JPH07316183A - Griseolic acid monoester derivative - Google Patents

Abstract

PURPOSE:To obtain a new compound having excellent intraocular pressure- lowering action and useful as an excellent therapeutic agent for glaucoma. CONSTITUTION:A compound of formula I (R<1> and R<2> are each H, OH, etc.; R<3> and R<4> are each H or R<3> and R<4> together exhibit a single bond; either one of R<5> and R<6> is H and the other is a protecting group removed in eyes) and its salt, e.g. griseolic acid-9'-pivaloyloxymethylester. The compound is obtained by reacting, e.g. a raw material compound of formula II with an one equivalent esterifying reagent of the formula R<5>' -X or R<6>' -X (X is a halogen, acetoxy, etc.) at a room temperature in a solvent such as DMF in the presence of 1,8- diazabicylo[5.4.0]undec-7-ene which is a deacidifying agent.

Description

Detailed Description of the Invention

[0001]

[Object of the Invention]

[0002]

FIELD OF THE INVENTION The present invention relates to a novel glyzeolic acid monoester derivative having an excellent intraocular pressure lowering effect.

[0003]

2. Description of the Related Art Glyzeo-acid diester derivatives are disclosed in JP-A-60-94992 and JP-A-61.
The following compounds described in Japanese Patent Publication No. 100593 are known.

[0004]

[Chemical 2]

[0005]

[Chemical 3]

[0006] (In the above formulas, R ¹ and R ² have the same meanings as described below, R 5 ^'and R ^6',. A methyl group or a diphenylmethyl group), however, these compounds intraocular pressure It has no effect.

[0007]

DISCLOSURE OF THE INVENTION As a result of years of intensive research on the synthesis and pharmacological activity of a glyzeolic acid derivative having an intraocular pressure lowering effect, the present inventors have found that the structure differs from that of a known ester derivative. The present invention has been completed by discovering that the novel derivative (1) has a good effect of lowering intraocular pressure and can be an excellent therapeutic agent for glaucoma.

[0008]

[Constitution of the invention]

[0009]

The novel glyzeolic acid monoester derivative of the present invention has the general formula

[0010]

[Chemical 4]

(In the formula, R ¹ and R ² are the same or different and represent a hydrogen atom, a hydroxyl group or a hydroxyl group protected by a group selected from the substituent group A, and R ³ and R ⁴ are the same and a hydrogen atom. Or R ³ and R ⁴ together represent a single bond, one of R ⁵ and R ⁶ represents a hydrogen atom, and the other represents a protecting group which is removed in the eye). .

[Substituent group A] Aliphatic acyl group, aromatic acyl group, tetrahydropyranyl or tetrahydrothiopyranyl group, tetrahydrofuranyl or tetrahydrothiofuranyl group, silyl group, alkoxymethyl group, substituted ethyl group, aralkyl Groups, alkoxycarbonyl groups, alkenyloxycarbonyl groups, aralkyloxycarbonyl groups, and pivaloyloxymethyloxycarbonyl groups.

In the above general formula (I), the "protecting group" defined in [Substituent group A] means a protecting group in the reaction and a protecting group for forming a prodrug when administered to a living body, For example, alkylcarbonyl groups such as formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, valeryl, isovaleryl, octanoyl, lauroyl, myristoyl, tridecanoyl, palmitoyl, stearoyl, chloroacetyl, dichloroacetyl, trichloroacetyl,
Aliphatic acyl groups such as halogenated alkylcarbonyl groups such as trifluoroacetyl, lower alkoxyalkylcarbonyl groups such as methoxyacetyl, unsaturated alkylcarbonyl groups such as (E) -2-methyl-2-butenoyl;
Arylcarbonyl groups such as benzoyl, α-naphthoyl, β-naphthoyl, halogenated arylcarbonyl groups such as 2-bromobenzoyl, 4-chlorobenzoyl,
Lower alkylated arylcarbonyl groups such as 2,4,6-trimethylbenzoyl, 4-toluoyl, lower alkoxylated arylcarbonyl groups such as 4-anisoyl, 4-nitrobenzoyl, 2-nitrobenzoyl Aromatic acyl such as lower nitrated arylcarbonyl group, lower alkoxycarbonylated arylcarbonyl group such as 2- (methoxycarbonyl) benzoyl, arylated arylcarbonyl group such as 4-phenylbenzoyl Group; tetrahydropyran-2-yl, 3-bromotetrahydropyran-2-yl,
Tetrahydropyranyl or tetrahydrothiopyranyl groups such as 4-methoxytetrahydropyran-4-yl, tetrahydrothiopyran-2-yl, 4-methoxytetrahydrothiopyran-4-yl; tetrahydrofuran-2-yl, tetrahydrothiofuran A tetrahydrofuranyl or tetrahydrothiofuranyl group such as -2-yl; tri-lower alkyl such as trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl, methyldiisopropylsilyl, methyldi-t-butylsilyl, triisopropylsilyl A silyl group such as a silyl group, a tri-lower alkylsilyl group substituted with 1 to 2 aryl groups such as diphenylmethylsilyl, diphenylbutylsilyl, diphenylisopropylsilyl and phenyldiisopropylsilyl; Lower alkoxymethyl group such as dimethyl, 1,1-dimethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, t-butoxymethyl, lower alkoxylated lower such as 2-methoxyethoxymethyl Alkoxymethyl groups such as alkoxymethyl group, halogenated lower alkoxymethyl such as 2,2,2-trichloroethoxymethyl and bis (2-chloroethoxy) methyl; 1-ethoxyethyl, 1-methyl-1-methoxyethyl, Substitution of a lower alkoxylated ethyl group such as 1- (isopropoxy) ethyl, a halogenated ethyl group such as 2,2,2-trichloroethyl, an aryl-selenylated ethyl group such as 2- (phenylzenyl) ethyl Ethyl group; benzyl, phenethyl, 3-phenylpropyl, α-naphthylmethyl, β-naphthylmethyl, diphe 1 to 3 such as nylmethyl, triphenylmethyl, α-naphthyldiphenylmethyl, 9-anthrylmethyl
Lower alkyl group substituted with 4 aryl groups, 4-methylbenzyl, 2,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4-methoxyphenyldiphenylmethyl, 2 -Nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl, 4-cyanobenzyl, 4-cyanobenzyldiphenylmethyl, bis (2-
Aralkyl groups such as lower alkyl groups substituted with 1 to 3 aryl groups in which the aryl ring is substituted with lower alkyl such as nitrophenyl) methyl, piperonyl, lower alkoxy, nitro, halogen, cyano group, etc. Methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl,
Lower alkoxycarbonyl group such as isobutoxycarbonyl, alkoxycarbonyl group such as lower alkoxycarbonyl group substituted with halogen or tri-lower alkylsilyl group such as 2,2,2-trichloroethoxycarbonyl, 2-trimethylsilylethoxycarbonyl; Alkenyloxycarbonyl groups such as vinyloxycarbonyl, allyloxycarbonyl; benzyloxycarbonyl,
An aryl group with 1 to 2 lower alkoxy or nitro groups such as 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl.
Of the aralkyloxycarbonyl group, which may be substituted on the ring, and a hydrolyzable group in vivo, such as pivaloyloxymethyloxycarbonyl, which is a prodrug for administration to a living body. It represents a protecting group, and is preferably an aliphatic acyl group or an aromatic acyl group.

