ₄ = linoleoyloxy) Group), 5-ethyl-4-linolenoyloxy-2-
Methyl-3 (2H) -furanone (R ₁ = ethyl group, R =
Methyl group, R ₄ = linoleoyloxy group), 2-ethyl-5-methyl-4-n-nonadecanoyloxy-3 (2
H) -furanone (R ₁ = methyl group, R = ethyl group, R ₄ =
n-nonadecanoyloxy group), 5-ethyl-2-methyl-4-n-nonadecanoyloxy-3 (2H) -furanone (R ₁ = ethyl group, R = methyl group, R ₄ = n-nona Decanoyloxy group), 4-n-eicosanoyloxy-
2-ethyl-5-methyl-3 (2H) -furanone (R ₁
= Methyl group, R = ethyl group, R ₄ = n-eicosanoyloxy group), 4-n-eicosanoyloxy-5-ethyl-2-methyl-3 (2H) -furanone (R ₁ = ethyl group) , R = methyl group, R ₄ = n-eicosanoyloxy group), 2-ethyl-4-n-heneicosanoyloxy-5-methyl-3 (2H) -furanone (R ₁ = methyl group, R = Ethyl group, R ₄ = n-eicosyloxy group),
5-ethyl-4-n-heneicosanoyloxy-2-
Methyl-3 (2H) -furanone (R ₁ = ethyl group, R =
Methyl group, R ₄ = n-heneicosanoyloxy group),
4-n-docosanoyloxy-2-ethyl-5-methyl-3 (2H) -furanone (R ₁ = methyl group, R = ethyl group, R ₄ = n-docosanoyloxy group), 4-n-docosa Noyloxy-5-ethyl-2-methyl-3 (2H)
-Furanone (R ₁ = ethyl group, R = methyl group, R ₄ = n-
Docosanoyloxy group), 4- (4,7,10,13,
16,19-docosahexaenoyloxy) -2-ethyl-5-methyl-3 (2H) -furanone (R ₁ = methyl group, R = ethyl group, R ₄ = 4,7,10,13,16,
19-docosahexaenoyloxy group), 4- (4,
7,10,13,16,19-docosahexaenoyloxy) -5-ethyl-2-methyl-3 (2H) -furanone (R ₁ = ethyl group, R = methyl group, R ₄ = 4,7, 1
0,13,16,19-docosahexaenoyloxy group), 2-ethyl-5-methyl-4-n-tricosanoyloxy-3 (2H) -furanone (R ₁ = methyl group, R ₁
= Ethyl group, R ₄ = n-tricosanoyloxy group), 5
-Ethyl-2-methyl-4-n-tricosanoyloxy-3 (2H) -furanone (R ₁ = ethyl group, R = methyl group, R ₄ = n-tricosanoyloxy group), 2-ethyl- 5-methyl-4-n-tetracosanoyloxy-3
(2H) -furanone (R ₁ = methyl group, R = ethyl group,
R ₄ = n-tetracosanoyloxy group), 5-ethyl-
2-methyl-4-n-tetracosanoyloxy-3 (2
H) -furanone (R ₁ = ethyl group, R = methyl group, R ₄ =
n-tetracosanoyloxy group), 2-ethyl-5-methyl-4-n-pentacosanoyloxy-3 (2H)-
Furanone (R ₁ = methyl group, R = ethyl group, R ₄ = n-pentacosanoyloxy group), 5-ethyl-2-methyl-
4-n-pentacosanoyloxy-3 (2H) -furanone (R ₁ = ethyl group, R = methyl group, R ₄ = n-pentacosanoyloxy group), 4-β-aminopropionyloxy-2-ethyl -5-methyl-3 (2H) -furanone (R ₁ = methyl group, R = ethyl group, R ₄ = β-aminopropionyloxy group), 4-β-aminopropionyloxy-5-ethyl-2-methyl- 3 (2H) -furanone (R ₁ = ethyl group, R = methyl group, R ₄ = β-aminopropionyloxy group), 4-γ-aminobutyryloxy-
2-ethyl-5-methyl-3 (2H) -furanone (R ₁
= Methyl group, R = ethyl group, R ₄ = γ-aminobutyryloxy group), 4-γ-aminobutyryloxy-5-ethyl-2-methyl-3 (2H) -furanone (R ₁ = ethyl group , R = methyl group, R ₄ = γ-aminobutyryloxy group), 4-β-aminoisobutyryloxy-2-ethyl-5-methyl-3 (2H) -furanone (R ₁ = methyl group, R ₁ = Ethyl group, R ₄ = β-aminoisobutyryloxy group), 4-β-aminoisobutyryloxy-5-ethyl-2-methyl-3 (2H) -furanone (R ₁ = ethyl group, R = Methyl group, R ₄ = β-aminoisobutyryloxy group), 4-δ-aminovaleryloxy-2-ethyl-
5-methyl-3 (2H) -furanone (R ₁ = methyl group,
R = ethyl group, R ₄ = δ-aminovaleryloxy-
Group), 4-δ-aminovaleryloxy-5-ethyl-2
-Methyl-3 (2H) -furanone (R ₁ = ethyl group, R
= Methyl group, R ₄ = δ-aminovaleryloxy- group),
4-γ-aminoisovaleryloxy-2-ethyl-5-
Methyl-3 (2H) -furanone (R ₁ = methyl group, R =
Ethyl group, R ₄ = γ-aminoisovaleryloxy group),
4-γ-aminoisovaleryloxy-5-ethyl-2-
Methyl-3 (2H) -furanone (R ₁ = ethyl group, R =
Methyl group, R ₄ = γ-aminoisovaleryloxy group),
4- (ε-amino-n-hexanoyloxy) -2-ethyl-5-methyl-3 (2H) -furanone (R ₁ = methyl group, R = ethyl group, R ₄ = ε-amino-n-hexa Noyloxy group), 4- (ε-amino-n-hexanoyloxy) -5-ethyl-2-methyl-3 (2H) -furanone (R ₁ = ethyl group, R = methyl group, R = ε-amino -N-hexanoyloxy group) and the like.

The 4-acyloxy-3 (2H) -furanone derivative is, for example, 4-hydroxy-3 of the above formula (2)
The (2H) -furanone derivative has the following formula:

Embedded image 中 In the formula, A has the same meaning as in the formula (3). Can be produced by reacting a carboxylic acid represented by｝ or a functional derivative thereof, for example, an acid halide, an acid anhydride, a reactive ester, or the like, but can also be produced by other methods (for example, JP-A-49-82
656). Also, 4-acyloxy-3 (2H)
-The furanone derivative can be converted to a salt if desired. This conversion to a salt is carried out by a usual salt formation reaction, for example, the formula (3)
When A in 3) has an amino group, the reaction is carried out by, for example, reacting the group with an acid such as hydrochloric acid.