The compound (I) of the present invention can be made into salts, and such salts are preferably alkali metal or alkaline earth metal salts such as sodium salt, potassium salt or calcium salt. Salts; salts of organic bases such as methylamine, ethylamine, morpholine, piperidine;
Hydrofluoride, Hydrochloride, Hydrobromide, Hydroiodide such as Hydroiodide, Inorganic acid such as Nitrate, Perchlorate, Sulfate, Phosphate; Methanesulfonic acid Salts, lower alkyl sulfonates such as trifluoromethane sulfonate, ethane sulfonate, benzene sulfonate,
Allyl sulfonates such as p-toluene sulfonate, fumarate, succinate, citrate, tartrate, oxalate, maleate and other organic acid salts and glutamate, aspartate Amino acid salts such as

The compound (I) of the present invention has stereoisomers each having an asymmetric carbon atom in the molecule and having S-coordination and R-coordination, and each of them may be a stereoisomer or a mixture thereof. Also included in the present invention.

In the compound (I), preferable compounds include (1) compounds in which R ¹ and R ² are the same or different and each is a hydrogen atom or a hydroxyl group which may be protected by an aliphatic acyl or aromatic acyl. (2) A compound in which R ¹ and R ² are the same or different and are a hydrogen atom or a hydroxyl group. (3) R ³ and R ⁴ are the same and represent a hydrogen atom, or R ³
Can be exemplified as R ⁴ compounds represents a single bond together (4) R ³ and R ⁴ compound represents a single bond together.

The glyzeoic acid monoester of the present invention is
It can be produced by the method described below.

[Method A]

[0019]

[Chemical 5]

[0020]

[Chemical 6]

[0021] Protection In the above ^{formulas, R 1, R 2, R} 3 and R ⁴ have the same meanings as defined above, R ^{5 'and} R ^6', which is removed in the eye in the definition of R ⁵ and R ⁶ R ¹² represents a lower alkylidene group such as methylidene, ethylidene, or isopropylidene; an aralkylidene group such as benzylidene or a dihydroxy-protecting group such as an alkoxyethylidene group such as methoxyethylidene or ethoxyethylidene. And is preferably isopropylidene.

[0022] The step A-1 is the raw material compound (1) in the presence of an acid acceptor in a solvent, one equivalent of the general formula R ⁵ '-X, or, R ^6' -X (wherein, R ^{5 ′} and R ^{6 ′} are as defined above, and X is
Halogen atoms such as chlorine, bromine, iodine; acetoxy,
Alkylcarbonyloxy groups such as propionyloxy, chloroacetyloxy, dichloroacetyloxy,
Halogenated alkylcarbonyloxy groups such as trichloroacetyloxy and trifluoroacetyloxy, lower alkoxyalkylcarbonyloxy groups such as methoxyacetyloxy, unsaturated alkylcarbonyloxy groups such as (E) -2-methyl-2-butenoyloxy Aliphatic acyloxy groups such as groups; arylcarbonyloxy groups such as benzoyloxy, 2-bromobenzoyloxy, 4
Of halogenated arylcarbonyloxy groups such as -chlorobenzoyloxy, lower alkylated arylcarbonyloxy groups such as 2,4,6-trimethylbenzoyloxy and 4-toluoyloxy, 4-anisoyloxy Aromatic alkoxyoxy groups such as lower alkoxylated arylcarbonyloxy groups, 4-nitrobenzoyloxy, nitrated arylcarbonyloxy groups such as 2-nitrobenzoyloxy; trihalogenomethyl such as trichloromethyloxy Oxy group; lower alkanesulfonyloxy group such as methanesulfonyloxy and ethanesulfonyloxy; halogeno lower alkanesulfonyloxy group such as trifluoromethanesulfonyloxy and pentafluoroethanesulfonyloxy; benzenesulfonyloxy, p Ants, such as toluene sulfonyloxy - Le sulfonyloxy group; represents a leaving group such as a diazo group. ) Is reacted with an esterification reagent represented by the formula (1) to remove the hydroxyl-protecting group of R ¹ or R ² , if desired, to give the compound of the present invention 8′-monoester (2) and 9′-monoester ( This is a process of manufacturing 3).

The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but is preferably dimethylformamide, dimethylacetamide or hexamethylphosphorotriamide. Examples thereof include amides; sulfoxides such as dimethyl sulfoxide, nitriles such as acetonitrile, and a mixed solvent of the above solvents.

The deoxidizing agent used is not particularly limited as long as it is used as a deoxidizing agent in a usual reaction, but preferably triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4-
(N, N-Dimethylamino) pyridine, N, N-dimethylaniline, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [2.2.2]
Organic bases such as octane, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) can be used, with DBU being particularly preferred.

The leaving group X of the esterification reagent is preferably a halogen atom such as chlorine, bromine or iodine, and particularly preferably an iodine atom.

The reaction temperature is 0 ° C. to 100 ° C., preferably 20 ° C. to 70 ° C., and particularly preferably room temperature.

The reaction time mainly depends on the reaction temperature, the starting compound,
The time is usually 1 hour to 4 days, varying depending on the type of solvent or deoxidizing agent used.

The step of deprotecting the desired hydroxyl-protecting group varies depending on the type of the protecting group, but is generally carried out as follows by a method well known in the art.

When a silyl group is used as a hydroxyl-protecting group, it is usually removed by treatment with a compound which produces a fluorine anion such as tetrabutylammonium fluoride. The reaction solvent is not particularly limited as long as it does not inhibit the reaction, but ethers such as tetrahydrofuran and dioxane are preferable. Although the reaction temperature and the reaction time are not particularly limited, the reaction is usually performed at room temperature for 10 to 18 hours.

When the hydroxyl-protecting group is an aralkyloxycarbonyl group or an aralkyl group, it can usually be removed by bringing it into contact with a reducing agent. For example, it is achieved by carrying out catalytic reduction at room temperature using a catalyst such as palladium carbon, platinum, Raney nickel. The reaction is carried out in the presence of a solvent, and the reaction solvent used is not particularly limited as long as it does not participate in this reaction, but alcohols such as methanol and ethanol, tetrahydrofuran, dioxane. Such ethers, fatty acids such as acetic acid, or a mixed solvent of these organic solvents and water is preferable. The reaction temperature and reaction time will differ depending on the starting materials and the reducing agent used, but are usually 0 ° C.
To room temperature, 5 minutes to 12 hours.