At this time, in the 4-hydroxy-3 (2H) -furanone derivative (2) used as a starting material, R ₁
And when the groups represented by R ₂ and R ₃ are different from each other, they show the same tautomerism as the above-mentioned 4-alkoxy-3 (2H) -furanone derivative, and each tautomer is in equilibrium. Exists. Examples of the 4-hydroxy-3 (2H) -furanone derivative include various tautomers, for example, 2 (or 5) -ethyl-4-hydroxy-5 (or 2) -methyl-3 (2H) -furanone, 4-hydroxy-5 (or 2) -methyl-2 (or 5) -n-propyl-3 (2
H) -Furanone, 4-hydroxy-2 (or 5) -isopropyl-5 (or 2) -methyl-3 (2H) -furanone, 2 (or 5) -n-butyl-4-hydroxy-5
(Or 2) -methyl-3 (2H) -furanone, 4-hydroxy-2 (or 5) -isobutyl-5 (or 2) -methyl-3 (2H) -furanone, 5 (or 2) -ethyl-
4-hydroxy-2 (or 5) -n-propyl-3 (2
H) -furanone, 5 (or 2) -ethyl-4-hydroxy-2 (or 5) -isobutyl-3 (2H) -furanone, and 2,5-dimethyl-4-hydroxy-3 (2
H) -Furanone, 2,5-diethyl-4-hydroxy-
3 (2H) -furanone, 4-hydroxy-3 (2H)-
Furanone and the like.

The 4-hydroxy-3 (2H)-
Examples of the carboxylic acid of Formula 13 to react with the furanone derivative include propionic acid, butyric acid, isobutyric acid, valeric acid,
Isovaleric acid, pelargonic acid, capric acid, undecanoic acid, lauric acid, tridecanoic acid, myristic acid, palmitic acid, stearic acid, behenic acid, crotonic acid, isocrotonic acid, vinyl acetic acid, pentenoic acid, angelic acid,
Tiglic acid, 2-hexenoic acid, 2-methyl-2-pentenoic acid, 3-methyl-2-pentenoic acid, 2-heptenoic acid,
2-octenoic acid, 4-dodecenoic acid, 4-tetradecenoic acid, oleic acid, elaidic acid, erucic acid, 2,4-hexadienoic acid, 9,12-octadecadienoic acid, 2,
4,6-octatrienoic acid, linolenic acid, arachidonic acid, docosahexaenoic acid, β-aminopropionic acid, γ
-Aminobutyric acid, β-aminoisobutyric acid, δ-aminovaleric acid, γ-aminoisovaleric acid, ε-amino-n-hexanoic acid, and the like. These carboxylic acids can be used in free form, but are usually used in the form of their functional derivatives, for example, acid halides, acid anhydrides and reactive esters.

When the carboxylic acid is allowed to react in a free state, an acid catalyst such as p-toluenesulfonic acid, sulfuric acid or an acidic ion exchange resin, or dicyclohexylcarbodiimide, trifluoroacetic anhydride, magnesium sulfate anhydride, molecular sieve 5A It is preferable to use a dehydrating agent such as polyphosphoric acid.

When reacting in the form of an acid halide such as acid chloride or acid bromide, pyridine, lutidine, dimethylaminopyridine, dimethylaniline,
It is advantageous to carry out in the presence of a basic substance such as trimethylamine, tetramethylurea, diisopropylethylamine, N-ethylpiperidine. In addition, an acid anhydride from two molecules of the carboxylic acid or a mixed acid anhydride of one molecule of the carboxylic acid and one molecule of another carboxylic acid or one molecule of ethyl chlorocarbonate or isobutyl chloroformate,
The reaction can be carried out using sulfuric acid, zinc chloride, sodium acetate, perchloric acid or the like as a catalyst, or the reaction can be carried out in the presence of the above basic substance such as pyridine. Alternatively, a lower ester such as a methyl ester, an ethyl ester, or an isopropenyl ester can be used and reacted with sulfuric acid or p-toluenesulfonic acid as a catalyst.

In this reaction, 4-hydroxy-3
When a tautomer mixture is used as the (2H) -furanone derivative, an acylated hydroxyl group at the 4-position corresponding to each tautomer is obtained. In the reaction, the starting material, 4-hydroxy-3 (2H) -furanone derivative, is preferably dissolved in a solvent, and a catalyst is added if necessary. It is carried out by dissolving in an appropriate solvent and adding little by little with stirring. At this time, if desired, the reaction can be promoted by heating to a temperature up to the boiling point of the solvent.

The solvent is not particularly limited as long as it is inert to the reaction.
Aromatic hydrocarbons such as benzene, toluene, xylene, halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, amides such as dimethylformamide, diethylacetamide, etc., are commonly used in esterification reactions. Organic solvents are used. When a basic catalyst such as pyridine or dimethylaniline is used, these can be used also as a solvent.

The 4-acyloxy-3 (2H) -furanone derivative as the target substance is separated and purified from the reaction mixture thus obtained by distillation, solvent extraction, fractional crystallization column chromatography, liquid chromatography, etc. Can be carried out using a commonly used method. The 4-acyloxy-3 (2H)-of the present invention thus obtained.
Identification of the furanone derivative can be performed by a mass spectrum, an infrared absorption spectrum, and a nuclear magnetic resonance spectrum.

Other than the above, the 3 (2H) -furanone derivative of the present invention can be produced. For example, the following method is used: 1) 5-methyl-3 (2H) -furanone and Schiff (Sc)
hiff) from the reaction of the base, 2,2-dimethyl-4-ethoxycarbonyl-3-oxo-5- (E) -styryl-3 (2H) -furanone (Synthesis, no.
1, p. 45-47, 1981), 2) Synthesis of dialkoxydiepoxyalkane-4-hydroxy-3 (2H) -furanone from α, α'-dibromo-1,2-dione in the presence of sodium alkoxide. (Synthesis, No. 9, p. 709, 1981)
3) Synthesis of 4,5-dihydro-3 (2H) -furanone by regiodominant hydration of 2-butyne-1,4-diol derivative, 4) Reduction reaction of △ 2-isoxazolines 3 (2
Production of H) -furanone derivatives (Tetrahedron)
Lett. 24, 2079-2082, 198
3 years), 5) Dihydro-3 starting from 1,3-dithiane
Synthesis of (2H) -furanone (Tetrahedron)
Lett. 25, 5567-5570, 198
4 years), 6) Synthesis of 3 (2H) -furanone derivative starting from ethyl 5-substituted 3-isoxazolecarboxylate (T
etrahedron Lett. , 25 volumes, 4313
4316, 1984), 7) 5-aryl-4,5-dibromo-2-methyl-
Synthesis of 3 (2H) -furanone derivatives by dehydrobromination of 1,2-epoxypentan-3-one (Zh. Org.
Khim. 21, Volume 1330-1334, 1985.
8) Aromatic aldehyde and 3-hydroxy-3-methyl-
Synthesis of 5-aryl-2,2-dimethyl-3 (2H) -furanone derivatives by condensation and bromine addition of 2-butanone, and alkali treatment (J. Heterocycl. Ch.
em. 23, 1199-1201, 1986.
Year), 9) 2-acetylmethyl-5-methylfuran or 2-
2 using benzoylmethyl-5-methylfuran as a raw material
-Acetylmethyl-5-methyl-3 (2H) -furanone, 2-acetylmethyl-5-phenyl-3 (2H)-
Synthesis of Furanone (Tetrahedron Let
t. , 28, 2297-2298, 1987), 10) Synthesis of 3 (2H) -furanone derivatives from propargyl alcohol, CO, and phenyl halide (Chem. Lett., No. 1, pp. 81-82; 1
988), 11) 3 from the reaction of 5-arylfuran-2,3-diones with acylmethylenetriphenylphosphoranes.
Synthesis of (2H) -furanone derivative (Pharmazi
e, 48, 99-106, 1993).

In the present invention, all of the furanone derivatives having 3 (2H) -furanone as a bone nucleus produced as described above and one or more kinds thereof are appropriately combined to produce the cataract of the present invention. Among them, 2,5-dimethyl-4-pivaloyloxy-3 (2,5-dimethyl-4-pivaloyloxy-3) can be used as a prophylactic or therapeutic agent.
H) -Furanone, 4-acetoxy-2,5-dimethyl-
3 (2H) -furanone, 2 (or 5) -ethyl-5 (or 2) -methyl-4-pivaloyloxy-3 (2H)-
Furanone, 4-acetoxy-2 (or 5) -ethyl-5
(Or 2) -methyl-3 (2H) -furanone, 4-butyryloxy-2 (or 5) -ethyl-5 (or 2) -methyl-3 (2H) -furanone, 2 (or 5) -ethyl-
4-linoleoyloxy-5 (or 2) -methyl-3
(2H) -furanone, 4-ethoxy-2 (or 5) -ethyl-5 (or 2) -methyl-3 (2H) -furanone are furthermore particularly preferred derivatives as 2,5-dimethyl-4-pivaloyloxy -3 (2H) -furanone, 2
(Or 5) -ethyl-5 (or 2) -methyl-4-pivaloyloxy-3 (2H) -furanone, 4-acetoxy-2 (or 5) -ethyl-5 (or 2) -methyl-3
(2H) -furanone, 2,5-dimethyl-4-isopropyloxy-3 (2H) -furanone, 4-tert-butoxy-2,5-dimethyl-3 (2H) -furanone,
2,5-dimethyl-4- (2-methyl-2-butoxy)
-3 (2H) -furanone, 2,5-dimethyl-4- (3
-Methyl-3-pentyloxy) -3 (2H) -furanone, 2,5-dimethyl-4- (1-methyl-1-cyclopentyloxy) -3 (2H) -furanone, 2,5-dimethyl-4- (1-Methyl-1-cyclohexyloxy) -3 (2H) -furanone is most particularly preferred as 2,5-dimethyl-4-pivaloyloxy-3.
(2H) -furanone and 4-tert-butoxy-2,
5-dimethyl-3 (2H) -furanone can be mentioned.

Also, pharmaceutically acceptable salts of the above furanone derivatives can be used as the preventive or therapeutic agent for cataract of the present invention. For example, alkali metal salts (eg, sodium salt, potassium salt, etc.), alkaline earth metal salts (eg, calcium salt, etc.), ammonium salt, ethanolamine salt, triethylamine salt, dicyclohexylamine salt and the like can be mentioned.

(Function) Since the furanone derivative of the present invention exhibits an extremely strong antioxidant activity, it is considered that the furanone derivative exhibits an anticataract effect by suppressing an oxidation reaction in the lens during cataract generation. A cataract treatment drug comprising a furanone derivative having 2 (5H) -furanone as a mother nucleus as an active ingredient is aldose reductase (aldos).
(e. reductase) activity to treat diabetic cataract. The therapeutic effect is exhibited by oral, intravenous, or intraperitoneal administration, but hardly appears by instillation. The present application does not inhibit aldose reductase activity. It has a therapeutic effect on cataracts based on oxidative disorders such as hereditary, naphthalene impairment, and senile cataracts. It shows a remarkable therapeutic effect not only by oral, intravenous and intraperitoneal administration but also by instillation. Therefore, the agent for preventing or treating cataract of the present application is completely different from the agent for treating cataract containing a furanone derivative whose main component is 2 (5H) -furanone as an active ingredient.

(Administration method) The preventive or therapeutic agent for cataract of the present invention is appropriately used orally or parenterally for the prevention and treatment of cataract based on oxidative disorders such as senile cataract.

(Formulation) As the form of the preparation, any form such as a solid preparation such as tablets, granules, powders and capsules or a liquid preparation such as eye drops and injections can be appropriately prepared by a known method. it can. These preparations usually include a binder, a disintegrant, a thickener, a dispersant, a resorption accelerator, a flavoring agent, a buffer, a surfactant, a solubilizer, a preservative, an emulsifier, an isotonic agent, Excipients such as stabilizers and pH adjusters may be used as appropriate.

(Dose (hereinafter referred to as “dose” in the present invention)) The dose of the furanone derivative of the present invention for the purpose of the present invention depends on the type of the derivative, age of the patient, body weight, dosage form and indication symptoms. Although different, for example, in the case of an injection, 0.01 to 1000 mg, preferably about 0.1 to 100 mg once a day for an adult, and in the case of oral administration, several times a day for an adult, a dose of about 0.1 to 1000 mg, preferably Is 1 to 1
It is preferable to administer about 000 mg. In the case of eye drops, a drop having a concentration of 0.01 to 10%, preferably about 0.5 to 2% is instilled 1 to 5 times a day, preferably about 2 to 5 times a day. Is good. In the present invention, the agent for preventing or treating cataract of the present invention and / or a component having another kind of medicinal effect may be appropriately contained.

(Production Example of the Furanone Derivative of the Present Application) 1) Production Example 1 2,5-dimethyl-4-pivaloyloxy-3 (2H)
Preparation of furanone In a 50 ml two-necked flask with a stream of argon, 2,5-
Dimethyl-4-hydroxy-3 (2H) -furanone
0 g and 0.05 g of 4-dimethylaminopyridine are dissolved in a mixture of 10 ml of pyridine and 10 ml of methylene chloride,
1.06 ml of pivaloyl chloride was added dropwise under ice cooling, and the mixture was stirred at room temperature for 1 hour. The mixture was poured into 10 ml of an ice-cooled 0.5N aqueous hydrochloric acid solution and extracted three times with 30 ml of diethyl ether. The ether layer was washed three times with a 0.5N aqueous hydrochloric acid solution, twice with a saturated aqueous sodium hydrogen carbonate solution, and once with a saturated saline solution, and then dried with sodium sulfate. Then, concentrated under reduced pressure,
By purifying with a silica gel column, 1.40 g of 2,5-dimethyl-4-pivaloyloxy-3 (2H) -furanone was obtained. (A) Property: colorless oil (b) Infrared absorption spectrum ν _max (film, c
m ^-1 ): 2980, 1760, 1720, 1640, ¹
480, 1410, 1310, 1270, 1190, 1
140, 1100, 1030, 1000 (c) 1H-nuclear magnetic resonance spectrum δ (ppm in
CDCl ₃ ): 1.32 (s, 9H), 1.49 (d,
J = 7.3 Hz, 3H), 2.13 (S, 3H), 4.
56 (q, J = 7.3 Hz, 1H)

2) Production Example 2 Production of 4-acetoxy-2,5-dimethyl-3 (2H) -furanone Same as Production Example 1 except that pivaloyl chloride (1.06 ml) was changed to acetyl chloride (0.60 ml). hand,
4-acetoxy-2,5-having the following physicochemical properties
1.05 g of dimethyl-3 (2H) -furanone was obtained. (A) Property: colorless oil (b) Infrared absorption spectrum ν _max (film, c
m ^-1 ): 2980, 1770, 1710, 1630, ¹
410, 1310, 1190, 1130, 1010, 1
100, 1070, 1040, 930, 880, 860 (c) 1H-nuclear magnetic resonance spectrum δ (ppm in
CDCl ₃ ): 1.50 (d, J = 7.3 Hz, 3
H), 2.17 (s, 3H), 2.27 (s, 3H),
4.57 (q, J = 7.3 Hz, 1H)