In liquid ammonia or methanol.
-78 in alcohols such as alcohol and ethanol
It can also be removed by reacting metallic lithium or sodium at -20 to -20 ° C.

Further, it can be removed by using aluminum chloride-sodium iodide or alkylsilyl halides such as trimethylsilyl iodide. The reaction is carried out in the presence of a solvent, and the reaction solvent used is not particularly limited as long as it does not participate in this reaction, but preferably, nitriles such as acetonitrile, methylene chloride, chloroform and the like. Halogenated hydrocarbons or mixed solvents thereof are used. The reaction temperature will differ depending on the starting materials and the like, but is usually 0 ° C to 50 ° C.

When the reaction substrate has a sulfur atom, aluminum chloride-sodium iodide is preferably used.

When the hydroxyl-protecting group is an aliphatic acyl group, an aromatic acyl group or an alkoxycarbonyl group, it can be removed by treating with a base in the presence of a solvent. The base is not particularly limited as long as it does not affect other parts of the compound, but is preferably a metal alcoholate such as sodium methoxide, an alkali metal carbonate such as sodium carbonate or potassium carbonate. It is carried out using salts, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, aqueous ammonia or concentrated ammonia-methanol. The solvent used is not particularly limited as long as it can be used in a usual hydrolysis reaction, and water, methanol, ethanol, alcohols such as n-propanol or tetrahydrofuran, dioxane. An organic solvent such as ethers or a mixed solvent of water and an organic solvent is preferable. The reaction temperature and reaction time vary depending on the starting materials, the base used, etc. and are not particularly limited, but in order to suppress side reactions, it is usually 0 ° C. to 150 ° C. and 1 to 10 hours.

The hydroxyl-protecting group is an alkoxymethyl group,
When it is a tetrahydropyranyl group, a tetrahydrofuranyl group or a substituted ethyl group, it can usually be removed by treating with an acid in a solvent. The acid used is preferably hydrochloric acid, acetic acid-sulfuric acid, p-toluenesulfonic acid, acetic acid or the like. The solvent used is not particularly limited as long as it does not participate in this reaction,
Preference is given to alcohols such as methanol and ethanol; ethers such as tetrahydrofuran and dioxane, or a mixed solvent of these organic solvents and water. The reaction temperature and reaction time will differ depending on the starting materials and the type of acid used, but they are generally 0 ° C. to 50 ° C., and 10 minutes to 18 hours.

When the hydroxyl-protecting group is an alkenyloxycarbonyl group, the removal reaction conditions are usually the same as when the hydroxyl-protecting group is an aliphatic acyl group, an aromatic acyl group or an alkoxycarbonyl group. It can be eliminated by treating with a base. In addition, in the case of allyloxycarbonyl, the method of removing using palladium and triphenylphosphine or nickel tetracarbonyl is especially simple and can be carried out with few side reactions.

After completion of the reaction, the target compound (2) or (3) of this reaction is collected from the reaction mixture according to a conventional method.
For example, add a water-immiscible organic solvent to the reaction mixture,
After washing with water, the solvent is distilled off. If necessary, the desired compound thus obtained can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography to obtain a single (2) or (3).

The step A-2 is 7'of the starting compound (1).
In this step, the hydroxyl group at the 9-position and the hydroxyl group at the 9′-position are protected with a protecting group for the dihydroxy group in the presence or absence of a solvent in the presence of an acid catalyst to produce compound (4). In this step, it is possible to use a dehydrating agent such as copper sulfate, sodium sulfate, calcium carbonate or molecular sieve, or to remove water by utilizing azeotropic distillation.

The reagents used in the step of protecting the dihydroxy group include formaldehyde, acetaldehyde,
Lower alkyl carbonyl compounds such as acetone; aryl carbonyl compounds such as benzaldehyde or lower alkyl orthoformates such as trimethyl orthoformate and triethyl orthoformate can be used, preferably lower alkylcarbonyl A compound, more preferably acetone.

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but preferably aromatic hydrocarbons such as benzene, toluene and xylene; Halogenated hydrocarbons such as methylene chloride and chloroform; Esters such as ethyl acetate and propyl acetate; Ethers such as ether, tetrahydrofuran, dioxane and dimethoxyethane; methanol, ethanol, Alcohols such as n-propanol, isopropanol, n-butanol, isobutanol, isoamyl alcohol; amides such as dimethylformamide, dimethylacetamide, hexamethylphosphorotriamide; dimethyl Can include sulfoxides such as sulfoxides; ketones such as acetone Acetone is used also as a solvent if acetone is used as the reagent protected.

The acid catalyst to be used is not particularly limited as long as it is used as an acid catalyst in a usual reaction, and preferably hydrochloric acid, hydrobromic acid, sulfuric acid or perchloric acid. An inorganic acid or a Bronsted acid such as an organic acid such as paratoluenesulfonic acid, trifluoroacetic acid, or trifluoromethanesulfonic acid, or a Lewis acid such as zinc chloride or tin tetrachloride can be used, and an organic acid is preferable. And more preferably a strong organic acid.

The reaction temperature is -10 ° C to 100 ° C, preferably 0 ° C to room temperature.

The reaction time is usually 10 minutes to 3 days, varying mainly depending on the reaction temperature, the raw material compound or the solvent used, and the kind of the acid catalyst.

After completion of the reaction, the target compound (4) of this reaction can be collected from the reaction mixture by a conventional method. For example, it can be obtained by adding an organic solvent immiscible with water to the reaction mixture, washing with water and distilling off the solvent. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation, chromatography or the like, but preferably an alkali metal carbonate such as sodium carbonate or calcium carbonate; sodium hydrogen carbonate, Alkali metal hydrogen carbonate such as potassium hydrogen carbonate; Alkali metal hydride such as lithium hydride, sodium hydride, potassium hydride; Alkali metal hydroxide such as sodium hydroxide, calcium hydroxide, barium hydroxide Neutralized with an organic solvent such as an insoluble base to remove insolubles, and then the solvent is distilled off, without any particular isolation and purification. It

In the step A-3 , compound (4) is added to the step A-
In this step, the compound (5) is produced by the same treatment as in step 1.

In the step A-4 , the protecting group for the dihydroxy group of the compound (5) is removed with an acid catalyst in the presence or absence of a solvent, and if desired, the 7'-position hydroxyl group is protected,
This is a step of producing the 8'-position monoester body (2) which is the compound of the present invention.

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but preferably aromatic hydrocarbons such as benzene, toluene and xylene; Halogenated hydrocarbons such as methylene chloride and chloroform; Esters such as ethyl acetate and propyl acetate; Ethers such as ether, tetrahydrofuran, dioxane and dimethoxyethane; methanol, ethanol, Alcohols such as n-propanol, isopropanol, n-butanol, isobutanol, isoamyl alcohol; amides such as dimethylformamide, dimethylacetamide, hexamethylphosphorotriamide; dimethyl Can include sulfoxides such as sulfoxides; ketones such as acetone .