3) Production Example 3 2-ethyl-5-methyl-4-pivaloyloxy-3
Preparation of (2H) -furanone In a 50 ml two-necked flask under a stream of argon, 1.0 g of 2 (or 5) -ethyl-4-hydroxy-5 (or 2) -methyl-3 (2H) -furanone and 4-g were added. 0.05 g of dimethylaminopyridine was dissolved in a mixture of 10 ml of pyridine and 10 ml of methylene chloride, and 0.95 ml of pivaloyl chloride was added dropwise under ice cooling, followed by stirring at room temperature for 1 hour. The mixture was poured into 10 ml of an ice-cooled 0.5N aqueous hydrochloric acid solution and extracted three times with 30 ml of diethyl ether. The ether layer was washed three times with a 0.5N aqueous hydrochloric acid solution, twice with a saturated aqueous sodium hydrogen carbonate solution, and once with a saturated saline solution, and then dried with sodium sulfate. Thereafter, the mixture was concentrated under reduced pressure, and purified by a silica gel column to obtain 2-ethyl-5-methyl-4-pivaloyloxy-3 (2H) -furanone. (A) Property: colorless oil (b) Infrared absorption spectrum ν _max (film, c
m ^-1 ): 3000, 1770, 1730, 1650, ¹
490, 1460, 1420, 1320, 1280, 1
200, 1110, 1140 (c) 1H-nuclear magnetic resonance spectrum δ (ppm in
CDCl ₃ ): 1.01 (t, J = 7.3 Hz, 3
H), 1.33 (s, 9H), 1.79-2.04
(M, 2H), 2.15 (s, 3H), 4.46 (t,
J = 5.7Hz, 1H)

4) Production Example 4 4-acetoxy-2-ethyl-5-methyl-3 (2H)
-Preparation of furanone (major), 4-acetoxy-5-ethyl-2-methyl-3 (2H) -furanone (minor) Manufacture except that pivaloyl chloride 0.95 ml was changed to acetyl chloride 0.54 ml As in Example 4,
4-acetoxy-2-ethyl-5-methyl-3 (2H) -furanone (measure) and 4-acetoxy-5-ethyl-2-methyl-3 (2H) having the following physicochemical properties:
1.08 g of a mixture of -furanone (minor) was obtained. (A) Property: colorless oil (b) Infrared absorption spectrum ν _max (film, c
m ^-1 ): 2980, 1780, 1710, 1630, ¹
420, 1370, 1320, 1190 (c) 1H-nuclear magnetic resonance spectrum δ (ppm in
CDCl ₃ ): 1.01 (t, J = 7.5 Hz, 3H)
(Measure), 1.22 (t, J = 7.5 Hz, 3H)
(Minor), 1.45 (d, J = 7.5 Hz, 3H)
(Minor), 1.80-2.04 (m, 2H) (major), 2.18 (s, 3H) (major), 2.27
(S, 3H), 2.65 (q, J = 7.5 Hz, 2H)
(Minor), 4.47-4.53 (1H, m)

5) Production Example 5 4-butyryloxy-2-ethyl-5-methyl-3 (2
H) -Furanone (major), 4-butyryloxy-5
Synthesis of -ethyl-2-methyl-3 (2H) -furanone (minor) 2 (or 5) -ethyl-4-hydroxy-5 (or 2) -methyl- 1.0 g of 3 (2H) -furanone and 0.05 g of 4-dimethylaminopyridine were dissolved in a mixture of 10 ml of pyridine and 10 ml of methylene chloride, and 1.2 g of butyric anhydride was added under ice cooling.
6 ml was added dropwise, and the mixture was stirred at room temperature for 12 hours. Ice cold 0.
Pour into 10 ml of 5N hydrochloric acid aqueous solution and add diethyl ether 30
Extracted three times with ml. The ether layer was washed three times with a 0.5N aqueous hydrochloric acid solution, twice with a saturated aqueous sodium hydrogen carbonate solution, and once with a saturated saline solution, and then dried with sodium sulfate. Thereafter, the mixture was concentrated under reduced pressure and purified with a silica gel column to give 4-butyryloxy-2-ethyl-5-methyl-3.
1.28 g of a mixture of (2H) -furanone (major) and 4-butyryloxy-5-ethyl-2-methyl-3 (2H) -furanone (minor) was obtained. (A) Property: colorless oil (b) Infrared absorption spectrum ν _max (film, c
m ^-1 ): 2980, 1760, 1710, 1630, ¹
420, 1320, 1190, 1130 (c) 1H-nuclear magnetic resonance spectrum δ (ppm in
CDCl ₃ ): 1.00 (t, J = 7.6 Hz, 3
H), 1.00 (t, J = 7.6 Hz, 3H) (major), 1.21 (t, J = 7.6 Hz, 3H) (minor), 1.42-1.97 (m , 2H), 1.49.
(D, J = 7.0 Hz, 3H) (minor), 1.70
−2.00 (m, 2H) (measure), 2.16 (s,
3H) (Measure), 2.35-2.60 (m, 2H)
(Minor), 2.44-2.60 (m, 2H), 4.
40-4.60 (m, 1H)

6) Production Example 6 2-ethyl-4-linoleoyloxy-5-methyl-3
Synthesis of (2H) -furanone (major), 5-ethyl-4-linoleoyloxy-2-methyl-3 (2H) -furanone (minor) In a 50 ml two-necked flask under an argon stream, 2 ( Or 5) -Ethyl-4-hydroxy-5 (or 2) -methyl-3 (2H) -furanone 1.0 g, 4-dimethylaminopyridine 0.05 g, and linoleic acid 1.97 g in methylene chloride 30 ml. Dissolve and add 1.80 g of dicyclohexylcarbodiimide while cooling to 0 ° C.
Stirred for hours. After the reaction, the deposited precipitate was separated by filtration and washed with methylene chloride three times. The combined filtrate and washings were washed sequentially with 0.5N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated saline, and then dried over sodium sulfate. Thereafter, the mixture is concentrated under reduced pressure and purified with a silica gel column to give 4-linoleoyloxy-2-ethyl-5-methyl-3 (2H) -furanone (major) and 4-linoleoyloxy-. 2.55 g of a mixture of 5-ethyl-2-methyl-3 (2H) -furanone (minor) was obtained. (A) Property: transparent yellow oil (b) Infrared absorption spectrum ν _max (film, c
m ^-1 ): 2980, 1770, 1720, 1640, ¹
190 (c) 1H-nuclear magnetic resonance spectrum δ (ppm in
CDCl ₃ ): 0.89 (t, J = 6.71 Hz, 3
H), 1.01 (t, J = 7.0 Hz, 3H) (measure), 1.13 to 2.03 (m, 22H), 1.13
2.03 (m, 4H) (minor), 2.17 (s, 3
H) (Measure), 2.30-2.70 (m, 2H)
(Minor), 2.50 (q = J = 7.5 Hz, 2H)
(Minor), 2.53 (t, J = 7.3 Hz, 2H)
(Measurement), 2.70-2.90 (m, 2H), 4.
35-4.60 (m, 1H), 5.20-5.55
(M, 4H), 2.70-2.90 (m, 2H)

7) Production Example 7 4-ethoxy-2-ethyl-5-methyl-3 (2H)-
Furanone (major), 4-ethoxy-5-ethyl-2
Synthesis of -methyl-3 (2H) -furanone (minor) 0.85 g of 60% sodium hydride was placed in a dried 100 ml three-necked flask, and the atmosphere was replaced with argon. After washing three times with pentane, 30 ml of dry tetrahydrofuran was added and suspended, and 2 (or 5) -ethyl-4-hydroxy-5 (or 2) -methyl-3 dissolved in 3.0 ml of dry tetrahydrofuran was added thereto. 3.0 g of (2H) -furanone was added dropwise under ice cooling. After stirring at room temperature for 30 minutes, 1.58 ml of ethyl bromide was added dropwise while cooling on ice again, and the mixture was further refluxed for 6 hours. After the reaction, the reaction solution was poured into a 1.0 N hydrochloric acid aqueous solution and extracted three times with 60 ml of ether. The ether layer was washed with water and saturated saline, and dried over sodium sulfate. After the volatile solvent was distilled off under reduced pressure, distillation under reduced pressure (65-67 ° C./2.5 mmH
g) to give 4-ethoxy-2-ethyl-5-
1.57 g of a mixture of methyl-3 (2H) -furanone (major) and 4-ethoxy-5-ethyl-2-methyl-3 (2H) -furanone (minor) was obtained. (A) Property: colorless liquid (b) Infrared absorption spectrum ν _max (film, c
m ^-1 ): 2980, 1710, 1630, 1430, ¹
320, 1200, 1040 (c) 1H-nuclear magnetic resonance spectrum δ (ppm in
CDCl ₃ ): 0.97 (t, J = 7.1 Hz, 3H)
(Measurement), 1.13 (t, J = 7.1 Hz, 3H)
(Minor), 1.26 (t, J = 7.1 Hz, 3
H), 1.43 (d, J = 7.1 Hz, 3H) (minor), 1.71-1.89 (m, 2H) (major)
2.20 (s, 3H) (measure), 2.57 (q, J
= 7.1 Hz, 2H), 4.06 (q, J = 7.1H)
z, 2H), 4.20-4.43 (m, 1H)

8) Production Example 8 4-tert-butoxy-2,5-dimethyl-3 (2
Synthesis of H) -furanone

Embedded image 4-hydroxy-2,5-dimethyl-2 (2
H) -furanone (6.1 g, 48 mol) was dissolved in dichloromethane (80 ml) and stirred at -75 ° C., to which was added phosphoric acid (0.40 g of P ₂ O ₅ and 1.1 m of 85% H ₃ PO _4).
1) and boron trifluoride etherate complex (47% B
F ₃ .Et ₂ O 2.0 ml) and liquid isobutylene (40
ml) was added thereto, and the reaction was carried out with stirring at -75 ° C for 1.5 hours, then left at room temperature and stirred overnight. After adding a 2N aqueous ammonia solution (80 ml), the mixture was extracted with dichloromethane, and purified by a conventional method. That is, after drying with sodium sulfate, the solvent is distilled off under reduced pressure. Further, this is purified by silica gel column chromatography and then purified by distillation under reduced pressure, and has the following physicochemical properties. 5.3 g (60% yield)
Was isolated. P ₂ O ₅ was used for dehydration of H ₃ PO ₄ . (A) Property: transparent oil (b) Infrared absorption spectrum ν _max cm ^-1 : 1705,1
620, 1370, 1310, 1205, 1170, 1
(C) 1H-nuclear magnetic resonance spectrum δ (200 MHz,
CDCl3): 1.31 (s, 9H), 1.44 (d,
J = 7.3 Hz, 3H), 2.19 (d, J = 1.0 H)
z, 3H), 4.40 (dq, J1 = 7.3 Hz, J2 =
1.0Hz, 1H (d) Boiling point: 73-74 ° C / 2mmHg

[0070]

Embedded image

9) Production Example 9 2,5-dimethyl-4- (2-methyl-2-butoxy)
Synthesis of -3 (2H) -furanone 4-Hydroxy-2,5-dimethyl-3 (2H) -furanone (5.0 g, 39 mmol) was added to dichloromethane (8
0 ml) and stirred at -75 ° C.
A mixture of 0.35 g of ₂ O ₅ and 0.90 ml of 85% H ₃ PO ₄ ), 47% BF ₃ .Et ₂ O (2.0 ml) and 2-
Methyl-1-butene (5.5 g, 78 mmol) was added, and the reaction was carried out with stirring at -75 ° C for 1.5 hours.
It was left at room temperature and stirred overnight. 2N ammonia water (66
After the addition of 2,5-dimethyl-4- (2-methyl-2-) having the following physicochemical properties and having the following physicochemical properties: (Butoxy) -3 (2H) -furanone (4.3
g, 56%). (A) Property: transparent oil (b) Infrared absorption spectrum ν _max cm ^-1 : 1700,1
620, 1370, 1310, 1200, 1165, 1
(C) 1H-nuclear magnetic resonance spectrum δ (200 MHz,
CDCl ₃ ): 0.97 (s, J = 7.4 Hz, 3
H), 1.22 (s, 3H), 1.23 (s, 3H),
1.43 (d, J = 7.0 Hz, 3H), 1.66
(Q, J = 7.4 Hz, 2H) 2.18 (d, J = 0.
8 Hz, 3H), 4.41 (dq, J ₁ = 7.4 Hz,
J ₂ = 0.8 Hz, 1 H) (d) Boiling point: 80-81 ° C./1 mmHg

[0072]

Embedded image

10) Production Example 10 Synthesis of 2,5-dimethyl-4- (3-methyl-3-pentyloxy) -3 (2H) -furanone 4-hydroxy-2,5-dimethyl-3 (2H)- Furanone (5.0 g, 40 mmol) was added to dichloromethane (8
0 ml) and stirred at -75 ° C.
68 ml (0.35 g of P ₂ O ₅ and 85% H ₃ PO ₄ 0.
90 ml) and 47% BF ₃ .Et ₂ O (1.9)
8 ml) and 2-ethyl-1-butene (6.7 g, 80 m
mol), and the reaction was carried out with stirring at -75 ° C for 1.5 hours, then left at room temperature and stirred overnight. After adding 2N aqueous ammonia (66 ml), the mixture was extracted with dichloromethane, and purified by a conventional method to give 2,5-dimethyl-4 having the following physicochemical properties,
-(3-methyl-3-pentyloxy) -3 (2H)-
Furanone (4.2 g, 51%) was isolated. (A) Property: transparent oil (b) Infrared absorption spectrum ν _max cm ^-1 : 1702,1
619, 1459, 1310, 1198, 1135, 1
004 (c) 1H-nuclear magnetic resonance spectrum δ (200 MHz,
CDCl ₃ ): 0.93 (dt, J ₁ = 7.6 Hz, J ₂
= 0.4 Hz, 3H), 1.14 (d, J = 4.4H)
z, 3H), 1.42 (d, J = 7.0 Hz, 3H),
1.46-1.76 (m, 4H), 4.41 (dq, J
_{1 = 7.0Hz, J 2 = 1.0Hz} , 1H)

[0074]