The acid catalyst to be used is not particularly limited as long as it is used as an acid catalyst in a usual reaction, and preferably hydrochloric acid, hydrobromic acid, sulfuric acid or perchloric acid. An inorganic acid or an aqueous solution of Bronsted acid such as paratoluenesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, or an organic acid such as citric acid can be mentioned, and preferably an aqueous solution of an organic acid is more preferable. Is an aqueous trifluoroacetic acid solution.

The reaction temperature is -10 ° C to 100 ° C, preferably 0 ° C to room temperature.

The reaction time is usually 10 minutes to 1 day, varying mainly depending on the reaction temperature, the starting compound or the solvent used and the kind of the acid catalyst.

Further, the protecting group can be removed by simply heating in the above water-containing solvent without using an acid catalyst.

If desired, the 2'-position and / or the 7'-position of the hydroxyl group may be converted into another functional group (for example, a hydrogen atom) according to the method described in JP-A-60-94992. it can.

After completion of the reaction, the target compound (2) of this reaction is collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding an organic solvent immiscible with water to the reaction mixture, washing with water and distilling off the solvent. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

The raw material compounds of the present invention are known compounds, for example, JP-A-56-68695, JP-A-60-94992, and JP-A-60-14939.
It can be manufactured by the methods described in JP-A No. 4 and JP-A No. 60-246396 and JP-A No. 61-100593.

Further, the esterification reagent of the present invention can be produced by a known method [eg, Chemical Pharmaceutical Bulletin, 32, 4316 (1984), 224).
18 (1984) or 33, 4870 (198)
5 years) described method] or a commercially available reagent is used.

[0056]

[Effect of the Invention] Normal rabbit intraocular pressure- lowering effect The intraocular pressure- lowering effect of the present compound was examined by using male New Zealand White rabbits (body weight: about 2.5 Kg) having no abnormalities in the eyes as a group of 3 birds. The animals were bred in a breeding room controlled at a temperature of 23 ° C., a relative humidity of 60%, and a lighting period of 7:00 to 19:00, and had a restricted feeding of food and water ad libitum.
The test substance was prepared by dissolving the present compound in 50 mM phosphate buffer (pH 7.0) containing 0.4% sodium chloride, and adjusting the concentration to about 1%.

Both eyes of the rabbit were anesthetized with an ophthalmic surface anesthetic (0.4% benoxyseal: Santen Pharmaceutical Co., Ltd.), and the intraocular pressure of both eyes was measured by PTG (Pneumatonograph: Alcon). After that, 50μ of the test substance to either the left or right eye (experimental eye)
l Eye drops (0.5% timolol 30 μl), 60
After the minute, the same amount was instilled again (two times in total). On the other hand, the other eye was not instilled and was used as a control eye. After the first instillation of the test substance, 30, 60, 90, 120, 150, 180 minutes later, the intraocular pressure of both eyes was measured, and the obtained measured value was substituted into the following formula to obtain the intraocular pressure drop value of the test substance. It was calculated.

Decrease of intraocular pressure (ΔP, mmHg) = (control eye intraocular pressure value-experimental eye intraocular pressure value)-(control eye intraocular pressure value immediately before first instillation-experimental eye intraocular pressure value immediately before first instillation) and each The average value of the intraocular pressure drop values during the measurement time was calculated, and 0.
The value of the test substance when the value of 5% timolol was set to 1 was calculated.

Normal rabbit intraocular pressure lowering effect of the compounds of Examples ───────────────────────────────────── Drug Drug concentration (%) Intraocular pressure lowering effect (ΔP) (timolol ratio) ──────────────────────────────── Glyzeolic acid 1.0-0.12 Compound of Example 1 1.0 2.38 Compound of Example 2 1.0 1.24 Compound of Example 3 1.0 0.90 Compound of Example 5 1.0 0.92 Example 7 1.0 0.79 Compound of Example 10 1.0 1.08 ──────────────────────────────────── As described above, the novel glyzeoic acid monoester derivative of the present invention has an excellent effect of lowering intraocular pressure and is not toxic, and therefore useful as a therapeutic agent for glaucoma.

Dosage forms of the compound (I) of the present invention include solutions, suspensions, gels, ointments or solid inserts,
It is preferably administered in the form of an ophthalmic pharmaceutical composition suitable for topical administration to the eye. The formulations of these compositions may contain 0.01 to 10%, especially 0.1 to 5% of the compound of the present invention. In addition to containing the compound of the present invention as a single drug, a β-blocker agent such as timolol maleate or a drug such as pilocarpine which is a parasympathomimetic stimulant may be included together. The pharmaceutical preparations containing the active compositions can be conveniently admixed with nontoxic pharmaceutical inorganic or organic carriers. Typical pharmaceutically acceptable carriers include, for example, water, water-miscible solvents such as lower alkanols or aralkanols, and mixtures of water, vegetable oils, polyalkylene glycols, petroleum-based jellies, ethyl cellulose. , Ethyl oleate, carboxymethylcellulose, polyvinylpyrrolidone, isopropyl myristate and other convenient carriers for convenient use. In addition, the pharmaceutical preparations include non-toxic auxiliary substances such as emulsifiers, preservatives, wetting agents, excipients, such as polyethylene glycols 200, 300, 400 and 600,
Carbowax 1,000, 1,500, 4,000,
6,000 and 10,000, quaternary ammonium compounds known to have pasteurizing properties and non-toxic to use, antibacterial agents such as phenylmercuric salts, thimerosal, methyl and propylparaben, benzyl alcohol , Phenylethanol, sodium chloride, sodium borate, buffer components such as sodium acetate, gluconate buffer,
And sorbitan monolaurate, triethanolamine, polyoxyethylene sorbitan monopalmitylate, dioctyl sodium sulfosuccinate, monothioglycerol, thiosorbitol, ethylenediaminetetraacetic acid and the like. In addition, suitable ophthalmic vehicles can be used as carrier media for the purposes of the present invention, including conventional phosphate buffer excipient systems, isotonic boric acid excipients, isotonic sodium chloride vehicles. Excipients, isotonic sodium borate excipients and the like are included. The pharmaceutical formulation can also be in the form of a solid intercalant that remains in a substantially complete state after administration of the drug or in the form of a biodisintegrable intercalant that dissolves in tear fluid or otherwise disintegrates. .

In general, per kg body weight of the compound of the invention,
About 0.001 to about 50 mg, preferably about 0.01
To about 20 mg can be used. Depending on the daily dose required, the administration can be single or multiple doses or unit doses.

Hereinafter, the present invention will be described more specifically with reference to Examples, Reference Examples and Formulation Examples.