Embedded image

11) Production Example 11 Synthesis of 2,5-dimethyl-4- (1-methyl-1-cyclopentoxy) -3 (2H) -furanone 4-hydroxy-2,5-dimethyl-3 (2H) -Furanone (3.0 g, 24 mmol) in dichloromethane (5
0 ml) and stirred at -75 ° C.
68 ml (0.20 g of P ₂ O ₅ and 85% H ₃ PO ₄ .
93% BF ₃ .Et ₂ O (0.9%)
6 ml) and 1-methyl-1-cyclopentene (3.9)
g, 48 mmol), and the reaction was carried out with stirring at -75 ° C for 1.5 hours, then left at room temperature and stirred overnight.
After adding 2N aqueous ammonia (40 ml), the mixture was extracted with dichloromethane and purified by a conventional method to give 2,5-dimethyl-4- (1-methyl) having the following physicochemical properties and represented by Chemical formula 27. -1-cyclopentyloxy)-
3 (2H) -furanone (1.6 g, 32%) was isolated. (A) Property: transparent oil (b) Infrared absorption spectrum ν _max cm ^-1 : 1705,1
619, 1450, 1370, 1310, 1195, 1
115, 1055, 1000, 930 (c) 1H-nuclear magnetic resonance spectrum δ (200 MHz,
CDCl ₃ ): 1.36 (s, 3H), 1.43 (d,
J = 7.2 Hz, 3H), 1.48-2.08 (m, 8
H), 2.18 (d, J = 0.8 Hz, 3H) 4.42
(Dq, J ₁ = 7.2 Hz, J ₂ = 0.8 Hz, 1H)

[0076]

Embedded image

12) Production Example 12 Synthesis of 2,5-dimethyl-4- (1-methyl-1-cyclohexyloxy) -3 (2H) -furanone 4-hydroxy-2,5-dimethyl-3 (2H)- Furanone (13.4 g, 105 mmol) was dissolved in dichloromethane (150 ml) and stirred at -75 ° C., to which 0.89 g of phosphoric acid (P ₂ O ₅ and 2.4 ml of 85% H ₃ PO _{4) was} added.
And BF ₃ .Et ₂ O (4.2 ml) and 1-methyl-1-cyclohexene (20 g, 210 mm)
ol), and the reaction was carried out with stirring at -75 ° C for 1.5 hours, then left at room temperature and stirred overnight. After adding 2N aqueous ammonia (87 ml), the mixture is extracted with dichloromethane to give 2,5-dimethyl-4- (1-methyl-1-cyclohexyloxy) having the following physicochemical properties and represented by Chemical formula 28. -3 (2H) -furanone (6.6
g, 28%). (A) Property: transparent oil (b) Infrared absorption spectrum ν _max cm ^-1 : 1705,1
615, 1445, 1415, 1370, 1310, 1
200, 1155, 1105, 1075, 1005 (c) 1H-nuclear magnetic resonance spectrum δ (200 MHz,
CDCl ₃ ): 1.22 (d, J = 5.6 Hz, 3
H), 1.3-2.0 (m, 10H), 1.43 (d,
J = 7.2 Hz, 3H), 2.19 (d, J = 0.8H)
z, 3H), 4.42 (dd, J ₁ = 7.2 Hz, J ₂ =
0.8Hz, 1H)

[0078]

Embedded image

13) Test Example 1 Anti-cataract effect on galactose cataract (in vivo)
(Tro test) (Test method) A lens extracted from a 7-week-old, male, Crj: Wistar rat was treated with 30 mM galactose-added T
The cells were immersed in 10 ml of C199 bicarbonate buffer medium (manufactured by Nissui Pharmaceutical) and cultured at 37 ° C. for 7 days in the presence of 5% CO ₂ . In a galactose-supplemented medium soaked with lens (5 / group),
0.5 mg, 0.1 mg and 0.01 mg of 5-dimethyl-4-pivaloyloxy-3 (2H) -furanone (hereinafter referred to as HDMF trimethylacetic acid monoester) were added. Also, 10 mg and 5 mg of reduced glutathione as an active ingredient of the therapeutic agent for cataract were added, respectively. As a control, each lens was cultured in a medium with or without galactose as described above. The medium to which these samples were added or not was changed every day. After culturing each lens for 7 days, the degree of lens opacity was determined by the method of Hattori et al. (Journal of the Japanese Ophthalmological Society, Vol. 95, No. 3, pp. 228-234, 1991).
The score was displayed. That is, score 0 indicates no opacity at all, score 1 indicates slight opacity in the cortex, score 3 indicates opacity throughout the cortex and higher opacity, and score 2 indicates a score between 2 and did. In addition, the wet weight of the lens after culturing for 7 days was measured, and the degree of lens swelling was compared and examined. Table 1 shows the results.

[0080]

[Table 1]

The lens cultured in the galactose-free medium maintained transparency (score 0), and no swelling was observed. However, the lens cultured in the galactose-supplemented medium showed remarkable cloudiness ( Swelling (increase in lens wet weight) was observed with a score of 2.6). On the other hand, both lenses cultured by adding 0.5 mg / 10 ml each of HDMF trimethyl acetate monoester to the galactose-containing medium and having the same transparency (score 0) and the same size as the lens cultured in the galactose-free medium. The effect of suppressing lens opacity was observed in a dose-dependent manner. It should be noted that reduced glutathione only showed a slight cataract inhibitory effect (score 1) at the added amount of 10 mg / 10 ml.

14) Test Example 2 Anti-cataract effect on spontaneously occurring cataract rats (ICR / f rats) (in vivo eye drop test) (Test method) 8 weeks old, male, ICR / f rats (7 to 8 rats / group, HDMF trimethyl acetic acid monoester was instilled three times a day (in the morning, afternoon and evening) for 3 weeks using an average body weight of 190 g). HDMF trimethyl acetate monoester ophthalmic solution is prepared by dissolving HDMF trimethyl acetate monoester in physiological saline at a rate of 1%, and then dipalmitoyl-phosphatidylcholesterol.
ine (DPPC; manufactured by NOF CORPORATION) was further added at a ratio of 0.5% to prepare a liposome body as a liposome solution containing HDMF trimethyl acetate monoester. Also,
Catalin (Cenju Pharmaceutical Co., Ltd.), a therapeutic agent for cataract, was instilled three times a day for 3 weeks as described above. As a control, physiological saline alone was instilled as described above. During the test period, after a mydriatic pupil every week with Midrin P (manufactured by Santen Pharmaceutical Co., Ltd.), a slit image of the crystalline lens and the entire anterior eye image were taken with a Nikon zoom slit lamp microscope FS-3 (manufactured by Nikon Corporation). Nishida et al.'S method (New Ophthalmology, Vol. 2, No. 9, 1307-131
(Page 2, 1985). The ICR / f rats used in this test were already in stage 3 at the start of the test (although opacity of the lens was not visually observed, but slight opacity was observed in the posterior subcapsular cortex in the slit image). During the test period, when the lens opacity progressed to the stage 4 in which the opacity of the lens was visually observed, the cataract was developed, and the cataract development rate (%) was calculated as the number of cataract development eyes / total number of eyes × 100. Calculated.

(Test Results) The test results are shown in FIG. In the control group in which only saline was instilled, remarkable lens opacity was observed after the first week of the instillation, and the cataract incidence rate at the third week of the instillation was 6%.
4%. On the other hand, in the HDMF trimethyl acetate monoester ophthalmic group, only slight opacity of the lens was observed after the second week of instillation, and the cataract incidence rate of the HDMF trimethyl acetate monoester ophthalmic group at the third week of instillation was 14%. .
In addition, the catalin instillation group showed a slight tendency of cataract progression at the second week of instillation, but at the third week of instillation, the cataract incidence rate was 64% as in the control group (FIG. 1).