[0063]

Example 1 Glyzeolic acid 9'-pivaloyloxymethyl ester
Le

[0064]

[Chemical 7]

5 g of glyzeolic acid was dissolved in 15 ml of dimethyl sulfoxide, and after adding 2.17 ml of 1,8-diazabicyclo [5.4.0] -7-undecene in a nitrogen stream, 15 ml of acetonitrile was added, and the mixture was cooled with ice. To
Add 3.83 g of iodomethyl pivalate and add 5 at room temperature.
Reacted for hours. Acetonitrile was distilled off, the residue was dissolved in 300 ml of ethyl acetate and 300 ml of water, 10 ml of a 10% cold sodium hydrogen carbonate aqueous solution was added, the aqueous layer was separated, and the ethyl acetate layer was further extracted with 100 ml of water, and the aqueous layers were combined. The pH was adjusted to 3.1 with 1N hydrochloric acid, and separated and purified using a prepacked column Rp-8 manufactured by Merck (5%, 10%.
%, 20% acetonitrile in water) and the fractions containing the target compound are collected and lyophilized to 688.
Obtained mg (11%) of the target compound. Nuclear magnetic resonance spectrum (270 MHz) δ ppm
(DMSO-d ₆ ) 8.33, 8.18 (1H, sx 2, 2- or 8-H); 6.49 (1H, s, 1 '
-H); 6.03 (1H, dd, J = 2.4, 4.9Hz, 3'-H); 5.08 (1H, d,
J = 2.4Hz, 5'-H); 4.58 (2H, m, 2'- and 7'-H); 7.40 (2
H, br.s, NH ₂ ); 6.26 (1H, d, J = 4.9Hz, 2'-OH); 6.02 (2
H, s, CH ₂ ); 1.16 (9H, s, CH ₃ )

[0066]

Example 2 Glyzeolic acid 9 '-[1- (isopropyloxycarboxyl
Lubonyloxy) ethyl] ester

[0067]

[Chemical 8]

2.0 g of glyzeolic acid was dissolved in 7 ml of dimethyl sulfoxide, and 0.87 ml of 1,8-diazabicyclo [5.4.0] -7-undecene was dissolved in a nitrogen stream.
After adding 5 ml of acetonitrile, and under ice cooling, 1
1.33 g of -bromoethyl isopropyloxycarboxylate was added and reacted at room temperature for 3 hours. Example 1
By the same procedure as in 7.
40 mg (19%) was obtained. Nuclear magnetic resonance spectrum (270 MHz) δppm (D
MSO-d ₆ ) 8.34, 8.18 (1H, sx 2, 2- or 8-H); 6.49 (1H, s, 1 '
-H); 6.06 (1H, dd, J = 2.4, 4.9Hz, 3'-H); 5.08 (1H, d,
J = 2.4Hz, 5'-H); 4.59 (2H, m, 2'- and 7'-H); 7.38 (2
H, br.s, NH ₂ ); 6.6 (1H, m, -O-CH-0-); 6.29 (1H, d, J
= 4.9Hz); 6.25 (1H, d, J = 4.9Hz); 5.5 (1H, m, 7'-OH);
1.2-1.5 (9H, m, CH ₃ )

[0069]

Example 3 Glyzeolic acid 9 '-(5-methyl-2-oxo-
1,3-Dioxolen-4-yl) methyl ester

[0070]

[Chemical 9]

In Example 1, 3 g of glyzeolic acid was used, and iodide (5-methyl-2-oxo-1,3-dioxolene-4) was used instead of iodomethyl pivalate.
0.14 g of the target compound was obtained in the same manner except that 7.6 g of -yl) methyl was used. Nuclear magnetic resonance spectrum (270 MHz) δppm (D
MSO-d ₆ ) 8.32, 8.16 (1H, sx 2, 2- or 8-H); 6.43 (1H, s, 1'-
H); 5.97 (1H, dd, J = 2.0, 4.9Hz, 3'-H); 4.95 (1H, d,
J = 2.0Hz, 5'-H); 4.44 (1H, d, J = 4.9Hz, 2'-H); 4.03 (1
H, br.s, 7'-H); 7.36 (2H, br.s, NH ₂ ); 5.00 (2H, s, C
H ₂ ); 2.17 (3H, s, CH ₃ )

[0072]

Example 4 Glyzeolic acid 9 '-(1-isovaleryloxyethyi
Le) Ester

[0073]

[Chemical 10]

Glyzeolic acid (500 mg) was dissolved in dimethyl sulfoxide (2.5 ml), and 1,8-diazabicyclo [5.4.0] -7-undecene (0.24) was added in a nitrogen stream.
ml was further added, 2 ml of acetonitrile was further added, 1.01 g of 1-iodoethyl isovalerate was added under ice cooling, and the mixture was reacted at room temperature for 3 to 4 hours and then left at 5 ° C. for 16 hours. After distilling off the acetonitrile, the residue was diluted with dilute hydrochloric acid 1
The mixture was dissolved in 5 ml and ethyl acetate (20 ml), the ethyl acetate layer was separated, the aqueous layer was saturated with sodium chloride, and the mixture was extracted twice with ethyl acetate. 5% combined ethyl acetate layers
Extraction was performed twice with a cold sodium hydrogen carbonate aqueous solution. The aqueous layers were combined, adjusted to pH 2.8 with 1N hydrochloric acid, and separated and purified using a prepacked column Rp-8 manufactured by Merck (10%, 15%).
%, Eluted with water containing 20% acetonitrile sequentially),
Fractions containing the target compound were collected and freeze-dried to obtain 137 mg (19%) of the target compound. Nuclear magnetic resonance spectrum (270 MHz) δppm (D
MSO-d ₆ ) 8.34, 8.18 (1H, sx 2, 2- or 8-H); 6.49 (1H, s, 1 '
-H); 6.06 (1H, dd, J = 2.4, 4.9Hz, 3'-H); 5.08 (1H, d,
J = 2.0Hz, 5'-H); 4.57 (1H, d, J = 5.2Hz, 2'-H); 4.56
(1H, s, 7'-H); 7.40 (2H, br.s, NH ₂ ); 6.79 (1H, m,-
OCHO-); 6.32 and 6.25 (1H, each d, J = 5.2Hz, 2'-OH); 5.
50 (1H, br.s, 7'-OH); 2.20 (2H, d, J = 7.0Hz, CH ₂ ); 2.
00 (1H, m, CH); 1.41 (3H, m, CH ₃ ); 0.91 (6H, m, CH ₃ )

[0075]

Example 5 Glyzeolic acid 9 '-(1-pivaloyloxyethyl
Le) Ester

[0076]

[Chemical 11]

Using the procedure of Example 4, 500 glyzeolic acid
mg, instead of using 1-iodoethyl isovalerate 0.68 g of 1-iodoethyl pivalate
98 mg of the target compound was obtained by the same operation except that was used. Nuclear magnetic resonance spectrum (270 MHz) δppm (D
MSO-d ₆ ) 8.34, 8.18 (1H, sx 2, 2- or 8-H); 6.49 (1H, s, 7 '
-H); 6.05 (1H, dd, J = 2.4, 4.9Hz, 3'-H); 5.08 (1H, d,
J = 2.4Hz, 5'-H); 4.57 (1H, d, J = 4.9Hz, 2'-H); 4.58
(1H, s, 7'-H); 7.40 (2H, br.s, NH ₂ ); 6.74 (1H, m,-
OCHO-); 6.31 and 6.25 (1H, each d, J = 4.9Hz, 2'-OH); 5.
49 (1H, br.m, 7'-OH); 1.42 (3H, m, CH ₃ ); 1.14 (9H,
m, CH ₃ )

[0078]

Example 6 Glyzeolic acid 9 '-(1-isobutyryloxy pro
Pill) ester

[0079]

[Chemical 12]

In Example 4, glyzeolic acid 500
mg, instead of using 1-iodoethylisovalerate, 1-iodopropyl isobutyrate (6
Target compound 10 was obtained by the same procedure except that
0 mg was obtained. Nuclear magnetic resonance spectrum (270 MHz) δppm (D
MSO-d ₆ ) 8.34, 8.18 (1H, sx 2, 2- or 8-H); 6.48 (1H, s, 1 '
-H); 6.06 (1H, dd, J = 2.4, 4.9Hz, 3'-H); 5.07 (1H, d,
J = 2.4Hz, 5'-H); 4.58 (2H, br.s, 2'- and 7'-H); 7.40
(2H, br.s, NH ₂ ); 6.67 (1H, m, -OCHO-); 6.31 and 6.23
(1H, each d, J = 4.4Hz, 2'-OH); 2.5 (1H, m, overlap with DMSO CH ₂ ); 1.7 (1H, m, CH); 1.0-1.1 (6H, m, CH ₃ ) ; 0.89
(3H, m, CH ₃ )

[0081]

Example 7 Glyzeolic acid 9 '-(1-n-butyryloxyethyi
Le) Ester

[0082]

[Chemical 13]

In Example 4, glyzeolic acid 500
41 mg of the target compound was obtained by the same operation except that 0.64 g of 1-iodoethyl butyrate was used instead of 1-iodoethyl isovalerate. Nuclear magnetic resonance spectrum (270 MHz) δppm (D
MSO-d ₆ ) 8.33, 8.19 (1H, sx 2, 2- or 8-H); 6.47 (1H, s, 1 '
-H); 6.03 (1H, dd, J = 2.9, 5.4Hz, 3'-H); 5.08 (1H, b
rd, 5'-H); 4.54 (2H, m, 2'- and 7'-H); 7.39 (2H, br.
s, NH ₂ ); 6.77 (1H, m, -OCHO-); 6.32 (1H, br.d); 6.22
(1H, br.d); 2.29 (2H, t, J
= 7.3 Hz, CH ₂ ); 1.54 (2H, m,
_{CH 2); 1.42 (3H,} m, CH 3);
0.93 (3H, m, CH ₃ )

[0084]

Example 8 Glyzeolic acid 9 '-(1-cyclohexylcarboate
Nyloxyethyl) ester

[0085]

[Chemical 14]

24 mg of the target compound was obtained by the same procedure as in Example 4, except that 500 mg of glyzeolic acid was used and 0.74 g of 1-iodoethyl cyclohexylcarboxylate was used instead of 1-iodoethyl isovalerate. Nuclear magnetic resonance spectrum (270 MHz) δppm (D
MSO-d ₆ ) 8.35, 8.19 (1H, sx 2, 2- or 8-H); 6.50 (1H, s, 1 '
-H); 6.06 (1H, dd, J = 2.4, 4.9Hz, 3'-H); 5.08 (1H, d,
J = 2.0Hz, 5'-H); 4.58 (2H, m, 2'- and 7'-H); 7.45 (2
H, br.s, NH ₂ ); 6.76 (1H, m, -OCHO-); 6.30 and 6.36
(Each 1H, d, J = 4.9Hz, 2'-OH); 2.33 (1H, m, hydrogen atom bonded to carbon atom of cyclohexyl group to which carbonyl group is bonded); 1.1-1.9 (13H, m, CH ₃ , hydrogen atoms other than those mentioned above for cyclohexyl)

[0087]

Example 9 7′-desoxyglyceolic acid 9 ′-(1-pivalo
Iloxyethyl) ester

[0088]

[Chemical 15]

7'-desoxyglyzeolic acid 500 m
g was dissolved in 4 ml of dimethyl sulfoxide, 0.24 ml of 1,8-diazabicyclo [5.4.0] -7-undecene was added in a nitrogen stream, and then 4 ml of acetonitrile,
Then, under ice cooling, 1-iodoethyl pivalate 693
mg was added and the mixture was allowed to stand at room temperature for 2.5 hours and at 5 ° C. for 16 hours. After the acetonitrile was distilled off, the residue was dissolved in 70 ml of ethyl acetate and 70 ml of a 3% sodium hydrogen carbonate aqueous solution containing ice, the aqueous layer was separated, and the ethyl acetate layer was further added with 30 ml of water.
Pre-packed column R manufactured by Merck & Co., Inc., treated with activated carbon and adjusted to pH 2.9 with 1N hydrochloric acid.
Using p-8, the product was sequentially eluted with water containing 10%, 20%, and 30% acetonitrile, and the target compound fractions were collected and lyophilized to obtain 18 mg. Nuclear magnetic resonance spectrum (270MHz) δppm (CD ₃
CN: D ₂ O = 1: 1): 8.19, 8.08 (1H, sx 2, 2- or 8-H); 6.4
3 (1H, s, 1'-H); 5.81 (1H, dd, J = 2.6, 4.8Hz, 3'-H);
5.00 (1H, d, J = 2.6Hz, 5'-H); 4.64 (1H, d, J = 4.8Hz,
2'-H); 3.00 (1H, d, J = 16.1Hz, 7'-H); 2.67 (1H, d, J =
16.1Hz, 7'-H); 6.77 (1H, q, J = 5.5Hz, -OCHO-); 1.48
(3H, d, J = 5.5Hz, CH ₃ ); 1.03 (9H, s, CH ₃ )

[0090]

Example 10 Glyzeolic acid 8'-pivaloyloxymethyl ester
Le

[0091]

[Chemical 16]