15) Test Example 3 Single Dose Toxicity Test (Test Method) Using 5-week-old, male, Crj: ICR mice (average body weight: 26 g) (5 to 6 mice / group), each of which received HDMF trimethyl acetate monoester. After intraperitoneal administration of 500 mg / Kg, observation was performed for 14 days. As a control, only physiological saline was similarly administered. After the end of the test period, the pathological dissection of all cases was performed, and the presence or absence of abnormalities in each body organ was confirmed. The results showed that no animals died on administration of HDMF trimethylacetic acid monoester, the mice did not show any clinical symptoms, and showed a good weight gain during the test period. In addition, no abnormalities were observed in the pathological anatomy of all cases after the test period.

16) Test Example 4 (Toxicity test) An ether derivative of furanone (4-tert)
-Butoxy-2,5-dimethyl-3 (2H) -furanone) (sample) was examined for toxicity tests. Animals are ICR / o
rj male mice (Charles River Japan) were purchased at the age of 6 weeks and used for experiments at the age of 7 weeks. The sample was 1% CMC-
It was suspended in a Na solution to obtain a stock solution. The sample was intraperitoneally administered to the mouse at 500 mg / kg. Immediately after the administration, the condition was observed, the body weight was measured for 2 weeks, and the condition was observed. Two weeks later, the mice were sacrificed by the cervical dislocation method, and appearance and internal organs and brain abnormalities were observed. Dead animals were dissected at any time and observed. The results showed that none of the derivatives died at an intraperitoneal dose of 500 mg / kg and no abnormality was observed even after 2 weeks of observation, indicating low toxicity.

17) Test 5 Anti-cataract effect test of various furanone derivatives The furanone derivatives synthesized as described above were subjected to an in vivo eye drop test for spontaneously occurring cataract rats (ICR / f rats) in the same manner as in Test Example 2. The anti-cataract effect was tested. The results are shown in Table 2.

[0087]

[Table 2]

18) Test Example 6 Anticataractic effect of HDMF trimethylacetic acid monoester and ethyl 3- (4-hydroxy-5-oxo-3-phenyl-2,5-dihydro-2-furyl) propionate on galactose cataract ( Comparison of In Vitro Test) 3- (4-Hydroxy-5) which is a furanone derivative having 3 (2H) -furanone as a mother nucleus of the present invention and a conventional furanone derivative having 2 (5H) -furanone as a mother nucleus. Ethyl oxo-3-phenyl-2,5-dihydro-2-furyl) propionate (JP-A-59-16884, JP-A-60-178879, JP-A-61-2675)
No. 66) was synthesized, and the anti-cataract effect against galactose cataract was compared with that of the present application.

3- (4-hydroxy-5-oxo-3-
Synthesis of ethyl phenyl-2,5-dihydro-2-furyl) propionate: methyl phenylpyruvate (4.34)
g) and ethyl 3-formylpropionate (6.3)
g) was dissolved in N, N-dimethylformamide (92 ml), and 1,8-diazabicyclo [4.3.0] undecene- (4.1 ml) was added dropwise with stirring at 0 ° C. After stirring the mixture at 0 ° C. for 2 hours, the solvent was distilled off under reduced pressure. The residue was poured into 20 ml of diluted hydrochloric acid (1N) and extracted three times with 60 ml of ethyl acetate. The organic layer was washed successively with diluted hydrochloric acid, water and saturated saline, dried over sodium sulfate, concentrated, and purified by silica gel column chromatography to obtain 3.60 g (53.5%) of 3- (4-hydroxy-). 5-oxo-3-phenyl-2,5-dihydro-
Ethyl 2-furyl) propionate was obtained. IR ν _max cm ^-1 : 1750, 1710, 146
0, 1460 (s), 1380, 1270, 1150;
NMR δ (60 MHz, CDCl ₃ ): 1.27 (t,
J = 7.1 Hz, 3H), 1.68 to 1.87 (m, 1
H), 2.39 to 2.68 (m, 3H), 4.16 (q,
J = 7.1 Hz, 2H), 5.51 (dd, J ₁ = 1.
_{6Hz, J 2 = 8.9Hz),} 7.36~7.79 (m,
5H)

In the same manner as in Test Example 1, 3- (4-hydroxy-5-oxo-3-phenyl-2,5-dihydro-
The anti-cataract effect on galactose cataract was tested using ethyl 2-furyl) propionate. For comparison, HDMF trimethylacetic acid monoester of the present invention was used as a control. Table 3 shows the results.

[0091]

[Table 3]

From the results in Table 3, it can be seen that the present invention is 2 (5
H) -Furanone derivatives having a furanone as a mother nucleus 3-
(4-hydroxy-5-oxo-3-phenyl-2,5
It can be seen that about 0.10 mg of the sample is about 7 times as effective as ethyl (dihydro-2-furyl) propionate.

19) Test Example 7 3- (4-hydroxy-5-oxo-3-phenyl-
Anti-cataract effect of 2,5-dihydro-2-furyl) propionic acid on spontaneously occurring cataract (ICR / f rats) (in vivo ophthalmic test) 3- (4-hydroxy-5-oxo-3-phenyl-2,5-dihydro-2-furyl) propionic acid, which is a furanone derivative having a nucleus as a core (JP-A-59-16884)
JP-A-60-178879, JP-A-60-178879
No. 267566), and about it, i
An n vivo eye drop test effect was performed.

3- (4-hydroxy-5-oxo-3-
Synthesis of phenyl-2,5-dihydro-2-furyl) propionic acid 3- (4-hydroxy-5-oxo-3-phenyl-
Ethyl 2,5-dihydro-2-furyl) propionate (2.0 g) was dissolved in 64 ml of a mixture of tetrahydrofuran and methanol (2: 1) and stirred at 0 ° C. To this, 21 ml of a 1N aqueous sodium hydroxide solution was added dropwise, and the mixture was returned to room temperature and stirred for 20 hours. After concentration under reduced pressure, the mixture was poured into a diluted hydrochloric acid solution (1N, 20 ml), and the mixture was diluted with 40 ml of ethyl acetate.
Extract twice. The organic layer was washed with saturated saline, dried over sodium sulfate, and concentrated. Further, it was purified by silica gel column chromatography to obtain 0.81 g (4
5.2%) of 3- (4-hydroxy-5-oxo-3-
Phenyl-2,5-dihydro-2-furyl) propionic acid was obtained. IR ν _max cm ^-1 : 3170, 1750 (s), 17
00, 1460 (s), 1380, 1320, 125
0, 1210, 1170; NMR δ (60 MHz, C
_{DCl 3): 1.63~1.80 (m,} 1H), 2.34
~2.56 (m, 3H), 5.51 (dd, J 1 = 2.1
Hz, J ₂ = 8.4 Hz), 7.40 to 7.80 (m, 5
H)

In the same manner as in Test Example 2, 3- (4-hydroxy-5-oxo-3-phenyl-2,5-dihydro-
The anti-cataract effect by in vivo eye drops was tested using 2-furyl) propionic acid. The result is shown in FIG. As shown in FIG. 2, the compound of the present invention is 3- (4-hydroxy-5-oxo-3-phenyl-2,5-dihydro-2-furyl) propion, which is a furanone derivative having 2 (5H) -furanone as a core. The acid is about 1 / 3.5 compared to the HDMF trimethylacetic acid monoester of the present application (see FIG. 1).
You can see that the effect is only.