Glyzeolic acid (1 g) and molecular sieve 4A (2.6 g) were suspended in acetone (26 ml), and the suspension was cooled with ice.
Add 0.83 ml of trifluoromethanesulfonic acid and add 2.
Reacted for hours. Add 0.35 g of calcium hydroxide,
After stirring for 10 minutes, 0.94 g of calcium carbonate was added, and after further stirring for 10 minutes, the insoluble matter was filtered off and the solvent was distilled off to obtain 7 ', 9'-O-isopropylidene griseol acid. Was obtained. This compound was added to dimethyl sulfoxide 5m.
1 and 8 ml of acetonitrile, 0.12 ml of 1,8-diazabicyclo [5.4.0] -7-undecene was added, and 1-iodomethyl pivalate 2.6 was added under ice cooling.
g was added, and the mixture was reacted at room temperature for 3 hours. Acetonitrile was distilled off, the residue was dissolved in 70 ml of ethyl acetate and 70 ml of water, and the organic layer was separated and washed twice with water. The ethyl acetate layer was dried over magnesium sulfate, the solvent was evaporated, and the residue was separated by silica gel chromatography (3% ethanol-methylene chloride) to give 1.4 g (27.1%) of 7 ',
9'-O-isopropylidene glyzeolic acid 8'-pivaloyloxymethyl ester was obtained. Nuclear magnetic resonance spectrum δppm (DMSO-d
₆ ) 8.31, 8.19 (1H, sx 2, 2-or 8-H); 7.39 (2H, br.s, NH
₂ ); 6.54 (1H, s, 1'-H); 6.08 (1H, dd, J = 2.4, 5.4Hz,
3'-H); 6.05 (1H, d, J = 4.4Hz, 2'-OH); 5.83 (1H, d, J =
5.9Hz, CH ₂ ); 5.80 (1H, d, J = 5.9Hz, CH ₂ ); 5.21 (1H,
d, J = 2.4Hz, 5'-H); 4.96 (1H, s, 7'-H); 4.67 (1H, t,
J = 4.4Hz, 2'-H) ; 1.56 (6H, s, CH 3); 1.07 (9H, s, a CH ₃₎ The above compound 240 mg, under ice-cooling, trifluoroacetic acid 5ml containing 1% of water After dissolution and reaction at room temperature for 5 hours, the solvent was distilled off and the residue was dissolved in 3% sodium hydrogen carbonate under ice cooling. The pH was adjusted to 2.3 with 1N hydrochloric acid, and pre-packed column Rp-8 manufactured by Merck & Co., Inc. was used to elute sequentially with 10% and 20% acetonitrile-water. Fractions of the target compound were collected and lyophilized to 213 mg (96%). The target compound of was obtained. Nuclear magnetic resonance spectrum δppm (DMSO-d ₆ ) 8.33, 8.31 (1H, sx 2, 2- or 8-H); 6.50 (1H, s, 1 '
-H); 6.08 (1H, dd, J = 2.4, 4.9Hz, 3'-H); 5.05 (1H, d,
J = 2.4Hz, 5'-H); 4.61 (1H, d, J = 4.9Hz, 2'-H); 4.46
(1H, s, 7'-H); 7.39 (2H, br.s, NH ₂ ); 5.79 (2H, d, J =
5.9Hz, CH ₂ ); 5.76 (2H, d, J = 5.9Hz, CH ₂ ); 1.10 (9H,
s, CH ₃ )

[0093]

Example 11 Glyzeolic acid 8 '-(1-isovaleryloxyethyi)
Le) Ester

[0094]

[Chemical 17]

At the time of column purification in Example 4, 20%
After eluting with acetonitrile-water to elute the compound of Example 4, the target compound eluted. 22 mg of the target compound was obtained by collecting and lyophilizing this fraction. Nuclear magnetic resonance spectrum δppm (DMSO-d ₆ ) 8.36, 8.21 (1H, sx 2, 2- or 8-H); 6.50 (1H, s, 1 '
-H); 6.08 (1H, dd, J = 2.4, 4.9Hz, 3'-H); 4.99 (1H, d,
J = 2.4Hz, 5'-H); 4.61 (1H, br.d, 2'-H); 4.46 (1H, s,
7'-H); 7.51 (2H, br.s, NH ₂ ); 6.81 (1H, q, J = 5.4Hz,
-OCHO-); 6.25 (1H, br.s, 2'-OH); 5.37 (1H, br.s, 5'-
OH); 2.18 (2H, m, CH ₂ ); 1.95 (1H, m, CH); 1.43 (3H,
d, J = 5.4Hz, CH ₃ ); 0.86 (6H, m, CH ₃ )

[0096]

Example 12 Glyzeolic acid 8 '-(1-pivaloyloxyethyl ester
Le) Ester

[0097]

[Chemical 18]

At the time of column purification in Example 5, 20%
After eluting the compound of Example 5 with acetonitrile-water, the target compound was eluted and freeze-dried to obtain 20 mg. Nuclear magnetic resonance spectrum δppm (DMSO-d ₆ ) 8.36, 8.20 (1H, sx 2, 2- or 8-H); 6.52 (1H, s, 1 '
-H); 6.08 (1H, dd, J = 2.4, 4.9Hz, 3'-H); 5.00 (1H, d,
J = 2.4Hz, 5'-H); 4.59 (1H, d, J = 4.9Hz, 2'-H); 4.48
(1H, s, 7'-H); 7.56 (2H, br.s, NH ₂ ); 6.78 (1H, q, J =
5.4Hz, -OCHO-); 6.26 (1H, br.s, 2'-OH); 5.30 (1H, b
rs, 5'-OH); 1.44 (3H, d, J = 5.4Hz, CH ₃ ); 1.11 (9H,
s, CH ₃ )

[0099]

Example 13 Glyzeolic acid 8 '-(1-isobutyryloxy pro
Pill) ester

[0100]

[Chemical 19]

At the time of column purification in Example 6, 20%
After eluting the compound of Example 6 with acetonitrile-water, the target compound was eluted and freeze-dried to obtain 20 mg. Nuclear magnetic resonance spectrum δppm (DMSO-d ₆ ) 8.33, 8.17 (1H, sx 2, 2- or 8-H); 6.51 (1H, s, 1 '
-H); 6.12 (1H, dd ,, J = 2.4, 4.9Hz, 3'-H); 5.02 (1H,
d, J = 2.0Hz, 5'-H); 4.59 (1H, d, J = 4.9Hz, 2'-H); 4.49
(1H, s, 7'-H); 7.41 (2H, br.s, NH ₂ ); 6.68 (1H, t, J
= 5.4Hz, -OCHO-); 6.21 (1H, br.s, 2'-OH); 5.36 (1H, b
rs, 7'-OH); 2.50 (2H, m, DMSO and CH ₂ overlap); 1.08
_{(6H, m, CH 3)} ; 0.91 (3H, t, J = 7.3Hz, CH 3)

[0102]

Example 14 Glyzeolic acid 8 '-(1-n-butyryloxyethylene
Le) Ester

[0103]

[Chemical 20]

At the time of column purification in Example 7, 20%
After eluting the compound of Example 7 with acetonitrile-water, the target compound was eluted and freeze-dried to obtain 15 mg. Nuclear magnetic resonance spectrum δppm (DMSO-d ₆ ) 8.38, 8.22 (1H, sx 2, 2- or 8-H); 6.51 (1H, s, 1 '
-H); 6.08 (1H, dd, J = 2.4, 4.9Hz, 3'-H); 6.08 (1H, d
d, J = 2.4, 4.9Hz); 5.02 (1H, d, J = 2.4Hz, 5'-H); 4.60
(1H, d, J = 4.9Hz, 2'-H); 4.48 (1H, s, 7'-H); 7.58 (2
H, br.s, NH ₂ ); 6.81 (1H, q, J = 5.9Hz, -OCHO-); 6.28
(1H, br.s, 2'-OH); 5.38 (1H, br.s, 5'-OH); 2.29 (2H,
t, J = 7.3Hz, CH ₂ ); 1.52 (2H, q, J = 7.3Hz, CH ₂ ); 1.43
(3H, d, J = 5.4Hz, CH ₃ ); 0.85 (3H, t, J = 7.3Hz, CH ₃ )

[0105]

Example 15 Glyzeolic acid 8 '-(1-cyclohexylcarbonic acid
Luoxyethyl) ester

[0106]

[Chemical 21]

At the time of column purification in Example 8, 20%
After eluting the compound of Example 8 with acetonitrile-water, the target compound was eluted and freeze-dried to obtain 22 mg. Nuclear magnetic resonance spectrum δppm (DMSO-d ₆ ) 8.34, 8.18 (1H, sx 2, 2- or 8-H); 6.50 (1H, s, 1 '
-H); 6.11 (1H, dd, J = 2.4, 4.9Hz, 3'-H); 5.00 (1H, d,
J = 2.0Hz, 5'-H); 4.60 (1H, d, J = 5.4Hz, 2'-H); 4.46
(1H, s, 7'-H); 7.41 (2H, br.s, NH ₂ ); 6.79 (1H, q, J =
5.4Hz, -OCHO-); 6.21 (1H, br.s, 2'-OH); 5.34 (1H, b
rs 7'-OH); 2.30 (1H, m, hydrogen atom bonded to carbon atom of cyclohexyl group to which carboxyl group is bonded); 1.1-1.8 (13H, m, CH ₃ , cyclohexyl group other than the above) Hydrogen atom)

[0108]

Example 16 7′-desoxyglyzeolic acid 8 ′-(1-pivalo
Iloxyethyl) ester

[0109]

[Chemical formula 22]

At the time of column purification in Example 9, the target compound was eluted after the compound of Example 9 was eluted with water containing 20% acetonitrile. This fraction was collected and freeze-dried to obtain 15 mg of the target compound. Nuclear magnetic resonance spectrum δppm (DMSO-d ₆ ) 8.31, 8.16 (1H, sx 2, 2- or 8-H); 6.46 (1H, s, 1 '
-H); 6.05 (1H, dd, J = 2.4, 4.9Hz, 3'-H); 4.98 (1H, d,
J = 2.4Hz, 5'-H); 4.56 (1H, t, J = 4.4Hz, 2'-H); 3.11
(1H, d, J = 17.1Hz, 7'-H); 2.77 (1H, d, J = 17.1Hz, 7'-
H); 7.40 (2H, br.s, NH ₂ ); 6.76 (1H, q, J = 5.4Hz, -OCH
O-); 5.97 (1H, d, J = 3.9Hz, 2'-OH); 1.43 (3H, d, J = 5.
4Hz, CH ₃ ); 1.10 (9H, s, CH ₃ )

[0111]

Example 17 7'-pivaloylglyzeolic acid 9 '-(1-isop
Ropyroxycarbonyloxyethyl) ester

[0112]

[Chemical formula 23]

Instead of glyzeolic acid in Example 2, 46 mg of 7'-pivaloylglyzeolic acid was used.
The same operation was performed to obtain 13 mg of the target compound. Nuclear magnetic resonance spectrum δppm (DMSO-d ₆ ) 8.36, 8.17 (1H, sx 2, 2- or 8-H); 6.49 (1H, s, 1 '
-H); 6.05 (1H, dd, J = 2.4, 4.9Hz, 3'-H); 4.98 and 5.03
(1H, d, J = 2.4Hz, 5'-H respectively); 4.61 (1H, dd, J = 4.4,
4.9Hz, 2'-H); 5.52 and 5.63 (each 1H, s, 7'-H); 7.40
(2H, br.s, NH ₂ ); 6.46 (1H, m, -OCHO-); 4.79 (1H, m,
CH); 1.44 (3H, d, J = 5.4Hz, CH ₃ ); 1.1-1.3 (15H, m, CH
₃ )

[0114]

[Formulation Example 1] (Eye drops) Compound of Example 1 1.0 g Disodium phosphate 0.716 g Monosodium phosphate 0.728 g Sodium chloride 0.400 g Methyl p-hydroxybenzoate 0.026 g Propyl p-hydroxybenzoate 0.014 g Sterile purification Water proper amount Sodium hydroxide proper amount ----------------------- Total volume 100 ml The ophthalmic solution was prepared by a conventional method with pH 7.0.

[0115]

[Formulation Example 2] (Eye drop) Compound of Example 2 1.0 g Disodium phosphate 0.500 g Monosodium phosphate 1.100 g Sodium chloride 0.300 g Benzatonium chloride 0.010 g Sterile purified water Appropriate amount --------------- ---------- The total amount of 100 ml was adjusted to pH 7.0 and an eye drop was prepared by a conventional method.

[0116]

[Formulation Example 3] (Eye drops) Compound of Example 5 1.0 g Disodium phosphate 0.400 g Monosodium phosphate 1.000 g Sodium chloride 0.690 g 10% Benzalkonium chloride solution 100 μl Sterile purified water Appropriate amount --- ------------- Eye drops were prepared by a conventional method with a total amount of 100 ml and pH of 7.0.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Tomihisa Yokoyama 1-258 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. (72) Inventor Mitsuro Yamazaki 1-258 Hiromachi, Shinagawa-ku, Tokyo Sankyo stock company

Claims (1)

[Claims] 1. A general formula: (Wherein R ¹ and R ² are the same or different and represent a hydrogen atom, a hydroxyl group or a hydroxyl group protected by a group selected from the substituent group A, and R ³ and R ⁴ are the same and represent a hydrogen atom. Or R ³ and R ⁴
Together represent a single bond, one of R ⁵ and R ⁶ represents a hydrogen atom, and the other represents a protecting group removed in the eye. And a salt thereof. [Substituent Group A] Aliphatic Acyl Group, Aromatic Acyl Group, Tetrahydropyranyl or Tetrahydrothiopyranyl Group, Tetrahydrofuranyl or Tetrahydrothiofuranyl Group,
A silyl group, an alkoxymethyl group, a substituted ethyl group, an aralkyl group, an alkoxycarbonyl group, an alkenyloxycarbonyl group, an aralkyloxycarbonyl group, and a pivaloyloxymethyloxycarbonyl group.