20) Test Example 8 In the test for the anti-cataract effect against galactose cataract (in vitro test) in Test Example 1, "2,5-dimethyl-4-pivaloyloxy-3" was used as a sample.
Instead of "(2H) -furanone", the five furanone ether derivatives of the present invention shown in the table were used. 0.1 mg ", and the assay was performed in exactly the same manner except that the measurement of the wet weight of the lens was not performed.
Table 4 summarizes the results.

[0097]

[Table 4]

From the results in Table 4, it can be seen that the lenses of the first and second sections without galactose showed slight opacity in the cortex (scores 0.2 and 0.4), but almost no transparency. Indicated. In contrast, it can be seen that the lenses of the third and fourth sections to which galactose was added show remarkable cloudiness (scores of 2.8 and 2.6), respectively. That is,
It can be seen that the lens to which galactose was added at a high concentration became cloudy. On the other hand, the lenses of the fifth to ninth categories to which the furanone ether derivative of the present invention was added, despite the addition of galactose at a high concentration, showed only slight turbidity in the cortex and were almost transparent ( Score 0.6-1.
From 2), it can be seen that the furanone ether derivative of the present invention has a cataract treatment effect. And it turns out that the furanone ether derivative of the present invention can be expected to more effectively prevent or treat senile cataract caused by oxidative damage and the like.

21) Test Example 9 (Toxicity test) Ether derivative of furanone (4-tert)
-Butoxy-2,5-dimethyl-3 (2H) -furanone) (sample) was examined for toxicity tests. Animals are ICR / o
rj male mice (Charles River Japan) were purchased at the age of 6 weeks and used for experiments at the age of 7 weeks. The sample was 1% CMC-
It was suspended in a Na solution to obtain a stock solution. The sample was intraperitoneally administered to the mouse at 500 mg / kg. Immediately after the administration, the condition was observed, the body weight was measured for 2 weeks, and the condition was observed. Two weeks later, the mice were sacrificed by the cervical dislocation method, and appearance and internal organs and brain abnormalities were observed. Dead animals were dissected at any time and observed. The results showed that none of the derivatives died at an intraperitoneal dose of 500 mg / kg, no abnormalities were observed even after 2 weeks of observation, and the toxicity was low.

[0100]

Examples Formulation Example 1 (Eye drops) HDMF trimethylacetic acid monoester 1.0 g Boric acid 0.7 g Sodium chloride 0.6 g Methyl p-oxybenzoate 0.02 g Chlorobutanol 0.3 g is dissolved in sterilized purified water and the whole amount is dissolved. 100 ml (note that p
H was prepared using sodium hydroxide at 6.0).

Formulation Example 2 (oral formulation) HDMF trimethylacetic acid monoester 100 mg Lactose 80 mg Starch 17 mg Magnesium stearate 3 mg One tablet or more was tableted.

Formulation Example 3 (Injection) HDMF Trimethylacetate Monoester 1.5 g Sodium Chloride 0.6 g Distilled Water for Injection 100 ml
Sterile filtration was performed using a filter (manufactured by Gelman Science). The filtrate was aseptically filled into glass ampoules in 2 ml portions and sealed to prepare injections.

[0103]

The cataract preventive or therapeutic agent of the present invention has very low toxicity and can be advantageously used for the prevention or treatment of senile cataract as shown in the test examples.

[Brief description of the drawings]

FIG. 1 shows the cataract suppression effect. The horizontal axis shows the experimental period (weeks) after the start of instillation of the drug, and the vertical axis shows the cataract incidence (%)
Is shown.

FIG. 2 shows a cataract suppression effect. The horizontal axis indicates the experimental period (weeks) after the start of the instillation of the drug, and the vertical axis indicates the cataract incidence (%).

 ──────────────────────────────────────────────────の Continued on the front page (72) Inventor Yukihiko Iwai 339 Noda, Noda City, Chiba Prefecture Kikkoman Corporation (72) Inventor Takanao Matsudo 339 Noda Noda City, Chiba Prefecture Kikkoman Corporation (72) Inventor Kenji Mori (72) Inventor Mamoru Kikuchi 339 Noda, Noda-shi, Chiba, Japan Kikkoman Corporation (72) Inventor Minoru Saito 339, Noda, Noda-shi, Chiba Prefecture Kikkoman Corporation (72) ) Inventor Koichi Kasai 339 Noda, Noda City, Chiba Prefecture Kikkoman Corporation

Claims (5)

[Claims] (1) The following formula: (Wherein, R ₁ , R ₂ , and R ₃ may be the same or different, and include a hydrogen atom, a hydroxyl group, an amino group, a halogen atom, a mercapto group, a carboxyl group, a carbamoyl group,
Alkyl group, alkenyl group, alkynyl group, aryl group, aralkyl group, alkoxyl group, acyloxy group,
An alkenyloxy group, an alkynyloxy group, an aryloxy group, or an alkoxycarbonyl group, R ₄ is a hydrogen atom, an amino group, a halogen atom, a mercapto group, a carboxyl group, an alkyl group, an alkenyl group, an alkynyl group,
It represents an aryl group, an aralkyl group, an alkoxyl group, an acyloxy group, an alkenyloxy group, an alkynyloxy group, an aryloxy group, or an alkoxycarbonyl group. ) A prophylactic or therapeutic agent for cataract comprising the furanone derivative or a salt thereof. 2. The method according to claim 1, wherein R ₁ , R ₂ ,
R ₃ may be the same or different and are a hydrogen atom, a hydroxyl group, a carboxyl group, an alkyl group, an alkenyl group, an aryl group, an aralkyl group, an alkoxycarbonyl group, and R ₄ is a hydrogen atom, a carboxyl group, an alkoxyl group, The agent for preventing or treating cataract according to claim 1, which is a furanone derivative represented by an acyloxy group or an alkoxycarbonyl group or a salt thereof. 3. The method according to claim 1, wherein R ₁ , R ₂ ,
R ₃ may be the same or different and is a hydrogen atom, a hydroxyl group or an alkyl group, and R ₄ is a furanone derivative represented by an acyloxy group, an alkoxyl group or an alkoxycarbonyl group or a salt thereof. The cataract prevention or treatment agent according to the above. 4. The method according to claim 1, wherein the furanone derivative or a salt thereof is 2,5-dimethyl-4-pivaloyloxy-3.
(2H) -furanone, 2 (or 5) -ethyl-5 (or 2) -methyl-4-pivaloyloxy-3 (2H) -furanone, 4-acetoxy-2 (or 5) -ethyl-5
(Or 2) -methyl-3 (2H) -furanone, 2,5-
Dimethyl-4-isopropyloxy-3 (2H) -furanone, 4-tert-butoxy-2,5-dimethyl-3
(2H) -furanone, 2,5-dimethyl-4- (2-methyl-2-butoxy) -3 (2H) -furanone, 2,5
-Dimethyl-4- (3-methyl-3-pentyloxy)
-3 (2H) -furanone, 2,5-dimethyl-4- (1
-Methyl-1-cyclopentyloxy) -3 (2H)-
Furanone, 2,5-dimethyl-4- (1-methyl-1-
The agent for preventing or treating cataract according to claim 1, which is cyclohexyloxy) -3 (2H) -furanone or a salt thereof. 5. The salt of the furanone derivative according to claim 1, 2 or 3, wherein the salt is an alkali metal salt, an alkaline earth metal salt,
An ammonium salt or an amine salt.
The cataract prevention or treatment agent according to the above.